Patent Publication Number: US-2021179713-A1

Title: Anti-pd-1 antibodies, activatable anti-pd-1 antibodies, and methods of use thereof

Description:
RELATED APPLICATIONS 
     This application is a divisional of U.S. application Ser. No. 15/209,385, filed on Jul. 13, 2016, which claims the benefit of U.S. Provisional Application No. 62/191,902, filed Jul. 13, 2015; U.S. Provisional Application No. 62/205,825, filed Aug. 17, 2015; U.S. Provisional Application No. 62/295,314, filed Feb. 15, 2016; U.S. Provisional Application No. 62/323,543, filed Apr. 15, 2016 and U.S. Provisional Application No. 62/333,629, filed May 9, 2016; the contents of each of which are incorporated herein by reference in their entirety. 
    
    
     DESCRIPTION OF THE TEXT FILE SUBMITTED ELECTRONICALLY 
     The contents of the text file submitted electronically herewith are incorporated herein by reference in their entirety: A computer readable format copy of the Sequence Listing (filename: CYTM_044_001_US_SubSeqList_ST25.txt, dated recorded Mar. 21, 2019, file size 1.37 MB) in U.S. patent application Ser. No. 15/209,385. 
     FIELD OF THE INVENTION 
     The invention relates generally to antibodies that specifically bind programmed cell death protein 1 (PD-1), activatable antibodies that specifically bind to PD-1 and methods of making and using these anti-PD-1 antibodies and anti-PD-1 activatable antibodies in a variety of therapeutic, diagnostic and prophylactic indications. 
     BACKGROUND OF THE INVENTION 
     Antibody-based therapies have proven effective treatments for several diseases but in some cases, toxicities due to broad target expression have limited their therapeutic effectiveness. In addition, antibody-based therapeutics have exhibited other limitations such as rapid clearance from the circulation following administration. 
     Under conditions of chronic stimulation, T cells upregulate and sustain expression of the inhibitory receptor PD-1 to negatively regulate the quality and magnitude of T cell responses. The primary ligand for PD-1, PD-L1 is upregulated on many tumor cells and has been associated with inhibition of anti-tumor T-cell immunity via its engagement of PD-1 on tumor-infiltrating T cells. Clinical trials have confirmed the capacity of antibody blockade of either PD-1 or PD-L1 to restore the activity of durable tumor-specific immunity in patients across multiple tumor types. (Herbst et al, 2014; Lipson et al, 2015). However, because similar mechanisms control anti-tumor immunity and self-tolerance, systemic delivery of these checkpoint-targeted therapies can also induce systemic autoimmunity that can be exacerbated with combination treatments; such as nivolumab or pembrolizumab (anti-PD-1) and ipilimumab (anti-CTLA4). New approaches are therefore needed that provide anti-tumor activity without deregulating systemic immunity. 
     In the realm of small molecule therapeutics, strategies have been developed to provide prodrugs of an active chemical entity. Such prodrugs are administered in a relatively inactive (or significantly less active) form. Once administered, the prodrug is metabolized in vivo into the active compound. Such prodrug strategies can provide for increased selectivity of the drug for its intended target and for a reduction of adverse effects. 
     Accordingly, there is a continued need in the field of antibody-based therapeutics for antibodies that mimic the desirable characteristics of the small molecule prodrug. 
     SUMMARY OF THE INVENTION 
     The disclosure provides antibodies or antigen-binding fragments thereof that specifically bind programmed cell death protein 1 (PD-1), also known as CD279, SLEB2, and/or hSLE1. The use of the term “PD-1” is intended to cover any variation thereof, such as, by way of non-limiting example, PD1 and/or PD 1, all variations are used herein interchangeably. Aberrant expression and/or activity of PD-1 and PD-1-related signaling has been implicated in the pathogenesis of many diseases and disorders, such as cancer. 
     The present invention provides monoclonal antibodies (mAbs), activatable antibodies, and antigen-binding fragments thereof that specifically bind PD-1. 
     In some embodiments, the antibody includes an antibody or antigen-binding fragment thereof that specifically binds PD-1. In some embodiments, the antibody or antigen-binding fragment thereof that binds PD-1 is a monoclonal antibody, domain antibody, single chain, Fab fragment, a F(ab′) 2  fragment, a scFv, a scAb, a dAb, a single domain heavy chain antibody, or a single domain light chain antibody. In some embodiments, such an antibody or antigen-binding fragment thereof that binds PD-1 is a mouse, other rodent, chimeric, humanized or fully human monoclonal antibody. 
     In some embodiments, the antibody includes an isolated antibody or antigen binding fragment thereof (AB) that specifically binds to mammalian PD-1, wherein the AB has one or more of the characteristics selected from the group consisting of: (a) the AB inhibits binding of mammalian PD-1 to mammalian PDL1 with an EC 50  value less than 5 nM; (b) the AB inhibits binding of mammalian PD-1 to mammalian PDL2 with an EC 50  value less than 5 nM; and (c) the AB specifically binds to human PD-1 and cynomolgus monkey PD-1. 
     In some embodiments, the antibody specifically binds to the mammalian PD-1 with a dissociation constant of 0.01 nM to 5 nM, 0.05 nM to 5 nM, 0.1 nM to 5 nM, 0.2 nM to 5 nM, 0.3 nM to 5 nM, 0.4 nM to 5 nM, 0.5 nM to 5 nM, 0.75 nM to 5 nM, 1 nM to 5 nM, 2 nM to 5 nM, 0.01 nM to 2 nM, 0.05 nM to 2 nM, 0.1 nM to 2 nM, 0.2 nM to 2 nM, 0.3 nM to 2 nM, 0.4 nM to 2 nM, 0.5 nM to 2 nM, 0.75 nM to 1 nM, 1 nM to 2 nM, 0.01 nM to 1 nM, 0.05 nM to 1 nM, 0.1 nM to 1 nM, 0.2 nM to 1 nM, 0.3 nM to 1 nM, 0.4 nM to 1 nM, 0.5 nM to 1 nM, 0.75 nM to 1 nM, 0.01 nM to 0.75 nM, 0.05 nM to 0.75 nM, 0.1 nM to 0.75 nM, 0.2 nM to 0.75 nM, 0.3 nM to 0.75 nM, 0.4 nM to 0.75 nM, 0.5 nM to 0.75 nM, 0.01 nM to 0.5 nM, 0.05 nM to 0.5 nM, 0.1 nM to 0.5 nM, 0.2 nM to 0.5 nM, 0.3 nM to 0.5 nM, 0.4 nM to 0.5 nM, 0.01 nM to 0.4 nM, 0.05 nM to 0.4 nM, 0.1 nM to 0.4 nM, 0.2 nM to 0.4 nM, 0.3 nM to 0.4 nM, 0.01 nM to 0.3 nM, 0.05 nM to 0.3 nM, 0.1 nM to 0.3 nM, 0.2 nM to 0.3 nM, 0.01 nM to 0.2 nM, 0.05 nM to 0.2 nM, 0.1 nM to 0.2 nM, 0.01 nM to 0.1 nM, 0.05 nM to 0.1 nM, or 0.01 nM to 0.05 nM. 
     In some embodiments, the mammalian PD-1 is selected from the group consisting of a human PD-1 and a cynomolgus monkey PD-1. In some embodiments, the mammalian PD-1 is a murine PD-1. In some embodiments, the antibody specifically binds to human PD-1 or cynomolgus monkey PD-1 with a dissociation constant of less than or equal to 1 nM. In some embodiments, the mammalian PD-1 is a human PD-1. 
     In some embodiments, the antibody or antigen binding fragment thereof specifically binds to the mammalian PD-1 with a dissociation constant is less than or equal to 0.01 nM, less than or equal to 0.05 nM, less than or equal to 0.1 nM, less than or equal to 0.2 nM, less than or equal to 0.3 nM, less than or equal to 0.4 nM, less than or equal to 0.5 nM, less than or equal to 0.75 nM, and less than or equal to 1 nM. 
     In some embodiments, the antibody has one or more of the characteristics selected from the group consisting of: (a) the AB specifically binds human PD-1 and cynomolgus monkey PD-1; (b) the AB inhibits binding of human PDL1 and human PDL2 to human PD-1; (c) the AB inhibits binding of cynomolgus monkey PDL1 and cynomolgus monkey PDL2 to cynomolgus monkey PD-1; (d) the AB specifically binds to murine PD-1; and (e) the AB inhibits binding of murine PDL1 and murine PDL2 to murine PD-1. 
     In some embodiments, the antibody blocks the ability of a natural ligand to bind to the mammalian PDL1 with an EC 50  of 0.1 nM to 10 nM, 0.1 nM to 5 nM, 0.1 nM to 3 nM, 0.1 nM to 2 nM, 0.1 nM to 1 nM, 0.1 nM to 0.5 nM, 0.1 nM to 0.25 nM, 0.25 nM to 10 nM, 0.25 nM to 5 nM, 0.25 nM to 3 nM, 0.25 nM to 2 nM, 0.25 nM to 1 nM, 0.25 nM to 0.5 nM, 0.5 nM to 10 nM, 0.5 nM to 5 nM, 0.5 nM to 3 nM, 0.5 nM to 2 nM, 0.5 nM to 1 nM, 1 nM to 10 nM, 1 nM to 5 nM, 1 nM to 3 nM, 1 nM to 2 nM, 2 nM to 10 nM, 2 nM to 5 nM, 2 nM to 3 nM, 3 nM to 10 nM, 3 nM to 5 nM, or 5 nM to 10 nM. In some embodiments, the natural ligand is a mammalian PDL1 or a mammalian PDL2. In some embodiments, the natural ligand is selected from the group consisting of: a human PDL1, a human PDL2, a cynomolgus monkey PDL1, and a cynomolgus monkey PDL2. In some embodiments, the natural ligand is a murine PDL1 or a murine PDL2. 
     In some embodiments, the antibody blocks the ability of a natural ligand to bind to the mammalian PDL1 with an EC 50  of less than or equal to 0.1 nM, less than or equal to 0.25 nM, less than or equal to 0.5 nM, less than or equal to 1 nM, less than or equal to 2 nM, less than or equal to 3 nM, less than or equal to 4 nM, less than or equal to 5 nM or less than or equal to 10 nM. 
     In some embodiments, the anti-PD-1 antibody includes a heavy chain that comprises or is derived from an amino acid sequence selected from the group consisting of SEQ ID NO: 1, 5, 9, 13, 17, 21, 23, 25, 27, 29, 31, 33, 35, and 37, and a light chain that comprises or is derived from an amino acid sequence selected from the group consisting of SEQ ID NO: 3, 7, 11, 15, 19, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59. 
     In some embodiments, the anti-PD-1 antibody includes a heavy chain that comprises or is derived from an amino acid sequence selected from the group consisting of SEQ ID NO: 21, 23, 25, 27, 29, 31, 33, 35, and 37, and a light chain that comprises or is derived from an amino acid sequence selected from the group consisting of SEQ ID NO: 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59. 
     In some embodiments, the anti-PD-1 antibody includes a heavy chain that comprises or is derived from amino acid sequence SEQ ID NO: 21. In some embodiments, the anti-PD-1 antibody includes a light chain that comprises or is derived from amino acid sequence SEQ ID NO: 45 or SEQ ID NO: 47. In some embodiments, the anti-PD-1 antibody includes a heavy chain that comprises or is derived from amino acid sequence SEQ ID NO: 21 and a light chain that comprises or is derived from amino acid sequence SEQ ID NO: 45 or SEQ ID NO: 47. In some embodiments, the anti-PD-1 antibody includes a heavy chain that comprises or is derived from amino acid sequence SEQ ID NO: 21 and a light chain that comprises or is derived from amino acid sequence SEQ ID NO: 45. In some embodiments, the anti-PD-1 antibody includes a heavy chain that comprises or is derived from amino acid sequence SEQ ID NO: 21 and a light chain that comprises or is derived from amino acid sequence SEQ ID NO: 47. 
     In some embodiments, the anti-PD-1 antibody includes the combination of the complementarity determining region (CDR) sequences of the heavy chain amino acid sequence of SEQ ID NO: 21. In some embodiments, the anti-PD-1 antibody includes the combination of the CDR sequences of the light chain amino acid sequence of SEQ ID NO: 45 or of SEQ ID NO: 47. In some embodiments, the anti-PD-1 antibody includes a combination of the CDR sequences of the heavy chain amino acid sequence of SEQ ID NO: 21, and the CDR sequences of the light chain amino acid sequence of SEQ ID NO: 45 or 47. In some embodiments, the anti-PD-1 antibody includes a combination of the CDR sequences of the heavy chain amino acid sequence of SEQ ID NO: 21, and the CDR sequences of the light chain amino acid sequence of SEQ ID NO: 45. In some embodiments, the anti-PD-1 antibody includes a combination of the CDR sequences of the heavy chain amino acid sequence of SEQ ID NO: 21, and the CDR sequences of the light chain amino acid sequence of SEQ ID NO: 47. 
     In some embodiments, the anti-PD-1 antibody includes: (a) a variable heavy chain complementarity determining region 1 (VH CDR1) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 653-657; (b) a variable heavy chain complementarity determining region 2 (VH CDR2) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 658-663; (c) a variable heavy chain complementarity determining region 3 (VH CDR3) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 664-668; (d) a variable light chain complementarity determining region 1 (VL CDR1) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 669-677; (e) a variable light chain complementarity determining region 2 (VL CDR2) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 678-682; and (f) variable light chain complementarity determining region 3 (VL CDR3) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 683-687. 
     In some embodiments, the anti-PD-1 antibody includes a combination of a variable heavy chain complementarity determining region 1 (VH CDR1, also referred to herein as CDRH1) sequence, a variable heavy chain complementarity determining region 2 (VH CDR2, also referred to herein as CDRH2) sequence, and a variable heavy chain complementarity determining region 3 (VH CDR3, also referred to herein as CDRH3) sequence, wherein the VH CDR1 sequence comprises GFTFSGYAMS (SEQ ID NO: 653); the VH CDR2 sequence comprises YISNSGGNAH (SEQ ID NO: 658); and the VH CDR3 sequence comprises EDYGTSPFVY (SEQ ID NO: 664). 
     In some embodiments, the anti-PD-1 antibody includes a combination of a variable light chain complementarity determining region 1 (VL CDR1, also referred to herein as CDRL1) sequence, a variable light chain complementarity determining region 2 (VL CDR2, also referred to herein as CDRL2) sequence, and a variable light chain complementarity determining region 3 (VL CDR3, also referred to herein as CDRL3) sequence, wherein the VL CDR1 sequence comprises RASESVDSYGISFMN (SEQ ID NO: 675) or RASESVDAYGISFMN (SEQ ID NO:676); the VL CDR2 sequence comprises AASNQGS (SEQ ID NO: 678); and the VL CDR3 sequence comprises QQSKDVPWT (SEQ ID NO: 683). In some embodiments, the anti-PD-1 antibody includes a combination of a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the VL CDR1 sequence comprises RASESVDSYGISFMN (SEQ ID NO: 675); the VL CDR2 sequence comprises AASNQGS (SEQ ID NO: 678); and the VL CDR3 sequence comprises QQSKDVPWT (SEQ ID NO: 683). In some embodiments, the anti-PD-1 antibody includes a combination of a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the VL CDR1 sequence comprises RASESVDAYGISFMN (SEQ ID NO:676); the VL CDR2 sequence comprises AASNQGS (SEQ ID NO: 678); and the VL CDR3 sequence comprises QQSKDVPWT (SEQ ID NO: 683). 
     In some embodiments, the anti-PD-1 antibody includes a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the VH CDR1 sequence comprises GFTFSGYAMS (SEQ ID NO: 653); the VH CDR2 sequence comprises YISNSGGNAH (SEQ ID NO: 658); and the VH CDR3 sequence comprises EDYGTSPFVY (SEQ ID NO: 664); the VL CDR1 sequence comprises RASESVDSYGISFMN (SEQ ID NO: 675) or RASESVDAYGISFMN (SEQ ID NO:676); the VL CDR2 sequence comprises AASNQGS (SEQ ID NO: 678); and the VL CDR3 sequence comprises QQSKDVPWT (SEQ ID NO: 683). In some embodiments, the anti-PD-1 antibody includes a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the VH CDR1 sequence comprises GFTFSGYAMS (SEQ ID NO: 653); the VH CDR2 sequence comprises YISNSGGNAH (SEQ ID NO: 658); and the VH CDR3 sequence comprises EDYGTSPFVY (SEQ ID NO: 664); the VL CDR1 sequence comprises RASESVDSYGISFMN (SEQ ID NO: 675); the VL CDR2 sequence comprises AASNQGS (SEQ ID NO: 678); and the VL CDR3 sequence comprises QQSKDVPWT (SEQ ID NO: 683). In some embodiments, the anti-PD-1 antibody includes a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the VH CDR1 sequence comprises GFTFSGYAMS (SEQ ID NO: 653); the VH CDR2 sequence comprises YISNSGGNAH (SEQ ID NO: 658); and the VH CDR3 sequence comprises EDYGTSPFVY (SEQ ID NO: 664); the VL CDR1 sequence comprises RASESVDAYGISFMN (SEQ ID NO:676); the VL CDR2 sequence comprises AASNQGS (SEQ ID NO: 678); and the VL CDR3 sequence comprises QQSKDVPWT (SEQ ID NO: 683). 
     In some embodiments, the anti-PD-1 antibody includes a heavy chain that comprises or is derived from the amino acid sequence of SEQ ID NO: 1346, and a light chain that comprises or is derived from the amino acid sequence of SEQ ID NO: 626. 
     In some embodiments, the anti-PD-1 antibody includes a heavy chain that comprises or is derived from the amino acid sequence of SEQ ID NO: 1514, and a light chain that comprises or is derived from the amino acid sequence of SEQ ID NO: 638. 
     In some embodiments, the anti-PD-1 antibody includes the combination of the complementarity determining region (CDR) sequences of the heavy chain amino acid sequence of SEQ ID NO: 1346. In some embodiments, the anti-PD-1 antibody includes the combination of the CDR sequences of the light chain amino acid sequence of SEQ ID NO: 626. In some embodiments, the anti-PD-1 antibody includes a combination of the CDR sequences of the heavy chain amino acid sequence of SEQ ID NO: 1346, and the CDR sequences of the light chain amino acid sequence of SEQ ID NO: 626. 
     In some embodiments, the anti-PD-1 antibody includes a combination of a variable heavy chain complementarity determining region 1 (VH CDR1, also referred to herein as CDRH1) sequence, a variable heavy chain complementarity determining region 2 (VH CDR2, also referred to herein as CDRH2) sequence, and a variable heavy chain complementarity determining region 3 (VH CDR3, also referred to herein as CDRH3) sequence, wherein the VH CDR1 sequence comprises GITFSNSG (SEQ ID NO: 1705); the VH CDR2 sequence comprises IWYDGSKR (SEQ ID NO: 1706); and the VH CDR3 sequence comprises TNDDY (SEQ ID NO: 1707). 
     In some embodiments, the anti-PD-1 antibody includes a combination of a variable light chain complementarity determining region 1 (VL CDR1, also referred to herein as CDRL1) sequence, a variable light chain complementarity determining region 2 (VL CDR2, also referred to herein as CDRL2) sequence, and a variable light chain complementarity determining region 3 (VL CDR3, also referred to herein as CDRL3) sequence, wherein the VL CDR1 sequence comprises QSVSSY (SEQ ID NO: 1708); the VL CDR2 sequence comprises DAS (SEQ ID NO: 1709); and the VL CDR3 sequence comprises QQSSNWPRT (SEQ ID NO: 1710). 
     In some embodiments, the anti-PD-1 antibody includes a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the VH CDR1 sequence comprises GITFSNSG (SEQ ID NO: 1705); the VH CDR2 sequence comprises IWYDGSKR (SEQ ID NO: 1706); the VH CDR3 sequence comprises TNDDY (SEQ ID NO: 1707); the VL CDR1 sequence comprises QSVSSY (SEQ ID NO: 1708); the VL CDR2 sequence comprises DAS (SEQ ID NO: 1709); and the VL CDR3 sequence comprises QQSSNWPRT (SEQ ID NO: 1710). 
     In some embodiments, the anti-PD-1 antibody includes the combination of the complementarity determining region (CDR) sequences of the heavy chain amino acid sequence of SEQ ID NO: 1514. In some embodiments, the anti-PD-1 antibody includes the combination of the CDR sequences of the light chain amino acid sequence of SEQ ID NO: 638. In some embodiments, the anti-PD-1 antibody includes a combination of the CDR sequences of the heavy chain amino acid sequence of SEQ ID NO: 1514, and the CDR sequences of the light chain amino acid sequence of SEQ ID NO: 638. 
     In some embodiments, the anti-PD-1 antibody includes a combination of a variable heavy chain complementarity determining region 1 (VH CDR1, also referred to herein as CDRH1) sequence, a variable heavy chain complementarity determining region 2 (VH CDR2, also referred to herein as CDRH2) sequence, and a variable heavy chain complementarity determining region 3 (VH CDR3, also referred to herein as CDRH3) sequence, wherein the VH CDR1 sequence comprises GYTFTNYY (SEQ ID NO: 1711); the VH CDR2 sequence comprises INPSNGGT (SEQ ID NO: 1712); and the VH CDR3 sequence comprises RRDYRFDMGFDY (SEQ ID NO: 1713). 
     In some embodiments, the anti-PD-1 antibody includes a combination of a variable light chain complementarity determining region 1 (VL CDR1, also referred to herein as CDRL1) sequence, a variable light chain complementarity determining region 2 (VL CDR2, also referred to herein as CDRL2) sequence, and a variable light chain complementarity determining region 3 (VL CDR3, also referred to herein as CDRL3) sequence, wherein the VL CDR1 sequence comprises KGVSTSGYSY (SEQ ID NO: 1714); the VL CDR2 sequence comprises LAS (SEQ ID NO: 1715); and the VL CDR3 sequence comprises QHSRDLPLT (SEQ ID NO: 1716). 
     In some embodiments, the anti-PD-1 antibody includes a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the VH CDR1 sequence comprises GYTFTNYY (SEQ ID NO: 1711); the VH CDR2 sequence comprises INPSNGGT (SEQ ID NO: 1712); the VH CDR3 sequence comprises RRDYRFDMGFDY (SEQ ID NO: 1713); the VL CDR1 sequence comprises KGVSTSGYSY (SEQ ID NO: 1714); the VL CDR2 sequence comprises LAS (SEQ ID NO: 1715); and the VL CDR3 sequence comprises QHSRDLPLT (SEQ ID NO: 1716). 
     In some embodiments, the antibody comprises a heavy chain amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NO: 1, 5, 9, 13, 17, 21, 23, 25, 27, 29, 31, 33, 35, and 37. In some embodiments, the antibody comprises a light chain amino acid that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NO: 3, 7, 11, 15, 19, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59. In some embodiments, the antibody comprises a heavy chain amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NO: 1, 5, 9, 13, 17, 21, 23, 25, 27, 29, 31, 33, 35, and 37, and a light chain amino acid that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NO: 3, 7, 11, 15, 19, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59. 
     In some embodiments, the antibody comprises a heavy chain amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NO: 21, 23, 25, 27, 29, 31, 33, 35, and 37. In some embodiments, the antibody comprises a light chain amino acid that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NO: 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59. In some embodiments, the antibody comprises a heavy chain amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NO: 21, 23, 25, 27, 29, 31, 33, 35, and 37, and a light chain amino acid that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NO: 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59. In some embodiments, the anti-PD-1 antibody includes a heavy chain sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 21, and a light chain sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 45 or SEQ ID NO: 47. In some embodiments, the anti-PD-1 antibody includes a heavy chain sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 21, and a light chain sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 45. In some embodiments, the anti-PD-1 antibody includes a heavy chain sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 21, and a light chain sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 47. 
     In some embodiments, the anti-PD-1 antibody includes a heavy chain amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 1346, and a light chain amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 626. 
     In some embodiments, the anti-PD-1 antibody includes a heavy chain amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 1514, and a light chain amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 638. 
     In some embodiments, the antibody comprises a combination of a variable heavy chain complementarity determining region 1 (VH CDR1, also referred to herein as CDRH1) sequence, a variable heavy chain complementarity determining region 2 (VH CDR2, also referred to herein as CDRH2) sequence, a variable heavy chain complementarity determining region 3 (VH CDR3, also referred to herein as CDRH3) sequence, a variable light chain complementarity determining region 1 (VL CDR1, also referred to herein as CDRL1) sequence, a variable light chain complementarity determining region 2 (VL CDR2, also referred to herein as CDRL2) sequence, and a variable light chain complementarity determining region 3 (VL CDR3, also referred to herein as CDRL3) sequence, wherein at least one CDR sequence is selected from the group consisting of a VH CDR1 sequence shown in Table 8; a VH CDR2 sequence shown in Table 8; a VH CDR3 sequence shown in Table 8; a VL CDR1 sequence shown in Table 8; a VL CDR2 sequence shown in Table 8; and a VL CDR3 sequence shown in Table 8. 
     In some embodiments, the antibody comprises a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein at least one CDR sequence is selected from the group consisting of a VH CDR1 sequence that includes a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to a VH CDR1 sequence shown in Table 8; a VH CD2 sequence that includes a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to a VH CDR2 sequence shown in Table 8; a VH CDR3 sequence that includes a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to a VH CDR3 sequence shown in Table 8; a VL CDR1 sequence that includes a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to a VL CDR1 sequence shown in Table 8; a VL CDR2 sequence that includes a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to a VL CDR2 sequence shown in Table 8; and a VL CDR3 sequence that includes a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to a VL CDR3 sequence shown in Table 8. 
     In some embodiments, the antibody comprises a heavy chain that comprises a combination of a VH CDR1 sequence, a VH CDR2 sequence, and a VH CDR3 sequence, wherein the combination is a combination of the three heavy chain CDR sequences (VH CDR1, VH CDR2, VH CDR3) shown in a single row in Table 8. 
     In some embodiments, the antibody comprises a light chain that comprises a combination of a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the combination is a combination of the three light chain CDR sequences (VL CDR1, VL CDR2, VL CDR3) shown in a single row in Table 8. 
     In some embodiments, the antibody comprises a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence shown in a single row in Table 8, and a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence shown in a single row in Table 8. 
     In some embodiments, the antibody comprises a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence shown in a single row in Table 8, and a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence shown in a single row in Table 8, wherein each CDR sequence in the combination comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to the corresponding VH CDR sequence shown in a single row in Table 8 and the corresponding VL CDR shown in a single row in Table 8. 
     In some embodiments, the antibody comprises a heavy chain that comprises a combination of a VH CDR1 sequence, a VH CDR2 sequence, and a VH CDR3 sequence, wherein each CDR sequence in the combination comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to the corresponding CDR sequence in a combination of three heavy chain CDR sequences (VH CDR1, VH CDR2, VH CDR3) shown in a single row in Table 8. 
     In some embodiments, the antibody comprises a light chain that comprises a combination of a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein each CDR sequence in the combination comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to the corresponding CDR sequence in a combination of three light chain CDR sequences (VL CDR1, VL CDR2, VL CDR3) shown in a single row in Table 8. 
     In some embodiments, the antibody includes a combination of a VH CDR1 sequence, a VH CDR2 sequence, and a VH CDR3 sequence, wherein the VH CDR1 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to GITFSNSG (SEQ ID NO: 1705); the VH CDR2 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to IWYDGSKR (SEQ ID NO: 1706); and the VH CDR3 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to TNDDY (SEQ ID NO: 1707). 
     In some embodiments, the anti-PD-1 antibody includes a combination of a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the VL CDR1 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to QSVSSY (SEQ ID NO: 1708); the VL CDR2 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to DAS (SEQ ID NO: 1709); and the VL CDR3 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to QQSSNWPRT (SEQ ID NO: 1710). 
     In some embodiments, the anti-PD-1 antibody includes a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the VH CDR1 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to GITFSNSG (SEQ ID NO: 1705); the VH CDR2 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to IWYDGSKR (SEQ ID NO: 1706); the VH CDR3 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to TNDDY (SEQ ID NO: 1707); the VL CDR1 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to QSVSSY (SEQ ID NO: 1708); the VL CDR2 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to DAS (SEQ ID NO: 1709); and the VL CDR3 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to QQSSNWPRT (SEQ ID NO: 1710). 
     In some embodiments, the antibody includes a combination of a VH CDR1 sequence, a VH CDR2 sequence, and a VH CDR3 sequence, wherein the VH CDR1 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to GYTFTNYY (SEQ ID NO: 1711); the VH CDR2 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to INPSNGGT (SEQ ID NO: 1712); and the VH CDR3 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to RRDYRFDMGFDY (SEQ ID NO: 1713). 
     In some embodiments, the anti-PD-1 antibody includes a combination of a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the VL CDR1 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to KGVSTSGYSY (SEQ ID NO: 1714); the VL CDR2 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to LAS (SEQ ID NO: 1715); and the VL CDR3 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to QHSRDLPLT (SEQ ID NO: 1716). 
     In some embodiments, the anti-PD-1 antibody includes a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the VH CDR1 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to GYTFTNYY (SEQ ID NO: 1711); the VH CDR2 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to INPSNGGT (SEQ ID NO: 1712); the VH CDR3 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to RRDYRFDMGFDY (SEQ ID NO: 1713); the VL CDR1 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to KGVSTSGYSY (SEQ ID NO: 1714); the VL CDR2 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to LAS (SEQ ID NO: 1715); and the VL CDR3 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to QHSRDLPLT (SEQ ID NO: 1716). 
     In some embodiments, the antibody is encoded by a nucleic acid sequence that comprises a nucleic acid sequence encoding a heavy chain amino acid sequence selected from the group consisting of SEQ ID NO: 1, 5, 9, 13, 17, 21, 23, 25, 27, 29, 31, 33, 35, and 37. In some embodiments, the antibody is encoded by a nucleic acid sequence that comprises a nucleic acid sequence encoding a heavy chain amino acid sequence selected from the group consisting of SEQ ID NO: 21, 23, 25, 27, 29, 31, 33, 35, and 37. 
     In some embodiments, the antibody is encoded by a nucleic acid sequence that comprises a nucleic acid sequence encoding a light chain amino acid sequence selected from the group consisting of SEQ ID NO: 3, 7, 11, 15, 19, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59. In some embodiments, the antibody is encoded by a nucleic acid sequence that comprises a nucleic acid sequence encoding a light chain amino acid sequence selected from the group consisting of SEQ ID NO: 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59. 
     In some embodiments, the antibody is encoded by a nucleic acid sequence that comprises a nucleic acid sequence encoding a heavy chain amino acid sequence selected from the group consisting of SEQ ID NO: 1, 5, 9, 13, 17, 21, 23, 25, 27, 29, 31, 33, 35, and 37, and a nucleic acid sequence that comprises a nucleic acid sequence encoding a light chain amino acid sequence selected from the group consisting of SEQ ID NO: 3, 7, 11, 15, 19, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59. 
     In some embodiments, the antibody is encoded by a nucleic acid sequence that comprises a nucleic acid sequence encoding a heavy chain amino acid sequence selected from the group consisting of SEQ ID NO: 21, 23, 25, 27, 29, 31, 33, 35, and 37, and a nucleic acid sequence that comprises a nucleic acid sequence encoding a light chain amino acid sequence selected from the group consisting of SEQ ID NO: 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59. 
     In some embodiments, the anti-PD-1 is encoded by a nucleic acid sequence that comprises a nucleic acid sequence encoding a heavy chain that comprises or is derived from the amino acid sequence of SEQ ID NO: 1346, and a nucleic acid sequence that comprises a nucleic acid sequence encoding a light chain that comprises or is derived from the amino acid sequence of SEQ ID NO: 626. 
     In some embodiments, the anti-PD-1 antibody is encoded by a nucleic acid sequence that comprises a nucleic acid sequence encoding a heavy chain that comprises or is derived from the amino acid sequence of SEQ ID NO: 1514, and a nucleic acid sequence that comprises a nucleic acid sequence encoding a light chain that comprises or is derived from the amino acid sequence of SEQ ID NO: 638. 
     In some embodiments, the antibody is encoded by a nucleic acid sequence that comprises a nucleic acid sequence encoding a heavy chain amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NO: 1, 5, 9, 13, 17, 21, 23, 25, 27, 29, 31, 33, 35, and 37. In some embodiments, the antibody is encoded by a nucleic acid sequence that comprises a nucleic acid sequence encoding a heavy chain amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NO: 21, 23, 25, 27, 29, 31, 33, 35, and 37. 
     In some embodiments, the antibody is encoded by a nucleic acid sequence that comprises a nucleic acid sequence encoding a light chain amino acid that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence selected from the group consisting of SEQ ID NO: 3, 7, 11, 15, 19, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59. In some embodiments, the antibody is encoded by a nucleic acid sequence that comprises a nucleic acid sequence encoding a light chain amino acid that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence selected from the group consisting of SEQ ID NO: 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59. 
     In some embodiments, the antibody is encoded by a nucleic acid sequence that comprises a nucleic acid sequence encoding a heavy chain amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NO: 1, 5, 9, 13, 17, 21, 23, 25, 27, 29, 31, 33, 35, and 37, and a nucleic acid sequence encoding a light chain amino acid that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence selected from the group consisting of SEQ ID NO: 3, 7, 11, 15, 19, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59. 
     In some embodiments, the antibody is encoded by a nucleic acid sequence that comprises a nucleic acid sequence encoding a heavy chain amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NO: 21, 23, 25, 27, 29, 31, 33, 35, and 37, and a nucleic acid sequence that comprises a nucleic acid sequence encoding a light chain amino acid that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence selected from the group consisting of SEQ ID NO: 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59. 
     In some embodiments, the anti-PD-1 is encoded by a nucleic acid sequence that comprises a nucleic acid sequence encoding a heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 1346, and a nucleic acid sequence that comprises a nucleic acid sequence encoding a light chain t that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 626. 
     In some embodiments, the anti-PD-1 antibody is encoded by a nucleic acid sequence that comprises a nucleic acid sequence encoding a heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 1514, and a nucleic acid sequence that comprises a nucleic acid sequence encoding a light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 638. 
     In some embodiments, the antibody is encoded by a heavy chain nucleic acid sequence selected from the group consisting of SEQ ID NO: 2, 6, 10, 14, 18, 22, 24, 26, 28, 30, 32, 34, 36, and 38. In some embodiments, the antibody is encoded by a heavy chain nucleic acid sequence selected from the group consisting of SEQ ID NO: 22, 24, 26, 28, 30, 32, 34, 36, and 38. 
     In some embodiments, the antibody is encoded by a light chain nucleic acid sequence selected from the group consisting of SEQ ID NO: 4, 8, 12, 16, 20, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, and 60. In some embodiments, the antibody is encoded by a light chain nucleic acid sequence selected from the group consisting of SEQ ID NO: 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, and 60. 
     In some embodiments, the antibody is encoded by heavy chain nucleic acid sequence selected from the group consisting of SEQ ID NO: selected from the group consisting of SEQ ID NO: 2, 6, 10, 14, 18, 22, 24, 26, 28, 30, 32, 34, 36, and 38, and a light chain nucleic acid sequence selected from the group consisting of SEQ ID NO: 4, 8, 12, 16, 20, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, and 60. In some embodiments, the antibody is encoded by heavy chain nucleic acid sequence selected from the group consisting of SEQ ID NO: selected from the group consisting of SEQ ID NO: 22, 24, 26, 28, 30, 32, 34, 36, and 38, and a light chain nucleic acid sequence selected from the group consisting of SEQ ID NO: 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, and 60. 
     In some embodiments, the antibody is encoded by a nucleic acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to a heavy chain nucleic acid sequence selected from the group consisting of SEQ ID NO: 2, 6, 10, 14, 18, 22, 24, 26, 28, 30, 32, 34, 36, and 38. In some embodiments, the antibody is encoded by a nucleic acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to a heavy chain nucleic acid sequence selected from the group consisting of SEQ ID NO: 22, 24, 26, 28, 30, 32, 34, 36, and 38. 
     In some embodiments, the antibody is encoded by a nucleic acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to a light chain nucleic acid sequence selected from the group consisting of SEQ ID NO: 4, 8, 12, 16, 20, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, and 60. In some embodiments, the antibody is encoded by a nucleic acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to a light chain nucleic acid sequence selected from the group consisting of SEQ ID NO: 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, and 60. 
     In some embodiments, the antibody is encoded by a nucleic acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to a heavy chain nucleic acid sequence selected from the group consisting of SEQ ID NO: 2, 6, 10, 14, 18, 22, 24, 26, 28, 30, 32, 34, 36, and 38, and a nucleic acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to a light chain nucleic acid sequence selected from the group consisting of SEQ ID NO: 4, 8, 12, 16, 20, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, and 60. In some embodiments, the antibody is encoded by a nucleic acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to a heavy chain nucleic acid sequence selected from the group consisting of SEQ ID NO: 22, 24, 26, 28, 30, 32, 34, 36, and 38, and a nucleic acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to a light chain nucleic acid sequence selected from the group consisting of SEQ ID NO: 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, and 60. 
     In some embodiments, the antibody or antigen-binding fragment thereof is incorporated in a multispecific antibody or antigen-binding fragment thereof, where at least one arm of the multispecific antibody specifically binds PD-1. In some embodiments, the antibody or antigen-binding fragment thereof is incorporated in a bispecific antibody or antigen-binding fragment thereof, where at least one arm of the bispecific antibody specifically binds PD-1. 
     In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, comprises a heavy chain amino acid sequence selected from the group consisting of SEQ ID NO: 1, 5, 9, 13, 17, 21, 23, 25, 27, 29, 31, 33, 35, and 37. In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, comprises a heavy chain amino acid sequence selected from the group consisting of SEQ ID NO: 21, 23, 25, 27, 29, 31, 33, 35, and 37. 
     In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, comprises a light chain amino acid sequence selected from the group consisting of SEQ ID NO: 3, 7, 11, 15, 19, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59. In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, comprises a light chain amino acid sequence selected from the group consisting of SEQ ID NO: 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59. 
     In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, includes a heavy chain amino acid sequence comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 1, 5, 9, 13, 17, 21, 23, 25, 27, 29, 31, 33, 35, and 37, and a light chain amino acid sequence selected from the group consisting of SEQ ID NO: 3, 7, 11, 15, 19, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59. In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, includes a heavy chain amino acid sequence comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 21, 23, 25, 27, 29, 31, 33, 35, and 37, and a light chain amino acid sequence selected from the group consisting of SEQ ID NO: 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59. 
     In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, includes a heavy chain that comprises or is derived from amino acid sequence SEQ ID NO: 21. In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, includes a light chain that comprises or is derived from amino acid sequence SEQ ID NO: 45 or SEQ ID NO: 47. In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, includes a heavy chain that comprises or is derived from amino acid sequence SEQ ID NO: 21 and a light chain that comprises or is derived from amino acid sequence SEQ ID NO: 45 or SEQ ID NO: 47. In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, includes a heavy chain that comprises or is derived from amino acid sequence SEQ ID NO: 21 and a light chain that comprises or is derived from amino acid sequence SEQ ID NO: 45. In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, includes a heavy chain that comprises or is derived from amino acid sequence SEQ ID NO: 21 and a light chain that comprises or is derived from amino acid sequence SEQ ID NO: 47. 
     In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, includes the combination of the complementarity determining region (CDR) sequences of the heavy chain amino acid sequence of SEQ ID NO: 21. In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, includes the combination of the CDR sequences of the light chain amino acid sequence of SEQ ID NO: 45 or of SEQ ID NO: 47. In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, includes a combination of the CDR sequences of the heavy chain amino acid sequence of SEQ ID NO: 21, and the CDR sequences of the light chain amino acid sequence of SEQ ID NO: 45 or 47. In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, includes a combination of the CDR sequences of the heavy chain amino acid sequence of SEQ ID NO: 21, and the CDR sequences of the light chain amino acid sequence of SEQ ID NO: 45. In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, includes a combination of the CDR sequences of the heavy chain amino acid sequence of SEQ ID NO: 21, and the CDR sequences of the light chain amino acid sequence of SEQ ID NO: 47. 
     In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody includes: (a) a variable heavy chain complementarity determining region 1 (VH CDR1) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 653-657; (b) a variable heavy chain complementarity determining region 2 (VH CDR2) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 658-663; (c) a variable heavy chain complementarity determining region 3 (VH CDR3) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 664-668; (d) a variable light chain complementarity determining region 1 (VL CDR1) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 669-677; (e) a variable light chain complementarity determining region 2 (VL CDR2) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 678-682; and (f) variable light chain complementarity determining region 3 (VL CDR3) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 683-687 
     In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, includes a combination of a variable heavy chain complementarity determining region 1 (VH CDR1, also referred to herein as CDRH1) sequence, a variable heavy chain complementarity determining region 2 (VH CDR2, also referred to herein as CDRH2) sequence, and a variable heavy chain complementarity determining region 3 (VH CDR3, also referred to herein as CDRH3) sequence, wherein the VH CDR1 sequence comprises GFTFSGYAMS (SEQ ID NO: 653); the VH CDR2 sequence comprises YISNSGGNAH (SEQ ID NO: 658); and the VH CDR3 sequence comprises EDYGTSPFVY (SEQ ID NO: 664). 
     In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, includes a combination of a variable light chain complementarity determining region 1 (VL CDR1, also referred to herein as CDRL1) sequence, a variable light chain complementarity determining region 2 (VL CDR2, also referred to herein as CDRL2) sequence, and a variable light chain complementarity determining region 3 (VL CDR3, also referred to herein as CDRL3) sequence, wherein the VL CDR1 sequence comprises RASESVDSYGISFMN (SEQ ID NO: 675) or RASESVDAYGISFMN (SEQ ID NO:676); the VL CDR2 sequence comprises AASNQGS (SEQ ID NO: 678); and the VL CDR3 sequence comprises QQSKDVPWT (SEQ ID NO: 683). In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, includes a combination of a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the VL CDR1 sequence comprises RASESVDSYGISFMN (SEQ ID NO: 675); the VL CDR2 sequence comprises AASNQGS (SEQ ID NO: 678); and the VL CDR3 sequence comprises QQSKDVPWT (SEQ ID NO: 683). In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, includes a combination of a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the VL CDR1 sequence comprises RASESVDAYGISFMN (SEQ ID NO:676); the VL CDR2 sequence comprises AASNQGS (SEQ ID NO: 678); and the VL CDR3 sequence comprises QQSKDVPWT (SEQ ID NO: 683). 
     In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, includes a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the VH CDR1 sequence comprises GFTFSGYAMS (SEQ ID NO: 653); the VH CDR2 sequence comprises YISNSGGNAH (SEQ ID NO: 658); and the VH CDR3 sequence comprises EDYGTSPFVY (SEQ ID NO: 664); the VL CDR1 sequence comprises RASESVDSYGISFMN (SEQ ID NO: 675) or RASESVDAYGISFMN (SEQ ID NO:676); the VL CDR2 sequence comprises AASNQGS (SEQ ID NO: 678); and the VL CDR3 sequence comprises QQSKDVPWT (SEQ ID NO: 683). In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, includes a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the VH CDR1 sequence comprises GFTFSGYAMS (SEQ ID NO: 653); the VH CDR2 sequence comprises YISNSGGNAH (SEQ ID NO: 658); and the VH CDR3 sequence comprises EDYGTSPFVY (SEQ ID NO: 664); the VL CDR1 sequence comprises RASESVDSYGISFMN (SEQ ID NO: 675); the VL CDR2 sequence comprises AASNQGS (SEQ ID NO: 678); and the VL CDR3 sequence comprises QQSKDVPWT (SEQ ID NO: 683). In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, includes a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the VH CDR1 sequence comprises GFTFSGYAMS (SEQ ID NO: 653); the VH CDR2 sequence comprises YISNSGGNAH (SEQ ID NO: 658); and the VH CDR3 sequence comprises EDYGTSPFVY (SEQ ID NO: 664); the VL CDR1 sequence comprises RASESVDAYGISFMN (SEQ ID NO:676); the VL CDR2 sequence comprises AASNQGS (SEQ ID NO: 678); and the VL CDR3 sequence comprises QQSKDVPWT (SEQ ID NO: 683). 
     In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, includes a heavy chain that comprises or is derived from the amino acid sequence of SEQ ID NO: 1346, and a light chain that comprises or is derived from the amino acid sequence of SEQ ID NO: 626. 
     In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, includes a heavy chain that comprises or is derived from the amino acid sequence of SEQ ID NO: 1514, and a light chain that comprises or is derived from the amino acid sequence of SEQ ID NO: 638. 
     In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, includes the combination of the complementarity determining region (CDR) sequences of the heavy chain amino acid sequence of SEQ ID NO: 1346. In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, includes the combination of the CDR sequences of the light chain amino acid sequence of SEQ ID NO: 626. In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, includes a combination of the CDR sequences of the heavy chain amino acid sequence of SEQ ID NO: 1346, and the CDR sequences of the light chain amino acid sequence of SEQ ID NO: 626. 
     In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, includes a combination of a variable heavy chain complementarity determining region 1 (VH CDR1, also referred to herein as CDRH1) sequence, a variable heavy chain complementarity determining region 2 (VH CDR2, also referred to herein as CDRH2) sequence, and a variable heavy chain complementarity determining region 3 (VH CDR3, also referred to herein as CDRH3) sequence, wherein the VH CDR1 sequence comprises GITFSNSG (SEQ ID NO: 1705); the VH CDR2 sequence comprises IWYDGSKR (SEQ ID NO: 1706); and the VH CDR3 sequence comprises TNDDY (SEQ ID NO: 1707). 
     In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, includes a combination of a variable light chain complementarity determining region 1 (VL CDR1, also referred to herein as CDRL1) sequence, a variable light chain complementarity determining region 2 (VL CDR2, also referred to herein as CDRL2) sequence, and a variable light chain complementarity determining region 3 (VL CDR3, also referred to herein as CDRL3) sequence, wherein the VL CDR1 sequence comprises QSVSSY (SEQ ID NO: 1708); the VL CDR2 sequence comprises DAS (SEQ ID NO: 1709); and the VL CDR3 sequence comprises QQSSNWPRT (SEQ ID NO: 1710). 
     In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, includes a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the VH CDR1 sequence comprises GITFSNSG (SEQ ID NO: 1705); the VH CDR2 sequence comprises IWYDGSKR (SEQ ID NO: 1706); the VH CDR3 sequence comprises TNDDY (SEQ ID NO: 1707); the VL CDR1 sequence comprises QSVSSY (SEQ ID NO: 1708); the VL CDR2 sequence comprises DAS (SEQ ID NO: 1709); and the VL CDR3 sequence comprises QQSSNWPRT (SEQ ID NO: 1710). 
     In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, includes the combination of the complementarity determining region (CDR) sequences of the heavy chain amino acid sequence of SEQ ID NO: 1514. In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, includes the combination of the CDR sequences of the light chain amino acid sequence of SEQ ID NO: 638. In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, includes a combination of the CDR sequences of the heavy chain amino acid sequence of SEQ ID NO: 1514, and the CDR sequences of the light chain amino acid sequence of SEQ ID NO: 638. 
     In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, includes a combination of a variable heavy chain complementarity determining region 1 (VH CDR1, also referred to herein as CDRH1) sequence, a variable heavy chain complementarity determining region 2 (VH CDR2, also referred to herein as CDRH2) sequence, and a variable heavy chain complementarity determining region 3 (VH CDR3, also referred to herein as CDRH3) sequence, wherein the VH CDR1 sequence comprises GYTFTNYY (SEQ ID NO: 1711); the VH CDR2 sequence comprises INPSNGGT (SEQ ID NO: 1712); and the VH CDR3 sequence comprises RRDYRFDMGFDY (SEQ ID NO: 1713). 
     In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, includes a combination of a variable light chain complementarity determining region 1 (VL CDR1, also referred to herein as CDRL1) sequence, a variable light chain complementarity determining region 2 (VL CDR2, also referred to herein as CDRL2) sequence, and a variable light chain complementarity determining region 3 (VL CDR3, also referred to herein as CDRL3) sequence, wherein the VL CDR1 sequence comprises KGVSTSGYSY (SEQ ID NO: 1714); the VL CDR2 sequence comprises LAS (SEQ ID NO: 1715); and the VL CDR3 sequence comprises QHSRDLPLT (SEQ ID NO: 1716). 
     In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, includes a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the VH CDR1 sequence comprises GYTFTNYY (SEQ ID NO: 1711); the VH CDR2 sequence comprises INPSNGGT (SEQ ID NO: 1712); the VH CDR3 sequence comprises RRDYRFDMGFDY (SEQ ID NO: 1713); the VL CDR1 sequence comprises KGVSTSGYSY (SEQ ID NO: 1714); the VL CDR2 sequence comprises LAS (SEQ ID NO: 1715); and the VL CDR3 sequence comprises QHSRDLPLT (SEQ ID NO: 1716). 
     In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, comprises a heavy chain amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NO: 1, 5, 9, 13, 17, 21, 23, 25, 27, 29, 31, 33, 35, and 37. In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, comprises a heavy chain amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NO: 21, 23, 25, 27, 29, 31, 33, 35, and 37. 
     In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, comprises a light chain amino acid that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NO: 3, 7, 11, 15, 19, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59. In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, comprises a light chain amino acid that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NO: 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59. 
     In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, comprises a heavy chain amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NO: 1, 5, 9, 13, 17, 21, 23, 25, 27, 29, 31, 33, 35, and 37, and a light chain amino acid that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NO: 3, 7, 11, 15, 19, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59. 
     In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, includes a heavy chain amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 1346, and a light chain amino acid that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 626. 
     In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, includes a heavy chain amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 1514, and a light chain amino acid that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 638. 
     In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, includes a combination of a VH CDR1 sequence, a VH CDR2 sequence, and a VH CDR3 sequence, wherein the VH CDR1 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to GITFSNSG (SEQ ID NO: 1705); the VH CDR2 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to IWYDGSKR (SEQ ID NO: 1706); and the VH CDR3 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to TNDDY (SEQ ID NO: 1707). 
     In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, includes a combination of a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the VL CDR1 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to QSVSSY (SEQ ID NO: 1708); the VL CDR2 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to DAS (SEQ ID NO: 1709); and the VL CDR3 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to QQSSNWPRT (SEQ ID NO: 1710). 
     In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, includes a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the VH CDR1 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to GITFSNSG (SEQ ID NO: 1705); the VH CDR2 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to IWYDGSKR (SEQ ID NO: 1706); the VH CDR3 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to TNDDY (SEQ ID NO: 1707); the VL CDR1 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to QSVSSY (SEQ ID NO: 1708); the VL CDR2 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to DAS (SEQ ID NO: 1709); and the VL CDR3 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to QQSSNWPRT (SEQ ID NO: 1710). 
     In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, includes a combination of a VH CDR1 sequence, a VH CDR2 sequence, and a VH CDR3 sequence, wherein the VH CDR1 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to GYTFTNYY (SEQ ID NO: 1711); the VH CDR2 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to INPSNGGT (SEQ ID NO: 1712); and the VH CDR3 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to RRDYRFDMGFDY (SEQ ID NO: 1713). 
     In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, includes a combination of a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the VL CDR1 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to KGVSTSGYSY (SEQ ID NO: 1714); the VL CDR2 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to LAS (SEQ ID NO: 1715); and the VL CDR3 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to QHSRDLPLT (SEQ ID NO: 1716). 
     In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, includes a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the VH CDR1 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to GYTFTNYY (SEQ ID NO: 1711); the VH CDR2 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to INPSNGGT (SEQ ID NO: 1712); the VH CDR3 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to RRDYRFDMGFDY (SEQ ID NO: 1713); the VL CDR1 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to KGVSTSGYSY (SEQ ID NO: 1714); the VL CDR2 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to LAS (SEQ ID NO: 1715); and the VL CDR3 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to QHSRDLPLT (SEQ ID NO: 1716). 
     In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, comprises a combination of a variable heavy chain complementarity determining region 1 (VH CDR1, also referred to herein as CDRH1) sequence, a variable heavy chain complementarity determining region 2 (VH CDR2, also referred to herein as CDRH2) sequence, a variable heavy chain complementarity determining region 3 (VH CDR3, also referred to herein as CDRH3) sequence, a variable light chain complementarity determining region 1 (VL CDR1, also referred to herein as CDRL1) sequence, a variable light chain complementarity determining region 2 (VL CDR2, also referred to herein as CDRL2) sequence, and a variable light chain complementarity determining region 3 (VL CDR3, also referred to herein as CDRL3) sequence, wherein at least one CDR sequence is selected from the group consisting of a VH CDR1 sequence shown in Table 8; a VH CDR2 sequence shown in Table 8; a VH CDR3 sequence shown in Table 8; a VL CDR1 sequence shown in Table 8; a VL CDR2 sequence shown in Table 8; and a VL CDR3 sequence shown in Table 8. 
     In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, comprises a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein at least one CDR sequence is selected from the group consisting of a VH CDR1 sequence that includes a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to a VH CDR1 sequence shown in Table 8; a VH CD2 sequence that includes a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to a VH CDR2 sequence shown in Table 8; a VH CDR3 sequence that includes a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to a VH CDR3 sequence shown in Table 8; a VL CDR1 sequence that includes a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to a VL CDR1 sequence shown in Table 8; a VL CDR2 sequence that includes a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to a VL CDR2 sequence shown in Table 8; and a VL CDR3 sequence that includes a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to a VL CDR3 sequence shown in Table 8. 
     In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, comprises a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the combination is a combination of the six CDR sequences (VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3) shown in a single row in Table 8. 
     In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, comprises a heavy chain that comprises a combination of a VH CDR1 sequence, a VH CDR2 sequence, and a VH CDR3 sequence, wherein the combination is a combination of the three heavy chain CDR sequences (VH CDR1, VH CDR2, VH CDR3) shown in a single row in Table 8. 
     In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, comprises a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence shown in a single row in Table 8, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence shown in a single row in Table 8, wherein each CDR sequence in the combination comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to the corresponding VH CDR sequence shown in a single row in Table 8 and the corresponding VL CDR shown in a single row in Table 8. 
     In some embodiments, at least one arm of the multispecific antibody, e.g., a bispecific antibody, comprises a heavy chain that comprises a combination of a VH CDR1 sequence, a VH CDR2 sequence, and a VH CDR3 sequence, wherein each CDR sequence in the combination comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to the corresponding CDR sequence in a combination of three heavy chain CDR sequences (VH CDR1, VH CDR2, VH CDR3) shown in a single row in Table 8. 
     The disclosure also provides activatable antibodies that include an antibody or antigen-binding fragment thereof that specifically binds PD-1 coupled to a masking moiety (MM), such that coupling of the MM reduces the ability of the antibody or antigen-binding fragment thereof to bind PD-1. In some embodiments, the MM is coupled via a cleavable moiety (CM) that includes sequence that functions as a substrate for a protease. The activatable anti-PD-1 antibodies of the disclosure are activated when the cleavable moiety is cleaved by a protease. For example, the protease is produced by a tumor that is in proximity to T cells that express PD-1. In some embodiments, the protease is produced by a tumor that is co-localized with T cells that express PD-1. 
     The activatable anti-PD-1 antibodies provided herein, also referred to herein as anti-PD-1 activatable antibodies or PD-1 activatable antibodies, are stable in circulation, activated at intended sites of therapy and/or diagnosis but not in normal, e.g., healthy tissue or other tissue not targeted for treatment and/or diagnosis, and, when activated, exhibit binding to PD-1 that is at least comparable to the corresponding, unmodified antibody. 
     The invention also provides methods of treating, preventing and/or delaying the onset or progression of, or alleviating a symptom associated with aberrant expression and/or activity of PD-1 in a subject using antibodies or activatable antibodies that bind PD-1, particularly activatable antibodies that bind and neutralize or otherwise inhibit at least one biological activity of PD-1. 
     In some embodiments, the activatable anti-PD-1 antibody comprises an activatable antibody that, in an activated state, specifically binds to mammalian PD-1, wherein said activatable antibody comprises: an antibody or an antigen binding fragment thereof (AB) that specifically binds to mammalian PD-1; a masking moiety (MM) that inhibits the binding of the AB to mammalian PD-1 when the activatable antibody is in an uncleaved state; and a cleavable moiety (CM) coupled to the AB, wherein the CM is a polypeptide that functions as a substrate for a protease. 
     In some embodiments, the activatable anti-PD-1 antibody comprises an activatable antibody that, in an activated state, (a) specifically binds to mammalian PD-1; and (b) specifically blocks a natural ligand of PD-1 from binding to the mammalian PD-1, wherein the activatable antibody comprises: an antibody or an antigen binding fragment thereof (AB) that specifically binds to mammalian PD-1; a masking moiety (MM) that inhibits the binding of the AB to mammalian PD-1 when the activatable antibody is in an uncleaved state; and a cleavable moiety (CM) coupled to the AB, wherein the CM is a polypeptide that functions as a substrate for a protease. 
     In some embodiments, the activatable antibody in an uncleaved state specifically binds to the mammalian PD-1 with a dissociation constant of 0.5 nM to 1 nM, 0.5 nM to 2 nM, 0.5 nM to 5 nM, 0.5 nM to 10 nM, 0.5 nM to 15 nM, 0.5 nM to 20 nM, 0.5 nM to 25 nM, 0.5 nM to 50 nM, 0.5 nM to 75 nM, 0.5 nM to 100 nM, 0.5 nM to 150 nM, 0.5 nM to 200 nM, 0.5 nM to 300 nM, 0.5 nM to 400 nM, 1 nM to 2 nM, 1 nM to 5 nM, 1 nM to 10 nM, 1 nM to 15 nM, 1 nM to 20 nM, 1 nM to 25 nM, 1 nM to 50 nM, 1 nM to 75 nM, 1 nM to 100 nM, 1 nM to 150 nM, 1 nM to 200 nM, 1 nM to 300 nM, 1 nM to 400 nM, 2 nM to 5 nM, 2 nM to 10 nM, 2 nM to 15 nM, 2 nM to 20 nM, 2 nM to 25 nM, 2 nM to 50 nM, 2 nM to 75 nM, 2 nM to 100 nM, 2 nM to 150 nM, 2 nM to 200 nM, 2 nM to 300 nM, 2 nM to 400 nM, 5 nM to 10 nM, 5 nM to 15 nM, 5 nM to 20 nM, 5 nM to 25 nM, 5 nM to 50 nM, 5 nM to 75 nM, 5 nM to 100 nM, 5 nM to 150 nM, 5 nM to 200 nM, 5 nM to 300 nM, 5 nM to 400 nM, 10 nM to 15 nM, 10 nM to 20 nM, 10 nM to 25 nM, 10 nM to 50 nM, 10 nM to 75 nM, 10 nM to 100 nM, 10 nM to 150 nM, 10 nM to 200 nM, 10 nM to 300 nM, 10 nM to 400 nM, 15 nM to 20 nM, 15 nM to 25 nM, 15 nM to 50 nM, 15 nM to 75 nM, 15 nM to 100 nM, 15 nM to 150 nM, 15 nM to 200 nM, 15 nM to 300 nM, 15 nM to 400 nM, 20 nM to 25 nM, 20 nM to 50 nM, 20 nM to 75 nM, 20 nM to 100 nM, 20 nM to 150 nM, 20 nM to 200 nM, 20 nM to 300 nM, 20 nM to 400 nM, 25 nM to 50 nM, 25 nM to 75 nM, 25 nM to 100 nM, 25 nM to 150 nM, 25 nM to 200 nM, 25 nM to 300 nM, 25 nM to 400 nM, 50 nM to 75 nM, 50 nM to 100 nM, 50 nM to 150 nM, 50 nM to 200 nM, 50 nM to 300 nM, 50 nM to 400 nM, 75 nM to 100 nM, 75 nM to 150 nM, 75 nM to 200 nM, 75 nM to 300 nM, 75 nM to 400 nM, 100 nM to 150 nM, 100 nM to 200 nM, 100 nM to 300 nM, 100 nM to 400 nM, 150 nM to 200 nM, 150 nM to 300 nM, 150 nM to 400 nM, 200 nM to 300 nM, 200 nM to 400 nM, or 300 nM to 400 nM. 
     In some embodiments, the activatable antibody in an activated state specifically binds to the mammalian PD-1 with a dissociation constant of 0.01 nM to 5 nM, 0.05 nM to 5 nM, 0.1 nM to 5 nM, 0.2 nM to 5 nM, 0.3 nM to 5 nM, 0.4 nM to 5 nM, 0.5 nM to 5 nM, 0.75 nM to 5 nM, 1 nM to 5 nM, 2 nM to 5 nM, 0.01 nM to 2 nM, 0.05 nM to 2 nM, 0.1 nM to 2 nM, 0.2 nM to 2 nM, 0.3 nM to 2 nM, 0.4 nM to 2 nM, 0.5 nM to 2 nM, 0.75 nM to 1 nM, 1 nM to 2 nM, 0.01 nM to 1 nM, 0.05 nM to 1 nM, 0.1 nM to 1 nM, 0.2 nM to 1 nM, 0.3 nM to 1 nM, 0.4 nM to 1 nM, 0.5 nM to 1 nM, 0.75 nM to 1 nM, 0.01 nM to 0.75 nM, 0.05 nM to 0.75 nM, 0.1 nM to 0.75 nM, 0.2 nM to 0.75 nM, 0.3 nM to 0.75 nM, 0.4 nM to 0.75 nM, 0.5 nM to 0.75 nM, 0.01 nM to 0.5 nM, 0.05 nM to 0.5 nM, 0.1 nM to 0.5 nM, 0.2 nM to 0.5 nM, 0.3 nM to 0.5 nM, 0.4 nM to 0.5 nM, 0.01 nM to 0.4 nM, 0.05 nM to 0.4 nM, 0.1 nM to 0.4 nM, 0.2 nM to 0.4 nM, 0.3 nM to 0.4 nM, 0.01 nM to 0.3 nM, 0.05 nM to 0.3 nM, 0.1 nM to 0.3 nM, 0.2 nM to 0.3 nM, 0.01 nM to 0.2 nM, 0.05 nM to 0.2 nM, 0.1 nM to 0.2 nM, 0.01 nM to 0.1 nM, 0.05 nM to 0.1 nM, or 0.01 nM to 0.05 nM. 
     In some embodiments, the activatable antibody comprises an AB that specifically binds to the mammalian PD-1 with a dissociation constant of 0.01 nM to 5 nM, 0.05 nM to 5 nM, 0.1 nM to 5 nM, 0.2 nM to 5 nM, 0.3 nM to 5 nM, 0.4 nM to 5 nM, 0.5 nM to 5 nM, 0.75 nM to 5 nM, 1 nM to 5 nM, 2 nM to 5 nM, 0.01 nM to 2 nM, 0.05 nM to 2 nM, 0.1 nM to 2 nM, 0.2 nM to 2 nM, 0.3 nM to 2 nM, 0.4 nM to 2 nM, 0.5 nM to 2 nM, 0.75 nM to 1 nM, 1 nM to 2 nM, 0.01 nM to 1 nM, 0.05 nM to 1 nM, 0.1 nM to 1 nM, 0.2 nM to 1 nM, 0.3 nM to 1 nM, 0.4 nM to 1 nM, 0.5 nM to 1 nM, 0.75 nM to 1 nM, 0.01 nM to 0.75 nM, 0.05 nM to 0.75 nM, 0.1 nM to 0.75 nM, 0.2 nM to 0.75 nM, 0.3 nM to 0.75 nM, 0.4 nM to 0.75 nM, 0.5 nM to 0.75 nM, 0.01 nM to 0.5 nM, 0.05 nM to 0.5 nM, 0.1 nM to 0.5 nM, 0.2 nM to 0.5 nM, 0.3 nM to 0.5 nM, 0.4 nM to 0.5 nM, 0.01 nM to 0.4 nM, 0.05 nM to 0.4 nM, 0.1 nM to 0.4 nM, 0.2 nM to 0.4 nM, 0.3 nM to 0.4 nM, 0.01 nM to 0.3 nM, 0.05 nM to 0.3 nM, 0.1 nM to 0.3 nM, 0.2 nM to 0.3 nM, 0.01 nM to 0.2 nM, 0.05 nM to 0.2 nM, 0.1 nM to 0.2 nM, 0.01 nM to 0.1 nM, 0.05 nM to 0.1 nM, or 0.01 nM to 0.05 nM. 
     In some embodiments, the mammalian PD-1 is selected from the group consisting of a human PD-1 and a cynomolgus monkey PD-1. In some embodiments, the AB specifically binds to human PD-1 or cynomolgus monkey PD-1 with a dissociation constant of less than or equal to 1 nM. In some embodiments, the mammalian PD-1 is a human PD-1. In some embodiments, the AB has one or more of the characteristics selected from the group consisting of: (a) the AB specifically binds human PD-1 and cynomolgus monkey PD-1; (b) the AB inhibits binding of human PDL1 and human PDL2 to human PD-1; and (c) the AB inhibits binding of cynomolgus monkey PDL1 and cynomolgus monkey PDL2 to cynomolgus monkey PD-1. 
     In some embodiments, the mammalian PD-1 is mouse PD-1. In some embodiments, the activatable antibody comprises an AB that specifically binds mouse PD-1 or inhibits binding of mouse PDL1 and mouse PDL2 to mouse PD1. 
     In some embodiments, the activatable antibody in an uncleaved state specifically binds to the mammalian PD-1 with a dissociation constant greater than or equal to 0.5 nM, greater than or equal to 1 nM, greater than or equal to 2 nM, greater than or equal to 3 nM, greater than or equal to 4 nM, greater than or equal to 5 nM, greater than or equal to 10 nM, greater than or equal to 15 nM, greater than or equal to 20 nM, greater than or equal to 25 nM, greater than or equal to 50 nM, greater than or equal to 75 nM, greater than or equal to 100 nM, greater than or equal to 150 nM, greater than or equal to 200 nM, greater than or equal to 300 nM and/or greater than or equal to 400 nM. 
     In some embodiments, the activatable antibody in an activated state specifically binds to the mammalian PD-1 with a dissociation constant less than or equal to 0.01 nM, less than or equal to 0.05 nM, less than or equal to 0.1 nM, less than or equal to 0.2 nM, less than or equal to 0.3 nM, less than or equal to 0.4 nM, less than or equal to 0.5 nM, less than or equal to 0.75 nM, and less than or equal to 1 nM. 
     In some embodiments, the activatable antibody comprises an AB that specifically binds to the mammalian PD-1 with a dissociation constant less than or equal to 0.01 nM, less than or equal to 0.05 nM, less than or equal to 0.1 nM, less than or equal to 0.2 nM, less than or equal to 0.3 nM, less than or equal to 0.4 nM, less than or equal to 0.5 nM, less than or equal to 0.75 nM, and less than or equal to 1 nM. 
     In some embodiments, the activatable antibody comprises an AB blocks the ability of a natural ligand to bind to the mammalian PDL1 with an EC 50  of 0.1 nM to 10 nM, 0.1 nM to 5 nM, 0.1 nM to 3 nM, 0.1 nM to 2 nM, 0.1 nM to 1 nM, 0.1 nM to 0.5 nM, 0.1 nM to 0.25 nM, 0.25 nM to 10 nM, 0.25 nM to 5 nM, 0.25 nM to 3 nM, 0.25 nM to 2 nM, 0.25 nM to 1 nM, 0.25 nM to 0.5 nM, 0.5 nM to 10 nM, 0.5 nM to 5 nM, 0.5 nM to 3 nM, 0.5 nM to 2 nM, 0.5 nM to 1 nM, 1 nM to 10 nM, 1 nM to 5 nM, 1 nM to 3 nM, 1 nM to 2 nM, 2 nM to 10 nM, 2 nM to 5 nM, 2 nM to 3 nM, 3 nM to 10 nM, 3 nM to 5 nM, or 5 nM to 10 nM. 
     In some embodiments, the natural ligand is a mammalian PDL1 or a mammalian PDL2. In some embodiments, the natural ligand is selected from the group consisting of: a human PDL1, a human PDL2, a cynomolgus monkey PDL1, and a cynomolgus monkey PDL2. 
     In some embodiments, the activatable antibody has one or more of the following characteristics: (a) the AB induces type 1 diabetes in a non-obese diabetic (NOD) mouse; and (b) the activatable antibody in an uncleaved state inhibits the induction of type 1 diabetes in a NOD mouse. 
     In some embodiments, the activatable antibody inhibits the induction of type 1 diabetes in the NOD mouse after administration of the activatable antibody at a single dose of 0.5 mg/kg to 15 mg/kg, 1 mg/kg to 15 mg/kg, 2 mg/kg to 15 mg/kg, 3 mg/kg to 15 mg/kg, 5 mg/kg to 15 mg/kg, 10 mg/kg to 15 mg/kg, 0.5 mg/kg to 10 mg/kg, 1 mg/kg to 10 mg/kg, 2 mg/kg to 10 mg/kg, 3 mg/kg to 10 mg/kg, 5 mg/kg to 10 mg/kg, 0.5 mg/kg to 5 mg/kg, 1 mg/kg to 5 mg/kg, 2 mg/kg to 5 mg/kg, 3 mg/kg to 5 mg/kg, 0.5 mg/kg to 3 mg/kg, 1 mg/kg to 3 mg/kg, 2 mg/kg to 3 mg/kg, 0.5 mg/kg to 2 mg/kg, 1 mg/kg to 2 mg/kg, or 0.5 mg/kg to 1 mg/kg. In some embodiments, the activatable antibody inhibits the induction of type 1 diabetes in the NOD mouse after administration of the activatable antibody at a single dose of 3 mg/kg to 10 mg/kg, 3 mg/kg or 10 mg/kg. In some embodiments, the activatable antibody inhibits the induction of type 1 diabetes in the NOD mouse after administration of the activatable antibody at a single dose of 3 mg/kg to 10 mg/kg. In some embodiments, the activatable antibody inhibits the induction of type 1 diabetes in the NOD mouse after administration of the activatable antibody at a single dose of 3 mg/kg. In some embodiments, the activatable antibody inhibits the induction of type 1 diabetes in the NOD mouse after administration of the activatable antibody at a single dose of 10 mg/kg. 
     In some embodiments, the AB induces type 1 diabetes in the NOD mouse after administration of the AB at a single dose of 0.5 mg/kg to 15 mg/kg, 1 mg/kg to 15 mg/kg, 2 mg/kg to 15 mg/kg, 3 mg/kg to 15 mg/kg, 5 mg/kg to 15 mg/kg, 10 mg/kg to 15 mg/kg, 0.5 mg/kg to 10 mg/kg, 1 mg/kg to 10 mg/kg, 2 mg/kg to 10 mg/kg, 3 mg/kg to 10 mg/kg, 5 mg/kg to 10 mg/kg, 0.5 mg/kg to 5 mg/kg, 1 mg/kg to 5 mg/kg, 2 mg/kg to 5 mg/kg, 3 mg/kg to 5 mg/kg, 0.5 mg/kg to 3 mg/kg, 1 mg/kg to 3 mg/kg, 2 mg/kg to 3 mg/kg, 0.5 mg/kg to 2 mg/kg, 1 mg/kg to 2 mg/kg, or 0.5 mg/kg to 1 mg/kg. In some embodiments, the AB induces type 1 diabetes in the NOD mouse after administration of the AB at a single dose of 1 mg/kg to 20 mg/kg, 1 mg/kg, 3 mg/kg, 5 mg/kg, 10 mg/kg, or 20 mg/kg. In some embodiments, the AB induces type 1 diabetes in the NOD mouse after administration of the AB at a single dose of 1 mg/kg to 20 mg/kg. In some embodiments, the AB induces type 1 diabetes in the NOD mouse after administration of the AB at a single dose of 1 mg/kg. In some embodiments, the AB induces type 1 diabetes in the NOD mouse after administration of the AB at a single dose of 3 mg/kg. In some embodiments, the AB induces type 1 diabetes in the NOD mouse after administration of the AB at a single dose of 5 mg/kg. In some embodiments, the AB induces type 1 diabetes in the NOD mouse after administration of the AB at a single dose of 10 mg/kg. In some embodiments, the AB induces type 1 diabetes in the NOD mouse after administration of the AB at a single dose of 20 mg/kg. 
     In some embodiments, the activatable antibody has one or more of the following characteristics: (a) the activatable antibody in an uncleaved state does not induce type 1 diabetes in greater than 50% of a population of non-obese diabetic (NOD) mice, and (b) the AB induces type 1 diabetes in greater than 50%, greater than 60%, greater than 70%, greater than 80%, between 50% to 100%, between 50% and 75%, or between 70% and 90% of a population of NOD mice. 
     In some embodiments, the activatable antibody does not induce type 1 diabetes in greater than 50%, greater than 60%, greater than 70%, greater than 80%, between 50% to 100%, between 50% and 75%, or between 70% and 90% of the population of NOD mice after administration to each mouse in the population a single dose of the activatable antibody at a dosage of: 0.5 mg/kg to 15 mg/kg, 1 mg/kg to 15 mg/kg, 2 mg/kg to 15 mg/kg, 3 mg/kg to 15 mg/kg, 5 mg/kg to 15 mg/kg, 10 mg/kg to 15 mg/kg, 0.5 mg/kg to 10 mg/kg, 1 mg/kg to 10 mg/kg, 2 mg/kg to 10 mg/kg, 3 mg/kg to 10 mg/kg, 5 mg/kg to 10 mg/kg, 0.5 mg/kg to 5 mg/kg, 1 mg/kg to 5 mg/kg, 2 mg/kg to 5 mg/kg, 3 mg/kg to 5 mg/kg, 0.5 mg/kg to 3 mg/kg, 1 mg/kg to 3 mg/kg, 2 mg/kg to 3 mg/kg, 0.5 mg/kg to 2 mg/kg, 1 mg/kg to 2 mg/kg, or 0.5 mg/kg to 1 mg/kg. In some embodiments, the activatable antibody inhibits the induction of type 1 diabetes in the NOD mouse after administration of the activatable antibody at a single dose of 3 mg/kg to 10 mg/kg, 3 mg/kg or 10 mg/kg. In some embodiments the dose is a single dose of 3 mg/kg to 10 mg/kg. In some embodiments the dose is a single dose of 3 mg/kg. In some embodiments the dose is a single dose of 10 mg/kg. 
     In some embodiments, the activatable antibody has one or more of the following characteristics: (a) the activatable antibody in an uncleaved state does not induce type 1 diabetes in greater than 50%, greater than 60%, greater than 70%, greater than 80%, between 50% to 100%, between 50% and 75%, or between 70% and 90% of a population of non-obese diabetic (NOD) mice when administered at a single dose of 3 mg/kg; and (b) the AB induces type 1 diabetes in greater than 50%, greater than 60%, greater than 70%, greater than 80%, between 50% to 100%, between 50% and 75%, or between 70% and 90% of a population of NOD mice, when administered at a single dose of 3 mg/kg. 
     In some embodiments, the activatable antibody has one or more of the following characteristics: (a) the activatable antibody in an uncleaved state does not induce type 1 diabetes in greater than 50%, greater than 60%, greater than 70%, greater than 80%, between 50% to 100%, between 50% and 75%, or between 70% and 90% of a population of non-obese diabetic (NOD) mice when administered at a single dose of 10 mg/kg; and (b) the AB induces type 1 diabetes in greater than 50%, greater than 60%, greater than 70%, greater than 80%, between 50% to 100%, between 50% and 75%, or between 70% and 90% of a population of NOD mice, when administered at a single dose of 10 mg/kg. 
     In some embodiments, the AB induces type 1 diabetes in greater than 50%, greater than 60%, greater than 70%, greater than 80%, between 50% to 100%, between 50% and 75%, or between 70% and 90% of the population of the NOD mice after administration to each mouse in the population a single dose of the AB at a dosage of: 2 mg/kg to 15 mg/kg, 3 mg/kg to 15 mg/kg, 5 mg/kg to 15 mg/kg, 10 mg/kg to 15 mg/kg, 2 mg/kg to 10 mg/kg, 3 mg/kg to 10 mg/kg, 5 mg/kg to 10 mg/kg, 2 mg/kg to 5 mg/kg, 3 mg/kg to 5 mg/kg, or 2 mg/kg to 3 mg/kg. In some embodiments the dose is a single dose of 3 mg/kg to 20 mg/kg, 3 mg/kg, 5 mg/kg, 10 mg/kg, or 20 mg/kg. In some embodiments the dose is a single dose of 3 mg/kg to 20 mg/kg. In some embodiments the dose is a single dose of 3 mg/kg. In some embodiments the dose is a single dose of 5 mg/kg. In some embodiments the dose is a single dose of 10 mg/kg. In some embodiments the dose is a single dose of 20 mg/kg. 
     In some embodiments, the activatable antibody in an uncleaved state does not induce type 1 diabetes in greater than 50% of a population of non-obese diabetic (NOD) mice, wherein the population of NOD mice are concurrently dosed with an anti-CTLA4 antibody. 
     In some embodiments, the population of NOD mice are each administered a single dose of the activatable antibody at a dosage of 2 mg/kg to 15 mg/kg, 3 mg/kg to 15 mg/kg, 5 mg/kg to 15 mg/kg, 10 mg/kg to 15 mg/kg, 2 mg/kg to 10 mg/kg, 3 mg/kg to 10 mg/kg, 5 mg/kg to 10 mg/kg, 2 mg/kg to 5 mg/kg, 3 mg/kg to 5 mg/kg, or 2 mg/kg to 3 mg/kg concurrently with a dose of an anti-CTLA4 antibody. In some embodiments, the population of NOD mice are each administered a single dose of the activatable antibody at a dosage of 10 mg/kg concurrently with a dose of an anti-CTLA4 antibody. 
     In some embodiments, the population of NOD mice is each administered a single dose of the anti-CTLA4 antibody at a dosage of 2 mg/kg to 15 mg/kg, 3 mg/kg to 15 mg/kg, 5 mg/kg to 15 mg/kg, or 10 mg/kg to 15 mg/kg concurrently with a dose of an anti-PD-1 activatable antibody. In some embodiments, the population of NOD mice is each administered a single dose of the anti-CTLA4 antibody at a dosage of 10 mg/kg concurrently with a dose of an anti-PD-1 activatable antibody. 
     In some embodiments, the population of NOD mice is each administered a single dose of the activatable antibody at a dosage of 5 mg/kg to 15 mg/kg and a single dose of the anti-CTLA4 antibody at a dosage of 5 mg/kg to 15 mg/kg. In some embodiments, the population of NOD mice is each administered a single dose of the activatable antibody at a dosage of 10 mg/kg concurrently with a single dose of an anti-CTLA4 antibody at a dosage of 10 mg/kg. 
     In some embodiments, the NOD mouse is a female NOD/ShiLtJ mouse substrain. In some embodiments, the population of NOD mice is each 5 weeks old when the activatable antibody is first administered. In some embodiments, the population of NOD mice is each 10 weeks old when the activatable antibody is first administered. 
     The activatable antibodies in an activated state bind PD-1 and include (i) an antibody or an antigen binding fragment thereof (AB) that specifically binds to PD-1; (ii) a masking moiety (MM) that, when the activatable antibody is in an uncleaved state, inhibits the binding of the AB to PD-1; and (c) a cleavable moiety (CM) coupled to the AB, wherein the CM is a polypeptide that functions as a substrate for a protease. 
     In some embodiments, the activatable antibody in the uncleaved state has the structural arrangement from N-terminus to C-terminus as follows: MM-CM-AB or AB-CM-MM. 
     In some embodiments, the activatable antibody comprises a linking peptide between the MM and the CM. 
     In some embodiments, the activatable antibody comprises a linking peptide between the CM and the AB. 
     In some embodiments, the activatable antibody comprises a first linking peptide (LP1) and a second linking peptide (LP2), and wherein the activatable antibody in the uncleaved state has the structural arrangement from N-terminus to C-terminus as follows: MM-LP1-CM-LP2-AB or AB-LP2-CM-LP1-MM. In some embodiments, the two linking peptides need not be identical to each other. In some embodiments, each of LP1 and LP2 is a peptide of about 1 to 20 amino acids in length. 
     In some embodiments, at least one of LP1 or LP2 comprises an amino acid sequence selected from the group consisting of (GS) n , (GGS) n , (GSGGS) n  (SEQ ID NO: 363) and (GGGS) n  (SEQ ID NO: 364), where n is an integer of at least one. 
     In some embodiments, at least one of LP1 or LP2 comprises an amino acid sequence selected from the group consisting of GGSG (SEQ ID NO: 365), GGSGG (SEQ ID NO: 366), GSGSG (SEQ ID NO: 367), GSGGG (SEQ ID NO: 368), GGGSG (SEQ ID NO: 369), and GSSSG (SEQ ID NO: 370). 
     In some embodiments, LP1 comprises the amino acid sequence GSSGGSGGSGGSG (SEQ ID NO: 371), GSSGGSGGSGG (SEQ ID NO: 372), GSSGGSGGSGGS (SEQ ID NO: 373), GSSGGSGGSGGSGGGS (SEQ ID NO: 374), GSSGGSGGSG (SEQ ID NO: 375), GSSGGSGGSGS (SEQ ID NO: 376), GGGSSGGS (SEQ ID NO: 65), or GGGSSGG (SEQ ID NO: 1040). 
     In some embodiments, LP2 comprises the amino acid sequence GSS, GGS, GGGS (SEQ ID NO: 377), GSSGT (SEQ ID NO: 378) or GSSG (SEQ ID NO: 379). 
     In some embodiments, the AB has a dissociation constant (K d ) of about 100 nM or less for binding to PD-1. 
     In some embodiments, the activatable antibody includes an antibody or antigen-binding fragment thereof (AB) that specifically binds PD-1. In some embodiments, the antibody or antigen-binding fragment thereof that binds PD-1 is a monoclonal antibody, domain antibody, single chain, Fab fragment, a F(ab′) 2  fragment, a scFv, a scAb, a dAb, a single domain heavy chain antibody, or a single domain light chain antibody. In some embodiments, such an antibody or antigen-binding fragment thereof that binds PD-1 is a mouse, other rodent, chimeric, humanized or fully human monoclonal antibody. 
     In some embodiments, the activatable antibody comprises a heavy chain amino acid sequence that comprises or is derived from an amino acid sequence selected from the group consisting of SEQ ID NO: 1, 5, 9, 13, 17, 21, 23, 25, 27, 29, 31, 33, 35, and 37. In some embodiments, the activatable antibody comprises a light chain amino acid sequence selected from the group consisting of SEQ ID NO: 3, 7, 11, 15, 19, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59. 
     In some embodiments, the activatable anti-PD-1 antibody includes a heavy chain that comprises or is derived from an amino acid sequence selected from the group consisting of SEQ ID NO: 21, 23, 25, 27, 29, 31, 33, 35, and 37, and a light chain that comprises or is derived from an amino acid sequence selected from the group consisting of SEQ ID NO: 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59. 
     In some embodiments, the activatable anti-PD-1 antibody includes a heavy chain that comprises or is derived from amino acid sequence SEQ ID NO: 21. In some embodiments, the activatable anti-PD-1 antibody includes a light chain that comprises or is derived from amino acid sequence SEQ ID NO: 45 or SEQ ID NO: 47. In some embodiments, the activatable anti-PD-1 antibody includes a heavy chain that comprises or is derived from amino acid sequence SEQ ID NO: 21 and a light chain that comprises or is derived from amino acid sequence SEQ ID NO: 45 or SEQ ID NO: 47. In some embodiments, the activatable anti-PD-1 antibody includes a heavy chain that comprises or is derived from amino acid sequence SEQ ID NO: 21 and a light chain that comprises or is derived from amino acid sequence SEQ ID NO: 45. In some embodiments, the activatable anti-PD-1 antibody includes a heavy chain that comprises or is derived from amino acid sequence SEQ ID NO: 21 and a light chain that comprises or is derived from amino acid sequence SEQ ID NO: 47. 
     In some embodiments, the activatable anti-PD-1 antibody includes the combination of the complementarity determining region (CDR) sequences of the heavy chain amino acid sequence of SEQ ID NO: 21. In some embodiments, the activatable anti-PD-1 antibody includes the combination of the CDR sequences of the light chain amino acid sequence of SEQ ID NO: 45 or of SEQ ID NO: 47. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDR sequences of the heavy chain amino acid sequence of SEQ ID NO: 21, and the CDR sequences of the light chain amino acid sequence of SEQ ID NO: 45 or 47. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDR sequences of the heavy chain amino acid sequence of SEQ ID NO: 21, and the CDR sequences of the light chain amino acid sequence of SEQ ID NO: 45. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDR sequences of the heavy chain amino acid sequence of SEQ ID NO: 21, and the CDR sequences of the light chain amino acid sequence of SEQ ID NO: 47. 
     In some embodiments, the activatable anti-PD-1 antibody includes: (a) a variable heavy chain complementarity determining region 1 (VH CDR1) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 653-657; (b) a variable heavy chain complementarity determining region 2 (VH CDR2) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 658-663; (c) a variable heavy chain complementarity determining region 3 (VH CDR3) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 664-668; (d) a variable light chain complementarity determining region 1 (VL CDR1) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 669-677; (e) a variable light chain complementarity determining region 2 (VL CDR2) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 678-682; and (f) variable light chain complementarity determining region 3 (VL CDR3) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 683-687. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of a variable heavy chain complementarity determining region 1 (VH CDR1, also referred to herein as CDRH1) sequence, a variable heavy chain complementarity determining region 2 (VH CDR2, also referred to herein as CDRH2) sequence, and a variable heavy chain complementarity determining region 3 (VH CDR3, also referred to herein as CDRH3) sequence, wherein the VH CDR1 sequence comprises GFTFSGYAMS (SEQ ID NO: 653); the VH CDR2 sequence comprises YISNSGGNAH (SEQ ID NO: 658); and the VH CDR3 sequence comprises EDYGTSPFVY (SEQ ID NO: 664). 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of a variable light chain complementarity determining region 1 (VL CDR1, also referred to herein as CDRL1) sequence, a variable light chain complementarity determining region 2 (VL CDR2, also referred to herein as CDRL2) sequence, and a variable light chain complementarity determining region 3 (VL CDR3, also referred to herein as CDRL3) sequence, wherein the VL CDR1 sequence comprises RASESVDSYGISFMN (SEQ ID NO: 675) or RASESVDAYGISFMN (SEQ ID NO:676); the VL CDR2 sequence comprises AASNQGS (SEQ ID NO: 678); and the VL CDR3 sequence comprises QQSKDVPWT (SEQ ID NO: 683). In some embodiments, the activatable anti-PD-1 antibody includes a combination of a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the VL CDR1 sequence comprises RASESVDSYGISFMN (SEQ ID NO: 675); the VL CDR2 sequence comprises AASNQGS (SEQ ID NO: 678); and the VL CDR3 sequence comprises QQSKDVPWT (SEQ ID NO: 683). In some embodiments, the activatable anti-PD-1 antibody includes a combination of a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the VL CDR1 sequence comprises RASESVDAYGISFMN (SEQ ID NO:676); the VL CDR2 sequence comprises AASNQGS (SEQ ID NO: 678); and the VL CDR3 sequence comprises QQSKDVPWT (SEQ ID NO: 683). 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the VH CDR1 sequence comprises GFTFSGYAMS (SEQ ID NO: 653); the VH CDR2 sequence comprises YISNSGGNAH (SEQ ID NO: 658); and the VH CDR3 sequence comprises EDYGTSPFVY (SEQ ID NO: 664); the VL CDR1 sequence comprises RASESVDSYGISFMN (SEQ ID NO: 675) or RASESVDAYGISFMN (SEQ ID NO:676); the VL CDR2 sequence comprises AASNQGS (SEQ ID NO: 678); and the VL CDR3 sequence comprises QQSKDVPWT (SEQ ID NO: 683). In some embodiments, the activatable anti-PD-1 antibody includes a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the VH CDR1 sequence comprises GFTFSGYAMS (SEQ ID NO: 653); the VH CDR2 sequence comprises YISNSGGNAH (SEQ ID NO: 658); and the VH CDR3 sequence comprises EDYGTSPFVY (SEQ ID NO: 664); the VL CDR1 sequence comprises RASESVDSYGISFMN (SEQ ID NO: 675); the VL CDR2 sequence comprises AASNQGS (SEQ ID NO: 678); and the VL CDR3 sequence comprises QQSKDVPWT (SEQ ID NO: 683). In some embodiments, the activatable anti-PD-1 antibody includes a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the VH CDR1 sequence comprises GFTFSGYAMS (SEQ ID NO: 653); the VH CDR2 sequence comprises YISNSGGNAH (SEQ ID NO: 658); and the VH CDR3 sequence comprises EDYGTSPFVY (SEQ ID NO: 664); the VL CDR1 sequence comprises RASESVDAYGISFMN (SEQ ID NO:676); the VL CDR2 sequence comprises AASNQGS (SEQ ID NO: 678); and the VL CDR3 sequence comprises QQSKDVPWT (SEQ ID NO: 683). 
     In some embodiments, the activatable anti-PD-1 antibody includes a heavy chain that comprises or is derived from the amino acid sequence of SEQ ID NO: 1346, and a light chain that comprises or is derived from the amino acid sequence of SEQ ID NO: 626. 
     In some embodiments, the activatable anti-PD-1 antibody includes a heavy chain that comprises or is derived from the amino acid sequence of SEQ ID NO: 1514, and a light chain that comprises or is derived from the amino acid sequence of SEQ ID NO: 638. 
     In some embodiments, the activatable anti-PD-1 antibody includes the combination of the complementarity determining region (CDR) sequences of the heavy chain amino acid sequence of SEQ ID NO: 1346. In some embodiments, the activatable anti-PD-1 antibody includes the combination of the CDR sequences of the light chain amino acid sequence of SEQ ID NO: 626. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDR sequences of the heavy chain amino acid sequence of SEQ ID NO: 1346, and the CDR sequences of the light chain amino acid sequence of SEQ ID NO: 626. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of a variable heavy chain complementarity determining region 1 (VH CDR1, also referred to herein as CDRH1) sequence, a variable heavy chain complementarity determining region 2 (VH CDR2, also referred to herein as CDRH2) sequence, and a variable heavy chain complementarity determining region 3 (VH CDR3, also referred to herein as CDRH3) sequence, wherein the VH CDR1 sequence comprises GITFSNSG (SEQ ID NO: 1705); the VH CDR2 sequence comprises IWYDGSKR (SEQ ID NO: 1706); and the VH CDR3 sequence comprises TNDDY (SEQ ID NO: 1707). 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of a variable light chain complementarity determining region 1 (VL CDR1, also referred to herein as CDRL1) sequence, a variable light chain complementarity determining region 2 (VL CDR2, also referred to herein as CDRL2) sequence, and a variable light chain complementarity determining region 3 (VL CDR3, also referred to herein as CDRL3) sequence, wherein the VL CDR1 sequence comprises QSVSSY (SEQ ID NO: 1708); the VL CDR2 sequence comprises DAS (SEQ ID NO: 1709); and the VL CDR3 sequence comprises QQSSNWPRT (SEQ ID NO: 1710). 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the VH CDR1 sequence comprises GITFSNSG (SEQ ID NO: 1705); the VH CDR2 sequence comprises IWYDGSKR (SEQ ID NO: 1706); the VH CDR3 sequence comprises TNDDY (SEQ ID NO: 1707); the VL CDR1 sequence comprises QSVSSY (SEQ ID NO: 1708); the VL CDR2 sequence comprises DAS (SEQ ID NO: 1709); and the VL CDR3 sequence comprises QQSSNWPRT (SEQ ID NO: 1710). 
     In some embodiments, the activatable anti-PD-1 antibody includes the combination of the complementarity determining region (CDR) sequences of the heavy chain amino acid sequence of SEQ ID NO: 1514. In some embodiments, the activatable anti-PD-1 antibody includes the combination of the CDR sequences of the light chain amino acid sequence of SEQ ID NO: 638. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDR sequences of the heavy chain amino acid sequence of SEQ ID NO: 1514, and the CDR sequences of the light chain amino acid sequence of SEQ ID NO: 638. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of a variable heavy chain complementarity determining region 1 (VH CDR1, also referred to herein as CDRH1) sequence, a variable heavy chain complementarity determining region 2 (VH CDR2, also referred to herein as CDRH2) sequence, and a variable heavy chain complementarity determining region 3 (VH CDR3, also referred to herein as CDRH3) sequence, wherein the VH CDR1 sequence comprises GYTFTNYY (SEQ ID NO: 1711); the VH CDR2 sequence comprises INPSNGGT (SEQ ID NO: 1712); and the VH CDR3 sequence comprises RRDYRFDMGFDY (SEQ ID NO: 1713). 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of a variable light chain complementarity determining region 1 (VL CDR1, also referred to herein as CDRL1) sequence, a variable light chain complementarity determining region 2 (VL CDR2, also referred to herein as CDRL2) sequence, and a variable light chain complementarity determining region 3 (VL CDR3, also referred to herein as CDRL3) sequence, wherein the VL CDR1 sequence comprises KGVSTSGYSY (SEQ ID NO: 1714); the VL CDR2 sequence comprises LAS (SEQ ID NO: 1715); and the VL CDR3 sequence comprises QHSRDLPLT (SEQ ID NO: 1716). 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the VH CDR1 sequence comprises GYTFTNYY (SEQ ID NO: 1711); the VH CDR2 sequence comprises INPSNGGT (SEQ ID NO: 1712); the VH CDR3 sequence comprises RRDYRFDMGFDY (SEQ ID NO: 1713); the VL CDR1 sequence comprises KGVSTSGYSY (SEQ ID NO: 1714); the VL CDR2 sequence comprises LAS (SEQ ID NO: 1715); and the VL CDR3 sequence comprises QHSRDLPLT (SEQ ID NO: 1716). 
     In some embodiments, the activatable antibody comprises a heavy chain amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NO: 1, 5, 9, 13, 17, 21, 23, 25, 27, 29, 31, 33, 35, and 37. In some embodiments, the activatable antibody comprises a light chain amino acid that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence amino acid sequence selected from the group consisting of SEQ ID NO: 3, 7, 11, 15, 19, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59. In some embodiments, the activatable antibody comprises a heavy chain amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NO: 1, 5, 9, 13, 17, 21, 23, 25, 27, 29, 31, 33, 35, and 37, and a light chain amino acid that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence amino acid sequence selected from the group consisting of SEQ ID NO: 3, 7, 11, 15, 19, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59. 
     In some embodiments, the activatable antibody comprises a heavy chain amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NO: 21, 23, 25, 27, 29, 31, 33, 35, and 37. In some embodiments, the activatable antibody comprises a light chain amino acid that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence amino acid sequence selected from the group consisting of SEQ ID NO: 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59. In some embodiments, the activatable antibody comprises a heavy chain amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NO: 21, 23, 25, 27, 29, 31, 33, 35, and 37, and a light chain amino acid that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence amino acid sequence selected from the group consisting of SEQ ID NO: 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59. In some embodiments, the activatable anti-PD-1 antibody includes a heavy chain sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 21, and a light chain sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 45 or SEQ ID NO: 47. In some embodiments, the activatable anti-PD-1 antibody includes a heavy chain sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 21, and a light chain sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 45. In some embodiments, the activatable anti-PD-1 antibody includes a heavy chain sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 21, and a light chain sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 47. 
     In some embodiments, the activatable anti-PD-1 antibody includes a heavy chain sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 1346, and a light chain sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 626. 
     In some embodiments, the activatable anti-PD-1 antibody includes a heavy chain sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 1514, and a light chain sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 638. 
     In some embodiments, the AB of the activatable anti-PD-1 antibody comprises a heavy chain amino acid sequence selected from the group consisting of the heavy chain sequences shown in Table 7. In some embodiments, the AB of the activatable anti-PD-1 antibody comprises a light chain amino acid sequence selected from the group consisting of the light chain sequences shown in Table 7. In some embodiments, the AB of the activatable anti-PD-1 antibody comprises a heavy chain amino acid sequence selected from the group consisting of the heavy chain sequences shown in Table 7 and a light chain amino acid sequence selected from the group consisting of the light chain sequences shown in Table 7. 
     In some embodiments, the AB of the activatable anti-PD-1 antibody comprises a heavy chain amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence selected from the group consisting of the heavy chain sequences shown in Table 7. In some embodiments, the AB of the activatable anti-PD-1 antibody comprises a light chain amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence selected from the group consisting of the light chain sequences shown in Table 7. In some embodiments, the AB of the activatable anti-PD-1 antibody comprises a heavy chain amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence selected from the group consisting of the heavy chain sequences shown in Table 7 and a light chain amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence selected from the group consisting of the light chain sequences shown in Table 7. 
     In some embodiments, the AB of the activatable antibody includes a combination of a VH CDR1 sequence, a VH CDR2 sequence, and a VH CDR3 sequence, wherein the VH CDR1 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to GITFSNSG (SEQ ID NO: 1705); the VH CDR2 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to IWYDGSKR (SEQ ID NO: 1706); and the VH CDR3 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to TNDDY (SEQ ID NO: 1707). 
     In some embodiments, the AB of the activatable antibody includes a combination of a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the VL CDR1 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to QSVSSY (SEQ ID NO: 1708); the VL CDR2 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to DAS (SEQ ID NO: 1709); and the VL CDR3 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to QQSSNWPRT (SEQ ID NO: 1710). 
     In some embodiments, the AB of the activatable antibody includes a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the VH CDR1 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to GITFSNSG (SEQ ID NO: 1705); the VH CDR2 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to IWYDGSKR (SEQ ID NO: 1706); the VH CDR3 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to TNDDY (SEQ ID NO: 1707); the VL CDR1 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to QSVSSY (SEQ ID NO: 1708); the VL CDR2 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to DAS (SEQ ID NO: 1709); and the VL CDR3 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to QQSSNWPRT (SEQ ID NO: 1710). 
     In some embodiments, the AB of the activatable antibody includes a combination of a VH CDR1 sequence, a VH CDR2 sequence, and a VH CDR3 sequence, wherein the VH CDR1 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to GYTFTNYY (SEQ ID NO: 1711); the VH CDR2 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to INPSNGGT (SEQ ID NO: 1712); and the VH CDR3 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to RRDYRFDMGFDY (SEQ ID NO: 1713). 
     In some embodiments, the AB of the activatable antibody includes a combination of a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the VL CDR1 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to KGVSTSGYSY (SEQ ID NO: 1714); the VL CDR2 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to LAS (SEQ ID NO: 1715); and the VL CDR3 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to QHSRDLPLT (SEQ ID NO: 1716). 
     In some embodiments, the AB of the activatable antibody includes a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the VH CDR1 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to GYTFTNYY (SEQ ID NO: 1711); the VH CDR2 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to INPSNGGT (SEQ ID NO: 1712); the VH CDR3 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to RRDYRFDMGFDY (SEQ ID NO: 1713); the VL CDR1 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to KGVSTSGYSY (SEQ ID NO: 1714); the VL CDR2 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to LAS (SEQ ID NO: 1715); and the VL CDR3 sequence comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to QHSRDLPLT (SEQ ID NO: 1716). 
     In some embodiments, the activatable antibody comprises a combination of a variable heavy chain complementarity determining region 1 (VH CDR1, also referred to herein as CDRH1) sequence, a variable heavy chain complementarity determining region 2 (VH CDR2, also referred to herein as CDRH2) sequence, a variable heavy chain complementarity determining region 3 (VH CDR3, also referred to herein as CDRH3) sequence, a variable light chain complementarity determining region 1 (VL CDR1, also referred to herein as CDRL1) sequence, a variable light chain complementarity determining region 2 (VL CDR2, also referred to herein as CDRL2) sequence, and a variable light chain complementarity determining region 3 (VL CDR3, also referred to herein as CDRL3) sequence, wherein at least one CDR sequence is selected from the group consisting of a VH CDR1 sequence shown in Table 8; a VH CDR2 sequence shown in Table 8; a VH CDR3 sequence shown in Table 8; a VL CDR1 sequence shown in Table 8; a VL CDR2 sequence shown in Table 8; and a VL CDR3 sequence shown in Table 8. 
     In some embodiments, the activatable antibody comprises a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein at least one CDR sequence is selected from the group consisting of a VH CDR1 sequence that includes a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to a VH CDR1 sequence shown in Table 8; a VH CD2 sequence that includes a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to a VH CDR2 sequence shown in Table 8; a VH CDR3 sequence that includes a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to a VH CDR3 sequence shown in Table 8; a VL CDR1 sequence that includes a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to a VL CDR1 sequence shown in Table 8; a VL CDR2 sequence that includes a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to a VL CDR2 sequence shown in Table 8; and a VL CDR3 sequence that includes a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to a VL CDR3 sequence shown in Table 8. 
     In some embodiments, the activatable antibody comprises a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence shown in a single row in Table 8, and a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence shown in a single row in Table 8. 
     In some embodiments, the antibody comprises a heavy chain that comprises a combination of a VH CDR1 sequence, a VH CDR2 sequence, and a VH CDR3 sequence, wherein the combination is a combination of the three heavy chain CDR sequences (VH CDR1, VH CDR2, VH CDR3) shown in a single row in Table 8. 
     In some embodiments, the activatable antibody comprises a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence shown in a single row in Table 8, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence shown in a single row in Table 8, wherein each CDR sequence in the combination comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to the corresponding CDR sequence in a combination of the three VH CDR sequences (VH CDR1, VH CDR2, VH CDR3) shown in a single row in Table 8 and in a combination of the three VL CDR sequences (VL CDR1, VL CDR2, and VL CDR3) shown in a single row in Table 8. 
     In some embodiments, the antibody comprises a heavy chain that comprises a combination of a VH CDR1 sequence, a VH CDR2 sequence, and a VH CDR3 sequence, wherein each CDR sequence in the combination comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to the corresponding CDR sequence in a combination of three heavy chain CDR sequences (VH CDR1, VH CDR2, VH CDR3) shown in a single row in Table 8. 
     In some embodiments, the activatable antibody comprises a combination of a variable heavy chain complementarity determining region 1 (VH CDR1, also referred to herein as CDRH1) sequence, a variable heavy chain complementarity determining region 2 (VH CDR2, also referred to herein as CDRH2) sequence, a variable heavy chain complementarity determining region 3 (VH CDR3, also referred to herein as CDRH3) sequence, a variable light chain complementarity determining region 1 (VL CDR1, also referred to herein as CDRL1) sequence, a variable light chain complementarity determining region 2 (VL CDR2, also referred to herein as CDRL2) sequence, and a variable light chain complementarity determining region 3 (VL CDR3, also referred to herein as CDRL3) sequence, wherein at least one CDR sequence is selected from the group consisting of a VH CDR1 sequence shown in Table 9; a VH CDR2 sequence shown in Table 9; a VH CDR3 sequence shown in Table 9; a VL CDR1 sequence shown in Table 9; a VL CDR2 sequence shown in Table 9; and a VL CDR3 sequence shown in Table 9. 
     In some embodiments, the activatable antibody comprises a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein at least one CDR sequence is selected from the group consisting of a VH CDR1 sequence that includes a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to a VH CDR1 sequence shown in Table 9; a VH CD2 sequence that includes a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to a VH CDR2 sequence shown in Table 9; a VH CDR3 sequence that includes a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to a VH CDR3 sequence shown in Table 9; a VL CDR1 sequence that includes a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to a VL CDR1 sequence shown in Table 9; a VL CDR2 sequence that includes a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to a VL CDR2 sequence shown in Table 9; and a VL CDR3 sequence that includes a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to a VL CDR3 sequence shown in Table 9. 
     In some embodiments, the activatable antibody comprises a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the combination is a combination shown in Table 9. 
     In some embodiments, the activatable antibody comprises a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein each CDR sequence in the combination comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to the corresponding CDR sequence in a combination shown in Table 9. 
     In some embodiments, the activatable antibody comprises a masking moiety (MM) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 66, 67, 70, 71, 74, 77, 81, 82, 84, 90, 91, 93, 99; a cleavable moiety (CM) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 214, 294, 300, 302, 303, 305, 308, 318, 347, 361, 1092-1102, 1111, and 1157; and a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the combination comprises the VL CDR1 sequence of SEQ ID NO: 675 or SEQ ID NO: 676; the VL CDR2 sequence of SEQ ID NO: 678; the VL CDR3 sequence of SEQ ID NO: 683; the VH CDR1 sequence of SEQ ID NO: 653; the VH CDR2 sequence of SEQ ID NO: 658; and the VH CDR3 sequence of SEQ ID NO: 664. 
     In some embodiments, the activatable antibody comprises a masking moiety (MM) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 66, 67, 70, 71, 74, 77, 81, 82, 84, 90, 91, 93, 99; a cleavable moiety; a cleavable moiety (CM) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 214, 294, 300, 302, 303, 305, 308, 318, 347, 361, 1092-1102, 1111, and 1157; a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the combination comprises the VL CDR1 sequence of SEQ ID NO: 675 or SEQ ID NO: 676; the VL CDR2 sequence of SEQ ID NO: 678; the VL CDR3 sequence of SEQ ID NO: 683; the VH CDR1 sequence of SEQ ID NO: 653; the VH CDR2 sequence of SEQ ID NO: 658; and the VH CDR3 sequence of SEQ ID NO: 664, and a human immunoglobulin light chain constant domain. In some embodiments, the human immunoglobulin light chain constant domain is a human kappa constant domain comprising SEQ ID NO: 61 or SEQ ID NO: 1344. 
     In some embodiments, the activatable antibody comprises a masking moiety (MM) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 66, 67, 70, 71, 74, 77, 81, 82, 84, 90, 91, 93, 99; a cleavable moiety (CM) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 214, 294, 300, 302, 303, 305, 308, 318, 347, 361, 1092-1102, 1111, and 1157; a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the combination comprises the VL CDR1 sequence of SEQ ID NO: 675 or SEQ ID NO: 676; the VL CDR2 sequence of SEQ ID NO: 678; the VL CDR3 sequence of SEQ ID NO: 683; the VH CDR1 sequence of SEQ ID NO: 653; the VH CDR2 sequence of SEQ ID NO: 658; and the VH CDR3 sequence of SEQ ID NO: 664, and a human immunoglobulin heavy chain constant domain. In some embodiments, the human immunoglobulin heavy chain constant domain comprises an amino acid sequence selected from the group consisting of 381, 382, 383, and 1807. 
     In some embodiments, the activatable antibody comprises a masking moiety (MM) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 66, 67, 70, 71, 74, 77, 81, 82, 84, 90, 91, 93, 99; a cleavable moiety (CM) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 214, 294, 300, 302, 303, 305, 308, 318, 347, 361, 1092-1102, 1111, and 1157; a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the combination comprises the VL CDR1 sequence of SEQ ID NO: 675 or SEQ ID NO: 676; the VL CDR2 sequence of SEQ ID NO: 678; the VL CDR3 sequence of SEQ ID NO: 683; the VH CDR1 sequence of SEQ ID NO: 653; the VH CDR2 sequence of SEQ ID NO: 658; and the VH CDR3 sequence of SEQ ID NO: 664, a human immunoglobulin heavy chain constant region, and a human immunoglobulin light chain constant domain. In some embodiments, the human immunoglobulin heavy chain constant domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 63, 381, 382, 383, and 1807, and the human immunoglobulin light chain constant domain is a human kappa constant domain comprising SEQ ID NO: 61 or SEQ ID NO: 1344. 
     n some embodiments, the activatable antibody comprises a masking moiety (MM) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 66, 67, 70, 71, 74, 77, 81, 82, 84, 90, 91, 93, 99; a cleavable moiety (CM) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 214, 294, 300, 302, 303, 305, 308, 318, 347, 361, 1092-1102, 1111, and 1157; a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the combination comprises the VL CDR1 sequence of SEQ ID NO: 675; the VL CDR2 sequence of SEQ ID NO: 678; the VL CDR3 sequence of SEQ ID NO: 683; the VH CDR1 sequence of SEQ ID NO: 653; the VH CDR2 sequence of SEQ ID NO: 658; and the VH CDR3 sequence of SEQ ID NO: 664. 
     In some embodiments, the activatable antibody comprises a masking moiety (MM) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 66, 67, 70, 71, 74, 77, 81, 82, 84, 90, 91, 93, 99; a cleavable moiety (CM) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 214, 294, 300, 302, 303, 305, 308, 318, 347, 361, 1092-1102, 1111, and 1157; a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the combination comprises the VL CDR1 sequence of SEQ ID NO: 675; the VL CDR2 sequence of SEQ ID NO: 678; the VL CDR3 sequence of SEQ ID NO: 683; the VH CDR1 sequence of SEQ ID NO: 653; the VH CDR2 sequence of SEQ ID NO: 658; and the VH CDR3 sequence of SEQ ID NO: 664, and a human immunoglobulin light chain constant domain. In some embodiments, the human immunoglobulin light chain constant domain is a human kappa constant domain comprising SEQ ID NO: 61 or SEQ ID NO: 1344. 
     In some embodiments, the activatable antibody comprises a masking moiety (MM) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 66, 67, 70, 71, 74, 77, 81, 82, 84, 90, 91, 93, 99; a cleavable moiety (CM) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 214, 294, 300, 302, 303, 305, 308, 318, 347, 361, 1092-1102, 1111, and 1157; a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the combination comprises the VL CDR1 sequence of SEQ ID NO: 675; the VL CDR2 sequence of SEQ ID NO: 678; the VL CDR3 sequence of SEQ ID NO: 683; the VH CDR1 sequence of SEQ ID NO: 653; the VH CDR2 sequence of SEQ ID NO: 658; and the VH CDR3 sequence of SEQ ID NO: 664, and a human immunoglobulin heavy chain constant domain. In some embodiments, the human immunoglobulin heavy chain constant domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 63, 381, 382, 383, and 1807. 
     In some embodiments, the activatable antibody comprises a masking moiety (MM) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 66, 67, 70, 71, 74, 77, 81, 82, 84, 90, 91, 93, 99; a cleavable moiety (CM) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 214, 294, 300, 302, 303, 305, 308, 318, 347, 361, 1092-1102, 1111, and 1157; a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the combination comprises the VL CDR1 sequence of SEQ ID NO: 675; the VL CDR2 sequence of SEQ ID NO: 678; the VL CDR3 sequence of SEQ ID NO: 683; the VH CDR1 sequence of SEQ ID NO: 653; the VH CDR2 sequence of SEQ ID NO: 658; and the VH CDR3 sequence of SEQ ID NO: 664, a human immunoglobulin heavy chain constant region, and a human immunoglobulin light chain constant domain. In some embodiments, the human immunoglobulin heavy chain constant domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 63, 381, 382, 383, and 1807, and the human immunoglobulin light chain constant domain is a human kappa constant domain comprising SEQ ID NO: 61 or SEQ ID NO: 1344. 
     In some embodiments, the activatable antibody comprises a masking moiety (MM) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 66, 67, 70, 71, 74, 77, 81, 82, 84, 90, 91, 93, 99; a cleavable moiety (CM) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 214, 294, 300, 302, 303, 305, 308, 318, 347, 361, 1092-1102, 1111, and 1157; and a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the combination comprises the VL CDR1 sequence of SEQ ID NO: 676; the VL CDR2 sequence of SEQ ID NO: 678; the VL CDR3 sequence of SEQ ID NO: 683; the VH CDR1 sequence of SEQ ID NO: 653; the VH CDR2 sequence of SEQ ID NO: 658; and the VH CDR3 sequence of SEQ ID NO: 664. 
     In some embodiments, the activatable antibody comprises a masking moiety (MM) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 66, 67, 70, 71, 74, 77, 81, 82, 84, 90, 91, 93, 99; a cleavable moiety (CM) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 214, 294, 300, 302, 303, 305, 308, 318, 347, 361, 1092-1102, 1111, and 1157; a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the combination comprises the VL CDR1 sequence of SEQ ID NO: 676; the VL CDR2 sequence of SEQ ID NO: 678; the VL CDR3 sequence of SEQ ID NO: 683; the VH CDR1 sequence of SEQ ID NO: 653; the VH CDR2 sequence of SEQ ID NO: 658; and the VH CDR3 sequence of SEQ ID NO: 664, and a human immunoglobulin light chain constant domain. In some embodiments, the human immunoglobulin light chain constant domain is a human kappa constant domain comprising SEQ ID NO: 61 or SEQ ID NO: 1344. 
     In some embodiments, the activatable antibody comprises a masking moiety (MM) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 66, 67, 70, 71, 74, 77, 81, 82, 84, 90, 91, 93, 99; a cleavable moiety (CM) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 214, 294, 300, 302, 303, 305, 308, 318, 347, 361, 1092-1102, 1111, and 1157; a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the combination comprises the VL CDR1 sequence of SEQ ID NO: 676; the VL CDR2 sequence of SEQ ID NO: 678; the VL CDR3 sequence of SEQ ID NO: 683; the VH CDR1 sequence of SEQ ID NO: 653; the VH CDR2 sequence of SEQ ID NO: 658; and the VH CDR3 sequence of SEQ ID NO: 664, and a human immunoglobulin heavy chain constant domain. In some embodiments, the human immunoglobulin heavy chain constant domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 63, 381, 382, 383, and 1807. 
     In some embodiments, the activatable antibody comprises a masking moiety (MM) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 66, 67, 70, 71, 74, 77, 81, 82, 84, 90, 91, 93, 99; a cleavable moiety (CM) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 214, 294, 300, 302, 303, 305, 308, 318, 347, 361, 1092-1102, 1111, and 1157; a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the combination comprises the VL CDR1 sequence of SEQ ID NO: 676; the VL CDR2 sequence of SEQ ID NO: 678; the VL CDR3 sequence of SEQ ID NO: 683; the VH CDR1 sequence of SEQ ID NO: 653; the VH CDR2 sequence of SEQ ID NO: 658; and the VH CDR3 sequence of SEQ ID NO: 664, a human immunoglobulin heavy chain constant region, and a human immunoglobulin light chain constant domain. In some embodiments, the human immunoglobulin heavy chain constant domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 63, 381, 382, 383, and 1807, and the human immunoglobulin light chain constant domain is a human kappa constant domain comprising SEQ ID NO: 61 or SEQ ID NO: 1344. 
     In some embodiments, the activatable antibody comprises a MM comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 66, 67, 70, 71, 74, 77, 81, 82, 84, 90, 91, 93, 99; a CM comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 214, 294, 300, 302, 303, 305, 308, 318, 347, 361, 1092-1102, 1111, and 1157; and a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the combination comprises the VH CDR sequences of the variable heavy chain sequence of SEQ ID NO: 21 and the VL CDR sequences of the variable light chain sequence of SEQ ID NO: 47. In some embodiments, the combination further comprises a human immunoglobulin heavy chain constant region, a human immunoglobulin light chain constant domain, or both a human immunoglobulin heavy chain constant region and a human immunoglobulin light chain constant domain. In some embodiments, the human immunoglobulin heavy chain constant domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 63, 381, 382, 383, and 1807. In some embodiments, the human immunoglobulin light chain constant domain is a human kappa constant domain comprising SEQ ID NO: 61 or SEQ ID NO: 1344. 
     In some embodiments, the activatable antibody comprises a MM comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 66, 67, 70, 71, 74, 77, 81, 82, 84, 90, 91, 93, 99; a CM comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 214, 294, 300, 302, 303, 305, 308, 318, 347, 361, 1092-1102, 1111, and 1157; and a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the combination comprises the VL CDR1 sequence of SEQ ID NO: 676; the VL CDR2 sequence of SEQ ID NO: 678; the VL CDR3 sequence of SEQ ID NO: 683; the VH CDR1 sequence of SEQ ID NO: 653; the VH CDR2 sequence of SEQ ID NO: 658; and the VH CDR3 sequence of SEQ ID NO: 664. In some embodiments, the combination further comprises a human immunoglobulin heavy chain constant region, a human immunoglobulin light chain constant domain, or both a human immunoglobulin heavy chain constant region and a human immunoglobulin light chain constant domain. In some embodiments, the human immunoglobulin heavy chain constant domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 63, 381, 382, 383, and 1807. In some embodiments, the human immunoglobulin light chain constant domain is a human kappa constant domain comprising SEQ ID NO: 61 or SEQ ID NO: 1344. 
     In some embodiments, the activatable antibody comprises a MM comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 66, 67, 70, 71, 74, 77, 81, 82, 84, 90, 91, 93, 99; a cleavable moiety (CM) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 214, 294, 300, 302, 303, 305, 308, 318, 347, 361, 1092-1102, 1111, and 1157; and a combination of a variable heavy chain (VH) sequence of SEQ ID NO: 21 and a variable light chain (VL) sequence of SEQ ID NO: 47. In some embodiments, the combination further comprises a human immunoglobulin heavy chain constant region, a human immunoglobulin light chain constant domain, or both a human immunoglobulin heavy chain constant region and a human immunoglobulin light chain constant domain. In some embodiments, the human immunoglobulin heavy chain constant domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 63, 381, 382, 383, and 1807. In some embodiments, the human immunoglobulin light chain constant domain is a human kappa constant domain comprising SEQ ID NO: 61 or SEQ ID NO: 1344. 
     In some embodiments, the activatable antibody comprises a masking moiety (MM) comprising the amino acid sequence TSYCSIEHYPCNTHH (SEQ ID NO: 99), which is referred to herein as mask PD034 or PD34, a cleavable moiety (CM) comprising the amino acid sequence ISSGLLSGRSDNP (SEQ ID NO: 1100), which is also referred to herein as substrate 2011, and a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the combination comprises the VH CDR sequences of the variable heavy chain sequence of SEQ ID NO: 21 and the VL CDR sequences of the variable light chain sequence of SEQ ID NO: 47. In some embodiments, the combination further comprises a human immunoglobulin heavy chain constant region, a human immunoglobulin light chain constant domain, or both a human immunoglobulin heavy chain constant region and a human immunoglobulin light chain constant domain. In some embodiments, the human immunoglobulin heavy chain constant domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 63, 381, 382, 383, and 1807. In some embodiments, the human immunoglobulin light chain constant domain is a human kappa constant domain comprising SEQ ID NO: 61 or SEQ ID NO: 1344. 
     In some embodiments, the activatable antibody comprises a masking moiety (MM) comprising the amino acid sequence TSYCSIEHYPCNTHH (SEQ ID NO: 99), a cleavable moiety (CM) comprising the amino acid sequence ISSGLLSGRSDNP (SEQ ID NO: 1100), and a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the combination comprises the VL CDR1 sequence of SEQ ID NO: 676; the VL CDR2 sequence of SEQ ID NO: 678; the VL CDR3 sequence of SEQ ID NO: 683; the VH CDR1 sequence of SEQ ID NO: 653; the VH CDR2 sequence of SEQ ID NO: 658; and the VH CDR3 sequence of SEQ ID NO: 664. In some embodiments, the combination further comprises a human immunoglobulin heavy chain constant region, a human immunoglobulin light chain constant domain, or both a human immunoglobulin heavy chain constant region and a human immunoglobulin light chain constant domain. In some embodiments, the human immunoglobulin heavy chain constant domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 63, 381, 382, 383, and 1807. In some embodiments, the human immunoglobulin light chain constant domain is a human kappa constant domain comprising SEQ ID NO: 61 or SEQ ID NO: 1344. 
     In some embodiments, the activatable antibody comprises a masking moiety (MM) comprising the amino acid sequence TSYCSIEHYPCNTHH (SEQ ID NO: 99), a cleavable moiety (CM) comprising the amino acid sequence ISSGLLSGRSDNP (SEQ ID NO: 1100), and a combination of a variable heavy chain (VH) sequence of SEQ ID NO: 21 and a variable light chain (VL) sequence of SEQ ID NO: 47. In some embodiments, the combination further comprises a human immunoglobulin heavy chain constant region, a human immunoglobulin light chain constant domain, or both a human immunoglobulin heavy chain constant region and a human immunoglobulin light chain constant domain. In some embodiments, the human immunoglobulin heavy chain constant domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 63, 381, 382, 383, and 1807. In some embodiments, the human immunoglobulin light chain constant domain is a human kappa constant domain comprising SEQ ID NO: 61 or SEQ ID NO: 1344. 
     In some embodiments, the activatable antibody comprises a masking moiety (MM) comprising the amino acid sequence TSYCSIEHYPCNTHH (SEQ ID NO: 99), which is referred to herein as mask PD034 or PD34, a cleavable moiety (CM) comprising the amino acid sequence ISSGLLSGRSANP (SEQ ID NO: 1101), which is also referred to herein as substrate 2012, and a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the combination comprises the VH CDR sequences of the variable heavy chain sequence of SEQ ID NO: 21 and the VL CDR sequences of the variable light chain sequence of SEQ ID NO: 47. In some embodiments, the combination further comprises a human immunoglobulin heavy chain constant region, a human immunoglobulin light chain constant domain, or both a human immunoglobulin heavy chain constant region and a human immunoglobulin light chain constant domain. In some embodiments, the human immunoglobulin heavy chain constant domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 63, 381, 382, 383, and 1807. In some embodiments, the human immunoglobulin light chain constant domain is a human kappa constant domain comprising SEQ ID NO: 61 or SEQ ID NO: 1344. 
     In some embodiments, the activatable antibody comprises a masking moiety (MM) comprising the amino acid sequence TSYCSIEHYPCNTHH (SEQ ID NO: 99), a cleavable moiety (CM) comprising the amino acid sequence ISSGLLSGRSANP (SEQ ID NO: 1101), and a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the combination comprises the VL CDR1 sequence of SEQ ID NO: 676; the VL CDR2 sequence of SEQ ID NO: 678; the VL CDR3 sequence of SEQ ID NO: 683; the VH CDR1 sequence of SEQ ID NO: 653; the VH CDR2 sequence of SEQ ID NO: 658; and the VH CDR3 sequence of SEQ ID NO: 664. In some embodiments, the combination further comprises a human immunoglobulin heavy chain constant region, a human immunoglobulin light chain constant domain, or both a human immunoglobulin heavy chain constant region and a human immunoglobulin light chain constant domain. In some embodiments, the human immunoglobulin heavy chain constant domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 63, 381, 382, 383, and 1807. In some embodiments, the human immunoglobulin light chain constant domain is a human kappa constant domain comprising SEQ ID NO: 61 or SEQ ID NO: 1344. 
     In some embodiments, the activatable antibody comprises a masking moiety (MM) comprising the amino acid sequence TSYCSIEHYPCNTHH (SEQ ID NO: 99), a cleavable moiety (CM) comprising the amino acid sequence ISSGLLSGRSANP (SEQ ID NO: 1101), and a combination of a variable heavy chain (VH) sequence of SEQ ID NO: 21 and a variable light chain (VL) sequence of SEQ ID NO: 47. In some embodiments, the combination further comprises a human immunoglobulin heavy chain constant region, a human immunoglobulin light chain constant domain, or both a human immunoglobulin heavy chain constant region and a human immunoglobulin light chain constant domain. In some embodiments, the human immunoglobulin heavy chain constant domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 63, 381, 382, 383, and 1807. In some embodiments, the human immunoglobulin light chain constant domain is a human kappa constant domain comprising SEQ ID NO: 61 or SEQ ID NO: 1344. 
     In some embodiments, the activatable antibody comprises a masking moiety (MM) comprising the amino acid sequence TSYCSIEHYPCNTHH (SEQ ID NO: 99), which is referred to herein as mask PD034 or PD34, a cleavable moiety (CM) comprising the amino acid sequence ISSGLLSGRSDNP (SEQ ID NO: 1100), which is also referred to herein as substrate 2011, and a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the combination comprises the VH CDR sequences of the variable heavy chain sequence of SEQ ID NO: 21 and the VL CDR sequences of the variable light chain sequence of SEQ ID NO: 47. In some embodiments, the combination further comprises a human immunoglobulin heavy chain constant region, or both a human immunoglobulin heavy chain constant region and a human immunoglobulin light chain constant domain. In some embodiments, the human immunoglobulin heavy chain constant domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 63, 381, 382, 383, and 1807. In some embodiments, the human immunoglobulin light chain constant domain is a human kappa constant domain comprising SEQ ID NO: 61 or SEQ ID NO: 1344. 
     In some embodiments, the activatable antibody comprises a masking moiety (MM) comprising the amino acid sequence TSYCSIEHYPCNTHH (SEQ ID NO: 99), a cleavable moiety (CM) comprising the amino acid sequence ISSGLLSGRSDNP (SEQ ID NO: 1100), and a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the combination comprises the VL CDR1 sequence of SEQ ID NO: 676; the VL CDR2 sequence of SEQ ID NO: 678; the VL CDR3 sequence of SEQ ID NO: 683; the VH CDR1 sequence of SEQ ID NO: 653; the VH CDR2 sequence of SEQ ID NO: 658; and the VH CDR3 sequence of SEQ ID NO: 664. In some embodiments, the combination further comprises a human immunoglobulin heavy chain constant region, a human immunoglobulin light chain constant domain, or both a human immunoglobulin heavy chain constant region and a human immunoglobulin light chain constant domain. In some embodiments, the human immunoglobulin heavy chain constant domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 63, 381, 382, 383, and 1807. In some embodiments, the human immunoglobulin light chain constant domain is a human kappa constant domain comprising SEQ ID NO: 61 or SEQ ID NO: 1344. 
     In some embodiments, the activatable antibody comprises a masking moiety (MM) comprising the amino acid sequence TSYCSIEHYPCNTHH (SEQ ID NO: 99), a cleavable moiety (CM) comprising the amino acid sequence ISSGLLSGRSDNP (SEQ ID NO: 1100), and a combination of a variable heavy chain (VH) sequence of SEQ ID NO: 21 and a variable light chain (VL) sequence of SEQ ID NO: 47. In some embodiments, the combination further comprises a human immunoglobulin heavy chain constant region, a human immunoglobulin light chain constant domain, or both a human immunoglobulin heavy chain constant region and a human immunoglobulin light chain constant domain. In some embodiments, the human immunoglobulin heavy chain constant domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 63, 381, 382, 383, and 1807. In some embodiments, the human immunoglobulin light chain constant domain is a human kappa constant domain comprising SEQ ID NO: 61 or SEQ ID NO: 1344. 
     In some embodiments, the activatable antibody comprises a masking moiety (MM) comprising the amino acid sequence TSYCSIEHYPCNTHH (SEQ ID NO: 99), which is referred to herein as mask PD034 or PD34, a cleavable moiety (CM) comprising the amino acid sequence ISSGLLSGRSDNH (SEQ ID NO: 214), which is also referred to herein as substrate 2001, and a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the combination comprises the VH CDR sequences of the variable heavy chain sequence of SEQ ID NO: 21 and the VL CDR sequences of the variable light chain sequence of SEQ ID NO: 47. In some embodiments, the combination further comprises a human immunoglobulin heavy chain constant region, a human immunoglobulin light chain constant domain, or both a human immunoglobulin heavy chain constant region and a human immunoglobulin light chain constant domain. In some embodiments, the human immunoglobulin heavy chain constant domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 63, 381, 382, 383, and 1807. In some embodiments, the human immunoglobulin light chain constant domain is a human kappa constant domain comprising SEQ ID NO: 61 or SEQ ID NO: 1344. 
     In some embodiments, the activatable antibody comprises a masking moiety (MM) comprising the amino acid sequence TSYCSIEHYPCNTHH (SEQ ID NO: 99), a cleavable moiety (CM) comprising the amino acid sequence ISSGLLSGRSDNH (SEQ ID NO: 214), and a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the combination comprises the VL CDR1 sequence of SEQ ID NO: 676; the VL CDR2 sequence of SEQ ID NO: 678; the VL CDR3 sequence of SEQ ID NO: 683; the VH CDR1 sequence of SEQ ID NO: 653; the VH CDR2 sequence of SEQ ID NO: 658; and the VH CDR3 sequence of SEQ ID NO: 664. In some embodiments, the combination further comprises a human immunoglobulin heavy chain constant region, a human immunoglobulin light chain constant domain, or both a human immunoglobulin heavy chain constant region and a human immunoglobulin light chain constant domain. In some embodiments, the human immunoglobulin heavy chain constant domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 63, 381, 382, 383, and 1807. In some embodiments, the human immunoglobulin light chain constant domain is a human kappa constant domain comprising SEQ ID NO: 61 or SEQ ID NO: 1344. 
     In some embodiments, the activatable antibody comprises a masking moiety (MM) comprising the amino acid sequence TSYCSIEHYPCNTHH (SEQ ID NO: 99), a cleavable moiety (CM) comprising the amino acid sequence ISSGLLSGRSDNH (SEQ ID NO: 214), and a combination of a variable heavy chain (VH) sequence of SEQ ID NO: 21 and a variable light chain (VL) sequence of SEQ ID NO: 47. In some embodiments, the combination further comprises a human immunoglobulin heavy chain constant region, a human immunoglobulin light chain constant domain, or both a human immunoglobulin heavy chain constant region and a human immunoglobulin light chain constant domain. In some embodiments, the human immunoglobulin heavy chain constant domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 63, 381, 382, 383, and 1807. In some embodiments, the human immunoglobulin light chain constant domain is a human kappa constant domain comprising SEQ ID NO: 61 or SEQ ID NO: 1344. 
     In some embodiments, the activatable antibody comprises a masking moiety (MM) comprising the amino acid sequence TSYCSIEHYPCNTHH (SEQ ID NO: 99), a cleavable moiety (CM) comprising the amino acid sequence ISSGLLSGRSGNH (SEQ ID NO: 361), which is also referred to herein as substrate 2002, and a combination selected from the group consisting of (a) a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the combination comprises the VH CDR sequences of the variable heavy chain sequence of SEQ ID NO: 21 and the VL CDR sequences of the variable light chain sequence of SEQ ID NO: 47; (b) a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the combination comprises the VL CDR1 sequence of SEQ ID NO: 676; the VL CDR2 sequence of SEQ ID NO: 678; the VL CDR3 sequence of SEQ ID NO: 683; the VH CDR1 sequence of SEQ ID NO: 653; the VH CDR2 sequence of SEQ ID NO: 658; and the VH CDR3 sequence of SEQ ID NO: 664; and (c) a combination of a variable heavy chain (VH) sequence of SEQ ID NO: 21 and a variable light chain (VL) sequence of SEQ ID NO: 47. In some embodiments, the combination further comprises a human immunoglobulin heavy chain constant region, a human immunoglobulin light chain constant domain, or both a human immunoglobulin heavy chain constant region and a human immunoglobulin light chain constant domain. In some embodiments, the human immunoglobulin heavy chain constant domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 63, 381, 382, 383, and 1807. In some embodiments, the human immunoglobulin light chain constant domain is a human kappa constant domain comprising SEQ ID NO: 61 or SEQ ID NO: 1344. 
     In some embodiments, the activatable antibody comprises a masking moiety (MM) comprising the amino acid sequence TSYCSIEHYPCNTHH (SEQ ID NO: 99), a cleavable moiety (CM) comprising the amino acid sequence ISSGLLSGRSANPRG (SEQ ID NO: 1092), which is also referred to herein as substrate 2003, and a combination selected from the group consisting of (a) a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the combination comprises the VH CDR sequences of the variable heavy chain sequence of SEQ ID NO: 21 and the VL CDR sequences of the variable light chain sequence of SEQ ID NO: 47; (b) a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the combination comprises the VL CDR1 sequence of SEQ ID NO: 676; the VL CDR2 sequence of SEQ ID NO: 678; the VL CDR3 sequence of SEQ ID NO: 683; the VH CDR1 sequence of SEQ ID NO: 653; the VH CDR2 sequence of SEQ ID NO: 658; and the VH CDR3 sequence of SEQ ID NO: 664; and (c) a combination of a variable heavy chain (VH) sequence of SEQ ID NO: 21 and a variable light chain (VL) sequence of SEQ ID NO: 47. In some embodiments, the combination further comprises a human immunoglobulin heavy chain constant region, a human immunoglobulin light chain constant domain, or both a human immunoglobulin heavy chain constant region and a human immunoglobulin light chain constant domain. In some embodiments, the human immunoglobulin heavy chain constant domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 63, 381, 382, 383, and 1807. In some embodiments, the human immunoglobulin light chain constant domain is a human kappa constant domain comprising SEQ ID NO: 61 or SEQ ID NO: 1344. 
     In some embodiments, the activatable antibody comprises a masking moiety (MM) comprising the amino acid sequence TSYCSIEHYPCNTHH (SEQ ID NO: 99), a cleavable moiety (CM) comprising the amino acid sequence ISSGLLSGRSDDH (SEQ ID NO: 1095), which is also referred to herein as substrate 2006, and a combination selected from the group consisting of (a) a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the combination comprises the VH CDR sequences of the variable heavy chain sequence of SEQ ID NO: 21 and the VL CDR sequences of the variable light chain sequence of SEQ ID NO: 47; (b) a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the combination comprises the VL CDR1 sequence of SEQ ID NO: 676; the VL CDR2 sequence of SEQ ID NO: 678; the VL CDR3 sequence of SEQ ID NO: 683; the VH CDR1 sequence of SEQ ID NO: 653; the VH CDR2 sequence of SEQ ID NO: 658; and the VH CDR3 sequence of SEQ ID NO: 664; and (c) a combination of a variable heavy chain (VH) sequence of SEQ ID NO: 21 and a variable light chain (VL) sequence of SEQ ID NO: 47. In some embodiments, the combination further comprises a human immunoglobulin heavy chain constant region, a human immunoglobulin light chain constant domain, or both a human immunoglobulin heavy chain constant region and a human immunoglobulin light chain constant domain. In some embodiments, the human immunoglobulin heavy chain constant domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 63, 381, 382, 383, and 1807. In some embodiments, the human immunoglobulin light chain constant domain is a human kappa constant domain comprising SEQ ID NO: 61 or SEQ ID NO: 1344. 
     In some embodiments, the activatable antibody comprises a masking moiety (MM) comprising the amino acid sequence TSYCSIEHYPCNTHH (SEQ ID NO: 99), a cleavable moiety (CM) comprising the amino acid sequence ISSGLLSGRSDIH (SEQ ID NO: 1096), which is also referred to herein as substrate 2007, and a combination selected from the group consisting of (a) a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the combination comprises the VH CDR sequences of the variable heavy chain sequence of SEQ ID NO: 21 and the VL CDR sequences of the variable light chain sequence of SEQ ID NO: 47; (b) a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the combination comprises the VL CDR1 sequence of SEQ ID NO: 676; the VL CDR2 sequence of SEQ ID NO: 678; the VL CDR3 sequence of SEQ ID NO: 683; the VH CDR1 sequence of SEQ ID NO: 653; the VH CDR2 sequence of SEQ ID NO: 658; and the VH CDR3 sequence of SEQ ID NO: 664; and (c) a combination of a variable heavy chain (VH) sequence of SEQ ID NO: 21 and a variable light chain (VL) sequence of SEQ ID NO: 47. In some embodiments, the combination further comprises a human immunoglobulin heavy chain constant region, a human immunoglobulin light chain constant domain, or both a human immunoglobulin heavy chain constant region and a human immunoglobulin light chain constant domain. In some embodiments, the human immunoglobulin heavy chain constant domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 63, 381, 382, 383, and 1807. In some embodiments, the human immunoglobulin light chain constant domain is a human kappa constant domain comprising SEQ ID NO: 61 or SEQ ID NO: 1344. 
     In some embodiments, the activatable antibody comprises a masking moiety (MM) comprising the amino acid sequence TSYCSIEHYPCNTHH (SEQ ID NO: 99), a cleavable moiety (CM) comprising the amino acid sequence ISSGLLSGRSDQH (SEQ ID NO: 1097), which is also referred to herein as 2008, and a combination selected from the group consisting of (a) a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the combination comprises the VH CDR sequences of the variable heavy chain sequence of SEQ ID NO: 21 and the VL CDR sequences of the variable light chain sequence of SEQ ID NO: 47; (b) a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the combination comprises the VL CDR1 sequence of SEQ ID NO: 676; the VL CDR2 sequence of SEQ ID NO: 678; the VL CDR3 sequence of SEQ ID NO: 683; the VH CDR1 sequence of SEQ ID NO: 653; the VH CDR2 sequence of SEQ ID NO: 658; and the VH CDR3 sequence of SEQ ID NO: 664; and (c) a combination of a variable heavy chain (VH) sequence of SEQ ID NO: 21 and a variable light chain (VL) sequence of SEQ ID NO: 47. In some embodiments, the combination further comprises a human immunoglobulin heavy chain constant region, a human immunoglobulin light chain constant domain, or both a human immunoglobulin heavy chain constant region and a human immunoglobulin light chain constant domain. In some embodiments, the human immunoglobulin heavy chain constant domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 63, 381, 382, 383, and 1807. In some embodiments, the human immunoglobulin light chain constant domain is a human kappa constant domain comprising SEQ ID NO: 61 or SEQ ID NO: 1344. 
     In some embodiments, the activatable antibody comprises a masking moiety (MM) comprising the amino acid sequence TSYCSIEHYPCNTHH (SEQ ID NO: 99), a cleavable moiety (CM) comprising the amino acid sequence ISSGLLSGRSDTH (SEQ ID NO: 1098), which is also referred to herein as substrate 2009, and a combination selected from the group consisting of (a) a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the combination comprises the VH CDR sequences of the variable heavy chain sequence of SEQ ID NO: 21 and the VL CDR sequences of the variable light chain sequence of SEQ ID NO: 47; (b) a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the combination comprises the VL CDR1 sequence of SEQ ID NO: 676; the VL CDR2 sequence of SEQ ID NO: 678; the VL CDR3 sequence of SEQ ID NO: 683; the VH CDR1 sequence of SEQ ID NO: 653; the VH CDR2 sequence of SEQ ID NO: 658; and the VH CDR3 sequence of SEQ ID NO: 664; and (c) a combination of a variable heavy chain (VH) sequence of SEQ ID NO: 21 and a variable light chain (VL) sequence of SEQ ID NO: 47. In some embodiments, the combination further comprises a human immunoglobulin heavy chain constant region, a human immunoglobulin light chain constant domain, or both a human immunoglobulin heavy chain constant region and a human immunoglobulin light chain constant domain. In some embodiments, the human immunoglobulin heavy chain constant domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 63, 381, 382, 383, and 1807. In some embodiments, the human immunoglobulin light chain constant domain is a human kappa constant domain comprising SEQ ID NO: 61 or SEQ ID NO: 1344. 
     In some embodiments, the activatable antibody comprises a masking moiety (MM) comprising the amino acid sequence TSYCSIEHYPCNTHH (SEQ ID NO: 99), a cleavable moiety (CM) comprising the amino acid sequence ISSGLLSGRSDYH (SEQ ID NO: 1099), which is also referred to herein as 2010, and a combination selected from the group consisting of (a) a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the combination comprises the VH CDR sequences of the variable heavy chain sequence of SEQ ID NO: 21 and the VL CDR sequences of the variable light chain sequence of SEQ ID NO: 47; (b) a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the combination comprises the VL CDR1 sequence of SEQ ID NO: 676; the VL CDR2 sequence of SEQ ID NO: 678; the VL CDR3 sequence of SEQ ID NO: 683; the VH CDR1 sequence of SEQ ID NO: 653; the VH CDR2 sequence of SEQ ID NO: 658; and the VH CDR3 sequence of SEQ ID NO: 664; and (c) a combination of a variable heavy chain (VH) sequence of SEQ ID NO: 21 and a variable light chain (VL) sequence of SEQ ID NO: 47. In some embodiments, the combination further comprises a human immunoglobulin heavy chain constant region, a human immunoglobulin light chain constant domain, or both a human immunoglobulin heavy chain constant region and a human immunoglobulin light chain constant domain. In some embodiments, the human immunoglobulin heavy chain constant domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 63, 381, 382, 383, and 1807. In some embodiments, the human immunoglobulin light chain constant domain is a human kappa constant domain comprising SEQ ID NO: 61 or SEQ ID NO: 1344. 
     In some embodiments, the activatable antibody comprises a masking moiety (MM) comprising the amino acid sequence TSYCSIEHYPCNTHH (SEQ ID NO: 99), a cleavable moiety (CM) comprising the amino acid sequence ISSGLLSGRSANI (SEQ ID NO: 1102), which is also referred to herein as substrate 2013, and a combination selected from the group consisting of (a) a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the combination comprises the VH CDR sequences of the variable heavy chain sequence of SEQ ID NO: 21 and the VL CDR sequences of the variable light chain sequence of SEQ ID NO: 47; (b) a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the combination comprises the VL CDR1 sequence of SEQ ID NO: 676; the VL CDR2 sequence of SEQ ID NO: 678; the VL CDR3 sequence of SEQ ID NO: 683; the VH CDR1 sequence of SEQ ID NO: 653; the VH CDR2 sequence of SEQ ID NO: 658; and the VH CDR3 sequence of SEQ ID NO: 664; and (c) a combination of a variable heavy chain (VH) sequence of SEQ ID NO: 21 and a variable light chain (VL) sequence of SEQ ID NO: 47. In some embodiments, the combination further comprises a human immunoglobulin heavy chain constant region, a human immunoglobulin light chain constant domain, or both a human immunoglobulin heavy chain constant region and a human immunoglobulin light chain constant domain. In some embodiments, the human immunoglobulin heavy chain constant domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 63, 381, 382, 383, and 1807. In some embodiments, the human immunoglobulin light chain constant domain is a human kappa constant domain comprising SEQ ID NO: 61 or SEQ ID NO: 1344. 
     In some embodiments, the activatable antibody comprises a masking moiety (MM) comprising the amino acid sequence TSYCSIEHYPCNTHH (SEQ ID NO: 99), a cleavable moiety (CM) comprising the amino acid sequence ISSGLLSGRSDNI (SEQ ID NO: 1111), which is also referred to herein as substrate 2014, and a combination selected from the group consisting of (a) a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the combination comprises the VH CDR sequences of the variable heavy chain sequence of SEQ ID NO: 21 and the VL CDR sequences of the variable light chain sequence of SEQ ID NO: 47; (b) a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the combination comprises the VL CDR1 sequence of SEQ ID NO: 676; the VL CDR2 sequence of SEQ ID NO: 678; the VL CDR3 sequence of SEQ ID NO: 683; the VH CDR1 sequence of SEQ ID NO: 653; the VH CDR2 sequence of SEQ ID NO: 658; and the VH CDR3 sequence of SEQ ID NO: 664; and (c) a combination of a variable heavy chain (VH) sequence of SEQ ID NO: 21 and a variable light chain (VL) sequence of SEQ ID NO: 47. In some embodiments, the combination further comprises a human immunoglobulin heavy chain constant region, a human immunoglobulin light chain constant domain, or both a human immunoglobulin heavy chain constant region and a human immunoglobulin light chain constant domain. In some embodiments, the human immunoglobulin heavy chain constant domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 63, 381, 382, 383, and 1807. In some embodiments, the human immunoglobulin light chain constant domain is a human kappa constant domain comprising SEQ ID NO: 61 or SEQ ID NO: 1344. 
     In some embodiments, the activatable antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 1151; and a heavy chain comprising the amino acid sequence of SEQ ID NO:21. 
     In some embodiments, the activatable antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 1152; and a heavy chain comprising the amino acid sequence of SEQ ID NO:21. 
     In some embodiments, the activatable antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 1190; and a heavy chain comprising the amino acid sequence of SEQ ID NO:21. 
     In some embodiments, the activatable antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 1191; and a heavy chain comprising the amino acid sequence of SEQ ID NO:21. 
     In some embodiments, the activatable antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 1198; and a heavy chain comprising the amino acid sequence of SEQ ID NO:21. 
     In some embodiments, the activatable antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 1199; and a heavy chain comprising the amino acid sequence of SEQ ID NO:21. 
     In some embodiments, the activatable antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 2055; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 2052. 
     In some embodiments, the activatable antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 2054; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 2052. 
     In some embodiments, the activatable antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 2057; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 2052. 
     In some embodiments, the activatable antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 2056; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 2052. 
     In some embodiments, the activatable antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 2059; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 2052. 
     In some embodiments, the activatable antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 2058; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 2052. 
     In some embodiments, the activatable antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 2055; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 2053. 
     In some embodiments, the activatable antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 2054; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 2053. 
     In some embodiments, the activatable antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 2057; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 2053. 
     In some embodiments, the activatable antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 2056; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 2053. 
     In some embodiments, the activatable antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 2059; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 2053. 
     In some embodiments, the activatable antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 2058; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 2053. 
     In some embodiments, the activatable antibody comprises a masking moiety (MM) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1351-1362; a cleavable moiety (CM) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 214, 294, 300, 302, 303, 305, 308, 318, 347, 361, 1092-1102, 1111, and 1157; and a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the combination comprises the VH CDR sequences of the variable heavy chain sequence of SEQ ID NO: 1514 and the VL CDR sequences of the variable light chain sequence of SEQ ID NO: 638. In some embodiments, the combination further comprises a human immunoglobulin heavy chain constant region, a human immunoglobulin light chain constant domain, or both a human immunoglobulin heavy chain constant region and a human immunoglobulin light chain constant domain. In some embodiments, the human immunoglobulin heavy chain constant domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 63, 381, 382, 383, and 1807. In some embodiments, the human immunoglobulin light chain constant domain is a human kappa constant domain comprising SEQ ID NO: 61 or SEQ ID NO: 1344. 
     In some embodiments, the activatable antibody comprises a MM comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1351-1362; a CM comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 214, 294, 300, 302, 303, 305, 308, 318, 347, 361, 1092-1102, 1111, and 1157; and a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the VH CDR1 sequence comprises GYTFTNYY (SEQ ID NO: 1711); the VH CDR2 sequence comprises INPSNGGT (SEQ ID NO: 1712); the VH CDR3 sequence comprises RRDYRFDMGFDY (SEQ ID NO: 1713); the VL CDR1 sequence comprises KGVSTSGYSY (SEQ ID NO: 1714); the VL CDR2 sequence comprises LAS (SEQ ID NO: 1715); and the VL CDR3 sequence comprises QHSRDLPLT (SEQ ID NO: 1716). In some embodiments, the combination further comprises a human immunoglobulin heavy chain constant region, a human immunoglobulin light chain constant domain, or both a human immunoglobulin heavy chain constant region and a human immunoglobulin light chain constant domain. In some embodiments, the human immunoglobulin heavy chain constant domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 63, 381, 382, 383, and 1807. In some embodiments, the human immunoglobulin light chain constant domain is a human kappa constant domain comprising SEQ ID NO: 61 or SEQ ID NO: 1344. 
     In some embodiments, the activatable antibody comprises a MM comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1351-1362; a CM comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 214, 294, 300, 302, 303, 305, 308, 318, 347, 361, 1092-1102, 1111, and 1157; the VH sequence of SEQ ID NO: 1514 and the VL sequence of SEQ ID NO: 638. In some embodiments, the combination further comprises a human immunoglobulin heavy chain constant region, a human immunoglobulin light chain constant domain, or both a human immunoglobulin heavy chain constant region and a human immunoglobulin light chain constant domain. In some embodiments, the human immunoglobulin heavy chain constant domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 63, 381, 382, 383, and 1807. In some embodiments, the human immunoglobulin light chain constant domain is a human kappa constant domain comprising SEQ ID NO: 61 or SEQ ID NO: 1344. 
     In some embodiments, the activatable antibody comprises a MM comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1206-1217; a CM comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 214, 294, 300, 302, 303, 305, 308, 318, 347, 361, 1092-1102, 1111, and 1157; and a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the combination comprises the VH CDR sequences of the variable heavy chain sequence of SEQ ID NO: 1346 and the VL CDR sequences of the variable light chain sequence of SEQ ID NO: 626. In some embodiments, the combination further comprises a human immunoglobulin heavy chain constant region, or both a human immunoglobulin heavy chain constant region and a human immunoglobulin light chain constant domain. In some embodiments, the human immunoglobulin heavy chain constant domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 63, 381, 382, 383, and 1807. In some embodiments, the human immunoglobulin light chain constant domain is a human kappa constant domain comprising SEQ ID NO: 61 or SEQ ID NO: 1344. 
     In some embodiments, the activatable antibody comprises a MM comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1206-1217; a CM comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 214, 294, 300, 302, 303, 305, 308, 318, 347, 361, 1092-1102, 1111, and 1157; and a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the VH CDR1 sequence comprises GITFSNSG (SEQ ID NO: 1705); the VH CDR2 sequence comprises IWYDGSKR (SEQ ID NO: 1706); the VH CDR3 sequence comprises TNDDY (SEQ ID NO: 1707); the VL CDR1 sequence comprises QSVSSY (SEQ ID NO: 1708); the VL CDR2 sequence comprises DAS (SEQ ID NO: 1709); and the VL CDR3 sequence comprises QQSSNWPRT (SEQ ID NO: 1710). In some embodiments, the combination further comprises a human immunoglobulin heavy chain constant region, a human immunoglobulin light chain constant domain, or both a human immunoglobulin heavy chain constant region and a human immunoglobulin light chain constant domain. In some embodiments, the human immunoglobulin heavy chain constant domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 63, 381, 382, 383, and 1807. In some embodiments, the human immunoglobulin light chain constant domain is a human kappa constant domain comprising SEQ ID NO: 61 or SEQ ID NO: 1344. 
     In some embodiments, the activatable antibody comprises a MM comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1206-1217; a CM comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 214, 294, 300, 302, 303, 305, 308, 318, 347, 361, 1092-1102, 1111, and 1157; the VH sequence of SEQ ID NO: 1346 and the VL sequence of SEQ ID NO: 626. In some embodiments, the combination further comprises a human immunoglobulin heavy chain constant region, a human immunoglobulin light chain constant domain, or both a human immunoglobulin heavy chain constant region and a human immunoglobulin light chain constant domain. In some embodiments, the human immunoglobulin heavy chain constant domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 63, 381, 382, 383, and 1807. In some embodiments, the human immunoglobulin light chain constant domain is a human kappa constant domain comprising SEQ ID NO: 61 or SEQ ID NO: 1344. 
     In some embodiments, the activatable antibody comprises a MM comprising the amino acid sequence ACRICQDHPATKWNS (SEQ ID NO: 549), a CM comprising the amino acid sequence ISSGLLSGRSANP (SEQ ID NO: 1101), which is also referred to herein as substrate 2012; the heavy chain (HC) sequence of SEQ ID NO: 546, and the light chain (LC) sequence of SEQ ID NO: 543. 
     In some embodiments, the activatable antibody comprises a MM comprising the amino acid sequence ACRICQDHPATKWNS (SEQ ID NO: 549), a CM comprising the amino acid sequence ISSGLLSGRSDNP (SEQ ID NO: 1100), which is also referred to herein as substrate 2011; the heavy chain (HC) sequence of SEQ ID NO: 546, and the light chain (LC) sequence of SEQ ID NO: 543. 
     In some embodiments, the activatable antibody comprises a MM comprising the amino acid sequence ACRICQDHPATKWNS (SEQ ID NO: 549), a CM comprising the amino acid sequence ISSGLLSGRSDNH (SEQ ID NO: 214), which is also referred to herein as substrate 2001; the heavy chain (HC) sequence of SEQ ID NO: 546, and the light chain (LC) sequence of SEQ ID NO: 543. 
     In some embodiments, the activatable antibody comprises a MM comprising the amino acid sequence ACRICQDHPATKWNS (SEQ ID NO: 549), a CM comprising the amino acid sequence ISSGLLSGRSGNH (SEQ ID NO: 361), which is also referred to herein as substrate 2002; the heavy chain (HC) sequence of SEQ ID NO: 546, and the light chain (LC) sequence of SEQ ID NO: 543. 
     In some embodiments, the activatable antibody comprises a MM comprising the amino acid sequence ACRICQDHPATKWNS (SEQ ID NO: 549), a CM comprising the amino acid sequence ISSGLLSGRSANPRG (SEQ ID NO: 1092), which is also referred to herein as substrate 2003; the heavy chain (HC) sequence of SEQ ID NO: 546, and the light chain (LC) sequence of SEQ ID NO: 543. 
     In some embodiments, the activatable antibody comprises a MM comprising the amino acid sequence ACRICQDHPATKWNS (SEQ ID NO: 549), a CM comprising the amino acid sequence ISSGLLSGRSDDH (SEQ ID NO: 1095), which is also referred to herein as substrate 2006; the heavy chain (HC) sequence of SEQ ID NO: 546, and the light chain (LC) sequence of SEQ ID NO: 543. 
     In some embodiments, the activatable antibody comprises a MM comprising the amino acid sequence ACRICQDHPATKWNS (SEQ ID NO: 549), a CM comprising the amino acid sequence ISSGLLSGRSDIH (SEQ ID NO: 1096), which is also referred to herein as substrate 2007; the heavy chain (HC) sequence of SEQ ID NO: 546, and the light chain (LC) sequence of SEQ ID NO: 543. 
     In some embodiments, the activatable antibody comprises a MM comprising the amino acid sequence ACRICQDHPATKWNS (SEQ ID NO: 549), a CM comprising the amino acid sequence ISSGLLSGRSDQH (SEQ ID NO: 1097), which is also referred to herein as substrate 2008; the heavy chain (HC) sequence of SEQ ID NO: 546, and the light chain (LC) sequence of SEQ ID NO: 543. 
     In some embodiments, the activatable antibody comprises a MM comprising the amino acid sequence ACRICQDHPATKWNS (SEQ ID NO: 549), a CM comprising the amino acid sequence ISSGLLSGRSDTH (SEQ ID NO: 1098), which is also referred to herein as substrate 2009; the heavy chain (HC) sequence of SEQ ID NO: 546, and the light chain (LC) sequence of SEQ ID NO: 543. 
     In some embodiments, the activatable antibody comprises a MM comprising the amino acid sequence ACRICQDHPATKWNS (SEQ ID NO: 549), a CM comprising the amino acid sequence ISSGLLSGRSDQH (SEQ ID NO: 1099), which is also referred to herein as substrate 2010; the heavy chain (HC) sequence of SEQ ID NO: 546, and the light chain (LC) sequence of SEQ ID NO: 543. 
     In some embodiments, the activatable antibody comprises a MM comprising the amino acid sequence ACRICQDHPATKWNS (SEQ ID NO: 549), a CM comprising the amino acid sequence ISSGLLSGRSANI (SEQ ID NO: 1102), which is also referred to herein as substrate 2013; the heavy chain (HC) sequence of SEQ ID NO: 546, and the light chain (LC) sequence of SEQ ID NO: 543. 
     In some embodiments, the activatable antibody comprises a MM comprising the amino acid sequence ACRICQDHPATKWNS (SEQ ID NO: 549), a CM comprising the amino acid sequence ISSGLLSGRSDNI (SEQ ID NO: 1111), which is also referred to herein as substrate 2014; the heavy chain (HC) sequence of SEQ ID NO: 546, and the light chain (LC) sequence of SEQ ID NO: 543. 
     In some embodiments, the activatable antibody comprises a MM comprising the amino acid sequence ACRICQDHPATKWNS (SEQ ID NO: 549), a CM comprising the amino acid sequence ISSGLLSGRSANP (SEQ ID NO: 1101), which is also referred to herein as substrate 2012; the variable heavy chain region (VH) of the heavy chain (HC) sequence of SEQ ID NO: 546, and the variable light chain region (VL) of the light chain (LC) sequence of SEQ ID NO: 543. 
     In some embodiments, the activatable antibody comprises a MM comprising the amino acid sequence ACRICQDHPATKWNS (SEQ ID NO: 549), a CM comprising the amino acid sequence ISSGLLSGRSDNP (SEQ ID NO: 1100), which is also referred to herein as substrate 2011; the variable heavy chain region (VH) of the heavy chain (HC) sequence of SEQ ID NO: 546, and the variable light chain region (VL) of the light chain (LC) sequence of SEQ ID NO: 543. 
     In some embodiments, the activatable antibody comprises a MM comprising the amino acid sequence ACRICQDHPATKWNS (SEQ ID NO: 549), a CM comprising the amino acid sequence ISSGLLSGRSDNH (SEQ ID NO: 214), which is also referred to herein as substrate 2001; the variable heavy chain region (VH) of the heavy chain (HC) sequence of SEQ ID NO: 546, and the variable light chain region (VL) of the light chain (LC) sequence of SEQ ID NO: 543. 
     In some embodiments, the activatable antibody comprises a MM comprising the amino acid sequence ACRICQDHPATKWNS (SEQ ID NO: 549), a CM comprising the amino acid sequence ISSGLLSGRSGNH (SEQ ID NO: 361), which is also referred to herein as substrate 2002; the variable heavy chain region (VH) of the heavy chain (HC) sequence of SEQ ID NO: 546, and the variable light chain region (VL) of the light chain (LC) sequence of SEQ ID NO: 543. 
     In some embodiments, the activatable antibody comprises a MM comprising the amino acid sequence ACRICQDHPATKWNS (SEQ ID NO: 549), a CM comprising the amino acid sequence ISSGLLSGRSANPRG (SEQ ID NO: 1092), which is also referred to herein as substrate 2003; the variable heavy chain region (VH) of the heavy chain (HC) sequence of SEQ ID NO: 546, and the variable light chain region (VL) of the light chain (LC) sequence of SEQ ID NO: 543. 
     In some embodiments, the activatable antibody comprises a MM comprising the amino acid sequence ACRICQDHPATKWNS (SEQ ID NO: 549), a CM comprising the amino acid sequence ISSGLLSGRSDDH (SEQ ID NO: 1095), which is also referred to herein as substrate 2006; the variable heavy chain region (VH) of the heavy chain (HC) sequence of SEQ ID NO: 546, and the variable light chain region (VL) of the light chain (LC) sequence of SEQ ID NO: 543. 
     In some embodiments, the activatable antibody comprises a MM comprising the amino acid sequence ACRICQDHPATKWNS (SEQ ID NO: 549), a CM comprising the amino acid sequence ISSGLLSGRSDIH (SEQ ID NO: 1096), which is also referred to herein as substrate 2007; the variable heavy chain region (VH) of the heavy chain (HC) sequence of SEQ ID NO: 546, and the variable light chain region (VL) of the light chain (LC) sequence of SEQ ID NO: 543. 
     In some embodiments, the activatable antibody comprises a MM comprising the amino acid sequence ACRICQDHPATKWNS (SEQ ID NO: 549), a CM comprising the amino acid sequence ISSGLLSGRSDQH (SEQ ID NO: 1097), which is also referred to herein as substrate 2008; the variable heavy chain region (VH) of the heavy chain (HC) sequence of SEQ ID NO: 546, and the variable light chain region (VL) of the light chain (LC) sequence of SEQ ID NO: 543. 
     In some embodiments, the activatable antibody comprises a MM comprising the amino acid sequence ACRICQDHPATKWNS (SEQ ID NO: 549), a CM comprising the amino acid sequence ISSGLLSGRSDTH (SEQ ID NO: 1098), which is also referred to herein as substrate 2009; the variable heavy chain region (VH) of the heavy chain (HC) sequence of SEQ ID NO: 546, and the variable light chain region (VL) of the light chain (LC) sequence of SEQ ID NO: 543. 
     In some embodiments, the activatable antibody comprises a MM comprising the amino acid sequence ACRICQDHPATKWNS (SEQ ID NO: 549), a CM comprising the amino acid sequence ISSGLLSGRSDYH (SEQ ID NO: 1099), which is also referred to herein as substrate 2010; the variable heavy chain region (VH) of the heavy chain (HC) sequence of SEQ ID NO: 546, and the variable light chain region (VL) of the light chain (LC) sequence of SEQ ID NO: 543. 
     In some embodiments, the activatable antibody comprises a MM comprising the amino acid sequence ACRICQDHPATKWNS (SEQ ID NO: 549), a CM comprising the amino acid sequence ISSGLLSGRSANI (SEQ ID NO: 1102), which is also referred to herein as substrate 2013; the variable heavy chain region (VH) of the heavy chain (HC) sequence of SEQ ID NO: 546, and the variable light chain region (VL) of the light chain (LC) sequence of SEQ ID NO: 543. 
     In some embodiments, the activatable antibody comprises a MM comprising the amino acid sequence ACRICQDHPATKWNS (SEQ ID NO: 549), a CM comprising the amino acid sequence ISSGLLSGRSDNI (SEQ ID NO: 1111), which is also referred to herein as substrate 2014; the variable heavy chain region (VH) of the heavy chain (HC) sequence of SEQ ID NO: 546, and the variable light chain region (VL) of the light chain (LC) sequence of SEQ ID NO: 543. 
     In some embodiments, the activatable antibody comprises a MM comprising the amino acid sequence ACRICQDHPATKWNS (SEQ ID NO: 549), a CM comprising the amino acid sequence ISSGLLSGRSANP (SEQ ID NO: 1101), which is also referred to herein as substrate 2012; the heavy chain complementarity determining regions (CDRs) of the heavy chain (HC) sequence of SEQ ID NO: 546, and the light chain complementarity determining regions (CDRs) of the light chain (LC) sequence of SEQ ID NO: 543. 
     In some embodiments, the activatable antibody comprises a MM comprising the amino acid sequence ACRICQDHPATKWNS (SEQ ID NO: 549), a CM comprising the amino acid sequence ISSGLLSGRSDNP (SEQ ID NO: 1100), which is also referred to herein as substrate 2011; the heavy chain complementarity determining regions (CDRs) of the heavy chain (HC) sequence of SEQ ID NO: 546, and the light chain complementarity determining regions (CDRs) of the light chain (LC) sequence of SEQ ID NO: 543. 
     In some embodiments, the activatable antibody comprises a MM comprising the amino acid sequence ACRICQDHPATKWNS (SEQ ID NO: 549), a CM comprising the amino acid sequence ISSGLLSGRSDNH (SEQ ID NO: 214), which is also referred to herein as substrate 2001; the heavy chain complementarity determining regions (CDRs) of the heavy chain (HC) sequence of SEQ ID NO: 546, and the light chain complementarity determining regions (CDRs) of the light chain (LC) sequence of SEQ ID NO: 543. 
     In some embodiments, the activatable antibody comprises a MM comprising the amino acid sequence ACRICQDHPATKWNS (SEQ ID NO: 549), a CM comprising the amino acid sequence ISSGLLSGRSGNH (SEQ ID NO: 361), which is also referred to herein as substrate 2002; the heavy chain complementarity determining regions (CDRs) of the heavy chain (HC) sequence of SEQ ID NO: 546, and the light chain complementarity determining regions (CDRs) of the light chain (LC) sequence of SEQ ID NO: 543. 
     In some embodiments, the activatable antibody comprises a MM comprising the amino acid sequence ACRICQDHPATKWNS (SEQ ID NO: 549), a CM comprising the amino acid sequence ISSGLLSGRSANPRG (SEQ ID NO: 1092), which is also referred to herein as substrate 2003; the heavy chain complementarity determining regions (CDRs) of the heavy chain (HC) sequence of SEQ ID NO: 546, and the light chain complementarity determining regions (CDRs) of the light chain (LC) sequence of SEQ ID NO: 543. 
     In some embodiments, the activatable antibody comprises a MM comprising the amino acid sequence ACRICQDHPATKWNS (SEQ ID NO: 549), a CM comprising the amino acid sequence ISSGLLSGRSDDH (SEQ ID NO: 1095), which is also referred to herein as substrate 2006; the heavy chain complementarity determining regions (CDRs) of the heavy chain (HC) sequence of SEQ ID NO: 546, and the light chain complementarity determining regions (CDRs) of the light chain (LC) sequence of SEQ ID NO: 543. 
     In some embodiments, the activatable antibody comprises a MM comprising the amino acid sequence ACRICQDHPATKWNS (SEQ ID NO: 549), a CM comprising the amino acid sequence ISSGLLSGRSDIH (SEQ ID NO: 1096), which is also referred to herein as substrate 2007; the heavy chain complementarity determining regions (CDRs) of the heavy chain (HC) sequence of SEQ ID NO: 546, and the light chain complementarity determining regions (CDRs) of the light chain (LC) sequence of SEQ ID NO: 543. 
     In some embodiments, the activatable antibody comprises a MM comprising the amino acid sequence ACRICQDHPATKWNS (SEQ ID NO: 549), a CM comprising the amino acid sequence ISSGLLSGRSDQH (SEQ ID NO: 1097), which is also referred to herein as substrate 2008; the heavy chain complementarity determining regions (CDRs) of the heavy chain (HC) sequence of SEQ ID NO: 546, and the light chain complementarity determining regions (CDRs) of the light chain (LC) sequence of SEQ ID NO: 543. 
     In some embodiments, the activatable antibody comprises a MM comprising the amino acid sequence ACRICQDHPATKWNS (SEQ ID NO: 549), a CM comprising the amino acid sequence ISSGLLSGRSDTH (SEQ ID NO: 1098), which is also referred to herein as substrate 2009; the heavy chain complementarity determining regions (CDRs) of the heavy chain (HC) sequence of SEQ ID NO: 546, and the light chain complementarity determining regions (CDRs) of the light chain (LC) sequence of SEQ ID NO: 543. 
     In some embodiments, the activatable antibody comprises a MM comprising the amino acid sequence ACRICQDHPATKWNS (SEQ ID NO: 549), a CM comprising the amino acid sequence ISSGLLSGRSDYH (SEQ ID NO: 1099), which is also referred to herein as substrate 2010; the heavy chain complementarity determining regions (CDRs) of the heavy chain (HC) sequence of SEQ ID NO: 546, and the light chain complementarity determining regions (CDRs) of the light chain (LC) sequence of SEQ ID NO: 543. 
     In some embodiments, the activatable antibody comprises a MM comprising the amino acid sequence ACRICQDHPATKWNS (SEQ ID NO: 549), a CM comprising the amino acid sequence ISSGLLSGRSANI (SEQ ID NO: 1102), which is also referred to herein as substrate 2013; the heavy chain complementarity determining regions (CDRs) of the heavy chain (HC) sequence of SEQ ID NO: 546, and the light chain complementarity determining regions (CDRs) of the light chain (LC) sequence of SEQ ID NO: 543. 
     In some embodiments, the activatable antibody comprises a MM comprising the amino acid sequence ACRICQDHPATKWNS (SEQ ID NO: 549), a CM comprising the amino acid sequence ISSGLLSGRSDNI (SEQ ID NO: 1111), which is also referred to herein as substrate 2014; the heavy chain complementarity determining regions (CDRs) of the heavy chain (HC) sequence of SEQ ID NO: 546, and the light chain complementarity determining regions (CDRs) of the light chain (LC) sequence of SEQ ID NO: 543. 
     In some embodiments, the activatable antibody comprises a light chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1808, 1810, 1812, 1814, 1816, 1818, 1820, 1822, 1824, 1826, 1828, and 1830; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 546. 
     In some embodiments, the activatable antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 1808; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 546. 
     In some embodiments, the activatable antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 1810; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 546. 
     In some embodiments, the activatable antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 1812; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 546. 
     In some embodiments, the activatable antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 1814; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 546. 
     In some embodiments, the activatable antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 1816; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 546. 
     In some embodiments, the activatable antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 1818; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 546. 
     In some embodiments, the activatable antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 1820; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 546. 
     In some embodiments, the activatable antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 1822; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 546. 
     In some embodiments, the activatable antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 1824; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 546. 
     In some embodiments, the activatable antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 1826; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 546. 
     In some embodiments, the activatable antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 1828; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 546. 
     In some embodiments, the activatable antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 1830; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 546. 
     In some embodiments, the activatable antibody is encoded by a nucleic acid sequence that comprises a nucleic acid sequence encoding a heavy chain amino acid sequence selected from the group consisting of SEQ ID NO: 1, 5, 9, 13, 17, 21, 23, 25, 27, 29, 31, 33, 35, and 37. In some embodiments, the activatable antibody is encoded by a nucleic acid sequence that comprises a nucleic acid sequence encoding a heavy chain amino acid sequence selected from the group consisting of SEQ ID NO: 21, 23, 25, 27, 29, 31, 33, 35, and 37. 
     In some embodiments, the activatable antibody is encoded by a nucleic acid sequence that comprises a nucleic acid sequence encoding a light chain amino acid sequence selected from the group consisting of SEQ ID NO: 3, 7, 11, 15, 19, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59. In some embodiments, the activatable antibody is encoded by a nucleic acid sequence that comprises a nucleic acid sequence encoding a light chain amino acid sequence selected from the group consisting of SEQ ID NO: 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59. 
     In some embodiments, the activatable antibody is encoded by a nucleic acid sequence that comprises a nucleic acid sequence encoding a heavy chain amino acid sequence selected from the group consisting of SEQ ID NO: 1, 5, 9, 13, 17, 21, 23, 25, 27, 29, 31, 33, 35, and 37, and a nucleic acid sequence that comprises a nucleic acid sequence encoding a light chain amino acid sequence selected from the group consisting of SEQ ID NO: 3, 7, 11, 15, 19, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59. 
     In some embodiments, the activatable antibody is encoded by a nucleic acid sequence that comprises a nucleic acid sequence encoding a heavy chain amino acid sequence selected from the group consisting of SEQ ID NO: 21, 23, 25, 27, 29, 31, 33, 35, and 37, and a nucleic acid sequence that comprises a nucleic acid sequence encoding a light chain amino acid sequence selected from the group consisting of SEQ ID NO: 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59. 
     In some embodiments, the activatable antibody is encoded by a nucleic acid sequence that comprises a nucleic acid sequence encoding a heavy chain amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NO: 1, 5, 9, 13, 17, 21, 23, 25, 27, 29, 31, 33, 35, and 37. In some embodiments, the activatable antibody is encoded by a nucleic acid sequence that comprises a nucleic acid sequence encoding a heavy chain amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NO: 21, 23, 25, 27, 29, 31, 33, 35, and 37. 
     In some embodiments, the activatable antibody is encoded by a nucleic acid sequence that comprises a nucleic acid sequence encoding a light chain amino acid that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence selected from the group consisting of SEQ ID NO: 3, 7, 11, 15, 19, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59. In some embodiments, the activatable antibody is encoded by a nucleic acid sequence that comprises a nucleic acid sequence encoding a light chain amino acid that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence selected from the group consisting of SEQ ID NO: 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59. 
     In some embodiments, the activatable antibody is encoded by a nucleic acid sequence that comprises a nucleic acid sequence encoding a heavy chain amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NO: 1, 5, 9, 13, 17, 21, 23, 25, 27, 29, 31, 33, 35, and 37, and a nucleic acid sequence encoding a light chain amino acid that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence selected from the group consisting of SEQ ID NO: 3, 7, 11, 15, 19, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59. 
     In some embodiments, the activatable antibody is encoded by a nucleic acid sequence that comprises a nucleic acid sequence encoding a heavy chain amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NO: 21, 23, 25, 27, 29, 31, 33, 35, and 37, and a nucleic acid sequence that comprises a nucleic acid sequence encoding a light chain amino acid that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence selected from the group consisting of SEQ ID NO: 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59. 
     In some embodiments, the activatable antibody is encoded by a heavy chain nucleic acid sequence selected from the group consisting of SEQ ID NO: 2, 6, 10, 14, 18, 22, 24, 26, 28, 30, 32, 34, 36, and 38. In some embodiments, the activatable antibody is encoded by a heavy chain nucleic acid sequence selected from the group consisting of SEQ ID NO: 22, 24, 26, 28, 30, 32, 34, 36, and 38. 
     In some embodiments, the activatable antibody is encoded by a light chain nucleic acid sequence selected from the group consisting of SEQ ID NO: 4, 8, 12, 16, 20, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, and 60. In some embodiments, the activatable antibody is encoded by a light chain nucleic acid sequence selected from the group consisting of SEQ ID NO: 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, and 60. 
     In some embodiments, the activatable antibody is encoded by heavy chain nucleic acid sequence selected from the group consisting of SEQ ID NO: selected from the group consisting of SEQ ID NO: 2, 6, 10, 14, 18, 22, 24, 26, 28, 30, 32, 34, 36, and 38, and a light chain nucleic acid sequence selected from the group consisting of SEQ ID NO: 4, 8, 12, 16, 20, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, and 60. In some embodiments, the activatable antibody is encoded by heavy chain nucleic acid sequence selected from the group consisting of SEQ ID NO: selected from the group consisting of SEQ ID NO: 22, 24, 26, 28, 30, 32, 34, 36, and 38, and a light chain nucleic acid sequence selected from the group consisting of SEQ ID NO: 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, and 60. 
     In some embodiments, the activatable antibody is encoded by a nucleic acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to a heavy chain nucleic acid sequence selected from the group consisting of SEQ ID NO: 2, 6, 10, 14, 18, 22, 24, 26, 28, 30, 32, 34, 36, and 38. In some embodiments, the activatable antibody is encoded by a nucleic acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to a heavy chain nucleic acid sequence selected from the group consisting of SEQ ID NO: 22, 24, 26, 28, 30, 32, 34, 36, and 38. 
     In some embodiments, the activatable antibody is encoded by a nucleic acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to a light chain nucleic acid sequence selected from the group consisting of SEQ ID NO: 4, 8, 12, 16, 20, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, and 60. In some embodiments, the activatable antibody is encoded by a nucleic acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to a light chain nucleic acid sequence selected from the group consisting of SEQ ID NO: 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, and 60. 
     In some embodiments, the activatable antibody is encoded by a nucleic acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to a heavy chain nucleic acid sequence selected from the group consisting of SEQ ID NO: 2, 6, 10, 14, 18, 22, 24, 26, 28, 30, 32, 34, 36, and 38, and a nucleic acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to a light chain nucleic acid sequence selected from the group consisting of SEQ ID NO: 4, 8, 12, 16, 20, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, and 60. In some embodiments, the activatable antibody is encoded by a nucleic acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to a heavy chain nucleic acid sequence selected from the group consisting of SEQ ID NO: 22, 24, 26, 28, 30, 32, 34, 36, and 38, and a nucleic acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to a light chain nucleic acid sequence selected from the group consisting of SEQ ID NO: 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, and 60. 
     In some embodiments, the MM has a dissociation constant, i.e., dissociation constant at an equilibrium state, K d  for binding to the AB that is greater than the K d  for binding of the AB to PD-1. 
     In some embodiments, the MM has a K d  for binding to the AB that is no more than the K d  for binding of the AB to PD-1. 
     In some embodiments, the MM has a K d  for binding to the AB that is no less than the K d  for binding of the AB to PD-1. 
     In some embodiments, the MM has a K d  for binding to the AB that is approximately equal to the K d  for binding of the AB to PD-1. 
     In some embodiments, the MM has a K d  for binding to the AB that is less than the K d  for binding of the AB to PD-1. 
     In some embodiments, the MM has a K d  for binding to the AB that is no more than 2, 3, 4, 5, 10, 25, 50, 100, 250, 500, or 1,000 fold greater than the K d  for binding of the AB to PD-1. In some embodiments, the MM has a K d  for binding to the AB that is between 1-5, 2-5, 2-10, 5-10, 5-20, 5-50, 5-100, 10-100, 10-1,000, 20-100, 20-1000, or 100-1,000 fold greater than the K d  for binding of the AB to PD-1. 
     In some embodiments, the MM has an affinity for binding to the AB that is less than the affinity of binding of the AB to PD-1. 
     In some embodiments, the MM has an affinity for binding to the AB that is no more than the affinity of binding of the AB to PD-1. 
     In some embodiments, the MM has an affinity for binding to the AB that is approximately equal of the affinity of binding of the AB to PD-1. 
     In some embodiments, the MM has an affinity for binding to the AB that is no less than the affinity of binding of the AB to PD-1. 
     In some embodiments, the MM has an affinity for binding to the AB that is greater than the affinity of binding of the AB to PD-1. 
     In some embodiments, the MM has an affinity for binding to the AB that is 2, 3, 4, 5, 10, 25, 50, 100, 250, 500, or 1,000 less than the affinity of binding of the AB to PD-1. I In some embodiments, the MM has an affinity for binding to the AB that is between 1-5, 2-5, 2-10, 5-10, 5-20, 5-50, 5-100, 10-100, 10-1,000, 20-100, 20-1000, or 100-1,000 fold less than the affinity of binding of the AB to PD-1. In some embodiments, the MM has an affinity for binding to the AB that is 2 to 20 fold less than the affinity of binding of the AB to PD-1. In some embodiments, a MM not covalently linked to the AB and at equimolar concentration to the AB does not inhibit the binding of the AB to PD-1. 
     In some embodiments, the MM does not interfere or compete with the AB for binding to PD-1 when the activatable antibody is in a cleaved state. 
     In some embodiments, the MM is a polypeptide of about 2 to 40 amino acids in length. In some embodiments, the MM is a polypeptide of up to about 40 amino acids in length. 
     In some embodiments, the MM is a polypeptide of no more than 40 amino acids in length. 
     In some embodiments, the MM polypeptide sequence is different from that of PD-1. In some embodiments, the MM polypeptide sequence is different from that of human PD-1. In some embodiments, the MM polypeptide sequence is no more than 50% identical to any natural binding partner of the AB. In some embodiments, the MM polypeptide sequence is different from that of PD-1 and is no more than 40%, 30%, 25%, 20%, 15%, or 10% identical to any natural binding partner of the AB. In some embodiments, the MM polypeptide sequence is no more than 50% identical to human PD-1. In some embodiments, the MM polypeptide sequence is different from that of PD-1 and is no more than 40%, 30%, 25%, 20%, 15%, or 10% identical to human PD-1. 
     In some embodiments, the MM comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 66-213, 384-514, 548-571, 1206-1295, and 1351-1465. In some embodiments, the MM comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 66-213, 384-514, 548-571, 1206-1295, and 1351-1465. In some embodiments, the MM comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 66, 67, 70, 71, 74, 77, 81, 82, 84, 90, 91, 93, and 99. In some embodiments, the MM comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 66, 71, 74, 77, 82, 84, 90, 91, 93, and 99. In some embodiments, the MM comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1206-1217. In some embodiments, the MM comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1351-1362. 
     In some embodiments, the MM comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 66-213. In some embodiments, the MM comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 66-213. 
     In some embodiments, the MM comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 384-514. In some embodiments, the MM comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 384-514. 
     In some embodiments, the MM comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 548-571. In some embodiments, the MM comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 548-571. 
     In some embodiments, the MM comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1206-1295. In some embodiments, the MM comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 1206-1295. 
     In some embodiments, the MM comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1351-1465. In some embodiments, the MM comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 1351-1465. 
     In some embodiments, the antibody or activatable antibody comprises a heavy chain comprising an amino acid selected from the group consisting of SEQ ID NOs: 2052 and 2053. 
     In some embodiments, the antibody or activatable antibody comprises a light chain comprising an amino acid selected from the group consisting of SEQ ID NOs: 2054 to 2059. 
     In some embodiments, the antibody or activatable antibody comprises a heavy chain comprising an amino acid selected from the group consisting of SEQ ID NOs: 2052 and 2053 and a light chain comprising an amino acid selected from the group consisting of SEQ ID NOs: 2054 to 2059. 
     In some embodiments, the coupling of the MM to the AB reduces the ability of the AB to bind PD-1 such that the dissociation constant (K d ) of the AB when coupled to the MM towards PD-1 is at least two times greater than the K d  of the AB when not coupled to the MM towards PD-1. 
     In some embodiments, the coupling of the MM to the AB reduces the ability of the AB to bind PD-1 such that the dissociation constant (K d ) of the AB when coupled to the MM towards PD-1 is at least five times greater than the K d  of the AB when not coupled to the MM towards PD-1. 
     In some embodiments, the coupling of the MM to the AB reduces the ability of the AB to bind PD-1 such that the dissociation constant (K d ) of the AB when coupled to the MM towards PD-1 is at least 10 times greater than the K d  of the AB when not coupled to the MM towards PD-1. 
     In some embodiments, the coupling of the MM to the AB reduces the ability of the AB to bind PD-1 such that the dissociation constant (K d ) of the AB when coupled to the MM towards PD-1 is at least 20 times greater than the K d  of the AB when not coupled to the MM towards PD-1. 
     In some embodiments, the coupling of the MM to the AB reduces the ability of the AB to bind PD-1 such that the dissociation constant (K d ) of the AB when coupled to the MM towards PD-1 is at least 40 times greater than the K d  of the AB when not coupled to the MM towards PD-1. 
     In some embodiments, the coupling of the MM to the AB reduces the ability of the AB to bind PD-1 such that the dissociation constant (K d ) of the AB when coupled to the MM towards PD-1 is at least 100 times greater than the K d  of the AB when not coupled to the MM towards PD-1. 
     In some embodiments, the coupling of the MM to the AB reduces the ability of the AB to bind PD-1 such that the dissociation constant (K d ) of the AB when coupled to the MM towards PD-1 is at least 1000 times greater than the K d  of the AB when not coupled to the MM towards PD-1. 
     In some embodiments, the coupling of the MM to the AB reduces the ability of the AB to bind PD-1 such that the dissociation constant (K d ) of the AB when coupled to the MM towards PD-1 is at least 10,000 times greater than the K d  of the AB when not coupled to the MM towards PD-1. 
     In some embodiments, in the presence of PD-1, the MM reduces the ability of the AB to bind PD-1 by at least 90% when the CM is uncleaved, as compared to when the CM is cleaved when assayed in vitro using a target displacement assay such as, for example, the assay described in PCT Publication No. WO 2010/081173, the contents of which are hereby incorporated by reference in their entirety. 
     In some embodiments, the protease that cleaves the CM is active, e.g., up-regulated, in diseased tissue, and the protease cleaves the CM in the activatable antibody when the activatable antibody is exposed to the protease. 
     In some embodiments, the protease is produced by a tumor that is in proximity to T cells that express PD-1, and the protease cleaves the CM in the activatable antibody when the activatable antibody is exposed to the protease. In some embodiments, the protease is produced by a tumor that is co-localized with T cells that express PD-1, and the protease cleaves the CM in the activatable antibody when the activatable antibody is exposed to the protease. 
     In some embodiments, the CM is positioned in the activatable antibody such that when the activatable antibody is in the uncleaved state, binding of the activatable antibody to PD-1 is reduced to occur with a dissociation constant that is at least twofold greater than the dissociation constant of an unmodified AB binding to PD-1, whereas in the cleaved state (i.e., when the activatable antibody is in the cleaved state), the AB binds PD-1. 
     In some embodiments, the CM is positioned in the activatable antibody such that when the activatable antibody is in the uncleaved state, binding of the activatable antibody to PD-1 is reduced to occur with a dissociation constant that is at least fivefold greater than the dissociation constant of an unmodified AB binding to PD-1, whereas in the cleaved state (i.e., when the activatable antibody is in the cleaved state), the AB binds PD-1. 
     In some embodiments, the CM is positioned in the activatable antibody such that when the activatable antibody is in the uncleaved state, binding of the activatable antibody to PD-1 is reduced to occur with a dissociation constant that is at least 10-fold greater than the dissociation constant of an unmodified AB binding to PD-1, whereas in the cleaved state (i.e., when the activatable antibody is in the cleaved state), the AB binds PD-1. 
     In some embodiments, the CM is positioned in the activatable antibody such that when the activatable antibody is in the uncleaved state, binding of the activatable antibody to PD-1 is reduced to occur with a dissociation constant that is at least 20-fold greater than the dissociation constant of an unmodified AB binding to PD-1, whereas in the cleaved state (i.e., when the activatable antibody is in the cleaved state), the AB binds PD-1. 
     In some embodiments, the CM is positioned in the activatable antibody such that when the activatable antibody is in the uncleaved state, binding of the activatable antibody to PD-1 is reduced to occur with a dissociation constant that is at least 40-fold greater than the dissociation constant of an unmodified AB binding to PD-1, whereas in the cleaved state, the AB binds PD-1. 
     In some embodiments, the CM is positioned in the activatable antibody such that when the activatable antibody is in the uncleaved state, binding of the activatable antibody to PD-1 is reduced to occur with a dissociation constant that is at least 50-fold greater than the dissociation constant of an unmodified AB binding to PD-1, whereas in the cleaved state, the AB binds PD-1. 
     In some embodiments, the CM is positioned in the activatable antibody such that when the activatable antibody is in the uncleaved state, binding of the activatable antibody to PD-1 is reduced to occur with a dissociation constant that is at least 100-fold greater than the dissociation constant of an unmodified AB binding to PD-1, whereas in the cleaved state, the AB binds PD-1. 
     In some embodiments, the CM is positioned in the activatable antibody such that when the activatable antibody is in the uncleaved state, binding of the activatable antibody to PD-1 is reduced to occur with a dissociation constant that is at least 200-fold greater than the dissociation constant of an unmodified AB binding to PD-1, whereas in the cleaved state, the AB binds PD-1. 
     In some embodiments, the CM is a polypeptide of up to 15 amino acids in length. 
     In some embodiments, the CM is a polypeptide that includes a first cleavable moiety (CM1) that is a substrate for at least one matrix metalloprotease (MMP) and a second cleavable moiety (CM2) that is a substrate for at least one serine protease (SP). In some embodiments, each of the CM1 substrate sequence and the CM2 substrate sequence of the CM1-CM2 substrate is independently a polypeptide of up to 15 amino acids in length. 
     In some embodiments, the CM is a substrate for at least one protease that is or is believed to be up-regulated in cancer. In some embodiments, the CM is a substrate for at least one protease that is or is believed to be up-regulated in inflammation. In some embodiments, the CM is a substrate for at least one protease that is or is believed to be up-regulated in autoimmunity. 
     In some embodiments, the CM is a substrate for at least one protease selected from the group consisting of a matrix metalloprotease (MMP), thrombin, a neutrophil elastase, a cysteine protease, legumain, and a serine protease, such as matriptase (MT-SP1), and urokinase (uPA). Without being bound by theory, it is believed that these proteases are up-regulated in at least one of cancer, inflammation, and/or autoimmunity. 
     Exemplary substrates include but are not limited to substrates cleavable by one or more of the following enzymes or proteases listed in Table 3. 
     In some embodiments, the CM is selected for use with a specific protease, for example a protease that is known to be co-localized with the target of the activatable antibody. For example, the protease is produced by a tumor that is in proximity to T cells that express PD-1. In some embodiments, the protease is produced by a tumor that is co-localized with T cells that express PD-1. 
     In some embodiments, the CM is a substrate for at least one MMP. Examples of MMPs include the MMPs listed in the Table 3. In some embodiments, the CM is a substrate for a protease selected from the group consisting of MMP 9, MMP14, MMP1, MMP3, MMP13, MMP17, MMP11, and MMP19. In some embodiments the CM is a substrate for MMP9. In some embodiments, the CM is a substrate for MMP14. 
     In some embodiments, the CM is a substrate that includes the sequence TGRGPSWV (SEQ ID NO: 295); SARGPSRW (SEQ ID NO: 319); TARGPSFK (SEQ ID NO: 297); LSGRSDNH (SEQ ID NO: 294); GGWHTGRN (SEQ ID NO: 320); HTGRSGAL (SEQ ID NO: 321); PLTGRSGG (SEQ ID NO: 296); AARGPAIH (SEQ ID NO: 322); RGPAFNPM (SEQ ID NO: 323); SSRGPAYL (SEQ ID NO: 324); RGPATPIM (SEQ ID NO: 325); RGPA (SEQ ID NO: 326); GGQPSGMWGW (SEQ ID NO: 327); FPRPLGITGL (SEQ ID NO: 328); VHMPLGFLGP (SEQ ID NO: 302); SPLTGRSG (SEQ ID NO: 329); SAGFSLPA (SEQ ID NO: 330); LAPLGLQRR (SEQ ID NO: 331); SGGPLGVR (SEQ ID NO: 332); PLGL (SEQ ID NO: 333); LSGRSGNH (SEQ ID NO: 1157); SGRSANPRG (SEQ ID NO: 1158); LSGRSDDH (SEQ ID NO: 1161); LSGRSDIH (SEQ ID NO: 1162); LSGRSDQH (SEQ ID NO: 1165); LSGRSDTH (SEQ ID NO: 1166); LSGRSDDH (SEQ ID NO: 1169); LSGRSDNP (SEQ ID NO: 1520); LSGRSANP (SEQ ID NO: 1695); LSGRSANI (SEQ ID NO: 1696); and/or LSGRSDNI (SEQ ID NO: 1697). 
     In some embodiments, the CM comprises the amino acid sequence LSGRSDNH (SEQ ID NO: 294). In some embodiments, the CM comprises the amino acid sequence TGRGPSWV (SEQ ID NO: 295). In some embodiments, the CM comprises the amino acid sequence PLTGRSGG (SEQ ID NO: 296). In some embodiments, the CM comprises the amino acid sequence GGQPSGMWGW (SEQ ID NO: 327). In some embodiments, the CM comprises the amino acid sequence FPRPLGITGL (SEQ ID NO: 328). In some embodiments, the CM comprises the amino acid sequence VHMPLGFLGP (SEQ ID NO: 302). In some embodiments, the CM comprises the amino acid sequence PLGL (SEQ ID NO: 333). In some embodiments, the CM comprises the amino acid sequence SARGPSRW (SEQ ID NO: 319). In some embodiments, the CM comprises the amino acid sequence TARGPSFK (SEQ ID NO: 297). In some embodiments, the CM comprises the amino acid sequence GGWHTGRN (SEQ ID NO: 320). In some embodiments, the CM comprises the amino acid sequence HTGRSGAL (SEQ ID NO: 321). In some embodiments, the CM comprises the amino acid sequence AARGPAIH (SEQ ID NO: 322). In some embodiments, the CM comprises the amino acid sequence RGPAFNPM (SEQ ID NO: 323). In some embodiments, the CM comprises the amino acid sequence SSRGPAYL (SEQ ID NO: 324). In some embodiments, the CM comprises the amino acid sequence RGPATPIM (SEQ ID NO: 325). In some embodiments, the CM comprises the amino acid sequence RGPA (SEQ ID NO: 326). In some embodiments, the CM comprises the amino acid sequence LSGRSGNH (SEQ ID NO: 1157). In some embodiments, the CM comprises the amino acid sequence SGRSANPRG (SEQ ID NO: 1158). In some embodiments, the CM comprises the amino acid sequence LSGRSDDH (SEQ ID NO: 1161). In some embodiments, the CM comprises the amino acid sequence LSGRSDIH (SEQ ID NO: 1162). In some embodiments, the CM comprises the amino acid sequence LSGRSDQH (SEQ ID NO: 1165). In some embodiments, the CM comprises the amino acid sequence LSGRSDTH (SEQ ID NO: 1166). In some embodiments, the CM comprises the amino acid sequence LSGRSDYH (SEQ ID NO: 1169). In some embodiments, the CM comprises the amino acid sequence LSGRSDNP (SEQ ID NO: 1520). In some embodiments, the CM comprises the amino acid sequence LSGRSANP (SEQ ID NO: 1695). In some embodiments, the CM comprises the amino acid sequence LSGRSANI (SEQ ID NO: 1696). In some embodiments, the CM comprises the amino acid sequence LSGRSDNI (SEQ ID NO: 1697). 
     In some embodiments, the CM is a substrate for an MMP and includes the sequence ISSGLSS (SEQ ID NO: 334); QNQALRMA (SEQ ID NO: 305); AQNLLGMV (SEQ ID NO: 304); STFPFGMF (SEQ ID NO: 307); PVGYTSSL (SEQ ID NO: 335); DWLYWPGI (SEQ ID NO: 336), ISSGLLSS (SEQ ID NO: 308), LKAAPRWA (SEQ ID NO: 337); GPSHLVLT (SEQ ID NO: 338); LPGGLSPW (SEQ ID NO: 339); MGLFSEAG (SEQ ID NO: 340); SPLPLRVP (SEQ ID NO: 341); RMHLRSLG (SEQ ID NO: 342); LAAPLGLL (SEQ ID NO: 306); AVGLLAPP (SEQ ID NO: 303); LLAPSHRA (SEQ ID NO: 343); PAGLWLDP (SEQ ID NO: 309); MIAPVAYR (SEQ ID NO: 1698); RPSPMWAY (SEQ ID NO: 1699); WATPRPMR (SEQ ID NO: 1700); FRLLDWQW (SEQ ID NO: 1701); ISSGL (SEQ ID NO: 1702); ISSGLLS (SEQ ID NO: 1703); and/or ISSGLL (SEQ ID NO: 1704). 
     In some embodiments, the CM comprises the amino acid sequence ISSGLSS (SEQ ID NO: 334). In some embodiments, the CM comprises the amino acid sequence QNQALRMA (SEQ ID NO: 305). In some embodiments, the CM comprises the amino acid sequence AQNLLGMV (SEQ ID NO: 304). In some embodiments, the CM comprises the amino acid sequence STFPFGMF (SEQ ID NO: 307). In some embodiments, the CM comprises the amino acid sequence PVGYTSSL (SEQ ID NO: 335). In some embodiments, the CM comprises the amino acid sequence DWLYWPGI (SEQ ID NO: 336). In some embodiments, the CM comprises the amino acid sequence ISSGLLSS (SEQ ID NO: 308). In some embodiments, the CM comprises the amino acid sequence LKAAPRWA (SEQ ID NO: 337). In some embodiments, the CM comprises the amino acid sequence GPSHLVLT (SEQ ID NO: 338). In some embodiments, the CM comprises the amino acid sequence LPGGLSPW (SEQ ID NO: 339). In some embodiments, the CM comprises the amino acid sequence MGLFSEAG (SEQ ID NO: 340). In some embodiments, the CM comprises the amino acid sequence SPLPLRVP (SEQ ID NO: 341). In some embodiments, the CM comprises the amino acid sequence RMHLRSLG (SEQ ID NO: 342). In some embodiments, the CM comprises the amino acid sequence LAAPLGLL (SEQ ID NO: 306). In some embodiments, the CM comprises the amino acid sequence AVGLLAPP (SEQ ID NO: 303). In some embodiments, the CM comprises the amino acid sequence LLAPSHRA (SEQ ID NO: 343). In some embodiments, the CM comprises the amino acid sequence PAGLWLDP (SEQ ID NO: 309). In some embodiments, the CM comprises the amino acid sequence MIAPVAYR (SEQ ID NO: 1698). In some embodiments, the CM comprises the amino acid sequence RPSPMWAY (SEQ ID NO: 1699). In some embodiments, the CM comprises the amino acid sequence WATPRPMR (SEQ ID NO: 1700). In some embodiments, the CM comprises the amino acid sequence FRLLDWQW (SEQ ID NO: 1701). In some embodiments, the CM comprises the amino acid sequence ISSGL (SEQ ID NO: 1702). In some embodiments, the CM comprises the amino acid sequence ISSGLLS (SEQ ID NO: 1703). In some embodiments, the CM comprises the amino acid sequence ISSGLL (SEQ ID NO: 1704). 
     In some embodiments, the CM is a substrate for thrombin. In some embodiments, the CM is a substrate for thrombin and includes the sequence GPRSFGL (SEQ ID NO: 344) or GPRSFG (SEQ ID NO: 345). In some embodiments, the CM comprises the amino acid sequence GPRSFGL (SEQ ID NO: 344). In some embodiments, the CM comprises the amino acid sequence GPRSFG (SEQ ID NO: 345). 
     In some embodiments, the CM comprises an amino acid sequence selected from the group consisting of NTLSGRSENHSG (SEQ ID NO: 298); NTLSGRSGNHGS (SEQ ID NO: 299); TSTSGRSANPRG (SEQ ID NO: 300); TSGRSANP (SEQ ID NO: 301); VAGRSMRP (SEQ ID NO: 310); VVPEGRRS (SEQ ID NO: 311); ILPRSPAF (SEQ ID NO: 312); MVLGRSLL (SEQ ID NO: 313); QGRAITFI (SEQ ID NO: 314); SPRSIMLA (SEQ ID NO: 315); and SMLRSMPL (SEQ ID NO: 316). 
     In some embodiments, the CM comprises the amino acid sequence NTLSGRSENHSG (SEQ ID NO: 298). In some embodiments, the CM comprises the amino acid sequence NTLSGRSGNHGS (SEQ ID NO: 299). In some embodiments, the CM comprises the amino acid sequence TSTSGRSANPRG (SEQ ID NO: 300). In some embodiments, the CM comprises the amino acid sequence TSGRSANP (SEQ ID NO: 301). In some embodiments, the CM comprises the amino acid sequence VAGRSMRP (SEQ ID NO: 310). In some embodiments, the CM comprises the amino acid sequence VVPEGRRS (SEQ ID NO: 311). In some embodiments, the CM comprises the amino acid sequence ILPRSPAF (SEQ ID NO: 312). In some embodiments, the CM comprises the amino acid sequence MVLGRSLL (SEQ ID NO: 313). In some embodiments, the CM comprises the amino acid sequence QGRAITFI (SEQ ID NO: 314). In some embodiments, the CM comprises the amino acid sequence SPRSIMLA (SEQ ID NO: 315). In some embodiments, the CM comprises the amino acid sequence SMLRSMPL (SEQ ID NO: 316). 
     In some embodiments, the CM comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 214, 294-361, 1092-1112, 1157, 1158, 1161, 1162, 1165, 1166, 1169, 1520, and 1695-1704. In some embodiments, the CM comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 214, 294, 300, 302, 303, 305, 308, 318, 347, 361, 1092-1102, 1111, and 1157. 
     In some embodiments, the CM is a substrate for a neutrophil elastase. In some embodiments, the CM is a substrate for a serine protease. In some embodiments, the CM is a substrate for uPA. In some embodiments, the CM is a substrate for legumain. In some embodiments, the CM is a substrate for matriptase. In some embodiments, the CM is a substrate for a cysteine protease. In some embodiments, the CM is a substrate for a cysteine protease, such as a cathepsin. 
     In some embodiments, the CM is a CM1-CM2 substrate and includes the sequence ISSGLLSGRSDNH (SEQ ID NO: 214); ISSGLLSSGGSGGSLSGRSDNH (SEQ ID NO: 346); AVGLLAPPGGTSTSGRSANPRG (SEQ ID NO: 347); TSTSGRSANPRGGGAVGLLAPP (SEQ ID NO: 348); VHMPLGFLGPGGTSTSGRSANPRG (SEQ ID NO: 349); TSTSGRSANPRGGGVHMPLGFLGP (SEQ ID NO: 350); AVGLLAPPGGLSGRSDNH (SEQ ID NO: 318); LSGRSDNHGGAVGLLAPP (SEQ ID NO: 351); VHMPLGFLGPGGLSGRSDNH (SEQ ID NO: 352); LSGRSDNHGGVHMPLGFLGP (SEQ ID NO: 353); LSGRSDNHGGSGGSISSGLLSS (SEQ ID NO: 354); LSGRSGNHGGSGGSISSGLLSS (SEQ ID NO: 355); ISSGLLSSGGSGGSLSGRSGNH (SEQ ID NO: 356); LSGRSDNHGGSGGSQNQALRMA (SEQ ID NO: 357); QNQALRMAGGSGGSLSGRSDNH (SEQ ID NO: 358); LSGRSGNHGGSGGSQNQALRMA (SEQ ID NO: 359); QNQALRMAGGSGGSLSGRSGNH (SEQ ID NO: 360); ISSGLLSGRSGNH (SEQ ID NO: 361); ISSGLLSGRSANPRG (SEQ ID NO: 1092); AVGLLAPPTSGRSANPRG (SEQ ID NO: 1093); AVGLLAPPSGRSANPRG (SEQ ID NO: 1094); ISSGLLSGRSDDH (SEQ ID NO: 1095); ISSGLLSGRSDIH (SEQ ID NO: 1096); ISSGLLSGRSDQH (SEQ ID NO: 1097); ISSGLLSGRSDTH (SEQ ID NO: 1098); ISSGLLSGRSDDH (SEQ ID NO: 1099); ISSGLLSGRSDNP (SEQ ID NO: 1100); ISSGLLSGRSANP (SEQ ID NO: 1101); ISSGLLSGRSANI (SEQ ID NO: 1102); AVGLLAPPGGLSGRSDDH (SEQ ID NO: 1103); AVGLLAPPGGLSGRSDIH (SEQ ID NO: 1104); AVGLLAPPGGLSGRSDQH (SEQ ID NO: 1105); AVGLLAPPGGLSGRSDTH (SEQ ID NO: 1106); AVGLLAPPGGLSGRSDDH (SEQ ID NO: 1107); AVGLLAPPGGLSGRSDNP (SEQ ID NO: 1108); AVGLLAPPGGLSGRSANP (SEQ ID NO: 1109); AVGLLAPPGGLSGRSANI (SEQ ID NO: 1110); ISSGLLSGRSDNI (SEQ ID NO: 1111); and/or AVGLLAPPGGLSGRSDNI (SEQ ID NO: 1112). 
     In some embodiments, the CM1-CM2 substrate includes the sequence ISSGLLSGRSDNH (SEQ ID NO: 214), which is also referred to herein as substrate 2001. In some embodiments, the CM1-CM2 substrate includes the sequence ISSGLLSSGGSGGSLSGRSDNH (SEQ ID NO: 346), which is also referred to herein as substrate 1001/LP′/0001, where LP′ as used in this CM1-CM2 substrate is the amino acid sequence GGSGGS (SEQ ID NO: 1519). In some embodiments, the CM1-CM2 substrate includes the sequence AVGLLAPPGGTSTSGRSANPRG (SEQ ID NO: 347), which is also referred to herein as substrate 1004/LP′/0003, where LP′ as used in this CM1-CM2 substrate is the amino acid sequence GG. In some embodiments, the CM1-CM2 substrate includes the sequence TSTSGRSANPRGGGAVGLLAPP (SEQ ID NO: 348), which is also referred to herein as substrate 0003/LP′/1004, where LP′ as used in this CM1-CM2 substrate is the amino acid sequence GG. In some embodiments, the CM1-CM2 substrate includes the sequence VHMPLGFLGPGGTSTSGRSANPRG (SEQ ID NO: 349), which is also referred to herein as substrate 1003/LP′/0003, where LP′ as used in this CM1-CM2 substrate is the amino acid sequence GG. In some embodiments, the CM1-CM2 substrate includes the sequence TSTSGRSANPRGGGVHMPLGFLGP (SEQ ID NO: 350), which is also referred to herein as substrate 0003/LP′/1003, where LP′ as used in this CM1-CM2 substrate is the amino acid sequence GG. In some embodiments, the CM1-CM2 substrate includes the sequence AVGLLAPPGGLSGRSDNH (SEQ ID NO: 318), which is also referred to herein as substrate 1004/LP′/0001, where LP′ as used in this CM1-CM2 substrate is the amino acid sequence GG. In some embodiments, the CM1-CM2 substrate includes the sequence LSGRSDNHGGAVGLLAPP (SEQ ID NO: 351), which is also referred to herein as substrate 0001/LP′/1004, where LP′ as used in this CM1-CM2 substrate is the amino acid sequence GG. In some embodiments, the CM1-CM2 substrate includes the sequence VHMPLGFLGPGGLSGRSDNH (SEQ ID NO: 352), which is also referred to herein as substrate 1003/LP′/0001, where LP′ as used in this CM1-CM2 substrate is the amino acid sequence GG. In some embodiments, the CM1-CM2 substrate includes the sequence LSGRSDNHGGVHMPLGFLGP (SEQ ID NO: 353), which is also referred to herein as substrate 0001/LP′/1003, where LP′ as used in this CM1-CM2 substrate is the amino acid sequence GG. In some embodiments, the CM1-CM2 substrate includes the sequence LSGRSDNHGGSGGSISSGLLSS (SEQ ID NO: 354), which is also referred to herein as substrate 0001/LP′/1001, where LP′ as used in this CM1-CM2 substrate is the amino acid sequence GGSGGS (SEQ ID NO: 1519). In some embodiments, the CM1-CM2 substrate includes the sequence LSGRSGNHGGSGGSISSGLLSS (SEQ ID NO: 355), which is also referred to herein as substrate 0002/LP′/1001, where LP′ as used in this CM1-CM2 substrate is the amino acid sequence GGSGGS (SEQ ID NO: 1519). In some embodiments, the CM1-CM2 substrate includes the sequence ISSGLLSSGGSGGSLSGRSGNH (SEQ ID NO: 356), which is also referred to herein as substrate 1001/LP′/0002, where LP′ as used in this CM1-CM2 substrate is the amino acid sequence GGSGGS (SEQ ID NO: 1519). In some embodiments, the CM1-CM2 substrate includes the sequence LSGRSDNHGGSGGSQNQALRMA (SEQ ID NO: 357), which is also referred to herein as substrate 0001/LP′/1002, where LP′ as used in this CM1-CM2 substrate is the amino acid sequence GGSGGS (SEQ ID NO: 1519). In some embodiments, the CM1-CM2 substrate includes the sequence QNQALRMAGGSGGSLSGRSDNH (SEQ ID NO: 358), which is also referred to herein as substrate 1002/LP′/0001, where LP′ as used in this CM1-CM2 substrate is the amino acid sequence GGSGGS (SEQ ID NO: 1519). In some embodiments, the CM1-CM2 substrate includes the sequence LSGRSGNHGGSGGSQNQALRMA (SEQ ID NO: 359), which is also referred to herein as substrate 0002/LP′/1002, where LP′ as used in this CM1-CM2 substrate is the amino acid sequence GGSGGS (SEQ ID NO: 1519). In some embodiments, the CM1-CM2 substrate includes the sequence QNQALRMAGGSGGSLSGRSGNH (SEQ ID NO: 360), which is also referred to herein as substrate 1002/LP′/0002, where LP′ as used in this CM1-CM2 substrate is the amino acid sequence GGSGGS (SEQ ID NO: 1519). In some embodiments, the CM1-CM2 substrate includes the sequence ISSGLLSGRSGNH (SEQ ID NO: 361), which is also referred to herein as substrate 2002. In some embodiments, the CM1-CM2 substrate includes the sequence ISSGLLSGRSANPRG (SEQ ID NO: 1092), which is also referred to herein as substrate 2003. In some embodiments, the CM1-CM2 substrate includes the sequence AVGLLAPPTSGRSANPRG (SEQ ID NO: 1093), which is also referred to herein as substrate 2004. In some embodiments, the CM1-CM2 substrate includes the sequence AVGLLAPPSGRSANPRG (SEQ ID NO: 1094), which is also referred to herein as substrate 2005. In some embodiments, the CM1-CM2 substrate includes the sequence ISSGLLSGRSDDH (SEQ ID NO: 1095), which is also referred to herein as substrate 2006. In some embodiments, the CM1-CM2 substrate includes the sequence ISSGLLSGRSDIH (SEQ ID NO: 1096), which is also referred to herein as substrate 2007. In some embodiments, the CM1-CM2 substrate includes the sequence ISSGLLSGRSDQH (SEQ ID NO: 1097), which is also referred to herein as substrate 2008. In some embodiments, the CM1-CM2 substrate includes the sequence ISSGLLSGRSDTH (SEQ ID NO: 1098), which is also referred to herein as substrate 2009. In some embodiments, the CM1-CM2 substrate includes the sequence ISSGLLSGRSDDH (SEQ ID NO: 1099), which is also referred to herein as substrate 2010. In some embodiments, the CM1-CM2 substrate includes the sequence ISSGLLSGRSDNP (SEQ ID NO: 1100), which is also referred to herein as substrate 2011. In some embodiments, the CM1-CM2 substrate includes the sequence ISSGLLSGRSANP (SEQ ID NO: 1101), which is also referred to herein as substrate 2012. In some embodiments, the CM1-CM2 substrate includes the sequence ISSGLLSGRSANI (SEQ ID NO: 1102), which is also referred to herein as substrate 2013. In some embodiments, the CM1-CM2 substrate includes the sequence AVGLLAPPGGLSGRSDDH (SEQ ID NO: 1103), which is also referred to herein as substrate 3006. In some embodiments, the CM1-CM2 substrate includes the sequence AVGLLAPPGGLSGRSDIH (SEQ ID NO: 1104), which is also referred to herein as substrate 3007. In some embodiments, the CM1-CM2 substrate includes the sequence AVGLLAPPGGLSGRSDQH (SEQ ID NO: 1105), which is also referred to herein as substrate 3008. In some embodiments, the CM1-CM2 substrate includes the sequence AVGLLAPPGGLSGRSDTH (SEQ ID NO: 1106), which is also referred to herein as substrate 3009. In some embodiments, the CM1-CM2 substrate includes the sequence AVGLLAPPGGLSGRSDDH (SEQ ID NO: 1107), which is also referred to herein as substrate 3010. In some embodiments, the CM1-CM2 substrate includes the sequence AVGLLAPPGGLSGRSDNP (SEQ ID NO: 1108), which is also referred to herein as substrate 3011. In some embodiments, the CM1-CM2 substrate includes the sequence AVGLLAPPGGLSGRSANP (SEQ ID NO: 1109), which is also referred to herein as substrate 3012. In some embodiments, the CM1-CM2 substrate includes the sequence AVGLLAPPGGLSGRSANI (SEQ ID NO: 1110), which is also referred to herein as substrate 3013. In some embodiments, the CM1-CM2 substrate includes the sequence ISSGLLSGRSDNI (SEQ ID NO: 1111), which is also referred to herein as substrate 2014. In some embodiments, the CM1-CM2 substrate includes the sequence and/or AVGLLAPPGGLSGRSDNI (SEQ ID NO: 1112), which is also referred to herein as substrate 3014. In some embodiments, the CM1-CM2 substrate includes the sequence GLSGRSDNHGGAVGLLAPP (SEQ ID NO: 1970), which is also referred to herein as substrate 0001/LP′/1004, where LP′ as used in this CM1-CM2 substrate is the amino acid sequence GG. In some embodiments, the CM1-CM2 substrate includes the sequence GLSGRSDNHGGVHMPLGFLGP (SEQ ID NO: 1971), which is also referred to herein as substrate 0001/LP′/1003, where LP′ as used in this CM1-CM2 substrate is the amino acid sequence GG. 
     In some embodiments, the CM is a substrate for at least two proteases. In some embodiments, each protease is selected from the group consisting of those shown in Table 3. In some embodiments, the CM is a substrate for at least two proteases, wherein one of the proteases is selected from the group consisting of a MMP, thrombin, a neutrophil elastase, a cysteine protease, uPA, legumain and matriptase and the other protease is selected from the group consisting of those shown in Table 3. In some embodiments, the CM is a substrate for at least two proteases selected from the group consisting of a MMP, thrombin, a neutrophil elastase, a cysteine protease, uPA, legumain and matriptase. 
     In some embodiments, the activatable antibody includes at least a first CM and a second CM. In some embodiments, the first CM and the second CM are each polypeptides of no more than 15 amino acids long. In some embodiments, the first CM and the second CM in the activatable antibody in the uncleaved state have the structural arrangement from N-terminus to C-terminus as follows: MM-CM1-CM2-AB or AB-CM2-CM1-MM. In some embodiments, at least one of the first CM and the second CM is a polypeptide that functions as a substrate for a protease selected from the group consisting of a MMP, thrombin, a neutrophil elastase, a cysteine protease, uPA, legumain, and matriptase. In some embodiments, the first CM is cleaved by a first cleaving agent selected from the group consisting of a MMP, thrombin, a neutrophil elastase, a cysteine protease, uPA, legumain, and matriptase in a target tissue and the second CM is cleaved by a second cleaving agent in a target tissue. In some embodiments, the other protease is selected from the group consisting of those shown in Table 3. In some embodiments, the first cleaving agent and the second cleaving agent are the same protease selected from the group consisting of a MMP, thrombin, a neutrophil elastase, a cysteine protease, uPA, legumain, and matriptase, and the first CM and the second CM are different substrates for the enzyme. In some embodiments, the first cleaving agent and the second cleaving agent are the same protease selected from the group consisting of those shown in Table 3. In some embodiments, the first cleaving agent and the second cleaving agent are different proteases. In some embodiments, the first cleaving agent and the second cleaving agent are co-localized in the target tissue. In some embodiments, the first CM and the second CM are cleaved by at least one cleaving agent in the target tissue. 
     In some embodiments, the activatable antibody is exposed to and cleaved by a protease such that, in the activated or cleaved state, the activated antibody includes a light chain amino acid sequence that includes at least a portion of LP2 and/or CM sequence after the protease has cleaved the CM. 
     In some embodiments, the activatable antibody also includes an agent conjugated to the AB. In some embodiments, the agent conjugated to the AB or the AB of an activatable antibody is a therapeutic agent. In some embodiments, the agent is conjugated to the AB via a cleavable linker. In some embodiments, the agent is conjugated to the AB via a linker that includes at least one CM1-CM2 substrate sequence. In some embodiments, the agent is conjugated to the AB via a noncleavable linker. 
     In some embodiments, the agent is an anti-inflammatory agent. 
     In some embodiments, the activatable antibody also includes a detectable moiety. In some embodiments, the detectable moiety is a diagnostic agent. 
     In some embodiments, the activatable antibody also includes a signal peptide. In some embodiments, the signal peptide is conjugated to the activatable antibody via a spacer. In some embodiments, the spacer is conjugated to the activatable antibody in the absence of a signal peptide. In some embodiments, the spacer is joined directly to the MM of the activatable antibody. In some embodiments, the spacer is joined directly to the MM of the activatable antibody in the structural arrangement from N-terminus to C-terminus of spacer-MM-CM-AB. An example of a spacer joined directly to the N-terminus of MM of the activatable antibody is selected from the group consisting of QGQSGQG (SEQ ID NO: 362), QGQSGQ (SEQ ID NO: 913), QGQSG (SEQ ID NO: 914), QGQS (SEQ ID NO: 915), QGQ (SEQ ID NO: 916), QG (SEQ ID NO: 917), and Q. Additional examples of spacers include GQSGQG (SEQ ID NO: 2042), QSGQG (SEQ ID NO: 2043), SGQG (SEQ ID NO: 2044), GQG(SEQ ID NO: 2045), QG(SEQ ID NO: 2046), and G. In some embodiments, the spacer includes at least the amino acid sequence QGQSGQG (SEQ ID NO: 362). In some embodiments, the spacer includes at least the amino acid sequence QGQSGQ (SEQ ID NO: 913). In some embodiments, the spacer includes at least the amino acid sequence QGQSG (SEQ ID NO: 914). In some embodiments, the spacer includes at least the amino acid sequence QGQS (SEQ ID NO: 915), In some embodiments, the spacer includes at least the amino acid sequence QGQ (SEQ ID NO: 916). In some embodiments, the spacer includes at least the amino acid sequence QG (SEQ ID NO: 917). In some embodiments, the spacer includes at least the amino acid residue Q. In some embodiments, the spacer includes at least the amino acid sequence GQSGQG (SEQ ID NO: 2042). In some embodiments, the spacer includes at least the amino acid sequence QSGQG (SEQ ID NO: 2043). In some embodiments, the spacer includes at least the amino acid sequence SGQG (SEQ ID NO: 2044). In some embodiments, the spacer includes at least the amino acid sequence GQG(SEQ ID NO: 2045). In some embodiments, the spacer includes at least the amino acid sequence QG (SEQ ID NO: 2046). In some embodiments, the spacer includes at least the amino acid sequence G. In some embodiments, the activatable antibody does not include a spacer sequence. 
     In some embodiments, the AB of the activatable antibody naturally contains one or more disulfide bonds. In some embodiments, the AB can be engineered to include one or more disulfide bonds. 
     In some embodiments, the serum half-life of the activatable antibody is longer than that of the corresponding antibody; e.g., the pK of the activatable antibody is longer than that of the corresponding antibody. In some embodiments, the serum half-life of the activatable antibody is similar to that of the corresponding antibody. In some embodiments, the serum half-life of the activatable antibody is at least 15 days when administered to an organism. In some embodiments, the serum half-life of the activatable antibody is at least 12 days when administered to an organism. In some embodiments, the serum half-life of the activatable antibody is at least 11 days when administered to an organism. In some embodiments, the serum half-life of the activatable antibody is at least 10 days when administered to an organism. In some embodiments, the serum half-life of the activatable antibody is at least 9 days when administered to an organism. In some embodiments, the serum half-life of the activatable antibody is at least 8 days when administered to an organism. In some embodiments, the serum half-life of the activatable antibody is at least 7 days when administered to an organism. In some embodiments, the serum half-life of the activatable antibody is at least 6 days when administered to an organism. In some embodiments, the serum half-life of the activatable antibody is at least 5 days when administered to an organism. In some embodiments, the serum half-life of the activatable antibody is at least 4 days when administered to an organism. In some embodiments, the serum half-life of the activatable antibody is at least 3 days when administered to an organism. In some embodiments, the serum half-life of the activatable antibody is at least 2 days when administered to an organism. In some embodiments, the serum half-life of the activatable antibody is at least 24 hours when administered to an organism. In some embodiments, the serum half-life of the activatable antibody is at least 20 hours when administered to an organism. In some embodiments, the serum half-life of the activatable antibody is at least 18 hours when administered to an organism. In some embodiments, the serum half-life of the activatable antibody is at least 16 hours when administered to an organism. In some embodiments, the serum half-life of the activatable antibody is at least 14 hours when administered to an organism. In some embodiments, the serum half-life of the activatable antibody is at least 12 hours when administered to an organism. In some embodiments, the serum half-life of the activatable antibody is at least 10 hours when administered to an organism. In some embodiments, the serum half-life of the activatable antibody is at least 8 hours when administered to an organism. In some embodiments, the serum half-life of the activatable antibody is at least 6 hours when administered to an organism. In some embodiments, the serum half-life of the activatable antibody is at least 4 hours when administered to an organism. In some embodiments, the serum half-life of the activatable antibody is at least 3 hours when administered to an organism. 
     In some embodiments, the activatable anti-PD-1 antibody is monospecific. 
     In some embodiments, the activatable anti-PD-1 antibody is multispecific, e.g., by way of non-limiting example, bispecific or trifunctional. In some embodiments, the activatable anti-PD-1 antibody is formulated as part of a pro-Bispecific T Cell Engager (BITE) molecule, i.e., the BITE includes a masking moiety and a cleavable moiety. In some embodiments, the activatable anti-PD-1 antibody is formulated as part of a pro-Chimeric Antigen Receptor (CAR) modified T cell, modified NK cell, or other modified immune effector cell. In some embodiments, an activatable anti-PD-1 antibody is formulated as part of another engineered receptor on an immune effector cell; i.e., the pro-CAR or other pro-engineered receptor includes a masking moiety and a cleavable moiety. 
     In some embodiments, the activatable antibody or antigen-binding fragment thereof is incorporated in a multispecific activatable antibody or antigen-binding fragment thereof, where at least one arm of the multispecific activatable antibody specifically binds PD-1. In some embodiments, the activatable antibody or antigen-binding fragment thereof is incorporated in a bispecific activatable antibody or antigen-binding fragment thereof, where at least one arm of the bispecific activatable antibody specifically binds PD-1. 
     In some embodiments, at least one arm of the multispecific activatable antibody, e.g., a bispecific activatable antibody, comprises a heavy chain amino acid sequence selected from the group consisting of SEQ ID NO: 1, 5, 9, 13, 17, 21, 23, 25, 27, 29, 31, 33, 35, and 37. In some embodiments, at least one arm of the multispecific activatable antibody, e.g., a bispecific activatable antibody, comprises a heavy chain amino acid sequence selected from the group consisting of SEQ ID NO: 21, 23, 25, 27, 29, 31, 33, 35, and 37. 
     In some embodiments, at least one arm of the multispecific activatable antibody, e.g., a bispecific activatable antibody, comprises a light chain amino acid sequence selected from the group consisting of SEQ ID NO: 3, 7, 11, 15, 19, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59. In some embodiments, at least one arm of the multispecific activatable antibody, e.g., a bispecific activatable antibody, comprises a light chain amino acid sequence selected from the group consisting of SEQ ID NO: 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59. 
     In some embodiments, at least one arm of the multispecific activatable antibody, e.g., a bispecific activatable antibody, a heavy chain amino acid sequence comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 1, 5, 9, 13, 17, 21, 23, 25, 27, 29, 31, 33, 35, and 37, and a light chain amino acid sequence selected from the group consisting of SEQ ID NO: 3, 7, 11, 15, 19, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59. In some embodiments, at least one arm of the multispecific activatable antibody, e.g., a bispecific activatable antibody, a heavy chain amino acid sequence comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 21, 23, 25, 27, 29, 31, 33, 35, and 37, and a light chain amino acid sequence selected from the group consisting of SEQ ID NO: 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59. In some embodiments, at least one arm of the multispecific activatable antibody, e.g., a bispecific activatable antibody, includes a heavy chain that comprises or is derived from amino acid sequence SEQ ID NO: 21. In some embodiments, at least one arm of the multispecific activatable antibody, e.g., a bispecific activatable antibody, includes a light chain that comprises or is derived from amino acid sequence SEQ ID NO: 45 or SEQ ID NO: 47. In some embodiments, at least one arm of the multispecific activatable antibody, e.g., a bispecific activatable antibody, includes a heavy chain that comprises or is derived from amino acid sequence SEQ ID NO: 21 and a light chain that comprises or is derived from amino acid sequence SEQ ID NO: 45 or SEQ ID NO: 47. In some embodiments, at least one arm of the multispecific activatable antibody, e.g., a bispecific activatable antibody, includes a heavy chain that comprises or is derived from amino acid sequence SEQ ID NO: 21 and a light chain that comprises or is derived from amino acid sequence SEQ ID NO: 45. In some embodiments, at least one arm of the multispecific activatable antibody, e.g., a bispecific activatable antibody, includes a heavy chain that comprises or is derived from amino acid sequence SEQ ID NO: 21 and a light chain that comprises or is derived from amino acid sequence SEQ ID NO: 47. 
     In some embodiments, at least one arm of the multispecific activatable antibody, e.g., a bispecific activatable antibody, includes the combination of the complementarity determining region (CDR) sequences of the heavy chain amino acid sequence of SEQ ID NO: 21. In some embodiments, at least one arm of the multispecific activatable antibody, e.g., a bispecific activatable antibody, includes the combination of the CDR sequences of the light chain amino acid sequence of SEQ ID NO: 45 or of SEQ ID NO: 47. In some embodiments, at least one arm of the multispecific activatable antibody, e.g., a bispecific activatable antibody, includes a combination of the CDR sequences of the heavy chain amino acid sequence of SEQ ID NO: 21, and the CDR sequences of the light chain amino acid sequence of SEQ ID NO: 45 or 47. In some embodiments, at least one arm of the multispecific activatable antibody, e.g., a bispecific activatable antibody, includes a combination of the CDR sequences of the heavy chain amino acid sequence of SEQ ID NO: 21, and the CDR sequences of the light chain amino acid sequence of SEQ ID NO: 45. In some embodiments, at least one arm of the multispecific activatable antibody, e.g., a bispecific activatable antibody, includes a combination of the CDR sequences of the heavy chain amino acid sequence of SEQ ID NO: 21, and the CDR sequences of the light chain amino acid sequence of SEQ ID NO: 47. 
     In some embodiments, at least one arm of the multispecific activatable antibody, e.g., a bispecific activatable antibody includes: (a) a variable heavy chain complementarity determining region 1 (VH CDR1) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 653-657; (b) a variable heavy chain complementarity determining region 2 (VH CDR2) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 658-663; (c) a variable heavy chain complementarity determining region 3 (VH CDR3) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 664-668; (d) a variable light chain complementarity determining region 1 (VL CDR1) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 669-677; (e) a variable light chain complementarity determining region 2 (VL CDR2) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 678-682; and (f) variable light chain complementarity determining region 3 (VL CDR3) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 683-687 
     In some embodiments, at least one arm of the multispecific activatable antibody, e.g., a bispecific activatable antibody, includes a combination of a variable heavy chain complementarity determining region 1 (VH CDR1, also referred to herein as CDRH1) sequence, a variable heavy chain complementarity determining region 2 (VH CDR2, also referred to herein as CDRH2) sequence, and a variable heavy chain complementarity determining region 3 (VH CDR3, also referred to herein as CDRH3) sequence, wherein the VH CDR1 sequence comprises GFTFSGYAMS (SEQ ID NO: 653); the VH CDR2 sequence comprises YISNSGGNAH (SEQ ID NO: 658); and the VH CDR3 sequence comprises EDYGTSPFVY (SEQ ID NO: 664). 
     In some embodiments, at least one arm of the multispecific activatable antibody, e.g., a bispecific activatable antibody, includes a combination of a variable light chain complementarity determining region 1 (VL CDR1, also referred to herein as CDRL1) sequence, a variable light chain complementarity determining region 2 (VL CDR2, also referred to herein as CDRL2) sequence, and a variable light chain complementarity determining region 3 (VL CDR3, also referred to herein as CDRL3) sequence, wherein the VL CDR1 sequence comprises RASESVDSYGISFMN (SEQ ID NO: 675) or RASESVDAYGISFMN (SEQ ID NO:676); the VL CDR2 sequence comprises AASNQGS (SEQ ID NO: 678); and the VL CDR3 sequence comprises QQSKDVPWT (SEQ ID NO: 683). In some embodiments, at least one arm of the multispecific activatable antibody, e.g., a bispecific activatable antibody, includes a combination of a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the VL CDR1 sequence comprises RASESVDSYGISFMN (SEQ ID NO: 675); the VL CDR2 sequence comprises AASNQGS (SEQ ID NO: 678); and the VL CDR3 sequence comprises QQSKDVPWT (SEQ ID NO: 683). In some embodiments, at least one arm of the multispecific activatable antibody, e.g., a bispecific activatable antibody, includes a combination of a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the VL CDR1 sequence comprises RASESVDAYGISFMN (SEQ ID NO:676); the VL CDR2 sequence comprises AASNQGS (SEQ ID NO: 678); and the VL CDR3 sequence comprises QQSKDVPWT (SEQ ID NO: 683). 
     In some embodiments, at least one arm of the multispecific activatable antibody, e.g., a bispecific activatable antibody, includes a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the VH CDR1 sequence comprises GFTFSGYAMS (SEQ ID NO: 653); the VH CDR2 sequence comprises YISNSGGNAH (SEQ ID NO: 658); and the VH CDR3 sequence comprises EDYGTSPFVY (SEQ ID NO: 664); the VL CDR1 sequence comprises RASESVDSYGISFMN (SEQ ID NO: 675) or RASESVDAYGISFMN (SEQ ID NO:676); the VL CDR2 sequence comprises AASNQGS (SEQ ID NO: 678); and the VL CDR3 sequence comprises QQSKDVPWT (SEQ ID NO: 683). In some embodiments, at least one arm of the multispecific activatable antibody, e.g., a bispecific activatable antibody, includes a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the VH CDR1 sequence comprises GFTFSGYAMS (SEQ ID NO: 653); the VH CDR2 sequence comprises YISNSGGNAH (SEQ ID NO: 658); and the VH CDR3 sequence comprises EDYGTSPFVY (SEQ ID NO: 664); the VL CDR1 sequence comprises RASESVDSYGISFMN (SEQ ID NO: 675); the VL CDR2 sequence comprises AASNQGS (SEQ ID NO: 678); and the VL CDR3 sequence comprises QQSKDVPWT (SEQ ID NO: 683). In some embodiments, at least one arm of the multispecific activatable antibody, e.g., a bispecific activatable antibody, includes a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the VH CDR1 sequence comprises GFTFSGYAMS (SEQ ID NO: 653); the VH CDR2 sequence comprises YISNSGGNAH (SEQ ID NO: 658); and the VH CDR3 sequence comprises EDYGTSPFVY (SEQ ID NO: 664); the VL CDR1 sequence comprises RASESVDAYGISFMN (SEQ ID NO:676); the VL CDR2 sequence comprises AASNQGS (SEQ ID NO: 678); and the VL CDR3 sequence comprises QQSKDVPWT (SEQ ID NO: 683). 
     In some embodiments, at least one arm of the multispecific activatable antibody, e.g., a bispecific activatable antibody, includes a heavy chain that comprises or is derived from the amino acid sequence of SEQ ID NO: 1346, and a light chain that comprises or is derived from the amino acid sequence of SEQ ID NO: 626. 
     In some embodiments, at least one arm of the multispecific activatable antibody, e.g., a bispecific activatable antibody, includes a heavy chain that comprises or is derived from the amino acid sequence of SEQ ID NO: 1514, and a light chain that comprises or is derived from the amino acid sequence of SEQ ID NO: 638. 
     In some embodiments, at least one arm of the multispecific activatable antibody, e.g., a bispecific activatable antibody, includes the combination of the complementarity determining region (CDR) sequences of the heavy chain amino acid sequence of SEQ ID NO: 1346. In some embodiments, at least one arm of the multispecific activatable antibody, e.g., a bispecific activatable antibody, includes the combination of the CDR sequences of the light chain amino acid sequence of SEQ ID NO: 626. In some embodiments, at least one arm of the multispecific activatable antibody, e.g., a bispecific activatable antibody, includes a combination of the CDR sequences of the heavy chain amino acid sequence of SEQ ID NO: 1346, and the CDR sequences of the light chain amino acid sequence of SEQ ID NO: 626. 
     In some embodiments, at least one arm of the multispecific activatable antibody, e.g., a bispecific activatable antibody, includes a combination of a variable heavy chain complementarity determining region 1 (VH CDR1, also referred to herein as CDRH1) sequence, a variable heavy chain complementarity determining region 2 (VH CDR2, also referred to herein as CDRH2) sequence, and a variable heavy chain complementarity determining region 3 (VH CDR3, also referred to herein as CDRH3) sequence, wherein the VH CDR1 sequence comprises GITFSNSG (SEQ ID NO: 1705); the VH CDR2 sequence comprises IWYDGSKR (SEQ ID NO: 1706); and the VH CDR3 sequence comprises TNDDY (SEQ ID NO: 1707). 
     In some embodiments, at least one arm of the multispecific activatable antibody, e.g., a bispecific activatable antibody, includes a combination of a variable light chain complementarity determining region 1 (VL CDR1, also referred to herein as CDRL1) sequence, a variable light chain complementarity determining region 2 (VL CDR2, also referred to herein as CDRL2) sequence, and a variable light chain complementarity determining region 3 (VL CDR3, also referred to herein as CDRL3) sequence, wherein the VL CDR1 sequence comprises QSVSSY (SEQ ID NO: 1708); the VL CDR2 sequence comprises DAS (SEQ ID NO: 1709); and the VL CDR3 sequence comprises QQSSNWPRT (SEQ ID NO: 1710). 
     In some embodiments, at least one arm of the multispecific activatable antibody, e.g., a bispecific activatable antibody, includes a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the VH CDR1 sequence comprises GITFSNSG (SEQ ID NO: 1705); the VH CDR2 sequence comprises IWYDGSKR (SEQ ID NO: 1706); the VH CDR3 sequence comprises TNDDY (SEQ ID NO: 1707); the VL CDR1 sequence comprises QSVSSY (SEQ ID NO: 1708); the VL CDR2 sequence comprises DAS (SEQ ID NO: 1709); and the VL CDR3 sequence comprises QQSSNWPRT (SEQ ID NO: 1710). 
     In some embodiments, at least one arm of the multispecific activatable antibody, e.g., a bispecific activatable antibody, includes the combination of the complementarity determining region (CDR) sequences of the heavy chain amino acid sequence of SEQ ID NO: 1514. In some embodiments, at least one arm of the multispecific activatable antibody, e.g., a bispecific activatable antibody, includes the combination of the CDR sequences of the light chain amino acid sequence of SEQ ID NO: 638. In some embodiments, at least one arm of the multispecific activatable antibody, e.g., a bispecific activatable antibody, includes a combination of the CDR sequences of the heavy chain amino acid sequence of SEQ ID NO: 1514, and the CDR sequences of the light chain amino acid sequence of SEQ ID NO: 638. 
     In some embodiments, at least one arm of the multispecific activatable antibody, e.g., a bispecific activatable antibody, includes a combination of a variable heavy chain complementarity determining region 1 (VH CDR1, also referred to herein as CDRH1) sequence, a variable heavy chain complementarity determining region 2 (VH CDR2, also referred to herein as CDRH2) sequence, and a variable heavy chain complementarity determining region 3 (VH CDR3, also referred to herein as CDRH3) sequence, wherein the VH CDR1 sequence comprises GYTFTNYY (SEQ ID NO: 1711); the VH CDR2 sequence comprises INPSNGGT (SEQ ID NO: 1712); and the VH CDR3 sequence comprises RRDYRFDMGFDY (SEQ ID NO: 1713). 
     In some embodiments, at least one arm of the multispecific activatable antibody, e.g., a bispecific activatable antibody, includes a combination of a variable light chain complementarity determining region 1 (VL CDR1, also referred to herein as CDRL1) sequence, a variable light chain complementarity determining region 2 (VL CDR2, also referred to herein as CDRL2) sequence, and a variable light chain complementarity determining region 3 (VL CDR3, also referred to herein as CDRL3) sequence, wherein the VL CDR1 sequence comprises KGVSTSGYSY (SEQ ID NO: 1714); the VL CDR2 sequence comprises LAS (SEQ ID NO: 1715); and the VL CDR3 sequence comprises QHSRDLPLT (SEQ ID NO: 1716). 
     In some embodiments, at least one arm of the multispecific activatable antibody, e.g., a bispecific activatable antibody, includes a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the VH CDR1 sequence comprises GYTFTNYY (SEQ ID NO: 1711); the VH CDR2 sequence comprises INPSNGGT (SEQ ID NO: 1712); the VH CDR3 sequence comprises RRDYRFDMGFDY (SEQ ID NO: 1713); the VL CDR1 sequence comprises KGVSTSGYSY (SEQ ID NO: 1714); the VL CDR2 sequence comprises LAS (SEQ ID NO: 1715); and the VL CDR3 sequence comprises QHSRDLPLT (SEQ ID NO: 1716). 
     In some embodiments, at least one arm of the multispecific activatable antibody, e.g., a bispecific activatable antibody, comprises a heavy chain amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NO: 1, 5, 9, 13, 17, 21, 23, 25, 27, 29, 31, 33, 35, and 37. In some embodiments, at least one arm of the multispecific activatable antibody, e.g., a bispecific activatable antibody, comprises a heavy chain amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NO: 21, 23, 25, 27, 29, 31, 33, 35, and 37. 
     In some embodiments, at least one arm of the multispecific activatable antibody, e.g., a bispecific activatable antibody, comprises a light chain amino acid that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NO: 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59. 
     In some embodiments, at least one arm of the multispecific activatable antibody, e.g., a bispecific activatable antibody, comprises a heavy chain amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NO: 1, 5, 9, 13, 17, 21, 23, 25, 27, 29, 31, 33, 35, and 37, and a light chain amino acid that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NO: 3, 7, 11, 15, 19, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59. In some embodiments, at least one arm of the multispecific activatable antibody, e.g., a bispecific activatable antibody, comprises a heavy chain amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NO: 21, 23, 25, 27, 29, 31, 33, 35, and 37, and a light chain amino acid that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NO: 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59. 
     In some embodiments, at least one arm of the multispecific activatable antibody, e.g., a bispecific activatable antibody, includes a heavy chain amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 1346, and a light chain amino acid that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 626. 
     In some embodiments, at least one arm of the multispecific activatable antibody, e.g., a bispecific activatable antibody, includes a heavy chain amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 1514, and a light chain amino acid that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 638. 
     In some embodiments, at least one arm of the multispecific activatable antibody, e.g., a bispecific activatable antibody, comprises a combination of a variable heavy chain complementarity determining region 1 (VH CDR1, also referred to herein as CDRH1) sequence, a variable heavy chain complementarity determining region 2 (VH CDR2, also referred to herein as CDRH2) sequence, a variable heavy chain complementarity determining region 3 (VH CDR3, also referred to herein as CDRH3) sequence, a variable light chain complementarity determining region 1 (VL CDR1, also referred to herein as CDRL1) sequence, a variable light chain complementarity determining region 2 (VL CDR2, also referred to herein as CDRL2) sequence, and a variable light chain complementarity determining region 3 (VL CDR3, also referred to herein as CDRL3) sequence, wherein at least one CDR sequence is selected from the group consisting of a VH CDR1 sequence shown in Table 8; a VH CDR2 sequence shown in Table 8; a VH CDR3 sequence shown in Table 8; a VL CDR1 sequence shown in Table 8; a VL CDR2 sequence shown in Table 8; and a VL CDR3 sequence shown in Table 8. 
     In some embodiments, at least one arm of the multispecific activatable antibody, e.g., a bispecific activatable antibody, comprises a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein at least one CDR sequence is selected from the group consisting of a VH CDR1 sequence that includes a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to a VH CDR1 sequence shown in Table 8; a VH CD2 sequence that includes a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to a VH CDR2 sequence shown in Table 8; a VH CDR3 sequence that includes a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to a VH CDR3 sequence shown in Table 8; a VL CDR1 sequence that includes a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to a VL CDR1 sequence shown in Table 8; a VL CDR2 sequence that includes a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to a VL CDR2 sequence shown in Table 8; and a VL CDR3 sequence that includes a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to a VL CDR3 sequence shown in Table 8. 
     In some embodiments, at least one arm of the multispecific activatable antibody, e.g., a bispecific activatable antibody, comprises a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence shown in a single row in Table 8, and a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence shown in a single row in Table 8. 
     In some embodiments, the antibody comprises a heavy chain that comprises a combination of a VH CDR1 sequence, a VH CDR2 sequence, and a VH CDR3 sequence, wherein the combination is a combination of the three heavy chain CDR sequences (VH CDR1, VH CDR2, VH CDR3) shown in a single row in Table 8. 
     In some embodiments, at least one arm of the multispecific activatable antibody, e.g., a bispecific activatable antibody, comprises a combination of a VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence shown in a single row in Table 8, and a VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence shown in a single row in Table 8, wherein each CDR sequence in the combination comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to the corresponding VH CDR sequence shown in a single row in Table 8 and the corresponding VL CDR sequence shown in a single row in Table 8. 
     In some embodiments, the antibody comprises a heavy chain that comprises a combination of a VH CDR1 sequence, a VH CDR2 sequence, and a VH CDR3 sequence, wherein each CDR sequence in the combination comprises a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to the corresponding CDR sequence in a combination of three heavy chain CDR sequences (VH CDR1, VH CDR2, VH CDR3) shown in a single row in Table 8. 
     In some embodiments, the anti-PD-1 antibodies and/or activatable anti-PD-1 antibodies described herein are used in conjunction with one or more additional agents or a combination of additional agents. Suitable additional agents include other experimental anti-cancer agents in development for specific applications, current pharmaceutical and/or surgical therapies for an intended application, such as, for example, cancer. For example, the anti-PD-1 antibodies and/or activatable anti-PD-1 antibodies can be used in conjunction with an additional chemotherapeutic or anti-neoplastic agent. 
     In some embodiments, the additional agent includes at least one experimental anti-cancer agent in development for specific applications. In some embodiments, the additional agent includes at least one agent that is already approved for one indication but is being tested in another. In some embodiments, the additional agent includes at least one agent that is not currently approved in any indication but is being tested in one or more indications for the purposes of obtaining regulatory approval. In some embodiments, the additional agent includes at least one agent that is a pharmaceutical therapy for an intended application. In some embodiments, the additional agent includes at least one agent that is a surgical therapy for cancer. In some embodiments, the additional agent includes at least one agent that is a pharmaceutical therapy for an intended application. In some embodiments, the additional agent includes at least one agent that is a surgical therapy for cancer. In some embodiments, the additional agent is a chemotherapeutic agent. In some embodiments, the additional agent is an anti-neoplastic agent. In some embodiments, the additional agents are a combination of any two or more of these agents. 
     In some embodiments, the additional agent(s) is a chemotherapeutic agent, such as a chemotherapeutic agent selected from the group consisting of docetaxel, paclitaxel, abraxane (i.e., albumin-conjugated paclitaxel), doxorubicin, oxaliplatin, carboplatin, cisplatin, irinotecan, and gemcitabine. 
     In some embodiments, the additional agent(s) is a checkpoint inhibitor, a kinase inhibitor, an agent targeting inhibitors in the tumor microenvironment, and/or a T cell or NK agonist. In some embodiments, the additional agent(s) is radiation therapy, alone or in combination with another additional agent(s) such as a chemotherapeutic or anti-neoplastic agent. In some embodiments, the additional agent(s) is a vaccine, an oncovirus, and/or a DC-activating agent such as, by way of non-limiting example, a toll-like receptor (TLR) agonist and/or α-CD40. In some embodiments, the additional agent(s) is a tumor-targeted antibody designed to kill the tumor via ADCC or via direct conjugation to a toxin (e.g., an antibody drug conjugate (ADC). 
     In some embodiments, the checkpoint inhibitor is an inhibitor of a target selected from the group consisting of CTLA-4, LAG-3, PD-1, PD-1, TIGIT, TIM-3, B7H4, BTLA, and Vista. In some embodiments, the kinase inhibitor is selected from the group consisting of B-RAFi, MEKi, and Btk inhibitors, such as ibrutinib. In some embodiments, the kinase inhibitor is crizotinib. In some embodiments, the B-RAF inhibitor is vemurafenib. In some embodiments, the tumor microenvironment inhibitor is selected from the group consisting of an IDO inhibitor, an α-CSF1R inhibitor, an α-CCR4 inhibitor, a TGF-beta, a myeloid-derived suppressor cell, or a T-regulatory cell. In some embodiments, the agonist is selected from the group consisting of Ox40, GITR, CD137, ICOS, CD27, and HVEM. 
     In some embodiments, the inhibitor is a CTLA-4 inhibitor. In some embodiments, the inhibitor is a LAG-3 inhibitor. In some embodiments, the inhibitor is a PD-1 inhibitor. In some embodiments, the inhibitor is a PD-1 inhibitor. In some embodiments, the inhibitor is a TIGIT inhibitor. In some embodiments, the inhibitor is a TIM-3 inhibitor. In some embodiments, the inhibitor is a B7H4 inhibitor. In some embodiments, the inhibitor is a Vista inhibitor. In some embodiments, the inhibitor is a B-RAFi inhibitor. In some embodiments, the inhibitor is a MEKi inhibitor. In some embodiments, the inhibitor is a Btk inhibitor. In some embodiments, the inhibitor is ibrutinib. In some embodiments, the inhibitor is crizotinib. In some embodiments, the inhibitor is an IDO inhibitor. In some embodiments, the inhibitor is an α-CSF1R inhibitor. In some embodiments, the inhibitor is an α-CCR4 inhibitor. In some embodiments, the inhibitor is a TGF-beta. In some embodiments, the inhibitor is a myeloid-derived suppressor cell. In some embodiments, the inhibitor is a T-regulatory cell. 
     In some embodiments, the agonist is O×40. In some embodiments, the agonist is GITR. In some embodiments, the agonist is CD137. In some embodiments, the agonist is ICOS. In some embodiments, the agonist is CD27. In some embodiments, the agonist is HVEM. 
     In some embodiments, the anti-PD-1 antibody and/or activatable antibody is administered during and/or after treatment in combination with one or more additional agents such as, for example, a chemotherapeutic agent, an anti-inflammatory agent, and/or an immunosuppressive agent. In some embodiments, the anti-PD-1 antibody and/or activatable anti-PD-1 antibody and the additional agent are formulated into a single therapeutic composition, and the anti-PD-1 antibody and/or activatable anti-PD-1 antibody and additional agent are administered simultaneously. Alternatively, the anti-PD-1 antibody and/or activatable anti-PD-1 antibody and additional agent are separate from each other, e.g., each is formulated into a separate therapeutic composition, and the anti-PD-1 antibody and/or activatable anti-PD-1 antibody and the additional agent are administered simultaneously, or the anti-PD-1 antibody and/or activatable anti-PD-1 antibody and the additional agent are administered at different times during a treatment regimen. For example, the anti-PD-1 antibody and/or activatable anti-PD-1 antibody is administered prior to the administration of the additional agent, the anti-PD-1 antibody and/or activatable anti-PD-1 antibody is administered subsequent to the administration of the additional agent, or the anti-PD-1 antibody and/or activatable anti-PD-1 antibody and the additional agent are administered in an alternating fashion. As described herein, the anti-PD-1 antibody and/or activatable anti-PD-1 antibody and additional agent are administered in single doses or in multiple doses. 
     In some embodiments, the anti-PD-1 antibody and/or activatable anti-PD-1 antibody and the additional agent(s) are administered simultaneously. For example, the anti-PD-1 antibody and/or activatable anti-PD-1 antibody and the additional agent(s) can be formulated in a single composition or administered as two or more separate compositions. In some embodiments, the anti-PD-1 antibody and/or activatable anti-PD-1 antibody and the additional agent(s) are administered sequentially, or the anti-PD-1 antibody and/or activatable anti-PD-1 antibody and the additional agent are administered at different times during a treatment regimen. 
     In some embodiments, the anti-PD-1 antibody and/or activatable anti-PD-1 antibody is administered during and/or after treatment in combination with one or more additional agents such as, by way of non-limiting example, a chemotherapeutic agent, an anti-inflammatory agent, and/or an immunosuppressive agent, such as an alkylating agent, an anti-metabolite, an anti-microtubule agent, a topoisomerase inhibitor, a cytotoxic antibiotic, and/or any other nucleic acid damaging agent. In some embodiments, the additional agent is a taxane, such as paclitaxel (e.g., Abraxane®). In some embodiments, the additional agent is an anti-metabolite, such as gemcitabine. In some embodiments, the additional agent is an alkylating agent, such as platinum-based chemotherapy, such as carboplatin or cisplatin. In some embodiments, the additional agent is a targeted agent, such as a kinase inhibitor, e.g., sorafenib or erlotinib. In some embodiments, the additional agent is a targeted agent, such as another antibody, e.g., a monoclonal antibody (e.g., bevacizumab), a bispecific antibody, or a multispecific antibody. In some embodiments, the additional agent is a proteosome inhibitor, such as bortezomib or carfilzomib. In some embodiments, the additional agent is an immune modulating agent, such as lenolidominde or IL-2. In some embodiments, the additional agent is radiation. In some embodiments, the additional agent is an agent considered standard of care by those skilled in the art. In some embodiments, the additional agent is a chemotherapeutic agent well known to those skilled in the art. 
     In some embodiments, the additional agent is another antibody or antigen-binding fragment thereof and/or another activatable antibody or antigen-binding fragment thereof. In some embodiments the additional agent is another antibody or antigen-binding fragment thereof and/or another activatable antibody or antigen-binding fragment thereof against the same target as the first antibody or antigen-binding fragment thereof and/or an activatable antibody or antigen-binding fragment thereof, e.g., against PD-1. In some embodiments the additional agent is another antibody or antigen-binding fragment thereof and/or another activatable antibody or antigen-binding fragment thereof against a target different than the target of the first antibody or antigen-binding fragment thereof, the first conjugated antibody or antigen-binding fragment thereof and/or activatable antibody or antigen-binding fragment thereof. 
     As a non-limiting example, the antibody or antigen-binding fragment and/or the AB of an activatable antibody is a binding partner for any target listed in Table 1. 
     
       
         
           
               
             
               
                 TABLE 1 
               
               
                   
               
               
                 Exemplary Targets 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 1-92-LFA-3 
                 CD52 
                 DL44 
                 HVEM 
                 LIF-R 
                 STEAP1 
               
               
                 Alpha-4 
                 CD56 
                 DLK1 
                 Hyaluronidase 
                 Lewis X 
                 STEAP2 
               
               
                 integrin 
                   
                   
                   
                   
                   
               
               
                 Alpha-V 
                 CD64 
                 DLL4 
                 ICOS 
                 LIGHT 
                 TAG-72 
               
               
                 integrin 
                   
                   
                   
                   
                   
               
               
                 alpha4beta1 
                 CD70 
                 DPP-4 
                 IFNalpha 
                 LRP4 
                 TAPA1 
               
               
                 integrin 
                   
                   
                   
                   
                   
               
               
                 alpha4beta7 
                 CD71 
                 DSG1 
                 IFNbeta 
                 LRRC26 
                 TGFbeta 
               
               
                 integrin 
                   
                   
                   
                   
                   
               
               
                 AGR2 
                 CD74 
                 EGFR 
                 IFNgamma 
                 MCSP 
                 TIGIT 
               
               
                 Anti-Lewis-Y 
                   
                 EGFRviii 
                 IgE 
                 Mesothelin 
                 TIM-3 
               
               
                 Apelin J 
                 CD80 
                 Endothelin B 
                 IgE Receptor  
                 MRP4 
                 TLR2 
               
               
                 receptor 
                   
                 receptor 
                 (FceRI) 
                   
                   
               
               
                   
                   
                 (ETBR) 
                   
                   
                   
               
               
                 APRIL 
                 CD81 
                 ENPP3 
                 IGF 
                 MUC1 
                 TLR4 
               
               
                 B7-H4 
                 CD86 
                 EpCAM 
                 IGF1R 
                 Mucin-16 
                 TLR6 
               
               
                   
                   
                   
                   
                 (MUC16, 
                   
               
               
                   
                   
                   
                   
                 CA-125) 
                   
               
               
                 BAFF 
                 CD95 
                 EPHA2 
                 IL1B 
                 Na/K ATPase  
                 TLR7 
               
               
                 BTLA 
                 CD117 
                 EPHB2 
                 IL1R 
                 Neutrophil 
                 TLR8 
               
               
                   
                   
                   
                   
                 elastase 
                   
               
               
                 C5 
                 CD125 
                 ERBB3 
                 IL2 
                 NGF 
                 TLR9 
               
               
                 complement 
                   
                   
                   
                   
                   
               
               
                 C-242 
                 CD132 
                 F protein of 
                 IL11 
                 Nicastrin 
                 TMEM31 
               
               
                   
                 (IL-2RG) 
                 RSV 
                   
                   
                   
               
               
                 CA9 
                 CD133 
                 FAP 
                 IL12 
                 Notch 
                 TNFalpha 
               
               
                   
                   
                   
                   
                 Receptors 
                   
               
               
                 CA19-9 
                 CD137 
                 FGF-2 
                 IL12p40 
                 Notch 1 
                 TNFR 
               
               
                 (Lewis a) 
                   
                   
                   
                   
                   
               
               
                 Carbonic 
                 CD138 
                 FGF8 
                 IL-12R, 
                 Notch 2 
                 TNFRS12 
               
               
                 anhydrase 9 
                   
                   
                 IL-12Rbeta1 
                   
                 A 
               
               
                 CD2 
                 CD166 
                 FGFR1 
                 IL13 
                 Notch 3 
                 TRAIL-R1 
               
               
                 CD3 
                 CD172A 
                 FGFR2 
                 IL13R 
                 Notch 4 
                 TRAIL-R2 
               
               
                 CD6 
                 CD248 
                 FGFR3 
                 IL15 
                 NOV 
                 Transferrin 
               
               
                 CD9 
                 CDH6 
                 FGFR4 
                 IL17 
                 OSM-R 
                 Transferrin 
               
               
                   
                   
                   
                   
                   
                 receptor 
               
               
                 CD11a 
                 CEACAM5 
                 Folate 
                 IL18 
                 OX-40 
                 TRK-A 
               
               
                   
                 (CEA) 
                 receptor 
                   
                   
                   
               
               
                 CD19 
                 CEACAM6 
                 GAL3ST1 
                 IL21 
                 PAR2 
                 TRK-B 
               
               
                   
                 (NCA-90) 
                   
                   
                   
                   
               
               
                 CD20 
                 CLAUDIN-3 
                 G-CSF 
                 IL23 
                 PDGF-AA 
                 uPAR 
               
               
                 CD22 
                 CLAUDIN-4 
                 G-CSFR 
                 IL23R 
                 PDGF-BB 
                 VAP1 
               
               
                 CD24 
                 cMet 
                 GD2 
                 IL27/IL27R 
                 PDGFRalpha 
                 VCAM-1 
               
               
                   
                   
                   
                 (wsx1) 
                   
                   
               
               
                 CD25 
                 Collagen 
                 GITR 
                 IL29 
                 PDGFRbeta 
                 VEGF 
               
               
                 CD27 
                 Cripto 
                 GLUT1 
                 IL-31R 
                 PD-1 
                 VEGF-A 
               
               
                 CD28 
                 CSFR 
                 GLUT4 
                 IL31/IL31R 
                 PD-L1 
                 VEGF-B 
               
               
                 CD30 
                 CSFR-1 
                 GM-CSF 
                 IL2R 
                 PD-L2 
                 VEGF-C 
               
               
                 CD33 
                 CTLA-4 
                 GM-CSFR 
                 IL4 
                 Phosphatidyl- 
                 VEGF-D 
               
               
                   
                   
                   
                   
                 serine 
                   
               
               
                 CD38 
                 CTGF 
                 GP IIb/IIIa  
                 IL4R 
                 P1GF 
                 VEGFR1 
               
               
                   
                   
                 receptors 
                   
                   
                   
               
               
                 CD40 
                 CXCL10 
                 Gp130 
                 IL6, IL6R 
                 PSCA 
                 VEGFR2 
               
               
                 CD40L 
                 CXCL13 
                 GPIIB/IIIA 
                 Insulin 
                 PSMA 
                 VEGFR3 
               
               
                   
                   
                   
                 Receptor 
                   
                   
               
               
                 CD41 
                 CXCR1 
                 GPNMB 
                 Jagged 
                 RAAG12 
                 VISTA 
               
               
                   
                   
                   
                 Ligands 
                   
                   
               
               
                 CD44 
                 CXCR2 
                 GRP78 
                 Jagged 1 
                 RAGE 
                 WISP-1 
               
               
                 CD44v6 
                   
                 HER2/neu 
                 Jagged 2 
                 SLC44A4 
                 WISP-2 
               
               
                 CD47 
                 CXCR4 
                 HGF 
                 LAG-3 
                 Sphingosine 1 
                 WISP-3 
               
               
                   
                   
                   
                   
                 Phosphate 
                   
               
               
                 CD51 
                 CYR61 
                 hGH 
               
               
                   
               
            
           
         
       
     
     As a non-limiting example, the antibody or antigen-binding fragment and/or the AB of an activatable antibody is or is derived from an antibody listed in Table 2. 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Exemplary sources for Abs 
               
            
           
           
               
               
            
               
                 Antibody Trade Name (antibody name) 
                 Target 
               
               
                   
               
               
                 Avastin ™ (bevacizumab) 
                 VEGF 
               
               
                 Lucentis ™ (ranibizumab) 
                 VEGF 
               
               
                 Erbitux ™ (cetuximab) 
                 EGFR 
               
               
                 Vectibix ™ (panitumumab) 
                 EGFR 
               
               
                 Remicade ™ (infliximab) 
                 TNFα 
               
               
                 Humira ™ (adalimumab) 
                 TNFα 
               
               
                 Tysabri ™ (natalizumab) 
                 Integrinα4 
               
               
                 Simulect ™ (basiliximab) 
                 IL2R 
               
               
                 Soliris ™ (eculizumab)  
                 Complement C5 
               
               
                 Raptiva ™ (efalizumab) 
                 CD11a 
               
               
                 Bexxar ™ (tositumomab) 
                 CD20 
               
               
                 Zevalin ™ (ibritumomab tiuxetan) 
                 CD20 
               
               
                 Rituxan ™ (rituximab) 
                 CD20 
               
               
                 Ocrelizumab 
                 CD20 
               
               
                 Arzerra ™ (ofatumumab) 
                 CD20 
               
               
                 Gazyva ™ (Obinutuzumab) 
                 CD20 
               
               
                 Zenapax ™ (daclizumab) 
                 CD25 
               
               
                 Adcetris ™ (brentuximab vedotin) 
                 CD30 
               
               
                 Myelotarg ™ (gemtuzumab) 
                 CD33 
               
               
                 Mylotarg ™ (gemtuzumab ozogamicin) 
                 CD33 
               
               
                 Campath ™ (alemtuzumab) 
                 CD52 
               
               
                 ReoPro ™ (abiciximab) 
                 Glycoprotein receptor IIb/IIIa 
               
               
                 Xolair ™ (omalizumab) 
                 IgE 
               
               
                 Herceptin ™ (trastuzumab) 
                 Her2 
               
               
                 Kadcyla ™ (trastuzumab emtansine) 
                 Her2 
               
               
                 Synagis ™ (palivizumab) 
                 F protein of RSV 
               
               
                 (ipilimumab) 
                 CTLA-4 
               
               
                 (tremelimumab) 
                 CTLA-4 
               
               
                 Hu5c8 
                 CD40L 
               
               
                 (pertuzumab) 
                 Her2-neu 
               
               
                 (ertumaxomab) 
                 CD3/Her2-neu 
               
               
                 Orencia ™ (abatacept) 
                 CTLA-4 
               
               
                 (tanezumab) 
                 NGF 
               
               
                 (bavituximab) 
                 Phosphatidylserine 
               
               
                 (zalutumumab) 
                 EGFR 
               
               
                 (mapatumumab) 
                 EGFR 
               
               
                 (matuzumab) 
                 EGFR 
               
               
                 (nimotuzumab) 
                 EGFR 
               
               
                 ICR62 
                 EGFR 
               
               
                 mAb 528 
                 EGFR 
               
               
                 CH806 
                 EGFR 
               
               
                 MDX-447 
                 EGFR/CD64 
               
               
                 (edrecolomab) 
                 EpCAM 
               
               
                 RAV12 
                 RAAG12 
               
               
                 huJ591 
                 PSMA 
               
               
                 Enbrel ™ (etanercept) 
                 TNF-R 
               
               
                 Amevive ™ (alefacept) 
                 1-92-LFA-3 
               
               
                 Antril ™, Kineret ™ (ankinra) 
                 IL-1Ra 
               
               
                 GC1008 
                 TGFbeta 
               
               
                   
                 Notch, e.g., Notch 1 
               
               
                   
                 Jagged 1 or Jagged 2 
               
               
                 (adecatumumab) 
                 EpCAM 
               
               
                 (figitumumab) 
                 IGF1R 
               
               
                 (tocilizumab) 
                 IL-6 receptor 
               
               
                 Stelara ™ (ustekinumab) 
                 IL-12/IL-23 
               
               
                 Prolia ™ (denosumab) 
                 RANKL 
               
               
                   
               
            
           
         
       
     
     In some embodiments, the additional antibody or antigen binding fragment thereof and/or activatable antibody or antigen binding fragment thereof is a monoclonal antibody, domain antibody, single chain, Fab fragment, a F(ab′) 2  fragment, a scFv, a scAb, a dAb, a single domain heavy chain antibody, or a single domain light chain antibody. In some embodiments, the additional antibody or antigen binding fragment thereof and/or activatable antibody or antigen binding fragment thereof is a mouse, other rodent, chimeric, humanized or fully human monoclonal antibody. 
     The disclosure also provides methods of producing an anti-PD-1 antibody and/or activatable anti-PD-1 antibody polypeptide by culturing a cell under conditions that lead to expression of the polypeptide, wherein the cell comprises an isolated nucleic acid molecule encoding an antibody and/or an activatable antibody described herein, and/or vectors that include these isolated nucleic acid sequences. The disclosure provides methods of producing an antibody and/or activatable antibody by culturing a cell under conditions that lead to expression of the antibody and/or activatable antibody, wherein the cell comprises an isolated nucleic acid molecule encoding an antibody and/or an activatable antibody described herein, and/or vectors that include these isolated nucleic acid sequences. 
     The invention also provides a method of manufacturing activatable antibodies that in an activated state binds PD-1 by (a) culturing a cell comprising a nucleic acid construct that encodes the activatable antibody under conditions that lead to expression of the activatable antibody, wherein the activatable antibody comprises a masking moiety (MM), a cleavable moiety (CM), and an antibody or an antigen binding fragment thereof (AB) that specifically binds PD-1, (i) wherein the CM is a polypeptide that functions as a substrate for a protease; and (ii) wherein the CM is positioned in the activatable antibody such that, when the activatable antibody is in an uncleaved state, the MM interferes with specific binding of the AB to PD-1 and in a cleaved state the MM does not interfere or compete with specific binding of the AB to PD-1; and (b) recovering the activatable antibody. Suitable AB, MM, and/or CM include any of the AB, MM, and/or CM disclosed herein. 
     In some embodiments, the activatable antibody in the uncleaved state has the structural arrangement from N-terminus to C-terminus as follows: MM-CM-AB or AB-CM-MM. In some embodiments, the activatable antibody comprises a linking peptide between the MM and the CM. In some embodiments, the activatable antibody comprises a linking peptide between the CM and the AB. In some embodiments, the activatable antibody comprises a first linking peptide (LP1) and a second linking peptide (LP2), and wherein the activatable antibody in the uncleaved state has the structural arrangement from N-terminus to C-terminus as follows: MM-LP1-CM-LP2-AB or AB-LP2-CM-LP1-MM. In some embodiments, the activatable antibody in the uncleaved state has the structural arrangement from N-terminus to C-terminus as follows: spacer-MM-LP1-CM-LP2-AB or AB-LP2-CM-LP1-MM-spacer. 
     In some embodiments, the two linking peptides need not be identical to each other. 
     In some embodiments, at least one of LP1 or LP2 comprises an amino acid sequence selected from the group consisting of (GS) n , (GGS) n , (GSGGS) n  (SEQ ID NO: 363) and (GGGS) n  (SEQ ID NO: 364), where n is an integer of at least one. 
     In some embodiments, at least one of LP1 or LP2 comprises an amino acid sequence selected from the group consisting of GGSG (SEQ ID NO: 365), GGSGG (SEQ ID NO: 366), GSGSG (SEQ ID NO: 367), GSGGG (SEQ ID NO: 368), GGGSG (SEQ ID NO: 369), and GSSSG (SEQ ID NO: 370). 
     In some embodiments, LP1 comprises the amino acid sequence GSSGGSGGSGGSG (SEQ ID NO: 371), GSSGGSGGSGG (SEQ ID NO: 372), GSSGGSGGSGGS (SEQ ID NO: 373), GSSGGSGGSGGSGGGS (SEQ ID NO: 374), GSSGGSGGSG (SEQ ID NO: 375), GSSGGSGGSGS (SEQ ID NO: 376), GGGSSGGS (SEQ ID NO: 65), or GGGSSGG (SEQ ID NO: 1040). 
     In some embodiments, LP2 comprises the amino acid sequence GSS, GGS, GGGS (SEQ ID NO: 377), GSSGT (SEQ ID NO: 378) or GSSG (SEQ ID NO: 379). 
     The invention provides methods of preventing, delaying the progression of, treating, alleviating a symptom of, or otherwise ameliorating a disorder or disease in a subject by administering to a subject in need thereof a therapeutically effective amount of an anti-PD-1 antibody, conjugated anti-PD-1 antibody, activatable anti-PD-1 antibody and/or conjugated activatable anti-PD-1 antibody described herein. 
     The invention also provides a method of reducing immune suppression comprising administering to a subject in need thereof a therapeutically effective amount of an anti-PD-1 antibody and/or activatable anti-PD-1 antibody described herein. In some embodiments, the immune suppression is suppression of T cell activity. In some embodiments, the immune suppression is mediated by engagement of PD-1 on T cells to PD-L1 or PD-L2 on tumor cells or other immune cells. In some embodiments, the invention provides a method to reduce or inhibit binding of PD-L1 (also referred to herein as PDL1) and/or PD-L2 (also referred to herein as PDL2), to PD-1 on T cells. The ligands PD-L1 and/or PD-L2 are often found on tumor cells or other immune cells. 
     The invention also provides methods of preventing, delaying the progression of, treating, alleviating a symptom of, or otherwise ameliorating cancer in a subject by administering a therapeutically effective amount of an anti-PD-1 antibody and/or activatable anti-PD-1 antibody described herein to a subject in need thereof. PD-1 is known to be expressed on immune cells, such as T cells, in a variety of cancers, such as, by way of non-limiting example, melanoma, non-small cell lung cancer, nasopharyngeal cancer, glioblastoma/mixed glioma, colon adenocarcinoma, hepatocellular carcinoma, urothelial cancer, multiple myeloma, ovarian cancer, gastric carcinoma, esophageal cancer, pancreatic cancer, renal cell carcinoma (RCC), breast cancer, lymphomas, such as Hodgkin&#39;s lymphoma, and leukemias. (See e.g., Chen et al., “Molecular Pathways: Next-Generation Immunotherapy—Inhibiting Programmed Death-Ligand 1 and Programmed Death-1,” Clin. Can. Res., vol. 18: 6580-6587 (2012), the contents of which are hereby incorporated by reference in their entirety). 
     In some embodiments, the cancer is a bladder cancer, a bone cancer, a breast cancer, a carcinoid, a cervical cancer, a cholangiocarcinoma, a colon cancer, an endometrial cancer, a glioma, a head and neck cancer, a liver cancer, a lung cancer, a lymphoma, such as Hodgkin&#39;s lymphoma, a melanoma, an ovarian cancer, a pancreatic cancer, a prostate cancer, a renal cancer, a sarcoma, a skin cancer, a stomach cancer, a testis cancer, a thymus cancer, a thyroid cancer, a urogenital cancer, and/or a urothelial cancer. 
     In some embodiments, the cancer is selected from the group consisting of melanoma (MEL), renal cell carcinoma (RCC), squamous non-small cell lung cancer (NSCLC), non-squamous NSCLC, colorectal cancer (CRC), castration-resistant prostate cancer (CRPC), hepatocellular carcinoma (HCC), squamous cell carcinoma of the head and neck, thymoma, carcinomas of the esophagus, ovary, gastrointestinal tract and breast, or a hematologic malignancy such as multiple myeloma, B-cell lymphoma, T-cell lymphoma, Hodgkin&#39;s lymphoma, primary mediastinal B-cell lymphoma, and chronic myelogenous leukemia. 
     The invention also provides methods of treating cancer patients with an autoimmune or inflammatory disease by administering a therapeutically effective amount of an anti-PD-1 antibody and/or activatable anti-PD-1 antibody described herein to a subject in need thereof. In some embodiments, the autoimmune disease is colitis, RA, pancreatitis, diabetes, or pneumonitis. 
     An anti-PD-1 antibody and/or an activatable anti-PD-1 antibody used in any of the embodiments of these methods and uses can be administered at any stage of the disease. For example, such an anti-PD-1 antibody and/or activatable anti-PD-1 antibody can be administered to a patient suffering cancer of any stage, from early to metastatic. The terms subject and patient are used interchangeably herein. 
     In some embodiments, the subject is a mammal, such as a human, non-human primate, companion animal (e.g., cat, dog, horse), farm animal, work animal, or zoo animal. In some embodiments, the subject is a human. In some embodiments, the subject is a companion animal. In some embodiments, the subject is an animal in the care of a veterinarian. 
     The anti-PD-1 antibody and/or activatable anti-PD-1 antibody and therapeutic formulations thereof are administered to a subject suffering from or susceptible to a disease or disorder associated with immune suppression, such as immune suppression mediated by engagement of PD-1 on T cells by PD-L1 or PD-L2 on tumor cells or other immune cells. In some embodiments, the immune suppression is suppression of T cell activity. A subject suffering from or susceptible to a disease or disorder associated with such immune suppression is identified using any of a variety of methods known in the art. For example, subjects suffering from cancer or other neoplastic condition are identified using any of a variety of clinical and/or laboratory tests such as, physical examination and blood, urine and/or stool analysis to evaluate health status. For example, subjects suffering from inflammation and/or an inflammatory disorder are identified using any of a variety of clinical and/or laboratory tests such as physical examination and/or bodily fluid analysis, e.g., blood, urine and/or stool analysis, to evaluate health status. 
     Administration of an anti-PD-1 antibody and/or activatable anti-PD-1 antibody to a patient suffering from a disease or disorder associated with immune suppression, such as immune suppression mediated by engagement of PD-1 on T cells by PD-L1 or PD-L2 on tumor cells or other immune cells, is considered successful if any of a variety of laboratory or clinical objectives is achieved. For example, administration of an anti-PD-1 antibody, and/or activatable anti-PD-1 antibody to a patient suffering from a disease or disorder associated with such immune suppression is considered successful if one or more of the symptoms associated with the disease or disorder is alleviated, reduced, inhibited or does not progress to a further, i.e., worse, state. Administration of an anti-PD-1 antibody and/or conjugated activatable anti-PD-1 antibody to a patient suffering from a disease or disorder associated with immune suppression, such as immune suppression mediated by engagement of PD-1 on T cells to PD-L1 or PD-L2 on tumor cells or other immune cells, is considered successful if the disease or disorder enters remission or does not progress to a further, i.e., worse, state. 
     In some embodiments, the anti-PD-1 antibody and/or conjugated activatable anti-PD-1 antibody is administered during and/or after treatment in combination with one or more additional agents such as, for example, a chemotherapeutic agent, an anti-inflammatory agent, and/or an immunosuppressive agent. In some embodiments, the anti-PD-1 antibody and/or activatable anti-PD-1 antibody and the additional agent(s) are administered simultaneously. For example, the anti-PD-1 antibody and/or activatable anti-PD-1 antibody and the additional agent(s) can be formulated in a single composition or administered as two or more separate compositions. In some embodiments, the anti-PD-1 antibody and/or activatable anti-PD-1 antibody and the additional agent(s) are administered sequentially. 
     The invention also provides methods and kits for using the activatable anti-PD-1 antibodies in a variety of diagnostic and/or prophylactic indications. For example, the invention provides methods and kits for detecting the presence or absence of a cleaving agent and a target of interest in a subject or a sample by (i) contacting a subject or sample with an anti-PD-1 activatable antibody, wherein the anti-PD-1 activatable antibody comprises a masking moiety (MM), a cleavable moiety (CM) that is cleaved by the cleaving agent, and an antigen binding domain or fragment thereof (AB) that specifically binds the target of interest, wherein the anti-PD-1 activatable antibody in an uncleaved, non-activated state comprises a structural arrangement from N-terminus to C-terminus as follows: MM-CM-AB or AB-CM-MM; (a) wherein the MM is a peptide that inhibits binding of the AB to PD-1, and wherein the MM does not have an amino acid sequence of a naturally occurring binding partner of the AB and is not a modified form of a natural binding partner of the AB; and (b) wherein, when the AB is in an uncleaved, non-activated state, the MM interferes with specific binding of the AB to PD-1, and when the AB is in a cleaved, activated state the MM does not interfere or compete with specific binding of the AB to PD-1; and (ii) measuring a level of activated anti-PD-1 activatable antibody in the subject or sample, wherein a detectable level of activated anti-PD-1 activatable antibody in the subject or sample indicates that the cleaving agent and PD-1 are present in the subject or sample and wherein no detectable level of activated anti-PD-1 activatable antibody in the subject or sample indicates that the cleaving agent, PD-1 or both the cleaving agent and PD-1 are absent in the subject or sample. 
     In some embodiments, the activatable anti-PD-1 antibody is an activatable anti-PD-1 antibody to which a therapeutic agent is conjugated. In some embodiments, the activatable anti-PD-1 antibody is not conjugated to an agent. In some embodiments, the activatable anti-PD-1 antibody comprises a detectable label. In some embodiments, the detectable label is positioned on the AB. In some embodiments, measuring the level of activatable anti-PD-1 antibody in the subject or sample is accomplished using a secondary reagent that specifically binds to the activated antibody, wherein the reagent comprises a detectable label. In some embodiments, the secondary reagent is an antibody comprising a detectable label. 
     In some embodiments of these methods and kits, the activatable anti-PD-1 antibody includes a detectable label. In some embodiments of these methods and kits, the detectable label includes an imaging agent, a contrasting agent, an enzyme, a fluorescent label, a chromophore, a dye, one or more metal ions, or a ligand-based label. In some embodiments of these methods and kits, the imaging agent comprises a radioisotope. In some embodiments of these methods and kits, the radioisotope is indium or technetium. In some embodiments of these methods and kits, the contrasting agent comprises iodine, gadolinium or iron oxide. In some embodiments of these methods and kits, the enzyme comprises horseradish peroxidase, alkaline phosphatase, or β-galactosidase. In some embodiments of these methods and kits, the fluorescent label comprises yellow fluorescent protein (YFP), cyan fluorescent protein (CFP), green fluorescent protein (GFP), modified red fluorescent protein (mRFP), red fluorescent protein tdimer2 (RFP tdimer2), HCRED, or a europium derivative. In some embodiments of these methods and kits, the luminescent label comprises an N-methylacrydium derivative. In some embodiments of these methods, the label comprises an Alexa Fluor® label, such as Alex Fluor® 680 or Alexa Fluor® 750. In some embodiments of these methods and kits, the ligand-based label comprises biotin, avidin, streptavidin or one or more haptens. 
     In some embodiments of these methods and kits, the subject is a mammal. In some embodiments of these methods, the subject is a human. In some embodiments, the subject is a non-human mammal, such as a non-human primate, companion animal (e.g., cat, dog, horse), farm animal, work animal, or zoo animal. In some embodiments, the subject is a rodent. 
     In some embodiments of these methods and kits, the method is an in vivo method. In some embodiments of these methods, the method is an in situ method. In some embodiments of these methods, the method is an ex vivo method. In some embodiments of these methods, the method is an in vitro method. 
     In some embodiments of the methods and kits, the method is used to identify or otherwise refine a patient population suitable for treatment with an anti-PD-1 activatable antibody of the disclosure, followed by treatment by administering that activatable anti-PD-1 antibody to a subject in need thereof. For example, patients that test positive for both the target (e.g., PD-1) and a protease that cleaves the substrate in the cleavable moiety (CM) of the anti-PD-1 activatable antibody being tested in these methods are identified as suitable candidates for treatment with such an anti-PD-1 activatable antibody comprising such a CM, and the patient is then administered a therapeutically effective amount of the activatable anti-PD-1 antibody that was tested. Likewise, patients that test negative for either or both of the target (e.g., PD-1) and the protease that cleaves the substrate in the CM in the activatable antibody being tested using these methods might be identified as suitable candidates for another form of therapy. In some embodiments, such patients can be tested with other anti-PD-1 activatable antibodies until a suitable anti-PD-1 activatable antibody for treatment is identified (e.g., an anti-PD-1 activatable antibody comprising a CM that is cleaved by the patient at the site of disease). In some embodiments, the patient is then administered a therapeutically effective amount of the activatable anti-PD-1 antibody for which the patient tested positive. Suitable AB, MM, and/or CM include any of the AB, MM, and/or CM disclosed herein. 
     Pharmaceutical compositions according to the invention can include an antibody of the invention and a carrier. These pharmaceutical compositions can be included in kits, such as, for example, diagnostic kits. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  is graph depicting the results of an ELISA binding assay using various murine antibodies that bind human PD-1 (i.e., anti-hPD-1 antibodies) referred to herein as 245-M3, also referred to herein as M3 (VH: SEQ ID NO: 9; VL: SEQ ID NO: 11), 245-M5, also referred to herein as M5 (VH: SEQ ID NO: 13; VL: SEQ ID NO: 15), 136-M13, also referred to herein as M13 (VH: SEQ ID NO: 1; VL: SEQ ID NO: 3), 136-M19, also referred to herein as M19 (VH: SEQ ID NO: 5; VL: SEQ ID NO: 7), and 136-M14, also referred to herein as M14 (VH: SEQ ID NO: 17; VL: SEQ ID NO: 19). The anti-PD-1 antibodies nivolumab (also referred to herein as “nivo” or “NV1”) and pembrolizumab (also referred to herein as “pembro” or “PM1” or “PM1 AB”) were used as positive controls. 
         FIG. 2  is a series of graphs demonstrating that various murine anti-hPD-1 antibodies block binding of the ligands human PD-L1 (hPD-L1) and human PD-L2 (hPD-L2) to human PD-1. 
         FIG. 3  is a series of graphs demonstrating that various murine anti-hPD-1 antibodies block binding of the ligands human PD-L1 (hPD-L1) and human PD-L2 (hPD-L2) to human PD-1. 
         FIG. 4  is a graph depicting binding to human PD-1 of various anti-hPD-1 antibodies of the disclosure referred to herein as A1.0 (VH: SEQ ID NO: 21; VL: SEQ ID NO: 39), A1.2 (VH: SEQ ID NO: 21; VL: SEQ ID NO: 43), and A1.4 (VH: SEQ ID NO: 21; VL: SEQ ID NO: 45) as determined by ELISA. The anti-PD-1 antibody pembrolizumab (“PM1”) was used as positive control. 
         FIG. 5  is a graph depicting binding to human PD-1 of various anti-hPD-1 antibodies of the disclosure referred to herein as A1.5 (VH: SEQ ID NO: 21; VL: SEQ ID NO: 47), A1.6 (VH: SEQ ID NO: 21; VL: SEQ ID NO: 49), Ba2 (VH: SEQ ID NO: 29; VL: SEQ ID NO: 57), Bb2 (VH: SEQ ID NO: 31; VL: SEQ ID NO: 57), C1.1 (VH: SEQ ID NO: 33; VL: SEQ ID NO: 41), and D4 (VH: SEQ ID NO: 37; VL: SEQ ID NO: 59) as determined by ELISA. The anti-PD-1 antibodies nivolumab (“NV1”) and pembrolizumab (“PM1”) were used as positive controls. 
         FIG. 6  is a series of graphs depicting the ability of various anti-hPD-1 antibodies of the disclosure referred to herein as A1.0, A1.2, and A1.4 to inhibit binding between human PD-1 (hPD-1) and both human PDL-1 (hPDL-1) and human PDL-2 (hPDL-2) as determined by ELISA. The anti-PD-1 antibody pembrolizumab (“PM1”) was used as positive control. 
         FIG. 7  is a series of graphs depicting the ability of various anti-hPD-1 antibodies of the disclosure referred to herein as A1.5 and C1.1 to inhibit binding between hPD-1 and both hPDL-1 and hPDL-2 as determined by ELISA. The anti-PD-1 antibodies nivolumab (“NV1”) and pembrolizumab (“PM1”) were used as positive controls. 
         FIG. 8  is a graph depicting the ability of various anti-hPD-1 antibodies of the disclosure referred to herein as A1.5, Ba2, Bb2, C1.1, and D4 to inhibit binding between hPD-1 and hPDL-1 as determined by ELISA. The anti-PD-1 antibodies nivolumab (“NV1”) and pembrolizumab (“PM1”) were used as positive controls. 
         FIG. 9  is a graph depicting the ability of various anti-hPD-1 antibodies of the disclosure referred to herein as A1.5, Ba2, Bb2, C1.1, and D4 to inhibit binding between hPD-1 and hPDL-2 as determined by ELISA. The anti-PD-1 antibodies nivolumab (“NV1”) and pembrolizumab (“PM1”) were used as positive controls. 
         FIG. 10  is a graph depicting that the anti-PD-1 antibody referred to herein as A1.5 specifically binds hPD-1 as determined by ELISA. The A1.5 anti-PD-1 antibody was tested against a panel of human and mouse proteins. 
         FIGS. 11A and 11B  are a series of graphs depicting the ability of the anti-PD-1 antibody A1.5 to block Fab fragments of the anti-PD-1 antibodies nivolumab (“NV1”) and pembrolizumab (“PM1”) from binding to PD-1. These graphs also demonstrate that the anti-PD-1 antibody A1.5 binds a distinct epitope from either NV1 and/or PM1. 
         FIG. 12  is a graph demonstrating that the anti-PD-1 antibody A1.5 has a potency similar to that of nivolumab (“NV1”) and pembrolizumab (“PM1”) measured in a T-cell restimulation assay. In  FIG. 12 , PMBCs were treated as follows: PBMCs: CMV+HemaCare Donor C were plated at 2×10 5  cells/well; stimulated with 5 μg/mL CMV lysate+/−anti-PD-1 or isotype control; IFN-γ ELISA assay performed on day 4 supernatant. 
         FIG. 13  is a series of graphs demonstrating that the anti-PD-1 antibodies A1.5 and Ba2 bind monomeric human PD-1 (hPD1) with similar or higher affinity than the anti-PD-1 antibodies nivolumab (“Nivo”) and pembrolizumab (“Pembro”). 
         FIG. 14  is a series of graphs depicting the binding to human PD-1 by anti-PD-1 antibody A1.4 and by various activatable anti-PD-1 antibodies that include the various masking moieties referred to herein as PD01 (SEQ ID NO: 66), PD02 (SEQ ID NO: 67), PD03 (SEQ ID NO: 68), PD08 (SEQ ID NO: 73), PD09 (SEQ ID NO: 74), and PD10 (SEQ ID NO: 75) as determined by ELISA. 
         FIG. 15  is a series of graphs depicting the binding to hPD-1 by anti-PD-1 antibody A1.5 and by various activatable anti-PD-1 antibodies that include the anti-PD-1 antibody A1.5 and the masking moieties referred to herein as PD01 (SEQ ID NO: 66), PD02 (SEQ ID NO: 67), PD03 (SEQ ID NO: 68), PD05 (SEQ ID NO: 70), PD06 (SEQ ID NO: 71) (Plate 1); PD08 (SEQ ID NO: 73), PD09 (SEQ ID NO: 74), PD10 (SEQ ID NO: 75), PD11 (SEQ ID NO: 76), PD12 (SEQ ID NO: 77) (Plate 2); PD13 (SEQ ID NO: 78), PD14 (SEQ ID NO: 79), PD15 (SEQ ID NO: 80), PD16 (SEQ ID NO: 81), PD17 (SEQ ID NO: 82) (Plate 3); PD18 (SEQ ID NO: 83), PD19 (SEQ ID NO: 84), PD20 (SEQ ID NO: 85), PD21 (SEQ ID NO: 86), PD22 (SEQ ID NO: 87) (Plate 4); and PD23 (SEQ ID NO: 88), PD24 (SEQ ID NO: 89) (Plate 5). 
         FIG. 16  is a graph depicting the binding to hPD-1 by anti-PD-1 antibody A1.5 and various activatable anti-PD-1 antibodies that include the anti-PD-1 antibody A1.5, the cleavable moiety referred to herein as 3001, which includes the sequence AVGLLAPPGGLSGRSDNH (SEQ ID NO: 318), and the masking moieties referred to herein as PD02, PD12, and PD16. 
         FIG. 17  is a series of graphs depicting the binding to hPD-1 by the anti-PD-1 antibody A1.5 and by various activatable anti-PD-1 antibodies that include the anti-PD-1 antibody A1.5, the cleavable moiety referred to herein as 2001, which includes the sequence ISSGLLSGRSDNH (SEQ ID NO: 214), and the masking moieties referred to herein as PD05 (SEQ ID NO: 70), PD06 (SEQ ID NO: 71), PD09 (SEQ ID NO: 74) (upper left panel); PD12 (SEQ ID NO: 77), PD23 (SEQ ID NO: 88), PD25 (SEQ ID NO: 90) (upper right panel); PD26 (SEQ ID NO: 91), PD27 (SEQ ID NO: 92), PD28 (SEQ ID NO: 93) (lower left panel); and PD30 (SEQ ID NO: 95), PD33 (SEQ ID NO: 98), PD35 (SEQ ID NO: 100) (lower right panel). 
         FIG. 18  is a series of graphs depicting the binding to hPD-1 by the anti-PD-1 antibody A1.5 and by various activatable anti-PD-1 antibodies that include the anti-PD-1 antibody A1.5 and the masking moieties referred to herein as PD34 (SEQ ID NO: 99), PD06 (SEQ ID NO: 71), PD09 (SEQ ID NO: 74) (upper left panel); PD34 (SEQ ID NO: 99), PD12 (SEQ ID NO: 77), PD17 (SEQ ID NO: 82) (upper right panel); PD34 (SEQ ID NO: 99), PD19 (SEQ ID NO: 84), PD25 (SEQ ID NO: 90) (lower left panel); and PD34 (SEQ ID NO: 99), PD26 (SEQ ID NO: 91), PD28 (SEQ ID NO: 93) (lower right panel). 
         FIG. 19  is a graph depicting the ability of anti-PD1 A1.5 activatable antibodies of the disclosure to increase CMV-stimulated IFN-gamma secretion as compared to control hIgG4, but with decreased potency relative to anti-PD1 A1.5 parental antibody. The tested activatable antibodies include the anti-PD-1 antibody A1.5, the cleavable moiety referred to herein as 2001, and the masking moieties referred to herein as PD06, PD05, PD11, PD12, PD14, and PD19. In  FIG. 19 , PMBCs were treated as follows: PBMCs: CMV+ HemaCare Donor C were plated at 2×10 5  cells/well; stimulated with 5 μg/mL CMV lysate+/−anti-PD-1 or isotype control; IFN-γ ELISA assay performed on day 4 supernatant. 
         FIGS. 20A and 20B  are a series of graphs depicting the ability of the anti-PD-1 antibody referred to herein as J43v2 (Heavy Chain (HC): SEQ ID NO: 546; Light Chain (LC): SEQ ID NO: 543) to block murine PD-L1 (mPD-L1) and murine PD-L2 (mPD-L2) from binding to cells expressing murine PD-1 (mPD-1) with single digit nM EC 50  values. 
         FIG. 21  is a graph depicting the dose-dependent induction of diabetes in NOD mice by the antibody referred to herein as J43v2 m2a (HC: SEQ ID NO: 546; LC: SEQ ID NO: 543). 
         FIG. 22  is a series of graphs depicting the binding to hPD-1 by anti-PD-1 antibody J43v2 m2a and by various activatable anti-PD-1 antibodies that include the anti-PD-1 antibody J43v2 m2a and the masking moieties referred to herein as MP01 (SEQ ID NO: 384), MP02 (SEQ ID NO: 385), MP03 (SEQ ID NO: 386), MP04 (SEQ ID NO: 387), MP05 (SEQ ID NO: 388) (upper left panel); MP06 (SEQ ID NO: 389), MP07 (SEQ ID NO: 390), MP08 (SEQ ID NO: 391), MP09 (SEQ ID NO: 392), MP10, also referred to herein as MP010 (SEQ ID NO: 393) (upper right panel); MP11, also referred to herein as MP011 (SEQ ID NO: 394), MP12, also referred to herein as MP012 (SEQ ID NO: 395), MP13, also referred to herein as MP013 (SEQ ID NO: 396), MP14, also referred to herein as MP014 (SEQ ID NO: 397) (bottom panel). 
         FIG. 23  is a graph depicting the binding to hPD-1 by the anti-PD-1 antibody J43v2 m2a and by various activatable anti-PD-1 antibodies that include the anti-PD-1 antibody J43v2 m2a, the cleavable moiety referred to herein as 2001, and the masking moieties referred to herein as MP5-2 (SEQ ID NO: 565), MP7-1 (SEQ ID NO: 558), MP7-5 (SEQ ID NO: 562), MP8-2 (SEQ ID NO: 549) (upper panel); and MP7-1 (SEQ ID NO: 558), MP8-9 (SEQ ID NO: 556), MP8-8 (SEQ ID NO: 555) (lower panel). 
         FIG. 24  is a graph depicting that the anti-PD-1 J43v2 antibody induced diabetes in NOD mice with increased frequency as dosage increased and that anti-PD-1 J43v2 activatable antibodies exhibited reduced diabetes compared to antibodies at similar doses. 
         FIGS. 25A and 25B  are a series of graphs depicting the binding to hPD-1 by the anti-PD-1 antibody A1.5 and by of various activatable antibodies of the disclosure comprising the anti-PD1 antibody A1.5, the masking moiety referred to herein as PD34 (SEQ ID NO: 99), and for  FIG. 25A , the substrates referred to herein as 2006 (SEQ ID NO: 1095), 2007 (SEQ ID NO: 1096), 2008 (SEQ ID NO: 1097), 2009 (SEQ ID NO: 1098), and 2001 (SEQ ID NO: 214), and for  FIG. 25B , the substrates referred to herein as 2001 (SEQ ID NO: 214), 2008 (SEQ ID NO: 1097), 2012 (SEQ ID NO: 1101), 2011 (SEQ ID NO: 1100), and 2003 (SEQ ID NO: 1092). 
         FIGS. 26A, 26B, and 26C  are a series of graphs depicting the binding to hPD-1 by the anti-PD-1 antibody nivolumab (NV1) and by of various activatable antibodies of the disclosure comprising the anti-PD1 antibody NV1, the substrate referred to herein as 2001 (SEQ ID NO: 214), and the masking moieties referred to herein NV01 (SEQ ID NO: 1206), NV02 (SEQ ID NO: 1207), NV03 (SEQ ID NO: 1208), NV04 (SEQ ID NO: 1209), NV05 (SEQ ID NO: 1210), NV06 (SEQ ID NO: 1211), NV07 (SEQ ID NO: 1212), NV08 (SEQ ID NO: 1213), NV09 (SEQ ID NO: 1214), NV10 (SEQ ID NO: 1215), NV11 (SEQ ID NO: 1216), and NV12 (SEQ ID NO: 1217). 
         FIGS. 27A, 27B, and 27C  are a series of graphs depicting the binding to hPD-1 by the anti-PD-1 antibody pembrolizumab (PM1) and by various activatable antibodies of the disclosure comprising the anti-PD1 antibody PM1, the substrate referred to herein as 2001 (SEQ ID NO: 214), and the masking moieties referred to herein PM01 (SEQ ID NO: 1351), PM02 (SEQ ID NO: 1352), PM03 (SEQ ID NO: 1353), PM04 (SEQ ID NO: 1354), PM05 (SEQ ID NO: 1355), PM06 (SEQ ID NO: 1356), PM07 (SEQ ID NO: 1357), PM08 (SEQ ID NO: 1358), PM09 (SEQ ID NO: 1359), PM10 (SEQ ID NO: 1360), PM11 (SEQ ID NO: 1361), and PM12 (SEQ ID NO: 1362). 
         FIG. 28  is a graph depicting the masking moiety specificity for various activatable antibodies of the disclosure that comprise the anti-PD-1 A1.5 (PD) antibody, the NV1 (NV) antibody, and the PM1 (PM) antibody and a variety of mask and substrate combinations. 
         FIGS. 29A and 29B  are a series of graphs depicting the binding to PD1 by the IgG2a effector negative (EN) anti-PD1 antibody J43 (J43 m2a EN) and by various activatable antibodies of the disclosure comprising the IgG2a effector negative (EN) anti-PD1 antibody J43 (J43 m2a EN) and a variety of mask and substrate combinations. 
         FIG. 30  is a graph depicting that the anti-PD-1 J43m2a EN antibody induced diabetes in NOD mice with increased frequency as dosage increased and that anti-PD-1 J43m2a EN activatable antibodies exhibited reduced diabetes compared to antibodies at similar doses. 
         FIGS. 31A and 31B  are a series of graphs depicting that anti-PD1 activatable antibodies of the disclosure MP7-1 2001 m2a EN and MP8-2 2001 m2a EN inhibit the growth of MC38 syngeneic tumors in a manner similar to positive control anti-PD1 antibody J43 m2a EN both as single agents ( FIG. 31A ) and in combination with the commercially available anti-CTLA4 antibody 9D9 mIgG2b ( FIG. 31B ). 
         FIGS. 32A, 32B, 32C, 32D, and 32E  are a series of graphs depicting that the anti-human PD1 antibody referred to herein as A1.5 Ab (i.e., VH of SEQ ID NO: 21 and VL of SEQ ID NO: 47) blocks PD-L1/PD-L2 binding to PD1 and potently activates T cells in an antigen recall assay.  FIG. 31A  shows the binding of the anti-human PD-1 A1.5 Ab to immobilized human PD1 as detected by standard plate ELISA, and  FIG. 31B  shows the binding of A1.5 Ab to cynomolgus PD1 as detected by ELISA.  FIG. 32C  depicts the inhibition of biotinylated human PD-L1 to immobilized PD1 by A1.5 Ab as determined by ELISA, and  FIG. 32D  depicts the inhibition of biotinylated human PD-L2 to immobilized PD1 as determined by ELISA.  FIG. 32E  demonstrations that the A1.5 Ab enhances IFN-γ production in a CMV T cell restimulation assay. 
         FIGS. 33A and 33B  are a series of graphs depicting that the activatable anti-PD1 antibody referred to herein as A1.5 PD34 2001 (i.e., VH of SEQ ID NO: 21, VL of SEQ ID NO: 47, masking moiety of SEQ ID NO: 99, and cleavable moiety of SEQ ID NO: 214) binds human PD1 with decreased affinity relative to the parental PD-1 Ab, i.e., A1.5 Ab ( FIG. 33A ), and the A1.5 PD34 2001 activatable antibody shows functional masking in a CMV T cell antigen recall assay ( FIG. 33B ). 
         FIG. 34  is a graph and a table depicting the results of pharmacokinetic (PK) analysis of plasma samples from cynomolgus monkeys after dosing with a single IV bolus dose of either the A1.5 antibody or the activatable antibody referred to herein as A1.5 PD34 2001 at 1 mg/kg or at 5 mg/kg. Mean PK parameters shown for both A1.5 and A1.5 PD34 2001. 
         FIG. 35  is a graph depicting that the combination of 10 mg/kg anti-PD-1 J43 antibody plus 10 mg/kg anti-CTLA-4 antibody dosed on days 0, 4 and 7 induced diabetes in 50% of NOD mice by day eleven while the same dosing schedule of activatable anti-PD-1 J43 antibodies with CTLA-4 antibody resulted in no induction of diabetes to day eighteen. 
         FIG. 36  is a graph depicting that the anti-PD1 activatable antibodies MP8-2 2012 m2a EN and MP8-2 2011 m2a EN inhibit the growth of MC38 syngeneic tumors similar to positive control anti-PD1 antibody J43 m2a EN, both as single agents and in combination with anti-CTLA4 antibody 9D9 mIgG2b. 
         FIG. 37  is a series of graphs depicting that combination CTLA4 antibody and J43 activatable antibody treatment protects mice against rechallenge with MC38 tumor cells. 
         FIG. 38  is a graph depicting that an anti-PD-1 antibody administered alone or in combination with an anti-CTLA4 antibody induced diabetes in NOD mice, whereas an anti-PD-1 activatable antibody as a single agent or in combination with an anti-CTLA4 antibody resulted in no induction of diabetes to day fifteen. 
         FIG. 39  is a graph demonstrating that anti-PD-1 activatable A1.5 and activatable nivolumab antibodies of the embodiments enhance IFN-gamma production in a CMV T cell restimulation assay as compared to a control antibody, but not to the extent effected by anti-PD-1 antibody A1.5 or nivolumab. 
         FIG. 40  is a graph demonstrating that an anti-PD-1 activatable pembrolizumab antibody of the embodiments enhances IFN-gamma production in a CMV T cell restimulation assay as compared to a control antibody, but not to the extent effected by anti-PD-1 antibody A1.5 or pembrolizumab. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The present invention provides monoclonal antibodies (mAbs), activatable antibodies, and antigen-binding fragments thereof that specifically bind programmed cell death protein 1 (PD-1), also known as CD279. The use of the term “PD-1” is intended to cover any variation thereof, such as, by way of non-limiting example, PD1 and/or PD 1, all variations are used herein interchangeably. Aberrant expression and/or activity of PD-1 and PD-1-related signaling has been implicated in the pathogenesis of many diseases and disorders, such as cancer. 
     PD-1, a cell surface receptor that belongs to the immunoglobulin superfamily, is expressed on T cells and pro-B cells. PD-1 is known to bind two ligands, PD-L1 and PD-L2. PD-1 is expressed on the surface of activated T cells, and the interaction between PD-1 and PD-L1 and/or PD-L2 functions as an immune checkpoint, as the binding of PD-L1 or PD-L2 to PD-1 inactivates the T cell. Thus, PD-1 plays a role in down-regulating the immune system by preventing the activation of T-cells, which, in turn, reduces autoimmunity and promotes self-tolerance. 
     The anti-PD-1 monoclonal antibodies and activated activatable anti-PD-1 antibodies of the disclosure bind and neutralize or otherwise inhibit the ability of PD-1 to bind or otherwise interact with PD-L1 and/or PD-L2. The anti-PD-1 monoclonal antibodies and activated activatable anti-PD-1 antibodies of the disclosure bind and neutralize or otherwise inhibit at least one biological activity of PD-1. For example, the anti-PD-1 monoclonal antibodies and activated activatable anti-PD-1 antibodies of the disclosure bind PD-1 and block or otherwise inhibit ligand activation of PD-1 on activated T cells. In contrast to traditional chemotherapies and other targeted anti-cancer therapies, which exert their effects by direct cytotoxic or tumor growth inhibition, the monoclonal antibodies and activatable antibodies of the disclosure block a negative regulator of T-cell activation and response, thereby allowing the immune system to attack the tumor. 
     The activatable anti-PD-1 antibodies of the disclosure include an antibody or antigen-binding fragment thereof that specifically binds PD-1 coupled to a masking moiety (MM), such that coupling of the MM reduces the ability of the antibody or antigen-binding fragment thereof to bind PD-1. The MM is coupled via a cleavable moiety (CM) that includes a sequence that functions as a substrate for a protease. 
     The activatable anti-PD-1 antibodies of the disclosure are activated when the cleavable moiety is cleaved by a protease. For example, the protease is produced by a tumor that is in proximity to T cells that express PD-1. In some embodiments, the protease is produced by a tumor that is co-localized with T cells that express PD-1. In the activated, i.e., cleaved state, the activatable anti-PD-1 antibodies of the disclosure bind PD-1 expressed on a T cell surface. 
     The activatable anti-PD-1 antibodies are used in methods of treating, preventing, delaying the progression of, ameliorating and/or alleviating a symptom of a disease or disorder associated with binding of a ligand selected from the group consisting of PD-L1 and PD-L2 to PD-1 on a T cell. Such ligands are often found on tumor cells and other immune cells. Binding of such ligands to PD-1 can lead to immune suppression, such as suppression of T cell activity, which is reduced by anti-PD1 antibodies and activatable anti-PD-1 antibodies of the disclosure. For example, the activatable anti-PD-1 antibodies are used in methods of treating, preventing, delaying the progression of, ameliorating and/or alleviating a symptom of a cancer or other neoplastic condition. 
     Exemplary activatable anti-PD-1 antibodies of the invention include, for example, activatable antibodies that include a heavy chain and a light chain that are, or are derived from, antibodies described in the Examples, for example in Examples 1, 2, 8, 9, 14, and 15. 
     In some embodiments, the activatable anti-PD-1 antibody includes a heavy chain that comprises or is derived from an amino acid sequence selected from the group consisting of SEQ ID NO: 1, 5, 9, 13, 17, 21, 23, 25, 27, 29, 31, 33, 35, and 37, and a light chain that comprises or is derived from an amino acid sequence selected from the group consisting of SEQ ID NO: 3, 7, 11, 15, 19, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 215, 217, 219, 221, 223, 225, 227, 229, 231, 233, 235, 237, 239, 241, 245, 247, 249, 251, 253, 255, 257, 259, 261, 263, 265, 267, 269, 271, 273, 275, 277, 279, 281, 283, 285, 287, 289, 291, 293, 515, 517, 519, 521, 523, 525, 527, 529, 531, 533, 535, 537, 539, 541, 572, 574, 576, 578, 580, 582, 919, 921, 923, 925, 927, 929, 931, 933, 935, 937, 939, 941, 943, 945, 947, 949, 951, 953, 955, 957, 959, 961, 963, 965, 967, 969, 971, 973, 975, 977, 979, 981, 983, 985, 987, 989, 991, 993, 995, 997, 999, 1001, 1003, 1005, 1007, 1009, 1011, 1013, 1015, 1017, 1019, 1021, 1023, 1025, 1027, 1030, 1032, 1034, 1036, 1039, 1041-1090, 1113-1120, 1123, 1124, 1127, 1128, 1131, 1132, 1134, 1135, 1138, 1139, 1143, 1144, 1147, 1148, 1151, 1152, 1155, 1156, 1159, 1160, 1163, 1164, 1167, 1168, 1170, 1171, 1174, 1175, 1178, 1179, 1182, 1183, 1186, 1187, 1190, 1191, 1194, 1195, 1198, 1199, 1202, 1203, 2055, 2054, 2057, 2056, 2059, and 2058. 
     In some embodiments, the activatable anti-PD-1 antibody includes a heavy chain that comprises or is derived from an amino acid sequence selected from the group consisting of SEQ ID NO: 21, 23, 25, 27, 29, 31, 33, 35, and 37, and a light chain that comprises or is derived from an amino acid sequence selected from the group consisting of SEQ ID NO: 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 215, 217, 219, 221, 223, 225, 227, 229, 231, 233, 235, 237, 239, 241, 245, 247, 249, 251, 253, 255, 257, 259, 261, 263, 265, 267, 269, 271, 273, 275, 277, 279, 281, 283, 285, 287, 289, 291, 293, 515, 517, 519, 521, 523, 525, 527, 529, 531, 533, 535, 537, 539, 541, 572, 574, 576, 578, 580, 582, 584, 919, 921, 923, 925, 927, 929, 931, 933, 935, 937, 939, 941, 943, 945, 947, 949, 951, 953, 955, 957, 959, 961, 963, 965, 967, 969, 971, 973, 975, 977, 979, 981, 983, 985, 987, 989, 991, 993, 995, 997, 999, 1001, 1003, 1005, 1007, 1009, 1011, 1013, 1015, 1017, 1019, 1021, 1023, 1025, 1027, 1029, 1030, 1032, 1034, 1036, 1039, 1041-1090, 1113-1120, 1123, 1127, 1131, 1134, 1138, 1144, 1148, 1152, 1156, 1160, 1164, 1168, 1170, 1174, 1178, 1182, 1186, 1190, 1194, 1198, 1203, 2055, 2054, 2057, 2056, 2059, and 2058. 
     In some embodiments, the light chain comprises or is derived from an amino acid sequence selected from the group consisting of SEQ ID NO: 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59. In some embodiments, the light chain comprises or is derived from an amino acid sequence selected from the group consisting of SEQ ID NO: 215, 217, 219, 221, 223, 225, 227, 229, 231, 233, 235, 237, 239, 241, 245, 247, 249, 251, 253, 255, 257, 259, 261, 263, 265, 267, 269, 271, 273, 275, 277, 279, 281, 283, 285, 287, 289, 291, 293, 584, 919, 921, 923, 925, 927, 929, 931, 933, 935, 937, 939, 941, 943, 945, 947, 949, 951, 953, 955, 957, 959, 961, 963, 965, 967, 969, 971, 973, 975, 977, 979, 981, 983, 985, 987, 989, 991, 993, 995, and 997. 
     In some embodiments, the activatable anti-PD-1 antibody includes a heavy chain that comprises or is derived from an amino acid sequence selected from the group consisting of SEQ ID NO: 21, 23, 25, 27, 29, 31, 33, 35, and 37, and a light chain that comprises or is derived from an amino acid sequence selected from the group consisting of 215, 217, 219, 221, 223, 225, 227, 229, 231, 233, 235, 237, 239, 241, 243, 245, 247, 249, 251, 253, 255, 257, 259, 261, 263, 265, 267, 269, 271, 273, 275, 277, 279, 281, 283, 285, 287, 289, 291, 293, 572, 574, 576, 578, 580, 582, 1029, 1120, 1124, 1128, 1132, 1135, 1139, 1143, 1147, 1151, 1155, 1159, 1163, 1167, 1171, 1175, 1179, 1183, 1187, 1191, 1195, 1199, 1203, 2055, 2054, 2057, 2056, 2059, and 2058. 
     In some embodiments, the light chain comprises or is derived from an amino acid sequence selected from the group consisting of SEQ ID NO: 515, 517, 519, 521, 523, 525, 527, 529, 531, 533, 535, 537, 539, 541, 572, 574, 576, 578, 580, 582, 999, 1001, 1003, 1005, 1007, 1009, 1011, 1013, 1015, 1017, 1019, 1021, 1023, 1025, 1027, 1029, 1030, 1032, 1034, 1036, 1039, 1041-1090, 1113-1120, 1123, 1127, 1131, 1134, 1138, 1144, 1148, 1152, 1156, 1160, 1164, 1168, 1170, 1174, 1178, 1182, 1186, 1190, 1194, 1198, 1203, 2055, 2054, 2057, 2056, 2059, and 2058. 
     In some embodiments, the activatable anti-PD-1 antibody includes a light chain that comprises or is derived from an amino acid sequence selected from the group consisting of SEQ ID NOs: 215, 217, 219, 221, 223, 225, 227, 229, 231, 233, 235, 237, 239, 241, 243, 245, 247, 249, 251, 253, 255, 257, 259, 261, 263, 265, 267, 269, 271, 273, 275, 277, 279, 281, 283, 285, 287, 289, 291, 293, 515, 517, 519, 521, 523, 525, 527, 529, 531, 533, 535, 537, 539, 541, 572, 574, 576, 578, 580, 582, 919, 921, 923, 925, 927, 929, 931, 933, 935, 937, 939, 941, 943, 945, 947, 949, 951, 953, 955, 957, 959, 961, 963, 965, 967, 969, 971, 973, 975, 977, 979, 981, 983, 985, 987, 989, 991, 993, 995, 997, 1027, 1028, 1029, 1030, 1032, 1034, 1036, 1039, 1041-1076, 1113-1120, 1123, 1124, 1127, 1128, 1131, 1132, 1134, 1135, 1138, 1139, 1143, 1144, 1147, 1148, 1151, 1152, 1155, 1156, 1159, 1160, 1163, 1164, 1167, 1168, 1170, 1171, 1174, 1175, 1178, 1179, 1182, 1183, 1186, 1187, 1190, 1191, 1194, 1195, 1198, 1199, 1202, 12032055, 2054, 2057, 2056, 2059, and 2058. 
     In some embodiments, the activatable anti-PD-1 antibody includes a heavy chain that comprises or is derived from an amino acid sequence selected from the group consisting of SEQ ID NO: 21, 23, 25, 27, 29, 31, 33, 35, and 37, and a light chain that comprises or is derived from an amino acid sequence selected from the group consisting of SEQ ID NOs: 215, 217, 219, 221, 223, 225, 227, 229, 231, 233, 235, 237, 239, 241, 243, 245, 247, 249, 251, 253, 255, 257, 259, 261, 263, 265, 267, 269, 271, 273, 275, 277, 279, 281, 283, 285, 287, 289, 291, 293, 919, 921, 923, 925, 927, 929, 931, 933, 935, 937, 939, 941, 943, 945, 947, 949, 951, 953, 955, 957, 959, 961, 963, 965, 967, 969, 971, 973, 975, 977, 979, 981, 983, 985, 987, 989, 991, 993, 995, 997, 1028, 1029, 1041-1076, 1138, 1139, 1143, 1144, 1147, 1148, 1151, 1152, 1155, 1156, 1159, 1160, 1163, 1164, 1167, 1168, 1170, 1171, 1174, 1175, 1178, 1179, 1182, 1183, 1186, 1187, 1190, 1191, 1194, 1195, 1198, 1199, 1202, 1203, 2055, 2054, 2057, 2056, 2059, and 2058. 
     In some embodiments, the light chain comprises or is derived from an amino acid sequence selected from the group consisting of SEQ ID NOs: 919, 921, 923, 925, 927, 929, 931, 933, 935, 937, 939, 941, 943, 945, 947, 949, 951, 953, 955, 957, 959, 961, 963, 965, 967, 969, 971, 973, 975, 977, 979, 981, 983, 985, 987, 989, 991, 993, 995, 997, 1028, 1041-1076, 1138, 1144, 1148, 1152, 1156, 1160, 1164, 1168, 1170, 1174, 1178, 1182, 1186, 1190, 1194, 1198, 1202, 2055, 2057, and 2059. 
     In some embodiments, the light chain comprises or is derived from an amino acid sequence selected from the group consisting of SEQ ID NOs: 215, 217, 219, 221, 223, 225, 227, 229, 231, 233, 235, 237, 239, 241, 243, 245, 247, 249, 251, 253, 255, 257, 259, 261, 263, 265, 267, 269, 271, 273, 275, 277, 279, 281, 283, 285, 287, 289, 291, 293, 1029, 1139, 1143, 1147, 1151, 1155, 1159, 1163, 1167, 1171, 1175, 1179, 1183, 1187, 1191, 1195, 1199, 1203, 2054, 2056, and 2058. 
     In some embodiments, the activatable anti-PD-1 antibody includes a heavy chain that comprises or is derived from an amino acid sequence selected from the group consisting of SEQ ID NO: 546 and a light chain that comprises or is derived from an amino acid sequence selected from the group consisting of SEQ ID NOs: 515, 517, 519, 521, 523, 525, 527, 529, 531, 533, 535, 537, 539, 541, 572, 574, 576, 578, 580, 582, 999, 1001, 1003, 1005, 1007, 1009, 1011, 1013, 1015, 1017, 1019, 1021, 1023, 1025, 1027, 1030, 1032, 1034, 1036, 1039, 1077-1090, 1113-1120, 1123, 1124, 1127, 1128, 1131, 1132, 1134, and 1135. 
     In some embodiments, the activatable anti-PD-1 antibody includes a light chain that comprises or is derived from an amino acid sequence selected from the group consisting of SEQ ID NOS: 999, 1001, 1003, 1005, 1007, 1009, 1011, 1013, 1015, 1017, 1019, 1021, 1023, 1025, 1027, 1030, 1032, 1034, 1036, 1039, 1070-1090, 1119, 1123, 1127, 1131, and 1134. 
     In some embodiments, the activatable anti-PD-1 antibody includes a light chain that comprises or is derived from an amino acid sequence selected from the group consisting of SEQ ID NOS: 515, 517, 519, 521, 523, 525, 527, 529, 531, 533, 535, 537, 539, 541, 572, 574, 576, 578, 580, 582, 1120, 1124, 1128, 1132, and 1135. 
     In some embodiments, the activatable anti-PD-1 antibody includes a heavy chain that comprises or is derived from a heavy chain amino acid sequence shown in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a light chain that comprises or is derived from a light chain amino acid sequence shown in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a heavy chain that comprises or is derived from a heavy chain amino acid sequence shown in Table 7, and a light chain that comprises or is derived from a light chain amino acid sequence shown in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of a heavy chain variable region sequence and a light chain variable region sequence from the combinations shown in Group A in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of a heavy chain variable region sequence and a light chain variable region sequence from the combinations shown in Group B in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of a heavy chain variable region sequence and a light chain variable region sequence from the combinations shown in Group C in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of a heavy chain variable region sequence and a light chain variable region sequence from the combinations shown in Group D in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of a heavy chain variable region sequence and a light chain variable region sequence from the combinations shown in Group E in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of a heavy chain variable region sequence and a light chain variable region sequence from the combinations shown in Group F in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of a heavy chain variable region sequence and a light chain variable region sequence from the combinations shown in Group H in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of a heavy chain variable region sequence and a light chain variable region sequence from the combinations shown in Group I in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of a heavy chain variable region sequence and a light chain variable region sequence from the combinations shown in Group J in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of a heavy chain variable region sequence and a light chain variable region sequence from the combinations shown in Group K in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of a heavy chain variable region sequence and a light chain variable region sequence from the combinations shown in Group L in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of a heavy chain variable region sequence and a light chain variable region sequence from the combinations shown in Group M in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the heavy chain variable region sequence and the light chain variable region sequence as shown in Group N in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the heavy chain variable region sequence and the light chain variable region sequence as shown in Group O in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of a heavy chain variable region sequence and a light chain variable region sequence from the combinations shown in Group P in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of a heavy chain variable region sequence and a light chain variable region sequence from the combinations shown in Group Q in Table 7. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of the complementarity determining region (CDR) sequences of a heavy chain sequence from the heavy chain sequences shown in Group A in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a light chain sequence from the light chain sequences shown in Group A in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a heavy chain sequence from the heavy chain sequences shown in Group A in Table 7 and the CDRs of a light chain sequence from the heavy chain sequences shown in Group A in Table 7. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of CDRs of a heavy chain sequence from the heavy chain sequences shown in Group B in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a light chain sequence from the light chain sequences shown in Group B in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a heavy chain sequence from the heavy chain sequences shown in Group B in Table 7 and the CDRs of a light chain sequence from the heavy chain sequences shown in Group B in Table 7. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a heavy chain sequence from the heavy chain sequences shown in Group C in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a light chain sequence from the light chain sequences shown in Group C in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a heavy chain sequence from the heavy chain sequences shown in Group C in Table 7 and the CDRs of a light chain sequence from the heavy chain sequences shown in Group C in Table 7. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a heavy chain sequence from the heavy chain sequences shown in Group D in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a light chain sequence from the light chain sequences shown in Group D in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a heavy chain sequence from the heavy chain sequences shown in Group D in Table 7 and the CDRs of a light chain sequence from the heavy chain sequences shown in Group D in Table 7. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a heavy chain sequence from the heavy chain sequences shown in Group E in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a light chain sequence from the light chain sequences shown in Group E in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a heavy chain sequence from the heavy chain sequences shown in Group E in Table 7 and the CDRs of a light chain sequence from the heavy chain sequences shown in Group E in Table 7. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a heavy chain sequence from the heavy chain sequences shown in Group F in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a light chain sequence from the light chain sequences shown in Group F in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a heavy chain sequence from the heavy chain sequences shown in Group F in Table 7 and the CDRs of a light chain sequence from the heavy chain sequences shown in Group F in Table 7. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a heavy chain sequence from the heavy chain sequences shown in Group G in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a light chain sequence from the light chain sequences shown in Group G in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a heavy chain sequence from the heavy chain sequences shown in Group G in Table 7 and the CDRs of a light chain sequence from the heavy chain sequences shown in Group G in Table 7. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a heavy chain sequence from the heavy chain sequences shown in Group H in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a light chain sequence from the light chain sequences shown in Group H in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a heavy chain sequence from the heavy chain sequences shown in Group H in Table 7 and the CDRs of a light chain sequence from the heavy chain sequences shown in Group H in Table 7. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a heavy chain sequence from the heavy chain sequences shown in Group I in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a light chain sequence from the light chain sequences shown in Group I in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a heavy chain sequence from the heavy chain sequences shown in Group I in Table 7 and the CDRs of a light chain sequence from the heavy chain sequences shown in Group I in Table 7. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a heavy chain sequence from the heavy chain sequences shown in Group J in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a light chain sequence from the light chain sequences shown in Group J in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a heavy chain sequence from the heavy chain sequences shown in Group J in Table 7 and the CDRs of a light chain sequence from the heavy chain sequences shown in Group J in Table 7. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a heavy chain sequence from the heavy chain sequences shown in Group K in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a light chain sequence from the light chain sequences shown in Group K in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a heavy chain sequence from the heavy chain sequences shown in Group K in Table 7 and the CDRs of a light chain sequence from the heavy chain sequences shown in Group K in Table 7. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a heavy chain sequence from the heavy chain sequences shown in Group L in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a light chain sequence from the light chain sequences shown in Group L in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a heavy chain sequence from the heavy chain sequences shown in Group L in Table 7 and the CDRs of a light chain sequence from the heavy chain sequences shown in Group L in Table 7. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a heavy chain sequence from the heavy chain sequences shown in Group M in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a light chain sequence from the light chain sequences shown in Group M in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a heavy chain sequence from the heavy chain sequences shown in Group M in Table 7 and the CDRs of a light chain sequence from the heavy chain sequences shown in Group M in Table 7. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a heavy chain sequence from the heavy chain sequences shown in Group N in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a light chain sequence from the light chain sequences shown in Group N in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a heavy chain sequence from the heavy chain sequences shown in Group N in Table 7 and the CDRs of a light chain sequence from the heavy chain sequences shown in Group N in Table 7. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a heavy chain sequence from the heavy chain sequences shown in Group O in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a light chain sequence from the light chain sequences shown in Group O in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a heavy chain sequence from the heavy chain sequences shown in Group O in Table 7 and the CDRs of a light chain sequence from the heavy chain sequences shown in Group O in Table 7. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a heavy chain sequence from the heavy chain sequences shown in Group P in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a light chain sequence from the light chain sequences shown in Group P in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a heavy chain sequence from the heavy chain sequences shown in Group P in Table 7 and the CDRs of a light chain sequence from the heavy chain sequences shown in Group P in Table 7. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a heavy chain sequence from the heavy chain sequences shown in Group Q in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a light chain sequence from the light chain sequences shown in Group Q in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a heavy chain sequence from the heavy chain sequences shown in Group Q in Table 7 and the CDRs of a light chain sequence from the heavy chain sequences shown in Group Q in Table 7. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a heavy chain sequence from the heavy chain sequences shown in Group R in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a light chain sequence from the light chain sequences shown in Group R in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a heavy chain sequence from the heavy chain sequences shown in Group R in Table 7 and the CDRs of a light chain sequence from the heavy chain sequences shown in Group R in Table 7. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a heavy chain sequence from the heavy chain sequences shown in Group S in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a light chain sequence from the light chain sequences shown in Group S in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a heavy chain sequence from the heavy chain sequences shown in Group S in Table 7 and the CDRs of a light chain sequence from the heavy chain sequences shown in Group S in Table 7. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a heavy chain sequence from the heavy chain sequences shown in Group T in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a light chain sequence from the light chain sequences shown in Group T in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a heavy chain sequence from the heavy chain sequences shown in Group T in Table 7 and the CDRs of a light chain sequence from the heavy chain sequences shown in Group T in Table 7. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a heavy chain sequence from the heavy chain sequences shown in Group U in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a light chain sequence from the light chain sequences shown in Group U in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a heavy chain sequence from the heavy chain sequences shown in Group U in Table 7 and the CDRs of a light chain sequence from the heavy chain sequences shown in Group U in Table 7. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a heavy chain sequence from the heavy chain sequences shown in Group V in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a light chain sequence from the light chain sequences shown in Group V in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a heavy chain sequence from the heavy chain sequences shown in Group V in Table 7 and the CDRs of a light chain sequence from the heavy chain sequences shown in Group V in Table 7. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of the heavy chain sequence of SEQ ID NO: 619 and a combination of the CDRs of the light chain sequence of SEQ ID NO: 1856 as shown in Group V in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the heavy chain sequence of SEQ ID NO: 619 and the light chain sequence of SEQ ID NO: 1856 as shown in Group V in Table 7. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of the heavy chain sequence of SEQ ID NO: 1846 and a combination of the CDRs of the light chain sequence of SEQ ID NO: 1858 as shown in Group V in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the heavy chain sequence of SEQ ID NO: 1846 and the light chain sequence of SEQ ID NO: 1858 as shown in Group V in Table 7. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of the heavy chain sequence of SEQ ID NO: 1843 and a combination of the CDRs of the light chain sequence of SEQ ID NO: 1859 as shown in Group V in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the heavy chain sequence of SEQ ID NO: 1843 and the light chain sequence of SEQ ID NO: 1859 as shown in Group V in Table 7. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of the heavy chain sequence of SEQ ID NO: 1847 and a combination of the CDRs of the light chain sequence of SEQ ID NO: 737 as shown in Group V in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the heavy chain sequence of SEQ ID NO: 1847 and the light chain sequence of SEQ ID NO: 737 as shown in Group V in Table 7. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of the heavy chain sequence of SEQ ID NO: 1848 and a combination of the CDRs of the light chain sequence of SEQ ID NO: 1860 as shown in Group V in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the heavy chain sequence of SEQ ID NO: 1848 and the light chain sequence of SEQ ID NO: 1860 as shown in Group V in Table 7. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of the heavy chain sequence of SEQ ID NO: 1844 and a combination of the CDRs of the light chain sequence of SEQ ID NO: 1861 as shown in Group V in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the heavy chain sequence of SEQ ID NO: 1844 and the light chain sequence of SEQ ID NO: 1861 as shown in Group V in Table 7. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of the heavy chain sequence of SEQ ID NO: 1841 and a combination of the CDRs of the light chain sequence of SEQ ID NO: 737 as shown in Group V in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the heavy chain sequence of SEQ ID NO: 1841 and the light chain sequence of SEQ ID NO: 737 as shown in Group V in Table 7. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of the heavy chain sequence of SEQ ID NO: 1842 and a combination of the CDRs of the light chain sequence of SEQ ID NO: 737 as shown in Group V in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the heavy chain sequence of SEQ ID NO: 1842 and the light chain sequence of SEQ ID NO: 737 as shown in Group V in Table 7. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of the heavy chain sequence of SEQ ID NO: 1845 and a combination of the CDRs of the light chain sequence of SEQ ID NO: 737 as shown in Group V in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the heavy chain sequence of SEQ ID NO: 1845 and the light chain sequence of SEQ ID NO: 737 as shown in Group V in Table 7. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of the heavy chain sequence of SEQ ID NO: 1835 and a combination of the CDRs of the light chain sequence of SEQ ID NO: 1857 as shown in Group V in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the heavy chain sequence of SEQ ID NO: 1835 and the light chain sequence of SEQ ID NO: 1857 as shown in Group V in Table 7. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of the heavy chain sequence of SEQ ID NO: 1836 and a combination of the CDRs of the light chain sequence of SEQ ID NO: 1862 as shown in Group V in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the heavy chain sequence of SEQ ID NO: 1836 and the light chain sequence of SEQ ID NO: 1862 as shown in Group V in Table 7. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of the heavy chain sequence of SEQ ID NO: 1837 and a combination of the CDRs of the light chain sequence of SEQ ID NO: 1863 as shown in Group V in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the heavy chain sequence of SEQ ID NO: 1837 and the light chain sequence of SEQ ID NO: 1863 as shown in Group V in Table 7. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of the heavy chain sequence of SEQ ID NO: 1838 and a combination of the CDRs of the light chain sequence of SEQ ID NO: 1864 as shown in Group V in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the heavy chain sequence of SEQ ID NO: 1838 and the light chain sequence of SEQ ID NO: 1864 as shown in Group V in Table 7. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of the heavy chain sequence of SEQ ID NO: 1838 and a combination of the CDRs of the light chain sequence of SEQ ID NO: 1865 as shown in Group V in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the heavy chain sequence of SEQ ID NO: 1838 and the light chain sequence of SEQ ID NO: 1865 as shown in Group V in Table 7. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of the heavy chain sequence of SEQ ID NO: 1839 and a combination of the CDRs of the light chain sequence of SEQ ID NO: 1864 as shown in Group V in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the heavy chain sequence of SEQ ID NO: 1839 and the light chain sequence of SEQ ID NO: 1864 as shown in Group V in Table 7. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of the heavy chain sequence of SEQ ID NO: 1839 and a combination of the CDRs of the light chain sequence of SEQ ID NO: 1865 as shown in Group V in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the heavy chain sequence of SEQ ID NO: 1839 and the light chain sequence of SEQ ID NO: 1865 as shown in Group V in Table 7. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of the heavy chain sequence of SEQ ID NO: 1840 and a combination of the CDRs of the light chain sequence of SEQ ID NO: 1866 as shown in Group V in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the heavy chain sequence of SEQ ID NO: 1840 and the light chain sequence of SEQ ID NO: 1866 as shown in Group V in Table 7. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of the heavy chain sequence of SEQ ID NO: 1841 and a combination of the CDRs of the light chain sequence of SEQ ID NO: 1867 as shown in Group V in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the heavy chain sequence of SEQ ID NO: 1841 and the light chain sequence of SEQ ID NO: 1867 as shown in Group V in Table 7. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of the heavy chain sequence of SEQ ID NO: 1841 and a combination of the CDRs of the light chain sequence of SEQ ID NO: 1868 as shown in Group V in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the heavy chain sequence of SEQ ID NO: 1841 and the light chain sequence of SEQ ID NO: 1868 as shown in Group V in Table 7. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of the heavy chain sequence of SEQ ID NO: 1849 and a combination of the CDRs of the light chain sequence of SEQ ID NO: 1858 as shown in Group V in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the heavy chain sequence of SEQ ID NO: 1849 and the light chain sequence of SEQ ID NO: 1858 as shown in Group V in Table 7. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of the heavy chain sequence of SEQ ID NO: 1853 and a combination of the CDRs of the light chain sequence of SEQ ID NO: 1859 as shown in Group V in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the heavy chain sequence of SEQ ID NO: 1853 and the light chain sequence of SEQ ID NO: 1859 as shown in Group V in Table 7. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of the heavy chain sequence of SEQ ID NO: 1869 and a combination of the CDRs of the light chain sequence of SEQ ID NO: 737 as shown in Group V in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the heavy chain sequence of SEQ ID NO: 1869 and the light chain sequence of SEQ ID NO: 737 as shown in Group V in Table 7. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of the heavy chain sequence of SEQ ID NO: 1850 and a combination of the CDRs of the light chain sequence of SEQ ID NO: 1860 as shown in Group V in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the heavy chain sequence of SEQ ID NO: 1850 and the light chain sequence of SEQ ID NO: 1860 as shown in Group V in Table 7. 
     n some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of the heavy chain sequence of SEQ ID NO: 1851 and a combination of the CDRs of the light chain sequence of SEQ ID NO: 1861 as shown in Group V in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the heavy chain sequence of SEQ ID NO: 1851 and the light chain sequence of SEQ ID NO: 1861 as shown in Group V in Table 7. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of the heavy chain sequence of SEQ ID NO: 1852 and a combination of the CDRs of the light chain sequence of SEQ ID NO: 737 as shown in Group V in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the heavy chain sequence of SEQ ID NO: 1852 and the light chain sequence of SEQ ID NO: 737 as shown in Group V in Table 7. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of the heavy chain sequence of SEQ ID NO: 1854 and a combination of the CDRs of the light chain sequence of SEQ ID NO: 737 as shown in Group V in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the heavy chain sequence of SEQ ID NO: 1854 and the light chain sequence of SEQ ID NO: 737 as shown in Group V in Table 7. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of the heavy chain sequence of SEQ ID NO: 1855 and a combination of the CDRs of the light chain sequence of SEQ ID NO: 737 as shown in Group V in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the heavy chain sequence of SEQ ID NO: 1855 and the light chain sequence of SEQ ID NO: 737 as shown in Group V in Table 7. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a heavy chain sequence from the heavy chain sequences shown in Group W in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a light chain sequence from the light chain sequences shown in Group W in Table 7. In some embodiments, the activatable anti-PD-1 antibody includes a combination of the CDRs of a heavy chain sequence from the heavy chain sequences shown in Group W in Table 7 and the CDRs of a light chain sequence from the heavy chain sequences shown in Group W in Table 7. 
     
       
         
           
               
             
               
                 TABLE 7 
               
               
                   
               
               
                 Variable Heavy Chain Region (VH) and Variable Light Chain Region 
               
               
                 (VL) Sequences for Activatable Antibodies that Bind PD-1 
               
               
                   
               
             
            
               
                 Group A 
               
            
           
           
               
               
            
               
                 VH 
                 QVQLVESGGDVVQPGGSLRLSCAASGVAFSNYGMHWVRQAPGKGLEWVAVIWYDGSNKYYADSVKGRFTISR 
               
               
                   
                 DNSKNMLYLQMNSLRAEDTAMYYCARNDDYWGQGTLVTVSS (SEQ ID NO: 615) 
               
               
                   
               
               
                 VH 
                 QVQLVESGGDVVQPGRSLRLSCAASGLTFTNYGFHWVRQAPGKGLEWVAVIWYDGSKKYYADSVKGRFTISR 
               
               
                   
                 DNSKNTLYLQMNNLRAEDTAVYYCATGDDYWGQGTLVTVSS (SEQ ID NO: 617) 
               
               
                   
               
               
                 VH 
                 QVYLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHWVRQAPGKGLEWVALIWYDGSNKYYADSVKGRFTISR 
               
               
                   
                 DNSKNTLYLQMTSLRVEDTAVYYCASNVDHWGQGTLVTVSS (SEQ ID NO: 618) 
               
               
                   
               
               
                 VH 
                 QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRYYADSVKGRFTISR 
               
               
                   
                 DNSKNTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSS (SEQ ID NO: 1346) 
               
               
                   
               
               
                 VH 
                 QLQLQESGPGLVKPSETLSLTCTVSGGSLSRSSFFWGWIRQPPGKGLEWIGSIYYSGSTYYNPSLKSRVTIS 
               
               
                   
                 VDTSKNQFSLKLSSVTAADTAVYYCVRDYDILTGDEDYWGQGTLVTVSS (SEQ ID NO: 620) 
               
               
                   
               
               
                 VH 
                 QVQLVESGGGVVQPGRSLRLSCTTSGITFSSYGFHWVRQAPGKGLEWVAVIWYDGSKKYYADSVKGRFTLSR 
               
               
                   
                 DDSKNTLYLQMNSLRAEDTAVYYCVTGDDYWGQGTLVTVSS (SEQ ID NO: 621) 
               
               
                   
               
               
                 VH 
                 QLQLQESGPGLVKPSETLSLTCSVSGGSLSRSSYFWGWIRQPPGKGLEWIASIFYSGETYFNPSLKSRVTIS 
               
               
                   
                 VDTSRNQFSLKLSSVTAADTAVYYCARDYDILTGDEDYWGQGTLVTVSS (SEQ ID NO: 623) 
               
               
                   
               
               
                 VL 
                 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLIIYDASNRATGIPARFSGSGSGTDFT 
               
               
                   
                 LTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIK (SEQ ID NO: 624) 
               
               
                   
               
               
                 VL 
                 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDTSNRATGIPARFSGSGSGTDFT 
               
               
                   
                 LTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIK (SEQ ID NO: 625) 
               
               
                   
               
               
                 VL 
                 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFT 
               
               
                   
                 LTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIK (SEQ ID NO: 626) 
               
               
                   
               
               
                 VL 
                 DIQMTQSPSSLSASVGDRVSITCRASQGISSWLAWYQQKPEKAPKSLIYAASNLRSGVPSRFSGSGSGTDFT 
               
               
                   
                 LTISSLQPEDFATYYCQQYYSYPRTFGQGTKVEIK (SEQ ID NO: 628) 
               
               
                   
               
               
                 VL 
                 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFT 
               
               
                   
                 LTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIK (SEQ ID NO: 629) 
               
               
                   
               
               
                 VL 
                 DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQKPEKAPKSLIYAASSLQSGVPSRFSGSGSGTDFT 
               
               
                   
                 LTISSLQPEDFATYYCQQYYSYPRTFGQGTKVEIK (SEQ ID NO: 630) 
               
               
                   
               
            
           
           
               
            
               
                 Group B 
               
            
           
           
               
               
            
               
                 VH 
                 QVQLQQPGAELVKPGASVKLSCKASGYTFTSYYLYWMKQRPGQGLEWIGGVNPSNGGTNFSEKFKSKATLTV 
               
               
                   
                 DKSSSTAYMQLSSLTSEDSAVYYCTRRDSNYDGGFDYWGQGTTLTVSSAK (SEQ ID NO: 631) 
               
               
                   
               
               
                 VH 
                 QVQLQQPGAELVKPGTSVKLSCKASGYTFTNYYMYWVKQRPGQGLEWIGGINPSNGGTNFNEKFKNKATLTV 
               
               
                   
                 DSSSSTTYMQLSSLTSEDSAVYYCTRRDYRFDMGFDYWGQGTTLTVSSAK (SEQ ID NO: 632) 
               
               
                   
               
               
                 VH 
                 MDWTWSILFLVAAPTGAHSQVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGINP 
               
               
                   
                 SNGGTNFNEKFKNRVTLTTDSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYWGQGTTVTVSS (SEQ 
               
               
                   
                 ID NO: 633) 
               
               
                   
               
               
                 VH 
                 QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGINPSNGGTNFNEKFKNRVTLTT 
               
               
                   
                 DSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYWGQGTTVTVSS (SEQ ID NO: 634) 
               
               
                   
               
               
                 VH 
                 EVQLVLSGGGFVQPGGSLKLSCAASGFTFSSYAMSWVRQNPERRLVWVATITGGGRNTYYPDSVKGRFTISR 
               
               
                   
                 DNAKNTLYLQMSSLRSEDTAMYYCTRQGYDGYTWFAYWGQGTLVTVS (627) 
               
               
                   
               
               
                 VL 
                 DIVLTQSPTSLAVSLGQRATISCRASKSVSTSGFSYLHWYQQKPGQPPKLLIFLASNLESGVPARFSGSGSG 
               
               
                   
                 TDFTLNIHPVEEEDAATYYCQHSWELPLTFGAGTKLELK (SEQ ID NO: 635) 
               
               
                   
               
               
                 VL 
                 DIVLTQSPASLAVSLGQRAAISCRASKGVSTSGYSYLHWYQQKPGQSPKLLIYLASYLESGVPARFSGSGSG 
               
               
                   
                 TDFTLNIHPVEEEDAATYYCQHSRDLPLTFGTGTKLELK (SEQ ID NO: 636) 
               
               
                   
               
               
                 VL 
                 MAPVQLLGLLVLFLPAMRCEIVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIY 
               
               
                   
                 LASYLESGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIK (SEQ ID 
               
               
                   
                 NO: 637) 
               
               
                   
               
               
                 VL 
                 EIVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLESGVPARFSGSGSG 
               
               
                   
                 TDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIK (SEQ ID NO: 638) 
               
               
                   
               
               
                 VL 
                 MAPVQLLGLLVLFLPAMRCEIVLTQSPLSLPVTPGEPASISCRASKGVSTSGYSYLHWYLQKPGQSPQLLIY 
               
               
                   
                 LASYLESGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCQHSRDLPLTFGQGTKLEIK (SEQ ID 
               
               
                   
                 NO: 639) 
               
               
                   
               
               
                 VL 
                 EIVLTQSPLSLPVTPGEPASISCRASKGVSTSGYSYLHWYLQKPGQSPQLLIYLASYLESGVPDRFSGSGSG 
               
               
                   
                 TDFTLKISRVEAEDVGVYYCQHSRDLPLTFGQGTKLEIK (SEQ ID NO: 640) 
               
               
                   
               
               
                 VL 
                 MAPVQLLGLLVLFLPAMRCDIVMTQTPLSLPVTPGEPASISCRASKGVSTSGYSYLHWYLQKPGQSPQLLIY 
               
               
                   
                 LASYLESGVPDRFSGSGSGTAFTLKISRVEAEDVGLYYCQHSRDLPLTFGQGTKLEIK (SEQ ID 
               
               
                   
                 NO: 641) 
               
               
                   
               
               
                 VL 
                 DIVMTQTPLSLPVTPGEPASISCRASKGVSTSGYSYLHWYLQKPGQSPQLLIYLASYLESGVPDRFSGSGSG 
               
               
                   
                 TAFTLKISRVEAEDVGLYYCQHSRDLPLTFGQGTKLEIK (SEQ ID NO: 642) 
               
               
                   
               
               
                 VL 
                 DIVLTQSPTSLAVSLGQRATISCRASESVDNSGISFMNWFQQKPGQPPKLLIYAASNPGSGVPARFSGSGSG 
               
               
                   
                 TDFSLNIHPMEEDDTAMYFCQQSKEVPWTFGGGTELEIKR (SEQ ID NO: 725) 
               
               
                   
               
               
                 HC 
                 MAVLGLLFCLVTFPSCVLSQVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGINP 
               
               
                   
                 SNGGTNFNEKFKNRVTLTTDSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYWGQGTTVTVSSASTKG 
               
               
                   
                 PSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG 
               
               
                   
                 TKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQE 
               
               
                   
                 DPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKG 
               
               
                   
                 QPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVD 
               
               
                   
                 KSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 643) 
               
               
                   
               
               
                 HC 
                 QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGINPSNGGTNFNEKFKNRVTLTT 
               
               
                   
                 DSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAA 
               
               
                   
                 LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDK 
               
               
                   
                 RVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAK 
               
               
                   
                 TKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTK 
               
               
                   
                 NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEAL 
               
               
                   
                 HNHYTQKSLSLSLGK (SEQ ID NO: 644) 
               
               
                   
               
               
                 HC 
                 MAVLGLLFCLVTFPSCVLSQVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGINP 
               
               
                   
                 SNGGTNFNEKFKNRVTLTTDSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYWGQGTTVTVSSASTKG 
               
               
                   
                 PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG 
               
               
                   
                 TQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV 
               
               
                   
                 SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK 
               
               
                   
                 AKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL 
               
               
                   
                 TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 645) 
               
               
                   
               
               
                 HC 
                 QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGINPSNGGTNFNEKFKNRVTLTT 
               
               
                   
                 DSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAA 
               
               
                   
                 LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDK 
               
               
                   
                 KVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH 
               
               
                   
                 NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDE 
               
               
                   
                 LTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH 
               
               
                   
                 EALHNHYTQKSLSLSPGK (SEQ ID NO: 646) 
               
               
                   
               
               
                 LC 
                 MAPVQLLGLLVLFLPAMRCEIVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIY 
               
               
                   
                 LASYLESGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIKRTVAAPSVFIFPPS 
               
               
                   
                 DEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYA 
               
               
                   
                 CEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 647) 
               
               
                   
               
               
                 LC 
                 EIVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLESGVPARFSGSGSG 
               
               
                   
                 TDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY 
               
               
                   
                 PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRG 
               
               
                   
                 EC (SEQ ID NO: 648) 
               
               
                   
               
               
                 LC 
                 MAPVQLLGLLVLFLPAMRCEIVLTQSPLSLPVTPGEPASISCRASKGVSTSGYSYLHWYLQKPGQSPQLLIY 
               
               
                   
                 LASYLESGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCQHSRDLPLTFGQGTKLEIKRTVAAPSVFIFPPS 
               
               
                   
                 DEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYA 
               
               
                   
                 CEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 649) 
               
               
                   
               
               
                 LC 
                 EIVLTQSPLSLPVTPGEPASISCRASKGVSTSGYSYLHWYLQKPGQSPQLLIYLASYLESGVPDRFSGSGSG 
               
               
                   
                 TDFTLKISRVEAEDVGVYYCQHSRDLPLTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY 
               
               
                   
                 PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRG 
               
               
                   
                 EC (SEQ ID NO: 650) 
               
               
                   
               
               
                 LC 
                 MAPVQLLGLLVLFLPAMRCDIVMTQTPLSLPVTPGEPASISCRASKGVSTSGYSYLHWYLQKPGQSPQLLIY 
               
               
                   
                 LASYLESGVPDRFSGSGSGTAFTLKISRVEAEDVGLYYCQHSRDLPLTFGQGTKLEIKRTVAAPSVFIFPPS 
               
               
                   
                 DEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYA 
               
               
                   
                 CEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 651) 
               
               
                   
               
               
                 LC 
                 DIVMTQTPLSLPVTPGEPASISCRASKGVSTSGYSYLHWYLQKPGQSPQLLIYLASYLESGVPDRFSGSGSG 
               
               
                   
                 TAFTLKISRVEAEDVGLYYCQHSRDLPLTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY 
               
               
                   
                 PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRG 
               
               
                   
                 EC (SEQ ID NO: 652) 
               
               
                   
               
            
           
           
               
            
               
                 Group C 
               
            
           
           
               
               
            
               
                 VH 
                 DVQLQESGPGLVKPSQSLSLTCTVTGYSITSDYAWNWIRQFPGNKLEWMGYINYSGSTSYNPSLKSRISITR 
               
               
                   
                 DTSKNQFFLQLNSVTTEDTATYYCARWIGSSAWYFDVWGAGTTVTV (SEQ ID NO: 726) 
               
               
                   
               
               
                 VL 
                 DVLMTQTPLSLPVSLGDQASISCRSGQNIVHSNGNTYLEWYLQKPGQSPKLLIYKVSNRFFGVPDRISGSGS 
               
               
                   
                 GTDFTLKISRVEAEDLGVYFCFQGSHVPFTFGSGTKLEIK (SEQ ID NO: 727) 
               
               
                   
               
               
                 VH 
                 QVQLQQPGAELVKPGASVKLSCKASGYTFTTYYLYWVRQRPGQGLEWIGGINPSNGGTNFNEKFKSKATLTV 
               
               
                   
                 DKSSSTAYMQLNSLTSEDSAVYYCTRRDYRYDRGFDYWGQGTSVTV (SEQ ID NO: 728) 
               
               
                   
               
               
                 VL 
                 DIVLTQSPASLAVSLGQRATISCRASKSVSTSGFNYIHWYQQKPGQPPKLLIYLASNLESGVPARFSGSGSG 
               
               
                   
                 TDFTLNIHPVEDEDAATYYCQHSRELPLTFGAGTKLEIK (SEQ ID NO: 729) 
               
               
                   
               
               
                 VH 
                 QVQLQQSGAELVKPGASVKMSCKAFGYTFTTYPIEWMKQNHGKSLEWIGNFHPYNDDTKYNEKFKGKAKLTV 
               
               
                   
                 EKSSTTVYLELSRLTSDDSAVYYCARENYGSHGGFVYWGQGTLVTV (SEQ ID NO: 730) 
               
               
                   
               
               
                 VL 
                 ENVLTQSPAIMSASPGEKVTMTCRASSSVISSYLHWYQQKSGASPKLWIYSTSNLASGVPDRFSGSGSGTSY 
               
               
                   
                 SLTISSVEAEDAATYYCQQYNGYPLTFGAGTKLEIK (SEQ ID NO: 731) 
               
               
                   
               
            
           
           
               
            
               
                 Group D 
               
            
           
           
               
               
            
               
                   
                 LFTVTVPKELYIIEHGSNVTLECNFDTGSHVNLGAITASLQKVENDTSPHRERATLLEEQLPLGKASFHIPQ 
               
               
                   
                 VQVRDEGQYQCIIIYGVAWDYKYLTLKVKASYRKINTHILKVPETDEVELTCQATGYPLAEVSWPNVSVPAN 
               
               
                   
                 TSHSRTPEGLYQVTSVLRLKPPPGRNFSCVFWNTHVRELTLASIDLQSQMEPRTHPTWEPKSCDKTHTCPPC 
               
               
                   
                 PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR 
               
               
                   
                 VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFY 
               
               
                   
                 PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP 
               
               
                   
                 GK (SEQ ID NO: 732) 
               
               
                   
               
            
           
           
               
            
               
                 Group E 
               
            
           
           
               
               
            
               
                 VH 
                 EVQLVQSGAEVKKPGASVKVSCKASGYRFTSYGISWVRQAPGQGLEWMGWISAYNGNTNYAQKLQGRVTMTT 
               
               
                   
                 DTSTNTAYMELRSLRSDDTAVYYCARDADYSSGSGYWGQGTLVTVSS (SEQ ID NO: 733) 
               
               
                   
               
               
                 VH 
                 QVQLVQSGAEVKKPGASVRVSCKASGYTLTSYYIHWVRQAPGQGLEWMGIINPRGATISYAQKFQGRVTMTR 
               
               
                   
                 DTSTSTVYMELRNLKSEDTALYYCATAGIYGFDFDYWGRGTLVTVSS (SEQ ID NO: 734) 
               
               
                   
               
               
                 VH 
                 QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGAYYWSWIRQHPGKGLEWIGYIYYNGNTYYNPSLRSLVTIS 
               
               
                   
                 VDASKNQFSLKLSSVTAADTAVYYCARASDYVWGGYRYMDAFDIWGRGTLITVSS (SEQ ID NO: 735) 
               
               
                   
               
               
                 VH 
                 GAHSEVQLVQSGGGVVQPGRSLRLSCAASGFTFSSYWCDRMSWVRQAPGKGLEWVSAISGSGGSTYYADSVK 
               
               
                   
                 GRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKENWGSYFDLWGQGTTVTVSS (SEQ ID NO: 736) 
               
               
                   
               
               
                 VL 
                 SYELTQPPSVSVSPGQTARITCSGDALPKQYAYWYQQKPGQAPVMVIYKDTERPSGIPERFSGSSSGTKVTL 
               
               
                   
                 TISGVQAEDEADYYCQSADNSITYRVFGGGTKVTVL (SEQ ID NO: 737) 
               
               
                   
               
               
                 VL 
                 QSALTQPASVSGSPGQSITISCTGTSNDVGGYNYVSWYQHHPGKAPKLIIYDVTNRPSGVSDRFSGSKSGNT 
               
               
                   
                 ASLTISGLLAEDEGDYYCSSYTIVTNFEVLFGGGTKLTV (SEQ ID NO: 738) 
               
               
                   
               
               
                 VL 
                 QSVLTQPPSASGTPGQRVTISCSGSNSNIGSNSVNWYQQLPGTAPKLLIYGNNQRPSGVPDRFSGSKSGTSA 
               
               
                   
                 SLAISGLQSENEADYYCAAWDDSLNGPVFGRGTKVTVLGE (SEQ ID NO: 739) 
               
               
                   
               
               
                 VL 
                 GVHSDIVMTQSPSTLSASVGDRVTITCRASQGISSWLAWYQQKPGRAPKVLIYKASTLESGVPSRFSGSGSG 
               
               
                   
                 TDFTLTISSLQPEDFATYYCQQSYSTPWTFGQGTKLEIKR (SEQ ID NO: 740) 
               
               
                   
               
            
           
           
               
            
               
                 Group F 
               
            
           
           
               
               
            
               
                 VH 
                 QVQLVQSGHEVKQPGASVKMSCKASGYSFTSSWIHWVKQAPGQGLEWIGYIYPSTGFTEYNQKFKDRATLTA 
               
               
                   
                 DKSTSTAYMELSSLRSEDTAVYYCARWRDSSGYHAMDYWGQGTLVTVSS (SEQ ID NO: 741) 
               
               
                   
               
               
                 VH 
                 QVQLVQSGHEVKQPGASVKMSCKASGYSFTSSWIHWVRQAPGQGLEWIGYIYPSTGFTEYNQKFKDRATLTA 
               
               
                   
                 DKSTSTAYMELSSLRSEDTAVYYCARWRDSSGYHAMDYWGQGTLVTVSS (SEQ ID NO: 742) 
               
               
                   
               
               
                 VL 
                 EIVLTQSPATLSLSPGQRLTISCRASQSVSTSGYSYMHWYQQKPDQSPKLLIKFGSNLESGIPARFSGSGSG 
               
               
                   
                 TDFTLTISSLEPEDFATYYCQHSWEIPYTFGQGTKLEIK (SEQ ID NO: 743) 
               
               
                   
               
               
                 VL 
                 DIVLTQSPATLSLSPGQRLTISCRASQSVSTSGYSYMHWYQQKPDQSPKLLIKFGSNLESGIPARFSGSGSG 
               
               
                   
                 TDFTLTISSLEPEDFAVYYCQHSWEIPYTFGQGTKLEIK (SEQ ID NO: 744) 
               
               
                   
               
            
           
           
               
            
               
                 Group H 
               
            
           
           
               
               
            
               
                 VH 
                 QGQLVQSGAEVKKPGASVKVSCKASGYTFTDYEMHWVRQAPIHGLEWIGVIESETGGTAYNQKFKGRVTITA 
               
               
                   
                 DKSTSTAYMELSSLRSEDTAVYYCAREGITTVATTYYWYFDVWGQGTTVTVSS (SEQ ID NO: 745) 
               
               
                   
               
               
                 VL 
                 DVVMTQSPLSLPVTLGQPASISCRSSQSIVHSNGNTYLEWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGS 
               
               
                   
                 GTDFTLKISRVEAEDVGVYYCFQGSHVPLTFGQGTKLEIK (SEQ ID NO: 746) 
               
               
                   
               
            
           
           
               
            
               
                 Group I 
               
            
           
           
               
               
            
               
                 VH 
                 MGLGLQWVFFVALLKGVHCEVRLLESGGGLVKPEGSLKLSCVASGFTFSDYFMSWVRQAPGKGLEWVAHIYT 
               
               
                   
                 KSYNYATYYSGSVKGRFTISRDDSRSMVYLQMNNLRTEDTATYYCTRDGSGYPSLDFWGQGTQVTVSSATTT 
               
               
                   
                 APSVYPLAPACDSTTKS (SEQ ID NO: 747) 
               
               
                   
               
               
                 VL 
                 YELTQPPSASVNVGETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPERISGSSSGTTATLT 
               
               
                   
                 IRDVRAEDEGDYYCFSGYVDSDSKLYVFGSGTQLTVLGGPKSSPKVTVFPPSPEELRTNKATLVCLVNDFYP 
               
               
                   
                 GSATVTWKANGATINDGVKTTKPSKQGQNYMTSSYLSLTADQWKSHNRVSCQVTHEGETVEKSLSPAECL 
               
               
                   
                 (SEQ ID NO: 748) 
               
               
                   
               
               
                 Bs 
                 METDTLLLWVLLLWVPGSTGDAAQPARRARRTKLGTELGSPGLQEFEVRLLESGGGLVKPEGSLKLSCVASG 
               
               
                 Ab 
                 FTFSDYFMSWVRQAPGKGLEWVAHIYTKSYNYATYYSGSVKGRFTISRDDSRSMVYLQMNNLRTEDTATYYC 
               
               
                   
                 TRDGSGYPSLDFWGQGTQVTVSSGGGGSDIQMTQSPSSLPASLGDRVTINCQASQDISNYLNWYQQKPGKAP 
               
               
                   
                 KLLIYYTNKLADGVPSRFSGSGSGRDSSFTISSLESEDIGSYYCQQYYNYPWTFGPGTKLEIKGGGGSGGGG 
               
               
                   
                 SGGGGSEVQLVESGGGLVQPGKSLKLSCEASGFTFSGYGMHWVRQAPGRGLESVAYITSSSINIKYADAVKG 
               
               
                   
                 RFTVSRDNAKNLLFLQMNILKSEDTAMYYCARFDWDKNYWGQGTMVTVSSGGGGSYELTQPPSASVNVGETV 
               
               
                   
                 KITCSGDQLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPERISGSSSGTTATLTIRDVRAEDEGDYYCFSG 
               
               
                   
                 YVDSDSKLYVFGSGTQLTVLGPRGGPEQKLISEEDLNSAVDHHHHHH (SEQ ID NO: 749) 
               
               
                   
               
            
           
           
               
            
               
                 Group J 
               
            
           
           
               
               
            
               
                 VH 
                 QLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMGWISAYNGNTNYAQKLQGRVTMTTDT 
               
               
                   
                 STSTATMELRSLRSDDTAVYYCARGRGYSYGIDAFDIWGQGTMVT (SEQ ID NO: 750) 
               
               
                   
               
               
                 VH 
                 LSYVLTQPPSVSVSPGQTARITCSGDALPKQYAYWYQQKPGQAPVLVIYKDSERPSGIPERFSGSSSGTTVT 
               
               
                   
                 LTISGVQAEDEADYYCQSADSSGTYVVFGGGTKLTVLGQP (SEQ ID NO: 751) 
               
               
                   
               
            
           
           
               
            
               
                 Group K 
               
            
           
           
               
               
            
               
                 VH 
                 QVQLQQSGPGLVRPSQTLSLSCDISGDSVSSNSATWNWIRQSPSRGLEWLGRTFYRSKWYHDYALSVKSRIT 
               
               
                   
                 INPDTSKNQFSLQLNSVSPGDTAVYFCVREDIDGRLDYWGQGTLVTVSS (SEQ ID NO: 752) 
               
               
                   
               
               
                 VH 
                 QVQLVQSGSELKKPGASVKISCKASGYIFSDNGVNWVRQAPGQGLEWMGWINTKIGNPTYAQGFTGRFVFSL 
               
               
                   
                 DTSVSTTYLQISSLQAGDTAVYYCAREHDYYYGMDVWGQGTTVTVSS (SEQ ID NO: 753) 
               
               
                   
               
               
                 VH 
                 MAEVQLLESGAEVKKPGASVKVSCKASGYTFTSHYMHWVRQAPGQGLEWMGVINPSGGSTSYAQKFQGRVTM 
               
               
                   
                 TRDTSTSTVYMDLSSLRSEDTAVYYCARRSEAYYHGMDVWGQGTTVTVSS (SEQ ID NO: 754) 
               
               
                   
               
               
                 VH 
                 EVQLVQSGSELKKPGASVKISCKASGYIFSDNGVNWVRQAPGQGLEWMGWINTKIGNPTYAQGFTGRFVFSL 
               
               
                   
                 DTSISTTYLQISSLQAGDTAVYYCAREHDYYYGMDVWGQGTTVTVSS (SEQ ID NO: 755) 
               
               
                   
               
               
                 VH 
                 QVQLVESGGGLVQPGGSLRLSCEATGFTFSRYWMHWVRQAPGKGLEWVSSISSSSSYIYYADSVKGRFTISR 
               
               
                   
                 DNAKNSLYLQMNSLRAEDTAVYYCARDTLEYYGSGILENAMGYYGMDVWGQGTTVTVSS (SEQ ID 
               
               
                   
                 NO: 756) 
               
               
                   
               
               
                 VH 
                 EVQLVESGGGLVRPGGSLRLACAASGFSFSDYYMTWIRQAPGRGLEWIAYISDSGQTVHYADSVKGRFTISR 
               
               
                   
                 DNTKNSLFLQVNTLRAEDTAVYYCAREDLLGYYLQSWGQGTLVTVSS (SEQ ID NO: 757) 
               
               
                   
               
               
                 VH 
                 EVQLVESGGGVVQPGRSLRLSCAASGFTFSSYWMSWVRQAPGKGLEWVANIKQDGSEKYYVDSVKGRFTISR 
               
               
                   
                 DNAKNSLYLQMNSLRAEDTAVYYCAREGEHDAFDIWGQGTMVTVSS (SEQ ID NO: 758) 
               
               
                   
               
               
                 VH 
                 QVQLVQSGSELKKPGASVKISCKASGYIFSDNGVNWVRQAPGQGLEWMGWINTKIGNPTYAQGFTGRFVFSL 
               
               
                   
                 DTSVSTTYLQISSLQAGDTAVYYCAREHDYYYGMDVWGQGTTVTVSS (SEQ ID NO: 759) 
               
               
                   
               
               
                 VH 
                 QVQLVQSGSELKKPGASVKISCKASGYIFSDNGVNWVRQAPGQGLEWMGWINTKIGNPTYAQGFTGRFVFSL 
               
               
                   
                 DTSVSTTYLQISSLQAGDTAVYYCAREHDYYYGMDVWGQGTTVTVSS (SEQ ID NO: 760) 
               
               
                   
               
               
                 VH 
                 QVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQRLEWMGWINAGNGNTKYSQKFQGRVTITR 
               
               
                   
                 DTSASTAYMELSSLRSEDTAVYYCAKVSAGTESWFDPWGQGTLVTVSS (SEQ ID NO: 761) 
               
               
                   
               
               
                 VH 
                 QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMGWISAYNGNTNYAQKLQGRVTMTT 
               
               
                   
                 DTSTSTAYMELRSLRSDDTAVYYCARGLYGDEDYWGQGTLVTVSS (SEQ ID NO: 762) 
               
               
                   
               
               
                 VH 
                 QVQLVQSGSELKKPGASVKISCKASGYIFSDNGVNWVRQAPGQGLEWMGWINTKIGNPTYAQGFTGRFVFSL 
               
               
                   
                 DTSISTTYLQISSLQAGDTAVYYCAREHDYYYGMDVWGQGTTVTVSS (SEQ ID NO: 763) 
               
               
                   
               
               
                 VH 
                 QMQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGIIYPGDSDTRYSPSFQGQVTISA 
               
               
                   
                 DKSISTAYLQWSSLKASDTAMYYCASGVTRKRYSSSWPPFDYWGQGTLVTVSS (SEQ ID NO: 764) 
               
               
                   
               
               
                 VH 
                 QVQLQQWGAGLLKSSETLSLSCAVYGGTFRDDHWSWIRQPPGKGLEWIGESHHTGRTIYNPSLRSRVTMSID 
               
               
                   
                 TSKNEFSLILRSVTAADTATYFCARGNNYVWGNQEDFWGQGTLVTVSS (SEQ ID NO: 765) 
               
               
                   
               
               
                 VH 
                 QVQLQQSGPGLVRPSQTLSLSCDISGDSVSSNSATWNWIRQSPSRGLEWLGRTFYRSKWYHDYALSVKSRIT 
               
               
                   
                 INPDTSKNQFSLQLNSVSPGDTAVYFCVREDIDGRLDYWGQGTLVTVSS (SEQ ID NO: 766) 
               
               
                   
               
               
                 VH 
                 EVQLVESGGALVQPGGSLRLSCAVSGFTFSDHYMDWVRQAPGKGLEWVARSRNKGNSYTTEYAASVRGRFTI 
               
               
                   
                 SRDDSKNSLYLQMNSLKTEDTAVYYCVRVGVVPALDGMDVWGQGTTVTVSS (SEQ ID NO: 767) 
               
               
                   
               
               
                 VH 
                 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMHWVRQAPGKGLEWVSSISSSSSYIYYADSVKGRFTISR 
               
               
                   
                 DNAKNSLYLQMNSLRAEDTAVYYCARDTLEYYGSGILENAMGYYGMDVWGQGTTVTVSS (SEQ ID 
               
               
                   
                 NO: 768) 
               
               
                   
               
               
                 VH 
                 EVQLLESGGGVVQTGRSLRLSCSDSGSTERSQAMHWVRQTPGKGLEWLAVTSHDGSKTYYADSVKGRFTISR 
               
               
                   
                 DNSKNTLYLQMNSLRGEDTAVYYCARGGRGYTYDHSFFDYWGQGTLVTVSS (SEQ ID NO: 769) 
               
               
                   
               
               
                 VH 
                 QVQLVQSGSELKKPGASVKISCKASGYIFSDNGVNWVRQAPGQGLEWMGWINTKDGNPTYAQGFTGRFVFSL 
               
               
                   
                 DTSISTTYLQISSLQAGDTAVYYCAREHDYYYGMDVWGQGTTVTVSS (SEQ ID NO: 770) 
               
               
                   
               
               
                 VH 
                 QVQLVQSGSELKKPGASVKISCKASGYIFSDNGVNWVRQAPGQGLEWMGWINTKTGNPTYAQGFTGRFVFSL 
               
               
                   
                 DTSISTTYLQISSLQAGDTAVYYCAREHDYYYGMDVWGQGTTVTVSS (SEQ ID NO: 771) 
               
               
                   
               
               
                 VH 
                 QVQLVQSGSELKKPGASVKISCKASGYTFSDNGVNWVRQAPGQGLEWMGWINTKDGNPTYAQGFTGRFVFSL 
               
               
                   
                 DTSISTTYLQISSLQAGDTAVYYCAREHDYYYGMDVWGQGTTVTVSS (SEQ ID NO: 772) 
               
               
                   
               
               
                 VH 
                 QVQLVQSGSELKKPGASVKISCKASGYTFSDNGVNWVRQAPGQGLEWMGWINTKTGNPTYAQGFTGRFVFSL 
               
               
                   
                 DTSISTTYLQISSLQAGDTAVYYCAREHDYYYGMDVWGQGTTVTVS (SEQ ID NO: 773) 
               
               
                   
               
               
                 VH 
                 QVQLVQSGSELKKPGASVKISCKASGYKFSDNGVNWVRQAPGQGLEWMGWINTKSGNPTYAQGFTGRFVFSL 
               
               
                   
                 DTSISTTYLQISSLQAGDTAVYYCAREHDYYYGMDVWGQGTTVTVSS (SEQ ID NO: 774) 
               
               
                   
               
               
                 VH 
                 QVQLVQSGSELKKPGASVKISCKASGYTFSDNGVNWVRQAPGQGLEWMGWINTKSGNPTYAQGFTGRFVFSL 
               
               
                   
                 DTSISTTYLQISSLQAGDTAVYYCAREHDYYYGMDVWGQGTTVTVSS (SEQ ID NO: 775) 
               
               
                   
               
               
                 VH 
                 QVQLVQSGSELKKPGASVKISCKASGYKFSDNGVNWVRQAPGQGLEWMGWINTKDGNPTYAQGFTGRFVFSL 
               
               
                   
                 DTSISTTYLQISSLQAGDTAVYYCAREHDYYYGMDVWGQGTTVTVSS (SEQ ID NO: 776) 
               
               
                   
               
               
                 VL 
                 LPVLTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYEVSKRPSGVPDRFSGSKSGNT 
               
               
                   
                 ASLTVSGLQAEDEADYYCSAWDDSLNADVFGGGTKLTVL (SEQ ID NO: 777) 
               
               
                   
               
               
                 VL 
                 QPVLTQPPSASGTPGQRVTISCSGSSSNIGTNTVNWYQQVPGTAPKLLIHGNDQRPSGVPDRFSGSKSDTSA 
               
               
                   
                 SLAITGLQSDDDADYYCSAWDDSLNADVFGGGTKLTVL (SEQ ID NO: 778) 
               
               
                   
               
               
                 VL 
                 QAVLTQPPSASATPGQRVTISCSGSDSNIGTNYVYWYQQFPGTAPQPLIYRDNQRPSGVPDRFSGSKSGTSA 
               
               
                   
                 SLAISGLRSEDEATYFCSTWDDSLNGWVFGGGTKLTVL (SEQ ID NO: 779) 
               
               
                   
               
               
                 VL 
                 QPVLTQPRSVSGSPGQSITTSCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYEVSNRPSGVSNRFSGSKSGNT 
               
               
                   
                 ASLTISGLQAEDEADYYCSSYTSSSTLEVFGTGTKVTVL (SEQ ID NO: 780) 
               
               
                   
               
               
                 VL 
                 YELMQPPSVSGAPGQRVTISCTGSSSNIGAAYDVHWYQQLPGKAPKLVMFANSNRPSGVPDRFSGSKSGTSA 
               
               
                   
                 SLAITGLQAEDEADYYCQSYDISLRAYVFGTGTKLTVL (SEQ ID NO: 781) 
               
               
                   
               
               
                 VL 
                 SYELMQPPSASGTPGQRVTISCSGSSSNIGTNTVNWYQHLPGTAPKLLIYSNNQRPSGVPDRFSGSKSGTSA 
               
               
                   
                 SLAISGLQSEDEADYYCATWDDSPNGWVFGGGTKLTVL (SEQ ID NO: 782) 
               
               
                   
               
               
                 VL 
                 QAVLTQPPSVSAAPGQRVTISCSGSNSNIADTYVSWYQQLPGTAPRLLIYDNDQRPSGIPDRFSGSKSGTSA 
               
               
                   
                 TLGITGLQTGDEADYYCGTWDSSLSGVFGTGTKVTVL (SEQ ID NO: 783) 
               
               
                   
               
               
                 VL 
                 QSVLTQPASVSGSPGQSVTISCTGSSSDVGAYNFVSWYRQYPGKAPKLLIYEVNKRPSDVPDRFSGSKFGNT 
               
               
                   
                 ASLTVSGLQADDEADYYCSSYAGSTDVFGTGTKVTVL (SEQ ID NO: 784) 
               
               
                   
               
               
                 VL 
                 LPVLTQPPSVSGTPGQRVTISCSGSSSNIGSNTVNWYQQLPGTAPKLLIYTNNQRPSGVPDRFSGSKSGTSA 
               
               
                   
                 SLAISGLQSEDEADYYCAAWDESLNGDVFGTGTKVTVL (SEQ ID NO: 785) 
               
               
                   
               
               
                 VL 
                 AIRMTQSPSFLSASVGDRVTITCRTSQNIYNYLNWYQQKPGKAPELLIFVASSLQSGVPSRFSGSGSGTDFT 
               
               
                   
                 LTISSLQPEDFATYFCLQDHSYPYTFGQGTKVEIK (SEQ ID NO: 786) 
               
               
                   
               
               
                 VL 
                 LPVLTQPPSVSEVPGQRVTISCSGGISNIGSNAVNWYQHFPGKAPKLLIYYNDLLPSGVSDRFSASKSGTSA 
               
               
                   
                 SLAISGLRSEDEADYYCAAWDDNLSAYVFATGTKVTVL (SEQ ID NO: 787) 
               
               
                   
               
               
                 VL 
                 QSALTQPPSASGSPGQSVTISCTGTSSDVGGYNYVSWYQHHPGKAPKLMIYEVSKRPSGVPDRFSGSKSAIT 
               
               
                   
                 ASLTISGLLTEDEADYYCSAWDDSLNADVFGGGTKVTVL (SEQ ID NO: 788) 
               
               
                   
               
               
                 VL 
                 DIQMTQSPSSLSASVGDRVTITCRASQSISTYLNWYQQKPGKAPKVLITDASSLETGVPSRFSGSGSGTDFT 
               
               
                   
                 FTISSLQPEDTATYFCQQYDDLPPTFGQGTKLEIK (SEQ ID NO: 789) 
               
               
                   
               
               
                 VL 
                 QAGLTQPRSVSGSPGQSVTISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVTKRPSGVSNRFSGSKSGNT 
               
               
                   
                 ASLTISGLQAEDEADYYCSSYTSSSTYVFGTGTKVTVL (SEQ ID NO: 790) 
               
               
                   
               
               
                 VL 
                 QPVLTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSKSGNT 
               
               
                   
                 ASLAITGLQSDDDADYYCSAWDDSLNADVFGGGTKLTVL (SEQ ID NO: 791) 
               
               
                   
               
               
                 VL 
                 QAGLTQPPSVSKGLRQTATLTCTGNSNNIGDQGAAWLQQHQGHPPRLLSYRNNNRPSGISERLSASRSGNIA 
               
               
                   
                 SLTITGLQPEDEADYYCSAWDSSLSVWVFGGGTKLTVL (SEQ ID NO: 792) 
               
               
                   
               
               
                 VL 
                 QAVLTQPPSASGTPGQRVTISCSGSSSNIGSNTVNWYQQLPGTAPKLLIYSNNQRPSGVPDRFSGSKSGTSA 
               
               
                   
                 SLAISGLQSEDEADYYCAAWDDSLNGYVFGTGTKLTVL (SEQ ID NO: 793) 
               
               
                   
               
               
                 VL 
                 AIRMTQSPSTLSASVGDRVTITCRASENIRNLLAWYQQKPGKAPELLIHGASTLGTGVPSRFSGGGSGTEFT 
               
               
                   
                 LTISSLQPDDFATYYCQQYESYFNTFGQGTKVEIK (SEQ ID NO: 794) 
               
               
                   
               
            
           
           
               
            
               
                 Group L 
               
            
           
           
               
               
            
               
                 VH 
                 QVQLVESGPGVKKPGSSLKLSCTVSGFTFSSYDYYMHWVRQAPGNGLEWMAVIWYSGSNTYYNDSLKSRFSI 
               
               
                   
                 TRDNSKNTAYMQLNSLRAEDTAVYYCARAYFGVDVWGQGTLVTVSS (SEQ ID NO: 795) 
               
               
                   
               
               
                 VL 
                 DIVMTQSPASLSVSVGDRATISCRASQGIGNTLAWYQQKPGQAPKRLLIYRASQGIGNTLAGVPARFSGDGD 
               
               
                   
                 GTDFTLTIDDLEEPEDFATYYCQQYDHVPLTFGQGTKLEIK (SEQ ID NO: 796) 
               
               
                   
               
            
           
           
               
            
               
                 Group M 
               
            
           
           
               
               
            
               
                 VH 
                 EVQLVQSGAEVKKPGASVKVSCKAFGYTFTTYPIEWMRQAHGQGLEWIGNFHPYNDDTKYNEKFKGRVTMTV 
               
               
                   
                 DKSTTTVYMELSSLRSEDTAVYYCARENYGSHGGFVYWGQGTLVTVS (SEQ ID NO: 797) 
               
               
                   
               
               
                 VH 
                 EVQLVQSGAEVKKPGASVKVSCKAFGYTFTTYPIEWMRQAHGQGLEWIGNFHPYNDDTKYNEKFKGRVTMTR 
               
               
                   
                 DTSTSTVYMELSSLRSEDTAVYYCARENYGSHGGFVYWGQGTLVTVS (SEQ ID NO: 798) 
               
               
                   
               
               
                 VH 
                 EVQLVQSGAEVKKPGASVKVSCKAFGYTFTTYPIEWVRQAPGQGLEWMGNFHPYNDDTKYNEKFKGRVTMTR 
               
               
                   
                 DTSTSTVYMELSSLRSEDTAVYYCARENYGSHGGFVYWGQGTLVTVS (SEQ ID NO: 799) 
               
               
                   
               
               
                 VH 
                 EVQLVQSGAEVKKPGSSVKVSCKASGYTFTTYPIEWVRQAPGQGLEWMGNFHPYNDDTKYNEKFKGRVTITA 
               
               
                   
                 DKSTSTAYMELSSLRSEDTAVYYCARENYGSHGGFVYWGQGTLVTVS (SEQ ID NO: 800) 
               
               
                   
               
               
                 VH 
                 EVQLVQSGAEVKKPGSSVKVSCKAFGYTFTTYPIEWMRQAHGQGLEWIGNFHPYNDDTKYNEKFKGRVTITV 
               
               
                   
                 DKSTTTVYMELSSLRSEDTAVYYCARENYGSHGGFVYWGQGTLVTVS (SEQ ID NO: 801) 
               
               
                   
               
               
                 VH 
                 EVQLVQSGAEVKKPGSSVKVSCKAFGYTFTTYPIEWMRQAHGQGLEWIGNFHPYNDDTKYNEKFKGRVTITA 
               
               
                   
                 DKSTSTAYMELSSLRSEDTAVYYCARENYGSHGGFVYWGQGTLVTVS (SEQ ID NO: 802) 
               
               
                   
               
               
                 VL 
                 ENVLTQSPFSLSASVGDRVTITCRASSSVISSYLHWYQQKPAKAPKLWIYSTSNLASGVPDRFSGSGSGTSY 
               
               
                   
                 TLTISSLQPEDFATYYCQQYNGYPLTFGGGTKVEIK (SEQ ID NO: 803) 
               
               
                   
               
               
                 VL 
                 ENVLTQSPFSLSASVGDRVTITCRASSSVISSYLHWYQQKPAKAPKLFIYSTSNLASGVPSRFSGSGSGTDY 
               
               
                   
                 TLTISSLQPEDFATYYCQQYNGYPLTFGGGTKVEIK (SEQ ID NO: 804) 
               
               
                   
               
               
                 VL 
                 ENVLTQSPFSLSASVGDRVTITCRASSSVISSYLHWYQQKPAKAPKLWIYSTSNLASGVPDRFSGSGSGTSY 
               
               
                   
                 TLTISSLQPEDFATYYCQQYNSYPLTFGGGTKVEIK (SEQ ID NO: 805) 
               
               
                   
               
               
                 VL 
                 ENVMTQSPFSLSASVGDRVTITCRASSSVISSYLHWYQQKPAKAPKLFIYSTSNLASGVPSRFSGSGSGTDY 
               
               
                   
                 TLTISSLQPEDFATYYCQQYNGYPLTFGGGTKVEIK (SEQ ID NO: 806) 
               
               
                   
               
               
                 VL 
                 ENVMTQSPFSLSASVGDRVTITCRASSSVISSYLHWYQQKPAKAPKLFIYSTSNLASGVPSRFSGSGSGTDY 
               
               
                   
                 TLTISSLQPEDFATYYCQQYNSYPLTFGGGTKVEIK (SEQ ID NO: 807) 
               
               
                   
               
               
                 VL 
                 ENVLTQSPFSLSASVGDRVTITCRASSSVISSYLHWYQQKPAKAPKLFIYSTSNLASGVPSRFSGSGSGTDY 
               
               
                   
                 TLTISSLQPEDFATYYCQQYNSYPLTFGGGTKVEIK (SEQ ID NO: 808) 
               
               
                   
               
               
                 VL 
                 ENVLTQSPGTLSLSPGERATLSCRASSSVISSYLHWYQQKPGQAPRLWIYSTSNLASGVPDRFSGSGSGTSY 
               
               
                   
                 TLTISRLEPEDFATYYCQQYNGYPLTFGGGTKVEIK (SEQ ID NO: 809) 
               
               
                   
               
               
                 VL 
                 ENVLTQSPGTLSLSPGERATLSCRASSSVISSYLHWYQQKPGQAPRLWIYSTSNLASGVPDRFSGSGSGTSY 
               
               
                   
                 TLTISRLEPEDFATYYCQQYNSYPLTFGGGTKVEIK (SEQ ID NO: 810) 
               
               
                   
               
            
           
           
               
            
               
                 Group N 
               
            
           
           
               
               
            
               
                 VH 
                 QVQLQQPGAELVKPGASVKLSCKASGYTFTSYYLYWMKQRPGQGLEWIGGVNPSNGGTNFSEKFKSKATLTV 
               
               
                   
                 DKSSSTAYMQLSSLTSEDSAVYYCTRRDSNYDGGFDYWGQGTTLTVSSAK (SEQ ID NO: 631) 
               
               
                   
               
               
                 VL 
                 DIVLTQSPTSLAVSLGQRATISCRASKSVSTSGFSYLHWYQQKPGQPPKLLIFLASNLESGVPARFSGSGSG 
               
               
                   
                 TDFTLNIHPVEEEDAATYYCQHSWELPLTFGAGTKLELK (SEQ ID NO: 635) 
               
               
                   
               
            
           
           
               
            
               
                 Group O 
               
            
           
           
               
               
            
               
                 VH 
                 EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYGMHWVRQAPGKGLEWVAYISSGSYTIYSADSVKGRFTISR 
               
               
                   
                 DNAKNTLYLQMSSLRAEDTAVYYCARRGYGSFYEYYFDYWGQGTTVTVS (SEQ ID NO: 1521) 
               
               
                   
               
               
                 VL 
                 QIVLTQSPATLSLSPGERATLSCSASSSVSYMYWYQQKPGQAPRLLIYLTSNRATGIPARFSGSGSGTDYTL 
               
               
                   
                 TISSLEPEDFAVYYCQQWSSNPFTFGQGTKLEIK (SEQ ID NO: 1522) 
               
               
                   
               
            
           
           
               
            
               
                 Group P 
               
            
           
           
               
               
            
               
                 VH 
                 EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNFDEKFKNRVTITA 
               
               
                   
                 DKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSS (SEQ ID NO: 1523) 
               
               
                   
               
               
                 VH 
                 EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWIRQSPSRGLEWLGNIYPGTGGSNFDEKFKNRFTISR 
               
               
                   
                 DNSKNTLYLQMNSLRAEDTAVYYCTRWTTGTGAYWGQGTTVTVSS (SEQ ID NO: 1524) 
               
               
                   
               
               
                 VH 
                 EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQAPGQGLEWMGNIYPGTGGSNFDEKFKNRFTISR 
               
               
                   
                 DNSKNTLYLQMNSLRAEDTAVYYCTRWTTGTGAYWGQGTTVTVSS (SEQ ID NO: 1525) 
               
               
                   
               
               
                 VL 
                 EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTWYQQKPGQAPRLLIYWASTRESGVPSRFSGSG 
               
               
                   
                 SGTEFTLTISSLQPDDFATYYCQNDYSYPYTFGQGTKVEIK (SEQ ID NO: 1526) 
               
               
                   
               
               
                 VL 
                 DIQMTQSPSSLSASVGDRVTITCKSSQSLLDSGNQKNFLTWYQQKPGQAPRLLIYWASTRESGIPPRFSGSG 
               
               
                   
                 YGTDFTLTINNIESEDAAYYFCQNDYSYPYTFGQGTKVEIK (SEQ ID NO: 1527) 
               
               
                   
               
               
                 VL 
                 EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTWYQQKPGKAPKLLIYWASTRESGVPSRFSGSG 
               
               
                   
                 SGTDFTFTISSLQPEDIATYYCQNDYSYPYTFGQGTKVEIK (SEQ ID NO: 1528) 
               
               
                   
               
               
                 VL 
                 DIVMTQTPLSLPVTPGEPASISCKSSQSLLDSGNQKNFLTWYQQKPGQAPRLLIYWASTRESGVPSRFSGSG 
               
               
                   
                 SGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIK (SEQ ID NO: 1529) 
               
               
                   
               
               
                 VL 
                 EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTWYQQKPGKAPKLLIYWASTRESGVPSRFSGSG 
               
               
                   
                 SGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIK (SEQ ID NO: 1530) 
               
               
                   
               
               
                 VL 
                 EIVLTQSPDFQSVTPKEKVTITCKSSQSLLDSGNQKNFLTWYQQKPGQAPRLLIYWASTRESGVPSRFSGSG 
               
               
                   
                 SGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIK (SEQ ID NO: 1531) 
               
               
                   
               
               
                 VL 
                 EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTWYQQKPGQAPRLLIYWASTRESGVPSRFSGSG 
               
               
                   
                 SGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIK (SEQ ID NO: 1532) 
               
               
                   
               
               
                 VL 
                 DIQMTQSPSSLSASVGDRVTITCKSSQSLLDSGNQKNFLTWYLQKPGQSPQLLIYWASTRESGVPSRFSGSG 
               
               
                   
                 SGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIK (SEQ ID NO: 1533) 
               
               
                   
               
               
                 VL 
                 DVVMTQSPLSLPVTLGQPASISCKSSQSLLDSGNQKNFLTWYQQKPGKAPKLLIYWASTRESGVPSRFSGSG 
               
               
                   
                 SGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIK (SEQ ID NO: 1534) 
               
               
                   
               
               
                 HC 
                 EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNFDEKFKNRVTITA 
               
               
                   
                 DKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGC 
               
               
                   
                 LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVE 
               
               
                   
                 SKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKP 
               
               
                   
                 REEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQV 
               
               
                   
                 SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNH 
               
               
                   
                 YTQKSLSLSLGK (SEQ ID NO: 1535) 
               
               
                   
               
               
                 HC 
                 QVQLVQSGAEVKKPGASVKVSCKASGYTFTTYWMHWIRQSPSRGLEWLGNIYPGTGGSNFDEKFKNRFTISR 
               
               
                   
                 DNSKNTLYLQMNSLRAEDTAVYYCTRWTTGTGAYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGC 
               
               
                   
                 LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVE 
               
               
                   
                 SKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKP 
               
               
                   
                 REEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQV 
               
               
                   
                 SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNH 
               
               
                   
                 YTQKSLSLSLGK (SEQ ID NO: 1536) 
               
               
                   
               
               
                 HC 
                 EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWIRQSPSRGLEWLGNIYPGTGGSNFDEKFKNRFTISR 
               
               
                   
                 DNSKNTLYLQMNSLRAEDTAVYYCTRWTTGTGAYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGC 
               
               
                   
                 LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVE 
               
               
                   
                 SKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKP 
               
               
                   
                 REEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQV 
               
               
                   
                 SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNH 
               
               
                   
                 YTQKSLSLSLGK (SEQ ID NO: 1537) 
               
               
                   
               
               
                 HC 
                 EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQAPGQGLEWMGNIYPGTGGSNFDEKFKNRFTISR 
               
               
                   
                 DNSKNTLYLQMNSLRAEDTAVYYCTRWTTGTGAYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGC 
               
               
                   
                 LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVE 
               
               
                   
                 SKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKP 
               
               
                   
                 REEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQV 
               
               
                   
                 SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNH 
               
               
                   
                 YTQKSLSLSLGK (SEQ ID NO: 1538) 
               
               
                   
               
               
                 HC 
                 EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNFDEKFKNRVTITA 
               
               
                   
                 DKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGC 
               
               
                   
                 LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVE 
               
               
                   
                 SKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKP 
               
               
                   
                 REEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQV 
               
               
                   
                 SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNH 
               
               
                   
                 YTQKSLSLSLG (SEQ ID NO: 1539) 
               
               
                   
               
               
                 HC 
                 EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWIRQSPSRGLEWLGNIYPGTGGSNFDEKFKNRFTISR 
               
               
                   
                 DNSKNTLYLQMNSLRAEDTAVYYCTRWTTGTGAYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGC 
               
               
                   
                 LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVE 
               
               
                   
                 SKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKP 
               
               
                   
                 REEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQV 
               
               
                   
                 SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNH 
               
               
                   
                 YTQKSLSLSLG (SEQ ID NO: 1540) 
               
               
                   
               
               
                 LC 
                 EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTWYQQKPGQAPRLLIYWASTRESGVPSRFSGSG 
               
               
                   
                 SGTEFTLTISSLQPDDFATYYCQNDYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNN 
               
               
                   
                 FYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN 
               
               
                   
                 RGEC (SEQ ID NO: 1541) 
               
               
                   
               
               
                 LC 
                 DIQMTQSPSSLSASVGDRVTITCKSSQSLLDSGNQKNFLTWYQQKPGQAPRLLIYWASTRESGIPPRFSGSG 
               
               
                   
                 YGTDFTLTINNIESEDAAYYFCQNDYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNN 
               
               
                   
                 FYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN 
               
               
                   
                 RGEC (SEQ ID NO: 1542) 
               
               
                   
               
               
                 LC 
                 EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTWYQQKPGKAPKLLIYWASTRESGVPSRFSGSG 
               
               
                   
                 SGTDFTFTISSLQPEDIATYYCQNDYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNN 
               
               
                   
                 FYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN 
               
               
                   
                 RGEC (SEQ ID NO: 1543) 
               
               
                   
               
               
                 LC 
                 DIVMTQTPLSLPVTPGEPASISCKSSQSLLDSGNQKNFLTWYQQKPGQAPRLLIYWASTRESGVPSRFSGSG 
               
               
                   
                 SGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNN 
               
               
                   
                 FYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN 
               
               
                   
                 RGEC (SEQ ID NO: 1544) 
               
               
                   
               
               
                 LC 
                 EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTWYQQKPGKAPKLLIYWASTRESGVPSRFSGSG 
               
               
                   
                 SGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNN 
               
               
                   
                 FYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN 
               
               
                   
                 RGEC (SEQ ID NO: 1545) 
               
               
                   
               
               
                 LC 
                 EIVLTQSPDFQSVTPKEKVTITCKSSQSLLDSGNQKNFLTWYQQKPGQAPRLLIYWASTRESGVPSRFSGSG 
               
               
                   
                 SGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNN 
               
               
                   
                 FYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN 
               
               
                   
                 RGEC (SEQ ID NO: 1546) 
               
               
                   
               
               
                 LC 
                 DIQMTQSPSSLSASVGDRVTITCKSSQSLLDSGNQKNFLTWYLQKPGQSPQLLIYWASTRESGVPSRFSGSG 
               
               
                   
                 SGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNN 
               
               
                   
                 FYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN 
               
               
                   
                 RGEC (SEQ ID NO: 1547) 
               
               
                   
               
               
                 LC 
                 DVVMTQSPLSLPVTLGQPASISCKSSQSLLDSGNQKNFLTWYQQKPGKAPKLLIYWASTRESGVPSRFSGSG 
               
               
                   
                 SGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNN 
               
               
                   
                 FYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN 
               
               
                   
                 RGEC (SEQ ID NO: 1548) 
               
               
                   
               
               
                 LC 
                 EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTWYQQKPGQAPRLLIYWASTRESGVPSRFSGSG 
               
               
                   
                 SGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNN 
               
               
                   
                 FYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN 
               
               
                   
                 RGEC (SEQ ID NO: 1834) 
               
               
                   
               
            
           
           
               
            
               
                 Group Q 
               
            
           
           
               
               
            
               
                 VH 
                 EVQLLESGGGLVQPGGSLRLSCSAS GFTFSSYT MNWVRQAPGKGLEWVSG ISDTGGNT YYTDSVKGRFTVSR 
               
               
                   
                 DNSKNTLSLQMNSLRAEDTAVYYC AKDQGGSYPYYFHY WGQGSLVTVSS (SEQ ID NO: 1549) 
               
               
                   
               
               
                 VH 
                 EVQLVESGGGLVQPGGSLRLSCAAS GFTVSNNY MSWVRQAPGKGLEWVSV IYSGGFT YYTDSVKGRFTISRH 
               
               
                   
                 NSKNTLYLQMNSLRAEDTAVYYC ARYYYDTSDYWTFFDY WGQGTLVTVSS (SEQ ID NO: 1550) 
               
               
                   
               
               
                 VH 
                 QVQLVESGGGVVQSGRSLRLSCAAS GFTFSSYG MHWVRQAPGKGLEWVAV IWYDGSNI YYSDSVKGRFTISR 
               
               
                   
                 ANSKNTLYLQMNSLRAEDTAVYYC ARPGHWNYFFEY WGQGTLVTVSS (SEQ ID NO: 1551) 
               
               
                   
               
               
                 VH 
                 EVQLVESGGGLVQPGGSLRLSCGAS GFTFRNYD MHWVRQITGKGLEWVSA IGSAGDT YYPDSVKGRFTISRE 
               
               
                   
                 NAKNSLYLQMNSLRVGDTAVYYC TRDIHCSSTRCYGMDV WGQGTTVTVSS (SEQ ID NO: 1552) 
               
               
                   
               
               
                 VH 
                 EVQLVESGGGLVKPGGSLRLSCAAS GFKFSNEW MSWVRQAPGKGLEWVGR IKSKTDGGTT DYAAPVKGRFTI 
               
               
                   
                 SRDDSKNTLYLQMNSLKTEDTAVYYC TTDQDFWSGYYTGADYYGMDV WGQGTMVTVSS (SEQ ID 
               
               
                   
                 NO: 1553) 
               
               
                   
               
               
                 VH 
                 QMQLQQWGAGLLKPSETLSLTCVVY GGSLNGYY WSWIRQSPGKGLEWIGE IDHSGST NYNPSLKNRVTMSVD 
               
               
                   
                 TSKIQFSLKLTSVTVADTAVYYC AREGLLPFDY WGQGTLVTVSS (SEQ ID NO: 1554) 
               
               
                   
               
               
                 VH 
                 QLQLQESGPDLVKPSDTLSLTCTVS DDSISSTTYY WAWIRQPPGKGLEWIGS MSYNGNN YYNPSLKSRVAIS 
               
               
                   
                 AGTSQKQFSLKLTSVTAADTAVYHC ARHLGYNGNWYPFDF WGQGILVTVSS (SEQ ID NO: 1555) 
               
               
                   
               
               
                 VH 
                 EVQVVESGGGLVEPGRSLRLSCKAS GFTFDDYA MHWVRQTPGKALEWVSG INWSGNNI GYADSVKGRFTISK 
               
               
                   
                 DDAKNSLYLQMNSLRPEDTALYYC TKDISITGTLDAFDV WGQGTMVTVSS (SEQ ID NO: 1556) 
               
               
                   
               
               
                 VH 
                 QVQLVESGGGVVQPGRSLRLSCAAS GFTFSSYG MHWVRQAPGKGLEWVAI IWSDGDSE YNLDSVKGRFTISR 
               
               
                   
                 DNSKNTLYLQMNSLRVEDSAVYYC ARDRDLEDI WGQGTMVTSS (SEQ ID NO: 1557) 
               
               
                   
               
               
                 VH 
                 EVQLLESGGVLVQPGGSLRLSCAAS GFTFSNFG MTWVRQAPGKGLEWVSG ISGGGRDT YFADSVKGRFTISR 
               
               
                   
                 DNSKNTLYLQMNSLKGEDTAVYYC VKWGNIYFDY WGQGTLVTVSS (SEQ ID NO: 1558) 
               
               
                   
               
               
                 VH 
                 EVQLVESGGGVVRPGGSLRLSCAAS GFTFDDYG MSWVRQVPGKGLEWVSG ISWNDGKT VYAESVKGRFIISR 
               
               
                   
                 DNAKNSLYLEMNSLRAEDTALYYC ARDWQYLIERYFDY WGQGTLVTVSS (SEQ ID NO: 1559) 
               
               
                   
               
               
                 VH 
                 EVQLVESGGGVVRPGGSLRLSCTAS GFTFDDYG MSWVRQAPGKGLEWISG IGWTGGRS SYADSVRGRFTISR 
               
               
                   
                 DNAKNSLYLQMNSLGAEDTALYYC ARDRQWLVQWYFDY WGQGTLVTVSS (SEQ ID NO: 1560) 
               
               
                   
               
               
                 VH 
                 EVQLVESGGRVVRPGGSLRLSCAAS GFTFDDYG MSWVRQLPGKGLEWVAG ISWNDGKT VYAESVKGRFIISR 
               
               
                   
                 DNAKNSLHLEMNSLRAEDTALYYC ARDWQYLIDRYFDF WGQGTLVTVSS (SEQ ID NO: 1561) 
               
               
                   
               
               
                 VH 
                 EVQLVESGGGLVQPGGSLRLSCAAS GFTFDDYA MHWVRQAPGKGLEWVSG IGWSSGSI GYADSVKGRFTISR 
               
               
                   
                 DNAKNSLYLQMDSLRPEDSALYYC AKAYTFMITLYFDY WGQGTLVTVSS (SEQ ID NO: 1562) 
               
               
                   
               
               
                 VH 
                 EVQLVESGGGLVQPGRSLRLSCAAS GFTFDDYD MHWVRQAPGKGLEWVSG SGWNRGSL GYADSVKGRFTISR 
               
               
                   
                 DNAKKSLYLQMNSVRVEDTALYYC AKGFVVVSAAYFDY WGQGTLVTVSS (SEQ ID NO: 1563) 
               
               
                   
               
               
                 VH 
                 QVQLVQSGAEVKRPGSSVKVSCKVS GVTFRNFA IIWVRQAPGQGLEWMGG IIPFFSAA NYAQSFQGRVTITP 
               
               
                   
                 DESTSTAFMELASLRSEDTAVYYC AREGERGHTYGFDY WGQGTLVTVSS (SEQ ID NO: 1564) 
               
               
                   
               
               
                 VH 
                 EVQLVESGGGLVQSGRSLRLSCAAS GFTFDDYA MHWVRQPPGKGLEWVSG INWNRGRT GYADSVKGRFTISR 
               
               
                   
                 DNAKNSLYLQMNDLRVEDTALYYC AKAEQWLDEGYFDY WGQGTLVTVSS (SEQ ID NO: 1565) 
               
               
                   
               
               
                 VH 
                 EVQLVESGGGLVQRGGSLRLSCAASGFSFSSYAMNWVRQAPGKGLEWVST ISDSGGST YYADSVKGRFTISR 
               
               
                   
                 DNSKNTLSLQMNSLRAEDTAVYYC AKDQGGSYPYYFHY WGQGTLVTVSS (SEQ ID NO: 1566) 
               
               
                   
               
               
                 VH 
                 EVQLVESGGGLVQPGRSLRLSCAAS GFTFEDYA MHWVRQAPGKGLEWVSG IGWSNVKI GYADSVKGRFTISR 
               
               
                   
                 DNVRNSLYLQMNSLRTEDTAFYYC VKAYTSMLTLYFDY WGQGTLVTVSS (SEQ ID NO: 1567) 
               
               
                   
               
               
                 VH 
                 QVQLVQSGAEVKRPGASVKVSCKAS GYTFTSFY MYWVRQAPGQGLEWMGI INPSDGST SNAQKFQGRVTMTR 
               
               
                   
                 DTSTSTVYMELSSLRSEDTAVYYC ARRVAGDIFDI WGQGTMTVSS (SEQ ID NO: 1568) 
               
               
                   
               
               
                 VH 
                 QVQLQESGPGLVKPSETLSLTCTVS GGSISSYH WNWIRQSPGKGLEWIGY IYYIGST DYNPSLESRVTISVD 
               
               
                   
                 TSKNQFSLKLSSVTAADTAVYYC ARVPVGATGASDV WGQGTMVTVSS (SEQ ID NO: 1569) 
               
               
                   
               
               
                 VH 
                 EVQLVESGGSVVRPGGSLRLSCVVS GFTFEDYG LSWVRQIPGKGLEWVSG ISWTGGNT GYADSVKGRFTISR 
               
               
                   
                 DNAKNSLYLQMNSLRAEDTALYHC TRDRQWLMQWYFDY WGQGTLVTVSS (SEQ ID NO: 1570) 
               
               
                   
               
               
                 VH 
                 QVQLVESGGGVVQPGRSLRLSCSAS GFTFSAYA MHWVRQAPGKGLEWVAA ISYGGSDK YYADSVKGRFTISR 
               
               
                   
                 DNSKNTLYLQMNSLRTDDTAVYYC AKSAHWNFFFDY WGQGTLVTVSS (SEQ ID NO: 1571) 
               
               
                   
               
               
                 VH 
                 EVQLVESGGGLVQPGRSLRLSCVAS GFALHDYA MHWVRQVPGKGLEWVSS ISWNSGVI GYADSLKGRFTISR 
               
               
                   
                 DNAKNSLYLQMNSLRAEDTALYYC AKGSGSYYVSWFDP WGQGTLVTVSS (SEQ ID NO: 1572) 
               
               
                   
               
               
                 VH 
                 QLQLQESGPGLVQPSETLSLTCTVS GDSISSTAYH WDWIRQPPGKGLEWIGT ITYNGNT YFNPSLKSRVTIS 
               
               
                   
                 VDTSKNQFSLKLLSMTAAETAVFYC ARHLGYNSDFFPFDF WGQGTLVTVSS (SEQ ID NO: 1573) 
               
               
                   
               
               
                 VH 
                 EVQLVESGGGLVRPGGSLRLSCAAS GFTFSTYA MAWVRQTPGKGLEGVSA IGGSGDST YYVDSVKGRFTISR 
               
               
                   
                 DNSKSTLFLQMNSLRAEDTAVYYC VKVRNYDGSFDI WGQGTMVTVSS (SEQ ID NO: 1574) 
               
               
                   
               
               
                 VL 
                 DIQMTQSPSSLSASVGDRVTITCRAS QSISSY LIWYQQKPGTAPKFLIYAASSLQSGVPSRFSGCGSGTDFT 
               
               
                   
                 LTISSLQPEDFATYYC QQSYSTPPIT FGQGTRLEIK (SEQ ID NO: 1575) 
               
               
                   
               
               
                 VL 
                 EIVMTQSPATLSVSPGERATLSCRAS QSVSSN LAWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFT 
               
               
                   
                 LTISSLQSGDFAVYYC QQYNNWPLT FGGGTKVEIN (SEQ ID NO: 1576) 
               
               
                   
               
               
                 VL 
                 EIVMTQSPATLSVSPGERATLSCRAS QSVSSN LAWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFT 
               
               
                   
                 LTISSLQSGDFAVYYC QQYNNWPLT FGGGTKVEIN (SEQ ID NO: 1577) 
               
               
                   
               
               
                 VL 
                 DIQMTQSPSSLSASVGDRVTITCRAS QSINNY LNWYQQKPGKAPKLLIYTASSLQSGVPSRFSGSGSGTDFT 
               
               
                   
                 LTISSLQPEDFATYYC QQSYSTPPLT FGQGTQLEIK (SEQ ID NO: 1578) 
               
               
                   
               
               
                 VL 
                 DIQMTQSPSSLSASVGDRVTITCRAS QSISNY LNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFT 
               
               
                   
                 LTISSLQPEDFATYYC QQSYSTPPIT FGQGTRLEIK (SEQ ID NO: 1579) 
               
               
                   
               
               
                 VL 
                 DIQMTQSPSSLSASVGDRVTITCRAS QSISSY LNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFT 
               
               
                   
                 LTISSLQPEDFATYYC QQSYSTPPIT FGQGTRLEIK (SEQ ID NO: 1580) 
               
               
                   
               
               
                 VL 
                 EIVLTQSPGTLSLSPGERVTLSCRAS QSVYSNY LAWYQQNPGQAPRLLIYAASNRATGIPDRFSGSGSGTDF 
               
               
                   
                 TLTISRLEPEDFAVYYC HQYATSPWT FGQGTKVEIK (SEQ ID NO: 1581) 
               
               
                   
               
               
                 VL 
                 EIVLTQSPGTLSLSPGERATLSCRAS QSVSSSY LAWYQQKPGQAPRLLIYGASSRTTGIPDRFSGSGSGTDF 
               
               
                   
                 TLTISRLEPEDFAVYYC QQYGSSPWT FGQGTKVEIK (SEQ ID NO: 1582) 
               
               
                   
               
               
                 VL 
                 DIQMTQSPISVSASVGDRVTITCRAS QGISNW LAWYQQKPGIAPKLLIYSASSLQSGVPSRFRGSGSGTDFT 
               
               
                   
                 LTIGSLQPEDFATYYC QQAHSFPLT FGGGTKVEIK (SEQ ID NO: 1583) 
               
               
                   
               
               
                 VL 
                 DIQMTQSPSSLSASVGDRVTITCRAS QGIRND LGWYQQKPGKAPKRLIYAASNLQSGVPSRFSGSGSGTEFT 
               
               
                   
                 LTISSLQPEDFATYYC LQHNSYPLT FGGGTKVEIK (SEQ ID NO: 1584) 
               
               
                   
               
               
                 VL 
                 DIQMTQSPSSLSASVGDSITITCRAS LSINTF LNWYQQKPGKAPNLLIYAASSLHGGVPSRFSGSGSGTDFT 
               
               
                   
                 LTIRTLQPEDFATYYC QQSSNTPFT FGPGTVVDFR (SEQ ID NO: 1585) 
               
               
                   
               
               
                 VL 
                 EIVLTQSPGTLSLSPGERATLSCRAS QSVSSS YLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDF 
               
               
                   
                 TLTISRLEPEDFAVYYC QQYGSSPWT FGQGTKVEIK (SEQ ID NO: 1586) 
               
               
                   
               
               
                 VL 
                 DIQMTQSPSSLSASVGDRVTITCRAS QSISSY LNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFT 
               
               
                   
                 LTISSLQPEDFATYYC QQSYSTPPIT FGQGTRLEIK (SEQ ID NO: 1587) 
               
               
                   
               
               
                 HC 
                 EVQLLESGGVLVQPGGSLRLSCAAS GFTFSNFG MTWVRQAPGKGLEWVSG ISGGGRDT YFADSVKGRFTISR 
               
               
                   
                 DNSKNTLYLQMNSLKGEDTAVYYC VKWGNIYFDY WGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGC 
               
               
                   
                 LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVE 
               
               
                   
                 SKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKP 
               
               
                   
                 REEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQV 
               
               
                   
                 SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNH 
               
               
                   
                 YTQKSLSLSLGK (SEQ ID NO: 1588) 
               
               
                   
               
               
                 HC 
                 EVQVVESGGGLVEPGRSLRLSCKAS GFTFDDYA MHWVRQTPGKALEWVSGISWSGNNIGYADSVKGRFTISK 
               
               
                   
                 DDAKNSLYLQMNSLRPEDTALYYC TKDISITGTLDAFDV WGQGTMVTVSSASTKGPSVFPLAPCSRSTSEST 
               
               
                   
                 AALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKV 
               
               
                   
                 DKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHN 
               
               
                   
                 AKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEM 
               
               
                   
                 TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHE 
               
               
                   
                 ALHNHYTQKSLSLSLGK (SEQ ID NO: 1589) 
               
               
                   
               
               
                 HC 
                 EVQLVESGGGLVRPGGSLRLSCAAS GFTFSTYA MAWVRQTPGKGLEGVSA IGGSGDST YYVDSVKGRFTISR 
               
               
                   
                 DNSKSTLFLQMNSLRAEDTAVYYC VKVRNYDGSFDI WGQGTMVTVSSASTKGPSVFPLAPCSRSTSESTAAL 
               
               
                   
                 GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKR 
               
               
                   
                 VESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKT 
               
               
                   
                 KPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKN 
               
               
                   
                 QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALH 
               
               
                   
                 NHYTQKSLSLSLGK (SEQ ID NO: 1590) 
               
               
                   
               
               
                 HC 
                 QVQLVQSGAEVKRPGSSVKVSCKVS GVTFRNFA IIWVRQAPGQGLEWMGG IIPFFSAA NYAQSFQGRVTITP 
               
               
                   
                 DESTSTAFMELASLRSEDTAVYYC AREGERGHTYGFDY WGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTA 
               
               
                   
                 ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVD 
               
               
                   
                 KRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNA 
               
               
                   
                 KTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMT 
               
               
                   
                 KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEA 
               
               
                   
                 LHNHYTQKSLSLSLGK (SEQ ID NO: 1591) 
               
               
                   
               
               
                 LC 
                 DIQMTQSPSSLSASVGDSITITCRAS LSINTF LNWYQQKPGKAPNLLIYAASSLHGGVPSRFSGSGSGTDFT 
               
               
                   
                 LTIRTLQPEDFATYYC QQSSNTPFT FGPGTVVDFRRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREA 
               
               
                   
                 KVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 
               
               
                   
                 (SEQ ID NO: 1592) 
               
               
                   
               
               
                 LC 
                 DIQMTQSPISVSASVGDRVTITCRAS QGISNW LAWYQQKPGIAPKLLIYSASSLQSGVPSRFRGSGSGTDFT 
               
               
                   
                 LTIGSLQPEDFATYYC QQAHSFPLT FGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREA 
               
               
                   
                 KVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 
               
               
                   
                 (SEQ ID NO: 1593) 
               
               
                   
               
               
                 LC 
                 EIVLTQSPGTLSLSPGERATLSCRAS QSVSSSY LAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDF 
               
               
                   
                 TLTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE 
               
               
                   
                 AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 
               
               
                   
                 (SEQ ID NO: 1594) 
               
               
                   
               
               
                 LC 
                 DIQMTQSPSSLSASVGDRVTITCRAS QSISSY LNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFT 
               
               
                   
                 LTISSLQPEDFATYYC QQSYSTPPIT FGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE 
               
               
                   
                 AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 
               
               
                   
                 (SEQ ID NO: 1595) 
               
            
           
           
               
            
               
                 Group R 
               
            
           
           
               
               
            
               
                 VH 
                 EVKLVESGGGLVKPGGSLKLSCAASGFTFS SYGMS WLRQTPEKRLEWVA TMSGGGRDIYYPDSMKG RFTISR 
               
               
                   
                 DNAKNNLYLQMSSLRSEDTALYYCAR QYYDDWFAY WGQGTLVTVSA (SEQ ID NO: 1719) 
               
               
                   
               
               
                 VH 
                 QVQLKQSGPGLVQPSQNLSVTCTVSGFSLT TYGVH WVRQSPGKGLEWLG VIWSGGSTDYNAAFIS RLTISKD 
               
               
                   
                 NARSQVFFKMNSLQVNDTAMYYCAR EKSVYGNYVGAMDY WGQGTSVTVSS (SEQ ID NO: 1720) 
               
               
                   
               
               
                 VH 
                 EVKLVESGGGLVKPGGSLKLSCGASGFTFS SYGMS WVRQTPEKRLEWVA TISGGGRDIYYPDSVKG RLTISR 
               
               
                   
                 DNAKNNLYLQMSSLRSEDTALYYCVR QYYDDWFAY WGQGTLVTVSA (SEQ ID NO: 1721) 
               
               
                   
               
               
                 VH 
                 DVQLQESGPGLVKPSQSLSLTCTVTGYSIT SDYAWN WIRQFPGNQLEWMA YISYSGYTSYNPSLKS RISITR 
               
               
                   
                 DTSKNQFFLQLNSVTTEDTATYYCAR SLDYDYGTMDY WGQGTSVTVSS (SEQ ID NO: 1722) 
               
               
                   
               
               
                 VH 
                 EVKLVESGGGLVKPGGSLKLSCAASGFAFR SYDMS WVRQTPEKILEWVA TISGGGSYTYYQDSVKG RFTISR 
               
               
                   
                 DNARNTLYLQMSSLRSEDTALYYCAS PYGPYFDY WGQGTTLTVSS (SEQ ID NO: 1723) 
               
               
                   
               
               
                 VH 
                 DVQLQESGPGLVKPSQSLSLTCTVTGYSIT SDYAWN WIRQFPGNQLEWMA YISYSGYTSYNPSLKS RISITR 
               
               
                   
                 DTSRNQFFLQLNSVTTEDTATYYCAR SLDYDYGTMDY WGQGTSVTVSS (SEQ ID NO: 1724) 
               
               
                   
               
               
                 VH 
                 EVKLVESGGGLVKPGGSLKLSCSASGFSFS YYDMS WVRQTPEKGLEWVA TISGGGRNTYFIDSVKG RFTISR 
               
               
                   
                 DNVKNNLYLLMSSLRSEDTALYYCAS PYEGAVDF WGQGTSVTVSS (SEQ ID NO: 1725) 
               
               
                   
               
               
                 VH 
                 EVKLVESGGGLVKPGGSLKLSCAASGFTFS SYGMS WVRQTPEKRLEWA TISGGGRDTYYLDSVKG RFTISRD 
               
               
                   
                 NAKNNLYLQMSSLRSEDTALYYCVR QYYDDWFAY WGQGTLVSNSA (SEQ ID NO: 1726) 
               
               
                   
               
               
                 VH 
                 QVQLQQSGDELVRPGTSVKMSCKAAGYTFT NNWIG WVKQRPGHGLEWIG DFYPGGGYTNYNEKFKG KATLTA 
               
               
                   
                 DTSSSTAYMQLSSLTSEDSAIYYCAR GYGTNYWYFDV WGAGTTVTVSS (SEQ ID NO: 1727) 
               
               
                   
               
               
                 VH 
                 QIHLVQSGPELKKPGETVKISCKASGYTFT NFGMN WVKQAPGKGLKWMG WISGYTREPTYAADFKG RFAISL 
               
               
                   
                 ETSASTAYLQINDLKNEDMATYFCAR DVFDY WGQGTTLTVSS (SEQ ID NO: 1728) 
               
               
                   
               
               
                 VH 
                 QIQLVQSGSELKKPGASVKVSCKASGYTFT NFGMN WVRQAPGQGLKWMG WISGYTREPTYAADFKG RFVISL 
               
               
                   
                 DTSVSTAYLQISSLKAEDTAVYYCAR DVFDY WGQGTLVTVSS (SEQ ID NO: 1729) 
               
               
                   
               
               
                 VH 
                 QVQLQESGPGLVKPSQTLSLTCTVSGYSIS SDYAWN WIRQPPGKGLEWMA YISYSGYTSYNPSLKS RITISR 
               
               
                   
                 DTSKNQFSLKLSSVTAADTAVYYCAR SLDYDYGTMDY WGQGTLVTVSS (SEQ ID NO: 1730) 
               
               
                   
               
               
                 VL 
                 DIVLTQTPATLSVTPGDSVSLSC RASQSISNNLH WYQQKSHESPRLLIK YASQSIS GIPSRFSGSGSGTDFT 
               
               
                   
                 LNINSVETEDFGMYFC QQSNSWPLT FGAGTKLELKR (SEQ ID NO: 1731) 
               
               
                   
               
               
                 VL 
                 SIVMTQTPKFLLVSAGDRVTITC KASQSVSDDVA WYQQKPGQSPKLLIY YAFNRYT GVPDRFTGSGYGTDFT 
               
               
                   
                 FTISTVQSEDLAVYFC QQDYRSPWT FGGGTKLEIKR (SEQ ID NO: 1732) 
               
               
                   
               
               
                 VL 
                 DIVLTQSPATLSVTPGDSVSLSC RASQSISNDLH WYQQKSHESPRLLIK YVSQSIS GIPSRFSGSGSGTDFT 
               
               
                   
                 LSINSVETEDFGMYFC QQSDSWPLT FGAGTKLELKR (SEQ ID NO: 1733) 
               
               
                   
               
               
                 VL 
                 QIVLSQSPAILSASPGEKVTMTC RANSSVSSMH WYQQKPGSSPEPWIY AISNLAF GVPTRFSGSGSGTSYSL 
               
               
                   
                 TISRVEAEDAATYFC QQWSSRPPT FGGGTKLEIKR (SEQ ID NO: 1734) 
               
               
                   
               
               
                 VL 
                 DIQMNQSPSSLSASLGDTITITC HASQSINVWLS WYQQKPGNIPKLLIYR ASNLHT GVPSRFSGSGSGTGFT 
               
               
                   
                 LTISSLQPDDIATYYC QQGQSYPWT FGGGTKLEIKR (SEQ ID NO: 1735) 
               
               
                   
               
               
                 VL 
                 QIVLSQSPAILSASPGEKVTMTC RANSSVSSMH WYQQKPGSSPEPWIY AISNLAF GVPARFSGSGSGTSYSL 
               
               
                   
                 TISRVEAEDAATYFC QQWNSRPPT FGGGTKLEIKR (SEQ ID NO: 1736) 
               
               
                   
               
               
                 VL 
                 DIVMTQSHKVMSTSVGDRVSITC KASQDVDNAVA WYQQNPGQSPKLLIK WASTRHH GVPDRFTGSGSGTDFT 
               
               
                   
                 LTISTVQSEDLADFFC QQYSTFPYT FGGGTKLEIKR (SEQ ID NO: 1737) 
               
               
                   
               
               
                 VL 
                 DIVLTQTPATLSVTPGDSVSLSC RASQSLSNNLH WYQQKSHESPRLLIK YASQSIS GIPSRFSGSGSGTDFT 
               
               
                   
                 LSINSVETEDFGMYFC QQSNSWPLT FGAGTKLEMKR (SEQ ID NO: 1738) 
               
               
                   
               
               
                 VL 
                 NIVMTQTPKILFISAGDRVTITC KASQSVSNDVA WYQQKPGQSPKLLIY YAFTRYI GVPDRFTGSGYGTDFT 
               
               
                   
                 FTISTVQAEDLAVYFC QQDYSSPYT FGGGTKLEIKR (SEQ ID NO: 1739) 
               
               
                   
               
               
                 VL 
                 DIVLTQSPASLAVSLGQRATISC RASESVDNYGYSFMN WFQQKPGQPPKLLIY RASNLES GIPARFSGSGSR 
               
               
                   
                 TNFTLTINPVEADDVATYFC QQSNADPT FGGGTNLEIKR (SEQ ID NO: 1740) 
               
               
                   
               
               
                 VL 
                 DIVLTQSPASLAVSPGQRATITC RASESVDNYGYSFMN WFQQKPGQPPKLLIY RASNLES GVPARFSGSGSR 
               
               
                   
                 TDFTLTINPVEANDTANYYC QQSNADPT FGQGTKLEIK (SEQ ID NO: 1741) 
               
               
                   
               
               
                 VL 
                 EIVLTQSPATLSLSPGERATLSC RANSSVSSMH WYQQKPGQSPEPWIY AISNLAF GVPARFSGSGSGTDYTL 
               
               
                   
                 TISSLEPEDFAVYYC QQWSSRPPT FGQGTKLEIK (SEQ ID NO: 1742) 
               
               
                   
               
            
           
           
               
            
               
                 Group S 
               
            
           
           
               
               
            
               
                 VH 
                 QVQLVQSGSEVKKSGSSVKVSCKTSGGTFSITNYAINWVRQAPGQGLEWMGGILPIFGAAKYAQKFQDRVTI 
               
               
                   
                 TADESTNTAYLELSSLTSEDTAMYYCARGKRWLQSDLQYWGQGTLVTVSS (SEQ ID NO: 1743) 
               
               
                   
               
               
                 VL 
                 QPVLTQPASVSGSPGQSITISCTGSSSDVGSYDLVSWYQQSPGKVPKLLIYEGVKRPSGVSNRFSGSKSGNT 
               
               
                   
                 ASLTISGLQAEDEADYYCSSYAGTRNFVFGGGTQLTVL (SEQ ID NO: 1744) 
               
               
                   
               
            
           
           
               
            
               
                 Group T 
               
            
           
           
               
               
            
               
                 VH 
                 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYYMYWVKQAPGQGLEWIGGINPSNGGTNYNEKFKNKATLTA 
               
               
                   
                 DKSTSTAYMELSSLRSEDTAVYYCTR RDYRYDMGFDY WGQGTTVTVSS (SEQ ID NO: 1745) 
               
               
                   
               
               
                 VH 
                 QVQLVQSGAEVKKPGASVKVSCKAS GYTFTSYYMY WVRQAPGQGLEWMG GVNPSNGGTNFNEKFKS RVTITA 
               
               
                   
                 DKSTSTAYMELSSLRSEDTAVYYCAR RDYRYDMGFDY WGQGTTVTVSS (SEQ ID NO: 1746) 
               
               
                   
               
               
                 VH 
                 EVQLQQSGPELVKPGASVKISCKASGYTFTNYYMYWVKQSHGKSLEWIGGINPSNGGTNYNEKFKNKATLTV 
               
               
                   
                 DKSSSTAYMELNSLTSEDSAVYYCAR RDYRYDMGFDY WGAGTTVTVSS (SEQ ID NO: 1747) 
               
               
                   
               
               
                 VH 
                 EVQLQQSGPVLVKPGASVKMSCKAS GYTFTSYYMY WVKQSHGKSLEWIG GVNPSNGGTNFNEKFKS KATLTV 
               
               
                   
                 DKSSSTAYMELNSLTSEDSAVYYCARRDYRYDMGFDYWGQGTTLTVSS (SEQ ID NO: 1748) 
               
               
                   
               
               
                 VL 
                 EIVLTQSPATLSLSPGERATISC RASKGVSTSGYSYLH WYQQKPGQAPRLLIY LASYLE SGVPARFSGSGSG 
               
               
                   
                 TDFTLTISSLEPEDFATYYC QHSRELPLT FGTGTKVEIK (SEQ ID NO: 1749) 
               
               
                   
               
               
                 VL 
                 QIVLTQSPAIMSASPGEKVTMTC RASKGVSTSGYSYLH WYQQKPGSSPRLLIY LASYLE SGVPVRFSGSGSG 
               
               
                   
                 TSYSLTISRMEAEDAATYYC QHSRELPLT FGTGTRLEIK (SEQ ID NO: 1750) 
               
               
                   
               
            
           
           
               
            
               
                 Group U 
               
            
           
           
               
               
            
               
                 VH 
                 QVQLQQSGAELMKPGASVKMSCKTT GYIFSSY WIGWVKQRPGHGLEWIGKI FPGSGS ADYNENFKGKATFTV 
               
               
                   
                 DTSSNTAYMQLSSLTSEDSAVYYCAR GYGNYLYFDV WGAGTTVTVSS (SEQ ID NO: 619) 
               
               
                   
               
               
                 VH 
                 DVQLQESGPGLVKPSQSLSLTCTVTGHSITSDYAWNWIRQFPGNKLEWMG YISYSGRTSYNPSLTS RISITR 
               
               
                   
                 DTSKNQFFLQLNSVTTEDTATYYCAR GYALDY WGQGTSVTVSS (SEQ ID NO: 1835) 
               
               
                   
               
               
                 VH 
                 EVKLVESGGGLVSPGGSLKLSCAAS GFTFSTF GMSWVRQTPEKRLEWVA TISGGGSDTYYPDSVQG RFIISR 
               
               
                   
                 YNAKNNLYLQMNSLRPEDTALYYCAR QGYDVYSWFAY WGQGTLVTVSA (SEQ ID NO: 1836) 
               
               
                   
               
               
                 VH 
                 EVKLVESGGGLVKPGGSLKLSCAASGFTFSTYGMSWVRQTPEKRLQWVATISGGGSNTYYSDSVKGRFTISR 
               
               
                   
                 DNAKNNLYLQMSSLRSEDTALYYCAR QRDSAWFAS WGQGTLVTVSA (SEQ ID NO: 1837) 
               
               
                   
               
               
                 VH 
                 EVQLVESGGGLVKPGGSLRLSCAASGFTFSTFGMSWVRQAPGKGLEWVSTISGGGSDTYYPDSVQGRFTISR 
               
               
                   
                 DNAKNSLYLQMNSLRAEDTAVYYCAR QGYDVYSWFAY WGQGTLVTVSS (SEQ ID NO: 1838) 
               
               
                   
               
               
                 VH 
                 EVQLVESGGGLVQPGGSLRLSCAASGFTFSTFGMSWVRQAPGKGLEWVATISGGGSDTYYPDSVQGRFTISR 
               
               
                   
                 DNAKNSLYLQMNSLRAEDTAVYYCAR QGYDVYSWFAY WGQGTLVTVSS (SEQ ID NO: 1839) 
               
               
                   
               
               
                 VH 
                 EVQLVESGGGLVKPGGSLRLSCAASGFTFSTYGMSWVRQAPGKGLEWVATISGGGSNTYYSDSVKGRFTISR 
               
               
                   
                 DDSKNTLYLQMNSLKTEDTAVYYCAR QRDSAWFAS WGQGTLVTVSS (SEQ ID NO: 1840) 
               
               
                   
               
               
                 VH 
                 EVQLVQSGAEVKKPGASVKVSCKAS GYRFPHY GISWVRQAPGQGLEWMGWI SAYNGN TNYAQKLQGRVTMTT 
               
               
                   
                 DTSTNTAYMELRSLRSDDTAVYYCAR DVDYGTGSGY WGQGTLVTVSS (SEQ ID NO: 1841) 
               
               
                   
               
               
                 VH 
                 EVQLVQSGAEVKKPGASVKVSCKAS GYRFTRQ GISWVRQAPGQGLEWMGWI SAYNGN TKYAQKLQGRVTMTT 
               
               
                   
                 DTSTNTAYMELRSLRSDDTAVYYCAR DVDYGSGSGY WGQGTLVTVSS (SEQ ID NO: 1842) 
               
               
                   
               
               
                 VH 
                 EVQLVQSGAEVKKPGASVKVSCKAS GYRFSTF GISWVRQAPGQGLEWMGWI SAYNGN TNYAQKLQGRVTMTT 
               
               
                   
                 DTSTNTAYMELRSLRSDDTAVYYCAR DVDYSSGSGY WGQGTLVTVSS (SEQ ID NO: 1843) 
               
               
                   
               
               
                 VH 
                 EVQLVQSGAEVKKPGASVKVSCKAS GYRFTRY GISWVRQAPGQGLEWMGWV SAHNGN TNYAQKLQGRVTMTT 
               
               
                   
                 DTSTNTAYMELRSLRSDDTAVYYCAR DADYGSGSGY WGQGTLVTVSS (SEQ ID NO: 1844) 
               
               
                   
               
               
                 VH 
                 EVQLVQSGAEVKKPGASVKVSCKAS GYRFPHY GISWVRQAPGQGLEWMGWI SAYNGN TNYAQKLQGRVTMTT 
               
               
                   
                 DTSTNTAYMELRSLRSDDTAVYYCAR DAEYGSGSGY WGQGTLVTVSS (SEQ ID NO: 1845) 
               
               
                   
               
               
                 VH 
                 EVQLVQSGAEVKKPGASVKVSCKASGYRFT WYGIS WVRQAPGQGLEWMGWI SAYNGN TNYAQKLQGRVTMTT 
               
               
                   
                 DTSTNTAYMELRSLRSDDTAVYYCAR DSEYSSGSGY WGQGTLVTVSS (SEQ ID NO: 1846) 
               
               
                   
               
               
                 VH 
                 EVQLVQSGAEVKKPGASVKVSCKASGYRFE TYGIS WVRQAPGQGLEWMGWI SAYNGN TNYAQKLQGRVTMTT 
               
               
                   
                 DTSTNTAYMELRSLRSDDTAVYYCAR DAEYSLGSGY WGQGTLVTVSS (SEQ ID NO: 1847) 
               
               
                   
               
               
                 VH 
                 EVQLVQSGAEVKKPGASVKVSCKASGYRFR QYGIS WVRQAPGQGLEWMGWI SAYNGN TNYAQKLQGRVTMTT 
               
               
                   
                 DTSTNTAYMELRSLRSDDTAVYYCAR DAEYGSGSGY WGQGTLVTVSS (SEQ ID NO: 1848) 
               
               
                   
               
               
                 VH 
                 EVQLVQSGAEVKKPGASVKVSCKASGYRFTWYGISWVRQAPGQGLEWMGWISAYNGNTNYAQKLQGRVTMTT 
               
               
                   
                 DTSTNTAYMELRSLRSDDTAVYYCARDSEYRSGSGYWGQGTLVTVSS (SEQ ID NO: 1849) 
               
               
                   
               
               
                 VH 
                 EVQLVQSGAEVKKPGASVKVSCKASGYRFRQYGISWVRQAPGQGLEWMGWISAYNGNTNYAQKLQGRVTMTT 
               
               
                   
                 DTSTNTAYMELRSLRSDDTAVYYCARDAEYRSGSGYWGQGTLVTVSS (SEQ ID NO: 1850) 
               
               
                   
               
               
                 VH 
                 EVQLVQSGAEVKKPGASVKVSCKASGYRFTRYGISWVRQAPGQGLEWMGWVSAHNGNTNYAQKLQGRVTMTT 
               
               
                   
                 DTSTNTAYMELRSLRSDDTAVYYCARDADYRSGSGYWGQGTLVTVSSS (SEQ ID NO: 1851) 
               
               
                   
               
               
                 VH 
                 EVQLVQSGAEVKKPGASVKVSCKASGYRFPHYGISWVRQAPGQGLEWMGWISAYNGNTNYAQKLQGRVTMTT 
               
               
                   
                 DTSTNTAYMELRSLRSDDTAVYYCARDVDYRTGSGYWGQGTLVTVSS (SEQ ID NO: 1852) 
               
               
                   
               
               
                 VH 
                 EVQLVQSGAEVKKPGASVKVSCKASGYRFSTFGISWVRQAPGQGLEWMGWISAYNGNTNYAQKLQGRVTMTT 
               
               
                   
                 DTSTNTAYMELRSLRSDDTAVYYCARDVDYRSGSGYWGQGTLVTVSS (SEQ ID NO: 1853) 
               
               
                   
               
               
                 VH 
                 EVQLVQSGAEVKKPGASVKVSCKASGYRFTRQGISWVRQAPGQGLEWMGWISAYNGNTKYAQKLQGRVTMTT 
               
               
                   
                 DTSTNTAYMELRSLRSDDTAVYYCARDVDYRSGSGYWGQGTLVTVSS (SEQ ID NO: 1854) 
               
               
                   
               
               
                 VH 
                 EVQLVQSGAEVKKPGASVKVSCKASGYRFPHYGISWVRQAPGQGLEWMGWISAYNGNTNYAQKLQGRVTMTT 
               
               
                   
                 DTSTNTAYMELRSLRSDDTAVYYCARDAEYRSGSGYWGQGTLVTVSS (SEQ ID NO: 1855) 
               
               
                   
               
               
                 VH 
                 EVQLVQSGAEVKKPGASVKVSCKASGYRFETYGISWVRQAPGQGLEWMGWISAYNGNTNYAQKLQGRVTMTT 
               
               
                   
                 DTSTNTAYMELRSLRSDDTAVYYCARDAEYRLGSGYWGQGTLVTVSS (SEQ ID NO: 1869) 
               
               
                   
               
               
                 VL 
                 NIVMTQTPKFLLVSAGDRITITC KASQSVSDDVA WYQQKPGQSPKLLIS YAFKRYI GVPDRFTGSGYGTDFT 
               
               
                   
                 FTISTVQAEDLAVYFC QQNYNSPYT FGGGTKLELKR (SEQ ID NO: 1856) 
               
               
                   
               
               
                 VL 
                 QIVLSQSPAILSASPGEKVTMTC RTSSSVNYMH WFQQKPGSSPKPWIY ATSKLAS GVPARFSGSGSGTSYSL 
               
               
                   
                 TISRVEAEDAATYFC QQWISDPWT FGGGTKLEIK (SEQ ID NO: 1857) 
               
               
                   
               
               
                 VL 
                 SYELTQPPSVSVSPGQTARITC SGDALTTQYAY WYQQKPGQAPVMVIY KDTERPS GIPERFSGSSSGTKVTL 
               
               
                   
                 TISGVQAEDEADYYC QSADNSITYRV FGGGTKVTVL (SEQ ID NO: 1858) 
               
               
                   
               
               
                 VL 
                 SYELTQPPSVSVSPGQTARITC SGDALSEQYAY WYQQKPGQAPVMVIY KDTERPS GIPERFSGSSSGTKVTL 
               
               
                   
                 TISGVQAEDEADYYC QSADNSITYRV FGGGTKVTVL (SEQ ID NO: 1859) 
               
               
                   
               
               
                 VL 
                 SYELTQPPSVSVSPGQTARITCSGDALPKQYAYWYQQKPGQAPVMVIYKDTERPSGIPERFSGSSSGTKVTL 
               
               
                   
                 TISGVQAEDEADYYCQSADNSITYRVFGGGTKVTVL (SEQ ID NO: 737) 
               
               
                   
               
               
                 VL 
                 SYELTQPPSVSVSPGQTARITCSGDALPMQYGYWYQQKPGQAPVMVLYKDTERPSGIPERFSGSSSGTKVTL 
               
               
                   
                 TISGVQAEDEDYYCQSDNSITYRVFGGGTKVTVL (SEQ ID NO: 1860) 
               
               
                   
               
               
                 VL 
                 SYELTQPPSVSVSPGQTARITC SGDALPMQYGY WYQQKPGQAPVMVIY KDTERPS GIPERFSGSSSGTKVTL 
               
               
                   
                 TISGVQAEDEADYYC QSADNSITYRV FGGGTKVTVL (SEQ ID NO: 1861) 
               
               
                   
               
               
                 VL 
                 DIILTQSPASLAVSLGQRAAISCRASESVDNSGISFMSWFQQKPGQPPKLLIYTASNQGSGVPARFSGSGSG 
               
               
                   
                 TEFSLNIHPMEEDDTAMYFCQQSKEVPWTFGGGTKLEIR (SEQ ID NO: 1862) 
               
               
                   
               
               
                 VL 
                 DIVLTQSPASLAVSLGQRATISCRASENVDDYGVSFMNWFQQKPGQPPKLLIYPASNQGSGVPARFSGSGSG 
               
               
                   
                 TDFSLNIHPMEEDDTAMYFCQQSKEVPWTFGGGTKLEIK (SEQ ID NO: 1863) 
               
               
                   
               
               
                 VL 
                 DIQLTQSPSFLSASVGDRVTITCRASESVDNSGISFMSWYQQKPGKAPKLLIYTASNQGSGVPSRFSGSGSG 
               
               
                   
                 TEFTLTISSLQPEDFATYYCQQSKEVPWTFGQGTKVEIK (SEQ ID NO: 1864) 
               
               
                   
               
               
                 VL 
                 EIVLTQSPATLSLSPGERATLSCRASESVDNSGISFMSWYQQKPGQAPRLLIYTASNQGSGIPARFSGSGSG 
               
               
                   
                 TDFTLTISSLEPEDFAVYYCQQSKEVPWTFGQGTKVEIK (SEQ ID NO: 1865) 
               
               
                   
               
               
                 VL 
                 EIVLTQSPATLSLSPGERATLSCRASENVDDYGVSFMNWYQQKPGQAPRLLIYPASNQGSGIPARFSGSGSG 
               
               
                   
                 TDFTLTISSLEPEDFAVYYCQQSKEVPWTFGQGTKVEIK (SEQ ID NO: 1866) 
               
               
                   
               
               
                 VL 
                 EIVLTQSPGTLSLSPGERATLSCRASENVDDYGVSFMNWYQQKPGQAPRLLIYPASNQGSGIPDRFSGSGSG 
               
               
                   
                 TDFTLTISRLEPEDFAVYYCQQSKEVPWTFGQGTKVEIK (SEQ ID NO: 1867) 
               
               
                   
               
               
                 VL 
                 DIVMTQSPDSLAVSLGERATINCRASENVDDYGVSFMNWYQQKPGQPPKLLIYPASNQGSGVPDRFSGSGSG 
               
               
                   
                 TDFTLTISSLQAEDVAVYYCQQSKEVPWTFGGGTKLEIK (SEQ ID NO: 1868) 
               
               
                   
               
            
           
           
               
            
               
                 Group V 
               
            
           
           
               
               
            
               
                 VH 
                 QVQLVQSGAEVKKPGASVKVSCKAS GYTFTSYWIN WVRQAPGQGLEWMG NIYPGSSLTNYNEKFKN RVTMTR 
               
               
                   
                 DTSTSTVYMELSSLRSEDTAVYYCAR LLTGTFAY WGQGTLVTVSS (SEQ ID NO: 1870) 
               
               
                   
               
               
                 VH 
                 QVQLVQSGAEVKKPGASVKVSCKAS GYTFTSYWIN WVRQAPGQGLEWMG NIYPGSSLTNYNEKFKN RVTMTR 
               
               
                   
                 DTSTSTVYMELSSLRSEDTAVYYCAR LSTGTFAY WGQGTLVTVSS (SEQ ID NO: 1871) 
               
               
                   
               
               
                 VH 
                 QVQLVQSGAEVKKPGASVKVSCKAS GYTFTSYWIN WVRQAPGQGLEWMG NIYPGSSITNYNEKFKN RVTMTR 
               
               
                   
                 DTSTSTVYMELSSLRSEDTAVYYCAR LTTGTFAY WGQGTLVTVSS (SEQ ID NO: 1872) 
               
               
                   
               
               
                 VH 
                 QVQLVQSGAEVKKPGASVKVSCKAS GYTFTSYWIN WVRQAPGQGLEWMG NIWPGSSLTNYNEKFKN RVTMTR 
               
               
                   
                 DTSTSTVYMELSSLRSEDTAVYYCAR LLTGTFAY WGQGTLVTVSS (SEQ ID NO: 1873) 
               
               
                   
               
               
                 VH 
                 DIVMTQSPDSLAVSLGERATINC KSSQSLWDSGNQKNFLT WYQQKPGQPPKLLIY WTSTRES GVPDRFSGSG 
               
               
                   
                 SGTDFTLTISSLQAEDVAVYYC QNDYFYPLT FGGGTKVEIK (SEQ ID NO: 1874) 
               
               
                   
               
               
                 VL 
                 DIVMTQSPDSLAVSLGERATINC KSSQSLWDSGNQKNFLT WYQQKPGQPPKLLIY WTSYRES GVPDRFSGSG 
               
               
                   
                 SGTDFTLTISSLQAEDVAVYYC QNDYFYPLT FGGGTKVEIK (SEQ ID NO: 1875) 
               
               
                   
               
               
                 VL 
                 DIVMTQSPDSLAVSLGERATINC KSSQSLWDSGNQKNFLT WYQQKPGQPPKLLIY WTSYRES GVPDRFSGSG 
               
               
                   
                 SGTDFTLTISSLQAEDVAVYYC QNDYFYPHT FGGGTKVEIK (SEQ ID NO: 1876) 
               
               
                   
               
               
                 VL 
                 DIVMTQSPDSLAVSLGERATINC KSSQSLWDSTNQKNFLT WYQQKPGQPPKLLIY WTSTRES GVPDRFSGSG 
               
               
                   
                 SGTDFTLTISSLQAEDVAVYYC QNDYFYPLT FGGGTKVEIK (SEQ ID NO: 1877) 
               
               
                   
               
               
                 HC 
                 QVQLVQSGAEVKKPGASVKVSCKAS GYTFTSYWIN WVRQAPGQGLEWMG NIYPGSSLTNYNEKFKN RVTMTR 
               
               
                   
                 DTSTSTVYMELSSLRSEDTAVYYCAR LSTGTFAY WGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGC 
               
               
                   
                 LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVE 
               
               
                   
                 SKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKP 
               
               
                   
                 REEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQV 
               
               
                   
                 SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNH 
               
               
                   
                 YTQKSLSLSLGK (SEQ ID NO: 1878) 
               
               
                   
               
               
                 HC 
                 QVQLVQSGAEVKKPGASVKVSCKAS GYTFTSYWIN WVRQAPGQGLEWMG NIYPGSSLTNYNEKFKN RVTMTR 
               
               
                   
                 DTSTSTVYMELSSLRSEDTAVYYCAR LSTGTFAY WGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGC 
               
               
                   
                 LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVE 
               
               
                   
                 SKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKP 
               
               
                   
                 REEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQV 
               
               
                   
                 SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNH 
               
               
                   
                 YTQKSLSLSLG (SEQ ID NO: 1879) 
               
               
                   
               
               
                 LC 
                 DIVMTQSPDSLAVSLGERATINC KSSQSLWDSGNQKNFLT WYQQKPGQPPKLLIY WTSYRES GVPDRFSGSG 
               
               
                   
                 SGTDFTLTISSLQAEDVAVYYC QNDYFYPHT FGGGTKVEIKRGTVAAPSVFIFPPSDEQLKSGTASVVCLLN 
               
               
                   
                 NFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF 
               
               
                   
                 NRGEC (SEQ ID NO: 1880) 
               
               
                   
               
            
           
           
               
            
               
                 Group W 
               
            
           
           
               
               
            
               
                 VH 
                 EVQLQESGPELVRPGASVKMSCKASGYTFTSYWMHWVKQRPGQGLEWIGMIDPSNSETSLNQKFKDKATLNV 
               
               
                   
                 DKSTNTAYMQLSSLTSEDSAVYYCARSRGNYAYEMDYWGQGTSVTVSS (SEQ ID NO: 1972) 
               
               
                   
               
               
                 VH 
                 EVQLQESGPELVRPGASVKMSCKASGYTFTSYWMHWVKQRPGQGLEWIGMIEPSSSETSLNQKFKDKATLNV 
               
               
                   
                 DKSSNTAYMQLSSLTSEDSAVYYCARSRGNYAYEMDYWGQGTSVTVSS (SEQ ID NO: 1973) 
               
               
                   
               
               
                 VH 
                 EVQLQESGPELVRPGASVKMSCKASGYTFTSYWMHWVKQRPGQGLEWIGMIDPYSSETSLNQKFKDKATLNV 
               
               
                   
                 DKISNTAYMQLSSLTSEDSAVYFCARSRGNYAYDMDYWGQGTSVTVSS (SEQ ID NO: 1974) 
               
               
                   
               
               
                 VH 
                 EVQLQESGPELVRPGASVKMSCKASGYTFTSYWMHWVKQRPGQGLEWIGMIDPSNSETSLNQKFKDKATLNV 
               
               
                   
                 DKSSKTAYMQLSSLTSEDSAVYYCARSRGNYAYDMDYWGQGTSVTVSS (SEQ ID NO: 1975) 
               
               
                   
               
               
                 VH 
                 EVQLQESGAELVMPGASVKMSCKASGYTFTDYWMHWVKQRPGQGLEWIGAIDTSDSYTSYHQNFKGKATLTE 
               
               
                   
                 DESSSTAYMQLSSLTSEDSAIYYCARRDYGGFGYWGQGTTLTVSS (SEQ ID NO: 1976) 
               
               
                   
               
               
                 VH 
                 EVQLQESGPELVKPGASVKIPCKASGYTFTDYNMDWVKKSHGKSLEWIGDIDPNNGGTIYNQKFKGKATLTV 
               
               
                   
                 DKSSRTAYMELRSLTSEDTAVYYCARWRSSMDYWGQGTSVTVSS (SEQ ID NO: 1977) 
               
               
                   
               
               
                 VH 
                 EVQLQESGPELVKPGASVKIPCRASGYIFTDYNMDWVKQSHGKSLEWIGDIDPNNGGTIYNQKFKDKTTLTV 
               
               
                   
                 DKSSRTAYMELRSLTSEDTAVYYCARWRSSMDYWGQGTSVTVSS (SEQ ID NO: 1978) 
               
               
                   
               
               
                 VH 
                 EVQLQESGPELVKPGASVKIPCKASGYTFTDYNMDWVKQNHGKSLEWIGDIDPNNGDTIYNQKFKGKATLTV 
               
               
                   
                 DKSSRTAYMELRSLTSEDTAVYYCARWRSSMDYWGQGTSVTVSS (SEQ ID NO: 1979) 
               
               
                   
               
               
                 VH 
                 EVQLQESGPELVKPGASVKIPCKASGYTFTDYNMDWVKQSHGKSLEWIGDIDPNSGGSIYNQKFKGKATLTV 
               
               
                   
                 DKSSRTVYMELRSLTSEDTAVYYCARWRSSMDYWGQGTSVTVSS (SEQ ID NO: 1980) 
               
               
                   
               
               
                 VH 
                 EVQLQESGPELVKPGASVKITCKASGYTFTDYNMDWVKQSHGKSLEWIGDIDPNNGGTIYNQKFKGKATLTV 
               
               
                   
                 DKSSNTAYMELRSLASEDTAVYYCARWRSSMDYWGQGTSVSVSS (SEQ ID NO: 1981) 
               
               
                   
               
               
                 VH 
                 EVQLQESGPELVKPGASVKIPCKASGYTFTDYNMDWVKQSHGKSLEWIGDIDPNNGGTIYNQNFKGKATLTV 
               
               
                   
                 DKSSSTAYMELRSLTSEDTAVYYCARWRSSMDYWGQGTSVTVSS (SEQ ID NO: 1982) 
               
               
                   
               
               
                 VH 
                 EVQLQESGPELVKPGASVKIPCKASGYTFTDYNMDWVKQSHGKSLEWIGDIDPNNGGIIYNQKFKGKAALTV 
               
               
                   
                 DKSSSTAYMELRSLTSEDTAVYYCARWRSSMDYWGQGTSVTVSS (SEQ ID NO: 1983) 
               
               
                   
               
               
                 VH 
                 EVQLQESGPELVKPGASVKIPCKASGYTFTDYNMDWVKQSHGKSLEWIGDIDPNNGGIIYNQKFKGKAALTV 
               
               
                   
                 DKSSSTAYMELRSLTSEDTAVYYCTRWRSSMDYWGQGTSVTVSS (SEQ ID NO: 1984) 
               
               
                   
               
               
                 VH 
                 EVQLQESGPELVKPGASVKIPCKASGYTFTDYNMDWVKQSHGKSLEWIGDIDPNNGNTIYNQKFKGKATLTV 
               
               
                   
                 DKSSSTAYMELRSLTSEDTAVYYCTKWRSSMDYWGQGTSVTVSS (SEQ ID NO: 1985) 
               
               
                   
               
               
                 VH 
                 EVQLQESGPELVRPGASVKIPCKASGYTFTDYNMDWVMQSHGKSLEWIGDIDPNNGGTIYNQKFKGKATLTV 
               
               
                   
                 DKSSSTAYMELRSLTSEDTAVYYCTRWRSSMDYWGQGTSVTVSS (SEQ ID NO: 1986) 
               
               
                   
               
               
                 VH 
                 EVQLQESGPELVKPGASVKIPCKASGYTFTDYNVDWVKQSHGKSLEWIGDIDPNNGGTFYNQKFKGKATLTV 
               
               
                   
                 DKSSSTAHMELRSLTSEDTAVYYCVRWRSSMDYWGQGTSVTVSS (SEQ ID NO: 1987) 
               
               
                   
               
               
                 VH 
                 EVQLQESGPELVKPGASVKIPCKASGYTFTDYNMDWVKQSHGKSLEWIGDIDPNTGTTFYNQDFKGKATLTV 
               
               
                   
                 DKSSSTAYMELRSLTSEDTAVYYCARWRSSMDYWGQGTSLTVSS (SEQ ID NO: 1988) 
               
               
                   
               
               
                 VH 
                 EVQLQESGAELVRPGASVTLSCKASGYTFTDYEMHWVKQTPVHGLEWIGVIDPGTGGTAYNQKFKVKALLTA 
               
               
                   
                 DKSSNTAYMELRSLTSEDSAVYYCTSEKFGSNYYFDYWGQGTTLTVSS (SEQ ID NO: 1989) 
               
               
                   
               
               
                 VH 
                 EVQLQESGAELVRPGASVTLSCKASGYTFTDYEIHWVKQTPVHGLEWIGAIDPETGGTAYNQKFKGKAILTA 
               
               
                   
                 DKSSSTAYMELRSLTSEDSAVYYCTSEKFGSSYYFDYWGQGTTFTVSS (SEQ ID NO: 1990) 
               
               
                   
               
               
                 VH 
                 EVQLQESGPGLVKPSQSLSLTCTVTGYSITSDYAWNWIRQFPGNKLEWMGYITYSGSPTYNPSLKSQFSITR 
               
               
                   
                 DTSKNQFFLQLNSLTTEDTATYYCARGLGGHYFDYWGQGTTLTVSS (SEQ ID NO: 1991) 
               
               
                   
               
               
                 VH 
                 EVQLQESGPGLVKPSQSLSLTCTVTGYSITSDYAWNWIRQFPGNKLEWMGYITYSGSPTYNPSLKSQFSITR 
               
               
                   
                 DTSKNQFFLQLNSVTTEDTATYYCARGLGGHYFDYWGQGTTLTVSS (SEQ ID NO: 1992) 
               
               
                   
               
               
                 VH 
                 EVQLQESGPDLVKPSQSLSLTCTVTGYSITSGYSWHWIRQFPGNKLEWMGFIHYSGDTNYNPSLKSRFSITR 
               
               
                   
                 DTSKNQFFLHLNSVTPEDTATYYCASPSRLLFDYWGHGTTLTVSS (SEQ ID NO: 1993) 
               
               
                   
               
               
                 VH 
                 EVQLQESGPGLVAPSQSLSITCTVSGFSLTNYGVDWVRQSPGKGLEWLGVIWGVGSTNYNSALKSRLSISKD 
               
               
                   
                 NSKSQVFLKMNSLQTDDTAMYYCASDGFVYWGQGTLVTVSS (SEQ ID NO: 1994) 
               
               
                   
               
               
                 VH 
                 EVQLQESGPGLVAPSQSLSITCTVSGFSLTSYGVDWVRQSPGKGLEWLGVIWGIGSTNYNSALKSRLSISKD 
               
               
                   
                 NSKSQVFLKMNSLQSDDTAMYYCASDGFVYWGQGTLVTVSS (SEQ ID NO: 1995) 
               
               
                   
               
               
                 VH 
                 EVQLQESGPSLVQPSQSLSITCTVSGFSLTSYGVHWVRQSPGKGLEWLGVIWRGGNTDYNAAFMSRLSITKD 
               
               
                   
                 NSKSQVFFKMNSLQADDTAIYYCAASMIGGYWGQGTTLTVSS (SEQ ID NO: 1996) 
               
               
                   
               
               
                 VH 
                 EVQLQESGPSLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWRGGNTDYNAAFMSRLSITKD 
               
               
                   
                 NSKSQVFFKFHSLQTDDTAIYYCAASMIGGYWGQGTTLTVSS (SEQ ID NO: 1997) 
               
               
                   
               
               
                 VH 
                 QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWMHWVRQAPGQGLEWMGMIDPSNSETSLNQKFQGRVTMTV 
               
               
                   
                 DKSTNTVYMELSSLRSEDTAVYYCARSRGNYAYEMDYWGQGTLVTVSS (SEQ ID NO: 1998) 
               
               
                   
               
               
                 VH 
                 EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWMHWVRQAPGQGLEWMGMIDPSNSETSLNQKFQGRVTLNV 
               
               
                   
                 DKSTNTAYMELSSLRSEDTAVYYCARSRGNYAYEMDYWGQGTLVTVSS (SEQ ID NO: 1999) 
               
               
                   
               
               
                 VH 
                 EVQLVQSGTEVTKPGASVKVSCKASGYTFTSYWMHWVRQAPGQGLEWLGMIDPSNSETTLNQKFQGRVTMTV 
               
               
                   
                 DKSTNTVYMELTSLRSEDTAVYYCARSRGNYAYEMDYWGQGTLVTVSS (SEQ ID NO: 2000) 
               
               
                   
               
               
                 VH 
                 EVQLVQSGAEVKKPGASVKVSCKASGYTFTDYEMHWVRQAPGQGLEWMGIIDPGTGGTAYNQKFQGRVTMTA 
               
               
                   
                 DKSTSTVYMELSSLRSEDTAVYYCTSEKFGSNYYFDYWGQGTLVTVSS (SEQ ID NO: 2001) 
               
               
                   
               
               
                 VH 
                 EVQLVQSGAEVKKPGASVKVSCKASGYTFTDYEMHWVRQAPGQGLEWMGIIDPGTGGTAYNQKFQGRVTMTA 
               
               
                   
                 DKSTNTVYMELSSLRSEDTAVYYCTSEKFGSNYYFDYWGQGTLVTVSS (SEQ ID NO: 2002) 
               
               
                   
               
               
                 VH 
                 EVQLVQSGAEVKKPGASVKVSCKASGYTFTDYEMHWVRQAPGQRLEWMGVIDPGTGGTAYNQKFQGRVTITA 
               
               
                   
                 DKSASTAYMELSSLRSEDTAVYYCTSEKFGSNYYFDYWGQGTLVTVSS (SEQ ID NO: 2003) 
               
               
                   
               
               
                 VL 
                 DIVLTQTPAIMSASPGEKVTLTCSASSSVSSNYLYWYQQRPGSSPKLWIYSTSNLASGVPARFSGSGSGTSY 
               
               
                   
                 SLTISSMEAEDAASYFCHQWSSYPPTFGSGTKLEIK (SEQ ID NO: 2004) 
               
               
                   
               
               
                 VL 
                 DIVITQTTAIMSASPGEKVTLTCSASSSVSSNYLYWYQQRPGSSPKLWIYSTSNLASGVPARFSGSGSGTSY 
               
               
                   
                 SLTISSMEAEDAASYFCHQWSSYPPTFGSGTKLEIK (SEQ ID NO: 2005) 
               
               
                   
               
               
                 VL 
                 DIVMTQTPATMSASPGEKVTLTCSASSSVNSNYLYWYQQKPGSSPKVWIYSTSNLASGVPARFSGSGSGTSY 
               
               
                   
                 SLTISSMEAEDAASYFCHQWSSYPPTFGSGTKLELK (SEQ ID NO: 2006) 
               
               
                   
               
               
                 VL 
                 DIVMTQTTATMSASPGEKVTLTCSASSSVNSNYLYWYQQKPGSSPKVWIYSTSNLASGVPARFSGSGSGTSY 
               
               
                   
                 SLTISSMEAEDAASYFCHQWSSYPPTFGSGTKLELK (SEQ ID NO: 2007) 
               
               
                   
               
               
                 VL 
                 DIVLTQSTAIMSASPGEKVTLTCSASSGVNSNYLYWYQQKPGSSPKLWIYSTSNLASGVPARFSGSGSGTSY 
               
               
                   
                 SLTISSVEAEDAASYFCHQWSSYPPTFGSGTKLEIK (SEQ ID NO: 2008) 
               
               
                   
               
               
                 VL 
                 DIVLTQTPSSLSASLGDRVTISCSASQGISNYLNWYQQKPDGTVKLLIYYTSSLHSGVPSRFSGSGSGTDYS 
               
               
                   
                 LTISNLEPEDIATYYCQQYSKLPWTFGGGTKLEIK (SEQ ID NO: 2009) 
               
               
                   
               
               
                 VL 
                 DIVLTQSPSSLSASLGDRVTISCSASQGISNYLNWYQQKPDGTVKLLIYYTSSLHSGVPSRFSGSGSGTDYS 
               
               
                   
                 LTISNLEPEDIATYYCQQYSKLPWTFGGGTKLEIK (SEQ ID NO: 2010) 
               
               
                   
               
               
                 VL 
                 DIVITQSPSSLSASLGDRVTISCSASQGISNYLNWYQQKPDGTVKLLIYYTSSLHSGVPSRFSGSGSGTDYS 
               
               
                   
                 LTISNLEPEDIATYYCQQYSELPWTFGGGTKLEIK (SEQ ID NO: 2011) 
               
               
                   
               
               
                 VL 
                 DIVMTQSPSSLSASLGDRVTISCSASQGISNYLNWYQQRPDGTVKLLIYYTSSLHSGVPSRFSGSGSGTDYS 
               
               
                   
                 LTISNLEPEDIATYYCQQYSNLPWTFGGGTKLEIK (SEQ ID NO: 2012) 
               
               
                   
               
               
                 VL 
                 DIVMTQSPSSLSASLGDRVTISCSASQGISNYLNWYQQKPDGTVKLLIYYTSSLHSGVPSRFSGSGSGTDYS 
               
               
                   
                 LTISNLEPEDIATYYCQQYSELPWTFGGGTKLEIK (SEQ ID NO: 2013) 
               
               
                   
               
               
                 VL 
                 DIVMTQSTSSLSASLGDRVTISCSASQGISHYLNWYQQKPDGTVKLLIYYTSSLHSGVPSRFSGSGSGTDYS 
               
               
                   
                 LTIRNLEPEDIATYYCQQYSELPWTFGGGTKLEIK (SEQ ID NO: 2014) 
               
               
                   
               
               
                 VL 
                 DIVMTQSPSSLSASLGDRVTISCSASQGISHYLNWYQQKPDGTVKLLIYYTSSLHSGVPSRFSGSGSGTDYS 
               
               
                   
                 LTIRNLEPEDIATYYCQQYSELPWTFGGGTKLEIK (SEQ ID NO: 2015) 
               
               
                   
               
               
                 VL 
                 DIVMTQSPSSLSASLGDRVTISCSASQDISSYLNWYQQKPDGTVKLLIYYTSSLHSGVPSRFSGSGSGTDYS 
               
               
                   
                 LTISNLEPEDIATYYCQQYSELPWTFGGGTKLEIK (SEQ ID NO: 2016) 
               
               
                   
               
               
                 VL 
                 DIVMTQTPSSLSASLGDRVTISCSASQGISYYLNWYQQKPDGTIKLLIYYTLSLHSGVPSRFSGSGSGTDYS 
               
               
                   
                 LTISNLEPEDIATYYCQQYSELPWTFGGGTKLEIK (SEQ ID NO: 2017) 
               
               
                   
               
               
                 VL 
                 DIVMTQTPSSMSASLGDRVTISCSASQGISNYLNWYQQKPDGTVKLLIYYTSSLHSGVPSRFSGSGSGTDYS 
               
               
                   
                 LTISNLEPEDIATYYCQQYSYLPWTFGGGTKLEIK (SEQ ID NO: 2018) 
               
               
                   
               
               
                 VL 
                 DIVMTQTPSSLSASLGDRVTISCSASQGIGNYLNWYQQKPDGTVKLLIYYTSNLHSGVPSRFSGRGSGTDYS 
               
               
                   
                 LTISNLEPEDIATYYCQQYSNLPWTFGGGTKLEIK (SEQ ID NO: 2019) 
               
               
                   
               
               
                 VL 
                 DIVMTQSPSSLSASLGDRVTISCSASQGISNYLNWYQQKPDGTVKLLIYYTSNLHSGVPSRFSGSGSGTDYS 
               
               
                   
                 LTISDLAPEDIATYYCQQYSYLPWTFGGGTKLEIK (SEQ ID NO: 2020) 
               
               
                   
               
               
                 VL 
                 DIVITQSPLSLPVGLGDQASISCRSSQSLVHSNGNTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGS 
               
               
                   
                 GTDFTLKISRVEAEDLGVYFCSQSTHVPYTFGGGTKLEIK (SEQ ID NO: 2021) 
               
               
                   
               
               
                 VL 
                 DIVLTQTPLSLPVSLGDQASISCRSSQSIVHSNGNTYLEWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGS 
               
               
                   
                 GTNFTLKISRVEAEDLGVYYCFQGSHVPLTFGAGTKLELK (SEQ ID NO: 2022) 
               
               
                   
               
               
                 VL 
                 DIVLTQSPLSLPVSLGDQASISCRSSQSIVHSDGNTYLEWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGS 
               
               
                   
                 GTDFTLKISRVEAEDLGIYYCFQGSHVPLTFGAGTKLELK (SEQ ID NO: 2023) 
               
               
                   
               
               
                 VL 
                 DIVITQTPLSLPVSLGDQASISCRSSQTIVHSDGNTYLEWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGS 
               
               
                   
                 GTDFTLKISRVEAEDLGVYYCFQGSHVPLTFGAGTKLEIK (SEQ ID NO: 2024) 
               
               
                   
               
               
                 VL 
                 DIVMTQSTLSLPVSLGDQVSISCRSSQSIVHSDGNTYLEWYLQKPGQSPNLLIYKVSNRFSGVPDRFSGSGS 
               
               
                   
                 GTDFTLKISRVEAEDLGVYYCFQGSHVPLTFGAGTKLELK (SEQ ID NO: 2025) 
               
               
                   
               
               
                 VL 
                 DIVLTQDELSNPVTSGESVSISCRSSKSLLYKDGKTYLNWFLQRPGQSPQVLIYFMSTRASGVSDRFSGSGS 
               
               
                   
                 GTDFTLEISRVKAEDVGVYYCQQLVDFPFTFGSGTKLELK (SEQ ID NO: 2026) 
               
               
                   
               
               
                 VL 
                 DIVMTQDELYNPVTSGESVSISCRSSKSLLYKDGKTYLNWFLQRPGQSPQVLIYFMSTRASGVSDRFSGSGS 
               
               
                   
                 GTDFTLEISRVKAEDVGVYYCQQLVDFPFTFGSGTKLEIK (SEQ ID NO: 2027) 
               
               
                   
               
               
                 VL 
                 DIVMTQSPSSLTVTAGEKVTMSCKSSQSLLNSGTQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFTGSG 
               
               
                   
                 SGTDFTLTISSVQAEDLAVYYCQNDYSYPLTFGAGTKLEIK (SEQ ID NO: 2028) 
               
               
                   
               
               
                 VL 
                 DIVLTQTTATLSVTPGDRVSLSCRASQSISDYLHWYQQKSHESPRLLIKYASQSISGIPSRFSGSGSGSDFT 
               
               
                   
                 LTVNSVEPEDVGVYYCQNGHSYPYTFGGGTKLEIK (SEQ ID NO: 2029) 
               
               
                   
               
               
                 VL 
                 DIVLTQSPDTLSVTPGDRVSLSCRASQSISDYLHWYQQKSHESPRLLIKYASQSISGIPSRFSGSGSGSDFT 
               
               
                   
                 LSINSVEPEDVGVYYCQNGHSYPYTFGGGTKLELK (SEQ ID NO: 2030) 
               
               
                   
               
               
                 VL 
                 EIVLTQSPATLSLSPGERATLSCRASSSVSSNYLYWYQQKPGQAPRLLIYSTSNRATGIPARFSGSGSGTDY 
               
               
                   
                 TLTISSLEPEDFAVYYCHQWSSYPPTFGQGTKLEIK (SEQ ID NO: 2031) 
               
               
                   
               
               
                 VL 
                 DIVLTQSPATLSLSPGERATLSCRASSSVSSNYLYWYQQKPGQAPRLLIYSTSNLATGIPARFSGSGSGTDY 
               
               
                   
                 TLTISSLEPEDFAVYFCHQWSSYPPTFGQGTKLEIK (SEQ ID NO: 2032) 
               
               
                   
               
               
                 VL 
                 DIVLTQSPGTLSLSPGEKVTLSCRASSSVSSNYLYWYQQKPGQAPRLVIYSTSNLATGIPDRFSGSGSGTDY 
               
               
                   
                 TLTISRLEPEDFAVYFCHQWSSYPPTFGQGTKVEIK (SEQ ID NO: 2034) 
               
               
                   
               
               
                 VL 
                 DVVMTQSPLSLPVTLGQPASISCRSSQTIVHSDGNTYLEWYQQRPGQSPRLLIYKVSNRFSGVPDRFSGSGS 
               
               
                   
                 GTDFTLKISRVEAEDVGVYYCFQGSHVPLTFGQGTKLEIK (SEQ ID NO: 2035) 
               
               
                   
               
               
                 VL 
                 DIVMTQSPLSLPVTLGQPASISCRSSQTIVHSDGNTYLEWYQQRPGQSPKLLIYKVSNRFSGVPDRFSGSGS 
               
               
                   
                 GTDFTLKISRVEAEDVGVYYCFQGSHVPLTFGQGTKLEIK (SEQ ID NO: 2036) 
               
               
                   
               
               
                 VL 
                 DIVMTQTPLSSPVTLGQPASISCRSSQTIVHSDGNTYLEWYQQRPGQPPRLLIYKVSNRFSGVPDRFSGSGA 
               
               
                   
                 GTDFTLKISRVEAEDVGVYYCFQGSHVPLTFGQGTKLEIK (SEQ ID NO: 2037) 
               
               
                   
               
            
           
         
       
     
     In some embodiments, the activatable anti-PD-1 antibody includes a CDR sequence shown in Table 8, a combination of VL CDR sequences (VL CDR1, VL CDR2, VL CDR3) selected from the group consisting of those combinations shown in a single row Table 8, a combination of VH CDR sequences (VH CDR1, VH CDR2, VH CDR3) selected from the group consisting of those combinations shown in Table 8, or a combination of VL CDR and VH CDR sequences (VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, VH CDR3) selected the group consisting of those combinations shown in Table 8. The CDR regions were defined according to AbM definition as described in the CDR definition table in Andrew C. R. Martin&#39;s Bioinformatics Group website at UCL. 
     
       
         
           
               
             
               
                 TABLE 8 
               
             
            
               
                   
               
               
                 CDR Sequences for Antibodies and Activatable Antibodies that Bind PD-1 
               
            
           
           
               
               
               
            
               
                   
                 VH 
                 VL 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 CDR1 
                 CDR2 
                   
                   
                 CDR2 
                 CDR3 
               
               
                 AB 
                 (SEQ ID 
                 (SEQ ID 
                 CDR3 (SEQ 
                 CDR1 (SEQ ID 
                 (SEQ ID 
                 (SEQ ID 
               
               
                 Name 
                 NO) 
                 NO) 
                 ID NO) 
                 NO) 
                 NO) 
                 NO) 
               
               
                   
               
               
                 M13 
                 GFTFSGYAMS 
                 YISNSGGNAH 
                 EDYGTSPFVY 
                 RASESVDNYGIS 
                 AASNQGS 
                 QQSKDVPWT 
               
               
                   
                 (653) 
                 (658) 
                 (664) 
                 FMN (669) 
                 (678) 
                 (683) 
               
               
                   
               
               
                 M19 
                 GYTFTDYYMD 
                 YIYPKNGGSS 
                 KVVATDY 
                 KSSQSLLYSSNQ 
                 WASIRES 
                 QQCDSYPWT 
               
               
                   
                 (654) 
                 (659) 
                 (665) 
                 KNYL (670) 
                 (679) 
                 (684) 
               
               
                   
               
               
                 M3 
                 GFTFSNYAMS 
                 YISNGGGDTH 
                 ENYGTSPFVY 
                 RASESVDNYGIS 
                 AASNQGS 
                 QQSKDVPWT 
               
               
                   
                 (655) 
                 (660) 
                 (666) 
                 FMN (669) 
                 (678) 
                 (683) 
               
               
                   
               
               
                 M5 
                 GFSFSSYDMS 
                 TISGGGRYTY 
                 NYYGFDY 
                 KASQDVGTAVA 
                 WASTRHT 
                 QQYSSYPWT 
               
               
                   
                 (656) 
                 (661) 
                 (667) 
                 (671) 
                 (680) 
                 (685) 
               
               
                   
               
               
                 M14 
                 GFTFSSYGMS 
                 TISGGGRDIY 
                 LYLGFDY 
                 LASQTIGTWLA 
                 AATSLAD 
                 QQLYSIPWT 
               
               
                   
                 (657) 
                 (662) 
                 (668) 
                 (672) 
                 (681) 
                 (686) 
               
               
                   
               
               
                 A 
                 GFTFSGYAMS 
                 YISNSGGNAH 
                 EDYGTSPFVY 
                   
                   
                   
               
               
                   
                 (653) 
                 (658) 
                 (664) 
                   
                   
                   
               
               
                   
               
               
                 Ab 
                 GFTFSGYAMS 
                 YISNSGGNAH 
                 EDYGTSPFVY 
                   
                   
                   
               
               
                   
                 (653) 
                 (658) 
                 (664) 
                   
                   
                   
               
               
                   
               
               
                 Ae 
                 GFTFSGYAMS 
                 YISNSGGNTH 
                 EDYGTSPFVY 
                   
                   
                   
               
               
                   
                 (653) 
                 (663) 
                 (664) 
                   
                   
                   
               
               
                   
               
               
                 Af 
                 GFTFSGYAMS 
                 YISNSGGNTH 
                 EDYGTSPFVY 
                   
                   
                   
               
               
                   
                 (653) 
                 (663) 
                 (664) 
                   
                   
                   
               
               
                   
               
               
                 Ba 
                 GYTFTDYYMD 
                 YIYPKNGGSS 
                 KVVATDY 
                   
                   
                   
               
               
                   
                 (654) 
                 (659) 
                 (665) 
                   
                   
                   
               
               
                   
               
               
                 Bb 
                 GYTFTDYYMD 
                 YIYPKNGGSS 
                 KVVATDY 
                   
                   
                   
               
               
                   
                 (654) 
                 (659) 
                 (665) 
                   
                   
                   
               
               
                   
               
               
                 C 
                 GFTFSNYAMS 
                 YISNGGGDTH 
                 ENYGTSPFVY 
                   
                   
                   
               
               
                   
                 (655) 
                 (660) 
                 (666) 
                   
                   
                   
               
               
                   
               
               
                 Ca 
                 GFTFSNYAMS 
                 AYISNQGGDT 
                 ENYGTSPFVY 
                   
                   
                   
               
               
                   
                 (655) 
                 H (2041) 
                 (666) 
                   
                   
                   
               
               
                   
               
               
                 D 
                 GFSFSSYDMS 
                 TISGGGRYTY 
                 NYYGFDY 
                   
                   
                   
               
               
                   
                 (656) 
                 (661) 
                 (667) 
                   
                   
                   
               
               
                   
               
               
                 1.0 
                   
                   
                   
                 RASESVDNYGIS 
                 AASNQGS 
                 QQSKDVPWT 
               
               
                   
                   
                   
                   
                 FMN (673) 
                 (678) 
                 (683) 
               
               
                   
               
               
                 1.1 
                   
                   
                   
                 RASESVDNYGIS 
                 AASNQGS 
                 QQSKDVPWT 
               
               
                   
                   
                   
                   
                 FMN (673) 
                 (678) 
                 (683) 
               
               
                   
               
               
                 1.2 
                   
                   
                   
                 RASESVDQYGIS 
                 AASNQGS 
                 QQSKDVPWT 
               
               
                   
                   
                   
                   
                 FMN (674) 
                 (678) 
                 (683) 
               
               
                   
               
               
                 1.4 
                   
                   
                   
                 RASESVDSYGIS 
                 AASNQGS 
                 QQSKDVPWT 
               
               
                   
                   
                   
                   
                 FMN (675) 
                 (678) 
                 (683) 
               
               
                   
               
               
                 1.5 
                   
                   
                   
                 RASESVDAYGIS 
                 AASNQGS 
                 QQSKDVPWT 
               
               
                   
                   
                   
                   
                 FMN (676) 
                 (678) 
                 (683) 
               
               
                   
               
               
                 1.6 
                   
                   
                   
                 RASESVDNYGIS 
                 AASDQGS 
                 QQSKDVPWT 
               
               
                   
                   
                   
                   
                 FMN (673) 
                 (682) 
                 (683) 
               
               
                   
               
               
                 cl 
                   
                   
                   
                 RASESVDAYGIS 
                 AASNQGS 
                 QQSKDVPWT 
               
               
                 1.7 
                   
                   
                   
                 FMN (676) 
                 (678) 
                 (683) 
               
               
                   
               
               
                 1.9 
                   
                   
                   
                 RASESVDAY 
                 AASNQGS 
                 QQSKDVPWT 
               
               
                   
                   
                   
                   
                 (676)GISFMN 
                 (678) 
                 (683) 
               
               
                   
               
               
                 1.10 
                   
                   
                   
                 RASESVDAYGIS 
                 AASNQGS 
                 QQSKDVPWT 
               
               
                   
                   
                   
                   
                 FMN (676) 
                 (678) 
                 (683) 
               
               
                   
               
               
                 2 
                   
                   
                   
                 KSSQSLLYSSNQ 
                 WASIRES 
                 QQSDSYPWT 
               
               
                   
                   
                   
                   
                 KNYLA (677) 
                 (679) 
                 (687) 
               
               
                   
               
               
                 4 
                   
                   
                   
                 KASQDVGTAVA 
                 WASTRHT 
                 QQYSSYPWT 
               
               
                   
                   
                   
                   
                 (671) 
                 (680) 
                 (685) 
               
               
                   
               
            
           
         
       
     
     In some embodiments, the activatable anti-PD-1 antibody comprises or is derived from an antibody that is manufactured, secreted or otherwise produced by a hybridoma, such as, for example, the hybridoma(s) disclosed in U.S. Pat. No. 8,927,697 and US Patent Application Publication Nos. US 2011-0171215 and US 2015-0152180, and deposited at the European Collection of Cell Cultures (ECACC) under Accession Number 08090902; 08090903; and Ser. No. 08/090,901. 
     In some embodiments, the activatable anti-PD-1 antibody comprises or is derived from an antibody that is manufactured, secreted or otherwise produced by a hybridoma, such as, for example, the hybridoma(s) disclosed in US Patent Application Publication No. US 2014-0335093, and deposited at the Collection Nationale De Cultures De Microorganismes (CNCM) under deposit number 1-4122. 
     In some embodiments, the activatable anti-PD-1 antibody comprises or is derived from an antibody that is manufactured, secreted or otherwise produced by a hybridoma, such as, for example, the hybridoma(s) disclosed in PCT Publication Nos. WO 2015/058573 or WO 2014/206107, and deposited at the China Culture Collection Committee General Microbiology Center under Accession no. 8351. 
     In some embodiments, the activatable anti-PD-1 antibody comprises or is derived from an antibody that is manufactured, secreted or otherwise produced by a hybridoma, such as, for example, the hybridoma(s) disclosed in US Patent Application Publication No. US2011177088, and deposited at the Collection Nationale De Cultures De Microorganismes (CNCM) under deposit number 1-3745. 
     In some embodiments, the activatable anti-PD-1 antibody includes a CDR sequence shown in Table 9, a combination of VL CDR sequences selected from the group consisting of those combinations shown in Table 9, and/or a combination of VH CDR sequences selected from the group consisting of those combinations shown in Table 9. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of heavy chain CDR sequences selected from the group consisting of the combinations shown in Group A in Table 9. In some embodiments, the activatable anti-PD-1 antibody includes a combination of light chain CDR sequences selected from the group consisting of the combinations shown in Group A in Table 9. In some embodiments, the activatable anti-PD-1 antibody includes a combination of heavy chain CDR sequences selected from the group consisting of the combinations shown in Group A in Table 9, and a combination of light chain CDR sequences selected from the group consisting of the combinations shown in Group A in Table 9. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of heavy chain CDR sequences selected from the group consisting of the combinations shown in Group B in Table 9. In some embodiments, the activatable anti-PD-1 antibody includes a combination of light chain CDR sequences selected from the group consisting of the combinations shown in Group B in Table 9. In some embodiments, the activatable anti-PD-1 antibody includes a combination of heavy chain CDR sequences selected from the group consisting of the combinations shown in Group B in Table 9, and a combination of light chain CDR sequences selected from the group consisting of the combinations shown in Group B in Table 9. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of heavy chain CDR sequences selected from the group consisting of the combinations shown in Group C in Table 9. In some embodiments, the activatable anti-PD-1 antibody includes a combination of light chain CDR sequences selected from the group consisting of the combinations shown in Group C in Table 9. In some embodiments, the activatable anti-PD-1 antibody includes a combination of heavy chain CDR sequences selected from the group consisting of the combinations shown in Group C in Table 9, and a combination of light chain CDR sequences selected from the group consisting of the combinations shown in Group C in Table 9. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of heavy chain CDR sequences selected from the group consisting of the combinations shown in Group E in Table 9. In some embodiments, the activatable anti-PD-1 antibody includes a combination of light chain CDR sequences selected from the group consisting of the combinations shown in Group E in Table 9. In some embodiments, the activatable anti-PD-1 antibody includes a combination of heavy chain CDR sequences selected from the group consisting of the combinations shown in Group E in Table 9, and a combination of light chain CDR sequences selected from the group consisting of the combinations shown in Group E in Table 9. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of heavy chain CDR sequences selected from the group consisting of the combinations shown in Group F in Table 9. In some embodiments, the activatable anti-PD-1 antibody includes a combination of light chain CDR sequences selected from the group consisting of the combinations shown in Group F in Table 9. In some embodiments, the activatable anti-PD-1 antibody includes a combination of heavy chain CDR sequences selected from the group consisting of the combinations shown in Group F in Table 9, and a combination of light chain CDR sequences selected from the group consisting of the combinations shown in Group F in Table 9. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of heavy chain CDR sequences selected from the group consisting of the combinations shown in Group G in Table 9. In some embodiments, the activatable anti-PD-1 antibody includes a combination of light chain CDR sequences selected from the group consisting of the combinations shown in Group Gin Table 9. In some embodiments, the activatable anti-PD-1 antibody includes a combination of heavy chain CDR sequences selected from the group consisting of the combinations shown in Group Gin Table 9, and a combination of light chain CDR sequences selected from the group consisting of the combinations shown in Group G in Table 9. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of heavy chain CDR sequences selected from the group consisting of the combinations shown in Group H in Table 9. In some embodiments, the activatable anti-PD-1 antibody includes a combination of light chain CDR sequences selected from the group consisting of the combinations shown in Group H in Table 9. In some embodiments, the activatable anti-PD-1 antibody includes a combination of heavy chain CDR sequences selected from the group consisting of the combinations shown in Group H in Table 9, and a combination of light chain CDR sequences selected from the group consisting of the combinations shown in Group H in Table 9. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of heavy chain CDR sequences selected from the group consisting of the combinations shown in Group L in Table 9. In some embodiments, the activatable anti-PD-1 antibody includes a combination of light chain CDR sequences selected from the group consisting of the combinations shown in Group L in Table 9. In some embodiments, the activatable anti-PD-1 antibody includes a combination of heavy chain CDR sequences selected from the group consisting of the combinations shown in Group L in Table 9, and a combination of light chain CDR sequences selected from the group consisting of the combinations shown in Group L in Table 9. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of heavy chain CDR sequences selected from the group consisting of the combinations shown in Group M in Table 9. In some embodiments, the activatable anti-PD-1 antibody includes a combination of light chain CDR sequences selected from the group consisting of the combinations shown in Group M in Table 9. In some embodiments, the activatable anti-PD-1 antibody includes a combination of heavy chain CDR sequences selected from the group consisting of the combinations shown in Group M in Table 9, and a combination of light chain CDR sequences selected from the group consisting of the combinations shown in Group M in Table 9. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of heavy chain CDR sequences selected from the group consisting of the combinations shown in Group N in Table 9. In some embodiments, the activatable anti-PD-1 antibody includes a combination of light chain CDR sequences selected from the group consisting of the combinations shown in Group N in Table 9. In some embodiments, the activatable anti-PD-1 antibody includes a combination of heavy chain CDR sequences selected from the group consisting of the combinations shown in Group N in Table 9, and a combination of light chain CDR sequences selected from the group consisting of the combinations shown in Group N in Table 9. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of heavy chain CDR sequences selected from the group consisting of the combinations shown in Group O in Table 9. In some embodiments, the activatable anti-PD-1 antibody includes a combination of light chain CDR sequences selected from the group consisting of the combinations shown in Group O in Table 9. In some embodiments, the activatable anti-PD-1 antibody includes a combination of heavy chain CDR sequences selected from the group consisting of the combinations shown in Group O in Table 9, and a combination of light chain CDR sequences selected from the group consisting of the combinations shown in Group O in Table 9. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of heavy chain CDR sequences selected from the group consisting of the combinations shown in Group P in Table 9. In some embodiments, the activatable anti-PD-1 antibody includes a combination of light chain CDR sequences selected from the group consisting of the combinations shown in Group P in Table 9. In some embodiments, the activatable anti-PD-1 antibody includes a combination of heavy chain CDR sequences selected from the group consisting of the combinations shown in Group P in Table 9, and a combination of light chain CDR sequences selected from the group consisting of the combinations shown in Group P in Table 9. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of heavy chain CDR sequences selected from the group consisting of the combinations shown in Group Q in Table 9. In some embodiments, the activatable anti-PD-1 antibody includes a combination of light chain CDR sequences selected from the group consisting of the combinations shown in Group Q in Table 9. In some embodiments, the activatable anti-PD-1 antibody includes a combination of heavy chain CDR sequences selected from the group consisting of the combinations shown in Group Q in Table 9, and a combination of light chain CDR sequences selected from the group consisting of the combinations shown in Group Q in Table 9. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of heavy chain CDR sequences selected from the group consisting of the combinations shown in Group R in Table 9. In some embodiments, the activatable anti-PD-1 antibody includes a combination of light chain CDR sequences selected from the group consisting of the combinations shown in Group R in Table 9. In some embodiments, the activatable anti-PD-1 antibody includes a combination of heavy chain CDR sequences selected from the group consisting of the combinations shown in Group R in Table 9, and a combination of light chain CDR sequences selected from the group consisting of the combinations shown in Group R in Table 9. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of heavy chain CDR sequences selected from the group consisting of the combinations shown in Group T in Table 9. In some embodiments, the activatable anti-PD-1 antibody includes a combination of light chain CDR sequences selected from the group consisting of the combinations shown in Group T in Table 9. In some embodiments, the activatable anti-PD-1 antibody includes a combination of heavy chain CDR sequences selected from the group consisting of the combinations shown in Group T in Table 9, and a combination of light chain CDR sequences selected from the group consisting of the combinations shown in Group T in Table 9. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of heavy chain CDR sequences selected from the group consisting of the combinations shown in Group U in Table 9. In some embodiments, the activatable anti-PD-1 antibody includes a combination of light chain CDR sequences selected from the group consisting of the combinations shown in Group U in Table 9. In some embodiments, the activatable anti-PD-1 antibody includes a combination of heavy chain CDR sequences selected from the group consisting of the combinations shown in Group U in Table 9, and a combination of light chain CDR sequences selected from the group consisting of the combinations shown in Group U in Table 9. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of heavy chain CDR sequences selected from the group consisting of the combinations shown in Group V in Table 9. In some embodiments, the activatable anti-PD-1 antibody includes a combination of light chain CDR sequences selected from the group consisting of the combinations shown in Group V in Table 9. In some embodiments, the activatable anti-PD-1 antibody includes a combination of heavy chain CDR sequences selected from the group consisting of the combinations shown in Group V in Table 9, and a combination of light chain CDR sequences selected from the group consisting of the combinations shown in Group V in Table 9. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of heavy chain CDR sequences selected from the group consisting of the combinations shown in Group W in Table 9. In some embodiments, the activatable anti-PD-1 antibody includes a combination of light chain CDR sequences selected from the group consisting of the combinations shown in Group W in Table 9. In some embodiments, the activatable anti-PD-1 antibody includes a combination of heavy chain CDR sequences selected from the group consisting of the combinations shown in Group W in Table 9, and a combination of light chain CDR sequences selected from the group consisting of the combinations shown in Group W in Table 9. 
     In some embodiments, the activatable anti-PD-1 antibody includes a combination of heavy chain CDR sequences selected from the group consisting of the combinations shown in Group X in Table 9. In some embodiments, the activatable anti-PD-1 antibody includes a combination of light chain CDR sequences selected from the group consisting of the combinations shown in Group X in Table 9. In some embodiments, the activatable anti-PD-1 antibody includes a combination of heavy chain CDR sequences selected from the group consisting of the combinations shown in Group X in Table 9, and a combination of light chain CDR sequences selected from the group consisting of the combinations shown in Group X in Table 9. 
     
       
         
           
               
             
               
                 TABLE 9 
               
             
            
               
                   
               
               
                 Additional CDR Sequences for Antibodies and Activatable Antibodies that Bind PD-1 
               
            
           
           
               
               
            
               
                 VH 
                 VL 
               
            
           
           
               
               
               
               
               
               
            
               
                 CDR1 
                 CDR2 
                 CDR3 
                 CDR1 
                 CDR2 
                 CDR3 
               
               
                 (SEQ ID NO:) 
                 (SEQ ID NO:) 
                 (SEQ ID NO:) 
                 (SEQ ID NO:) 
                 (SEQ ID NO:) 
                 (SEQ ID NO:) 
               
               
                   
               
            
           
           
               
            
               
                 Group A 
               
            
           
           
               
               
               
               
               
               
            
               
                 NYGMH 
                 VIWYDGSNKYYADSVKG 
                 NDDY (700) 
                 RASQSVSSYLA 
                 DASNRAT 
                 QQRSNWPLT 
               
               
                 (688) 
                 (694) 
                   
                 (704) 
                 (706) 
                 (710) 
               
               
                   
               
               
                 NYGFH 
                 VIWYDGSKKYYADSVKG 
                 GDDY (701) 
                 RASQSVSSYLA 
                 DTSNRAT 
                 QQRSNWPLT 
               
               
                 (689) 
                 (695) 
                   
                 (704) 
                 (707) 
                 (710) 
               
               
                   
               
               
                 NYGMH 
                 LIWYDGSNKYYADSVKG 
                 NVDH (702) 
                 RASQSVSSYLA 
                 DASNRAT 
                 QQSSNWPRT 
               
               
                 (688) 
                 (696) 
                   
                 (704) 
                 (706) 
                 (711) 
               
               
                   
               
               
                 NSGMH 
                 VIWYDGSKRYYADSVKG 
                 NDDY (700) 
                 RASQSVSSYLA 
                 DASNRAT 
                 QQSSNWPRT 
               
               
                 (690) 
                 (697) 
                   
                 (704) 
                 (706) 
                 (711) 
               
               
                   
               
               
                 RSSFFWG 
                 SIYYSGSTYYNPSLKS 
                 DYDILTGDEDY 
                 RASQGISSWLA 
                 AASNLRS 
                 QQYYSYPRT 
               
               
                 (691) 
                 (698) 
                 (703) 
                 (705) 
                 (708) 
                 (712) 
               
               
                   
               
               
                 SYGFH 
                 VIWYDGSKKYYADSVKG 
                 GDDY (701) 
                 RASQSVSSYLA 
                 DASNRAT 
                 QQRSNWPLT 
               
               
                 (692) 
                 (695) 
                   
                 (704) 
                 (706) 
                 (710) 
               
               
                   
               
               
                 RSSYFWG 
                 SIFYSGETYFNPSLKS 
                 DYDILTGDEDY 
                 RASQGISSWLA 
                 AASSLQS 
                 QQYYSYPRT 
               
               
                 (693) 
                 (699) 
                 (703) 
                 (705) 
                 (709) 
                 (712) 
               
               
                   
               
            
           
           
               
            
               
                 Group B 
               
            
           
           
               
               
               
               
               
               
            
               
                 SYYLY 
                 GVNPSNGGTNFSEKFK 
                 RDSNYDGGFDY 
                 RASKSVSTSGFSY 
                 LASNLES 
                 QHSWELPLT 
               
               
                 (713) 
                 S (715) 
                 (717) 
                 LH (719) 
                 (721) 
                 (723) 
               
               
                   
               
               
                 NYYMY 
                 GINPSNGGTNFNEKFK 
                 RDYRFDMGFDY 
                 RASKGVSTSGYSY 
                 LASYLES 
                 QHSRDLPLT 
               
               
                 (714) 
                 N (716) 
                 (718) 
                 LH (720) 
                 (722) 
                 (724) 
               
               
                   
               
               
                 AASGFTFS 
                 TITGGGRNTYYPDSVK 
                 QGYDGYTWFAY 
                 RASESVDNSGISF 
                 AASNPGS 
                 QQSKEVPWT 
               
               
                 SYAMS 
                 G (817) 
                 (823) 
                 MN (830) 
                 (836) 
                 (840) 
               
               
                 (627) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AASGFTFS 
                 TISGGGSNTYYPDSVK 
                 IYDVAWFAY 
                 RSSQTIVHSDGNT 
                 AASNQGS 
                 FQGSHVPYT 
               
               
                 SFGMS 
                 (818) 
                 (824) 
                 YLE (831) 
                 (678) 
                 (841) 
               
               
                 (811) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 KGSGYSFT 
                 VISTHYGDTVYNQRFK 
                 EGYGSLFYFDQ 
                 RASESVDSYGNSF 
                 KVSNRFS 
                 QQNNEVPLT 
               
               
                 DYALH 
                 G (1832) 
                 (825) 
                 MN (832) 
                 (837) 
                 (842) 
               
               
                 (812) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 KASGYAFT 
                 YIDLYNGDTSYNEKF 
                 EGRLSFDY 
                 RSSQSIVQSNGNT 
                 LASNLDS 
                 FQGSHVPYT 
               
               
                 SYNIY 
                 (819) 
                 (826) 
                 YLE (833) 
                 (838) 
                 (843) 
               
               
                 (813) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AASGFTFS 
                 YISGGGGNTYYPDTL 
                 ISLTGIFDY 
                 RSSQTIVHGNGNT 
                 SASTLAS 
                 QQGFGTSNVE 
               
               
                 NYDMS 
                 (820) 
                 (827) 
                 YLE (834) 
                 (839) 
                 NP (844) 
               
               
                 (814) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AASGFTFN 
                 TISGGGSYTYYPDSVQ 
                 GNYVYVMDY 
                 QASENIYSSLA 
                   
                   
               
               
                 SYGMS 
                 G (821) 
                 (828) 
                 (835) 
                   
                   
               
               
                 (815) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 KGSGYIFT 
                 VISTYYSNINYNQKFK 
                 EGFGRPYWYFD 
                   
                   
                   
               
               
                 DYVMH 
                 G (822) 
                 V (829) 
                   
                   
                   
               
               
                 (816) 
                   
                   
                   
                   
                   
               
               
                   
               
            
           
           
               
            
               
                 Group C 
               
            
           
           
               
               
               
               
               
               
            
               
                 GYSITSDY 
                 YINYSGSTSYNPSLKS 
                 WIGSSAWYFDV 
                 RSGQNIVHSNGNTY 
                 KVSNRFF 
                 FQGSHVPFT 
               
               
                 AWN 
                 (847) 
                 (849) 
                 LE (851) 
                 (853) 
                 (855) 
               
               
                 (845) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 GYTFTTYY 
                 GINPSNGGINFNEKFK 
                 RDYRYDRGFDY 
                 RASKSVSTSGFNYI 
                 LASNLES 
                 QHSRELPLT 
               
               
                 LY (846) 
                 (848) 
                 (850) 
                 H (852) 
                 (721) 
                 (856) 
               
               
                   
               
            
           
           
               
            
               
                 Group E 
               
            
           
           
               
               
               
               
               
               
            
               
                 SYGIS 
                 WISAYNGNTNYAQ 
                 DADYSSGSGY 
                 SGDALPKQYAY 
                 KDTERPS 
                 QSADNSITYR 
               
               
                 (857) 
                 KLQG (861) 
                 (865) 
                 (869) 
                 (872) 
                 V (876) 
               
               
                   
               
               
                 SYYIH 
                 IINPRGATISYAQ 
                 AGIYGFDFDY 
                 TGTSNDVGGYNYVS 
                 DVTNRPS 
                 SSYTIVTNFE 
               
               
                 (858) 
                 KFQG (862) 
                 (866) 
                 (870) 
                 (873) 
                 VL (877) 
               
               
                   
               
               
                 SGAYYWS 
                 YIYYNGNTYYNPS 
                 ASDYVWGGYRYM 
                 SGSNSNIGSNSVN 
                 GNNQRPS 
                 AAWDDSLNGP 
               
               
                 (859) 
                 LRS (863) 
                 DAFDI (867) 
                 (871) 
                 (874) 
                 V (878) 
               
               
                   
               
               
                 SSYWMS 
                 AISGSGGSTYYAD 
                 ENWGSYFDL 
                 RASQGISSWLA 
                 KASTLES 
                 QQSYSTPWT 
               
               
                 (860) 
                 SVKG (864) 
                 (868) 
                 (705) 
                 (875) 
                 (879) 
               
               
                   
               
            
           
           
               
            
               
                 Group F 
               
            
           
           
               
               
               
               
               
               
            
               
                 SSWIH 
                 YIYPSTGFTEYNQ 
                 WRDSSGYHAMDY 
                 RASQSVSTSGYSYMH 
                 FGSNLES 
                 QHSWEIPYT 
               
               
                 (880) 
                 KFKD (881) 
                 (882) 
                 (883) 
                 (884) 
                 (885) 
               
               
                   
               
            
           
           
               
            
               
                 Group L 
               
            
           
           
               
               
               
               
               
               
            
               
                 GFTFSSYD 
                 VIWYSGSNTYYND 
                 AYFGVDV 
                 RASQGIGNTLA 
                 RASQGIG 
                 QQYDHVPLT 
               
               
                 YYMH 
                 SLKS (887) 
                 (888) 
                 (889) 
                 NTLA 
                 (891) 
               
               
                 (886) 
                   
                   
                   
                 (889) 
                   
               
               
                   
               
            
           
           
               
            
               
                 Group G 
               
            
           
           
               
               
               
               
               
            
               
                 GFSLTSYG 
                 VIWAGGSTNYNSA 
                 GFSLTSYGVH 
                 KASQSVSNDVA 
                 YAFHRFT 
               
               
                 VH (892) 
                 LMS (895) 
                 (896) 
                 (898) 
                 (900) 
               
               
                   
               
               
                 VIWAGGST 
                 ARAYGNYWYIDV 
                 ARAYGNYWYIDV 
                 KSSESVSNDVA 
                   
               
               
                 NYNPSLKS 
                 (896) 
                 (897) 
                 (899) 
                   
               
               
                 (893) 
                   
                   
                   
                   
               
               
                   
               
               
                 VIYAGGST 
                 HQAYSSPYT 
                   
                   
                   
               
               
                 NYNPSLKS 
                 (895) 
                   
                   
                   
               
               
                 (894) 
                   
                   
                   
                   
               
               
                   
               
            
           
           
               
            
               
                 Group H 
               
            
           
           
               
               
               
               
               
               
            
               
                 DYEMH 
                 VIESETGGTAYNQ 
                 EGITTVATTYYW 
                 RSSQSIVHSNGNTYLE 
                 KVSNRFS 
                 FQGSHVPLT 
               
               
                 (901) 
                 KFKG (902) 
                 YFDV (903) 
                 (904) 
                 (905) 
                 (906) 
               
               
                   
               
            
           
           
               
            
               
                 Group M 
               
            
           
           
               
               
               
               
               
               
            
               
                 GYTFTTYP 
                 NFHPYNDDTKYNE 
                   
                 RASSSVISSYLH 
                 STSNLAS 
                 QQYNGYPLT 
               
               
                 IE (907) 
                 KFK (908) 
                   
                 (909) 
                 (910) 
                 (911) 
               
               
                   
                   
                   
                   
                   
                 QQYNSYPLT 
               
               
                   
                   
                   
                   
                   
                 (912) 
               
               
                   
               
            
           
           
               
            
               
                 Group N 
               
            
           
           
               
               
               
               
               
               
            
               
                 SYYLY 
                 GVNPSNGGTNFSE 
                 RDSNYDGGFDY 
                 RASKSVSTSGFSYLH 
                 LASNLES 
                 QHSWELPLT 
               
               
                 (713) 
                 KFK (1596) 
                 (717) 
                 (719) 
                 (721) 
                 (723) 
               
               
                   
               
            
           
           
               
            
               
                 Group P 
               
            
           
           
               
               
               
               
               
               
            
               
                 GYTFTTY 
                 YPGTGG (1597) 
                 WTTGTGAY 
                 SQSLLDSGNQKNF 
                 WAS 
                 DYSYPY 
               
               
                 (854) 
                   
                 (1598) 
                 (1599) 
                 (1600) 
                 (1601) 
               
               
                   
               
               
                 TYWMH 
                 NIYPGTGGSNFDE 
                   
                 KSSQSLLDSGNQKNFL 
                 WASTRES 
                 QNDYSYPYT 
               
               
                 (1602) 
                 KFK (1603) 
                   
                 (1833) 
                 (1604) 
                 (1605) 
               
               
                   
               
               
                 GYTFTTYW 
                   
                   
                   
                   
                   
               
               
                 MH 
                   
                   
                   
                   
                   
               
               
                 (1606) 
                   
                   
                   
                   
                   
               
               
                   
               
            
           
           
               
            
               
                 Group Q 
               
            
           
           
               
               
               
               
               
               
            
               
                 GFTFSSYT 
                 ISDTGGNT 
                 AKDQGGSYPYYF 
                 QSISSY (1610) 
                 AAS 
                 QQSYSTPPIT 
               
               
                 (1607) 
                 (1608) 
                 HY (1609) 
                   
                 (1611) 
                 (1612) 
               
               
                   
               
               
                 GFTVSNNY 
                 IYSGGFT 
                 ARYYYDTSDYWT 
                 QSVSSN (1616) 
                 GAS 
                 QQYNNWPLT 
               
               
                 (1613) 
                 (1614) 
                 FFDY (1615) 
                   
                 (1617) 
                 (1618) 
               
               
                   
               
               
                 GFTFSSYG 
                 IWYDGSNI 
                 ARPGHWNYFFEY 
                 QSINNY (1622) 
                 TAS 
                 QQSYSTPPLT 
               
               
                 (1619) 
                 (1620) 
                 (1621) 
                   
                 (1623) 
                 (1624) 
               
               
                   
               
               
                 GFTFRNYD 
                 IGSAGDT 
                 TRDIHCSSTRCY 
                 QSISNY (1628) 
                 AAS 
                 QQSYSTPPIT 
               
               
                 (1625) 
                 (1626) 
                 GMDV (1627) 
                   
                 (1611) 
                 (1612) 
               
               
                   
               
               
                 GFKFSNEW 
                 IKSKTDGGTT 
                 TTDQDFWSGYYT 
                   
                 AAS 
                 QQSYSTPPIT 
               
               
                 (1629) 
                 (1630) 
                 GADYYGMDV 
                   
                 (1611) 
                 (1612) 
               
               
                   
                   
                 (1631) 
                   
                   
                   
               
               
                   
               
               
                 GGSLNGYY 
                 IDHSGST 
                 AREGLLPFDY 
                 QSVYSNY (1635) 
                 AAS 
                 HQYATSPWT 
               
               
                 (1632) 
                 (1633) 
                 (1634) 
                   
                 (1611) 
                 (1636) 
               
               
                   
               
               
                 DDSISSTT 
                 MSYNGNN 
                 ARHLGYNGNWYP 
                 QSVSSSY (1639) 
                 GAS 
                 QQYGSSPWT 
               
               
                 YY 
                 (622) 
                 FDF (1638) 
                   
                 (1640) 
                 (1641) 
               
               
                 (1637) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 GFTFDDYA 
                 INWSGNNI 
                 TKDISITGTLDA 
                 QGISNW (1645) 
                 SAS 
                 QQAHSFPLT 
               
               
                 (1642) 
                 (1643) 
                 FDV (1644) 
                   
                 (1646) 
                 (1647) 
               
               
                   
               
               
                 GFTFSSYG 
                 IWSDGDSE 
                 ARDRDLEDI 
                 QGIRND (1650) 
                 AAS 
                 LQHNSYPLT 
               
               
                 (1619) 
                 (1648) 
                 (1649) 
                   
                 (1611) 
                 (1651) 
               
               
                   
               
               
                 GFTFSNFG 
                 ISGGGRDT 
                 VKWGNIYFDY 
                 LSINTF (1655) 
                 AAS 
                 QQSSNTPFT 
               
               
                 (1652) 
                 (1653) 
                 (1654) 
                   
                 (1611) 
                 (1656) 
               
               
                   
               
               
                 GFTFDDYG 
                 ISWNDGKT 
                 ARDWQYLIERYF 
                 QSVSSSY (1639) 
                 GAS 
                 QQYGSSPWT 
               
               
                 (1657) 
                 (1658) 
                 DY (1659) 
                   
                 (1640) 
                 (1641) 
               
               
                   
               
               
                 GFTFDDYG 
                 IGWTGGRS 
                 ARDRQWLVQWYF 
                 QSISSY (1610) 
                 AAS 
                 QQSYSTPPIT 
               
               
                 (1657) 
                 (1660) 
                 DY (1661) 
                   
                 (1611) 
                 (1612) 
               
               
                   
               
               
                 GFTFDDYG 
                 ISWNDGKT 
                 ARDWQYLIDRYF 
                   
                   
                   
               
               
                 (1657) 
                 (1658) 
                 DF (1662) 
                   
                   
                   
               
               
                   
               
               
                 GFTFDDYA 
                 IGWSSGSI 
                 AKAYTFMITLYF 
                   
                   
                   
               
               
                 (1642) 
                 (1663) 
                 DY (1664) 
                   
                   
                   
               
               
                   
               
               
                 GFTFDDYD 
                 SGWNRGSL 
                 AKGFVVVSAAYF 
                   
                   
                   
               
               
                 (1665) 
                 (1666) 
                 DY (1667) 
                   
                   
                   
               
               
                   
               
               
                 GVTFRNFA 
                 IIPFFSAA 
                 AREGERGHTYGF 
                   
                   
                   
               
               
                 (1668) 
                 (1669) 
                 DY (1670) 
                   
                   
                   
               
               
                   
               
               
                 GFTFDDYA 
                 INWNRGRT 
                 AKAEQWLDEGYF 
                   
                   
                   
               
               
                 (1642) 
                 (1671) 
                 DY (1672) 
                   
                   
                   
               
               
                   
               
               
                 GFTFEDYA 
                 ISDSGGST 
                 AKDQGGSYPYYF 
                   
                   
                   
               
               
                 (1673) 
                 (1674) 
                 HY (1609) 
                   
                   
                   
               
               
                   
               
               
                 GYTFTSFY 
                 IGWSNVKI 
                 VKAYTSMLTLYF 
                   
                   
                   
               
               
                 (1675) 
                 (1676) 
                 DY (1677) 
                   
                   
                   
               
               
                   
               
               
                 GGSISSYH 
                 INPSDGST 
                 ARRVAGDIFDI 
                   
                   
                   
               
               
                 (1678) 
                 (1679) 
                 (1680) 
                   
                   
                   
               
               
                   
               
               
                 GFTFEDYG 
                 IYYIGST 
                 ARVPVGATGASD 
                   
                   
                   
               
               
                 (1681) 
                 (1682) 
                 V (1683) 
                   
                   
                   
               
               
                   
               
               
                 GFTFSAYA 
                 ISWTGGNT 
                 TRDRQWLMQWYF 
                   
                   
                   
               
               
                 (1684) 
                 (1685) 
                 DY (1686) 
                   
                   
                   
               
               
                   
               
               
                 GFALHDYA 
                 ISYGGSDK 
                 AKSAHWNFFFDY 
                   
                   
                   
               
               
                 (1687) 
                 (1688) 
                 (1689) 
                   
                   
                   
               
               
                   
               
               
                 GDSISSTA 
                 ISWNSGVI 
                 AKGSGSYYVSWF 
                   
                   
                   
               
               
                 YH 
                 (1717) 
                 DP (1718) 
                   
                   
                   
               
               
                 (1687) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 GFTFSTYA 
                 ITYNGNT 
                 ARHLGYNSDFFP 
                   
                   
                   
               
               
                 (1690) 
                 (1691) 
                 FDF (1692) 
                   
                   
                   
               
               
                   
                 IGGSGDST 
                 VKVRNYDGSFDI 
                   
                   
                   
               
               
                   
                 (1693) 
                 (1694) 
                   
                   
                   
               
               
                   
               
            
           
           
               
            
               
                 Group R 
               
            
           
           
               
               
               
               
               
               
            
               
                 SYGMS 
                 TMSGGGRDIYYPD 
                 QYYDDWFAY 
                 RASQSISNNLH 
                 YASQSIS 
                 QQSNSWPLT 
               
               
                 (1751) 
                 SMKG (1752) 
                 (1753) 
                 (1754) 
                 (1755) 
                 (1756) 
               
               
                   
               
               
                 TYGVH 
                 VIWSGGSTDYNAA 
                 EKSVYGNYVGAM 
                 KASQSVSDDVA 
                 YAFNRYT 
                 QQDYRSPWT 
               
               
                 (1757) 
                 FIS (1758) 
                 DY (1759) 
                 (1760) 
                 (1761) 
                 (1762) 
               
               
                   
               
               
                 SYGMS 
                 TISGGGRDIYYPD 
                 QYYDDWFAY 
                 RASQSISNDLH 
                 YVSQSIS 
                 QQSDSWPLT 
               
               
                 (1751) 
                 SVKG (1763) 
                 (1753) 
                 (1764) 
                 (1765) 
                 (1766) 
               
               
                   
               
               
                 SDYAWN 
                 YISYSGYTSYNPS 
                 SLDYDYGTMDY 
                 RANSSVSSMH 
                 AISNLAF 
                 QQWSSRPPT 
               
               
                 (1767) 
                 LKS (1768) 
                 (1769) 
                 (1770) 
                 (1771) 
                 (1772) 
               
               
                   
               
               
                 SYDMS 
                 TISGGGSYTYYQD 
                 PYGPYFDY 
                 HASQSINVWLS 
                 ASNLHT 
                 QQGQSYPWT 
               
               
                 (1773) 
                 SVKG (1774) 
                 (1775) 
                 (1776) 
                 (1777) 
                 (1778) 
               
               
                   
               
               
                 SDYAWN 
                 YISYSGYTSYNPS 
                 SLDYDYGTMDY 
                 RANSSVSSMH 
                 AISNLAF 
                 QQWNSRPPT 
               
               
                 (1767) 
                 LKS (1768) 
                 (1769) 
                 (1770) 
                 (1771) 
                 (1779) 
               
               
                   
               
               
                 YYDMS 
                 TISGGGRNTYFID 
                 PYEGAVDF 
                 KASQDVDNAVA 
                 WASTRHH 
                 QQYSTFPYT 
               
               
                 (1780) 
                 SVKG (1781) 
                 (1782) 
                 (1783) 
                 (1784) 
                 (1785) 
               
               
                   
               
               
                 SYGMS 
                 TISGGGRDTYYLD 
                 QYYDDWFAY 
                 RASQSLSNNLH 
                 YASQSIS 
                 QQSNSWPLT 
               
               
                 (1751) 
                 SVKG (1786) 
                 (1753) 
                 (1787) 
                 (1755) 
                 (1756) 
               
               
                   
               
               
                 NNWIG 
                 DFYPGGGYTNYNE 
                 GYGTNYWYFDV 
                 KASQSVSNDVA 
                 YAFTRYI 
                 QQDYSSPYT 
               
               
                 (1788) 
                 KFKG (1789) 
                 (1790) 
                 (1791) 
                 (1792) 
                 (1793) 
               
               
                   
               
               
                 NFGMN 
                 WISGYTREPTYAA 
                 DVFDY (1796) 
                 RASESVDNYGYSFMN 
                 RASNLES 
                 QQSNADPT 
               
               
                 (1794) 
                 DFKG (1795) 
                   
                 (1797) 
                 (1798) 
                 (1799) 
               
               
                   
               
            
           
           
               
            
               
                 Group T 
               
            
           
           
               
               
               
               
               
               
            
               
                 GYTFTSYY 
                 GVNPSNGGTNFNE 
                 RDYRYDMGFDY 
                 RASKGVSTSGYSYLH 
                 LASYLE 
                 QHSRELPLT 
               
               
                 MY 
                 KFKS (1801) 
                 (1802) 
                 (1803) 
                 (1804) 
                 (1805) 
               
               
                 (1800) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 GYTFTNYY 
                 GINPSNGGTNYNE 
                 RDYRYDMGFDY 
                   
                   
                   
               
               
                 MY 
                 KFKN (890) 
                 (1802) 
                   
                   
                   
               
               
                 (1806) 
                   
                   
                   
                   
                   
               
               
                   
               
            
           
           
               
            
               
                 Group U 
               
            
           
           
               
               
               
               
               
               
            
               
                 G 
                 W (I/V) S A 
                 (Q/—) GY 
                 S G D A L 
                   
                 Q Q 
               
               
                 (T/R/I) 
                 (Y/H) N G N T 
                 (G/D)(N/V)Y 
                 (P/T/S) 
                   
                 (N/S/W) 
               
               
                 (F/L) 
                 (K/N) Y A Q K 
                 (L/S)(Y/W) 
                 (M/T/E/K) Q Y 
                   
                 (Y/K/I) 
               
               
                 (S/E/ 
                 L Q G (1882) 
                 (D/A)(Y/V) 
                 (G/A) Y (1884) 
                   
                 (N/E/S) 
               
               
                 T/P/R) 
                   
                 (1883) 
                   
                   
                 (S/V/D/T) 
               
               
                 (T/S/ 
                   
                   
                   
                   
                 P (Y/W) T 
               
               
                 H/Q/R/ 
                   
                   
                   
                   
                 (1885) 
               
               
                 W) 
                   
                   
                   
                   
                   
               
               
                 (F/Y/Q) 
                   
                   
                   
                   
                   
               
               
                 (1881) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (T/R/W/Q/ 
                 (T/A) I S G 
                 D 
                   
                   
                   
               
               
                 H/S) 
                 (S/G) G 
                 (A/V/S)(D/E) Y 
                   
                   
                   
               
               
                 (Y/F/Q) 
                 (S/G).(S/D/N) 
                 (S/G/R)(S/L/ 
                   
                   
                   
               
               
                 G (M/I) 
                 T Y Y (A/P/S) 
                 T) (1888), 
                   
                   
                   
               
               
                 (1886) 
                 D S V (K/Q) G 
                 with the 
                   
                   
                   
               
               
                   
                 (1887) 
                 proviso that 
                   
                   
                   
               
               
                   
                   
                 if A at 
                   
                   
                   
               
               
                   
                   
                 position 2, 
                   
                   
                   
               
               
                   
                   
                 then not D 
                   
                   
                   
               
               
                   
                   
                 or S in 
                   
                   
                   
               
               
                   
                   
                 position 5 
                   
                   
                   
               
               
                   
               
               
                   
                   
                 GYALDY 
                   
                   
                   
               
               
                   
                   
                 (2038) 
                   
                   
                   
               
               
                   
               
               
                 GYIFSSY 
                 FPGSGS (1890) 
                 GYGNYLYFDV 
                 KASQSVSDDVA 
                 YAFKRYI 
                 QQNYNSPYT 
               
               
                 (1889) 
                   
                 (1891) 
                 (1760) 
                 (1892) 
                 (1893) 
               
               
                   
               
               
                 SYWIG 
                 KIFPGSGSADYNE 
                 DSEYSSGSGY 
                 SGDALTTQYAY 
                 KDTERPS 
                 QSADNSITYR 
               
               
                 (1894) 
                 NFKG (1895) 
                 (1896) 
                 (1897) 
                 (872) 
                 V (876) 
               
               
                   
               
               
                   
                   
                 QRDSAWFAS 
                 RASESVDNSGISFMS 
                 ATSKLAS 
                 QQWISDPWT 
               
               
                   
                   
                 (2039) 
                 (1898) 
                 (1899) 
                 (1900) 
               
               
                   
               
               
                   
                   
                   
                 SGDALSEQYAY 
                 TASNQGS 
                 QQSKEVPWT 
               
               
                   
                   
                   
                 (1901) 
                 (1902) 
                 (840) 
               
               
                   
               
               
                   
                   
                   
                 SGDALPKQYAY 
                   
                   
               
               
                   
                   
                   
                 (869) 
                   
                   
               
               
                   
               
               
                   
                   
                   
                 SGDALPMQYGY 
                   
                   
               
               
                   
                   
                   
                 (1903) 
                   
                   
               
               
                   
               
               
                   
                   
                   
                 RTSSSVNYMH 
                   
                   
               
               
                   
                   
                   
                 (1904) 
                   
                   
               
               
                   
               
               
                 GYRFTWY 
                 SAYNGN (1906) 
                 DVDYSSGSGY 
                   
                   
                   
               
               
                 (1905) 
                   
                 (1907) 
                   
                   
                   
               
               
                   
               
               
                 WYGIS 
                 WISAYNGNTNYAQ 
                 DAEYSLGSGY 
                   
                   
                   
               
               
                 (1908) 
                 KLQG (861) 
                 (1909) 
                   
                   
                   
               
               
                   
               
               
                 GYRFSTF 
                 SAHNGN (1911) 
                 DAEYGSGSGY 
                   
                   
                   
               
               
                 (1910) 
                   
                 (1912) 
                   
                   
                   
               
               
                   
               
               
                 TFGIS 
                 WVSAHNGNTNYAQ 
                 DADYGSGSGY 
                   
                   
                   
               
               
                 (1913) 
                 KLQG (1914) 
                 (1915) 
                   
                   
                   
               
               
                   
               
               
                 GYRFETY 
                 SYSGR (1917) 
                 DVDYGTGSGY 
                   
                   
                   
               
               
                 (1916) 
                   
                 (1918) 
                   
                   
                   
               
               
                   
               
               
                 GYRFRQY 
                 YISYSGRTSYNPS 
                 DVDYGSGSGY 
                   
                   
                   
               
               
                 (1919) 
                 LTS (1920) 
                 (1921) 
                   
                   
                   
               
               
                   
               
               
                 QYGIS 
                 SGGGSD (1923) 
                 DAEYGSGSGY 
                   
                   
                   
               
               
                 (1922) 
                   
                 (1912) 
                   
                   
                   
               
               
                   
               
               
                 GYRFTRY 
                 TISGGGSDTYYPD 
                 GYALDY 
                   
                   
                   
               
               
                 (1924) 
                 SVQG (1925) 
                 (2038) 
                   
                   
                   
               
               
                   
               
               
                 RYGIS 
                   
                 QGYDVYSWFAY 
                   
                   
                   
               
               
                 (1926) 
                   
                 (1927) 
                   
                   
                   
               
               
                   
               
               
                 GYRFPHY 
                   
                   
                   
                   
                   
               
               
                 (1928) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 HYGIS 
                   
                   
                   
                   
                   
               
               
                 (1929) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 GYRFTRQ 
                   
                   
                   
                   
                   
               
               
                 (1930) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 RQGIS 
                   
                   
                   
                   
                   
               
               
                 (1931) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 GHSITSDY 
                   
                   
                   
                   
                   
               
               
                 (1932) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 SDYAWN 
                   
                   
                   
                   
                   
               
               
                 (1767) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 GFTFSTF 
                   
                   
                   
                   
                   
               
               
                 (1933) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 TFGMS 
                   
                   
                   
                   
                   
               
               
                 (1934) 
                   
                   
                   
                   
                   
               
               
                   
               
            
           
           
               
            
               
                 Group V 
               
            
           
           
               
               
               
               
               
               
            
               
                 GWSLTGPG 
                 IYGDGST 
                 AYEYAMDW 
                 WSVSTSGKSY 
                 LLS 
                 YHIRDLT 
               
               
                 (1935) 
                 (1936) 
                 (1937) 
                 (1938) 
                 (1939) 
                 (2040) 
               
               
                   
               
            
           
           
               
            
               
                 Group W 
               
            
           
           
               
               
               
               
               
               
            
               
                 GYTFTSYW 
                 YPGSSL (1941) 
                 LSTGTFAY 
                 KSSQSLWDSTNQKNFL 
                 WTSTRES 
                 QNDYFYPLT 
               
               
                 IN 
                   
                 (1942) 
                 T (1943) 
                 (1944) 
                 (1945) 
               
               
                 (1940) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 GYTFTSY 
                 NIYPGSSLTNYNE 
                 LTTGTFAY 
                 KSSQSLWDSGNQKNFL 
                 WTSYRES 
                 QNDYFYPHT 
               
               
                 (1946) 
                 KFKN (1947) 
                 (1948) 
                 T (1949) 
                 (1950) 
                 (1951) 
               
               
                   
               
               
                 SYWIN 
                 YPGSSI (1953) 
                 LLTGTFAY 
                 KSSQSLLDSGNQKNFL 
                 WTS 
                 QNDYSYPLT 
               
               
                 (1952) 
                   
                 (1954) 
                 T (1955) 
                 (T/Y) 
                 (1957) 
               
               
                   
                   
                   
                   
                 RES 
                   
               
               
                   
                   
                   
                   
                 (1956) 
                   
               
               
                   
               
               
                   
                 NIYPGSSITNYNE 
                 L(L/S)TGTFAY 
                 KSSQSL(W/L)DS(G/ 
                   
                 QNDY(F/S)Y 
               
               
                   
                 KFKN (1958) 
                 (1959) 
                 T)NQKNFLT (1960) 
                   
                 P(L/H)T 
               
               
                   
                   
                   
                   
                   
                 (1961) 
               
               
                   
               
               
                   
                 WPGSSL (1962) 
                   
                   
                   
                   
               
               
                   
               
               
                   
                 NIWPGSSLTNYNE 
                   
                   
                   
                   
               
               
                   
                 KFKN (1963) 
                   
                   
                   
                   
               
               
                   
               
               
                   
                 NIYPGSSSTNYNE 
                   
                   
                   
                   
               
               
                   
                 KFKN (1964) 
                   
                   
                   
                   
               
               
                   
               
               
                   
                 NI(Y/W)PGSS 
                   
                   
                   
                   
               
               
                   
                 (L/I/S)TNYNEK 
                   
                   
                   
                   
               
               
                   
                 FKN (1965) 
                   
                   
                   
                   
               
               
                   
               
            
           
           
               
            
               
                 Group X 
               
            
           
           
               
               
               
               
               
               
            
               
                 GLTFSSSG 
                 IWYDGSKR 
                 ATNNDY 
                 RASQSVSSYLA 
                 TASNRAT 
                 QQYSNWPRT 
               
               
                 (1966) 
                 (1706) 
                 (1967) 
                 (704) 
                 (1968) 
                 (1969) 
               
               
                   
               
            
           
         
       
     
     The ABs in the activatable antibodies of the disclosure specifically bind a PD-1 target, such as, for example, mammalian PD-1. In some embodiments, such Abs bind mammalian PD-1. In some embodiments, such Abs bind human PD-1. In some embodiments, such Abs bind non-human primate PD-1. Also included in the disclosure are ABs that bind to the same PD-1 epitope as an antibody of the disclosure and/or an activated activatable antibody described herein. Also included in the disclosure are ABs that compete with an anti-PD-1 antibody and/or an activated anti-PD-1 activatable antibody described herein for binding to a PD-1 target, e.g., human PD-1. Also included in the disclosure are ABs that cross-compete with an anti-PD-1 antibody and/or an activated anti-PD-1 activatable antibody described herein for binding to a PD-1 target, e.g., human PD-1. 
     The activatable anti-PD-1 antibodies provided herein include a masking moiety. In some embodiments, the masking moiety is an amino acid sequence that is coupled or otherwise attached to the anti-PD-1 antibody and is positioned within the activatable anti-PD-1 antibody construct such that the masking moiety reduces the ability of the anti-PD-1 antibody to specifically bind PD-1. Suitable masking moieties are identified using any of a variety of known techniques. For example, peptide masking moieties are identified using the methods described in PCT Publication No. WO 2009/025846 by Daugherty et al., the contents of which are hereby incorporated by reference in their entirety. 
     The activatable anti-PD-1 antibodies provided herein include a cleavable moiety. In some embodiments, the cleavable moiety includes an amino acid sequence that is a substrate for a protease, usually an extracellular protease. Suitable substrates are identified using any of a variety of known techniques. For example, peptide substrates are identified using the methods described in U.S. Pat. No. 7,666,817 by Daugherty et al.; in U.S. Pat. No. 8,563,269 by Stagliano et al.; and in PCT Publication No. WO 2014/026136 by La Porte et al., the contents of each of which are hereby incorporated by reference in their entirety. (See also Boulware et al. “Evolutionary optimization of peptide substrates for proteases that exhibit rapid hydrolysis kinetics.” Biotechnol Bioeng. 106.3 (2010): 339-46). 
     Exemplary substrates include but are not limited to substrates cleavable by one or more of the following enzymes or proteases listed in Table 3. 
     
       
         
           
               
             
               
                 TABLE 3 
               
               
                   
               
               
                 Exemplary Proteases and/or Enzymes 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                 ADAMS, ADAMTS,  
                 Cysteine proteinases,  
                 Serine proteases, e.g., 
               
               
                 e.g. ADAM8 
                 e.g., Cruzipain 
                 activated protein C 
               
               
                 ADAM9 
                 Legumain 
                 Cathepsin A 
               
               
                 ADAM 10 
                 Otubain-2 
                 Cathepsin G 
               
               
                 ADAM12 
                 KLKs, e.g.,  
                 Chymase 
               
               
                 ADAM15 
                 KLK4  
                 coagulation factor proteases 
               
               
                 ADAM17/TACE 
                 KLK5   
                 (e.g., FVIIa, FIXa, FXa,  
               
               
                 ADAMDEC1 
                 KLK6  
                 FXIa, FXIIa) 
               
               
                 ADAMTS1 
                 KLK7  
                 Elastase 
               
               
                 ADAMTS4 
                 KLK8  
                 Granzyme B 
               
               
                 ADAMTS5 
                 KLK10 
                 Guanidinobenzoatase 
               
               
                 Aspartate proteases,  
                 KLK11 
                 HtrA1 
               
               
                 e.g., BACE 
                 KLK13 
                 Human Neutrophil Elastase 
               
               
                 Renin 
                 KLK14  
                 Lactoferrin 
               
               
                 Aspartic cathepsins,  
                 Metallo proteinases,  
                 Marapsin 
               
               
                 e.g., Cathepsin D 
                 e.g., Meprin 
                 NS3/4A 
               
               
                 Cathepsin E 
                 Neprilysin 
                 PACE4 
               
               
                 Caspases, e.g., 
                 PSMA 
                 Plasmin 
               
               
                 Caspase 1 
                 BMP-1 
                 PSA 
               
               
                 Caspase 2 
                 MMPs, e.g.,  
                 tPA 
               
               
                 Caspase 3 
                 MMP1  
                 Thrombin 
               
               
                 Caspase 4 
                 MMP2  
                 Tryptase 
               
               
                 Caspase 5 
                 MMP3  
                 uPA 
               
               
                 Caspase 6 
                 MMP7  
                 Type II Transmembrane 
               
               
                 Caspase 7 
                 MMP8  
                 Serine Proteases (TTSPs),  
               
               
                 Caspase 8 
                 MMP9  
                 e.g., DESC1 
               
               
                 Caspase 9 
                 MMP10  
                 DPP-4 
               
               
                 Caspase 10 
                 MMP11  
                 FAP 
               
               
                 Caspase 14 
                 MMP12 
                 Hepsin 
               
               
                 Cysteine cathepsins,  
                 MMP13 
                 Matriptase-2 
               
               
                 e.g., Cathepsin B 
                 MMP14 
                 MT-SP1/Matriptase 
               
               
                 Cathepsin C 
                 MMP15  
                 TMPRSS2 
               
               
                 Cathepsin K 
                 MMP16 
                 TMPRSS3 
               
               
                 Cathepsin L 
                 MMP17 
                 TMPRSS4 
               
               
                 Cathepsin S 
                 MMP19 
                   
               
               
                 Cathepsin V/L2 
                 MMP20 
                   
               
               
                 Cathepsin X/Z/P 
                 MMP23 
                   
               
               
                   
                 MMP24 
                   
               
               
                   
                 MMP26 
                   
               
               
                   
                 MMP27 
               
               
                   
               
            
           
         
       
     
     The activatable anti-PD-1 antibodies described herein overcome a limitation of antibody therapeutics, particularly antibody therapeutics that are known to be toxic to at least some degree in vivo. Target-mediated toxicity constitutes a major limitation for the development of therapeutic antibodies. The activatable anti-PD-1 antibodies provided herein are designed to address the toxicity associated with the inhibition of the target in normal tissues by traditional therapeutic antibodies. These activatable anti-PD-1 antibodies remain masked until proteolytically activated at the site of disease. Starting with an anti-PD-1 antibody as a parental therapeutic antibody, the activatable anti-PD-1 antibodies of the invention were engineered by coupling the antibody to an inhibitory mask through a linker that incorporates a protease substrate. 
     When the AB is modified with a MM and is in the presence of the target, specific binding of the AB to its target is reduced or inhibited, as compared to the specific binding of the AB not modified with an MM or the specific binding of the parental AB to the target. 
     The K d  of the AB modified with a MM towards the target is at least 5, 10, 25, 50, 100, 250, 500, 1,000, 2,500, 5,000, 10,000, 50,000, 100,000, 500,000, 1,000,000, 5,000,000, 10,000,000, 50,000,000 or greater, or between 5-10, 10-100, 10-1,000, 10-10,000, 10-100,000, 10-1,000,000, 10-10,000,000, 100-1,000, 100-10,000, 100-100,000, 100-1,000,000, 100-10,000,000, 1,000-10,000, 1,000-100,000, 1,000-1,000,000, 1000-10,000,000, 10,000-100,000, 10,000-1,000,000, 10,000-10,000,000, 100,000-1,000,000, or 100,000-10,000,000 times greater than the K d  of the AB not modified with an MM or of the parental AB towards the target. Conversely, the binding affinity of the AB modified with a MM towards the target is at least 2, 3, 4, 5, 10, 25, 50, 100, 250, 500, 1,000, 2,500, 5,000, 10,000, 50,000, 100,000, 500,000, 1,000,000, 5,000,000, 10,000,000, 50,000,000 or greater, or between 5-10, 10-100, 10-1,000, 10-10,000, 10-100,000, 10-1,000,000, 10-10,000,000, 100-1,000, 100-10,000, 100-100,000, 100-1,000,000, 100-10,000,000, 1,000-10,000, 1,000-100,000, 1,000-1,000,000, 1000-10,000,000, 10,000-100,000, 10,000-1,000,000, 10,000-10,000,000, 100,000-1,000,000, or 100,000-10,000,000 times lower than the binding affinity of the AB not modified with an MM or of the parental AB towards the target. 
     In some embodiments, the dissociation constant (K d ) of the MM towards the AB is generally greater than the K d  of the AB towards the target. The K d  of the MM towards the AB can be at least 5, 10, 25, 50, 100, 250, 500, 1,000, 2,500, 5,000, 10,000, 100,000, 1,000,000 or even 10,000,000 times greater than the K d  of the AB towards the target. Conversely, the binding affinity of the MM towards the AB is generally lower than the binding affinity of the AB towards the target. The binding affinity of MM towards the AB can be at least 5, 10, 25, 50, 100, 250, 500, 1,000, 2,500, 5,000, 10,000, 100,000, 1,000,000 or even 10,000,000 times lower than the binding affinity of the AB towards the target. 
     In some embodiments, the dissociation constant (K d ) of the MM towards the AB is approximately equal to the K d  of the AB towards the target. In some embodiments, the dissociation constant (K d ) of the MM towards the AB is no more than the dissociation constant of the AB towards the target. 
     In some embodiments, the dissociation constant (K d ) of the MM towards the AB is less than the dissociation constant of the AB towards the target. 
     In some embodiments, the dissociation constant (K d ) of the MM towards the AB is greater than the dissociation constant of the AB towards the target. 
     In some embodiments, the MM has a K d  for binding to the AB that is no more than the K d  for binding of the AB to the target. 
     In some embodiments, the MM has a K d  for binding to the AB that is no less than the K d  for binding of the AB to the target. 
     In some embodiments, the MM has a K d  for binding to the AB that is approximately equal to the K d  for binding of the AB to the target. 
     In some embodiments, the MM has a K d  for binding to the AB that is less than the K d  for binding of the AB to the target. 
     In some embodiments, the MM has a K d  for binding to the AB that is greater than the K d  for binding of the AB to the target. 
     In some embodiments, the MM has a K d  for binding to the AB that is no more than 2, 3, 4, 5, 10, 25, 50, 100, 250, 500, or 1,000 fold greater than the K d  for binding of the AB to the target. In some embodiments, the MM has a K d  for binding to the AB that is between 1-5, 2-5, 2-10, 5-10, 5-20, 5-50, 5-100, 10-100, 10-1,000, 20-100, 20-1000, or 100-1,000 fold greater than the K d  for binding of the AB to the target. 
     In some embodiments, the MM has an affinity for binding to the AB that is less than the affinity of binding of the AB to the target. 
     In some embodiments, the MM has an affinity for binding to the AB that is no more than the affinity of binding of the AB to the target. 
     In some embodiments, the MM has an affinity for binding to the AB that is approximately equal of the affinity of binding of the AB to the target. 
     In some embodiments, the MM has an affinity for binding to the AB that is no less than the affinity of binding of the AB to the target. 
     In some embodiments, the MM has an affinity for binding to the AB that is greater than the affinity of binding of the AB to the target. 
     In some embodiments, the MM has an affinity for binding to the AB that is 2, 3, 4, 5, 10, 25, 50, 100, 250, 500, or 1,000 less than the affinity of binding of the AB to the target. I In some embodiments, the MM has an affinity for binding to the AB that is between 1-5, 2-5, 2-10, 5-10, 5-20, 5-50, 5-100, 10-100, 10-1,000, 20-100, 20-1000, or 100-1,000 fold less than the affinity of binding of the AB to the target. In some embodiments, the MM has an affinity for binding to the AB that is 2 to 20 fold less than the affinity of binding of the AB to the target. In some embodiments, a MM not covalently linked to the AB and at equimolar concentration to the AB does not inhibit the binding of the AB to the target. 
     When the AB is modified with a MM and is in the presence of the target specific binding of the AB to its target is reduced or inhibited, as compared to the specific binding of the AB not modified with an MM or the specific binding of the parental AB to the target. When compared to the binding of the AB not modified with an MM or the binding of the parental AB to the target the AB&#39;s ability to bind the target when modified with an MM can be reduced by at least 50%, 60%, 70%, 80%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and even 100% for at least 2, 4, 6, 8, 12, 28, 24, 30, 36, 48, 60, 72, 84, or 96 hours, or 5, 10, 15, 30, 45, 60, 90, 120, 150, or 180 days, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months or more when measured in vivo or in an in vitro assay. 
     The MM inhibits the binding of the AB to the target. The MM binds the antigen binding domain of the AB and inhibits binding of the AB to the target. The MM can sterically inhibit the binding of the AB to the target. The MM can allosterically inhibit the binding of the AB to its target. In these embodiments when the AB is modified or coupled to a MM and in the presence of target there is no binding or substantially no binding of the AB to the target, or no more than 0.001%, 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, or 50% binding of the AB to the target, as compared to the binding of the AB not modified with an MM, the parental AB, or the AB not coupled to an MM to the target, for at least 2, 4, 6, 8, 12, 28, 24, 30, 36, 48, 60, 72, 84, or 96 hours, or 5, 10, 15, 30, 45, 60, 90, 120, 150, or 180 days, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months or longer when measured in vivo or in an in vitro assay. 
     When an AB is coupled to or modified by a MM, the MM ‘masks’ or reduces or otherwise inhibits the specific binding of the AB to the target. When an AB is coupled to or modified by a MM, such coupling or modification can effect a structural change that reduces or inhibits the ability of the AB to specifically bind its target. 
     An AB coupled to or modified with an MM can be represented by the following formulae (in order from an amino (N) terminal region to carboxyl (C) terminal region: 
       (MM)-(AB) 
       (AB)-(MM) 
       (MM)-L-(AB) 
       (AB)-L-(MM) 
     where MM is a masking moiety, the AB is an antibody or antibody fragment thereof, and the L is a linker. In many embodiments, it can be desirable to insert one or more linkers, e.g., flexible linkers, into the composition so as to provide for flexibility. 
     In certain embodiments, the MM is not a natural binding partner of the AB. In some embodiments, the MM contains no or substantially no homology to any natural binding partner of the AB. In some embodiments, the MM is no more than 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% similar to any natural binding partner of the AB. In some embodiments, the MM is no more than 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% identical to any natural binding partner of the AB. In some embodiments, the MM is no more than 25% identical to any natural binding partner of the AB. In some embodiments, the MM is no more than 50% identical to any natural binding partner of the AB. In some embodiments, the MM is no more than 20% identical to any natural binding partner of the AB. In some embodiments, the MM is no more than 10% identical to any natural binding partner of the AB. 
     In some embodiments, the activatable antibodies include an AB that is modified by an MM and also includes one or more cleavable moieties (CM). Such activatable antibodies exhibit activatable/switchable binding, to the AB&#39;s target. Activatable antibodies generally include an antibody or antibody fragment (AB), modified by or coupled to a masking moiety (MM) and a modifiable or cleavable moiety (CM). In some embodiments, the CM contains an amino acid sequence that serves as a substrate for at least one protease. 
     The elements of the activatable antibodies are arranged so that the MM and CM are positioned such that in a cleaved (or relatively active) state and in the presence of a target, the AB binds a target while the activatable antibody is in an uncleaved (or relatively inactive) state in the presence of the target, specific binding of the AB to its target is reduced or inhibited. The specific binding of the AB to its target can be reduced due to the inhibition or masking of the AB&#39;s ability to specifically bind its target by the MM. 
     The K d  of the AB modified with a MM and a CM towards the target is at least 5, 10, 25, 50, 100, 250, 500, 1,000, 2,500, 5,000, 10,000, 50,000, 100,000, 500,000, 1,000,000, 5,000,000, 10,000,000, 50,000,000 or greater, or between 5-10, 10-100, 10-1,000, 10-10,000, 10-100,000, 10-1,000,000, 10-10,000,000, 100-1,000, 100-10,000, 100-100,000, 100-1,000,000, 100-10,000,000, 1,000-10,000, 1,000-100,000, 1,000-1,000,000, 1000-10,000,000, 10,000-100,000, 10,000-1,000,000, 10,000-10,000,000, 100,000-1,000,000, or 100,000-10,000,000 times greater than the K d  of the AB not modified with an MM and a CM or of the parental AB towards the target. Conversely, the binding affinity of the AB modified with a MM and a CM towards the target is at least 5, 10, 25, 50, 100, 250, 500, 1,000, 2,500, 5,000, 10,000, 50,000, 100,000, 500,000, 1,000,000, 5,000,000, 10,000,000, 50,000,000 or greater, or between 5-10, 10-100, 10-1,000, 10-10,000, 10-100,000, 10-1,000,000, 10-10,000,000, 100-1,000, 100-10,000, 100-100,000, 100-1,000,000, 100-10,000,000, 1,000-10,000, 1,000-100,000, 1,000-1,000,000, 1000-10,000,000, 10,000-100,000, 10,000-1,000,000, 10,000-10,000,000, 100,000-1,000,000, or 100,000-10,000,000 times lower than the binding affinity of the AB not modified with an MM and a CM or of the parental AB towards the target. 
     When the AB is modified with a MM and a CM and is in the presence of the target but not in the presence of a modifying agent (for example at least one protease), specific binding of the AB to its target is reduced or inhibited, as compared to the specific binding of the AB not modified with an MM and a CM or of the parental AB to the target. When compared to the binding of the parental AB or the binding of an AB not modified with an MM and a CM to its target, the AB&#39;s ability to bind the target when modified with an MM and a CM can be reduced by at least 50%, 60%, 70%, 80%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and even 100% for at least 2, 4, 6, 8, 12, 28, 24, 30, 36, 48, 60, 72, 84, or 96 hours or 5, 10, 15, 30, 45, 60, 90, 120, 150, or 180 days, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months or longer when measured in vivo or in an in vitro assay. 
     As used herein, the term cleaved state refers to the condition of the activatable antibodies following modification of the CM by at least one protease. The term uncleaved state, as used herein, refers to the condition of the activatable antibodies in the absence of cleavage of the CM by a protease. As discussed above, the term “activatable antibodies” is used herein to refer to an activatable antibody in both its uncleaved (native) state, as well as in its cleaved state. It will be apparent to the ordinarily skilled artisan that in some embodiments a cleaved activatable antibody can lack an MM due to cleavage of the CM by protease, resulting in release of at least the MM (e.g., where the MM is not joined to the activatable antibodies by a covalent bond (e.g., a disulfide bond between cysteine residues). 
     By activatable or switchable is meant that the activatable antibody exhibits a first level of binding to a target when the activatable antibody is in a inhibited, masked or uncleaved state (i.e., a first conformation), and a second level of binding to the target in the uninhibited, unmasked and/or cleaved state (i.e., a second conformation), where the second level of target binding is greater than the first level of binding. In general, the access of target to the AB of the activatable antibody is greater in the presence of a cleaving agent capable of cleaving the CM, i.e., a protease, than in the absence of such a cleaving agent. Thus, when the activatable antibody is in the uncleaved state, the AB is inhibited from target binding and can be masked from target binding (i.e., the first conformation is such the AB cannot bind the target), and in the cleaved state the AB is not inhibited or is unmasked to target binding. 
     The CM and AB of the activatable antibodies are selected so that the AB represents a binding moiety for a given target, and the CM represents a substrate for a protease. In some embodiments, the protease is co-localized with the target at a treatment site or diagnostic site in a subject. As used herein, co-localized refers to being at the same site or relatively close nearby. In some embodiments, a protease cleaves a CM yielding an activated antibody that binds to a target located nearby the cleavage site. The activatable antibodies disclosed herein find particular use where, for example, a protease capable of cleaving a site in the CM, i.e., a protease, is present at relatively higher levels in or in close proximity to target-containing tissue of a treatment site or diagnostic site than in tissue of non-treatment sites (for example in healthy tissue). In some embodiments, a CM of the disclosure is also cleaved by one or more other proteases. In some embodiments, it is the one or more other proteases that is co-localized with the target and that is responsible for cleavage of the CM in vivo. 
     In some embodiments activatable antibodies provide for reduced toxicity and/or adverse side effects that could otherwise result from binding of the AB at non-treatment sites if the AB were not masked or otherwise inhibited from binding to the target. 
     In general, an activatable antibody can be designed by selecting an AB of interest and constructing the remainder of the activatable antibody so that, when conformationally constrained, the MM provides for masking of the AB or reduction of binding of the AB to its target. Structural design criteria can be to be taken into account to provide for this functional feature. 
     Activatable antibodies exhibiting a switchable phenotype of a desired dynamic range for target binding in an inhibited versus an uninhibited conformation are provided. Dynamic range generally refers to a ratio of (a) a maximum detected level of a parameter under a first set of conditions to (b) a minimum detected value of that parameter under a second set of conditions. For example, in the context of an activatable antibody, the dynamic range refers to the ratio of (a) a maximum detected level of target protein binding to an activatable antibody in the presence of at least one protease capable of cleaving the CM of the activatable antibodies to (b) a minimum detected level of target protein binding to an activatable antibody in the absence of the protease. The dynamic range of an activatable antibody can be calculated as the ratio of the dissociation constant of an activatable antibody cleaving agent (e.g., enzyme) treatment to the dissociation constant of the activatable antibodies cleaving agent treatment. The greater the dynamic range of an activatable antibody, the better the switchable phenotype of the activatable antibody. Activatable antibodies having relatively higher dynamic range values (e.g., greater than 1) exhibit more desirable switching phenotypes such that target protein binding by the activatable antibodies occurs to a greater extent (e.g., predominantly occurs) in the presence of a cleaving agent (e.g., enzyme) capable of cleaving the CM of the activatable antibodies than in the absence of a cleaving agent. 
     Activatable antibodies can be provided in a variety of structural configurations. Exemplary formulae for activatable antibodies are provided below. It is specifically contemplated that the N- to C-terminal order of the AB, MM and CM can be reversed within an activatable antibody. It is also specifically contemplated that the CM and MM can overlap in amino acid sequence, e.g., such that the CM is contained within the MM. 
     For example, activatable antibodies can be represented by the following formula (in order from an amino (N) terminal region to carboxyl (C) terminal region: 
       (MM)-(CM)-(AB) 
       (AB)-(CM)-(MM) 
     where MM is a masking moiety, CM is a cleavable moiety, and AB is an antibody or fragment thereof. It should be noted that although MM and CM are indicated as distinct components in the formulae above, in all exemplary embodiments (including formulae) disclosed herein it is contemplated that the amino acid sequences of the MM and the CM could overlap, e.g., such that the CM is completely or partially contained within the MM. In addition, the formulae above provide for additional amino acid sequences that can be positioned N-terminal or C-terminal to the activatable antibodies elements. 
     In certain embodiments, the MM is not a natural binding partner of the AB. In some embodiments, the MM contains no or substantially no homology to any natural binding partner of the AB. In some embodiments, the MM is no more than 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% similar to any natural binding partner of the AB. In some embodiments, the MM is no more than 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% identical to any natural binding partner of the AB. In some embodiments, the MM is no more than 50% identical to any natural binding partner of the AB. In some embodiments, the MM is no more than 25% identical to any natural binding partner of the AB. In some embodiments, the MM is no more than 20% identical to any natural binding partner of the AB. In some embodiments, the MM is no more than 10% identical to any natural binding partner of the AB. 
     In many embodiments it can be desirable to insert one or more linkers, e.g., flexible linkers, into the activatable antibody construct so as to provide for flexibility at one or more of the MM-CM junction, the CM-AB junction, or both. For example, the AB, MM, and/or CM may not contain a sufficient number of residues (e.g., Gly, Ser, Asp, Asn, especially Gly and Ser, particularly Gly) to provide the desired flexibility. As such, the switchable phenotype of such activatable antibody constructs can benefit from introduction of one or more amino acids to provide for a flexible linker. In addition, as described below, where the activatable antibody is provided as a conformationally constrained construct, a flexible linker can be operably inserted to facilitate formation and maintenance of a cyclic structure in the uncleaved activatable antibody. 
     For example, in certain embodiments an activatable antibody comprises one of the following formulae (where the formula below represent an amino acid sequence in either N- to C-terminal direction or C- to N-terminal direction): 
       (MM)-L1-(CM)-(AB) 
       (MM)-(CM)-L2-(AB) 
       (MM)-L1-(CM)-L2-(AB) 
     wherein MM, CM, and AB are as defined above; wherein L1 and L2 are each independently and optionally present or absent, are the same or different flexible linkers that include at least 1 flexible amino acid (e.g., Gly). In addition, the formulae above provide for additional amino acid sequences that can be positioned N-terminal or C-terminal to the activatable antibodies elements. Examples include, but are not limited to, targeting moieties (e.g., a ligand for a receptor of a cell present in a target tissue) and serum half-life extending moieties (e.g., polypeptides that bind serum proteins, such as immunoglobulin (e.g., IgG) or serum albumin (e.g., human serum albumin (HAS)). 
     The CM is specifically cleaved by at least one protease at a rate of about 0.001-1500×10 4 M −1 S −1  or at least 0.001, 0.005, 0.01, 0.05, 0.1, 0.5, 1, 2.5, 5, 7.5, 10, 15, 20, 25, 50, 75, 100, 125, 150, 200, 250, 500, 750, 1000, 1250, or 1500×10 4  M −1 S −1 . In some embodiments, the CM is specifically cleaved at a rate of about 100,000 M −1 S −1 . In some embodiments, the CM is specifically cleaved at a rate from about 1×10E2 to about 1×10E6 M −1 S −1  (i.e., from about 1×10 2  to about 1×10 6 M −1 S −1 ). 
     For specific cleavage by an enzyme, contact between the enzyme and CM is made. When the activatable antibody comprising an AB coupled to a MM and a CM is in the presence of target and sufficient enzyme activity, the CM can be cleaved. Sufficient enzyme activity can refer to the ability of the enzyme to make contact with the CM and effect cleavage. It can readily be envisioned that an enzyme can be in the vicinity of the CM but unable to cleave because of other cellular factors or protein modification of the enzyme. 
     Linkers suitable for use in compositions described herein are generally ones that provide flexibility of the modified AB or the activatable antibodies to facilitate the inhibition of the binding of the AB to the target. Such linkers are generally referred to as flexible linkers. Suitable linkers can be readily selected and can be of any of a suitable of different lengths, such as from 1 amino acid (e.g., Gly) to 20 amino acids, from 2 amino acids to 15 amino acids, from 3 amino acids to 12 amino acids, including 4 amino acids to 10 amino acids, 5 amino acids to 9 amino acids, 6 amino acids to 8 amino acids, or 7 amino acids to 8 amino acids, and can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acids in length. 
     Exemplary flexible linkers include glycine polymers (G)n, glycine-serine polymers (including, for example, (GS)n, (GSGGS) n (SEQ ID NO: 363) and (GGGS)n (SEQ ID NO: 364), where n is an integer of at least one), glycine-alanine polymers, alanine-serine polymers, and other flexible linkers known in the art. Glycine and glycine-serine polymers are relatively unstructured, and therefore can be able to serve as a neutral tether between components. Glycine accesses significantly more phi-psi space than even alanine, and is much less restricted than residues with longer side chains (see Scheraga, Rev. Computational Chem. 11173-142 (1992)). Exemplary flexible linkers include, but are not limited to GGSG (SEQ ID NO: 365), GGSGG (SEQ ID NO: 366), GSGSG (SEQ ID NO: 367), GSGGG (SEQ ID NO: 368), GGGSG (SEQ ID NO: 369), GSSSG (SEQ ID NO: 370), and the like. The ordinarily skilled artisan will recognize that design of an activatable antibodies can include linkers that are all or partially flexible, such that the linker can include a flexible linker as well as one or more portions that confer less flexible structure to provide for a desired activatable antibodies structure. 
     The disclosure also provides compositions and methods that include an activatable anti-PD-1 antibody that includes an antibody or antibody fragment (AB) that specifically binds PD-1, where the AB is coupled to a masking moiety (MM) that decreases the ability of the AB to bind its target. In some embodiments, the activatable anti-PD-1 antibody further includes a cleavable moiety (CM) that is a substrate for a protease. The compositions and methods provided herein enable the attachment of one or more agents to one or more cysteine residues in the AB without compromising the activity (e.g., the masking, activating or binding activity) of the activatable anti-PD-1 antibody. In some embodiments, the compositions and methods provided herein enable the attachment of one or more agents to one or more cysteine residues in the AB without reducing or otherwise disturbing one or more disulfide bonds within the MM. The compositions and methods provided herein produce an activatable anti-PD-1 antibody that is conjugated to one or more agents, e.g., any of a variety of therapeutic, diagnostic and/or prophylactic agents, for example, in some embodiments, without any of the agent(s) being conjugated to the MM of the activatable anti-PD-1 antibody. The compositions and methods provided herein produce conjugated activatable anti-PD-1 antibodies in which the MM retains the ability to effectively and efficiently mask the AB of the activatable antibody in an uncleaved state. The compositions and methods provided herein produce conjugated activatable anti-PD-1 antibodies in which the activatable antibody is still activated, i.e., cleaved, in the presence of a protease that can cleave the CM. 
     The activatable anti-PD-1 antibodies have at least one point of conjugation for an agent, but in the methods and compositions provided herein less than all possible points of conjugation are available for conjugation to an agent. In some embodiments, the one or more points of conjugation are sulfur atoms involved in disulfide bonds. In some embodiments, the one or more points of conjugation are sulfur atoms involved in interchain disulfide bonds. In some embodiments, the one or more points of conjugation are sulfur atoms involved in interchain sulfide bonds, but not sulfur atoms involved in intrachain disulfide bonds. In some embodiments, the one or more points of conjugation are sulfur atoms of cysteine or other amino acid residues containing a sulfur atom. Such residues can occur naturally in the antibody structure or can be incorporated into the antibody by site-directed mutagenesis, chemical conversion, or mis-incorporation of non-natural amino acids. 
     Also provided are methods of preparing a conjugate of an activatable anti-PD-1 antibody having one or more interchain disulfide bonds in the AB and one or more intrachain disulfide bonds in the MM, and a drug reactive with free thiols is provided. The method generally includes partially reducing interchain disulfide bonds in the activatable antibody with a reducing agent, such as, for example, TCEP; and conjugating the drug reactive with free thiols to the partially reduced activatable antibody. As used herein, the term partial reduction refers to situations where an activatable anti-PD-1 antibody is contacted with a reducing agent and less than all disulfide bonds, e.g., less than all possible sites of conjugation are reduced. In some embodiments, less than 99%, 98%, 97%, 96%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10% or less than 5% of all possible sites of conjugation are reduced. 
     In yet other embodiments, a method of reducing and conjugating an agent, e.g., a drug, to an activatable anti-PD-1 antibody resulting in selectivity in the placement of the agent is provided. The method generally includes partially reducing the activatable anti-PD-1 antibody with a reducing agent such that any conjugation sites in the masking moiety or other non-AB portion of the activatable antibody are not reduced, and conjugating the agent to interchain thiols in the AB. The conjugation site(s) are selected so as to allow desired placement of an agent to allow conjugation to occur at a desired site. The reducing agent is, for example, TCEP. The reduction reaction conditions such as, for example, the ratio of reducing agent to activatable antibody, the length of incubation, the temperature during the incubation, the pH of the reducing reaction solution, etc., are determined by identifying the conditions that produce a conjugated activatable antibody in which the MM retains the ability to effectively and efficiently mask the AB of the activatable antibody in an uncleaved state. The ratio of reduction agent to activatable anti-PD-1 antibody will vary depending on the activatable antibody. In some embodiments, the ratio of reducing agent to activatable anti-PD-1 antibody will be in a range from about 20:1 to 1:1, from about 10:1 to 1:1, from about 9:1 to 1:1, from about 8:1 to 1:1, from about 7:1 to 1:1, from about 6:1 to 1:1, from about 5:1 to 1:1, from about 4:1 to 1:1, from about 3:1 to 1:1, from about 2:1 to 1:1, from about 20:1 to 1:1.5, from about 10:1 to 1:1.5, from about 9:1 to 1:1.5, from about 8:1 to 1:1.5, from about 7:1 to 1:1.5, from about 6:1 to 1:1.5, from about 5:1 to 1:1.5, from about 4:1 to 1:1.5, from about 3:1 to 1:1.5, from about 2:1 to 1:1.5, from about 1.5:1 to 1:1.5, or from about 1:1 to 1:1.5. In some embodiments, the ratio is in a range of from about 5:1 to 1:1. In some embodiments, the ratio is in a range of from about 5:1 to 1.5:1. In some embodiments, the ratio is in a range of from about 4:1 to 1:1. In some embodiments, the ratio is in a range from about 4:1 to 1.5:1. In some embodiments, the ratio is in a range from about 8:1 to about 1:1. In some embodiments, the ratio is in a range of from about 2.5:1 to 1:1. 
     In some embodiments, a method of reducing interchain disulfide bonds in the AB of an activatable anti-PD-1 antibody and conjugating an agent, e.g., a thiol-containing agent such as a drug, to the resulting interchain thiols to selectively locate agent(s) on the AB is provided. The method generally includes partially reducing the AB with a reducing agent to form at least two interchain thiols without forming all possible interchain thiols in the activatable antibody; and conjugating the agent to the interchain thiols of the partially reduced AB. For example, the AB of the activatable antibody is partially reduced for about 1 hour at about 37° C. at a desired ratio of reducing agent:activatable antibody. In some embodiments, the ratio of reducing agent to activatable antibody will be in a range from about 20:1 to 1:1, from about 10:1 to 1:1, from about 9:1 to 1:1, from about 8:1 to 1:1, from about 7:1 to 1:1, from about 6:1 to 1:1, from about 5:1 to 1:1, from about 4:1 to 1:1, from about 3:1 to 1:1, from about 2:1 to 1:1, from about 20:1 to 1:1.5, from about 10:1 to 1:1.5, from about 9:1 to 1:1.5, from about 8:1 to 1:1.5, from about 7:1 to 1:1.5, from about 6:1 to 1:1.5, from about 5:1 to 1:1.5, from about 4:1 to 1:1.5, from about 3:1 to 1:1.5, from about 2:1 to 1:1.5, from about 1.5:1 to 1:1.5, or from about 1:1 to 1:1.5. In some embodiments, the ratio is in a range of from about 5:1 to 1:1. In some embodiments, the ratio is in a range of from about 5:1 to 1.5:1. In some embodiments, the ratio is in a range of from about 4:1 to 1:1. In some embodiments, the ratio is in a range from about 4:1 to 1.5:1. In some embodiments, the ratio is in a range from about 8:1 to about 1:1. In some embodiments, the ratio is in a range of from about 2.5:1 to 1:1. 
     The thiol-containing reagent can be, for example, cysteine or N-acetyl cysteine. The reducing agent can be, for example, TCEP. In some embodiments, the reduced activatable antibody can be purified prior to conjugation, using for example, column chromatography, dialysis, or diafiltration. Alternatively, the reduced antibody is not purified after partial reduction and prior to conjugation. 
     The invention also provides partially reduced activatable anti-PD-1 antibodies in which at least one interchain disulfide bond in the activatable antibody has been reduced with a reducing agent without disturbing any intrachain disulfide bonds in the activatable antibody, wherein the activatable antibody includes an antibody or an antigen binding fragment thereof (AB) that specifically binds to PD-1, a masking moiety (MM) that inhibits the binding of the AB of the activatable antibody in an uncleaved state to the PD-1 target, and a cleavable moiety (CM) coupled to the AB, wherein the CM is a polypeptide that functions as a substrate for a protease. In some embodiments the MM is coupled to the AB via the CM. In some embodiments, one or more intrachain disulfide bond(s) of the activatable antibody is not disturbed by the reducing agent. In some embodiments, one or more intrachain disulfide bond(s) of the MM within the activatable antibody is not disturbed by the reducing agent. In some embodiments, the activatable antibody in the uncleaved state has the structural arrangement from N-terminus to C-terminus as follows: MM-CM-AB or AB-CM-MM. In some embodiments, reducing agent is TCEP. 
     The disclosure also provides partially reduced activatable antibodies in which at least one interchain disulfide bond in the activatable antibody has been reduced with a reducing agent without disturbing any intrachain disulfide bonds in the activatable antibody, wherein the activatable antibody includes an antibody or an antigen binding fragment thereof (AB) that specifically binds to the target, e.g., PD-1, a masking moiety (MM) that inhibits the binding of the AB of the activatable antibody in an uncleaved state to the target, and a cleavable moiety (CM) coupled to the AB, wherein the CM is a polypeptide that functions as a substrate for at least one protease. In some embodiments, the MM is coupled to the AB via the CM. In some embodiments, one or more intrachain disulfide bond(s) of the activatable antibody is not disturbed by the reducing agent. In some embodiments, one or more intrachain disulfide bond(s) of the MM within the activatable antibody is not disturbed by the reducing agent. In some embodiments, the activatable antibody in the uncleaved state has the structural arrangement from N-terminus to C-terminus as follows: MM-CM-AB or AB-CM-MM. In some embodiments, reducing agent is TCEP. 
     In some embodiments, the activatable antibodies described herein also include an agent conjugated to the activatable antibody. In some embodiments, the conjugated agent is a therapeutic agent, such as an anti-inflammatory. In such embodiments, the agent is conjugated to a carbohydrate moiety of the activatable antibody, for example, in some embodiments, where the carbohydrate moiety is located outside the antigen-binding region of the antibody or antigen-binding fragment in the activatable antibody. In some embodiments, the agent is conjugated to a sulfhydryl group of the antibody or antigen-binding fragment in the activatable antibody. 
     In some embodiments, the agent is a detectable moiety such as, for example, a label or other marker. For example, the agent is or includes a radiolabeled amino acid, one or more biotinyl moieties that can be detected by marked avidin (e.g., streptavidin containing a fluorescent marker or enzymatic activity that can be detected by optical or calorimetric methods), one or more radioisotopes or radionuclides, one or more fluorescent labels, one or more enzymatic labels, and/or one or more chemiluminescent agents. In some embodiments, detectable moieties are attached by spacer molecules. 
     Those of ordinary skill in the art will recognize that a large variety of possible moieties can be coupled to the resultant antibodies of the disclosure. (See, for example, “Conjugate Vaccines”, Contributions to Microbiology and Immunology, J. M. Cruse and R. E. Lewis, Jr (eds), Carger Press, New York, (1989), the entire contents of which are incorporated herein by reference). 
     Coupling can be accomplished by any chemical reaction that will bind the two molecules so long as the antibody and the other moiety retain their respective activities. This linkage can include many chemical mechanisms, for instance covalent binding, affinity binding, intercalation, coordinate binding and complexation. In some embodiments, the binding is, however, covalent binding. Covalent binding can be achieved either by direct condensation of existing side chains or by the incorporation of external bridging molecules. Many bivalent or polyvalent linking agents are useful in coupling protein molecules, such as the antibodies of the present disclosure, to other molecules. For example, representative coupling agents can include organic compounds such as thioesters, carbodiimides, succinimide esters, diisocyanates, glutaraldehyde, diazobenzenes and hexamethylene diamines. This listing is not intended to be exhaustive of the various classes of coupling agents known in the art but, rather, is exemplary of the more common coupling agents. (See Killen and Lindstrom, Jour. Immun. 133:1335-2549 (1984); Jansen et al., Immunological Reviews 62:185-216 (1982); and Vitetta et al., Science 238:1098 (1987). 
     In some embodiments, in addition to the compositions and methods provided herein, the conjugated activatable antibody can also be modified for site-specific conjugation through modified amino acid sequences inserted or otherwise included in the activatable antibody sequence. These modified amino acid sequences are designed to allow for controlled placement and/or dosage of the conjugated agent within a conjugated activatable antibody. For example, the activatable antibody can be engineered to include cysteine substitutions at positions on light and heavy chains that provide reactive thiol groups and do not negatively impact protein folding and assembly, nor alter antigen binding. In some embodiments, the activatable antibody can be engineered to include or otherwise introduce one or more non-natural amino acid residues within the activatable antibody to provide suitable sites for conjugation. In some embodiments, the activatable antibody can be engineered to include or otherwise introduce enzymatically activatable peptide sequences within the activatable antibody sequence. 
     Suitable linkers are described in the literature. (See, for example, Ramakrishnan, S. et al., Cancer Res. 44:201-208 (1984) describing use of MBS (M-maleimidobenzoyl-N-hydroxysuccinimide ester). See also, U.S. Pat. No. 5,030,719, describing use of halogenated acetyl hydrazide derivative coupled to an antibody by way of an oligopeptide linker. In some embodiments, suitable linkers include: (i) EDC (1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride; (ii) SMPT (4-succinimidyloxycarbonyl-alpha-methyl-alpha-(2-pridyl-dithio)-toluene (Pierce Chem. Co., Cat. (21558G); (iii) SPDP (succinimidyl-6 [3-(2-pyridyldithio) propionamido]hexanoate (Pierce Chem. Co., Cat #21651G); (iv) Sulfo-LC-SPDP (sulfosuccinimidyl 6 [3-(2-pyridyldithio)-propianamide] hexanoate (Pierce Chem. Co. Cat. #2165-G); and (v) sulfo-NHS (N-hydroxysulfo-succinimide: Pierce Chem. Co., Cat. #24510) conjugated to EDC. Additional linkers include, but are not limited to, SMCC, sulfo-SMCC, SPDB, or sulfo-SPDB. 
     The linkers described above contain components that have different attributes, thus leading to conjugates with differing physio-chemical properties. For example, sulfo-NHS esters of alkyl carboxylates are more stable than sulfo-NHS esters of aromatic carboxylates. NETS-ester containing linkers are less soluble than sulfo-NHS esters. Further, the linker SMPT contains a sterically hindered disulfide bond, and can form conjugates with increased stability. Disulfide linkages, are in general, less stable than other linkages because the disulfide linkage is cleaved in vitro, resulting in less conjugate available. Sulfo-NHS, in particular, can enhance the stability of carbodimide couplings. Carbodimide couplings (such as EDC) when used in conjunction with sulfo-NHS, forms esters that are more resistant to hydrolysis than the carbodimide coupling reaction alone. 
     In some embodiments, the linkers are cleavable. In some embodiments, the linkers are non-cleavable. In some embodiments, two or more linkers are present. The two or more linkers are all the same, i.e., cleavable or non-cleavable, or the two or more linkers are different, i.e., at least one cleavable and at least one non-cleavable. 
     The present disclosure utilizes several methods for attaching agents to ABs: (a) attachment to the carbohydrate moieties of the AB, or (b) attachment to sulfhydryl groups of the AB, or (c) attachment to amino groups of the AB, or (d) attachment to carboxylate groups of the AB. According to the disclosure, ABs can be covalently attached to an agent through an intermediate linker having at least two reactive groups, one to react with AB and one to react with the agent. The linker, which can include any compatible organic compound, can be chosen such that the reaction with AB (or agent) does not adversely affect AB reactivity and selectivity. Furthermore, the attachment of linker to agent might not destroy the activity of the agent. Suitable linkers for reaction with oxidized antibodies or oxidized antibody fragments include those containing an amine selected from the group consisting of primary amine, secondary amine, hydrazine, hydrazide, hydroxylamine, phenylhydrazine, semicarbazide and thiosemicarbazide groups. Such reactive functional groups can exist as part of the structure of the linker, or can be introduced by suitable chemical modification of linkers not containing such groups. 
     According to the present disclosure, suitable linkers for attachment to reduced ABs include those having certain reactive groups capable of reaction with a sulfhydryl group of a reduced antibody or fragment. Such reactive groups include, but are not limited to: reactive haloalkyl groups (including, for example, haloacetyl groups), p-mercuribenzoate groups and groups capable of Michael-type addition reactions (including, for example, maleimides and groups of the type described by Mitra and Lawton, 1979, J. Amer. Chem. Soc. 101: 3097-3110). 
     According to the present disclosure, suitable linkers for attachment to neither oxidized nor reduced Abs include those having certain functional groups capable of reaction with the primary amino groups present in unmodified lysine residues in the Ab. Such reactive groups include, but are not limited to, NHS carboxylic or carbonic esters, sulfo-NHS carboxylic or carbonic esters, 4-nitrophenyl carboxylic or carbonic esters, pentafluorophenyl carboxylic or carbonic esters, acyl imidazoles, isocyanates, and isothiocyanates. 
     According to the present disclosure, suitable linkers for attachment to neither oxidized nor reduced Abs include those having certain functional groups capable of reaction with the carboxylic acid groups present in aspartate or glutamate residues in the Ab, which have been activated with suitable reagents. Suitable activating reagents include EDC, with or without added NHS or sulfo-NHS, and other dehydrating agents utilized for carboxamide formation. In these instances, the functional groups present in the suitable linkers would include primary and secondary amines, hydrazines, hydroxylamines, and hydrazides. 
     The agent can be attached to the linker before or after the linker is attached to the AB. In certain applications it can be desirable to first produce an AB-linker intermediate in which the linker is free of an associated agent. Depending upon the particular application, a specific agent can then be covalently attached to the linker. In some embodiments, the AB is first attached to the MM, CM and associated linkers and then attached to the linker for conjugation purposes. 
     Branched Linkers: 
     In specific embodiments, branched linkers that have multiple sites for attachment of agents are utilized. For multiple site linkers, a single covalent attachment to an AB would result in an AB-linker intermediate capable of binding an agent at a number of sites. The sites can be aldehyde or sulfhydryl groups or any chemical site to which agents can be attached. 
     In some embodiments, higher specific activity (or higher ratio of agents to AB) can be achieved by attachment of a single site linker at a plurality of sites on the AB. This plurality of sites can be introduced into the AB by either of two methods. First, one can generate multiple aldehyde groups and/or sulfhydryl groups in the same AB. Second, one can attach to an aldehyde or sulfhydryl of the AB a “branched linker” having multiple functional sites for subsequent attachment to linkers. The functional sites of the branched linker or multiple site linker can be aldehyde or sulfhydryl groups, or can be any chemical site to which linkers can be attached. Still higher specific activities can be obtained by combining these two approaches, that is, attaching multiple site linkers at several sites on the AB. 
     Cleavable Linkers: 
     Peptide linkers that are susceptible to cleavage by enzymes of the complement system, such as but not limited to u-plasminogen activator, tissue plasminogen activator, trypsin, plasmin, or another enzyme having proteolytic activity can be used in one embodiment of the present disclosure. According to one method of the present disclosure, an agent is attached via a linker susceptible to cleavage by complement. The antibody is selected from a class that can activate complement. The antibody-agent conjugate, thus, activates the complement cascade and releases the agent at the target site. According to another method of the present disclosure, an agent is attached via a linker susceptible to cleavage by enzymes having a proteolytic activity such as a u-plasminogen activator, a tissue plasminogen activator, plasmin, or trypsin. 
     Non-limiting examples of cleavable linker sequences are provided in Table 5. 
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 Exemplary Linker Sequences for Conjugation 
               
            
           
           
               
               
            
               
                 Types of Cleavable Sequences 
                 Amino Acid Sequence 
               
               
                   
               
               
                 Plasmin cleavable sequences 
                   
               
               
                 Pro-urokinase 
                 PRFKIIGG (SEQ ID NO: 587) 
               
               
                   
                 PRFRIIGG (SEQ ID NO: 588) 
               
               
                   
               
               
                 TGFβ 
                 SSRHRRALD (SEQ ID NO: 589) 
               
               
                   
               
               
                 Plasminogen 
                 RKSSIIIRMRDVVL (SEQ ID NO: 590) 
               
               
                   
               
               
                 Staphylokinase 
                 SSSFDKGKYKKGDDA (SEQ ID NO: 591) 
               
               
                   
                 SSSFDKGKYKRGDDA (SEQ ID NO: 592) 
               
               
                   
               
               
                 Factor Xa cleavable sequences 
                 IEGR (SEQ ID NO: 593) 
               
               
                   
                 IDGR (SEQ ID NO: 594) 
               
               
                   
                 GGSIDGR (SEQ ID NO: 595) 
               
               
                   
               
               
                 MMP cleavable sequences 
                   
               
               
                 Gelatinase A 
                 PLGLWA (SEQ ID NO: 596) 
               
               
                   
               
               
                 Collagenase cleavable sequences 
                   
               
               
                 Calf skin collagen (α1(I) chain) 
                 GPQGIAGQ (SEQ ID NO: 597) 
               
               
                   
               
               
                 Calf skin collagen (α2(I) chain) 
                 GPQGLLGA (SEQ ID NO: 598) 
               
               
                   
               
               
                 Bovine cartilage collagen (α1(II) chain) 
                 GIAGQ (SEQ ID NO: 599) 
               
               
                   
               
               
                 Human liver collagen (α1(III) chain) 
                 GPLGIAGI (SEQ ID NO: 600) 
               
               
                   
               
               
                 Human α 2 M 
                 GPEGLRVG (SEQ ID NO: 601) 
               
               
                   
               
               
                 Human PZP 
                 YGAGLGVV (SEQ ID NO: 602) 
               
               
                   
                 AGLGVVER (SEQ ID NO: 603) 
               
               
                   
                 AGLGISST (SEQ ID NO: 604) 
               
               
                   
               
               
                 Rat α 1 M 
                 EPQALAMS (SEQ ID NO: 605) 
               
               
                   
                 QALAMSAI (SEQ ID NO: 606) 
               
               
                   
               
               
                 Rat α 2 M 
                 AAYHLVSQ (SEQ ID NO: 607) 
               
               
                   
                 MDAFLESS (SEQ ID NO: 608) 
               
               
                   
               
               
                 Rat α 1 I 3 (2J) 
                 ESLPVVAV (SEQ ID NO: 609) 
               
               
                   
               
               
                 Rat α 1 I 3 (27J) 
                 SAPAVESE (SEQ ID NO: 610) 
               
               
                   
               
               
                 Human fibroblast collagenase 
                 DVAQFVLT (SEQ ID NO: 611) 
               
               
                 (autolytic cleavages) 
                 VAQFVLTE (SEQ ID NO: 612) 
               
               
                   
                 AQFVLTEG (SEQ ID NO: 613) 
               
               
                   
                 PVQPIGPQ (SEQ ID NO: 614) 
               
               
                   
               
            
           
         
       
     
     In addition, agents can be attached via disulfide bonds (for example, the disulfide bonds on a cysteine molecule) to the AB. Since many tumors naturally release high levels of glutathione (a reducing agent) this can reduce the disulfide bonds with subsequent release of the agent at the site of delivery. In some embodiments, the reducing agent that would modify a CM would also modify the linker of the conjugated activatable antibody. 
     Spacers and Cleavable Elements: In some embodiments, it can be necessary to construct the linker in such a way as to optimize the spacing between the agent and the AB of the activatable antibody. This can be accomplished by use of a linker of the general structure: 
       W—(CH 2 ) n -Q
 
     wherein
 
W is either —NH—CH 2 — or —CH 2 —;
 
Q is an amino acid, peptide; and
 
n is an integer from 0 to 20.
 
     In some embodiments, the linker can comprise a spacer element and a cleavable element. The spacer element serves to position the cleavable element away from the core of the AB such that the cleavable element is more accessible to the enzyme responsible for cleavage. Certain of the branched linkers described above can serve as spacer elements. 
     Throughout this discussion, it should be understood that the attachment of linker to agent (or of spacer element to cleavable element, or cleavable element to agent) need not be particular mode of attachment or reaction. Any reaction providing a product of suitable stability and biological compatibility is acceptable. 
     Serum Complement and Selection of Linkers: 
     According to one method of the present disclosure, when release of an agent is desired, an AB that is an antibody of a class that can activate complement is used. The resulting conjugate retains both the ability to bind antigen and activate the complement cascade. Thus, according to this embodiment of the present disclosure, an agent is joined to one end of the cleavable linker or cleavable element and the other end of the linker group is attached to a specific site on the AB. For example, if the agent has an hydroxy group or an amino group, it can be attached to the carboxy terminus of a peptide, amino acid or other suitably chosen linker via an ester or amide bond, respectively. For example, such agents can be attached to the linker peptide via a carbodimide reaction. If the agent contains functional groups that would interfere with attachment to the linker, these interfering functional groups can be blocked before attachment and deblocked once the product conjugate or intermediate is made. The opposite or amino terminus of the linker is then used either directly or after further modification for binding to an AB that is capable of activating complement. 
     Linkers (or spacer elements of linkers) can be of any desired length, one end of which can be covalently attached to specific sites on the AB of the activatable antibody. The other end of the linker or spacer element can be attached to an amino acid or peptide linker. 
     Thus when these conjugates bind to antigen in the presence of complement the amide or ester bond that attaches the agent to the linker will be cleaved, resulting in release of the agent in its active form. These conjugates, when administered to a subject, will accomplish delivery and release of the agent at the target site, and are particularly effective for the in vivo delivery of pharmaceutical agents, antibiotics, antimetabolites, antiproliferative agents and the like as presented in but not limited to those in Table 5. 
     Linkers for Release without Complement Activation: 
     In yet another application of targeted delivery, release of the agent without complement activation is desired since activation of the complement cascade will ultimately lyse the target cell. Hence, this approach is useful when delivery and release of the agent should be accomplished without killing the target cell. Such is the goal when delivery of cell mediators such as hormones, enzymes, corticosteroids, neurotransmitters, genes or enzymes to target cells is desired. These conjugates can be prepared by attaching the agent to an AB that is not capable of activating complement via a linker that is mildly susceptible to cleavage by serum proteases. When this conjugate is administered to an individual, antigen-antibody complexes will form quickly whereas cleavage of the agent will occur slowly, thus resulting in release of the compound at the target site. 
     Biochemical Cross Linkers: 
     In some embodiments, the activatable antibody can be conjugated to one or more therapeutic agents using certain biochemical cross-linkers. Cross-linking reagents form molecular bridges that tie together functional groups of two different molecules. To link two different proteins in a step-wise manner, hetero-bifunctional cross-linkers can be used that eliminate unwanted homopolymer formation. 
     Peptidyl linkers cleavable by lysosomal proteases are also useful, for example, Val-Cit, Val-Ala or other dipeptides. In addition, acid-labile linkers cleavable in the low-pH environment of the lysosome can be used, for example: bis-sialyl ether. Other suitable linkers include cathepsin-labile substrates, particularly those that show optimal function at an acidic pH. 
     Exemplary hetero-bifunctional cross-linkers are referenced in Table 6. 
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 Exemplary Hetero-Bifunctional Cross Linkers 
               
               
                 HETERO-BIFUNCTIONAL CROSS-LINKERS 
               
            
           
           
               
               
               
               
            
               
                   
                   
                   
                 Spacer Arm 
               
               
                   
                   
                   
                 Length after 
               
               
                   
                 Reactive  
                 Advantages and  
                 cross-linking 
               
               
                 Linker 
                 Toward 
                 Applications 
                 (Angstroms) 
               
               
                   
               
               
                 SMPT 
                 Primary amines 
                 Greater stability 
                 11.2 Å 
               
               
                   
                 Sulfhydryls 
                   
                   
               
               
                 SPDP 
                 Primary amines 
                 Thiolation 
                  6.8 Å 
               
               
                   
                 Sulfhydryls 
                 Cleavable cross-linking 
                   
               
               
                 LC- 
                 Primary amines 
                 Extended spacer arm 
                 15.6 Å 
               
               
                 SPDP 
                 Sulfhydryls 
                   
                   
               
               
                 Sulfo- 
                 Primary amines 
                 Extender spacer arm 
                 15.6 Å 
               
               
                 LC- 
                 Sulfhydryls 
                 Water-soluble 
                   
               
               
                 SPDP 
                   
                   
                   
               
               
                 SMCC 
                 Primary amines 
                 Stable maleimide reactive  
                 11.6 Å 
               
               
                   
                   
                 group 
                   
               
               
                   
                 Sulfhydryls 
                 Enzyme-antibody conjugation 
                   
               
               
                   
                   
                 Hapten-carrier protein 
                   
               
               
                   
                   
                 conjugation 
                   
               
               
                 Sulfo- 
                 Primary amines 
                 Stable maleimide reactive  
                 11.6 Å 
               
               
                 SMCC 
                   
                 group 
                   
               
               
                   
                 Sulfhydryls 
                 Water-soluble 
                   
               
               
                   
                   
                 Enzyme-antibody conjugation 
                   
               
               
                 MBS 
                 Primary amines 
                 Enzyme-antibody conjugation 
                  9.9 Å 
               
               
                   
                 Sulfhydryls 
                 Hapten-carrier protein 
                   
               
               
                   
                   
                 conjugation 
                   
               
               
                 Sulfo- 
                 Primary amines 
                 Water-soluble 
                  9.9 Å 
               
               
                 MBS 
                 Sulfhydryls 
                   
                   
               
               
                 SIAB 
                 Primary amines 
                 Enzyme-antibody conjugation 
                 10.6 Å 
               
               
                   
                 Sulfhydryls 
                   
                   
               
               
                 Sulfo- 
                 Primary amines 
                 Water-soluble 
                 10.6 Å 
               
               
                 SIAB 
                 Sulfhydryls 
                   
                   
               
               
                 SMPB 
                 Primary amines 
                 Extended spacer arm 
                 14.5 Å 
               
               
                   
                 Sulfhydryls 
                 Enzyme-antibody conjugation 
                   
               
               
                 Sulfo- 
                 Primary amines 
                 Extended spacer arm 
                 14.5 Å 
               
               
                 SMPB 
                 Sulfhydryls 
                 Water-soluble 
                   
               
               
                 EDE/ 
                 Primary amines 
                 Hapten-Carrier conjugation 
                 0 
               
               
                 Sulfo- 
                 Carboxyl groups 
                   
                   
               
               
                 NHS 
                   
                   
                   
               
               
                 ABH 
                 Carbohydrates 
                 Reacts with sugar groups 
                 11.9 Å 
               
               
                   
                 Nonselective 
               
               
                   
               
            
           
         
       
     
     Non-Cleavable Linkers or Direct Attachment: 
     In some embodiments of the disclosure, the conjugate can be designed so that the agent is delivered to the target but not released. This can be accomplished by attaching an agent to an AB either directly or via a non-cleavable linker. 
     These non-cleavable linkers can include amino acids, peptides, D-amino acids or other organic compounds that can be modified to include functional groups that can subsequently be utilized in attachment to ABs by the methods described herein. A-general formula for such an organic linker could be 
       W—(CH 2 ) n -Q
 
     wherein
 
W is either —NH—CH 2 — or —CH 2 —;
 
Q is an amino acid, peptide; and
 
n is an integer from 0 to 20.
 
     Non-Cleavable Conjugates: 
     In some embodiments, a compound can be attached to ABs that do not activate complement. When using ABs that are incapable of complement activation, this attachment can be accomplished using linkers that are susceptible to cleavage by activated complement or using linkers that are not susceptible to cleavage by activated complement. 
     The antibodies disclosed herein can also be formulated as immunoliposomes. Liposomes containing the antibody are prepared by methods known in the art, such as described in Epstein et al., Proc. Natl. Acad. Sci. USA, 82: 3688 (1985); Hwang et al., Proc. Natl Acad. Sci. USA, 77: 4030 (1980); and U.S. Pat. Nos. 4,485,045 and 4,544,545. Liposomes with enhanced circulation time are disclosed in U.S. Pat. No. 5,013,556. 
     Particularly useful liposomes can be generated by the reverse-phase evaporation method with a lipid composition comprising phosphatidylcholine, cholesterol, and PEG-derivatized phosphatidylethanolamine (PEG-PE). Liposomes are extruded through filters of defined pore size to yield liposomes with the desired diameter. Fab′ fragments of the antibody of the present disclosure can be conjugated to the liposomes as described in Martin et al., J. Biol. Chem., 257: 286-288 (1982) via a disulfide-interchange reaction. 
     Definitions 
     Unless otherwise defined, scientific and technical terms used in connection with the present disclosure shall have the meanings that are commonly understood by those of ordinary skill in the art. The term “a” entity or “an” entity refers to one or more of that entity. For example, a compound refers to one or more compounds. As such, the terms “a”, “an”, “one or more” and “at least one” can be used interchangeably. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. Generally, nomenclatures utilized in connection with, and techniques of, cell and tissue culture, molecular biology, and protein and oligo- or polynucleotide chemistry and hybridization described herein are those well-known and commonly used in the art. Standard techniques are used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection). Enzymatic reactions and purification techniques are performed according to manufacturer&#39;s specifications or as commonly accomplished in the art or as described herein. The foregoing techniques and procedures are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. See e.g., Sambrook et al. Molecular Cloning: A Laboratory Manual (2d ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1989)). The nomenclatures utilized in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well-known and commonly used in the art. Standard techniques are used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients. 
     As utilized in accordance with the present disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings: 
     As used herein, the term “antibody” refers to immunoglobulin molecules and antigen-binding portions of immunoglobulin (Ig) molecules, i.e., molecules that contain an antigen binding site that specifically binds (immunoreacts with) an antigen. By “specifically bind” or “immunoreacts with” or “immunospecifically bind” is meant that the antibody reacts with one or more antigenic determinants of the desired antigen and does not react with other polypeptides or binds at much lower affinity (K d &gt;10 −6 ). Antibodies include, but are not limited to, polyclonal, monoclonal, chimeric, domain antibody, single chain, Fab, and F(ab′) 2  fragments, scFvs, and an Fab expression library. 
     The basic antibody structural unit is known to comprise a tetramer. Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one “light” (about 25 kDa) and one “heavy” chain (about 50-70 kDa). The amino-terminal portion of each chain includes a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The carboxy-terminal portion of each chain defines a constant region primarily responsible for effector function. In general, antibody molecules obtained from humans relate to any of the classes IgG, IgM, IgA, IgE and IgD, which differ from one another by the nature of the heavy chain present in the molecule. Certain classes have subclasses as well, such as IgG 1 , IgG 2 , and others. Furthermore, in humans, the light chain can be a kappa chain or a lambda chain. 
     The term “monoclonal antibody” (mAb) or “monoclonal antibody composition”, as used herein, refers to a population of antibody molecules that contain only one molecular species of antibody molecule consisting of a unique light chain gene product and a unique heavy chain gene product. In particular, the complementarity determining regions (CDRs) of the monoclonal antibody are identical in all the molecules of the population. MAbs contain an antigen binding site capable of immunoreacting with a particular epitope of the antigen characterized by a unique binding affinity for it. 
     The term “antigen-binding site” or “binding portion” refers to the part of the immunoglobulin molecule that participates in antigen binding. The antigen binding site is formed by amino acid residues of the N-terminal variable (“V”) regions of the heavy (“H”) and light (“L”) chains. Three highly divergent stretches within the V regions of the heavy and light chains, referred to as “hypervariable regions,” are interposed between more conserved flanking stretches known as “framework regions,” or “FRs”. Thus, the term “FR” refers to amino acid sequences that are naturally found between, and adjacent to, hypervariable regions in immunoglobulins. In an antibody molecule, the three hypervariable regions of a light chain and the three hypervariable regions of a heavy chain are disposed relative to each other in three dimensional space to form an antigen-binding surface. The antigen-binding surface is complementary to the three-dimensional surface of a bound antigen, and the three hypervariable regions of each of the heavy and light chains are referred to as “complementarity-determining regions,” or “CDRs.” The assignment of amino acids to each domain is in accordance with the definitions of Kabat Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md. (1987 and 1991)), or Chothia &amp; Lesk J. Mol. Biol. 196:901-917 (1987), Chothia et al. Nature 342:878-883 (1989). 
     As used herein, the term “epitope” includes any protein determinant capable of specific binding to an immunoglobulin, an scFv, or a T-cell receptor. The term “epitope” includes any protein determinant capable of specific binding to an immunoglobulin or T-cell receptor. Epitopic determinants usually consist of chemically active surface groupings of molecules such as amino acids or sugar side chains and usually have specific three dimensional structural characteristics, as well as specific charge characteristics. For example, antibodies can be raised against N-terminal or C-terminal peptides of a polypeptide. An antibody is said to specifically bind an antigen when the dissociation constant is ≤1 μM; in some embodiments, ≤100 nM and in some embodiments, ≤10 nM. 
     As used herein, the terms “specific binding,” “immunological binding,” and “immunological binding properties” refer to the non-covalent interactions of the type which occur between an immunoglobulin molecule and an antigen for which the immunoglobulin is specific. The strength, or affinity of immunological binding interactions can be expressed in terms of the dissociation constant (K d ) of the interaction, wherein a smaller K d  represents a greater affinity. Immunological binding properties of selected polypeptides can be quantified using methods well known in the art. One such method entails measuring the rates of antigen-binding site/antigen complex formation and dissociation, wherein those rates depend on the concentrations of the complex partners, the affinity of the interaction, and geometric parameters that equally influence the rate in both directions. Thus, both the “on rate constant” (K on ) and the “off rate constant” (K off ) can be determined by calculation of the concentrations and the actual rates of association and dissociation. (See Nature 361:186-87 (1993)). The ratio of K off /K on  is equal to the dissociation constant K d . (See, generally, Davies et al. (1990) Annual Rev Biochem 59:439-473). An antibody of the present disclosure is said to specifically bind to the target, when the binding constant (K d ) is ≤1 μM, in some embodiments ≤100 nM, in some embodiments 10 nM, and in some embodiments ≤100 μM to about 1 μM, as measured by assays such as radioligand binding assays or similar assays known to those skilled in the art. 
     The term “isolated polynucleotide” as used herein shall mean a polynucleotide of genomic, cDNA, or synthetic origin or some combination thereof, which by virtue of its origin the “isolated polynucleotide” (1) is not associated with all or a portion of a polynucleotide in which the “isolated polynucleotide” is found in nature, (2) is operably linked to a polynucleotide which it is not linked to in nature, or (3) does not occur in nature as part of a larger sequence. Polynucleotides in accordance with the disclosure include the nucleic acid molecules encoding the heavy chain immunoglobulin molecules shown herein, and nucleic acid molecules encoding the light chain immunoglobulin molecules shown herein. 
     The term “isolated protein” referred to herein means a protein of cDNA, recombinant RNA, or synthetic origin or some combination thereof, which by virtue of its origin, or source of derivation, the “isolated protein” (1) is not associated with proteins found in nature, (2) is free of other proteins from the same source, e.g., free of murine proteins, (3) is expressed by a cell from a different species, or (4) does not occur in nature. 
     The term “polypeptide” is used herein as a generic term to refer to native protein, fragments, or analogs of a polypeptide sequence. Hence, native protein fragments, and analogs are species of the polypeptide genus. Polypeptides in accordance with the disclosure comprise the heavy chain immunoglobulin molecules shown herein, and the light chain immunoglobulin molecules shown herein, as well as antibody molecules formed by combinations comprising the heavy chain immunoglobulin molecules with light chain immunoglobulin molecules, such as kappa light chain immunoglobulin molecules, and vice versa, as well as fragments and analogs thereof. 
     The term “naturally-occurring” as used herein as applied to an object refers to the fact that an object can be found in nature. For example, a polypeptide or polynucleotide sequence that is present in an organism (including viruses) that can be isolated from a source in nature and that has not been intentionally modified by man in the laboratory or otherwise is naturally-occurring. 
     The term “operably linked” as used herein refers to positions of components so described are in a relationship permitting them to function in their intended manner. A control sequence “operably linked” to a coding sequence is ligated in such a way that expression of the coding sequence is achieved under conditions compatible with the control sequences. 
     The term “control sequence” as used herein refers to polynucleotide sequences that are necessary to effect the expression and processing of coding sequences to which they are ligated. The nature of such control sequences differs depending upon the host organism in prokaryotes, such control sequences generally include promoter, ribosomal binding site, and transcription termination sequence in eukaryotes, generally, such control sequences include promoters and transcription termination sequence. The term “control sequences” is intended to include, at a minimum, all components whose presence is essential for expression and processing, and can also include additional components whose presence is advantageous, for example, leader sequences and fusion partner sequences. The term “polynucleotide” as referred to herein means nucleotides of at least 10 bases in length, either ribonucleotides or deoxynucleotides or a modified form of either type of nucleotide. The term includes single and double stranded forms of DNA. 
     The term oligonucleotide referred to herein includes naturally occurring, and modified nucleotides linked together by naturally occurring, and non-naturally occurring oligonucleotide linkages. Oligonucleotides are a polynucleotide subset generally comprising a length of 200 bases or fewer. In some embodiments, oligonucleotides are 10 to 60 bases in length and in some embodiments, 12, 13, 14, 15, 16, 17, 18, 19, or 20 to 40 bases in length. Oligonucleotides are usually single stranded, e.g., for probes, although oligonucleotides can be double stranded, e.g., for use in the construction of a gene mutant. Oligonucleotides of the disclosure are either sense or antisense oligonucleotides. 
     The term “naturally occurring nucleotides” referred to herein includes deoxyribonucleotides and ribonucleotides. The term “modified nucleotides” referred to herein includes nucleotides with modified or substituted sugar groups and the like. The term “oligonucleotide linkages” referred to herein includes oligonucleotide linkages such as phosphorothioate, phosphorodithioate, phosphoroselerloate, phosphorodiselenoate, phosphoroanilothioate, phoshoraniladate, phosphoronmidate, and the like. See e.g., LaPlanche et al. Nucl. Acids Res. 14:9081 (1986); Stec et al. J. Am. Chem. Soc. 106:6077 (1984), Stein et al. Nucl. Acids Res. 16:3209 (1988), Zon et al. Anti Cancer Drug Design 6:539 (1991); Zon et al. Oligonucleotides and Analogues: A Practical Approach, pp. 87-108 (F. Eckstein, Ed., Oxford University Press, Oxford England (1991)); Stec et al. U.S. Pat. No. 5,151,510; Uhlmann and Peyman Chemical Reviews 90:543 (1990). An oligonucleotide can include a label for detection, if desired. 
     As used herein, the twenty conventional amino acids and their abbreviations follow conventional usage. See Immunology—A Synthesis (2nd Edition, E. S. Golub and D. R. Green, Eds., Sinauer Associates, Sunderland, Mass. (1991)). Stereoisomers (e.g., D-amino acids) of the twenty conventional amino acids, unnatural amino acids such as α-, α-disubstituted amino acids, N-alkyl amino acids, lactic acid, and other unconventional amino acids can also be suitable components for polypeptides of the present disclosure. Examples of unconventional amino acids include: 4 hydroxyproline, γ-carboxyglutamate, ε-N,N,N-trimethyllysine, ε-N-acetyllysine, O-phosphoserine, N-acetylserine, N-formylmethionine, 3-methylhistidine, 5-hydroxylysine, σ-N-methylarginine, and other similar amino acids and imino acids (e.g., 4-hydroxyproline). In the polypeptide notation used herein, the left-hand direction is the amino terminal direction and the right-hand direction is the carboxy-terminal direction, in accordance with standard usage and convention. 
     Similarly, unless specified otherwise, the left-hand end of single-stranded polynucleotide sequences is the 5′ end the left-hand direction of double-stranded polynucleotide sequences is referred to as the 5′ direction. The direction of 5′ to 3′ addition of nascent RNA transcripts is referred to as the transcription direction sequence regions on the DNA strand having the same sequence as the RNA and that are 5′ to the 5′ end of the RNA transcript are referred to as “upstream sequences”, sequence regions on the DNA strand having the same sequence as the RNA and that are 3′ to the 3′ end of the RNA transcript are referred to as “downstream sequences”. 
     As applied to polypeptides, the term “substantial identity” means that two peptide sequences, when optimally aligned, such as by the programs GAP or BESTFIT using default gap weights, share at least 80 percent sequence identity, in some embodiments, at least 90 percent sequence identity, in some embodiments, at least 95 percent sequence identity, and in some embodiments, at least 99 percent sequence identity. 
     In some embodiments, residue positions that are not identical differ by conservative amino acid substitutions. 
     As discussed herein, minor variations in the amino acid sequences of antibodies or immunoglobulin molecules are contemplated as being encompassed by the present disclosure, providing that the variations in the amino acid sequence maintain at least 75%, in some embodiments, at least 80%, 90%, 95%, and in some embodiments, 99%. In particular, conservative amino acid replacements are contemplated. Conservative replacements are those that take place within a family of amino acids that are related in their side chains. Genetically encoded amino acids are generally divided into families: (1) acidic amino acids are aspartate, glutamate; (2) basic amino acids are lysine, arginine, histidine; (3) non-polar amino acids are alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan, and (4) uncharged polar amino acids are glycine, asparagine, glutamine, cysteine, serine, threonine, tyrosine. The hydrophilic amino acids include arginine, asparagine, aspartate, glutamine, glutamate, histidine, lysine, serine, and threonine. The hydrophobic amino acids include alanine, cysteine, isoleucine, leucine, methionine, phenylalanine, proline, tryptophan, tyrosine and valine. Other families of amino acids include (i) serine and threonine, which are the aliphatic-hydroxy family; (ii) asparagine and glutamine, which are the amide containing family; (iii) alanine, valine, leucine and isoleucine, which are the aliphatic family; and (iv) phenylalanine, tryptophan, and tyrosine, which are the aromatic family. For example, it is reasonable to expect that an isolated replacement of a leucine with an isoleucine or valine, an aspartate with a glutamate, a threonine with a serine, or a similar replacement of an amino acid with a structurally related amino acid will not have a major effect on the binding or properties of the resulting molecule, especially if the replacement does not involve an amino acid within a framework site. Whether an amino acid change results in a functional peptide can readily be determined by assaying the specific activity of the polypeptide derivative. Assays are described in detail herein. Fragments or analogs of antibodies or immunoglobulin molecules can be readily prepared by those of ordinary skill in the art. Suitable amino- and carboxy-termini of fragments or analogs occur near boundaries of functional domains. Structural and functional domains can be identified by comparison of the nucleotide and/or amino acid sequence data to public or proprietary sequence databases. In some embodiments, computerized comparison methods are used to identify sequence motifs or predicted protein conformation domains that occur in other proteins of known structure and/or function. Methods to identify protein sequences that fold into a known three-dimensional structure are known. Bowie et al. Science 253:164 (1991). Thus, the foregoing examples demonstrate that those of skill in the art can recognize sequence motifs and structural conformations that can be used to define structural and functional domains in accordance with the disclosure. 
     Suitable amino acid substitutions are those that: (1) reduce susceptibility to proteolysis, (2) reduce susceptibility to oxidation, (3) alter binding affinity for forming protein complexes, (4) alter binding affinities, and (5) confer or modify other physicochemical or functional properties of such analogs. Analogs can include various muteins of a sequence other than the naturally-occurring peptide sequence. For example, single or multiple amino acid substitutions (for example, conservative amino acid substitutions) can be made in the naturally-occurring sequence (for example, in the portion of the polypeptide outside the domain(s) forming intermolecular contacts. A conservative amino acid substitution should not substantially change the structural characteristics of the parent sequence (e.g., a replacement amino acid should not tend to break a helix that occurs in the parent sequence, or disrupt other types of secondary structure that characterizes the parent sequence). Examples of art-recognized polypeptide secondary and tertiary structures are described in Proteins, Structures and Molecular Principles (Creighton, Ed., W. H. Freeman and Company, New York (1984)); Introduction to Protein Structure (C. Branden and J. Tooze, eds., Garland Publishing, New York, N.Y. (1991)); and Thornton et at. Nature 354:105 (1991). 
     The term “polypeptide fragment” as used herein refers to a polypeptide that has an amino terminal and/or carboxy-terminal deletion and/or one or more internal deletion(s), but where the remaining amino acid sequence is identical to the corresponding positions in the naturally-occurring sequence deduced, for example, from a full length cDNA sequence. Fragments typically are at least 5, 6, 8 or 10 amino acids long, in some embodiments, at least 14 amino acids long, in some embodiments, at least 20 amino acids long, usually at least 50 amino acids long, and in some embodiments, at least 70 amino acids long. The term “analog” as used herein refers to polypeptides that are comprised of a segment of at least 25 amino acids that has substantial identity to a portion of a deduced amino acid sequence and that has specific binding to the target, under suitable binding conditions. Typically, polypeptide analogs comprise a conservative amino acid substitution (or addition or deletion) with respect to the naturally-occurring sequence. Analogs typically are at least 20 amino acids long, in some embodiments, at least 50 amino acids long or longer, and can often be as long as a full-length naturally-occurring polypeptide. 
     The term “agent” is used herein to denote a chemical compound, a mixture of chemical compounds, a biological macromolecule, or an extract made from biological materials. 
     As used herein, the terms “label” or “labeled” refers to incorporation of a detectable marker, e.g., by incorporation of a radiolabeled amino acid or attachment to a polypeptide of biotinyl moieties that can be detected by marked avidin (e.g., streptavidin containing a fluorescent marker or enzymatic activity that can be detected by optical or calorimetric methods). In certain situations, the label or marker can also be therapeutic. Various methods of labeling polypeptides and glycoproteins are known in the art and can be used. Examples of labels for polypeptides include, but are not limited to, the following: radioisotopes  3 H,  14 C,  15 N,  35 S,  90 Y,  99 Tc,  111 In,  125 I,  131 I), or radionuclides (e.g., fluorescent labels (e.g., FITC, rhodamine, lanthanide phosphors), enzymatic labels (e.g., horseradish peroxidase, p-galactosidase, luciferase, alkaline phosphatase), chemiluminescent, biotinyl groups, predetermined polypeptide epitopes recognized by a secondary reporter (e.g., leucine zipper pair sequences, binding sites for secondary antibodies, metal binding domains, epitope tags). In some embodiments, labels are attached by spacer arms of various lengths to reduce potential steric hindrance. The term “pharmaceutical agent or drug” as used herein refers to a chemical compound or composition capable of inducing a desired therapeutic effect when properly administered to a patient. 
     Other chemistry terms herein are used according to conventional usage in the art, as exemplified by The McGraw-Hill Dictionary of Chemical Terms (Parker, S., Ed., McGraw-Hill, San Francisco (1985)). 
     As used herein, “substantially pure” means an object species is the predominant species present (i.e., on a molar basis it is more abundant than any other individual species in the composition), and in some embodiments, a substantially purified fraction is a composition wherein the object species comprises at least about 50 percent (on a molar basis) of all macromolecular species present. 
     Generally, a substantially pure composition will comprise more than about 80 percent of all macromolecular species present in the composition, in some embodiments, more than about 85%, 90%, 95%, and 99%. In some embodiments, the object species is purified to essential homogeneity (contaminant species cannot be detected in the composition by conventional detection methods) wherein the composition consists essentially of a single macromolecular species. 
     The term patient includes human and veterinary subjects. 
     Antibodies and/or activatable antibodies of the disclosure specifically bind a given target, e.g., a human target protein such as human PD-1. Also included in the disclosure are antibodies and/or activatable antibodies that bind to the same epitope as the antibodies and/or activatable antibodies described herein. Also included in the disclosure are antibodies and/or antibodies activatable antibodies that compete with an anti-PD-1 antibody and/or an anti-PD-1 activatable antibody described herein for binding to PD-1, e.g., human PD-1. Also included in the disclosure are antibodies and/or antibodies activatable antibodies that cross-compete with an anti-PD-1 antibody and/or an anti-PD-1 activatable antibody described herein for binding to PD-1, e.g., human PD-1. 
     Those skilled in the art will recognize that it is possible to determine, without undue experimentation, if a monoclonal antibody (e.g., a murine monoclonal or humanized antibody) has the same specificity as a monoclonal antibody used in the methods described herein by ascertaining whether the former prevents the latter from binding to the target. If the monoclonal antibody being tested competes with the monoclonal antibody of the disclosure, as shown by a decrease in binding by the monoclonal antibody of the disclosure, then the two monoclonal antibodies bind to the same, or a closely related, epitope. An alternative method for determining whether a monoclonal antibody has the specificity of a monoclonal antibody of the disclosure is to pre-incubate the monoclonal antibody of the disclosure with the target and then add the monoclonal antibody being tested to determine if the monoclonal antibody being tested is inhibited in its ability to bind the target. If the monoclonal antibody being tested is inhibited then, in all likelihood, it has the same, or functionally equivalent, epitopic specificity as the monoclonal antibody of the disclosure. 
     Multispecific Activatable Antibodies 
     The disclosure also provides multispecific anti-PD-1 activatable antibodies. The multispecific activatable antibodies provided herein are multispecific antibodies that recognize PD-1 and at least one or more different antigens or epitopes and that include at least one masking moiety (MM) linked to at least one antigen- or epitope-binding domain of the multispecific antibody such that coupling of the MM reduces the ability of the antigen- or epitope-binding domain to bind its target. In some embodiments, the MM is coupled to the antigen- or epitope-binding domain of the multispecific antibody via a cleavable moiety (CM) that functions as a substrate for at least one protease. The activatable multispecific antibodies provided herein are stable in circulation, activated at intended sites of therapy and/or diagnosis but not in normal, i.e., healthy tissue, and, when activated, exhibit binding to a target that is at least comparable to the corresponding, unmodified multispecific antibody. 
     In some embodiments, the multispecific activatable antibodies are designed to engage immune effector cells, also referred to herein as immune-effector cell engaging multispecific activatable antibodies. In some embodiments, the multispecific activatable antibodies are designed to engage leukocytes, also referred to herein as leukocyte engaging multispecific activatable antibodies. In some embodiments, the multispecific activatable antibodies are designed to engage T cells, also referred to herein as T-cell engaging multispecific activatable antibodies. In some embodiments, the multispecific activatable antibodies engage a surface antigen on a leukocyte, such as on a T cell, on a natural killer (NK) cell, on a myeloid mononuclear cell, on a macrophage, and/or on another immune effector cell. In some embodiments, the immune effector cell is a leukocyte. In some embodiments, the immune effector cell is a T cell. In some embodiments, the immune effector cell is a NK cell. In some embodiments, the immune effector cell is a mononuclear cell, such as a myeloid mononuclear cell. In some embodiments, the multispecific activatable antibodies are designed to bind or otherwise interact with more than one target and/or more than one epitope, also referred to herein as multi-antigen targeting activatable antibodies. As used herein, the terms “target” and “antigen” are used interchangeably. 
     In some embodiments, immune effector cell engaging multispecific activatable antibodies of the disclosure include a targeting antibody or antigen-binding fragment thereof that binds PD-1 and an immune effector cell engaging antibody or antigen-binding portion thereof, where at least one of the targeting antibody or antigen-binding fragment thereof and/or the immune effector cell engaging antibody or antigen-binding portion thereof is masked. In some embodiments, the immune effector cell engaging antibody or antigen binding fragment thereof includes a first antibody or antigen-binding fragment thereof (AB1) that binds a first, immune effector cell engaging target, where the AB1 is attached to a masking moiety (MM1) such that coupling of the MM1 reduces the ability of the AB1 to bind the first target. In some embodiments, the targeting antibody or antigen-binding fragment thereof includes a second antibody or fragment thereof that includes a second antibody or antigen-binding fragment thereof (AB2) that binds PD-1, where the AB2 is attached to a masking moiety (MM2) such that coupling of the MM2 reduces the ability of the AB2 to bind PD-1. In some embodiments, the immune effector cell engaging antibody or antigen binding fragment thereof includes a first antibody or antigen-binding fragment thereof (AB1) that binds a first, immune effector cell engaging target, where the AB1 is attached to a masking moiety (MM1) such that coupling of the MIMI reduces the ability of the AB1 to bind the first target, and the targeting antibody or antigen-binding fragment thereof includes a second antibody or fragment thereof that includes a second antibody or antigen-binding fragment thereof (AB2) that binds PD-1, where the AB2 is attached to a masking moiety (MM2) such that coupling of the MM2 reduces the ability of the AB2 to bind PD-1. In some embodiments, the non-immune effector cell engaging antibody is a cancer targeting antibody. In some embodiments the non-immune cell effector antibody is an IgG. In some embodiments the immune effector cell engaging antibody is a scFv. In some embodiments the PD-1-targeting antibody (e.g., non-immune cell effector antibody) is an IgG and the immune effector cell engaging antibody is a scFv. In some embodiments, the immune effector cell is a leukocyte. In some embodiments, the immune effector cell is a T cell. In some embodiments, the immune effector cell is a NK cell. In some embodiments, the immune effector cell is a myeloid mononuclear cell. 
     In some embodiments, T-cell engaging multispecific activatable antibodies of the disclosure include a PD-1-targeting antibody or antigen-binding fragment thereof and a T-cell engaging antibody or antigen-binding portion thereof, where at least one of the PD-1-targeting antibody or antigen-binding fragment thereof and/or the T-cell engaging antibody or antigen-binding portion thereof is masked. In some embodiments, the T-cell engaging antibody or antigen binding fragment thereof includes a first antibody or antigen-binding fragment thereof (AB1) that binds a first, T-cell engaging target, where the AB1 is attached to a masking moiety (MM1) such that coupling of the MM1 reduces the ability of the AB1 to bind the first target. In some embodiments, the targeting antibody or antigen-binding fragment thereof includes a second antibody or fragment thereof that includes a second antibody or antigen-binding fragment thereof (AB2) that binds PD-1, where the AB2 is attached to a masking moiety (MM2) such that coupling of the MM2 reduces the ability of the AB2 to bind PD-1. In some embodiments, the T-cell engaging antibody or antigen binding fragment thereof includes a first antibody or antigen-binding fragment thereof (AB1) that binds a first, T-cell engaging target, where the AB1 is attached to a masking moiety (MM1) such that coupling of the MM1 reduces the ability of the AB1 to bind the first target, and the targeting antibody or antigen-binding fragment thereof includes a second antibody or fragment thereof that includes a second antibody or antigen-binding fragment thereof (AB2) that binds PD-1, where the AB2 is attached to a masking moiety (MM2) such that coupling of the MM2 reduces the ability of the AB2 to bind PD-1. 
     In some embodiments of an immune effector cell engaging multispecific activatable antibody, one antigen is PD-1, and another antigen is typically a stimulatory or inhibitory receptor present on the surface of a T-cell, natural killer (NK) cell, myeloid mononuclear cell, macrophage, and/or other immune effector cell, such as, but not limited to, B7-H4, BTLA, CD3, CD4, CD8, CD16a, CD25, CD27, CD28, CD32, CD56, CD137, CTLA-4, GITR, HVEM, ICOS, LAG3, NKG2D, OX40, TIGIT, TIM3, or VISTA. In some embodiments, the antigen is a stimulatory receptor present on the surface of a T cell or NK cell; examples of such stimulatory receptors include, but are not limited to, CD3, CD27, CD28, CD137 (also referred to as 4-1BB), GITR, HVEM, ICOS, NKG2D, and OX40. In some embodiments, the antigen is an inhibitory receptor present on the surface of a T-cell; examples of such inhibitory receptors include, but are not limited to, BTLA, CTLA-4, LAG3, TIGIT, TIM3, and NK-expressed KIRs. The antibody domain conferring specificity to the T-cell surface antigen can also be substituted by a ligand or ligand domain that binds to a T-cell receptor, a NK-cell receptor, a macrophage receptor, and/or other immune effector cell receptor, such as, but not limited to, B7-1, B7-2, B7H3, PDL1, PDL2, or TNFSF9. 
     In some embodiments, the T-cell engaging multispecific activatable antibody includes an anti-CD3 epsilon (CD3ε, also referred to herein as CD3e and CD3) scFv and a targeting antibody or antigen-binding fragment thereof, where at least one of the anti-CD3ε scFv and/or the targeting antibody or antigen-binding portion thereof is masked. In some embodiments, the CD3ε scFv includes a first antibody or antigen-binding fragment thereof (AB1) that binds CD3ε, where the AB1 is attached to a masking moiety (MM1) such that coupling of the MM1 reduces the ability of the AB1 to bind CD3ε. In some embodiments, the targeting antibody or antigen-binding fragment thereof includes a second antibody or fragment thereof that includes a second antibody or antigen-binding fragment thereof (AB2) that binds PD-1, where the AB2 is attached to a masking moiety (MM2) such that coupling of the MM2 reduces the ability of the AB2 to bind PD-1. In some embodiments, the CD3ε scFv includes a first antibody or antigen-binding fragment thereof (AB1) that binds CD3ε, where the AB1 is attached to a masking moiety (MM1) such that coupling of the MM1 reduces the ability of the AB1 to bind CD3ε, and the targeting antibody or antigen-binding fragment thereof includes a second antibody or fragment thereof that includes a second antibody or antigen-binding fragment thereof (AB2) that binds PD-1, where the AB2 is attached to a masking moiety (MM2) such that coupling of the MM2 reduces the ability of the AB2 to bind PD-1. 
     In some embodiments, the multi-antigen targeting antibodies and/or multi-antigen targeting activatable antibodies include at least a first antibody or antigen-binding fragment thereof that binds a first target and/or first epitope and a second antibody or antigen-binding fragment thereof that binds a second target and/or a second epitope. In some embodiments, the multi-antigen targeting antibodies and/or multi-antigen targeting activatable antibodies bind two or more different targets. In some embodiments, the multi-antigen targeting antibodies and/or multi-antigen targeting activatable antibodies bind two or more different epitopes on the same target. In some embodiments, the multi-antigen targeting antibodies and/or multi-antigen targeting activatable antibodies bind a combination of two or more different targets and two or more different epitopes on the same target. 
     In some embodiments, a multispecific activatable antibody comprising an IgG has the IgG variable domains masked. In some embodiments, a multispecific activatable antibody comprising a scFv has the scFv domains masked. In some embodiments, a multispecific activatable antibody has both IgG variable domains and scFv domains, where at least one of the IgG variable domains is coupled to a masking moiety. In some embodiments, a multispecific activatable antibody has both IgG variable domains and scFv domains, where at least one of the scFv domains is coupled to a masking moiety. In some embodiments, a multispecific activatable antibody has both IgG variable domains and scFv domains, where at least one of the IgG variable domains is coupled to a masking moiety and at least one of the scFv domains is coupled to a masking moiety. In some embodiments, a multispecific activatable antibody has both IgG variable domains and scFv domains, where each of the IgG variable domains and the scFv domains is coupled to its own masking moiety. In some embodiments, one antibody domain of a multispecific activatable antibody has specificity for a target antigen and another antibody domain has specificity for a T-cell surface antigen. In some embodiments, one antibody domain of a multispecific activatable antibody has specificity for a target antigen and another antibody domain has specificity for another target antigen. In some embodiments, one antibody domain of a multispecific activatable antibody has specificity for an epitope of a target antigen and another antibody domain has specificity for another epitope of the target antigen. 
     In a multispecific activatable antibody, a scFv can be fused to the carboxyl terminus of the heavy chain of an IgG activatable antibody, to the carboxyl terminus of the light chain of an IgG activatable antibody, or to the carboxyl termini of both the heavy and light chains of an IgG activatable antibody. In a multispecific activatable antibody, a scFv can be fused to the amino terminus of the heavy chain of an IgG activatable antibody, to the amino terminus of the light chain of an IgG activatable antibody, or to the amino termini of both the heavy and light chains of an IgG activatable antibody. In a multispecific activatable antibody, a scFv can be fused to any combination of one or more carboxyl termini and one or more amino termini of an IgG activatable antibody. In some embodiments, a masking moiety (MM) linked to a cleavable moiety (CM) is attached to and masks an antigen binding domain of the IgG. In some embodiments, a masking moiety (MM) linked to a cleavable moiety (CM) is attached to and masks an antigen binding domain of at least one scFv. In some embodiments, a masking moiety (MM) linked to a cleavable moiety (CM) is attached to and masks an antigen binding domain of an IgG and a masking moiety (MM) linked to a cleavable moiety (CM) is attached to and masks an antigen binding domain of at least one scFv. 
     The disclosure provides examples of multispecific activatable antibody structures which include, but are not limited to, the following: (VL-CL) 2 :(VH-CH1-CH2-CH3-L4-VH*-L3-VL*-L2-CM-L1-MM) 2 ; (VL-CL) 2 :(VH-CH1-CH2-CH3-L4-VL*-L3-VH*-L2-CM-L1-MM) 2 ; (MM-L1-CM-L2-VL-CL) 2 :(VH-CH1-CH2-CH3-L4-VH*-L3-VL*) 2 ; (MM-L1-CM-L2-VL-CL) 2 :(VH-CH1-CH2-CH3-L4-VL*-L3-VH*) 2 ; (VL-CL) 2 :(MM-L1-CM-L2-VL*-L3-VH*-L4-VH-CH1-CH2-CH3) 2 ; (VL-CL) 2 :(MM-L1-CM-L2-VH*-L3-VL*-L4-VH-CH1-CH2-CH3) 2 ; (MM-L1-CM-L2-VL-CL) 2 :(VL*-L3-VH*-L4-VH-CH1-CH2-CH3) 2 ; (MM-L1-CM-L2-VL-CL) 2 :(VH*-L3-VL*-L4-VH-CH1-CH2-CH3) 2 ; (VL-CL-L4-VH*-L3-VL*-L2-CM-L1-MM) 2 : (VH-CH1-CH2-CH3) 2 ; (VL-CL-L4-VL*-L3-VH*-L2-CM-L1-MM) 2 : (VH-CH1-CH2-CH3) 2 ; (MM-L1-CM-L2-VL*-L3-VH*-L4-VL-CL) 2 :(VH-CH1-CH2-CH3) 2 ; (MM-L1-CM-L2-VH*-L3-VL*-L4-VL-CL) 2 :(VH-CH1-CH2-CH3) 2 ; (VL-CL-L4-VH*-L3-VL*-L2-CM-L1-MM) 2 : (MM-L1-CM-L2-VL*-L3-VH*-L4-VH-CH1-CH2-CH3) 2 ; (VL-CL-L4-VH*-L3-VL*-L2-CM-L1-MM) 2 : (MM-L1-CM-L2-VH*-L3-VL*-L4-VH-CH1-CH2-CH3) 2 ; (VL-CL-L4-VL*-L3-VH*-L2-CM-L1-MM) 2 : (MM-L1-CM-L2-VL*-L3-VH*-L4-VH-CH1-CH2-CH3) 2 ; (VL-CL-L4-VL*-L3-VH*-L2-CM-L1-MM) 2 : (MM-L1-CM-L2-VH*-L3-VL*-L4-VH-CH1-CH2-CH3) 2 ; (VL-CL-L4-VH*-L3-VL*) 2 : (MM-L1-CM-L2-VL*-L3-VH*-L4-VH-CH1-CH2-CH3) 2 ; (VL-CL-L4-VH*-L3-VL*) 2 : (MM-L1-CM-L2-VH*-L3-VL*-L4-VH-CH1-CH2-CH3) 2 ; (VL-CL-L4-VL*-L3-VH*) 2 : (MM-L1-CM-L2-VL*-L3-VH*-L4-VH-CH1-CH2-CH3) 2 ; (VL-CL-L4-VL*-L3-VH*) 2 : (MM-L1-CM-L2-VH*-L3-VL*-L4-VH-CH1-CH2-CH3) 2 ; (VL-CL-L4-VH*-L3-VL*-L2-CM-L1-MM) 2 : (VL*-L3-VH*-L4-VH-CH1-CH2-CH3) 2 ; (VL-CL-L4-VH*-L3-VL*-L2-CM-L1-MM) 2 : (VH*-L3-VL*-L4-VH-CH1-CH2-CH3) 2 ; (VL-CL-L4-VL*-L3-VH*-L2-CM-L1-MM) 2 : (VL*-L3-VH*-L4-VH-CH1-CH2-CH3) 2 ; or (VL-CL-L4-VL*-L3-VH*-L2-CM-L1-MM) 2 : (VH*-L3-VL*-L4-VH-CH1-CH2-CH3) 2 , wherein: VL and VH represent the light and heavy variable domains of the first specificity, contained in the IgG; VL* and VH* represent the variable domains of the second specificity, contained in the scFv; L1 is a linker peptide connecting the masking moiety (MM) and the cleavable moiety (CM); L2 is a linker peptide connecting the cleavable moiety (CM), and the antibody; L3 is a linker peptide connecting the variable domains of the scFv; L4 is a linker peptide connecting the antibody of the first specificity to the antibody of the second specificity; CL is the light-chain constant domain; and CH1, CH2, CH3 are the heavy chain constant domains. The first and second specificities can be toward any antigen or epitope. 
     In some embodiments of a T-cell engaging multispecific activatable antibody, one antigen is PD-1, and another antigen is typically a stimulatory (also referred to herein as activating) or inhibitory receptor present on the surface of a T-cell, natural killer (NK) cell, myeloid mononuclear cell, macrophage, and/or other immune effector cell, such as, but not limited to, B7-H4, BTLA, CD3, CD4, CD8, CD16a, CD25, CD27, CD28, CD32, CD56, CD137 (also referred to as TNFRSF9), CTLA-4, GITR, HVEM, ICOS, LAG3, NKG2D, OX40, PD-1, TIGIT, TIM3, or VISTA. The antibody domain conferring specificity to the T-cell surface antigen can also be substituted by a ligand or ligand domain that binds to a T-cell receptor, a NK-cell receptor, a macrophage receptor, and/or other immune effector cell receptor. 
     In some embodiments, the targeting antibody is an anti-PD-1 antibody disclosed herein. In some embodiments, the targeting antibody can be in the form an activatable antibody. In some embodiments, the scFv(s) can be in the form of a Pro-scFv (see, e.g., WO 2009/025846, WO 2010/081173). 
     In some embodiments, the scFv is specific for binding CDR, and comprises or is derived from an antibody or fragment thereof that binds CD3ε, e.g., CH2527, FN18, H2C, OKT3, 2C11, UCHT1, or V9. In some embodiments, the scFv is specific for binding CTLA-4 (also referred to herein as CTLA and CTLA4). 
     In some embodiments, the anti-CTLA-4 scFv includes the amino acid sequence: 
     
       
         
           
               
            
               
                 (SEQ ID NO: 585) 
               
               
                 GGGSGGGGSGSGGGSGGGGSGGGEIVLTQSPGTLSLSPGERATLSCRASQ 
               
               
                   
               
               
                 SVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTIS 
               
               
                   
               
               
                 RLEPEDFAVYYCQQYGSSPLTFGGGTKVEIKRSGGSTITSYNVYYTKLSS 
               
               
                   
               
               
                 SGTQVQLVQTGGGVVQPGRSLRLSCAASGSTFSSYAMSWVRQAPGKGLEW 
               
               
                   
               
               
                 VSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCA 
               
               
                   
               
               
                 TNSLYWYFDLWGRGTLVTVSSAS 
               
            
           
         
       
     
     In some embodiments, the anti-CTLA-4 scFv includes the amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to the amino acid sequence of SEQ ID NO: 585. 
     In some embodiments, the anti-CDR scFv includes the amino acid sequence: 
     
       
         
           
               
            
               
                 (SEQ ID NO: 586) 
               
               
                 GGGSGGGGSGSGGGSGGGGSGGGQVQLQQSGAELARPGASVKMSCKASGY 
               
               
                   
               
               
                 TFTRYTMHWVKQRPGQGLEWIGYINPSRGYTNYNQKFKDKATLTTDKSSS 
               
               
                   
               
               
                 TAYMQLSSLTSEDSAVYYCARYYDDHYCLDYWGQGTTLTVSSGGGGSG 
               
               
                   
               
               
                 GGGSGGGGSQIVLTQSPAIMSASPGEKVTMTCSASSSVSYMNWYQQKS 
               
               
                   
               
               
                 GTSPKRWIYDTSKLASGVPAHFRGSGSGTSYSLTISGMEAEDAATYYCQ 
               
               
                   
               
               
                 QWSSNPFTFGSGTKLEINR 
               
            
           
         
       
     
     In some embodiments, the anti-CDR scFv includes the amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to the amino acid sequence of SEQ ID NO: 586. 
     In some embodiments, the scFv is specific for binding one or more T-cells, one or more NK-cells and/or one or more macrophages. In some embodiments, the scFv is specific for binding a target selected from the group consisting of B7-H4, BTLA, CD3, CD4, CD8, CD16a, CD25, CD27, CD28, CD32, CD56, CD137, CTLA-4, GITR, HVEM, ICOS, LAG3, NKG2D, OX40, TIGIT, TIM3, or VISTA. 
     In some embodiments, the multispecific activatable antibody also includes an agent conjugated to the AB. In some embodiments, the agent is a therapeutic agent. In some embodiments, the agent is conjugated to the multispecific activatable antibody via a linker. In some embodiments, the agent is conjugated to the AB via a cleavable linker. In some embodiments, the linker is a non-cleavable linker. 
     In some embodiments, the multispecific activatable antibody also includes a detectable moiety. In some embodiments, the detectable moiety is a diagnostic agent. 
     In some embodiments, the multispecific activatable antibody naturally contains one or more disulfide bonds. In some embodiments, the multispecific activatable antibody can be engineered to include one or more disulfide bonds. 
     The disclosure also provides an isolated nucleic acid molecule encoding a multispecific activatable antibody described herein, as well as vectors that include these isolated nucleic acid sequences. The disclosure provides methods of producing a multispecific activatable antibody by culturing a cell under conditions that lead to expression of the activatable antibody, wherein the cell comprises such a nucleic acid molecule. In some embodiments, the cell comprises such a vector. 
     The disclosure also provides a method of manufacturing multispecific activatable antibodies of the disclosure by (a) culturing a cell comprising a nucleic acid construct that encodes the multispecific activatable antibody under conditions that lead to expression of the multispecific activatable, and (b) recovering the multispecific activatable antibody. Suitable AB, MM, and/or CM include any of the AB, MM, and/or CM disclosed herein. 
     The disclosure also provides multispecific activatable antibodies and/or multispecific activatable antibody compositions that include at least a first antibody or antigen-binding fragment thereof (AB1) that specifically binds a first target or first epitope and a second antibody or antigen-biding fragment thereof (AB2) that binds a second target or a second epitope, where at least AB1 is coupled or otherwise attached to a masking moiety (MM1), such that coupling of the MM1 reduces the ability of AB1 to bind its target. In some embodiments, the MM1 is coupled to AB1 via a first cleavable moiety (CM1) sequence that includes a substrate for a protease, for example, a protease that is co-localized with the target of AB1 at a treatment site or a diagnostic site in a subject. The multispecific activatable antibodies provided herein are stable in circulation, activated at intended sites of therapy and/or diagnosis but not in normal, i.e., healthy tissue, and, when activated, exhibit binding to the target of AB1 that is at least comparable to the corresponding, unmodified multispecific antibody. Suitable AB, MM, and/or CM include any of the AB, MM, and/or CM disclosed herein. 
     The disclosure also provides compositions and methods that include a multispecific activatable antibody that includes at least a first antibody or antibody fragment (AB1) that specifically binds a target and a second antibody or antibody fragment (AB2), where at least the first AB in the multispecific activatable antibody is coupled to a masking moiety (MM1) that decreases the ability of AB1 to bind its target. In some embodiments, each AB is coupled to a MM that decreases the ability of its corresponding AB to each target. For example, in bispecific activatable antibody embodiments, AB1 is coupled to a first masking moiety (MM1) that decreases the ability of AB1 to bind its target, and AB2 is coupled to a second masking moiety (MM2) that decreases the ability of AB2 to bind its target. In some embodiments, the multispecific activatable antibody comprises more than two AB regions; in such embodiments, AB1 is coupled to a first masking moiety (MM1) that decreases the ability of AB1 to bind its target, AB2 is coupled to a second masking moiety (MM2) that decreases the ability of AB2 to bind its target, AB3 is coupled to a third masking moiety (MM3) that decreases the ability of AB3 to bind its target, and so on for each AB in the multispecific activatable antibody. Suitable AB, MM, and/or CM include any of the AB, MM, and/or CM disclosed herein. 
     In some embodiments, the multispecific activatable antibody further includes at least one cleavable moiety (CM) that is a substrate for a protease, where the CM links a MM to an AB. For example, in some embodiments, the multispecific activatable antibody includes at least a first antibody or antibody fragment (AB1) that specifically binds a target and a second antibody or antibody fragment (AB2), where at least the first AB in the multispecific activatable antibody is coupled via a first cleavable moiety (CM1) to a masking moiety (MM1) that decreases the ability of AB1 to bind its target. In some bispecific activatable antibody embodiments, AB1 is coupled via CM1 to MM1, and AB2 is coupled via a second cleavable moiety (CM2) to a second masking moiety (MM2) that decreases the ability of AB2 to bind its target. In some embodiments, the multispecific activatable antibody comprises more than two AB regions; in some of these embodiments, AB1 is coupled via CM1 to MM1, AB2 is coupled via CM2 to MM2, and AB3 is coupled via a third cleavable moiety (CM3) to a third masking moiety (MM3) that decreases the ability of AB3 to bind its target, and so on for each AB in the multispecific activatable antibody. Suitable AB, MM, and/or CM include any of the AB, MM, and/or CM disclosed herein. 
     Activatable Antibodies Having Non-Binding Steric Moieties or Binding Partners for Non-Binding Steric Moieties 
     The disclosure also provides activatable antibodies that include non-binding steric moieties (NB) or binding partners (BP) for non-binding steric moieties, where the BP recruits or otherwise attracts the NB to the activatable antibody. The activatable antibodies provided herein include, for example, an activatable antibody that includes a non-binding steric moiety (NB), a cleavable linker (CL) and antibody or antibody fragment (AB) that binds a target; an activatable antibody that includes a binding partner for a non-binding steric moiety (BP), a CL and an AB; and an activatable antibody that includes a BP to which an NB has been recruited, a CL and an AB that binds the target. Activatable antibodies in which the NB is covalently linked to the CL and AB of the activatable antibody or is associated by interaction with a BP that is covalently linked to the CL and AB of the activatable antibody are referred to herein as “NB-containing activatable antibodies.” By activatable or switchable is meant that the activatable antibody exhibits a first level of binding to a target when the activatable antibody is in an inhibited, masked or uncleaved state (i.e., a first conformation), and a second level of binding to the target when the activatable antibody is in an uninhibited, unmasked and/or cleaved state (i.e., a second conformation, i.e., activated antibody), where the second level of target binding is greater than the first level of target binding. The activatable antibody compositions can exhibit increased bioavailability and more favorable biodistribution compared to conventional antibody therapeutics. 
     In some embodiments, activatable antibodies provide for reduced toxicity and/or adverse side effects that could otherwise result from binding of the at non-treatment sites and/or non-diagnostic sites if the AB were not masked or otherwise inhibited from binding to such a site. 
     Anti-PD-1 activatable antibodies that include a non-binding steric moiety (NB) can be made using the methods set forth in PCT Publication No. WO 2013/192546, the contents of which are hereby incorporated by reference in their entirety. 
     Use of Antibodies and Activatable Antibodies 
     It will be appreciated that administration of therapeutic entities in accordance with the disclosure will be administered with suitable carriers, excipients, and other agents that are incorporated into formulations to provide improved transfer, delivery, tolerance, and the like. A multitude of appropriate formulations can be found in the formulary known to all pharmaceutical chemists: Remington&#39;s Pharmaceutical Sciences (15th ed, Mack Publishing Company, Easton, Pa. (1975)), particularly Chapter 87 by Blaug, Seymour, therein. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (such as Lipofectin™), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. Any of the foregoing mixtures can be appropriate in treatments and therapies in accordance with the present disclosure, provided that the active ingredient in the formulation is not inactivated by the formulation and the formulation is physiologically compatible and tolerable with the route of administration. See also Baldrick P. “Pharmaceutical excipient development: the need for preclinical guidance.” Regul. Toxicol Pharmacol. 32(2):210-8 (2000), Wang W. “Lyophilization and development of solid protein pharmaceuticals.” Int. J. Pharm. 203(1-2):1-60 (2000), Charman W N “Lipids, lipophilic drugs, and oral drug delivery-some emerging concepts.” J Pharm Sci. 89(8):967-78 (2000), Powell et al. “Compendium of excipients for parenteral formulations” PDA J Pharm Sci Technol. 52:238-311 (1998) and the citations therein for additional information related to formulations, excipients and carriers well known to pharmaceutical chemists. 
     Therapeutic formulations of the disclosure, which include an anti-PD-1 antibody and/or activatable anti-PD-1 antibody, such as by way of non-limiting example, an antibody and/or an activatable antibody, are used to prevent, treat or otherwise ameliorate a disease or disorder associated with aberrant target expression and/or activity. For example, therapeutic formulations of the disclosure, which include an antibody and/or an activatable antibody, are used to treat or otherwise ameliorate a cancer or other neoplastic condition, inflammation, an inflammatory disorder, and/or an autoimmune disease. In some embodiments, the cancer is a solid tumor or a hematologic malignancy where the target is expressed. In some embodiments, the cancer is a solid tumor where the target is expressed. In some embodiments, the cancer is a hematologic malignancy where the target is expressed. In some embodiments, the target is expressed on parenchyma (e.g., in cancer, the portion of an organ or tissue that often carries out function(s) of the organ or tissue). In some embodiments, the target is expressed on a cell, tissue, or organ. In some embodiments, the target is expressed on stroma (i.e., the connective supportive framework of a cell, tissue, or organ). In some embodiments, the target is expressed on an osteoblast. In some embodiments, the target is expressed on the endothelium (vasculature). In some embodiments, the target is expressed on a cancer stem cell. 
     Efficaciousness of prevention, amelioration or treatment is determined in association with any known method for diagnosing or treating the disease or disorder associated with target expression and/or activity, such as, for example, aberrant target expression and/or activity. Prolonging the survival of a subject or otherwise delaying the progression of the disease or disorder associated with target expression and/or activity, e.g., aberrant target expression and/or activity, in a subject indicates that the antibody and/or activatable antibody confers a clinical benefit. 
     An antibody and/or an activatable antibody can be administered in the form of pharmaceutical compositions. Principles and considerations involved in preparing such compositions, as well as guidance in the choice of components are provided, for example, in Remington: The Science And Practice Of Pharmacy 19th ed. (Alfonso R. Gennaro, et al., editors) Mack Pub. Co., Easton, Pa.: 1995; Drug Absorption Enhancement: Concepts, Possibilities, Limitations, And Trends, Harwood Academic Publishers, Langhorne, Pa., 1994; and Peptide And Protein Drug Delivery (Advances In Parenteral Sciences, Vol. 4), 1991, M. Dekker, New York. 
     In some embodiments where antibody fragments are used, the smallest fragment that specifically binds to the binding domain of the target protein is selected. For example, based upon the variable-region sequences of an antibody, peptide molecules can be designed that retain the ability to bind the target protein sequence. Such peptides can be synthesized chemically and/or produced by recombinant DNA technology. (See, e.g., Marasco et al., Proc. Natl. Acad. Sci. USA, 90: 7889-7893 (1993)). The formulation can also contain more than one active compounds as necessary for the particular indication being treated, for example, in some embodiments, those with complementary activities that do not adversely affect each other. In some embodiments, or in addition, the composition can comprise an agent that enhances its function, such as, for example, a cytotoxic agent, cytokine, chemotherapeutic agent, or growth-inhibitory agent. Such molecules are suitably present in combination in amounts that are effective for the purpose intended. 
     The active ingredients can also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles, and nanocapsules) or in macroemulsions. 
     The formulations to be used for in vivo administration must be sterile. This is readily accomplished by filtration through sterile filtration membranes. 
     Sustained-release preparations can be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and γ ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(−)-3-hydroxybutyric acid. While polymers such as ethylene-vinyl acetate and lactic acid-glycolic acid enable release of molecules for over 100 days, certain hydrogels release proteins for shorter time periods. 
     In some embodiments, the antibody and/or activatable antibody contains a detectable label. An intact antibody, or a fragment thereof (e.g., Fab, scFv, or F(ab) 2 ) is used. The term “labeled”, with regard to the probe or antibody, is intended to encompass direct labeling of the probe or antibody by coupling (i.e., physically linking) a detectable substance to the probe or antibody, as well as indirect labeling of the probe or antibody by reactivity with another reagent that is directly labeled. Examples of indirect labeling include detection of a primary antibody using a fluorescently-labeled secondary antibody and end-labeling of a DNA probe with biotin such that it can be detected with fluorescently-labeled streptavidin. The term “biological sample” is intended to include tissues, cells and biological fluids isolated from a subject, as well as tissues, cells and fluids present within a subject. Included within the usage of the term “biological sample”, therefore, is blood and a fraction or component of blood including blood serum, blood plasma, or lymph. That is, the detection method of the disclosure can be used to detect an analyte mRNA, protein, or genomic DNA in a biological sample in vitro as well as in vivo. For example, in vitro techniques for detection of an analyte mRNA include Northern hybridizations and in situ hybridizations. In vitro techniques for detection of an analyte protein include enzyme linked immunosorbent assays (ELISAs), Western blots, immunoprecipitations, immunochemical staining, and immunofluorescence. In vitro techniques for detection of an analyte genomic DNA include Southern hybridizations. Procedures for conducting immunoassays are described, for example in “ELISA: Theory and Practice: Methods in Molecular Biology”, Vol. 42, J. R. Crowther (Ed.) Human Press, Totowa, N.J., 1995; “Immunoassay”, E. Diamandis and T. Christopoulus, Academic Press, Inc., San Diego, Calif., 1996; and “Practice and Theory of Enzyme Immunoassays”, P. Tijssen, Elsevier Science Publishers, Amsterdam, 1985. Furthermore, in vivo techniques for detection of an analyte protein include introducing into a subject a labeled anti-analyte protein antibody. For example, the antibody can be labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques. 
     The antibodies and/or activatable antibodies of the disclosure are also useful in a variety of diagnostic and prophylactic formulations. In one embodiment, an antibody and/or an activatable antibody is administered to patients that are at risk of developing one or more of the aforementioned disorders. A patient&#39;s or organ&#39;s predisposition to one or more of the aforementioned disorders can be determined using genotypic, serological or biochemical markers. 
     In some embodiments of the disclosure, an antibody and/or an activatable antibody is administered to human individuals diagnosed with a clinical indication associated with one or more of the aforementioned disorders. Upon diagnosis, an antibody and/or an activatable antibody is administered to mitigate or reverse the effects of the clinical indication. 
     An antibody and/or an activatable antibody of the disclosure is also useful in the detection of a target in patient samples and accordingly are useful as diagnostics. For example, the antibodies and/or activatable antibodies, and conjugated versions thereof, of the disclosure are used in in vitro assays, e.g., ELISA, to detect target levels in a patient sample. 
     In some embodiments, anti-PDL1 antibodies are used as a diagnostic for patients who are more likely to respond favorably to treatment with an anti-PD-1 antibody and/or activatable antibody of the disclosure. In these embodiments, PD-L1 expression in tumor biopsies on both tumor cells and infiltrating immune cells and PD-L1 expression on immune cells in blood are used to indicate the presence of active immunity and, thus, potential for suppression of T cell activity through the engagement of PD-1 by PD-L1. 
     In one embodiment, an antibody, a conjugated antibody, an activatable antibody and/or a conjugated activatable antibody of the disclosure is immobilized on a solid support (e.g., the well(s) of a microtiter plate). The immobilized antibody, conjugated antibody, activatable antibody and/or conjugated activatable antibody serves as a capture antibody for any target that can be present in a test sample. Prior to contacting the immobilized antibody and/or activatable antibody, and/or conjugated versions thereof, with a patient sample, the solid support is rinsed and treated with a blocking agent such as milk protein or albumin to prevent nonspecific adsorption of the analyte. 
     Subsequently the wells are treated with a test sample suspected of containing the antigen, or with a solution containing a standard amount of the antigen. Such a sample is, e.g., a serum sample from a subject suspected of having levels of circulating antigen considered to be diagnostic of a pathology. After rinsing away the test sample or standard, the solid support is treated with a second antibody that is detectably labeled. The labeled second antibody serves as a detecting antibody. The level of detectable label is measured, and the concentration of target antigen in the test sample is determined by comparison with a standard curve developed from the standard samples. 
     It will be appreciated that based on the results obtained using the antibodies and activatable antibodies of the disclosure, and conjugated versions thereof, in an in vitro diagnostic assay, it is possible to stage a disease in a subject based on expression levels of the target antigen. For a given disease, samples of blood are taken from subjects diagnosed as being at various stages in the progression of the disease, and/or at various points in the therapeutic treatment of the disease. Using a population of samples that provides statistically significant results for each stage of progression or therapy, a range of concentrations of the antigen that can be considered characteristic of each stage is designated. 
     An antibody, a conjugated antibody, an activatable antibody and/or a conjugated activatable antibody can also be used in diagnostic and/or imaging methods. In some embodiments, such methods are in vitro methods. In some embodiments, such methods are in vivo methods. In some embodiments, such methods are in situ methods. In some embodiments, such methods are ex vivo methods. For example, activatable antibodies having an enzymatically cleavable CM can be used to detect the presence or absence of an enzyme that is capable of cleaving the CM. Such activatable antibodies can be used in diagnostics, which can include in vivo detection (e.g., qualitative or quantitative) of enzyme activity (or, in some embodiments, an environment of increased reduction potential such as that which can provide for reduction of a disulfide bond) through measured accumulation of activated antibodies (i.e., antibodies resulting from cleavage of an activatable antibody) in a given cell or tissue of a given host organism. Such accumulation of activated antibodies indicates not only that the tissue expresses enzymatic activity (or an increased reduction potential depending on the nature of the CM) but also that the tissue expresses target to which the activated antibody binds. 
     For example, the CM can be selected to be substrate for at least one protease found at the site of a tumor, at the site of a viral or bacterial infection at a biologically confined site (e.g., such as in an abscess, in an organ, and the like), and the like. The AB can be one that binds a target antigen. Using methods as disclosed herein, or when appropriate, methods familiar to one skilled in the art, a detectable label (e.g., a fluorescent label or radioactive label or radiotracer) can be conjugated to an AB or other region of an antibody and/or activatable antibody. Suitable detectable labels are discussed in the context of the above screening methods and additional specific examples are provided below. Using an AB specific to a protein or peptide of the disease state, along with at least one protease whose activity is elevated in the disease tissue of interest, activatable antibodies will exhibit an increased rate of binding to disease tissue relative to tissues where the CM specific enzyme is not present at a detectable level or is present at a lower level than in disease tissue or is inactive (e.g., in zymogen form or in complex with an inhibitor). Since small proteins and peptides are rapidly cleared from the blood by the renal filtration system, and because the enzyme specific for the CM is not present at a detectable level (or is present at lower levels in non-disease tissues or is present in inactive conformation), accumulation of activated antibodies in the disease tissue is enhanced relative to non-disease tissues. 
     In another example, activatable antibodies can be used to detect the presence or absence of a cleaving agent in a sample. For example, where the activatable antibodies contain a CM susceptible to cleavage by an enzyme, the activatable antibodies can be used to detect (either qualitatively or quantitatively) the presence of an enzyme in the sample. In another example, where the activatable antibodies contain a CM susceptible to cleavage by reducing agent, the activatable antibodies can be used to detect (either qualitatively or quantitatively) the presence of reducing conditions in a sample. To facilitate analysis in these methods, the activatable antibodies can be detectably labeled, and can be bound to a support (e.g., a solid support, such as a slide or bead). The detectable label can be positioned on a portion of the activatable antibody that is not released following cleavage, for example, the detectable label can be a quenched fluorescent label or other label that is not detectable until cleavage has occurred. The assay can be conducted by, for example, contacting the immobilized, detectably labeled activatable antibodies with a sample suspected of containing an enzyme and/or reducing agent for a time sufficient for cleavage to occur, then washing to remove excess sample and contaminants. The presence or absence of the cleaving agent (e.g., enzyme or reducing agent) in the sample is then assessed by a change in detectable signal of the activatable antibodies prior to contacting with the sample e.g., the presence of and/or an increase in detectable signal due to cleavage of the activatable antibody by the cleaving agent in the sample. 
     Such detection methods can be adapted to also provide for detection of the presence or absence of a target that is capable of binding the AB of the activatable antibodies when cleaved. Thus, the assays can be adapted to assess the presence or absence of a cleaving agent and the presence or absence of a target of interest. The presence or absence of the cleaving agent can be detected by the presence of and/or an increase in detectable label of the activatable antibodies as described above, and the presence or absence of the target can be detected by detection of a target-AB complex e.g., by use of a detectably labeled anti-target antibody. 
     Activatable antibodies are also useful in in situ imaging for the validation of activatable antibody activation, e.g., by protease cleavage, and binding to a particular target. In situ imaging is a technique that enables localization of proteolytic activity and target in biological samples such as cell cultures or tissue sections. Using this technique, it is possible to confirm both binding to a given target and proteolytic activity based on the presence of a detectable label (e.g., a fluorescent label). 
     These techniques are useful with any frozen cells or tissue derived from a disease site (e.g. tumor tissue) or healthy tissues. These techniques are also useful with fresh cell or tissue samples. 
     In these techniques, an activatable antibody is labeled with a detectable label. The detectable label can be a fluorescent dye, (e.g. a fluorophore, Fluorescein Isothiocyanate (FITC), Rhodamine Isothiocyanate (TRITC), an Alexa Fluor® label), a near infrared (NIR) dye (e.g., Qdot® nanocrystals), a colloidal metal, a hapten, a radioactive marker, biotin and an amplification reagent such as streptavidin, or an enzyme (e.g. horseradish peroxidase or alkaline phosphatase). 
     Detection of the label in a sample that has been incubated with the labeled, activatable antibody indicates that the sample contains the target and contains a protease that is specific for the CM of the activatable antibody. In some embodiments, the presence of the protease can be confirmed using broad spectrum protease inhibitors such as those described herein, and/or by using an agent that is specific for the protease, for example, an antibody such as A11, which is specific for the protease matriptase and inhibits the proteolytic activity of matriptase; see e.g., International Publication Number WO 2010/129609, published 11 Nov. 2010. The same approach of using broad spectrum protease inhibitors such as those described herein, and/or by using a more selective inhibitory agent can be used to identify a protease that is specific for the CM of the activatable antibody. In some embodiments, the presence of the target can be confirmed using an agent that is specific for the target, e.g., another antibody, or the detectable label can be competed with unlabeled target. In some embodiments, unlabeled activatable antibody could be used, with detection by a labeled secondary antibody or more complex detection system. 
     Similar techniques are also useful for in vivo imaging where detection of the fluorescent signal in a subject, e.g., a mammal, including a human, indicates that the disease site contains the target and contains a protease that is specific for the CM of the activatable antibody. 
     These techniques are also useful in kits and/or as reagents for the detection, identification or characterization of protease activity in a variety of cells, tissues, and organisms based on the protease-specific CM in the activatable antibody. 
     The disclosure provides methods of using the antibodies and/or activatable antibodies in a variety of diagnostic and/or prophylactic indications. For example, the disclosure provides methods of detecting presence or absence of a cleaving agent and a target of interest in a subject or a sample by (i) contacting a subject or sample with an activatable antibody, wherein the activatable antibody comprises a masking moiety (MM), a cleavable moiety (CM) that is cleaved by the cleaving agent, e.g., a protease, and an antigen binding domain or fragment thereof (AB) that specifically binds the target of interest, wherein the activatable antibody in an uncleaved, non-activated state comprises a structural arrangement from N-terminus to C-terminus as follows: MM-CM-AB or AB-CM-MM; (a) wherein the MM is a peptide that inhibits binding of the AB to the target, and wherein the MM does not have an amino acid sequence of a naturally occurring binding partner of the AB and is not a modified form of a natural binding partner of the AB; and (b) wherein, in an uncleaved, non-activated state, the MM interferes with specific binding of the AB to the target, and in a cleaved, activated state the MM does not interfere or compete with specific binding of the AB to the target; and (ii) measuring a level of activated activatable antibody in the subject or sample, wherein a detectable level of activated activatable antibody in the subject or sample indicates that the cleaving agent and the target are present in the subject or sample and wherein no detectable level of activated activatable antibody in the subject or sample indicates that the cleaving agent, the target or both the cleaving agent and the target are absent and/or not sufficiently present in the subject or sample. In some embodiments, the activatable antibody is an activatable antibody to which a therapeutic agent is conjugated. In some embodiments, the activatable antibody is not conjugated to an agent. In some embodiments, the activatable antibody comprises a detectable label. In some embodiments, the detectable label is positioned on the AB. In some embodiments, measuring the level of activatable antibody in the subject or sample is accomplished using a secondary reagent that specifically binds to the activated antibody, wherein the reagent comprises a detectable label. In some embodiments, the secondary reagent is an antibody comprising a detectable label. 
     The disclosure also provides methods of detecting presence or absence of a cleaving agent in a subject or a sample by (i) contacting a subject or sample with an activatable antibody in the presence of a target of interest, e.g., the target, wherein the activatable antibody comprises a masking moiety (MM), a cleavable moiety (CM) that is cleaved by the cleaving agent, e.g., a protease, and an antigen binding domain or fragment thereof (AB) that specifically binds the target of interest, wherein the activatable antibody in an uncleaved, non-activated state comprises a structural arrangement from N-terminus to C-terminus as follows: MM-CM-AB or AB-CM-MM; (a) wherein the MM is a peptide that inhibits binding of the AB to the target, and wherein the MM does not have an amino acid sequence of a naturally occurring binding partner of the AB and is not a modified form of a natural binding partner of the AB; and (b) wherein, in an uncleaved, non-activated state, the MM interferes with specific binding of the AB to the target, and in a cleaved, activated state the MM does not interfere or compete with specific binding of the AB to the target; and (ii) measuring a level of activated activatable antibody in the subject or sample, wherein a detectable level of activated activatable antibody in the subject or sample indicates that the cleaving agent is present in the subject or sample and wherein no detectable level of activated activatable antibody in the subject or sample indicates that the cleaving agent is absent and/or not sufficiently present in the subject or sample. In some embodiments, the activatable antibody is an activatable antibody to which a therapeutic agent is conjugated. In some embodiments, the activatable antibody is not conjugated to an agent. In some embodiments, the activatable antibody comprises a detectable label. In some embodiments, the detectable label is positioned on the AB. In some embodiments, measuring the level of activatable antibody in the subject or sample is accomplished using a secondary reagent that specifically binds to the activated antibody, wherein the reagent comprises a detectable label. In some embodiments, the secondary reagent is an antibody comprising a detectable label. 
     The disclosure also provides kits for use in methods of detecting presence or absence of a cleaving agent and the target in a subject or a sample, where the kits include at least an activatable antibody comprises a masking moiety (MM), a cleavable moiety (CM) that is cleaved by the cleaving agent, e.g., a protease, and an antigen binding domain or fragment thereof (AB) that specifically binds the target of interest, wherein the activatable antibody in an uncleaved, non-activated state comprises a structural arrangement from N-terminus to C-terminus as follows: MM-CM-AB or AB-CM-MM; (a) wherein the MM is a peptide that inhibits binding of the AB to the target, and wherein the MM does not have an amino acid sequence of a naturally occurring binding partner of the AB and is not a modified form of a natural binding partner of the AB; and (b) wherein, in an uncleaved, non-activated state, the MM interferes with specific binding of the AB to the target, and in a cleaved, activated state the MM does not interfere or compete with specific binding of the AB to the target; and (ii) measuring a level of activated activatable antibody in the subject or sample, wherein a detectable level of activated activatable antibody in the subject or sample indicates that the cleaving agent is present in the subject or sample and wherein no detectable level of activated activatable antibody in the subject or sample indicates that the cleaving agent is absent and/or not sufficiently present in the subject or sample. In some embodiments, the activatable antibody is an activatable antibody to which a therapeutic agent is conjugated. In some embodiments, the activatable antibody is not conjugated to an agent. In some embodiments, the activatable antibody comprises a detectable label. In some embodiments, the detectable label is positioned on the AB. In some embodiments, measuring the level of activatable antibody in the subject or sample is accomplished using a secondary reagent that specifically binds to the activated antibody, wherein the reagent comprises a detectable label. In some embodiments, the secondary reagent is an antibody comprising a detectable label. 
     The disclosure also provides methods of detecting presence or absence of a cleaving agent in a subject or a sample by (i) contacting a subject or sample with an activatable antibody, wherein the activatable antibody comprises a masking moiety (MM), a cleavable moiety (CM) that is cleaved by the cleaving agent, e.g., a protease, an antigen binding domain (AB) that specifically binds the target, and a detectable label, wherein the activatable antibody in an uncleaved, non-activated state comprises a structural arrangement from N-terminus to C-terminus as follows: MM-CM-AB or AB-CM-MM; wherein the MM is a peptide that inhibits binding of the AB to the target, and wherein the MM does not have an amino acid sequence of a naturally occurring binding partner of the AB and is not a modified form of a natural binding partner of the AB; wherein, in an uncleaved, non-activated state, the MM interferes with specific binding of the AB to the target, and in a cleaved, activated state the MM does not interfere or compete with specific binding of the AB to the target; and wherein the detectable label is positioned on a portion of the activatable antibody that is released following cleavage of the CM; and (ii) measuring a level of detectable label in the subject or sample, wherein a detectable level of the detectable label in the subject or sample indicates that the cleaving agent is absent and/or not sufficiently present in the subject or sample and wherein no detectable level of the detectable label in the subject or sample indicates that the cleaving agent is present in the subject or sample. In some embodiments, the activatable antibody is an activatable antibody to which a therapeutic agent is conjugated. In some embodiments, the activatable antibody is not conjugated to an agent. In some embodiments, the activatable antibody comprises a detectable label. In some embodiments, the detectable label is positioned on the AB. In some embodiments, measuring the level of activatable antibody in the subject or sample is accomplished using a secondary reagent that specifically binds to the activated antibody, wherein the reagent comprises a detectable label. In some embodiments, the secondary reagent is an antibody comprising a detectable label. 
     The disclosure also provides kits for use in methods of detecting presence or absence of a cleaving agent and the target in a subject or a sample, where the kits include at least an activatable antibody and/or conjugated activatable antibody (e.g., an activatable antibody to which a therapeutic agent is conjugated) described herein for use in contacting a subject or biological sample and means for detecting the level of activated activatable antibody and/or conjugated activatable antibody in the subject or biological sample, wherein a detectable level of activated activatable antibody in the subject or biological sample indicates that the cleaving agent and the target are present in the subject or biological sample and wherein no detectable level of activated activatable antibody in the subject or biological sample indicates that the cleaving agent, the target or both the cleaving agent and the target are absent and/or not sufficiently present in the subject or biological sample, such that the target binding and/or protease cleavage of the activatable antibody cannot be detected in the subject or biological sample. 
     The disclosure also provides methods of detecting presence or absence of a cleaving agent in a subject or a sample by (i) contacting a subject or biological sample with an activatable antibody in the presence of the target, and (ii) measuring a level of activated activatable antibody in the subject or biological sample, wherein a detectable level of activated activatable antibody in the subject or biological sample indicates that the cleaving agent is present in the subject or biological sample and wherein no detectable level of activated activatable antibody in the subject or biological sample indicates that the cleaving agent is absent and/or not sufficiently present in the subject or biological sample at a detectable level, such that protease cleavage of the activatable antibody cannot be detected in the subject or biological sample. Such an activatable antibody includes a masking moiety (MM), a cleavable moiety (CM) that is cleaved by the cleaving agent, e.g., a protease, and an antigen binding domain or fragment thereof (AB) that specifically binds the target, wherein the activatable antibody in an uncleaved (i.e., non-activated) state comprises a structural arrangement from N-terminus to C-terminus as follows: MM-CM-AB or AB-CM-MM; (a) wherein the MM is a peptide that inhibits binding of the AB to the target, and wherein the MM does not have an amino acid sequence of a naturally occurring binding partner of the AB; and (b) wherein the MM of the activatable antibody in an uncleaved state interferes with specific binding of the AB to the target, and wherein the MM of an activatable antibody in a cleaved (i.e., activated) state does not interfere or compete with specific binding of the AB to the target. In some embodiments, the activatable antibody is an activatable antibody to which a therapeutic agent is conjugated. In some embodiments, the activatable antibody is not conjugated to an agent. In some embodiments, the detectable label is attached to the masking moiety. In some embodiments, the detectable label is attached to the cleavable moiety N-terminal to the protease cleavage site. In some embodiments, a single antigen binding site of the AB is masked. In some embodiments wherein an antibody of the disclosure has at least two antigen binding sites, at least one antigen binding site is masked and at least one antigen binding site is not masked. In some embodiments all antigen binding sites are masked. In some embodiments, the measuring step includes use of a secondary reagent comprising a detectable label. 
     The disclosure also provides kits for use in methods of detecting presence or absence of a cleaving agent and the target in a subject or a sample, where the kits include at least an activatable antibody and/or conjugated activatable antibody described herein for use in contacting a subject or biological sample with an activatable antibody in the presence of the target, and measuring a level of activated activatable antibody in the subject or biological sample, wherein a detectable level of activated activatable antibody in the subject or biological sample indicates that the cleaving agent is present in the subject or biological sample and wherein no detectable level of activated activatable antibody in the subject or biological sample indicates that the cleaving agent is absent and/or not sufficiently present in the subject or biological sample at a detectable level, such that protease cleavage of the activatable antibody cannot be detected in the subject or biological sample. Such an activatable antibody includes a masking moiety (MM), a cleavable moiety (CM) that is cleaved by the cleaving agent, e.g., a protease, and an antigen binding domain or fragment thereof (AB) that specifically binds the target, wherein the activatable antibody in an uncleaved (i.e., non-activated) state comprises a structural arrangement from N-terminus to C-terminus as follows: MM-CM-AB or AB-CM-MM; (a) wherein the MM is a peptide that inhibits binding of the AB to the target, and wherein the MM does not have an amino acid sequence of a naturally occurring binding partner of the AB; and (b) wherein the MM of the activatable antibody in an uncleaved state interferes with specific binding of the AB to the target, and wherein the MM of an activatable antibody in a cleaved (i.e., activated) state does not interfere or compete with specific binding of the AB to the target. In some embodiments, the activatable antibody is an activatable antibody to which a therapeutic agent is conjugated. In some embodiments, the activatable antibody is not conjugated to an agent. In some embodiments, the detectable label is attached to the masking moiety. In some embodiments, the detectable label is attached to the cleavable moiety N-terminal to the protease cleavage site. In some embodiments, a single antigen binding site of the AB is masked. In some embodiments wherein an antibody of the disclosure has at least two antigen binding sites, at least one antigen binding site is masked and at least one antigen binding site is not masked. In some embodiments all antigen binding sites are masked. In some embodiments, the measuring step includes use of a secondary reagent comprising a detectable label. 
     The disclosure also provides kits for use in methods of detecting presence or absence of a cleaving agent in a subject or a sample, where the kits include at least an activatable antibody and/or conjugated activatable antibody described herein for use in contacting a subject or biological sample and means for detecting the level of activated activatable antibody and/or conjugated activatable antibody in the subject or biological sample, wherein the activatable antibody includes a detectable label that is positioned on a portion of the activatable antibody that is released following cleavage of the CM, wherein a detectable level of activated activatable antibody in the subject or biological sample indicates that the cleaving agent is absent and/or not sufficiently present in the subject or biological sample such that the target binding and/or protease cleavage of the activatable antibody cannot be detected in the subject or biological sample, and wherein no detectable level of activated activatable antibody in the subject or biological sample indicates that the cleaving agent is present in the subject or biological sample at a detectable level. 
     The disclosure provides methods of detecting presence or absence of a cleaving agent and the target in a subject or a sample by (i) contacting a subject or biological sample with an activatable antibody, wherein the activatable antibody includes a detectable label that is positioned on a portion of the activatable antibody that is released following cleavage of the CM and (ii) measuring a level of activated activatable antibody in the subject or biological sample, wherein a detectable level of activated activatable antibody in the subject or biological sample indicates that the cleaving agent, the target or both the cleaving agent and the target are absent and/or not sufficiently present in the subject or biological sample, such that the target binding and/or protease cleavage of the activatable antibody cannot be detected in the subject or biological sample, and wherein a reduced detectable level of activated activatable antibody in the subject or biological sample indicates that the cleaving agent and the target are present in the subject or biological sample. A reduced level of detectable label is, for example, a reduction of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95% and/or about 100%. Such an activatable antibody includes a masking moiety (MM), a cleavable moiety (CM) that is cleaved by the cleaving agent, and an antigen binding domain or fragment thereof (AB) that specifically binds the target, wherein the activatable antibody in an uncleaved (i.e., non-activated) state comprises a structural arrangement from N-terminus to C-terminus as follows: MM-CM-AB or AB-CM-MM; (a) wherein the MM is a peptide that inhibits binding of the AB to the target, and wherein the MM does not have an amino acid sequence of a naturally occurring binding partner of the AB; and (b) wherein the MM of the activatable antibody in an uncleaved state interferes with specific binding of the AB to the target, and wherein the MM of an activatable antibody in a cleaved (i.e., activated) state does not interfere or compete with specific binding of the AB to the target. In some embodiments, the activatable antibody is an activatable antibody to which a therapeutic agent is conjugated. In some embodiments, the activatable antibody is not conjugated to an agent. In some embodiments, the activatable antibody comprises a detectable label. In some embodiments, the detectable label is positioned on the AB. In some embodiments, measuring the level of activatable antibody in the subject or sample is accomplished using a secondary reagent that specifically binds to the activated antibody, wherein the reagent comprises a detectable label. In some embodiments, the secondary reagent is an antibody comprising a detectable label. 
     The disclosure also provides kits for use in methods of detecting presence or absence of a cleaving agent and the target in a subject or a sample, where the kits include at least an activatable antibody and/or conjugated activatable antibody described herein for use in contacting a subject or biological sample and means for detecting the level of activated activatable antibody and/or conjugated activatable antibody in the subject or biological sample, wherein a detectable level of activated activatable antibody in the subject or biological sample indicates that the cleaving agent, the target or both the cleaving agent and the target are absent and/or not sufficiently present in the subject or biological sample, such that the target binding and/or protease cleavage of the activatable antibody cannot be detected in the subject or biological sample, and wherein a reduced detectable level of activated activatable antibody in the subject or biological sample indicates that the cleaving agent and the target are present in the subject or biological sample. A reduced level of detectable label is, for example, a reduction of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95% and/or about 100%. 
     The disclosure also provides methods of detecting presence or absence of a cleaving agent in a subject or a sample by (i) contacting a subject or biological sample with an activatable antibody, wherein the activatable antibody includes a detectable label that is positioned on a portion of the activatable antibody that is released following cleavage of the CM; and (ii) measuring a level of detectable label in the subject or biological sample, wherein a detectable level of the detectable label in the subject or biological sample indicates that the cleaving agent is absent and/or not sufficiently present in the subject or biological sample at a detectable level, such that protease cleavage of the activatable antibody cannot be detected in the subject or biological sample, and wherein a reduced detectable level of the detectable label in the subject or biological sample indicates that the cleaving agent is present in the subject or biological sample. A reduced level of detectable label is, for example, a reduction of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95% and/or about 100%. Such an activatable antibody includes a masking moiety (MM), a cleavable moiety (CM) that is cleaved by the cleaving agent, and an antigen binding domain or fragment thereof (AB) that specifically binds the target, wherein the activatable antibody in an uncleaved (i.e., non-activated) state comprises a structural arrangement from N-terminus to C-terminus as follows: MM-CM-AB or AB-CM-MM; (a) wherein the MM is a peptide that inhibits binding of the AB to the target, and wherein the MM does not have an amino acid sequence of a naturally occurring binding partner of the AB; and (b) wherein the MM of the activatable antibody in an uncleaved state interferes with specific binding of the AB to the target, and wherein the MM of an activatable antibody in a cleaved (i.e., activated) state does not interfere or compete with specific binding of the AB to the target. In some embodiments, the activatable antibody is an activatable antibody to which a therapeutic agent is conjugated. In some embodiments, the activatable antibody is not conjugated to an agent. In some embodiments, the activatable antibody comprises a detectable label. In some embodiments, the detectable label is positioned on the AB. In some embodiments, measuring the level of activatable antibody in the subject or sample is accomplished using a secondary reagent that specifically binds to the activated antibody, wherein the reagent comprises a detectable label. In some embodiments, the secondary reagent is an antibody comprising a detectable label. 
     The disclosure also provides kits for use in methods of detecting presence or absence of a cleaving agent of interest in a subject or a sample, where the kits include at least an activatable antibody and/or conjugated activatable antibody described herein for use in contacting a subject or biological sample and means for detecting the level of activated activatable antibody and/or conjugated activatable antibody in the subject or biological sample, wherein the activatable antibody includes a detectable label that is positioned on a portion of the activatable antibody that is released following cleavage of the CM, wherein a detectable level of the detectable label in the subject or biological sample indicates that the cleaving agent, the target, or both the cleaving agent and the target are absent and/or not sufficiently present in the subject or biological sample, such that the target binding and/or protease cleavage of the activatable antibody cannot be detected in the subject or biological sample, and wherein a reduced detectable level of the detectable label in the subject or biological sample indicates that the cleaving agent and the target are present in the subject or biological sample. A reduced level of detectable label is, for example, a reduction of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95% and/or about 100%. 
     In some embodiments of these methods and kits, the activatable antibody includes a detectable label. In some embodiments of these methods and kits, the detectable label includes an imaging agent, a contrasting agent, an enzyme, a fluorescent label, a chromophore, a dye, one or more metal ions, or a ligand-based label. In some embodiments of these methods and kits, the imaging agent comprises a radioisotope. In some embodiments of these methods and kits, the radioisotope is indium or technetium. In some embodiments of these methods and kits, the contrasting agent comprises iodine, gadolinium or iron oxide. In some embodiments of these methods and kits, the enzyme comprises horseradish peroxidase, alkaline phosphatase, or (3-galactosidase. In some embodiments of these methods and kits, the fluorescent label comprises yellow fluorescent protein (YFP), cyan fluorescent protein (CFP), green fluorescent protein (GFP), modified red fluorescent protein (mRFP), red fluorescent protein tdimer2 (RFP tdimer2), HCRED, or a europium derivative. In some embodiments of these methods and kits, the luminescent label comprises an N-methylacrydium derivative. In some embodiments of these methods, the label comprises an Alexa Fluor® label, such as Alex Fluor® 680 or Alexa Fluor® 750. In some embodiments of these methods and kits, the ligand-based label comprises biotin, avidin, streptavidin or one or more haptens. 
     In some embodiments of these methods and kits, the subject is a mammal. In some embodiments of these methods and kits, the subject is a human. In some embodiments, the subject is a non-human mammal, such as a non-human primate, companion animal (e.g., cat, dog, horse), farm animal, work animal, or zoo animal. In some embodiments, the subject is a rodent. 
     In some embodiments of these methods, the method is an in vivo method. In some embodiments of these methods, the method is an in situ method. In some embodiments of these methods, the method is an ex vivo method. In some embodiments of these methods, the method is an in vitro method. 
     In some embodiments, in situ imaging and/or in vivo imaging are useful in methods to identify which patients to treat. For example, in in situ imaging, the activatable antibodies are used to screen patient samples to identify those patients having the appropriate protease(s) and target(s) at the appropriate location, e.g., at a tumor site. 
     In some embodiments in situ imaging is used to identify or otherwise refine a patient population suitable for treatment with an activatable antibody of the disclosure. For example, patients that test positive for both the target (e.g., the target) and a protease that cleaves the substrate in the cleavable moiety (CM) of the activatable antibody being tested (e.g., accumulate activated antibodies at the disease site) are identified as suitable candidates for treatment with such an activatable antibody comprising such a CM. Likewise, patients that test negative for either or both of the target (e.g., the target) and the protease that cleaves the substrate in the CM in the activatable antibody being tested using these methods might be identified as suitable candidates for another form of therapy. In some embodiments, such patients that test negative with respect to a first activatable antibody can be tested with other activatable antibodies comprising different CMs until a suitable activatable antibody for treatment is identified (e.g., an activatable antibody comprising a CM that is cleaved by the patient at the site of disease). In some embodiments, the patient is then administered a therapeutically effective amount of the activatable antibody for which the patient tested positive. 
     In some embodiments in vivo imaging is used to identify or otherwise refine a patient population suitable for treatment with an activatable antibody of the disclosure. For example, patients that test positive for both the target (e.g., the target) and a protease that cleaves the substrate in the cleavable moiety (CM) of the activatable antibody being tested (e.g., accumulate activated antibodies at the disease site) are identified as suitable candidates for treatment with such an activatable antibody comprising such a CM. Likewise, patients that test negative might be identified as suitable candidates for another form of therapy. In some embodiments, such patients that test negative with respect to a first activatable antibody can be tested with other activatable antibodies comprising different CMs until a suitable activatable antibody for treatment is identified (e.g., an activatable antibody comprising a CM that is cleaved by the patient at the site of disease). In some embodiments, the patient is then administered a therapeutically effective amount of the activatable antibody for which the patient tested positive. 
     In some embodiments of the methods and kits, the method or kit is used to identify or otherwise refine a patient population suitable for treatment with an activatable antibody of the disclosure. For example, patients that test positive for both the target (e.g., the target) and a protease that cleaves the substrate in the cleavable moiety (CM) of the activatable antibody being tested in these methods are identified as suitable candidates for treatment with such an activatable antibody comprising such a CM. Likewise, patients that test negative for both of the targets (e.g., the target) and the protease that cleaves the substrate in the CM in the activatable antibody being tested using these methods might be identified as suitable candidates for another form of therapy. In some embodiments, such patients can be tested with other activatable antibodies until a suitable activatable antibody for treatment is identified (e.g., an activatable antibody comprising a CM that is cleaved by the patient at the site of disease). In some embodiments, patients that test negative for either of the target (e.g., the target) are identified as suitable candidates for treatment with such an activatable antibody comprising such a CM. In some embodiments, patients that test negative for either of the target (e.g., the target) are identified as not being suitable candidates for treatment with such an activatable antibody comprising such a CM. In some embodiments, such patients can be tested with other activatable antibodies until a suitable activatable antibody for treatment is identified (e.g., an activatable antibody comprising a CM that is cleaved by the patient at the site of disease). In some embodiments, the activatable antibody is an activatable antibody to which a therapeutic agent is conjugated. In some embodiments, the activatable antibody is not conjugated to an agent. In some embodiments, the activatable antibody comprises a detectable label. In some embodiments, the detectable label is positioned on the AB. In some embodiments, measuring the level of activatable antibody in the subject or sample is accomplished using a secondary reagent that specifically binds to the activated antibody, wherein the reagent comprises a detectable label. In some embodiments, the secondary reagent is an antibody comprising a detectable label. 
     In some embodiments, a method or kit is used to identify or otherwise refine a patient population suitable for treatment with an anti-the target activatable antibody and/or conjugated activatable antibody (e.g., activatable antibody to which a therapeutic agent is conjugated) of the disclosure, followed by treatment by administering that activatable antibody and/or conjugated activatable antibody to a subject in need thereof. For example, patients that test positive for both the targets (e.g., the target) and a protease that cleaves the substrate in the cleavable moiety (CM) of the activatable antibody and/or conjugated activatable antibody being tested in these methods are identified as suitable candidates for treatment with such antibody and/or such a conjugated activatable antibody comprising such a CM, and the patient is then administered a therapeutically effective amount of the activatable antibody and/or conjugated activatable antibody that was tested. Likewise, patients that test negative for either or both of the target (e.g., the target) and the protease that cleaves the substrate in the CM in the activatable antibody being tested using these methods might be identified as suitable candidates for another form of therapy. In some embodiments, such patients can be tested with other antibody and/or conjugated activatable antibody until a suitable antibody and/or conjugated activatable antibody for treatment is identified (e.g., an activatable antibody and/or conjugated activatable antibody comprising a CM that is cleaved by the patient at the site of disease). In some embodiments, the patient is then administered a therapeutically effective amount of the activatable antibody and/or conjugated activatable antibody for which the patient tested positive. 
     In some embodiments of these methods and kits, the MM is a peptide having a length from about 4 to 40 amino acids. In some embodiments of these methods and kits, the activatable antibody comprises a linker peptide, wherein the linker peptide is positioned between the MM and the CM. In some embodiments of these methods and kits, the activatable antibody comprises a linker peptide, where the linker peptide is positioned between the AB and the CM. In some embodiments of these methods and kits, the activatable antibody comprises a first linker peptide (L1) and a second linker peptide (L2), wherein the first linker peptide is positioned between the MM and the CM and the second linker peptide is positioned between the AB and the CM. In some embodiments of these methods and kits, each of L1 and L2 is a peptide of about 1 to 20 amino acids in length, and wherein each of L1 and L2 need not be the same linker. In some embodiments of these methods and kits, one or both of L1 and L2 comprises a glycine-serine polymer. In some embodiments of these methods and kits, at least one of L1 and L2 comprises an amino acid sequence selected from the group consisting of (GS) n , (GSGGS) n  (SEQ ID NO: 363) and (GGGS) n  (SEQ ID NO: 364), where n is an integer of at least one. In some embodiments of these methods and kits, at least one of L1 and L2 comprises an amino acid sequence having the formula (GGS) n , where n is an integer of at least one. In some embodiments of these methods and kits, at least one of L1 and L2 comprises an amino acid sequence selected from the group consisting of GGSG (SEQ ID NO: 365), GGSGG (SEQ ID NO: 366), GSGSG (SEQ ID NO: 367), GSGGG (SEQ ID NO: 368), GGGSG (SEQ ID NO: 369), and GSSSG (SEQ ID NO: 370). 
     In some embodiments of these methods and kits, the AB comprises an antibody or antibody fragment sequence selected from the cross-reactive antibody sequences presented herein. In some embodiments of these methods and kits, the AB comprises a Fab fragment, a scFv or a single chain antibody (scAb). 
     In some embodiments of these methods and kits, the cleaving agent is a protease that is co-localized in the subject or sample with the target and the CM is a polypeptide that functions as a substrate for the protease, wherein the protease cleaves the CM in the activatable antibody when the activatable antibody is exposed to the protease. In some embodiments of these methods and kits, the CM is a polypeptide of up to 15 amino acids in length. In some embodiments of these methods and kits, the CM is coupled to the N-terminus of the AB. In some embodiments of these methods and kits, the CM is coupled to the C-terminus of the AB. In some embodiments of these methods and kits, the CM is coupled to the N-terminus of a VL chain of the AB. 
     The antibodies and/or activatable antibodies of the disclosure are used in diagnostic and prophylactic formulations. In one embodiment, an activatable antibody is administered to patients that are at risk of developing one or more of the aforementioned inflammation, inflammatory disorders, cancer or other disorders. 
     A patient&#39;s or organ&#39;s predisposition to one or more of the aforementioned disorders can be determined using genotypic, serological or biochemical markers. 
     In some embodiments of the disclosure, an antibody and/or an activatable antibody is administered to human individuals diagnosed with a clinical indication associated with one or more of the aforementioned disorders. Upon diagnosis, an antibody and/or an activatable antibody is administered to mitigate or reverse the effects of the clinical indication. 
     Antibodies and/or activatable antibodies of the disclosure are also useful in the detection of the target in patient samples and accordingly are useful as diagnostics. For example, the antibodies and/or activatable antibodies of the disclosure are used in in vitro assays, e.g., ELISA, to detect target levels in a patient sample. 
     In some embodiments, anti-PDL1 antibodies are used as a diagnostic for patients who are more likely to respond favorably to treatment with an anti-PD-1 antibody and/or activatable antibody of the disclosure. In these embodiments, PD-L1 expression in tumor biopsies on both tumor cells and infiltrating immune cells and PD-L1 expression on immune cells in blood are used to indicate the presence of active immunity and, thus, potential for suppression of T cell activity through the engagement of PD-1 by PD-L1. 
     In one embodiment, an antibody and/or activatable antibody of the disclosure is immobilized on a solid support (e.g., the well(s) of a microtiter plate). The immobilized antibody and/or activatable antibody serves as a capture antibody for any target that can be present in a test sample. Prior to contacting the immobilized antibody and/or activatable antibody with a patient sample, the solid support is rinsed and treated with a blocking agent such as milk protein or albumin to prevent nonspecific adsorption of the analyte. 
     Subsequently the wells are treated with a test sample suspected of containing the antigen, or with a solution containing a standard amount of the antigen. Such a sample is, e.g., a serum sample from a subject suspected of having levels of circulating antigen considered to be diagnostic of a pathology. After rinsing away the test sample or standard, the solid support is treated with a second antibody that is detectably labeled. The labeled second antibody serves as a detecting antibody. The level of detectable label is measured, and the concentration of target antigen in the test sample is determined by comparison with a standard curve developed from the standard samples. 
     It will be appreciated that based on the results obtained using the antibodies and/or activatable antibodies of the disclosure in an in vitro diagnostic assay, it is possible to stage a disease in a subject based on expression levels of the target antigen. For a given disease, samples of blood are taken from subjects diagnosed as being at various stages in the progression of the disease, and/or at various points in the therapeutic treatment of the disease. Using a population of samples that provides statistically significant results for each stage of progression or therapy, a range of concentrations of the antigen that can be considered characteristic of each stage is designated. 
     Antibodies, conjugated antibodies, activatable antibodies and/or conjugated activatable antibodies can also be used in diagnostic and/or imaging methods. In some embodiments, such methods are in vitro methods. In some embodiments, such methods are in vivo methods. In some embodiments, such methods are in situ methods. In some embodiments, such methods are ex vivo methods. For example, activatable antibodies having an enzymatically cleavable CM can be used to detect the presence or absence of an enzyme that is capable of cleaving the CM. Such activatable antibodies can be used in diagnostics, which can include in vivo detection (e.g., qualitative or quantitative) of enzyme activity (or, in some embodiments, an environment of increased reduction potential such as that which can provide for reduction of a disulfide bond) through measured accumulation of activated antibodies (i.e., antibodies resulting from cleavage of an activatable antibody) in a given cell or tissue of a given host organism. Such accumulation of activated antibodies indicates not only that the tissue expresses enzymatic activity (or an increased reduction potential depending on the nature of the CM) but also that the tissue expresses target to which the activated antibody binds. 
     For example, the CM can be selected to be a protease substrate for a protease found at the site of a tumor, at the site of a viral or bacterial infection at a biologically confined site (e.g., such as in an abscess, in an organ, and the like), and the like. The AB can be one that binds a target antigen. Using methods familiar to one skilled in the art, a detectable label (e.g., a fluorescent label or radioactive label or radiotracer) can be conjugated to an AB or other region of an activatable antibody. Suitable detectable labels are discussed in the context of the above screening methods and additional specific examples are provided below. Using an AB specific to a protein or peptide of the disease state, along with a protease whose activity is elevated in the disease tissue of interest, activatable antibodies will exhibit an increased rate of binding to disease tissue relative to tissues where the CM specific enzyme is not present at a detectable level or is present at a lower level than in disease tissue or is inactive (e.g., in zymogen form or in complex with an inhibitor). Since small proteins and peptides are rapidly cleared from the blood by the renal filtration system, and because the enzyme specific for the CM is not present at a detectable level (or is present at lower levels in non-disease tissues or is present in inactive conformation), accumulation of activated antibodies in the disease tissue is enhanced relative to non-disease tissues. 
     In another example, activatable antibodies can be used to detect the presence or absence of a cleaving agent in a sample. For example, where the activatable antibodies contain a CM susceptible to cleavage by an enzyme, the activatable antibodies can be used to detect (either qualitatively or quantitatively) the presence of an enzyme in the sample. In another example, where the activatable antibodies contain a CM susceptible to cleavage by reducing agent, the activatable antibodies can be used to detect (either qualitatively or quantitatively) the presence of reducing conditions in a sample. To facilitate analysis in these methods, the activatable antibodies can be detectably labeled, and can be bound to a support (e.g., a solid support, such as a slide or bead). The detectable label can be positioned on a portion of the activatable antibody that is not released following cleavage, for example, the detectable label can be a quenched fluorescent label or other label that is not detectable until cleavage has occurred. The assay can be conducted by, for example, contacting the immobilized, detectably labeled activatable antibodies with a sample suspected of containing an enzyme and/or reducing agent for a time sufficient for cleavage to occur, then washing to remove excess sample and contaminants. The presence or absence of the cleaving agent (e.g., enzyme or reducing agent) in the sample is then assessed by a change in detectable signal of the activatable antibodies prior to contacting with the sample e.g., the presence of and/or an increase in detectable signal due to cleavage of the activatable antibody by the cleaving agent in the sample. 
     Such detection methods can be adapted to also provide for detection of the presence or absence of a target that is capable of binding the AB of the activatable antibodies when cleaved. Thus, the assays can be adapted to assess the presence or absence of a cleaving agent and the presence or absence of a target of interest. The presence or absence of the cleaving agent can be detected by the presence of and/or an increase in detectable label of the activatable antibodies as described above, and the presence or absence of the target can be detected by detection of a target-AB complex e.g., by use of a detectably labeled anti-target antibody. 
     Activatable antibodies are also useful in in situ imaging for the validation of activatable antibody activation, e.g., by protease cleavage, and binding to a particular target. In situ imaging is a technique that enables localization of proteolytic activity and target in biological samples such as cell cultures or tissue sections. Using this technique, it is possible to confirm both binding to a given target and proteolytic activity based on the presence of a detectable label (e.g., a fluorescent label). 
     These techniques are useful with any frozen cells or tissue derived from a disease site (e.g. tumor tissue) or healthy tissues. These techniques are also useful with fresh cell or tissue samples. 
     In these techniques, an activatable antibody is labeled with a detectable label. The detectable label can be a fluorescent dye, (e.g. Fluorescein Isothiocyanate (FITC), Rhodamine Isothiocyanate (TRITC), a near infrared (NIR) dye (e.g., Qdot® nanocrystals), a colloidal metal, a hapten, a radioactive marker, biotin and an amplification reagent such as streptavidin, or an enzyme (e.g. horseradish peroxidase or alkaline phosphatase). 
     Detection of the label in a sample that has been incubated with the labeled, activatable antibody indicates that the sample contains the target and contains a protease that is specific for the CM of the activatable antibody. In some embodiments, the presence of the protease can be confirmed using broad spectrum protease inhibitors such as those described herein, and/or by using an agent that is specific for the protease, for example, an antibody such as A11, which is specific for the protease matriptase and inhibits the proteolytic activity of matriptase; see e.g., International Publication Number WO 2010/129609, published 11 Nov. 2010. The same approach of using broad spectrum protease inhibitors such as those described herein, and/or by using a more selective inhibitory agent can be used to identify a protease or class of proteases specific for the CM of the activatable antibody. In some embodiments, the presence of the target can be confirmed using an agent that is specific for the target, e.g., another antibody, or the detectable label can be competed with unlabeled target. In some embodiments, unlabeled activatable antibody could be used, with detection by a labeled secondary antibody or more complex detection system. 
     Similar techniques are also useful for in vivo imaging where detection of the fluorescent signal in a subject, e.g., a mammal, including a human, indicates that the disease site contains the target and contains a protease that is specific for the CM of the activatable antibody. 
     These techniques are also useful in kits and/or as reagents for the detection, identification or characterization of protease activity in a variety of cells, tissues, and organisms based on the protease-specific CM in the activatable antibody. 
     In some embodiments, in situ imaging and/or in vivo imaging are useful in methods to identify which patients to treat. For example, in in situ imaging, the activatable antibodies are used to screen patient samples to identify those patients having the appropriate protease(s) and target(s) at the appropriate location, e.g., at a tumor site. 
     In some embodiments in situ imaging is used to identify or otherwise refine a patient population suitable for treatment with an activatable antibody of the disclosure. For example, patients that test positive for both the target and a protease that cleaves the substrate in the cleavable moiety (CM) of the activatable antibody being tested (e.g., accumulate activated antibodies at the disease site) are identified as suitable candidates for treatment with such an activatable antibody comprising such a CM. Likewise, patients that test negative for either or both of the target and the protease that cleaves the substrate in the CM in the activatable antibody being tested using these methods are identified as suitable candidates for another form of therapy (i.e., not suitable for treatment with the activatable antibody being tested). In some embodiments, such patients that test negative with respect to a first activatable antibody can be tested with other activatable antibodies comprising different CMs until a suitable activatable antibody for treatment is identified (e.g., an activatable antibody comprising a CM that is cleaved by the patient at the site of disease). 
     In some embodiments in vivo imaging is used to identify or otherwise refine a patient population suitable for treatment with an activatable antibody of the disclosure. For example, patients that test positive for both the target and a protease that cleaves the substrate in the cleavable moiety (CM) of the activatable antibody being tested (e.g., accumulate activated antibodies at the disease site) are identified as suitable candidates for treatment with such an activatable antibody comprising such a CM. Likewise, patients that test negative are identified as suitable candidates for another form of therapy (i.e., not suitable for treatment with the activatable antibody being tested). In some embodiments, such patients that test negative with respect to a first activatable antibody can be tested with other activatable antibodies comprising different CMs until a suitable activatable antibody for treatment is identified (e.g., an activatable antibody comprising a CM that is cleaved by the patient at the site of disease). 
     Pharmaceutical Compositions 
     The antibodies and/or activatable antibodies of the disclosure (also referred to herein as “active compounds”), and derivatives, fragments, analogs and homologs thereof, can be incorporated into pharmaceutical compositions suitable for administration. Such compositions typically comprise the antibody and/or activatable antibody and a pharmaceutically acceptable carrier. As used herein, the term “pharmaceutically acceptable carrier” is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Suitable carriers are described in the most recent edition of Remington&#39;s Pharmaceutical Sciences, a standard reference text in the field, which is incorporated herein by reference. Suitable examples of such carriers or diluents include, but are not limited to, water, saline, ringer&#39;s solutions, dextrose solution, and 5% human serum albumin. Liposomes and non-aqueous vehicles such as fixed oils can also be used. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions. 
     A pharmaceutical composition of the disclosure is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (i.e., topical), transmucosal, and rectal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. 
     Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In some embodiments, it will be desirable to include isotonic agents, for example, sugars, polyalcohols such as manitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate and gelatin. 
     Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. 
     Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. 
     For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser that contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer. 
     Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art. 
     The compounds can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery. 
     In one embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811. 
     It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the disclosure are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals. 
     The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration. 
     The invention will be further described in the following examples, which do not limit the scope of the invention described in the claims. 
     EXAMPLES 
     Example 1. Generation of Mouse Antibodies of the Embodiments that Bind Human PD-1 and Block hPD-L1 and hPD-L2 Binding to Human PD-1 
     This example demonstrates mouse antibodies of the disclosure that bind human PD-1 can be isolated from hybridomas derived from mouse immunization with recombinant human PD-1 protein, and that such binding can inhibit PD-1 binding to PDL1 and PDL2. 
     Six NZBWF1/J female mice (Jackson Laboratories, Sacramento, Calif.; cat #100008) were immunized in the right flank with recombinant human PD-1 (Sino Biological, Beijing, P.R. China; cat # ABIN2181605) on days 0, 7 and 21. Serum was taken from immunized mice on day 28 and binding to HEK293-hPD-1 (cells transfected with an expression vector encoding human PD-1 (Origene, cat # SC117011)) was measured. All six mice showed positive binding. Splenocytes were isolated from mouse 1, 3 and 6 and fused with SP0 mouse B-cells; likewise splenocytes were isolated from mouse 2, 4 and 5 and fused with SP0 mouse B-cells, giving rise to pools of hybridomas, m136 and m245. The hybridoma pools, m136 and m245, arising from the two fusions were plated for single clones, and clonal culture supernatants were assayed for antibodies capable of binding to HEK293-hPD-1, and not to un-transfected HEK293, cells. Hybridoma clones expressing anti-PD-1 antibodies were chosen for further analysis. 
     The sequences of the antibodies used in the studies presented herein are shown below: 
     m136-M13-MHC723 mIgG1/K 
                    MHC723HC.1 Variable Heavy Chain         Region Amino Acid Sequence:       (SEQ ID NO: 1)       EVKLVESGGGLVKPGGSLKLSCAAS GFTFSGYAMS WVRQTPAKRLEWVA Y                   ISNSGGNAH YPDSVKGRFTISRDNAKNTLYLQMSSLRSEDTAMYYCTR ED                   YGTSPFVY WGQGTLVTVSA               MHC723HC.1 Variable Heavy Chain        Region Nucleic Acid Sequence:        (SEQ ID NO: 2)       GAAGTGAAGCTGGTGGAGTCTGGGGGAGGCTTAGTGAAACCTGGAGGGTC               CCTGAAACTCTCCTGTGCAGCCTCTGGATTCACTTTCAGTGGCTATGCCA               TGTCTTGGGTTCGCCAGACTCCGGCGAAGAGGCTGGAGTGGGTCGCATAC               ATTAGTAATAGTGGTGGTAACGCCCACTATCCAGACAGTGTAAAGGGCCG               ATTCACCATCTCCAGAGACAATGCCAAGAACACCCTATACCTGCAAATGA               GCAGTCTGAGGTCTGAGGACACGGCCATGTATTACTGTACAAGAGAGGAC               TACGGTACTAGTCCTTTTGTTTACTGGGGCCAAGGGACTCTGGTCACTGT               CTCTGCA               MHC723LC.3 Variable Light Chain        Region Amino Acid Sequence:        (SEQ ID NO: 3)       DIVLTQSPASLAVSLGQRTTISC RASESVDNYGISFMN WFQQKPGQPPKL               LIY AASNQGS GVPARFSGSGSGTDFSLNIHPMEEDDTAVYFC QQSKDVPW                   T FGGGTKLEIR               MHC723LC.3 Variable Light Chain        Region Nucleic Acid Sequence:        (SEQ ID NO: 4)       GACATTGTGCTGACCCAATCTCCAGCTTCTTTGGCTGTGTCTCTTGGGCA               GAGGACCACCATCTCCTGCAGAGCCAGCGAAAGTGTTGATAATTATGGCA               TTAGTTTTATGAACTGGTTCCAACAGAAACCAGGACAGCCACCCAAACTC               CTCATCTATGCTGCATCCAACCAAGGATCCGGGGTCCCTGCCAGGTTTAG               TGGCAGTGGGTCTGGGACAGACTTCAGCCTCAACATCCATCCTATGGAGG               AGGATGATACTGCAGTGTATTTCTGTCAGCAAAGTAAGGACGTTCCGTGG               ACGTTCGGTGGAGGCACCAAGCTGGAAATCAGAC            
m136-M19-MHC725 mIgG2b/K
 
                        (SEQ ID NO: 5)           MEIC725HC.2 Variable heavy chain region amino acid sequence:           EVQLQQSGPELVKPGDSVKMSCKASGYTFTDYYMDWVKQSHGKSLEWIGYIYPKNGGSSYNQKF               KGKATLTVDKSSSTAYMELHSLTSEDSAVYYCARKVVATDYWGQGTTLTVSS                       (SEQ ID NO: 6)           MEIC725HC.2 Variable heavy chain region nucleic acid sequence:           GAGGTCCAGCTGCAACAGTCTGGACCTGAGCTGGTGAAGCCTGGGGATTCAGTGAAGATGTCCT               GCAAGGCTTCTGGCTACACATTCACTGACTACTACATGGACTGGGTGAAGCAGAGCCATGGAAA               GAGCCITGAGIGGATTGGATATATTTATCCTAAAAATGGIGGITCCAGCTACAATCAGAAGTTC               AAGGGCAAGGCCACATTGACTGTAGACAAGTCCTCCAGCACAGCCTACATGGAGCTCCACAGCC               TGACATCTGAGGACTCTGCAGICTATTACTGTGCAAGAAAGGICGTAGCTACGGACTACTGGGG               CCAAGGCACCACTCTCACAGTCTCCTCA                (SEQ ID NO: 7)           MEIC725LC.2 Variable light chain region amino acid sequence:                             DIVMSQSPSSLAVSVGEKVTMSCKSSQSLLYSSNQKNYLAWYQQKPGQSPKLLIFWASIRESGV                       PDRFTGSGSGTDFTLTISSVKAEDRAVYYCQQCDSYPWTFGGGTKLEIK                    (SEQ ID NO: 8)               MIIC725LC.2 Variable light chain region nucleic acid sequence:               GACATTGTGATGTCACAGTCTCCATCCTCCCTAGCTGTGTCAGTTGGAGAGAAGGTTACTATGA                   GCTGCAAGTCCAGTCAGAGCCTTTTATATAGTAGCAATCAAAAGAACTACTTGGCCTGGTACCA                   GCAGAAACCAGGGCAGTCTCCTAAACTGCTGATTTTCTGGGCATCTATTAGGGAATCTGGGGTC                   CCTGATCGCTTCACAGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTGTGAAGG                   CTGAAGACCGGGCAGTTTATTACTGTCAGCAATGTGATAGCTATCCGTGGACGTTCGGTGGAGG                   CACCAAACTGGAAATCAAAC                 
m245-M3-MHC728 mIgG2a/K
 
                        (SEQ ID NO: 9)           MIIC728HC.4 Variable heavy chain region amino acid sequence:           EVKLVESGGGLVKPGGSLKLSCAASGFTFSNYAMSWVRQTPAKRLEWVAYISNGGGDTHYPDSL               KGRFTVSRDNAKNTLYLQMSSLKSEDTAMYYCARENYGTSPFVYWGQGTLVTVSA               (SEQ ID NO: 10)           MIIC728HC.4 Variable heavy chain region nucleic acid sequence:           GAAGTGAAGCTGGTGGAGTCTGGGGGAGGCTTAGTGAAACCTGGAGGGTCCCTGAAACTCTCCT               GTGCAGCCTCTGGATTCACTTTCAGTAACTATGCCATGTCTTGGGTTCGCCAGACTCCGGCGAA               GAGGCTGGAGTGGGTCGCATACATTAGTAATGGTGGTGGTGACACCCACTATCCAGACAGTTTA               AAGGGCCGATTCACCGTCTCCAGAGACAATGCCAAGAACACCCTGTACCTACAAATGAGCAGTC               TGAAGTCTGAGGACACGGCCATGTATTACTGTGCAAGAGAAAACTACGGTACTAGTCCCTTTGT               TTACTGGGGCCAAGGGACTCTGGTCACTGTCTCTGCA               (SEQ ID NO: 11)           MIIC728LC.2Variable light chain region amino acid sequence:           DIVLTQSPASLAVSLGQRATISCRASESVDNYGISFMNWFQQKPGQPPKLLIYAASNQGSGVPA               RFSGSGSGTDFSLNIHPMEEDDTAMYFCQQSKDVPWTFGGGTKLEIK               (SEQ ID NO: 12)           MIIC728LC.2 Variable light chain region nucleic acid sequence:           GACATTGTGCTGACCCAATCTCCAGCTTCTTTGGCTGTGTCTCTAGGGCAGAGGGCCACCATCT               CCTGCAGAGCCAGCGAAAGTGTTGATAATTATGGCATTAGTTTTATGAACTGGTTCCAACAGAA               ACCAGGACAGCCACCCAAACTCCTCATCTATGCTGCATCCAACCAAGGATCCGGGGTCCCTGCC               AGGTTTAGTGGCAGTGGGTCTGGGACAGACTTCAGCCTCAACATCCATCCTATGGAGGAGGATG               ATACTGCAATGTATTTCTGTCAGCAAAGTAAAGATGTTCCGTGGACGTTCGGTGGAGGCACCAA               GCTGGAAATCAAAC            
m245-M5-MHC729 mIgG1/K
 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 13) 
                   
               
               
                 MEIC729HC.1 Variable heavy chain region amino acid sequence: 
                   
               
               
                 EVQLVESGGGLVKSGGSLKLSCAHSGFSFSSYDMSWVRQTPAKRLEWVATISGGGRYTYYPDSV 
               
               
                   
               
               
                 KGRFTISRDNAKNTLYLQMSGLRSEDTAMYYCASNYYGFDYWGQGTTLTVSS 
               
               
                   
               
               
                 (SEQ ID NO: 14) 
                   
               
               
                 MEIC729HC.1 Variable heavy chain region nucleic acid sequence: 
                   
               
               
                 GAAGTGCAGCTGGTGGAGICIGGGGGAGGCTTAGTGAAGICTGGAGGGICCCTGAAACTCTCCT 
               
               
                   
               
               
                 GTGCGCATTCTGGATTCAGTTTTAGTAGTTATGACATGTCTTGGGTTCGCCAGACTCCGGCGAA 
               
               
                   
               
               
                 GAGGCTGGAGTGGGTCGCAACCATTAGTGGTGGTGGTCGTTACACCTACTATCCAGACAGTGTG 
               
               
                   
               
               
                 AAGGGCCGATTCACCATCTCCAGAGACAATGCCAAGAACACCCTGTACCTGCAAATGAGCGGIC 
               
               
                   
               
               
                 TGAGGTCTGAGGACACAGCCATGTATTACTGTGCAAGTAATTACTACGGTTTTGACTACTGGGG 
               
               
                   
               
               
                 CCAAGGCACCACTCTCACAGTCTCTTCA 
               
               
                   
               
               
                 (SEQ ID NO: 15) 
                   
               
               
                 MEIC729LC.3 Variable light chain region amino acid sequence: 
                   
               
               
                 DIVMTQSHKFMSTSVGDRVSITCKASQDVGTAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFTG 
               
               
                   
               
               
                 SGSGTDFTLTISNVQSEDLADYFCQQYSSYPWTFGGGTKLEIK 
               
               
                   
               
               
                 (SEQ ID NO: 16) 
                   
               
               
                 MEIC729LC.3 Variable light chain region nucleic acid sequence: 
                   
               
               
                 GATATIGTGATGACCCAGICTCACAAATTCATGTCCACATCAGTAGGAGACAGGGICAGCATCA 
               
               
                   
               
               
                 CCTGCAAGGCCAGTCAGGATGTGGGTACTGCTGTAGCCIGGTATCAACAGAAACCAGGGCAATC 
               
               
                   
               
               
                 TCCTAAACTACTGATTTACTGGGCATCCACCCGGCACACTGGAGTCCCTGATCGCTICACGGGC 
               
               
                   
               
               
                 AGTGGATCTGGGACAGATTTCACTCTCACCATTAGCAATGTGCAGTCTGAAGACTTGGCAGATT 
               
               
                   
               
               
                 ATTTCTGTCAGCAATATAGCAGCTATCCGTGGACGTTCGGTGGAGGCACCAAGCTGGAAATCAA 
               
               
                   
               
               
                 AC 
               
            
           
         
       
     
     m136-M14-MHC724 mIgG2a/K 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 17) 
                   
               
               
                 MEIC724HC.3 Variable heavy chain region amino acid sequence: 
                   
               
               
                 KVMLVESGGDLVKPGGSLKLSCAASGFTFSSYGMSWVRQTPEKRLEWVATISGGGRDIYYADTV 
               
               
                   
               
               
                 KGRFTISRDNAKNTLYLQMSSLRSEDTALYFCARLYLGFDYWGQGTTLTVSS 
               
               
                   
               
               
                 (SEQ ID NO: 18) 
                   
               
               
                 MEIC724HC.3 Variable heavy chain region nucleic acid sequence: 
                   
               
               
                 AAAGTGATGCTGGTGGAGICTGGGGGAGACTTAGTGAAGCCTGGAGGGICCCTGAAACTCTCCT 
               
               
                   
               
               
                 GTGCAGCCTCTGGATTCACTTTCAGTAGCTATGGCATGTCTTGGGTTCGCCAGACTCCGGAGAA 
               
               
                   
               
               
                 GAGGCTGGAGTGGGTCGCAACCATTAGTGGTGGTGGTAGAGACATCTACTACGCAGACACTGTG 
               
               
                   
               
               
                 AAGGGCCGATTCACCATCTCCAGAGACAATGCCAAGAACACCCTGTACCTACAAATGAGCAGTC 
               
               
                   
               
               
                 TGAGGTCTGAGGACACGGCCTTGTATTTCTGTGCAAGGCTCTACCTGGGGTTTGACTACTGGGG 
               
               
                   
               
               
                 CCAAGGCACCACTCTCACAGTCTCCTCA 
               
               
                   
               
               
                 (SEQ ID NO: 19) 
                   
               
               
                 MEIC724LC.1 Variable light chain region amino acid sequence: 
                   
               
               
                 DIQMTQSPASQSASLGESVTITCLASQTIGTWLAWYQQKPGKSPQLLIYAATSLADGVPSRFSG 
               
               
                   
               
               
                 SGSGTKFSFKISSLQAEDFVSYYCQQLYSIPWTFGGGTKLEIK 
               
               
                   
               
               
                 (SEQ ID NO: 20) 
                   
               
               
                 MEIC724LC.1 Variable light chain region nucleic acid sequence: 
                   
               
               
                 GACATICAGATGACCCAGICTCCTGCCTCCCAGTCTGCATCTCTGGGAGAAAGTGTCACCATCA 
               
               
                   
               
               
                 CATGCCTGGCAAGTCAGACCATTGGTACATGGITAGCATGGTATCAGCAGAAACCAGGGAAATC 
               
               
                   
               
               
                 TCCTCAGCTCCTGATTTATGCTGCAACCAGCTTGGCAGATGGGGTCCCATCAAGGTTCAGTGGT 
               
               
                   
               
               
                 AGTGGATCTGGCACAAAATTITCTTICAAGATCAGCAGCCTACAGGCTGAAGATTITGTAAGTT 
               
               
                   
               
               
                 ATTACTGTCAACAACTITACAGTATTCCGTGGACATTCGGIGGAGGCACCAAGCTGGAAATCAA 
               
               
                   
               
               
                 AC 
               
            
           
         
       
     
     Binding of mouse antibodies m136-M13, m136-M19, m245-M3, m245-M5 and m136-M14 to human PD-1 was confirmed by ELISA ( FIG. 1 ). Briefly, human PD-1-Fc (R and D systems, Minneapolis, Minn.) was adsorbed to the wells of a 96-well ELISA plate. Purified anti-PD-1 antibodies were applied to the plate in serial dilution and allowed to bind. Plates were washed with PBST (PBS, pH 7.2+0.05% Tween-20). Bound antibody was detected with an anti-mouse IgG-HRP conjugate (Sigma, St Louis, Mo.) and visualized with the chromogenic substrate TMB (Thermo Scientific, Rockford, Ill.). Plots were generated in Prizm (Sigma Plot) and the data were fit to a model of single site saturation binding. Anti-PD-1 antibodies nivolumab (NV1) and/or pembrolizumab (PM1) were used as positive controls in binding assays with anti-human IgG-HRP conjugate, FAb-specific (Sigma, St Louis, Mo.) for detection. The K d  for each antibody tested is shown in Table 10 below: 
     
       
         
           
               
             
               
                 TABLE 10 
               
             
            
               
                   
               
               
                 K d  values for tested antibodies: 
               
            
           
           
               
               
               
            
               
                   
                 Clone 
                 K d , nM 
               
               
                   
                   
               
               
                   
                 245-M3  
                 0.22 
               
               
                   
                 245-M5  
                 0.34 
               
               
                   
                 136-M13 
                 0.19 
               
               
                   
                 136-M19 
                 0.23 
               
               
                   
                 136-M14 
                 0.19 
               
               
                   
                 NV1 nivo 
                 0.28 
               
               
                   
                 PM1 pembro 
                 0.35 
               
               
                   
                   
               
            
           
         
       
     
     Binding of mouse antibodies m136-M13, m136-M19, m245-M3, m245-M5 and m136-M14 to human PD-1 inhibited PD-1 binding to PDL1 and PDL2 in an inhibition ELISA assay ( FIGS. 2-3 ). Inhibition ELISAs were performed as follows. Human PD-1-Fc (R and D systems, Minneapolis, Minn.) was adsorbed to the wells of a 96-well ELISA plate. Purified anti-PD-1 antibodies were applied to the plate in serial dilution in the presence of 2 nM biotinylated PD-L1 or 2 nM biotinylated PDL2. Binding of biotinylated PD-L1 and PD-L2 was detected by Pierce™ Streptavidin-poly HRP conjugate (Thermo Scientific, Rockford, Ill.) and visualized with TMB. Plots were generated in Prizm (Sigma Plot) and the data were fit to a model of single site competition binding and an IC 50  was determined. The IC 50  values for the M13 and M14 antibodies are shown in Table 11 below: 
     
       
         
           
               
             
               
                 TABLE 11 
               
             
            
               
                   
               
               
                 IC 50  values for antibodies tested 
               
            
           
           
               
               
               
            
               
                 IC50 (nM) 
                 hPDL1/Fc 
                 hPDL2/Fc 
               
               
                   
               
               
                 M13 
                 3.3 
                 2   
               
               
                 M14 
                 4.8 
                 2.8 
               
               
                   
               
            
           
         
       
     
     Example 2. Production and Testing of Humanized Anti-PD-1 Antibodies 
     This example demonstrates that mouse antibodies of the disclosure that bind human PD-1 can be converted to humanized IgG antibodies that retain PD-1 binding and inhibition of PDL1 and PDL2 binding to PD-1. 
     Variable domains of the mouse anti-PD-1 antibodies produced as described in Example 1 were humanized and expressed as full length hIgG4/hKappa antibodies. Fully human IgGs anti-PD-1 antibodies were expressed from transiently transfected HEK-293 cells and purified from the culture supernatant by Protein A chromatography. 
     The sequences of the humanized antibodies used in the studies presented herein are shown below: 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 21) 
                   
               
               
                 PD-1 A Hv Variable heavy chain region amino acid sequence: 
                   
               
               
                 EVQLVESGGGLVQPGGSLRLSCAAS GFTFSGYAMS WVRQAPGKGLEWVAY ISNSGGNAH YADSV 
               
               
                   
               
               
                 KGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTR EDYGTSPFVY WGQGTLVTVSS 
               
               
                   
               
               
                 (SEQ ID NO: 22) 
                   
               
               
                 PD-1 A Hv Variable heavy chain region nucleic acid sequence: 
                   
               
               
                 GAAGTGCAGCTGGTGGAATCTGGCGGCGGACTGGTGCAGCCTGGCGGATCTCTGAGACTGAGCT 
               
               
                   
               
               
                 GTGCCGCCAGCGGCTTCACCTTTAGCGGCTACGCCATGAGCTGGGTGCGCCAGGCTCCTGGCAA 
               
               
                   
               
               
                 AGGCCTGGAATGGGTGGCCTACATCAGCAACAGCGGCGGCAATGCCCACTACGCCGATAGCGTG 
               
               
                   
               
               
                 AAGGGCCGGTTCACCATCAGCCGGGACAACAGCAAGAACACCCTGTACCTGCAGATGAACAGCC 
               
               
                   
               
               
                 TGCGGGCCGAGGACACCGCCGTGTACTACTGCACCAGAGAGGACTACGGCACCAGCCCCTTCGT 
               
               
                   
               
               
                 GTATTGGGGCCAGGGTACCCTCGTGACCGTCTCCTCA 
               
               
                   
               
               
                 (SEQ ID NO: 23) 
                   
               
               
                 PD-1 Ab Hv Variable heavy chain region amino acid sequence: 
                   
               
               
                 EVQLVESGGGLVQPGGSLRLSCAAS GFTFSGYAMS WVRQAPGKGLEWVSY ISNSGGNAH YADSV 
               
               
                   
               
               
                 KGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAK EDYGTSPFVY WGQGTLVTVSS 
               
               
                   
               
               
                 (SEQ ID NO: 24) 
                   
               
               
                 PD-1 Ab Hv Variable heavy chain region nucleic acid sequence: 
                   
               
               
                 GAAGTGCAGCTGGTGGAATCTGGCGGCGGACTGGTGCAGCCTGGCGGATCTCTGAGACTGAGCT 
               
               
                   
               
               
                 GTGCCGCCAGCGGCTTCACCTTTAGCGGCTACGCCATGAGCTGGGTGCGCCAGGCTCCTGGCAA 
               
               
                   
               
               
                 AGGCCTGGAATGGGTGAGTTACATCAGCAACAGCGGCGGCAATGCCCACTACGCCGATAGCGTG 
               
               
                   
               
               
                 AAGGGCCGGTTCACCATCAGCCGGGACAACAGCAAGAACACCCTGTACCTGCAGATGAACAGCC 
               
               
                   
               
               
                 TGCGGGCCGAGGACACCGCCGTGTACTACTGCGCCAAGGAGGACTACGGCACCAGCCCCTTCGT 
               
               
                   
               
               
                 GTATTGGGGCCAGGGTACCCTCGTGACCGTCTCCTCA 
               
               
                   
               
               
                 (SEQ ID NO: 25) 
                   
               
               
                 PD-1 Ae Hv Variable heavy chain region amino acid sequence: 
                   
               
               
                 EVQLVESGGGLVQPGGSLRLSCAASG FTFSGYAMS WVRQAPGKGLEWVA YISNSGGNTH YADSV 
               
               
                   
               
               
                 KGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR EDYGTSPFVY WGQGTLVTVSS 
               
               
                   
               
               
                 (SEQ ID NO: 26) 
                   
               
               
                 PD-1 Ae Hv Variable heavy chain region nucleic acid sequence: 
                   
               
               
                 GAAGTGCAGCTGGTGGAATCTGGCGGCGGACTGGTGCAGCCTGGCGGATCTCTGAGACTGAGCT 
               
               
                   
               
               
                 GTGCCGCCAGCGGCTTCACCTTTAGCGGCTACGCCATGAGCTGGGTGCGCCAGGCTCCTGGCAA 
               
               
                   
               
               
                 AGGCCTGGAATGGGTGGCCTACATCAGCAACAGCGGCGGCAATACCCACTACGCCGATAGCGTG 
               
               
                   
               
               
                 AAGGGCCGGTTCACCATCAGCCGGGACAACAGCAAGAACACCCTGTACCTGCAGATGAACAGCC 
               
               
                   
               
               
                 TGCGGGCCGAGGACACCGCCGTGTACTACTGCGCCAGAGAGGACTACGGCACCAGCCCCTTCGT 
               
               
                   
               
               
                 GTATTGGGGCCAGGGTACCCTCGTGACCGTCTCCTCA 
               
               
                   
               
               
                 (SEQ ID NO: 27) 
                   
               
               
                 PD-1 Af Hv Variable heavy chain region amino acid sequence: 
                   
               
               
                 EVQLVESGGGLVQPGGSLRLSCAAS GFTFSGYAMS WVRQAPGKGLEWVA YISNSGGNTH YADSL 
               
               
                   
               
               
                 KGRFTVSRDNSKNTLYLQMNSLRAEDTAVYYCAR EDYGTSPFVY WGQGTLVTVSS 
               
               
                   
               
               
                 (SEQ ID NO: 28) 
                   
               
               
                 PD-1 Af Hv Variable heavy chain region nucleic acid sequence: 
                   
               
               
                 GAAGTGCAGCTGGTGGAATCTGGCGGCGGACTGGTGCAGCCTGGCGGATCTCTGAGACTGAGCT 
               
               
                   
               
               
                 GTGCCGCCAGCGGCTTCACCTTTAGCGGCTACGCCATGAGCTGGGTGCGCCAGGCTCCTGGCAA 
               
               
                   
               
               
                 AGGCCTGGAATGGGTGGCCTACATCAGCAACAGCGGCGGCAATACCCACTACGCCGATAGCCTG 
               
               
                   
               
               
                 AAGGGCCGGTTCACCGTCAGCCGGGACAACAGCAAGAACACCCTGTACCTGCAGATGAACAGCC 
               
               
                   
               
               
                 TGCGGGCCGAGGACACCGCCGTGTACTACTGCGCCAGAGAGGACTACGGCACCAGCCCCTTCGT 
               
               
                   
               
               
                 GTATTGGGGCCAGGGTACCCTCGTGACCGTCTCCTCA 
               
               
                   
               
               
                 (SEQ ID NO: 29) 
                   
               
               
                 PD-1 Ba Hv Variable heavy chain region amino acid sequence: 
                   
               
               
                 QVQLVQSGAEVKKPGASVKMSCKAS GYTFTDYYMD WVRQAPGQGLEWIG YIYPKNGGSS YAQKF 
               
               
                   
               
               
                 QGRATLTVDTSTSTAYMELSSLRSEDTAVYYCAR KVVATDY WGQGTLLTVSS 
               
               
                   
               
               
                 (SEQ ID NO: 30) 
                   
               
               
                 PD-1 Ba Hv Variable heavy chain region nucleic acid sequence: 
                   
               
               
                 CAGGIGCAGCTGGTGCAGICIGGCGCCGAAGTGAAGAAACCAGGCGCCAGCGTGAAGATGAGCT 
               
               
                   
               
               
                 GCAAGGCCAGCGGCTACACCTTCACCGACTACTACATGGACTGGGTGCGCCAGGCCCCTGGACA 
               
               
                   
               
               
                 GGGACTGGAATGGATCGGCTACATCTACCCCAAGAACGGCGGCAGCAGCTACGCCCAGAAGTTC 
               
               
                   
               
               
                 CAGGGCAGAGCCACCCTGACCGTGGACACCAGCACAAGCACCGCCTACATGGAACTGAGCAGCC 
               
               
                   
               
               
                 TGCGGAGCGAGGACACCGCCGTGTACTACTGCGCCAGAAAGGIGGTGGCCACAGACTACTGGGG 
               
               
                   
               
               
                 CCAGGGTACCCTGCTGACCGTGTCTAGT 
               
               
                   
               
               
                 (SEQ ID NO: 31) 
                   
               
               
                 PD-1 Bb Hv Variable heavy chain region amino acid sequence: 
                   
               
               
                 QVQLVQSGAEVKKPGASVKMSCKAS GYTFTDYYMD WVRQAPGQGLEWIG YIYPKNGGSS YAQKF 
               
               
                   
               
               
                 QGRATLTVDKSTSTAYMELSSLRSEDTAVYYCAR KVVATDY WGQGTLLTVSS 
               
               
                   
               
               
                 (SEQ ID NO: 32) 
                   
               
               
                 PD-1 Bb Hv Variable heavy chain region nucleic acid sequence: 
                   
               
               
                 CAGGIGCAGCTGGTGCAGICIGGCGCCGAAGTGAAGAAACCAGGCGCCAGCGTGAAGATGAGCT 
               
               
                   
               
               
                 GCAAGGCCAGCGGCTACACCTTCACCGACTACTACATGGACTGGGTGCGCCAGGCCCCTGGACA 
               
               
                   
               
               
                 GGGACTGGAATGGATCGGCTACATCTACCCCAAGAACGGCGGCAGCAGCTACGCCCAGAAGTTC 
               
               
                   
               
               
                 CAGGGCAGAGCCACCCTGACCGTGGACAAGAGCACCAGCACCGCCTACATGGAACTGAGCAGCC 
               
               
                   
               
               
                 TGCGGAGCGAGGACACCGCCGTGTACTACTGCGCCAGAAAGGIGGTGGCCACAGACTACTGGGG 
               
               
                   
               
               
                 CCAGGGTACCCTGCTGACCGTGTCTAGT 
               
               
                   
               
               
                 (SEQ ID NO: 33) 
                   
               
               
                 PD-1 C Hy Variable heavy chain region amino acid sequence: 
                   
               
               
                 EVQLVESGGGLVQPGGSLRLSCAAS GFTFSNYAMS WVRQAPGKGLEWVA YISNGGGDTH YADSL 
               
               
                   
               
               
                 KGRFTVSRDNSKNTLYLQMNSLRAEDTAVYYCAR ENYGTSPFVY WGQGTLVTVSS 
               
               
                   
               
               
                 (SEQ ID NO: 34) 
                   
               
               
                 PD-1 C Hy Variable heavy chain region nucleic acid sequence: 
                   
               
               
                 GAAGTGCAGCTGGTGGAATCTGGCGGCGGACTGGTGCAGCCTGGCGGATCTCTGAGACTGAGCT 
               
               
                   
               
               
                 GTGCCGCCAGCGGCTICACCTICAGCAACTACGCCATGAGCTGGGTGCGCCAGGCCCCTGGAAA 
               
               
                   
               
               
                 AGGCCTGGAATGGGTGGCCTACATCAGCAACGGCGGAGGCGATACCCACTACGCCGATAGCCTG 
               
               
                   
               
               
                 AAGGGCCGGTTCACCGTGTCCAGAGACAACAGCAAGAACACCCTGTACCTGCAGATGAACAGCC 
               
               
                   
               
               
                 TGCGGGCCGAGGACACCGCCGTGTACTATTGCGCCAGAGAGAACTACGGCACCAGCCCCTTCGT 
               
               
                   
               
               
                 GTACTGGGGCCAGGGTACCCTCGTGACCGTGTCCTCT 
               
               
                   
               
               
                 (SEQ ID NO: 35) 
                   
               
               
                 PD-1 Ca Hy Variable heavy chain region amino acid sequence: 
                   
               
               
                 EVQLVESGGGLVQPGGSLRLSCAAS GFTFSNYAMS WVRQAPGKGLEWV AYISNQGGDTH YADSL 
               
               
                   
               
               
                 KGRFTVSRDNSKNTLYLQMNSLRAEDTAVYYCAR ENYGTSPFVY WGQGTLVTVSS 
               
               
                   
               
               
                 (SEQ ID NO: 36) 
                   
               
               
                 PD-1 Ca Hy Variable heavy chain region nucleic acid sequence: 
                   
               
               
                 GAAGTGCAGCTGGTGGAATCTGGCGGCGGACTGGTGCAGCCTGGCGGATCTCTGAGACTGAGCT 
               
               
                   
               
               
                 GTGCCGCCAGCGGCTICACCTICAGCAACTACGCCATGAGCTGGGTGCGCCAGGCCCCTGGAAA 
               
               
                   
               
               
                 AGGCCTGGAATGGGTGGCCTACATCAGCCAAGGCGGAGGCGATACCCACTACGCCGATAGCCTG 
               
               
                   
               
               
                 AAGGGCCGGTTCACCGTGTCCAGAGACAACAGCAAGAACACCCTGTACCTGCAGATGAACAGCC 
               
               
                   
               
               
                 TGCGGGCCGAGGACACCGCCGTGTACTATTGCGCCAGAGAGAACTACGGCACCAGCCCCTTCGT 
               
               
                   
               
               
                 GTACTGGGGCCAGGGTACCCTCGTGACCGTGTCCTCT 
               
               
                   
               
               
                 (SQ ID NO: 37) 
                   
               
               
                 PD-1 D Hv Variable heavy chain region amino acid sequence: 
                   
               
               
                 EVQLVESGGGLVQPGGSLRLSCAHS GFSFSSYDMS WVRQAPGKGLEWVA TISGGGRYTY YADSV 
               
               
                   
               
               
                 KGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAS NYYGFDY WGQGTLLTVSS 
               
               
                   
               
               
                 (SEQ ID NO: 38) 
                   
               
               
                 PD-1 D Hv Variable heavy chain region nucleic acid sequence: 
                   
               
               
                 GAAGTGCAGCTGGTGGAATCTGGCGGCGGACTGGTGCAGCCTGGCGGATCTCTGAGACTGAGCT 
               
               
                   
               
               
                 GTGCCCACAGCGGCTTCAGCTTCAGCAGCTACGACATGAGCTGGGTGCGCCAGGCCCCTGGCAA 
               
               
                   
               
               
                 AGGACTGGAATGGGTGGCCACAATCAGCGGCGGAGGCCGGTACACCTACTACGCCGATAGCGTG 
               
               
                   
               
               
                 AAGGGCCGGTTCACCATCAGCCGGGACAACAGCAAGAACACCCTGTACCTGCAGATGAACAGCC 
               
               
                   
               
               
                 TGCGGGCCGAGGACACCGCCGTGTACTACTGCGCCAGCAACTACTACGGCTTCGACTACTGGGG 
               
               
                   
               
               
                 CCAGGGTACCCTGCTGACCGTGTCATCT 
               
               
                   
               
               
                 (SEQ ID NO: 39) 
                   
               
               
                 PD-1 1.0 Lv Variable light chain region amino acid sequence: 
                   
               
               
                 DIQLTQSPSSLSASVGDRVTITC RASESVDNYGISFMN WFQQKPGKAPKLLIY AASNQGS GVPS 
               
               
                   
               
               
                 RFSGSGSGTDFTLTISSMQPEDFATYYC QQSKDVPWT FGQGTKLEIK 
               
               
                   
               
               
                 (SEQ ID NO: 40) 
                   
               
               
                 PD-1 1.0 Lv Variable light chain region nucleic acid sequence: 
                   
               
               
                 GACATCCAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGACAGAGTGACCATCA 
               
               
                   
               
               
                 CCTGTAGAGCCAGCGAGAGCGTGGACAACTACGGCATCAGCTTCATGAACTGGTTCCAGCAGAA 
               
               
                   
               
               
                 GCCCGGCAAGGCCCCCAAGCTGCTGATCTACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGC 
               
               
                   
               
               
                 AGATTTTCCGGCTCTGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGCCCGAGG 
               
               
                   
               
               
                 ACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGGACCTTTGGCCAGGGTACCAA 
               
               
                   
               
               
                 GCTGGAAATCAAG 
               
               
                   
               
               
                 (SEQ ID NO: 41) 
                   
               
               
                 PD-1 1.1 Lv Variable light chain region amino acid sequence: 
                   
               
               
                 DIQLTQSPSSLSVSVGDRATITC RASESVDNYGISFMN WFQQKPGKAPKLLIY AASNQGS GVPS 
               
               
                   
               
               
                 RFSGSGSGTDFTLTISSMQPEDFATYYC QQSKDVPWT FGQGTKLEIK 
               
               
                   
               
               
                 (SEQ ID NO: 42) 
                   
               
               
                 PD-1 1.1 Lv Variable light chain region nucleic acid sequence: 
                   
               
               
                 GACATCCAGCTGACCCAGAGCCCTAGCAGCCTGTCCGTGTCCGTGGGCGACAGAGCCACCATCA 
               
               
                   
               
               
                 CCTGTAGAGCCAGCGAGAGCGTGGACAACTACGGCATCAGCTTCATGAACTGGTTCCAGCAGAA 
               
               
                   
               
               
                 GCCCGGCAAGGCCCCCAAGCTGCTGATCTACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGC 
               
               
                   
               
               
                 AGATTTTCCGGCTCTGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGCCCGAGG 
               
               
                   
               
               
                 ACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGGACCTTTGGCCAGGGTACCAA 
               
               
                   
               
               
                 GCTGGAAATCAAG 
               
               
                   
               
               
                 (SEQ ID NO: 43) 
                   
               
               
                 PD-1 1.2 Lv Variable light chain region amino acid sequence: 
                   
               
               
                 DIQLTQSPSSLSASVGDRVTITC RASESVDQYGISFMN WFQQKPGKAPKLLIY AASNQGS GVPS 
               
               
                   
               
               
                 RFSGSGSGTDFTLTISSMQPEDFATYYC QQSKDVPW FGQGTKLEIK 
               
               
                   
               
               
                 (SEQ ID NO: 44) 
                   
               
               
                 PD-1 1.2 Lv Variable light chain region nucleic acid sequence: 
                   
               
               
                 GACATCCAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGACAGAGTGACCATCA 
               
               
                   
               
               
                 CCTGTAGAGCCAGCGAGAGCGTGGACCAATACGGCATCAGCTTCATGAACTGGTTCCAGCAGAA 
               
               
                   
               
               
                 GCCCGGCAAGGCCCCCAAGCTGCTGATCTACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGC 
               
               
                   
               
               
                 AGATTTTCCGGCTCTGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGCCCGAGG 
               
               
                   
               
               
                 ACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGGACCTTTGGCCAGGGTACCAA 
               
               
                   
               
               
                 GCTGGAAATCAAG 
               
               
                   
               
               
                 (SEQ ID NO: 45) 
                   
               
               
                 PD-1 1.4 Lv Variable light chain region amino acid sequence: 
                   
               
               
                 DIQLTQSPSSLSASVGDRVTITC RASESVDSYGISFMN WFQQKPGKAPKLLIY AASNQGS GVPS 
               
               
                   
               
               
                 RFSGSGSGTDFTLTISSMQPEDFATYYC QQSKDVPWT FGQGTKLEIK 
               
               
                   
               
               
                 (SEQ ID NO: 46) 
                   
               
               
                 PD-1 1.4 Lv Variable light chain region nucleic acid sequence: 
                   
               
               
                 GACATCCAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGACAGAGTGACCATCA 
               
               
                   
               
               
                 CCTGTAGAGCCAGCGAGAGCGTGGACAGTTACGGCATCAGCTTCATGAACTGGTTCCAGCAGAA 
               
               
                   
               
               
                 GCCCGGCAAGGCCCCCAAGCTGCTGATCTACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGC 
               
               
                   
               
               
                 AGATTTTCCGGCTCTGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGCCCGAGG 
               
               
                   
               
               
                 ACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGGACCTTTGGCCAGGGTACCAA 
               
               
                   
               
               
                 GCTGGAAATCAAG 
               
               
                   
               
               
                 (SEQ ID NO: 47) 
                   
               
               
                 PD-1 1.5 Lv Variable light chain region amino acid sequence: 
                   
               
               
                 DIQLTQSPSSLSASVGDRVTITC RASESVDAYGISFMN WFQQKPGKAPKLLIY AASNQGS GVPS 
               
               
                   
               
               
                 RFSGSGSGTDFTLTISSMQPEDFATYYC QQSKDVPWT FGQGTKLEIK 
               
               
                   
               
               
                   
               
               
                 (SEQ ID NO: 48) 
                   
               
               
                 PD-1 1.5 Lv Variable light chain region nucleic acid sequence: 
                   
               
               
                 GACATCCAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGACAGAGTGACCATCA 
               
               
                   
               
               
                 CCTGTAGAGCCAGCGAGAGCGTGGACGCTTACGGCATCAGCTTCATGAACTGGTTCCAGCAGAA 
               
               
                   
               
               
                 GCCCGGCAAGGCCCCCAAGCTGCTGATCTACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGC 
               
               
                   
               
               
                 AGATTTTCCGGCTCTGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGCCCGAGG 
               
               
                   
               
               
                 ACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGGACCTTTGGCCAGGGTACCAA 
               
               
                   
               
               
                 GCTGGAAATCAAG 
               
               
                   
               
               
                 (SEQ ID NO: 49) 
                   
               
               
                 PD-1 1.6 Lv Variable light chain region amino acid sequence: 
                   
               
               
                 DIQLTQSPSSLSASVGDRVTITC RASESVDNYGISFMN WFQQKPGKAPKLLIY AASDQGS GVPS 
               
               
                   
               
               
                 RFSGSGSGTDFTLTISSMQPEDFATYYC QQSKDVPWT FGQGTKLEIK 
               
               
                   
               
               
                 (SEQ ID NO: 50) 
                   
               
               
                 PD-1 1.6 Lv Variable light chain region nucleic acid sequence: 
                   
               
               
                 GACATCCAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGACAGAGTGACCATCA 
               
               
                   
               
               
                 CCTGTAGAGCCAGCGAGAGCGTGGACAACTACGGCATCAGCTTCATGAACTGGTTCCAGCAGAA 
               
               
                   
               
               
                 GCCCGGCAAGGCCCCCAAGCTGCTGATCTACGCCGCCAGCGATCAGGGCAGCGGCGTGCCAAGC 
               
               
                   
               
               
                 AGATTTTCCGGCTCTGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGCCCGAGG 
               
               
                   
               
               
                 ACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGGACCTTTGGCCAGGGTACCAA 
               
               
                   
               
               
                 GCTGGAAATCAAG 
               
               
                   
               
               
                 (SEQ ID NO: 51) 
                   
               
               
                 PD-1 1.7 Lv Variable light chain region amino acid sequence: 
                   
               
               
                 DIQLTQSPSSLSVSVGDRATITC RASESVDAYGISFMN WFQQKPGKAPKLLIY AASNQGS GVPS 
               
               
                   
               
               
                 RFSGSGSGTDFTLTISSMQPEDFATYYC QQSKDVPWT FGQGTKLEIK 
               
               
                   
               
               
                 (SEQ ID NO: 52) 
                   
               
               
                 PD-1 1.7 Lv Variable light chain region nucleic acid sequence: 
                   
               
               
                 GACATCCAGCTGACCCAGAGCCCTAGCAGCCTGTCCGTGTCCGTGGGCGACAGAGCCACCATCA 
               
               
                   
               
               
                 CCTGTAGAGCCAGCGAGAGCGTGGACGCTTACGGCATCAGCTTCATGAACTGGTTCCAGCAGAA 
               
               
                   
               
               
                 GCCCGGCAAGGCCCCCAAGCTGCTGATCTACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGC 
               
               
                   
               
               
                 AGATTTTCCGGCTCTGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGCCCGAGG 
               
               
                   
               
               
                 ACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGGACCTTTGGCCAGGGTACCAA 
               
               
                   
               
               
                 GCTGGAAATCAAG 
               
               
                   
               
               
                 (SEQ ID NO: 53) 
                   
               
               
                 PD-1 1.9 Lv Variable light chain region amino acid sequence: 
                   
               
               
                 DIQLTQSPSSLSASVGDRVTITC RASESVDAYGISFMN WFQQKPGKAPKLLIY AASNQGS GVPS 
               
               
                   
               
               
                 RFSGSGSGTDFTLTISSMQPEDFATYYC QQSKDVPWT FGQGTKVEIK 
               
               
                   
               
               
                 (SEQ ID NO: 54) 
                   
               
               
                 PD-1 1.9 Lv Variable light chain region nucleic acid sequence: 
                   
               
               
                 GACATCCAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGACAGAGTGACCATCA 
               
               
                   
               
               
                 CCTGTAGAGCCAGCGAGAGCGTGGACGCTTACGGCATCAGCTTCATGAACTGGTTCCAGCAGAA 
               
               
                   
               
               
                 GCCCGGCAAGGCCCCCAAGCTGCTGATCTACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGC 
               
               
                   
               
               
                 AGATTTTCCGGCTCTGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGCCCGAGG 
               
               
                   
               
               
                 ACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGGACCTTTGGCCAGGGTACCAA 
               
               
                   
               
               
                 GGTGGAAATCAAG 
               
               
                   
               
               
                 (SEQ ID NO: 55) 
                   
               
               
                 PD-1 1.10 Lv Variable light chain region amino acid sequence: 
                   
               
               
                 DIQLTQSPSSLSASVGDRVTITC RASESVDAYGISFMN WFQQKPGKAPKLLIY AASNQGS GVPS 
               
               
                   
               
               
                 RFSGSGSGTDFTLTISSMQPEDFATYYC QQSKDVPYT FGQGTKLEIK 
               
               
                   
               
               
                 (SEQ ID NO: 56) 
                   
               
               
                 PD-1 1.10 Lv Variable light chain region nucleic acid sequence: 
                   
               
               
                 GACATCCAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGACAGAGTGACCATCA 
               
               
                   
               
               
                 CCTGTAGAGCCAGCGAGAGCGTGGACGCTTACGGCATCAGCTTCATGAACTGGTTCCAGCAGAA 
               
               
                   
               
               
                 GCCCGGCAAGGCCCCCAAGCTGCTGATCTACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGC 
               
               
                   
               
               
                 AGATTTTCCGGCTCTGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGCCCGAGG 
               
               
                   
               
               
                 ACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTACACCTTTGGCCAGGGTACCAA 
               
               
                   
               
               
                 GCTGGAAATCAAG 
               
               
                   
               
               
                 (SEQ ID NO: 57) 
                   
               
               
                 PD-1 2 Lv Variable light chain region amino acid sequence: 
                   
               
               
                 DIQMTQSPSSLSASVGDRVTMTC KSSQSLLYSSNQKNYLAW YQQKPGKAPKLLIF WASIRES GV 
               
               
                   
               
               
                 PSRFSGSGSGTDFTLTISSVQPEDFATYYC QQSDSYPWT FGQGTKLEIK 
               
               
                   
               
               
                 (SEQ ID NO: 58) 
                   
               
               
                 PD-1 2 Lv Variable light chain region nucleic acid sequence: 
                   
               
               
                 GACATCCAGATGACCCAGAGCCCCAGCAGCCTGTCTGCCAGCGTGGGCGATAGAGTGACCATGA 
               
               
                   
               
               
                 CCTGCAAGAGCAGCCAGAGCCTGCTGTACTCCAGCAACCAGAAGAACTACCTGGCCTGGTATCA 
               
               
                   
               
               
                 GCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATCTTCTGGGCCAGCATCCGGGAAAGCGGCGTG 
               
               
                   
               
               
                 CCCAGCAGATTTTCTGGCTCTGGCAGCGGCACCGACTTCACCCTGACAATCAGCAGCGTGCAGC 
               
               
                   
               
               
                 CCGAGGACTTCGCCACCTACTACTGCCAGCAGAGCGACAGCTACCCCTGGACCTTTGGCCAGGG 
               
               
                   
               
               
                 TACCAAGCTGGAAATCAAG 
               
               
                   
               
               
                 (SEQ ID NO: 59) 
                   
               
               
                 PD-1 4 Lv Variable light chain region amino acid sequence: 
                   
               
               
                 DIQMTQSPSSLSASVGDRVTITC KASQDVGTAVA WYQQKPGKAPKLLIYWASTRHTGVPSRFSG 
               
               
                   
               
               
                 SGSGTDFTLTISSVQPEDFATYYCQQYSSYPWTFGQGTKLEIK 
               
               
                   
               
               
                 (SEQ ID NO: 60) 
                   
               
               
                 PD-1 4 Lv Variable light chain region nucleic acid sequence: 
                   
               
               
                 GACATCCAGATGACCCAGAGCCCCAGCAGCCTGTCTGCCAGCGTGGGCGACAGAGTGACCATCA 
               
               
                   
               
               
                 CATGCAAGGCCAGCCAGGACGTGGGAACAGCCGTGGCCTGGTATCAGCAGAAGCCTGGCAAGGC 
               
               
                   
               
               
                 CCCCAAGCTGCTGATCTACTGGGCCAGCACCAGACACACCGGCGTGCCCAGCAGATTTTCTGGC 
               
               
                   
               
               
                 AGCGGCTCCGGCACCGACTTCACCCTGACAATCAGCAGCGTGCAGCCCGAGGACTTCGCCACCT 
               
               
                   
               
               
                 ACTACTGCCAGCAGTACAGCAGCTACCCCTGGACCTTTGGCCAGGGTACCAAGCTGGAAATCAA 
               
               
                   
               
               
                 G 
               
               
                   
               
               
                 (SEQ ID NO: 61) 
                   
               
               
                 Kappa constant region amino acid sequence: 
                   
               
               
                 RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS 
               
               
                   
               
               
                 TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 
               
               
                   
               
               
                 (SEQ ID NO: 62) 
                   
               
               
                 Kappa constant region nucleic acid sequence: 
                   
               
               
                 CGTACGGIGGCTGCACCATCTGICTICATCTICCCGCCATCTGATGAGCAGTTGAAATCTGGAA 
               
               
                   
               
               
                 CTGCCTCTGTTGTGTGCCTGCTGAATAACTICTATCCCAGAGAGGCCAAAGTACAGTGGAAGGT 
               
               
                   
               
               
                 GGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGC 
               
               
                   
               
               
                 ACCTACAGCCICAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGICTACG 
               
               
                   
               
               
                 CCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTICAACAGGGGAGAGTG 
               
               
                   
               
               
                 T 
               
               
                   
               
               
                 (SEQ ID NO: 63) 
                   
               
               
                 hIgG4 S228P amino acid sequence: 
                   
               
               
                 ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS 
               
               
                   
               
               
                 LSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPK 
               
               
                   
               
               
                 DTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQD 
               
               
                   
               
               
                 WLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSD 
               
               
                   
               
               
                 IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKS 
               
               
                   
               
               
                 LSLSLGK 
               
               
                   
               
               
                 (SEQ ID NO: 64) 
                   
               
               
                 hIgG4 S228P nucleic acid sequence: 
                   
               
               
                 GCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTGTAGCAGAAGCACCAGCGAGTCTA 
               
               
                   
               
               
                 CAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTC 
               
               
                   
               
               
                 AGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCC 
               
               
                   
               
               
                 CTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCAAGACCTACACCTGTAACGTGG 
               
               
                   
               
               
                 ACCACAAGCCCAGCAACACCAAGGTGGACAAGCGGGTGGAATCTAAGTACGGCCCTCCCTGCCC 
               
               
                   
               
               
                 TCCTTGCCCAGCCCCTGAATTICTGGGGGGACCGTCAGICTICCTCTICCCCCCAAAACCCAAG 
               
               
                   
               
               
                 GACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCAGGAAG 
               
               
                   
               
               
                 ACCCTGAGGICCAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCC 
               
               
                   
               
               
                 GCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGAC 
               
               
                   
               
               
                 TGGCTGAATGGCAAGGAGTACAAGTGCAAGGICTCCAACAAAGGCCTGCCCAGCTCCATCGAGA 
               
               
                   
               
               
                 AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGIGTACACCCTGCCCCCATCCCA 
               
               
                   
               
               
                 GGAGGAGATGACCAAGAACCAGGICAGCCTGACCTGCCTGGICAAAGGCTICTATCCCAGCGAC 
               
               
                   
               
               
                 ATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC 
               
               
                   
               
               
                 TGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGACTCACCGTGGACAAGAGCAGGTGGCAGGA 
               
               
                   
               
               
                 AGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGC 
               
               
                   
               
               
                 CTCTCCCTGTCTCTGGGTAAA 
               
            
           
         
       
     
     These variable heavy chain regions (VH) and variable light chain regions (VL) can be used in a variety of combinations to produce anti-PD-1 antibodies of the disclosure. For example, the antibody referred to herein as A1.0 includes the VH sequence of SEQ ID NO: 21 and the VL sequence of SEQ ID NO: 39, the A1.5 antibody includes the VH sequence of SEQ ID NO: 21 and the VL sequence of SEQ ID NO: 47; the antibody referred to herein as C1.1 includes the VH sequence of SEQ ID NO: 33 and the VL sequence of SEQ ID NO: 41, and so on. 
     As shown in  FIGS. 4-5 , humanized anti-PD-1 antibodies bound to hPD-1 in a standard ELISA in a manner similar to that of nivolumab and/or pembrolizumab, and binding of the humanized antibodies inhibited the binding of PD-1 to PDL1 and PDL2 ( FIGS. 6-9 ) in inhibition ELISAs. ELISAs were performed as follows. For hPD-1 binding ELISAs, human PD-1-Fc (R and D systems, Minneapolis, Minn.) was adsorbed to the wells of a 96-well ELISA plate. Purified anti-PD-1 antibodies were applied to the plate in serial dilution and allowed to bind. Bound antibody was detected with an anti-human IgG-HRP conjugate (FAb-specific) (Sigma, St Louis, Mo.) and visualized with the chromogenic substrate TMB (Thermo Scientific, Rockford, Ill.). Plots were generated in Prizm (Sigma Plot) and the data were fit to a model of single site saturation binding. For ligand inhibition ELISAs, human PD-1-Fc (R and D systems, Minneapolis, Minn.) was adsorbed to the wells of a 96-well ELISA plate. Purified anti-PD-1 antibodies were applied to the plate in serial dilution in the presence of 2 nM biotinylated hPD-L1 or 2 nM biotinylated hPD-L2. Pierce™ Streptavidin-poly HRP conjugate (Thermo Scientific, Rockford, Ill.) and visualized with TMB. Plots were generated in Prizm (Sigma Plot) and the data were fit to a model of single site competition binding and an IC 50  was determined. 
     Example 3: Anti-PD-1 Antibodies Shows Specificity in Binding 
     Example 3 shows that humanized anti-PD-1 antibody groups A1 and C1 of the disclosure bind specifically to hPD-1 by plate ELISA. 
     The binding of anti-PD-1 antibody A1.5 of the disclosure was highly specific to hPD-1-Fc in a standard ELISA against a panel of numerous human and mouse proteins (FIG.  10 ). Binding of anti-PD-1 A1.5 was detected with an anti-human IgG-HRP conjugate (FAb-specific) (Sigma, St Louis, Mo.) and visualized with the chromogenic substrate TMB (Thermo Scientific, Rockford, Ill.). Plots were generated in Prizm (Sigma Plot) and the data were fit to a model of single site saturation binding. 
     Example 4: Anti-PD-1 Epitope Binding 
     This example compares the epitopes bound by humanized anti-PD-1 antibodies of the disclosure, nivolumab, and pembrolizumab. 
     Nivolumab and pembrolizumab anti-PD-1 antibodies each bind human PD-1 and such binding by each inhibits the binding of PD-1 to PDL1 and PDL2. To map the epitopes of humanized groups A1 and C1 antibodies of the disclosure, anti-PD-1 inhibition ELISAs were performed, and compared with nivolumab and pembrolizumab inhibition. Dilution series of nivolumab, pembrolizumab, A1 and C1 antibodies were incubated in the presence of biotinylated nivolumab FAb or biotinylated pembrolizumab FAb at a concentration of 0.3 nM in a standard plate ELISA format with hPD-1-Fc (R &amp; D systems, Minneapolis, Minn.). Binding of biotinylated FAb was detected by Pierce™ Streptavidin-poly HRP conjugate (Thermo Scientific, Rockford, Ill.) and visualized with TMB (Thermo Scientific, Rockford Ill.) and 1N HCl. Antibodies belonging to the A1 and C1 groups of the disclosure blocked biotinylated Pembrolizumab FAb binding to PD-1 similarly to Pembrolizumab antibody and more completely than nivolumab antibody ( FIG. 11A ). The same A1 and C1 antibodies of the disclosure blocked biotinylated nivolumab binding similarly to nivolumab antibody and more completely than pembrolizumab antibody ( FIG. 11B ). The data in  FIGS. 11A and 11B  show that A1 and C1 antibodies of the disclosure completely block both nivolumab and pembrolizumab, whereas nivolumab and pembrolizumab incompletely block each other. 
     Example 5: Anti-PD-1 A1.5 Enhances CMV-Stimulated Cytokine Secretion by PBMCs from a CMV-Positive Donor 
     In this example, peripheral blood mononuclear cells from a CMV-positive donor were incubated in the presence of CMV viral lysate and anti-PD-1 antibodies of the disclosure to assess the effect of such anti-PD-1 antibodies on interferon gamma (IFN-gamma, IFNg, IFN-g, IFNγ, or IFN-γ) cytokine secretion. 
     PBMCs from a CMV-positive donor (Hemacare) were plated at 2×10 5  cells/well in the presence of CMV viral lysate (Astarte) and either anti-PD-1 antibody A1.5 of the disclosure or a hIgG4 isotype control antibody. After four days, supernatant was removed from each well, and IFN-gamma levels were assayed using IFN-gamma ELISA kit (Life Technologies, Carlsbad, Calif.) ( FIG. 12 ). Anti-PD-1 antibody A1.5 increased CMV-stimulated IFN-gamma secretion compared with control hIgG4 and with potency similar to anti-PD-1 nivolumab and pembrolizumab antibodies. 
     Example 6: Anti-PD-1 Antibodies Bind to Monomeric hPD-1 with High Affinity and Slow Dissociation Kinetics 
     In this example, humanized anti-PD-1 antibodies of the disclosure are shown to bind with high affinity and slow dissociation to monomeric PD-1. 
     Activatable antibodies can be activated singly, creating a monovalent binding moiety, or doubly, creating a bivalent binding moiety. Single-arm activation of antibodies with differing avidities can favor binding and biological activity of activatable antibodies with higher monovalent affinities. Anti-PD-1 antibodies A1.5 and Bba2 of the disclosure, as well as nivolumab and pembrolizumab were immobilized at equivalent densities on Forte-Bio Octet BioLayer Inferometry (Pall ForteBio, Menlo Park, Calif.) sensors and allowed to bind to a serial dilution of human PD-1-His (R &amp; D systems, Minneapolis, Minn.) in solution. Kinetic analysis was performed with ForteBio Data Analysis software. Results ( FIG. 13 ) show PD-1 antibodies of the disclosure bind monomeric PD-1 with similar or higher affinities and similar or slower dissociation constants than nivolumab or pembrolizumab. 
     Example 7: Activatable Anti-PD-1 M13/A1.4/A1.5 Antibody Masking Moieties 
     This example describes identification of masking moieties (MM) that reduce binding of anti-PD-1 antibodies of the disclosure to their target. 
     Anti-PD-1 antibodies m136-M13, A1.4 and A1.5 were used to screen libraries using a method similar to that described in PCT International Publication Number WO 2010/081173, published 15 Jul. 2010. The screening consisted of one round of MACS and five rounds of FACS sorting. For the initial MACS, approximately 2×10 11  cells were incubated with m136-M13 antibody at a concentration of 100 nM, and 6×10 6  binders were collected using Protein-G Dynabeads (Invitrogen). FACS rounds were conducted labeling cells with DyLight 650 (Thermo-Fisher) labeled m136-M19 antibody for FACS rounds 1-4 as follows: 100 nM FACS round 1 (F1), 10 nM FACS round 2 (F2), 2 nM FACS round 3 (F3) and 1 nM FACS round 4 (F4), with increasingly small percentages of binders as assessed by fluorescence collected at each round. For FACS round 5 (F5), cells were labeled with 1 nM DyLight 650 labeled A1.5 antibody and the brightest 0.2-4% of cells were collected. Individual peptide clones from F3, F4 and F5 were identified by sequence analysis and subsequently verified for their ability to bind DyLight-650 A1.4 or DyLight-650 A1.5. 
     The sequences of the anti-PD-1 m136-M13, A1.4 and A1.5 masking moieties are listed in Table 12 (masking moiety PD001 is also referred to in the disclosure as PD01 and/or PD-01; masking moiety PD002 is also referred to herein as PD02 and/or PD-02, and so on): 
     
       
         
           
               
               
             
               
                   
                 TABLE 12 
               
             
            
               
                   
                   
               
               
                   
                 Masking Moieties 
               
            
           
           
               
               
               
               
            
               
                   
                 Mask 
                 Amino Acid Sequence 
                 SEQ ID NO: 
               
               
                   
                   
               
               
                   
                 PD001 
                 AMSGCSWSAFCPYLA 
                 66 
               
               
                   
                 PD002 
                 DVNCAIWYSVCTTVP 
                 67 
               
               
                   
                 PD003 
                 LVCPLYALSSGVCMG 
                 68 
               
               
                   
                 PD004 
                 SVNCRIWSAVCAGYE 
                 69 
               
               
                   
                 PD005 
                 MLVCSLQPTAMCERV 
                 70 
               
               
                   
                 PD006 
                 APRCYMFASYCKSQY 
                 71 
               
               
                   
                 PD007 
                 VGPCELTPKPVCNTY 
                 72 
               
               
                   
                 PD008 
                 ETCNQYERSSGLCFA 
                 73 
               
               
                   
                 PD009 
                 APRTCYTYQCSSFYT 
                 74 
               
               
                   
                 PD010 
                 GLCSWYLSSSGLCVD 
                 75 
               
               
                   
                 PD011 
                 VPWCQLTPRVMCMWA 
                 76 
               
               
                   
                 PD012 
                 NWLDCQFYSECSVYG 
                 77 
               
               
                   
                 PD013 
                 SCPLYVMSSFGGCWD 
                 78 
               
               
                   
                 PD014 
                 MSHCWMFSSSCDGVK 
                 79 
               
               
                   
                 PD015 
                 VSYCTWLIEVTCLRG 
                 80 
               
               
                   
                 PD016 
                 VLCAAYALSSGICGG 
                 81 
               
               
                   
                 PD017 
                 TTCNLYQQSSMFCNA 
                 82 
               
               
                   
                 PD018 
                 APRCYMFASYCKSQY 
                 83 
               
               
                   
                 PD019 
                 PCDQNPYFYPYVCHA 
                 84 
               
               
                   
                 PD020 
                 SVCPMYALSSMLCGA 
                 85 
               
               
                   
                 PD021 
                 LSVECYVFSRCSSLP 
                 86 
               
               
                   
                 PD022 
                 FYCTYLVSLTCHPQ 
                 87 
               
               
                   
                 PD023 
                 SMAGCQWSSFCVQRD 
                 88 
               
               
                   
                 PD024 
                 IYSCYMFASRCTSDK 
                 89 
               
               
                   
                 PD025 
                 SRCSVYEVSSGLCDW 
                 90 
               
               
                   
                 PD026 
                 GMCSAYAYSSKLCTI 
                 91 
               
               
                   
                 PD027 
                 MTTNTCNLLCQQFLT 
                 92 
               
               
                   
                 PD028 
                 FQPCLMFASSCFTSK 
                 93 
               
               
                   
                 PD029 
                 WNCHPAGVGPVFCEV 
                 94 
               
               
                   
                 PD030 
                 ALCSMYLASSGLCNK 
                 95 
               
               
                   
                 PD031 
                 NYLSCQFFQNCYETY 
                 96 
               
               
                   
                 PD032 
                 GWCLFSDMWLGLCSA 
                 97 
               
               
                   
                 PD033 
                 EFCARDWLPYQCSSF 
                 98 
               
               
                   
                 PD034 
                 TSYCSIEHYPCNTHH 
                 99 
               
               
                   
                 PD035 
                 PYICSSFPLDCQAGQ 
                 100 
               
               
                   
                 PD036 
                 VGCEWYMSSSGMCSR 
                 101 
               
               
                   
                 PD037 
                 EVCGGCSMQSVSCWP 
                 102 
               
               
                   
                 PD038 
                 FTECQLSPKAICMSN 
                 103 
               
               
                   
                 PD039 
                 KYCLFSEYVEGTCLN 
                 104 
               
               
                   
                 PD040 
                 SGCPMYAWGWDECWR 
                 105 
               
               
                   
                 PD041 
                 VDCPWYASSSAICSR 
                 106 
               
               
                   
                 PD042 
                 DMLLCQIRGSCAAWG 
                 107 
               
               
                   
                 PD043 
                 ECHPYQASASLWCGY 
                 108 
               
            
           
           
               
               
               
               
               
            
               
                   
                 PD044 
                 MMMGCMWSAWCPPSR 
                 109 
                   
               
               
                   
                 PD045 
                 NAYFRCSLMCNMIMF 
                 110 
                   
               
               
                   
                 PD046 
                 ACCKESVHSVHDCKR 
                 111 
                   
               
               
                   
                 PD047 
                 ACIGINSYMSNYCYL 
                 112 
                   
               
               
                   
                 PD048 
                 ANCSFLELTNKFCTI 
                 113 
                   
               
               
                   
                 PD049 
                 AYCSYLMFASNPCII 
                 114 
                   
               
               
                   
                 PD050 
                 CFTSKCPCLCYSLLA 
                 115 
                   
               
               
                   
                 PD051 
                 CLCRDINCWLGCSKT 
                 116 
                   
               
               
                   
                 PD052 
                 CWCDIYCSPYQCSSF 
                 117 
                   
               
               
                   
                 PD053 
                 DCIYYYQQSANLCSY 
                 118 
                   
               
               
                   
                 PD054 
                 DCTGVNYYIDKHCTN 
                 119 
                   
               
               
                   
                 PD055 
                 DECHGYLRSSGLCGG 
                 120 
                   
               
               
                   
                 PD056 
                 DICSAYAASSGFCYY 
                 121 
                   
               
               
                   
                 PD057 
                 DIICVLTPTAWCGRT 
                 122 
                   
               
               
                   
                 PD058 
                 DNCCMYCSWWIACRD 
                 123 
                   
               
               
                   
                 PD059 
                 DSCQWYMLSADLCGT 
                 124 
                   
               
               
                   
                 PD060 
                 DSVCFSSSSFLCHKS 
                 125 
                   
               
               
                   
                 PD061 
                 DTMCAIWWTVCSGGR 
                 126 
                   
               
               
                   
                 PD062 
                 ECTYQTSSFHEACMS 
                 127 
                   
               
               
                   
                 PD063 
                 EGCNLYERSSYGCNN 
                 128 
                   
               
               
                   
                 PD064 
                 EGCTAFAMSAGICGG 
                 129 
                   
               
               
                   
                 PD065 
                 EQSCSLTPIAFCWSE 
                 130 
                   
               
               
                   
                 PD066 
                 EWCNAYISSSKLCST 
                 131 
                   
               
               
                   
                 PD067 
                 FEVCYMFASACRNGM 
                 132 
                   
               
               
                   
                 PD068 
                 FSCSWYAESSSLCDI 
                 133 
                   
               
               
                   
                 PD069 
                 FVCQMFEASSGLCGG 
                 134 
                   
               
               
                   
                 PD070 
                 FYCPCCMFASSCGSR 
                 135 
                   
               
               
                   
                 PD071 
                 FYCSYLPGASHQCSH 
                 136 
                   
               
               
                   
                 PD072 
                 FYCSYLYMCEVCCYE 
                 137 
                   
               
               
                   
                 PD073 
                 GFCTQHTVLTWCPTS 
                 138 
                   
               
               
                   
                 PD074 
                 GSCPSYAVSAGLCYA 
                 139 
                   
               
               
                   
                 PD075 
                 GSQCFLTPTAFCTHT 
                 140 
                   
               
               
                   
                 PD076 
                 GTCHPYMQSSKICNN 
                 141 
                   
               
               
                   
                 PD077 
                 GVECFVFTGGCGGYG 
                 142 
                   
               
               
                   
                 PD078 
                 HELCNGHWVPCCWAY 
                 143 
                   
               
               
                   
                 PD079 
                 ICDSYYAVSSGLCLL 
                 144 
                   
               
               
                   
                 PD080 
                 IGCAWYVSSAGWCSP 
                 145 
                   
               
               
                   
                 PD081 
                 INLCWMFASECGEHH 
                 146 
                   
               
               
                   
                 PD082 
                 KCWLAEMTNLEHCNM 
                 147 
                   
               
               
                   
                 PD083 
                 KHCSDFAYSSRLCDR 
                 148 
                   
               
               
                   
                 PD084 
                 KVCSSYASSSGLCGW 
                 149 
                   
               
               
                   
                 PD085 
                 LDSCYMFASYCVQAV 
                 150 
                   
               
               
                   
                 PD086 
                 LLACHPIFVTVCQTR 
                 151 
                   
               
               
                   
                 PD087 
                 LLSCPYNPEHVCHTS 
                 152 
                   
               
               
                   
                 PD088 
                 LMCSLYALSSNLCGR 
                 153 
                   
               
               
                   
                 PD089 
                 LMWCVLFLWSWCCRI 
                 154 
                   
               
               
                   
                 PD090 
                 LPICHLTPTAVCTHI 
                 155 
                   
               
               
                   
                 PD091 
                 LSNMCLAFGSCLYAW 
                 156 
                   
               
               
                   
                 PD092 
                 LSRCHPIWYTICQNP 
                 157 
                   
               
               
                   
                 PD093 
                 LTQCMSVHKECGGYE 
                 158 
                   
               
               
                   
                 PD094 
                 LVNCRIWSWVCEEAT 
                 159 
                   
               
               
                   
                 PD095 
                 LYCSWYQMSSAVCKE 
                 160 
                   
               
               
                   
                 PD096 
                 MECGWYALSARFCEV 
                 161 
                   
               
               
                   
                 PD097 
                 MTCSPYAMSAHFCNE 
                 162 
                   
               
               
                   
                 PD098 
                 MVCSLYAYSASLCGA 
                 163 
                   
               
               
                   
                 PD099 
                 NALCWSTFSWWCDMD 
                 164 
                   
               
               
                   
                 PD-100 
                 NFTCMLTPKAYCVQT 
                 165 
                   
               
               
                   
                 PD-101 
                 NGACIFTLSWCTNKT 
                 166 
                   
               
               
                   
                 PD-102 
                 NGCELYAAASGLCRT 
                 167 
                   
               
               
                   
                 PD-103 
                 NIECSVFGRCCCDNY 
                 168 
                   
               
               
                   
                 PD-104 
                 PACRPMFWNRSCDNI 
                 169 
                   
               
               
                   
                 PD-105 
                 PCRVSNMFFPYNCLD 
                 170 
                   
               
               
                   
                 PD-106 
                 PIMCMLLPESYCWIW 
                 171 
                   
               
               
                   
                 PD-107 
                 PQSCYMFASLCMPNG 
                 172 
                   
               
               
                   
                 PD-108 
                 PRCPQGLPLYQCSSF 
                 173 
                   
               
               
                   
                 PD-109 
                 PSVECLVFKRCYALP 
                 174 
                   
               
               
                   
                 PD-110 
                 PVCQRSATIYNCNWF 
                 175 
                   
               
               
                   
                 PD-111 
                 QCAAYYISSFGGCSN 
                 176 
                   
               
               
                   
                 PD-112 
                 QFGCFMLARDFCGTY 
                 177 
                   
               
               
                   
                 PD-113 
                 QMMCPYNPEHKCHQK 
                 178 
                   
               
               
                   
                 PD-114 
                 QRECWMFASSCNSKN 
                 179 
                   
               
               
                   
                 PD-115 
                 QSNMCTTYICSSFNY 
                 180 
                   
               
               
                   
                 PD-116 
                 QSRCHSLAPYLCSSF 
                 181 
                   
               
               
                   
                 PD-117 
                 RAYCSLLFADSCNNN 
                 182 
                   
               
               
                   
                 PD-118 
                 RCIGINQYIDSNCYN 
                 183 
                   
               
               
                   
                 PD-119 
                 RLSCFMFASQCALEF 
                 184 
                   
               
               
                   
                 PD-120 
                 RQCIILMNHRQCFFK 
                 185 
                   
               
               
                   
                 PD-121 
                 RSCTPYMMSSSLCNT 
                 186 
                   
               
            
           
           
               
               
               
               
            
               
                   
                 PD-122 
                 RYCHYWKMPYECSSF 
                 187 
               
               
                   
                 PD-123 
                 SCVSLSWFDMLKCYE 
                 188 
               
               
                   
                 PD-124 
                 SDNCEIWWTVCSAAM 
                 189 
               
               
                   
                 PD-125 
                 SFCWSYLVSSGLCGV 
                 190 
               
               
                   
                 PD-126 
                 SMCMNNYGTTIMCGN 
                 191 
               
               
                   
                 PD-127 
                 SMVGCGWSTFCPSRG 
                 192 
               
               
                   
                 PD-128 
                 SSLHCANGHTCPFCL 
                 193 
               
               
                   
                 PD-129 
                 SVCSYYEESSGICSP 
                 194 
               
               
                   
                 PD-130 
                 SWCGWYAASSGVCAL 
                 195 
               
               
                   
                 PD-131 
                 TCISQTIDSYLNCVN 
                 196 
               
               
                   
                 PD-132 
                 TFCNLYTKSSNICMS 
                 197 
               
               
                   
                 PD-133 
                 TYCVFHEYLDNTCNN 
                 198 
               
               
                   
                 PD-134 
                 VATGCPNLMLCGSWP 
                 199 
               
               
                   
                 PD-135 
                 VEYCSLLLGNRCDYW 
                 200 
               
               
                   
                 PD-136 
                 VGCNMYLMSAGLCVD 
                 201 
               
               
                   
                 PD-137 
                 VLYCSWDSGTCVGSH 
                 202 
               
               
                   
                 PD-138 
                 VMFSCYYLETCAPGV 
                 203 
               
               
                   
                 PD-139 
                 VRIGLCPESCLVSGF 
                 204 
               
               
                   
                 PD-140 
                 VTCTYYATSSSLCNT 
                 205 
               
               
                   
                 PD-141 
                 VTGCILLPKAWCWGD 
                 206 
               
               
                   
                 PD-142 
                 VWCSIYEYSSNLCSR 
                 207 
               
               
                   
                 PD-143 
                 WMLECQYNNTCNNMT 
                 208 
               
               
                   
                 PD-144 
                 WPCSPLEYYNNICNV 
                 209 
               
               
                   
                 PD-145 
                 WTYDCHLNQTCPTYY 
                 210 
               
               
                   
                 PD-146 
                 YCSINMYLIGGNCMY 
                 211 
               
               
                   
                 PD-147 
                 YFCSLYANSAGFCGG 
                 212 
               
               
                   
                 PD-148 
                 YVSCYMFSSSCPSTW 
                 213 
               
               
                   
                   
               
            
           
         
       
     
     Example 8: Activatable Anti-PD-1 A1.4 and A1.5 Antibodies 
     This example describes examples of activatable anti-PD-1 A1.4 and A1.5 antibodies of the disclosure. 
     Activatable anti-PD-1 A1.4 antibodies comprising an anti-PD-1 M13 masking moiety, a cleavable moiety, and an anti-PD-1 A1.4 antibody of the disclosure and activatable anti-PD-1 A1.5 antibodies comprising an anti-PD-1 M13 or an anti-PD-1 A1.5 masking moiety, a cleavable moiety selected from the group consisting of a cleavable moiety, and an anti-PD-1 A1.5 antibody were produced according to methods similar to those described in PCT Publication Nos. WO 2009/025846 and WO 2010/081173, the contents of which are hereby incorporated by reference in their entirety. In some embodiments, the cleavable moiety was selected from the group consisting of a cleavable moiety referred to herein as “2001” and comprising the sequence ISSGLLSGRSDNH (SEQ ID NO: 214) and a cleavable moiety referred to herein as “3001” and comprising the sequence AVGLLAPPGGLSGRSDNH (SEQ ID NO: 318). The amino acid and nucleic acid sequences of several activatable anti-PD-1 antibody variable domains of the disclosure are provided below. Antibodies were produced as hIgG4 containing a single amino acid substitution, S228P (Angal, et al. 1993. Mol Immunol 30:105-8.) HC and hK LC format. 
     In some embodiments, the activatable antibody also includes a spacer sequence. In some embodiments, the spacer is joined directly to the MM of the activatable antibody. In some embodiments, the spacer is joined directly to the MM of the activatable antibody in the structural arrangement from N-terminus to C-terminus of spacer-MM-CM-AB. In some embodiments, the spacer joined directly to the N-terminus of MM of the activatable antibody is selected from the group consisting of QGQSGQG (SEQ ID NO: 362), QGQSGQ (SEQ ID NO: 913), QGQSG (SEQ ID NO: 914), QGQS (SEQ ID NO: 915), QGQ (SEQ ID NO: 916), QG (SEQ ID NO: 917), and Q. In some embodiments, the spacer includes at least the amino acid sequence QGQSGQG (SEQ ID NO: 362). In some embodiments, the spacer includes at least the amino acid sequence QGQSGQ (SEQ ID NO: 913). In some embodiments, the spacer includes at least the amino acid sequence QGQSG (SEQ ID NO: 914). In some embodiments, the spacer includes at least the amino acid sequence QGQS (SEQ ID NO: 915), In some embodiments, the spacer includes at least the amino acid sequence QGQ (SEQ ID NO: 916). In some embodiments, the spacer includes at least the amino acid sequence QG (SEQ ID NO: 917). In some embodiments, the spacer includes at least the amino acid residue Q. In some embodiments, the activatable antibody does not include a spacer sequence. 
     While the sequences shown below include the spacer sequence of SEQ ID NO: 362, those of ordinary skill in the art appreciate that the activatable anti-PD-1 antibodies of the disclosure can include any suitable spacer sequence, such as, for example, a spacer sequence selected from the group consisting of QGQSGQG (SEQ ID NO: 362), QGQSGQ (SEQ ID NO: 913), QGQSG (SEQ ID NO: 914), QGQS (SEQ ID NO: 915), QGQ (SEQ ID NO: 916), QG (SEQ ID NO: 917), and Q. Additional examples of spacers include GQSGQG (SEQ ID NO: 2042), QSGQG (SEQ ID NO: 2043), SGQG (SEQ ID NO: 2044), GQG(SEQ ID NO: 2045), QG(SEQ ID NO: 2046), and G. While the sequences shown below include the spacer sequence of SEQ ID NO: 362, those of ordinary skill in the art will also appreciate that activatable anti-PD-1 antibodies of the disclosure in some embodiments do not include a spacer sequence. 
     Activatable Anti-PD-1 Variable Domains: 
       
     
       
         
           
               
            
               
                 [Spacer (SEQ ID NO: 362)]  
               
               
                 [PD-1 1.4 PD001 2001 (SEQ ID NO: 919)] 
               
               
                 (SEQ ID NO: 215) 
               
               
                 [QGQSGQG][AMSGCSWSAFCPYLAGGGSSGGSISSGLLSGRSDNHG 
               
               
                   
               
               
                 GGSDIQLTQSPSSLSASVGDRVTITCRASESVDSYGISFMNWFQQ 
               
               
                   
               
               
                 KPGKAPKLLIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYY 
               
               
                   
               
               
                 CQQSKDVPWTFGQGTKLEIK] 
               
               
                   
               
               
                 PD-1 1.4 PD001 2001 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 1041) 
               
               
                 AMSGCSWSAFCPYLAGGGSSGGSISSGLLSGRSDNHGGGSDIQLTQSPSS 
               
               
                   
               
               
                 LSASVGDRVTITCRASESVDSYGISFMNWFQQKPGKAPKLLIYAASNQGS 
               
               
                   
               
               
                 GVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEI 
               
               
                   
               
               
                 K 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)] 
               
               
                 [PD-1 1.4 PD001 2001 (SEQ ID NO: 920)] 
               
               
                 (SEQ ID NO: 216) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][GCGATGAGTGGGTGCTCGTGGT 
               
               
                   
               
               
                 CTGCTTTTTGCCCGTATTTGGCGGGAGGTGGCTCGAGCGGCGGCTC 
               
               
                   
               
               
                 TATCTCTTCCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGAGGA 
               
               
                   
               
               
                 TCCGACATCCAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGG 
               
               
                   
               
               
                 GCGACAGAGTGACCATCACCTGTAGAGCCAGCGAGAGCGTGGACAGTTA 
               
               
                   
               
               
                 CGGCATCAGCTTCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCC 
               
               
                   
               
               
                 AAGCTGCTGATCTACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCA 
               
               
                   
               
               
                 GATTTTCCGGCTCTGGCAGCGGCACCGACTTCACCCTGACCATCAGCAG 
               
               
                   
               
               
                 CATGCAGCCCGAGGACTTCGCCACCTACTACTGCCAGCAGAGCAAGGAC 
               
               
                   
               
               
                 GTGCCCTGGACCTTTGGCCAGGGTACCAAGCTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [PD-1 1.4 PD002 2001 (SEQ ID NO: 921)] 
               
               
                 (SEQ ID NO: 217) 
               
               
                 [QGQSGQG][DVNCAIWYSVCTTVPGGGSSGGSISSGLLSGRSDNHG 
               
               
                   
               
               
                 GGSDIQLTQSPSSLSASVGDRVTITCRASESVDSYGISFMNWFQQ 
               
               
                   
               
               
                 KPGKAPKLLIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYY 
               
               
                   
               
               
                 CQQSKDVPWTFGQGTKLEIK] 
               
               
                   
               
               
                 PD-1 1.4 PD002 2001 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 1042) 
               
               
                 DVNCAIWYSVCTTVPGGGSSGGSISSGLLSGRSDNHGGGSDIQLTQSPSS 
               
               
                   
               
               
                 LSASVGDRVTITCRASESVDSYGISFMNWFQQKPGKAPKLLIYAASNQGS 
               
               
                   
               
               
                 GVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEI 
               
               
                   
               
               
                 K 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)]  
               
               
                 [PD-1 1.4 PD002 2001 (SEQ ID NO: 922)] 
               
               
                 (SEQ ID NO: 218) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][GATGTTAATTGCGCTATTTGGTA 
               
               
                   
               
               
                 TTCGGTGTGCACTACTGTTCCTGGAGGTGGCTCGAGCGGCGGCTC 
               
               
                   
               
               
                 TATCTCTTCCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGAGGA 
               
               
                   
               
               
                 TCCGACATCCAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGG 
               
               
                   
               
               
                 GCGACAGAGTGACCATCACCTGTAGAGCCAGCGAGAGCGTGGACAGTTA 
               
               
                   
               
               
                 CGGCATCAGCTTCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCC 
               
               
                   
               
               
                 AAGCTGCTGATCTACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCA 
               
               
                   
               
               
                 GATTTTCCGGCTCTGGCAGCGGCACCGACTTCACCCTGACCATCAGCAG 
               
               
                   
               
               
                 CATGCAGCCCGAGGACTTCGCCACCTACTACTGCCAGCAGAGCAAGGAC 
               
               
                   
               
               
                 GTGCCCTGGACCTTTGGCCAGGGTACCAAGCTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)]  
               
               
                 [PD-1 1.4 PD003 2001 (SEQ ID NO: 923)] 
               
               
                 (SEQ ID NO: 219) 
               
               
                 [QGQSGQG][LVCPLYALSSGVCMGGGGSSGGSISSGLLSGRSDNHG 
               
               
                   
               
               
                 GGSDIQLTQSPSSLSASVGDRVTITCRASESVDSYGISFMNWFQQ 
               
               
                   
               
               
                 KPGKAPKLLIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYY 
               
               
                   
               
               
                 CQQSKDVPWTFGQGTKLEIK] 
               
               
                   
               
               
                 PD-1 1.4 PD003 2001 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 1043) 
               
               
                 LVCPLYALSSGVCMGGGGSSGGSISSGLLSGRSDNHGGGSDIQLTQSPSS 
               
               
                   
               
               
                 LSASVGDRVTITCRASESVDSYGISFMNWFQQKPGKAPKLLIYAASNQGS 
               
               
                   
               
               
                 GVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEI 
               
               
                   
               
               
                 K 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)]  
               
               
                 [PD-1 1.4 PD003 2001 (SEQ ID NO: 924)] 
               
               
                 (SEQ ID NO: 220) 
               
               
                 [PD-1 1.4 PD003 2001 (SEQ ID NO: 924)] 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][TTGGTTTGCCCTTTGTATGCATT 
               
               
                   
               
               
                 GAGTTCTGGGGTGTGCATGGGGGGAGGTGGCTCGAGCGGCGGCTC 
               
               
                   
               
               
                 TATCTCTTCCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGAGGA 
               
               
                   
               
               
                 TCCGACATCCAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGG 
               
               
                   
               
               
                 GCGACAGAGTGACCATCACCTGTAGAGCCAGCGAGAGCGTGGACAGTTA 
               
               
                   
               
               
                 CGGCATCAGCTTCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCC 
               
               
                   
               
               
                 AAGCTGCTGATCTACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCA 
               
               
                   
               
               
                 GATTTTCCGGCTCTGGCAGCGGCACCGACTTCACCCTGACCATCAGCAG 
               
               
                   
               
               
                 CATGCAGCCCGAGGACTTCGCCACCTACTACTGCCAGCAGAGCAAGGAC 
               
               
                   
               
               
                 GTGCCCTGGACCT 
               
               
                   
               
               
                 TTGGCCAGGGTACCAAGCTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)]  
               
               
                 [PD-1 1.4 PD008 2001 (SEQ ID NO: 925)] 
               
               
                 (SEQ ID NO: 221) 
               
               
                 [QGQSGQG][ETCNQYERSSGLCFAGGGSSGGSISSGLLSGRSDNHG 
               
               
                   
               
               
                 GGSDIQLTQSPSSLSASVGDRVTITCRASESVDSYGISFMNWFQQ 
               
               
                   
               
               
                 KPGKAPKLLIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYY 
               
               
                   
               
               
                 CQQSKDVPWTFGQGTKLEIK] 
               
               
                   
               
               
                 PD-1 1.4 PD008 2001 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 1044) 
               
               
                 ETCNQYERSSGLCFAGGGSSGGSISSGLLSGRSDNHGGGSDIQLTQSPSS 
               
               
                   
               
               
                 LSASVGDRVTITCRASESVDSYGISFMNWFQQKPGKAPKLLIYAASNQGS 
               
               
                   
               
               
                 GVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEI 
               
               
                   
               
               
                 K 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)]  
               
               
                 [PD-1 1.4 PD008 2001 (SEQ ID NO: 926)] 
               
               
                 (SEQ ID NO: 222) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][GAGACTTGCAATCAGTATGAGAG 
               
               
                   
               
               
                 GTCGAGTGGTTTGTGCTTTGCGGGAGGTGGCTCGAGCGGCGGCTC 
               
               
                   
               
               
                 TATCTCTTCCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGAGGA 
               
               
                   
               
               
                 TCCGACATCCAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGG 
               
               
                   
               
               
                 GCGACAGAGTGACCATCACCTGTAGAGCCAGCGAGAGCGTGGACAGTTA 
               
               
                   
               
               
                 CGGCATCAGCTTCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCC 
               
               
                   
               
               
                 AAGCTGCTGATCTACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCA 
               
               
                   
               
               
                 GATTTTCCGGCTCTGGCAGCGGCACCGACTTCACCCTGACCATCAGCAG 
               
               
                   
               
               
                 CATGCAGCCCGAGGACTTCGCCACCTACTACTGCCAGCAGAGCAAGGAC 
               
               
                   
               
               
                 GTGCCCTGGACCTTTGGCCAGGGTACCAAGCTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)]  
               
               
                 [PD-1 1.4 PD009 2001 (SEQ ID NO: 927)] 
               
               
                 (SEQ ID NO: 223) 
               
               
                 [QGQSGQG][APRTCYTYQCSSFYTGGGSSGGSISSGLLSGRSDNHG 
               
               
                   
               
               
                 GGSDIQLTQSPSSLSASVGDRVTITCRASESVDSYGISFMNWFQQ 
               
               
                   
               
               
                 KPGKAPKLLIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYY 
               
               
                   
               
               
                 CQQSKDVPWTFGQGTKLEIK] 
               
               
                   
               
               
                 PD-1 1.4 PD009 2001 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 1045) 
               
               
                 APRTCYTYQCSSFYTGGGSSGGSISSGLLSGRSDNHGGGSDIQLTQSPSS 
               
               
                   
               
               
                 LSASVGDRVTITCRASESVDSYGISFMNWFQQKPGKAPKLLIYAASNQGS 
               
               
                   
               
               
                 GVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEI 
               
               
                   
               
               
                 K 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)]  
               
               
                 [PD-1 1.4 PD009 2001 (SEQ ID NO: 928)] 
               
               
                 (SEQ ID NO: 224) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][GCGCCGCGGACGTGCTATACGTA 
               
               
                   
               
               
                 TCAGTGCTCTAGTTTTTATACTGGAGGTGGCTCGAGCGGCGGCTC 
               
               
                   
               
               
                 TATCTCTTCCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGAGGA 
               
               
                   
               
               
                 TCCGACATCCAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGG 
               
               
                   
               
               
                 GCGACAGAGTGACCATCACCTGTAGAGCCAGCGAGAGCGTGGACAGTTA 
               
               
                   
               
               
                 CGGCATCAGCTTCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCC 
               
               
                   
               
               
                 AAGCTGCTGATCTACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCA 
               
               
                   
               
               
                 GATTTTCCGGCTCTGGCAGCGGCACCGACTTCACCCTGACCATCAGCAG 
               
               
                   
               
               
                 CATGCAGCCCGAGGACTTCGCCACCTACTACTGCCAGCAGAGCAAGGAC 
               
               
                   
               
               
                 GTGCCCTGGACCTTTGGCCAGGGTACCAAGCTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)]  
               
               
                 [PD-1 1.4 PD010 2001 (SEQ ID NO: 929)] 
               
               
                 (SEQ ID NO: 225) 
               
               
                 [QGQSGQG][GLCSWYLSSSGLCVDGGGSSGGSISSGLLSGRSDNHG 
               
               
                   
               
               
                 GGSDIQLTQSPSSLSASVGDRVTITCRASESVDSYGISFMNWFQQ 
               
               
                   
               
               
                 KPGKAPKLLIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYY 
               
               
                   
               
               
                 CQQSKDVPWTFGQGTKLEIK] 
               
               
                   
               
               
                 PD-1 1.4 PD010 2001 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 1046) 
               
               
                 GLCSWYLSSSGLCVDGGGSSGGSISSGLLSGRSDNHGGGSDIQLTQSPSS 
               
               
                   
               
               
                 LSASVGDRVTITCRASESVDSYGISFMNWFQQKPGKAPKLLIYAASNQGS 
               
               
                   
               
               
                 GVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEI 
               
               
                   
               
               
                 K 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)]  
               
               
                 [PD-1 1.4 PD010 2001 (SEQ ID NO: 930)] 
               
               
                 (SEQ ID NO: 226) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][GGTCTTTGCAGTTGGTATCT 
               
               
                   
               
               
                 TAGTAGTTCGGGTTTGTGCGTGGATGGAGGTGGCTCGAGCGGCGGCTCTA 
               
               
                   
               
               
                 TCTCTTCCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGAGGATCC 
               
               
                   
               
               
                 GACATCCAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGA 
               
               
                   
               
               
                 CAGAGTGACCATCACCTGTAGAGCCAGCGAGAGCGTGGACAGTTACGGCA 
               
               
                   
               
               
                 TCAGCTTCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCCAAGCTG 
               
               
                   
               
               
                 CTGATCTACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCAGATTTTC 
               
               
                   
               
               
                 CGGCTCTGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGC 
               
               
                   
               
               
                 CCGAGGACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGG 
               
               
                   
               
               
                 ACCTTTGGCCAGGGTACCAAGCTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)]  
               
               
                 [PD-1 1.5 PD01 2001 (SEQ ID NO: 931)] 
               
               
                 (SEQ ID NO: 227) 
               
               
                 [QGQSGQG][AMSGCSWSAFCPYLAGGGSSGGSISSGLLSGRSD 
               
               
                   
               
               
                 NHGGGSDIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKP 
               
               
                   
               
               
                 GKAPKLLIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQ 
               
               
                   
               
               
                 SKDVPWTFGQGTKLEIK] 
               
               
                   
               
               
                 PD-1 1.5 PD01 2001 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 1047) 
               
               
                 AMSGCSWSAFCPYLAGGGSSGGSISSGLLSGRSDNHGGGSDIQLTQSPSS 
               
               
                   
               
               
                 LSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQGS 
               
               
                   
               
               
                 GVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEI 
               
               
                   
               
               
                 K 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)]  
               
               
                 [PD-1 1.5 PD001 2001 (SEQ ID NO: 932)] 
               
               
                 (SEQ ID NO: 228) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][GCGATGAGTGGGTGCTCGTG 
               
               
                   
               
               
                 GTCTGCTTTTTGCCCGTATTTGGCGGGAGGTGGCTCGAGCGGCGGCTCTA 
               
               
                   
               
               
                 TCTCTTCCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGAGGATCC 
               
               
                   
               
               
                 GATATCCAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGA 
               
               
                   
               
               
                 CAGAGTGACCATCACCTGTAGAGCCAGCGAGAGCGTGGACGCTTACGGCA 
               
               
                   
               
               
                 TCAGCTTCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCCAAGCTG 
               
               
                   
               
               
                 CTGATCTACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCAGATTTTC 
               
               
                   
               
               
                 CGGCTCTGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGC 
               
               
                   
               
               
                 CCGAGGACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGG 
               
               
                   
               
               
                 ACCTTTGGCCAGGGTACCAAGCTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)]  
               
               
                 [PD-1 1.5 PD002 2001 (SEQ ID NO: 933)] 
               
               
                 (SEQ ID NO: 229) 
               
               
                 [QGQSGQG][DVNCAIWYSVCTTVPGGGSSGGSISSGLLSGRSD 
               
               
                   
               
               
                 NHGGGSDIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKP 
               
               
                   
               
               
                 GKAPKLLIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQ 
               
               
                   
               
               
                 SKDVPWTFGQGTKLEIK] 
               
               
                   
               
               
                 PD-1 1.5 PD002 2001 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 1048) 
               
               
                 DVNCAIWYSVCTTVPGGGSSGGSISSGLLSGRSDNHGGGSDIQLTQSPSS 
               
               
                   
               
               
                 LSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQGS 
               
               
                   
               
               
                 GVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEI 
               
               
                   
               
               
                 K 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)]  
               
               
                 [PD-1 1.5 PD002 2001 (SEQ ID NO: 934)] 
               
               
                 (SEQ ID NO: 230) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][GATGTTAATTGCGCTATTTG 
               
               
                   
               
               
                 GTATTCGGTGTGCACTACTGTTCCTGGAGGTGGCTCGAGCGGCGGCTCTA 
               
               
                   
               
               
                 TCTCTTCCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGAGGATCC 
               
               
                   
               
               
                 GATATCCAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGA 
               
               
                   
               
               
                 CAGAGTGACCATCACCTGTAGAGCCAGCGAGAGCGTGGACGCTTACGGCA 
               
               
                   
               
               
                 TCAGCTTCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCCAAGCTG 
               
               
                   
               
               
                 CTGATCTACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCAGATTTTC 
               
               
                   
               
               
                 CGGCTCTGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGC 
               
               
                   
               
               
                 CCGAGGACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGG 
               
               
                   
               
               
                 ACCTTTGGCCAGGGTACCAAGCTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)]  
               
               
                 [PD-1 1.5 PD003 2001 (SEQ ID NO: 935)] 
               
               
                 (SEQ ID NO: 231) 
               
               
                 [QGQSGQG][LVCPLYALSSGVCMGGGGSSGGSISSGLLSGRSD 
               
               
                   
               
               
                 NHGGGSDIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKP 
               
               
                   
               
               
                 GKAPKLLIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQ 
               
               
                   
               
               
                 SKDVPWTFGQGTKLEIK] 
               
               
                   
               
               
                 PD-1 1.5 PD003 2001 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 1049) 
               
               
                 LVCPLYALSSGVCMGGGGSSGGSISSGLLSGRSDNHGGGSDIQLTQSPSS 
               
               
                   
               
               
                 LSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQGS 
               
               
                   
               
               
                 GVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEI 
               
               
                   
               
               
                 K 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)]  
               
               
                 [PD-1 1.5 PD003 2001 (SEQ ID NO: 936)] 
               
               
                 (SEQ ID NO: 232) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][TTGGTTTGCCCTTTGTATGC 
               
               
                   
               
               
                 ATTGAGTTCTGGGGTGTGCATGGGGGGAGGTGGCTCGAGCGGCGGCTCTA 
               
               
                   
               
               
                 TCTCTTCCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGAGGATCC 
               
               
                   
               
               
                 GATATCCAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGA 
               
               
                   
               
               
                 CAGAGTGACCATCACCTGTAGAGCCAGCGAGAGCGTGGACGCTTACGGCA 
               
               
                   
               
               
                 TCAGCTTCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCCAAGCTG 
               
               
                   
               
               
                 CTGATCTACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCAGATTTTC 
               
               
                   
               
               
                 CGGCTCTGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGC 
               
               
                   
               
               
                 CCGAGGACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGG 
               
               
                   
               
               
                 ACCTTTGGCCAGGGTACCAAGCTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)]  
               
               
                 [PD-1 1.5 PD004 2001 (SEQ ID NO: 937)] 
               
               
                 (SEQ ID NO: 233) 
               
               
                 [QGQSGQG][SVNCRIWSAVCAGYEGGGSSGGSISSGLLSGRSD 
               
               
                   
               
               
                 NHGGGSDIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKP 
               
               
                   
               
               
                 GKAPKLLIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQ 
               
               
                   
               
               
                 SKDVPWTFGQGTKLEIK] 
               
               
                   
               
               
                 PD-1 1.5 PD004 2001 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 1050) 
               
               
                 SVNCRIWSAVCAGYEGGGSSGGSISSGLLSGRSDNHGGGSDIQLTQSPSS 
               
               
                   
               
               
                 LSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQGS 
               
               
                   
               
               
                 GVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEI 
               
               
                   
               
               
                 K 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)]  
               
               
                 [PD-1 1.5 PD004 2001 (SEQ ID NO: 938)] 
               
               
                 (SEQ ID NO: 234) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][TCTGTGAATTGCCGGATTTG 
               
               
                   
               
               
                 GTCGGCTGTTTGCGCGGGGTATGAGGGAGGTGGCTCGAGCGGCGGCTCTA 
               
               
                   
               
               
                 TCTCTTCCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGAGGATCC 
               
               
                   
               
               
                 GATATCCAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGA 
               
               
                   
               
               
                 CAGAGTGACCATCACCTGTAGAGCCAGCGAGAGCGTGGACGCTTACGGCA 
               
               
                   
               
               
                 TCAGCTTCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCCAAGCTG 
               
               
                   
               
               
                 CTGATCTACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCAGATTTTC 
               
               
                   
               
               
                 CGGCTCTGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGC 
               
               
                   
               
               
                 CCGAGGACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGG 
               
               
                   
               
               
                 ACCTTTGGCCAGGGTACCAAGCTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)]  
               
               
                 [PD-1 1.5 PD005 2001 (SEQ ID NO: 939)] 
               
               
                 (SEQ ID NO: 235) 
               
               
                 [QGQSGQG][MLVCSLQPTAMCERVGGGSSGGSISSGLLSGRSD 
               
               
                   
               
               
                 NHGGGSDIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKP 
               
               
                   
               
               
                 GKAPKLLIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQ 
               
               
                   
               
               
                 SKDVPWTFGQGTKLEIK] 
               
               
                   
               
               
                 PD-1 1.5 PD005 2001 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 1051) 
               
               
                 MLVCSLQPTAMCERVGGGSSGGSISSGLLSGRSDNHGGGSDIQLTQSPSS 
               
               
                   
               
               
                 LSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQGS 
               
               
                   
               
               
                 GVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEI 
               
               
                   
               
               
                 K 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)]  
               
               
                 [PD-1 1.5 PD005 2001 (SEQ ID NO: 940)] 
               
               
                 (SEQ ID NO: 236) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][ATGCTTGTGTGCTCGTTGCAGCCTAC 
               
               
                   
               
               
                 TGCGATGTGCGAGCGGGTGGGAGGTGGCTCGAGCGGCGGCTCTATCTCTT 
               
               
                   
               
               
                 CCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGAGGATCCGATATC 
               
               
                   
               
               
                 CAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGACAGAGT 
               
               
                   
               
               
                 GACCATCACCTGTAGAGCCAGCGAGAGCGTGGACGCTTACGGCATCAGCT 
               
               
                   
               
               
                 TCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATC 
               
               
                   
               
               
                 TACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCAGATTTTCCGGCTC 
               
               
                   
               
               
                 TGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGCCCGAGG 
               
               
                   
               
               
                 ACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGGACCTTT 
               
               
                   
               
               
                 GGCCAGGGTACCAAGCTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)]  
               
               
                 [PD-1 1.5 PD006 2001 (SEQ ID NO: 941)] 
               
               
                 (SEQ ID NO: 237) 
               
               
                 [QGQSGQG][APRCYMFASYCKSQYGGGSSGGSISSGLLSGRSDNHGGGS 
               
               
                   
               
               
                 DIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKL 
               
               
                   
               
               
                 LIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPW 
               
               
                   
               
               
                 TFGQGTKLEIK] 
               
               
                   
               
               
                 PD-1 1.5 PD006 2001 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 941) 
               
               
                 APRCYMFASYCKSQYGGGSSGGSISSGLLSGRSDNHGGGSDIQLTQSPSS 
               
               
                   
               
               
                 LSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQGS 
               
               
                   
               
               
                 GVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEI 
               
               
                   
               
               
                 K 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)]  
               
               
                 [PD-1 1.5 PD006 2001 (SEQ ID NO: 942)] 
               
               
                 (SEQ ID NO: 238) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][GCGCCTAGGTGCTATATGTTTGCGTC 
               
               
                   
               
               
                 GTATTGCAAGAGTCAGTATGGAGGTGGCTCGAGCGGCGGCTCTATCTCTT 
               
               
                   
               
               
                 CCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGAGGATCCGATATC 
               
               
                   
               
               
                 CAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGACAGAGT 
               
               
                   
               
               
                 GACCATCACCTGTAGAGCCAGCGAGAGCGTGGACGCTTACGGCATCAGCT 
               
               
                   
               
               
                 TCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATC 
               
               
                   
               
               
                 TACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCAGATTTTCCGGCTC 
               
               
                   
               
               
                 TGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGCCCGAGG 
               
               
                   
               
               
                 ACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGGACCTTT 
               
               
                   
               
               
                 GGCCAGGGTACCAAGCTGGAAATCAAG] 
               
               
                   
               
               
                 PD-1 1.5 PD006 2001 Nucleic Acid Sequence: 
               
               
                 (SEQ ID NO: 942) 
               
               
                 GCGCCTAGGTGCTATATGTTTGCGTCGTATTGCAAGAGTCAGTATGGAGG 
               
               
                   
               
               
                 TGGCTCGAGCGGCGGCTCTATCTCTTCCGGACTGCTGTCCGGCAGATCCG 
               
               
                   
               
               
                 ACAATCACGGCGGAGGATCCGATATCCAGCTGACCCAGAGCCCTAGCAGC 
               
               
                   
               
               
                 CTGTCTGCCAGCGTGGGCGACAGAGTGACCATCACCTGTAGAGCCAGCGA 
               
               
                   
               
               
                 GAGCGTGGACGCTTACGGCATCAGCTTCATGAACTGGTTCCAGCAGAAGC 
               
               
                   
               
               
                 CCGGCAAGGCCCCCAAGCTGCTGATCTACGCCGCCAGCAATCAGGGCAGC 
               
               
                   
               
               
                 GGCGTGCCAAGCAGATTTTCCGGCTCTGGCAGCGGCACCGACTTCACCCT 
               
               
                   
               
               
                 GACCATCAGCAGCATGCAGCCCGAGGACTTCGCCACCTACTACTGCCAGC 
               
               
                   
               
               
                 AGAGCAAGGACGTGCCCTGGACCTTTGGCCAGGGTACCAAGCTGGAAATC 
               
               
                   
               
               
                 AAG 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)]  
               
               
                 [PD-1 1.5 PD007 2001 (SEQ ID NO: 943)] 
               
               
                 (SEQ ID NO: 239) 
               
               
                 [QGQSGQG][VGPCELTPKPVCNTYGGGSSGGSISSGLLSGRSDNHGGGS 
               
               
                   
               
               
                 DIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKL 
               
               
                   
               
               
                 LIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPW 
               
               
                   
               
               
                 TFGQGTKLEIK] 
               
               
                   
               
               
                 PD-1 1.5 PD007 2001 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 1052) 
               
               
                 VGPCELTPKPVCNTYGGGSSGGSISSGLLSGRSDNHGGGSDIQLTQSPSS 
               
               
                   
               
               
                 LSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQGS 
               
               
                   
               
               
                 GVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEI 
               
               
                   
               
               
                 K 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)]  
               
               
                 [PD-1 1.5 PD007 2001 (SEQ ID NO: 944)] 
               
               
                 (SEQ ID NO: 240) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][GTGGGGCCTTGCGAGTTGACGCCGAA 
               
               
                   
               
               
                 GCCTGTTTGCAATACGTATGGAGGTGGCTCGAGCGGCGGCTCTATCTCTT 
               
               
                   
               
               
                 CCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGAGGATCCGATATC 
               
               
                   
               
               
                 CAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGACAGAGT 
               
               
                   
               
               
                 GACCATCACCTGTAGAGCCAGCGAGAGCGTGGACGCTTACGGCATCAGCT 
               
               
                   
               
               
                 TCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATC 
               
               
                   
               
               
                 TACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCAGATTTTCCGGCTC 
               
               
                   
               
               
                 TGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGCCCGAGG 
               
               
                   
               
               
                 ACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGGACCTTT 
               
               
                   
               
               
                 GGCCAGGGTACCAAGCTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)]  
               
               
                 [PD-1 1.5 PD008 2001 (SEQ ID NO: 945)] 
               
               
                 (SEQ ID NO: 241) 
               
               
                 [QGQSGQG][ETCNQYERSSGLCFAGGGSSGGSISSGLLSGRSDNHGGGS 
               
               
                   
               
               
                 DIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKL 
               
               
                   
               
               
                 LIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPW 
               
               
                   
               
               
                 TFGQGTKLEIK] 
               
               
                   
               
               
                 PD-1 1.5 PD008 2001 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 1053) 
               
               
                 ETCNQYERSSGLCFAGGGSSGGSISSGLLSGRSDNHGGGSDIQLTQSPSS 
               
               
                   
               
               
                 LSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQGS 
               
               
                   
               
               
                 GVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEI 
               
               
                   
               
               
                 K 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)]  
               
               
                 [PD-1 1.5 PD008 2001 (SEQ ID NO: 946)] 
               
               
                 (SEQ ID NO: 242) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][GAGACTTGCAATCAGTATGAGAGGTC 
               
               
                   
               
               
                 GAGTGGTTTGTGCTTTGCGGGAGGTGGCTCGAGCGGCGGCTCTATCTCTT 
               
               
                   
               
               
                 CCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGAGGATCCGATATC 
               
               
                   
               
               
                 CAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGACAGAGT 
               
               
                   
               
               
                 GACCATCACCTGTAGAGCCAGCGAGAGCGTGGACGCTTACGGCATCAGCT 
               
               
                   
               
               
                 TCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATC 
               
               
                   
               
               
                 TACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCAGATTTTCCGGCTC 
               
               
                   
               
               
                 TGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGCCCGAGG 
               
               
                   
               
               
                 ACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGGACCTTT 
               
               
                   
               
               
                 GGCCAGGGTACCAAGCTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)]  
               
               
                 [PD-1 1.5 PD009 2001 (SEQ ID NO: 947)] 
               
               
                 (SEQ ID NO: 243) 
               
               
                 [QGQSGQG][APRTCYTYQCSSFYTGGGSSGGSISSGLLSGRSDNHGGGS 
               
               
                   
               
               
                 DIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKL 
               
               
                   
               
               
                 LIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPW 
               
               
                   
               
               
                 TFGQGTKLEIK] 
               
               
                   
               
               
                 PD-1 1.5 PD009 2001 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 1054) 
               
               
                 APRTCYTYQCSSFYTGGGSSGGSISSGLLSGRSDNHGGGSDIQLTQSPSS 
               
               
                   
               
               
                 LSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQGS 
               
               
                   
               
               
                 GVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEI 
               
               
                   
               
               
                 K 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)]  
               
               
                 [PD-1 1.5 PD009 2001 (SEQ ID NO: 948)] 
               
               
                 (SEQ ID NO: 244) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][GCGCCGCGGACGTGCTATACGTATCA 
               
               
                   
               
               
                 GTGCTCTAGTTTTTATACTGGAGGTGGCTCGAGCGGCGGCTCTATCTCTT 
               
               
                   
               
               
                 CCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGAGGATCCGATATC 
               
               
                   
               
               
                 CAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGACAGAGT 
               
               
                   
               
               
                 GACCATCACCTGTAGAGCCAGCGAGAGCGTGGACGCTTACGGCATCAGCT 
               
               
                   
               
               
                 TCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATC 
               
               
                   
               
               
                 TACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCAGATTTTCCGGCTC 
               
               
                   
               
               
                 TGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGCCCGAGG 
               
               
                   
               
               
                 ACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGGACCTTT 
               
               
                   
               
               
                 GGCCAGGGTACCAAGCTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)]  
               
               
                 [PD-1 1.5 PD010 2001 (SEQ ID NO: 949)] 
               
               
                 (SEQ ID NO: 245) 
               
               
                 [QGQSGQG][GLCSWYLSSSGLCVDGGGSSGGSISSGLLSGRSDNHGGGS 
               
               
                   
               
               
                 DIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKL 
               
               
                   
               
               
                 LIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPW 
               
               
                   
               
               
                 TFGQGTKLEIK] 
               
               
                   
               
               
                 PD-1 1.5 PD010 2001 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 1055) 
               
               
                 GLCSWYLSSSGLCVDGGGSSGGSISSGLLSGRSDNHGGGSDIQLTQSPSS 
               
               
                   
               
               
                 LSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQGS 
               
               
                   
               
               
                 GVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEI 
               
               
                   
               
               
                 K 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)]  
               
               
                 [PD-1 1.5 PD010 2001 (SEQ ID NO: 950)] 
               
               
                 (SEQ ID NO: 246) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][GGTCTTTGCAGTTGGTATCTTAGTAG 
               
               
                   
               
               
                 TTCGGGTTTGTGCGTGGATGGAGGTGGCTCGAGCGGCGGCTCTATCTCTT 
               
               
                   
               
               
                 CCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGAGGATCCGATATC 
               
               
                   
               
               
                 CAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGACAGAGT 
               
               
                   
               
               
                 GACCATCACCTGTAGAGCCAGCGAGAGCGTGGACGCTTACGGCATCAGCT 
               
               
                   
               
               
                 TCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATC 
               
               
                   
               
               
                 TACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCAGATTTTCCGGCTC 
               
               
                   
               
               
                 TGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGCCCGAGG 
               
               
                   
               
               
                 ACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGGACCTTT 
               
               
                   
               
               
                 GGCCAGGGTACCAAGCTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)]  
               
               
                 [PD-1 1.5 PD011 2001 (SEQ ID NO: 951)] 
               
               
                 (SEQ ID NO: 247) 
               
               
                 [QGQSGQG][VPWCQLTPRVMCMWAGGGSSGGSISSGLLSGRSDNHGGGS 
               
               
                   
               
               
                 DIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKL 
               
               
                   
               
               
                 LIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPW 
               
               
                   
               
               
                 TFGQGTKLEIK] 
               
               
                   
               
               
                 PD-1 1.5 PD011 2001 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 1056) 
               
               
                 VPWCQLTPRVMCMWAGGGSSGGSISSGLLSGRSDNHGGGSDIQLTQSPSS 
               
               
                   
               
               
                 LSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQGS 
               
               
                   
               
               
                 GVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEI 
               
               
                   
               
               
                 K 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)]  
               
               
                 [PD-1 1.5 PD011 2001 (SEQ ID NO: 952)] 
               
               
                 (SEQ ID NO: 248) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][GTGCCTTGGTGCCAGTTGACGCCGCG 
               
               
                   
               
               
                 GGTTATGTGCATGTGGGCGGGAGGTGGCTCGAGCGGCGGCTCTATCTCTT 
               
               
                   
               
               
                 CCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGAGGATCCGATATC 
               
               
                   
               
               
                 CAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGACAGAGT 
               
               
                   
               
               
                 GACCATCACCTGTAGAGCCAGCGAGAGCGTGGACGCTTACGGCATCAGCT 
               
               
                   
               
               
                 TCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATC 
               
               
                   
               
               
                 TACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCAGATTTTCCGGCTC 
               
               
                   
               
               
                 TGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGCCCGAGG 
               
               
                   
               
               
                 ACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGGACCTTT 
               
               
                   
               
               
                 GGCCAGGGTACCAAGCTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)]  
               
               
                 [PD-1 1.5 PD012 2001 (SEQ ID NO: 953)] 
               
               
                 (SEQ ID NO: 249) 
               
               
                 [QGQSGQG][NWLDCQFYSECSVYGGGGSSGGSISSGLLSGRSDNHGGGS 
               
               
                   
               
               
                 DIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKL 
               
               
                   
               
               
                 LIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPW 
               
               
                   
               
               
                 TFGQGTKLEIK] 
               
               
                   
               
               
                 PD-1 1.5 PD012 2001 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 953) 
               
               
                 NWLDCQFYSECSVYGGGGSSGGSISSGLLSGRSDNHGGGSDIQLTQSPSS 
               
               
                   
               
               
                 LSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQGS 
               
               
                   
               
               
                 GVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEI 
               
               
                   
               
               
                 K 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)]  
               
               
                 [PD-1 1.5 PD012 2001 (SEQ ID NO: 954)] 
               
               
                 (SEQ ID NO: 250) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][AATTGGTTGGATTGCCAGTTTTATTC 
               
               
                   
               
               
                 TGAGTGCTCTGTTTATGGTGGAGGTGGCTCGAGCGGCGGCTCTATCTCTT 
               
               
                   
               
               
                 CCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGAGGATCCGATATC 
               
               
                   
               
               
                 CAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGACAGAGT 
               
               
                   
               
               
                 GACCATCACCTGTAGAGCCAGCGAGAGCGTGGACGCTTACGGCATCAGCT 
               
               
                   
               
               
                 TCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATC 
               
               
                   
               
               
                 TACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCAGATTTTCCGGCTC 
               
               
                   
               
               
                 TGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGCCCGAGG 
               
               
                   
               
               
                 ACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGGACCTTT 
               
               
                   
               
               
                 GGCCAGGGTACCAAGCTGGAAATCAAG] 
               
               
                   
               
               
                 PD-1 1.5 PD012 2001 Nucleic Acid Sequence: 
               
               
                 (SEQ ID NO: 954) 
               
               
                 AATTGGTTGGATTGCCAGTTTTATTCTGAGTGCTCTGTTTATGGTGGAGG 
               
               
                   
               
               
                 TGGCTCGAGCGGCGGCTCTATCTCTTCCGGACTGCTGTCCGGCAGATCCG 
               
               
                   
               
               
                 ACAATCACGGCGGAGGATCCGATATCCAGCTGACCCAGAGCCCTAGCAGC 
               
               
                   
               
               
                 CTGTCTGCCAGCGTGGGCGACAGAGTGACCATCACCTGTAGAGCCAGCGA 
               
               
                   
               
               
                 GAGCGTGGACGCTTACGGCATCAGCTTCATGAACTGGTTCCAGCAGAAGC 
               
               
                   
               
               
                 CCGGCAAGGCCCCCAAGCTGCTGATCTACGCCGCCAGCAATCAGGGCAGC 
               
               
                   
               
               
                 GGCGTGCCAAGCAGATTTTCCGGCTCTGGCAGCGGCACCGACTTCACCCT 
               
               
                   
               
               
                 GACCATCAGCAGCATGCAGCCCGAGGACTTCGCCACCTACTACTGCCAGC 
               
               
                   
               
               
                 AGAGCAAGGACGTGCCCTGGACCTTTGGCCAGGGTACCAAGCTGGAAATC 
               
               
                   
               
               
                 AAG 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)]  
               
               
                 [PD-1 1.5 PD013 2001 (SEQ ID NO: 955)] 
               
               
                 (SEQ ID NO: 251) 
               
               
                 [QGQSGQG][SCPLYVMSSFGGCWDGGGSSGGSISSGLLSGRSDNHGGGS 
               
               
                   
               
               
                 DIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKL 
               
               
                   
               
               
                 LIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPW 
               
               
                   
               
               
                 TFGQGTKLEIK] 
               
               
                   
               
               
                 PD-1 1.5 PD013 2001 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 1057) 
               
               
                 SCPLYVMSSFGGCWDGGGSSGGSISSGLLSGRSDNHGGGSDIQLTQSPSS 
               
               
                   
               
               
                 LSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQGS 
               
               
                   
               
               
                 GVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEI 
               
               
                   
               
               
                 K 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)]  
               
               
                 [PD-1 1.5 PD013 2001 (SEQ ID NO: 956)] 
               
               
                 (SEQ ID NO: 252) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][TCGTGCCCTTTGTATGTGATGTCTAG 
               
               
                   
               
               
                 TTTTGGTGGGTGCTGGGATGGAGGTGGCTCGAGCGGCGGCTCTATCTCTT 
               
               
                   
               
               
                 CCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGAGGATCCGATATC 
               
               
                   
               
               
                 CAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGACAGAGT 
               
               
                   
               
               
                 GACCATCACCTGTAGAGCCAGCGAGAGCGTGGACGCTTACGGCATCAGCT 
               
               
                   
               
               
                 TCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATC 
               
               
                   
               
               
                 TACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCAGATTTTCCGGCTC 
               
               
                   
               
               
                 TGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGCCCGAGG 
               
               
                   
               
               
                 ACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGGACCTTT 
               
               
                   
               
               
                 GGCCAGGGTACCAAGCTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)]  
               
               
                 [PD-1 1.5 PD014 2001 (SEQ ID NO: 957)] 
               
               
                 (SEQ ID NO: 253) 
               
               
                 [QGQSGQG][MSHCWMFSSSCDGVKGGGSSGGSISSGLLSGRSDNHGGGS 
               
               
                   
               
               
                 DIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKL 
               
               
                   
               
               
                 LIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPW 
               
               
                   
               
               
                 TFGQGTKLEIK] 
               
               
                   
               
               
                 PD-1 1.5 PD014 2001 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 1058) 
               
               
                 MSHCWMFSSSCDGVKGGGSSGGSISSGLLSGRSDNHGGGSDIQLTQSPSS 
               
               
                   
               
               
                 LSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQGS 
               
               
                   
               
               
                 GVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEI 
               
               
                   
               
               
                 K 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)]  
               
               
                 [PD-1 1.5 PD014 2001 (SEQ ID NO: 958)] 
               
               
                 (SEQ ID NO: 254) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][ATGAGTCATTGCTGGATGTTTTCGAG 
               
               
                   
               
               
                 TTCTTGCGATGGGGTGAAGGGAGGTGGCTCGAGCGGCGGCTCTATCTCTT 
               
               
                   
               
               
                 CCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGAGGATCCGATATC 
               
               
                   
               
               
                 CAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGACAGAGT 
               
               
                   
               
               
                 GACCATCACCTGTAGAGCCAGCGAGAGCGTGGACGCTTACGGCATCAGCT 
               
               
                   
               
               
                 TCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATC 
               
               
                   
               
               
                 TACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCAGATTTTCCGGCTC 
               
               
                   
               
               
                 TGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGCCCGAGG 
               
               
                   
               
               
                 ACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGGACCTTT 
               
               
                   
               
               
                 GGCCAGGGTACCAAGCTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)]  
               
               
                 [PD-1 1.5 PD015 2001 (SEQ ID NO: 959)] 
               
               
                 (SEQ ID NO: 255) 
               
               
                 [QGQSGQG][VSYCTWLIEVTCLRGGGGSSGGSISSGLLSGRSDNHGGGS 
               
               
                   
               
               
                 DIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKL 
               
               
                   
               
               
                 LIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPW 
               
               
                   
               
               
                 TFGQGTKLEIK] 
               
               
                   
               
               
                 PD-1 1.5 PD015 2001 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 1059) 
               
               
                 VSYCTWLIEVTCLRGGGGSSGGSISSGLLSGRSDNHGGGSDIQLTQSPSS 
               
               
                   
               
               
                 LSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQGS 
               
               
                   
               
               
                 GVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEI 
               
               
                   
               
               
                 K 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)]  
               
               
                 [PD-1 1.5 PD015 2001 (SEQ ID NO: 960)] 
               
               
                 (SEQ ID NO: 256) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][GTTTCGTATTGCACGTGGTTGATTGA 
               
               
                   
               
               
                 GGTGACTTGCCTGAGGGGTGGAGGTGGCTCGAGCGGCGGCTCTATCTCTT 
               
               
                   
               
               
                 CCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGAGGATCCGATATC 
               
               
                   
               
               
                 CAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGACAGAGT 
               
               
                   
               
               
                 GACCATCACCTGTAGAGCCAGCGAGAGCGTGGACGCTTACGGCATCAGCT 
               
               
                   
               
               
                 TCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATC 
               
               
                   
               
               
                 TACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCAGATTTTCCGGCTC 
               
               
                   
               
               
                 TGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGCCCGAGG 
               
               
                   
               
               
                 ACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGGACCTTT 
               
               
                   
               
               
                 GGCCAGGGTACCAAGCTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)]  
               
               
                 [PD-1 1.5 PD016 2001 (SEQ ID NO: 961)] 
               
               
                 (SEQ ID NO: 257) 
               
               
                 [QGQSGQG][VLCAAYALSSGICGGGGGSSGGSISSGLLSGRSDNHGGGS 
               
               
                   
               
               
                 DIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKL 
               
               
                   
               
               
                 LIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPW 
               
               
                   
               
               
                 TFGQGTKLEIK] 
               
               
                   
               
               
                 PD-1 1.5 PD016 2001 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 1060) 
               
               
                 VLCAAYALSSGICGGGGGSSGGSISSGLLSGRSDNHGGGSDIQLTQSPSS 
               
               
                   
               
               
                 LSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQGS 
               
               
                   
               
               
                 GVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEI 
               
               
                   
               
               
                 K 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)]  
               
               
                 [PD-1 1.5 PD016 2001 (SEQ ID NO: 962)] 
               
               
                 (SEQ ID NO: 258) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][GTTTTGTGCGCTGCTTATGCTTTGAG 
               
               
                   
               
               
                 TTCGGGTATTTGCGGTGGGGGAGGTGGCTCGAGCGGCGGCTCTATCTCTT 
               
               
                   
               
               
                 CCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGAGGATCCGATATC 
               
               
                   
               
               
                 CAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGACAGAGT 
               
               
                   
               
               
                 GACCATCACCTGTAGAGCCAGCGAGAGCGTGGACGCTTACGGCATCAGCT 
               
               
                   
               
               
                 TCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATC 
               
               
                   
               
               
                 TACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCAGATTTTCCGGCTC 
               
               
                   
               
               
                 TGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGCCCGAGG 
               
               
                   
               
               
                 ACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGGACCTTT 
               
               
                   
               
               
                 GGCCAGGGTACCAAGCTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)]  
               
               
                 [PD-1 1.5 PD017 2001 (SEQ ID NO: 963)] 
               
               
                 (SEQ ID NO: 259) 
               
               
                 [QGQSGQG][TTCNLYQQSSMFCNAGGGSSGGSISSGLLSGRSDNHGGGS 
               
               
                   
               
               
                 DIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKL 
               
               
                   
               
               
                 LIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPW 
               
               
                   
               
               
                 TFGQGTKLEIK] 
               
               
                   
               
               
                 PD-1 1.5 PD017 2001 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 1061) 
               
               
                 TTCNLYQQSSMFCNAGGGSSGGSISSGLLSGRSDNHGGGSDIQLTQSPSS 
               
               
                   
               
               
                 LSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQGS 
               
               
                   
               
               
                 GVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEI 
               
               
                   
               
               
                 K 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)]  
               
               
                 [PD-1 1.5 PD017 2001 (SEQ ID NO: 964)] 
               
               
                 (SEQ ID NO: 260) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][ACGACTTGCAATCTGTATCAGCAGTC 
               
               
                   
               
               
                 TTCTATGTTTTGCAATGCTGGAGGTGGCTCGAGCGGCGGCTCTATCTCTT 
               
               
                   
               
               
                 CCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGAGGATCCGATATC 
               
               
                   
               
               
                 CAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGACAGAGT 
               
               
                   
               
               
                 GACCATCACCTGTAGAGCCAGCGAGAGCGTGGACGCTTACGGCATCAGCT 
               
               
                   
               
               
                 TCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATC 
               
               
                   
               
               
                 TACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCAGATTTTCCGGCTC 
               
               
                   
               
               
                 TGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGCCCGAGG 
               
               
                   
               
               
                 ACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGGACCTTT 
               
               
                   
               
               
                 GGCCAGGGTACCAAGCTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)]  
               
               
                 [PD-1 1.5 PD018 2001 (SEQ ID NO: 965)] 
               
               
                 (SEQ ID NO: 261) 
               
               
                 [QGQSGQG][APRCYMFASYCKSQYGGGSSGGSISSGLLSGRSDNHGGGS 
               
               
                   
               
               
                 DIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKL 
               
               
                   
               
               
                 LIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPW 
               
               
                   
               
               
                 TFGQGTKLEIK] 
               
               
                   
               
               
                 PD-1 1.5 PD018 2001 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 1062) 
               
               
                 APRCYMFASYCKSQYGGGSSGGSISSGLLSGRSDNHGGGSDIQLTQSPSS 
               
               
                   
               
               
                 LSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQGS 
               
               
                   
               
               
                 GVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEI 
               
               
                   
               
               
                 K] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)]  
               
               
                 [PD-1 1.5 PD018 2001 (SEQ ID NO: 966)] 
               
               
                 (SEQ ID NO: 262) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][GCGCCTAGGTGCTATATGTTTGCGTC 
               
               
                   
               
               
                 GTATTGCAAGAGTCAGTATGGAGGTGGCTCGAGCGGCGGCTCTATCTCTT 
               
               
                   
               
               
                 CCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGAGGATCCGATATC 
               
               
                   
               
               
                 CAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGACAGAGT 
               
               
                   
               
               
                 GACCATCACCTGTAGAGCCAGCGAGAGCGTGGACGCTTACGGCATCAGCT 
               
               
                   
               
               
                 TCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATC 
               
               
                   
               
               
                 TACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCAGATTTTCCGGCTC 
               
               
                   
               
               
                 TGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGCCCGAGG 
               
               
                   
               
               
                 ACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGGACCTTT 
               
               
                   
               
               
                 GGCCAGGGTACCAAGCTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)]  
               
               
                 [PD-1 1.5 PD019 2001 (SEQ ID NO: 967)] 
               
               
                 (SEQ ID NO: 263) 
               
               
                 [PD-1 1.5 PD019 2001 (SEQ ID NO: 967)] 
               
               
                 [QGQSGQG][PCDQNPYFYPYVCHAGGGSSGGSISSGLLSGRSDNHGGGS 
               
               
                   
               
               
                 DIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKL 
               
               
                   
               
               
                 LIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPW 
               
               
                   
               
               
                 TFGQGTKLEIK] 
               
               
                   
               
               
                 PD-1 1.5 PD019 2001 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 967) 
               
               
                 PCDQNPYFYPYVCHAGGGSSGGSISSGLLSGRSDNHGGGSDIQLTQSPSS 
               
               
                   
               
               
                 LSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQGS 
               
               
                   
               
               
                 GVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEI 
               
               
                   
               
               
                 K 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)]  
               
               
                 [PD-1 1.5 PD019 2001 (SEQ ID NO: 968)] 
               
               
                 (SEQ ID NO: 264) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][CCTTGCGATCAGAATCCGTATTTTTA 
               
               
                   
               
               
                 TCCGTATGTGTGCCATGCGGGAGGTGGCTCGAGCGGCGGCTCTATCTCTT 
               
               
                   
               
               
                 CCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGAGGATCCGATATC 
               
               
                   
               
               
                 CAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGACAGAGT 
               
               
                   
               
               
                 GACCATCACCTGTAGAGCCAGCGAGAGCGTGGACGCTTACGGCATCAGCT 
               
               
                   
               
               
                 TCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATC 
               
               
                   
               
               
                 TACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCAGATTTTCCGGCTC 
               
               
                   
               
               
                 TGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGCCCGAGG 
               
               
                   
               
               
                 ACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGGACCTTT 
               
               
                   
               
               
                 GGCCAGGGTACCAAGCTGGAAATCAAG] 
               
               
                   
               
               
                 PD-1 1.5 PD019 2001 Nucleic Acid Sequence: 
               
               
                 (SEQ ID NO: 968) 
               
               
                 CCTTGCGATCAGAATCCGTATTTTTATCCGTATGTGTGCCATGCGGGAGG 
               
               
                   
               
               
                 TGGCTCGAGCGGCGGCTCTATCTCTTCCGGACTGCTGTCCGGCAGATCCG 
               
               
                   
               
               
                 ACAATCACGGCGGAGGATCCGATATCCAGCTGACCCAGAGCCCTAGCAGC 
               
               
                   
               
               
                 CTGTCTGCCAGCGTGGGCGACAGAGTGACCATCACCTGTAGAGCCAGCGA 
               
               
                   
               
               
                 GAGCGTGGACGCTTACGGCATCAGCTTCATGAACTGGTTCCAGCAGAAGC 
               
               
                   
               
               
                 CCGGCAAGGCCCCCAAGCTGCTGATCTACGCCGCCAGCAATCAGGGCAGC 
               
               
                   
               
               
                 GGCGTGCCAAGCAGATTTTCCGGCTCTGGCAGCGGCACCGACTTCACCCT 
               
               
                   
               
               
                 GACCATCAGCAGCATGCAGCCCGAGGACTTCGCCACCTACTACTGCCAGC 
               
               
                   
               
               
                 AGAGCAAGGACGTGCCCTGGACCTTTGGCCAGGGTACCAAGCTGGAAATC 
               
               
                   
               
               
                 AAG 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)]  
               
               
                 [PD-1 1.5 PD020 2001 (SEQ ID NO: 969)] 
               
               
                 (SEQ ID NO: 265) 
               
               
                 [QGQSGQG][SVCPMYALSSMLCGAGGGSSGGSISSGLLSGRSDNHGGGS 
               
               
                   
               
               
                 DIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKL 
               
               
                   
               
               
                 LIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPW 
               
               
                   
               
               
                 TFGQGTKLEIK] 
               
               
                   
               
               
                 PD-1 1.5 PD020 2001 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 1063) 
               
               
                 SVCPMYALSSMLCGAGGGSSGGSISSGLLSGRSDNHGGGSDIQLTQSPSS 
               
               
                   
               
               
                 LSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQGS 
               
               
                   
               
               
                 GVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEI 
               
               
                   
               
               
                 K 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)]  
               
               
                 [PD-1 1.5 PD020 2001 (SEQ ID NO: 970)] 
               
               
                 (SEQ ID NO: 266) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][TCTGTGTGCCCTATGTATGCGTTGAG 
               
               
                   
               
               
                 TTCTATGTTGTGCGGTGCGGGAGGTGGCTCGAGCGGCGGCTCTATCTCTT 
               
               
                   
               
               
                 CCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGAGGATCCGATATC 
               
               
                   
               
               
                 CAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGACAGAGT 
               
               
                   
               
               
                 GACCATCACCTGTAGAGCCAGCGAGAGCGTGGACGCTTACGGCATCAGCT 
               
               
                   
               
               
                 TCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATC 
               
               
                   
               
               
                 TACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCAGATTTTCCGGCTC 
               
               
                   
               
               
                 TGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGCCCGAGG 
               
               
                   
               
               
                 ACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGGACCTTT 
               
               
                   
               
               
                 GGCCAGGGTACCAAGCTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)]  
               
               
                 [PD-1 1.5 PD021 2001 (SEQ ID NO: 971)] 
               
               
                 (SEQ ID NO: 267) 
               
               
                 [QGQSGQG][LSVECYVFSRCSSLPGGGSSGGSISSGLLSGRSDNHGGGS 
               
               
                   
               
               
                 DIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKL 
               
               
                   
               
               
                 LIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPW 
               
               
                   
               
               
                 TFGQGTKLEIK] 
               
               
                   
               
               
                 PD-1 1.5 PD021 2001 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 1064) 
               
               
                 LSVECYVFSRCSSLPGGGSSGGSISSGLLSGRSDNHGGGSDIQLTQSPSS 
               
               
                   
               
               
                 LSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQGS 
               
               
                   
               
               
                 GVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEI 
               
               
                   
               
               
                 K] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)]  
               
               
                 [PD-1 1.5 PD021 2001 (SEQ ID NO: 972)] 
               
               
                 (SEQ ID NO: 268) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][TTGTCTGTGGAGTGCTATGTGTTTTC 
               
               
                   
               
               
                 GCGGTGCAGTAGTCTGCCGGGAGGTGGCTCGAGCGGCGGCTCTATCTCTT 
               
               
                   
               
               
                 CCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGAGGATCCGATATC 
               
               
                   
               
               
                 CAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGACAGAGT 
               
               
                   
               
               
                 GACCATCACCTGTAGAGCCAGCGAGAGCGTGGACGCTTACGGCATCAGCT 
               
               
                   
               
               
                 TCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATC 
               
               
                   
               
               
                 TACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCAGATTTTCCGGCTC 
               
               
                   
               
               
                 TGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGCCCGAGG 
               
               
                   
               
               
                 ACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGGACCTTT 
               
               
                   
               
               
                 GGCCAGGGTACCAAGCTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)]  
               
               
                 [PD-1 1.5 PD022 2001 (SEQ ID NO: 973)] 
               
               
                 (SEQ ID NO: 269) 
               
               
                 [QGQSGQG][FYCTYLVSLTCHPQGGGSSGGSISSGLLSGRSDNHGGGSD 
               
               
                   
               
               
                 IQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLL 
               
               
                   
               
               
                 IYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWT 
               
               
                   
               
               
                 FGQGTKLEIK] 
               
               
                   
               
               
                 PD-1 1.5 PD022 2001 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 1065) 
               
               
                 FYCTYLVSLTCHPQGGGSSGGSISSGLLSGRSDNHGGGSDIQLTQSPSSL 
               
               
                   
               
               
                 SASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQGSG 
               
               
                   
               
               
                 VPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEIK 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)]  
               
               
                 [PD-1 1.5 PD022 2001 (SEQ ID NO: 974)] 
               
               
                 (SEQ ID NO: 270) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][TTTTATTGCACTTATTTGGTGTCTTT 
               
               
                   
               
               
                 GACTTGCCATCCGCAGGGAGGTGGCTCGAGCGGCGGCTCTATCTCTTCCG 
               
               
                   
               
               
                 GACTGCTGTCCGGCAGATCCGACAATCACGGCGGAGGATCCGATATCCAG 
               
               
                   
               
               
                 CTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGACAGAGTGAC 
               
               
                   
               
               
                 CATCACCTGTAGAGCCAGCGAGAGCGTGGACGCTTACGGCATCAGCTTCA 
               
               
                   
               
               
                 TGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATCTAC 
               
               
                   
               
               
                 GCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCAGATTTTCCGGCTCTGG 
               
               
                   
               
               
                 CAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGCCCGAGGACT 
               
               
                   
               
               
                 TCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGGACCTTTGGC 
               
               
                   
               
               
                 CAGGGTACCAAGCTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)]  
               
               
                 [PD-1 1.5 PD023 2001 (SEQ ID NO: 975)] 
               
               
                 (SEQ ID NO: 271) 
               
               
                 [QGQSGQG][SMAGCQWSSFCVQRDGGGSSGGSISSGLLSGRSDNHGGGS 
               
               
                   
               
               
                 DIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKL 
               
               
                   
               
               
                 LIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPW 
               
               
                   
               
               
                 TFGQGTKLEIK] 
               
               
                   
               
               
                 PD-1 1.5 PD023 2001 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 1066) 
               
               
                 SMAGCQWSSFCVQRDGGGSSGGSISSGLLSGRSDNHGGGSDIQLTQSPSS 
               
               
                   
               
               
                 LSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQGS 
               
               
                   
               
               
                 GVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEI 
               
               
                   
               
               
                 K 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)]  
               
               
                 [PD-1 1.5 PD023 2001 (SEQ ID NO: 976)] 
               
               
                 (SEQ ID NO: 272) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][TCTATGGCGGGTTGCCAGTGGAGTTC 
               
               
                   
               
               
                 GTTTTGCGTGCAGCGGGATGGAGGTGGCTCGAGCGGCGGCTCTATCTCTT 
               
               
                   
               
               
                 CCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGAGGATCCGATATC 
               
               
                   
               
               
                 CAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGACAGAGT 
               
               
                   
               
               
                 GACCATCACCTGTAGAGCCAGCGAGAGCGTGGACGCTTACGGCATCAGCT 
               
               
                   
               
               
                 TCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATC 
               
               
                   
               
               
                 TACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCAGATTTTCCGGCTC 
               
               
                   
               
               
                 TGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGCCCGAGG 
               
               
                   
               
               
                 ACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGGACCTTT 
               
               
                   
               
               
                 GGCCAGGGTACCAAGCTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)]  
               
               
                 [PD-1 1.5 PD024 2001 (SEQ ID NO: 977)] 
               
               
                 (SEQ ID NO: 273) 
               
               
                 [QGQSGQG][IYSCYMFASRCTSDKGGGSSGGSISSGLLSGRSDNHGGGS 
               
               
                   
               
               
                 DIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKL 
               
               
                   
               
               
                 LIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPW 
               
               
                   
               
               
                 TFGQGTKLEIK] 
               
               
                   
               
               
                 PD-1 1.5 PD024 2001 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 1067) 
               
               
                 IYSCYMFASRCTSDKGGGSSGGSISSGLLSGRSDNHGGGSDIQLTQSPSS 
               
               
                   
               
               
                 LSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQGS 
               
               
                   
               
               
                 GVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEI 
               
               
                   
               
               
                 K] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)]  
               
               
                 [PD-1 1.5 PD024 2001 (SEQ ID NO: 978)] 
               
               
                 (SEQ ID NO: 274) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][ATTTATTCGTGCTATATGTTTGCTTC 
               
               
                   
               
               
                 GCGGTGCACGTCTGATAAGGGAGGTGGCTCGAGCGGCGGCTCTATCTCTT 
               
               
                   
               
               
                 CCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGAGGATCCGATATC 
               
               
                   
               
               
                 CAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGACAGAGT 
               
               
                   
               
               
                 GACCATCACCTGTAGAGCCAGCGAGAGCGTGGACGCTTACGGCATCAGCT 
               
               
                   
               
               
                 TCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATC 
               
               
                   
               
               
                 TACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCAGATTTTCCGGCTC 
               
               
                   
               
               
                 TGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGCCCGAGG 
               
               
                   
               
               
                 ACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGGACCTTT 
               
               
                   
               
               
                 GGCCAGGGTACCAAGCTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)]  
               
               
                 [PD-1 1.5 PD002 3001 (SEQ ID NO: 979)] 
               
               
                 (SEQ ID NO: 275) 
               
               
                 [QGQSGQG][DVNCAIWYSVCTTVPGGGSSGGAVGLLAPPGGLSGRSDNH 
               
               
                   
               
               
                 GGSDIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKA 
               
               
                   
               
               
                 PKLLIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKD 
               
               
                   
               
               
                 VPWTFGQGTKLEIK] 
               
               
                   
               
               
                 PD-1 1.5 PD002 3001 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 1068) 
               
               
                 DVNCAIWYSVCTTVPGGGSSGGAVGLLAPPGGLSGRSDNHGGSDIQLTQS 
               
               
                   
               
               
                 PSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASN 
               
               
                   
               
               
                 QGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTK 
               
               
                   
               
               
                 LEIK 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)]  
               
               
                 [PD-1 1.5 PD002 3001 (SEQ ID NO: 980)] 
               
               
                 (SEQ ID NO: 276) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT]CAAGGCCAGTCTGGCCAAGGTGATGTT 
               
               
                   
               
               
                 AATTGCGCTATTTGGTATTCGGTGTGCACTACTGTTCCTGGAGGTGGCTC 
               
               
                   
               
               
                 GAGCGGCGGCTCTATCTCTTCCGGACTGCTGTCCGGCAGATCCGACAATC 
               
               
                   
               
               
                 ACGGCGGAGGATCCGGAGGTGGCTCGAGCGGCGGCGCTGTGGGACTGCTG 
               
               
                   
               
               
                 GCTCCTCCTGGTGGCCTGTCTGGCAGATCTGATAACCACGGAGGATCCGA 
               
               
                   
               
               
                 TATCCAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGACA 
               
               
                   
               
               
                 GAGTGACCATCACCTGTAGAGCCAGCGAGAGCGTGGACGCTTACGGCATC 
               
               
                   
               
               
                 AGCTTCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCT 
               
               
                   
               
               
                 GATCTACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCAGATTTTCCG 
               
               
                   
               
               
                 GCTCTGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGCCC 
               
               
                   
               
               
                 GAGGACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGGAC 
               
               
                   
               
               
                 CTTTGGCCAGGGTACCAAGCTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)]  
               
               
                 [PD-1 1.5 PD-12 3001 (SEQ ID NO: 981)] 
               
               
                 (SEQ ID NO: 277) 
               
               
                 [QGQSGQG][NWLDCQFYSECSVYGGGGSSGGAVGLLAPPGGLSGRSDNH 
               
               
                   
               
               
                 GGSDIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKA 
               
               
                   
               
               
                 PKLLIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKD 
               
               
                   
               
               
                 VPWTFGQGTKLEIK] 
               
               
                   
               
               
                 PD-1 1.5 PD-12 3001 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 1069) 
               
               
                 NWLDCQFYSECSVYGGGGSSGGAVGLLAPPGGLSGRSDNHGGSDIQLTQS 
               
               
                   
               
               
                 PSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASN 
               
               
                   
               
               
                 QGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTK 
               
               
                   
               
               
                 LEIK] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)]  
               
               
                 [PD-1 1.5 PD-12 3001 (SEQ ID NO: 982)] 
               
               
                 (SEQ ID NO: 278) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][AATTGGTTGGATTGCCAGTTTTATTC 
               
               
                   
               
               
                 TGAGTGCTCTGTTTATGGTGGAGGTGGCTCGAGCGGCGGCTCTATCTCTT 
               
               
                   
               
               
                 CCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGAGGATCCGGAGGT 
               
               
                   
               
               
                 GGCTCGAGCGGCGGCGCTGTGGGACTGCTGGCTCCTCCTGGTGGCCTGTC 
               
               
                   
               
               
                 TGGCAGATCTGATAACCACGGAGGATCCGATATCCAGCTGACCCAGAGCC 
               
               
                   
               
               
                 CTAGCAGCCTGTCTGCCAGCGTGGGCGACAGAGTGACCATCACCTGTAGA 
               
               
                   
               
               
                 GCCAGCGAGAGCGTGGACGCTTACGGCATCAGCTTCATGAACTGGTTCCA 
               
               
                   
               
               
                 GCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATCTACGCCGCCAGCAATC 
               
               
                   
               
               
                 AGGGCAGCGGCGTGCCAAGCAGATTTTCCGGCTCTGGCAGCGGCACCGAC 
               
               
                   
               
               
                 TTCACCCTGACCATCAGCAGCATGCAGCCCGAGGACTTCGCCACCTACTA 
               
               
                   
               
               
                 CTGCCAGCAGAGCAAGGACGTGCCCTGGACCTTTGGCCAGGGTACCAAGC 
               
               
                   
               
               
                 TGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)]  
               
               
                 [PD-1 1.5 PD-16 3001 (SEQ ID NO: 983)] 
               
               
                 (SEQ ID NO: 279) 
               
               
                 [QGQSGQG][VLCAAYALSSGICGGGGGSSGGAVGLLAPPGGLSGRSDNH 
               
               
                   
               
               
                 GGSDIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKA 
               
               
                   
               
               
                 PKLLIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKD 
               
               
                   
               
               
                 VPWTFGQGTKLEIK] 
               
               
                   
               
               
                 PD-1 1.5 PD-16 3001 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 1070) 
               
               
                 VLCAAYALSSGICGGGGGSSGGAVGLLAPPGGLSGRSDNHGGSDIQLTQS 
               
               
                   
               
               
                 PSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASN 
               
               
                   
               
               
                 QGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTK 
               
               
                   
               
               
                 LEIK 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)]  
               
               
                 [PD-1 1.5 PD-16 3001 (SEQ ID NO: 984)] 
               
               
                 (SEQ ID NO: 280) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][GTTTTGTGCGCTGCTTATGCTTTGAG 
               
               
                   
               
               
                 TTCGGGTATTTGCGGTGGGGGAGGTGGCTCGAGCGGCGGCTCTATCTCTT 
               
               
                   
               
               
                 CCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGAGGATCCGGAGGT 
               
               
                   
               
               
                 GGCTCGAGCGGCGGCGCTGTGGGACTGCTGGCTCCTCCTGGTGGCCTGTC 
               
               
                   
               
               
                 TGGCAGATCTGATAACCACGGAGGATCCGATATCCAGCTGACCCAGAGCC 
               
               
                   
               
               
                 CTAGCAGCCTGTCTGCCAGCGTGGGCGACAGAGTGACCATCACCTGTAGA 
               
               
                   
               
               
                 GCCAGCGAGAGCGTGGACGCTTACGGCATCAGCTTCATGAACTGGTTCCA 
               
               
                   
               
               
                 GCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATCTACGCCGCCAGCAATC 
               
               
                   
               
               
                 AGGGCAGCGGCGTGCCAAGCAGATTTTCCGGCTCTGGCAGCGGCACCGAC 
               
               
                   
               
               
                 TTCACCCTGACCATCAGCAGCATGCAGCCCGAGGACTTCGCCACCTACTA 
               
               
                   
               
               
                 CTGCCAGCAGAGCAAGGACGTGCCCTGGACCTTTGGCCAGGGTACCAAGC 
               
               
                   
               
               
                 TGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)]  
               
               
                 [PD-1 1.5 PD025 2001 (SEQ ID NO: 985)] 
               
               
                 (SEQ ID NO: 281) 
               
               
                 [QGQSGQG][SRCSVYEVSSGLCDWGGGSSGGSISSGLLSGRSDNHGGGS 
               
               
                   
               
               
                 DIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKL 
               
               
                   
               
               
                 LIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPW 
               
               
                   
               
               
                 TFGQGTKLEIK] 
               
               
                   
               
               
                 PD-1 1.5 PD025 2001 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 1071) 
               
               
                 SRCSVYEVSSGLCDWGGGSSGGSISSGLLSGRSDNHGGGSDIQLTQSPSS 
               
               
                   
               
               
                 LSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQGS 
               
               
                   
               
               
                 GVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEI 
               
               
                   
               
               
                 K 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)]  
               
               
                 [PD-1 1.5 PD025 2001 (SEQ ID NO: 986)] 
               
               
                 (SEQ ID NO: 282) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][TCTCGTTGCTCTGTGTATGAGGTTTC 
               
               
                   
               
               
                 GTCGGGGCTGTGCGATTGGGGAGGTGGCTCGAGCGGCGGCTCTATCTCTT 
               
               
                   
               
               
                 CCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGAGGATCCGATATC 
               
               
                   
               
               
                 CAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGACAGAGT 
               
               
                   
               
               
                 GACCATCACCTGTAGAGCCAGCGAGAGCGTGGACGCTTACGGCATCAGCT 
               
               
                   
               
               
                 TCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATC 
               
               
                   
               
               
                 TACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCAGATTTTCCGGCTC 
               
               
                   
               
               
                 TGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGCCCGAGG 
               
               
                   
               
               
                 ACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGGACCTTT 
               
               
                   
               
               
                 GGCCAGGGTACCAAGCTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)]  
               
               
                 [PD-1 1.5 PD026 2001 (SEQ ID NO: 987)] 
               
               
                 (SEQ ID NO: 283) 
               
               
                 [QGQSGQG][GMCSAYAYSSKLCTIGGGSSGGSISSGLLSGRSDNHGGGS 
               
               
                   
               
               
                 DIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKL 
               
               
                   
               
               
                 LIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPW 
               
               
                   
               
               
                 TFGQGTKLEIK] 
               
               
                   
               
               
                 PD-1 1.5 PD026 2001 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 1072) 
               
               
                 GMCSAYAYSSKLCTIGGGSSGGSISSGLLSGRSDNHGGGSDIQLTQSPSS 
               
               
                   
               
               
                 LSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQGS 
               
               
                   
               
               
                 GVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEI 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)]  
               
               
                 [PD-1 1.5 PD026 2001 (SEQ ID NO: 988)] 
               
               
                 (SEQ ID NO: 284) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][GGGATGTGCTCGGCGTATGCTTATTC 
               
               
                   
               
               
                 GAGTAAGTTGTGCACTATTGGAGGTGGCTCGAGCGGCGGCTCTATCTCTT 
               
               
                   
               
               
                 CCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGAGGATCCGATATC 
               
               
                   
               
               
                 CAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGACAGAGT 
               
               
                   
               
               
                 GACCATCACCTGTAGAGCCAGCGAGAGCGTGGACGCTTACGGCATCAGCT 
               
               
                   
               
               
                 TCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATC 
               
               
                   
               
               
                 TACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCAGATTTTCCGGCTC 
               
               
                   
               
               
                 TGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGCCCGAGG 
               
               
                   
               
               
                 ACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGGACCTTT 
               
               
                   
               
               
                 GGCCAGGGTACCAAGCTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)]  
               
               
                 [PD-1 1.5 PD027 2001 (SEQ ID NO: 989)] 
               
               
                 (SEQ ID NO: 285) 
               
               
                 [QGQSGQG][MTTNTCNLLCQQFLTGGGSSGGSISSGLLSGRSDNHGGGS 
               
               
                   
               
               
                 DIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKL 
               
               
                   
               
               
                 LIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPW 
               
               
                   
               
               
                 TFGQGTKLEIK] 
               
               
                   
               
               
                 PD-1 1.5 PD027 2001 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 1073) 
               
               
                 MTTNTCNLLCQQFLTGGGSSGGSISSGLLSGRSDNHGGGSDIQLTQSPSS 
               
               
                   
               
               
                 LSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQGS 
               
               
                   
               
               
                 GVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEI 
               
               
                   
               
               
                 K] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)]  
               
               
                 [PD-1 1.5 PD027 2001 (SEQ ID NO: 990)] 
               
               
                 (SEQ ID NO: 286) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][ATGACTACGAATACTTGCAATCTGTT 
               
               
                   
               
               
                 GTGCCAGCAGTTTTTGACGGGAGGTGGCTCGAGCGGCGGCTCTATCTCTT 
               
               
                   
               
               
                 CCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGAGGATCCGATATC 
               
               
                   
               
               
                 CAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGACAGAGT 
               
               
                   
               
               
                 GACCATCACCTGTAGAGCCAGCGAGAGCGTGGACGCTTACGGCATCAGCT 
               
               
                   
               
               
                 TCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATC 
               
               
                   
               
               
                 TACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCAGATTTTCCGGCTC 
               
               
                   
               
               
                 TGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGCCCGAGG 
               
               
                   
               
               
                 ACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGGACCTTT 
               
               
                   
               
               
                 GGCCAGGGTACCAAGCTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)]  
               
               
                 [PD-1 1.5 PD028 2001 (SEQ ID NO: 991)] 
               
               
                 (SEQ ID NO: 287) 
               
               
                 [QGQSGQG][FQPCLMFASSCFTSKGGGSSGGSISSGLLSGRSDNHGGGS 
               
               
                   
               
               
                 DIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKL 
               
               
                   
               
               
                 LIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPW 
               
               
                   
               
               
                 TFGQGTKLEIK] 
               
               
                   
               
               
                 PD-1 1.5 PD028 2001 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 991) 
               
               
                 FQPCLMFASSCFTSKGGGSSGGSISSGLLSGRSDNHGGGSDIQLTQSPSS 
               
               
                   
               
               
                 LSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQGS 
               
               
                   
               
               
                 GVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEI 
               
               
                   
               
               
                 K 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)]  
               
               
                 [PD-1 1.5 PD028 2001 (SEQ ID NO: 992)] 
               
               
                 (SEQ ID NO: 288) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][TTTCAGCCGTGCCTGATGTTTGCGAG 
               
               
                   
               
               
                 TAGTTGCTTTACTAGTAAGGGAGGTGGCTCGAGCGGCGGCTCTATCTCTT 
               
               
                   
               
               
                 CCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGAGGATCCGATATC 
               
               
                   
               
               
                 CAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGACAGAGT 
               
               
                   
               
               
                 GACCATCACCTGTAGAGCCAGCGAGAGCGTGGACGCTTACGGCATCAGCT 
               
               
                   
               
               
                 TCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATC 
               
               
                   
               
               
                 TACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCAGATTTTCCGGCTC 
               
               
                   
               
               
                 TGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGCCCGAGG 
               
               
                   
               
               
                 ACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGGACCTTT 
               
               
                   
               
               
                 GGCCAGGGTACCAAGCTGGAAATCAAG] 
               
               
                   
               
               
                 PD-1 1.5 PD028 2001 Nucleic Acid Sequence: 
               
               
                 (SEQ ID NO: 992) 
               
               
                 TTTCAGCCGTGCCTGATGTTTGCGAGTAGTTGCTTTACTAGTAAGGGAGG 
               
               
                   
               
               
                 TGGCTCGAGCGGCGGCTCTATCTCTTCCGGACTGCTGTCCGGCAGATCCG 
               
               
                   
               
               
                 ACAATCACGGCGGAGGATCCGATATCCAGCTGACCCAGAGCCCTAGCAGC 
               
               
                   
               
               
                 CTGTCTGCCAGCGTGGGCGACAGAGTGACCATCACCTGTAGAGCCAGCGA 
               
               
                   
               
               
                 GAGCGTGGACGCTTACGGCATCAGCTTCATGAACTGGTTCCAGCAGAAGC 
               
               
                   
               
               
                 CCGGCAAGGCCCCCAAGCTGCTGATCTACGCCGCCAGCAATCAGGGCAGC 
               
               
                   
               
               
                 GGCGTGCCAAGCAGATTTTCCGGCTCTGGCAGCGGCACCGACTTCACCCT 
               
               
                   
               
               
                 GACCATCAGCAGCATGCAGCCCGAGGACTTCGCCACCTACTACTGCCAGC 
               
               
                   
               
               
                 AGAGCAAGGACGTGCCCTGGACCTTTGGCCAGGGTACCAAGCTGGAAATC 
               
               
                   
               
               
                 AAG 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)]  
               
               
                 [PD-1 1.5 PD030 2001 (SEQ ID NO: 993)] 
               
               
                 (SEQ ID NO: 289) 
               
               
                 [QGQSGQG][ALCSMYLASSGLCNKGGGSSGGSISSGLLSGRSDNHGGGS 
               
               
                   
               
               
                 DIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKL 
               
               
                   
               
               
                 LIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPW 
               
               
                   
               
               
                 TFGQGTKLEIK] 
               
               
                   
               
               
                 PD-1 1.5 PD030 2001 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 1074) 
               
               
                 ALCSMYLASSGLCNKGGGSSGGSISSGLLSGRSDNHGGGSDIQLTQSPSS 
               
               
                   
               
               
                 LSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQGS 
               
               
                   
               
               
                 GVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEI 
               
               
                   
               
               
                 K 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)]  
               
               
                 [PD-1 1.5 PD030 2001 (SEQ ID NO: 994)] 
               
               
                 (SEQ ID NO: 290) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][GCGCTTTGCAGTATGTATCTTGCTAG 
               
               
                   
               
               
                 TTCTGGGCTGTGCAATAAGGGAGGTGGCTCGAGCGGCGGCTCTATCTCTT 
               
               
                   
               
               
                 CCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGAGGATCCGATATC 
               
               
                   
               
               
                 CAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGACAGAGT 
               
               
                   
               
               
                 GACCATCACCTGTAGAGCCAGCGAGAGCGTGGACGCTTACGGCATCAGCT 
               
               
                   
               
               
                 TCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATC 
               
               
                   
               
               
                 TACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCAGATTTTCCGGCTC 
               
               
                   
               
               
                 TGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGCCCGAGG 
               
               
                   
               
               
                 ACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGGACCTTT 
               
               
                   
               
               
                 GGCCAGGGTACCAAGCTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)]  
               
               
                 [PD-1 1.5 PD033 2001 (SEQ ID NO: 995)] 
               
               
                 (SEQ ID NO: 291) 
               
               
                 [QGQSGQG][EFCARDWLPYQCSSFGGGSSGGSISSGLLSGRSDNHGGGS 
               
               
                   
               
               
                 DIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKL 
               
               
                   
               
               
                 LIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPW 
               
               
                   
               
               
                 TFGQGTKLEIK] 
               
               
                   
               
               
                 PD-1 1.5 PD033 2001 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 1075) 
               
               
                 EFCARDWLPYQCSSFGGGSSGGSISSGLLSGRSDNHGGGSDIQLTQSPSS 
               
               
                   
               
               
                 LSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQGS 
               
               
                   
               
               
                 GVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEI 
               
               
                   
               
               
                 K] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)]  
               
               
                 [PD-1 1.5 PD033 2001 (SEQ ID NO: 996)] 
               
               
                 (SEQ ID NO: 292) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][GAGTTTTGCGCTCGGGATTGGCTGCC 
               
               
                   
               
               
                 GTATCAGTGCTCGAGTTTTGGAGGTGGCTCGAGCGGCGGCTCTATCTCTT 
               
               
                   
               
               
                 CCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGAGGATCCGATATC 
               
               
                   
               
               
                 CAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGACAGAGT 
               
               
                   
               
               
                 GACCATCACCTGTAGAGCCAGCGAGAGCGTGGACGCTTACGGCATCAGCT 
               
               
                   
               
               
                 TCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATC 
               
               
                   
               
               
                 TACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCAGATTTTCCGGCTC 
               
               
                   
               
               
                 TGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGCCCGAGG 
               
               
                   
               
               
                 ACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGGACCTTT 
               
               
                   
               
               
                 GGCCAGGGTACCAAGCTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)]  
               
               
                 [PD-1 1.5 PD034 2001 (SEQ ID NO: 1028)] 
               
               
                 (SEQ ID NO: 1029) 
               
               
                 [QGQSGQG][TSYCSIEHYPCNTHHGGGSSGGSISSGLLSGRSDNHG 
               
               
                   
               
               
                 GGSDIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQ 
               
               
                   
               
               
                 KPGKAPKLLIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYY 
               
               
                   
               
               
                 CQQSKDVPWTFGQGTKLEIK] 
               
               
                   
               
               
                 PD-1 1.5 PD034 2001 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 1028) 
               
               
                 TSYCSIEHYPCNTHHGGGSSGGSISSGLLSGRSDNHGGGSDIQLTQSPS 
               
               
                   
               
               
                 SLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQ 
               
               
                   
               
               
                 GSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTK 
               
               
                   
               
               
                 LEIK 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)]  
               
               
                 [PD-1 1.5 PD034 2001 (SEQ ID NO: 1030) 
               
               
                 (SEQ ID NO: 1031) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][ACGTCATACTGCAGTATTGAGCAT 
               
               
                   
               
               
                 TACCCCTGCAATACACATCATGGAGGTGGCTCGAGCGGCGGCTCTATCTC 
               
               
                   
               
               
                 TTCCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGAGGATCCGATA 
               
               
                   
               
               
                 TCCAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGACAG 
               
               
                   
               
               
                 AGTGACCATCACCTGTAGAGCCAGCGAGAGCGTGGACGCTTACGGCATC 
               
               
                   
               
               
                 AGCTTCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGC 
               
               
                   
               
               
                 TGATCTACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCAGATTTTC 
               
               
                   
               
               
                 CGGCTCTGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAG 
               
               
                   
               
               
                 CCCGAGGACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCC 
               
               
                   
               
               
                 TGGACCTTTGGCCAGGGTACCAAGCTGGAAATCAAG] 
               
               
                   
               
               
                 PD-1 1.5 PD034 2001 Nucleic Acid Sequence: 
               
               
                 (SEQ ID NO: 1030) 
               
               
                 ACGTCATACTGCAGTATTGAGCATTACCCCTGCAATACACATCATGGAG 
               
               
                   
               
               
                 GTGGCTCGAGCGGCGGCTCTATCTCTTCCGGACTGCTGTCCGGCAGATC 
               
               
                   
               
               
                 CGACAATCACGGCGGAGGATCCGATATCCAGCTGACCCAGAGCCCTAGC 
               
               
                   
               
               
                 AGCCTGTCTGCCAGCGTGGGCGACAGAGTGACCATCACCTGTAGAGCCA 
               
               
                   
               
               
                 GCGAGAGCGTGGACGCTTACGGCATCAGCTTCATGAACTGGTTCCAGCA 
               
               
                   
               
               
                 GAAGCCCGGCAAGGCCCCCAAGCTGCTGATCTACGCCGCCAGCAATCAG 
               
               
                   
               
               
                 GGCAGCGGCGTGCCAAGCAGATTTTCCGGCTCTGGCAGCGGCACCGACT 
               
               
                   
               
               
                 TCACCCTGACCATCAGCAGCATGCAGCCCGAGGACTTCGCCACCTACTA 
               
               
                   
               
               
                 CTGCCAGCAGAGCAAGGACGTGCCCTGGACCTTTGGCCAGGGTACCAAG 
               
               
                   
               
               
                 CTGGAAATCAAG 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)]  
               
               
                 [PD-1 1.5 PD035 2001 (SEQ ID NO: 997)] 
               
               
                 (SEQ ID NO: 293) 
               
               
                 [QGQSGQG][PYICSSFPLDCQAGQGGGSSGGSISSGLLSGRSDNHGG 
               
               
                   
               
               
                 GSDIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAP 
               
               
                   
               
               
                 KLLIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDV 
               
               
                   
               
               
                 PWTFGQGTKLEIK] 
               
               
                   
               
               
                 PD-1 1.5 PD035 2001 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 1076) 
               
               
                 PYICSSFPLDCQAGQGGGSSGGSISSGLLSGRSDNHGGGSDIQLTQSPS 
               
               
                   
               
               
                 SLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQ 
               
               
                   
               
               
                 GSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTK 
               
               
                   
               
               
                 LEIK] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)]  
               
               
                 [PD-1 1.5 PD035 2001 (SEQ ID NO: 998)] 
               
               
                 (SEQ ID NO: 584) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][CCTTATATTTGCTCTAGTTTTCCGTT 
               
               
                   
               
               
                 GGATTGCCAGGCGGGTCAGGGAGGTGGCTCGAGCGGCGGCTCTATCTCTT 
               
               
                   
               
               
                 CCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGAGGATCCGATATC 
               
               
                   
               
               
                 CAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGACAGAG 
               
               
                   
               
               
                 TGACCATCACCTGTAGAGCCAGCGAGAGCGTGGACGCTTACGGCATCAG 
               
               
                   
               
               
                 CTTCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTG 
               
               
                   
               
               
                 ATCTACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCAGATTTTCCG 
               
               
                   
               
               
                 GCTCTGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGCC 
               
               
                   
               
               
                 CGAGGACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGG 
               
               
                   
               
               
                 ACCTTTGGCCAGGGTACCAAGCTGGAAATCAAG] 
               
            
           
         
       
     
     Example 9: Anti-PD-1 Activatable Antibodies of the Disclosure 
     This example demonstrates that anti-PD-1 activatable antibodies of the disclosure can be made in a variety of combinations of MM, CM, VL, and VH domains, as well as in a variety of distinct Ig isotypes. In addition, this example demonstrates that anti-PD-1 activatable antibodies of the disclosure can be made in a variety of combinations of MM, CM, VLCDR1, VLCDR2, VLCDR3, VHCDR1, VHCDR2, and VHCDR3 domains, as well as in a variety of distinct Ig isotypes. 
     
       
         
           
               
               
               
               
               
             
               
                 TABLE 13A 
               
             
            
               
                   
               
               
                   
                 VL 
                   
                 VL CDRs 
                 VH CDRs 
               
               
                   
                 SEQ 
                 VH 
                 SEQ ID NO: 
                 SEQ ID NO: 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                 Mask Sequence 
                 Substrates: 
                 ID NO: 
                 SEQ ID NO: 
                 CDR1 
                 CDR2 
                 CDR3 
                 CDR1 
                 CDR2 
                 CDR3 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                 AMSGCSWSAFCPYLA 
                 LSGRSDNH 
                 1 
                 3 
                 653 
                 658 
                 664 
                 669 
                 678 
                 683 
               
               
                 (SEQ ID NO: 66) 
                 (SEQ ID NO: 294) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 DVNCAIWYSVCITVP 
                 TGRGPSWV 
                 5 
                 7 
                 654 
                 659 
                 665 
                 670 
                 679 
                 684 
               
               
                 (SEQ ID NO: 67) 
                 (SEQ ID NO: 295) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 LVCPLYALSSGVCMG 
                 PLTGRSGG 
                 9 
                 11 
                 655 
                 660 
                 666 
                 671 
                 680 
                 685 
               
               
                 (SEQ ID NO: 68) 
                 (SEQ ID NO: 296) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 SVNCRIWSAVCAGYE 
                 TARGPSFK 
                 13 
                 15 
                 656 
                 661 
                 667 
                 672 
                 681 
                 686 
               
               
                 (SEQ ID NO: 69) 
                 (SEQ ID NO: 297) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 MLVCSLQPTAMCERV 
                 NTLSGRSENHSG 
                 17 
                 19 
                 657 
                 662 
                 668 
                 673 
                 682 
                 687 
               
               
                 (SEQ ID NO: 70) 
                 (SEQ ID NO: 298) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 APRCYMFASYCKSQY 
                 NTLSGRSGNHGS 
                 21 
                 39 
                   
                 663 
                   
                 674 
                   
                   
               
               
                 (SEQ ID NO: 71) 
                 (SEQ ID NO: 299) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 VGPCELTPKPVCNTY 
                 TSTSGRSANPRG 
                 23 
                 41 
                   
                   
                   
                 675 
                   
                   
               
               
                 (SEQ ID NO: 72) 
                 (SEQ ID NO: 300) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 ETCNQYERSSGLCFA 
                 TSGRSANP 
                 25 
                 43 
                   
                   
                   
                 676 
                   
                   
               
               
                 (SEQ ID NO: 73) 
                 (SEQ ID NO: 301) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 APRTCYTYQCSSFYT 
                 VHMPLGFLGP 
                 27 
                 45 
                   
                   
                   
                 677 
                   
                   
               
               
                 (SEQ ID NO: 74) 
                 (SEQ ID NO: 302) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 GLCSWYLSSSGLCVD 
                 AVGLLAPP 
                 29 
                 47 
                 VL CDRs of SEQ ID 
                 VH CDRs of SEQ ID 
               
               
                 (SEQ ID NO: 75) 
                 (SEQ ID NO: 303) 
                   
                   
                 NO: 1 
                 NO: 3 
               
               
                   
               
               
                 VPWCQLTPRVMCMWA 
                 AQNLLGMV 
                 31 
                 49 
                 VL CDRs of SEQ ID 
                 VH CDRs of SEQ ID 
               
               
                 (SEQ ID NO: 76) 
                 (SEQ ID NO: 304) 
                   
                   
                 NO: 5 
                 NO: 7 
               
               
                   
               
               
                 NWLDCQFYSECSVYG 
                 QNQALRMA 
                 33 
                 51 
                 VL CDRs of SEQ ID 
                 VH CDRs of SEQ ID 
               
               
                 (SEQ ID NO: 77) 
                 (SEQ ID NO: 305) 
                   
                   
                 NO: 9 
                 NO: 11 
               
               
                   
               
               
                 SCPLYVMSSFGGCWD 
                 LAAPLGLL 
                 35 
                 53 
                 VL CDRs of SEQ ID 
                 VH CDRs of SEQ ID 
               
               
                 (SEQ ID NO: 78) 
                 (SEQ ID NO: 306) 
                   
                   
                 NO: 13 
                 NO: 15 
               
               
                   
               
               
                 MSHCWMFSSSCDGVK 
                 STFPFGMF 
                 37 
                 55 
                 VL CDRs of SEQ ID 
                 VH CDRs of SEQ ID 
               
               
                 (SEQ ID NO: 79) 
                 (SEQ ID NO: 307) 
                   
                   
                 NO: 17 
                 NO: 19 
               
               
                   
               
               
                 VSYCTWLIEVICLRG 
                 ISSGLLSS 
                   
                 57 
                 VL CDRs of SEQ ID 
                 VH CDRs of SEQ ID 
               
               
                 (SEQ ID NO: 80) 
                 (SEQ ID NO: 308) 
                   
                   
                 NO: 21 
                 NO: 39 
               
               
                   
               
               
                 VLCAAYALSSGICGG 
                 PAGLWLDP 
                   
                 59 
                 VL CDRs of SEQ ID 
                 VH CDRs of SEQ ID 
               
               
                 (SEQ ID NO: 81) 
                 (SEQ ID NO: 309) 
                   
                   
                 NO: 23 
                 NO: 41 
               
               
                   
               
               
                 TTCNLYQQSSMFCNA 
                 VAGRSMRP 
                   
                   
                 VL CDRs of SEQ ID 
                 VH CDRs of SEQ ID 
               
               
                 (SEQ ID NO: 82) 
                 (SEQ ID NO: 310) 
                   
                   
                 NO: 25 
                 NO: 43 
               
               
                   
               
               
                 APRCYMFASYCKSQY 
                 VVPEGRRS 
                   
                   
                 VL CDRs of SEQ ID 
                 VH CDRs of SEQ ID 
               
               
                 (SEQ ID NO: 83) 
                 (SEQ ID NO: 311) 
                   
                   
                 NO: 27 
                 NO: 45 
               
               
                   
               
               
                 PCDQNPYFYPYVCHA 
                 ILPRSPAF 
                   
                   
                 VL CDRs of SEQ ID 
                 VH CDRs of SEQ ID 
               
               
                 (SEQ ID NO: 84) 
                 (SEQ ID NO: 312) 
                   
                   
                 NO: 29 
                 NO: 47 
               
               
                   
               
               
                 SVCPMYALSSMLCGA 
                 MVLGRSLL 
                   
                   
                 VL CDRs of SEQ ID 
                 VH CDRs of SEQ ID 
               
               
                 (SEQ ID NO: 85) 
                 (SEQ ID NO: 313) 
                   
                   
                 NO: 31 
                 NO: 49 
               
               
                   
               
               
                 LSVECYVFSRCSSLP 
                 QGRAITFI 
                   
                   
                 VL CDRs of SEQ ID 
                 VH CDRs of SEQ ID 
               
               
                 (SEQ ID NO: 86) 
                 (SEQ ID NO: 314) 
                   
                   
                 NO: 33 
                 NO: 51 
               
               
                   
               
               
                 FYCTYLVSLTCHPQ 
                 SPRSIMLA 
                   
                   
                 VL CDRs of SEQ ID 
                 VH CDRs of SEQ ID 
               
               
                 (SEQ ID NO: 87) 
                 (SEQ ID NO: 315) 
                   
                   
                 NO: 35 
                 NO: 53 
               
               
                   
               
               
                 SMAGCQWSSFCVQRD 
                 SMLRSMPL 
                   
                   
                 VL CDRs of SEQ ID 
                 VH CDRs of SEQ ID 
               
               
                 (SEQ ID NO: 88) 
                 (SEQ ID NO: 316) 
                   
                   
                 NO: 37 
                 NO: 55 
               
               
                   
               
               
                 IYSCYMFASRCTSDK 
                 SARGPSRW 
                   
                   
                   
                 VH CDRs of SEQ ID 
               
               
                 (SEQ ID NO: 89) 
                 (SEQ ID NO: 319) 
                   
                   
                   
                 NO: 57 
               
               
                   
               
               
                 SRCSVYEVSSGLCDW 
                 GWHTGRN 
                   
                   
                   
                 VH CDRs of SEQ ID 
               
               
                 (SEQ ID NO: 90) 
                 (SEQ ID NO: 320) 
                   
                   
                   
                 NO: 59 
               
               
                   
               
               
                 GMCSAYAYSSKLCTI 
                 HTGRSGAL 
                   
                   
                 LC CDRs of SEQ ID 
                 HC CDRs of SEQ ID 
               
               
                 (SEQ ID NO: 91) 
                 (SEQ ID NO: 321) 
                   
                   
                 NO: 543 
                 NO: 546 
               
               
                   
               
               
                 MTTNTCNLLCQQFLT 
                 AARGPAIH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 92) 
                 (SEQ ID NO: 322) 
                   
                   
                   
                   
               
               
                   
               
               
                 FQPCLMFASSCFTSK 
                 RGPAFNPM 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 93) 
                 (SEQ ID NO: 323) 
                   
                   
                   
                   
               
               
                   
               
               
                 WNCHPAGVGPVFCEV 
                 SSRGPAYL 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 94) 
                 (SEQ ID NO: 324) 
                   
                   
                   
                   
               
               
                   
               
               
                 ALCSMYLASSGLCNK 
                 RGPATPIM 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 95) 
                 (SEQ ID NO: 325) 
                   
                   
                   
                   
               
               
                   
               
               
                 NYLSCQFFQNCYETY 
                 RGPA 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 96) 
                 (SEQ ID NO: 326) 
                   
                   
                   
                   
               
               
                   
               
               
                 GWCLFSDMWLGLCSA 
                 GGQPSGMWGW 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 97) 
                 (SEQ ID NO: 327) 
                   
                   
                   
                   
               
               
                   
               
               
                 EFCARDWLPYQCSSF 
                 FPRPLGITGL 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 98) 
                 (SEQ ID NO: 328) 
                   
                   
                   
                   
               
               
                   
               
               
                 TSYCSIEHYPCNTHH 
                 SPLTGRSG 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 99) 
                 (SEQ ID NO: 329) 
                   
                   
                   
                   
               
               
                   
               
               
                 PYICSSFPLDCQAGQ 
                 SAGFSLPA 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 100) 
                 (SEQ ID NO: 330) 
                   
                   
                   
                   
               
               
                   
               
               
                 VGCEWYMSSSGMCSR 
                 LAPLGLQRR 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 101) 
                 (SEQ ID NO: 331) 
                   
                   
                   
                   
               
               
                   
               
               
                 EVCGGCSMQSVSCWP 
                 SGGPLGVR 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 102) 
                 (SEQ ID NO: 332) 
                   
                   
                   
                   
               
               
                   
               
               
                 FTECQLSPKAICMSN 
                 PLGL 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 103) 
                 (SEQ ID NO: 333) 
                   
                   
                   
                   
               
               
                   
               
               
                 KYCLFSEYVEGTCLN 
                 ISSGLSS 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 104) 
                 (SEQ ID NO: 334) 
                   
                   
                   
                   
               
               
                   
               
               
                 SGCPMYAWGWDECWR 
                 PVGYTSSL 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 105) 
                 (SEQ ID NO: 335) 
                   
                   
                   
                   
               
               
                   
               
               
                 VDCPWYASSSAICSR 
                 DWLYWPGI 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 106) 
                 (SEQ ID NO: 336) 
                   
                   
                   
                   
               
               
                   
               
               
                 DMLLCQIRGSCAAWG 
                 LKAAPRWA 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 107) 
                 (SEQ ID NO: 337) 
                   
                   
                   
                   
               
               
                   
               
               
                 ECHPYQASASLWCGY 
                 GPSHLVLT 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 108) 
                 (SEQ ID NO: 338) 
                   
                   
                   
                   
               
               
                   
               
               
                 MMMGCMWSAWCPPSR 
                 LPGGLSPW 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 109) 
                 (SEQ ID NO: 339) 
                   
                   
                   
                   
               
               
                   
               
               
                 NAYFRCSLMCNMIMF 
                 MGLFSEAG 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 110) 
                 (SEQ ID NO: 340) 
                   
                   
                   
                   
               
               
                   
               
               
                 ACCKESVHSVHDCKR 
                 SPLPLRVP 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 111) 
                 (SEQ ID NO: 341) 
                   
                   
                   
                   
               
               
                   
               
               
                 ACIGINSYMSNYCYL 
                 RMHLRSLG 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 112) 
                 (SEQ ID NO: 342) 
                   
                   
                   
                   
               
               
                   
               
               
                 ANCSFLELTNKFCTI 
                 LLAPSHRA 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 113) 
                 (SEQ ID NO: 343) 
                   
                   
                   
                   
               
               
                   
               
               
                 AYCSYLMFASNPCII 
                 GPRSFGL 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 114) 
                 (SEQ ID NO: 344) 
                   
                   
                   
                   
               
               
                   
               
               
                 CFTSKCPCLCYSLLA 
                 GPRSFG 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 115) 
                 (SEQ ID NO: 345) 
                   
                   
                   
                   
               
               
                   
               
               
                 CLCRDINCWLGCSKT 
                 LSGRSGNH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 116) 
                 (SEQ ID NO: 1157) 
                   
                   
                   
                   
               
               
                   
               
               
                 CWCDIYCSPYQCSSF 
                 SGRSANPRG 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 117) 
                 (SEQ ID NO: 1158) 
                   
                   
                   
                   
               
               
                   
               
               
                 DCIYYYQQSANLCSY 
                 LSGRSDDH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 118) 
                 (SEQ ID NO: 1161) 
                   
                   
                   
                   
               
               
                   
               
               
                 DCTGVNYYIDKHCIN 
                 LSGRSDIH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 119) 
                 (SEQ ID NO: 1162) 
                   
                   
                   
                   
               
               
                   
               
               
                 DECHGYLRSSGLCGG 
                 LSGRSDQH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 120) 
                 (SEQ ID NO: 1165) 
                   
                   
                   
                   
               
               
                   
               
               
                 DICSAYAASSGFCYY 
                 LSGRSDTH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 121) 
                 (SEQ ID NO: 1166) 
                   
                   
                   
                   
               
               
                   
               
               
                 DIICVLIPTAWCGRT 
                 LSGRSDYH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 122) 
                 (SEQ ID NO: 1169) 
                   
                   
                   
                   
               
               
                   
               
               
                 DNCCMYCSWWIACRD 
                 LSGRSDNP 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 123) 
                 (SEQ ID NO: 1520) 
                   
                   
                   
                   
               
               
                   
               
               
                 DSCQWYMLSADLCGT 
                 LSGRSANP 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 124) 
                 (SEQ ID NO: 1695) 
                   
                   
                   
                   
               
               
                   
               
               
                 DSVCFSSSSFLCHKS 
                 LSGRSANI 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 125) 
                 (SEQ ID NO: 1696) 
                   
                   
                   
                   
               
               
                   
               
               
                 DTMCAIWWTVCSGGR 
                 LSGRSDNI 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 126) 
                 (SEQ ID NO: 1697) 
                   
                   
                   
                   
               
               
                   
               
               
                 ECTYQTSSFHEACMS 
                 MIAPVAYR 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 127) 
                 (SEQ ID NO: 1698) 
                   
                   
                   
                   
               
               
                   
               
               
                 EGCNLYERSSYGCNN 
                 RPSPMWAY 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 128) 
                 (SEQ ID NO: 1699) 
                   
                   
                   
                   
               
               
                   
               
               
                 EGCTAFAMSAGICGG 
                 WATPRPMR 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 129) 
                 (SEQ ID NO: 1700) 
                   
                   
                   
                   
               
               
                   
               
               
                 EQSCSLTPIAFCWSE 
                 FRLLDWQW 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 130) 
                 (SEQ ID NO: 1701) 
                   
                   
                   
                   
               
               
                   
               
               
                 EWCNAYISSSKLCST 
                 ISSGL 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 131) 
                 (SEQ ID NO: 1702) 
                   
                   
                   
                   
               
               
                   
               
               
                 FEVCYMFASACRNGM 
                 ISSGLLS 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 132) 
                 (SEQ ID NO: 1703) 
                   
                   
                   
                   
               
               
                   
               
               
                 FSCSWYAESSSLCDI 
                 ISSGLL 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 133) 
                 (SEQ ID NO: 1704) 
                   
                   
                   
                   
               
               
                   
               
               
                 FVCQMFEASSGLCGG 
                 ISSGLLSGRSDNH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 134) 
                 (SEQ ID NO: 214) 
                   
                   
                   
                   
               
               
                   
               
               
                 FYCPCCMFASSCGSR 
                 AVGLLAPPGGLSGRSDNH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 135) 
                 (SEQ ID NO: 318) 
                   
                   
                   
                   
               
               
                   
               
               
                 FYCSYLPGASHQCSH 
                 ISSGLLSSGGSGGSLSGRSDNH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 136) 
                 (SEQ ID NO: 346) 
                   
                   
                   
                   
               
               
                   
               
               
                 FYCSYLYMCEVCCYE 
                 ISSGLLSSGGSGGSLSGRSDNH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 137) 
                 (SEQ ID NO: 346) 
                   
                   
                   
                   
               
               
                   
               
               
                 GFCTQHTVLTWCPTS 
                 AVGLLAPPGGTSTSGRSANPRG 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 138) 
                 (SEQ ID NO: 347) 
                   
                   
                   
                   
               
               
                   
               
               
                 GSCPSYAVSAGLCYA 
                 TSTSGRSANPRGGGAVGLLAPP 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 139) 
                 (SEQ ID NO: 348) 
                   
                   
                   
                   
               
               
                   
               
               
                 GSQCFLTPTAFCTHT 
                 VHMPLGFLGPGGTSTSGRSANPRG 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 140) 
                 (SEQ ID NO: 349) 
                   
                   
                   
                   
               
               
                   
               
               
                 GTCHPYMQSSKICNN 
                 TSTSGRSANPRGGGVHMPLGFLGP 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 141) 
                 (SEQ ID NO: 350) 
                   
                   
                   
                   
               
               
                   
               
               
                 GVECFVFTGGCGGYG 
                 LSGRSDNHGGAVGLLAPP 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 142) 
                 (SEQ ID NO: 351) 
                   
                   
                   
                   
               
               
                   
               
               
                 HELCNGHWVPCCWAY 
                 VHMPLGFLGPGGLSGRSDNH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 143) 
                 (SEQ ID NO: 352) 
                   
                   
                   
                   
               
               
                   
               
               
                 ICDSYYAVSSGLCLL 
                 LSGRSDNHGGVHMPLGFLGP 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 144) 
                 (SEQ ID NO: 353) 
                   
                   
                   
                   
               
               
                   
               
               
                 IGCAWYVSSAGWCSP 
                 LSGRSDNHGGSGGSISSGLLSS 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 145) 
                 (SEQ ID NO: 354) 
                   
                   
                   
                   
               
               
                   
               
               
                 INLCWMFASECGEHH 
                 LSGRSGNHGGSGGSISSGLLSS 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 146) 
                 (SEQ ID NO: 355) 
                   
                   
                   
                   
               
               
                   
               
               
                 KCWLAEMTNLEHCNM 
                 ISSGLLSSGGSGGSLSGRSGNH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 147) 
                 (SEQ ID NO: 356) 
                   
                   
                   
                   
               
               
                   
               
               
                 KHCSDFAYSSRLCDR 
                 LSGRSDNHGGSGGSQNQALRMA 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 148) 
                 (SEQ ID NO: 357) 
                   
                   
                   
                   
               
               
                   
               
               
                 KVCSSYASSSGLCGW 
                 QNQALRMAGGSGGSLSGRSDNH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 149) 
                 (SEQ ID NO: 358) 
                   
                   
                   
                   
               
               
                   
               
               
                 LDS CYMFASYCVQAV 
                 LSGRSGNHGGSGGSQNQALRMA 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 150) 
                 (SEQ ID NO: 359) 
                   
                   
                   
                   
               
               
                   
               
               
                 LLACHPIFVTVCQTR 
                 QNQALRMAGGSGGSLSGRSGNH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 151) 
                 (SEQ ID NO: 360) 
                   
                   
                   
                   
               
               
                   
               
               
                 LLSCPYNPEHVCHTS 
                 ISSGLLSGRSGNH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 152) 
                 (SEQ ID NO: 361) 
                   
                   
                   
                   
               
               
                   
               
               
                 LMCSLYALSSNLCGR 
                 ISSGLLSSGGSGGSLSGRNH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 153) 
                 (SEQ ID NO: 1091) 
                   
                   
                   
                   
               
               
                   
               
               
                 LMWCVLFLWSWCCRI 
                 ISSGLLSGRSANPRG 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 154) 
                 (SEQ ID NO: 1092) 
                   
                   
                   
                   
               
               
                   
               
               
                 LPI CHLTPTAVCTHI 
                 AVGLLAPPTSGRSANPRG 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 155) 
                 (SEQ ID NO: 1093) 
                   
                   
                   
                   
               
               
                   
               
               
                 LSNMCLAFGSCLYAW 
                 AVGLLAPPSGRSANPRG 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 156) 
                 (SEQ ID NO: 1094) 
                   
                   
                   
                   
               
               
                   
               
               
                 LSRCHPIWYTICQNP 
                 ISSGLLSGRSDDH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 157) 
                 (SEQ ID NO: 1095) 
                   
                   
                   
                   
               
               
                   
               
               
                 LTQCMSVHKECGGYE 
                 ISSGLLSGRSDIH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 158) 
                 (SEQ ID NO: 1096) 
                   
                   
                   
                   
               
               
                   
               
               
                 LVNCRIWSWVCEEAT 
                 ISSGLLSGRSDQH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 159) 
                 (SEQ ID NO: 1097) 
                   
                   
                   
                   
               
               
                   
               
               
                 LYCSWYQMSSAVCKE 
                 ISSGLLSGRSDTH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 160) 
                 (SEQ ID NO: 1098) 
                   
                   
                   
                   
               
               
                   
               
               
                 MECGWYALSARFCEV 
                 ISSGLLSGRSDYH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 161) 
                 (SEQ ID NO: 1099) 
                   
                   
                   
                   
               
               
                   
               
               
                 MTCSPYAMSAHFCNE 
                 ISSGLLSGRSDNP 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 162) 
                 (SEQ ID NO: 1100) 
                   
                   
                   
                   
               
               
                   
               
               
                 MVCSLYAYSASLCGA 
                 ISSGLLSGRSANP 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 163) 
                 (SEQ ID NO: 1101) 
                   
                   
                   
                   
               
               
                   
               
               
                 NALCWSTFSWWCDMD 
                 ISSGLLSGRSANI 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 164) 
                 (SEQ ID NO: 1102) 
                   
                   
                   
                   
               
               
                   
               
               
                 NFTCMLTPKAYCVQT 
                 AVGLLAPPGGLSGRSDDH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 165) 
                 (SEQ ID NO: 1103) 
                   
                   
                   
                   
               
               
                   
               
               
                 NGACIFILSWCINKT 
                 AVGLLAPPGGLSGRSDIH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 166) 
                 (SEQ ID NO: 1104) 
                   
                   
                   
                   
               
               
                   
               
               
                 NGCELYAAASGLCRT 
                 AVGLLAPPGGLSGRSDQH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 167) 
                 (SEQ ID NO: 1105) 
                   
                   
                   
                   
               
               
                   
               
               
                 NIECSVFGRCCCDNY 
                 AVGLLAPPGGLSGRSDTH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 168) 
                 (SEQ ID NO: 1106) 
                   
                   
                   
                   
               
               
                   
               
               
                 PACRPMFWNRSCDNI 
                 AVGLLAPPGGLSGRSDYH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 169) 
                 (SEQ ID NO: 1107) 
                   
                   
                   
                   
               
               
                   
               
               
                 PCRVSNMFFPYNCLD 
                 AVGLLAPPGGLSGRSDNP 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 170) 
                 (SEQ ID NO: 1108) 
                   
                   
                   
                   
               
               
                   
               
               
                 PIMCMLLPESYCWIW 
                 AVGLLAPPGGLSGRSANP 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 171) 
                 (SEQ ID NO: 1109) 
                   
                   
                   
                   
               
               
                   
               
               
                 PQSCYMFASLCMPNG 
                 AVGLLAPPGGLSGRSANI 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 172) 
                 (SEQ ID NO: 1110) 
                   
                   
                   
                   
               
               
                   
               
               
                 PRCPQGLPLYQCSSF 
                 ISSGLLSGRSDNI 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 173) 
                 (SEQ ID NO: 1111) 
                   
                   
                   
                   
               
               
                   
               
               
                 PSVECLVFKRCYALP 
                 AVGLLAPPGGLSGRSDNI 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 174) 
                 (SEQ ID NO: 1112) 
                   
                   
                   
                   
               
               
                   
               
               
                 PVCQRSATIYNCNWF 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 175) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 QCAAYYISSFGGCSN 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 176) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 QFGCFMLARDFCGTY 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 177) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 QMMCPYNPEHKCHQK 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 178) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 QRECWMFASSCNSKN 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 179) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 QSNMCITYICSSFNY 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 180) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 QSRCHSLAPYLCSSF 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 181) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 RAYCSLLFADSCNNN 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 182) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 RCIGINQYIDSNCYN 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 (SEQ ID NO: 183) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 RLSCFMFASQCALEF 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 184) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 RQCIILMNHRQCFFK 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 185) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 RSCTPYMMSSSLCNT 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 186) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 RYCHYWKMPYECSSF 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 187) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 SCVSLSWFDMLKCYE 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 188) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 SDNCEIWWTVCSAAM 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 189) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 SFCWSYLVSSGLCGV 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 190) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 SMCMNNYGTTIMCGN 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 191) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 SMVGCGWSTFCPSRG 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 192) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 SSLHCANGHTCPFCL 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 193) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 SVCSYYEESSGICSP 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 194) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 SWCGWYAASSGVCAL 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 195) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 TCISQTIDSYLNCVN 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 196) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 TFCNLYTKSSNICMS 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 197) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 TYCVFHEYLDNTCNN 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 198) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 VATGCPNLMLCGSWP 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 199) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 VEYCSLLLGNRCDYW 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 200) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 VGCNMYLMSAGLCVD 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 201) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 VLYCSWDSGTCVGSH 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 202) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 VMFSCYYLETCAPGV 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 203) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 VRIGLCPESCLVSGF 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 204) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 VTCTYYATSSSLCNT 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 205) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 VTGCILLPKAWCWGD 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 206) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 VWCSIYEYSSNLCSR 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 207) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 WMLECQYNNTCNNMT 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 208) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 WPCSPLEYYNNICNV 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 209) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 WTYDCHLNQTCPTYY 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 210) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 YCSINMYLIGGNCMY 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 211) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 YFCSLYANSAGFCGG 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 212) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 YVSCYMFSSSCPSTW 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 213) 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
             
               
                 TABLE 13B 
               
             
            
               
                   
               
               
                   
                 VL 
                 VH 
                 VL CDRs 
                 VH CDRs 
               
               
                   
                 SEQ 
                 SEQ 
                 SEQ ID NO: 
                 SEQ ID NO: 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                 Mask Sequence 
                 Substrates: 
                 ID NO: 
                 ID NO: 
                 CDR1 
                 CDR2 
                 CDR3 
                 CDR1 
                 CDR2 
                 CDR3 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 RYCHAANPDRFCGIY 
                 LSGRSDNH 
                 626 
                 1346 
                 VL CDRs of SEQ ID 
                 VH CDRs of SEQ ID 
               
               
                 (SEQ ID NO: 1206) 
                 (SEQ ID NO: 294) 
                   
                   
                 NO: 626 
                 NO: 1346 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                 PRVCSTDGGDYCLLP 
                 TGRGPSWV 
                   
                   
                 1705 
                 1706 
                 1707 
                 1708 
                 1709 
                 1710 
               
               
                 (SEQ ID NO: 1207) 
                 (SEQ ID NO: 295) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 PRPQCHHRHNCPDHP 
                 PLTGRSGG 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1208) 
                 (SEQ ID NO: 296) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 KCSRPAHQNPDRCSR 
                 TARGPSFK 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1209) 
                 (SEQ ID NO: 297) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 ASYRCPDYKCSHTKH 
                 NTLSGRSENHSG 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1210) 
                 (SEQ ID NO: 298) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 LPRCPDHPIKCIETK 
                 NTLSGRSGNHGS 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1211) 
                 (SEQ ID NO: 299) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 YTFGCPDRYCDRAAT 
                 TSTSGRSANPRG 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1212) 
                 (SEQ ID NO: 300) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 RGCPDFNPPSHCYTA 
                 TSGRSANP 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1213) 
                 (SEQ ID NO: 301) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 RDYCGPQSPDYCHEI 
                 VHMPLGFLGP 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1214) 
                 (SEQ ID NO: 302) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 PNKPCPDLQCYVTNY 
                 AVGLLAPP 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1215) 
                 (SEQ ID NO: 303) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 PRVACGEPDLCYSNT 
                 AQNLLGMV 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1216) 
                 (SEQ ID NO: 304) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 RGCKKHTISTLTCPD 
                 QNQALRMA 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1217) 
                 (SEQ ID NO: 305) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 PAYRCPDRPPCKNQM 
                 LAAPLGLL 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1218) 
                 (SEQ ID NO: 306) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 NARCYPYFGDNCHMN 
                 STFPFGMF 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1220) 
                 (SEQ ID NO: 307) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 PTLRCPDRWCYDSPR 
                 ISSGLLSS 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1221) 
                 (SEQ ID NO: 308) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 PSNLCPDKWCQTWRS 
                 PAGLWLDP 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1222) 
                 (SEQ ID NO: 309) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 TPRYCAASYCPAHGY 
                 VAGRSMRP 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1223) 
                 (SEQ ID NO: 310) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 RPGCGAVSPRCPDAP 
                 VVPEGRRS 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1224) 
                 (SEQ ID NO: 311) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 VLRCHKQNPDNCNNH 
                 ILPRSPAF 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1225) 
                 (SEQ ID NO: 312) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 GVKSCREPDFCSRGS 
                 MVLGRSLL 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1226) 
                 (SEQ ID NO: 313) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 RNNLCPDYSCNNHNS 
                 QGRAITFI 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1227) 
                 (SEQ ID NO: 314) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 RAACHRLNPDACTNG 
                 SPRSIMLA 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1228) 
                 (SEQ ID NO: 315) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 VCQSDRIPDYVICTD 
                 SMLRSMPL 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1229) 
                 (SEQ ID NO: 316) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 RNCRIASINPDYCNI 
                 SARGPSRW 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1230) 
                 (SEQ ID NO: 319) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 KEWRCPDYKCKPSYH 
                 GWHTGRN 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1231) 
                 (SEQ ID NO: 320) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 NLRICHKSLCPDYIK 
                 HTGRSGAL 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1232) 
                 (SEQ ID NO: 321) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 NTHKCSNTNICPSFN 
                 AARGPAIH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1233) 
                 (SEQ ID NO: 322) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 STRYCQASQCQMSPY 
                 RGPAFNPM 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1234) 
                 (SEQ ID NO: 323) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 THRFCTASLCNKNTS 
                 SSRGPAYL 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1235) 
                 (SEQ ID NO: 324) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 YTLCNTRSPDWCPNK 
                 RGPATPIM 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1236) 
                 (SEQ ID NO: 325) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 IRCTTGQSPDYCPQS 
                 RGPA 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1237) 
                 (SEQ ID NO: 326) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 RCNQPDKNDQMLCNI 
                 GGQPSGMWGW 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1238) 
                 (SEQ ID NO: 327) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 GTCRTDHQSPDYCYY 
                 FPRPLGITGL 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1239) 
                 (SEQ ID NO: 328) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 RGCFRSGDSLGMCPD 
                 SPLTGRSG 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1240) 
                 (SEQ ID NO: 329) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 SGCFDSNEHRHCSRI 
                 SAGFSLPA 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1241) 
                 (SEQ ID NO: 330) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 NRCMKLWYNPDCVAR 
                 LAPLGLQRR 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1242) 
                 (SEQ ID NO: 331) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 PLCARPHYWSPCDQS 
                 SGGPLGVR 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1243) 
                 (SEQ ID NO: 332) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 DSKCHPNSPDYCFNS 
                 PLGL 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1244) 
                 (SEQ ID NO: 333) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 NGSCRPLGGDFCGNR 
                 ISSGLSS 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1245) 
                 (SEQ ID NO: 334) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 KTRCIEMSGDYCAKS 
                 PVGYTSSL 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1246) 
                 (SEQ ID NO: 335) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 IRPCMYNWGDLCNQF 
                 DWLYWPGI 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1247) 
                 (SEQ ID NO: 336) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 VKTCMENNPDYCYNN 
                 LKAAPRWA 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1248) 
                 (SEQ ID NO: 337) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 LRMCFEASGDYCDQQ 
                 GPSHLVLT 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1249) 
                 (SEQ ID NO: 338) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 IRKCQLDGPDQCMLT 
                 LPGGLSPW 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1250) 
                 (SEQ ID NO: 339) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 KWKCHKNNPNYCNNR 
                 MGLFSEAG 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1251) 
                 (SEQ ID NO: 340) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 RTMCLDTNPDYCQSH 
                 SPLPLRVP 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1252) 
                 (SEQ ID NO: 341) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 LAACHSMDSHRCPDY 
                 RMHLRSLG 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1253) 
                 (SEQ ID NO: 342) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 RSPCIHNATMCPDYT 
                 LLAPSHRA 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1254) 
                 (SEQ ID NO: 343) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 MPRCPDWPPRCSMVI 
                 GPRSFGL 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1255) 
                 (SEQ ID NO: 344) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 VRQLCRLPDYCPSGK 
                 GPRSFG 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1256) 
                 (SEQ ID NO: 345) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 PRPPCAQSLNCPDRA 
                 LSGRSGNH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1257) 
                 (SEQ ID NO: 1157) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 SFGRCTLVRTCPDFM 
                 SGRSANPRG 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1258) 
                 (SEQ ID NO: 1158) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 RDKPCPDFSCATIHY 
                 LSGRSDDH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1259) 
                 (SEQ ID NO: 1161) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 ATKPCPDRWCTMSTL 
                 LSGRSDIH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1260) 
                 (SEQ ID NO: 1162) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 SSNRCPDLRCTHHNM 
                 LSGRSDQH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1261) 
                 (SEQ ID NO: 1165) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 RGSMCPDLHCSLSHI 
                 LSGRSDTH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1262) 
                 (SEQ ID NO: 1166) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 NYQRCPDRTCMHNII 
                 LSGRSDYH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1263) 
                 (SEQ ID NO: 1169) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 QKRPCPDRKCHAHYN 
                 LSGRSDNP 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1264) 
                 (SEQ ID NO: 1520) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 QNHRCPDRWCNKTTN 
                 LSGRSANP 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1265) 
                 (SEQ ID NO: 1695) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 RLNLCPDKHCHMTNL 
                 LSGRSANI 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1266) 
                 (SEQ ID NO: 1696) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 PQDRCPDKRCTNPGN 
                 LSGRSDNI 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1267) 
                 (SEQ ID NO: 1697) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 SRWRCPDYKCEHGKY 
                 MIAPVAYR 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1268) 
                 (SEQ ID NO: 1698) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 YENQCPDLYCNRYSM 
                 RPSPMWAY 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1269) 
                 (SEQ ID NO: 1699) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 TARSCPVFNCPDNNS 
                 WATPRPMR 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1270) 
                 (SEQ ID NO: 1700) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 MDQRCPDAWCTSKPK 
                 FRLLDWQW 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1271) 
                 (SEQ ID NO: 1701) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 GDLRCPDRLCPRHSL 
                 ISSGL 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1272) 
                 (SEQ ID NO: 1702) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 IQYLCPDYHCKASNN 
                 ISSGLLS 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1273) 
                 (SEQ ID NO: 1703) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 QHHRCPDRYCNSNNN 
                 ISSGLL 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1274) 
                 (SEQ ID NO: 1704) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 TVALCPDYSCYHINN 
                 ISSGLLSGRSDNH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1275) 
                 (SEQ ID NO: 214) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 SPWRCPDRYCLSNHD 
                 AVGLLAPPGGLSGRSDNH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1276) 
                 (SEQ ID NO: 318) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 SSKRCPDRFCNKTHA 
                 ISSGLLSSGGSGGSLSGRSDNH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1277) 
                 (SEQ ID NO: 346) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 HTDRCPDYKCSQNHF 
                 ISSGLLSSGGSGGSLSGRSDNH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1278) 
                 (SEQ ID NO: 346) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 SRSNCTPQRCNSDYH 
                 AVGLLAPPGGTSTSGRSANPRG 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1279) 
                 (SEQ ID NO: 347) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 FAARCPDKYCAIHTN 
                 TSTSGRSANPRGGGAVGLLAPP 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1280) 
                 (SEQ ID NO: 348) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 GSARCPDLVCQQTKQ 
                 VHMPLGFLGPGGTSTSGRSANPRG 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1281) 
                 (SEQ ID NO: 349) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 RNLMCPDKFCNKNTK 
                 TSTSGRSANPRGGGVHMPLGFLGP 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1282) 
                 (SEQ ID NO: 350) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 NIRLCPDKVCTPTWV 
                 LSGRSDNHGGAVGLLAPP 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1283) 
                 (SEQ ID NO: 351) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 MTDLCPDAHCAKTHM 
                 VHMPLGFLGPGGLSGRSDNH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1284) 
                 (SEQ ID NO: 352) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 PYSRLCAYPCPDFVG 
                 LSGRSDNHGGVHMPLGFLGP 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1285) 
                 (SEQ ID NO: 353) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 LCGCARSPDYCKCRG 
                 LSGRSDNHGGSGGSISSGLLSS 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1286) 
                 (SEQ ID NO: 354) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 WGRCERVPDCCCPRG 
                 LSGRSGNHGGSGGSISSGLLSS 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1287) 
                 (SEQ ID NO: 355) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 TRNTCHTRICYGMAC 
                 ISSGLLSSGGSGGSLSGRSGNH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1288) 
                 (SEQ ID NO: 356) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 CVCTSCSSYWTLCPD 
                 LSGRSDNHGGSGGSQNQALRMA 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1289) 
                 (SEQ ID NO: 357) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 LCCSRGSNCPDRCTW 
                 QNQALRMAGGSGGSLSGRSDNH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1290) 
                 (SEQ ID NO: 358) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 CCPLCQANMCPDNQS 
                 LSGRSGNHGGSGGSQNQALRMA 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1291) 
                 (SEQ ID NO: 359) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 ECKLCCPDLYCGGTM 
                 QNQALRMAGGSGGSLSGRSGNH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1292) 
                 (SEQ ID NO: 360) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 CSNPMCAYCCPDLIL 
                 ISSGLLSGRSGNH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1293) 
                 (SEQ ID NO: 361) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 CPRCNTYSKHDCYHQ 
                 ISSGLLSSGGSGGSLSGRNH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1294) 
                 (SEQ ID NO: 1091) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 FCCASKMPAPSNCHT 
                 ISSGLLSGRSANPRG 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1295) 
                 (SEQ ID NO: 1092) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                   
                 AVGLLAPPTSGRSANPRG 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
                 (SEQ ID NO: 1093) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                   
                 AVGLLAPPSGRSANPRG 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
                 (SEQ ID NO: 1094) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                   
                 ISSGLLSGRSDDH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
                 (SEQ ID NO: 1095) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                   
                 ISSGLLSGRSDIH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
                 (SEQ ID NO: 1096) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                   
                 ISSGLLSGRSDQH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
                 (SEQ ID NO: 1097) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                   
                 ISSGLLSGRSDTH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
                 (SEQ ID NO: 1098) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                   
                 ISSGLLSGRSDYH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
                 (SEQ ID NO: 1099) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                   
                 ISSGLLSGRSDNP 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
                 (SEQ ID NO: 1100) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                   
                 ISSGLLSGRSANP 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
                 (SEQ ID NO: 1101) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                   
                 ISSGLLSGRSANI 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
                 (SEQ ID NO: 1102) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                   
                 AVGLLAPPGGLSGRSDDH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
                 (SEQ ID NO: 1103) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                   
                 AVGLLAPPGGLSGRSDIH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
                 (SEQ ID NO: 1104) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                   
                 AVGLLAPPGGLSGRSDQH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
                 (SEQ ID NO: 1105) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                   
                 AVGLLAPPGGLSGRSDTH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
                 (SEQ ID NO: 1106) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                   
                 AVGLLAPPGGLSGRSDYH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
                 (SEQ ID NO: 1107) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                   
                 AVGLLAPPGGLSGRSDNP 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
                 (SEQ ID NO: 1108) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                   
                 AVGLLAPPGGLSGRSANP 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
                 (SEQ ID NO: 1109) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                   
                 AVGLLAPPGGLSGRSANI 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
                 (SEQ ID NO: 1110) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                   
                 ISSGLLSGRSDNI 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
                 (SEQ ID NO: 1111) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                   
                 AVGLLAPPGGLSGRSDNI 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
                 (SEQ ID NO: 1112) 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
             
               
                 TABLE 13C 
               
             
            
               
                   
               
               
                   
                 VL 
                 VH 
                 VL CDRs 
                 VH CDRs 
               
               
                   
                 SEQ 
                 SEQ 
                 SEQ ID NO: 
                 SEQ ID NO: 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                 Mask Sequence 
                 Substrates: 
                 ID NO: 
                 ID NO: 
                 CDR1 
                 CDR2 
                 CDR3 
                 CDR1 
                 CDR2 
                 CDR3 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 GCDFTSAKHNCGSGW 
                 LSGRSDNH 
                 638 
                 1514 
                 VL CDRs of SEQ ID 
                 VH CDRs of SEQ ID 
               
               
                 (SEQ ID NO: 1351) 
                 (SEQ ID NO: 294) 
                   
                   
                 NO: 638 
                 NO: 1514 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                 VGSNCWTGPACALTS 
                 TGRGPSWV 
                   
                   
                 1711 
                 1712 
                 1713 
                 1714 
                 1715 
                 1716 
               
               
                 (SEQ ID NO: 1352) 
                 (SEQ ID NO: 295) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 FCAVMFDFLSDRCLH 
                 PLTGRSGG 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1353) 
                 (SEQ ID NO: 296) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 FCPPWLDYLGNKCMT 
                 TARGPSFK 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1354) 
                 (SEQ ID NO: 297) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 MSCWDFSSAQGCGQH 
                 NTLSGRSENHSG 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1355) 
                 (SEQ ID NO: 298) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 LMCADLHYNHYNCKY 
                 NTLSGRSGNHGS 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1356) 
                 (SEQ ID NO: 299) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 ELCGWQSFSGVCTSE 
                 TSTSGRSANPRG 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1357) 
                 (SEQ ID NO: 300) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 WTYENCWASCQPHLE 
                 TSGRSANP 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1358) 
                 (SEQ ID NO: 301) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 KLTEDFSSAA (SEQ 
                 VHMPLGFLGP 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 ID NO: 1359) 
                 (SEQ ID NO: 302) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 VGQSCFSGLVCDRQL 
                 AVGLLAPP 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1360) 
                 (SEQ ID NO: 303) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 ISHYCFSGKSCRD 
                 AQNLLGMV 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1361) 
                 (SEQ ID NO: 304) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 HCIPDFTSAAGDCMR 
                 QNQALRMA 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1362) 
                 (SEQ ID NO: 305) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 RLVSAYSFS (SEQ ID 
                 LAAPLGLL 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 NO: 1363) 
                 (SEQ ID NO: 306) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 KFHHSHPLVHDFTSA 
                 STFPFGMF 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1364) 
                 (SEQ ID NO: 307) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 ASYPDFSSANGVGLR 
                 ISSGLLSS 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1365) 
                 (SEQ ID NO: 308) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 GLATTLSNVDFTSAG 
                 PAGLWLDP 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1366) 
                 (SEQ ID NO: 309) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 DFTSANSAFSGDAST 
                 VAGRSMRP 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1367) 
                 (SEQ ID NO: 310) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 GRLPGHSVVDFTSAW 
                 VVPEGRRS 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1368) 
                 (SEQ ID NO: 311) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 SGSFYSSSAFDFTSA 
                 ILPRSPAF 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1369) 
                 (SEQ ID NO: 312) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 CDDFTSAQHSRINEC 
                 MVLGRSLL 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1370) 
                 (SEQ ID NO: 313) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 CDFTSAQGKKCRTAL 
                 QGRAITFI 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1371) 
                 (SEQ ID NO: 314) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 YYIDKYQSPSYGPVL 
                 SPRSIMLA 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1372) 
                 (SEQ ID NO: 315) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 FSVARARSSADFTSS 
                 SMLRSMPL 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1373) 
                 (SEQ ID NO: 316) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 DSDFTSAGSADSRSR 
                 SARGPSRW 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1374) 
                 (SEQ ID NO: 319) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 CDFTSATSISKRCDH 
                 GWHTGRN 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1375) 
                 (SEQ ID NO: 320) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 IESSASSWGLQASRN 
                 HTGRSGAL 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1376) 
                 (SEQ ID NO: 321) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 PRYHNLNFTTPALSPGS 
                 AARGPAIH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1377) 
                 (SEQ ID NO: 322) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 DLFARFPLDRDFTSA 
                 RGPAFNPM 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1378) 
                 (SEQ ID NO: 323) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 HCNFTTPPYCSSTLW 
                 SSRGPAYL 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1379) 
                 (SEQ ID NO: 324) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 NVPIILLTDRQLLSG 
                 RGPATPIM 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1380) 
                 (SEQ ID NO: 325) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 NPTACDFTSSMATYC 
                 RGPA 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1381) 
                 (SEQ ID NO: 326) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 FVRTVRFSNSMFSVP 
                 GGQPSGMWGW 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1382) 
                 (SEQ ID NO: 327) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 YDFSSASNSSPSRQT 
                 FPRPLGITGL 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1383) 
                 (SEQ ID NO: 328) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AHPDFSSAMRGNLLG 
                 SPLTGRSG 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1384) 
                 (SEQ ID NO: 329) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 SSHVVHKDFTSANSR 
                 SAGFSLPA 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1385) 
                 (SEQ ID NO: 330) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 CPDFTSANGGGCWQM 
                 LAPLGLQRR 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1386) 
                 (SEQ ID NO: 331) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 SLGQSYPTDFTCPGC 
                 SGGPLGVR 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1387) 
                 (SEQ ID NO: 332) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 ASMRSHEQRDFTSAY 
                 PLGL 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1388) 
                 (SEQ ID NO: 333) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 SCQFWFTLCSGGVFH 
                 ISSGLSS 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1389) 
                 (SEQ ID NO: 334) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 PYPNNRTGMHDFTSA 
                 PVGYTSSL 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1390) 
                 (SEQ ID NO: 335) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 KPFPIDFTSAGTSGT 
                 DWLYWPGI 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1391) 
                 (SEQ ID NO: 336) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 SIKSFIPRDDFTSAA 
                 LKAAPRWA 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1392) 
                 (SEQ ID NO: 337) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 GIKNPATPFVDFTSA 
                 GPSHLVLT 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1393) 
                 (SEQ ID NO: 338) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 LSHTYPRGSSTIEAS 
                 LPGGLSPW 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1394) 
                 (SEQ ID NO: 339) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 PSLDFSSAT (SEQ ID 
                 MGLFSEAG 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 NO: 1395) 
                 (SEQ ID NO: 340) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AFTPRIAPTFDVMKE 
                 SPLPLRVP 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1396) 
                 (SEQ ID NO: 341) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 LCGLQIPPDCERS 
                 RMHLRSLG 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1397) 
                 (SEQ ID NO: 342) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AAKMVSHSERDFTSA 
                 LLAPSHRA 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1398) 
                 (SEQ ID NO: 343) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 VSVECFSGMQCPHYY 
                 GPRSFGL 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1399) 
                 (SEQ ID NO: 344) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 ASKCRLPCMASTQIY 
                 GPRSFG 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1400) 
                 (SEQ ID NO: 345) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 GLRSCNIYFSIPCTY 
                 LSGRSGNH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1401) 
                 (SEQ ID NO: 1157) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 RGTSDGTLDFTTARS 
                 SGRSANPRG 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1402) 
                 (SEQ ID NO: 1158) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 SMYPSASRLLHPQYP 
                 LSGRSDDH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1403) 
                 (SEQ ID NO: 1161) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 HCISCYDFTSAAGSF 
                 LSGRSDIH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1404) 
                 (SEQ ID NO: 1162) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 SSGRWGDAWACARIC 
                 LSGRSDQH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1405) 
                 (SEQ ID NO: 1165) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 RVFSDFTSASHSFGG 
                 LSGRSDTH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1406) 
                 (SEQ ID NO: 1166) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 TDRHSASGRDFTSAH 
                 LSGRSDYH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1407) 
                 (SEQ ID NO: 1169) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AHCEDFSSAERIATMGC 
                 LSGRSDNP 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1408) 
                 (SEQ ID NO: 1520) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 ACDPYSFSIPCDDRL 
                 LSGRSANP 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1409) 
                 (SEQ ID NO: 1695) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 NSPFTLSHIYDR (SEQ 
                 LSGRSANI 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 ID NO: 1410) 
                 (SEQ ID NO: 1696) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 IGINFTTPSAFVAFP 
                 LSGRSDNI 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1411) 
                 (SEQ ID NO: 1697) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 RDAFPIYRNADFSTP 
                 MIAPVAYR 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1412) 
                 (SEQ ID NO: 1698) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 SIPNASSYNFTSSSG 
                 RPSPMWAY 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1413) 
                 (SEQ ID NO: 1699) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AGIPDKRHTYDFTSA 
                 WATPRPMR 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1414) 
                 (SEQ ID NO: 1700) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 WPLAHDSRDWNFTTP 
                 FRLLDWQW 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1415) 
                 (SEQ ID NO: 1701) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 RHSPSSGHVDFTSAG 
                 ISSGL 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1416) 
                 (SEQ ID NO: 1702) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 SCFAWTDPVWNRCSW 
                 ISSGLLS 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1417) 
                 (SEQ ID NO: 1703) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 MPCDWTGPGKIWCGG 
                 ISSGLL 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1418) 
                 (SEQ ID NO: 1704) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 RDCDFSTANFRSCNK 
                 ISSGLLSGRSDNH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1419) 
                 (SEQ ID NO: 214) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 LSCVVSPNYLHCNDH 
                 AVGLLAPPGGLSGRSDNH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1420) 
                 (SEQ ID NO: 318) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 FVCGLYSFSGVCQGV 
                 ISSGLLSSGGSGGSLSGRSDNH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1421) 
                 (SEQ ID NO: 346) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 IGLMCFSGLQCPMLA 
                 ISSGLLSSGGSGGSLSGRSDNH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1422) 
                 (SEQ ID NO: 346) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 PGMNCFSGEICQMST 
                 AVGLLAPPGGTSTSGRSANPRG 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1423) 
                 (SEQ ID NO: 347) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 GDVGSCWASCGLQGG 
                 TSTSGRSANPRGGGAVGLLAPP 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1424) 
                 (SEQ ID NO: 348) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 SQFQDCWASCGASFT 
                 VHMPLGFLGPGGTSTSGRSANPRG 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1425) 
                 (SEQ ID NO: 349) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 VGSLNCWYSCGDIWL 
                 TSTSGRSANPRGGGVHMPLGFLGP 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1426) 
                 (SEQ ID NO: 350) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 MCESWLNFLGDQCGM 
                 LSGRSDNHGGAVGLLAPP 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1427) 
                 (SEQ ID NO: 351) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 RCMISQSSFSGMCGM 
                 VHMPLGFLGPGGLSGRSDNH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1428) 
                 (SEQ ID NO: 352) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 NCAPWTSNMSNHCLK 
                 LSGRSDNHGGVHMPLGFLGP 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1429) 
                 (SEQ ID NO: 353) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 LCGVGSATGLELCGV 
                 LSGRSDNHGGSGGSISSGLLSS 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1430) 
                 (SEQ ID NO: 354) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 GCDFSSLGGRQPCTP 
                 LSGRSGNHGGSGGSISSGLLSS 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1431) 
                 (SEQ ID NO: 355) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 MGCNFTTYPYHTCNT 
                 ISSGLLSSGGSGGSLSGRSGNH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1432) 
                 (SEQ ID NO: 356) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 GSCDFTSGAGKKCGS 
                 LSGRSDNHGGSGGSQNQALRMA 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1433) 
                 (SEQ ID NO: 357) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 VSCDFTSSHARMCSR 
                 QNQALRMAGGSGGSLSGRSDNH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1434) 
                 (SEQ ID NO: 358) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 MRCIDFYYNHINCIG 
                 LSGRSGNHGGSGGSQNQALRMA 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1435) 
                 (SEQ ID NO: 359) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 RSCDFTSAANKYCAT 
                 QNQALRMAGGSGGSLSGRSGNH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1436) 
                 (SEQ ID NO: 360) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 LYCDSFSVPRPNCAP 
                 ISSGLLSGRSGNH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1437) 
                 (SEQ ID NO: 361) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 NSCDFTSARVSKCST 
                 ISSGLLSSGGSGGSLSGRNH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1438) 
                 (SEQ ID NO: 1091) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 STCSDNFTTPMPCNT 
                 ISSGLLSGRSANPRG 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1439) 
                 (SEQ ID NO: 1092) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 DICNDRPNLTHCHYF 
                 AVGLLAPPTSGRSANPRG 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1440) 
                 (SEQ ID NO: 1093) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 LRCDDFTSAIGCRGY 
                 AVGLLAPPSGRSANPRG 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1441) 
                 (SEQ ID NO: 1094) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 EGCDFTSALHSCNNY 
                 ISSGLLSGRSDDH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1442) 
                 (SEQ ID NO: 1095) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 RKGCGDFTSASCFVV 
                 ISSGLLSGRSDIH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1443) 
                 (SEQ ID NO: 1096) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 GMLCAGSSFGLCESM 
                 ISSGLLSGRSDQH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1444) 
                 (SEQ ID NO: 1097) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 RESCFGSSLGLCTNK 
                 ISSGLLSGRSDTH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1445) 
                 (SEQ ID NO: 1098) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 ILRCYDIPTNCMNFN 
                 ISSGLLSGRSDYH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1446) 
                 (SEQ ID NO: 1099) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 NSECTFGAMYCRNKP 
                 ISSGLLSGRSDNP 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1447) 
                 (SEQ ID NO: 1100) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 ASGCFDEDIRCSGGA 
                 ISSGLLSGRSANP 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1448) 
                 (SEQ ID NO: 1101) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 HYFCNQSNPSCQTAP 
                 ISSGLLSGRSANI 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1449) 
                 (SEQ ID NO: 1102) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AMGCELGGAGCIGSP 
                 AVGLLAPPGGLSGRSDDH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1450) 
                 (SEQ ID NO: 1103) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 TLKCHMPRKLCANDP 
                 AVGLLAPPGGLSGRSDIH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1451) 
                 (SEQ ID NO: 1104) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 RPACRDLPHNCITST 
                 AVGLLAPPGGLSGRSDQH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1452) 
                 (SEQ ID NO: 1105) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 QMSCHGNFTTCHSNP 
                 AVGLLAPPGGLSGRSDTH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1453) 
                 (SEQ ID NO: 1106) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 LTGCARGARPCRLRV 
                 AVGLLAPPGGLSGRSDYH 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1454) 
                 (SEQ ID NO: 1107) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 WSELCLAGPSCGWVG 
                 AVGLLAPPGGLSGRSDNP 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1455) 
                 (SEQ ID NO: 1108) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 VTKSCWQLPHCITAP 
                 AVGLLAPPGGLSGRSANP 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1456) 
                 (SEQ ID NO: 1109) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 KAASCPHNQICNMTA 
                 AVGLLAPPGGLSGRSANI 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1457) 
                 (SEQ ID NO: 1110) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 VSKNCFSGMMCPVFA 
                 ISSGLLSGRSDNI 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1458) 
                 (SEQ ID NO: 1111) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 NRSSCWTGPTCHVLH 
                 AVGLLAPPGGLSGRSDNI 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1459) 
                 (SEQ ID NO: 1112) 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 ARTGCSGPVCLNDVS 
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1460) 
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 STRTCLAFTCINGNT 
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1461) 
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 MLDGNCWYACSYKNT 
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1462) 
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 FSRSDCWSACAPWRV 
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1463) 
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 GGRMDCWASCQPLSR 
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1464) 
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 NSPHSCMTNCDFTSA 
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 1465) 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
             
               
                 TABLE 13D 
               
             
            
               
                   
               
               
                   
                   
                   
                 LC CDRs 
                 HC CDRs 
               
               
                   
                 LC 
                 HC 
                 SEQ ID NO: 
                 SEQ ID NO: 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                 Mask Sequence 
                 Substrates: 
                 SEQ ID NO: 
                 SEQ ID NO: 
                 CDR1 
                 CDR2 
                 CDR3 
                 CDR1 
                 CDR2 
                 CDR3 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 DYTYCRWVNWCLSGV 
                 LSGRSDNH 
                 543 
                 546 
                 LC CDRs of 
                 HC CDRs of 
               
               
                 (SEQ ID NO: 384) 
                 (SEQ ID NO: 294) 
                   
                   
                 SEQ ID NO: 543 
                 SEQ ID NO: 546 
               
               
                   
               
               
                 ILCPEDPWGHKCKLP 
                 TGRGPSWV 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 385) 
                 (SEQ ID NO: 295) 
                   
                   
                   
                   
               
               
                   
               
               
                 TNIWSCQTYCDHKHK 
                 PLTGRSGG 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 386) 
                 (SEQ ID NO: 296) 
                   
                   
                   
                   
               
               
                   
               
               
                 SDHKCKLQNCMNTKV 
                 TARGPSFK 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 387) 
                 (SEQ ID NO: 297) 
                   
                   
                   
                   
               
               
                   
               
               
                 PGNCHPMQKEMCQFI 
                 NTLSGRSENHSG 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 388) 
                 (SEQ ID NO: 298) 
                   
                   
                   
                   
               
               
                   
               
               
                 VEHLCYTHNKCKHPD 
                 NTLSGRSGNHGS 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 389) 
                 (SEQ ID NO: 299) 
                   
                   
                   
                   
               
               
                   
               
               
                 TIPRCGQHPKCKDTL 
                 TSTSGRSANPRG 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 390) 
                 (SEQ ID NO: 300) 
                   
                   
                   
                   
               
               
                   
               
               
                 ACRICQDHPKTKWNS 
                 TSGRSANP 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 391) 
                 (SEQ ID NO: 301) 
                   
                   
                   
                   
               
               
                   
               
               
                 LIQCTGNLDHKCKHY 
                 VHMPLGFLGP 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 392) 
                 (SEQ ID NO: 302) 
                   
                   
                   
                   
               
               
                   
               
               
                 IPCHHSADHKHKCTS 
                 AVGLLAPP 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 393) 
                 (SEQ ID NO: 303) 
                   
                   
                   
                   
               
               
                   
               
               
                 SRQICADYNCHNKYK 
                 AQNLLGMV 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 394) 
                 (SEQ ID NO: 304) 
                   
                   
                   
                   
               
               
                   
               
               
                 QPCNPQIDHKIKCIY 
                 QNQALRMA 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 395) 
                 (SEQ ID NO: 305) 
                   
                   
                   
                   
               
               
                   
               
               
                 HYTICMTHNKCKDMA 
                 LAAPLGLL 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 396) 
                 (SEQ ID NO: 306) 
                   
                   
                   
                   
               
               
                   
               
               
                 ANSCLAVEHKCKHNY 
                 STFPFGMF 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 397) 
                 (SEQ ID NO: 307) 
                   
                   
                   
                   
               
               
                   
               
               
                 AALHCTEHKCKNHIK 
                 ISSGLLSS 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 398) 
                 (SEQ ID NO: 308) 
                   
                   
                   
                   
               
               
                   
               
               
                 APCIINTVDWKSCEI 
                 PAGLWLDP 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 399) 
                 (SEQ ID NO: 309) 
                   
                   
                   
                   
               
               
                   
               
               
                 ATNWCTHKQKCKQDM 
                 VAGRSMRP 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 400) 
                 (SEQ ID NO: 310) 
                   
                   
                   
                   
               
               
                   
               
               
                 DCYNEHKLKTRVCNN 
                 VVPEGRRS 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 401) 
                 (SEQ ID NO: 311) 
                   
                   
                   
                   
               
               
                   
               
               
                 DEMQCSHKQKCTNSK 
                 ILPRSPAF 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 402) 
                 (SEQ ID NO: 312) 
                   
                   
                   
                   
               
               
                   
               
               
                 DVGICSQHNKCKPTK 
                 MVLGRSLL 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 403) 
                 (SEQ ID NO: 313) 
                   
                   
                   
                   
               
               
                   
               
               
                 EKYCSSDDHKCKITL 
                 QGRAITFI 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 404) 
                 (SEQ ID NO: 314) 
                   
                   
                   
                   
               
               
                   
               
               
                 ELECSHNKVKNCIQI 
                 SPRSIMLA 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 405) 
                 (SEQ ID NO: 315) 
                   
                   
                   
                   
               
               
                   
               
               
                 ELHPCNTHKCKPIVN 
                 SMLRSMPL 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 406) 
                 (SEQ ID NO: 316) 
                   
                   
                   
                   
               
               
                   
               
               
                 EVGSCNHPKCKSNNY 
                 SARGPSRW 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 407) 
                 (SEQ ID NO: 319) 
                   
                   
                   
                   
               
               
                   
               
               
                 EYSPSLAHPKLKDNA 
                 GWHTGRN 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 408) 
                 (SEQ ID NO: 320) 
                   
                   
                   
                   
               
               
                   
               
               
                 FESLHPKGKHPEDLG 
                 HTGRSGAL 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 409) 
                 (SEQ ID NO: 321) 
                   
                   
                   
                   
               
               
                   
               
               
                 FPLCVRADRVCGDAQ 
                 AARGPAIH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 410) 
                 (SEQ ID NO: 322) 
                   
                   
                   
                   
               
               
                   
               
               
                 FQAPPASHNKLKPSL 
                 RGPAFNPM 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 411) 
                 (SEQ ID NO: 323) 
                   
                   
                   
                   
               
               
                   
               
               
                 GAIDSCHHKCKSPHY 
                 SSRGPAYL 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 412) 
                 (SEQ ID NO: 324) 
                   
                   
                   
                   
               
               
                   
               
               
                 GKIYTCEHNCTFGYS 
                 RGPATPIM 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 413) 
                 (SEQ ID NO: 325) 
                   
                   
                   
                   
               
               
                   
               
               
                 HCTVNNHSSDHKCKI 
                 RGPA 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 414) 
                 (SEQ ID NO: 326) 
                   
                   
                   
                   
               
               
                   
               
               
                 HGTQCTHNKCKPILS 
                 GGQPSGMWGW 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 415) 
                 (SEQ ID NO: 327) 
                   
                   
                   
                   
               
               
                   
               
               
                 HIGWCLHPKCKTTTT 
                 FPRPLGITGL 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 416) 
                 (SEQ ID NO: 328) 
                   
                   
                   
                   
               
               
                   
               
               
                 HLRTCIQKWCEHKMK 
                 SPLTGRSG 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 417) 
                 (SEQ ID NO: 329) 
                   
                   
                   
                   
               
               
                   
               
               
                 HTDCTMMSNHKCKIN 
                 SAGFSLPA 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 418) 
                 (SEQ ID NO: 330) 
                   
                   
                   
                   
               
               
                   
               
               
                 IRQQCTALACLLKVH 
                 LAPLGLQRR 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 419) 
                 (SEQ ID NO: 331) 
                   
                   
                   
                   
               
               
                   
               
               
                 KGCSTHKMRAYCNQM 
                 SGGPLGVR 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 420) 
                 (SEQ ID NO: 332) 
                   
                   
                   
                   
               
               
                   
               
               
                 KMFTPCKIWCNNSYN 
                 PLGL 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 421) 
                 (SEQ ID NO: 333) 
                   
                   
                   
                   
               
               
                   
               
               
                 KTMCSGHKQKCNNSS 
                 ISSGLSS 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 422) 
                 (SEQ ID NO: 334) 
                   
                   
                   
                   
               
               
                   
               
               
                 LACHSASLVDHKCKL 
                 PVGYTSSL 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 423) 
                 (SEQ ID NO: 335) 
                   
                   
                   
                   
               
               
                   
               
               
                 LCNVSMDHKHKPCYL 
                 DWLYWPGI 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 424) 
                 (SEQ ID NO: 336) 
                   
                   
                   
                   
               
               
                   
               
               
                 LGLNCFSEHKCKEHM 
                 LKAAPRWA 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 425) 
                 (SEQ ID NO: 337) 
                   
                   
                   
                   
               
               
                   
               
               
                 LGTCTHKHKNCNYTL 
                 GPSHLVLT 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 426) 
                 (SEQ ID NO: 338) 
                   
                   
                   
                   
               
               
                   
               
               
                 LHEGCTTHNKCKPIA 
                 LPGGLSPW 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 427) 
                 (SEQ ID NO: 339) 
                   
                   
                   
                   
               
               
                   
               
               
                 LKRSCTGHWTCYTNW 
                 MGLFSEAG 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 428) 
                 (SEQ ID NO: 340) 
                   
                   
                   
                   
               
               
                   
               
               
                 LQRCTHKEKYCHAIH 
                 SPLPLRVP 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 429) 
                 (SEQ ID NO: 341) 
                   
                   
                   
                   
               
               
                   
               
               
                 LSHCYDHKRKCSYIV 
                 RMHLRSLG 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 430) 
                 (SEQ ID NO: 342) 
                   
                   
                   
                   
               
               
                   
               
               
                 LSKCHNKEKNCSNNN 
                 LLAPSHRA 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 431) 
                 (SEQ ID NO: 343) 
                   
                   
                   
                   
               
               
                   
               
               
                 MDTCEMHKQKCRPSF 
                 GPRSFGL 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 432) 
                 (SEQ ID NO: 344) 
                   
                   
                   
                   
               
               
                   
               
               
                 MHNECLTHKCKVPIT 
                 GPRSFG 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 433) 
                 (SEQ ID NO: 345) 
                   
                   
                   
                   
               
               
                   
               
               
                 MLTLCNTNACHKEKN 
                 LSGRSGNH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 434) 
                 (SEQ ID NO: 1157) 
                   
                   
                   
                   
               
               
                   
               
               
                 MRPCLNNLEHKCKHY 
                 SGRSANPRG 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 435) 
                 (SEQ ID NO: 1158) 
                   
                   
                   
                   
               
               
                   
               
               
                 MSRCPTHKMKCSLNI 
                 LSGRSDDH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 436) 
                 (SEQ ID NO: 1161) 
                   
                   
                   
                   
               
               
                   
               
               
                 MWICQEHKLKCMTDT 
                 LSGRSDIH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 437) 
                 (SEQ ID NO: 1162) 
                   
                   
                   
                   
               
               
                   
               
               
                 MYYCKRRSAFYCTLN 
                 LSGRSDQH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 438) 
                 (SEQ ID NO: 1165) 
                   
                   
                   
                   
               
               
                   
               
               
                 NDCQHDKQMHKCKMH 
                 LSGRSDTH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 439) 
                 (SEQ ID NO: 1166) 
                   
                   
                   
                   
               
               
                   
               
               
                 NFGPCPMLLGCFGFR 
                 LSGRSDYH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 440) 
                 (SEQ ID NO: 1169) 
                   
                   
                   
                   
               
               
                   
               
               
                 NHTDCSHPKCKSHDS 
                 LSGRSDNP 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 441) 
                 (SEQ ID NO: 1520) 
                   
                   
                   
                   
               
               
                   
               
               
                 NLNCPHKQKNCDKYH 
                 LSGRSANP 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 442) 
                 (SEQ ID NO: 1695) 
                   
                   
                   
                   
               
               
                   
               
               
                 NPQCTPIDHKCKTHH 
                 LSGRSANI 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 443) 
                 (SEQ ID NO: 1696) 
                   
                   
                   
                   
               
               
                   
               
               
                 NTTSCTHPKCKHQGK 
                 LSGRSDNI 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 444) 
                 (SEQ ID NO: 1697) 
                   
                   
                   
                   
               
               
                   
               
               
                 NVGGCDNYGCHKLKN 
                 MIAPVAYR 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 445) 
                 (SEQ ID NO: 1698) 
                   
                   
                   
                   
               
               
                   
               
               
                 PCSPGNLTWDHKCKY 
                 RPSPMWAY 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 446) 
                 (SEQ ID NO: 1699) 
                   
                   
                   
                   
               
               
                   
               
               
                 PFTKCHGFNKCKEHT 
                 WATPRPMR 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 447) 
                 (SEQ ID NO: 1700) 
                   
                   
                   
                   
               
               
                   
               
               
                 PGDKCTHKEKCYYNN 
                 FRLLDWQW 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 448) 
                 (SEQ ID NO: 1701) 
                   
                   
                   
                   
               
               
                   
               
               
                 PNICNLDHKRKCRIN 
                 ISSGL 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 449) 
                 (SEQ ID NO: 1702) 
                   
                   
                   
                   
               
               
                   
               
               
                 PQLACKHPKCKDAGN 
                 ISSGLLS 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 450) 
                 (SEQ ID NO: 1703) 
                   
                   
                   
                   
               
               
                   
               
               
                 PSCTMWTHGGVCKHA 
                 ISSGLL 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 451) 
                 (SEQ ID NO: 1704) 
                   
                   
                   
                   
               
               
                   
               
               
                 PSHRHPLAKPGFRVE 
                 ISSGLLSGRSDNH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 452) 
                 (SEQ ID NO: 214) 
                   
                   
                   
                   
               
               
                   
               
               
                 PTCFKTHNKSKCNRV 
                 AVGLLAPPGGLSGRSDNH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 453) 
                 (SEQ ID NO: 318) 
                   
                   
                   
                   
               
               
                   
               
               
                 PTPVCHHNFHCFGYD 
                 ISSGLLSSGGSGGSLSGRSDNH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 454) 
                 (SEQ ID NO: 346) 
                   
                   
                   
                   
               
               
                   
               
               
                 QATCQWKKRSKCHNK 
                 ISSGLLSSGGSGGSLSGRSDNH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 455) 
                 (SEQ ID NO: 346) 
                   
                   
                   
                   
               
               
                   
               
               
                 QHSWCQHKAKCNYGN 
                 AVGLLAPPGGTSTSGRSANPRG 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 456) 
                 (SEQ ID NO: 347) 
                   
                   
                   
                   
               
               
                   
               
               
                 QNCSPTYTTHKCKLT 
                 TSTSGRSANPRGGGAVGLLAPP 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 457) 
                 (SEQ ID NO: 348) 
                   
                   
                   
                   
               
               
                   
               
               
                 QSSNCEHKRKCSSIS 
                 VHMPLGFLGPGGTSTSGRSANPRG 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 458) 
                 (SEQ ID NO: 349) 
                   
                   
                   
                   
               
               
                   
               
               
                 RPCLLGLVPDHKCKL 
                 TSTSGRSANPRGGGVHMPLGFLGP 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 459) 
                 (SEQ ID NO: 350) 
                   
                   
                   
                   
               
               
                   
               
               
                 RRSCMRSINTCKQKY 
                 LSGRSDNHGGAVGLLAPP 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 460) 
                 (SEQ ID NO: 351) 
                   
                   
                   
                   
               
               
                   
               
               
                 RSSCPTVTPQNCENQ 
                 VHMPLGFLGPGGLSGRSDNH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 461) 
                 (SEQ ID NO: 352) 
                   
                   
                   
                   
               
               
                   
               
               
                 RTMCLDLNHKCKPSN 
                 LSGRSDNHGGVHMPLGFLGP 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 462) 
                 (SEQ ID NO: 353) 
                   
                   
                   
                   
               
               
                   
               
               
                 RTYWCTNHNKCKHNM 
                 LSGRSDNHGGSGGSISSGLLSS 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 463) 
                 (SEQ ID NO: 354) 
                   
                   
                   
                   
               
               
                   
               
               
                 RVENCEHNQYCHKWK 
                 LSGRSGNHGGSGGSISSGLLSS 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 464) 
                 (SEQ ID NO: 355) 
                   
                   
                   
                   
               
               
                   
               
               
                 SCHEDDHKNKNICSL 
                 ISSGLLSSGGSGGSLSGRSGNH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 465) 
                 (SEQ ID NO: 356) 
                   
                   
                   
                   
               
               
                   
               
               
                 SDTCVMNHPKCKRDN 
                 LSGRSDNHGGSGGSQNQALRMA 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 466) 
                 (SEQ ID NO: 357) 
                   
                   
                   
                   
               
               
                   
               
               
                 SSTCFHPNQKECMTK 
                 QNQALRMAGGSGGSLSGRSDNH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 467) 
                 (SEQ ID NO: 358) 
                   
                   
                   
                   
               
               
                   
               
               
                 SSYCGGITMRCRRAM 
                 LSGRSGNHGGSGGSQNQALRMA 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 468) 
                 (SEQ ID NO: 359) 
                   
                   
                   
                   
               
               
                   
               
               
                 STGYCTYVNWCNYTN 
                 QNQALRMAGGSGGSLSGRSGNH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 469) 
                 (SEQ ID NO: 360) 
                   
                   
                   
                   
               
               
                   
               
               
                 THKCKLHLQVCTQTT 
                 ISSGLLSGRSGNH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 470) 
                 (SEQ ID NO: 361) 
                   
                   
                   
                   
               
               
                   
               
               
                 TMNCTHPKQKCQHTN 
                 ISSGLLSSGGSGGSLSGRNH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 471) 
                 (SEQ ID NO: 1091) 
                   
                   
                   
                   
               
               
                   
               
               
                 TNVLCESHNCDHKNK 
                 ISSGLLSGRSANPRG 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 472) 
                 (SEQ ID NO: 1092) 
                   
                   
                   
                   
               
               
                   
               
               
                 TQHAASLGVEHKSKI 
                 AVGLLAPPTSGRSANPRG 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 473) 
                 (SEQ ID NO: 1093) 
                   
                   
                   
                   
               
               
                   
               
               
                 TQLPCFDDHKCKNTN 
                 AVGLLAPPSGRSANPRG 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 474) 
                 (SEQ ID NO: 1094) 
                   
                   
                   
                   
               
               
                   
               
               
                 TSDSCMRQKCEHKEK 
                 ISSGLLSGRSDDH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 475) 
                 (SEQ ID NO: 1095) 
                   
                   
                   
                   
               
               
                   
               
               
                 TTCDDHKYKHKCAQL 
                 ISSGLLSGRSDIH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 476) 
                 (SEQ ID NO: 1096) 
                   
                   
                   
                   
               
               
                   
               
               
                 TTCGAHKEKQHCIYT 
                 ISSGLLSGRSDQH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 477) 
                 (SEQ ID NO: 1097) 
                   
                   
                   
                   
               
               
                   
               
               
                 TTYCAYWHNKCKFET 
                 ISSGLLSGRSDTH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 478) 
                 (SEQ ID NO: 1098) 
                   
                   
                   
                   
               
               
                   
               
               
                 VGPTCGHAKCKQSEV 
                 ISSGLLSGRSDYH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 479) 
                 (SEQ ID NO: 1099) 
                   
                   
                   
                   
               
               
                   
               
               
                 VSHPCNTHKCKTNIV 
                 ISSGLLSGRSDNP 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 480) 
                 (SEQ ID NO: 1100) 
                   
                   
                   
                   
               
               
                   
               
               
                 WDCRNTSHPKLKCHN 
                 ISSGLLSGRSANP 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 481) 
                 (SEQ ID NO: 1101) 
                   
                   
                   
                   
               
               
                   
               
               
                 WSPCNSDHKRKCNNG 
                 ISSGLLSGRSANI 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 482) 
                 (SEQ ID NO: 1102) 
                   
                   
                   
                   
               
               
                   
               
               
                 YANMSCEYDCHKMKY 
                 AVGLLAPPGGLSGRSDDH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 483) 
                 (SEQ ID NO: 1103) 
                   
                   
                   
                   
               
               
                   
               
               
                 YANPCTHKEKCHFKN 
                 AVGLLAPPGGLSGRSDIH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 484) 
                 (SEQ ID NO: 1104) 
                   
                   
                   
                   
               
               
                   
               
               
                 YDCSPSWTHPKCKHK 
                 AVGLLAPPGGLSGRSDQH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 485) 
                 (SEQ ID NO: 1105) 
                   
                   
                   
                   
               
               
                   
               
               
                 YGWTCTTHPKCKTTN 
                 AVGLLAPPGGLSGRSDTH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 486) 
                 (SEQ ID NO: 1106) 
                   
                   
                   
                   
               
               
                   
               
               
                 YQKCHPKAKDCGNNT 
                 AVGLLAPPGGLSGRSDYH 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 487) 
                 (SEQ ID NO: 1107) 
                   
                   
                   
                   
               
               
                   
               
               
                 YWECPNMEHNKCKNN 
                 AVGLLAPPGGLSGRSDNP 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 488) 
                 (SEQ ID NO: 1108) 
                   
                   
                   
                   
               
               
                   
               
               
                 PMGNRYCVLDHPKLK 
                 AVGLLAPPGGLSGRSANP 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 489) 
                 (SEQ ID NO: 1109) 
                   
                   
                   
                   
               
               
                   
               
               
                 GHKSCCQKHCEYTQT 
                 AVGLLAPPGGLSGRSANI 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 490) 
                 (SEQ ID NO: 1110) 
                   
                   
                   
                   
               
               
                   
               
               
                 LYLEMCSCCCWESIT 
                 ISSGLLSGRSDNI 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 491) 
                 (SEQ ID NO: 1111) 
                   
                   
                   
                   
               
               
                   
               
               
                 ACQAQHCYKTYACKP 
                 AVGLLAPPGGLSGRSDNI 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 492) 
                 (SEQ ID NO: 1112) 
                   
                   
                   
                   
               
               
                   
               
               
                 CCYTCSVHPKCKNQL 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 493) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 CKHRCSHKEKCPANH 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 494) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 CHVLFCLMQCCRWSL 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 495) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 LNSSLVFDHPKAKPN 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 496) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 MCLLCRSKFGCKVKG 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 497) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 IICNDHKCKQNQCNN 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 498) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 IRCSLRDSLCGCERM 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 499) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 TSCQPPKHKCTCNHG 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 500) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 TQCPHRCVKPNCWLH 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 501) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 KCCETKRNHKHCTYK 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 502) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 LPHCCHKAKHCNHTS 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 503) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 PAMCAAIHEKCCIKV 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 504) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 PRSCGNQLCPCHYYK 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 505) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 TNKCSCNHNMKCINY 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 506) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 VETCCQHNKCKYPFI 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 507) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 IFCCSNHEDHKCKTN 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 508) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 VCRLICPLTCVIGVG 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 509) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 FHGCCSVYSCLTNPG 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 510) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 ALACHPKQKPLEGQL 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 511) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 SIICCATSSCPLKHL 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 512) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 APCCRPHKEKPIDSR 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 513) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 WELCCPSADCRVAMG 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 514) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 QDHPKTKWNS (SEQ 
                   
                   
                   
                   
                   
               
               
                 ID NO: 548) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 ACRICQDHPATKWNS 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 549) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 ACRICQDHPKTAWNS 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 550) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 ACRICQDAPKTKWNS 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 551) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 ACRICQDHAKTKWNS 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 552) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 DHPATKWNS 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 553) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 DHPKTAWNS 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 554) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 DAPKTKWNS 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 555) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 DAPATKWNS 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 556) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 ACRICQDHP 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 557) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 HPQSKDTL 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 558) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 HPKSQDTL 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 559) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 TIPRCGQHPLCLDTL 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 560) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 HPLSLDTL 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 561) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 HPASKDTL 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 562) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 HPKSADTL 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 563) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 PGNCHPLQKELCQFI 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 564) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 HPLQKELAQFI 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 565) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 HPLALELAQFI 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 566) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 PGNCHPLQLELCQFI 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 567) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 TNIWSCQTYCDHAHA 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 568) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 TNIWSCQTYCDHAHL 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 569) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 TNIWSCQTYCDHLHA 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 570) 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 TNIWSCQTYCDHKHA 
                   
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 571) 
               
               
                   
               
            
           
         
       
     
     Any of the combinations described in Tables 13A, 13B, 13C, and/or 13D can be combined with human immunoglobulin constant regions to result in fully humanized IgGs including IgG1, IgG2, IgG4 or mutated constant regions to result in human IgGs with altered functions such as IgG1 N297A, IgG1 N297Q, or IgG4 S228P. Additional examples are known to those skilled in the art. Examples of Ig heavy chain constant region amino acids in which mutations in at least one amino acid leads to reduced Fc function include, but are not limited to, mutations in amino acid 228, 233, 234, 235, 236, 237, 239, 252, 254, 256, 265, 270, 297, 318, 320, 322, 327, 329, 330, and 331 of the heavy constant region. Examples of combinations of mutated amino acids are also known in the art, such as, but not limited to a combination of mutations in amino acids 234, 235, and 331, such as L234F, L235E, and P331S or a combination of amino acids 318, 320, and 322, such as E318A, K320A, and K322A. 
     As an example a masking moiety comprising SEQ ID NO: 66 can be combined with a substrate comprising SEQ ID NO: 294, and a VL region comprising SEQ ID NO: 39 in combination with a human kappa constant domain comprising SEQ ID NO: 61 to produce a light chain, which may or may not include linker regions. One such example is SEQ ID NO: 380, although other embodiments having longer linker sequences are also contemplated. In some embodiments, for example, a VH region comprising SEQ ID NO: 21 can be combined a with human immunoglobulin heavy chain constant domain to give an IgG1 heavy chain (SEQ ID NO: 2048), an IgG4 heavy chain (SEQ ID NO: 2051), an IgG4 S228P heavy chain (SEQ ID NO: 2047), a mutated IgG1 N297A heavy chain (SEQ ID NO: 2049) or a mutated IgG1 N297Q heavy chain (SEQ ID NO: 2050). Co-expression of SEQ ID NO: 380 with SEQ ID NO: 2048 will yield an IgG1 anti-PD-1 activatable antibody. Co-expression of SEQ ID NO: 380 with SEQ ID NO: 2051 will yield an IgG4 anti-PD-1 activatable antibody. Co-expression of SEQ ID NO: 380 with SEQ ID NO: 2047 will yield an IgG4S228P anti-PD-1 activatable antibody. Co-expression of SEQ ID NO: 380 with SEQ ID NO: 2049 will yield an IgG1 N297A anti-PD-1 activatable antibody. Co-expression of SEQ ID NO: 380 with SEQ ID NO: 2050 will yield an IgG1 N297Q anti-PD-1 activatable antibody. 
     In some embodiments, a masking moiety comprising SEQ ID NO: 99 is combined with a substrate comprising SEQ ID NO: 214 and a VL region comprising SEQ ID NO: 47 in combination with a human kappa constant domain comprising SEQ ID NO: 61 to produce a light chain comprising SEQ ID NO: 2055. In some embodiments, spacer QGQSGQG (SEQ ID NO: 362) is added to the N-terminus of SEQ ID NO: 2055 to form SEQ ID NO: 2054. In some embodiments, a masking moiety comprising SEQ ID NO: 99 is combined with a substrate comprising SEQ ID NO: 1100 and a VL region comprising SEQ ID NO: 47 in combination with a human kappa constant domain comprising SEQ ID NO: 61 to produce a light chain comprising SEQ ID NO: 2057. In some embodiments, spacer QGQSGQG (SEQ ID NO: 362) is added to the N-terminus of SEQ ID NO: 2057 to form SEQ ID NO: 2056. In some embodiments, a masking moiety comprising SEQ ID NO: 99 is combined with a substrate comprising SEQ ID NO: 1101, and a VL region comprising SEQ ID NO: 47 in combination with a human kappa constant domain comprising SEQ ID NO: 61 to produce a light chain comprising SEQ ID NO: 2059. In some embodiments, spacer QGQSGQG (SEQ ID NO: 362) is added to the N-terminus of SEQ ID NO: 2059 to form SEQ ID NO: 2058. In some embodiments, a VH region comprising SEQ ID NO: 21 can be combined with an IgG4 S228P human immunoglobulin heavy chain constant domain comprising SEQ ID NO: 63 to produce a heavy chain comprising SEQ ID NO: 2052. In some embodiments, the C-terminal lysine of SEQ ID NO: 2052 is missing to form an amino acid sequence having SEQ ID NO: 2053. Co-expression of any one of these light chains with any one of these heavy chains will lead to production of an activatable antibody of the embodiments. 
     Constant region amino acid sequences are shown below in SEQ ID NO: 381, 382, 383, and 1807. 
     
       
         
           
               
               
            
               
                 IgG1 Hc CH1-end amino acid sequence: 
                   
               
               
                 (SEQ ID NO: 381) 
                   
               
               
                 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS 
                   
               
               
                   
               
               
                 LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPP 
               
               
                   
               
               
                 KPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY  STYRVVSVLTVL 
               
               
                   
               
               
                 HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFY 
               
               
                   
               
               
                 PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT 
               
               
                   
               
               
                 QKSLSLSPG 
               
               
                   
               
               
                 IgG1NA CH1-end amino acid sequence: 
               
               
                 (SEQ ID NO: 382) 
                   
               
               
                 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS 
                   
               
               
                   
               
               
                 LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPP 
               
               
                   
               
               
                 KPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY  STYRVVSVLTVL 
               
               
                   
               
               
                 HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFY 
               
               
                   
               
               
                 PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT 
               
               
                   
               
               
                 QKSLSLSPG 
               
               
                   
               
               
                 IgG1NQ CH1-end amino acid sequence: 
               
               
                 (SEQ ID NO: 1807) 
                   
               
               
                 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS 
                   
               
               
                   
               
               
                 LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPP 
               
               
                   
               
               
                 KPKDTLMISRTPEVICVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY  STYRVVSVLTVL 
               
               
                   
               
               
                 HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFY 
               
               
                   
               
               
                 PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT 
               
               
                   
               
               
                 QKSLSLSPG 
               
               
                   
               
               
                 IgG4 Hc CH1-end amino acid sequence: 
               
               
                 (SEQ ID NO: 383) 
                   
               
               
                 ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS 
                   
               
               
                   
               
               
                 LSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCP  CPAPEFLGGPSVFLFPPKPK 
               
               
                   
               
               
                 DTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQD 
               
               
                   
               
               
                 WLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSD 
               
               
                   
               
               
                 IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKS 
               
               
                   
               
               
                 LSLSLG 
               
               
                   
               
               
                 Light Chain (Lc) amino acid sequence: 
               
               
                 AMSGCSWSAFCPYLA[X1] n LSGRSDNH[X2] n DIQLTQSPSSLSASVGDRVTITCRASESVD 
               
               
                   
               
               
                 NYGISFMNWFQQKPGKAPKLLIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYC 
               
               
                   
               
               
                 QQSKDVPWTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKV 
               
               
                   
               
               
                 DNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRG 
               
               
                   
               
               
                 EC 
               
               
                   
               
               
                 where each of [X1] n  and [X2] n  independently can be a 
               
               
                   
               
               
                 linking peptide of between 0 and 20 amino acids (SEQ ID NO: 
               
               
                   
               
               
                 380), or any other suitable length. 
               
               
                   
               
               
                 IgG4 S228P Heavy Chain (Hc) amino acid sequence: 
               
               
                 (SEQ ID NO: 2047) 
                   
               
               
                 EVQLVESGGGLVQPGGSLRLSCAAS GFTFSGYAMS WVRQAPGKGLEWVA YISNSGGNAH YADSV 
                   
               
               
                   
               
               
                 KGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTR EDYGTSPFVY WGQGTLVTVSSASTKGPSVF 
               
               
                   
               
               
                 PLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS 
               
               
                   
               
               
                 SSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTP 
               
               
                   
               
               
                 EVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKC 
               
               
                   
               
               
                 KVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNG 
               
               
                   
               
               
                 QPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK 
               
               
                   
               
               
                 IgG1 Heavy Chain (Hc) amino acid sequence: 
               
               
                 (SEQ ID NO: 2048) 
                   
               
               
                 EVQLVESGGGLVQPGGSLRLSCAASGFTFSGYAMSWVRQAPGKGLEWVAYISNSGGNAHYADSV 
                   
               
               
                   
               
               
                 KGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTREDYGTSPFVYWGQGTLVTVSS 
               
               
                   
               
               
                 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS 
               
               
                   
               
               
                 LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPP 
               
               
                   
               
               
                 KPKDTLMISRTPEVICVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY  STYRVVSVLTVL 
               
               
                   
               
               
                 HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFY 
               
               
                   
               
               
                 PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT 
               
               
                   
               
               
                 QKSLSLSPG 
               
               
                   
               
               
                 IgG1NA Hc amino acid sequence: 
               
               
                 (SEQ ID NO: 2049) 
                   
               
               
                 EVQLVESGGGLVQPGGSLRLSCAASGFTFSGYAMSWVRQAPGKGLEWVAYISNSGGNAHYADSV 
                   
               
               
                   
               
               
                 KGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTREDYGTSPFVYWGQGTLVTVSS 
               
               
                   
               
               
                 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS 
               
               
                   
               
               
                 LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPP 
               
               
                   
               
               
                 KPKDTLMISRTPEVICVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY  STYRVVSVLTVL 
               
               
                   
               
               
                 HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFY 
               
               
                   
               
               
                 PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT 
               
               
                   
               
               
                 QKSLSLSPG 
               
               
                   
               
               
                 IgG1NQ Hc amino acid sequence: 
               
               
                 (SEQ ID NO: 2050) 
                   
               
               
                 EVQLVESGGGLVQPGGSLRLSCAASGFTFSGYAMSWVRQAPGKGLEWVAYISNSGGNAHYADSV 
                   
               
               
                   
               
               
                 KGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTREDYGTSPFVYWGQGTLVTVSS 
               
               
                   
               
               
                 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS 
               
               
                   
               
               
                 LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPP 
               
               
                   
               
               
                 KPKDTLMISRTPEVICVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY  STYRVVSVLTVL 
               
               
                   
               
               
                 HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFY 
               
               
                   
               
               
                 PSDIAVEWESNGQPENNYKTIPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT 
               
               
                   
               
               
                 QKSLSLSPG 
               
               
                   
               
               
                 IgG4 Hc amino acid sequence: 
               
               
                 (SEQ ID NO: 2051) 
                   
               
               
                 EVQLVESGGGLVQPGGSLRLSCAASGFTFSGYAMSWVRQAPGKGLEWVAYISNSGGNAHYADSV 
                   
               
               
                   
               
               
                 KGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTREDYGTSPFVYWGQGTLVTVSS 
               
               
                   
               
               
                 ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS 
               
               
                   
               
               
                 LSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCP  CPAPEFLGGPSVFLFPPKPK 
               
               
                   
               
               
                 DTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQD 
               
               
                   
               
               
                 WLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSD 
               
               
                   
               
               
                 IAVEWESNGQPENNYKTIPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKS 
               
               
                   
               
               
                 LSLSLG 
               
               
                   
               
               
                 Heavy Chain 1 Amino Acid Sequence (SEQ ID NO: 2052): 
               
               
                 EVQLVESGGGLVQPGGSLRLSCAASGFTFSGYAMSWVRQAPGKGLEWVAYISNSGGNA 
               
               
                   
               
               
                 HYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTREDYGTSPFVYWGQGTLVT 
               
               
                   
               
               
                 VSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL 
               
               
                   
               
               
                 QSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGG 
               
               
                   
               
               
                 PSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQF 
               
               
                   
               
               
                 NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ 
               
               
                   
               
               
                 EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDK 
               
               
                   
               
               
                 SRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK 
               
               
                   
               
               
                 Heavy Chain 2 Amino Acid Sequence (SEQ ID NO: 2053): 
               
               
                 EVQLVESGGGLVQPGGSLRLSCAASGFTFSGYAMSWVRQAPGKGLEWVAYISNSGGNA 
               
               
                   
               
               
                 HYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTREDYGTSPFVYWGQGTLVT 
               
               
                   
               
               
                 VSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL 
               
               
                   
               
               
                 QSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGG 
               
               
                   
               
               
                 PSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQF 
               
               
                   
               
               
                 NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ 
               
               
                   
               
               
                 EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDK 
               
               
                   
               
               
                 SRWQEGNVFScSVMHEALHNHYTQKSLSLSLG 
               
               
                   
               
               
                 Light Chain 1 Amino Acid Sequence with spacer (SEQ ID NO: 2054): 
               
               
                 [QGQSGQG][TSYCSIEHYPCNTHHGGGSSGGSISSGLLSGRSDNHGGGSDIQLTQSPSSLS 
               
               
                   
               
               
                 ASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQGSGVPSRFSGSGS 
               
               
                   
               
               
                 GTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKS 
               
               
                   
               
               
                 GTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKAD 
               
               
                   
               
               
                 YEKHKVYACEVTHQGLSSPVTKSFNRGEC] 
               
               
                   
               
               
                 Light Chain 1 Amino Acid Sequence without spacer (SEQ ID NO: 2055): 
               
               
                 TSYCSIEHYPCNTHHGGGSSGGSISSGLLSGRSDNHGGGSDIQLTQSPSSLSASVGDRVTI 
               
               
                   
               
               
                 TCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQGSGVPSRFSGSGSGTDFTLTISS 
               
               
                   
               
               
                 MQPEDFATYYCQQSKDVPWTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLL 
               
               
                   
               
               
                 NNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYAC 
               
               
                   
               
               
                 EVTHQGLSSPVTKSFNRGEC 
               
               
                   
               
               
                 Light Chain 2 Amino Acid Sequence with spacer (SEQ ID NO: 2056): 
               
               
                 [QGQSGQG][TSYCSIEHYPCNTHHGGGSSGGSISSGLLSGRSDNPGGGSDIQLTQSPSSLS 
               
               
                   
               
               
                 ASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQGSGVPSRFSGSGS 
               
               
                   
               
               
                 GTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKS 
               
               
                   
               
               
                 GTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKAD 
               
               
                   
               
               
                 YEKHKVYACEVTHQGLSSPVTKSFNRGEC] 
               
               
                   
               
               
                 Light Chain 2 Amino Acid Sequence without spacer (SEQ ID NO: 2057): 
               
               
                 TSYCSIEHYPCNTHHGGGSSGGSISSGLLSGRSDNPGGGSDIQLTQSPSSLSASVGDRVTIT 
               
               
                   
               
               
                 CRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQGSGVPSRFSGSGSGTDFTLTISSM 
               
               
                   
               
               
                 QPEDFATYYCQQSKDVPWTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNN 
               
               
                   
               
               
                 FYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEV 
               
               
                   
               
               
                 THQGLSSPVTKSFNRGEC 
               
               
                   
               
               
                 Light Chain 3 Amino Acid Sequence with spacer (SEQ ID NO: 2058): 
               
               
                 [QGQSGQG][TSYCSIEHYPCNTHHGGGSSGGSISSGLLSGRSANPGGGSDIQLTQSPSSLS 
               
               
                   
               
               
                 ASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQGSGVPSRFSGSGS 
               
               
                   
               
               
                 GTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKS 
               
               
                   
               
               
                 GTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKAD 
               
               
                   
               
               
                 YEKHKVYACEVTHQGLSSPVTKSFNRGEC] 
               
               
                   
               
               
                 Light Chain 3 Amino Acid Sequence without spacer (SEQ ID NO: 2059): 
               
               
                 TSYCSIEHYPCNTHHGGGSSGGSISSGLLSGRSANPGGGSDIQLTQSPSSLSASVGDRVTIT 
               
               
                   
               
               
                 CRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQGSGVPSRFSGSGSGTDFTLTISSM 
               
               
                   
               
               
                 QPEDFATYYCQQSKDVPWTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNN 
               
               
                   
               
               
                 FYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEV 
               
               
                   
               
               
                 THQGLSSPVTKSFNRGEC 
               
            
           
         
       
     
     Example 10: Evaluation of Efficiency of Masking Moieties 
     This example describes activatable anti-PD-1 antibodies of the disclosure with reduced binding to hPD-1. 
     Masking the ability of an antibody to bind to its antigen is an example of inhibition of binding. The extent of inhibition is dependent on the affinity of the antibody for its antigen, the affinity of the masking moiety (also referred to herein as the mask) for the antibody and the concentration of all reactants. Local concentrations of the tethered peptide mask (inhibitor) is very high in the activatable antibody context, on the order of 10 mM, therefore moderate affinity peptides would effectively mask activatable antibody antigen binding. 
     Masking efficiencies were evaluated by standard plate ELISA. Briefly, human PD-1-Fc (R and D systems, Minneapolis, Minn.) was adsorbed to the wells of a 96-well ELISA plate. Purified anti-PD-1 antibodies and activatable antibodies were applied to the plate in serial dilution and allowed to bind. Bound antibody and activatable antibodies were detected with anti-human IgG-HRP conjugate, FAb-specific (Sigma, St Louis, Mo.) and visualized with the chromogenic substrate TMB (Thermo Scientific, Rockford, Ill.). Shown are plots of binding isotherms for anti-PD-1 A1.4 and anti-PD-1 A1.5 activatable antibodies ( FIGS. 14-18 ). Plots were generated in Prizm (Sigma Plot); the data were fit to a model of single site saturation binding, and the equilibrium dissociation constant, K d , was determined. Masking efficiency was calculated by dividing the K d  for binding of the activatable antibodies by the K d  of the parental antibody. The masking efficiency (ME) values for the tested antibodies are shown in Table 14 and Table 15 below (masking moiety PD001 is also referred to herein as PD01 and/or PD-01; masking moiety PD002 is also referred to herein as PD02 and/or PD-02, and so on), and the apparent K d  (nM) and masking efficiency (ME) values for the tested activatable antibodies are shown in Table 26: 
     
       
         
           
               
             
               
                 TABLE 14 
               
             
            
               
                   
               
               
                 Masking efficiency values for activatable 
               
               
                 antibodies tested in FIG. 14 
               
            
           
           
               
               
               
            
               
                   
                 Mask 
                 ME 
               
               
                   
                   
               
               
                   
                 PD01 
                 25 
               
               
                   
                 PD02 
                 18 
               
               
                   
                 PD03 
                  5 
               
               
                   
                 PD08 
                 13 
               
               
                   
                 PD09 
                  2 
               
               
                   
                  PD-10 
                 13 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 15 
               
             
            
               
                   
               
               
                 Masking efficiency values for activatable antibodies tested in FIG. 18 
               
            
           
           
               
               
            
               
                 Mask 
                 ME 
               
               
                   
               
               
                 None 
                  1 
               
               
                 PD06 
                 30 
               
               
                 PD09 
                  2 
               
               
                  PD-12 
                 10 
               
               
                  PD-17 
                 20 
               
               
                  PD-19 
                 30 
               
               
                 PD25 
                 30 
               
               
                 PD26 
                 20 
               
               
                 PD28 
                 25 
               
               
                 PD34 
                 42 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 26 
               
             
            
               
                   
               
               
                 Apparent Kd and Masking efficiency values for activatable 
               
               
                 antibodies tested in FIG. 15 
               
            
           
           
               
               
               
            
               
                 Molecule 
                 Apparent KD, nM 
                 Masking Efficiency 
               
               
                   
               
            
           
           
               
               
               
            
               
                 A1.5 (n = 5 avg) 
                 1.8 
                   
               
               
                 PD01 
                 348 
                 193 
               
               
                 PD02 
                 21 
                 12 
               
               
                 PD03 
                 109 
                 61 
               
               
                 PD05 
                 68 
                 38 
               
               
                 PD06 
                 71 
                 39 
               
               
                 PD08 
                 55 
                 31 
               
               
                 PD09 
                 10 
                 6 
               
               
                 PD10 
                 54 
                 30 
               
               
                 PD11 
                 67 
                 37 
               
               
                 PD12 
                 25 
                 14 
               
               
                 PD13 
                 151 
                 84 
               
               
                 PD14 
                 100 
                 56 
               
               
                 PD15 
                 117 
                 65 
               
               
                 PD16 
                 57 
                 32 
               
               
                 PD17 
                 22 
                 12 
               
               
                 PD18 
                 75 
                 42 
               
               
                 PD19 
                 93 
                 52 
               
               
                 PD20 
                 77 
                 43 
               
               
                 PD21 
                 49 
                 27 
               
               
                 PD22 
                 41 
                 23 
               
               
                 PD23 
                 31 
                 17 
               
               
                 PD24 
                 92 
                 51 
               
               
                   
               
            
           
         
       
     
     Example 11: Anti-PD-1 Activatable Antibodies of the Embodiments are Functionally Masked in a Human T-Cell Restimulation Assay 
     This example describes the effect of masking moieties on the biological function of the anti-PD-1 antibody. ( FIG. 19 ) 
     PBMCs from a CMV-positive donor (Hemacare) were plated at 2×10 5  cells/well in the presence of CMV viral lysate (Astarte) and either anti-PD-1 antibody A1.5, an anti-PD-1 activatable antibody of the disclosure, or hIgG4 isotype control antibody. After four days, supernatant was removed from each well and IFN-gamma levels were assayed using IFN-gamma ELISA kit (Life Technologies, Carlsbad, Calif.). Anti-PD-1 A1.5 activatable antibodies increased CMV-stimulated IFN-gamma secretion compared with control hIgG4 but with decreased potency relative to anti-PD-1 A1.5 parental antibody ( FIG. 19 ). 
     Example 12: Anti Mouse PD-1 J43v2 mIgG2a Antibody Binds Mouse PD-1 and Blocks Mouse PD-L1 and Mouse PD-L2 Binding 
     This example demonstrates that Armenian hamster anti mouse PD-1 J43 antibody (U.S. Pat. No. 7,858,746; Agata et al, 1996, International Immunology, Vol. 8 No. 5 pp 765-77) can be functionally expressed as a mouse IgG2a antibody. 
     Anti-mouse PD-1 antibody J43 was reformatted as a hamster LC (SEQ ID NO: 543 amino acid; SEQ ID NO: 544 or SEQ ID NO: 545 nucleotide), mouse IgG2a antibody by fusion of the heavy chain variable domain to mIgG2a, resulting in amino acid SEQ ID NO 546, nucleotide sequence SEQ ID NO 547. Full length J43v2 mIgG2a (also referred to as J43v2, J43 m2a and J43v2 m2a) was expressed by transient transfection of HEK293 cells and purified from the culture supernatant by Protein G chromatography. One embodiment of this disclosure is an antibody comprising a light chain comprising amino acid sequence SEQ ID NO: 543. One embodiment of this disclosure is an antibody comprising a heavy chain comprising amino acid sequence SEQ ID NO: 546. One embodiment of this disclosure is an antibody comprising a light chain comprising amino acid sequence SEQ ID NO: 543 and a heavy chain comprising amino acid sequence SEQ ID NO: 546. One embodiment of this disclosure is an antibody comprising the CDRs of an antibody comprising a light chain comprising amino acid sequence SEQ ID NO: 543 and a heavy chain comprising amino acid sequence SEQ ID NO: 546. 
     Functionality was assayed by binding of J43v2 m2a to HEK293 cells expressing mouse PD-1 and confirmation that binding of J43v2 m2a to HEK293-mPD-1 inhibited binding of biotinylated mPD-L1 and biotinylated mPD-L2 to HEK293-mPD-1 ( FIG. 20 ). About 100,000 mPD-1 HEK293 cells were transferred to a U-bottom 96-well plate. For the binding experiment, a 1:4 titration of J43v2 m2a antibody starting at 150 nM was added to cells. For blocking experiments, 20 nM of biotinylated-mPD-L1-Fc or 20 nM of biotinylated-mPD-L2-Fc were premixed with a 1:4 titration of J43v2 m2a starting at 150 nM and added to cells. Both were incubated for 1 hour on ice and cells were washed 3 times. J43v2 m2a antibody binding was detected using an anti-mouse secondary antibody (Jackson Immunoresearch, West Grove, Pa.). For the blocking experiment, biotinylated-PD-L1 or biotinylated-PD-L2 was detected using streptavidin-PE (Life Technologies, Carlsbad, Calif.). Both binding and blocking were incubated for 30 minutes on ice and were washed and read on a flow cytometer (MACSQuant). 
     Example 13: J43v2 m2a Induces Diabetes in NOD Mouse Model 
     In this Example, anti-PD-1 J43v2 m2a antibody was confirmed to induce diabetes in the NOD mouse model. 
     Antibody J43v2 m2a was confirmed to induce diabetes in NOD mice as follows. The NOD mice, substrain NOD/ShiLtJ were obtained from Jackson Laboratory at 8 weeks and acclimated on site for 2 weeks. At 10 weeks, mice were checked for diabetes prior to enrollment, grouped, and dosed as set forth in Table 16.  FIG. 21  shows the dose-dependent induction of diabetes in NOD mice by J43v2 m2a. At day eight after a single dose, 100% of mice in the mIgG2a isotype control group remained non-diabetic, while 0%, 14% and 86% of the 20 mg/kg, 3 mg/kg and 1 mg/kg groups, respectively, remained non-diabetic. 
     
       
         
           
               
             
               
                 TABLE 16 
               
             
            
               
                   
               
               
                 Study design 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                 Dose 
                   
                   
               
               
                   
                   
                   
                   
                 Dose 
                 volume 
                   
                   
               
               
                 Group 
                 Count 
                 Gender 
                 Treatment 
                 (mg/kg) 
                 (mL/kg) 
                 Schedule 
                 Route 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 1 
                 7 
                 F 
                 mIgG2a (C1.18.4) 
                 20 
                 10 
                 q7dx1 
                 IP 
               
               
                 2 
                 7 
                 F 
                 Anti-PD-1 (J43v2) 
                 20 
                 10 
                 q7dx1 
                 IP 
               
               
                 3 
                 7 
                 F 
                 Anti-PD-1 (J43v2) 
                 5 
                 10 
                 q7dx1 
                 IP 
               
               
                 4 
                 7 
                 F 
                 Anti-PD-1 (J43v2) 
                 1 
                 10 
                 q7dx1 
                 IP 
               
               
                   
               
            
           
         
       
     
     Example 14: Activatable Anti-Mouse PD-1 J43 Masking Moieties 
     This example describes identification of masking moieties (MM) that reduce binding of anti-PD-1 J43 antibody to its target. 
     Anti-PD-1 J43v2 mIgG2a was used to screen libraries using a method similar to that described in PCT International Publication Number WO 2010/081173, published 15 Jul. 2010. The screening consisted of one round of MACS and three rounds of FACS sorting. For the initial MACS, approximately 1×10 12  cells were incubated with J43v2 m2a antibody at a concentration of 200 nM, and approximately 9×10 7  binders were collected using Protein-G Dynabeads (Life Technologies, Carlsbad, Calif.). FACS rounds were conducted labeling cells with DyLight 650 (Thermo-Fisher) labeled J43v2 m2a antibody and collecting cells with strongest fluorescence as follows: 200 nM J43-650 collecting brightest 3% for FACS round 1 (F1), 20 nM J43-650 collecting brightest 8% for FACS round 2 (F2) and 1 nM J43-650 collecting two populations, the brightest 20% and the brightest 0.5% for FACS round 3 (F3-20 and F3-0.5). Individual peptide clones from F2, F3-20 and F3-0.5 were identified by sequence analysis (Table 17), and selected peptide clones MP001-MP014 were subsequently verified for their ability to bind J43-650 (masking moiety MP001 is also referred to herein as MP01 and/or MP-01; masking moiety MP002 is also referred to herein as MP02 and/or MP-02, and so on). 
     
       
         
           
               
             
               
                 TABLE 17 
               
             
            
               
                   
               
               
                 Masking moiety sequences 
               
            
           
           
               
               
               
               
            
               
                   
                 Mask 
                 Amino Acid Sequence 
                 SEQ ID NO: 
               
               
                   
                   
               
               
                   
                 MP001 
                 DYTYCRWVNWCLSGV 
                 384 
               
               
                   
                   
               
               
                   
                 MP002 
                 ILCPEDPWGHKCKLP 
                 385 
               
               
                   
                   
               
               
                   
                 MP003 
                 TNIWSCQTYCDHKHK 
                 386 
               
               
                   
                   
               
               
                   
                 MP004 
                 SDHKCKLQNCMNTKV 
                 387 
               
               
                   
                   
               
               
                   
                 MP005 
                 PGNCHPMQKEMCQFI 
                 388 
               
               
                   
                   
               
               
                   
                 MP006 
                 VEHLCYTHNKCKHPD 
                 389 
               
               
                   
                   
               
               
                   
                 MP007 
                 TIPRCGQHPKCKDTL 
                 390 
               
               
                   
                   
               
               
                   
                 MP008 
                 ACRICQDHPKTKWNS 
                 391 
               
               
                   
                   
               
               
                   
                 MP009 
                 LIQCTGNLDHKCKHY 
                 392 
               
               
                   
                   
               
               
                   
                 MP010 
                 IPCHHSADHKHKCTS 
                 393 
               
               
                   
                   
               
               
                   
                 MP011 
                 SRQICADYNCHNKYK 
                 394 
               
               
                   
                   
               
               
                   
                 MP012 
                 QPCNPQIDHKIKCIY 
                 395 
               
               
                   
                   
               
               
                   
                 MP013 
                 HYTICMTHNKCKDMA 
                 396 
               
               
                   
                   
               
               
                   
                 MP014 
                 ANSCLAVEHKCKHNY 
                 397 
               
               
                   
                   
               
               
                   
                 MP015 
                 AALHCTEHKCKNHIK 
                 398 
               
               
                   
                   
               
               
                   
                 MP016 
                 APCIINTVDWKSCEI 
                 399 
               
               
                   
                   
               
               
                   
                 MP017 
                 ATNWCTHKQKCKQDM 
                 400 
               
               
                   
                   
               
               
                   
                 MP018 
                 DCYNEHKLKTRVCNN 
                 401 
               
               
                   
                   
               
               
                   
                 MP019 
                 DEMQCSHKQKCTNSK 
                 402 
               
               
                   
                   
               
               
                   
                 MP020 
                 DVGICSQHNKCKPTK 
                 403 
               
               
                   
                   
               
               
                   
                 MP021 
                 EKYCSSDDHKCKITL 
                 404 
               
               
                   
                   
               
               
                   
                 MP022 
                 ELECSHNKVKNCIQI 
                 405 
               
               
                   
                   
               
               
                   
                 MP023 
                 ELHPCNTHKCKPIVN 
                 406 
               
               
                   
                   
               
               
                   
                 MP024 
                 EVGSCNHPKCKSNNY 
                 407 
               
               
                   
                   
               
               
                   
                 MP025 
                 EYSPSLAHPKLKDNA 
                 408 
               
               
                   
                   
               
               
                   
                 MP026 
                 FESLHPKGKHPEDLG 
                 409 
               
               
                   
                   
               
               
                   
                 MP027 
                 FPLCVRADRVCGDAQ 
                 410 
               
               
                   
                   
               
               
                   
                 MP028 
                 FQAPPASHNKLKPSL 
                 411 
               
               
                   
                   
               
               
                   
                 MP029 
                 GAIDSCHHKCKSPHY 
                 412 
               
               
                   
                   
               
               
                   
                 MP030 
                 GKIYTCEHNCTFGYS 
                 413 
               
               
                   
                   
               
               
                   
                 MP031 
                 HCTVNNHSSDHKCKI 
                 414 
               
               
                   
                   
               
               
                   
                 MP032 
                 HGTQCTHNKCKPILS 
                 415 
               
               
                   
                   
               
               
                   
                 MP033 
                 HIGWCLHPKCKTTTT 
                 416 
               
               
                   
                   
               
               
                   
                 MP034 
                 HLRTCIQKWCEHKMK 
                 417 
               
               
                   
                   
               
               
                   
                 MP035 
                 HTDCTMMSNHKCKIN 
                 418 
               
               
                   
                   
               
               
                   
                 MP036 
                 IRQQCTALACLLKVH 
                 419 
               
               
                   
                   
               
               
                   
                 MP037 
                 KGCSTHKMRAYCNQM 
                 420 
               
               
                   
                   
               
               
                   
                 MP038 
                 KMFTPCKIWCNNSYN 
                 421 
               
               
                   
                   
               
               
                   
                 MP039 
                 KTMCSGHKQKCNNSS 
                 422 
               
               
                   
                   
               
               
                   
                 MP040 
                 LACHSASLVDHKCKL 
                 423 
               
               
                   
                   
               
               
                   
                 MP041 
                 LCNVSMDHKHKPCYL 
                 424 
               
               
                   
                   
               
               
                   
                 MP042 
                 LGLNCFSEHKCKEHM 
                 425 
               
               
                   
                   
               
               
                   
                 MP043 
                 LGTCTHKHKNCNYTL 
                 426 
               
               
                   
                   
               
               
                   
                 MP044 
                 LHEGCTTHNKCKPIA 
                 427 
               
               
                   
                   
               
               
                   
                 MP045 
                 LKRSCTGHWTCYTNW 
                 428 
               
               
                   
                   
               
               
                   
                 MP046 
                 LQRCTHKEKYCHAIH 
                 429 
               
               
                   
                   
               
               
                   
                 MP047 
                 LSHCYDHKRKCSYIV 
                 430 
               
               
                   
                   
               
               
                   
                 MP048 
                 LSKCHNKEKNCSNNN 
                 431 
               
               
                   
                   
               
               
                   
                 MP049 
                 MDTCEMHKQKCRPSF 
                 432 
               
               
                   
                   
               
               
                   
                 MP050 
                 MHNECLTHKCKVPIT 
                 433 
               
               
                   
                   
               
               
                   
                 MP051 
                 MLTLCNTNACHKEKN 
                 434 
               
               
                   
                   
               
               
                   
                 MP052 
                 MRPCLNNLEHKCKHY 
                 435 
               
               
                   
                   
               
               
                   
                 MP053 
                 MSRCPTHKMKCSLNI 
                 436 
               
               
                   
                   
               
               
                   
                 MP054 
                 MWICQEHKLKCMTDT 
                 437 
               
               
                   
                   
               
               
                   
                 MP055 
                 MYYCKRRSAFYCTLN 
                 438 
               
               
                   
                   
               
               
                   
                 MP056 
                 NDCQHDKQMHKCKMH 
                 439 
               
               
                   
                   
               
               
                   
                 MP057 
                 NFGPCPMLLGCFGFR 
                 440 
               
               
                   
                   
               
               
                   
                 MP058 
                 NHTDCSHPKCKSHDS 
                 441 
               
               
                   
                   
               
               
                   
                 MP059 
                 NLNCPHKQKNCDKYH 
                 442 
               
               
                   
                   
               
               
                   
                 MP060 
                 NPQCTPIDHKCKTHH 
                 443 
               
               
                   
                   
               
               
                   
                 MP061 
                 NTTSCTHPKCKHQGK 
                 444 
               
               
                   
                   
               
               
                   
                 MP062 
                 NVGGCDNYGCHKLKN 
                 445 
               
               
                   
                   
               
               
                   
                 MP063 
                 PCSPGNLTWDHKCKY 
                 446 
               
               
                   
                   
               
               
                   
                 MP064 
                 PFTKCHGFNKCKEHT 
                 447 
               
               
                   
                   
               
               
                   
                 MP065 
                 PGDKCTHKEKCYYNN 
                 448 
               
               
                   
                   
               
               
                   
                 MP066 
                 PNICNLDHKRKCRIN 
                 449 
               
               
                   
                   
               
               
                   
                 MP067 
                 PQLACKHPKCKDAGN 
                 450 
               
               
                   
                   
               
               
                   
                 MP068 
                 PSCTMWTHGGVCKHA 
                 451 
               
               
                   
                   
               
               
                   
                 MP069 
                 PSHRHPLAKPGFRVE 
                 452 
               
               
                   
                   
               
               
                   
                 MP070 
                 PTCFKTHNKSKCNRV 
                 453 
               
               
                   
                   
               
               
                   
                 MP071 
                 PTPVCHHNFHCFGYD 
                 454 
               
               
                   
                   
               
               
                   
                 MP072 
                 QATCQWKKRSKCHNK 
                 455 
               
               
                   
                   
               
               
                   
                 MP073 
                 QHSWCQHKAKCNYGN 
                 456 
               
               
                   
                   
               
               
                   
                 MP074 
                 QNCSPTYTTHKCKLT 
                 457 
               
               
                   
                   
               
               
                   
                 MP075 
                 QSSNCEHKRKCSSTS 
                 458 
               
               
                   
                   
               
               
                   
                 MP076 
                 RPCLLGLVPDHKCKL 
                 459 
               
               
                   
                   
               
               
                   
                 MP077 
                 RRSCMRSINTCKQKY 
                 460 
               
               
                   
                   
               
               
                   
                 MP078 
                 RSSCPTVTPQNCENQ 
                 461 
               
               
                   
                   
               
               
                   
                 MP079 
                 RTMCLDLNHKCKPSN 
                 462 
               
               
                   
                   
               
               
                   
                 MP080 
                 RTYWCTNHNKCKHNM 
                 463 
               
               
                   
                   
               
               
                   
                 MP081 
                 RVENCEHNQYCHKWK 
                 464 
               
               
                   
                   
               
               
                   
                 MP082 
                 SCHEDDHKNKNICSL 
                 465 
               
               
                   
                   
               
               
                   
                 MP083 
                 SDTCVMNHPKCKRDN 
                 466 
               
               
                   
                   
               
               
                   
                 MP084 
                 SSTCFHPNQKECMTK 
                 467 
               
               
                   
                   
               
               
                   
                 MP085 
                 SSYCGGITMRCRRAM 
                 468 
               
               
                   
                   
               
               
                   
                 MP086 
                 STGYCTYVNWCNYTN 
                 469 
               
               
                   
                   
               
               
                   
                 MP087 
                 THKCKLHLQVCTQTT 
                 470 
               
               
                   
                   
               
               
                   
                 MP088 
                 TMNCTHPKQKCQHTN 
                 471 
               
               
                   
                   
               
               
                   
                 MP089 
                 TNVLCESHNCDHKNK 
                 472 
               
               
                   
                   
               
               
                   
                 MP090 
                 TQHAASLGVEHKSKI 
                 473 
               
               
                   
                   
               
               
                   
                 MP091 
                 TQLPCFDDHKCKNTN 
                 474 
               
               
                   
                   
               
               
                   
                 MP092 
                 TSDSCMRQKCEHKEK 
                 475 
               
               
                   
                   
               
               
                   
                 MP093 
                 TTCDDHKYKHKCAQL 
                 476 
               
               
                   
                   
               
               
                   
                 MP094 
                 TTCGAHKEKQHCIYT 
                 477 
               
               
                   
                   
               
               
                   
                 MP095 
                 TTYCAYWHNKCKFET 
                 478 
               
               
                   
                   
               
               
                   
                 MP096 
                 VGPTCGHAKCKQSEV 
                 479 
               
               
                   
                   
               
               
                   
                 MP097 
                 VSHPCNTHKCKTNIV 
                 480 
               
               
                   
                   
               
               
                   
                 MP098 
                 WDCRNTSHPKLKCHN 
                 481 
               
               
                   
                   
               
               
                   
                 MP099 
                 WSPCNSDHKRKCNNG 
                 482 
               
               
                   
                   
               
               
                   
                 MP100 
                 YANMSCEYDCHKMKY 
                 483 
               
               
                   
                   
               
               
                   
                 MP101 
                 YANPCTHKEKCHFKN 
                 484 
               
               
                   
                   
               
               
                   
                 MP102 
                 YDCSPSWTHPKCKHK 
                 485 
               
               
                   
                   
               
               
                   
                 MP103 
                 YGWTCTTHPKCKTTN 
                 486 
               
               
                   
                   
               
               
                   
                 MP104 
                 YQKCHPKAKDCGNNT 
                 487 
               
               
                   
                   
               
               
                   
                 MP105 
                 YWECPNMEHNKCKNN 
                 488 
               
               
                   
                   
               
               
                   
                 MP106 
                 PMGNRYCVLDHPKLK 
                 489 
               
               
                   
                   
               
               
                   
                 MP107 
                 GHKSCCQKHCEYTQT 
                 490 
               
               
                   
                   
               
               
                   
                 MP108 
                 LYLEMCSCCCWESIT 
                 491 
               
               
                   
                   
               
               
                   
                 MP109 
                 ACQAQHCYKTYACKP 
                 492 
               
               
                   
                   
               
               
                   
                 MP110 
                 CCYTCSVHPKCKNQL 
                 493 
               
               
                   
                   
               
               
                   
                 MP111 
                 CKHRCSHKEKCPANH 
                 494 
               
               
                   
                   
               
               
                   
                 MP112 
                 CHVLFCLMQCCRWSL 
                 495 
               
               
                   
                   
               
               
                   
                 MP113 
                 LNSSLVFDHPKAKPN 
                 496 
               
               
                   
                   
               
               
                   
                 MP114 
                 MCLLCRSKFGCKVKG 
                 497 
               
               
                   
                   
               
               
                   
                 MP115 
                 IICNDHKCKQNQCNN 
                 498 
               
               
                   
                   
               
               
                   
                 MP116 
                 IRCSLRDSLCGCERM 
                 499 
               
               
                   
                   
               
               
                   
                 MP117 
                 TSCQPPKHKCTCNHG 
                 500 
               
               
                   
                   
               
               
                   
                 MP118 
                 TQCPHRCVKPNCWLH 
                 501 
               
               
                   
                   
               
               
                   
                 MP119 
                 KCCETKRNHKHCTYK 
                 502 
               
               
                   
                   
               
               
                   
                 MP120 
                 LPHCCHKAKHCNHTS 
                 503 
               
               
                   
                   
               
               
                   
                 MP121 
                 PAMCAAIHEKCCIKV 
                 504 
               
               
                   
                   
               
               
                   
                 MP122 
                 PRSCGNQLCPCHYYK 
                 505 
               
               
                   
                   
               
               
                   
                 MP123 
                 TNKCSCNHNMKCINY 
                 506 
               
               
                   
                   
               
               
                   
                 MP124 
                 VETCCQHNKCKYPFI 
                 507 
               
               
                   
                   
               
               
                   
                 MP125 
                 IFCCSNHEDHKCKTN 
                 508 
               
               
                   
                   
               
               
                   
                 MP126 
                 VCRLICPLTCVIGVG 
                 509 
               
               
                   
                   
               
               
                   
                 MP127 
                 FHGCCSVYSCLTNPG 
                 510 
               
               
                   
                   
               
               
                   
                 MP128 
                 ALACHPKQKPLEGQL 
                 511 
               
               
                   
                   
               
               
                   
                 MP129 
                 SIICCATSSCPLKHL 
                 512 
               
               
                   
                   
               
               
                   
                 MP130 
                 APCCRPHKEKPIDSR 
                 513 
               
               
                   
                   
               
               
                   
                 MP131 
                 WELCCPSADCRVAMG 
                 514 
               
               
                   
                   
               
            
           
         
       
     
     Example 15: Characterization of Activatable Anti-Mouse PD-1 Antibodies 
     This example describes activatable anti-PD-1 antibodies of the disclosure with reduced binding to hPD-1 compared to binding by parental antibody. 
     Masking efficiencies were evaluated by standard plate ELISA. Briefly, mouse PD-1-Fc (R and D systems, Minneapolis, Minn.) was adsorbed to the wells of a 96-well ELISA plate. Purified J43v2 and activatable J43v2 antibodies comprising the indicated masks, cleavable moiety 2001, and antibody J43v2 were applied to the plate in serial dilution and allowed to bind. Bound antibody and activatable antibodies were detected with anti-mouse IgG-HRP conjugate (Sigma, St Louis, Mo.) and visualized with the chromogenic substrate TMB (Thermo Scientific, Rockford, Ill.). Plots were generated in Prizm (Sigma Plot). All activatable J43 antibodies showed strongly decreased binding compared with the parental J43 ( FIG. 22 ). 
     In some embodiments, the activatable antibody also includes a spacer sequence. In some embodiments, the spacer is joined directly to the MM of the activatable antibody. In some embodiments, the spacer is joined directly to the MM of the activatable antibody in the structural arrangement from N-terminus to C-terminus of spacer-MM-CM-AB. In some embodiments, the spacer joined directly to the N-terminus of MM of the activatable antibody is selected from the group consisting of QGQSGQG (SEQ ID NO: 362), QGQSGQ (SEQ ID NO: 913), QGQSG (SEQ ID NO: 914), QGQS (SEQ ID NO: 915), QGQ (SEQ ID NO: 916), QG (SEQ ID NO: 917), and Q. In some embodiments, the spacer includes at least the amino acid sequence QGQSGQG (SEQ ID NO: 362). In some embodiments, the spacer includes at least the amino acid sequence QGQSGQ (SEQ ID NO: 913). In some embodiments, the spacer includes at least the amino acid sequence QGQSG (SEQ ID NO: 914). In some embodiments, the spacer includes at least the amino acid sequence QGQS (SEQ ID NO: 915), In some embodiments, the spacer includes at least the amino acid sequence QGQ (SEQ ID NO: 916). In some embodiments, the spacer includes at least the amino acid sequence QG (SEQ ID NO: 917). In some embodiments, the spacer includes at least the amino acid residue Q. In some embodiments, the activatable antibody does not include a spacer sequence. 
     Additional examples of spacers include GQSGQG (SEQ ID NO: 2042), QSGQG (SEQ ID NO: 2043), SGQG (SEQ ID NO: 2044), GQG(SEQ ID NO: 2045), QG(SEQ ID NO: 2046), and G. 
     While the sequences shown below include the spacer sequence of SEQ ID NO: 362, those of ordinary skill in the art appreciate that the activatable anti-PD-1 antibodies of the disclosure can include any suitable spacer sequence, such as, for example, a spacer sequence selected from the group consisting of QGQSGQG (SEQ ID NO: 362), QGQSGQ (SEQ ID NO: 913), QGQSG (SEQ ID NO: 914), QGQS (SEQ ID NO: 915), QGQ (SEQ ID NO: 916), QG (SEQ ID NO: 917), and Q. Additional examples of spacers include GQSGQG (SEQ ID NO: 2042), QSGQG (SEQ ID NO: 2043), SGQG (SEQ ID NO: 2044), GQG(SEQ ID NO: 2045), QG(SEQ ID NO: 2046), and G. While the sequences shown below include the spacer sequence of SEQ ID NO: 362, those of ordinary skill in the art will also appreciate that activatable anti-PD-1 antibodies of the disclosure in some embodiments do not include a spacer sequence. 
     Activatable Anti-Mouse PD-1 Light Chain Variable Domains 
       
     
       
         
           
               
               
            
               
                 [spacer (SEQ ID NO: 362)][J43 MP001 2001 (SEQ ID NO: 999)] amino acid sequence: 
                   
               
               
                 (SEQ ID NO: 515) 
                   
               
               
                 [QGQSGQG][DYTYCRWVNWCLSGVGGGSSGGSISSGLLSGRSDNHGGGSYELTQPPSASVNVG 
                   
               
               
                 ETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPERISGSSSGTTATLTIRDVRA 
               
               
                 EDEGDYYCFSGYVDSDSKLYVFGSGTQLTVL] 
               
               
                   
               
               
                 J43 MP001 2001 amino acid sequence: 
               
               
                 (SEQ ID NO: 1077) 
                   
               
               
                 DYTYCRWVNWCLSGVGGGSSGGSISSGLLSGRSDNHGGGSYELTQPPSASVNVGETVKITCSGD 
                   
               
               
                 QLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPERISGSSSGTTATLTIRDVRAEDEGDYYCFS 
               
               
                 GYVDSDSKLYVFGSGTQLTVL 
               
               
                   
               
               
                 [spacer (SEQ ID NO: 918)][J43 MP001 2001 (SEQ ID NO: 1000)] nucleic acid sequence: 
               
               
                 (SEQ ID NO: 516) 
                   
               
               
                 [CAAGGCCAGTCTGGCCAAGGT]GATTATACGTATTGCCGTTGGGTTAATTGGTGCTTGTCTG 
                   
               
               
                   
               
               
                 GGGTGGGAGGTGGCTCGAGCGGCGGCTCTATCTCTTCCGGACTGCTGTCCGGCAGATCCGACAA 
               
               
                   
               
               
                 TCACGGCGGAGGCTCTTATGAGCTGACTCAGCCACCTTCAGCATCAGTCAATGTAGGAGAGACT 
               
               
                   
               
               
                 GTCAAAATCACCTGCTCTGGGGACCAATTGCCGAAATATTTTGCAGATTGGTTTCATCAAAGGT 
               
               
                   
               
               
                 CAGACCAGACCATTTTGCAAGTGATATATGATGATAATAAGCGCCCCTCGGGTATCCCTGAAAG 
               
               
                   
               
               
                 AATCTCTGGGTCCAGCTCAGGGACAACAGCCACCTTGACCATCAGAGATGTCCGGGCTGAGGAT 
               
               
                   
               
               
                 GAAGGTGACTATTACTGTTTCTCAGGATATGTTGATAGTGATAGCAAATTGTATGTTTTTGGCA 
               
               
                   
               
               
                 GCGGAACCCAGCTCACCGTCCT 
               
               
                   
               
               
                 [spacer (SEQ ID NO: 362)][J43 MP002 2001 (SEQ ID NO: 1001)] amino acid sequence: 
               
               
                 (SEQ ID NO: 517) 
                   
               
               
                 [QGQSGQG][ILCPEDPWGHKCKLPGGGSSGGSISSGLLSGRSDNHGGGSYELTQPPSASVNVG 
                   
               
               
                 ETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPERISGSSSGTTATLTIRDVRA 
               
               
                 EDEGDYYCFSGYVDSDSKLYVFGSGTQLTVL] 
               
               
                   
               
               
                 J43 MP002 2001 amino acid sequence: 
               
               
                 (SEQ ID NO: 1078) 
                   
               
               
                 ILCPEDPWGHKCKLPGGGSSGGSISSGLLSGRSDNHGGGSYELTQPPSASVNVGETVKITCSGD 
                   
               
               
                 QLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPERISGSSSGTTATLTIRDVRAEDEGDYYCFS 
               
               
                 GYVDSDSKLYVFGSGTQLTVL 
               
               
                   
               
               
                 [spacer (SEQ ID NO: 918)][J43 MP002 2001 (SEQ ID NO: 1002)] nucleic acid sequence: 
               
               
                 (SEQ ID NO: 518) 
                   
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][ATTCTGTGCCCGGAGGATCCGTGGGGGCATAAGTGCAAGC 
                   
               
               
                   
               
               
                 TGCCTGGAGGTGGCTCGAGCGGCGGCTCTATCTCTTCCGGACTGCTGTCCGGCAGATCCGACAA 
               
               
                   
               
               
                 TCACGGCGGAGGCTCTTATGAGCTGACTCAGCCACCTTCAGCATCAGTCAATGTAGGAGAGACT 
               
               
                   
               
               
                 GTCAAAATCACCTGCTCTGGGGACCAATTGCCGAAATATTTTGCAGATTGGTTTCATCAAAGGT 
               
               
                   
               
               
                 CAGACCAGACCATTTTGCAAGTGATATATGATGATAATAAGCGCCCCTCGGGTATCCCTGAAAG 
               
               
                   
               
               
                 AATCTCTGGGTCCAGCTCAGGGACAACAGCCACCTTGACCATCAGAGATGTCCGGGCTGAGGAT 
               
               
                   
               
               
                 GAAGGTGACTATTACTGTTTCTCAGGATATGTTGATAGTGATAGCAAATTGTATGTTTTTGGCA 
               
               
                   
               
               
                 GCGGAACCCAGCTCACCGTCCTA 
               
               
                   
               
               
                 [spacer (SEQ ID NO: 362)][J43 MP003 2001 (SEQ ID NO: 1003)] amino acid sequence: 
               
               
                 (SEQ ID NO: 519) 
                   
               
               
                 [QGQSGQG][TNIWSCQTYCDHKHKGGGSSGGSISSGLLSGRSDNHGGGSYELTQPPSASVNVG 
                   
               
               
                 ETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPERISGSSSGTTATLTIRDVRA 
               
               
                 EDEGDYYCFSGYVDSDSKLYVFGSGTQLTVL] 
               
               
                   
               
               
                 J43 MP003 2001 amino acid sequence: 
               
               
                 (SEQ ID NO: 1079) 
                   
               
               
                 TNIWSCQTYCDHKHKGGGSSGGSISSGLLSGRSDNHGGGSYELTQPPSASVNVGETVKITCSGD 
                   
               
               
                 QLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPERISGSSSGTTATLTIRDVRAEDEGDYYCFS 
               
               
                 GYVDSDSKLYVFGSGTQLTVL 
               
               
                   
               
               
                 [spacer (SEQ ID NO: 918)][J43 MP003 2001 (SEQ ID NO: 1004)] nucleic acid sequence: 
               
               
                 (SEQ ID NO: 520) 
                   
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][ACGAATATTTGGAGTTGCCAGACTTATTGCGATCATAAGC 
                   
               
               
                   
               
               
                 ATAAGGGAGGTGGCTCGAGCGGCGGCTCTATCTCTTCCGGACTGCTGTCCGGCAGATCCGACAA 
               
               
                   
               
               
                 TCACGGCGGAGGCTCTTATGAGCTGACTCAGCCACCTTCAGCATCAGTCAATGTAGGAGAGACT 
               
               
                   
               
               
                 GTCAAAATCACCTGCTCTGGGGACCAATTGCCGAAATATTTTGCAGATTGGTTTCATCAAAGGT 
               
               
                   
               
               
                 CAGACCAGACCATTTTGCAAGTGATATATGATGATAATAAGCGCCCCTCGGGTATCCCTGAAAG 
               
               
                   
               
               
                 AATCTCTGGGTCCAGCTCAGGGACAACAGCCACCTTGACCATCAGAGATGTCCGGGCTGAGGAT 
               
               
                   
               
               
                 GAAGGTGACTATTACTGTTTCTCAGGATATGTTGATAGTGATAGCAAATTGTATGTTTTTGGCA 
               
               
                   
               
               
                 GCGGAACCCAGCTCACCGTCCTA 
               
               
                   
               
               
                 [spacer (SEQ ID NO: 362)][J43 MP004 2001 (SEQ ID NO: 1005)] amino acid sequence: 
               
               
                 (SEQ ID NO: 521) 
                   
               
               
                 [QGQSGQG][SDHKCKLQNCMNTKVGGGSSGGSISSGLLSGRSDNHGGGSYELTQPPSASVNVG 
                   
               
               
                 ETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPERISGSSSGTTATLTIRDVRA 
               
               
                 EDEGDYYCFSGYVDSDSKLYVFGSGTQLTVL] 
               
               
                   
               
               
                 J43 MP004 2001 amino acid sequence: 
               
               
                 (SEQ ID NO: 1080) 
                   
               
               
                 SDHKCKLQNCMNTKVGGGSSGGSISSGLLSGRSDNHGGGSYELTQPPSASVNVGETVKITCSGD 
                   
               
               
                 QLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPERISGSSSGTTATLTIRDVRAEDEGDYYCFS 
               
               
                 GYVDSDSKLYVFGSGTQLTVL 
               
               
                   
               
               
                 [spacer (SEQ ID NO: 918)][J43 MP004 2001 (SEQ ID NO: 1006)] nucleic acid sequence: 
               
               
                 (SEQ ID NO: 522) 
                   
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][AGTGATCATAAGTGCAAGCTTCAGAATTGCATGAATACTA 
                   
               
               
                   
               
               
                 AGGTTGGAGGTGGCTCGAGCGGCGGCTCTATCTCTTCCGGACTGCTGTCCGGCAGATCCGACAA 
               
               
                   
               
               
                 TCACGGCGGAGGCTCTTATGAGCTGACTCAGCCACCTTCAGCATCAGTCAATGTAGGAGAGACT 
               
               
                   
               
               
                 GTCAAAATCACCTGCTCTGGGGACCAATTGCCGAAATATTTTGCAGATTGGTTTCATCAAAGGT 
               
               
                   
               
               
                 CAGACCAGACCATTTTGCAAGTGATATATGATGATAATAAGCGCCCCTCGGGTATCCCTGAAAG 
               
               
                   
               
               
                 AATCTCTGGGTCCAGCTCAGGGACAACAGCCACCTTGACCATCAGAGATGTCCGGGCTGAGGAT 
               
               
                   
               
               
                 GAAGGTGACTATTACTGTTTCTCAGGATATGTTGATAGTGATAGCAAATTGTATGTTTTTGGCA 
               
               
                   
               
               
                 GCGGAACCCAGCTCACCGTCCTA 
               
               
                   
               
               
                 [spacer (SEQ ID NO: 362)][J43 MP005 2001 (SEQ ID NO: 1007)] amino acid sequence: 
               
               
                 (SEQ ID NO: 523) 
                   
               
               
                 [QGQSGQG][PGNCHPMQKEMCQFIGGGSSGGSISSGLLSGRSDNHGGGSYELTQPPSASVNVG 
                   
               
               
                 ETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPERISGSSSGTTATLTIRDVRA 
               
               
                 EDEGDYYCFSGYVDSDSKLYVFGSGTQLTVL] 
               
               
                   
               
               
                 J43 MP005 2001 amino acid sequence: 
               
               
                 (SEQ ID NO: 1081) 
                   
               
               
                 PGNCHPMQKEMCQFIGGGSSGGSISSGLLSGRSDNHGGGSYELTQPPSASVNVGETVKITCSGD 
                   
               
               
                 QLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPERISGSSSGTTATLTIRDVRAEDEGDYYCFS 
               
               
                 GYVDSDSKLYVFGSGTQLTVL 
               
               
                   
               
               
                 [spacer (SEQ ID NO: 918)][J43 MP005 2001 (SEQ ID NO: 1008)] nucleic acid sequence: 
               
               
                 (SEQ ID NO: 524) 
                   
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][CCTGGTAATTGCCATCCTATGCAGAAGGAGATGTGCCAGT 
                   
               
               
                   
               
               
                 TTATTGGAGGTGGCTCGAGCGGCGGCTCTATCTCTTCCGGACTGCTGTCCGGCAGATCCGACAA 
               
               
                   
               
               
                 TCACGGCGGAGGCTCTTATGAGCTGACTCAGCCACCTTCAGCATCAGTCAATGTAGGAGAGACT 
               
               
                   
               
               
                 GTCAAAATCACCTGCTCTGGGGACCAATTGCCGAAATATTTTGCAGATTGGTTTCATCAAAGGT 
               
               
                   
               
               
                 CAGACCAGACCATTTTGCAAGTGATATATGATGATAATAAGCGCCCCTCGGGTATCCCTGAAAG 
               
               
                   
               
               
                 AATCTCTGGGTCCAGCTCAGGGACAACAGCCACCTTGACCATCAGAGATGTCCGGGCTGAGGAT 
               
               
                   
               
               
                 GAAGGTGACTATTACTGTTTCTCAGGATATGTTGATAGTGATAGCAAATTGTATGTTTTTGGCA 
               
               
                   
               
               
                 GCGGAACCCAGCTCACCGTCCTA 
               
               
                   
               
               
                 [spacer (SEQ ID NO: 362)][J43 MP006 2001 (SEQ ID NO: 1009)] amino acid sequence: 
               
               
                 (SEQ ID NO: 525) 
                   
               
               
                 [QGQSGQG][VEHLCYTHNKCKHPDGGGSSGGSISSGLLSGRSDNHGGGSYELTQPPSASVNVG 
                   
               
               
                 ETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPERISGSSSGTTATLTIRDVRA 
               
               
                 EDEGDYYCFSGYVDSDSKLYVFGSGTQLTVL] 
               
               
                   
               
               
                 J43 MP006 2001 amino acid sequence: 
               
               
                 (SEQ ID NO: 1082) 
                   
               
               
                 VEHLCYTHNKCKHPDGGGSSGGSISSGLLSGRSDNHGGGSYELTQPPSASVNVGETVKITCSGD 
                   
               
               
                 QLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPERISGSSSGTTATLTIRDVRAEDEGDYYCFS 
               
               
                 GYVDSDSKLYVFGSGTQLTVL 
               
               
                   
               
               
                 [spacer (SEQ ID NO: 918)][J43 MP006 2001 (SEQ ID NO: 1010)] nucleic acid sequence: 
               
               
                 (SEQ ID NO: 526) 
                   
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][GTTGAGCATTTGTGCTATACGCATAATAAGTGCAAGCATC 
                   
               
               
                   
               
               
                 CTGATGGAGGTGGCTCGAGCGGCGGCTCTATCTCTTCCGGACTGCTGTCCGGCAGATCCGACAA 
               
               
                   
               
               
                 TCACGGCGGAGGCTCTTATGAGCTGACTCAGCCACCTTCAGCATCAGTCAATGTAGGAGAGACT 
               
               
                   
               
               
                 GTCAAAATCACCTGCTCTGGGGACCAATTGCCGAAATATTTTGCAGATTGGTTTCATCAAAGGT 
               
               
                   
               
               
                 CAGACCAGACCATTTTGCAAGTGATATATGATGATAATAAGCGCCCCTCGGGTATCCCTGAAAG 
               
               
                   
               
               
                 AATCTCTGGGTCCAGCTCAGGGACAACAGCCACCTTGACCATCAGAGATGTCCGGGCTGAGGAT 
               
               
                   
               
               
                 GAAGGTGACTATTACTGTTTCTCAGGATATGTTGATAGTGATAGCAAATTGTATGTTTTTGGCA 
               
               
                   
               
               
                 GCGGAACCCAGCTCACCGTCCTA 
               
               
                   
               
               
                 [spacer (SEQ ID NO: 362)][J43 MP007 2001 (SEQ ID NO: 1011)] amino acid sequence: 
               
               
                 (SEQ ID NO: 527) 
                   
               
               
                 [QGQSGQG][TIPRCGQHPKCKDTLGGGSSGGSISSGLLSGRSDNHGGGSYELTQPPSASVNVG 
                   
               
               
                 ETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPERISGSSSGTTATLTIRDVRA 
               
               
                 EDEGDYYCFSGYVDSDSKLYVFGSGTQLTVL] 
               
               
                   
               
               
                 J43 MP007 2001 amino acid sequence: 
               
               
                 (SEQ ID NO: 1083) 
                   
               
               
                 TIPRCGQHPKCKDTLGGGSSGGSISSGLLSGRSDNHGGGSYELTQPPSASVNVGETVKITCSGD 
                   
               
               
                 QLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPERISGSSSGTTATLTIRDVRAEDEGDYYCFS 
               
               
                 GYVDSDSKLYVFGSGTQLTVL 
               
               
                   
               
               
                 [spacer (SEQ ID NO: 918)][J43 MP007 2001 (SEQ ID NO: 1012)] nucleic acid sequence: 
               
               
                 (SEQ ID NO: 528) 
                   
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][ACTATTCCGAGGTGCGGTCAGCATCCGAAGTGCAAGGATA 
                   
               
               
                   
               
               
                 CTTTGGGAGGTGGCTCGAGCGGCGGCTCTATCTCTTCCGGACTGCTGTCCGGCAGATCCGACAA 
               
               
                   
               
               
                 TCACGGCGGAGGCTCTTATGAGCTGACTCAGCCACCTTCAGCATCAGTCAATGTAGGAGAGACT 
               
               
                   
               
               
                 GTCAAAATCACCTGCTCTGGGGACCAATTGCCGAAATATTTTGCAGATTGGTTTCATCAAAGGT 
               
               
                   
               
               
                 CAGACCAGACCATTTTGCAAGTGATATATGATGATAATAAGCGCCCCTCGGGTATCCCTGAAAG 
               
               
                   
               
               
                 AATCTCTGGGTCCAGCTCAGGGACAACAGCCACCTTGACCATCAGAGATGTCCGGGCTGAGGAT 
               
               
                   
               
               
                 GAAGGTGACTATTACTGTTTCTCAGGATATGTTGATAGTGATAGCAAATTGTATGTTTTTGGCA 
               
               
                   
               
               
                 GCGGAACCCAGCTCACCGTCCTA 
               
               
                   
               
               
                 [spacer (SEQ ID NO: 362)][J43 MP008 2001 (SEQ ID NO: 1013)] amino acid sequence: 
               
               
                 (SEQ ID NO: 529) 
                   
               
               
                 [QGQSGQG][ACRICQDHPKTKWNSGGGSSGGSISSGLLSGRSDNHGGGSYELTQPPSASVNVG 
                   
               
               
                 ETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPERISGSSSGTTATLTIRDVRA 
               
               
                 EDEGDYYCFSGYVDSDSKLYVFGSGTQLTVL] 
               
               
                   
               
               
                 J43 MP008 2001 amino acid sequence: 
               
               
                 (SEQ ID NO: 1084) 
                   
               
               
                 ACRICQDHPKTKWNSGGGSSGGSISSGLLSGRSDNHGGGSYELTQPPSASVNVGETVKITCSGD 
                   
               
               
                 QLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPERISGSSSGTTATLTIRDVRAEDEGDYYCFS 
               
               
                 GYVDSDSKLYVFGSGTQLTVL 
               
               
                   
               
               
                 [spacer (SEQ ID NO: 918)][J43 MP008 2001 (SEQ ID NO: 1014)] nucleic acid sequence: 
               
               
                 (SEQ ID NO: 530) 
                   
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][GCGTGCCGTATTTGTCAGGATCATCCTAAGACGAAGTGGA 
                   
               
               
                   
               
               
                 ATTCTGGAGGTGGCTCGAGCGGCGGCTCTATCTCTTCCGGACTGCTGTCCGGCAGATCCGACAA 
               
               
                   
               
               
                 TCACGGCGGAGGCTCTTATGAGCTGACTCAGCCACCTTCAGCATCAGTCAATGTAGGAGAGACT 
               
               
                   
               
               
                 GTCAAAATCACCTGCTCTGGGGACCAATTGCCGAAATATTTTGCAGATTGGTTTCATCAAAGGT 
               
               
                   
               
               
                 CAGACCAGACCATTTTGCAAGTGATATATGATGATAATAAGCGCCCCTCGGGTATCCCTGAAAG 
               
               
                   
               
               
                 AATCTCTGGGTCCAGCTCAGGGACAACAGCCACCTTGACCATCAGAGATGTCCGGGCTGAGGAT 
               
               
                   
               
               
                 GAAGGTGACTATTACTGTTTCTCAGGATATGTTGATAGTGATAGCAAATTGTATGTTTTTGGCA 
               
               
                   
               
               
                 GCGGAACCCAGCTCACCGTCCTA 
               
               
                   
               
               
                 [spacer (SEQ ID NO: 362)][J43 MP009 2001 (SEQ ID NO: 1015)] amino acid sequence: 
               
               
                 (SEQ ID NO: 531) 
                   
               
               
                 [QGQSGQG][LIQCTGNLDHKCKHYGGGSSGGSISSGLLSGRSDNHGGGSYELTQPPSASVNVG 
                   
               
               
                 ETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPERISGSSSGTTATLTIRDVRA 
               
               
                 EDEGDYYCFSGYVDSDSKLYVFGSGTQLTVL] 
               
               
                   
               
               
                 J43 MP009 2001 amino acid sequence: 
               
               
                 (SEQ ID NO: 1085) 
                   
               
               
                 LIQCTGNLDHKCKHYGGGSSGGSISSGLLSGRSDNHGGGSYELTQPPSASVNVGETVKITCSGD 
                   
               
               
                 QLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPERISGSSSGTTATLTIRDVRAEDEGDYYCFS 
               
               
                 GYVDSDSKLYVFGSGTQLTVL 
               
               
                   
               
               
                 [spacer (SEQ ID NO: 918)][J43 MP009 2001 (SEQ ID NO: 1016)] nucleic acid sequence: 
               
               
                 (SEQ ID NO: 532) 
                   
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][CTTATTCAGTGCACTGGTAATCTTGATCATAAGTGCAAGC 
                   
               
               
                   
               
               
                 ATTATGGAGGTGGCTCGAGCGGCGGCTCTATCTCTTCCGGACTGCTGTCCGGCAGATCCGACAA 
               
               
                   
               
               
                 TCACGGCGGAGGCTCTTATGAGCTGACTCAGCCACCTTCAGCATCAGTCAATGTAGGAGAGACT 
               
               
                   
               
               
                 GTCAAAATCACCTGCTCTGGGGACCAATTGCCGAAATATTTTGCAGATTGGTTTCATCAAAGGT 
               
               
                   
               
               
                 CAGACCAGACCATTTTGCAAGTGATATATGATGATAATAAGCGCCCCTCGGGTATCCCTGAAAG 
               
               
                   
               
               
                 AATCTCTGGGTCCAGCTCAGGGACAACAGCCACCTTGACCATCAGAGATGTCCGGGCTGAGGAT 
               
               
                   
               
               
                 GAAGGTGACTATTACTGTTTCTCAGGATATGTTGATAGTGATAGCAAATTGTATGTTTTTGGCA 
               
               
                   
               
               
                 GCGGAACCCAGCTCACCGTCCT 
               
               
                   
               
               
                 [spacer (SEQ ID NO: 362)][J43 MP010 2001 (SEQ ID NO: 1017)] amino acid sequence: 
               
               
                 (SEQ ID NO: 533) 
                   
               
               
                 [QGQSGQG][IPCHHSADHKHKCTSGGGSSGGSISSGLLSGRSDNHGGGSYELTQPPSASVNVG 
                   
               
               
                 ETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPERISGSSSGTTATLTIRDVRA 
               
               
                 EDEGDYYCFSGYVDSDSKLYVFGSGTQLTVL] 
               
               
                   
               
               
                 J43 MP010 2001 amino acid sequence: 
               
               
                 (SEQ ID NO: 1086) 
                   
               
               
                 IPCHHSADHKHKCTSGGGSSGGSISSGLLSGRSDNHGGGSYELTQPPSASVNVGETVKITCSGD 
                   
               
               
                 QLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPERISGSSSGTTATLTIRDVRAEDEGDYYCFS 
               
               
                 GYVDSDSKLYVFGSGTQLTVL 
               
               
                   
               
               
                 [spacer (SEQ ID NO: 918)][J43 MP010 2001 (SEQ ID NO: 1018)] nucleic acid sequence: 
               
               
                 (SEQ ID NO: 534) 
                   
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][ATTCCTTGCCATCATAGTGCTGATCATAAGCATAAGTGCA 
                   
               
               
                   
               
               
                 CGAGTGGAGGTGGCTCGAGCGGCGGCTCTATCTCTTCCGGACTGCTGTCCGGCAGATCCGACAA 
               
               
                   
               
               
                 TCACGGCGGAGGCTCTTATGAGCTGACTCAGCCACCTTCAGCATCAGTCAATGTAGGAGAGACT 
               
               
                   
               
               
                 GTCAAAATCACCTGCTCTGGGGACCAATTGCCGAAATATTTTGCAGATTGGTTTCATCAAAGGT 
               
               
                   
               
               
                 CAGACCAGACCATTTTGCAAGTGATATATGATGATAATAAGCGCCCCTCGGGTATCCCTGAAAG 
               
               
                   
               
               
                 AATCTCTGGGTCCAGCTCAGGGACAACAGCCACCTTGACCATCAGAGATGTCCGGGCTGAGGAT 
               
               
                   
               
               
                 GAAGGTGACTATTACTGTTTCTCAGGATATGTTGATAGTGATAGCAAATTGTATGTTTTTGGCA 
               
               
                   
               
               
                 GCGGAACCCAGCTCACCGTCCTA 
               
               
                   
               
               
                 [spacer (SEQ ID NO: 362)][J43 MP011 2001 (SEQ ID NO: 1019)] amino acid sequence: 
               
               
                 (SEQ ID NO: 535) 
                   
               
               
                 [QGQSGQG][SRQICADYNCHNKYKGGGSSGGSISSGLLSGRSDNHGGGSYELTQPPSASVNVG 
                   
               
               
                 ETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPERISGSSSGTTATLTIRDVRA 
               
               
                 EDEGDYYCFSGYVDSDSKLYVFGSGTQLTVL] 
               
               
                   
               
               
                 J43 MP011 2001 amino acid sequence: 
               
               
                 (SEQ ID NO: 1087) 
                   
               
               
                 SRQICADYNCHNKYKGGGSSGGSISSGLLSGRSDNHGGGSYELTQPPSASVNVGETVKITCSGD 
                   
               
               
                 QLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPERISGSSSGTTATLTIRDVRAEDEGDYYCFS 
               
               
                 GYVDSDSKLYVFGSGTQLTVL 
               
               
                   
               
               
                 [spacer (SEQ ID NO: 918)][J43 MP011 2001 (SEQ ID NO: 1020)] nucleic acid sequence: 
               
               
                 (SEQ ID NO: 536) 
                   
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][TCGCGGCAGATTTGCGCTGATTATAATTGCCATAATAAGT 
                   
               
               
                   
               
               
                 ATAAGGGAGGTGGCTCGAGCGGCGGCTCTATCTCTTCCGGACTGCTGTCCGGCAGATCCGACAA 
               
               
                   
               
               
                 TCACGGCGGAGGCTCTTATGAGCTGACTCAGCCACCTTCAGCATCAGTCAATGTAGGAGAGACT 
               
               
                   
               
               
                 GTCAAAATCACCTGCTCTGGGGACCAATTGCCGAAATATTTTGCAGATTGGTTTCATCAAAGGT 
               
               
                   
               
               
                 CAGACCAGACCATTTTGCAAGTGATATATGATGATAATAAGCGCCCCTCGGGTATCCCTGAAAG 
               
               
                   
               
               
                 AATCTCTGGGTCCAGCTCAGGGACAACAGCCACCTTGACCATCAGAGATGTCCGGGCTGAGGAT 
               
               
                   
               
               
                 GAAGGTGACTATTACTGTTTCTCAGGATATGTTGATAGTGATAGCAAATTGTATGTTTTTGGCA 
               
               
                   
               
               
                 GCGGAACCCAGCTCACCGTCCTA 
               
               
                   
               
               
                 [spacer (SEQ ID NO: 362)][J43 MP012 2001 (SEQ ID NO: 1021)] amino acid sequence: 
               
               
                 (SEQ ID NO: 537) 
                   
               
               
                 [QGQSGQG][QPCNPQIDHKIKCIYGGGSSGGSISSGLLSGRSDNHGGGSYELTQPPSASVNVG 
                   
               
               
                 ETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPERISGSSSGTTATLTIRDVRA 
               
               
                 EDEGDYYCFSGYVDSDSKLYVFGSGTQLTVL 
               
               
                   
               
               
                 J43 MP012 2001 amino acid sequence: 
               
               
                 (SEQ ID NO: 1088) 
                   
               
               
                 QPCNPQIDHKIKCIYGGGSSGGSISSGLLSGRSDNHGGGSYELTQPPSASVNVGETVKITCSGD 
                   
               
               
                 QLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPERISGSSSGTTATLTIRDVRAEDEGDYYCFS 
               
               
                 GYVDSDSKLYVFGSGTQLTVL 
               
               
                   
               
               
                 [spacer (SEQ ID NO: 918)][J43 MP012 2001 (SEQ ID NO: 1022)] nucleic acid sequence: 
               
               
                 (SEQ ID NO: 538) 
                   
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][CAGCCTTGCAATCCGCAGATTGATCATAAGATTAAGTGCA 
                   
               
               
                   
               
               
                 TTTATGGAGGTGGCTCGAGCGGCGGCTCTATCTCTTCCGGACTGCTGTCCGGCAGATCCGACAA 
               
               
                   
               
               
                 TCACGGCGGAGGCTCTTATGAGCTGACTCAGCCACCTTCAGCATCAGTCAATGTAGGAGAGACT 
               
               
                   
               
               
                 GTCAAAATCACCTGCTCTGGGGACCAATTGCCGAAATATTTTGCAGATTGGTTTCATCAAAGGT 
               
               
                   
               
               
                 CAGACCAGACCATTTTGCAAGTGATATATGATGATAATAAGCGCCCCTCGGGTATCCCTGAAAG 
               
               
                   
               
               
                 AATCTCTGGGTCCAGCTCAGGGACAACAGCCACCTTGACCATCAGAGATGTCCGGGCTGAGGAT 
               
               
                   
               
               
                 GAAGGTGACTATTACTGTTTCTCAGGATATGTTGATAGTGATAGCAAATTGTATGTTTTTGGCA 
               
               
                   
               
               
                 GCGGAACCCAGCTCACCGTCCTA 
               
               
                   
               
               
                 [spacer (SEQ ID NO: 362)][J43 MP013 2001 (SEQ ID NO: 1023)] amino acid sequence: 
               
               
                 (SEQ ID NO: 539) 
                   
               
               
                 [QGQSGQG][HYTICMTHNKCKDMAGGGSSGGSISSGLLSGRSDNHGGGSYELTQPPSASVNVG 
                   
               
               
                 ETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPERISGSSSGTTATLTIRDVRA 
               
               
                 EDEGDYYCFSGYVDSDSKLYVFGSGTQLTVL] 
               
               
                   
               
               
                 J43 MP013 2001 amino acid sequence: 
               
               
                 (SEQ ID NO: 1089) 
                   
               
               
                 HYTICMTHNKCKDMAGGGSSGGSISSGLLSGRSDNHGGGSYELTQPPSASVNVGETVKITCSGD 
                   
               
               
                 QLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPERISGSSSGTTATLTIRDVRAEDEGDYYCFS 
               
               
                 GYVDSDSKLYVFGSGTQLTVL 
               
               
                   
               
               
                 [spacer (SEQ ID NO: 918)][J43 MP013 2001 (SEQ ID NO: 1024)] nucleic acid sequence: 
               
               
                 (SEQ ID NO: 540) 
                   
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][CATTATACTATTTGCATGACGCATAATAAGTGCAAGGATA 
                   
               
               
                   
               
               
                 TGGCGGGAGGTGGCTCGAGCGGCGGCTCTATCTCTTCCGGACTGCTGTCCGGCAGATCCGACAA 
               
               
                   
               
               
                 TCACGGCGGAGGCTCTTATGAGCTGACTCAGCCACCTTCAGCATCAGTCAATGTAGGAGAGACT 
               
               
                   
               
               
                 GTCAAAATCACCTGCTCTGGGGACCAATTGCCGAAATATTTTGCAGATTGGTTTCATCAAAGGT 
               
               
                   
               
               
                 CAGACCAGACCATTTTGCAAGTGATATATGATGATAATAAGCGCCCCTCGGGTATCCCTGAAAG 
               
               
                   
               
               
                 AATCTCTGGGTCCAGCTCAGGGACAACAGCCACCTTGACCATCAGAGATGTCCGGGCTGAGGAT 
               
               
                   
               
               
                 GAAGGTGACTATTACTGTTTCTCAGGATATGTTGATAGTGATAGCAAATTGTATGTTTTTGGCA 
               
               
                   
               
               
                 GCGGAACCCAGCTCACCGTCCTA 
               
               
                   
               
               
                 [spacer (SEQ ID NO: 362)][J43 MP014 2001 (SEQ ID NO: 1025)] amino acid sequence: 
               
               
                 (SEQ ID NO: 541) 
                   
               
               
                 [QGQSGQG[]ANSCLAVEHKCKHNYGGGSSGGSISSGLLSGRSDNHGGGSYELTQPPSASVNVG 
                   
               
               
                 ETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPERISGSSSGTTATLTIRDVRA 
               
               
                 EDEGDYYCFSGYVDSDSKLYVFGSGTQLTVL] 
               
               
                   
               
               
                 J43 MP014 2001 amino acid sequence: 
               
               
                 (SEQ ID NO: 1090) 
                   
               
               
                 ANSCLAVEHKCKHNYGGGSSGGSISSGLLSGRSDNHGGGSYELTQPPSASVNVGETVKITCSGD 
                   
               
               
                 QLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPERISGSSSGTTATLTIRDVRAEDEGDYYCFS 
               
               
                 GYVDSDSKLYVFGSGTQLTVL 
               
               
                   
               
               
                 [spacer (SEQ ID NO: 918)][J43 MP014 2001 (SEQ ID NO: 1026)] nucleic acid sequence: 
               
               
                 (SEQ ID NO: 542) 
                   
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][GCTAATAGTTGCCTTGCTGTTGAGCATAAGTGCAAGCATA 
                   
               
               
                   
               
               
                 ATTATGGAGGTGGCTCGAGCGGCGGCTCTATCTCTTCCGGACTGCTGTCCGGCAGATCCGACAA 
               
               
                   
               
               
                 TCACGGCGGAGGCTCTTATGAGCTGACTCAGCCACCTTCAGCATCAGTCAATGTAGGAGAGACT 
               
               
                   
               
               
                 GTCAAAATCACCTGCTCTGGGGACCAATTGCCGAAATATTTTGCAGATTGGTTTCATCAAAGGT 
               
               
                   
               
               
                 CAGACCAGACCATTTTGCAAGTGATATATGATGATAATAAGCGCCCCTCGGGTATCCCTGAAAG 
               
               
                   
               
               
                 AATCTCTGGGTCCAGCTCAGGGACAACAGCCACCTTGACCATCAGAGATGTCCGGGCTGAGGAT 
               
               
                   
               
               
                 GAAGGTGACTATTACTGTTTCTCAGGATATGTTGATAGTGATAGCAAATTGTATGTTTTTGGCA 
               
               
                   
               
               
                 GCGGAACCCAGCTCACCGTCCTA 
               
            
           
         
       
     
     Reformatted Anti-Mouse PD-1 Heavy and Light Chains: 
       
     
       
         
           
               
            
               
                 J43v2 light chain (LC) amino acid sequence: 
               
               
                 (SEQ ID NO: 543) 
               
               
                 YELTQPPSASVNVGETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDN 
               
               
                   
               
               
                 KRPSGIPERISGSSSGTTATLTIRDVRAEDEGDYYCFSGYVDSDSKLYVF 
               
               
                   
               
               
                 GSGTQLTVLGGPKSSPKVTVFPPSPEELRTNKATLVCLVNDFYPGSATVT 
               
               
                   
               
               
                 WKANGATINDGVKTTKPSKQGQNYMTSSYLSLTADQWKSHNRVSCQVTHE 
               
               
                   
               
               
                 GETVEKSLSPAECL 
               
               
                   
               
               
                 J43v2 LC nucleotide sequence 1: 
               
               
                 (SEQ ID NO: 544) 
               
               
                 TATGAGCTGACTCAGCCACCTTCAGCATCAGTCAATGTAGGAGAGACTGT 
               
               
                   
               
               
                 CAAAATCACCTGCTCTGGGGACCAATTGCCGAAATATTTTGCAGATTGGT 
               
               
                   
               
               
                 TTCATCAAAGGTCAGACCAGACCATTTTGCAAGTGATATATGATGATAAT 
               
               
                   
               
               
                 AAGCGCCCCTCGGGTATCCCTGAAAGAATCTCTGGGTCCAGCTCAGGGAC 
               
               
                   
               
               
                 AACAGCCACCTTGACCATCAGAGATGTCCGGGCTGAGGATGAAGGTGACT 
               
               
                   
               
               
                 ATTACTGTTTCTCAGGATATGTTGATAGTGATAGCAAATTGTATGTTTTT 
               
               
                   
               
               
                 GGCAGCGGAACCCAGCTCACCGTCCTAGGTGGACCCAAGTCTTCTCCCAA 
               
               
                   
               
               
                 AGTCACAGTGTTTCCACCTTCACCTGAGGAGCTCCGGACAAACAAAGCCA 
               
               
                   
               
               
                 CACTGGTGTGTCTGGTTAATGACTTCTACCCGGGTTCTGCAACAGTGACC 
               
               
                   
               
               
                 TGGAAGGCAAATGGAGCAACTATCAATGATGGGGTGAAGACTACAAAGCC 
               
               
                   
               
               
                 TTCCAAACAGGGCCAAAACTACATGACCAGCAGCTACCTAAGTTTGACAG 
               
               
                   
               
               
                 CAGACCAGTGGAAATCTCACAACAGGGTTTCCTGCCAAGTTACCCATGAA 
               
               
                   
               
               
                 GGGGAAACTGTGGAGAAGAGTTTGTCCCCTGCAGAATGTCTT 
               
               
                   
               
               
                 J43v2 LC nucleotide sequence 2: 
               
               
                 (SEQ ID NO: 545) 
               
               
                 TACGAGCTGACCCAGCCTCCTAGCGCCTCCGTGAATGTGGGCGAGACAGT 
               
               
                   
               
               
                 GAAGATCACCTGTAGCGGCGACCAGCTGCCCAAGTACTTCGCCGACTGGT 
               
               
                   
               
               
                 TCCACCAGCGGAGCGACCAGACAATCCTGCAAGTGATCTACGACGACAAC 
               
               
                   
               
               
                 AAGCGGCCCAGCGGCATCCCCGAGAGAATCAGCGGAAGCAGCAGCGGCAC 
               
               
                   
               
               
                 CACCGCCACCCTGACCATTAGAGATGTGCGGGCCGAGGACGAGGGCGACT 
               
               
                   
               
               
                 ACTACTGCTTTAGCGGCTACGTGGACAGCGACAGCAAGCTGTACGTGTTC 
               
               
                   
               
               
                 GGCTCCGGTACCCAGCTGACAGTGCTGGGCGGACCTAAGAGCAGCCCCAA 
               
               
                   
               
               
                 AGTGACCGTGTTCCCCCCAAGCCCCGAGGAACTGAGGACCAACAAGGCCA 
               
               
                   
               
               
                 CCCTCGTGTGCCTCGTGAACGACTTCTACCCTGGCAGCGCCACCGTGACC 
               
               
                   
               
               
                 TGGAAAGCCAATGGCGCCACCATCAACGACGGCGTGAAAACCACCAAGCC 
               
               
                   
               
               
                 CAGCAAGCAGGGCCAGAACTACATGACCAGCAGCTACCTGAGCCTGACCG 
               
               
                   
               
               
                 CCGACCAGTGGAAGTCCCACAACAGAGTGTCCTGCCAAGTGACCCACGAG 
               
               
                   
               
               
                 GGGGAAACCGTGGAAAAGAGCCTGAGCCCTGCCGAGTGCCTG 
               
               
                   
               
               
                 J43v2 mIgG2a heavy chain (HC) amino acid sequence: 
               
               
                 (SEQ ID NO: 546) 
               
               
                 EVRLLESGGGLVKPEGSLKLSCVASGFTFSDYFMSWVRQAPGKGLEWVAH 
               
               
                   
               
               
                 IYTKSYNYATYYSGSVKGRFTISRDDSRSMVYLQMNNLRTEDTATYYCTR 
               
               
                   
               
               
                 DGSGYPSLDFWGQGTQVTVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLV 
               
               
                   
               
               
                 KGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQS 
               
               
                   
               
               
                 ITCNVAHPASSTKVDKKIEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPK 
               
               
                   
               
               
                 IKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDY 
               
               
                   
               
               
                 NSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAP 
               
               
                   
               
               
                 QVYVLPPPEEEMTKKQVILTCMVTDPMPEDIYVEWINNGKTELNYKNTEP 
               
               
                   
               
               
                 VLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPG 
               
               
                   
               
               
                 K 
               
               
                   
               
               
                 J43v2 mIgG2a HC nucleic acid sequence: 
               
               
                 (SEQ ID NO: 547) 
               
               
                 GAGGTGCGGCTTCTGGAGTCTGGTGGAGGATTAGTGAAGCCTGAGGGGTC 
               
               
                   
               
               
                 ACTGAAACTCTCCTGTGTGGCCTCTGGATTCACCTTCAGTGACTATTTCA 
               
               
                   
               
               
                 TGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTTGCTCAC 
               
               
                   
               
               
                 ATATACACGAAAAGTTATAATTATGCAACTTATTACTCGGGTTCGGTGAA 
               
               
                   
               
               
                 AGGCAGATTCACCATCTCCAGAGATGATTCCCGAAGCATGGTCTACCTGC 
               
               
                   
               
               
                 AAATGAACAACCTGAGAACTGAGGACACGGCCACTTATTACTGTACAAGA 
               
               
                   
               
               
                 GATGGAAGCGGATATCCCTCTCTGGATTTCTGGGGTCAAGGGACCCAAGT 
               
               
                   
               
               
                 CACTGTCTCCTCAGCTAAAACAACAGCCCCATCGGTCTATCCACTGGCCC 
               
               
                   
               
               
                 CTGTGTGTGGAGATACAACTGGCTCCTCGGTGACTCTAGGATGCCTGGTC 
               
               
                   
               
               
                 AAGGGTTATTTCCCTGAGCCAGTGACCTTGACCTGGAACTCTGGATCCCT 
               
               
                   
               
               
                 GTCCAGTGGTGTGCACACCTTCCCAGCTGTCCTGCAGTCTGACCTCTACA 
               
               
                   
               
               
                 CCCTCAGCAGCTCAGTGACTGTAACCTCGAGCACCTGGCCCAGCCAGTCC 
               
               
                   
               
               
                 ATCACCTGCAATGTGGCCCACCCGGCAAGCAGCACCAAGGTGGACAAGAA 
               
               
                   
               
               
                 AATTGAGCCCAGAGGGCCCACAATCAAGCCCTGTCCTCCATGCAAATGCC 
               
               
                   
               
               
                 CAGCACCTAACCTCTTGGGTGGACCATCCGTCTTCATCTTCCCTCCAAAG 
               
               
                   
               
               
                 ATCAAGGATGTACTCATGATCTCCCTGAGCCCCATAGTCACATGTGTGGT 
               
               
                   
               
               
                 GGTGGATGTGAGCGAGGATGACCCAGATGTCCAGATCAGCTGGTTTGTGA 
               
               
                   
               
               
                 ACAACGTGGAAGTACACACAGCTCAGACACAAACCCATAGAGAGGATTAC 
               
               
                   
               
               
                 AACAGTACTCTCCGGGTGGTCAGTGCCCTCCCCATCCAGCACCAGGACTG 
               
               
                   
               
               
                 GATGAGTGGCAAGGAGTTCAAATGCAAGGTCAACAACAAAGACCTCCCAG 
               
               
                   
               
               
                 CGCCCATCGAGAGAACCATCTCAAAACCCAAAGGGTCAGTAAGAGCTCCA 
               
               
                   
               
               
                 CAGGTATATGTCTTGCCTCCACCAGAAGAAGAGATGACTAAGAAACAGGT 
               
               
                   
               
               
                 CACTCTGACCTGCATGGTCACAGACTTCATGCCTGAAGACATTTACGTGG 
               
               
                   
               
               
                 AGTGGACCAACAACGGGAAAACAGAGCTAAACTACAAGAACACTGAACCA 
               
               
                   
               
               
                 GTCCTGGACTCTGATGGTTCTTACTTCATGTACAGCAAGCTGAGAGTGGA 
               
               
                   
               
               
                 AAAGAAGAACTGGGTGGAAAGAAATAGCTACTCCTGTTCAGTGGTCCACG 
               
               
                   
               
               
                 AGGGTCTGCACAATCACCACACGACTAAGAGCTTCTCCCGGACTCCGGGT 
               
               
                   
               
               
                 AAA 
               
            
           
         
       
     
     Example 16: Activatable Anti-mPD-1 Antibodies with a Range of Masking Efficiencies 
     This example describes the modulation of anti-mPD-1 antibody masking efficiencies by masking moiety truncation and single amino-acid substitution. 
     Four J43 activatable antibodies were selected to generate families of activatable anti-mPD-1 antibodies by masking moiety truncation or amino acid substitution of one or more MM residues. Table 18 lists the designed MMs. Activatable J43v2 antibodies with the designed MM and 2001 substrate were produced by transfection of 30 mL HEK293 cells and selected activatable antibodies (sequences MPtrunc ELISA activatable antibody LCs) were evaluated for masking by ELISA as described in Example 15 ( FIG. 23 ). 
     In some embodiments, the activatable antibody also includes a spacer sequence. In some embodiments, the spacer is joined directly to the MM of the activatable antibody. In some embodiments, the spacer is joined directly to the MM of the activatable antibody in the structural arrangement from N-terminus to C-terminus of spacer-MM-CM-AB. In some embodiments, the spacer joined directly to the N-terminus of MM of the activatable antibody is selected from the group consisting of QGQSGQG (SEQ ID NO: 362), QGQSGQ (SEQ ID NO: 913), QGQSG (SEQ ID NO: 914), QGQS (SEQ ID NO: 915), QGQ (SEQ ID NO: 916), QG (SEQ ID NO: 917), and Q. In some embodiments, the spacer includes at least the amino acid sequence QGQSGQG (SEQ ID NO: 362). In some embodiments, the spacer includes at least the amino acid sequence QGQSGQ (SEQ ID NO: 913). In some embodiments, the spacer includes at least the amino acid sequence QGQSG (SEQ ID NO: 914). In some embodiments, the spacer includes at least the amino acid sequence QGQS (SEQ ID NO: 915). In some embodiments, the spacer includes at least the amino acid sequence QGQ (SEQ ID NO: 916). In some embodiments, the spacer includes at least the amino acid sequence QG (SEQ ID NO: 917). In some embodiments, the spacer includes at least the amino acid residue Q. In some embodiments, the activatable antibody does not include a spacer sequence. 
     While the sequences shown below include the spacer sequence of SEQ ID NO: 362, those of ordinary skill in the art appreciate that the activatable anti-PD-1 antibodies of the disclosure can include any suitable spacer sequence, such as, for example, a spacer sequence selected from the group consisting of QGQSGQG (SEQ ID NO: 362), QGQSGQ (SEQ ID NO: 913), QGQSG (SEQ ID NO: 914), QGQS (SEQ ID NO: 915), QGQ (SEQ ID NO: 916), QG (SEQ ID NO: 917), and Q. While the sequences shown below include the spacer sequence of SEQ ID NO: 362, those of ordinary skill in the art will also appreciate that activatable anti-PD-1 antibodies of the disclosure in some embodiments do not include a spacer sequence. 
     
       
         
           
               
             
               
                 TABLE 18 
               
             
            
               
                   
               
               
                 Masking moiety sequences 
               
            
           
           
               
               
               
               
            
               
                   
                 Mask 
                 Amino Acid Sequence 
                 SEQ ID NO: 
               
               
                   
               
               
                   
                 MP8-1 
                 QDHPKTKWNS 
                 548 
               
               
                   
               
               
                   
                 MP8-2 
                 ACRICQDHPATKWNS 
                 549 
               
               
                   
               
               
                   
                 MP8-3 
                 ACRICQDHPKTAWNS 
                 550 
               
               
                   
               
               
                   
                 MP8-4 
                 ACRICQDAPKTKWNS 
                 551 
               
               
                   
               
               
                   
                 MP8-5 
                 ACRICQDHAKTKWNS 
                 552 
               
               
                   
               
               
                   
                 MP8-6 
                 DHPATKWNS 
                 553 
               
               
                   
               
               
                   
                 MP8-7 
                 DHPKTAWNS 
                 554 
               
               
                   
               
               
                   
                 MP8-8 
                 DAPKTKWNS 
                 555 
               
               
                   
               
               
                   
                 MP8-9 
                 DAPATKWNS 
                 556 
               
               
                   
               
               
                   
                 MP8-10 
                 ACRICQDHP 
                 557 
               
               
                   
               
               
                   
                 MP7-1 
                 HPQSKDTL 
                 558 
               
               
                   
               
               
                   
                 MP7-2 
                 HPKSQDTL 
                 559 
               
               
                   
               
               
                   
                 MP7-3 
                 TIPRCGQHPLCLDTL 
                 560 
               
               
                   
               
               
                   
                 MP7-4 
                 HPLSLDTL 
                 561 
               
               
                   
               
               
                   
                 MP7-5 
                 HPASKDTL 
                 562 
               
               
                   
               
               
                   
                 MP7-6 
                 HPKSADTL 
                 563 
               
               
                   
               
               
                   
                 MP5-1 
                 PGNCHPLQKELCQFI 
                 564 
               
               
                   
               
               
                   
                 MP5-2 
                 HPLQKELAQFI 
                 565 
               
               
                   
               
               
                   
                 MP5-3 
                 HPLALELAQFI 
                 566 
               
               
                   
               
               
                   
                 MP5-4 
                 PGNCHPLQLELCQFI 
                 567 
               
               
                   
               
               
                   
                 MP3-1 
                 TNIWSCQTYCDHAHA 
                 568 
               
               
                   
               
               
                   
                 MP3-2 
                 TNIWSCQTYCDHAHL 
                 569 
               
               
                   
               
               
                   
                 MP3-3 
                 TNIWSCQTYCDHLHA 
                 570 
               
               
                   
               
               
                   
                 MP3-4 
                 TNIWSCQTYCDHKHA 
                 571 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
            
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [J43 MP5-2 2001 (SEQ ID NO: 1027)]  
               
               
                 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 572) 
               
               
                 [QGQSGQG][HPLQKELAQFIGGGSSGGSISSGLLSGRSDNHGGGSYE 
               
               
                   
               
               
                 LTQPPSASVNVGETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDNK 
               
               
                   
               
               
                 RPSGIPERISGSSSGTTATLTIRDVRAEDEGDYYCFSGYVDSDSKLYV 
               
               
                   
               
               
                 FGSGTQLTVL] 
               
               
                   
               
               
                 J43 MP5-2 2001 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1113) 
               
               
                 HPLQKELAQFIGGGSSGGSISSGLLSGRSDNHGGGSYELTQPPSASVNVG 
               
               
                   
               
               
                 ETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPERISGSS 
               
               
                   
               
               
                 SGTTATLTIRDVRAEDEGDYYCFSGYVDSDSKLYVFGSGTQLTVL 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)] 
               
               
                 [J43 MP5-2 2001 (SEQ ID NO: 1038)]  
               
               
                 Nucleic Acid Sequence:  
               
               
                 (SEQ ID NO: 573) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][CATCCTCTGCAGAAGGAGCTGGCCCA 
               
               
                   
               
               
                 GTTTATTGGAGGTGGCTCGAGCGGCGGCTCTATCTCTTCCGGACTGCTGT 
               
               
                   
               
               
                 CCGGCAGATCCGACAATCACGGCGGAGGCTCTTACGAGCTGACCCAGCCT 
               
               
                   
               
               
                 CCTAGCGCCTCCGTGAATGTGGGCGAGACAGTGAAGATCACCTGTAGCGG 
               
               
                   
               
               
                 CGACCAGCTGCCCAAGTACTTCGCCGACTGGTTCCACCAGCGGAGCGACC 
               
               
                   
               
               
                 AGACAATCCTGCAAGTGATCTACGACGACAACAAGCGGCCCAGCGGCATC 
               
               
                   
               
               
                 CCCGAGAGAATCAGCGGAAGCAGCAGCGGCACCACCGCCACCCTGACCAT 
               
               
                   
               
               
                 TAGAGATGTGCGGGCCGAGGACGAGGGCGACTACTACTGCTTTAGCGGCT 
               
               
                   
               
               
                 ACGTGGACAGCGACAGCAAGCTGTACGTGTTCGGCTCCGGTACCCAGCTG 
               
               
                   
               
               
                 ACAGTGCTGGGCGGACCTAAGAGCAGCCCCAAAGTGACCGTGTTCCCCCC 
               
               
                   
               
               
                 AAGCCCCGAGGAACTGAGGACCAACAAGGCCACCCTCGTGTGCCTCGTGA 
               
               
                   
               
               
                 ACGACTTCTACCCTGGCAGCGCCACCGTGACCTGGAAAGCCAATGGCGCC 
               
               
                   
               
               
                 ACCATCAACGACGGCGTGAAAACCACCAAGCCCAGCAAGCAGGGCCAGAA 
               
               
                   
               
               
                 CTACATGACCAGCAGCTACCTGAGCCTGACCGCCGACCAGTGGAAGTCCC 
               
               
                   
               
               
                 ACAACAGAGTGTCCTGCCAAGTGACCCACGAGGGGGAAACCGTGGAAAAG 
               
               
                   
               
               
                 AGCCTGAGCCCTGCCGAGTGCCTG 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [J43 MP7-1 2001 (SEQ ID NO: 1039)]  
               
               
                 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 574) 
               
               
                 [QGQSGQG][HPQSKDTLGGGSSGGSISSGLLSGRSDNHGGGSYELTQPP 
               
               
                   
               
               
                 SASVNVGETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDNKRPSGIP 
               
               
                   
               
               
                 ERISGSSSGTTATLTIRDVRAEDEGDYYCFSGYVDSDSKLYVFGSGTQLT 
               
               
                   
               
               
                 VL] 
               
               
                   
               
               
                 J43 MP7-1 2001 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1114) 
               
               
                 HPQSKDTLGGGSSGGSISSGLLSGRSDNHGGGSYELTQPPSASVNVGETV 
               
               
                   
               
               
                 KITCSGDQLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPERISGSSSGT 
               
               
                   
               
               
                 TATLTIRDVRAEDEGDYYCFSGYVDSDSKLYVFGSGTQLTVL 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)] 
               
               
                 [J43 MP7-1 2001 (SEQ ID NO: 2062  
               
               
                 Nucleic Acid Sequence:  
               
               
                 (SEQ ID NO: 575) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][CATCCGCAGTCTAAGGATACTTTGGG 
               
               
                   
               
               
                 AGGTGGCTCGAGCGGCGGCTCTATCTCTTCCGGACTGCTGTCCGGCAGAT 
               
               
                   
               
               
                 CCGACAATCACGGCGGAGGCTCTTACGAGCTGACCCAGCCTCCTAGCGCC 
               
               
                   
               
               
                 TCCGTGAATGTGGGCGAGACAGTGAAGATCACCTGTAGCGGCGACCAGCT 
               
               
                   
               
               
                 GCCCAAGTACTTCGCCGACTGGTTCCACCAGCGGAGCGACCAGACAATCC 
               
               
                   
               
               
                 TGCAAGTGATCTACGACGACAACAAGCGGCCCAGCGGCATCCCCGAGAGA 
               
               
                   
               
               
                 ATCAGCGGAAGCAGCAGCGGCACCACCGCCACCCTGACCATTAGAGATGT 
               
               
                   
               
               
                 GCGGGCCGAGGACGAGGGCGACTACTACTGCTTTAGCGGCTACGTGGACA 
               
               
                   
               
               
                 GCGACAGCAAGCTGTACGTGTTCGGCTCCGGTACCCAGCTGACAGTGCTG 
               
               
                   
               
               
                 GGCGGACCTAAGAGCAGCCCCAAAGTGACCGTGTTCCCCCCAAGCCCCGA 
               
               
                   
               
               
                 GGAACTGAGGACCAACAAGGCCACCCTCGTGTGCCTCGTGAACGACTTCT 
               
               
                   
               
               
                 ACCCTGGCAGCGCCACCGTGACCTGGAAAGCCAATGGCGCCACCATCAAC 
               
               
                   
               
               
                 GACGGCGTGAAAACCACCAAGCCCAGCAAGCAGGGCCAGAACTACATGAC 
               
               
                   
               
               
                 CAGCAGCTACCTGAGCCTGACCGCCGACCAGTGGAAGTCCCACAACAGAG 
               
               
                   
               
               
                 TGTCCTGCCAAGTGACCCACGAGGGGGAAACCGTGGAAAAGAGCCTGAGC 
               
               
                   
               
               
                 CCTGCCGAGTGCCTG 
               
            
           
         
       
     
     MPtrunc ELISA Activatable Antibody LCs: 
       
     
       
         
           
               
            
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [J43 MP7-5 2001 (SEQ ID NO: 1115)]  
               
               
                 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 576) 
               
               
                 [QGQSGQG][HPASKDTLGGGSSGGSISSGLLSGRSDNHGGGSYELTQPP 
               
               
                   
               
               
                 SASVNVGETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDNKRPSGIP 
               
               
                   
               
               
                 ERISGSSSGTTATLTIRDVRAEDEGDYYCFSGYVDSDSKLYVFGSGTQLT 
               
               
                   
               
               
                 VL] 
               
               
                   
               
               
                 J43 MP7-5 2001 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1115) 
               
               
                 HPASKDTLGGGSSGGSISSGLLSGRSDNHGGGSYELTQPPSASVNVGETV 
               
               
                   
               
               
                 KITCSGDQLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPERISGSSSGT 
               
               
                   
               
               
                 TATLTIRDVRAEDEGDYYCFSGYVDSDSKLYVFGSGTQLTVL 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)] 
               
               
                 [J43 MP7-5 2001 (SEQ ID NO: 2061]  
               
               
                 Nucleic Acid Sequence:  
               
               
                 (SEQ ID NO: 577) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][CATCCGGCGTCTAAGGATACTTTGGG 
               
               
                   
               
               
                 AGGTGGCTCGAGCGGCGGCTCTATCTCTTCCGGACTGCTGTCCGGCAGAT 
               
               
                   
               
               
                 CCGACAATCACGGCGGAGGCTCTTACGAGCTGACCCAGCCTCCTAGCGCC 
               
               
                   
               
               
                 TCCGTGAATGTGGGCGAGACAGTGAAGATCACCTGTAGCGGCGACCAGCT 
               
               
                   
               
               
                 GCCCAAGTACTTCGCCGACTGGTTCCACCAGCGGAGCGACCAGACAATCC 
               
               
                   
               
               
                 TGCAAGTGATCTACGACGACAACAAGCGGCCCAGCGGCATCCCCGAGAGA 
               
               
                   
               
               
                 ATCAGCGGAAGCAGCAGCGGCACCACCGCCACCCTGACCATTAGAGATGT 
               
               
                   
               
               
                 GCGGGCCGAGGACGAGGGCGACTACTACTGCTTTAGCGGCTACGTGGACA 
               
               
                   
               
               
                 GCGACAGCAAGCTGTACGTGTTCGGCTCCGGTACCCAGCTGACAGTGCTG 
               
               
                   
               
               
                 GGCGGACCTAAGAGCAGCCCCAAAGTGACCGTGTTCCCCCCAAGCCCCGA 
               
               
                   
               
               
                 GGAACTGAGGACCAACAAGGCCACCCTCGTGTGCCTCGTGAACGACTTCT 
               
               
                   
               
               
                 ACCCTGGCAGCGCCACCGTGACCTGGAAAGCCAATGGCGCCACCATCAAC 
               
               
                   
               
               
                 GACGGCGTGAAAACCACCAAGCCCAGCAAGCAGGGCCAGAACTACATGAC 
               
               
                   
               
               
                 CAGCAGCTACCTGAGCCTGACCGCCGACCAGTGGAAGTCCCACAACAGAG 
               
               
                   
               
               
                 TGTCCTGCCAAGTGACCCACGAGGGGGAAACCGTGGAAAAGAGCCTGAGC 
               
               
                   
               
               
                 CCTGCCGAGTGCCTG 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [J43 MP8-2 2001 (SEQ ID NO: 1032)]  
               
               
                 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 578) 
               
               
                 [QGQSGQG][ACRICQDHPATKWNSGGGSSGGSISSGLLSGRSDNHGGGS 
               
               
                   
               
               
                 YELTQPPSASVNVGETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDN 
               
               
                   
               
               
                 KRPSGIPERISGSSSGTTATLTIRDVRAEDEGDYYCFSGYVDSDSKLYVF 
               
               
                   
               
               
                 GSGTQLTVL] 
               
               
                   
               
               
                 J43 MP8-2 2001 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1116) 
               
               
                 ACRICQDHPATKWNSGGGSSGGSISSGLLSGRSDNHGGGSYELTQPPSAS 
               
               
                   
               
               
                 VNVGETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPERI 
               
               
                   
               
               
                 SGSSSGTTATLTIRDVRAEDEGDYYCFSGYVDSDSKLYVFGSGTQLTVL 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)] J43 MP8-2 2001 (SEQ ID  
               
               
                 NO: 1033)] Nucleic Acid Sequence:  
               
               
                 (SEQ ID NO: 579) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][GCGTGCCGTATTTGTCAGGATCATCC 
               
               
                   
               
               
                 TGCGACGAAGTGGAATTCTGGAGGTGGCTCGAGCGGCGGCTCTATCTCTT 
               
               
                   
               
               
                 CCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGAGGCTCTACGAGC 
               
               
                   
               
               
                 TGACCCAGCCTCCTAGCGCCTCCGTGAATGTGGGCGAGACAGTGAAGATC 
               
               
                   
               
               
                 ACCTGTAGCGGCGACCAGCTGCCCAAGTACTTCGCCGACTGGTTCCACCA 
               
               
                   
               
               
                 GCGGAGCGACCAGACAATCCTGCAAGTGATCTACGACGACAACAAGCGGC 
               
               
                   
               
               
                 CCAGCGGCATCCCCGAGAGAATCAGCGGAAGCAGCAGCGGCACCACCGCC 
               
               
                   
               
               
                 ACCCTGACCATTAGAGATGTGCGGGCCGAGGACGAGGGCGACTACTACTG 
               
               
                   
               
               
                 CTTTAGCGGCTACGTGGACAGCGACAGCAAGCTGTACGTGTTCGGCTCCG 
               
               
                   
               
               
                 GTACCCAGCTGACAGTGCTGGGCGGACCTAAGAGCAGCCCCAAAGTGACC 
               
               
                   
               
               
                 GTGTTCCCCCCAAGCCCCGAGGAACTGAGGACCAACAAGGCCACCCTCGT 
               
               
                   
               
               
                 GTGCCTCGTGAACGACTTCTACCCTGGCAGCGCCACCGTGACCTGGAAAG 
               
               
                   
               
               
                 CCAATGGCGCCACCATCAACGACGGCGTGAAAACCACCAAGCCCAGCAAG 
               
               
                   
               
               
                 CAGGGCCAGAACTACATGACCAGCAGCTACCTGAGCCTGACCGCCGACCA 
               
               
                   
               
               
                 GTGGAAGTCCCACAACAGAGTGTCCTGCCAAGTGACCCACGAGGGGGAAA 
               
               
                   
               
               
                 CCGTGGAAAAGAGCCTGAGCCCTGCCGAGTGCCTG 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [J43 MP8-8 2001 (SEQ ID NO: 1034)]  
               
               
                 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 580) 
               
               
                 [QGQSGQG][DAPKTKWNSGGGSSGGSISSGLLSGRSDNHGGGSYELTQP 
               
               
                   
               
               
                 PSASVNVGETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDNKRPSGI 
               
               
                   
               
               
                 PERISGSSSGTTATLTIRDVRAEDEGDYYCFSGYVDSDSKLYVFGSGTQL 
               
               
                   
               
               
                 TVL] 
               
               
                   
               
               
                 J43 MP8-8 2001 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1117) 
               
               
                 DAPKTKWNSGGGSSGGSISSGLLSGRSDNHGGGSYELTQPPSASVNVGET 
               
               
                   
               
               
                 VKITCSGDQLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPERISGSSSG 
               
               
                   
               
               
                 TTATLTIRDVRAEDEGDYYCFSGYVDSDSKLYVFGSGTQLTVL 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)] J43 MP8-8 2001 (SEQ ID  
               
               
                 NO: 1035)] Nucleic Acid Sequence:  
               
               
                 (SEQ ID NO: 581) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][GATGCTCCTAAGACGAAGTGGAATTC 
               
               
                   
               
               
                 TGGAGGTGGCTCGAGCGGCGGCTCTATCTCTTCCGGACTGCTGTCCGGCA 
               
               
                   
               
               
                 GATCCGACAATCACGGCGGAGGCTCTTACGAGCTGACCCAGCCTCCTAGC 
               
               
                   
               
               
                 GCCTCCGTGAATGTGGGCGAGACAGTGAAGATCACCTGTAGCGGCGACCA 
               
               
                   
               
               
                 GCTGCCCAAGTACTTCGCCGACTGGTTCCACCAGCGGAGCGACCAGACAA 
               
               
                   
               
               
                 TCCTGCAAGTGATCTACGACGACAACAAGCGGCCCAGCGGCATCCCCGAG 
               
               
                   
               
               
                 AGAATCAGCGGAAGCAGCAGCGGCACCACCGCCACCCTGACCATTAGAGA 
               
               
                   
               
               
                 TGTGCGGGCCGAGGACGAGGGCGACTACTACTGCTTTAGCGGCTACGTGG 
               
               
                   
               
               
                 ACAGCGACAGCAAGCTGTACGTGTTCGGCTCCGGTACCCAGCTGACAGTG 
               
               
                   
               
               
                 CTGGGCGGACCTAAGAGCAGCCCCAAAGTGACCGTGTTCCCCCCAAGCCC 
               
               
                   
               
               
                 CGAGGAACTGAGGACCAACAAGGCCACCCTCGTGTGCCTCGTGAACGACT 
               
               
                   
               
               
                 TCTACCCTGGCAGCGCCACCGTGACCTGGAAAGCCAATGGCGCCACCATC 
               
               
                   
               
               
                 AACGACGGCGTGAAAACCACCAAGCCCAGCAAGCAGGGCCAGAACTACAT 
               
               
                   
               
               
                 GACCAGCAGCTACCTGAGCCTGACCGCCGACCAGTGGAAGTCCCACAACA 
               
               
                   
               
               
                 GAGTGTCCTGCCAAGTGACCCACGAGGGGGAAACCGTGGAAAAGAGCCTG 
               
               
                   
               
               
                 AGCCCTGCCGAGTGCCTG 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [J43 MP8-9 2001 (SEQ ID NO: 1036)]  
               
               
                 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 582) 
               
               
                 [QGQSGQG][DAPATKWNSGGGSSGGSISSGLLSGRSDNHGGGSYELTQP 
               
               
                   
               
               
                 PSASVNVGETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDNKRPSGI 
               
               
                   
               
               
                 PERISGSSSGTTATLTIRDVRAEDEGDYYCFSGYVDSDSKLYVFGSGTQL 
               
               
                   
               
               
                 TVL] 
               
               
                   
               
               
                 J43 MP8-9 2001 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1118) 
               
               
                 DAPATKWNSGGGSSGGSISSGLLSGRSDNHGGGSYELTQPPSASVNVGET 
               
               
                   
               
               
                 VKITCSGDQLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPERISGSSSG 
               
               
                   
               
               
                 TTATLTIRDVRAEDEGDYYCFSGYVDSDSKLYVFGSGTQLTVL 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)] 
               
               
                 [J43 MP8-9 2001 (SEQ ID NO: 1037)]  
               
               
                 Nucleic Acid Sequence:  
               
               
                 (SEQ ID NO: 583) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][GATGCTCCTGCGACGAAGTGGAATTC 
               
               
                   
               
               
                 TGGAGGTGGCTCGAGCGGCGGCTCTATCTCTTCCGGACTGCTGTCCGGCA 
               
               
                   
               
               
                 GATCCGACAATCACGGCGGAGGCTCTTACGAGCTGACCCAGCCTCCTAGC 
               
               
                   
               
               
                 GCCTCCGTGAATGTGGGCGAGACAGTGAAGATCACCTGTAGCGGCGACCA 
               
               
                   
               
               
                 GCTGCCCAAGTACTTCGCCGACTGGTTCCACCAGCGGAGCGACCAGACAA 
               
               
                   
               
               
                 TCCTGCAAGTGATCTACGACGACAACAAGCGGCCCAGCGGCATCCCCGAG 
               
               
                   
               
               
                 AGAATCAGCGGAAGCAGCAGCGGCACCACCGCCACCCTGACCATTAGAGA 
               
               
                   
               
               
                 TGTGCGGGCCGAGGACGAGGGCGACTACTACTGCTTTAGCGGCTACGTGG 
               
               
                   
               
               
                 ACAGCGACAGCAAGCTGTACGTGTTCGGCTCCGGTACCCAGCTGACAGTG 
               
               
                   
               
               
                 CTGGGCGGACCTAAGAGCAGCCCCAAAGTGACCGTGTTCCCCCCAAGCCC 
               
               
                   
               
               
                 CGAGGAACTGAGGACCAACAAGGCCACCCTCGTGTGCCTCGTGAACGACT 
               
               
                   
               
               
                 TCTACCCTGGCAGCGCCACCGTGACCTGGAAAGCCAATGGCGCCACCATC 
               
               
                   
               
               
                 AACGACGGCGTGAAAACCACCAAGCCCAGCAAGCAGGGCCAGAACTACAT 
               
               
                   
               
               
                 GACCAGCAGCTACCTGAGCCTGACCGCCGACCAGTGGAAGTCCCACAACA 
               
               
                   
               
               
                 GAGTGTCCTGCCAAGTGACCCACGAGGGGGAAACCGTGGAAAAGAGCCTG 
               
               
                   
               
               
                 AGCCCTGCCGAGTGCCTG 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [J43 MP8-2 2003 (SEQ ID NO: 1119)  
               
               
                 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1120) 
               
               
                 [QGQSGQG][ACRICQDHPATKWNSGGGSSGGSISSGLLSGRSANPRGGGS 
               
               
                   
               
               
                 YELTQPPSASVNVGETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDN 
               
               
                   
               
               
                 KRPSGIPERISGSSSGTTATLTIRDVRAEDEGDYYCFSGYVDSDSKLYVF 
               
               
                   
               
               
                 GSGTQLTVL] 
               
               
                   
               
               
                 J43 MP8-2 2003 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1119) 
               
               
                 ACRICQDHPATKWNSGGGSSGGSISSGLLSGRSANPRGGGSYELTQPPSA 
               
               
                   
               
               
                 SVNVGETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPER 
               
               
                   
               
               
                 ISGSSSGTTATLTIRDVRAEDEGDYYCFSGYVDSDSKLYVFGSGTQLTVL 
               
               
                   
               
               
                 (SEQ ID NO: 1122) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][GCGTGCCGTATTTGTCAGGATCATCC 
               
               
                   
               
               
                 TGCGACGAAGTGGAATTCTGGAGGTGGCTCGAGCGGCGGCTCTATCTCTT 
               
               
                   
               
               
                 CCGGACTGCTGTCCGGCAGATCCGCCAATCCTCGTGGCGGAGGATCCTAC 
               
               
                   
               
               
                 GAGCTGACCCAGCCTCCTAGCGCCTCCGTGAATGTGGGCGAGACAGTGAA 
               
               
                   
               
               
                 GATCACCTGTAGCGGCGACCAGCTGCCCAAGTACTTCGCCGACTGGTTCC 
               
               
                   
               
               
                 ACCAGCGGAGCGACCAGACAATCCTGCAAGTGATCTACGACGACAACAAG 
               
               
                   
               
               
                 CGGCCCAGCGGCATCCCCGAGAGAATCAGCGGAAGCAGCAGCGGCACCAC 
               
               
                   
               
               
                 CGCCACCCTGACCATTAGAGATGTGCGGGCCGAGGACGAGGGCGACTACT 
               
               
                   
               
               
                 ACTGCTTTAGCGGCTACGTGGACAGCGACAGCAAGCTGTACGTGTTCGGC 
               
               
                   
               
               
                 TCCGGTACCCAGCTGACAGTGCTG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [J43 MP8-2 2005 (SEQ ID NO: 1123)  
               
               
                 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1124) 
               
               
                 [QGQSGQG][ACRICQDHPATKWNSGGGSSGGAVGLLAPPSGRSANPRGG 
               
               
                   
               
               
                 GSYELTQPPSASVNVGETVKITCSGDQLPKYFADWFHQRSDQTILQVIYD 
               
               
                   
               
               
                 DNKRPSGIPERISGSSSGTTATLTIRDVRAEDEGDYYCFSGYVDSDSKLY 
               
               
                   
               
               
                 VFGSGTQLTVL] 
               
               
                   
               
               
                 J43 MP8-2 2005 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1123) 
               
               
                 ACRICQDHPATKWNSGGGSSGGAVGLLAPPSGRSANPRGGGSYELTQPPS 
               
               
                   
               
               
                 ASVNVGETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPE 
               
               
                   
               
               
                 RISGSSSGTTATLTIRDVRAEDEGDYYCFSGYVDSDSKLYVFGSGTQLTV 
               
               
                   
               
               
                 L 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [J43 MP8-2 2008 (SEQ ID NO: 1127)  
               
               
                 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1128) 
               
               
                 [QGQSGQG][ACRICQDHPATKWNSGGGSSGGSISSGLLSGRSDGHGGGS 
               
               
                   
               
               
                 YELTQPPSASVNVGETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDN 
               
               
                   
               
               
                 KRPSGIPERISGSSSGTTATLTIRDVRAEDEGDYYCFSGYVDSDSKLYVF 
               
               
                   
               
               
                 GSGTQLTVL] 
               
               
                   
               
               
                 J43 MP8-2 2008 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1127) 
               
               
                 ACRICQDHPATKWNSGGGSSGGSISSGLLSGRSDGHGGGSYELTQPPSAS 
               
               
                   
               
               
                 VNVGETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPERI 
               
               
                   
               
               
                 SGSSSGTTATLTIRDVRAEDEGDYYCFSGYVDSDSKLYVFGSGTQLTVL 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)] 
               
               
                 [J43 MP8-2 2008 (SEQ ID NO: 1129)  
               
               
                 Nucleotide Sequence:  
               
               
                 (SEQ ID NO: 1130) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][GCGTGCCGTATTTGTCAGGATCATCC 
               
               
                   
               
               
                 TGCGACGAAGTGGAATTCTGGAGGTGGCTCGAGCGGCGGCTCTATCTCTT 
               
               
                   
               
               
                 CCGGACTGCTGTCCGGCAGATCCGACCAGCACGGCGGAGGATCCTACGA 
               
               
                   
               
               
                 GCTGACCCAGCCTCCTAGCGCCTCCGTGAATGTGGGCGAGACAGTGAAG 
               
               
                   
               
               
                 ATCACCTGTAGCGGCGACCAGCTGCCCAAGTACTTCGCCGACTGGTTCC 
               
               
                   
               
               
                 ACCAGCGGAGCGACCAGACAATCCTGCAAGTGATCTACGACGACAACA 
               
               
                   
               
               
                 AGCGGCCCAGCGGCATCCCCGAGAGAATCAGCGGAAGCAGCAGCGGC 
               
               
                   
               
               
                 ACCACCGCCACCCTGACCATTAGAGATGTGCGGGCCGAGGACGAGGG 
               
               
                   
               
               
                 CGACTACTACTGCTTTAGCGGCTACGTGGACAGCGACAGCAAGCTGTAC 
               
               
                   
               
               
                 GTGTTCGGCTCCGGTACCCAGCTGACAGTGCTG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [J43 MP8-2 2012 (SEQ ID NO: 1131)  
               
               
                 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1132) 
               
               
                 [QGQSGQG][ACRICQDHPATKWNSGGGSSGGSISSGLLSGRSANPGGG 
               
               
                   
               
               
                 SYELTQPPSASVNVGETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDD 
               
               
                   
               
               
                 NKRPSGIPERISGSSSGTTATLTIRDVRAEDEGDYYCFSGYVDSDSKLYV 
               
               
                   
               
               
                 FGSGTQLTVL] 
               
               
                   
               
               
                 J43 MP8-2 2012 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1131) 
               
               
                 ACRICQDHPATKWNSGGGSSGGSISSGLLSGRSANPGGGSYELTQPPSAS 
               
               
                   
               
               
                 VNVGETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPERI 
               
               
                   
               
               
                 SGSSSGTTATLTIRDVRAEDEGDYYCFSGYVDSDSKLYVFGSGTQLTVL 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)] 
               
               
                 [J43 MP8-2 2012 (SEQ ID NO: 616)  
               
               
                 Nucleotide Sequence:  
               
               
                 (SEQ ID NO: 1133) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][GCGTGCCGTATTTGTCAGGATCATC 
               
               
                   
               
               
                 CTGCGACGAAGTGGAATTCTGGAGGTGGCTCGAGCGGCGGCTCTATC 
               
               
                   
               
               
                 TCTTCCGGACTGCTGTCCGGCAGATCCGCTAATCCCGGCGGAGGA 
               
               
                   
               
               
                 TCCTACGAGCTGACCCAGCCTCCTAGCGCCTCCGTGAATGTGGGCGAGA 
               
               
                   
               
               
                 CAGTGAAGATCACCTGTAGCGGCGACCAGCTGCCCAAGTACTTCGCCGA 
               
               
                   
               
               
                 CTGGTTCCACCAGCGGAGCGACCAGACAATCCTGCAAGTGATCTACGAC 
               
               
                   
               
               
                 GACAACAAGCGGCCCAGCGGCATCCCCGAGAGAATCAGCGGAAGCAGCA 
               
               
                   
               
               
                 GCGGCACCACCGCCACCCTGACCATTAGAGATGTGCGGGCCGAGGACGA 
               
               
                   
               
               
                 GGGCGACTACTACTGCTTTAGCGGCTACGTGGACAGCGACAGCAAGCTG 
               
               
                   
               
               
                 TACGTGTTCGGCTCCGGTACCCAGCTGACAGTGCTG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [J43 MP8-2 2011 (SEQ ID NO: 1134)  
               
               
                 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1135) 
               
               
                 [QGQSGQG][ACRICQDHPATKWNSGGGSSGGSISSGLLSGRSDNP 
               
               
                   
               
               
                 GGGSYELTQPPSASVNVGETVKITCSGDQLPKYFADWFHQRSDQTI 
               
               
                   
               
               
                 LQVIYDDNKRPSGIPERISGSSSGTTATLTIRDVRAEDEGDYYCFSGYV 
               
               
                   
               
               
                 DSDSKLYVFGSGTQLTVL] 
               
               
                   
               
               
                 J43 MP8-2 2011 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1134) 
               
               
                 ACRICQDHPATKWNSGGGSSGGSISSGLLSGRSDNPGGGSYELTQPPSAS 
               
               
                   
               
               
                 VNVGETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPERI 
               
               
                   
               
               
                 SGSSSGTTATLTIRDVRAEDEGDYYCFSGYVDSDSKLYVFGSGTQLTVL 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)] 
               
               
                 [J43 MP8-2 2011 (SEQ ID NO: 1136)  
               
               
                 Nucleotide Sequence:  
               
               
                 (SEQ ID NO: 1137) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][GCGTGCCGTATTTGTCAGGATCA 
               
               
                   
               
               
                 TCCTGCGACGAAGTGGAATTCTGGAGGTGGCTCGAGCGGCGGCTC 
               
               
                   
               
               
                 TATCTCTTCCGGACTGCTGTCCGGCAGATCCGACAATCCCGGCGGAGGA 
               
               
                   
               
               
                 TCCTACGAGCTGACCCAGCCTCCTAGCGCCTCCGTGAATGTGGGCGAGA 
               
               
                   
               
               
                 CAGTGAAGATCACCTGTAGCGGCGACCAGCTGCCCAAGTACTTCGCCGA 
               
               
                   
               
               
                 CTGGTTCCACCAGCGGAGCGACCAGACAATCCTGCAAGTGATCTACGAC 
               
               
                   
               
               
                 GACAACAAGCGGCCCAGCGGCATCCCCGAGAGAATCAGCGGAAGCAGCA 
               
               
                   
               
               
                 GCGGCACCACCGCCACCCTGACCATTAGAGATGTGCGGGCCGAGGACGA 
               
               
                   
               
               
                 GGGCGACTACTACTGCTTTAGCGGCTACGTGGACAGCGACAGCAAGCTG 
               
               
                   
               
               
                 TACGTGTTCGGCTCCGGTACCCAGCTGACAGTGCTG] 
               
            
           
         
       
     
     Example 17: Activatable Anti-Mouse PD-1 J43 Antibodies Reduce Incidence of Diabetes in NOD Mice 
     In this Example, anti-PD-1 J43 activatable antibodies were analyzed for the ability to protect from anti-PD-1 induction of diabetes in NOD mice. The NOD mice, substrain NOD/ShiLtJ, were obtained from Jackson Laboratory at 8 weeks and acclimated on site for 2 weeks. At 10 weeks, mice were checked for diabetes prior to enrollment, grouped, and dosed as set forth in Table 4. 
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 Dosing regimen 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                 Dose 
                   
                   
               
               
                   
                   
                   
                   
                 Dose 
                 volume 
                   
                   
               
               
                 Group 
                 Count 
                 Gender 
                 Treatment 
                 (mg/kg) 
                 (mL/kg) 
                 Schedule 
                 Route 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 1 
                 7 
                 F 
                 mIgG2a (C1.18.4) 
                 10 
                 10 
                 q7dx1 
                 IP 
               
               
                 2 
                 7 
                 F 
                 Anti-PD-1 J43 m2a 
                 10 
                 10 
                 q7dx1 
                 IP 
               
               
                 3 
                 7 
                 F 
                 Anti-PD-1 J43 m2a 
                 3 
                 10 
                 q7dx1 
                 IP 
               
               
                 4 
                 7 
                 F 
                 Anti-PD-1 J43 m2a 
                 1 
                 10 
                 q7dx1 
                 IP 
               
               
                 5 
                 7 
                 F 
                 J43 MP7-1 2001 m2a 
                 10 
                 10 
                 q7dx1 
                 IP 
               
               
                 6 
                 7 
                 F 
                 J43 MP7-1 2001 m2a 
                 3 
                 10 
                 q7dx1 
                 IP 
               
               
                 7 
                 7 
                 F 
                 J43 MP8-2 2001 m2a 
                 10 
                 10 
                 q7dx1 
                 IP 
               
               
                 8 
                 7 
                 F 
                 J43 MP8-2 2001 m2a 
                 3 
                 10 
                 q7dx1 
                 IP 
               
               
                   
               
            
           
         
       
     
       FIG. 24  which plots % non-diabetic versus number of days post dose, shows that anti-PD-1 J43 antibody induced diabetes in NOD mice with increased frequency as dosage increased. At day fourteen post dose, the percentage of non-diabetic mice for the antibody-treated groups was 14%, 43% and 71% for the 20 mg/kg, 3 mg/kg and 1 mg/kg dose groups, respectively. Activatable antibodies J43 MP7-1 2001 m2a and J43 MP8-2 2001 m2a required increased doses to induce diabetes at frequencies comparable to the parental antibody. At day fourteen post dose with J43 MP7-1 2001 m2a, 57% of the 20 mg/kg group remained non-diabetic and all of the 3 mg/kg were non-diabetic. At day fourteen post dose with J43 MP8-2 2001 m2a, 71% of the 20 mg/kg group and 86% of the 3 mg/kg group remained non-diabetic. 
     Example 18: Evaluation of Efficiency of Masking Moieties 
     This example describes additional activatable anti-PD-1 antibodies that exhibit reduced binding to hPD-1. 
     Examples of additional activatable antibodies of the disclosure comprising anti-PD1 antibody A1.5 and a variety of mask and substrate combinations were produced using techniques as described herein. The amino acid and nucleic acid sequences of these activatable anti-PD-1 antibody variable domains of the disclosure are provided below. Antibodies were produced as hIgG4 containing a single amino acid substitution, S228P (Angal, et al. 1993. Mol Immunol 30:105-8.) HC and hK LC format. 
     Masking efficiencies of several of these activatable antibodies were determined as described herein. The results are shown in  FIGS. 25A and 25B . 
     In some embodiments, the activatable antibody also includes a spacer sequence. In some embodiments, the spacer is joined directly to the MM of the activatable antibody. In some embodiments, the spacer is joined directly to the MM of the activatable antibody in the structural arrangement from N-terminus to C-terminus of spacer-MM-CM-AB. In some embodiments, the spacer joined directly to the N-terminus of MM of the activatable antibody is selected from the group consisting of QGQSGQG (SEQ ID NO: 362), QGQSGQ (SEQ ID NO: 913), QGQSG (SEQ ID NO: 914), QGQS (SEQ ID NO: 915), QGQ (SEQ ID NO: 916), QG (SEQ ID NO: 917), and Q. In some embodiments, the spacer includes at least the amino acid sequence QGQSGQG (SEQ ID NO: 362). In some embodiments, the spacer includes at least the amino acid sequence QGQSGQ (SEQ ID NO: 913). In some embodiments, the spacer includes at least the amino acid sequence QGQSG (SEQ ID NO: 914). In some embodiments, the spacer includes at least the amino acid sequence QGQS (SEQ ID NO: 915), In some embodiments, the spacer includes at least the amino acid sequence QGQ (SEQ ID NO: 916). In some embodiments, the spacer includes at least the amino acid sequence QG (SEQ ID NO: 917). In some embodiments, the spacer includes at least the amino acid residue Q. In some embodiments, the activatable antibody does not include a spacer sequence. Additional examples of spacers include GQSGQG (SEQ ID NO: 2042), QSGQG (SEQ ID NO: 2043), SGQG (SEQ ID NO: 2044), GQG(SEQ ID NO: 2045), QG(SEQ ID NO: 2046), and G. 
     While the sequences shown below include the spacer sequence of SEQ ID NO: 362, those of ordinary skill in the art appreciate that the activatable anti-PD-1 antibodies of the disclosure can include any suitable spacer sequence, such as, for example, a spacer sequence selected from the group consisting of QGQSGQG (SEQ ID NO: 362), QGQSGQ (SEQ ID NO: 913), QGQSG (SEQ ID NO: 914), QGQS (SEQ ID NO: 915), QGQ (SEQ ID NO: 916), QG (SEQ ID NO: 917), and Q. Additional examples of spacers include GQSGQG (SEQ ID NO: 2042), QSGQG (SEQ ID NO: 2043), SGQG (SEQ ID NO: 2044), GQG(SEQ ID NO: 2045), QG(SEQ ID NO: 2046), and G While the sequences shown below include the spacer sequence of SEQ ID NO: 362, those of ordinary skill in the art will also appreciate that activatable anti-PD-1 antibodies of the disclosure in some embodiments do not include a spacer sequence. 
     
       
         
           
               
            
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [PD1 1.5 PD01 2003 (SEQ ID NO: 1138)  
               
               
                 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1139) 
               
               
                 [QGQSGQG][AMSGCSWSAFCPYLAGGGSSGGSISSGLLSGRSANPR 
               
               
                   
               
               
                 GGGSDIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQ 
               
               
                   
               
               
                 QKPGKAPKLLIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATY 
               
               
                   
               
               
                 YCQQSKDVPWTFGQGTKLEIK] 
               
               
                   
               
               
                 PD1 1.5 PD01 2003 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1138) 
               
               
                 AMSGCSWSAFCPYLAGGGSSGGSISSGLLSGRSANPRGGGSDIQLTQSPS 
               
               
                   
               
               
                 SLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQG 
               
               
                   
               
               
                 SGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLE 
               
               
                   
               
               
                 IK 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)] 
               
               
                 [PD1 1.5 PD001 2003 (SEQ ID NO: 1141)]  
               
               
                 Nucleotide Sequence:  
               
               
                 (SEQ ID NO: 1142) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][GCGATGAGTGGGTGCTCGTGGT 
               
               
                   
               
               
                 CTGCTTTTTGCCCGTATTTGGCGGGAGGTGGCTCGAGCGGCGGCTC 
               
               
                   
               
               
                 TATCTCTTCCGGACTGCTGTCCGGCAGATCCGCCAATCCTCGTGGCGGA 
               
               
                   
               
               
                 GGATCCGATATCCAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCG 
               
               
                   
               
               
                 TGGGCGACAGAGTGACCATCACCTGTAGAGCCAGCGAGAGCGTGGACGC 
               
               
                   
               
               
                 TTACGGCATCAGCTTCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCC 
               
               
                   
               
               
                 CCCAAGCTGCTGATCTACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAA 
               
               
                   
               
               
                 GCAGATTTTCCGGCTCTGGCAGCGGCACCGACTTCACCCTGACCATCAG 
               
               
                   
               
               
                 CAGCATGCAGCCCGAGGACTTCGCCACCTACTACTGCCAGCAGAGCAAG 
               
               
                   
               
               
                 GACGTGCCCTGGACCTTTGGCCAGGGTACCAAGCTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [PD1 1.5 PD01 2012 (SEQ ID NO: 1144)  
               
               
                 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1143) 
               
               
                 [QGQSGQG][AMSGCSWSAFCPYLGGGSSGGSISSGLLSGRSANPGG 
               
               
                   
               
               
                 GSDIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQK 
               
               
                   
               
               
                 PGKAPKLLIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYC 
               
               
                   
               
               
                 QQSKDVPWTFGQGTKLEIK] 
               
               
                   
               
               
                 PD1 1.5 PD01 2012 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1144) 
               
               
                 AMSGCSWSAFCPYLGGGSSGGSISSGLLSGRSANPGGGSDIQLTQSPSSL 
               
               
                   
               
               
                 SASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQGSG 
               
               
                   
               
               
                 VPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEIK 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)] 
               
               
                 [PD1 1.5 PD01 2012 (SEQ ID NO: 1145)]  
               
               
                 Nucleotide Sequence:  
               
               
                 (SEQ ID NO: 1146) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][GCGATGAGTGGGTGCTCGTGGTC 
               
               
                   
               
               
                 TGCTTTTTGCCCGTATTTGGCGGGAGGTGGCTCGAGCGGCGGCTC 
               
               
                   
               
               
                 TATCTCTTCCGGACTGCTGTCCGGCAGATCCGCTAATCCCGGCGGAGGA 
               
               
                   
               
               
                 TCCGATATCCAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGG 
               
               
                   
               
               
                 GCGACAGAGTGACCATCACCTGTAGAGCCAGCGAGAGCGTGGACGCTTA 
               
               
                   
               
               
                 CGGCATCAGCTTCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCC 
               
               
                   
               
               
                 AAGCTGCTGATCTACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCA 
               
               
                   
               
               
                 GATTTTCCGGCTCTGGCAGCGGCACCGACTTCACCCTGACCATCAGCAG 
               
               
                   
               
               
                 CATGCAGCCCGAGGACTTCGCCACCTACTACTGCCAGCAGAGCAAGGAC 
               
               
                   
               
               
                 GTGCCCTGGACCTTTGGCCAGGGTACCAAGCTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [PD1 1.5 PD01 2011 (SEQ ID NO: 1148)  
               
               
                 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1147) 
               
               
                 [QGQSGQG][AMSGCSWSAFCPYLGGGSSGGSISSGLLSGRSDNPG 
               
               
                   
               
               
                 GGSDIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQK 
               
               
                   
               
               
                 PGKAPKLLIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYC 
               
               
                   
               
               
                 QQSKDVPWTFGQGTKLEIK] 
               
               
                   
               
               
                 PD1 1.5 PD01 2011 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1148) 
               
               
                 AMSGCSWSAFCPYLGGGSSGGSISSGLLSGRSDNPGGGSDIQLTQSPSSL 
               
               
                   
               
               
                 SASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQGSG 
               
               
                   
               
               
                 VPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEIK 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)] 
               
               
                 [PD1 1.5 PD01 2011 (SEQ ID NO: 1149)]  
               
               
                 Nucleotide Sequence:  
               
               
                 (SEQ ID NO: 1150) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][GCGATGAGTGGGTGCTCGTGGTCTGC 
               
               
                   
               
               
                 TTTTTGCCCGTATTTGGCGGGAGGTGGCTCGAGCGGCGGCTCTATCTCTT 
               
               
                   
               
               
                 CCGGACTGCTGTCCGGCAGATCCGACAATCCCGGCGGAGGATCCGATATC 
               
               
                   
               
               
                 CAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGACAGAGT 
               
               
                   
               
               
                 GACCATCACCTGTAGAGCCAGCGAGAGCGTGGACGCTTACGGCATCAGCT 
               
               
                   
               
               
                 TCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATC 
               
               
                   
               
               
                 TACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCAGATTTTCCGGCTC 
               
               
                   
               
               
                 TGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGCCCGAGG 
               
               
                   
               
               
                 ACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGGACCTTT 
               
               
                   
               
               
                 GGCCAGGGTACCAAGCTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [PD1 1.5 PD34 2001 (SEQ ID NO: 1152)  
               
               
                 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1151) 
               
               
                 [QGQSGQG][TSYCSIEHYPCNTHHGGGSSGGSISSGLLSGRSDNHGGGS 
               
               
                   
               
               
                 DIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKL 
               
               
                   
               
               
                 LIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPW 
               
               
                   
               
               
                 TFGQGTKLEIK] 
               
               
                   
               
               
                 PD1 1.5 PD34 2001 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1152) 
               
               
                 TSYCSIEHYPCNTHHGGGSSGGSISSGLLSGRSDNHGGGSDIQLTQSPSS 
               
               
                   
               
               
                 LSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQGS 
               
               
                   
               
               
                 GVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEI 
               
               
                   
               
               
                 K 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 1125)] 
               
               
                 [PD1 1.5 PD034 2001 (SEQ ID NO: 1153)]  
               
               
                 Nucleotide Sequence:  
               
               
                 (SEQ ID NO: 1154) 
               
               
                 [CAGGGGCAATCTGGCCAGGGG][ACGTCTTACTGCAGTATTGAGCATTA 
               
               
                   
               
               
                 CCCCTGCAATACACATCATGGAGGTGGCTCGAGCGGCGGCTCTATCTCTT 
               
               
                   
               
               
                 CCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGAGGATCCGATATC 
               
               
                   
               
               
                 CAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGACAGAGT 
               
               
                   
               
               
                 GACCATCACCTGTAGAGCCAGCGAGAGCGTGGACGCTTACGGCATCAGCT 
               
               
                   
               
               
                 TCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATC 
               
               
                   
               
               
                 TACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCAGATTTTCCGGCTC 
               
               
                   
               
               
                 TGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGCCCGAGG 
               
               
                   
               
               
                 ACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGGACCTTT 
               
               
                   
               
               
                 GGCCAGGGTACCAAGCTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [PD1 1.5 PD34 1004/GG/0001 (SEQ ID NO: 1156)  
               
               
                 Amino Acid  
               
               
                 Sequence:  
               
               
                 (SEQ ID NO: 1155) 
               
               
                 [QGQSGQG][TSYCSIEHYPCNTHHGGGSSGGSAVGLLAPPGGLSGRSDN 
               
               
                   
               
               
                 HGGGSDIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKPG 
               
               
                   
               
               
                 KAPKLLIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQS 
               
               
                   
               
               
                 KDVPWTFGQGTKLEIK] 
               
               
                   
               
               
                 PD1 1.5 PD34 1004/GG/0001 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1156) 
               
               
                 TSYCSIEHYPCNTHHGGGSSGGSAVGLLAPPGGLSGRSDNHGGGSDIQLT 
               
               
                   
               
               
                 QSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAA 
               
               
                   
               
               
                 SNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQG 
               
               
                   
               
               
                 TKLEIK 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [PD1 1.5 PD34 2005 (SEQ ID NO: 1160)  
               
               
                 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1159) 
               
               
                 [QGQSGQG][TSYCSIEHYPCNTHHGGGSSGGSAVGLLAPPSGRSANPRG 
               
               
                   
               
               
                 GGGSDIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGK 
               
               
                   
               
               
                 APKLLIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSK 
               
               
                   
               
               
                 DVPWTFGQGTKLEIK] 
               
               
                   
               
               
                 PD1 1.5 PD34 2005 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1160) 
               
               
                 TSYCSIEHYPCNTHHGGGSSGGSAVGLLAPPSGRSANPRGGGGSDIQLTQ 
               
               
                   
               
               
                 SPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAAS 
               
               
                   
               
               
                 NQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGT 
               
               
                   
               
               
                 KLEIK 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [PD1 1.5 PD34 2010 (SEQ ID NO: 1164)  
               
               
                 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1163) 
               
               
                 [QGQSGQG][TSYCSIEHYPCNTHHGGGSSGGSISSGLLSGRSDYHGGGS 
               
               
                   
               
               
                 DIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKL 
               
               
                   
               
               
                 LIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPW 
               
               
                   
               
               
                 TFGQGTKLEIK] 
               
               
                   
               
               
                 PD1 1.5 PD34 2010 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1164) 
               
               
                 TSYCSIEHYPCNTHHGGGSSGGSISSGLLSGRSDYHGGGSDIQLTQSPSS 
               
               
                   
               
               
                 LSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQGS 
               
               
                   
               
               
                 GVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEI 
               
               
                   
               
               
                 K 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [PD1 1.5 PD34 2014 (SEQ ID NO: 1168)  
               
               
                 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1167) 
               
               
                 [QGQSGQG][TSYCSIEHYPCNTHHGGGSSGGSISSGLLSGRSDNIGGGS 
               
               
                   
               
               
                 DIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKL 
               
               
                   
               
               
                 LIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPW 
               
               
                   
               
               
                 TFGQGTKLEIK] 
               
               
                   
               
               
                 PD1 1.5 PD34 2014 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1168) 
               
               
                 TSYCSIEHYPCNTHHGGGSSGGSISSGLLSGRSDNIGGGSDIQLTQSPSS 
               
               
                   
               
               
                 LSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQGS 
               
               
                   
               
               
                 GVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEI 
               
               
                   
               
               
                 K 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [PD1 1.5 PD34 2003 (SEQ ID NO: 1170)  
               
               
                 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1171) 
               
               
                 [QGQSGQG][TSYCSIEHYPCNTHHGGGSSGGSISSGLLSGRSANPRGGG 
               
               
                   
               
               
                 SDIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPK 
               
               
                   
               
               
                 LLIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVP 
               
               
                   
               
               
                 WTFGQGTKLEIK] 
               
               
                   
               
               
                 PD1 1.5 PD34 2003 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1170) 
               
               
                 TSYCSIEHYPCNTHHGGGSSGGSISSGLLSGRSANPRGGGSDIQLTQSPS 
               
               
                   
               
               
                 SLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQG 
               
               
                   
               
               
                 SGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLE 
               
               
                   
               
               
                 IK 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 1125)] 
               
               
                 [PD1 1.5 PD034 2003 (SEQ ID NO: 1172)]  
               
               
                 Nucleotide Sequence:  
               
               
                 (SEQ ID NO: 1173) 
               
               
                 [CAGGGGCAATCTGGCCAGGGG][ACGTCTTACTGCAGTATTGAGCATTA 
               
               
                   
               
               
                 CCCCTGCAATACACATCATGGAGGTGGCTCGAGCGGCGGCTCTATCTCTT 
               
               
                   
               
               
                 CCGGACTGCTGTCCGGCAGATCCGCCAATCCTCGTGGCGGAGGATCCGAT 
               
               
                   
               
               
                 ATCCAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGACAG 
               
               
                   
               
               
                 AGTGACCATCACCTGTAGAGCCAGCGAGAGCGTGGACGCTTACGGCATCA 
               
               
                   
               
               
                 GCTTCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTG 
               
               
                   
               
               
                 ATCTACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCAGATTTTCCGG 
               
               
                   
               
               
                 CTCTGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGCCCG 
               
               
                   
               
               
                 AGGACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGGACC 
               
               
                   
               
               
                 TTTGGCCAGGGTACCAAGCTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [PD1 1.5 PD34 2006 (SEQ ID NO: 1174)  
               
               
                 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1175) 
               
               
                 [QGQSGQG][TSYCSIEHYPCNTHHGGGSSGGSISSGLLSGRSDDHGGGS 
               
               
                   
               
               
                 DIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKL 
               
               
                   
               
               
                 LIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPW 
               
               
                   
               
               
                 TFGQGTKLEIK] 
               
               
                   
               
               
                 PD1 1.5 PD34 2006 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1174) 
               
               
                 TSYCSIEHYPCNTHHGGGSSGGSISSGLLSGRSDDHGGGSDIQLTQSPSS 
               
               
                   
               
               
                 LSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQGS 
               
               
                   
               
               
                 GVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEI 
               
               
                   
               
               
                 K 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 1125)] 
               
               
                 [PD1 1.5 PD034 2006 (SEQ ID NO: 1176)]  
               
               
                 Nucleotide Sequence:  
               
               
                 (SEQ ID NO: 1177) 
               
               
                 [CAGGGGCAATCTGGCCAGGGG][ACGTCTTACTGCAGTATTGAGCATTA 
               
               
                   
               
               
                 CCCCTGCAATACACATCATGGAGGTGGCTCGAGCGGCGGCTCTATCTCTT 
               
               
                   
               
               
                 CCGGACTGCTGTCCGGCAGATCCGACGATCACGGCGGAGGATCCGATATC 
               
               
                   
               
               
                 CAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGACAGAGT 
               
               
                   
               
               
                 GACCATCACCTGTAGAGCCAGCGAGAGCGTGGACGCTTACGGCATCAGCT 
               
               
                   
               
               
                 TCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATC 
               
               
                   
               
               
                 TACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCAGATTTTCCGGCTC 
               
               
                   
               
               
                 TGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGCCCGAGG 
               
               
                   
               
               
                 ACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGGACCTTT 
               
               
                   
               
               
                 GGCCAGGGTACCAAGCTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [PD1 1.5 PD34 2007 (SEQ ID NO: 1178)  
               
               
                 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1179) 
               
               
                 [QGQSGQG][TSYCSIEHYPCNTHHGGGSSGGSISSGLLSGRSDIHGGGS 
               
               
                   
               
               
                 DIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKL 
               
               
                   
               
               
                 LIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPW 
               
               
                   
               
               
                 TFGQGTKLEIK] 
               
               
                   
               
               
                 PD1 1.5 PD34 2007 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1178) 
               
               
                 TSYCSIEHYPCNTHHGGGSSGGSISSGLLSGRSDIHGGGSDIQLTQSPSS 
               
               
                   
               
               
                 LSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQGS 
               
               
                   
               
               
                 GVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEI 
               
               
                   
               
               
                 K 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 1125)] 
               
               
                 [PD1 1.5 PD034 2007 (SEQ ID NO: 1180)]  
               
               
                 Nucleotide Sequence:  
               
               
                 (SEQ ID NO: 1181) 
               
               
                 [CAGGGGCAATCTGGCCAGGGG][ACGTCTTACTGCAGTATTGAGCATTA 
               
               
                   
               
               
                 CCCCTGCAATACACATCATGGAGGTGGCTCGAGCGGCGGCTCTATCTCTT 
               
               
                   
               
               
                 CCGGACTGCTGTCCGGCAGATCCGACATTCACGGCGGAGGATCCGATATC 
               
               
                   
               
               
                 CAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGACAGAGT 
               
               
                   
               
               
                 GACCATCACCTGTAGAGCCAGCGAGAGCGTGGACGCTTACGGCATCAGCT 
               
               
                   
               
               
                 TCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATC 
               
               
                   
               
               
                 TACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCAGATTTTCCGGCTC 
               
               
                   
               
               
                 TGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGCCCGAGG 
               
               
                   
               
               
                 ACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGGACCTTT 
               
               
                   
               
               
                 GGCCAGGGTACCAAGCTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [PD1 1.5 PD34 2009 (SEQ ID NO: 1182)  
               
               
                 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1183) 
               
               
                 [QGQSGQG][TSYCSIEHYPCNTHHGGGSSGGSISSGLLSGRSDTHGGGS 
               
               
                   
               
               
                 DIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKL 
               
               
                   
               
               
                 LIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPW 
               
               
                   
               
               
                 TFGQGTKLEIK] 
               
               
                   
               
               
                 [PD1 1.5 PD34 2009 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1182) 
               
               
                 TSYCSIEHYPCNTHHGGGSSGGSISSGLLSGRSDTHGGGSDIQLTQSPSS 
               
               
                   
               
               
                 LSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQGS 
               
               
                   
               
               
                 GVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEI 
               
               
                   
               
               
                 K 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 1125)] 
               
               
                 [PD1 1.5 PD034 2009 (SEQ ID NO: 1184)]  
               
               
                 Nucleotide Sequence:  
               
               
                 (SEQ ID NO: 1185) 
               
               
                 [CAGGGGCAATCTGGCCAGGGG][ACGTCTTACTGCAGTATTGAGCATTA 
               
               
                   
               
               
                 CCCCTGCAATACACATCATGGAGGTGGCTCGAGCGGCGGCTCTATCTCTT 
               
               
                   
               
               
                 CCGGACTGCTGTCCGGCAGATCCGACACTCACGGCGGAGGATCCGATATC 
               
               
                   
               
               
                 CAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGACAGAGT 
               
               
                   
               
               
                 GACCATCACCTGTAGAGCCAGCGAGAGCGTGGACGCTTACGGCATCAGCT 
               
               
                   
               
               
                 TCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATC 
               
               
                   
               
               
                 TACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCAGATTTTCCGGCTC 
               
               
                   
               
               
                 TGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGCCCGAGG 
               
               
                   
               
               
                 ACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGGACCTTT 
               
               
                   
               
               
                 GGCCAGGGTACCAAGCTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [PD1 1.5 PD34 2008 (SEQ ID NO: 1186)  
               
               
                 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1187) 
               
               
                 [QGQSGQG][TSYCSIEHYPCNTHHGGGSSGGSISSGLLSGRSDQHGGGS 
               
               
                   
               
               
                 DIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKL 
               
               
                   
               
               
                 LIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPW 
               
               
                   
               
               
                 TFGQGTKLEIK] 
               
               
                   
               
               
                 PD1 1.5 PD34 2008 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1186) 
               
               
                 TSYCSIEHYPCNTHHGGGSSGGSISSGLLSGRSDQHGGGSDIQLTQSPSS 
               
               
                   
               
               
                 LSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQGS 
               
               
                   
               
               
                 GVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEI 
               
               
                   
               
               
                 K 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 1125)] 
               
               
                 [PD1 1.5 PD034 2008 (SEQ ID NO: 1188)]  
               
               
                 Nucleotide Sequence:  
               
               
                 (SEQ ID NO: 1189) 
               
               
                 [CAGGGGCAATCTGGCCAGGGG][ACGTCTTACTGCAGTATTGAGCATTA 
               
               
                   
               
               
                 CCCCTGCAATACACATCATGGAGGTGGCTCGAGCGGCGGCTCTATCTCTT 
               
               
                   
               
               
                 CCGGACTGCTGTCCGGCAGATCCGACCAGCACGGCGGAGGATCCGATATC 
               
               
                   
               
               
                 CAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGACAGAGT 
               
               
                   
               
               
                 GACCATCACCTGTAGAGCCAGCGAGAGCGTGGACGCTTACGGCATCAGCT 
               
               
                   
               
               
                 TCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATC 
               
               
                   
               
               
                 TACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCAGATTTTCCGGCTC 
               
               
                   
               
               
                 TGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGCCCGAGG 
               
               
                   
               
               
                 ACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGGACCTTT 
               
               
                   
               
               
                 GGCCAGGGTACCAAGCTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [PD1 1.5 PD34 2012 (SEQ ID NO: 1190)  
               
               
                 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1191) 
               
               
                 [QGQSGQG][TSYCSIEHYPCNTHHGGGSSGGSISSGLLSGRSANPGGGS 
               
               
                   
               
               
                 DIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKL 
               
               
                   
               
               
                 LIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPW 
               
               
                   
               
               
                 TFGQGTKLEIK] 
               
               
                   
               
               
                 PD1 1.5 PD34 2012 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1190) 
               
               
                 TSYCSIEHYPCNTHHGGGSSGGSISSGLLSGRSANPGGGSDIQLTQSPSS 
               
               
                   
               
               
                 LSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQGS 
               
               
                   
               
               
                 GVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEI 
               
               
                   
               
               
                 K 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 1125)] 
               
               
                 [PD1 1.5 PD034 2012 (SEQ ID NO: 1192)]  
               
               
                 Nucleotide Sequence:  
               
               
                 (SEQ ID NO: 1193) 
               
               
                 [CAGGGGCAATCTGGCCAGGGG][ACGTCTTACTGCAGTATTGAGCAT 
               
               
                   
               
               
                 TACCCCTGCAATACACATCATGGAGGTGGCTCGAGCGGCGGCTCTATCT 
               
               
                   
               
               
                 CTTCCGGACTGCTGTCCGGCAGATCCGCTAATCCCGGCGGAGGATCCG 
               
               
                   
               
               
                 ATATCCAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGA 
               
               
                   
               
               
                 CAGAGTGACCATCACCTGTAGAGCCAGCGAGAGCGTGGACGCTTACGGCA 
               
               
                   
               
               
                 TCAGCTTCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCCAAGCTG 
               
               
                   
               
               
                 CTGATCTACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCAGATTTTC 
               
               
                   
               
               
                 CGGCTCTGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGC 
               
               
                   
               
               
                 CCGAGGACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGG 
               
               
                   
               
               
                 ACCTTTGGCCAGGGTACCAAGCTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [PD1 1.5 PD34 2013 (SEQ ID NO: 1194)  
               
               
                 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1195) 
               
               
                 [QGQSGQG][TSYCSIEHYPCNTHHGGGSSGGSISSGLLSGRSANIG 
               
               
                   
               
               
                 GGSDIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGK 
               
               
                   
               
               
                 APKLLIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQS 
               
               
                   
               
               
                 KDVPWTFGQGTKLEIK] 
               
               
                   
               
               
                 PD1 1.5 PD34 2013 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1194) 
               
               
                 TSYCSIEHYPCNTHHGGGSSGGSISSGLLSGRSANIGGGSDIQLTQSPSS 
               
               
                   
               
               
                 LSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQGS 
               
               
                   
               
               
                 GVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEI 
               
               
                   
               
               
                 K 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 1125)] 
               
               
                 [PD1 1.5 PD034 2013 (SEQ ID NO: 1196)]  
               
               
                 Nucleotide Sequence:  
               
               
                 (SEQ ID NO: 1197) 
               
               
                 [CAGGGGCAATCTGGCCAGGGG][ACGTCTTACTGCAGTATTGAGCA 
               
               
                   
               
               
                 TTACCCCTGCAATACACATCATGGAGGTGGCTCGAGCGGCGGCTCTATC 
               
               
                   
               
               
                 TCTTCCGGACTGCTGTCCGGCAGATCCGCTAATATTGGCGGAGGATCCG 
               
               
                   
               
               
                 ATATCCAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGA 
               
               
                   
               
               
                 CAGAGTGACCATCACCTGTAGAGCCAGCGAGAGCGTGGACGCTTACGGCA 
               
               
                   
               
               
                 TCAGCTTCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCCAAGCTG 
               
               
                   
               
               
                 CTGATCTACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCAGATTTTC 
               
               
                   
               
               
                 CGGCTCTGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGC 
               
               
                   
               
               
                 CCGAGGACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGG 
               
               
                   
               
               
                 ACCTTTGGCCAGGGTACCAAGCTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [PD1 1.5 PD34 2011 (SEQ ID NO: 1198)  
               
               
                 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1199) 
               
               
                 [QGQSGQG][TSYCSIEHYPCNTHHGGGSSGGSISSGLLSGRSDNPG 
               
               
                   
               
               
                 GGSDIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGK 
               
               
                   
               
               
                 APKLLIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQS 
               
               
                   
               
               
                 KDVPWTFGQGTKLEIK] 
               
               
                   
               
               
                 PD1 1.5 PD34 2011 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1198) 
               
               
                 TSYCSIEHYPCNTHHGGGSSGGSISSGLLSGRSDNPGGGSDIQLTQSPSS 
               
               
                   
               
               
                 LSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQGS 
               
               
                   
               
               
                 GVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLEI 
               
               
                   
               
               
                 K 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 1125)] 
               
               
                 [PD1 1.5 PD034 2011 (SEQ ID NO: 1200)]  
               
               
                 Nucleotide Sequence:  
               
               
                 (SEQ ID NO: 1201) 
               
               
                 [CAGGGGCAATCTGGCCAGGGG][ACGTCTTACTGCAGTATTGAGCAT 
               
               
                   
               
               
                 TACCCCTGCAATACACATCATGGAGGTGGCTCGAGCGGCGGCTCTATCT 
               
               
                   
               
               
                 CTTCCGGACTGCTGTCCGGCAGATCCGACAATCCCGGCGGAGGATCCGA 
               
               
                   
               
               
                 TATCCAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGCGAC 
               
               
                   
               
               
                 AGAGTGACCATCACCTGTAGAGCCAGCGAGAGCGTGGACGCTTACGGCA 
               
               
                   
               
               
                 TCAGCTTCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCCAAGCTG 
               
               
                   
               
               
                 CTGATCTACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCAGATTTTC 
               
               
                   
               
               
                 CGGCTCTGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGCAGC 
               
               
                   
               
               
                 CCGAGGACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCCTGG 
               
               
                   
               
               
                 ACCTTTGGCCAGGGTACCAAGCTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [PD1 1.5 PD006 2003 (SEQ ID NO: 1202)  
               
               
                 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1203) 
               
               
                 [QGQSGQG][APRCYMFASYCKSQYGGGSSGGSISSGLLSGRSANPRG 
               
               
                   
               
               
                 GGSDIQLTQSPSSLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGK 
               
               
                   
               
               
                 APKLLIYAASNQGSGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQS 
               
               
                   
               
               
                 KDVPWTFGQGTKLEIK] 
               
               
                   
               
               
                 PD1 1.5 PD006 2003 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1202) 
               
               
                 APRCYMFASYCKSQYGGGSSGGSISSGLLSGRSANPRGGGSDIQLTQSPS 
               
               
                   
               
               
                 SLSASVGDRVTITCRASESVDAYGISFMNWFQQKPGKAPKLLIYAASNQG 
               
               
                   
               
               
                 SGVPSRFSGSGSGTDFTLTISSMQPEDFATYYCQQSKDVPWTFGQGTKLE 
               
               
                   
               
               
                 IK 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)] 
               
               
                 [PD1 1.5 PD006 2003 (SEQ ID NO: 1204)]  
               
               
                 Nucleotide Sequence:  
               
               
                 (SEQ ID NO: 1205) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][GCGCCTAGGTGCTATATGTTTGCG 
               
               
                   
               
               
                 TCGTATTGCAAGAGTCAGTATGGAGGTGGCTCGAGCGGCGGCTCTATCT 
               
               
                   
               
               
                 CTTCCGGACTGCTGTCCGGCAGATCCGCCAATCCTCGTGGCGGAGGATC 
               
               
                   
               
               
                 CGATATCCAGCTGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTGGGC 
               
               
                   
               
               
                 GACAGAGTGACCATCACCTGTAGAGCCAGCGAGAGCGTGGACGCTTACG 
               
               
                   
               
               
                 GCATCAGCTTCATGAACTGGTTCCAGCAGAAGCCCGGCAAGGCCCCCAAG 
               
               
                   
               
               
                 CTGCTGATCTACGCCGCCAGCAATCAGGGCAGCGGCGTGCCAAGCAGATT 
               
               
                   
               
               
                 TTCCGGCTCTGGCAGCGGCACCGACTTCACCCTGACCATCAGCAGCATGC 
               
               
                   
               
               
                 AGCCCGAGGACTTCGCCACCTACTACTGCCAGCAGAGCAAGGACGTGCCC 
               
               
                   
               
               
                 TGGACCTTTGGCCAGGGTACCAAGCTGGAAATCAAG] 
               
            
           
         
       
     
     Example 19: Activatable Anti-PD1 Nivolumab Masking Moieties 
     This example describes identification of masking moieties (MM) that reduce binding of anti-PD1 Nivolumab antibody to its target. 
     Anti-PD1 Nivolumab (NV1) (see, e.g., U.S. Pat. No. 8,008,449) was used to screen libraries using a method similar to that described in PCT International Publication Number WO 2010/081173, published 15 Jul. 2010. The screening consisted of one round of MACS and four rounds of FACS sorting. For the initial MACS, approximately 6×10 11  cells were incubated with NV1 antibody at a concentration of 100 nM, and approximately 3×10 7  binders were collected using Protein-A Dynabeads (Life Technologies, Carlsbad, Calif.). FACS rounds were conducted labeling cells with DyLight 650 (Thermo-Fisher) labeled NV1 antibody and collecting cells with strongest fluorescence as follows: 20 nM NV1-650 collecting brightest 13% for FACS round 1 (F1), 2 nM NV1-650 collecting brightest 2% for FACS round 2 (F2-1), 1 nM NV1-650 collecting brightest 1% for FACS round 3 (F3-1b) and 1 nM NV1-650 collecting two populations, the brightest 88% and the brightest 1% for FACS round 4 (F4-1b.1 and F4-1b.2). Individual peptide clones from F4-1b.1 and F4-1b.2 were identified by sequence analysis (Table 19), and selected peptide clones NV01-NV12 were subsequently verified for their ability to bind NV1 (masking moiety NV001 is also referred to herein as NV01 and/or NV-01; masking moiety NV002 is also referred to herein as NV02 and/or NV-02, and so on). 
     
       
         
           
               
               
               
               
             
               
                 TABLE 19 
               
               
                   
               
               
                   
                 Mask 
                 Amino Acid Sequence 
                 SEQ ID NO: 
               
               
                   
               
             
            
               
                   
                 NV01 
                 RYCHAANPDRFCGIY 
                 1206 
               
               
                   
               
               
                   
                 NV02 
                 PRVCSTDGGDYCLLP 
                 1207 
               
               
                   
               
               
                   
                 NV03 
                 PRPQCHHRHNCPDHP 
                 1208 
               
               
                   
               
               
                   
                 NV04 
                 KCSRPAHQNPDRCSR 
                 1209 
               
               
                   
               
               
                   
                 NV05 
                 ASYRCPDYKCSHTKH 
                 1210 
               
               
                   
               
               
                   
                 NV06 
                 LPRCPDHPIKCIETK 
                 1211 
               
               
                   
               
               
                   
                 NV07 
                 YTFGCPDRYCDRAAT 
                 1212 
               
               
                   
               
               
                   
                 NV08 
                 RGCPDFNPPSHCYTA 
                 1213 
               
               
                   
               
               
                   
                 NV09 
                 RDYCGPQSPDYCHEI 
                 1214 
               
               
                   
               
               
                   
                 NV10 
                 PNKPCPDLQCYVTNY 
                 1215 
               
               
                   
               
               
                   
                 NV11 
                 PRVACGEPDLCYSNT 
                 1216 
               
               
                   
               
               
                   
                 NV12 
                 RGCKKHTISTLTCPD 
                 1217 
               
               
                   
               
               
                   
                 NV13 
                 PAYRCPDRPPCKNQM 
                 1218 
               
               
                   
               
               
                   
                 NV14 
                 NARCYPYFGDNCHMN 
                 1220 
               
               
                   
               
               
                   
                 NV15 
                 PTLRCPDRWCYDSPR 
                 1221 
               
               
                   
               
               
                   
                 NV16 
                 PSNLCPDKWCQTWRS 
                 1222 
               
               
                   
               
               
                   
                 NV17 
                 TPRYCAASYCPAHGY 
                 1223 
               
               
                   
               
               
                   
                 NV18 
                 RPGCGAVSPRCPDAP 
                 1224 
               
               
                   
               
               
                   
                 NV19 
                 VLRCHKQNPDNCNNH 
                 1225 
               
               
                   
               
               
                   
                 NV20 
                 GVKSCREPDFCSRGS 
                 1226 
               
               
                   
               
               
                   
                 NV21 
                 RNNLCPDYSCNNHNS 
                 1227 
               
               
                   
               
               
                   
                 NV22 
                 RAACHRLNPDACTNG 
                 1228 
               
               
                   
               
               
                   
                 NV23 
                 VCQSDRIPDYVTCTD 
                 1229 
               
               
                   
               
               
                   
                 NV24 
                 RNCRIASINPDYCNI 
                 1230 
               
               
                   
               
               
                   
                 NV25 
                 KEWRCPDYKCKPSYH 
                 1231 
               
               
                   
               
               
                   
                 NV26 
                 NLRICHKSLCPDYIK 
                 1232 
               
               
                   
               
               
                   
                 NV27 
                 NTHKCSNTNICPSFN 
                 1233 
               
               
                   
               
               
                   
                 NV28 
                 STRYCQASQCQMSPY 
                 1234 
               
               
                   
               
               
                   
                 NV29 
                 THRFCTASLCNKNTS 
                 1235 
               
               
                   
               
               
                   
                 NV30 
                 YTLCNTRSPDWCPNK 
                 1236 
               
               
                   
               
               
                   
                 NV31 
                 IRCTTGQSPDYCPQS 
                 1237 
               
               
                   
               
               
                   
                 NV32 
                 RCNQPDKNDQMLCNI 
                 1238 
               
               
                   
               
               
                   
                 NV33 
                 GTCRTDHQSPDYCYY 
                 1239 
               
               
                   
               
               
                   
                 NV34 
                 RGCFRSGDSLGMCPD 
                 1240 
               
               
                   
               
               
                   
                 NV35 
                 SGCFDSNEHRHCSRI 
                 1241 
               
               
                   
               
               
                   
                 NV36 
                 NRCMKLWYNPDCVAR 
                 1242 
               
               
                   
               
               
                   
                 NV37 
                 PLCARPHYWSPCDQS 
                 1243 
               
               
                   
               
               
                   
                 NV38 
                 DSKCHPNSPDYCFNS 
                 1244 
               
               
                   
               
               
                   
                 NV39 
                 NGSCRPLGGDFCGNR 
                 1245 
               
               
                   
               
               
                   
                 NV40 
                 KTRCIEMSGDYCAKS 
                 1246 
               
               
                   
               
               
                   
                 NV41 
                 IRPCMYNWGDLCNQF 
                 1247 
               
               
                   
               
               
                   
                 NV42 
                 VKTCMENNPDYCYNN 
                 1248 
               
               
                   
               
               
                   
                 NV43 
                 LRMCFEASGDYCDQQ 
                 1249 
               
               
                   
               
               
                   
                 NV44 
                 IRKCQLDGPDQCMLT 
                 1250 
               
               
                   
               
               
                   
                 NV45 
                 KWKCHKNNPNYCNNR 
                 1251 
               
               
                   
               
               
                   
                 NV46 
                 RTMCLDTNPDYCQSH 
                 1252 
               
               
                   
               
               
                   
                 NV47 
                 LAACHSMDSHRCPDY 
                 1253 
               
               
                   
               
               
                   
                 NV48 
                 RSPCIHNATMCPDYT 
                 1254 
               
               
                   
               
               
                   
                 NV49 
                 MPRCPDWPPRCSMVI 
                 1255 
               
               
                   
               
               
                   
                 NV50 
                 VRQLCRLPDYCPSGK 
                 1256 
               
               
                   
               
               
                   
                 NV51 
                 PRPPCAQSLNCPDRA 
                 1257 
               
               
                   
               
               
                   
                 NV52 
                 SFGRCTLVRTCPDFM 
                 1258 
               
               
                   
               
               
                   
                 NV53 
                 RDKPCPDFSCATIHY 
                 1259 
               
               
                   
               
               
                   
                 NV54 
                 ATKPCPDRWCTMSTL 
                 1260 
               
               
                   
               
               
                   
                 NV55 
                 SSNRCPDLRCTHHNM 
                 1261 
               
               
                   
               
               
                   
                 NV56 
                 RGSMCPDLHCSLSHI 
                 1262 
               
               
                   
               
               
                   
                 NV57 
                 NYQRCPDRTCMHNII 
                 1263 
               
               
                   
               
               
                   
                 NV58 
                 QKRPCPDRKCHAHYN 
                 1264 
               
               
                   
               
               
                   
                 NV59 
                 QNHRCPDRWCNKTTN 
                 1265 
               
               
                   
               
               
                   
                 NV60 
                 RLNLCPDKHCHMTNL 
                 1266 
               
               
                   
               
               
                   
                 NV61 
                 PQDRCPDKRCTNPGN 
                 1267 
               
               
                   
               
               
                   
                 NV62 
                 SRWRCPDYKCEHGKY 
                 1268 
               
               
                   
               
               
                   
                 NV63 
                 YENQCPDLYCNRYSM 
                 1269 
               
               
                   
               
               
                   
                 NV64 
                 TARSCPVFNCPDNNS 
                 1270 
               
               
                   
               
               
                   
                 NV65 
                 MDQRCPDAWCTSKPK 
                 1271 
               
               
                   
               
               
                   
                 NV66 
                 GDLRCPDRLCPRHSL 
                 1272 
               
               
                   
               
               
                   
                 NV67 
                 IQYLCPDYHCKASNN 
                 1273 
               
               
                   
               
               
                   
                 NV68 
                 QHHRCPDRYCNSNNN 
                 1274 
               
               
                   
               
               
                   
                 NV69 
                 TVALCPDYSCYHINN 
                 1275 
               
               
                   
               
               
                   
                 NV70 
                 SPWRCPDRYCLSNHD 
                 1276 
               
               
                   
               
               
                   
                 NV71 
                 SSKRCPDRFCNKTHA 
                 1277 
               
               
                   
               
               
                   
                 NV72 
                 HTDRCPDYKCSQNHF 
                 1278 
               
               
                   
               
               
                   
                 NV73 
                 SRSNCTPQRCNSDYH 
                 1279 
               
               
                   
               
               
                   
                 NV74 
                 FAARCPDKYCAIHTN 
                 1280 
               
               
                   
               
               
                   
                 NV75 
                 GSARCPDLVCQQTKQ 
                 1281 
               
               
                   
               
               
                   
                 NV76 
                 RNLMCPDKFCNKNTK 
                 1282 
               
               
                   
               
               
                   
                 NV77 
                 NIRLCPDKVCTPTWV 
                 1283 
               
               
                   
               
               
                   
                 NV78 
                 MTDLCPDAHCAKTHM 
                 1284 
               
               
                   
               
               
                   
                 NV79 
                 PYSRLCAYPCPDFVG 
                 1285 
               
               
                   
               
               
                   
                 NV80 
                 LCGCARSPDYCKCRG 
                 1286 
               
               
                   
               
               
                   
                 NV81 
                 WGRCERVPDCCCPRG 
                 1287 
               
               
                   
               
               
                   
                 NV82 
                 TRNTCHTRICYGMAC 
                 1288 
               
               
                   
               
               
                   
                 NV83 
                 CVCTSCSSYWTLCPD 
                 1289 
               
               
                   
               
               
                   
                 NV84 
                 LCCSRGSNCPDRCTW 
                 1290 
               
               
                   
               
               
                   
                 NV85 
                 CCPLCQANMCPDNQS 
                 1291 
               
               
                   
               
               
                   
                 NV86 
                 ECKLCCPDLYCGGTM 
                 1292 
               
               
                   
               
               
                   
                 NV87 
                 CSNPMCAYCCPDLIL 
                 1293 
               
               
                   
               
               
                   
                 NV88 
                 CPRCNTYSKHDCYHQ 
                 1294 
               
               
                   
               
               
                   
                 NV89 
                 FCCASKMPAPSNCHT 
                 1295 
               
               
                   
               
            
           
         
       
     
     Example 20: Activatable Anti-PD1 Nivolumab Antibodies 
     This example describes examples of activatable anti-PD1 Nivolumab antibodies of the disclosure. 
     Activatable anti-PD1 NV1 antibodies comprising an anti-PD1 NV1 masking moiety, a cleavable moiety, and an anti-PD1 NV1 antibody of the disclosure were produced according to methods similar to those described in PCT Publication Nos. WO 2009/025846 and WO 2010/081173. One embodiment of the disclosure is an anti-PD-1 activatable antibody comprising a heavy chain comprising amino acid sequence SEQ ID NO: 1346. One embodiment of the disclosure is an anti-PD-1 activatable antibody comprising a light chain comprising amino acid sequence SEQ ID NO: 626. One embodiment of the disclosure is an anti-PD-1 activatable antibody comprising a heavy chain comprising amino acid sequence SEQ ID NO: 1346 and a light chain comprising amino acid sequence SEQ ID NO: 626. One embodiment of the disclosure is an anti-PD-1 activatable antibody comprising the CDRs of an anti-PD-1 activatable antibody comprising a heavy chain comprising amino acid sequence SEQ ID NO: 1346 and a light chain comprising amino acid sequence SEQ ID NO: 626. 
     The amino acid and nucleic acid sequences of several activatable anti-PD1 antibody variable domains of the disclosure are provided below. Antibodies were produced as hIgG4 containing a single amino acid substitution, S228P (Angal, et al. 1993. Mol Immunol 30:105-8.) HC and hK LC format. 
     
       
         
           
               
            
               
                 NV1 Light Chain Sequence:  
               
               
                 (SEQ ID NO: 626) 
               
               
                 EIVLTQSPATLSLSPGERATLSCRAS QSVSSY LAWYQQKPGQAPRLLIY 
               
               
                   
               
               
                   DAS NRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYC QQSSNWPRT F 
               
               
                   
               
               
                 GQGTKVEIK 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [NV1 NV01 2001 (SEQ ID NO: 1296) Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1297) 
               
               
                 [QGQSGQG][RYCHAANPDRFCGIYGGGSSGGSISSGLLSGRSDNHGG 
               
               
                   
               
               
                 SEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLI 
               
               
                   
               
               
                 YDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRT 
               
               
                   
               
               
                 FGQGTKVEIK] 
               
               
                   
               
               
                 NV1 NV01 2001 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1296) 
               
               
                 RYCHAANPDRFCGIYGGGSSGGSISSGLLSGRSDNHGGSEIVLTQSPATL 
               
               
                   
               
               
                 SLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPAR 
               
               
                   
               
               
                 FSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIK 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)] 
               
               
                 [NV1 NV01 2001 (SEQ ID NO: 1298)]  
               
               
                 Nucleotide Sequence:  
               
               
                 (SEQ ID NO: 1299) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][CGGTATTGCCATGCTGCGAATCCT 
               
               
                   
               
               
                 GATCGGTTTTGCGGTATTTATGGAGGTGGCTCGAGCGGCGGCTCTATCT 
               
               
                   
               
               
                 CTTCCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGATCCGAGAT 
               
               
                   
               
               
                 CGTGCTGACACAGAGCCCTGCCACCCTGTCTCTGAGCCCTGGCGAAAGA 
               
               
                   
               
               
                 GCCACCCTGAGCTGTAGAGCCAGCCAGAGCGTGTCCAGCTACCTGGCCT 
               
               
                   
               
               
                 GGTATCAGCAGAAGCCCGGCCAGGCTCCCCGGCTGCTGATCTACGATGCC 
               
               
                   
               
               
                 AGCAATAGAGCCACCGGCATCCCCGCCAGATTTTCCGGCTCTGGCAGCGG 
               
               
                   
               
               
                 CACCGACTTCACCCTGACCATCAGCTCCCTGGAACCCGAGGACTTCGCCG 
               
               
                   
               
               
                 TGTACTACTGCCAGCAGAGCAGCAACTGGCCCCGGACATTTGGCCAGGGC 
               
               
                   
               
               
                 ACCAAGGTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [NV1 NV02 2001 (SEQ ID NO: 1300) Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1301) 
               
               
                 [QGQSGQG][PRVCSTDGGDYCLLPGGGSSGGSISSGLLSGRSD 
               
               
                   
               
               
                 NHGGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPR 
               
               
                   
               
               
                 LLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWP 
               
               
                   
               
               
                 RTFGQGTKVEIK] 
               
               
                   
               
               
                 NV1 NV02 2001 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1300) 
               
               
                 PRVCSTDGGDYCLLPGGGSSGGSISSGLLSGRSDNHGGSEIVLTQSPATL 
               
               
                   
               
               
                 SLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPAR 
               
               
                   
               
               
                 FSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIK 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)] 
               
               
                 [NV1 NV02 2001 (SEQ ID NO: 1302)]  
               
               
                 Nucleotide Sequence:  
               
               
                 (SEQ ID NO: 1303) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][CCTAGGGTTTGCTCTACTGA 
               
               
                   
               
               
                 TGGTGGTGATTATTGCTTGCTTCCTGGAGGTGGCTCGAGCGGCGGCTCTA 
               
               
                   
               
               
                 TCTCTTCCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGATCCGAG 
               
               
                   
               
               
                 ATCGTGCTGACACAGAGCCCTGCCACCCTGTCTCTGAGCCCTGGCGAAAG 
               
               
                   
               
               
                 AGCCACCCTGAGCTGTAGAGCCAGCCAGAGCGTGTCCAGCTACCTGGCCT 
               
               
                   
               
               
                 GGTATCAGCAGAAGCCCGGCCAGGCTCCCCGGCTGCTGATCTACGATGCC 
               
               
                   
               
               
                 AGCAATAGAGCCACCGGCATCCCCGCCAGATTTTCCGGCTCTGGCAGCGG 
               
               
                   
               
               
                 CACCGACTTCACCCTGACCATCAGCTCCCTGGAACCCGAGGACTTCGCCG 
               
               
                   
               
               
                 TGTACTACTGCCAGCAGAGCAGCAACTGGCCCCGGACATTTGGCCAGGGC 
               
               
                   
               
               
                 ACCAAGGTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [NV1 NV03 2001 (SEQ ID NO: 1304) Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1305) 
               
               
                 [QGQSGQG][PRPQCHHRHNCPDHPGGGSSGGSISSGLLSGRSD 
               
               
                   
               
               
                 NHGGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPR 
               
               
                   
               
               
                 LLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWP 
               
               
                   
               
               
                 RTFGQGTKVEIK] 
               
               
                   
               
               
                 (SEQ ID NO: 1304) 
               
               
                 PRPQCHHRHNCPDHPGGGSSGGSISSGLLSGRSDNHGGSEIVLTQSPATL 
               
               
                   
               
               
                 SLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPAR 
               
               
                   
               
               
                 FSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIK 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)] 
               
               
                 [NV1 NV03 2001 (SEQ ID NO: 1306)]  
               
               
                 Nucleotide Sequence:  
               
               
                 (SEQ ID NO: 1307) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][CCTCGTCCGCAGTGCCATCA 
               
               
                   
               
               
                 TCGGCATAATTGTCCTGATCATCCTGGAGGTGGCTCGAGCGGCGGCTCTA 
               
               
                   
               
               
                 TCTCTTCCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGATCCGAG 
               
               
                   
               
               
                 ATCGTGCTGACACAGAGCCCTGCCACCCTGTCTCTGAGCCCTGGCGAAAG 
               
               
                   
               
               
                 AGCCACCCTGAGCTGTAGAGCCAGCCAGAGCGTGTCCAGCTACCTGGCCT 
               
               
                   
               
               
                 GGTATCAGCAGAAGCCCGGCCAGGCTCCCCGGCTGCTGATCTACGATGCC 
               
               
                   
               
               
                 AGCAATAGAGCCACCGGCATCCCCGCCAGATTTTCCGGCTCTGGCAGCGG 
               
               
                   
               
               
                 CACCGACTTCACCCTGACCATCAGCTCCCTGGAACCCGAGGACTTCGCCG 
               
               
                   
               
               
                 TGTACTACTGCCAGCAGAGCAGCAACTGGCCCCGGACATTTGGCCAGGGC 
               
               
                   
               
               
                 ACCAAGGTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [NV1 NV04 2001 (SEQ ID NO: 1308) Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1309) 
               
               
                 [QGQSGQG][KCSRPAHQNPDRCSRGGGSSGGSISSGLLSGRSD 
               
               
                   
               
               
                 NHGGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPR 
               
               
                   
               
               
                 LLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWP 
               
               
                   
               
               
                 RTFGQGTKVEIK] 
               
               
                   
               
               
                 NV1 NV04 2001 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1308) 
               
               
                 KCSRPAHQNPDRCSRGGGSSGGSISSGLLSGRSDNHGGSEIVLTQSPATL 
               
               
                   
               
               
                 SLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPAR 
               
               
                   
               
               
                 FSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIK 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)] 
               
               
                 [NV1 NV04 2001 (SEQ ID NO: 1310)]  
               
               
                 Nucleotide Sequence:  
               
               
                 (SEQ ID NO: 1311) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][AAGTGCTCGCGGCCTGCTCA 
               
               
                   
               
               
                 TCAGAATCCGGATCGTTGCTCGCGAGGAGGTGGCTCGAGCGGCGGCTCTA 
               
               
                   
               
               
                 TCTCTTCCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGATCCGAG 
               
               
                   
               
               
                 ATCGTGCTGACACAGAGCCCTGCCACCCTGTCTCTGAGCCCTGGCGAAAG 
               
               
                   
               
               
                 AGCCACCCTGAGCTGTAGAGCCAGCCAGAGCGTGTCCAGCTACCTGGCCT 
               
               
                   
               
               
                 GGTATCAGCAGAAGCCCGGCCAGGCTCCCCGGCTGCTGATCTACGATGCC 
               
               
                   
               
               
                 AGCAATAGAGCCACCGGCATCCCCGCCAGATTTTCCGGCTCTGGCAGCGG 
               
               
                   
               
               
                 CACCGACTTCACCCTGACCATCAGCTCCCTGGAACCCGAGGACTTCGCCG 
               
               
                   
               
               
                 TGTACTACTGCCAGCAGAGCAGCAACTGGCCCCGGACATTTGGCCAGGGC 
               
               
                   
               
               
                 ACCAAGGTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [NV1 NV05 2001 (SEQ ID NO: 1312) Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1313) 
               
               
                 [QGQSGQG][ASYRCPDYKCSHTKHGGGSSGGSISSGLLSGRSD 
               
               
                   
               
               
                 NHGGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPR 
               
               
                   
               
               
                 LLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWP 
               
               
                   
               
               
                 RTFGQGTKVEIK] 
               
               
                   
               
               
                 NV1 NV05 2001 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1312) 
               
               
                 ASYRCPDYKCSHTKHGGGSSGGSISSGLLSGRSDNHGGSEIVLTQSPATL 
               
               
                   
               
               
                 SLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPAR 
               
               
                   
               
               
                 FSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIK 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)] 
               
               
                 [NV1 NV05 2001 (SEQ ID NO: 1314)]  
               
               
                 Nucleotide Sequence:  
               
               
                 (SEQ ID NO: 1315) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][GCTTCGTATCGGTGCCCTGA 
               
               
                   
               
               
                 TTATAAGTGCAGTCATACTAAGCATGGAGGTGGCTCGAGCGGCGGCTCTA 
               
               
                   
               
               
                 TCTCTTCCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGATCCGAG 
               
               
                   
               
               
                 ATCGTGCTGACACAGAGCCCTGCCACCCTGTCTCTGAGCCCTGGCGAAAG 
               
               
                   
               
               
                 AGCCACCCTGAGCTGTAGAGCCAGCCAGAGCGTGTCCAGCTACCTGGCCT 
               
               
                   
               
               
                 GGTATCAGCAGAAGCCCGGCCAGGCTCCCCGGCTGCTGATCTACGATGCC 
               
               
                   
               
               
                 AGCAATAGAGCCACCGGCATCCCCGCCAGATTTTCCGGCTCTGGCAGCGG 
               
               
                   
               
               
                 CACCGACTTCACCCTGACCATCAGCTCCCTGGAACCCGAGGACTTCGCCG 
               
               
                   
               
               
                 TGTACTACTGCCAGCAGAGCAGCAACTGGCCCCGGACATTTGGCCAGGGC 
               
               
                   
               
               
                 ACCAAGGTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [NV1 NV06 2001 (SEQ ID NO: 1316) Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1317) 
               
               
                 [QGQSGQG][LPRCPDHPIKCIETKGGGSSGGSISSGLLSGRSD 
               
               
                   
               
               
                 NHGGSEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPR 
               
               
                   
               
               
                 LLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWP 
               
               
                   
               
               
                 RTFGQGTKVEIK] 
               
               
                   
               
               
                 NV1 NV06 2001 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1316) 
               
               
                 LPRCPDHPIKCIETKGGGSSGGSISSGLLSGRSDNHGGSEIVLTQSPATL 
               
               
                   
               
               
                 SLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPAR 
               
               
                   
               
               
                 FSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIK 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)] 
               
               
                 [NV1 NV06 2001 (SEQ ID NO: 1318)]  
               
               
                 Nucleotide Sequence:  
               
               
                 (SEQ ID NO: 1319) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][TTGCCGAGGTGCCCGGATCA 
               
               
                   
               
               
                 TCCGATTAAGTGCATTGAGACTAAGGGAGGTGGCTCGAGCGGCGGCTCTA 
               
               
                   
               
               
                 TCTCTTCCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGATCCGAG 
               
               
                   
               
               
                 ATCGTGCTGACACAGAGCCCTGCCACCCTGTCTCTGAGCCCTGGCGAAAG 
               
               
                   
               
               
                 AGCCACCCTGAGCTGTAGAGCCAGCCAGAGCGTGTCCAGCTACCTGGCCT 
               
               
                   
               
               
                 GGTATCAGCAGAAGCCCGGCCAGGCTCCCCGGCTGCTGATCTACGATGCC 
               
               
                   
               
               
                 AGCAATAGAGCCACCGGCATCCCCGCCAGATTTTCCGGCTCTGGCAGCGG 
               
               
                   
               
               
                 CACCGACTTCACCCTGACCATCAGCTCCCTGGAACCCGAGGACTTCGCCG 
               
               
                   
               
               
                 TGTACTACTGCCAGCAGAGCAGCAACTGGCCCCGGACATTTGGCCAGGGC 
               
               
                   
               
               
                 ACCAAGGTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [NV1 NV07 2001 (SEQ ID NO: 1320) Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1321) 
               
               
                 [QGQSGQG][YTFGCPDRYCDRAATGGGSSGGSISSGLLSGRSDNHGGSE 
               
               
                   
               
               
                 IVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYD 
               
               
                   
               
               
                 ASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQ 
               
               
                   
               
               
                 GTKVEIK] 
               
               
                   
               
               
                 NV1 NV07 2001 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1320) 
               
               
                 YTFGCPDRYCDRAATGGGSSGGSISSGLLSGRSDNHGGSEIVLTQS 
               
               
                   
               
               
                 PATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNR 
               
               
                   
               
               
                 ATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQG 
               
               
                   
               
               
                 TKVEIK 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)] 
               
               
                 [NV1 NV07 2001 (SEQ ID NO: 1322)]  
               
               
                 Nucleotide Sequence:  
               
               
                 (SEQ ID NO: 1323) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][TATACGTTTGGTTGCCCTGATAGG 
               
               
                   
               
               
                 TATTGCGATCGTGCGGCGACGGGAGGTGGCTCGAGCGGCGGCTCTATCT 
               
               
                   
               
               
                 CTTCCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGATCCGAGAT 
               
               
                   
               
               
                 CGTGCTGACACAGAGCCCTGCCACCCTGTCTCTGAGCCCTGGCGAAAGAG 
               
               
                   
               
               
                 CCACCCTGAGCTGTAGAGCCAGCCAGAGCGTGTCCAGCTACCTGGCCTGG 
               
               
                   
               
               
                 TATCAGCAGAAGCCCGGCCAGGCTCCCCGGCTGCTGATCTACGATGCCAG 
               
               
                   
               
               
                 CAATAGAGCCACCGGCATCCCCGCCAGATTTTCCGGCTCTGGCAGCGGCA 
               
               
                   
               
               
                 CCGACTTCACCCTGACCATCAGCTCCCTGGAACCCGAGGACTTCGCCGTG 
               
               
                   
               
               
                 TACTACTGCCAGCAGAGCAGCAACTGGCCCCGGACATTTGGCCAGGGCAC 
               
               
                   
               
               
                 CAAGGTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [NV1 NV08 2001 (SEQ ID NO: 1324) Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1325) 
               
               
                 [QGQSGQG][RGCPDFNPPSHCYTAGGGSSGGSISSGLLSGRSDNHGGSE 
               
               
                   
               
               
                 IVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDA 
               
               
                   
               
               
                 SNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQG 
               
               
                   
               
               
                 TKVEIK] 
               
               
                   
               
               
                 NV1 NV08 2001 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1324) 
               
               
                 RGCPDFNPPSHCYTAGGGSSGGSISSGLLSGRSDNHGGSEIVLTQSPA 
               
               
                   
               
               
                 TLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGI 
               
               
                   
               
               
                 PARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIK 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)] 
               
               
                 [NV1 NV08 2001 (SEQ ID NO: 1326)]  
               
               
                 Nucleotide Sequence:  
               
               
                 (SEQ ID NO: 1327) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][CGTGGTTGTCCGGATTTTAATCCTCC 
               
               
                   
               
               
                 TTCTCATTGCTATACTGCTGGAGGTGGCTCGAGCGGCGGCTCTATCTCTT 
               
               
                   
               
               
                 CCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGATCCGAGATCGT 
               
               
                   
               
               
                 GCTGACACAGAGCCCTGCCACCCTGTCTCTGAGCCCTGGCGAAAGAGCC 
               
               
                   
               
               
                 ACCCTGAGCTGTAGAGCCAGCCAGAGCGTGTCCAGCTACCTGGCCTGGTA 
               
               
                   
               
               
                 TCAGCAGAAGCCCGGCCAGGCTCCCCGGCTGCTGATCTACGATGCCAGC 
               
               
                   
               
               
                 AATAGAGCCACCGGCATCCCCGCCAGATTTTCCGGCTCTGGCAGCGGCAC 
               
               
                   
               
               
                 CGACTTCACCCTGACCATCAGCTCCCTGGAACCCGAGGACTTCGCCGTGT 
               
               
                   
               
               
                 ACTACTGCCAGCAGAGCAGCAACTGGCCCCGGACATTTGGCCAGGGCAC 
               
               
                   
               
               
                 CAAGGTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [NV1 NV09 2001 (SEQ ID NO: 1328) Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1329) 
               
               
                 [QGQSGQG][RDYCGPQSPDYCHEIGGGSSGGSISSGLLSGRSDNHGG 
               
               
                   
               
               
                 SEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIY 
               
               
                   
               
               
                 DASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFG 
               
               
                   
               
               
                 QGTKVEIK] 
               
               
                   
               
               
                 NV1 NV09 2001 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1328) 
               
               
                 RDYCGPQSPDYCHEIGGGSSGGSISSGLLSGRSDNHGGSEIVLTQSPA 
               
               
                   
               
               
                 TLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGI 
               
               
                   
               
               
                 PARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIK 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)] 
               
               
                 [NV1 NV09 2001 (SEQ ID NO: 1330)]  
               
               
                 Nucleotide Sequence:  
               
               
                 (SEQ ID NO: 1331) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][AGGGATTATTGCGGGCCTCAGAGTCC 
               
               
                   
               
               
                 TGATTATTGCCATGAGATTGGAGGTGGCTCGAGCGGCGGCTCTATCTCTT 
               
               
                   
               
               
                 CCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGATCCGAGATCGT 
               
               
                   
               
               
                 GCTGACACAGAGCCCTGCCACCCTGTCTCTGAGCCCTGGCGAAAGAGCC 
               
               
                   
               
               
                 ACCCTGAGCTGTAGAGCCAGCCAGAGCGTGTCCAGCTACCTGGCCTGGTA 
               
               
                   
               
               
                 TCAGCAGAAGCCCGGCCAGGCTCCCCGGCTGCTGATCTACGATGCCAGCA 
               
               
                   
               
               
                 ATAGAGCCACCGGCATCCCCGCCAGATTTTCCGGCTCTGGCAGCGGCACC 
               
               
                   
               
               
                 GACTTCACCCTGACCATCAGCTCCCTGGAACCCGAGGACTTCGCCGTGTA 
               
               
                   
               
               
                 CTACTGCCAGCAGAGCAGCAACTGGCCCCGGACATTTGGCCAGGGCACCA 
               
               
                   
               
               
                 AGGTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [NV1 NV10 2001 (SEQ ID NO: 1332) Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1333) 
               
               
                 [QGQSGQG][PNKPCPDLQCYVTNYGGGSSGGSISSGLLSGRSDNHGG 
               
               
                   
               
               
                 SEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIY 
               
               
                   
               
               
                 DASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFG 
               
               
                   
               
               
                 QGTKVEIK] 
               
               
                   
               
               
                 NV1 NV10 2001 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1332) 
               
               
                 PNKPCPDLQCYVTNYGGGSSGGSISSGLLSGRSDNHGGSEIVLTQSPA 
               
               
                   
               
               
                 TLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGI 
               
               
                   
               
               
                 PARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIK 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)] 
               
               
                 [NV1 NV10 2001 (SEQ ID NO: 1334)]  
               
               
                 Nucleotide Sequence:  
               
               
                 (SEQ ID NO: 1335) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][CCGAATAAGCCTTGCCCGGATCTGC 
               
               
                   
               
               
                 AGTGCTATGTGACGAATTATGGAGGTGGCTCGAGCGGCGGCTCTATCTCT 
               
               
                   
               
               
                 TCCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGATCCGAGATCG 
               
               
                   
               
               
                 TGCTGACACAGAGCCCTGCCACCCTGTCTCTGAGCCCTGGCGAAAGAGCC 
               
               
                   
               
               
                 ACCCTGAGCTGTAGAGCCAGCCAGAGCGTGTCCAGCTACCTGGCCTGGTA 
               
               
                   
               
               
                 TCAGCAGAAGCCCGGCCAGGCTCCCCGGCTGCTGATCTACGATGCCAGC 
               
               
                   
               
               
                 AATAGAGCCACCGGCATCCCCGCCAGATTTTCCGGCTCTGGCAGCGGCAC 
               
               
                   
               
               
                 CGACTTCACCCTGACCATCAGCTCCCTGGAACCCGAGGACTTCGCCGTGT 
               
               
                   
               
               
                 ACTACTGCCAGCAGAGCAGCAACTGGCCCCGGACATTTGGCCAGGGCACC 
               
               
                   
               
               
                 AAGGTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [NV1 NV11 2001 (SEQ ID NO: 1336) Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1337) 
               
               
                 [QGQSGQG][PRVACGEPDLCYSNTGGGSSGGSISSGLLSGRSDNHGG 
               
               
                   
               
               
                 SEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIY 
               
               
                   
               
               
                 DASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTF 
               
               
                   
               
               
                 GQGTKVEIK] 
               
               
                   
               
               
                 NV1 NV11 2001 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1336) 
               
               
                 PRVACGEPDLCYSNTGGGSSGGSISSGLLSGRSDNHGGSEIVLTQSPA 
               
               
                   
               
               
                 TLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGI 
               
               
                   
               
               
                 PARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIK 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)] 
               
               
                 [NV1 NV11 2001 (SEQ ID NO: 1338)]  
               
               
                 Nucleotide Sequence:  
               
               
                 (SEQ ID NO: 1339) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][CCGCGGGTTGCTTGCGGTGAGCCT 
               
               
                   
               
               
                 GATCTTTGCTATTCTAATACTGGAGGTGGCTCGAGCGGCGGCTCTATCTC 
               
               
                   
               
               
                 TTCCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGATCCGAGATC 
               
               
                   
               
               
                 GTGCTGACACAGAGCCCTGCCACCCTGTCTCTGAGCCCTGGCGAAAGAGC 
               
               
                   
               
               
                 CACCCTGAGCTGTAGAGCCAGCCAGAGCGTGTCCAGCTACCTGGCCTGGT 
               
               
                   
               
               
                 ATCAGCAGAAGCCCGGCCAGGCTCCCCGGCTGCTGATCTACGATGCCAGC 
               
               
                   
               
               
                 AATAGAGCCACCGGCATCCCCGCCAGATTTTCCGGCTCTGGCAGCGGCAC 
               
               
                   
               
               
                 CGACTTCACCCTGACCATCAGCTCCCTGGAACCCGAGGACTTCGCCGTGT 
               
               
                   
               
               
                 ACTACTGCCAGCAGAGCAGCAACTGGCCCCGGACATTTGGCCAGGGCAC 
               
               
                   
               
               
                 CAAGGTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [NV1 NV12 2001 (SEQ ID NO: 1340) Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1341) 
               
               
                 [QGQSGQG][RGCKKHTISTLTCPDGGGSSGGSISSGLLSGRSDNHGG 
               
               
                   
               
               
                 SEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIY 
               
               
                   
               
               
                 DASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFG 
               
               
                   
               
               
                 QGTKVEIK] 
               
               
                   
               
               
                 NV1 NV12 2001 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1340) 
               
               
                 RGCKKHTISTLTCPDGGGSSGGSISSGLLSGRSDNHGGSEIVLTQSPATL 
               
               
                   
               
               
                 SLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPAR 
               
               
                   
               
               
                 FSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIK 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)] 
               
               
                 [NV1 NV12 2001 (SEQ ID NO: 1342)]  
               
               
                 Nucleotide Sequence:  
               
               
                 (SEQ ID NO: 1343) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][CGGGGGTGCAAGAAGCATACTATT 
               
               
                   
               
               
                 TCGACGCTTACGTGCCCTGATGGAGGTGGCTCGAGCGGCGGCTCTA 
               
               
                   
               
               
                 TCTCTTCCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGATCCGAG 
               
               
                   
               
               
                 ATCGTGCTGACACAGAGCCCTGCCACCCTGTCTCTGAGCCCTGGCGAAAG 
               
               
                   
               
               
                 AGCCACCCTGAGCTGTAGAGCCAGCCAGAGCGTGTCCAGCTACCTGGCCT 
               
               
                   
               
               
                 GGTATCAGCAGAAGCCCGGCCAGGCTCCCCGGCTGCTGATCTACGATGCC 
               
               
                   
               
               
                 AGCAATAGAGCCACCGGCATCCCCGCCAGATTTTCCGGCTCTGGCAGCGG 
               
               
                   
               
               
                 CACCGACTTCACCCTGACCATCAGCTCCCTGGAACCCGAGGACTTCGCCG 
               
               
                   
               
               
                 TGTACTACTGCCAGCAGAGCAGCAACTGGCCCCGGACATTTGGCCAGGGC 
               
               
                   
               
               
                 ACCAAGGTGGAAATCAAG] 
               
               
                   
               
               
                 Human Kappa Constant  
               
               
                 (SEQ ID NO: 1344) 
               
               
                 RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSG 
               
               
                   
               
               
                 NSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTK 
               
               
                   
               
               
                 SFNRGEC 
               
               
                   
               
               
                 Human Kappa Constant  
               
               
                 (SEQ ID NO: 1345) 
               
               
                 CGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCA 
               
               
                   
               
               
                 GTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATC 
               
               
                   
               
               
                 CCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGT 
               
               
                   
               
               
                 AACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG 
               
               
                   
               
               
                 CCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAG 
               
               
                   
               
               
                 TCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAG 
               
               
                   
               
               
                 AGCTTCAACAGGGGAGAGTGT 
               
               
                   
               
               
                 NV1 HC Variable  
               
               
                 (SEQ ID NO: 1346) 
               
               
                 QVQLVESGGGVVQPGRSLRLDCKAS GITFSNSG MHWVRQAPGKGLEWVAV 
               
               
                   
               
               
                   IWYDGSKR YYADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCA TND   
               
               
                   
               
               
                   DY WGQGTLVTVSS 
               
               
                   
               
               
                 NV1 HC Variable  
               
               
                 (SEQ ID NO: 1347) 
               
               
                 CAGGTGCAGCTGGTGGAATCTGGCGGCGGAGTGGTGCAGCCTGGCAGAAG 
               
               
                   
               
               
                 CCTGAGACTGGACTGCAAGGCCAGCGGCATCACCTTCAGCAACAGCGGCA 
               
               
                   
               
               
                 TGCACTGGGTGCGCCAGGCCCCTGGAAAAGGCCTGGAATGGGTGGCCGTG 
               
               
                   
               
               
                 ATTTGGTACGACGGCAGCAAGCGGTACTACGCCGACAGCGTGAAGGGCCG 
               
               
                   
               
               
                 GTTCACCATCAGCCGGGACAACAGCAAGAATACCCTGTTCCTGCAGATGA 
               
               
                   
               
               
                 ACAGCCTGCGGGCCGAGGACACCGCCGTGTACTACTGCGCCACCAACGAC 
               
               
                   
               
               
                 GACTATTGGGGCCAGGGCACACTCGTGACCGTGTCCTCT 
               
               
                   
               
               
                 hIgG4 S228P Constant  
               
               
                 (SEQ ID NO: 1348) 
               
               
                 ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV 
               
               
                   
               
               
                 HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVES 
               
               
                   
               
               
                 KYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQED 
               
               
                   
               
               
                 PEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYK 
               
               
                   
               
               
                 CKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVK 
               
               
                   
               
               
                 GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEG 
               
               
                   
               
               
                 NVFSCSVMHEALHNHYTQKSLSLSLGK 
               
               
                   
               
               
                 hIgG4 S228P Constant  
               
               
                 (SEQ ID NO: 1349) 
               
               
                 GCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTGTAGCAGAAG 
               
               
                   
               
               
                 CACCAGCGAGTCTACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCC 
               
               
                   
               
               
                 CCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG 
               
               
                   
               
               
                 CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAG 
               
               
                   
               
               
                 CGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCAAGACCTACACCTGTA 
               
               
                   
               
               
                 ACGTGGACCACAAGCCCAGCAACACCAAGGTGGACAAGCGGGTGGAATCT 
               
               
                   
               
               
                 AAGTACGGCCCTCCCTGCCCTCCTTGCCCAGCCCCTGAATTTCTGGGGGG 
               
               
                   
               
               
                 ACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCT 
               
               
                   
               
               
                 CCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCAGGAAGAC 
               
               
                   
               
               
                 CCTGAGGTCCAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGC 
               
               
                   
               
               
                 CAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCA 
               
               
                   
               
               
                 GCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAG 
               
               
                   
               
               
                 TGCAAGGTCTCCAACAAAGGCCTGCCCAGCTCCATCGAGAAAACCATCTC 
               
               
                   
               
               
                 CAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCAT 
               
               
                   
               
               
                 CCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAA 
               
               
                   
               
               
                 GGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCC 
               
               
                   
               
               
                 GGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCT 
               
               
                   
               
               
                 TCTTCCTCTACAGCAGACTCACCGTGGACAAGAGCAGGTGGCAGGAAGGG 
               
               
                   
               
               
                 AACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACAC 
               
               
                   
               
               
                 GCAGAAGAGCCTCTCCCTGTCTCTGGGTAAA 
               
            
           
         
       
     
     Example 21: Characterization of Activatable Anti-PD1 NV1 Antibodies 
     This example describes activatable anti-PD1 NV1 antibodies with reduced binding to hPD1. 
     Masking efficiencies were evaluated by standard plate ELISA. Briefly, human PD1-Fc (R and D systems, Minneapolis, Minn.) was adsorbed to the wells of a 96-well ELISA plate. Purified NV1 and activatable NV1 antibodies were applied to the plate in serial dilution and allowed to bind. Bound antibody and activatable antibodies were detected with anti-hu Fab-HRP conjugate (Sigma, St Louis, Mo.) and visualized with the chromogenic substrate TMB (Thermo Scientific, Rockford, Ill.). Plots were generated in Prizm (Sigma Plot). All activatable NV1 antibodies showed decreased binding compared with the parental NV1, as shown in  FIG. 26 . 
     Example 22: Activatable Anti-PD1 Pembrolizumab Masking Moieties 
     This example describes identification of masking moieties (MM) that reduce binding of anti-PD1 pembrolizumab antibody to its target. 
     Anti-PD1 Pembrolizumab (PM1) (see, e.g., U.S. Pat. No. 8,354,509) was used to screen libraries using a method similar to that described in PCT International Publication Number WO 2010/081173, published 15 Jul. 2010. The screening consisted of one round of MACS and three rounds of FACS sorting. For the initial MACS, approximately 1.6×10 12  cells were incubated with PM1 antibody at a concentration of 200 nM, and approximately 8×10 6  binders were collected using Protein-A Dynabeads (Life Technologies, Carlsbad, Calif.). FACS rounds were conducted labeling cells with DyLight 650 (Thermo-Fisher) labeled PM1 antibody and collecting cells with strongest fluorescence as follows: 100 nM PM1-650 collecting brightest 10% for FACS round 1 (5.6×10 5  for F1), 10 nM PM1-650 collecting brightest 1.5% for FACS round 2 (1.4×10 4  for F2), 1 nM PM1-650 collecting all binders above background (4,000) and the top 0.2% (820) for FACS round 3 (F3). Individual peptide clones from the two F3 populations were identified by sequence analysis (Table 20), and selected peptide clones PM01-PM12 were subsequently verified for their ability to bind PM1 (masking moiety PM001 is also referred to herein as PM01 and/or PM-01; masking moiety PM002 is also referred to herein as PM02 and/or PM-02, and so on). 
     
       
         
           
               
               
               
               
             
               
                 TABLE 20 
               
               
                   
               
               
                   
                 Mask 
                 Amino Acid Sequence 
                 SEQ ID NO: 
               
               
                   
               
             
            
               
                   
                 PM01 
                 GCDFTSAKHNCGSGW 
                 1351 
               
               
                   
               
               
                   
                 PM02 
                 VGSNCWTGPACALTS 
                 1352 
               
               
                   
               
               
                   
                 PM03 
                 FCAVMFDFLSDRCLH 
                 1353 
               
               
                   
               
               
                   
                 PM04 
                 FCPPWLDYLGNKCMT 
                 1354 
               
               
                   
               
               
                   
                 PM05 
                 MSCWDFSSAQGCGQH 
                 1355 
               
               
                   
               
               
                   
                 PM06 
                 LMCADLHYNHYNCKY 
                 1356 
               
               
                   
               
               
                   
                 PM07 
                 ELCGWQSFSGVCTSE 
                 1357 
               
               
                   
               
               
                   
                 PM08 
                 WTYENCWASCQPHLE 
                 1358 
               
               
                   
               
               
                   
                 PM09 
                 KLTEDFSSAA 
                 1359 
               
               
                   
               
               
                   
                 PM10 
                 VGQSCFSGLVCDRQL 
                 1360 
               
               
                   
               
               
                   
                 PM11 
                 ISHYCFSGKSCRD 
                 1361 
               
               
                   
               
               
                   
                 PM12 
                 HCIPDFTSAAGDCMR 
                 1362 
               
               
                   
               
               
                   
                 PM13 
                 RLVSAYSFS 
                 1363 
               
               
                   
               
               
                   
                 PM14 
                 KFHHSHPLVHDFTSA 
                 1364 
               
               
                   
               
               
                   
                 PM15 
                 ASYPDFSSANGVGLR 
                 1365 
               
               
                   
               
               
                   
                 PM16 
                 GLATTLSNVDFTSAG 
                 1366 
               
               
                   
               
               
                   
                 PM17 
                 DFTSANSAFSGDAST 
                 1367 
               
               
                   
               
               
                   
                 PM18 
                 GRLPGHSVVDFTSAW 
                 1368 
               
               
                   
               
               
                   
                 PM19 
                 SGSFYSSSAFDFTSA 
                 1369 
               
               
                   
               
               
                   
                 PM20 
                 CDDFTSAQHSRINEC 
                 1370 
               
               
                   
               
               
                   
                 PM21 
                 CDFTSAQGKKCRTAL 
                 1371 
               
               
                   
               
               
                   
                 PM22 
                 YYIDKYQSPSYGPVL 
                 1372 
               
               
                   
               
               
                   
                 PM23 
                 FSVARARSSADFTSS 
                 1373 
               
               
                   
               
               
                   
                 PM24 
                 DSDFTSAGSADSRSR 
                 1374 
               
               
                   
               
               
                   
                 PM25 
                 CDFTSATSISKRCDH 
                 1375 
               
               
                   
               
               
                   
                 PM26 
                 IESSASSWGLQASRN 
                 1376 
               
               
                   
               
               
                   
                 PM27 
                 PRYHNLNFTTPALSPGS 
                 1377 
               
               
                   
               
               
                   
                 PM28 
                 DLFARFPLDRDFTSA 
                 1378 
               
               
                   
               
               
                   
                 PM29 
                 HCNFTTPPYCSSTLW 
                 1379 
               
               
                   
               
               
                   
                 PM30 
                 NVPIILLTDRQLLSG 
                 1380 
               
               
                   
               
               
                   
                 PM31 
                 NPTACDFTSSMATYC 
                 1381 
               
               
                   
               
               
                   
                 PM32 
                 FVRTVRFSNSMFSVP 
                 1382 
               
               
                   
               
               
                   
                 PM33 
                 YDFSSASNSSPSRQT 
                 1383 
               
               
                   
               
               
                   
                 PM34 
                 AHPDFSSAMRGNLLG 
                 1384 
               
               
                   
               
               
                   
                 PM35 
                 SSHVVHKDFTSANSR 
                 1385 
               
               
                   
               
               
                   
                 PM36 
                 CPDFTSANGGGCWQM 
                 1386 
               
               
                   
               
               
                   
                 PM37 
                 SLGQSYPTDFTCPGC 
                 1387 
               
               
                   
               
               
                   
                 PM38 
                 ASMRSHEQRDFTSAY 
                 1388 
               
               
                   
               
               
                   
                 PM39 
                 SCQFWFTLCSGGVFH 
                 1389 
               
               
                   
               
               
                   
                 PM40 
                 PYPNNRTGMHDFTSA 
                 1390 
               
               
                   
               
               
                   
                 PM41 
                 KPFPIDFTSAGTSGT 
                 1391 
               
               
                   
               
               
                   
                 PM42 
                 SIKSFIPRDDFTSAA 
                 1392 
               
               
                   
               
               
                   
                 PM43 
                 GIKNPATPFVDFTSA 
                 1393 
               
               
                   
               
               
                   
                 PM44 
                 LSHTYPRGSSTIEAS 
                 1394 
               
               
                   
               
               
                   
                 PM45 
                 PSLDFSSAT 
                 1395 
               
               
                   
               
               
                   
                 PM46 
                 AFTPRIAPTFDVMKE 
                 1396 
               
               
                   
               
               
                   
                 PM47 
                 LCGLQIPPDCERS 
                 1397 
               
               
                   
               
               
                   
                 PM48 
                 AAKMVSHSERDFTSA 
                 1398 
               
               
                   
               
               
                   
                 PM49 
                 VSVECFSGMQCPHYY 
                 1399 
               
               
                   
               
               
                   
                 PM50 
                 ASKCRLPCMASTQIY 
                 1400 
               
               
                   
               
               
                   
                 PM51 
                 GLRSCNIYFSIPCTY 
                 1401 
               
               
                   
               
               
                   
                 PM52 
                 RGTSDGTLDFTTARS 
                 1402 
               
               
                   
               
               
                   
                 PM53 
                 SMYPSASRLLHPQYP 
                 1403 
               
               
                   
               
               
                   
                 PM54 
                 HCISCYDFTSAAGSF 
                 1404 
               
               
                   
               
               
                   
                 PM55 
                 SSGRWGDAWACARIC 
                 1405 
               
               
                   
               
               
                   
                 PM56 
                 RVFSDFTSASHSFGG 
                 1406 
               
               
                   
               
               
                   
                 PM57 
                 TDRHSASGRDFTSAH 
                 1407 
               
               
                   
               
               
                   
                 PM58 
                 AHCEDFSSAERIATMGC 
                 1408 
               
               
                   
               
               
                   
                 PM59 
                 ACDPYSFSIPCDDRL 
                 1409 
               
               
                   
               
               
                   
                 PM60 
                 NSPFTLSHIYDR 
                 1410 
               
               
                   
               
               
                   
                 PM61 
                 IGTNFTTPSAFVAFP 
                 1411 
               
               
                   
               
               
                   
                 PM62 
                 RDAFPIYRNADFSTP 
                 1412 
               
               
                   
               
               
                   
                 PM63 
                 SIPNASSYNFTSSSG 
                 1413 
               
               
                   
               
               
                   
                 PM64 
                 AGIPDKRHTYDFTSA 
                 1414 
               
               
                   
               
               
                   
                 PM65 
                 WPLAHDSRDWNFTTP 
                 1415 
               
               
                   
               
               
                   
                 PM66 
                 RHSPSSGHVDFTSAG 
                 1416 
               
               
                   
               
               
                   
                 PM67 
                 SCFAWTDPVWNRCSW 
                 1417 
               
               
                   
               
               
                   
                 PM68 
                 MPCDWTGPGKIWCGG 
                 1418 
               
               
                   
               
               
                   
                 PM69 
                 RDCDFSTANFRSCNK 
                 1419 
               
               
                   
               
               
                   
                 PM70 
                 LSCVVSPNYLHCNDH 
                 1420 
               
               
                   
               
               
                   
                 PM71 
                 FVCGLYSFSGVCQGV 
                 1421 
               
               
                   
               
               
                   
                 PM72 
                 IGLMCFSGLQCPMLA 
                 1422 
               
               
                   
               
               
                   
                 PM73 
                 PGMNCFSGEICQMST 
                 1423 
               
               
                   
               
               
                   
                 PM74 
                 GDVGSCWASCGLQGG 
                 1424 
               
               
                   
               
               
                   
                 PM75 
                 SQFQDCWASCGASFT 
                 1425 
               
               
                   
               
               
                   
                 PM76 
                 VGSLNCWYSCGDIWL 
                 1426 
               
               
                   
               
               
                   
                 PM77 
                 MCESWLNFLGDQCGM 
                 1427 
               
               
                   
               
               
                   
                 PM78 
                 RCMISQSSFSGMCGM 
                 1428 
               
               
                   
               
               
                   
                 PM79 
                 NCAPWTSNMSNHCLK 
                 1429 
               
               
                   
               
               
                   
                 PM80 
                 LCGVGSATGLELCGV 
                 1430 
               
               
                   
               
               
                   
                 PM81 
                 GCDFSSLGGRQPCTP 
                 1431 
               
               
                   
               
               
                   
                 PM82 
                 MGCNFTTYPYHTCNT 
                 1432 
               
               
                   
               
               
                   
                 PM83 
                 GSCDFTSGAGKKCGS 
                 1433 
               
               
                   
               
               
                   
                 PM84 
                 VSCDFTSSHARMCSR 
                 1434 
               
               
                   
               
               
                   
                 PM85 
                 MRCTDFYYNHTNCIG 
                 1435 
               
               
                   
               
               
                   
                 PM86 
                 RSCDFTSAANKYCAT 
                 1436 
               
               
                   
               
               
                   
                 PM87 
                 LYCDSFSVPRPNCAP 
                 1437 
               
               
                   
               
               
                   
                 PM88 
                 NSCDFTSARVSKCST 
                 1438 
               
               
                   
               
               
                   
                 PM89 
                 STCSDNFTTPMPCNT 
                 1439 
               
               
                   
               
               
                   
                 PM90 
                 DICNDRPNLTHCHYF 
                 1440 
               
               
                   
               
               
                   
                 PM91 
                 LRCDDFTSAIGCRGY 
                 1441 
               
               
                   
               
               
                   
                 PM92 
                 EGCDFTSALHSCNNY 
                 1442 
               
               
                   
               
               
                   
                 PM93 
                 RKGCGDFTSASCFVV 
                 1443 
               
               
                   
               
               
                   
                 PM94 
                 GMLCAGSSFGLCESM 
                 1444 
               
               
                   
               
               
                   
                 PM95 
                 RESCFGSSLGLCTNK 
                 1445 
               
               
                   
               
               
                   
                 PM96 
                 ILRCYDIPTNCMNFN 
                 1446 
               
               
                   
               
               
                   
                 PM97 
                 NSECTFGAMYCRNKP 
                 1447 
               
               
                   
               
               
                   
                 PM98 
                 ASGCFDEDIRCSGGA 
                 1448 
               
               
                   
               
               
                   
                 PM99 
                 HYFCNQSNPSCQTAP 
                 1449 
               
               
                   
               
               
                   
                 PM100 
                 AMGCELGGAGCIGSP 
                 1450 
               
               
                   
               
               
                   
                 PM101 
                 TLKCHMPRKLCANDP 
                 1451 
               
               
                   
               
               
                   
                 PM102 
                 RPACRDLPHNCITST 
                 1452 
               
               
                   
               
               
                   
                 PM103 
                 QMSCHGNFTTCHSNP 
                 1453 
               
               
                   
               
               
                   
                 PM104 
                 LTGCARGARPCRLRV 
                 1454 
               
               
                   
               
               
                   
                 PM105 
                 WSELCLAGPSCGWVG 
                 1455 
               
               
                   
               
               
                   
                 PM106 
                 VTKSCWQLPHCITAP 
                 1456 
               
               
                   
               
               
                   
                 PM107 
                 KAASCPHNQICNMTA 
                 1457 
               
               
                   
               
               
                   
                 PM108 
                 VSKNCFSGMMCPVFA 
                 1458 
               
               
                   
               
               
                   
                 PM109 
                 NRSSCWTGPTCHVLH 
                 1459 
               
               
                   
               
               
                   
                 PM110 
                 ARTGCSGPVCLNDVS 
                 1460 
               
               
                   
               
               
                   
                 PM111 
                 STRTCLAFTCINGNT 
                 1461 
               
               
                   
               
               
                   
                 PM112 
                 MLDGNCWYACSYKNT 
                 1462 
               
               
                   
               
               
                   
                 PM113 
                 FSRSDCWSACAPWRV 
                 1463 
               
               
                   
               
               
                   
                 PM114 
                 GGRMDCWASCQPLSR 
                 1464 
               
               
                   
               
               
                   
                 PM115 
                 NSPHSCMTNCDFTSA 
                 1465 
               
               
                   
               
            
           
         
       
     
     Example 23: Activatable Anti-PD1 Pembrolizumab Antibodies 
     This example describes examples of activatable anti-PD1 Pembrolizumab antibodies of the disclosure. 
     Activatable anti-PD1 PM1 antibodies comprising an anti-PD1 PM1 masking moiety, a cleavable moiety, and an anti-PD1 PM1 antibody of the disclosure were produced according to methods similar to those described in PCT Publication Nos. WO 2009/025846 and WO 2010/081173. One embodiment of the disclosure is an anti-PD-1 activatable antibody comprising a heavy chain comprising amino acid sequence SEQ ID NO: 1514. One embodiment of the disclosure is an anti-PD-1 activatable antibody comprising a light chain comprising amino acid sequence SEQ ID NO: 638. One embodiment of the disclosure is an anti-PD-1 activatable antibody comprising a heavy chain comprising amino acid sequence SEQ ID NO: 1514 and a light chain comprising amino acid sequence SEQ ID NO: 638. One embodiment of the disclosure is an anti-PD-1 activatable antibody comprising the CDRs of an anti-PD-1 activatable antibody comprising a heavy chain comprising amino acid sequence SEQ ID NO: 1514 and a light chain comprising amino acid sequence SEQ ID NO: 638. 
     The amino acid and nucleic acid sequences of several activatable anti-PD1 antibody variable domains of the disclosure are provided below. Antibodies were produced as hIgG4 containing a single amino acid substitution, S228P (Angal, et al. 1993. Mol Immunol 30:105-8.) HC and hK LC format. 
     
       
         
           
               
            
               
                 PM1 Light Chain Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 638) 
               
               
                 EIVLTQSPATLSLSPGERATLSCRAS KGVSTSGYSY LHWYQQKPGQAPRL 
               
               
                   
               
               
                 LIY LAS YLESGVPARFSGSGSGTDFTLTISSLEPEDFAVYYC QHSRDLPL   
               
               
                   
               
               
                   T FGGGTKVEIK 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [PM1 PM01 2001 (SEQ ID NO: 1466)]   
               
               
                 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 1467) 
               
               
                 [QGQSGQG][CDFTSAKHNCGSGWGSSGGSISSGLLSGRSDNHGGSEI 
               
               
                   
               
               
                 VLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLI 
               
               
                   
               
               
                 YLASYLESGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTF 
               
               
                   
               
               
                 GGGTKVEIK] 
               
               
                   
               
               
                 PM1 PM01 2001 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1466) 
               
               
                 CDFTSAKHNCGSGWGSSGGSISSGLLSGRSDNHGGSEIVLTQSPATLSLS 
               
               
                   
               
               
                 PGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLESGVPA 
               
               
                   
               
               
                 RFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIK 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 1126)] 
               
               
                 [PM1 PM01 2001 (SEQ ID NO: 1468)]  
               
               
                 Nucleotide Sequence:  
               
               
                 (SEQ ID NO: 1469) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGA][TGCGATTTTACTTCTGCCAAGCAC 
               
               
                   
               
               
                 AATTGCGGCTCTGGCTGGGGCTCGAGCGGCGGCTCTATCTCTTCCGGACT 
               
               
                   
               
               
                 GCTGTCCGGCAGATCCGACAATCACGGCGGATCCGAGATCGTGCTGACAC 
               
               
                   
               
               
                 AGAGCCCTGCCACCCTGTCTCTGAGCCCTGGCGAAAGAGCCACCCTGAGC 
               
               
                   
               
               
                 TGTAGAGCCTCTAAGGGCGTGTCCACCAGCGGCTACAGCTACCTGCACTG 
               
               
                   
               
               
                 GTATCAGCAGAAGCCCGGCCAGGCCCCCAGACTGCTGATCTACCTGGCCT 
               
               
                   
               
               
                 CCTACCTGGAAAGCGGCGTGCCCGCCAGATTTTCTGGCTCTGGCAGCGGC 
               
               
                   
               
               
                 ACCGACTTCACCCTGACAATCAGCAGCCTGGAACCCGAGGACTTCGCCGT 
               
               
                   
               
               
                 GTACTACTGCCAGCACAGCAGGGACCTGCCCCTGACATTTGGCGGAGGCA 
               
               
                   
               
               
                 CCAAGGTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [PM1 PM02 2001 (SEQ ID NO: 1470)]  
               
               
                 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1471) 
               
               
                 [QGQSGQG][VGSNCWTGPACALTSGGGSSGGSISSGLLSGRSDNHGG 
               
               
                   
               
               
                 SEIVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPR 
               
               
                   
               
               
                 LLIYLASYLESGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLP 
               
               
                   
               
               
                 LTFGGGTKVEIK] 
               
               
                   
               
               
                 PM1 PM02 2001 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1470) 
               
               
                 VGSNCWTGPACALTSGGGSSGGSISSGLLSGRSDNHGGSEIVLTQSPATL 
               
               
                   
               
               
                 SLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLESG 
               
               
                   
               
               
                 VPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIK 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)] 
               
               
                 [PM1 PM02 2001 (SEQ ID NO: 1472)]  
               
               
                 Nucleotide Sequence:  
               
               
                 (SEQ ID NO: 1473) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][GTTGGGTCGAATTGCTGGACGGGGCC 
               
               
                   
               
               
                 GGCGTGCGCTTTGACGTCGGGAGGTGGCTCGAGCGGCGGCTCTATCTCTT 
               
               
                   
               
               
                 CCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGATCCGAGATCGTG 
               
               
                   
               
               
                 CTGACACAGAGCCCTGCCACCCTGTCTCTGAGCCCTGGCGAAAGAGCCAC 
               
               
                   
               
               
                 CCTGAGCTGTAGAGCCTCTAAGGGCGTGTCCACCAGCGGCTACAGCTACC 
               
               
                   
               
               
                 TGCACTGGTATCAGCAGAAGCCCGGCCAGGCCCCCAGACTGCTGATCTAC 
               
               
                   
               
               
                 CTGGCCTCCTACCTGGAAAGCGGCGTGCCCGCCAGATTTTCTGGCTCTGG 
               
               
                   
               
               
                 CAGCGGCACCGACTTCACCCTGACAATCAGCAGCCTGGAACCCGAGGACT 
               
               
                   
               
               
                 TCGCCGTGTACTACTGCCAGCACAGCAGGGACCTGCCCCTGACATTTGGC 
               
               
                   
               
               
                 GGAGGCACCAAGGTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [PM1 PM03 2001 (SEQ ID NO: 1474)]  
               
               
                 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1475) 
               
               
                 [QGQSGQG][FCAVMFDFLSDRCLHGGGSSGGSISSGLLSGRSDNHGGSE 
               
               
                   
               
               
                 IVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLL 
               
               
                   
               
               
                 IYLASYLESGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLT 
               
               
                   
               
               
                 FGGGTKVEIK] 
               
               
                   
               
               
                 PM1 PM03 2001 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1474) 
               
               
                 FCAVMFDFLSDRCLHGGGSSGGSISSGLLSGRSDNHGGSEIVLTQSPATL 
               
               
                   
               
               
                 SLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLESG 
               
               
                   
               
               
                 VPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIK 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)] 
               
               
                 [PM1 PM03 2001 (SEQ ID NO: 1476)]  
               
               
                 Nucleotide Sequence:  
               
               
                 (SEQ ID NO: 1477) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][TTTTGCGCTGTGATGTTTGATTTTCT 
               
               
                   
               
               
                 GTCTGATCGGTGCCTGCATGGAGGTGGCTCGAGCGGCGGCTCTATCTCTT 
               
               
                   
               
               
                 CCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGATCCGAGATCGTG 
               
               
                   
               
               
                 CTGACACAGAGCCCTGCCACCCTGTCTCTGAGCCCTGGCGAAAGAGCCAC 
               
               
                   
               
               
                 CCTGAGCTGTAGAGCCTCTAAGGGCGTGTCCACCAGCGGCTACAGCTACC 
               
               
                   
               
               
                 TGCACTGGTATCAGCAGAAGCCCGGCCAGGCCCCCAGACTGCTGATCTAC 
               
               
                   
               
               
                 CTGGCCTCCTACCTGGAAAGCGGCGTGCCCGCCAGATTTTCTGGCTCTGG 
               
               
                   
               
               
                 CAGCGGCACCGACTTCACCCTGACAATCAGCAGCCTGGAACCCGAGGACT 
               
               
                   
               
               
                 TCGCCGTGTACTACTGCCAGCACAGCAGGGACCTGCCCCTGACATTTGGC 
               
               
                   
               
               
                 GGAGGCACCAAGGTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [PM1 PM04 2001 (SEQ ID NO: 1478)]  
               
               
                 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1479) 
               
               
                 [QGQSGQG][FCPPWLDYLGNKCMTGGGSSGGSISSGLLSGRSDNHGGSE 
               
               
                   
               
               
                 IVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLL 
               
               
                   
               
               
                 IYLASYLESGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLT 
               
               
                   
               
               
                 FGGGTKVEIK] 
               
               
                   
               
               
                 PM1 PM04 2001 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1478) 
               
               
                 FCPPWLDYLGNKCMTGGGSSGGSISSGLLSGRSDNHGGSEIVLTQSPATL 
               
               
                   
               
               
                 SLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLESG 
               
               
                   
               
               
                 VPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIK 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)] 
               
               
                 [PM1 PM04 2001 (SEQ ID NO: 1480)]  
               
               
                 Nucleotide Sequence:  
               
               
                 (SEQ ID NO: 1481) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][TTTTGCCCGCCGTGGTTGGATTATTT 
               
               
                   
               
               
                 GGGTAATAAGTGCATGACGGGAGGTGGCTCGAGCGGCGGCTCTATCTCTT 
               
               
                   
               
               
                 CCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGATCCGAGATCGTG 
               
               
                   
               
               
                 CTGACACAGAGCCCTGCCACCCTGTCTCTGAGCCCTGGCGAAAGAGCCAC 
               
               
                   
               
               
                 CCTGAGCTGTAGAGCCTCTAAGGGCGTGTCCACCAGCGGCTACAGCTACC 
               
               
                   
               
               
                 TGCACTGGTATCAGCAGAAGCCCGGCCAGGCCCCCAGACTGCTGATCTAC 
               
               
                   
               
               
                 CTGGCCTCCTACCTGGAAAGCGGCGTGCCCGCCAGATTTTCTGGCTCTGG 
               
               
                   
               
               
                 CAGCGGCACCGACTTCACCCTGACAATCAGCAGCCTGGAACCCGAGGACT 
               
               
                   
               
               
                 TCGCCGTGTACTACTGCCAGCACAGCAGGGACCTGCCCCTGACATTTGGC 
               
               
                   
               
               
                 GGAGGCACCAAGGTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [PM1 PM05 2001 (SEQ ID NO: 1482)]  
               
               
                 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1483) 
               
               
                 [QGQSGQG][MSCWDFSSAQGCGQHGGGSSGGSISSGLLSGRSDNHGGSE 
               
               
                   
               
               
                 IVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLL 
               
               
                   
               
               
                 IYLASYLESGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLT 
               
               
                   
               
               
                 FGGGTKVEIK] 
               
               
                   
               
               
                 PM1 PM05 2001 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1482) 
               
               
                 MSCWDFSSAQGCGQHGGGSSGGSISSGLLSGRSDNHGGSEIVLTQSPATL 
               
               
                   
               
               
                 SLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLESG 
               
               
                   
               
               
                 VPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIK 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)] 
               
               
                 [PM1 PM05 2001 (SEQ ID NO: 1484)]  
               
               
                 Nucleotide Sequence:  
               
               
                 (SEQ ID NO: 1485) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][ATGTCTTGCTGGGATTTTTCTTCGGC 
               
               
                   
               
               
                 TCAGGGGTGCGGTCAGCATGGAGGTGGCTCGAGCGGCGGCTCTATCTCTT 
               
               
                   
               
               
                 CCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGATCCGAGATCGTG 
               
               
                   
               
               
                 CTGACACAGAGCCCTGCCACCCTGTCTCTGAGCCCTGGCGAAAGAGCCAC 
               
               
                   
               
               
                 CCTGAGCTGTAGAGCCTCTAAGGGCGTGTCCACCAGCGGCTACAGCTACC 
               
               
                   
               
               
                 TGCACTGGTATCAGCAGAAGCCCGGCCAGGCCCCCAGACTGCTGATCTAC 
               
               
                   
               
               
                 CTGGCCTCCTACCTGGAAAGCGGCGTGCCCGCCAGATTTTCTGGCTCTGG 
               
               
                   
               
               
                 CAGCGGCACCGACTTCACCCTGACAATCAGCAGCCTGGAACCCGAGGACT 
               
               
                   
               
               
                 TCGCCGTGTACTACTGCCAGCACAGCAGGGACCTGCCCCTGACATTTGGC 
               
               
                   
               
               
                 GGAGGCACCAAGGTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [PM1 PM06 2001 (SEQ ID NO: 1486)]  
               
               
                 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1487) 
               
               
                 [QGQSGQG][LMCADLHYNHYNCKYGGGSSGGSISSGLLSGRSDNHGGSE 
               
               
                   
               
               
                 IVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLL 
               
               
                   
               
               
                 IYLASYLESGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLT 
               
               
                   
               
               
                 FGGGTKVEIK] 
               
               
                   
               
               
                 PM1 PM06 2001 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1486) 
               
               
                 LMCADLHYNHYNCKYGGGSSGGSISSGLLSGRSDNHGGSEIVLTQSPATL 
               
               
                   
               
               
                 SLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLESG 
               
               
                   
               
               
                 VPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIK 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)] 
               
               
                 [PM1 PM06 2001 (SEQ ID NO: 1488)]  
               
               
                 Nucleotide Sequence:  
               
               
                 (SEQ ID NO: 1489) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][TTGATGTGCGCTGATTTGCATTATAA 
               
               
                   
               
               
                 TCATTATAATTGCAAGTATGGAGGTGGCTCGAGCGGCGGCTCTATCTCTT 
               
               
                   
               
               
                 CCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGATCCGAGATCGTG 
               
               
                   
               
               
                 CTGACACAGAGCCCTGCCACCCTGTCTCTGAGCCCTGGCGAAAGAGCCAC 
               
               
                   
               
               
                 CCTGAGCTGTAGAGCCTCTAAGGGCGTGTCCACCAGCGGCTACAGCTACC 
               
               
                   
               
               
                 TGCACTGGTATCAGCAGAAGCCCGGCCAGGCCCCCAGACTGCTGATCTAC 
               
               
                   
               
               
                 CTGGCCTCCTACCTGGAAAGCGGCGTGCCCGCCAGATTTTCTGGCTCTGG 
               
               
                   
               
               
                 CAGCGGCACCGACTTCACCCTGACAATCAGCAGCCTGGAACCCGAGGACT 
               
               
                   
               
               
                 TCGCCGTGTACTACTGCCAGCACAGCAGGGACCTGCCCCTGACATTTGGC 
               
               
                   
               
               
                 GGAGGCACCAAGGTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [PM1 PM07 2001 (SEQ ID NO: 1490)]  
               
               
                 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1491) 
               
               
                 [QGQSGQG][ELCGWQSFSGVCTSEGGGSSGGSISSGLLSGRSDNHGGSE 
               
               
                   
               
               
                 IVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLL 
               
               
                   
               
               
                 IYLASYLESGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLT 
               
               
                   
               
               
                 FGGGTKVEIK] 
               
               
                   
               
               
                 PM1 PM07 2001 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1490) 
               
               
                 ELCGWQSFSGVCTSEGGGSSGGSISSGLLSGRSDNHGGSEIVLTQSPATL 
               
               
                   
               
               
                 SLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLESG 
               
               
                   
               
               
                 VPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIK 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)] 
               
               
                 [PM1 PM07 2001 (SEQ ID NO: 1492)]  
               
               
                 Nucleotide Sequence:  
               
               
                 (SEQ ID NO: 1493) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][GAGTTGTGCGGTTGGCAGAGTTTTTC 
               
               
                   
               
               
                 GGGGGTTTGCACTAGTGAGGGAGGTGGCTCGAGCGGCGGCTCTATCTCTT 
               
               
                   
               
               
                 CCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGATCCGAGATCGTG 
               
               
                   
               
               
                 CTGACACAGAGCCCTGCCACCCTGTCTCTGAGCCCTGGCGAAAGAGCCAC 
               
               
                   
               
               
                 CCTGAGCTGTAGAGCCTCTAAGGGCGTGTCCACCAGCGGCTACAGCTACC 
               
               
                   
               
               
                 TGCACTGGTATCAGCAGAAGCCCGGCCAGGCCCCCAGACTGCTGATCTAC 
               
               
                   
               
               
                 CTGGCCTCCTACCTGGAAAGCGGCGTGCCCGCCAGATTTTCTGGCTCTGG 
               
               
                   
               
               
                 CAGCGGCACCGACTTCACCCTGACAATCAGCAGCCTGGAACCCGAGGACT 
               
               
                   
               
               
                 TCGCCGTGTACTACTGCCAGCACAGCAGGGACCTGCCCCTGACATTTGGC 
               
               
                   
               
               
                 GGAGGCACCAAGGTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [PM1 PM08 2001 (SEQ ID NO: 1494)]  
               
               
                 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1495) 
               
               
                 [QGQSGQG][WTYENCWASCQPHLEGGGSSGGSISSGLLSGRSDNHGGSE 
               
               
                   
               
               
                 IVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLL 
               
               
                   
               
               
                 IYLASYLESGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLT 
               
               
                   
               
               
                 FGGGTKVEIK] 
               
               
                   
               
               
                 PM1 PM08 2001 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1494) 
               
               
                 WTYENCWASCQPHLEGGGSSGGSISSGLLSGRSDNHGGSEIVLTQSPATL 
               
               
                   
               
               
                 SLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLESG 
               
               
                   
               
               
                 VPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIK 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)] 
               
               
                 [PM1 PM08 2001 (SEQ ID NO: 1496)]  
               
               
                 Nucleotide Sequence:  
               
               
                 (SEQ ID NO: 1497) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][TGGACTTATGAGAATTGCTGGGCTTC 
               
               
                   
               
               
                 GTGCCAGCCTCATTTGGAGGGAGGTGGCTCGAGCGGCGGCTCTATCTCTT 
               
               
                   
               
               
                 CCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGATCCGAGATCGTG 
               
               
                   
               
               
                 CTGACACAGAGCCCTGCCACCCTGTCTCTGAGCCCTGGCGAAAGAGCCAC 
               
               
                   
               
               
                 CCTGAGCTGTAGAGCCTCTAAGGGCGTGTCCACCAGCGGCTACAGCTACC 
               
               
                   
               
               
                 TGCACTGGTATCAGCAGAAGCCCGGCCAGGCCCCCAGACTGCTGATCTAC 
               
               
                   
               
               
                 CTGGCCTCCTACCTGGAAAGCGGCGTGCCCGCCAGATTTTCTGGCTCTGG 
               
               
                   
               
               
                 CAGCGGCACCGACTTCACCCTGACAATCAGCAGCCTGGAACCCGAGGACT 
               
               
                   
               
               
                 TCGCCGTGTACTACTGCCAGCACAGCAGGGACCTGCCCCTGACATTTGGC 
               
               
                   
               
               
                 GGAGGCACCAAGGTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 913)] 
               
               
                 [PM1 PM09 2001 (SEQ ID NO: 1498)]  
               
               
                 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1499) 
               
               
                 [QGQSGQ][KLTEDFSSAAGSSGGSISSGLLSGRSDNHGGSEIVLTQSPA 
               
               
                   
               
               
                 TLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLE 
               
               
                   
               
               
                 SGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVE 
               
               
                   
               
               
                 IK] 
               
               
                   
               
               
                 PM1 PM09 2001 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1498) 
               
               
                 KLTEDFSSAAGSSGGSISSGLLSGRSDNHGGSEIVLTQSPATLSLSPGER 
               
               
                   
               
               
                 ATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLESGVPARFSG 
               
               
                   
               
               
                 SGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIK 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 1518)] 
               
               
                 [PM1 PM09 2001 (SEQ ID NO: 1500)]  
               
               
                 Nucleotide Sequence:  
               
               
                 (SEQ ID NO: 1501) 
               
               
                 [CAAGGCCAGTCTGGCCAA][AAGCTTACTGAGGATTTTTCTAGCGCAGC 
               
               
                   
               
               
                 AGGCTCGAGCGGCGGCTCTATCTCTTCCGGACTGCTGTCCGGCAGATCCG 
               
               
                   
               
               
                 ACAATCACGGCGGATCCGAGATCGTGCTGACACAGAGCCCTGCCACCCTG 
               
               
                   
               
               
                 TCTCTGAGCCCTGGCGAAAGAGCCACCCTGAGCTGTAGAGCCTCTAAGGG 
               
               
                   
               
               
                 CGTGTCCACCAGCGGCTACAGCTACCTGCACTGGTATCAGCAGAAGCCCG 
               
               
                   
               
               
                 GCCAGGCCCCCAGACTGCTGATCTACCTGGCCTCCTACCTGGAAAGCGGC 
               
               
                   
               
               
                 GTGCCCGCCAGATTTTCTGGCTCTGGCAGCGGCACCGACTTCACCCTGAC 
               
               
                   
               
               
                 AATCAGCAGCCTGGAACCCGAGGACTTCGCCGTGTACTACTGCCAGCACA 
               
               
                   
               
               
                 GCAGGGACCTGCCCCTGACATTTGGCGGAGGCACCAAGGTGGAAATC 
               
               
                   
               
               
                 AAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [PM1 PM10 2001 (SEQ ID NO: 1502)]  
               
               
                 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1503) 
               
               
                 [QGQSGQG][VGQSCFSGLVCDRQLGGGSSGGSISSGLLSGRSDNHGGSE 
               
               
                   
               
               
                 IVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLL 
               
               
                   
               
               
                 IYLASYLESGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLT 
               
               
                   
               
               
                 FGGGTKVEIK] 
               
               
                   
               
               
                 PM1 PM10 2001 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1502) 
               
               
                 VGQSCFSGLVCDRQLGGGSSGGSISSGLLSGRSDNHGGSEIVLTQSPATL 
               
               
                   
               
               
                 SLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLESG 
               
               
                   
               
               
                 VPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIK 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)] 
               
               
                 [PM1 PM10 2001 (SEQ ID NO: 1504)]  
               
               
                 Nucleotide Sequence:  
               
               
                 (SEQ ID NO: 1505) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][GTGGGGCAGAGTTGCTTTTCTGGGCT 
               
               
                   
               
               
                 GGTTTGCGATAGGCAGCTGGGAGGTGGCTCGAGCGGCGGCTCTATCTCTT 
               
               
                   
               
               
                 CCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGATCCGAGATCGTG 
               
               
                   
               
               
                 CTGACACAGAGCCCTGCCACCCTGTCTCTGAGCCCTGGCGAAAGAGCCAC 
               
               
                   
               
               
                 CCTGAGCTGTAGAGCCTCTAAGGGCGTGTCCACCAGCGGCTACAGCTACC 
               
               
                   
               
               
                 TGCACTGGTATCAGCAGAAGCCCGGCCAGGCCCCCAGACTGCTGATCTAC 
               
               
                   
               
               
                 CTGGCCTCCTACCTGGAAAGCGGCGTGCCCGCCAGATTTTCTGGCTCTGG 
               
               
                   
               
               
                 CAGCGGCACCGACTTCACCCTGACAATCAGCAGCCTGGAACCCGAGGACT 
               
               
                   
               
               
                 TCGCCGTGTACTACTGCCAGCACAGCAGGGACCTGCCCCTGACATTTGGC 
               
               
                   
               
               
                 GGAGGCACCAAGGTGGAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 913)] 
               
               
                 [PM1 PM11 2001 (SEQ ID NO: 1506)]  
               
               
                 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1507) 
               
               
                 [QGQSGQ][ISHYCFSGKSCRDGSSGGSISSGLLSGRSDNHGGSEIVLTQ 
               
               
                   
               
               
                 SPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLAS 
               
               
                   
               
               
                 YLESGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGT 
               
               
                   
               
               
                 KVEIK] 
               
               
                   
               
               
                 PM1 PM11 2001 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1506) 
               
               
                 ISHYCFSGKSCRDGSSGGSISSGLLSGRSDNHGGSEIVLTQSPATLSLSP 
               
               
                   
               
               
                 GERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLESGVPAR 
               
               
                   
               
               
                 FSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIK 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 1518)] 
               
               
                 [PM1 PM11 2001 (SEQ ID NO: 1508)]  
               
               
                 Nucleotide Sequence:  
               
               
                 (SEQ ID NO: 1509) 
               
               
                 [CAAGGCCAGTCTGGCCAA][ATCTCTCACTATTGTTTCAGTGGCAAATC 
               
               
                   
               
               
                 CTGCAGGGACGGCTCGAGCGGCGGCTCTATCTCTTCCGGACTGCTGTCCG 
               
               
                   
               
               
                 GCAGATCCGACAATCACGGCGGATCCGAGATCGTGCTGACACAGAGCCCT 
               
               
                   
               
               
                 GCCACCCTGTCTCTGAGCCCTGGCGAAAGAGCCACCCTGAGCTGTAGAGC 
               
               
                   
               
               
                 CTCTAAGGGCGTGTCCACCAGCGGCTACAGCTACCTGCACTGGTATCAGC 
               
               
                   
               
               
                 AGAAGCCCGGCCAGGCCCCCAGACTGCTGATCTACCTGGCCTCCTACCTG 
               
               
                   
               
               
                 GAAAGCGGCGTGCCCGCCAGATTTTCTGGCTCTGGCAGCGGCACCGACTT 
               
               
                   
               
               
                 CACCCTGACAATCAGCAGCCTGGAACCCGAGGACTTCGCCGTGTACTACT 
               
               
                   
               
               
                 GCCAGCACAGCAGGGACCTGCCCCTGACATTTGGCGGAGGCACCAAGGTG 
               
               
                   
               
               
                 GAAATCAAG] 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [PM1 PM12 2001 (SEQ ID NO: 1510)]  
               
               
                 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1511) 
               
               
                 [QGQSGQG][HCIPDFTSAAGDCMRGGGSSGGSISSGLLSGRSDNHGGSE 
               
               
                   
               
               
                 IVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLL 
               
               
                   
               
               
                 IYLASYLESGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLT 
               
               
                   
               
               
                 FGGGTKVEIK] 
               
               
                   
               
               
                 PM1 PM12 2001 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1510) 
               
               
                 HCIPDFTSAAGDCMRGGGSSGGSISSGLLSGRSDNHGGSEIVLTQSPATL 
               
               
                   
               
               
                 SLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLESG 
               
               
                   
               
               
                 VPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIK 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 918)] 
               
               
                 [PM1 PM12 2001 (SEQ ID NO: 1512)]  
               
               
                 Nucleotide Sequence:  
               
               
                 (SEQ ID NO: 1513) 
               
               
                 [CAAGGCCAGTCTGGCCAAGGT][CATTGCATTCCTGATTTTACTTCTGC 
               
               
                   
               
               
                 TGCTGGTGATTGCATGAGGGGAGGTGGCTCGAGCGGCGGCTCTATCTCTT 
               
               
                   
               
               
                 CCGGACTGCTGTCCGGCAGATCCGACAATCACGGCGGATCCGAGATCGTG 
               
               
                   
               
               
                 CTGACACAGAGCCCTGCCACCCTGTCTCTGAGCCCTGGCGAAAGAGCCAC 
               
               
                   
               
               
                 CCTGAGCTGTAGAGCCTCTAAGGGCGTGTCCACCAGCGGCTACAGCTACC 
               
               
                   
               
               
                 TGCACTGGTATCAGCAGAAGCCCGGCCAGGCCCCCAGACTGCTGATCTAC 
               
               
                   
               
               
                 CTGGCCTCCTACCTGGAAAGCGGCGTGCCCGCCAGATTTTCTGGCTCTGG 
               
               
                   
               
               
                 CAGCGGCACCGACTTCACCCTGACAATCAGCAGCCTGGAACCCGAGGACT 
               
               
                   
               
               
                 TCGCCGTGTACTACTGCCAGCACAGCAGGGACCTGCCCCTGACATTTGGC 
               
               
                   
               
               
                 GGAGGCACCAAGGTGGAAATCAAG] 
               
               
                   
               
               
                 PM1 HC Variable  
               
               
                 (SEQ ID NO: 1514) 
               
               
                 QVQLVQSGVEVKKPGASVKVSCKAS GYTFTNYY MYWVRQAPGQGLEWMGG 
               
               
                   
               
               
                   INPSNGGT NFNEKFKNRVTLTTDSSTTTAYMELKSLQFDDTAVYYCA RRD   
               
               
                   
               
               
                   YRFDMGFDY WGQGTTVTVSS 
               
               
                   
               
               
                 PM1 HC Variable  
               
               
                 (SEQ ID NO: 1515) 
               
               
                 CAGGTGCAGCTGGTGCAGTCTGGCGTGGAAGTGAAGAAACCAGGCGCCAG 
               
               
                   
               
               
                 CGTGAAGGTGTCCTGCAAGGCCAGCGGCTACACCTTTACCAACTACTACA 
               
               
                   
               
               
                 TGTACTGGGTGCGCCAGGCCCCAGGCCAGGGACTGGAATGGATGGGCGGC 
               
               
                   
               
               
                 ATCAACCCCAGCAACGGCGGCACCAACTTCAACGAGAAGTTCAAGAACAG 
               
               
                   
               
               
                 AGTGACCCTGACCACCGACAGCAGCACCACCACCGCCTACATGGAACTGA 
               
               
                   
               
               
                 AGTCCCTGCAGTTCGACGACACCGCCGTGTACTACTGCGCCAGACGGGAC 
               
               
                   
               
               
                 TACAGATTCGACATGGGCTTCGACTACTGGGGCCAGGGCACAACCGTGAC 
               
               
                   
               
               
                 CGTGTCTAGT 
               
            
           
         
       
     
     Example 24: Characterization of Activatable Anti-PD1 PM1 Antibodies 
     This example describes activatable anti-PD1 PM1 antibodies with reduced binding to hPD1. 
     Masking efficiencies were evaluated by standard plate ELISA. Briefly, human PD1-Fc (R and D systems, Minneapolis, Minn.) was adsorbed to the wells of a 96-well ELISA plate. Purified PM1 and activatable PM1 antibodies were applied to the plate in serial dilution and allowed to bind. Bound antibody and activatable antibodies were detected with anti-hu Fab-HRP conjugate (Sigma, St Louis, Mo.) and visualized with the chromogenic substrate TMB (Thermo Scientific, Rockford, Ill.). Plots were generated in Prizm (Sigma Plot). All activatable PM1 antibodies showed decreased binding compared with the parental PM1, as shown in  FIGS. 27A, 27B, and 27C . 
     Example 25: Characterization of Anti-PD1 Activatable Antibodies of the Disclosure 
     The binding properties of several masking moieties of the disclosure identified for A1.5 (PD), NV1 (NV) and PM1 (PM) antibodies were evaluated. Eight peptide clones from each mask discovery effort were grown overnight at 37° C., 850 rpm in 2 mL deep well plates in LB+Chloramphenicol+0.2% glucose, diluted 1:20 in LB+Chloramphenicol and grown 105 minutes at 37° C., 850 rpm. Peptide expression was induced by the addition of 0.04% arabinose for 35 minutes, and clones were stained with 1 nM A1.5-DyLight 650, 1 nM PM1-Dylight 650 and 1 nM NV1-Dylight 650 in cold PBS+0.5% BSA. Clones were pelleted, the staining solution was removed, and cells were resuspended in PBS+1% formaldehyde. Fluorescence was measured on a MACSQuant Analyzer 10 flow cytometer manufactured by Miltenyi Biotec, Inc. (San Diego, Calif.). As shown in  FIG. 28 , masking moieties bound to the anti-PD1 antibody used in the library screening from which they were identified. 
     Example 26: Evaluation of Masking Moiety Binding by Effector Negative Activatable Antibodies 
     This example describes additional activatable anti-PD-1 J43 antibodies that exhibit reduced binding to mouse PD-1. 
     Examples of additional activatable antibodies of the disclosure comprising an IgG2a effector negative (EN) anti-PD1 antibody J43 (J43 m2a EN) and a variety of mask and substrate combinations were produced using techniques as described herein. The amino acid and nucleic acid sequences of the constant region of the IgG2a EN antibody are provided below. A plasmid encoding this effector negative Fc region, pFUSE-mIgG2Ae1-Fc, is available from InvivoGen, San Diego, Calif. The Fc region of mIgG2a was engineered by mutating the following amino acids to reduce binding to FcR and C1q: L235E and E318A/K320A/K322A. 
     
       
         
           
               
            
               
                 +LT,1 &gt;mIgG2a EN  
               
               
                 (SEQ ID NO: 1516) 
               
               
                 AKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGV 
               
               
                   
               
               
                 HTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPR 
               
               
                   
               
               
                 GPTIKPCPPCKCPAPNLEGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVS 
               
               
                   
               
               
                 EDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGK 
               
               
                   
               
               
                 AFACAVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTC 
               
               
                   
               
               
                 MVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNW 
               
               
                   
               
               
                 VERNSYSCSVVHEGLHNHHTTKSFSRTPGK 
               
               
                   
               
               
                 &gt;mIgG2a EN  
               
               
                 (SEQ ID NO: 1517) 
               
               
                 GCCAAGACAACAGCCCCCAGCGTGTACCCTCTGGCCCCTGTGTGTGGCGA 
               
               
                   
               
               
                 TACCACAGGCAGCTCTGTGACCCTGGGCTGCCTCGTGAAGGGCTACTTCC 
               
               
                   
               
               
                 CTGAGCCAGTGACCCTGACCTGGAACAGCGGCTCTCTGTCTAGCGGCGTG 
               
               
                   
               
               
                 CACACCTTTCCAGCCGTGCTGCAGAGCGACCTGTACACCCTGAGCAGCAG 
               
               
                   
               
               
                 CGTGACCGTGACCAGCAGCACATGGCCCAGCCAGAGCATCACCTGTAACG 
               
               
                   
               
               
                 TGGCCCACCCTGCCAGCTCCACCAAGGTGGACAAGAAGATCGAGCCCAGA 
               
               
                   
               
               
                 GGCCCCACCATCAAGCCTTGCCCCCCTTGCAAATGCCCTGCCCCCAATCT 
               
               
                   
               
               
                 GGAAGGCGGCCCTAGCGTGTTCATCTTCCCACCCAAGATCAAGGACGTGC 
               
               
                   
               
               
                 TGATGATCAGCCTGAGCCCCATCGTGACCTGCGTGGTGGTGGACGTGTCC 
               
               
                   
               
               
                 GAGGACGACCCCGATGTGCAGATCAGTTGGTTCGTGAACAACGTGGAAGT 
               
               
                   
               
               
                 GCACACCGCCCAGACCCAGACACACAGAGAGGACTACAACAGCACCCTGA 
               
               
                   
               
               
                 GAGTGGTGTCCGCCCTGCCCATCCAGCACCAGGATTGGATGAGCGGCAAG 
               
               
                   
               
               
                 GCCTTCGCCTGCGCTGTGAACAACAAGGACCTGCCAGCCCCCATCGAGCG 
               
               
                   
               
               
                 GACCATCTCTAAGCCTAAGGGCAGCGTGCGGGCTCCCCAGGTGTACGTGC 
               
               
                   
               
               
                 TGCCTCCTCCAGAGGAAGAGATGACCAAGAAACAAGTGACACTGACATGC 
               
               
                   
               
               
                 ATGGTCACCGACTTCATGCCCGAGGACATCTACGTGGAATGGACCAACAA 
               
               
                   
               
               
                 CGGCAAGACCGAGCTGAACTACAAGAACACCGAGCCCGTGCTGGACAGCG 
               
               
                   
               
               
                 ACGGCAGCTACTTCATGTACAGCAAGCTGCGGGTGGAAAAGAAAAACTGG 
               
               
                   
               
               
                 GTGGAACGGAACAGCTACAGCTGCAGCGTGGTGCACGAGGGCCTGCACAA 
               
               
                   
               
               
                 TCACCACACCACCAAGAGCTTCAGCCGGACCCCTGGAAAA 
               
            
           
         
       
     
     Masking efficiencies of several of these activatable antibodies were determined as described herein. The results are shown in  FIG. 29A  and  FIG. 29B . 
     J43m2a EN Activatable Antibody LCs: 
       
     
       
         
           
               
            
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [J43m2a EN MP8-2 2001 (SEQ ID NO: 1808)] Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 1809) 
               
               
                 [QGQSGQG][ACRICQDHPATKWNSGGGSSGGSISSGLLSGRSDNHGGGS 
               
               
                   
               
               
                 YELTQPPSASVNVGETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDN 
               
               
                   
               
               
                 KRPSGIPERISGSSSGTTATLTIRDVRAEDEGDYYCFSGYVDSDSKLYVF 
               
               
                   
               
               
                 GSGTQLTVLGGPKSSPKVTVFPPSPEELRTNKATLVCLVNDFYPGSATVT 
               
               
                   
               
               
                 WKANGATINDGVKTTKPSKQGQNYMTSSYLSLTADQWKSHNRVSCQVTHE 
               
               
                   
               
               
                 GETVEKSLSPAECL] 
               
               
                   
               
               
                 J43m2a EN MP8-2 2001 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1808) 
               
               
                 ACRICQDHPATKWNSGGGSSGGSISSGLLSGRSDNHGGGSYELTQPPSAS 
               
               
                   
               
               
                 VNVGETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPERI 
               
               
                   
               
               
                 SGSSSGTTATLTIRDVRAEDEGDYYCFSGYVDSDSKLYVFGSGTQLTVLG 
               
               
                   
               
               
                 GPKSSPKVTVFPPSPEELRTNKATLVCLVNDFYPGSATVTWKANGATIND 
               
               
                   
               
               
                 GVKTTKPSKQGQNYMTSSYLSLTADQWKSHNRVSCQVTHEGETVEKSLSP 
               
               
                   
               
               
                 AECL 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [J43m2a EN MP8-2 2011 (SEQ ID NO: 1810)]  
               
               
                 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 1811) 
               
               
                 [QGQSGQG][ACRICQDHPATKWNSGGGSSGGSISSGLLSGRSDNPGGGS 
               
               
                   
               
               
                 YELTQPPSASVNVGETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDN 
               
               
                   
               
               
                 KRPSGIPERISGSSSGTTATLTIRDVRAEDEGDYYCFSGYVDSDSKLYVF 
               
               
                   
               
               
                 GSGTQLTVLGGPKSSPKVTVFPPSPEELRTNKATLVCLVNDFYPGSATVT 
               
               
                   
               
               
                 WKANGATINDGVKTTKPSKQGQNYMTSSYLSLTADQWKSHNRVSCQVTHE 
               
               
                   
               
               
                 GETVEKSLSPAECL] 
               
               
                   
               
               
                 J43m2a EN MP8-2 2011 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1810) 
               
               
                 ACRICQDHPATKWNSGGGSSGGSISSGLLSGRSDNPGGGSYELTQPPSAS 
               
               
                   
               
               
                 VNVGETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPERI 
               
               
                   
               
               
                 SGSSSGTTATLTIRDVRAEDEGDYYCFSGYVDSDSKLYVFGSGTQLTVLG 
               
               
                   
               
               
                 GPKSSPKVTVFPPSPEELRTNKATLVCLVNDFYPGSATVTWKANGATIND 
               
               
                   
               
               
                 GVKTTKPSKQGQNYMTSSYLSLTADQWKSHNRVSCQVTHEGETVEKSLSP 
               
               
                   
               
               
                 AECL 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [J43m2a EN MP8-2 2012 (SEQ ID NO: 1812)]  
               
               
                 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 1813) 
               
               
                 [QGQSGQG][ACRICQDHPATKWNSGGGSSGGSISSGLLSGRSANPGGGS 
               
               
                   
               
               
                 YELTQPPSASVNVGETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDN 
               
               
                   
               
               
                 KRPSGIPERISGSSSGTTATLTIRDVRAEDEGDYYCFSGYVDSDSKLYVF 
               
               
                   
               
               
                 GSGTQLTVLGGPKSSPKVTVFPPSPEELRTNKATLVCLVNDFYPGSATVT 
               
               
                   
               
               
                 WKANGATINDGVKTTKPSKQGQNYMTSSYLSLTADQWKSHNRVSCQVTHE 
               
               
                   
               
               
                 GETVEKSLSPAECL] 
               
               
                   
               
               
                 J43m2a EN MP8-2 2012 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1812) 
               
               
                 ACRICQDHPATKWNSGGGSSGGSISSGLLSGRSANPGGGSYELTQPPSAS 
               
               
                   
               
               
                 VNVGETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPERI 
               
               
                   
               
               
                 SGSSSGTTATLTIRDVRAEDEGDYYCFSGYVDSDSKLYVFGSGTQLTVLG 
               
               
                   
               
               
                 GPKSSPKVTVFPPSPEELRTNKATLVCLVNDFYPGSATVTWKANGATIND 
               
               
                   
               
               
                 GVKTTKPSKQGQNYMTSSYLSLTADQWKSHNRVSCQVTHEGETVEKSLSP 
               
               
                   
               
               
                 AECL 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [J43m2a EN MP8-2 2002 (SEQ ID NO: 1814)]  
               
               
                 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 1815) 
               
               
                 [QGQSGQG][ACRICQDHPATKWNSGGGSSGGSISSGLLSGRSGNHGGGS 
               
               
                   
               
               
                 YELTQPPSASVNVGETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDN 
               
               
                   
               
               
                 KRPSGIPERISGSSSGTTATLTIRDVRAEDEGDYYCFSGYVDSDSKLYVF 
               
               
                   
               
               
                 GSGTQLTVLGGPKSSPKVTVFPPSPEELRTNKATLVCLVNDFYPGSATVT 
               
               
                   
               
               
                 WKANGATINDGVKTTKPSKQGQNYMTSSYLSLTADQWKSHNRVSCQVTHE 
               
               
                   
               
               
                 GETVEKSLSPAECL] 
               
               
                   
               
               
                 J43m2a EN MP8-2 2002 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1814) 
               
               
                 ACRICQDHPATKWNSGGGSSGGSISSGLLSGRSGNHGGGSYELTQPPSAS 
               
               
                   
               
               
                 VNVGETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPERI 
               
               
                   
               
               
                 SGSSSGTTATLTIRDVRAEDEGDYYCFSGYVDSDSKLYVFGSGTQLTVLG 
               
               
                   
               
               
                 GPKSSPKVTVFPPSPEELRTNKATLVCLVNDFYPGSATVTWKANGATIND 
               
               
                   
               
               
                 GVKTTKPSKQGQNYMTSSYLSLTADQWKSHNRVSCQVTHEGETVEKSLSP 
               
               
                   
               
               
                 AECL 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [J43m2a EN MP8-2 2003 (SEQ ID NO: 1816)]  
               
               
                 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 1817) 
               
               
                 [QGQSGQG][ACRICQDHPATKWNSGGGSSGGSISSGLLSGRSANPRGGG 
               
               
                   
               
               
                 GSYELTQPPSASVNVGETVKITCSGDQLPKYFADWFHQRSDQTILQVIYD 
               
               
                   
               
               
                 DNKRPSGIPERISGSSSGTTATLTIRDVRAEDEGDYYCFSGYVDSDSKLY 
               
               
                   
               
               
                 VFGSGTQLTVLGGPKSSPKVTVFPPSPEELRTNKATLVCLVNDFYPGSAT 
               
               
                   
               
               
                 VTWKANGATINDGVKTTKPSKQGQNYMTSSYLSLTADQWKSHNRVSCQVT 
               
               
                   
               
               
                 HEGETVEKSLSPAECL] 
               
               
                   
               
               
                 J43m2a EN MP8-2 2003 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1816) 
               
               
                 ACRICQDHPATKWNSGGGSSGGSISSGLLSGRSANPRGGGGSYELTQPPS 
               
               
                   
               
               
                 ASVNVGETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPE 
               
               
                   
               
               
                 RISGSSSGTTATLTIRDVRAEDEGDYYCFSGYVDSDSKLYVFGSGTQLTV 
               
               
                   
               
               
                 LGGPKSSPKVTVFPPSPEELRTNKATLVCLVNDFYPGSATVTWKANGATI 
               
               
                   
               
               
                 NDGVKTTKPSKQGQNYMTSSYLSLTADQWKSHNRVSCQVTHEGETVEKSL 
               
               
                   
               
               
                 SPAECL 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [J43m2a EN MP8-2 2006 (SEQ ID NO: 1818)]  
               
               
                 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 1819) 
               
               
                 [QGQSGQG][ACRICQDHPATKWNSGGGSSGGSISSGLLSGRSDDHGGGS 
               
               
                   
               
               
                 YELTQPPSASVNVGETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDN 
               
               
                   
               
               
                 KRPSGIPERISGSSSGTTATLTIRDVRAEDEGDYYCFSGYVDSDSKLYVF 
               
               
                   
               
               
                 GSGTQLTVLGGPKSSPKVTVFPPSPEELRTNKATLVCLVNDFYPGSATVT 
               
               
                   
               
               
                 WKANGATINDGVKTTKPSKQGQNYMTSSYLSLTADQWKSHNRVSCQVTHE 
               
               
                   
               
               
                 GETVEKSLSPAECL] 
               
               
                   
               
               
                 J43m2a EN MP8-2 2006 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1818) 
               
               
                 ACRICQDHPATKWNSGGGSSGGSISSGLLSGRSDDHGGGSYELTQPPSAS 
               
               
                   
               
               
                 VNVGETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPERI 
               
               
                   
               
               
                 SGSSSGTTATLTIRDVRAEDEGDYYCFSGYVDSDSKLYVFGSGTQLTVLG 
               
               
                   
               
               
                 GPKSSPKVTVFPPSPEELRTNKATLVCLVNDFYPGSATVTWKANGATIND 
               
               
                   
               
               
                 GVKTTKPSKQGQNYMTSSYLSLTADQWKSHNRVSCQVTHEGETVEKSLSP 
               
               
                   
               
               
                 AECL 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [J43m2a EN MP8-2 2007 (SEQ ID NO: 1820)]  
               
               
                 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 1821) 
               
               
                 [QGQSGQG][ACRICQDHPATKWNSGGGSSGGSISSGLLSGRSDIHGGGS 
               
               
                   
               
               
                 YELTQPPSASVNVGETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDN 
               
               
                   
               
               
                 KRPSGIPERISGSSSGTTATLTIRDVRAEDEGDYYCFSGYVDSDSKLYVF 
               
               
                   
               
               
                 GSGTQLTVLGGPKSSPKVTVFPPSPEELRTNKATLVCLVNDFYPGSATVT 
               
               
                   
               
               
                 WKANGATINDGVKTTKPSKQGQNYMTSSYLSLTADQWKSHNRVSCQVTHE 
               
               
                   
               
               
                 GETVEKSLSPAECL] 
               
               
                   
               
               
                 J43m2a EN MP8-2 2007 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1820) 
               
               
                 ACRICQDHPATKWNSGGGSSGGSISSGLLSGRSDIHGGGSYELTQPPSAS 
               
               
                   
               
               
                 VNVGETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPERI 
               
               
                   
               
               
                 SGSSSGTTATLTIRDVRAEDEGDYYCFSGYVDSDSKLYVFGSGTQLTVLG 
               
               
                   
               
               
                 GPKSSPKVTVFPPSPEELRTNKATLVCLVNDFYPGSATVTWKANGATIND 
               
               
                   
               
               
                 GVKTTKPSKQGQNYMTSSYLSLTADQWKSHNRVSCQVTHEGETVEKSLSP 
               
               
                   
               
               
                 AECL 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [J43m2a EN MP8-2 2008 (SEQ ID NO: 1822)]  
               
               
                 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 1823) 
               
               
                 [QGQSGQG][ACRICQDHPATKWNSGGGSSGGSISSGLLSGRSDQHGGGS 
               
               
                   
               
               
                 YELTQPPSASVNVGETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDN 
               
               
                   
               
               
                 KRPSGIPERISGSSSGTTATLTIRDVRAEDEGDYYCFSGYVDSDSKLYVF 
               
               
                   
               
               
                 GSGTQLTVLGGPKSSPKVTVFPPSPEELRTNKATLVCLVNDFYPGSATVT 
               
               
                   
               
               
                 WKANGATINDGVKTTKPSKQGQNYMTSSYLSLTADQWKSHNRVSCQVTHE 
               
               
                   
               
               
                 GETVEKSLSPAECL] 
               
               
                   
               
               
                 J43m2a EN MP8-2 2008 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1822) 
               
               
                 ACRICQDHPATKWNSGGGSSGGSISSGLLSGRSDQHGGGSYELTQPPSAS 
               
               
                   
               
               
                 VNVGETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPERI 
               
               
                   
               
               
                 SGSSSGTTATLTIRDVRAEDEGDYYCFSGYVDSDSKLYVFGSGTQLTVLG 
               
               
                   
               
               
                 GPKSSPKVTVFPPSPEELRTNKATLVCLVNDFYPGSATVTWKANGATIND 
               
               
                   
               
               
                 GVKTTKPSKQGQNYMTSSYLSLTADQWKSHNRVSCQVTHEGETVEKSLSP 
               
               
                   
               
               
                 AECL 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [J43m2a EN MP8-2 2009 (SEQ ID NO: 1824)]  
               
               
                 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 1825) 
               
               
                 [QGQSGQG][ACRICQDHPATKWNSGGGSSGGSISSGLLSGRSDTHGGGS 
               
               
                   
               
               
                 YELTQPPSASVNVGETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDN 
               
               
                   
               
               
                 KRPSGIPERISGSSSGTTATLTIRDVRAEDEGDYYCFSGYVDSDSKLYVF 
               
               
                   
               
               
                 GSGTQLTVLGGPKSSPKVTVFPPSPEELRTNKATLVCLVNDFYPGSATVT 
               
               
                   
               
               
                 WKANGATINDGVKTTKPSKQGQNYMTSSYLSLTADQWKSHNRVSCQVTHE 
               
               
                   
               
               
                 GETVEKSLSPAECL] 
               
               
                   
               
               
                 J43m2a EN MP8-2 2009 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1824) 
               
               
                 ACRICQDHPATKWNSGGGSSGGSISSGLLSGRSDTHGGGSYELTQPPSAS 
               
               
                   
               
               
                 VNVGETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPERI 
               
               
                   
               
               
                 SGSSSGTTATLTIRDVRAEDEGDYYCFSGYVDSDSKLYVFGSGTQLTVLG 
               
               
                   
               
               
                 GPKSSPKVTVFPPSPEELRTNKATLVCLVNDFYPGSATVTWKANGATIND 
               
               
                   
               
               
                 GVKTTKPSKQGQNYMTSSYLSLTADQWKSHNRVSCQVTHEGETVEKSLSP 
               
               
                   
               
               
                 AECL 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [J43m2a EN MP8-2 2010 (SEQ ID NO: 1826)]  
               
               
                 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 1827) 
               
               
                 [QGQSGQG][ACRICQDHPATKWNSGGGSSGGSISSGLLSGRSDYHGGGS 
               
               
                   
               
               
                 YELTQPPSASVNVGETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDN 
               
               
                   
               
               
                 KRPSGIPERISGSSSGTTATLTIRDVRAEDEGDYYCFSGYVDSDSKLYVF 
               
               
                   
               
               
                 GSGTQLTVLGGPKSSPKVTVFPPSPEELRTNKATLVCLVNDFYPGSATVT 
               
               
                   
               
               
                 WKANGATINDGVKTTKPSKQGQNYMTSSYLSLTADQWKSHNRVSCQVTHE 
               
               
                   
               
               
                 GETVEKSLSPAECL] 
               
               
                   
               
               
                 J43m2a EN MP8-2 2010 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1826) 
               
               
                 ACRICQDHPATKWNSGGGSSGGSISSGLLSGRSDYHGGGSYELTQPPSAS 
               
               
                   
               
               
                 VNVGETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPERI 
               
               
                   
               
               
                 SGSSSGTTATLTIRDVRAEDEGDYYCFSGYVDSDSKLYVFGSGTQLTVLG 
               
               
                   
               
               
                 GPKSSPKVTVFPPSPEELRTNKATLVCLVNDFYPGSATVTWKANGATIND 
               
               
                   
               
               
                 GVKTTKPSKQGQNYMTSSYLSLTADQWKSHNRVSCQVTHEGETVEKSLSP 
               
               
                   
               
               
                 AECL 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [J43m2a EN MP8-2 2013 (SEQ ID NO: 1828)]  
               
               
                 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 1829) 
               
               
                 [QGQSGQG][ACRICQDHPATKWNSGGGSSGGSISSGLLSGRSANIGGGS 
               
               
                   
               
               
                 YELTQPPSASVNVGETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDN 
               
               
                   
               
               
                 KRPSGIPERISGSSSGTTATLTIRDVRAEDEGDYYCFSGYVDSDSKLYVF 
               
               
                   
               
               
                 GSGTQLTVLGGPKSSPKVTVFPPSPEELRTNKATLVCLVNDFYPGSATVT 
               
               
                   
               
               
                 WKANGATINDGVKTTKPSKQGQNYMTSSYLSLTADQWKSHNRVSCQVTHE 
               
               
                   
               
               
                 GETVEKSLSPAECL] 
               
               
                   
               
               
                 J43m2a EN MP8-2 2013 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1828) 
               
               
                 ACRICQDHPATKWNSGGGSSGGSISSGLLSGRSANIGGGSYELTQPPSAS 
               
               
                   
               
               
                 VNVGETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPERI 
               
               
                   
               
               
                 SGSSSGTTATLTIRDVRAEDEGDYYCFSGYVDSDSKLYVFGSGTQLTVLG 
               
               
                   
               
               
                 GPKSSPKVTVFPPSPEELRTNKATLVCLVNDFYPGSATVTWKANGATIND 
               
               
                   
               
               
                 GVKTTKPSKQGQNYMTSSYLSLTADQWKSHNRVSCQVTHEGETVEKSLSP 
               
               
                   
               
               
                 AECL 
               
               
                   
               
               
                 [Spacer (SEQ ID NO: 362)] 
               
               
                 [J43m2a EN MP8-2 2014 (SEQ ID NO: 1830)]  
               
               
                 Amino Acid Sequence: 
               
               
                 (SEQ ID NO: 1831) 
               
               
                 [QGQSGQG][ACRICQDHPATKWNSGGGSSGGSISSGLLSGRSDNIGGGS 
               
               
                   
               
               
                 YELTQPPSASVNVGETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDN 
               
               
                   
               
               
                 KRPSGIPERISGSSSGTTATLTIRDVRAEDEGDYYCFSGYVDSDSKLYVF 
               
               
                   
               
               
                 GSGTQLTVLGGPKSSPKVTVFPPSPEELRTNKATLVCLVNDFYPGSATVT 
               
               
                   
               
               
                 WKANGATINDGVKTTKPSKQGQNYMTSSYLSLTADQWKSHNRVSCQVTHE 
               
               
                   
               
               
                 GETVEKSLSPAECL] 
               
               
                   
               
               
                 J43m2a EN MP8-2 2014 Amino Acid Sequence:  
               
               
                 (SEQ ID NO: 1830) 
               
               
                 ACRICQDHPATKWNSGGGSSGGSISSGLLSGRSDNIGGGSYELTQPPSAS 
               
               
                   
               
               
                 VNVGETVKITCSGDQLPKYFADWFHQRSDQTILQVIYDDNKRPSGIPERI 
               
               
                   
               
               
                 SGSSSGTTATLTIRDVRAEDEGDYYCFSGYVDSDSKLYVFGSGTQLTVLG 
               
               
                   
               
               
                 GPKSSPKVTVFPPSPEELRTNKATLVCLVNDFYPGSATVTWKANGATIND 
               
               
                   
               
               
                 GVKTTKPSKQGQNYMTSSYLSLTADQWKSHNRVSCQVTHEGETVEKSLSP 
               
               
                   
               
               
                 AECL 
               
            
           
         
       
     
     Example 27: Activatable Anti-Mouse PD1 J43 m2a EN Antibodies Reduce Incidence of Diabetes in NOD Mice 
     In this Example, anti-PD1 J43 m2a EN (effector negative) activatable antibodies were analyzed for the ability to protect from PD1 m2a EN-mediated induction of diabetes in NOD mice. 
     The NOD mice, substrain NOD/ShiLtJ, were obtained from Jackson Laboratory at 8 weeks and acclimated on site for 2 weeks. At 10 weeks, mice were checked for diabetes prior to enrollment, grouped, and dosed as set forth in Table 21. 
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                   
               
               
                   
                   
                   
                   
                   
                 Dose 
                   
                   
               
               
                   
                   
                   
                   
                 Dose 
                 volume 
                   
                   
               
               
                 Group 
                 Count 
                 Gender 
                 Treatment 
                 (mg/kg) 
                 (mL/kg) 
                 Schedule 
                 Route 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 1 
                 7 
                 F 
                 mIgG2a (C1.18.4) 
                 10 
                 10 
                 q7dx1 
                 IP 
               
               
                 2 
                 7 
                 F 
                 Anti-PD-1 J43 m2a EN 
                 10 
                 10 
                 q7dx1 
                 IP 
               
               
                 3 
                 7 
                 F 
                 Anti-PD-1 J43 m2a EN 
                 3 
                 10 
                 q7dx1 
                 IP 
               
               
                 4 
                 7 
                 F 
                 Anti-PD-1 J43 m2a EN 
                 1 
                 10 
                 q7dx1 
                 IP 
               
               
                 5 
                 7 
                 F 
                 J43 MP7-1 2001 m2a EN 
                 10 
                 10 
                 q7dx1 
                 IP 
               
               
                 6 
                 7 
                 F 
                 J43 MP7-1 2001 m2a EN 
                 3 
                 10 
                 q7dx1 
                 IP 
               
               
                 7 
                 7 
                 F 
                 J43 MP8-2 2001 m2a EN 
                 10 
                 10 
                 q7dx1 
                 IP 
               
               
                 8 
                 7 
                 F 
                 J43 MP8-2 2001 m2a EN 
                 3 
                 10 
                 q7dx1 
                 IP 
               
               
                   
               
            
           
         
       
     
       FIG. 30  which plots % non-diabetic versus number of days post dose, shows that anti-PD-1 J43 antibody induced diabetes in NOD mice with increased frequency as dosage increased. At day eleven post dose, the percentage of non-diabetic mice for the antibody-treated groups was 29%, 43% and 71% for the 10 mg/kg, 3 mg/kg and 1 mg/kg dose groups, respectively. Activatable antibodies J43 MP7-1 2001 m2a EN and J43 MP8-2 2001 m2a EN required increased doses to induce diabetes at frequencies comparable to the parental antibody. At day eleven post dose with J43 MP7-1 2001 m2a EN, 71% of the 10 mg/kg group remained non-diabetic and 86% of the 3 mg/kg were non-diabetic. At day fourteen post dose with J43 MP8-2 2001 m2a EN, 86% of the 10 mg/kg group and 100% of the 3 mg/kg group remained non-diabetic. 
     Example 28. Activatable Anti-Mouse PD1 J43 m2a EN Antibodies Show Efficacy in the MC38 Syngeneic Tumor Model 
     This Example demonstrates that activatable antibodies of the embodiments are able to reduce the growth of MC38 syngeneic tumors. 
     In this Example, anti-PD1 activatable antibodies J43 MP7-1 2001 m2a EN and J43 MP8-2 2001 m2a EN were analyzed for the ability to reduce the growth of MC38 syngeneic tumors. 
     The mouse colon carcinoma cell line MC38 was obtained from ATCC. MC38 were grown in RPMI-1640 supplemented with 10% fetal bovine serum at 37° C. in an atmosphere of 5% CO 2  in air. Cells were harvested during the logarithmic growth period, resuspended in PBS with proper cell concentration, and kept on ice for tumor induction. 
     Each mouse was inoculated subcutaneously at the right flank with 1.5×10 6  of MC38 cells in PBS for tumor development. The treatments were started when the mean tumor size reached approximately 80 mm 3  (60-120 mm 3 ). Tumor sizes were measured twice weekly in two dimensions using a caliper, and the volume was expressed in mm 3  using the formula: V=0.5 a×b 2  where a and b are the long and short diameters of the tumor, respectively. 
     The mice were grouped and dosed as set forth in Table 22. 
     
       
         
           
               
               
               
               
               
               
               
             
               
                 TABLE 22 
               
               
                   
               
               
                   
                   
                   
                 Dose 
                 Dose volume 
                   
                   
               
               
                 Group 
                 Count 
                 Treatment 
                 (mg/kg) 
                 (mL/kg) 
                 Schedule 
                 Route 
               
               
                   
               
             
            
               
                 1 
                 10 
                 mIgG1 MOPC-21 + mIgG12b 
                 10 + 10 
                 10 
                 b.i.w. for 
                 IP 
               
               
                   
                   
                 MPC-11 
                   
                   
                 3 weeks 
                   
               
               
                 2 
                 10 
                 Anti-CTLA4 9D9 mIgG2b 
                 10 
                 10 
                 b.i.w. for 
                 IP 
               
               
                   
                   
                   
                   
                   
                 3 weeks 
                   
               
               
                 3 
                 10 
                 Anti-PD-1 (J43 m2a EN) 
                 10 
                 10 
                 b.i.w. for 
                 IP 
               
               
                   
                   
                   
                   
                   
                 3 weeks 
                   
               
               
                 4 
                 10 
                 J43 MP8-2 2001 m2a EN 
                 10 
                 10 
                 b.i.w. for 
                 IP 
               
               
                   
                   
                   
                   
                   
                 3 weeks 
                   
               
               
                 5 
                 10 
                 J43 MP7-1 2001 m2a EN 
                 10 
                 10 
                 b.i.w. for 
                 IP 
               
               
                   
                   
                   
                   
                   
                 3 weeks 
                   
               
               
                 6 
                 10 
                 Anti-PD-1 (J43 m2a EN) + 
                 10 + 10 
                 10 
                 b.i.w. for 
                 IP 
               
               
                   
                   
                 Anti-CTLA4 9D9 mIgG2b 
                   
                   
                 3 weeks 
                   
               
               
                 7 
                 10 
                 J43 MP8-2 2001 m2a EN + 
                 10 + 10 
                 10 
                 b.i.w. for 
                 IP 
               
               
                   
                   
                 Anti-CTLA4 9D9 mIgG2b 
                   
                   
                 3 weeks 
                   
               
               
                 8 
                 10 
                 J43 MP7-1 2001 m2a EN + 
                 10 + 10 
                 10 
                 b.i.w. for 
                 IP 
               
               
                   
                   
                 Anti-CTLA4 9D9 mIgG2b 
                   
                   
                 3 weeks 
               
               
                   
               
            
           
         
       
     
       FIGS. 31A and 31B , which plots tumor volume versus number of days post initial dose, demonstrates that anti-PD1 activatable antibodies MP7-1 2001 m2a EN and MP8-2 2001 m2a EN inhibit the growth of MC38 syngeneic tumors similar to positive control anti-PD1 antibody J43 m2a EN both as single agents and in combination with anti-CTLA4 antibody 9D9 mIgG2b (BioXCell, West Lebanon, N.H.). 
     Example 29. Evaluation of Anti-Human PD1 Antibodies and Activatable Anti-Human PD1 Antibodies in Antigen Recall Assay 
     This Example demonstrates that anti-PD1 antibodies and activated activatable anti-PD1 antibodies of the embodiments (i.e., activatable antibodies in which the CM has been cleaved by a protease) are able to block PD-L1/PD-L2 binding to PD1 and to activate T cells in an antigen recall assay. 
     As shown in  FIGS. 32A-32E , the anti-human PD1 antibody referred to herein as A1.5 Ab (i.e., VH of SEQ ID NO: 21 and VL of SEQ ID NO: 47) blocks PD-L1/PD-L2 binding to PD1 and potently activates T cells in an antigen recall assay. The binding of the anti-human PD-1 A1.5 Ab to immobilized human PD1 as detected by standard plate ELISA is shown in  FIG. 32A , and the binding of A1.5 Ab to cynomolgus PD1 (also referred to herein as cyno-PD1, Sino Biological Cat. #90311-CO2H) as detected by ELISA is shown in  FIG. 32B . The inhibition of biotinylated human PD-L1 (also referred to herein as biotin-PD-L1) to immobilized PD1 by A1.5 Ab as determined by ELISA is shown in  FIG. 32C , and the inhibition of biotinylated human PD-L2 (also referred to herein as biotin-PD-L2) to immobilized PD1 as determined by ELISA is shown in  FIG. 32D . 
     As shown in  FIG. 32E , the A1.5 Ab enhances IFN-γ production in a CMV T cell restimulation assay. Briefly, CMV +  human PBMCs were plated at 250,000 cells/well with isotype control antibody or with the A1.5 Ab and stimulated with 5 μg/mL CMV lysate for 4 days. Supernatant IFN-γ levels were measured by ELISA. 
     As shown in  FIGS. 33A and 33B , the activatable anti-PD1 antibody referred to herein as A1.5 PD34 2001 (i.e., VH of SEQ ID NO: 21, VL of SEQ ID NO: 47, masking moiety of SEQ ID NO: 99, and cleavable moiety of SEQ ID NO: 214) binds human PD1 with decreased affinity relative to the parental PD-1 Ab, i.e., A1.5 Ab ( FIG. 33A ), and the A1.5 PD34 2001 activatable antibody shows functional masking in a CMV T cell antigen recall assay ( FIG. 33B ). Briefly, 4 mg/mL of the A1.5 PD34 2001 activatable antibody was combined with 0 μg/mL or 60 μg/mL recombinant human urokinase (rh uPA, R&amp;D, Cat. #1310-SE) and incubated at 37° C. overnight. Binding of the activatable antibody incubated with uPA to hPD1 was assayed by standard plate ELISA. As shown in  FIG. 33 , the activatable anti-PD1 antibodies of the disclosure regain full binding activated after activation by a protease. 
     Example 30. Pharmacokinetic Evaluation of Activatable Anti-Human PD1 Antibodies in Non-Human Primate Model 
     This Example demonstrates pharmacokinetic and dose proportionality data for anti-PD-1 antibodies and anti-PD-1 activatable antibodies of the embodiments. 
     Briefly, female cynomolgus monkeys (n=2/group) were dosed with a single IV bolus dose of either the A1.5 antibody or the activatable antibody referred to herein as A1.5 PD34 2001 at 1 mg/kg or at 5 mg/kg. Plasma samples were analyzed for A1.5 and A1.5 PD34 2001 concentrations by a qualified anti-human sandwich ELISA. The results are shown in  FIG. 34 , where each line represents one individual. Mean PK parameters shown for both A1.5 and A1.5 PD34 2001. Similar results were seen for activatable antibodies A1.5 PD34 2012 and A1.5 PD34 2011 administered to cynomolgus monkeys in a similar study. 
     Example 31. Activatable Anti-Mouse PD-1 J43 Antibodies Reduce Incidence of Diabetes in NOD Mice Dosed with Anti-CTLA4 Antibody 
     In this Example, anti-PD-1 J43 activatable antibodies were analyzed for the ability to protect from anti-PD-1 induction of diabetes in NOD mice when dosed concurrently with anti-CTLA-4 9D9 mIgG2b antibody (BioXCell cat #BE0164). The NOD mice, substrain NOD/ShiLtJ, were obtained from Jackson Laboratory at 4 weeks and acclimated on site for 1 week. At 5 weeks, mice were checked for diabetes prior to enrollment, grouped, and dosed as set forth in Table 23. As used herein, the antibody referred to as “J43 m2a EN” (and variations thereof) comprises a heavy chain (HC) of SEQ ID NO: 546; a light chain (LC) of SEQ ID NO: 543; and a constant region of SEQ ID NO: 1516. As used herein, the activatable antibody referred to as “J43 MP8-2 2012 m2a EN” is an activatable antibody comprising the J43 m2a EN antibody, the MP8-2 masking moiety (SEQ ID NO: 549), and the 2012 substrate (SEQ ID NO: 1101), and the activatable antibody referred to as “J43 MP8-2 2001 m2a EN” is an activatable antibody comprising the J43 m2a EN antibody, the MP8-2 masking moiety (SEQ ID NO: 549), and the 2001 substrate (SEQ ID NO: 214). 
     
       
         
           
               
             
               
                 TABLE 23 
               
             
            
               
                   
               
               
                 Dosing regimen 
               
            
           
           
               
               
               
               
            
               
                   
                 Treatment 
                 Dose 
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                 Dose 
                 Article 
                 Dose 
                 volume 
                   
                   
               
               
                 Group 
                 Count 
                 Article #1 
                 (mg/kg) 
                 #2 
                 (mg/kg) 
                 (mL/kg) 
                 Schedule 
                 Route 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 1 
                 8 
                 mIgG1 
                 10 
                 mIgG2b 
                 10 
                 10 
                 d0, d4, d7 
                 IP 
               
               
                   
                   
                 MOPC-21 
                   
                 MPC-11 
                   
                   
                   
                   
               
               
                 2 
                 8 
                 Anti- 
                 10 
                 mIgG1 
                 10 
                 10 
                 d0, d4, d7 
                 IP 
               
               
                   
                   
                 CTLA4 
                   
                 MOPC- 
                   
                   
                   
                   
               
               
                   
                   
                 9D9 
                   
                 21 
                   
                   
                   
                   
               
               
                   
                   
                 mIgG2b 
                   
                   
                   
                   
                   
                   
               
               
                 3 
                 8 
                 Anti-PD-1 
                 10 
                 mIgG2b 
                 10 
                 10 
                 d0, d4, d7 
                 IP 
               
               
                   
                   
                 (J43 m2a 
                   
                 MPC-11 
                   
                   
                   
                   
               
               
                   
                   
                 EN) 
                   
                   
                   
                   
                   
                   
               
               
                 4 
                 8 
                 Anti-PD-1 
                 1 
                 mIgG2b 
                 10 
                 10 
                 d0, d4, d7 
                 IP 
               
               
                   
                   
                 (J43 m2a 
                   
                 MPC-11 
                   
                   
                   
                   
               
               
                   
                   
                 EN) 
                   
                   
                   
                   
                   
                   
               
               
                 5 
                 8 
                 Anti-PD-1 
                 10 
                 Anti- 
                 10 
                 10 
                 d0, d4, d7 
                 IP 
               
               
                   
                   
                 (J43 m2a 
                   
                 CTLA4 
                   
                   
                   
                   
               
               
                   
                   
                 EN) 
                   
                 9D9 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                 mIgG2b 
                   
                   
                   
                   
               
               
                 6 
                 8 
                 Anti-PD-1 
                 1 
                 Anti- 
                 10 
                 10 
                 d0, d4, d7 
                 IP 
               
               
                   
                   
                 (J43 m2a 
                   
                 CTLA4 
                   
                   
                   
                   
               
               
                   
                   
                 EN) 
                   
                 9D9 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                 mIgG2b 
                   
                   
                   
                   
               
               
                 7 
                 8 
                 J43 MP8-2 
                 10 
                 mIgG2b 
                 10 
                 10 
                 d0, d4, d7 
                 IP 
               
               
                   
                   
                 2012 m2a 
                   
                 MPC-11 
                   
                   
                   
                   
               
               
                   
                   
                 EN 
                   
                   
                   
                   
                   
                   
               
               
                 8 
                 8 
                 J43 MP8-2 
                 10 
                 Anti- 
                 10 
                 10 
                 d0, d4, d7 
                 IP 
               
               
                   
                   
                 2012 m2a 
                   
                 CTLA4 
                   
                   
                   
                   
               
               
                   
                   
                 EN 
                   
                 9D9 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                 mIgG2b 
                   
                   
                   
                   
               
               
                 9 
                 8 
                 J43 MP8-2 
                 10 
                 mIgG2b 
                 10 
                 10 
                 d0, d4, d7 
                 IP 
               
               
                   
                   
                 2001 m2a 
                   
                 MPC-11 
                   
                   
                   
                   
               
               
                   
                   
                 EN 
                   
                   
                   
                   
                   
                   
               
               
                 10 
                 8 
                 J43 MP8-2 
                 10 
                 Anti- 
                 10 
                 10 
                 d0, d4, d7 
                 IP 
               
               
                   
                   
                 2001 m2a 
                   
                 CTLA4 
                   
                   
                   
                   
               
               
                   
                   
                 EN 
                   
                 9D9 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                 mIgG2b 
               
               
                   
               
            
           
         
       
     
       FIG. 35  which plots % non-diabetic versus number of days post initial dose, shows that the combination of 10 mg/kg anti-PD-1 J43 antibody plus 10 mg/kg anti-CTLA-4 antibody dosed on days 0, 4 and 7 induced diabetes in 50% of NOD mice by day eleven while the same dosing schedule of activatable anti-PD-1 J43 antibodies with CTLA-4 antibody resulted in no induction of diabetes to day eighteen. 
     Example 32. Activatable Anti-Mouse PD1 J43 m2a EN Antibodies Show Enhanced Efficacy when Coadministered with Anti-CTLA4 Antibody in the MC38 Syngeneic Tumor Model 
     This Example demonstrates that activatable antibodies of the embodiments are able to reduce the growth of MC38 syngeneic tumors as single agents and induce MC38 tumor regression when coadministered with anti-CTLA4 antibody 9D9 mIgG2b. 
     In this Example, anti-PD1 activatable antibodies J43 MP8-2 2011 m2a EN and J43 MP8-2 2012 m2a EN were analyzed for the ability to slow the growth of or, in combination with anti-CTLA4 antibody, induce regression in MC38 syngeneic tumors. As used herein, the antibody referred to as “J43 m2a EN” (and variations thereof) comprises a heavy chain (HC) of SEQ ID NO: 546; a light chain (LC) of SEQ ID NO: 543; and a constant region of SEQ ID NO: 1516. As used herein, the activatable antibody referred to as “J43 MP8-2 2011 m2a EN” is an activatable antibody comprising the J43 m2a EN antibody, the MP8-2 masking moiety (SEQ ID NO: 549), and the 2011 substrate (SEQ ID NO: 1100), and the activatable antibody referred to as “J43 MP8-2 2012 m2a EN” is an activatable antibody comprising the J43 m2a EN antibody, the MP8-2 masking moiety (SEQ ID NO: 549), and the 2012 substrate (SEQ ID NO: 1101). 
     The mouse colon carcinoma cell line MC38 was obtained from ATCC. MC38 cells were grown in RPMI-1640 supplemented with 10% fetal bovine serum at 37° C. in an atmosphere of 5% CO 2  in air. Cells were harvested during the logarithmic growth period, resuspended in PBS with proper cell concentration, and kept on ice for tumor induction. 
     Each mouse was inoculated subcutaneously at the right flank with 1.5×10 6  MC38 cells in PBS for tumor development. The treatments were started when the mean tumor size reached approximately 60 mm 3  (45-80 mm 3 ). Tumor sizes were measured twice weekly in two dimensions using a caliper, and the volume was expressed in mm 3  using the formula: V=0.5 a×b 2  where a and b are the long and short diameters of the tumor, respectively. 
     The mice were grouped and dosed as set forth in Table 24. 
     
       
         
           
               
               
               
               
               
               
               
             
               
                 TABLE 24 
               
               
                   
               
               
                   
                   
                   
                   
                 Dose 
                   
                   
               
               
                   
                   
                   
                 Dose 
                 volume 
                   
                   
               
               
                 Group 
                 Count 
                 Treatment 
                 (mg/kg) 
                 (mL/kg) 
                 Schedule 
                 Route 
               
               
                   
               
             
            
               
                 1 
                 10 
                 mIgG1 MOPC-21 + 
                 10 + 10 
                 10 
                 b.i.w. for 3 
                 IP 
               
               
                   
                   
                 mIgG12b MPC-11 
                   
                   
                 weeks 
                   
               
               
                 2 
                 10 
                 Anti-CTLA4 9D9 mIgG2b 
                 10 
                 10 
                 b.i.w. for 3 
                 IP 
               
               
                   
                   
                   
                   
                   
                 weeks 
                   
               
               
                 3 
                 10 
                 Anti-PD-1 (J43 m2a EN) 
                 10 
                 10 
                 b.i.w. for 3 
                 IP 
               
               
                   
                   
                   
                   
                   
                 weeks 
                   
               
               
                 4 
                 10 
                 J43 MP8-2 2012 m2a EN 
                 10 
                 10 
                 b.i.w. for 3 
                 IP 
               
               
                   
                   
                   
                   
                   
                 weeks 
                   
               
               
                 5 
                 10 
                 J43 MP8-2 2011 m2a EN 
                 10 
                 10 
                 b.i.w. for 3 
                 IP 
               
               
                   
                   
                   
                   
                   
                 weeks 
                   
               
               
                 6 
                 10 
                 Anti-PD-1 (J43 m2a EN) + 
                 10 + 10 
                 10 
                 b.i.w. for 3 
                 IP 
               
               
                   
                   
                 Anti-CTLA4 9D9 mIgG2b 
                   
                   
                 weeks 
                   
               
               
                 7 
                 10 
                 J43 MP8-2 2012 m2a EN + 
                 10 + 10 
                 10 
                 b.i.w. for 3 
                 IP 
               
               
                   
                   
                 Anti-CTLA4 9D9 mIgG2b 
                   
                   
                 weeks 
                   
               
               
                 8 
                 10 
                 J43 MP8-2 2011 m2a EN + 
                 10 + 10 
                 10 
                 b.i.w. for 3 
                 IP 
               
               
                   
                   
                 Anti-CTLA4 9D9 mIgG2b 
                   
                   
                 weeks 
               
               
                   
               
            
           
         
       
     
       FIG. 36 , which plots tumor volume versus number of days post initial dose, demonstrates that anti-PD1 activatable antibodies MP8-2 2012 m2a EN and MP8-2 2011 m2a EN inhibit the growth of MC38 syngeneic tumors similar to positive control anti-PD1 antibody J43 m2a EN both as single agents and in combination with anti-CTLA4 antibody 9D9 mIgG2b (BioXCell, West Lebanon, N.H.). 
     Example 33. Activatable Anti-Mouse PD1 J43 m2a EN Antibodies Show Durable Anti-Tumor Activity when Coadministered with Anti-CTLA4 Antibody in the MC38 Syngeneic Tumor Model 
     This Example demonstrates anti-PD-1 activatable antibodies of the embodiments in combination with anti-CTLA4 antibodies induce durable anti-tumor complete responses in the MC38 syngeneic tumor model. 
     In this Example, all animals treated with combinations of anti-CTLA4 and anti-PD1 agents from Example 28 that showed sustained tumor regression ((i) anti-PD-1 J43 m2aEN+anti-CTLA4 9D9 mIgG2b (referred to in  FIG. 37  as “anti-PD-1 J43 m2aEN Antibody”+“anti-CTLA4 9D9 mIgG2b Antibody”) (n=8), (ii) activatable antibody anti-PD-1 J43 MP8-2 2012 m2a EN+anti-CTLA4 9D9 mIgG2b (referred to in  FIG. 37  as “J43 MP8-2 2012 m2a EN AA”+“anti-CTLA4 9D9 mIgG2b Antibody” where AA stands for activatable antibody) (n=8), and activatable antibody anti-PD-1 J43 MP8-2 2011 m2a EN+anti-CTLA4 9D9 mIgG2b (referred to in  FIG. 37  as “J43 MP8-2 2011 m2a EN AA”+“anti-CTLA4 9D9 mIgG2b Antibody” where AA stands for activatable antibody) (n=6)) were implanted at day 38 with 1.5×10 6  MC38 tumor cells in the left flank opposite to the original MC38 implantation. Five untreated mice were implanted with 1.5×10 6  MC38 tumor cells to confirm tumorigenic activity of the MC38 cells. 
       FIG. 37  shows that no mice previously treated with combinations of anti-PD1 and anti-CTLA4 agents showed regrowth of the original tumor sites (right flank) or growth of new tumors (left flank) while all five of the untreated control mice showed rapid tumor growth. 
     Example 34. Activatable Anti-Mouse PD-1 J43 Antibodies Reduce Incidence of Diabetes in NOD Mice Co-Dosed with Anti-CTLA4 Antibody 
     This Example demonstrates that anti-PD-1 activatable antibodies of the embodiments in combination with anti-CTLA4 antibodies protected NOD mice from PD1 m2a EN-mediated induction of diabetes. 
     In this Example, anti-PD-1 J43 activatable antibody MP8-2 2011 m2aEN was analyzed for the ability to protect from anti-PD-1 induction of diabetes in NOD mice when dosed concurrently with anti-CTLA-4 9D9 mIgG2b antibody (BioXcell cat #BE0164). The NOD mice, substrain NOD/ShiLtJ, were obtained from Jackson Laboratory at 4 weeks and acclimated on site for 1 week. At 5 weeks, mice were checked for diabetes prior to enrollment, grouped, and dosed as set forth in Table 25. 
     
       
         
           
               
             
               
                 TABLE 25 
               
             
            
               
                   
               
               
                 Dosing regimen 
               
            
           
           
               
               
               
               
            
               
                   
                 Treatment 
                 Dose 
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                 Dose 
                   
                 Dose 
                 volume 
                   
                   
               
               
                 Group 
                 Count 
                 Article #1 
                 (mg/kg) 
                 Article #2 
                 (mg/kg) 
                 (mL/kg) 
                 Schedule 
                 Route 
               
               
                   
               
               
                 1 
                 8 
                 Anti-CTLA4 
                 10 
                 mIgG1 
                 10 
                 10 
                 d0, d4, d7 
                 IP 
               
               
                   
                   
                 9D9 mIgG2b 
                   
                 MOPC-21 
                   
                   
                   
                   
               
               
                 2 
                 8 
                 Anti-PD-1 (J43 
                 10 
                 mIgG2b 
                 10 
                 10 
                 d0, d4, d7 
                 IP 
               
               
                   
                   
                 m2a EN) 
                   
                 MPC-11 
                   
                   
                   
                   
               
               
                 3 
                 8 
                 Anti-PD-1 (J43 
                 10 
                 Anti-CTLA4 
                 10 
                 10 
                 d0, d4, d7 
                 IP 
               
               
                   
                   
                 m2a EN) 
                   
                 9D9 mIgG2b 
                   
                   
                   
                   
               
               
                 4 
                 8 
                 J43 MP8-2 
                 10 
                 mIgG2b 
                 10 
                 10 
                 d0, d4, d7 
                 IP 
               
               
                   
                   
                 2011 m2a EN 
                   
                 MPC-11 
                   
                   
                   
                   
               
               
                 5 
                 8 
                 J43 MP8-2 
                 10 
                 Anti-CTLA4 
                 10 
                 10 
                 d0, d4, d7 
                 IP 
               
               
                   
                   
                 2011 m2a EN 
                   
                 9D9 mIgG2b 
               
               
                   
               
            
           
         
       
     
       FIG. 38 , which plots % non-diabetic versus number of days post initial dose, shows that the single agent anti-PD-1 J43 antibody (referred to in the figure as “anti-PD1 J43 Ab”) and the combination of 10 mg/kg anti-PD-1 J43 antibody plus 10 mg/kg anti-CTLA4 antibody (referred to in the figure as “anti-PD1 J43 Ab”+“anti-CTLA4 9D9 mIgG2b”) dosed on days 0, 4 and 7 induced diabetes in 25% of NOD mice by day nine. In contrast, the same dosing schedule of activatable antibody anti-PD-1 J43 MP8-2 2011 m2a EN (referred to in the figure as “J43 MP8-2 2011 m2a EN AA” where AA stands for activatable antibody) as a single agent or in combination with anti-CTLA4 antibody (referred to in the figure as “J43 MP8-2 2011 m2a EN AA+“anti-CTLA4 9D9 mIgG2b” where AA stands for activatable antibody) resulted in no induction of diabetes to day fifteen. 
     Example 35. Anti-PD-1 Nivolumab Activatable Antibodies of the Embodiments are Functionally Masked in a Human T-Cell Restimulation Assay 
     This Example describes the effect of masking moieties on the biological function of the anti-PD-1 nivolumab antibody. 
     PBMCs from a CMV-positive donor (Hemacare) were plated at 2×10 5  cells/well in the presence of CMV viral lysate (Astarte) and either anti-PD-1 antibody A1.5, anti-PD-1 activatable antibody A1.5 PD34 2001, anti-PD-1 antibody nivolumab (NV1), anti-PD-1 nivolumab activatable antibody NV1 NV07 2001, or an hIgG4 isotype control antibody. After four days, supernatant was removed from each well and IFN-gamma levels were assayed using an IFN-gamma ELISA kit (Life Technologies, Carlsbad, Calif.). 
       FIG. 39  demonstrates that the anti-PD-1 activatable antibody A1.5 PD34 2001 (referred to in the figure as “A1.5 PD34 2001 AA” where AA stands for activatable antibody) and anti-PD1 nivolumab activatable antibody NV1 NV07 2001 (referred to in the figure as “NV1 NV07 2001 AA” where AA stands for activatable antibody) effected increased CMV-stimulated IFN-gamma secretion compared to the control hIgG4 antibody (referred to in the figure as hIgG4) but decreased potency relative to anti-PD-1 parental antibody A1.5 (referred to in the figure as A1.5) or anti-PD-1 parental antibody nivolumab (referred to in the figure as NV1). 
     Example 36. Anti-PD-1 Pembrolizumab Activatable Antibodies of the Embodiments are Functionally Masked in a Human T-Cell Restimulation Assay 
     This example describes the effect of masking moieties on the biological function of the anti-PD-1 pembrolizumab antibody. 
     PBMCs from a CMV-positive donor (Hemacare) were plated at 2×10 5  cells/well in the presence of 4 ug/ml CMV viral lysate (Astarte) and either anti-PD-1 antibody A1.5, anti-PD-1 antibody pembrolizumab (PM1), anti-PD-1 pembrolizumab activatable antibody PM1 PM07 2001, or an hIgG4 isotype control antibody. After four days, supernatant was removed from each well and IFN-gamma levels were assayed using an IFN-gamma ELISA kit (Life Technologies, Carlsbad, Calif.). 
       FIG. 40  demonstrates that anti-PD1 pembrolizumab activatable antibody PM1 PM07 2001 (referred to in the figure as “PM1 PM07 2001 AA” where AA stands for activatable antibody) effected increased CMV-stimulated IFN-gamma secretion compared to the control hIgG4 antibody (referred to in the figure as hIgG4) but decreased potency relative to anti-PD-1 parental antibody A1.5 (referred to in the figure as A1.5) or anti-PD-1 parental antibody pembrolizumab (referred to in the figure as PM1). 
     OTHER EMBODIMENTS 
     While the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following.