Patent Publication Number: US-2019194340-A1

Title: Methods of making bispecific anti-cd307e and anti-bcma chimeric antigen receptors and uses of the same

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application claims the benefit of priority to U.S. Provisional Patent Application Ser. No. 62/566,025 filed Sep. 29, 2017, the contents of which are incorporated herein by reference in their entirety. 
    
    
     TECHNICAL FIELD 
     The present disclosure relates to the field of biotechnology, and more specifically to chimeric antigen receptors. 
     BACKGROUND 
     Millions of people suffer from cancer worldwide. Immunotherapy provides a targeted approach to selectively kill cancer cells by mobilizing the patient&#39;s immune system. 
     SUMMARY 
     The present invention is based on the discovery that bispecific chimeric antigen receptors that can specifically bind to both BCMA and CD307e can be used to selectively target cancer cells that express both BCMA and CD307e on their surface. This bispecific approach to treating cancer reduces the likelihood of tumors escaping therapy by losing one or the other antigens. Deeper responses due to more active chimeric antigen receptors targeting two antigens versus one antigen thus produces a durability of anti-tumor response which is longer than targeting a single antigen. 
     Provided herein are chimeric antigen receptors (CARs) that include: a first antigen-binding domain that binds specifically to B-cell maturation antigen (BCMA); a second antigen-binding domain that binds specifically to CD307e; a transmembrane domain; a co-stimulatory domain; and an intracellular signaling domain. Some embodiments of any of the CARs described herein further include a linker that is positioned between the first antigen-binding domain and the second antigen-binding domain. In some embodiments of any of the CARs described herein, the linker is a GS connector. Some embodiments of any of the CARs described herein further include a hinge sequence that is positioned between the second antigen-binding domain and the transmembrane domain. Some embodiments of any of the CARs described herein further include a hinge sequence that is positioned between the first antigen-binding domain and the transmembrane domain. In some embodiments of any of the CARs described herein, the hinge sequence is a CD8a hinge sequence or a CD28 hinge sequence. 
     In some embodiments of any of the CARs described herein, the CAR includes, going in the N-terminal to the C-terminal direction: the first antigen-binding domain, the linker, the second antigen-binding domain, the transmembrane domain, the co-stimulatory domain, and the intracellular signaling domain. Some embodiments of any of the CARs described herein further include a hinge sequence positioned between the second antigen-binding domain and the transmembrane domain. 
     In some embodiments of any of the CARs described herein, the CAR includes, going in the N-terminal to the C-terminal direction: the second antigen-binding domain, the linker, the first antigen-binding domain, the transmembrane domain, the co-stimulatory domain, and the intracellular signaling domain. Some embodiments of any of the CARs described herein further include a hinge sequence positioned between the first antigen-binding domain and the transmembrane domain. 
     In some embodiments of any of the CARs described herein, one or both of the first antigen-binding domain and the second antigen-binding domain is a single-chain variable fragment (scFv). In some embodiments of any of the CARs described herein, the first antigen-binding domain and the second antigen-binding domain are both a scFv. In some embodiments of any of the CARs described herein, the first antigen-binding domain includes, going in the N-terminal to the C-terminal direction, a V L  domain and a V H  domain separated by a first scFv linker. In some embodiments of any of the CARs described herein, the first antigen-binding domain includes, going in the N-terminal to the C-terminal direction, a V H  domain and a V L  domain separated by a first scFv linker. In some embodiments of any of the CARs described herein, the second antigen-binding domain comprises, going in the N-terminal to the C-terminal direction, a V L  domain and a V H  domain separated by a second scFv linker. In some embodiments of any of the CARs described herein, the second antigen-binding domain comprises, going in the N-terminal to the C-terminal direction, a V H  domain and a V L  domain separated by a second scFv linker. In some embodiments of any of the CARs described herein, one or both of the first scFv linker and the second scFv linker is a Whitlow linker. In some embodiments of any of the CARs described herein, both the first scFv linker and the second scFv linker are Whitlow linkers. 
     In some embodiments of any of the CARs described herein, the transmembrane domain is the transmembrane domain of CD28, CD3 epsilon, CD4, CD5, CD6, CD8a, CD9, CD16, CD22, CD33, CD37, CD45, CD64, CD80, CD86, CD134, 4-1BB, or CD154. In some embodiments of any of the CARs described herein, the co-stimulatory domain is the co-stimulatory domain of 4-1BB, CD28, CD2, CD4, CD8, GITR glucocorticoid-induced TNFR family related gene (GITR), nerve growth factor receptor (NGFR, CD271), or CD154. In some embodiments of any of the CARs described herein, the intracellular signaling domain is the intracellular signaling domain of CD3zeta, CD5, CD22, CD79, hematopoietic cell signal transducer (DAP-10, KAP10), or TYRO protein tyrosine kinase binding protein (DAP-12, KARAP) (see, e.g., Wilson et al. (2000) Immunol Res. 22(1):21-42). In some embodiments of any of the CARs described herein, the intracellular signaling domain is the intracellular signaling domain of CD3zeta and the co-stimulatory domain is the co-stimulatory domain of 4-1BB. 
     Also provided herein are nucleic acids that encode any of the CARs described herein. Also provided herein are vectors that include any of the nucleic acids encoding any of the CARs described herein. In some embodiments of any of the vectors described herein, the nucleic acid encoding any of the CARs described herein is operably linked to one or both of a promoter and an enhancer. 
     In some embodiments of any of the vectors described herein, the promoter is an inducible promoter. 
     Also provided herein are cells that include any of the nucleic acids encoding any of the CARs described herein described herein or any of the vectors described herein. In some embodiments of any of the cells described herein, the cell is a eukaryotic cell. In some embodiments of any of the cells described herein, the eukaryotic cell is a mammalian cell. In some embodiments of any of the cells described herein, the mammalian cell is a human cell. In some embodiments of any of the cells described herein, the mammalian cell is a cell selected from the group of: a T cell, a natural killer (NK) cell, a monocyte/macrophage, and a B cell. In some embodiments of any of the cells described herein, the mammalian cell is a mammalian cell obtained from a subject. In some embodiments of any of the cells described herein, the subject is diagnosed or identified as having a cancer. In some embodiments of any of the cells described herein, the cancer is characterized by cancer cells that express one or both of BCMA and CD307e. 
     Also provided herein are pharmaceutical compositions that include any of the cells described herein and a pharmaceutically acceptable carrier. Also provided herein are kits that include any of the pharmaceutical compositions described herein. 
     Also provided herein are pharmaceutical compositions including any of the nucleic acids encoding any of the CARs described herein and a pharmaceutically acceptable carrier. Also provided herein are kits that include any of the pharmaceutical compositions described herein. 
     Also provided herein are methods of generating a chimeric antigen receptor (CAR)-expressing cell that include introducing into a cell any of the nucleic acids encoding any of the CARs described herein, or any of the vectors described herein. In some embodiments of any of the methods described herein, the cell is a eukaryotic cell. In some embodiments of any of the methods described herein, the eukaryotic cell is a mammalian cell. In some embodiments of any of the methods described herein, the mammalian cell is a human cell. In some embodiments of any of the methods described herein, the mammalian cell is a cell selected from the group consisting of: a T cell, a NK cell, a macrophage/monocyte, and a B cell. In some embodiments of any of the methods described herein, the mammalian cell is a mammalian cell obtained from a subject. In some embodiments of any of the methods described herein, the subject is diagnosed or identified as having a cancer. In some embodiments of any of the methods described herein, the cancer is characterized by cancer cells that express one or both of BCMA and CD307e. Some embodiments of any of the methods described herein further include, after the introducing step: culturing the cell in a liquid culture medium. Some embodiments of any of the methods described herein can further include, before the introducing step: obtaining the cell from the subject. 
     Also provided herein are methods of treating a cancer in a subject that include: administering a therapeutically effective amount of any of the cells described herein to the subject. In some embodiments of any of the methods described herein, the cancer is characterized by cancer cells that express one or both of BCMA and CD307e. In some embodiments of any of the methods described herein, the cancer is a carcinoma, a sarcoma, a myeloma, a leukemia, or a lymphoma. In some embodiments of any of the methods described herein, the subject has been diagnosed or identified as having the cancer. Some embodiments of any of the methods described herein further include, prior the administering step: obtaining an initial cell from the subject; and introducing any of the nucleic acids encoding any of the CARs described herein, or any of the vectors described herein into the initial cell, to yield the cell that is administered to the subject. Some embodiments of any of the methods described herein further include, between the introducing step and the administering step, a step of culturing the cell that is administered to the subject in a liquid culture medium. In some embodiments of any of the methods described herein, the subject is a human. Also provided herein are methods of treating multiple myeloma in a subject that include administering to a subject a therapeutically effective amount of any of the cells described herein. In some embodiments of any of the methods described herein, the subject has been diagnosed or identified as having multiple myeloma. Some embodiments of any of the methods described herein further include, prior the administering step: obtaining an initial cell from the subject; and introducing any of the nucleic acids encoding any of the CARs described herein, or any of the vectors described herein into the initial cell, to yield the cell that is administered to the subject. Some embodiments of any of the methods described herein further include, between the introducing step and the administering step, a step of culturing the cell that is administered to the subject in a liquid culture medium. In some embodiments of any of the methods described herein, the subject is human. 
     Some embodiments of any of the methods described herein further include administering to the subject one or more additional anti-cancer therapies. In some embodiments of any of the methods described herein, the one or more additional anti-cancer therapies is selected from the group consisting of chemotherapy, immunotherapy, surgical resection, and radiation therapy. 
     The use of the term “a” before a noun is meant “one or more” of the particular noun. For example, the phrase “a mammalian cell” means “one or more mammalian cell.” 
     The terms “chimeric antigen receptor” and “CAR” are used interchangeably herein, and refer to artificial multi-module molecules capable of triggering or inhibiting the activation of an immune cell which generally but not exclusively comprise an extracellular domain (e.g., a ligand/antigen binding domain), a transmembrane domain and one or more intracellular signaling domains. Exemplary CARs, exemplary domains within CARs, and derivatives thereof (e.g., CAR variants) are described, e.g., in PCT Application No. US2014/016527; Fedorov et al. Sci Transl Med (2013); 5(215):215ra172; Glienke et al. Front Pharmacol (2015) 6:21; Kakarla &amp; Gottschalk 52 Cancer J (2014) 20(2):151-5; Riddell et al. Cancer J (2014) 20(2):141-4; Pegram et al. Cancer J (2014) 20(2):127-33; Cheadle et al. Immunol Rev (2014) 257(1):91-106; Barrett et al. Annu Rev Med (2014) 65:333-47; Sadelain et al. Cancer Discov (2013) 3(4):388-98; Cartellieri et al., J Biomed Biotechnol (2010) 956304; the disclosures of which are incorporated herein by reference in their entirety. 
     The term “transmembrane domain” means a domain of a polypeptide that includes at least one contiguous amino acid sequence that traverses a lipid bilayer when present in the corresponding endogenous polypeptide when expressed in a mammalian cell. For example, a transmembrane domain can include one, two, three, four, five, six, seven, eight, nine, or ten contiguous amino acid sequences that each traverse a lipid bilayer when present in the corresponding endogenous polypeptide when expressed in a mammalian cell. As is known in the art, a transmembrane domain can, e.g., include at least one (e.g., two, three, four, five, six, seven, eight, nine, or ten) contiguous amino acid sequence (that traverses a lipid bilayer when present in the corresponding endogenous polypeptide when expressed in a mammalian cell) that has α-helical secondary structure in the lipid bilayer. In some embodiments, a transmembrane domain can include two or more contiguous amino acid sequences (that each traverse a lipid bilayer when present in the corresponding endogenous polypeptide when expressed in a mammalian cell) that form a β-barrel secondary structure in the lipid bilayer. Non-limiting examples of transmembrane domains are described herein. Additional examples of transmembrane domains are known in the art. 
     The term “costimulatory domain” means a signaling domain from an endogenous co-stimulatory transmembrane polypeptide expressed in a T lymphocyte that promotes the downstream T-cell receptor signaling and/or T cell activation. Non-limiting examples of costimulatory domains are described herein. Additional examples of costimulatory domains are known in the art. See, e.g., Chen et al., Nature Reviews Immunol. 13:227-242, 2013. 
     A “intracellular signaling domain” is an intracellular domain in a transmembrane protein that is required for the activation and/or proliferation of a cell (e.g., any of the mammalian cells described herein, e.g., any of the T-cells, any of the B-cells, monocytes, macrophages, eosinophils, NK cells, and neutrophils described herein). Non-limiting examples of intracellular signaling domains are described herein. Additional examples of intracellular signaling domains are known in the art. 
     The term “antigen-binding domain” means a domain that binds specifically to a target antigen. In some examples, an antigen-binding domain can be formed from the amino acids present within a single-chain polypeptide. In other examples, an antigen-binding domain can be formed from amino acids present within a first single-chain polypeptide and the amino acids present in one or more additional single-chain polypeptides (e.g., a second single-chain polypeptide). Non-limiting examples of antigen-binding domains are described herein. Additional examples of antigen-binding domains are known in the art. 
     The phrase “treatment of cancer” or “treating cancer” means a reduction in the number, frequency, or severity of one or more (e.g., two, three, four, or five) symptoms of a cancer in a subject having a cancer. Non-limiting symptoms of cancer are described herein. Additional symptoms of cancer are known in the art. 
     Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials are described herein for use in the present invention; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. 
     Other features and advantages of the invention will be apparent from the following detailed description and figures, and from the claims. 
    
    
     
       BRIEF DESCRIPTION OF DRAWINGS 
         FIG. 1  is a schematic representation of a conventional chimeric antigen receptor (CAR) and a tandem CAR. 
         FIG. 2  is a schematic representation of two embodiments of the extracellular portion of a bi-specific CAR. 
         FIG. 3  shows representative FACS histogram plots for BCMA staining on immortalized cancer cell lines derived from patients with multiple myeloma (MM. 1R, MM. 1S, H929, OPM2, U266) and negative control cells (K562), unstained cells, and isotope control. 
         FIG. 4  is a representative graph showing the ability of the J6M0 scFv based CAR (J6M0_BBz) to kill multiple BCMA positive cell lines (MM. 1R, MM.1 S, H929, OPM2, U266), compared to untransduced T cells as a negative control. The effector to target (E:T) ratio used was 1:1. 
         FIG. 5  is a representative FACS histogram plot showing CD307e expression on K562 tumor cells that have been engineered to exogenously express CD307 and the parental negative control K562 cells that do not naturally express CD307, unstained cells, and isotope control. 
         FIG. 6  is a representative scatter plot of targeted cell lysis of K562 CD307  cells following incubation with m7D11, 1G7v85, 1G7v93, 13G9v1, 13G9v3, m13G9, 10A8, or m10A8. 
         FIG. 7A  is a representative plot of fragments per kilobase of transcript per million mapped reads (FPKM) of BCMA obtained from the CoMMpass™ study. 
         FIG. 7B  is a representative plot of FPKM of FCRL5 (CD307e) obtained from the CoMMpass™ study. 
         FIG. 8A  is a representative graph of CD307 antigen negative K562 tumor cell lysis at effector to target ratios (E:T) of 3:1, 1:1 and 1:3 using a humanized 10A8 scFv, a murine m10A8 scFv (m10A8), or untransduced (UNTR) control T cells. 
         FIG. 8B  is a representative graph of CD307 +  K562 tumor cell lysis at ratios (E:T) of 3:1, 1:1 and 1:3 using a humanized 10A8 scFv, a murine m10A8 scFv (m10A8), or untransduced (UNTR) control T cells. 
         FIG. 9A  is a representative graph of IFNγ levels following incubation of CD307 antigen-negative K562 tumor cells and CD307 +  K562 tumor cells with murine 10A8 (m10A8) or humanized 10A8 (10A8). * represents undetectable levels. 
         FIG. 9B  is a representative graph of IL-2 levels following incubation of antigen negative K562 tumor cells and CD307 +  K562 tumor cells with murine 10A8 (m10A8) or humanized 10A8 (10A8). * represents undetectable levels. 
         FIG. 10  is a schematic representation of three embodiments of the extracellular portion of a series of tandem CAR including J6M0/10A8 (TanCAR1), J6M0/10A8 (TanCAR2) and 10A8/J6M0 (TanCAR3). 
         FIG. 11  is representative FACS dot plots of untransduced (UNTR), anti-CD307 (10A8), and anti-BCMA (J6M0) expression in primary human T cells expressing conventional CARs. 
         FIG. 12  is representative FACS dot plots of tandem CARs carrying anti-CD307 (10A8) and anti-BCMA (J6M0) scFvs, expressed in primary human T cells. 
         FIG. 13A  is a representative graph of antigen negative K562 tumor cell lysis following incubation with TanCAR1, TanCAR2, TanCAR3, 10A8, J6M0, negative control, or untransduced (UNTR) control T cells. 
         FIG. 13B  is a representative graph of K562 CD307  tumor cell lysis following incubation with TanCAR1, TanCAR2, TanCAR3, 10A8, J6M0, negative control, or untransduced (UNTR) control T cells. 
         FIG. 13C  is a representative graph of K562 BCMA  tumor cell lysis following incubation with TanCAR1, TanCAR2, TanCAR3, 10A8, J6M0, negative control, or untransduced (UNTR) control T cells. 
         FIG. 13D  is a representative graph of K562 CD307/BCMA  tumor cell lysis following incubation with TanCAR1, TanCAR2, TanCAR3, 10A8, J6M0, negative control, or untransduced (UNTR) control T cells. 
         FIG. 14  is representative FACS dot plots of anti-CD307 and anti-BCMA CAR expression in primary human T cells expressing conventional CARs against CD307 (1G7.v85 and 1G7.v93), tandem CARs against BCMA and CD307 (J6M0/1G7v.85 and J6M0/1G7v.93), conventional CAR against BCMA (J6M0), or conventional CAR against CD19 (FMC63). 
         FIG. 15A  is a representative graph of antigen negative K562 tumor cell lysis following incubation with 1G7.v85, 1G7.v93, J6M0_1G7v85 TanCAR, J6M0_1G7v93 TanCAR, J6M0, negative control, or untransduced (UNTR) control T cells. 
         FIG. 15B  is a representative graph of CD307 +  K562 tumor cell lysis following incubation with 1G7.v85, 1G7.v93, J6M0_1G7v85 TanCAR, J6M0_1G7v93 TanCAR, J6M0, negative control, or untransduced (UNTR) control T cells. 
         FIG. 15C  is a representative graph of BCMA +  K562 tumor cell lysis following incubation with 1G7.v85, 1G7.v93, J6M0_1G7v85 TanCAR, J6M0_1G7v93 TanCAR, J6M0, negative control, or untransduced (UNTR) control T cells. 
         FIG. 15D  is a representative graph of CD307 +  BCMA +  K562 tumor cell lysis following incubation with 1G7.v85, 1G7.v93, J6M0_1G7v85 TanCAR, J6M0_1G7v93 TanCAR, J6M0, negative control, or untransduced (UNTR) control T cells. 
         FIG. 16  is a representative FACS histogram plot showing CD307 expression in antigen negative K-562 tumor cells, K562 CD307  tumor cells, REC-1 tumor cells, unstained cells, and isotope controls. 
         FIG. 17A  is a representative graph of antigen negative K562 tumor cell lysis following incubation with 1G7.v85, 1G7.v93, J6M0_1G7v85 TanCAR, J6M0_1G7v93 TanCAR, J6M0, FMC63 control, or untransduced (UNTR) T cells. The effector to target (E:T) ratio used was 1:1. 
         FIG. 17B  is a representative graph of REC-1 tumor cell lysis following incubation with 1G7.v85, 1G7.v93, J6M0_1G7v85 TanCAR, J6M0_1G7v93 TanCAR, J6M0, FMC63 control, or untransduced (UNTR) T cells. The effector to target (E:T) ratio used was 1:1. 
         FIG. 18  is a representative graph of IFNγ levels following incubation of T cells alone, antigen-negative K562 tumor cells and REC-1 tumor cells with 1G7.v85, 1G7.v93, J6M0_1G7v85 TanCAR, J6M0_1G7v93 TanCAR, J6M0, or FMC63 control T cells. 
     
    
    
     DETAILED DESCRIPTION 
     Accordingly, the present disclosure provides chimeric antigen receptors (CAR) that include a first antigen-binding domain that binds specifically to B-cell maturation antigen (BCMA); a second antigen-binding domain that binds specifically to CD307e; a transmembrane domain; a co-stimulatory domain; and an intracellular signaling domain. Also provided are nucleic acids the encode any of these CARs, vectors that include a nucleic acid encoding any of these CARs, and cells that express any of these CARs. Also provided are compositions that include any of the cells that express any of the CARs. Also provided are compositions that include any of the nucleic acids that encode any of the CARs described herein, or any of the vectors that include any of the nucleic acids encoding any of the CARs described herein. Also provided are kits that include any of the compositions described herein. Also provided here are methods of making a cell expressing any of the CARs described herein, and methods of treating a subject having a cancer that include administering any of the cells expressing any of the CARs described herein. 
     Various exemplary aspects of these CARs and methods are described below and can be used in any combination in the compositions and methods provided herein without limitation. Exemplary aspects of the provided methods are described below; however, one skilled in the art will appreciate that additional steps can be added to the methods described herein and other materials can be used to perform any of the steps of the methods described herein. 
     Chimeric Antigen Receptor (CAR) 
     A chimeric antigen receptor (CAR) is an artificially constructed hybrid protein or that includes at least one antigen-binding domain (e.g., a single chain variable fragment (scFv)), a transmembrane domain, and at least one cellular signaling domain (e.g., at least one co-stimulatory domain and at least one intracellular signaling domain). CARs have the ability to redirect T-cell specificity and reactivity toward a selected target in a non-MHC-restricted manner (e.g., a BCMA antigen or a CD307e antigen). CARs have been described in, e.g., Kershaw et al.,  Nature Reviews Immunol.  5(12):928-940, 2005; Eshhar et al.,  Proc. Natl. Acad. Sci. U.S.A.  90(2):720-724, 1993; Sadelain et al.,  Curr. Opin. Immunol.  21(2): 215-223, 2009; WO 2015/142675; WO 2015/150526; and WO 2014/134165, the disclosures of each of which are incorporated herein by reference in their entirety. 
     Provided herein are chimeric antigen receptors (CARs) that include a first antigen-binding domain that binds specifically to B-cell maturation antigen (BCMA); a second antigen-binding domain that binds specifically to CD307e; a transmembrane domain; a co-stimulatory domain; and an intracellular signaling domain. Non-limiting aspects and examples of first antigen-binding domains, second antigen-binding domains, transmembrane domains, co-stimulatory domains, and intracellular signaling domains are described herein. Additional aspects and examples of first antigen-binding domains, second antigen-binding domains, transmembrane domains, co-stimulatory domains, and intracellular signaling domains are known in the art. 
     In some examples of any of the CARs described herein, going in the N-terminal to the C-terminal direction, the intracellular portion of the CAR includes a co-stimulatory domain and an intracellular signaling domain. In some examples of any of the CARs described herein, going in the N-terminal to the C-terminal direction, the intracellular portion of the CAR includes an intracellular signaling domain and a co-stimulatory domain. 
     In some examples of any of the CARs described herein, going in the C-terminal to the N-terminal direction, the intracellular portion of the CAR includes a co-stimulatory domain and an intracellular signaling domain. In some examples of any of the CARs described herein, going in the C-terminal to the N-terminal direction, the intracellular portion of the CAR includes an intracellular signaling domain and a co-stimulatory domain. 
     Some embodiments of any of the CARs described herein further include a linker that is positioned between the first antigen-binding domain and the second antigen-binding domain. Non-limiting examples of linkers are described herein. In some embodiments, the linker is a GS connector. 
     Some embodiments of any of the CARs described herein further include a hinge sequence that is positioned between the second antigen-binding domain and the transmembrane domain. Some embodiments of any of the CARs described herein further include a hinge sequence that is positioned between the first antigen-binding domain and the transmembrane domain. In some embodiments, the hinge sequence is or includes a CD8a hinge sequence. In some embodiments, the hinge sequence is or includes CD28 hinge sequence. 
     In some embodiments of any of the CARs described herein, the CAR includes, going in the N-terminal to the C-terminal direction: the first antigen-binding domain, the linker, the second antigen-binding domain, the transmembrane domain, the co-stimulatory domain, and the intracellular signaling domain. In some embodiments of any of the CARs described herein, the CAR includes, going in the C-terminal to the N-terminal direction: the first antigen-binding domain, the linker, the second antigen-binding domain, the transmembrane domain, the co-stimulatory domain, and the intracellular signaling domain. Some embodiments of any of the CARs described herein include a hinge sequence positioned between the second antigen-binding domain and the transmembrane domain. 
     In some embodiments of any of the CARs described herein, the CAR includes, going in the N-terminal to the C-terminal direction: the second antigen-binding domain, the linker, the first antigen-binding domain, the transmembrane domain, the co-stimulatory domain, and the intracellular signaling domain. In some embodiments of any of the CARs described herein, the CAR includes, going in the C-terminal to the N-terminal direction: the second antigen-binding domain, the linker, the first antigen-binding domain, the transmembrane domain, the co-stimulatory domain, and the intracellular signaling domain. Some embodiments of any of the CARs described herein further include a hinge sequence positioned between the first antigen-binding domain and the transmembrane domain. 
     In some examples of any of the CARs described herein, one or both of the first antigen-binding domain and the second antigen-binding domain is a single-domain variable fragment (scFv). In some examples of any of the CARs described herein, both the first antigen-binding domain and the second antigen-binding domain are both a single-domain variable fragment (scFv). 
     In some embodiments of any of the CARs described herein, the first antigen-binding domain includes, going in the N-terminal to the C-terminal direction, a VL domain and a VH domain separated by a first scFv linker. In some embodiments of any of the CARs described herein, the first antigen-binding domain includes, going in the N-terminal to the C-terminal direction, a VH domain and a VL domain separated by a first scFv linker. 
     In some embodiments of any of the CARs described herein, the second antigen-binding domain includes, going in the N-terminal to the C-terminal direction, a VL domain and a VH domain separated by a second scFv linker. In some embodiments of any of the CARs described herein, the second antigen-binding domain includes, going in the N-terminal to the C-terminal direction, a VH domain and a VL domain separated by a second scFv linker. 
     Non-limiting aspects and examples of first and second scFv linkers are described herein. In some embodiments of any of the CARs described herein, one or both of the first scFv linker and the second scFv linker is a Whitlow linker. In some embodiments of any of the CARs described herein, both of the first scFv linker and the second scFv linker are Whitlow linkers. 
     In some embodiments of any of the CARs described herein, the transmembrane is or includes a transmembrane domain of CD28, CD3 epsilon, CD4, CD5, CD6, CD8a, CD9, CD16, CD22, CD33, CD37, CD45, CD64, CD80, CD86, CD134, 4-1BB, or CD154. Additional examples and aspects of transmembrane domains are described herein. 
     In some embodiments of any of the CARs described herein, the co-stimulatory domain is or includes the co-stimulatory domain of 4-1BB, CD28, CD2, CD4 or CD8. Additional examples and aspects of co-stimulatory domains are described herein. 
     In some embodiments of any of the CARs described herein, the intracellular signaling domain is or includes the intracellular signaling domain of CD3 zeta, CD5, CD22, DAP-10, DAP-12, CD5, CD22, or CD79. Additional examples and aspects of intracellular signaling domains are described herein. 
     In some embodiments of any of the CARs described herein, the intracellular signaling domain is CD3 zeta and the costimulatory domain is the co-stimulatory domain of 4-1BB or CD28. 
     A variety of methods that can be used to determine the K D  values of any of the CARs described herein are known in the art (e.g., an electrophoretic mobility shift assay, a filter binding assay, surface plasmon resonance, and a biomolecular binding kinetics assay, etc.). 
     Antigen-Binding Domains 
     In some embodiments, the first antigen-binding domain and the second antigen-binding domain are each independently selected from the group consisting of: a VHH domain, a VNAR domain, and a scFv. Additional examples of antigen-binding domains that can be used are known in the art. 
     A V H H domain is a single monomeric variable antibody domain that can be found in camelids. A V NAR  domain is a single monomeric variable antibody domain that can be found in cartilaginous fish. Non-limiting aspects of V H H domains and V NAR  domains are described in, e.g., Cromie et al.,  Curr Top. Med. Chem.  15:2543-2557, 2016; De Genst et al.,  Dev. Comp. Immunol.  30:187-198, 2006; De Meyer et al.,  Trends Biotechnol.  32:263-270, 2014; Kijanka et al.,  Nanomedicine  10:161-174, 2015; Kovaleva et al.,  Expert. Opin. Biol. Ther  14:1527-1539, 2014; Krah et al.,  Immunopharmacol. Immunotoxicol.  38:21-28, 2016; Mujic-Delic et al.,  Trends Pharmacol. Sci.  35:247-255, 2014; Muyldermans,  J. Biotechnol.  74:277-302, 2001; Muyldermans et al.,  Trends Biochem. Sci.  26:230-235, 2001; Muyldermans,  Ann. Rev. Biochem.  82:775-797, 2013; Rahbarizadeh et al.,  Immunol. Invest.  40:299-338, 2011; Van Audenhove et al.,  EBioMedicine  8:40-48, 2016; Van Bockstaele et al.,  Curr Opin. Investig. Drugs  10:1212-1224, 2009; Vincke et al.,  Methods Mol. Biol.  911:15-26, 2012; and Wesolowski et al.,  Med. Microbiol. Immunol.  198:157-174, 2009. 
     In some embodiments of any of the CARs described herein, the first antigen-binding domain and the second antigen-binding domain are both VHH domains, or at least one antigen-binding domain is a VHH domain. In some embodiments of any of the CARs described herein, the first antigen-binding domain and the second antigen-binding domain are both VNAR domains, or at least one antigen-binding domain is a VNAR domain. In some embodiments of any of the CARs described herein, the first antigen-binding domain and the second antigen-binding domain are both scFv domains, or at least one antigen-binding domain is a scFv domain. 
     In some examples, the first antigen-binding domain and/or the second antigen-binding domain is human. In some examples, the first antigen-binding domain and/or the second antigen-binding domain is humanized. 
     In some examples, the first antigen-binding domain is a scFv, e.g., a scFv derived from J6M0. 
     The light chain variable domain and the heavy chain variable domain of J6M0 are provided below. The three CDRs present in the light chain variable domain and the three CDRs present in the heavy chain variable domain are shown in bold. 
     Light Chain Variable Domain of J6M0 (SEQ ID NO: 1) (Each CDR is Shown in Bold.) 
       
     
       
         
           
               
            
               
                 DIQMTQSPSSLSASVGDRVTITC   SASQDISNYLN   WYQQKPGKAPKLLIY   Y     
               
               
                   
               
               
                     TSNLHS   GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC   QQYRKLPWT   FGQ 
               
               
                   
               
               
                 GTKLEIKR 
               
               
                   
               
               
                 Heavy Chain Variable Domain of J6M0 
               
               
                 (Each CDR is shown in bold.) 
               
            
           
           
               
            
               
                 (SEQ ID NO: 2) 
               
            
           
           
               
            
               
                 QVQLVQSGAEVKKPGSSVKVSCKASGGTFS   NYWMH   WVRQAPGQGLEWMG   A     
               
               
                   
               
               
                     TYRGHSDTYYNQKFKG   RV TITADKSTSTAYMELSSLRSEDTAVYYCAR GA     
               
               
                   
               
               
                     IYDGYDVLDN   WGQGTLVTVSS 
               
            
           
         
       
     
     The nucleic acid sequence encoding the light chain variable domain of J6M0 and the nucleic acid sequence encoding the heavy chain variable domain of J6M0. cDNA Encoding Light Chain Variable Domain of J6M0 (SEQ ID NO: 3) gatatacaaatgacccaaagcccaagctctctgagtgcgtccgtcggggacagagtgacaataacatgtagtgcgtct caggacatcagtaactacctgaactggtaccagcaaaaaccaggtaaggctcccaagctgcttatttattatacctcaa atctgcacagcggcgttccatcacgcttttctggctctggcagtgggacggacttcaccctcacaatttctagccttcaa ccagaagatttcgccacttactactgtcaacagtaccggaagctgccctggacgttcgggcagggaacaaaacttga 
     
       
         
           
               
            
               
                 cDNA Encoding Light Chain Variable Domain of J6M0 
               
            
           
           
               
            
               
                 (SEQ ID NO: 3) 
               
            
           
           
               
            
               
                 gatatacaaatgacccaaagcccaagctctctgagtgcgtccgtcgggga 
               
               
                   
               
               
                 cagagtgacaataacatgtagtgcgtctcaggacatcagtaactacctga 
               
               
                   
               
               
                 actggtaccagcaaaaaccaggtaaggctcccaagctgcttatttattat 
               
               
                   
               
               
                 acctcaaatctgcacagcggcgttccatcacgcttttctggctctggcag 
               
               
                   
               
               
                 tgggacggacttcaccctcacaatttctagccttcaaccagaagatttcg 
               
               
                   
               
               
                 ccacttactactgtcaacagtaccggaagctgccctggacgttcgggcag 
               
               
                   
               
               
                 ggaacaaaacttgaaatcaagcgg 
               
               
                   
               
               
                 cDNA Encoding Heavy Chain Variable Domain of J6M0  
               
            
           
           
               
            
               
                 (SEQ ID NO: 4) 
               
            
           
           
               
            
               
                 caagtccagctggttcaatccggagctgaggtgaaaaaaccaggctcaag 
               
               
                   
               
               
                 cgttaaggtttcttgcaaggccagtggggggactttctccaactactgga 
               
               
                   
               
               
                 tgcactgggtacggcaggcccccggtcaagggcttgaatggatgggtgcc 
               
               
                   
               
               
                 acgtacagaggacactcagacacatactataaccaaaaattcaaggggcg 
               
               
                   
               
               
                 agttactattactgcagacaagtcaacttctacagcctacatggaattgt 
               
               
                   
               
               
                 cctcccttaggtctgaagacacagcagtgtactattgcgcgcggggggcc 
               
               
                   
               
               
                 atatacgacggatacgacgtgcttgataactggggccagggcaccctcgt 
               
               
                   
               
               
                 gactgttagctcc 
               
            
           
         
       
     
     In some embodiments of the CARs described herein, the first antigen-binding domain includes a VL domain that is or includes a sequence that is at least 80% identical (e.g., at least 82%, at least 84%, at least 86%, at least 88%, at least 90%, at least 92%, at least 94%, at least 96%, at least 98%, or at least 99%) identical to the VL domain of J6M0, and/or includes a VH domain that is or includes a sequence that is at least 80% identical (e.g., at least 82%, at least 84%, at least 86%, at least 88%, at least 90%, at least 92%, at least 94%, at least 96%, at least 98%, or at least 99%) identical to the VH domain of J6M0. In some embodiments of the CARs described herein, the first antigen-binding domain includes a VL domain that is or includes the VL domain of J6M0, and/or a VH domain that is or includes the VH domain of J6M0. In some embodiments of any of the CARs described herein, the first antigen-binding domain includes a VL domain that is or includes the sequence of VL of J6M0, except that it includes one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or fifteen amino acid substitutions, and/or includes a VH domain that is or includes the sequence of VH of J6M0, except that it includes one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or fifteen amino acid substitutions. In some embodiments the first antigen-binding domain includes the three CDRs in the light chain variable domain of J6M0, and/or the three CDRs in the heavy chain variable domain of J6M0. 
     In some examples of any of the CARs described herein, the CAR can bind to a BCMA antigen (e.g., an epitope present in the extracellular domain of BCMA) with a dissociation equilibrium constant (K D ) of less than 1×10 −5  M, less than 0.5×10 −5  M, less than 1×10 6  M, less than 0.5×10 M, less than 1×10 −7  M, less than 0.5×10 −7  M, less than 1×10 −8  M, less than 0.5×10 −8  M, less than 1×10 −9  M, less than 0.5×10 −9 , less than 1×10 −10  M, less than 0.5×10 −10  M, or less than 1×10 −11  M (e.g., as measured using surface plasmon resonance). 
     In some examples of any of the CARs described herein, the CAR can bind to a BCMA antigen (e.g., an epitope present in the extracellular domain of BCMA) with a K D  of about 1×10 −11  M to about 1×10 −5  M, about 1×10 −11  M to about 0.5×10 −5  M, about 1×10 −11  M to about 1×10 6  M, about 1×10 −11  M to about 0.5×10 6  M, about 1×10 −11  M to about 1×10 −7  M, about 1×10 −11  M to about 0.5×10 −7  M, about 1×10 −11  M to about 1×10 −8  M, about 1×10 −11  M to about 0.5×10 −8  M, about 1×10 −11  M to about 1×10 −9  M, about 1×10 −11  M to about 0.5×10 −9  M, about 1×10 −11  M to about 1×10 −10  M, about 1×10 −11  M to about 0.5×10 −10  M; about 0.5×10 −10  M to about 1×10 −5  M, about 0.5×10 −10  M to about 0.5×10 −5  M, about 0.5×10 −10  M to about 1×10 −6  M, about 0.5×10 −10  M to about 0.5×10 6  M, about 0.5×10 −10  M to about 1×10 −7  M, about 0.5×10 −10  M to about 0.5×10 −7  M, about 0.5×10 −10  M to about 1×10 −8  M, about 0.5×10 −10  M to about 0.5×10 −8  M, about 0.5×10 −10  M to about 1×10 −9  M, about 0.5×10 −10  M to about 0.5×10 −9  M, about 0.5×10 −10  M to about 1×10 −10  M, about 1×10 −10  M to about 1×10 −5  M, about 1×10 −10  M to about 0.5×10 −5  M, about 1×10 −10  M to about 1×10 6  M, about 1×10 −10  M to about 0.5×10 6  M, about 1×10 −10  M to about 1×10 −7  M, about 1×10 −10  M to about 0.5×10 −7  M, about 1×10 −10  M to about 1×10 −8  M, about 1×10 −10  M to about 0.5×10 −8  M, about 1×10 −10  M to about 1×10 −9  M, about 1×10 −10  M to about 0.5×10 −9  M, about 0.5×10 −9  M to about 1×10 −5  M, about 0.5×10 −9  M to about 0.5×10 −5  M, about 0.5×10 −9  M to about 1×10 −6  M, about 0.5×10 −9  M to about 0.5×10 −6  M, about 0.5×10 −9  M to about 1×10 −7  M, about 0.5×10 −9  M to about 0.5×10 −7  M, about 0.5×10 −9  M to about 1×10 −8  M, about 0.5×10 −9  M to about 0.5×10 −8  M, about 0.5×10 −9  M to about 1×10 −9  M, about 1×10 −9  M to about 1×10 −5  M, about 1×10 −9  M to about 0.5×10 −5  M, about 1×10 −9  M to about 1×10 −6  M, about 1×10 −9  M to about 0.5×10 −6  M, about 1×10 −9  M to about 1×10 −7  M, about 1×10 −9  M to about 0.5×10 −7 M, about 1×10 −9  M to about 1×10 −8  M, about 1×10 −9  M to about 0.5×10 −8  M, about 0.5×10 −8  M to about 1×10 −5  M, about 0.5×10 −8  M to about 0.5×10 −5  M, about 0.5×10 −8  M to about 1×10 −6  M, about 0.5×10 −8  M to about 0.5×10 −6  M, about 0.5×10 −8  M to about 1×10 −7  M, about 0.5×10 −8  M to about 0.5×10 −7  M, about 0.5×10 −8  M to about 1×10 −8  M, about 1×10 −8  M to about 1×10 −5  M, about 1×10 −8  M to about 0.5×10 −5  M, about 1×10 −8  M to about 1×10 −6  M, about 1×10 −8  M to about 0.5×10 −6  M, about 1×10 −8  M to about 1×10 −7  M, about 1×10 −8 M to about 0.5×10 −7  M, about 0.5×10 −7  M to about 1×10 −5  M, about 0.5×10 −7  M to about 0.5×10 −5  M, about 0.5×10 −7  M to about 1×10 −6  M, about 0.5×10 −7  M to about 0.5×10 −6  M, about 0.5×10 −7  M to about 1×10 −7  M, about 1×10 −7  M to about 1×10 −5  M, about 1×10 −7  M to about 0.5×10 −5  M, about 1×10 −7  M to about 1×10 −6  M, about 1×10 −7  M to about 0.5×10 −6  M, about 0.5×10 −6  M to about 1×10 −5  M, about 0.5×10 −6  M to about 0.5×10 −5  M, about 0.5×10 −6  M to about 1×10 −6  M, about 1×10 −6  M to about 1×10 −5  M, about 1×10 M to about 0.5×10 −5 M, or about 0.5×10 −5  M to about 1×10 −5  M (e.g., as measured using surface plasmon resonance). 
     In some examples, the second antigen-binding domain is a scFv, e.g., a scFv derived from 10A8. 
     The light chain variable domain and the heavy chain variable domain of 10A8 are provided below. The three CDRs present in the light chain variable domain and the three CDRs present in the heavy chain variable domain are shown in bold. 
     
       
         
           
               
            
               
                 Human Light Chain Variable Domain of 10A8 
               
               
                 (Each CDR isshown in bold.) 
               
            
           
           
               
            
               
                 (SEQ ID NO: 5) 
               
            
           
           
               
            
               
                 DIQMTQSPSSLSASVGDRVTITC   KASQDVSTAVA   WYQQKPGKAPKLLIY   S     
               
               
                   
               
               
                     ASYRYT   GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC   QQHFSSPRT   FGQ 
               
               
                   
               
               
                 GTKVEIKR 
               
               
                   
               
               
                 Human Heavy Chain Variable Domain of 10A8 
               
               
                 (Each CDR isshown in bold.) 
               
            
           
           
               
            
               
                 (SEQ ID NO: 6) 
               
            
           
           
               
            
               
                 EVQLVESGGGLVQPGGSLRLSCAAS   GFTFSSYAVS   WVRQAPGKGLEWV   AT     
               
               
                   
               
               
                     ISSGGSLTFYLDSVR   GRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR   PI     
               
               
                   
               
               
                     PDYYALDY   VVGQGTLVTVSS 
               
               
                   
               
               
                 cDNA Encoding Human Light Chain Variable Domain of 
               
               
                 10A8 
               
            
           
           
               
            
               
                 (SEQ ID NO:7) 
               
            
           
           
               
            
               
                 gatatccagatgacccagtctcctagttccttgtccgcatcagtaggaga 
               
               
                   
               
               
                 cagggtcaccatcacctgcaaggccagtcaggatgtgagtactgctgtag 
               
               
                   
               
               
                 cctggtatcaacagaaaccaggaaaagctcctaaactactgatttattcg 
               
               
                   
               
               
                 gcatcctaccggtacactggagtcccttctcgcttctctggcagtggatc 
               
               
                   
               
               
                 tgggacggatttcactctcaccatcagcagtctgcagcctgaagactttg 
               
               
                   
               
               
                 caacttattactgtcagcaacattttagtagtcctcggacgttcggtcaa 
               
               
                   
               
               
                 ggtaccaaggtggagatcaaacga 
               
               
                   
               
               
                 cDNA Encoding Human Heavy Chain Variable Domain of 
               
               
                 10A8 
               
            
           
           
               
            
               
                 (SEQ IDNO: 8) 
               
            
           
           
               
            
               
                 gaagtgcagttggtggagtctgggggaggcttagtgcagcctggagggtc 
               
               
                   
               
               
                 cctgcgactctcctgtgcagcctctggattcactttcagtagctatgccg 
               
               
                   
               
               
                 tgtcttgggttcgccaggctccggggaagggactggagtgggtcgctacc 
               
               
                   
               
               
                 attagcagtggtggtagtttgaccttctatttagacagtgtgaggggtcg 
               
               
                   
               
               
                 attcaccatctccagagacaatagcaagaacaccctgtacctgcaaatga 
               
               
                   
               
               
                 atagtctgagggctgaagacacggccgtgtattactgtgcaaggcccatt 
               
               
                   
               
               
                 ccggattactatgctttggactactggggtcaaggaaccttagtcaccgt 
               
               
                   
               
               
                 ctcctca 
               
               
                   
               
               
                 Mouse Light Chain Variable Domain of 10A8 
               
               
                 (Each CDR isshown in bold.) 
               
            
           
           
               
            
               
                 (SEQ ID NO: 9) 
               
            
           
           
               
            
               
                 DIVMTQSHKFMSTSVRDRVSITC KASQDVSTAVA WYQQKPGQSPKLLIY S   
               
               
                   
               
               
                   ASYRYT GVPDRFTGSGSGTDFTFTISSVQAEDLAVYYC QQHFSSPRT FGG 
               
               
                   
               
               
                 GTKVEIKR 
               
               
                   
               
               
                 Mouse Heavy Chain Variable Domain of 10A8 
               
               
                 (Each CDRis shown in bold.) 
               
            
           
           
               
            
               
                 (SEQ ID NO: 10) 
               
            
           
           
               
            
               
                 EVQLVESGGGLVKPGGSLKISCAAS GFTFSSYAVS WVRQTPEKRLEWV AT   
               
               
                   
               
               
                   ISSGGSLTFYLDSVR GRFTISRDNAKNTLYLQMSSLRSEDTAMYYCAR PI   
               
               
                   
               
               
                   PDYYALDY WGQGTSVTVSS 
               
               
                   
               
               
                 cDNA Encoding Mouse Light Chain Variable Domain of 
               
               
                 10A8 
               
            
           
           
               
            
               
                 (SEQ ID NO:11) 
               
            
           
           
               
            
               
                 gatatcgtgatgacccagtctcataaattcatgtccacatcagtaagaga 
               
               
                   
               
               
                 cagggtcagcatcacctgcaaggccagtcaggatgtgagtactgctgtag 
               
               
                   
               
               
                 cctggtatcaacagaaaccaggacaatctcctaaactactgatttattcg 
               
               
                   
               
               
                 gcatcctaccggtacactggagtccctgatcgcttcactggcagtggatc 
               
               
                   
               
               
                 tgggacggatttcactttcaccatcagcagtgtgcaggctgaagacctgg 
               
               
                   
               
               
                 cagtttattactgtcagcaacattttagtagtcctcggacgttcggtgga 
               
               
                   
               
               
                 ggtaccaaggtggaga 
               
               
                   
               
               
                 tcaaacga 
               
               
                   
               
               
                 cDNA Encoding Mouse Heavy Chain Variable Domain of 
               
               
                 10A8 
               
            
           
           
               
            
               
                 (SEQ ID NO:12) 
               
            
           
           
               
            
               
                 gaagtgcagttggtggagtctgggggaggcttagtgaagcctggagggtc 
               
               
                   
               
               
                 cctgaaaatctcctgtgcagcctctggattcactttcagtagctatgccg 
               
               
                   
               
               
                 tgtcttgggttcgccagactccggagaagaggctggagtgggtcgctacc 
               
               
                   
               
               
                 attagcagtggtggtagtttgaccttctatttagacagtgtgaggggtcg 
               
               
                   
               
               
                 attcaccatctccagagacaatgccaagaacaccctgtacctgcaaatga 
               
               
                   
               
               
                 gcagtctgaggtctgaagacacggccatgtattactgtgcaaggcccatt 
               
               
                   
               
               
                 ccggattactatgctttggactactggggtcaaggaacctcagtcaccgt 
               
               
                   
               
               
                 ctcctca 
               
            
           
         
       
     
     The light chain variable domain and the heavy chain variable domain of human 1G7.v85 are provided below. The three CDRs present in the light chain variable domain and the three CDRs present in the heavy chain variable domain are shown in bold. 
     
       
         
           
               
            
               
                 Human Light Chain Variable Domain of 1G7.v85 
               
               
                 (EachCDR is shown in bold.) 
               
            
           
           
               
            
               
                 (SEQ ID NO: 13) 
               
            
           
           
               
            
               
                 DIQMTQSPSSLSASVGDRVTITC   KASQDVRNLVV   WFQQKPGKAPKLLIY   S     
               
               
                   
               
               
                     GSYRYS   GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC   QQHYSPPYT   FGQ 
               
               
                   
               
               
                 GTKVEIK 
               
               
                   
               
               
                 Human Heavy Chain Variable Domain of 1G7.v85 
               
               
                 (EachCDR is shown in bold.) 
               
            
           
           
               
            
               
                 (SEQ ID NO: 14) 
               
            
           
           
               
            
               
                 EVQLVESGPGLVKPSETLSLTCTVSGFSLT   RFGVH   WVRQPPGKGLEWLG   V     
               
               
                   
               
               
                     IWRGGSTDYNAAFV   SRLTISKDNSKNQVSLKLSSVTAADTAVYYCSN   HYY     
               
               
                   
               
               
                     GSSDYALDN   WGQGTLVTVSS 
               
               
                   
               
               
                 cDNA Encoding Human Light Chain Variable Domain of 
               
               
                 1G7.v85 
               
            
           
           
               
            
               
                 (SEQ IDNO: 15) 
               
            
           
           
               
            
               
                 gatattcagatgacccagagcccgagcagcctgagcgcgagcgtgggcga 
               
               
                   
               
               
                 tcgcgtgaccattacctgcaaagcgagccaggatgtgcgcaacctggtgg 
               
               
                   
               
               
                 tgtggtttcagcagaaaccgggcaaagcgccgaaactgctgatttatagc 
               
               
                   
               
               
                 ggcagctatcgctatagcggcgtgccgagccgctttagcggcagcggcag 
               
               
                   
               
               
                 cggcaccgattttaccctgaccattagcagcctgcagccggaagattttg 
               
               
                   
               
               
                 cgacctattattgccagcagcattatagcccgccgtatacctttggccag 
               
               
                   
               
               
                 ggcaccaaagtggaaattaaa 
               
               
                   
               
               
                 cDNA Encoding Human Heavy Chain Variable Domain of 
               
               
                 1G7.v85 
               
            
           
           
               
            
               
                 (SEQ IDNO: 16) 
               
            
           
           
               
            
               
                 gaagtgcagctggtggaaagcggcccaggcctggtgaaaccgagcgaaac 
               
               
                   
               
               
                 cctgagcctgacctgcaccgtgagcggctttagcctgacccgctttggcg 
               
               
                   
               
               
                 tgcattgggtgcgccagccgccgggcaaaggcctggaatggctgggcgtg 
               
               
                   
               
               
                 atttggcgcggcggcagcaccgattataacgcggcgtttgtgagccgcct 
               
               
                   
               
               
                 gaccattagcaaagataacagcaaaaaccaggtgagcctgaaactgagca 
               
               
                   
               
               
                 gcgtgaccgcggcggataccgcggtgtattattgcagcaaccattattat 
               
               
                   
               
               
                 ggcagcagcgattatgcgctggataactggggccagggcaccctggtgac 
               
               
                   
               
               
                 cgtgagcagc 
               
            
           
         
       
     
     The light chain variable domain and the heavy chain variable domain of human 1G7.v93 are provided below. The three CDRs present in the light chain variable domain and the three CDRs present in the heavy chain variable domain are shown in bold. 
     Human Light Chain Variable Domain of 1G7.v93 (SEQ ID NO: 17) (Each CDR is shown in bold.) 
     
       
         
           
               
            
               
                 Human Light Chain Variable Domain of 1G7.v93 
               
               
                 (EachCDR is shown in bold.) 
               
            
           
           
               
            
               
                 (SEQ ID NO: 17) 
               
            
           
           
               
            
               
                 DIQMTQSPSSLSASVGDRVTITC   KASQDVSNLVV   WFQQKPGKAPKLLIY   S     
               
               
                   
               
               
                     GSYRYS   GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC   QQHYSPPYT   FGQ 
               
               
                   
               
               
                 GTKVEIK 
               
               
                   
               
               
                 Human Heavy Chain Variable Domain of 1G7.v93 
               
               
                 (EachCDR is shown in bold.) 
               
            
           
           
               
            
               
                 (SEQ ID NO: 18) 
               
            
           
           
               
            
               
                 EVQLVESGPGLVKPSETLSLTCTVSGFSTT   RFGVH   WVRQPPGKGLEWLG   V     
               
               
                   
               
               
                     IWRGGSTDYNAAFVS   RLTISKDNSKNQVSLKLSSVTAADTAVYYCSN   HYY     
               
               
                   
               
               
                     GSPDYALDN   WGQGTLVTVSS 
               
               
                   
               
               
                 cDNA Encoding Human Light Chain Variable Domain of 
               
               
                 1G7.v93 
               
            
           
           
               
            
               
                 (SEQ IDNO: 19) 
               
            
           
           
               
            
               
                 gatattcagatgacccagagcccgagcagcctgagcgcgagcgtgggcga 
               
               
                   
               
               
                 tcgcgtgaccattacctgcaaagcgagccaggatgtgagcaacctggtgg 
               
               
                   
               
               
                 tgtggtttcagcagaaaccgggcaaagcgccgaaactgctgatttatagc 
               
               
                   
               
               
                 ggcagctatcgctatagcggcgtgccgagccgctttagcggcagcggcag 
               
               
                   
               
               
                 cggcaccgattttaccctgaccattagcagcctgcagccggaagattttg 
               
               
                   
               
               
                 cgacctattattgccagcagcattatagcccgccgtatacctttggccag 
               
               
                   
               
               
                 ggcaccaaagtggaaattaaa 
               
               
                   
               
               
                 cDNA Encoding Human Heavy Chain Variable Domain of 
               
               
                 1G7.v93 
               
            
           
           
               
            
               
                 (SEQ IDNO: 20) 
               
            
           
           
               
            
               
                 gaagtgcagctggtggaaagcggcccgggcctggtgaaaccgagcgaaac 
               
               
                   
               
               
                 cctgagcctgacctgcaccgtgagcggctttagcacgacccgctttggcg 
               
               
                   
               
               
                 tgcattgggtgcgccagccgccgggcaaaggcctggaatggctgggcgtg 
               
               
                   
               
               
                 atttggcgcggcggcagcaccgattataacgcggcgtttgtgagccgcct 
               
               
                   
               
               
                 gaccattagcaaagataacagcaaaaaccaggtgagcctgaaactgagca 
               
               
                   
               
               
                 gcgtgaccgcggcggataccgcggtgtattattgcagcaaccattattat 
               
               
                   
               
               
                 ggcagccccgattatgcgctggataactggggccagggcaccctggtgac 
               
               
                   
               
               
                 cgtgagcagc 
               
            
           
         
       
     
     In some embodiments of the CARs described herein, the first antigen-binding domain includes a VL domain that is or includes a sequence that is at least 80% identical (e.g., at least 82%, at least 84%, at least 86%, at least 88%, at least 90%, at least 92%, at least 94%, at least 96%, at least 98%, or at least 99%) identical to the VL domain of 10A8, and/or includes a VH domain that is or includes a sequence that is at least 80% identical (e.g., at least 82%, at least 84%, at least 86%, at least 88%, at least 90%, at least 92%, at least 94%, at least 96%, at least 98%, or at least 99%) identical to the VH domain of 10A8. In some embodiments of the CARs described herein, the first antigen-binding domain includes a VL domain that is or includes the VL domain of 10A8, and/or a VH domain that is or includes the VH domain of 10A8. In some embodiments of any of the CARs described herein, the first antigen-binding domain includes a VL domain that is or includes the sequence of VL of 10A8, except that it includes one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or fifteen amino acid substitutions, and/or includes a VH domain that is or includes the sequence of VH of 10A8, except that it includes one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or fifteen amino acid substitutions. In some embodiments, the second antigen-binding domain includes the three CDRs in the light chain variable domain of 10A8, and/or the three CDRs in the heavy chain variable domain of 10A8. 
     In some examples of any of the CARs described herein, the CAR can bind to a CD307e antigen (e.g., an epitope present in the extracellular domain of CD307e) with a dissociation equilibrium constant (K D ) of less than 1×10 −5  M, less than 0.5×10 −5  M, less than 1×10 −6  M, less than 0.5×10 6  M, less than 1×10 −7  M, less than 0.5×10 −7  M, less than 1×10 −8  M, less than 0.5×10 −8  M, less than 1×10 −9  M, less than 0.5×10 −9 , less than 1×10 −10  M, less than 0.5×10 −10  M, or less than 1×10 −11  M (e.g., as measured using surface plasmon resonance). 
     In some examples of any of the CARs described herein, the CAR can bind to a CD307e antigen (e.g., an epitope present in the extracellular domain of CD307e) with a K D  of about 1×10 −11  M to about 1×10 −5  M, about 1×10 −11  M to about 0.5×10 −5  M, about 1×10 −11  M to about 1×10 6  M, about 1×10 −11  M to about 0.5×10 −6  M, about 1×10 −11  M to about 1×10 7  M, about 1×10 −11  M to about 0.5×10 −7  M, about 1×10 −11  M to about 1×10 −8  M, about 1×10 −11  M to about 0.5×10 −8  M, about 1×10 −11  M to about 1×10 −9  M, about 1×10 −11  M to about 0.5×10 −9  M, about 1×10 11  M to about 1×10 −10  M, about 1×10 −11  M to about 0.5×10 −10  M; about 0.5×10 −10  M to about 1×10 −5  M, about 0.5×10 −10  M to about 0.5×10 −5  M, about 0.5×10 −10  M to about 1×10 −6  M, about 0.5×10 −10  M to about 0.5×10 −6  M, about 0.5×10 −10  M to about 1×10 −7  M, about 0.5×10 −10  M to about 0.5×10 −7  M, about 0.5×10 −10  M to about 1×10 −8  M, about 0.5×10 −10  M to about 0.5×10 −8  M, about 0.5×10 −10  M to about 1×10 −9  M, about 0.5×10 −10  M to about 0.5×10 −9  M, about 0.5×10 −10  M to about 1×10 −10  M, about 1×10 −10  M to about 1×10 −5  M, about 1× −10  M to about 0.5×10 −5  M, about 1× −10  M to about 1×10 −6  M, about 1× −10  M to about 0.5×10 −11  M, about 1× −10  M to about 1×10 −7  M, about 1×10 −10  M to about 0.5×10 −7  M, about 1×10 −10  M to about 1×10 −8  M, about 1×10 −10  M to about 0.5×10 −8  M, about 1×10 −10  M to about 1×10 −9  M, about 1×10 −10  M to about 0.5×10 −9  M, about 0.5×10 −9  M to about 1×10 −5  M, about 0.5×10 −9  M to about 0.5×10 −5  M, about 0.5×10 −9  M to about 1×10 6  M, about 0.5×10 −9  M to about 0.5×10 −6  M, about 0.5×10 −9  M to about 1×10 −7  M, about 0.5×10 −9  M to about 0.5×10 −7  M, about 0.5×10 −9  M to about 1×10 −8  M, about 0.5×10 −9  M to about 0.5×10 −8  M, about 0.5×10 −9  M to about 1×10 −9  M, about 1×10 −9  M to about 1×10 −5  M, about 1×10 −9  M to about 0.5×10 −5  M, about 1×10 −9  M to about 1×10 −6  M, about 1×10 −9  M to about 0.5×10 −6  M, about 1×10 −9  M to about 1×10 −7  M, about 1×10 −9  M to about 0.5×10 −7 M, about 1×10 −9  M to about 1×10 −8  M, about 1×10 −9  M to about 0.5×10 −8  M, about 0.5×10 −8  M to about 1×10 −5  M, about 0.5×10 −8  M to about 0.5×10 −5  M, about 0.5×10 −8  M to about 1×10 −6  M, about 0.5×10 −8  M to about 0.5×10 −6  M, about 0.5×10 −8  M to about 1×10 −7  M, about 0.5×10 −8  M to about 0.5×10 −7  M, about 0.5×10 −8  M to about 1×10 −8  M, about 1×10 −8  M to about 1×10 −5  M, about 1×10 −8  M to about 0.5×10 −5  M, about 1×10 −8  M to about 1×10 −6  M, about 1×10 −8  M to about 0.5×10 −6  M, about 1×10 −8  M to about 1×10 −7  M, about 1×10 −8 M to about 0.5×10 −7  M, about 0.5×10 −7  M to about 1×10 −5  M, about 0.5×10 −7  M to about 0.5×10 −5  M, about 0.5×10 −7  M to about 1×10 −6  M, about 0.5×10 −7  M to about 0.5×10 −6  M, about 0.5×10 −7  M to about 1×10 −7  M, about 1×10 −6  M to about 1×10 −5  M, about 1×10 −5  M to about 0.5×10 −5  M, about 1×10 −7  M to about 1×10 −6  M, about 1×10 −6  M to about 0.5×10 −6  M, about 0.5×10 6  M to about 1×10 −5  M, about 0.5×10 −6  M to about 0.5×10 −5  M, about 0.5×10 −6  M to about 1×10 −6  M, about 1×10 −6  M to about 1×10 −5  M, about 1×10 −6  M to about 0.5×10 −5 M, or about 0.5×10 −5  M to about 1×10 −5  M (e.g., as measured using surface plasmon resonance). 
     First scFv Linkers and Second scFv Linkers 
     In some embodiments, the first scFv linker and the second scFv linker are each independently, 1 amino acid to about 50 amino acids, 1 amino acid to about 48 amino acids, 1 amino acid to about 46 amino acids, 1 amino acid to about 44 amino acids, 1 amino acid to about 42 amino acids, 1 amino acid to about 40 amino acids, 1 amino acid to about 38 amino acids, 1 amino acid to about 36 amino acids, 1 amino acid to about 34 amino acids, 1 amino acid to about 32 amino acids, 1 amino acid to about 30 amino acids, 1 amino acid to about 28 amino acids, 1 amino acid to about 26 amino acids, 1 amino acid to about 24 amino acids, 1 amino acid to about 22 amino acids, 1 amino acid to about 20 amino acids, 1 amino acid to about 18 amino acids, 1 amino acid to about 16 amino acids, 1 amino acid to about 14 amino acids, 1 amino acid to about 12 amino acids, 1 amino acid to about 10 amino acids, 1 amino acid to about 8 amino acids, 1 amino acid to about 6 amino acids, 1 amino acid to about 4 amino acids, 1 amino acid to about 3 amino acids, about 2 amino acids to about 50 amino acids, about 2 amino acids to about 48 amino acids, about 2 amino acids to about 46 amino acids, about 2 amino acids to about 44 amino acids, about 2 amino acids to about 42 amino acids, about 2 amino acids to about 40 amino acids, about 2 amino acids to about 38 amino acids, about 2 amino acids to about 36 amino acids, about 2 amino acids to about 34 amino acids, about 2 amino acids to about 32 amino acids, about 2 amino acids to about 30 amino acids, about 2 amino acids to about 28 amino acids, about 2 amino acids to about 26 amino acids, about 2 amino acids to about 24 amino acids, about 2 amino acids to about 22 amino acids, about 2 amino acids to about 20 amino acids, about 2 amino acids to about 18 amino acids, about 2 amino acids to about 16 amino acids, about 2 amino acids to about 14 amino acids, about 2 amino acids to about 12 amino acids, about 2 amino acids to about 10 amino acids, about 2 amino acids to about 8 amino acids, about 2 amino acids to about 6 amino acids, about 2 amino acids to about 4 amino acids, about 4 amino acids to about 50 amino acids, about 4 amino acids to about 48 amino acids, about 4 amino acids to about 46 amino acids, about 4 amino acids to about 44 amino acids, about 4 amino acids to about 42 amino acids, about 4 amino acids to about 40 amino acids, about 4 amino acids to about 38 amino acids, about 4 amino acids to about 36 amino acids, about 4 amino acids to about 34 amino acids, about 4 amino acids to about 32 amino acids, about 4 amino acids to about 30 amino acids, about 4 amino acids to about 28 amino acids, about 4 amino acids to about 26 amino acids, about 4 amino acids to about 24 amino acids, about 4 amino acids to about 22 amino acids, about 4 amino acids to about 20 amino acids, about 4 amino acids to about 18 amino acids, about 4 amino acids to about 16 amino acids, about 4 amino acids to about 14 amino acids, about 4 amino acids to about 12 amino acids, about 4 amino acids to about 10 amino acids, about 4 amino acids to about 8 amino acids, about 4 amino acids to about 6 amino acids, about 6 amino acids to about 50 amino acids, about 6 amino acids to about 48 amino acids, about 6 amino acids to about 46 amino acids, about 6 amino acids to about 44 amino acids, about 6 amino acids to about 42 amino acids, about 6 amino acids to about 40 amino acids, about 6 amino acids to about 38 amino acids, about 6 amino acids to about 36 amino acids, about 6 amino acids to about 34 amino acids, about 6 amino acids to about 32 amino acids, about 6 amino acids to about 30 amino acids, about 6 amino acids to about 28 amino acids, about 6 amino acids to about 26 amino acids, about 6 amino acids to about 24 amino acids, about 6 amino acids to about 22 amino acids, about 6 amino acids to about 20 amino acids, about 6 amino acids to about 18 amino acids, about 6 amino acids to about 16 amino acids, about 6 amino acids to about 14 amino acids, about 6 amino acids to about 12 amino acids, about 6 amino acids to about 10 amino acids, about 6 amino acids to about 8 amino acids, about 8 amino acids to about 50 amino acids, about 8 amino acids to about 48 amino acids, about 8 amino acids to about 46 amino acids, about 8 amino acids to about 44 amino acids, about 8 amino acids to about 42 amino acids, about 8 amino acids to about 40 amino acids, about 8 amino acids to about 38 amino acids, about 8 amino acids to about 36 amino acids, about 8 amino acids to about 34 amino acids, about 8 amino acids to about 32 amino acids, about 8 amino acids to about 30 amino acids, about 8 amino acids to about 28 amino acids, about 8 amino acids to about 26 amino acids, about 8 amino acids to about 24 amino acids, about 8 amino acids to about 22 amino acids, about 8 amino acids to about 20 amino acids, about 8 amino acids to about 18 amino acids, about 8 amino acids to about 16 amino acids, about 8 amino acids to about 14 amino acids, about 8 amino acids to about 12 amino acids, about 8 amino acids to about 10 amino acids, about 10 amino acids to about 50 amino acids, about 10 amino acids to about 48 amino acids, about 10 amino acids to about 46 amino acids, about 10 amino acids to about 44 amino acids, about 10 amino acids to about 42 amino acids, about 10 amino acids to about 40 amino acids, about 10 amino acids to about 38 amino acids, about 10 amino acids to about 36 amino acids, about 10 amino acids to about 34 amino acids, about 10 amino acids to about 32 amino acids, about 10 amino acids to about 30 amino acids, about 10 amino acids to about 28 amino acids, about 10 amino acids to about 26 amino acids, about 10 amino acids to about 24 amino acids, about 10 amino acids to about 22 amino acids, about 10 amino acids to about 20 amino acids, about 10 amino acids to about 18 amino acids, about 10 amino acids to about 16 amino acids, about 10 amino acids to about 14 amino acids, about 10 amino acids to about 12 amino acids, about 12 amino acids to about 50 amino acids, about 12 amino acids to about 48 amino acids, about 12 amino acids to about 46 amino acids, about 12 amino acids to about 44 amino acids, about 12 amino acids to about 42 amino acids, about 12 amino acids to about 40 amino acids, about 12 amino acids to about 38 amino acids, about 12 amino acids to about 36 amino acids, about 12 amino acids to about 34 amino acids, about 12 amino acids to about 32 amino acids, about 12 amino acids to about 30 amino acids, about 12 amino acids to about 28 amino acids, about 12 amino acids to about 26 amino acids, about 12 amino acids to about 24 amino acids, about 12 amino acids to about 22 amino acids, about 12 amino acids to about 20 amino acids, about 12 amino acids to about 18 amino acids, about 12 amino acids to about 16 amino acids, about 12 amino acids to about 14 amino acids, about 14 amino acids to about 50 amino acids, about 14 amino acids to about 48 amino acids, about 14 amino acids to about 46 amino acids, about 14 amino acids to about 44 amino acids, about 14 amino acids to about 42 amino acids, about 14 amino acids to about 40 amino acids, about 14 amino acids to about 38 amino acids, about 14 amino acids to about 36 amino acids, about 14 amino acids to about 34 amino acids, about 14 amino acids to about 32 amino acids, about 14 amino acids to about 30 amino acids, about 14 amino acids to about 28 amino acids, about 14 amino acids to about 26 amino acids, about 14 amino acids to about 24 amino acids, about 14 amino acids to about 22 amino acids, about 14 amino acids to about 20 amino acids, about 14 amino acids to about 18 amino acids, about 14 amino acids to about 16 amino acids, about 16 amino acids to about 50 amino acids, about 16 amino acids to about 48 amino acids, about 16 amino acids to about 46 amino acids, about 16 amino acids to about 44 amino acids, about 16 amino acids to about 42 amino acids, about 16 amino acids to about 40 amino acids, about 16 amino acids to about 38 amino acids, about 16 amino acids to about 36 amino acids, about 16 amino acids to about 34 amino acids, about 16 amino acids to about 32 amino acids, about 16 amino acids to about 30 amino acids, about 16 amino acids to about 28 amino acids, about 16 amino acids to about 26 amino acids, about 16 amino acids to about 24 amino acids, about 16 amino acids to about 22 amino acids, about 16 amino acids to about 20 amino acids, about 16 amino acids to about 18 amino acids, about 18 amino acids to about 50 amino acids, about 18 amino acids to about 48 amino acids, about 18 amino acids to about 46 amino acids, about 18 amino acids to about 44 amino acids, about 18 amino acids to about 42 amino acids, about 18 amino acids to about 40 amino acids, about 18 amino acids to about 38 amino acids, about 18 amino acids to about 36 amino acids, about 18 amino acids to about 34 amino acids, about 18 amino acids to about 32 amino acids, about 18 amino acids to about 30 amino acids, about 18 amino acids to about 28 amino acids, about 18 amino acids to about 26 amino acids, about 18 amino acids to about 24 amino acids, about 18 amino acids to about 22 amino acids, about 18 amino acids to about 20 amino acids, about 20 amino acids to about 50 amino acids, about 20 amino acids to about 48 amino acids, about 20 amino acids to about 46 amino acids, about 20 amino acids to about 44 amino acids, about 20 amino acids to about 42 amino acids, about 20 amino acids to about 40 amino acids, about 20 amino acids to about 38 amino acids, about 20 amino acids to about 36 amino acids, about 20 amino acids to about 34 amino acids, about 20 amino acids to about 32 amino acids, about 20 amino acids to about 30 amino acids, about 20 amino acids to about 28 amino acids, about 20 amino acids to about 26 amino acids, about 20 amino acids to about 24 amino acids, about 20 amino acids to about 22 amino acids, about 22 amino acids to about 50 amino acids, about 22 amino acids to about 48 amino acids, about 22 amino acids to about 46 amino acids, about 22 amino acids to about 44 amino acids, about 22 amino acids to about 42 amino acids, about 22 amino acids to about 40 amino acids, about 22 amino acids to about 38 amino acids, about 22 amino acids to about 36 amino acids, about 22 amino acids to about 34 amino acids, about 22 amino acids to about 32 amino acids, about 22 amino acids to about 30 amino acids, about 22 amino acids to about 28 amino acids, about 22 amino acids to about 26 amino acids, about 22 amino acids to about 24 amino acids, about 24 amino acids to about 50 amino acids, about 24 amino acids to about 48 amino acids, about 24 amino acids to about 46 amino acids, about 24 amino acids to about 44 amino acids, about 24 amino acids to about 42 amino acids, about 24 amino acids to about 40 amino acids, about 24 amino acids to about 38 amino acids, about 24 amino acids to about 36 amino acids, about 24 amino acids to about 34 amino acids, about 24 amino acids to about 32 amino acids, about 24 amino acids to about 30 amino acids, about 24 amino acids to about 28 amino acids, about 24 amino acids to about 26 amino acids, about 26 amino acids to about 50 amino acids, about 26 amino acids to about 48 amino acids, about 26 amino acids to about 46 amino acids, about 26 amino acids to about 44 amino acids, about 26 amino acids to about 42 amino acids, about 26 amino acids to about 40 amino acids, about 26 amino acids to about 38 amino acids, about 26 amino acids to about 36 amino acids, about 26 amino acids to about 34 amino acids, about 26 amino acids to about 32 amino acids, about 26 amino acids to about 30 amino acids, about 26 amino acids to about 28 amino acids, about 28 amino acids to about 50 amino acids, about 28 amino acids to about 48 amino acids, about 28 amino acids to about 46 amino acids, about 28 amino acids to about 44 amino acids, about 28 amino acids to about 42 amino acids, about 28 amino acids to about 40 amino acids, about 28 amino acids to about 38 amino acids, about 28 amino acids to about 36 amino acids, about 28 amino acids to about 34 amino acids, about 28 amino acids to about 32 amino acids, about 28 amino acids to about 30 amino acids, about 30 amino acids to about 50 amino acids, about 30 amino acids to about 48 amino acids, about 30 amino acids to about 46 amino acids, about 30 amino acids to about 44 amino acids, about 30 amino acids to about 42 amino acids, about 30 amino acids to about 40 amino acids, about 30 amino acids to about 38 amino acids, about 30 amino acids to about 36 amino acids, about 30 amino acids to about 34 amino acids, about 30 amino acids to about 32 amino acids, about 32 amino acids to about 50 amino acids, about 32 amino acids to about 48 amino acids, about 32 amino acids to about 46 amino acids, about 32 amino acids to about 44 amino acids, about 32 amino acids to about 42 amino acids, about 32 amino acids to about 40 amino acids, about 32 amino acids to about 38 amino acids, about 32 amino acids to about 36 amino acids, about 32 amino acids to about 34 amino acids, about 34 amino acids to about 50 amino acids, about 34 amino acids to about 48 amino acids, about 34 amino acids to about 46 amino acids, about 34 amino acids to about 44 amino acids, about 34 amino acids to about 42 amino acids, about 34 amino acids to about 40 amino acids, about 34 amino acids to about 38 amino acids, about 34 amino acids to about 36 amino acids, about 36 amino acids to about 50 amino acids, about 36 amino acids to about 48 amino acids, about 36 amino acids to about 46 amino acids, about 36 amino acids to about 44 amino acids, about 36 amino acids to about 42 amino acids, about 36 amino acids to about 40 amino acids, about 36 amino acids to about 38 amino acids, about 38 amino acids to about 50 amino acids, about 38 amino acids to about 48 amino acids, about 38 amino acids to about 46 amino acids, about 38 amino acids to about 44 amino acids, about 38 amino acids to about 42 amino acids, about 38 amino acids to about 40 amino acids, about 40 amino acids to about 50 amino acids, about 40 amino acids to about 48 amino acids, about 40 amino acids to about 46 amino acids, about 40 amino acids to about 44 amino acids, about 40 amino acids to about 42 amino acids, about 42 amino acids to about 50 amino acids, about 42 amino acids to about 48 amino acids, about 42 amino acids to about 46 amino acids, about 42 amino acids to about 44 amino acids, about 44 amino acids to about 50 amino acids, about 44 amino acids to about 48 amino acids, about 44 amino acids to about 46 amino acids, about 46 amino acids to about 50 amino acids, about 46 amino acids to about 48 amino acids, or about 48 amino acids to about 50 amino acids. 
     In some embodiments, the first scFv linker and the second scFv linker can each independently be or comprise a sequence of (SG) n , where n can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25. In some embodiments, the first scFv linker and the second scFv linker can each independently be or comprise a sequence of (GS) n , where n can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25. 
     In some embodiments, the first scFv linker and the second scFv linker can each independently be or comprise a sequence of (SGGS) n , where n can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13. In some embodiments, the first scFv linker and the second scFv linker can each independently be or comprise a sequence of (SGGGS) n , where n can be 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, the first scFv linker and the second scFv linker can each independently be or comprise a sequence of (SGGGGS) n , where n can be 1, 2, 3, 4, 5, 6, 7, 8, or 9. 
     In some embodiments, the first scFv linker and/or the second scFv linker can be or include the sequence of SGGGGSGGGGSGGGG (SEQ ID NO: 21). 
     In some embodiments, the first scFv linker and/or the second scFv linker can be or include the sequence of ASTKGPSVFPLAPSSSGSG (SEQ ID NO: 22). 
     In some embodiments, the first scFv linker and/or the second scFv linker can be or include the sequence of GGGGSGGGGSGGGGS (SEQ ID NO: 23). 
     In some embodiments, the first scFv linker and/or the second scFv linker can be a Whitlow linker. In some embodiments, the Whitlow linker has the amino acid sequence of GSTSGSGKPGSGEGSTKG (SEQ ID NO: 12) or the nucleotide sequence encoding the Whitlow linker sequence of 
     
       
         
           
               
            
               
                 (SEQ ID NO: 24) 
               
            
           
           
               
            
               
                 ggcagcaccagcggcagcggcaaaccgggcagcggcgaaggcagcacca 
               
               
                   
               
               
                 aaggc. 
               
            
           
         
       
     
     In some embodiments, the first scFv linker and/or the second scFv linker can be a (G 4 S) 5  linker. In some embodiments, the (G 4 S) 5  linker has the amino acid sequence of GGGGSGGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 25) or the nucleotide sequence encoding the (G 4 S) 5  linker sequence of 
     
       
         
           
               
            
               
                 (SEQ ID NO: 26) 
               
            
           
           
               
            
               
                 ggcggtggtggttctggaggcggtggcagcggtggaggtggctcaggagg 
               
               
                   
               
               
                 aggaggtagcggcggcggagggagt. 
               
            
           
         
       
     
     In some embodiments, the first scFv linker and the second scFv linker can be or include the same sequence. In some embodiments, the first scFv linker and the second scFv linker can be or include different sequences. 
     Additional aspects and examples of first scFv linkers and second scFv linkers are known in the art. 
     Linkers 
     In some embodiments, the linker between the first antigen-binding domain and the second antigen-binding domain can be 1 amino acid to about 250 amino acids, 1 amino acid to about 240 amino acids, 1 amino acid to about 230 amino acids, 1 amino acid to about 220 amino acids, 1 amino acid to about 210 amino acids, 1 amino acid to about 200 amino acids, 1 amino acid to about 190 amino acids, 1 amino acid to about 180 amino acids, 1 amino acid to about 170 amino acids, 1 amino acid to about 160 amino acids, 1 amino acid to about 150 amino acids, 1 amino acid to about 140 amino acids, 1 amino acid to about 130 amino acids, 1 amino acid to about 120 amino acids, 1 amino acid to about 110 amino acids, 1 amino acid to about 100 amino acids, 1 amino acid to about 95 amino acids, 1 amino acid to about 90 amino acids, 1 amino acid to about 85 amino acids, 1 amino acid to about 80 amino acids, 1 amino acid to about 75 amino acids, 1 amino acid to about 70 amino acids, 1 amino acid to about 65 amino acids, 1 amino acid to about 60 amino acids, 1 amino acid to about 55 amino acids, 1 amino acid to about 50 amino acids, 1 amino acid to about 45 amino acids, 1 amino acid to about 40 amino acids, 1 amino acid to about 35 amino acids, 1 amino acid to about 30 amino acids, 1 amino acid to about 25 amino acids, 1 amino acid to about 20 amino acids, 1 amino acid to about 15 amino acids, 1 amino acid to about 10 amino acids, 1 amino acid to about 5 amino acids, about 5 amino acids to about 250 amino acids, about 5 amino acids to about 240 amino acids, about 5 amino acids to about 230 amino acids, about 5 amino acids to about 220 amino acids, about 5 amino acids to about 210 amino acids, about 5 amino acids to about 200 amino acids, about 5 amino acids to about 190 amino acids, about 5 amino acids to about 180 amino acids, about 5 amino acids to about 170 amino acids, about 5 amino acids to about 160 amino acids, about 5 amino acids to about 150 amino acids, about 5 amino acids to about 140 amino acids, about 5 amino acids to about 130 amino acids, about 5 amino acids to about 120 amino acids, about 5 amino acids to about 110 amino acids, about 5 amino acids to about 100 amino acids, about 5 amino acids to about 95 amino acids, about 5 amino acids to about 90 amino acids, about 5 amino acids to about 85 amino acids, about 5 amino acids to about 80 amino acids, about 5 amino acids to about 75 amino acids, about 5 amino acids to about 70 amino acids, about 5 amino acids to about 65 amino acids, about 5 amino acids to about 60 amino acids, about 5 amino acids to about 55 amino acids, about 5 amino acids to about 50 amino acids, about 5 amino acids to about 45 amino acids, about 5 amino acids to about 40 amino acids, about 5 amino acids to about 35 amino acids, about 5 amino acids to about 30 amino acids, about 5 amino acids to about 25 amino acids, about 5 amino acids to about 20 amino acids, about 5 amino acids to about 15 amino acids, about 5 amino acids to about 10 amino acids, about 10 amino acids to about 250 amino acids, about 10 amino acids to about 240 amino acids, about 10 amino acids to about 230 amino acids, about 10 amino acids to about 220 amino acids, about 10 amino acids to about 210 amino acids, about 10 amino acids to about 200 amino acids, about 10 amino acids to about 190 amino acids, about 10 amino acids to about 180 amino acids, about 10 amino acids to about 170 amino acids, about 10 amino acids to about 160 amino acids, about 10 amino acids to about 150 amino acids, about 10 amino acids to about 140 amino acids, about 10 amino acids to about 130 amino acids, about 10 amino acids to about 120 amino acids, about 10 amino acids to about 110 amino acids, about 10 amino acids to about 100 amino acids, about 10 amino acids to about 95 amino acids, about 10 amino acids to about 90 amino acids, about 10 amino acids to about 85 amino acids, about 10 amino acids to about 80 amino acids, about 10 amino acids to about 75 amino acids, about 10 amino acids to about 70 amino acids, about 10 amino acids to about 65 amino acids, about 10 amino acids to about 60 amino acids, about 10 amino acids to about 55 amino acids, about 10 amino acids to about 50 amino acids, about 10 amino acids to about 45 amino acids, about 10 amino acids to about 40 amino acids, about 10 amino acids to about 35 amino acids, about 10 amino acids to about 30 amino acids, about 10 amino acids to about 25 amino acids, about 10 amino acids to about 20 amino acids, about 10 amino acids to about 15 amino acids, about 15 amino acids to about 250 amino acids, about 15 amino acids to about 240 amino acids, about 15 amino acids to about 230 amino acids, about 15 amino acids to about 220 amino acids, about 15 amino acids to about 210 amino acids, about 15 amino acids to about 200 amino acids, about 15 amino acids to about 190 amino acids, about 15 amino acids to about 180 amino acids, about 15 amino acids to about 170 amino acids, about 15 amino acids to about 160 amino acids, about 15 amino acids to about 150 amino acids, about 15 amino acids to about 140 amino acids, about 15 amino acids to about 130 amino acids, about 15 amino acids to about 120 amino acids, about 15 amino acids to about 110 amino acids, about 15 amino acids to about 100 amino acids, about 15 amino acids to about 95 amino acids, about 15 amino acids to about 90 amino acids, about 15 amino acids to about 85 amino acids, about 15 amino acids to about 80 amino acids, about 15 amino acids to about 75 amino acids, about 15 amino acids to about 70 amino acids, about 15 amino acids to about 65 amino acids, about 15 amino acids to about 60 amino acids, about 15 amino acids to about 55 amino acids, about 15 amino acids to about 50 amino acids, about 15 amino acids to about 45 amino acids, about 15 amino acids to about 40 amino acids, about 15 amino acids to about 35 amino acids, about 15 amino acids to about 30 amino acids, about 15 amino acids to about 25 amino acids, about 15 amino acids to about 20 amino acids, about 20 amino acids to about 250 amino acids, about 20 amino acids to about 240 amino acids, about 20 amino acids to about 230 amino acids, about 20 amino acids to 220 amino acids, about 20 amino acids to about 210 amino acids, about 20 amino acids to about 200 amino acids, about 20 amino acids to about 190 amino acids, about 20 amino acids to about 180 amino acids, about 20 amino acids to about 170 amino acids, about 20 amino acids to about 160 amino acids, about 20 amino acids to about 150 amino acids, about 20 amino acids to about 140 amino acids, about 20 amino acids to about 130 amino acids, about 20 amino acids to about 120 amino acids, about 20 amino acids to about 110 amino acids, about 20 amino acids to about 100 amino acids, about 20 amino acids to about 95 amino acids, about 20 amino acids to about 90 amino acids, about 20 amino acids to about 85 amino acids, about 20 amino acids to about 80 amino acids, about 20 amino acids to about 75 amino acids, about 20 amino acids to about 70 amino acids, about 20 amino acids to about 65 amino acids, about 20 amino acids to about 60 amino acids, about 20 amino acids to about 55 amino acids, about 20 amino acids to about 50 amino acids, about 20 amino acids to about 45 amino acids, about 20 amino acids to about 40 amino acids, about 20 amino acids to about 35 amino acids, about 20 amino acids to about 30 amino acids, about 20 amino acids to about 25 amino acids, about 25 amino acids to about 250 amino acids, about 25 amino acids to about 240 amino acids, about 25 amino acids to about 230 amino acids, about 25 amino acids to about 220 amino acids, about 25 amino acids to about 210 amino acids, about 25 amino acids to about 200 amino acids, about 25 amino acids to about 190 amino acids, about 25 amino acids to about 180 amino acids, about 25 amino acids to about 170 amino acids, about 25 amino acids to about 160 amino acids, about 25 amino acids to about 150 amino acids, about 25 amino acids to about 140 amino acids, about 25 amino acids to about 130 amino acids, about 25 amino acids to about 120 amino acids, about 25 amino acids to about 110 amino acids, about 25 amino acids to about 100 amino acids, about 25 amino acids to about 95 amino acids, about 25 amino acids to about 90 amino acids, about 25 amino acids to about 85 amino acids, about 25 amino acids to about 80 amino acids, about 25 amino acids to about 75 amino acids, about 25 amino acids to about 70 amino acids, about 25 amino acids to about 65 amino acids, about 25 amino acids to about 60 amino acids, about 25 amino acids to about 55 amino acids, about 25 amino acids to about 50 amino acids, about 25 amino acids to about 45 amino acids, about 25 amino acids to about 40 amino acids, about 25 amino acids to about 35 amino acids, about 25 amino acids to about 30 amino acids, about 30 amino acids to about 250 amino acids, about 30 amino acids to about 240 amino acids, about 30 amino acids to about 230 amino acids, about 30 amino acids to about 220 amino acids, about 30 amino acids to about 210 amino acids, about 30 amino acids to about 200 amino acids, about 30 amino acids to about 190 amino acids, about 30 amino acids to about 180 amino acids, about 30 amino acids to about 170 amino acids, about 30 amino acids to about 160 amino acids, about 30 amino acids to about 150 amino acids, about 30 amino acids to about 140 amino acids, about 30 amino acids to about 130 amino acids, about 30 amino acids to about 120 amino acids, about 30 amino acids to about 110 amino acids, about 30 amino acids to about 100 amino acids, about 30 amino acids to about 95 amino acids, about 30 amino acids to about 90 amino acids, about 30 amino acids to about 85 amino acids, about 30 amino acids to about 80 amino acids, about 30 amino acids to about 75 amino acids, about 30 amino acids to about 70 amino acids, about 30 amino acids to about 65 amino acids, about 30 amino acids to about 60 amino acids, about 30 amino acids to about 55 amino acids, about 30 amino acids to about 50 amino acids, about 30 amino acids to about 45 amino acids, about 30 amino acids to about 40 amino acids, about 30 amino acids to about 35 amino acids, about 35 amino acids to about 250 amino acids, about 35 amino acids to about 240 amino acids, about 35 amino acids to about 230 amino acids, about 35 amino acids to about 220 amino acids, about 35 amino acids to about 210 amino acids, about 35 amino acids to about 200 amino acids, about 35 amino acids to about 190 amino acids, about 35 amino acids to about 180 amino acids, about 35 amino acids to about 170 amino acids, about 35 amino acids to about 160 amino acids, about 35 amino acids to about 150 amino acids, about 35 amino acids to about 140 amino acids, about 35 amino acids to about 130 amino acids, about 35 amino acids to about 120 amino acids, about 35 amino acids to about 110 amino acids, about 35 amino acids to about 100 amino acids, about 35 amino acids to about 95 amino acids, about 35 amino acids to about 90 amino acids, about 35 amino acids to about 85 amino acids, about 35 amino acids to about 80 amino acids, about 35 amino acids to about 75 amino acids, about 35 amino acids to about 70 amino acids, about 35 amino acids to about 65 amino acids, about 35 amino acids to about 60 amino acids, about 35 amino acids to about 55 amino acids, about 35 amino acids to about 50 amino acids, about 35 amino acids to about 45 amino acids, about 35 amino acids to about 40 amino acids, about 40 amino acids to about 250 amino acids, about 40 amino acids to about 240 amino acids, about 40 amino acids to about 230 amino acids, about 40 amino acids to about 220 amino acids, about 40 amino acids to about 210 amino acids, about 40 amino acids to about 200 amino acids, about 40 amino acids to about 190 amino acids, about 40 amino acids to about 180 amino acids, about 40 amino acids to about 170 amino acids, about 40 amino acids to about 160 amino acids, about 40 amino acids to about 150 amino acids, about 40 amino acids to about 140 amino acids, about 40 amino acids to about 130 amino acids, about 40 amino acids to about 120 amino acids, about 40 amino acids to about 110 amino acids, about 40 amino acids to about 100 amino acids, about 40 amino acids to about 95 amino acids, about 40 amino acids to about 90 amino acids, about 40 amino acids to about 85 amino acids, about 40 amino acids to about 80 amino acids, about 40 amino acids to about 75 amino acids, about 40 amino acids to about 70 amino acids, about 40 amino acids to about 65 amino acids, about 40 amino acids to about 60 amino acids, about 40 amino acids to about 55 amino acids, about 40 amino acids to about 50 amino acids, about 40 amino acids to about 45 amino acids, about 45 amino acids to about 250 amino acids, about 45 amino acids to about 240 amino acids, about 45 amino acids to about 230 amino acids, about 45 amino acids to about 220 amino acids, about 45 amino acids to about 210 amino acids, about 45 amino acids to about 200 amino acids, about 45 amino acids to about 190 amino acids, about 45 amino acids to about 180 amino acids, about 45 amino acids to about 170 amino acids, about 45 amino acids to about 160 amino acids, about 45 amino acids to about 150 amino acids, about 45 amino acids to about 140 amino acids, about 45 amino acids to about 130 amino acids, about 45 amino acids to about 120 amino acids, about 45 amino acids to about 110 amino acids, about 45 amino acids to about 100 amino acids, about 45 amino acids to about 95 amino acids, about 45 amino acids to about 90 amino acids, about 45 amino acids to about 85 amino acids, about 45 amino acids to about 80 amino acids, about 45 amino acids to about 75 amino acids, about 45 amino acids to about 70 amino acids, about 45 amino acids to about 65 amino acids, about 45 amino acids to about 60 amino acids, about 45 amino acids to about 55 amino acids, about 45 amino acids to about 50 amino acids, about 50 amino acids to about 250 amino acids, about 50 amino acids to about 240 amino acids, about 50 amino acids to about 230 amino acids, about 50 amino acids to about 220 amino acids, about 50 amino acids to about 210 amino acids, about 50 amino acids to about 200 amino acids, about 50 amino acids to about 190 amino acids, about 50 amino acids to about 180 amino acids, about 50 amino acids to about 170 amino acids, about 50 amino acids to about 160 amino acids, about 50 amino acids to about 150 amino acids, about 50 amino acids to about 140 amino acids, about 50 amino acids to about 130 amino acids, about 50 amino acids to about 120 amino acids, about 50 amino acids to about 110 amino acids, about 50 amino acids to about 100 amino acids, about 50 amino acids to about 95 amino acids, about 50 amino acids to about 90 amino acids, about 50 amino acids to about 85 amino acids, about 50 amino acids to about 80 amino acids, about 50 amino acids to about 75 amino acids, about 50 amino acids to about 70 amino acids, about 50 amino acids to about 65 amino acids, about 50 amino acids to about 60 amino acids, about 50 amino acids to about 55 amino acids, about 55 amino acids to about 250 amino acids, about 55 amino acids to about 240 amino acids, about 55 amino acids to about 230 amino acids, about 55 amino acids to about 220 amino acids, about 55 amino acids to about 210 amino acids, about 55 amino acids to about 200 amino acids, about 55 amino acids to about 190 amino acids, about 55 amino acids to about 180 amino acids, about 55 amino acids to about 170 amino acids, about 55 amino acids to about 160 amino acids, about 55 amino acids to about 150 amino acids, about 55 amino acids to about 140 amino acids, about 55 amino acids to about 130 amino acids, about 55 amino acids to about 120 amino acids, about 55 amino acids to about 110 amino acids, about 55 amino acids to about 100 amino acids, about 55 amino acids to about 95 amino acids, about 55 amino acids to about 90 amino acids, about 55 amino acids to about 85 amino acids, about 55 amino acids to about 80 amino acids, about 55 amino acids to about 75 amino acids, about 55 amino acids to about 70 amino acids, about 55 amino acids to about 65 amino acids, about 55 amino acids to about 60 amino acids, about 60 amino acids to about 250 amino acids, about 60 amino acids to about 240 amino acids, about 60 amino acids to about 230 amino acids, about 60 amino acids to about 220 amino acids, about 60 amino acids to about 210 amino acids, about 60 amino acids to about 200 amino acids, about 60 amino acids to about 190 amino acids, about 60 amino acids to about 180 amino acids, about 60 amino acids to about 170 amino acids, about 60 amino acids to about 160 amino acids, about 60 amino acids to about 150 amino acids, about 60 amino acids to about 140 amino acids, about 60 amino acids to about 130 amino acids, about 60 amino acids to about 120 amino acids, about 60 amino acids to about 110 amino acids, about 60 amino acids to about 100 amino acids, about 60 amino acids to about 95 amino acids, about 60 amino acids to about 90 amino acids, about 60 amino acids to about 85 amino acids, about 60 amino acids to about 80 amino acids, about 60 amino acids to about 75 amino acids, about 60 amino acids to about 70 amino acids, about 60 amino acids to about 65 amino acids, about 65 amino acids to about 250 amino acids, about 65 amino acids to about 240 amino acids, about 65 amino acids to about 230 amino acids, about 65 amino acids to about 220 amino acids, about 65 amino acids to about 210 amino acids, about 65 amino acids to about 200 amino acids, about 65 amino acids to about 190 amino acids, about 65 amino acids to about 180 amino acids, about 65 amino acids to about 170 amino acids, about 65 amino acids to about 160 amino acids, about 65 amino acids to about 150 amino acids, about 65 amino acids to about 140 amino acids, about 65 amino acids to about 130 amino acids, about 65 amino acids to about 120 amino acids, about 65 amino acids to about 110 amino acids, about 65 amino acids to about 100 amino acids, about 65 amino acids to about 95 amino acids, about 65 amino acids to about 90 amino acids, about 65 amino acids to about 85 amino acids, about 65 amino acids to about 80 amino acids, about 65 amino acids to about 75 amino acids, about 65 amino acids to about 70 amino acids, about 70 amino acids to about 250 amino acids, about 70 amino acids to about 240 amino acids, about 70 amino acids to about 230 amino acids, about 70 amino acids to about 220 amino acids, about 70 amino acids to about 210 amino acids, about 70 amino acids to about 200 amino acids, about 70 amino acids to about 190 amino acids, about 70 amino acids to about 180 amino acids, about 70 amino acids to about 170 amino acids, about 70 amino acids to about 160 amino acids, about 70 amino acids to about 150 amino acids, about 70 amino acids to about 140 amino acids, about 70 amino acids to about 130 amino acids, about 70 amino acids to about 120 amino acids, about 70 amino acids to about 110 amino acids, about 70 amino acids to about 100 amino acids, about 70 amino acids to about 95 amino acids, about 70 amino acids to about 90 amino acids, about 70 amino acids to about 85 amino acids, about 70 amino acids to about 80 amino acids, about 70 amino acids to about 75 amino acids, about 75 amino acids to about 250 amino acids, about 75 amino acids to about 240 amino acids, about 75 amino acids to about 230 amino acids, about 75 amino acids to about 220 amino acids, about 75 amino acids to about 210 amino acids, about 75 amino acids to about 200 amino acids, about 75 amino acids to about 190 amino acids, about 75 amino acids to about 180 amino acids, about 75 amino acids to about 170 amino acids, about 75 amino acids to about 160 amino acids, about 75 amino acids to about 150 amino acids, about 75 amino acids to about 140 amino acids, about 75 amino acids to about 130 amino acids, about 75 amino acids to about 120 amino acids, about 75 amino acids to about 110 amino acids, about 75 amino acids to about 100 amino acids, about 75 amino acids to about 95 amino acids, about 75 amino acids to about 90 amino acids, about 75 amino acids to about 85 amino acids, about 75 amino acids to about 80 amino acids, about 80 amino acids to about 250 amino acids, about 80 amino acids to about 240 amino acids, about 80 amino acids to about 230 amino acids, about 80 amino acids to about 220 amino acids, about 80 amino acids to about 210 amino acids, about 80 amino acids to about 200 amino acids, about 80 amino acids to about 190 amino acids, about 80 amino acids to about 180 amino acids, about 80 amino acids to about 170 amino acids, about 80 amino acids to about 160 amino acids, about 80 amino acids to about 150 amino acids, about 80 amino acids to about 140 amino acids, about 80 amino acids to about 130 amino acids, about 80 amino acids to about 120 amino acids, about 80 amino acids to about 110 amino acids, about 80 amino acids to about 100 amino acids, about 80 amino acids to about 95 amino acids, about 80 amino acids to about 90 amino acids, about 80 amino acids to about 85 amino acids, about 85 amino acids to about 250 amino acids, about 85 amino acids to about 240 amino acids, about 85 amino acids to about 230 amino acids, about 85 amino acids to about 220 amino acids, about 85 amino acids to about 210 amino acids, about 85 amino acids to about 200 amino acids, about 85 amino acids to about 190 amino acids, about 85 amino acids to about 180 amino acids, about 85 amino acids to about 170 amino acids, about 85 amino acids to about 160 amino acids, about 85 amino acids to about 150 amino acids, about 85 amino acids to about 140 amino acids, about 85 amino acids to about 130 amino acids, about 85 amino acids to about 120 amino acids, about 85 amino acids to about 110 amino acids, about 85 amino acids to about 100 amino acids, about 85 amino acids to about 95 amino acids, about 85 amino acids to about 90 amino acids, about 90 amino acids to about 250 amino acids, about 90 amino acids to about 240 amino acids, about 90 amino acids to about 230 amino acids, about 90 amino acids to about 220 amino acids, about 90 amino acids to about 210 amino acids, about 90 amino acids to about 200 amino acids, about 90 amino acids to about 190 amino acids, about 90 amino acids to about 180 amino acids, about 90 amino acids to about 170 amino acids, about 90 amino acids to about 160 amino acids, about 90 amino acids to about 150 amino acids, about 90 amino acids to about 140 amino acids, about 90 amino acids to about 130 amino acids, about 90 amino acids to about 120 amino acids, about 90 amino acids to about 110 amino acids, about 90 amino acids to about 100 amino acids, about 90 amino acids to about 95 amino acids, about 95 amino acids to about 250 amino acids, about 95 amino acids to about 240 amino acids, about 95 amino acids to about 230 amino acids, about 95 amino acids to about 220 amino acids, about 95 amino acids to about 210 amino acids, about 95 amino acids to about 200 amino acids, about 95 amino acids to about 190 amino acids, about 95 amino acids to about 180 amino acids, about 95 amino acids to about 170 amino acids, about 95 amino acids to about 160 amino acids, about 95 amino acids to about 150 amino acids, about 95 amino acids to about 140 amino acids, about 95 amino acids to about 130 amino acids, about 95 amino acids to about 120 amino acids, about 95 amino acids to about 110 amino acids, about 95 amino acids to about 100 amino acids, about 100 amino acids to about 250 amino acids, about 100 amino acids to about 240 amino acids, about 100 amino acids to about 230 amino acids, about 100 amino acids to about 220 amino acids, about 100 amino acids to about 210 amino acids, about 100 amino acids to about 200 amino acids, about 100 amino acids to about 190 amino acids, about 100 amino acids to about 180 amino acids, about 100 amino acids to about 170 amino acids, about 100 amino acids to about 160 amino acids, about 100 amino acids to about 150 amino acids, about 100 amino acids to about 140 amino acids, about 100 amino acids to about 130 amino acids, about 100 amino acids to about 120 amino acids, about 100 amino acids to about 110 amino acids, about 120 amino acids to about 250 amino acids, about 120 amino acids to about 240 amino acids, about 120 amino acids to about 230 amino acids, about 120 amino acids to about 220 amino acids, about 120 amino acids to about 210 amino acids, about 120 amino acids to about 200 amino acids, about 120 amino acids to about 190 amino acids, about 120 amino acids to about 180 amino acids, about 120 amino acids to about 170 amino acids, about 120 amino acids to about 160 amino acids, about 120 amino acids to about 150 amino acids, about 120 amino acids to about 140 amino acids, about 120 amino acids to about 130 amino acids, about 130 amino acids to about 250 amino acids, about 130 amino acids to about 240 amino acids, about 130 amino acids to about 230 amino acids, about 130 amino acids to about 220 amino acids, about 130 amino acids to about 210 amino acids, about 130 amino acids to about 200 amino acids, about 130 amino acids to about 190 amino acids, about 130 amino acids to about 180 amino acids, about 130 amino acids to about 170 amino acids, about 130 amino acids to about 160 amino acids, about 130 amino acids to about 150 amino acids, about 130 amino acids to about 140 amino acids, about 140 amino acids to about 250 amino acids, about 140 amino acids to about 240 amino acids, about 140 amino acids to about 230 amino acids, about 140 amino acids to about 220 amino acids, about 140 amino acids to about 210 amino acids, about 140 amino acids to about 200 amino acids, about 140 amino acids to about 190 amino acids, about 140 amino acids to about 180 amino acids, about 140 amino acids to about 170 amino acids, about 140 amino acids to about 160 amino acids, about 140 amino acids to about 150 amino acids, about 150 amino acids to about 250 amino acids, about 150 amino acids to about 240 amino acids, about 150 amino acids to about 230 amino acids, about 150 amino acids to about 220 amino acids, about 150 amino acids to about 210 amino acids, about 150 amino acids to about 200 amino acids, about 150 amino acids to about 190 amino acids, about 150 amino acids to about 180 amino acids, about 150 amino acids to about 170 amino acids, about 150 amino acids to about 160 amino acids, about 160 amino acids to about 250 amino acids, about 160 amino acids to about 240 amino acids, about 160 amino acids to about 230 amino acids, about 160 amino acids to about 220 amino acids, about 160 amino acids to about 210 amino acids, about 160 amino acids to about 200 amino acids, about 160 amino acids to about 190 amino acids, about 160 amino acids to about 180 amino acids, about 160 amino acids to about 170 amino acids, about 170 amino acids to about 250 amino acids, about 170 amino acids to about 240 amino acids, about 170 amino acids to about 230 amino acids, about 170 amino acids to about 220 amino acids, about 170 amino acids to about 210 amino acids, about 170 amino acids to about 200 amino acids, about 170 amino acids to about 190 amino acids, about 170 amino acids to about 180 amino acids, about 180 amino acids to about 250 amino acids, about 180 amino acids to about 240 amino acids, about 180 amino acids to about 230 amino acids, about 180 amino acids to about 220 amino acids, about 180 amino acids to about 210 amino acids, about 180 amino acids to about 200 amino acids, about 180 amino acids to about 190 amino acids, about 190 amino acids to about 250 amino acids, about 190 amino acids to about 240 amino acids, about 190 amino acids to about 230 amino acids, about 190 amino acids to about 220 amino acids, about 190 amino acids to about 210 amino acids, about 190 amino acids to about 200 amino acids, about 200 amino acids to about 250 amino acids, about 200 amino acids to about 240 amino acids, about 200 amino acids to about 230 amino acids, about 200 amino acids to 220 amino acids, about 200 amino acids to about 210 amino acids, about 210 amino acids to about 250 amino acids, about 210 amino acids to about 240 amino acids, about 210 amino acids to about 230 amino acids, about 210 amino acids to about 220 amino acids, about 220 amino acids to about 250 amino acids, about 220 amino acids to about 240 amino acids, about 220 amino acids to about 230 amino acids, about 230 amino acids to about 250 amino acids, about 230 amino acids to about 240 amino acids, or about 240 amino acids to about 250 amino acids. 
     In some embodiments, the linker can be or can include one or more of an IgG1, IgG2, IgG3, or IgG4 CH1, CH2, and CH3 domain. In some embodiments, the linker can be or can include CH2-CH3 human IgG1 domains. In some embodiments, the CH2-CH3 human IgG1 domains have a sequence of: 
     
       
         
           
               
            
               
                 (SEQ ID NO: 27) 
               
            
           
           
               
            
               
                 AEPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCWVDV 
               
               
                   
               
               
                 SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG 
               
               
                   
               
               
                 KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLT 
               
               
                   
               
               
                 CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR 
               
               
                   
               
               
                 WQQGNVFSCSVMHEALHNHYTQKSLSLSPGKKD. 
               
            
           
         
       
     
     In some embodiments, the linker can be or include a portion of the human CD8 extracellular sequence that is proximal to the human CD8 transmembrane domain. For example, the linker can be or include human CD8 sequence of 
     
       
         
           
               
            
               
                 (SEQ ID NO: 28) 
               
            
           
           
               
               
            
               
                   
                 TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDI. 
               
            
           
         
       
     
     In some embodiments, the linker can be or include a human IgG1 hinge sequence. In some embodiments, the human IgG1 hinge sequence is 
     
       
         
           
               
            
               
                 (SEQ ID NO: 29) 
               
            
           
           
               
               
            
               
                   
                 AEPKSPDKTHTCPPCPKDPK. 
               
            
           
         
       
     
     In some embodiments, the linker is or includes a GS connector. An example of a GS connector is a (G 4 S)5 linker. In some embodiments, the (G 4 S) 5  linker amino acid sequence is (SEQ ID NO: 25), or the nucleic acid encoding a (G4S)5 linker (SEQ ID NO: 26). 
     In some embodiments, the linker has an alpha helix structure. In some embodiments, the linker is a coiled coil domain. Additional aspects and examples of linkers are known in the art. 
     BCMA 
     As used herein “B-cell maturation protein (BCMA)”, “tumor necrosis factor receptor superfamily member 17 (TNFRSF17)” and “CD269” are interchangeable. The BCMA gene encodes a TNF superfamily receptor, a protein that is expressed in, e.g., mature B lymphocytes and plasma cells (see, e.g., Laabi et al.,  Nucleic Acid Res.  22:1147-1154, 1994; and O&#39;Connor et al.,  J. Exp. Med.  199: 91-97, 2004). BCMA binds to B-cell activating factor (BAF) and to a proliferation inducing ligand (APRIL) (see, e.g., Kalled,  Immunol. Rev.  204: 43-54, 2005; Mackay et al.,  Ann. Rev. Immunol.  231-264, 2003). BCMA is over-expressed in various cancer, including multiple myeloma (Novak et al.,  Blood  103(2): 689-694, 2004), glioblastoma (Deshayes et al.,  Oncogene  23(17):3005-3012, 2004), chronic lymphocytic leukemia (Novak et al.,  Blood  100(8): 2973-2979, 2002) and Hodgkin lymphoma (Chiu et al.,  Blood  109(2): 729-739, 2007). 
     Exemplary sequences of BCMA and exemplary sequences of nucleic acids encoding BCMA are provided below. 
     
       
         
           
               
               
            
               
                 Human BCMA. Extracellular domain shown in bold. 
                   
               
            
           
           
               
               
            
               
                 (SEQ ID NO: 30) 
                   
               
            
           
           
               
               
               
            
               
                 1 
                 
                   mlqmagqcsq neyfdsllha cipcqlrcss ntppltcqry cnasvtnsvk 
                 
                   
               
               
                   
                   gtna ilwtcl 
               
               
                   
               
               
                 61 
                 glsliislav fvlmfllrki nseplkdefk ntgsgllgma nidleksrtg deiilprgle 
               
               
                   
               
               
                 121 
                 ytveectced cikskpkvds dhcfplpame egatilvttk tndyckslpa 
               
               
                   
                 alsateieks 
               
               
                   
               
               
                 181 
                 isar 
               
               
                   
               
            
           
           
               
               
            
               
                 cDNA encoding Human BCMA. Sequence encoding 
                   
               
               
                 extracellular domain shown in bold. 
               
            
           
           
               
               
            
               
                 (SEQ ID NO: 31) 
                   
               
            
           
           
               
               
               
            
               
                 1 
                 aagactcaaa cttagaaact tgaattagat gtggtattca aatccttagc 
                   
               
               
                   
                 tgccgcgaag 
               
               
                   
               
               
                 61 
                 acacagacag cccccgtaag aacccacgaa gcaggcgaag ttcattgttc 
               
               
                   
                 tcaacattct 
               
               
                   
               
               
                 121 
                 agctgctctt gctgcatttg ctctggaatt cttgtagaga tattacttgt 
               
               
                   
                 ccttccaggc 
               
               
                   
               
               
                 181 
                 tgttctttct gtagctccct tgttttcttt ttgtgatcat gttgcagatg 
               
               
                   
                 gctgggcagt 
               
               
                   
               
               
                 241 
                 gctcccaaaa tgaatatttt gacagtttgt tgcatgcttg cataccttgt 
               
               
                   
                 caacttcgat 
               
               
                   
               
               
                 301 
                 gttcttctaa tactcctcct ctaacatgtc agcgttattg taatgcaagt 
               
               
                   
                 gtgaccaatt 
               
               
                   
               
               
                 361 
                 cagtgaaagg aacgaatgcg  attctctgga cctgtttggg actgagctta   
               
               
                   
                 
                   ataatttctt 
                 
               
               
                   
               
               
                 421 
                 
                   tggcagtttt cgtgctaatg tttttgctaa ggaagataaa ctctgaacca 
                 
               
               
                   
                 
                   ttaaaggacg 
                 
               
               
                   
               
               
                 481 
                   agtttaaaaa cacag gatca ggtctcctgg gcatggctaa cattgacctg 
               
               
                   
                 gaaaagagca 
               
               
                   
               
               
                 541 
                 ggactggtga tgaaattatt cttccgagag gcctcgagta cacggtggaa 
               
               
                   
                 gaatgcacct 
               
               
                   
               
               
                 601 
                 gtgaagactg catcaagagc aaaccgaagg tcgactctga ccattgcttt 
               
               
                   
                 ccactcccag 
               
               
                   
               
               
                 661 
                 ctatggagga aggcgcaacc attcttgtca ccacgaaaac gaatgactat 
               
               
                   
                 tgcaagagcc 
               
               
                   
               
               
                 721 
                 tgccagctgc tttgagtgct acggagatag agaaatcaat ttctgctagg 
               
               
                   
                 taattaacca 
               
               
                   
               
               
                 781 
                 tttcgactcg agcagtgcca ctttaaaaat cttttgtcag aatagatgat 
               
               
                   
                 gtgtcagatc 
               
               
                   
               
               
                 841 
                 tctttaggat gactgtattt ttcagttgcc gatacagctt tttgtcctct 
               
               
                   
                 aactgtggaa 
               
               
                   
               
               
                 901 
                 actctttatg ttagatatat ttctctaggt tactgttggg agcttaatgg 
               
               
                   
                 tagaaacttc 
               
               
                   
               
               
                 961 
                 cttggtttca tgattaaact cttttttttc ctga 
               
               
                   
               
            
           
           
               
               
            
               
                 Human BCMA Transcript Variant 4 
                   
               
            
           
           
               
               
            
               
                 (SEQ ID NO: 32) 
                   
               
            
           
           
               
               
               
            
               
                 1 
                 mlqmagqcsq neyfdsllha cipcqlrcss ntppltcqry cnarsgllgm 
                   
               
               
                   
                 anidleksrt 
               
               
                   
               
               
                 61 
                 gdeiilprgl eytveectce dcikskpkvd sdhcfplpam eegatilvtt 
               
               
                   
                 ktndyckslp 
               
               
                   
               
               
                 121 
                 aalsateiek sisar 
               
               
                   
               
            
           
           
               
               
            
               
                 cDNA Encoding Human BCMA Transcript Variant 4 
                   
               
            
           
           
               
               
            
               
                 (SEQ ID NO: 33) 
                   
               
            
           
           
               
               
               
            
               
                 1 
                 gttctcaaca ttctagctgc tcttgctgca tttgctctgg aattcttgta 
                   
               
               
                   
                 gagatattac 
               
               
                   
               
               
                 61 
                 ttgtccttcc aggctgttct ttctgtagct cccttgtttt ctttttgtga 
               
               
                   
                 tcatgttgca 
               
               
                   
               
               
                 121 
                 gatggctggg cagtgctccc aaaatgaata ttttgacagt ttgttgcatg 
               
               
                   
                 cttgcatacc 
               
               
                   
               
               
                 181 
                 ttgtcaactt cgatgttctt ctaatactcc tcctctaaca tgtcagcgtt 
               
               
                   
                 attgtaatgc 
               
               
                   
               
               
                 241 
                 aagatcaggt ctcctgggca tggctaacat tgacctggaa aagagcagga 
               
               
                   
                 ctggtgatga 
               
               
                   
               
               
                 301 
                 aattattctt ccgagaggcc tcgagtacac ggtggaagaa tgcacctgtg 
               
               
                   
                 aagactgcat 
               
               
                   
               
               
                 361 
                 caagagcaaa ccgaaggtcg actctgacca ttgctttcca ctcccagcta 
               
               
                   
                 tggaggaagg 
               
               
                   
               
               
                 421 
                 cgcaaccatt cttgtcacca cgaaaacgaa tgactattgc aagagcctgc 
               
               
                   
                 cagctgcttt 
               
               
                   
               
               
                 481 
                 gagtgctacg gagatagaga aatcaatttc tgctaggtaa ttaaccattt 
               
               
                   
                 cgactcgagc 
               
               
                   
               
               
                 541 
                 agtgccactt taaaaatctt ttgtcagaat agatgatgtg tcagatctct 
               
               
                   
                 ttaggatgac 
               
               
                   
               
               
                 601 
                 tgtatttttc agttgccgat acagcttttt gtcctctaac tgtggaaact 
               
               
                   
                 ctttatgtta 
               
               
                   
               
               
                 661 
                 gatatatt 
               
            
           
         
       
     
     CD307e 
     As used herein the terms “Fc receptor-like protein 5 (FCRL5)”, “CD307”, “CD307e”, “10A8”, “1G7”, “FcRH5” and “Immunoglobulin superfamily receptor translocation associated 2 (IRTA2)” are interchangeable. The FCRL5 gene encodes a member of the immunoglobulin receptor superfamily and the Fc-receptor like family, a protein that is expressed, e.g., in B cells and plasma cells (see, e.g. Li et al.,  J. Immunol.  196(10): 4064-4074, 2016). FCRL5 has been associated with diseases, e.g., multiple myeloma (Ise et al.,  Leukemia  21:169-174, 2007; and Elkins et al.,  Mol. Cancer Ther.  11:2222-2232, 2012), hairy cell leukemia (Janik,  Leuk. Lymphoma  52:69-71, 2011) and Burkitt lymphoma (Mohan et al.,  Blood  107(11):4433-4439, 2006). 
     Exemplary sequences of CD307e and exemplary sequences of nucleic acids encoding CD307e are provided below. 
     Human CD307e Isoform 1 Precursor Protein (SEQ ID NO: 34). 
     The signal sequence is underlined. The extracellular domain present in mature protein in shown in bold. 
                            1     mllwvillvl   apvsg   qfart prpiiflqpp wttvfqgerv tltckgfrfy                   spqktkwyhr                 61     ylgkeilret pdnilevqes geyrcqaqgs plsspvhldf ssaslilqap               lsvfegdsvv                 121     lrcrakaevt lnntiykndn vlaflnkrtd fhiphaclkd ngayrctgyk               esccpvssnt                 181     vkiqvqepft rpvlrassfq pisgnpvtlt cetqlslers dvplrfrffr               ddqtlglgws                 241     lspnfqitam wskdsgfywc kaatmpysvi sdsprswiqv qipashpvlt               lspekalnfe                 301     gtkvtlhcet qedslrtlyr fyhegvplrh ksvrcergas isfslttens               gnyyctadng                 361     lgakpskavs lsvtvpvshp vlnlsspedl ifegakvtlh ceaqrgslpi               lyqfhhegaa                 421     lerrsansag gvaisfslta ehsgnyycta dngfgpqrsk avslsvtvpv               shpvltlssa                 481     ealtfegatv tlhcevqrgs pqilyqfyhe dmplwssstp svgrvsfsfs               lteghsgnyy                 541     ctadngfgpq rsevvslfvt vpvsrpiltl rvpraqavvg dllelhceap               rgsppilywf                 601     yhedvtlgss sapsggeasf nlsltaehsg nysceanngl vaqhsdtisl               svivpvsrpi                 661     ltfrapraqa vvgdllelhc ealrgsspil ywfyhedvtl gkisapsggg               asfnlsltte                 721     hsgiyscead ngleaqrsem vtlkvavpvs rpvltlrapg thaavgdlle               lhcealrgsp                 781     lilyrffhed vtlgnrssps ggaslnlslt aehsgnysce adnglgaqrs               etvtlyitgl                 841     tanrsgpfat g vaggllsia glaagallly cwlsrkagrk pasdparsps           dsdsqeptyh               901   nvpaweelqp vytnanprge nvvysevrii qekkkhavas dprhlrnkgs           piiysevkva               961   stpvsgslfl assaphr            
cDNA Encoding Human CD307e Isoform 1 Precursor Protein (SEQ ID NO: 35).
 
     Sequence encoding the signal sequence is underlined. The sequence encoding the extracellular domain present in mature protein in shown in bold. 
     
       
         
           
               
               
               
            
               
                 1 
                 aattcactaa tgcattctgc tctttttgag agcacagctt ctcagatgtg 
                   
               
               
                   
                 ctccttggag 
               
               
                   
               
               
                 61 
                 ctggtgtgca gtgtcctgac tgtaagatca agtccaaacc tgttttggaa 
               
               
                   
                 ttgaggaaac 
               
               
                   
               
               
                 121 
                 ttctcttttg atctcagccc ttggtggtcc aggtcttc at   gctgctgtgg   
               
               
                   
                 
                   gtgatattac 
                 
               
               
                   
               
               
                 181 
                   tggtcctggc   tcctgtcagt   gga   cagtttg caaggacacc caggcccatt   
               
               
                   
                 
                   attttcctcc 
                 
               
               
                   
               
               
                 241 
                 
                   agcctccatg gaccacagtc ttccaaggag agagagtgac cctcacttgc 
                 
               
               
                   
                 
                   aagggatttc 
                 
               
               
                   
               
               
                 301 
                 
                   gcttctactc accacagaaa acaaaatggt accatcggta ccttgggaaa 
                 
               
               
                   
                 
                   gaaatactaa 
                 
               
               
                   
               
               
                 361 
                 
                   gagaaacccc agacaatatc cttgaggttc aggaatctgg agagtacaga 
                 
               
               
                   
                 
                   tgccaggccc 
                 
               
               
                   
               
               
                 421 
                 
                   agggctcccc tctcagtagc cctgtgcact tggatttttc ttcagcttcg 
                 
               
               
                   
                 
                   ctgatcctgc 
                 
               
               
                   
               
               
                 481 
                 
                   aagctccact ttctgtgttt gaaggagact ctgtggttct gaggtgccgg 
                 
               
               
                   
                 
                   gcaaaggcgg 
                 
               
               
                   
               
               
                 541 
                 
                   aagtaacact gaataatact atttacaaga atgataatgt cctggcattc 
                 
               
               
                   
                 
                   cttaataaaa 
                 
               
               
                   
               
               
                 601 
                 
                   gaactgactt ccatattcct catgcatgtc tcaaggacaa tggtgcatat 
                 
               
               
                   
                 
                   cgctgtactg 
                 
               
               
                   
               
               
                 661 
                 
                   gatataagga aagttgttgc cctgtttctt ccaatacagt caaaatccaa 
                 
               
               
                   
                 
                   gtccaagagc 
                 
               
               
                   
               
               
                 721 
                 
                   catttacacg tccagtgctg agagccagct ccttccagcc catcagcggg 
                 
               
               
                   
                 
                   aacccagtga 
                 
               
               
                   
               
               
                 781 
                 
                   ccctgacctg tgagacccag ctctctctag agaggtcaga tgtcccgctc 
                 
               
               
                   
                 
                   cggttccgct 
                 
               
               
                   
               
               
                 841 
                 
                   tcttcagaga tgaccagacc ctgggattag gctggagtct ctccccgaat 
                 
               
               
                   
                 
                   ttccagatta 
                 
               
               
                   
               
               
                 901 
                 
                   ctgccatgtg gagtaaagat tcagggttct actggtgtaa ggcagcaaca 
                 
               
               
                   
                 
                   atgccttaca 
                 
               
               
                   
               
               
                 961 
                 
                   gcgtcatatc tgacagcccg agatcctgga tacaggtgca gatccctgca 
                 
               
               
                   
                 
                   tctcatcctg 
                 
               
               
                   
               
               
                 1021 
                 
                   tcctcactct cagccctgaa aaggctctga attttgaggg aaccaaggtg 
                 
               
               
                   
                 
                   acacttcact 
                 
               
               
                   
               
               
                 1081 
                 
                   gtgaaaccca ggaagattct ctgcgcactt tgtacaggtt ttatcatgag 
                 
               
               
                   
                 
                   ggtgtccccc 
                 
               
               
                   
               
               
                 1141 
                 
                   tgaggcacaa gtcagtccgc tgtgaaaggg gagcatccat cagcttctca 
                 
               
               
                   
                 
                   ctgactacag 
                 
               
               
                   
               
               
                 1201 
                 
                   agaattcagg gaactactac tgcacagctg acaatggcct tggcgccaag 
                 
               
               
                   
                 
                   cccagtaagg 
                 
               
               
                   
               
               
                 1261 
                 
                   ctgtgagcct ctcagtcact gttcccgtgt ctcatcctgt cctcaacctc 
                 
               
               
                   
                 
                   agctctcctg 
                 
               
               
                   
               
               
                 1321 
                 
                   aggacctgat ttttgaggga gccaaggtga cacttcactg tgaagcccag 
                 
               
               
                   
                 
                   agaggttcac 
                 
               
               
                   
               
               
                 1381 
                 
                   tccccatcct gtaccagttt catcatgagg gtgctgccct ggagcgtagg 
                 
               
               
                   
                 
                   tcggccaact 
                 
               
               
                   
               
               
                 1441 
                 
                   ctgcaggagg agtggccatc agcttctctc tgactgcaga gcattcaggg 
                 
               
               
                   
                 
                   aactactact 
                 
               
               
                   
               
               
                 1501 
                 
                   gcacagctga caatggcttt ggcccccagc gcagtaaggc ggtgagcctc 
                 
               
               
                   
                 
                   tccgtcactg 
                 
               
               
                   
               
               
                 1561 
                 
                   tccctgtgtc tcatcctgtc ctcaccctca gctctgctga ggccctgact 
                 
               
               
                   
                 
                   tttgaaggag 
                 
               
               
                   
               
               
                 1621 
                 
                   ccactgtgac acttcactgt gaagtccaga gaggttcccc acaaatccta 
                 
               
               
                   
                 
                   taccagtttt 
                 
               
               
                   
               
               
                 1681 
                 
                   atcatgagga catgcccctg tggagcagct caacaccctc tgtgggaaga 
                 
               
               
                   
                 
                   gtgtccttca 
                 
               
               
                   
               
               
                 1741 
                 
                   gcttctctct gactgaagga cattcaggga attactactg cacagctgac 
                 
               
               
                   
                 
                   aatggctttg 
                 
               
               
                   
               
               
                 1801 
                 
                   gtccccagcg cagtgaagtg gtgagccttt ttgtcactgt tccagtgtct 
                 
               
               
                   
                 
                   cgccccatcc 
                 
               
               
                   
               
               
                 1861 
                 
                   tcaccctcag ggttcccagg gcccaggctg tggtggggga cctgctggag 
                 
               
               
                   
                 
                   cttcactgtg 
                 
               
               
                   
               
               
                 1921 
                 
                   aggccccgag aggctctccc ccaatcctgt actggtttta tcatgaggat 
                 
               
               
                   
                 
                   gtcaccctgg 
                 
               
               
                   
               
               
                 1981 
                 
                   ggagcagctc agccccctct ggaggagaag cttctttcaa cctctctctg 
                 
               
               
                   
                 
                   actgcagaac 
                 
               
               
                   
               
               
                 2041 
                 
                   attctggaaa ctactcatgt gaggccaaca atggcctagt ggcccagcac 
                 
               
               
                   
                 
                   agtgacacaa 
                 
               
               
                   
               
               
                 2101 
                 
                   tatcactcag tgttatagtt ccagtatctc gtcccatcct caccttcagg 
                 
               
               
                   
                 
                   gctcccaggg 
                 
               
               
                   
               
               
                 2161 
                 
                   cccaggctgt ggtgggggac ctgctggagc ttcactgtga ggccctgaga 
                 
               
               
                   
                 
                   ggctcctccc 
                 
               
               
                   
               
               
                 2221 
                 
                   caatcctgta ctggttttat catgaagatg tcaccctggg taagatctca 
                 
               
               
                   
                 
                   gccccctctg 
                 
               
               
                   
               
               
                 2281 
                 
                   gaggaggggc ctccttcaac ctctctctga ctacagaaca ttctggaatc 
                 
               
               
                   
                 
                   tactcctgtg 
                 
               
               
                   
               
               
                 2341 
                 
                   aggcagacaa tggtctggag gcccagcgca gtgagatggt gacactgaaa 
                 
               
               
                   
                 
                   gttgcagttc 
                 
               
               
                   
               
               
                 2401 
                 
                   cggtgtctcg cccggtcctc accctcaggg ctcccgggac ccatgctgcg 
                 
               
               
                   
                 
                   gtgggggacc 
                 
               
               
                   
               
               
                 2461 
                 
                   tgctggagct tcactgtgag gccctgagag gctctcccct gatcctgtac 
                 
               
               
                   
                 
                   cggttttttc 
                 
               
               
                   
               
               
                 2521 
                 
                   atgaggatgt caccctagga aataggtcgt ccccctctgg aggagcgtcc 
                 
               
               
                   
                 
                   ttaaacctct 
                 
               
               
                   
               
               
                 2581 
                 
                   ctctgactgc agagcactct ggaaactact cctgtgaggc cgacaatggc 
                 
               
               
                   
                 
                   ctcggggccc 
                 
               
               
                   
               
               
                 2641 
                 
                   agcgcagtga gacagtgaca ctttatatca cagggctgac cgcgaacaga 
                 
               
               
                   
                 
                   agtggccctt 
                 
               
               
                   
               
               
                 2701 
                   ttgccacagg a gtcgccggg ggcctgctca gcatagcagg ccttgctgcg 
               
               
                   
                 ggggcactgc 
               
               
                   
               
               
                 2761 
                 tgctctactg ctggctctcg agaaaagcag ggagaaagcc tgcctctgac 
               
               
                   
                 cccgccagga 
               
               
                   
               
               
                 2821 
                 gcccttcaga ctcggactcc caagagccca cctatcacaa tgtaccagcc 
               
               
                   
                 tgggaagagc 
               
               
                   
               
               
                 2881 
                 tgcaaccagt gtacactaat gcaaatccta gaggagaaaa tgtggtttac 
               
               
                   
                 tcagaagtac 
               
               
                   
               
               
                 2941 
                 ggatcatcca agagaaaaag aaacatgcag tggcctctga ccccaggcat 
               
               
                   
                 ctcaggaaca 
               
               
                   
               
               
                 3001 
                 agggttcccc tatcatctac tctgaagtta aggtggcgtc aaccccggtt 
               
               
                   
                 tccggatccc 
               
               
                   
               
               
                 3061 
                 tgttcttggc ttcctcagct cctcacagat gagtccacac gtctctccaa 
               
               
                   
                 ctgctgtttc 
               
               
                   
               
               
                 3121 
                 agcctctgca ccccaaagtt ccccttgggg gagaagcagc attgaagtgg 
               
               
                   
                 gaagatttag 
               
               
                   
               
               
                 3181 
                 gctgccccag accatatcta ctggcctttg tttcacatgt cctcattctc 
               
               
                   
                 agtctgacca 
               
               
                   
               
               
                 3241 
                 gaatgcaggg ccctgctgga ctgtcacctg tttcccagtt aaagccctga 
               
               
                   
                 ctggcaggtt 
               
               
                   
               
               
                 3301 
                 ttttaatcca gtggcaaggt gctcccactc cagggcccag cacatctcct 
               
               
                   
                 ggattcctta 
               
               
                   
               
               
                 3361 
                 gtgggcttca gctgtggttg ctgttctgag tactgctctc atcacacccc 
               
               
                   
                 cacagagggg 
               
               
                   
               
               
                 3421 
                 gtcttaccac acaaagggag agtgggcctt caggagatgc cgggctggcc 
               
               
                   
                 taacagctca 
               
               
                   
               
               
                 3481 
                 ggtgctccta aactccgaca cagagttcct gctttgggtg gatgcatttc 
               
               
                   
                 tcaattgtca 
               
               
                   
               
               
                 3541 
                 tcagcctggt ggggctactg cagtgtgctg ccaaatggga cagcacacag 
               
               
                   
                 cctgtgcaca 
               
               
                   
               
               
                 3601 
                 tgggacatgt gatgggtctc cccacggggg ctgcatttca cactcctcca 
               
               
                   
                 cctgtctcaa 
               
               
                   
               
               
                 3661 
                 actctaaggt cggcacttga caccaaggta acttctctcc tgctcatgtg 
               
               
                   
                 tcagtgtcta 
               
               
                   
               
               
                 3721 
                 cctgcccaag taagtggctt tcatacacca agtcccaagt tcttcccatc 
               
               
                   
                 ctaacagaag 
               
               
                   
               
               
                 3781 
                 taacccagca agtcaaggcc aggaggacca ggggtgcaga cagaacacat 
               
               
                   
                 actggaacac 
               
               
                   
               
               
                 3841 
                 aggaggtgct caattactat ttgactgact gactgaatga atgaatgaat 
               
               
                   
                 gaggaagaaa 
               
               
                   
               
               
                 3901 
                 actgtgggta atcaaactgg cataaaatcc agtgcactcc ctaggaaatc 
               
               
                   
                 cgggaggtat 
               
               
                   
               
               
                 3961 
                 tctggcttcc ctaagaaaca atggaagaga aggagcttgg atgaggaaac 
               
               
                   
                 tgttcagcaa 
               
               
                   
               
               
                 4021 
                 gaggaagggc ttctcacact ttcatgtgct tgtggatcac ctgaggatcc 
               
               
                   
                 tgtgaaaata 
               
               
                   
               
               
                 4081 
                 cagatactga ttcagtgggt ctgcgtagag cctgagactg ccattctaac 
               
               
                   
                 atgttcccag 
               
               
                   
               
               
                 4141 
                 gggatgctga tgctgctggc cctgggactg cactgcatgc atgtgaagcc 
               
               
                   
                 ctataggtct 
               
               
                   
               
               
                 4201 
                 cagcagaggc ccatggagag ggaatgtgtg gctctggctg cccagggccc 
               
               
                   
                 aactcggttc 
               
               
                   
               
               
                 4261 
                 acacggatcg tgctgctccc tggccagcct ttggccacag caccaccagc 
               
               
                   
                 tgctgttgct 
               
               
                   
               
               
                 4321 
                 gagagagctt cttctctgtg acatgttggc tttcatcagc caccctggga 
               
               
                   
                 agcggaaagt 
               
               
                   
               
               
                 4381 
                 agctgccact atctttgttt ccccacctca ggcctcacac tttcccatga 
               
               
                   
                 aaagggtgaa 
               
               
                   
               
               
                 4441 
                 tgtatataac ctgagccctc tccattcaga gttgttctcc catctctgag 
               
               
                   
                 caatgggatg 
               
               
                   
               
               
                 4501 
                 ttctgttccg cttttatgat atccatcaca tcttatcttg atctttgctc 
               
               
                   
                 ccagtggatt 
               
               
                   
               
               
                 4561 
                 gtacagtgat gacttttaag ccccacggcc ctgaaataaa atccttccaa 
               
               
                   
                 gggcattgga 
               
               
                   
               
               
                 4621 
                 agctcactcc acctgaacca tggcttttca tgcttccaag tgtcagggcc 
               
               
                   
                 ttgcccagat 
               
               
                   
               
               
                 4681 
                 agacagggct ggctctgctg ccccaacctt tcaaggagga aaccagacac 
               
               
                   
                 ctgagacagg 
               
               
                   
               
               
                 4741 
                 agcctgtatg cagcccagtg cagccttgca gaggacaagg ctggaggcat 
               
               
                   
                 ttgtcatcac 
               
               
                   
               
               
                 4801 
                 tacagatatg caactaaaat agacgtggag caagagaaat gcattcccac 
               
               
                   
                 cgaggccgct 
               
               
                   
               
               
                 4861 
                 tttttaggcc tagttgaaag tcaagaagga cagcagcaag cataggctca 
               
               
                   
                 ggattaaaga 
               
               
                   
               
               
                 4921 
                 aaaaaatctg ctcacagtct gttctggagg tcacatcacc aacaaagctc 
               
               
                   
                 acgccctatg 
               
               
                   
               
               
                 4981 
                 cagttctgag aaggtggagg caccaggctc aaaagaggaa atttagaatt 
               
               
                   
                 tctcattggg 
               
               
                   
               
               
                 5041 
                 agagtaaggt acccccatcc cagaatgata actgcacagt ggcagaacaa 
               
               
                   
                 actccaccct 
               
               
                   
               
               
                 5101 
                 aatgtgggtg gaccccgtcc agtctgttga aggcctgaat gtaacaaaag 
               
               
                   
                 ggcttattct 
               
               
                   
               
               
                 5161 
                 tcctcaagta agggggaact cctgctttgg gctgggacat aagtttttct 
               
               
                   
                 gctttcagac 
               
               
                   
               
               
                 5221 
                 gcaaactgaa aaatggctct tcttgggtct tgagcttgct ggcatatgga 
               
               
                   
                 ctgaaagaaa 
               
               
                   
               
               
                 5281 
                 ctatgctatt ggatctcctg gatctccagc ttgctgactg cagatcttga 
               
               
                   
                 gatatgtcag 
               
               
                   
               
               
                 5341 
                 cctctacagt cacaagagct aattcattct aataaaccaa tctttctgta aaaaa 
               
            
           
         
       
     
     Human CD307e Isoform 2 Precursor Protein (SEQ ID NO: 36). 
     The signal sequence is underlined. The extracellular domain present in mature protein in shown in bold. 
                        1     mllwvillvl   apvsg   qfart prpiiflqpp wttvfqgerv               tltckgfrfy spqktkwyhr                 61     ylgkeilret pdnilevqes geyrcqaqgs plsspvhldf               ssaslilqap lsvfegdsvv                 121     lrcrakaevt lnntiykndn vlaflnkrtd fhiphaclkd               ngayrctgyk esccpvssnt                 181     vkiqvqepft rpvlrassfq pisgnpvtlt cetqlslers               dvplrfrffr ddqtlglgws                 241     lspnfqitam wskdsgfywc kaatmpysvi sdsprswiqv               qipashpvlt lspekalnfe                 301     gtkvtlhcet qedslrtlyr fyhegvplrh ksvrcergas               isfslttens gnyyctadng                 361     lgakpskavs lsvtvpvshp vlnlsspedl ifegakvtlh               ceaqrgslpi lyqfhhegaa                 421     lerrsansag gvaisfslta ehsgnyycta dngfgpqrsk               avslsvtvpv shpvltlssa                 481     ealtfegatv tlhcevqrgs pqilyqfyhe dmplwssstp               svgrvsfsfs lteghsgnyy                 541     ctadngfgpq rsevvslfvt vpvsrpiltl rvpraqavvg               dllelhceap rgsppilywf                 601     yhedvtlgss sapsggeasf nlsltaehsg nysceanngl               vaqhsdtisl svivpvsrpi                 661     ltfrapraqa vvgdllelhc ealrgsspil ywfyhedvtl               gkisapsggg asfnlsltte                 721     hsgiyscead ngleaqrsem vtlkvavpvs rpvltlrapg               thaavgdlle lhcealrgsp                 781     lilyrffhed vtlgnrssps ggaslnlslt aehsgnysce               adnglgaqrs etvtlyitgl                 841     tanrsgpfat g vaggllsia glaagallly cwlsrkagrk           pasdparsps dsdsqeptyh               901   nvpaweelqp vytneekmwf tqkygsskrk rnmqwpltpg           isgtrvplss tlklrwrqpr               961   fpdpcswlpq lltdestrls nccfslctpk fplgekqh            
cDNA Encoding Human CD307e Isoform 2 Precursor Protein (SEQ ID NO: 37).
 
     Sequence encoding the signal sequence is underlined. The sequence encoding the extracellular domain present in mature protein in shown in bold. 
     
       
         
           
               
               
               
            
               
                 1 
                 aattcactaa tgcattctgc tctttttgag agcacagctt ctcagatgtg ctccttggag 
                   
               
               
                   
               
               
                 61 
                 ctggtgtgca gtgtcctgac tgtaagatca agtccaaacc tgttttggaa ttgaggaaac 
               
               
                   
               
               
                 121 
                 ttctcttttg atctcagccc ttggtggtcc aggtcttc at   gctgctgtgg   gtgatattac   
               
               
                   
               
               
                 181 
                   tggtcctggc   tcctgtcagt   gga   cagtttg caaggacacc caggcccatt attttcctcc   
               
               
                   
               
               
                 241 
                 
                   agcctccatg gaccacagtc ttccaaggag agagagtgac cctcacttgc aagggatttc 
                 
               
               
                   
               
               
                 301 
                 
                   gcttctactc accacagaaa acaaaatggt accatcggta ccttgggaaa gaaatactaa 
                 
               
               
                   
               
               
                 361 
                 
                   gagaaacccc agacaatatc cttgaggttc aggaatctgg agagtacaga tgccaggccc 
                 
               
               
                   
               
               
                 421 
                 
                   agggctcccc tctcagtagc cctgtgcact tggatttttc ttcagcttcg ctgatcctgc 
                 
               
               
                   
               
               
                 481 
                 
                   aagctccact ttctgtgttt gaaggagact ctgtggttct gaggtgccgg gcaaaggcgg 
                 
               
               
                   
               
               
                 541 
                 
                   aagtaacact gaataatact atttacaaga atgataatgt cctggcattc cttaataaaa 
                 
               
               
                   
               
               
                 601 
                 
                   gaactgactt ccatattcct catgcatgtc tcaaggacaa tggtgcatat cgctgtactg 
                 
               
               
                   
               
               
                 661 
                 
                   gatataagga aagttgttgc cctgtttctt ccaatacagt caaaatccaa gtccaagagc 
                 
               
               
                   
               
               
                 721 
                 
                   catttacacg tccagtgctg agagccagct ccttccagcc catcagcggg aacccagtga 
                 
               
               
                   
               
               
                 781 
                 
                   ccctgacctg tgagacccag ctctctctag agaggtcaga tgtcccgctc cggttccgct 
                 
               
               
                   
               
               
                 841 
                 
                   tcttcagaga tgaccagacc ctgggattag gctggagtct ctccccgaat ttccagatta 
                 
               
               
                   
               
               
                 901 
                 
                   ctgccatgtg gagtaaagat tcagggttct actggtgtaa ggcagcaaca atgccttaca 
                 
               
               
                   
               
               
                 961 
                 
                   gcgtcatatc tgacagcccg agatcctgga tacaggtgca gatccctgca tctcatcctg 
                 
               
               
                   
               
               
                 1021 
                 
                   tcctcactct cagccctgaa aaggctctga attttgaggg aaccaaggtg acacttcact 
                 
               
               
                   
               
               
                 1081 
                 
                   gtgaaaccca ggaagattct ctgcgcactt tgtacaggtt ttatcatgag ggtgtccccc 
                 
               
               
                   
               
               
                 1141 
                 
                   tgaggcacaa gtcagtccgc tgtgaaaggg gagcatccat cagcttctca ctgactacag 
                 
               
               
                   
               
               
                 1201 
                 
                   agaattcagg gaactactac tgcacagctg acaatggcct tggcgccaag cccagtaagg 
                 
               
               
                   
               
               
                 1261 
                 
                   ctgtgagcct ctcagtcact gttcccgtgt ctcatcctgt cctcaacctc agctctcctg 
                 
               
               
                   
               
               
                 1321 
                 
                   aggacctgat ttttgaggga gccaaggtga cacttcactg tgaagcccag agaggttcac 
                 
               
               
                   
               
               
                 1381 
                 
                   tccccatcct gtaccagttt catcatgagg gtgctgccct ggagcgtagg tcggccaact 
                 
               
               
                   
               
               
                 1441 
                 
                   ctgcaggagg agtggccatc agcttctctc tgactgcaga gcattcaggg aactactact 
                 
               
               
                   
               
               
                 1501 
                 
                   gcacagctga caatggcttt ggcccccagc gcagtaaggc ggtgagcctc tccgtcactg 
                 
               
               
                   
               
               
                 1561 
                 
                   tccctgtgtc tcatcctgtc ctcaccctca gctctgctga ggccctgact tttgaaggag 
                 
               
               
                   
               
               
                 1621 
                 
                   ccactgtgac acttcactgt gaagtccaga gaggttcccc acaaatccta taccagtttt 
                 
               
               
                   
               
               
                 1681 
                 
                   atcatgagga catgcccctg tggagcagct caacaccctc tgtgggaaga gtgtccttca 
                 
               
               
                   
               
               
                 1741 
                 
                   gcttctctct gactgaagga cattcaggga attactactg cacagctgac aatggctttg 
                 
               
               
                   
               
               
                 1801 
                 
                   gtccccagcg cagtgaagtg gtgagccttt ttgtcactgt tccagtgtct cgccccatcc 
                 
               
               
                   
               
               
                 1861 
                 
                   tcaccctcag ggttcccagg gcccaggctg tggtggggga cctgctggag cttcactgtg 
                 
               
               
                   
               
               
                 1921 
                 
                   aggccccgag aggctctccc ccaatcctgt actggtttta tcatgaggat gtcaccctgg 
                 
               
               
                   
               
               
                 1981 
                 
                   ggagcagctc agccccctct ggaggagaag cttctttcaa cctctctctg actgcagaac 
                 
               
               
                   
               
               
                 2041 
                 
                   attctggaaa ctactcatgt gaggccaaca atggcctagt ggcccagcac agtgacacaa 
                 
               
               
                   
               
               
                 2101 
                 
                   tatcactcag tgttatagtt ccagtatctc gtcccatcct caccttcagg gctcccaggg 
                 
               
               
                   
               
               
                 2161 
                 
                   cccaggctgt ggtgggggac ctgctggagc ttcactgtga ggccctgaga ggctcctccc 
                 
               
               
                   
               
               
                 2221 
                 
                   caatcctgta ctggttttat catgaagatg tcaccctggg taagatctca gccccctctg 
                 
               
               
                   
               
               
                 2281 
                 
                   gaggaggggc ctccttcaac ctctctctga ctacagaaca ttctggaatc tactcctgtg 
                 
               
               
                   
               
               
                 2341 
                 
                   aggcagacaa tggtctggag gcccagcgca gtgagatggt gacactgaaa gttgcagttc 
                 
               
               
                   
               
               
                 2401 
                 
                   cggtgtctcg cccggtcctc accctcaggg ctcccgggac ccatgctgcg gtgggggacc 
                 
               
               
                   
               
               
                 2461 
                 
                   tgctggagct tcactgtgag gccctgagag gctctcccct gatcctgtac cggttttttc 
                 
               
               
                   
               
               
                 2521 
                 
                   atgaggatgt caccctagga aataggtcgt ccccctctgg aggagcgtcc ttaaacctct 
                 
               
               
                   
               
               
                 2581 
                 
                   ctctgactgc agagcactct ggaaactact cctgtgaggc cgacaatggc ctcggggccc 
                 
               
               
                   
               
               
                 2641 
                 
                   agcgcagtga gacagtgaca ctttatatca cagggctgac cgcgaacaga agtggccctt 
                 
               
               
                   
               
               
                 2701 
                   ttgccacagg a gtcgccggg ggcctgctca gcatagcagg ccttgctgcg ggggcactgc 
               
               
                   
               
               
                 2761 
                 tgctctactg ctggctctcg agaaaagcag ggagaaagcc tgcctctgac cccgccagga 
               
               
                   
               
               
                 2821 
                 gcccttcaga ctcggactcc caagagccca cctatcacaa tgtaccagcc tgggaagagc 
               
               
                   
               
               
                 2881 
                 tgcaaccagt gtacactaat gaggagaaaa tgtggtttac tcagaagtac ggatcatcca 
               
               
                   
               
               
                 2941 
                 agagaaaaag aaacatgcag tggcctctga ccccaggcat ctcaggaaca agggttcccc 
               
               
                   
               
               
                 3001 
                 tatcatctac tctgaagtta aggtggcgtc aaccccggtt tccggatccc tgttcttggc 
               
               
                   
               
               
                 3061 
                 ttcctcagct cctcacagat gagtccacac gtctctccaa ctgctgtttc agcctctgca 
               
               
                   
               
               
                 3121 
                 ccccaaagtt ccccttgggg gagaagcagc attgaagtgg gaagatttag gctgccccag 
               
               
                   
               
               
                 3181 
                 accatatcta ctggcctttg tttcacatgt cctcattctc agtctgacca gaatgcaggg 
               
               
                   
               
               
                 3241 
                 ccctgctgga ctgtcacctg tttcccagtt aaagccctga ctggcaggtt ttttaatcca 
               
               
                   
               
               
                 3301 
                 gtggcaaggt gctcccactc cagggcccag cacatctcct ggattcctta gtgggcttca 
               
               
                   
               
               
                 3361 
                 gctgtggttg ctgttctgag tactgctctc atcacacccc cacagagggg gtcttaccac 
               
               
                   
               
               
                 3421 
                 acaaagggag agtgggcctt caggagatgc cgggctggcc taacagctca ggtgctccta 
               
               
                   
               
               
                 3481 
                 aactccgaca cagagttcct gctttgggtg gatgcatttc tcaattgtca tcagcctggt 
               
               
                   
               
               
                 3541 
                 ggggctactg cagtgtgctg ccaaatggga cagcacacag cctgtgcaca tgggacatgt 
               
               
                   
               
               
                 3601 
                 gatgggtctc cccacggggg ctgcatttca cactcctcca cctgtctcaa actctaaggt 
               
               
                   
               
               
                 3661 
                 cggcacttga caccaaggta acttctctcc tgctcatgtg tcagtgtcta cctgcccaag 
               
               
                   
               
               
                 3721 
                 taagtggctt tcatacacca agtcccaagt tcttcccatc ctaacagaag taacccagca 
               
               
                   
               
               
                 3781 
                 agtcaaggcc aggaggacca ggggtgcaga cagaacacat actggaacac aggaggtgct 
               
               
                   
               
               
                 3841 
                 caattactat ttgactgact gactgaatga atgaatgaat gaggaagaaa actgtgggta 
               
               
                   
               
               
                 3901 
                 atcaaactgg cataaaatcc agtgcactcc ctaggaaatc cgggaggtat tctggcttcc 
               
               
                   
               
               
                 3961 
                 ctaagaaaca atggaagaga aggagcttgg atgaggaaac tgttcagcaa gaggaagggc 
               
               
                   
               
               
                 4021 
                 ttctcacact ttcatgtgct tgtggatcac ctgaggatcc tgtgaaaata cagatactga 
               
               
                   
               
               
                 4081 
                 ttcagtgggt ctgcgtagag cctgagactg ccattctaac atgttcccag gggatgctga 
               
               
                   
               
               
                 4141 
                 tgctgctggc cctgggactg cactgcatgc atgtgaagcc ctataggtct cagcagaggc 
               
               
                   
               
               
                 4201 
                 ccatggagag ggaatgtgtg gctctggctg cccagggccc aactcggttc acacggatcg 
               
               
                   
               
               
                 4261 
                 tgctgctccc tggccagcct ttggccacag caccaccagc tgctgttgct gagagagctt 
               
               
                   
               
               
                 4321 
                 cttctctgtg acatgttggc tttcatcagc caccctggga agcggaaagt agctgccact 
               
               
                   
               
               
                 4381 
                 atctttgttt ccccacctca ggcctcacac tttcccatga aaagggtgaa tgtatataac 
               
               
                   
               
               
                 4441 
                 ctgagccctc tccattcaga gttgttctcc catctctgag caatgggatg ttctgttccg 
               
               
                   
               
               
                 4501 
                 cttttatgat atccatcaca tcttatcttg atctttgctc ccagtggatt gtacagtgat 
               
               
                   
               
               
                 4561 
                 gacttttaag ccccacggcc ctgaaataaa atccttccaa gggcattgga agctcactcc 
               
               
                   
               
               
                 4621 
                 acctgaacca tggcttttca tgcttccaag tgtcagggcc ttgcccagat agacagggct 
               
               
                   
               
               
                 4681 
                 ggctctgctg ccccaacctt tcaaggagga aaccagacac ctgagacagg agcctgtatg 
               
               
                   
               
               
                 4741 
                 cagcccagtg cagccttgca gaggacaagg ctggaggcat ttgtcatcac tacagatatg 
               
               
                   
               
               
                 4801 
                 caactaaaat agacgtggag caagagaaat gcattcccac cgaggccgct tttttaggcc 
               
               
                   
               
               
                 4861 
                 tagttgaaag tcaagaagga cagcagcaag cataggctca ggattaaaga aaaaaatctg 
               
               
                   
               
               
                 4921 
                 ctcacagtct gttctggagg tcacatcacc aacaaagctc acgccctatg cagttctgag 
               
               
                   
               
               
                 4981 
                 aaggtggagg caccaggctc aaaagaggaa atttagaatt tctcattggg agagtaaggt 
               
               
                   
               
               
                 5041 
                 acccccatcc cagaatgata actgcacagt ggcagaacaa actccaccct aatgtgggtg 
               
               
                   
               
               
                 5101 
                 gaccccgtcc agtctgttga aggcctgaat gtaacaaaag ggcttattct tcctcaagta 
               
               
                   
               
               
                 5161 
                 agggggaact cctgctttgg gctgggacat aagtttttct gctttcagac gcaaactgaa 
               
               
                   
               
               
                 5221 
                 aaatggctct tcttgggtct tgagcttgct ggcatatgga ctgaaagaaa ctatgctatt 
               
               
                   
               
               
                 5281 
                 ggatctcctg gatctccagc ttgctgactg cagatcttga gatatgtcag cctctacagt 
               
               
                   
               
               
                 5341 
                 cacaagagct aattcattct aataaaccaa tctttctgta 
               
            
           
         
       
     
     Transmembrane Domains 
     In some embodiments of any of the CARs described herein, the transmembrane domain is or comprises the transmembrane domain of CD28, CD3 epsilon, CD4, CD5, CD6, CD8a, CD9, CD16, CD22, CD33, CD37, CD45, CD64, CD80, CD86, CD134, CD137, GITR, NGFR, or CD154. Additional examples of suitable transmembrane domains are known in the art. 
     In some embodiments, the transmembrane domain is a single-pass transmembrane domain. In some embodiments, the transmembrane domain forms an alpha-helix. In some embodiments, the transmembrane domain forms a beta barrel. In some embodiments, the transmembrane domain is about 15 amino acids to about 200 amino acids, about 15 amino acids to about 180 amino acids, about 15 amino acids to about 160 amino acids, about 15 amino acids to about 140 amino acids, about 15 amino acids to about 120 amino acids, about 15 amino acids to about 100 amino acids, about 15 amino acids to about 80 amino acids, about 15 amino acids to about 60 amino acids, about 15 amino acids to about 50 amino acids, about 15 amino acids to about 45 amino acids, about 15 amino acids to about 40 amino acids, about 15 amino acids to about 35 amino acids, about 15 amino acids to about 30 amino acids, about 15 amino acids to about 25 amino acids, about 15 amino acids to about 22 amino acids, about 15 amino acids to about 20 amino acids, about 15 amino acids to about 18 amino acids, about 18 amino acids to about 200 amino acids, about 18 amino acids to about 180 amino acids, about 18 amino acids to about 160 amino acids, about 18 amino acids to about 140 amino acids, about 18 amino acids to about 120 amino acids, about 18 amino acids to about 100 amino acids, about 18 amino acids to about 80 amino acids, about 18 amino acids to about 60 amino acids, about 18 amino acids to about 50 amino acids, about 18 amino acids to about 45 amino acids, about 18 amino acids to about 40 amino acids, about 18 amino acids to about 35 amino acids, about 18 amino acids to about 30 amino acids, about 18 amino acids to about 25 amino acids, about 18 amino acids to about 22 amino acids, about 18 amino acids to about 20 amino acids, about 20 amino acids to about 200 amino acids, about 20 amino acids to about 180 amino acids, about 20 amino acids to about 160 amino acids, about 20 amino acids to about 140 amino acids, about 20 amino acids to about 120 amino acids, about 20 amino acids to about 100 amino acids, about 20 amino acids to about 80 amino acids, about 20 amino acids to about 60 amino acids, about 20 amino acids to about 50 amino acids, about 20 amino acids to about 45 amino acids, about 20 amino acids to about 40 amino acids, about 20 amino acids to about 35 amino acids, about 20 amino acids to about 30 amino acids, about 20 amino acids to about 25 amino acids, about 20 amino acids to about 22 amino acids, about 22 amino acids to about 200 amino acids, about 22 amino acids to about 180 amino acids, about 22 amino acids to about 160 amino acids, about 22 amino acids to about 140 amino acids, about 22 amino acids to about 120 amino acids, about 22 amino acids to about 100 amino acids, about 22 amino acids to about 80 amino acids, about 22 amino acids to about 60 amino acids, about 22 amino acids to about 50 amino acids, about 22 amino acids to about 45 amino acids, about 22 amino acids to about 40 amino acids, about 22 amino acids to about 35 amino acids, about 22 amino acids to about 30 amino acids, about 22 amino acids to about 25 amino acids, about 25 amino acids to about 200 amino acids, about 25 amino acids to about 180 amino acids, about 25 amino acids to about 160 amino acids, about 25 amino acids to about 140 amino acids, about 25 amino acids to about 120 amino acids, about 25 amino acids to about 100 amino acids, about 25 amino acids to about 80 amino acids, about 25 amino acids to about 60 amino acids, about 25 amino acids to about 50 amino acids, about 25 amino acids to about 45 amino acids, about 25 amino acids to about 40 amino acids, about 25 amino acids to about 35 amino acids, about 25 amino acids to about 30 amino acids, about 30 amino acids to about 200 amino acids, about 30 amino acids to about 180 amino acids, about 30 amino acids to about 160 amino acids, about 30 amino acids to about 140 amino acids, about 30 amino acids to about 120 amino acids, about 30 amino acids to about 100 amino acids, about 30 amino acids to about 80 amino acids, about 30 amino acids to about 60 amino acids, about 30 amino acids to about 50 amino acids, about 30 amino acids to about 45 amino acids, about 30 amino acids to about 40 amino acids, about 30 amino acids to about 35 amino acids, about 35 amino acids to about 200 amino acids, about 35 amino acids to about 180 amino acids, about 35 amino acids to about 160 amino acids, about 35 amino acids to about 140 amino acids, about 35 amino acids to about 120 amino acids, about 35 amino acids to about 100 amino acids, about 35 amino acids to about 80 amino acids, about 35 amino acids to about 60 amino acids, about 35 amino acids to about 50 amino acids, about 35 amino acids to about 45 amino acids, about 35 amino acids to about 40 amino acids, about 40 amino acids to about 200 amino acids, about 40 amino acids to about 180 amino acids, about 40 amino acids to about 160 amino acids, about 40 amino acids to about 140 amino acids, about 40 amino acids to about 120 amino acids, about 40 amino acids to about 100 amino acids, about 40 amino acids to about 80 amino acids, about 40 amino acids to about 60 amino acids, about 40 amino acids to about 50 amino acids, about 40 amino acids to about 45 amino acids, about 45 amino acids to about 200 amino acids, about 45 amino acids to about 180 amino acids, about 45 amino acids to about 160 amino acids, about 45 amino acids to about 140 amino acids, about 45 amino acids to about 120 amino acids, about 45 amino acids to about 100 amino acids, about 45 amino acids to about 80 amino acids, about 45 amino acids to about 60 amino acids, about 45 amino acids to about 50 amino acids, about 50 amino acids to about 200 amino acids, about 50 amino acids to about 180 amino acids, about 50 amino acids to about 160 amino acids, about 50 amino acids to about 140 amino acids, about 50 amino acids to about 120 amino acids, about 50 amino acids to about 100 amino acids, about 50 amino acids to about 80 amino acids, about 50 amino acids to about 60 amino acids, about 60 amino acids to about 200 amino acids, about 60 amino acids to about 180 amino acids, about 60 amino acids to about 160 amino acids, about 60 amino acids to about 140 amino acids, about 60 amino acids to about 120 amino acids, about 60 amino acids to about 100 amino acids, about 60 amino acids to about 80 amino acids, about 80 amino acids to about 200 amino acids, about 80 amino acids to about 180 amino acids, about 80 amino acids to about 160 amino acids, about 80 amino acids to about 140 amino acids, about 80 amino acids to about 120 amino acids, about 80 amino acids to about 100 amino acids, about 100 amino acids to about 200 amino acids, about 100 amino acids to about 180 amino acids, about 100 amino acids to about 160 amino acids, about 100 amino acids to about 140 amino acids, about 100 amino acids to about 120 amino acids, about 120 amino acids to about 200 amino acids, about 120 amino acids to about 180 amino acids, about 120 amino acids to about 160 amino acids, about 120 amino acids to about 140 amino acids, about 140 amino acids to about 200 amino acids, about 140 amino acids to about 180 amino acids, about 140 amino acids to about 160 amino acids, about 160 amino acids to about 200 amino acids, about 160 amino acids to about 180 amino acids, or about 180 amino acids to about 200 amino acids. 
     In some embodiments, the transmembrane domain is or comprises a sequence that is at least 80% identical (e.g., at least 82% identical, at least 84% identical, at least 86% identical, at least 88% identical, at least 90% identical, at least 92% identical, at least 94% identical, at least 96% identical, at least 98% identical, or at least 99% identical) to the transmembrane domain of CD28, CD3 epsilon, CD4, CD5, CD6, CD8a, CD9, CD16, CD22, CD33, CD37, CD45, CD64, CD80, CD86, CD134, 4-1BB, or CD154. In some embodiments, the transmembrane domain is or comprises a sequence that identical to the transmembrane domain of CD28, CD3 epsilon, CD4, CD5, CD6, CD8a, CD9, CD16, CD22, CD33, CD37, CD45, CD64, CD80, CD86, CD134, 4-1BB, or CD154, except that the sequence includes one, two, three, four, or five substitutions. In some embodiments, the transmembrane domain is or comprises a sequence that is identical to the transmembrane domain of CD28, CD3 epsilon, CD4, CD5, CD6, CD8a, CD9, CD16, CD22, CD33, CD37, CD45, CD64, CD80, CD86, CD134, 4-1BB, or CD154, except that is has one, two, three, four, or five amino acids deleted from its N-terminus and/or has one, two, three, four, or five amino acids deleted from its C-terminus. Exemplary sequences for the transmembrane domain of CD28, CD3 epsilon, CD4, CD5, CD6, CD8a, CD9, CD16, CD22, CD33, CD37, CD45, CD64, CD80, CD86, CD134, 4-1BB, and CD154 are shown below. Exemplary nucleic acids sequences encoding a transmembrane domain of CD28, CD3 epsilon, CD4, CD5, CD6, CD8a, CD9, CD16, CD22, CD33, CD37, CD45, CD64, CD80, CD86, CD134, 4-1BB, and CD154 are shown below. 
     
       
         
           
               
            
               
                 Human CD28 Transmembrane Domain 
               
            
           
           
               
            
               
                 (SEQ ID NO: 38) 
               
            
           
           
               
            
               
                 fwvlvvvggvlacysllvtvafiifwv 
               
               
                   
               
               
                 cDNA Encoding Human CD28 Transmembrane Domain 
               
            
           
           
               
            
               
                 (SEQ ID NO: 39) 
               
            
           
           
               
            
               
                 ttttgggtgctggtggtggttggtggagtcctggcttgctatagcttgct 
               
               
                   
               
               
                 agtaacagtggcctttattattttctgggtg 
               
               
                   
               
               
                 Human CD3 Epsilon Transmembrane Domain 
               
            
           
           
               
            
               
                 (SEQ ID NO: 40) 
               
            
           
           
               
            
               
                 vmsvativivdicitggllllvyyws 
               
               
                   
               
               
                 cDNA Encoding Human CD3 Epsilon Transmembrane 
               
               
                 Domain 
               
            
           
           
               
            
               
                 (SEQ ID NO: 41) 
               
            
           
           
               
            
               
                 gtgatgtcggtggccacaattgtcatagtggacatctgcatcactgggg 
               
               
                   
               
               
                 gcttgctgctgctggtttactactggagc 
               
               
                   
               
               
                 Human CD4 Transmembrane Domain 
               
            
           
           
               
            
               
                 (SEQ ID NO: 42) 
               
            
           
           
               
            
               
                 malivlggvaglllfiglgiff 
               
               
                   
               
               
                 cDNA Encoding Human CD4 Transmembrane Domain 
               
            
           
           
               
            
               
                 (SEQ ID NO: 43) 
               
            
           
           
               
            
               
                 atggccctgattgtgctggggggcgtcgccggcctcctgcttttcattgg 
               
               
                   
               
               
                 gctaggcatcttcttc 
               
               
                   
               
               
                 Human CD5 Transmembrane Domain 
               
            
           
           
               
            
               
                 (SEQ ID NO: 44) 
               
            
           
           
               
            
               
                 aglaagtvasiilalvllvvllvvcgplay 
               
               
                   
               
               
                 cDNA Encoding Human CD5 Transmembrane Domain 
               
            
           
           
               
            
               
                 (SEQ ID NO: 45) 
               
            
           
           
               
            
               
                 gcaggcctggccgcaggcacggtggcaagcatcatcctggccctggtgc 
               
               
                   
               
               
                 ggtggtgctgctggtcgtgtgcggcccccttgcctac 
               
               
                 tcct  
               
               
                 Human CD6 Transmembrane Domain 
               
            
           
           
               
            
               
                 (SEQ ID NO: 46) 
               
            
           
           
               
            
               
                 ipsivlgilllgslifiafil 
               
               
                   
               
               
                 cDNA Encoding Human CD6 Transmembrane Domain 
               
            
           
           
               
            
               
                 (SEQ ID NO: 47) 
               
            
           
           
               
            
               
                 atcccctccatcgttctgggaattctcctccttggctccctcatcttcat 
               
               
                   
               
               
                 agccttcatcctc 
               
               
                   
               
               
                 Human CD8a Transmembrane Domain 
               
            
           
           
               
            
               
                 (SEQ ID NO: 48) 
               
            
           
           
               
            
               
                 iyiwaplagtcgvlllslvit 
               
               
                   
               
               
                 cDNA Encoding Human CD8a Transmembrane Domain 
               
               
                 Isoform 1 
               
            
           
           
               
            
               
                 (SEQ ID NO: 49) 
               
            
           
           
               
            
               
                 atctacatctgggcgcccttggccgggacttgtggggtccttctcctgt 
               
               
                   
               
               
                 cactggttatcacc 
               
               
                   
               
               
                 Human CD9 Transmembrane Domain Isoform 1 
               
            
           
           
               
            
               
                 (SEQ ID NO: 50) 
               
            
           
           
               
            
               
                 LLFGFNFIFWLAGIAVLAIGL 
               
               
                   
               
               
                 cDNA Encoding Human CD9 Transmembrane Domain 
               
            
           
           
               
            
               
                 (SEQ ID NO: 51) 
               
            
           
           
               
            
               
                 CTGCTGTTCGGATTTAACTTCATCTTCTGGCTTGCCGGGATTGCTGTC 
               
               
                   
               
               
                 CTTGCCATTGGACTA 
               
               
                   
               
               
                 Human CD9 Transmembrane Domain Isoform 2 
               
            
           
           
               
            
               
                 (SEQ ID NO: 52) 
               
            
           
           
               
            
               
                 FYTGVYILIGAGALMMLVGFL 
               
               
                   
               
               
                 cDNA Encoding Human CD9 Transmembrane Domain 
               
               
                 Isoform 2 
               
            
           
           
               
            
               
                 (SEQ ID NO: 53) 
               
            
           
           
               
            
               
                 TTCTACACAGGAGTCTATATTCTGATCGGAGCCGGCGCCCTCATGAT 
               
               
                   
               
               
                 GCTGGTGGGCTTCCTG 
               
               
                   
               
               
                 Human CD9 Transmembrane Domain Isoform 3 
               
            
           
           
               
            
               
                 (SEQ ID NO: 54) 
               
            
           
           
               
            
               
                 MLGLFFGFLLVIFAIEIAAAIWGY 
               
               
                   
               
               
                 cDNA Encoding Human CD9 Transmembrane Domain 
               
               
                 Isoform 3 
               
            
           
           
               
            
               
                 (SEQ ID NO: 55) 
               
            
           
           
               
            
               
                 ATGCTGGGACTGTTCTTCGGCTTCCTCTTGGTGATATTCGCCATTGA 
               
               
                   
               
               
                 AATAGCTGCGGCCATCTGGGGATAT 
               
               
                   
               
               
                 Human CD9 Transmembrane Domain Isoform 4 
               
            
           
           
               
            
               
                 (SEQ ID NO: 56) 
               
            
           
           
               
            
               
                 IGAVGIGIAVVMIFGMIFSMILCCAI 
               
               
                   
               
               
                 cDNA Encoding Human CD9 Transmembrane Domain 
               
               
                 Isoform 4 
               
            
           
           
               
            
               
                 (SEQ ID NO: 57) 
               
            
           
           
               
            
               
                 ATCGGCGCAGTGGGCATCGGCATTGCCGTGGTCATGATATTTGGCAT 
               
               
                   
               
               
                 GATCTTCAGTATGATCTTGTGCTGTGCTATC 
               
               
                   
               
               
                 Human CD16 Transmembrane Domain 
               
            
           
           
               
            
               
                 (SEQ ID NO: 58) 
               
            
           
           
               
            
               
                 VSFCLVMVLLFAVDTGLYFSV 
               
               
                   
               
               
                 Human CD22 Transmembrane Domain 
               
            
           
           
               
            
               
                 (SEQ ID NO: 59) 
               
            
           
           
               
            
               
                 VAVGLGSCLAILILAICGL 
               
               
                   
               
               
                 Human CD33 Transmembrane Domain 
               
            
           
           
               
            
               
                 (SEQ ID NO: 60) 
               
            
           
           
               
            
               
                 GAIGGAGVTALLALCLCLIFFIV 
               
               
                   
               
               
                 Human CD37 Transmembrane Domain Isoform 1 
               
            
           
           
               
            
               
                 (SEQ ID NO: 61) 
               
            
           
           
               
            
               
                 VLAISGIFTMGIALL 
               
               
                   
               
               
                 cDNA Encoding Human CD37 Transmembrane Domain 
               
               
                 Isoform 1 
               
            
           
           
               
            
               
                 (SEQ ID NO: 62) 
               
            
           
           
               
            
               
                 GTCCTGGCCATCTCAGGAATCTTCACCATGGGCATCGCCCTCCTG 
               
               
                   
               
               
                 Human CD37 Transmembrane Domain Isoform 2 
               
            
           
           
               
            
               
                 (SEQ ID NO: 63) 
               
            
           
           
               
            
               
                 LLGLYFGMLLLLFATQITLGILISTQ 
               
               
                   
               
               
                 cDNA Encoding Human CD37 Transmembrane Domain 
               
               
                 Isoform 2 
               
            
           
           
               
            
               
                 (SEQ ID NO: 64) 
               
            
           
           
               
            
               
                 CTCCTGGGCCTGTATTTTGGGATGCTGCTGCTCCTGTTTGCCACA 
               
               
                   
               
               
                 CAGATCACCCTGGGAATCCTCATCTCCACTCAG 
               
               
                   
               
               
                 Human CD37 Transmembrane Domain Isoform 3 
               
            
           
           
               
            
               
                 (SEQ ID NO: 65) 
               
            
           
           
               
            
               
                 LISIVGICLGVGLLELGFMTLSIFL 
               
               
                   
               
               
                 cDNA Encoding Human CD37 Transmembrane Domain 
               
               
                 Isoform 3 
               
            
           
           
               
            
               
                 (SEQ ID NO: 66) 
               
            
           
           
               
            
               
                 CTTATTTCCATAGTGGGCATTTGCCTGGGCGTCGGCCTACTCGAG 
               
               
                   
               
               
                 CTCGGGTTCATGACGCTCTCGATATTCCTG 
               
               
                   
               
               
                 Human CD37 Transmembrane Domain Isoform 4 
               
            
           
           
               
            
               
                 (SEQ ID NO: 67) 
               
            
           
           
               
            
               
                 FNLFFFVLGSLIFCFGIWILI 
               
               
                   
               
               
                 cDNA Encoding Human CD37 Transmembrane Domain 
               
               
                 Isoform 4 
               
            
           
           
               
            
               
                 (SEQ ID NO: 68) 
               
            
           
           
               
            
               
                 TTCAACCTCTTCTTCTTCGTCCTCGGCAGCCTGATCTTCTGCTTCGG 
               
               
                   
               
               
                 CATCTGGATCCTCATT 
               
               
                   
               
               
                 Human CD64 Transmembrane Domain 
               
            
           
           
               
            
               
                 (SEQ ID NO: 69) 
               
            
           
           
               
            
               
                 VLFYLAVGIMFLVNTVLWVTI 
               
               
                   
               
               
                 cDNA Encoding Human CD64 Transmembrane Domain 
               
            
           
           
               
            
               
                 (SEQ ID NO: 70) 
               
            
           
           
               
            
               
                 GTCCTTTTCTATCTGGCAGTGGGAATAATGTTTTTAGTGAACACTGT 
               
               
                   
               
               
                 TCTCTGGGTGACAATA 
               
               
                   
               
               
                 Human CD80 Transmembrane Domain 
               
            
           
           
               
            
               
                 (SEQ ID NO: 71) 
               
            
           
           
               
            
               
                 LLPSWAITLISVNGIFVICCL 
               
               
                   
               
               
                 cDNA Encoding Human CD80 Transmembrane Domain 
               
            
           
           
               
            
               
                 (SEQ ID NO: 72) 
               
            
           
           
               
            
               
                 CTGCTCCCATCCTGGGCCATTACCTTAATCTCAGTAAATGGAATTT 
               
               
                   
               
               
                 TTGTGATATGCTGCCTG 
               
               
                   
               
               
                 Human CD86 Transmembrane Domain 
               
            
           
           
               
            
               
                 (SEQ ID NO: 73) 
               
            
           
           
               
            
               
                 WITAVLPTVIICVMVFCLILW 
               
               
                   
               
               
                 Human CD134 Transmembrane Domain 
               
            
           
           
               
            
               
                 (SEQ ID NO: 74) 
               
            
           
           
               
            
               
                 VAAILGLGLVLGLLGPLAILL 
               
               
                   
               
               
                 cDNA Encoding Human CD134 Transmembrane Domain 
               
            
           
           
               
            
               
                 (SEQ ID NO: 75) 
               
            
           
           
               
            
               
                 GTTGCCGCCATCCTGGGCCTGGGCCTGGTGCTGGGGCTGCTGGGCC 
               
               
                   
               
               
                 CCCTGGCCATCCTGCTG 
               
               
                   
               
               
                 Human 4-1BB Transmembrane Domain 
               
            
           
           
               
            
               
                 (SEQ ID NO: 76) 
               
            
           
           
               
            
               
                 IISFFLALTSTALLFLLFFLTLRFSVV 
               
               
                   
               
               
                 cDNA Encoding Human 4-1BB Transmembrane Domain 
               
            
           
           
               
            
               
                 (SEQ ID NO: 77) 
               
            
           
           
               
            
               
                 ATCATCTCCTTCTTTCTTGCGCTGACGTCGACTGCGTTGCTCTTCCTG 
               
               
                   
               
               
                 CTGTTCTTCCTCACGCTCCGTTTCTCTGTTGTT 
               
               
                   
               
               
                 Human CD154 Transmembrane Domain 
               
            
           
           
               
            
               
                 (SEQ ID NO: 78) 
               
            
           
           
               
            
               
                 ifmylltvflitqmigsalfavyl 
               
               
                   
               
               
                 cDNA Encoding Human CD154 Transmembrane Domain 
               
            
           
           
               
            
               
                 (SEQ ID NO: 79) 
               
            
           
           
               
            
               
                 atttttatgtatttacttactgtttttcttatcacccagatgattgggt 
               
               
                   
               
               
                 cagcactttttgctgtgtatctt 
               
            
           
         
       
     
     In some embodiments of any of the CARs described herein, the transmembrane domain is or comprises the transmembrane domain of CD28 or the transmembrane domain of CD8a. In some embodiments of any of the CARs described herein, the transmembrane domain can include the transmembrane domain of any protein that has a transmembrane domain. 
     Hinge Sequences 
     In some embodiments, the linker between the first antigen-binding domain and the second antigen-binding domain can be 1 amino acid to about 250 amino acids (or any of the subranges of this range described herein). For example, a hinge sequence can include a portion of a transmembrane protein that is extracellular, but proximal to a transmembrane domain, and which does not specifically bind to a ligand or soluble protein. Non-limiting examples of a hinge sequence include an extracellular portion of human CD8a, an extracellular portion of human IgG4, or an extracellular portion of CD28. 
     In some embodiments, the hinge sequence is or includes the hinge of human CD28. An exemplary sequence of the hinge of CD28 is IEVMYPPPYLDNEKSNGTII HVKGKHLCPS PLFPGPSKP (SEQ ID NO: 80) or a fragment thereof (e.g., shortened by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids from its N-terminus and/or shortened by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids from its C-terminus). In some embodiments, the hinge sequence can be at least 80% (e.g., at least 82%, at least 84%, at least 86%, at least 88%, at least 90%, at least 92%, at least 94%, at least 96%, at least 98%, or at least 99%) identical to the sequence of the hinge of human CD28. In some embodiments, the hinge sequence is or include the hinge of human CD8a. An exemplary sequence of the hinge of human CD8a is: TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACD (SEQ ID NO: 81) or a fragment thereof (e.g., shortened by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids from its N-terminus and/or shortened by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids from its C-terminus). In some embodiments, the hinge sequence can be at least 80% (e.g., at least 82%, at least 84%, at least 86%, at least 88%, at least 90%, at least 92%, at least 94%, at least 96%, at least 98%, or at least 99%) identical to the sequence of the hinge of human CD8a. 
     In some embodiments, the hinge of human CD8a is encoded by the sequence of: 
     
       
         
           
               
            
               
                 (SEQ ID NO: 82) 
               
            
           
           
               
            
               
                 ACCACGACGCCAGCGCCGCGACCACCAACACCGGCGCCCACCATCGC 
               
               
                   
               
               
                 GTCGCAGCCCCTGTCCCTGCGCCCAGAGGCGTGCCGGCCAGCGGCGGG 
               
               
                   
               
               
                 GGGCGCAGTGCACACGAGGGGGCTG GACTTCGCCTGTGAT. 
               
            
           
         
       
     
     In some embodiments, the hinge sequence is or include the hinge of human IgG4. An exemplary sequence of the hinge of human IgG4 is: ESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQED PEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKE YKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLV KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE GNVFSCSVMHEALHNHYTQKSLSLSLGKM (SEQ ID NO: 83), or a fragment thereof (e.g., shortened by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 amino acids from its N-terminus and/or shortened by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 from its C-terminus). In some embodiments, the hinge sequence can be at least 80% (e.g., at least 82%, at least 84%, at least 86%, at least 88%, at least 90%, at least 92%, at least 94%, at least 96%, at least 98%, or at least 99%) identical to the sequence of the hinge of human IgG4. 
     In some embodiments, the hinge of human IgG4 is encoded by the sequence of: 
     
       
         
           
               
            
               
                 (SEQ ID NO: 84) 
               
            
           
           
               
            
               
                 GAGAGCAAGTACGGCCCTCCCTGCCCCCCTTGCCCTGCCCCCGAGTTCCT 
               
               
                   
               
               
                 GGGCGGACCCAGCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGA 
               
               
                   
               
               
                 TGATCAGCCGGACCCCCGAGGTGACCTGTGTGGTGGTGGACGTGTCCCAG 
               
               
                   
               
               
                 GAGGACCCCGAGGTCCAGTTCAACTGGTACGTGGACGGCGTGGAGGTGC 
               
               
                   
               
               
                 ACAACGCCAAGACCAAGCCCCGGGAGGAGCAGTTCAATAGCACCTACCG 
               
               
                   
               
               
                 GGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAG 
               
               
                   
               
               
                 GAATACAAGTGTAAGGTGTCCAACAAGGGCCTGCCCAGCAGCATCGAGAA 
               
               
                   
               
               
                 AACCATCAGCAAGGCCAAGGGCCAGCCTCGGGAGCCCCAGGTGTACAC 
               
               
                   
               
               
                 CCTGCCCCCTAGCCAAGAGGAGATGACCAAGAACCAGGTGTCCCTGACC 
               
               
                   
               
               
                 TGCCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGA 
               
               
                   
               
               
                 GCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCTGTGCTGGA 
               
               
                   
               
               
                 CAGCGACGGCAGCTTCTTCCTGTACAGCCGGCTGACCGTGGACAAGAGCC 
               
               
                   
               
               
                 GGTGGCAGGAGGGCAACGTCTTTAGCTGCTCCGTGATGCACGAGGCCCTG 
               
               
                   
               
               
                 CACAACCACTACACCCAGAAGAG CCTGAGCCTGTCCCTGGGCAAGATG 
               
            
           
         
       
     
     Intracellular Signaling Domains 
     In some embodiments, the intracellular signaling domain includes 20 amino acids to about 250 amino acids (or any subrange of this range described herein). In some embodiments of any of the CARs described herein, the intracellular signaling domain is the intracellular signaling domain of human 4-1BB, human CD28, human CD3zeta, human CD5, human CD22, human CD79, human DAP-10, or human DAP-12. 
     In some embodiments, the intracellular signaling sequence is or includes the intracellular signaling sequence of human CD3 zeta. An exemplary sequence of the human CD3 zeta intracellular signaling sequence is: RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGK PRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTA TKDTYDALHMQALPPR (SEQ ID NO: 85) or a fragment thereof (e.g., shortened by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 amino acids from its N-terminus and/or shortened by 11, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 amino acids from its C-terminus). In some embodiments, the intracellular signaling sequence can be at least 80% (e.g., at least 82%, at least 84%, at least 86%, at least 88%, at least 90%, at least 92%, at least 94%, at least 96%, at least 98%, or at least 99%) identical to the sequence of the intracellular signaling sequence of human CD3 zeta. In some embodiments, the intracellular signaling sequence is at least 50 contiguous amino acids, at least 55 contiguous amino acids, at least 60 contiguous amino acids, at least 65 contiguous amino acids, at least 70 contiguous amino acids, at least 75 contiguous amino acids, at least 80 contiguous amino acids, at least 85 contiguous amino acids, at least 90 contiguous amino acids, at least 95 contiguous amino acids, or at least 100 contiguous amino acids of the intracellular signaling sequence of human CD3 zeta. 
     In some embodiments, the intracellular signaling sequence is or includes the intracellular signaling sequence of human 4-1BB. An exemplary sequence of the human 4-1BB intracellular signaling sequence is: KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL (SEQ ID NO: 86) or a fragment thereof (e.g., shortened by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids from its N-terminus and/or shortened by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids from its C-terminus). In some embodiments, the intracellular signaling sequence can be at least 80% (e.g., at least 82%, at least 84%, at least 86%, at least 88%, at least 90%, at least 92%, at least 94%, at least 96%, at least 98%, or at least 99%) identical to the sequence of the intracellular signaling sequence of human 4-1BB. In some embodiments, the intracellular signaling sequence is at least 10 contiguous amino acids, at least 15 contiguous amino acids, at least 20 contiguous amino acids, at least 25 contiguous amino acids, at least 35 contiguous amino acids, or at least 40 contiguous amino acids of the intracellular signaling sequence of human 4-1BB. In some embodiments, a human 4-1BB intracellular signaling sequence is encoded by: 
     
       
         
           
               
            
               
                 (SEQ ID NO: 87) 
               
            
           
           
               
            
               
                 AAACGGGGCAGAAAGAAACTCCTGTATATATTCAAACAACCATTTATG 
               
               
                   
               
               
                 AGACCAGTACAAACTACTCAAGAGGAAGATGGCTGTAGCTGCCGATTT 
               
               
                   
               
               
                 CCAGAAGAAGAAGAAGGAGGATGT GAACTG. 
               
            
           
         
       
     
     In some embodiments, the intracellular signaling sequence is or includes the intracellular signaling sequence of human CD28. An exemplary sequence of the human CD28 intracellular signaling sequence is: RSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS (SEQ ID NO: 88) or a fragment thereof (e.g., shortened by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids from its N-terminus and/or shortened by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids from its C-terminus). In some embodiments, the intracellular signaling sequence can be at least 80% (e.g., at least 82%, at least 84%, at least 86%, at least 88%, at least 90%, at least 92%, at least 94%, at least 96%, at least 98%, or at least 99%) identical to the sequence of the intracellular signaling sequence of human CD28. In some embodiments, the intracellular signaling sequence is at least 10 contiguous amino acids, at least 15 contiguous amino acids, at least 20 contiguous amino acids, at least 25 contiguous amino acids, or at least 35 contiguous amino acids of the intracellular signaling sequence of human CD28. 
     In some embodiments, the intracellular signaling sequence is or includes the intracellular signaling sequence of human CD5. An exemplary sequence of the human CD5 intracellular signaling sequence is: KKLVKKFRQKKQRQWIGPTGMNQNMSFHRNHTATVRSHAENPTASHVD NEYSQPPRNSHLSAYPALEGALHRSSMQPDNSSDSDYDLHGAQRL (SEQ ID NO: 89) or a fragment thereof (e.g., shortened by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 amino acids from its N-terminus and/or shortened by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 amino acids from its C-terminus). In some embodiments, the intracellular signaling sequence can be at least 80% (e.g., at least 82%, at least 84%, at least 86%, at least 88%, at least 90%, at least 92%, at least 94%, at least 96%, at least 98%, or at least 99%) identical to the sequence of the intracellular signaling sequence of human CD5. In some embodiments, the intracellular signaling sequence is at least 10 contiguous amino acids, at least 15 contiguous amino acids, at least 20 contiguous amino acids, at least 25 contiguous amino acids, or at least 35 contiguous amino acids, at least 40 contiguous amino acids, at least 45 contiguous amino acids, at least 50 contiguous amino acids, at least 55 contiguous amino acids, at least 60 contiguous amino acids, at least 65 contiguous amino acids, at least 70 contiguous amino acids, at least 75 contiguous amino acids, at least 80 contiguous amino acids, at least 85 contiguous amino acids, or at least 90 contiguous amino acids of the intracellular signaling sequence of human CD28. 
     In some embodiments, the intracellular signaling sequence is or includes the intracellular signaling sequence of human CD22. An exemplary sequence of the human CD22 intracellular signaling sequence is: KLQRRWKRTQSQQGLQENSSGQSFFVRNKKVRRAPLSEGPHSLGCYNPM MEDGISYTTLRFPEMNIPRTGDAESSEMQRPPPDCDDTVTYSALHKRQVG DYENVIPDFPEDEGIHYSELIQFGVGERPQAQENVDYVILKH (SEQ ID NO: 90) or a fragment thereof (e.g., shortened by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 amino acids from its N-terminus and/or shortened by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 amino acids from its C-terminus). In some embodiments, the intracellular signaling sequence can be at least 80% (e.g., at least 82%, at least 84%, at least 86%, at least 88%, at least 90%, at least 92%, at least 94%, at least 96%, at least 98%, or at least 99%) identical to the sequence of the intracellular signaling sequence of human CD22. In some embodiments, the intracellular signaling sequence is at least 10 contiguous amino acids, at least 15 contiguous amino acids, at least 20 contiguous amino acids, at least 25 contiguous amino acids, or at least 35 contiguous amino acids, at least 40 contiguous amino acids, at least 45 contiguous amino acids, at least 50 contiguous amino acids, at least 55 contiguous amino acids, at least 60 contiguous amino acids, at least 65 contiguous amino acids, at least 70 contiguous amino acids, at least 75 contiguous amino acids, at least 80 contiguous amino acids, at least 85 contiguous amino acids, at least 90 contiguous amino acids, at least 95 contiguous amino acids, at least 100 contiguous amino acids, at least 105 contiguous amino acids, at least 110 contiguous amino acids, at least 115 contiguous amino acids, at least 120 contiguous amino acids, at least 125 contiguous amino acids, at least 130 contiguous amino acids, or at least 135 contiguous amino acids of the intracellular signaling sequence of human CD22. 
     In some embodiments, the intracellular signaling sequence is or includes the intracellular signaling sequence of human CD79. An exemplary sequence of the human CD79 intracellular signaling sequence is: RKRWQNEKLGLDAGDEYEDENLYEGLNLDDCSMYEDISRGLQGTYQDV GSLNIGDVQLEKP (SEQ ID NO: 91) or a fragment thereof (e.g., shortened by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acids from its N-terminus and/or shortened by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acids from its C-terminus). In some embodiments, the intracellular signaling sequence can be at least 80% (e.g., at least 82%, at least 84%, at least 86%, at least 88%, at least 90%, at least 92%, at least 94%, at least 96%, at least 98%, or at least 99%) identical to the sequence of the intracellular signaling sequence of human CD79. In some embodiments, the intracellular signaling sequence is at least 10 contiguous amino acids, at least 15 contiguous amino acids, at least 20 contiguous amino acids, at least 25 contiguous amino acids, or at least 35 contiguous amino acids, at least 40 contiguous amino acids, at least 45 contiguous amino acids, at least 50 contiguous amino acids, or at least 55 contiguous amino acids of the intracellular signaling sequence of human CD79. Additional aspects and examples of intracellular signaling sequences are known in the art. 
     Co-Stimulatory Domains In some embodiments, a co-stimulatory domain can include a sequence of 20 amino acids to 250 amino acids (or any subranges of this range described herein). 
     In some embodiments of any of the CARs described herein, the co-stimulatory domain is the co-stimulatory domain of 4-1BB, CD28, CD2, CD4, CD27, CD8, or CD137. 
     In some embodiments, the costimulatory domain is or includes the costimulatory domain of human 4-1BB. An exemplary sequence of the human 4-1BB costimulatory domain is: KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL (SEQ ID NO: 92) or a fragment thereof (e.g., shortened by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids from its N-terminus and/or shortened by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids from its C-terminus). In some embodiments, the costimulatory domain can be at least 80% (e.g., at least 82%, at least 84%, at least 86%, at least 88%, at least 90%, at least 92%, at least 94%, at least 96%, at least 98%, or at least 99%) identical to the sequence of the co-stimulatory domain of human 4-1BB. In some embodiments, the co-stimulatory domain is at least 10 contiguous amino acids, at least 15 contiguous amino acids, at least 20 contiguous amino acids, at least 25 contiguous amino acids, at least 30 contiguous amino acids, or at least 35 contiguous amino acids of the co-stimulatory domain of human 4-1BB. 
     In some embodiments, the costimulatory domain is or includes the costimulatory domain of human CD28. An exemplary sequence of the human 4-1BB costimulatory domain is: RSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS (SEQ ID NO: 93) or a fragment thereof (e.g., shortened by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids from its N-terminus and/or shortened by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids from its C-terminus). In some embodiments, the costimulatory domain can be at least 80% (e.g., at least 82%, at least 84%, at least 86%, at least 88%, at least 90%, at least 92%, at least 94%, at least 96%, at least 98%, or at least 99%) identical to the sequence of the co-stimulatory domain of human CD28. In some embodiments, the co-stimulatory domain is at least 10 contiguous amino acids, at least 15 contiguous amino acids, at least 20 contiguous amino acids, at least 25 contiguous amino acids, at least 30 contiguous amino acids, or at least 35 contiguous amino acids of the co-stimulatory domain of human CD28. 
     In some embodiments, the costimulatory domain is or includes the costimulatory domain of human CD4. An exemplary sequence of the human CD4 costimulatory domain is: CVRCRHRRRQAERMSQIKRLLSEKKTCQCPHRFQKTCSPI (SEQ ID NO: 94) or a fragment thereof (e.g., shortened by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids from its N-terminus and/or shortened by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids from its C-terminus). In some embodiments, the costimulatory domain can be at least 80% (e.g., at least 82%, at least 84%, at least 86%, at least 88%, at least 90%, at least 92%, at least 94%, at least 96%, at least 98%, or at least 99%) identical to the sequence of the co-stimulatory domain of human CD4. In some embodiments, the co-stimulatory domain is at least 10 contiguous amino acids, at least 15 contiguous amino acids, at least 20 contiguous amino acids, at least 25 contiguous amino acids, at least 30 contiguous amino acids, or at least 35 contiguous amino acids of the co-stimulatory domain of human CD4. 
     In some embodiments, the costimulatory domain is or includes the costimulatory domain of human CD27. An exemplary sequence of the human CD27 costimulatory domain is: QRRKYRSNKGESPVEPAEPCHYSCPREEEGSTIPIQEDYRKPEPACSP (SEQ ID NO: 95) or a fragment thereof (e.g., shortened by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 amino acids from its N-terminus and/or shortened by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 amino acids from its C-terminus). In some embodiments, the costimulatory domain can be at least 80% (e.g., at least 82%, at least 84%, at least 86%, at least 88%, at least 90%, at least 92%, at least 94%, at least 96%, at least 98%, or at least 99%) identical to the sequence of the co-stimulatory domain of human CD27. In some embodiments, the co-stimulatory domain is at least 10 contiguous amino acids, at least 15 contiguous amino acids, at least 20 contiguous amino acids, at least 25 contiguous amino acids, at least 30 contiguous amino acids, at least 35 contiguous amino acids, or at least 40 contiguous amino acids of the co-stimulatory domain of human CD27. 
     In some embodiments, the costimulatory domain is or includes the costimulatory domain of human CD8. An exemplary sequence of the human CD8 costimulatory domain is: LYCNHRNRRRVCKCPRPVVKSGDKPSLSARYV (SEQ ID NO: 96) or a fragment thereof (e.g., shortened by 1, 2, 3, 4, or 5 amino acids from its N-terminus and/or shortened by 1, 2, 3, 4, or 5 amino acids from its C-terminus). In some embodiments, the costimulatory domain can be at least 80% (e.g., at least 82%, at least 84%, at least 86%, at least 88%, at least 90%, at least 92%, at least 94%, at least 96%, at least 98%, or at least 99%) identical to the sequence of the co-stimulatory domain of human CD8. In some embodiments, the co-stimulatory domain is at least 10 contiguous amino acids, at least 15 contiguous amino acids, at least 20 contiguous amino acids, at least 25 contiguous amino acids, or at least 30 contiguous amino acids of the co-stimulatory domain of human CD8. 
     In some embodiments, the costimulatory domain is or includes the costimulatory domain of human CD2. An exemplary sequence of the human CD2 costimulatory domain is: KRKKQRSRRNDEELETRAHRVATEERGRKPHQIPASTPQNPATSQHPPPPP GHRSQAPSHRPPPPGHRVQHQPQKRPPAPSGTQVHQQKGPPLPRPRVQPK PPHGAAENSLSPSSN (SEQ ID NO: 97) or a fragment thereof (e.g., shortened by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, or 55 amino acids from its N-terminus and/or shortened by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, or 55 amino acids from its C-terminus). In some embodiments, the costimulatory domain can be at least 80% (e.g., at least 82%, at least 84%, at least 86%, at least 88%, at least 90%, at least 92%, at least 94%, at least 96%, at least 98%, or at least 99%) identical to the sequence of the co-stimulatory domain of human CD2. In some embodiments, the co-stimulatory domain is at least 10 contiguous amino acids, at least 15 contiguous amino acids, at least 20 contiguous amino acids, at least 25 contiguous amino acids, at least 30 contiguous amino acids, at least 35 contiguous amino acids, at least 40 contiguous amino acids, at least 45 contiguous amino acids, at least 50 contiguous amino acids, at least 55 contiguous amino acids, at least 60 contiguous amino acids, at least 65 contiguous amino acids, at least 70 contiguous amino acids, at least 75 contiguous amino acids, at least 80 contiguous amino acids, at least 85 contiguous amino acids, at least 90 contiguous amino acids, at least 95 contiguous amino acids, at least 100 contiguous amino acids, at least 105 contiguous amino acids, or at least 110 contiguous amino acids of the co-stimulatory domain of human CD2. 
     In some embodiments, the costimulatory domain is or includes the costimulatory domain of human CD137. An exemplary sequence of the human CD137 costimulatory domain is: KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL (SEQ ID NO: 98) or a fragment thereof (e.g., shortened by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids from its N-terminus and/or shortened by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids from its C-terminus). In some embodiments, the costimulatory domain can be at least 80% (e.g., at least 82%, at least 84%, at least 86%, at least 88%, at least 90%, at least 92%, at least 94%, at least 96%, at least 98%, or at least 99%) identical to the sequence of the co-stimulatory domain of human CD137. In some embodiments, the co-stimulatory domain is at least 10 contiguous amino acids, at least 15 contiguous amino acids, at least 20 contiguous amino acids, at least 25 contiguous amino acids, at least 30 contiguous amino acids, or at least 35 contiguous amino acids of the co-stimulatory domain of human CD137. An exemplary CD137 co-stimulatory domain is encoded by the nucleic acid sequence of: 
     
       
         
           
               
            
               
                 (SEQ ID NO: 99) 
               
            
           
           
               
            
               
                 AAACGGGGCAGAAAGAAACTCCTGTATATATTCAAACAACCATTTATG 
               
               
                   
               
               
                 AGACCAGTACAAACTACTCAAGAGGAAGATGGCTGTAGCTGCCGATTT 
               
               
                   
               
               
                 CCAG AAGAAGAAGAAGGAGGATGTGAACTG. 
               
            
           
         
       
     
     Additional aspects and examples of costimulatory domains are known in the art. 
     Method of Generating a Chimeric Antigen Receptor (CAR)-Expressing Cell 
     Also provided herein are methods of generating a chimeric antigen receptor (CAR)-expressing cell that include introducing into a cell (e.g., any of the cells described herein) any of the nucleic acids encoding any of the CARs described herein or any of the vectors described herein. In some examples, the cell can be a eukaryotic cell. In some examples, the eukaryotic cell can be mammalian cell (e.g., a human cell). In some embodiments of any of the methods described herein, the mammalian cell can be, e.g., a T-cell (CD4+ T-cell, a CD8+ T-cell, a TH1 cell, a TH2 cell, or a Treg cell), a B-cell (e.g., a memory B cell), a NK cell, a neutrophil, a macrophage, or a monocyte. In some embodiments of any of the methods described herein, the mammalian cell is chronic myelogenous leukemia (CML) K-562 cell (ATCCR CCL-243™). 
     Non-limiting methods for introducing a nucleic acid or vector described herein into a cell are described herein. Additional methods for introducing a nucleic acid or vector into a cell are known in the art. 
     In some embodiments of any of the methods described herein, the mammalian cell can be a cell obtained from a subject (e.g., a human subject). In some examples, the subject (e.g., a human) has been diagnosed or identified as having a cancer (e.g., a cancer characterized by cancer cells that express one or both of BCMA and CD307e). Some embodiments of any of the methods described herein can further include, before the introducing step, obtaining a cell from a subject (e.g., any of the subjects described herein). 
     Some embodiments of any of these methods can further include, after the introducing step, a step of culturing the cell in a liquid culture medium (e.g., under conditions that allow the cells to proliferate). Liquid culture media that can be used in the culturing of these cells are known in the art. 
     Eukaryotic Cells 
     The methods and compositions described herein can involve the use of, or comprise, eukaryotic cells. Non-limiting examples of eukaryotic cells include mammalian cells (e.g., mouse cells, rat cells, hamster cells, rabbit cells, canine cells, feline cells, monkey cells, or human cells). In some embodiments of any of the methods described herein, the mammalian cell can be, e.g., a T-cell (CD4+ T-cell, a CD8+ T-cell, a TH1 cell, a TH2 cell, or a Treg cell), a B-cell (e.g., a memory B cell), a NK cell, a neutrophil, a macrophage, or a monocyte. 
     In some examples of any of the cells described herein, the cell can be obtained from a subject (e.g., and optionally, later administered back to the same subject after introduction of a nucleic acid encoding any of the CARs described herein, or any of the vectors described herein). In such embodiments, the subject can be a subject diagnosed or identified as having a cancer (e.g., a cancer characterized by cancer cells that express one or both of BCMA and CD307e). 
     Methods of culturing mammalian cells are well known in the art. Mammalian cells can be maintained in vitro under conditions that allow for proliferation, differentiation, and/or growth. Briefly, mammalian cells can be cultured by contacting a cell (e.g., any cell) with a cell culture medium that includes the necessary growth factors and supplements to support cell viability and growth. 
     Methods of introducing nucleic acids and vectors into a cell (e.g., a eukaryotic cell) are known in the art. Non-limiting examples of methods that can be used to introduce a nucleic acid or vector into a cell include lipofection, transfection, electroporation, microinjection, calcium phosphate transfection, dendrimer-based transfection, cationic polymer transfection, cell squeezing, sonoporation, optical transfection, impalection, hydrodynamic delivery, magnetofection, viral transduction (e.g., adenoviral and lentiviral transduction), and nanoparticle transfection. 
     Methods of Treatment 
     Also provided herein are methods of treating a cancer in a subject that include: administering a therapeutically effective amount of any of the cells described herein (e.g., any cells expressing any of the CARs described herein). In some embodiments of any of the methods described herein, the cancer is characterized by cancer cells that express one or both of BCMA and CD307e. In some embodiments of any of the methods described herein, the cancer is a carcinoma, a sarcoma (e.g., Ewing sarcoma, Kaposi sarcoma, osteosarcoma, and soft tissue sarcoma), a myeloma (e.g., multiple myeloma), a leukemia (e.g., a B-cell leukemia, e.g., chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia, B-cell prolymphocytic leukemia, precursor B lymphoblastic leukemia, and hairy cell leukemia, acute myeloid leukemia (AML), chronic myelogenous leukemia (CML)), or a lymphoma (e.g., a B-cell lymphoma, e.g., small lymphocytic lymphoma, Burkitt lymphoma, cutaneous T-cell lymphoma, Hodgkin&#39;s lymphoma, non-Hodgkin&#39;s lymphoma, primary central nervous system lymphoma, or T-cell lymphoma). In some embodiments, the cancer is a carcinoma, a sarcoma, a myeloma, a leukemia, or a lymphoma that is characterized by cancer cells that express one or both of BCMA and CD307e. Methods for detecting cancer cell expression of BCMA and CD307e can be performed using methods known in the art (e.g., staining, sorting, or imaging cancer cells from the subject with a labeled antibody that binds to BCMA and a labeled antibody that binds specifically to CD307e). 
     In some embodiments of any of the methods described herein, the subject has been diagnosed or identified as having the cancer. Some embodiments of the methods described herein further include diagnosing or identifying the subject as having the cancer. Some embodiments of the methods described herein can further include selecting a subject having a cancer for treatment using any of the methods described herein. 
     In some embodiments of any of the methods described herein, the method further includes, prior to the administering step: obtaining an initial cell from the subject (e.g., any of the exemplary types of mammalian cells described herein); and introducing a nucleic acid (e.g., any of the nucleic acids encoding any of the CARs described herein) or a vector (e.g., any of the vectors described herein) into the initial cell, to yield the cell that is administered to the subject. In some embodiments of any of the methods described herein, the method further includes between the introducing step and the administering step, a step of culturing the cell that is administered to the subject in a liquid culture medium (e.g., under conditions that allow for proliferation). 
     Also provided herein are methods of treating multiple myeloma in a subject that include: administering to a subject a therapeutically effective amount of any of the cells described herein (e.g., any of the cells expressing any of the CARs described herein) to the subject. In some embodiments of any of the methods described herein, the subject has been diagnosed or identified as having multiple myeloma. In some embodiments, the subject has been identified as having multiple myeloma characterized by cancer cells that express one or both of BCMA and CD307e. 
     Some embodiments of the methods described herein further include diagnosing or identifying the subject as having multiple myeloma. Some embodiments of the methods described herein can further include selecting a subject having multiple myeloma for treatment using any of the methods described herein. 
     In some embodiments of any of the methods described herein, the method further includes, prior to the administering step: obtaining an initial cell from the subject having multiple myeloma (e.g., any of the exemplary types of mammalian cells described herein); and introducing a nucleic acid (e.g., any of the nucleic acids encoding any of the CARs described herein) or a vector (e.g., any of the vectors described herein) into the initial cell, to yield the cell that is administered to the subject. In some embodiments of any of the methods described herein, the method further includes between the introducing step and the administering step, a step of culturing the cell that is administered to the subject in a liquid culture medium (e.g., under conditions that allow for proliferation). In any of the methods described herein, the initial cell, as described herein, is not a cancer cell. In some embodiments of any of the methods described herein, the subject is human. The term “subject” refers to any mammal, e.g., a dog, feline (e.g., a cat), equine (e.g., a horse), ovine, bovine, porcine, caprine, primate, e.g., a simian (e.g., a monkey (e.g., marmoset, baboon), or an ape (e.g., a gorilla, chimpanzee, orangutan, or gibbon) or a human; or rodent (e.g., a mouse, a guinea pig, a hamster, or a rat). In some embodiments, the subject may be a non-human mammal, especially mammals that are conventionally used as models for demonstrating therapeutic efficacy in humans (e.g., murine, lapine, porcine, canine or primate animals) may be employed. For example, the non-human mammal may be an animal cancer model (e.g., an animal cancer model of any of the specific types of cancer described herein). 
     In some embodiments of any of the methods described herein, the cancer is a solid cancer. In some embodiments of any of the methods described herein, the cancer is a non-metastatic cancer. In some embodiments of any of the methods described herein, the cancer is a metastatic cancer. 
     Some embodiments of any of the methods described herein further include administering to the subject one or more additional anti-cancer therapies. In some embodiments of any of the methods described herein, the one or more additional anti-cancer therapies is selected from the group consisting of chemotherapy, immunotherapy, surgical resection, and radiation therapy. 
     In some embodiments of any of the methods described herein, the subject has previously been administered another anti-cancer therapy, and the anti-cancer therapy was unsuccessful. 
     Compositions and Kits 
     Also provided herein are compositions (e.g., pharmaceutical compositions) that include at least one of any of the cells described herein (e.g., any of the cells described herein that express a CAR described herein) and a pharmaceutically acceptable carrier. Examples of pharmaceutically acceptable carriers are known in the art and include, e.g., phosphate buffered saline, saline, and Ringer&#39;s solution. Also provided herein are compositions that include at least one of any of the cells described herein (e.g., any of the cells described herein that express a CAR described herein) and a cell freezing medium or storage. Examples of cell-freezing medium are known in the art, and can include one or more of, e.g., dimethyl sulfoxide (DMSO), carboxymethylcellulose sodium, and glycerol. Non-limiting examples of storage media can include one or more of, e.g., a buffered isotonic solution, a buffered solution, a culture medium, and serum (e.g., human serum). In some embodiments of these compositions, the compositions described herein are frozen or thawed. In some embodiments of these compositions, the compositions are not frozen. 
     In some embodiments, the compositions are formulated for intravenous administration. The compositions can be provided in a dosage form that includes a sufficient quantity of the cells effective to treat a disease (e.g., cancer) in a subject. 
     Also provided are compositions that include any of the nucleic acids encoding any of the CARs described herein, or any of the vectors described herein and, optionally, a pharmaceutically acceptable carrier. 
     Also provided herein are kits that include any of the compositions (e.g., pharmaceutical compositions) described herein. In some embodiments, the kits can further include instructions for performing any of the methods described herein. In some embodiments, the kits can include at least one dose of any of the compositions described herein. In some embodiments, the kits can further include a cell culture medium useful for propagating the cells. In some embodiments, the kit can further include a sterile containing, wherein the cells are disposed in the sterile container. In some embodiments, the kit can include one or more agents useful for introducing a nucleic acid or a vector in a mammalian cell. 
     EXAMPLES 
     The invention is further described in the following examples, which do not limit the scope of the invention described in the claims. 
     Example 1. Exemplary CARs 
     Without wishing to be bound by theory, the present inventors generated various embodiments of bispecific chimeric antigen receptors (CARs) that can bind specifically to both BCMA and CD307e ( FIGS. 1-2  and Table 1). An example of a tandem CAR is provided in  FIG. 1 . In some embodiments, a bispecific CAR is a single polypeptide chain in which the first antigen-binding domain is a single-chain variable fragments (scFv) that binds to CD307 (10A8) and the second antigen-binding domain is a scFV that binds to BCMA (J6M0), the co-stimulatory binding domain is 4-1BB (CD137), and the intracellular signaling domain is CD3 zeta. In some embodiments of any of the CARs described herein, the first and second antigen-binding domains are linked by a GS connector ( FIG. 2 ). In some embodiments, the first antigen-binding domain includes a light chain variable domain (V L ) and a heavy chain variable domain (V H ) that are connected via a first scFv linker. In some embodiments, the second antigen-binding domain includes a light chain variable domain (VL) and a heavy chain variable domain (VH). In some embodiments, the VL and VH domain of the second antigen-binding domain are connected via a second scFv linker. In some embodiments, a variable domain (VH or VL) of the first or second antigen-binding domain is linked to a hinge sequence (e.g., a CD8a hinge sequence). 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Summary of Exemplary CARs 
               
            
           
           
               
               
            
               
                   
                 CAR 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 J6M0 
                 m10A8 
                 10A8 
                 1G7.v85 
                 1G7v.93 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Antigen 
                 BCMA 
                 CD307 
                 CD307 
                 CD307 
                 CD307 
               
               
                 V L  Domain 
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
               
               
                   
                 NO: 1 
                 NO: 9 
                 NO: 5 
                 NO: 13 
                 NO: 17 
               
            
           
           
               
               
            
               
                 Linker 
                 Whitlow Linker (SEQ ID NO: 12) 
               
            
           
           
               
               
               
               
               
               
            
               
                 V H  Domain 
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
               
               
                   
                 NO: 2 
                 NO: 10 
                 NO: 6 
                 NO: 14 
                 NO: 18 
               
            
           
           
               
               
            
               
                 Hinge 
                 CD8α (SEQ ID NO: 81) 
               
               
                 Transmembrane 
                 CD8α (SEQ ID NO: 48) 
               
               
                 Domain 
               
               
                 Co-stimulatory 
                 4-1BB (SEQ ID NO: 93) 
               
               
                 Domain 
               
               
                 Intracellular- 
                 CD3ζ (SEQ ID NO: 85) 
               
               
                 Signaling 
               
               
                 Domain 
               
               
                   
               
            
           
         
       
     
     Example 2. Tandem CARs 
     Multiple myeloma is an incurable plasma cell malignancy. While cell-based CAR therapies produce dramatic remissions, antigen negative escape variants have been detected in some multiple myeloma patients whom relapse. Without wishing to be bound by theory, the present inventors have discovered that targeting two disease-associated antigens may reduce the risk of antigen escape. BCMA and FCRL5 (CD307e) are lineage-specific markers that are highly expressed in multiple myeloma. Table 2 provides a summary of the generated Tandem CARs. 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Summary of Exemplary Tandem CARs 
               
            
           
           
               
               
            
               
                   
                 Tandem CAR 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                 J6M0/ 
                 J6M0/ 
               
               
                   
                 J6M0/m10A8 
                 J6M0/10A8 
                 10A8/J6M0 
                 1G7.v85 
                 1G7v.93 
               
               
                   
                 (TanCAR1) 
                 (TanCAR2) 
                 (TanCAR3) 
                 Tandem 
                 Tandem 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 First 
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
               
               
                 V L  Domain 
                 NO: 1 
                 NO: 1 
                 NO: 5 
                 NO: 1 
                 NO: 1 
               
            
           
           
               
               
            
               
                 Linker 
                 Whitlow Linker (SEQ ID NO: 12) 
               
            
           
           
               
               
               
               
               
               
            
               
                 First 
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
               
               
                 V H  Domain 
                 NO: 2 
                 NO: 2 
                 NO: 6 
                 NO: 2 
                 NO: 2 
               
            
           
           
               
               
            
               
                 Connector 
                 (G 4 S)5 connector (SEQ ID NO: 25) 
               
            
           
           
               
               
               
               
               
               
            
               
                 Second 
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
               
               
                 V L  Domain 
                 NO: 9 
                 NO: 5 
                 NO: 1 
                 NO: 13 
                 NO: 17 
               
            
           
           
               
               
            
               
                 Linker 
                 Whitlow Linker (SEQ ID NO: 12) 
               
            
           
           
               
               
               
               
               
               
            
               
                 Second 
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
               
               
                 V H  Domain 
                 NO: 10 
                 NO: 6 
                 NO: 2 
                 NO: 14 
                 NO: 18 
               
            
           
           
               
               
            
               
                 Hinge 
                 CD8α (SEQ ID NO: 81) 
               
               
                 Transmembrane 
                 CD8α (SEQ ID NO: 48) 
               
               
                 Domain 
               
               
                 Co-stimulatory 
                 4-1BB (SEQ ID NO: 93) 
               
               
                 Domain 
               
               
                 Intracellular- 
                 CD3ζ (SEQ ID NO: 85) 
               
               
                 Signaling 
               
               
                 Domain 
               
               
                   
               
            
           
         
       
     
     As shown in  FIGS. 3, 7A -B, and  16 , BCMA and CD307 are ubiquitously expressed by patient-derived multiple myeloma tumor cells.  FIGS. 6 and 8B  show that over 50% of cell lysis was seen in CD307 +  K562 cells following incubation with a murine 10A8 scFv CAR and a humanized 10A8 scFv CAR.  FIG. 9A  showed that high IFNγ levels were detected in CD307 +  K562 cells following incubation with human 10A8 scFv CAR, while IFNγ was undetected in antigen-negative K562 cells.  FIG. 9B  showed that high IL-2 levels were detected in CD307 +  K562 cells following incubation with human 10A8 scFv CAR and murine 10A8 scFv CAR, while IL-2 was undetected in antigen-negative K562 cells.  FIGS. 13A-D  showed cell lysis using 10A8 scFv/J6M0 scFv bispecific CARs expressing either CD307, BCMA, or both. Expression of conventional (mono-specific) CARs and bispecific CARs against BCMA and CD307 in primary T cells was assessed ( FIGS. 11 and 12 ). 
     Example 3. Optimization Studies 
     Without wishing to be bound by theory, optimization strategies were developed to allow for incorporation of multiple dual-targeting approaches.  FIGS. 17A, 17B , &amp;  18  showed that 1G7 recognized endogenous levels of CD307 and generated high levels of IFNγ, however, high background cytotoxicity was also detected (data not shown).  FIG. 14  showed expression of 1G7 tandem CARs in primary human T cells. Next, cell lysis was determined in K562 cells following incubation with 1G7 tandem CARs ( FIGS. 15A-D  and Table 2). To further test the sensitivity of 1 G7 tandem CARs, the effect of 1 G7 tandem CARs in cells expressing endogenous levels of CD307e was tested. As shown in  FIG. 16 , CD307e +  K562 cells express much higher levels of CD307e as compared to REC-1 cells, which express endogenous levels of CD307e. The 1G7 based tandem CAR was shown to be capable of killing the REC-1 cells ( FIG. 17  A-B) and produced cytokine in response to CD307 presented on this target cell line ( FIG. 18 ). In addition, the moderate background cytotoxicity observed from the conventional CAR was abrogated when the 1G7 scFv was included in the tandem CAR design ( FIG. 17A ). 
     The following materials and methods were used in the experiments described below. 
     OTHER EMBODIMENTS 
     It is to be understood that 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 claims.