Patent Publication Number: US-2023138045-A1

Title: Wnt super agonists

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application claims priority to U.S. Provisional Application No. 62/980,870, filed on Feb. 24, 2020 and U.S. Provisional Application No. 63/114,368, filed on Nov. 16, 2020, each of which is herein incorporated by reference in its entirety. 
    
    
     STATEMENT REGARDING SEQUENCE LISTING 
     The Sequence Listing associated with this application is provided in text format in lieu of a paper copy, and is hereby incorporated by reference into the specification. The name of the text file containing the Sequence Listing is SRZN_018_02WO_ST25.txt. The text file is 1,179 KB, created on Feb. 24, 2021, and is being submitted electronically vis EFS-Web. 
     FIELD OF THE INVENTION 
     The present invention provides antigen binding formats having both WNT agonist and WNT enhancer activities or WNT agonist or WNT enhancer activities alone. 
     BACKGROUND OF THE INVENTION 
     WNT (“Wingless-related integration site” or “Wingless and Int-1” or “Wingless-Int”) ligands and their signals play key roles in the control of development, homeostasis and regeneration of many essential organs and tissues, including bone, liver, skin, stomach, intestine, kidney, central nervous system, mammary gland, taste bud, ovary, cochlea and many other tissues (reviewed, e.g., by Clevers, Loh, and Nusse (2014)  Science;  346:54). Modulation of WNT signaling pathways has potential for treatment of degenerative diseases and tissue injuries. 
     The seven-pass transmembrane receptor Frizzled (FZD) is critical for nearly all WNT signaling, and the N-terminal FZD cysteine rich domain (CRD) serves as the WNT binding domain. In addition to FZD, the WNT/β-catenin pathway requires the Low-density lipoprotein receptor related proteins 5 and 6 (LRP5/6) to serve as co-receptors. LRP5 and LRP6 are functionally redundant single-pass transmembrane receptors. Biochemical studies of LRP6 indicate that different WNTs may bind to different extracellular domains of the LRP5/6 proteins. The LRP6 extracellular domain contains four repeating sequences of β-propeller and epidermal growth factor-like (βP-E) domains. The crystal structures of the extracellular LRP6 regions indicate that the βP-E repeats represent two discrete, compact, rigid structures, each containing two βP-E pairs. WNT9b binds the first two βP-E repeats on the extracellular domain of LRP6, whereas WNT3a binds the last two βP-E domains. 
     Non-WNT agonists or enhancers include Norrin and R-Spondin (RSPO), respectively. Norrin is a Fz4-specific ligand that, in conjunction with binding and activation of another WNT receptor, LRP5, forms a WNT surrogate or mimetic molecule. 
     The four RSPO genes represent a family of conserved secreted proteins that can enhance the WNT pathway signaling. LGR4/5/6 (leucine-rich repeat-containing GPCRs 4, 5, and 6) are receptors for RSPOs. 
     The role of RSPOs appears to be to stabilize the WNT receptors, FZD and LRP5/6, to promote or enhance WNT signaling. RSPO 1-4 are a family of ligands that amplify WNT signals. Each of the RSPOs work through a receptor complex that contains Zinc and Ring Finger 3 (ZNRF3) or Ring Finger Protein 43 (RNF43) on one end and a Leucine-rich repeat-containing G-protein coupled receptor 4-6 (LGR4-6) on the other (reviewed, e.g., by Knight and Hankenson 2014, Matrix Biology; 37: 157-161). RSPO might also work through additional mechanisms of action (Lebensohn and Rohatgi 2018, eLife, 7:e33126). ZNRF3 and RNF43 are two membrane-bound E3 ligases specifically targeting WNT receptors (FZD1-10 and LRP5 or LRP6) for degradation. Binding of an RSPO to ZNRF3/RNF43 and LGR4-6 causes clearance or sequestration of the ternary complex, which removes E3 ligases from WNT receptors and stabilizes WNT receptors, resulting in enhanced WNT signals. Each RSPO contains two Furin domains (1 and 2), with Furin domain 1 binding to ZNRF3/RNF43, and Furin domain 2 binding to LGR4-6. Fragments of RSPOs containing Furin domains 1 and 2 are sufficient for amplifying WNT signaling. 
     Antibodies are a well-established and rapidly growing drug class with at least 45 antibody-based products currently marketed for imaging or therapy in the United States and/or Europe with ˜$100 billion in total worldwide sales. This major clinical and commercial success with antibody therapeutics has fueled much interest in developing the next generation antibody drugs including bispecific antibodies. As their name implies, bispecific antibodies or multispecific antibodies (collectively “MsAbs”) bind to at least two different antigens, or at least two different epitopes on the same antigen, as first demonstrated more than 50 years ago. Engineering monospecific antibodies for multispecificity opens up many new potential therapeutic applications as evidenced by &gt;30 BsAb in clinical development. 
     Bispecific or multispecific antibodies are a class of engineered antibody and antibody-like proteins that, in contrast to ‘regular’ monospecific antibodies, combine two or more different specific antigen binding elements in a single construct. Since bispecific antibodies do not typically occur in nature, they are constructed either chemically or biologically, using techniques such as cell fusion or recombinant DNA technologies. The ability to bind two or more different epitopes with a single molecule offers a number of potential advantages. One approach is to use the specificity of one arm as a targeting site for individual molecules, cellular markers or organisms, such as bacteria and viruses, while the other arm functions as an effector site for the recruitment of effector cells or delivery of molecular payloads to the target, such as drugs, cytokines or toxins. Alternatively, bispecifics can be used to dual target, allowing detection or binding of a target cell type with much higher specificity than monospecific antibodies. 
     The modular architecture of immunoglobulins has been exploited to create a growing number (&gt;60) of alternative MsAb formats (see, e.g., Spiess et al. (2015) Mol. Immunol. 67:95-106). MsAb are classified here into five distinct structural groups: (i) bispecific IgG (BsIgG) (ii) IgG appended with an additional antigen-binding moiety (iii) MsAb fragments (iv) Multispecific fusion proteins and (v) MsAb conjugates. Each of these different MsAb formats brings different properties in binding valency for each antigen, geometry of antigen-binding sites, pharmacokinetic half-life, and in some cases effector functions. 
     For antagonistic MsAbs antibodies, which represent the vast majority of the MsAb molecules in development, the geometry of the antigen binding modules is less critical. However, for agonistic MsAbs, these molecules need to faithfully mimic the activity of the natural ligand, the binding geometry could be crucial (see, e.g., Shi, et al. (2018)  J. Biol. Chem.  293:5909-5919). Such is true of WNT surrogate molecules, which are required to bind and activate two spatially separated WNT receptors, FZD and LRP. 
     WNT surrogate molecules which can bind to the hetero-oligomeric WNT/LRP receptor complex have been described previously (see, e.g., WO2019/126398, US 2020-0308287 A1, U.S. Ser. No. 17/257,817 and WO2020/010308) as have WNT enhancers using RSPO (see, e.g., WO2018/140821, US 2020-0048324 A1, WO2018/132572, US 2020-0024338 A1, 17/257,820 and WO2020/014271). However, a combination WNT surrogate molecule and enhancer, e.g., a WNT surrogate molecule that facilitates hetero-oligomerization in specific tissues along with WNT enhancement facilitated by RSPO or a mimetic thereof, has not been previously disclosed, Thus, a need exists to develop different antigen binding formats that mimic the binding of a natural ligand, e.g., FZD and LRP receptors, to hetero-oligomeric complexes that elicit agonistic biological activity, as well as enhancing WNT activity, e.g., using RSPO mimetics. The present invention fulfills this need by providing flexible structures of multispecific antibody (MsAb) formats that bind to different receptors (co-receptors) and acting either as a mimetic or antagonist of the natural ligand. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIGS.  1 A-M  show the structure-function analysis of different configurations of WNT surrogate molecules in tandem scFv-IgG, Fv-IgG, Fab-IgG, and Fv-Fab formats: (A) schematic drawing of the different structures created using anti-LRP and anti-FZD antibody fragments is shown; (B) shows relative activity of these WNT surrogate molecules or WNT3A on WNT-responsive HEK293 STF reporter cell lines; (C) shows the ability of RSPO to potentiate the activity of these WNT surrogates; and (D-M) show the ability of Fv-IgG structures containing different FZD-binders to stimulate WNT pathways in the presence of RSPO. 
         FIGS.  2 A-E  show the structure-function analysis of anti-FZD binders fused with a mutant RPSO (RSPO2-RA) in different configurations: schematic drawing (A), WNT signaling activity (B), and effects on receptor levels (C) of Fv-IgGs fused to RSPOR2A are shown (in (C), at 103, the lines from top to bottom correspond to: anti-GFP, untreated, anti-GFP-RSPO2A, F12578-RSPO2RA, and no stain); (D) shows the activity of additional FZD binders fused to RSPO2RA; and (E) shows the activity of monovalent fusion proteins. “F” indicates anti-FZD binder, and “aGFP” indicates antiGFP antibody serving as negative control. 
         FIGS.  3 A-M  shows the activity of trispecific, hexavalent molecules containing FZD, LRP, and E3-ligase binding moieties: (A) shows a schematic drawing of a WNT surrogate (anti-FZD, anti-LRP bispecific antibody) fused to RSPO2-RA; (B-K) show that molecules constructed with RSPO2RA and FZD binders of different specificity all demonstrate both WNT surrogate and RSPO mimetic activities (E, F, G, K are from HEK293 cells transfected with FZD4, FZD9, FZD10, and FZD4, respectively); (J) shows additional attachment sites for RSPO2RA on the WNT mimetic molecule; (K) shows the activity of molecules with the formats shown in (J) (at log −8 of the left graph, the lines from top to bottom correspond to: L6-F4-2+20 nM Rspo, L6-F4-2-RSPO2RA-CH, L6-F4-2-RSPO2RA-NL, L6-F4-2-RSPO2RA-CL, and L6-F4-2; at log −8 of the right graph, the lines from top to bottom correspond to: L6-F4-RSPO2RA-CL, L6-F4+20 nM RSPO2, L6-F4-RSPO2RA-CH, L6-F4-RSPO2RA-NL, and L6-F4); and (L) and (M) show the activity of additional RSPO2RA fusions containing FZD binders with and without an LRP binder and fused at other locations on the IgG. 
         FIGS.  4 A-C  show the activity of additional trispecific molecules containing FZD, LRP, and E3-ligase binding moieties: (A) shows a schematic drawing a WNT surrogate (anti-FZD, anti-LRP bispecific antibody in various scFv-IgG configurations, top two structures) fused to RSPO2RA (bottom four structures); and (B-C) show the activity of molecules in (A) in the presence or absence of RSPO. In (B), at log −8, the symbols from top to bottom correspond to: L6-F12578 (Fv-IgG)+RSPO2, HC1-L6-F12578-RSPO2RA-KH+HC2-L6-F12578-HF, HC1-L6-F12578-RSPO2RA-KH+HC2-F12578-HF-RSPO2RA, HC1-L6-F12578-RSPO2RA-KH+HC2-F12578-HF, L6-F12578 (Fv-IgG), and HC1-L6-F12578-KH+HC2-F12578-HF). 
         FIGS.  5 A-H  shows WNT super agonist stimulates the expansion of several mouse and human organoids: (A, C, E, G) representative brightfield images of organoid outgrowth after 7 or 14 days. Scale bars, 400 μm. (B, D, F, H) quantification of cell viability using CellTiter-Glo®. Each datapoint represents an independent experiment. A) Outgrowth of mouse small intestinal organoids after 7 days using 0.1 nM of surrogate molecules and B) quantification of cell viability. C) Outgrowth of human small intestinal organoids after 7 days using 1 nM of surrogate molecules and D) quantification of cell viability. E) Outgrowth of mouse hepatocyte organoids after 14 days using 1 nM of surrogate molecules and F) quantification of cell viability. G) Outgrowth of human tubuloids after 7 days using 1 nM of surrogate molecules and H) quantification of cell viability. 
         FIGS.  6 A-H  show in vivo effects of WNT mimetic molecules. To test the in vivo effect of WNT mimetics with different FZD specificity, the panel of WNT mimetics were dosed at 3 mg per kg intraperitoneally on day 0, 3, 7 and 10 in C57Bl/6J mice. (A-C) The relative changes (%) of bone mineral densities (BMD) of whole body (A), femur (B) and lumbar (C) of the various treatment groups on day 7 and 13 by DEXA analysis. (D) The temporal body weight changes. (E) The relative changes (%) of body fat content on day 7 and 13. (F-H) The organ weight of salivary gland (F), liver (G), and small intestine (H) at the takedown on day 14. Statistical Analyses: One-way ANOVA, with post hoc Holm-Sidak test (GraphPad Prism). All comparisons made with the anti-GFP group. Data are show as mean standard deviation (SD). *p&lt;0.05, **p&lt;0.01, ***p&lt;0.001, ****p&lt;0.0001. 
         FIG.  7    shows formats of illustrative WNT surrogate molecules. For the Fab-IgG structure shown (and other structures), the Fab regions of the FZD binding domain and the LRP5/6 binding domain are indicated as being derived from the heavy chain or light chain of a parental antibody, but all other combinations of Fabs are also contemplated, e.g., HC-HC or LC-LC Fabs in either the heavy chain or light chain of the Fab-IgG construct, or switching the order of the two Fabs in either or both arms of the construct. 
         FIG.  8    shows formats of illustrative WNT super agonist molecules. 
     
    
    
     SUMMARY OF THE INVENTION 
     The present invention provides an WNT super agonist molecule comprising a plurality of antigen binding domains, wherein the binding domains bind to at least one first WNT receptor and at least one second WNT receptor, and a WNT enhancer. In certain embodiments, a surrogate molecule is an agonist mimicking a natural ligand by facilitating the hetero-oligomerization of at least two different receptors in the present of a tissue targeting moiety. In certain embodiments, the binding domains are engineered to mimic a natural WNT ligand. In further embodiments, the binding domains are fused directly together. In yet further embodiments, the binding domains of the super agonist are fused together with a peptide linker. In some embodiments, the peptide linker is about 1 amino acid in length to about 30 amino acids in length. In other embodiments, the peptide linker is about 5 amino acids in length to about 15 amino acids in length. In another embodiment, the peptide linker comprises one or more glycine and/or serine residues. In one embodiment, at least one of the binding domains is selected from the group consisting of: an scFv, a VHH/sdAb, a Fab fragment, a Fab′2 fragment, a diabody, and an Fv fragment. In a further embodiment, at least one of the binding domains is fused to an Fc fragment. In a further embodiment, the structure is an Fv-IgG. 
     In particular embodiments, the disclosure provides a WNT super agonist molecule, comprising: a) a Frizzled (FZD) binding domain; b) an LRP5/6 binding domain; and c) an E3 ligase binding domain, wherein the super agonist molecule activates the canonical WNT signaling pathway in a cell. In certain embodiments: the FZD binding domain binds one or more FZD receptor; the LRP5/6 binding domain binds one or more of LRP5 and/or LRP6; and the E3 ligase binding domain binds ZNRF3 and/or RNF43. In certain embodiments, the WNT super agonist comprises one or more polypeptides, wherein at least one polypeptide comprises a FZD binding domain fused to an LRP5/6 binding domain, and wherein at least one polypeptide comprises an E3 ligase binding domain fused to a FZD binding domain or an LRP5/6 binding domain. In particular embodiments, the fused binding domains are fused directly together and/or fused via a peptide linker. In some embodiments, the peptide linker is about 1 amino acid in length to about 30 amino acids in length, or about 5 amino acids in length to about 15 amino acids in length, optionally 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acids in length. In some embodiments, the peptide linker comprises one or more glycine and/or serine residues. In particular embodiments of WNT super agonist molecules, at least one of the binding domains is selected from the group consisting of: an scFv, a VHH/sdAb, a Fab fragment, a Fab′2 fragment, a diabody, and an Fv fragment. In particular embodiments of WNT super agonist molecules, at least one of the binding domains is fused to an Fc fragment, optionally wherein the Fc fragment is from an IgG, IgM, IgA, IgD or IgE antibody isotype or an α, δ, ε, γ, or μ antibody heavy chain. In certain embodiments, the WNT super agonist molecule has ro comprises a structure depicted in Table 3 or Table 4, e.g., the Fv-IgG structure. In certain embodiments, the WNT enhancer domain of the WNT super agonist molecule comprises an E3 ligase binding domain selected from the group consisting of: a mutant R-spondin (RSPO) protein and an antibody or functional fragment thereof. In some embodiments, the mutant RSPO protein has reduced binding to Leucine-rich repeat-containing G-protein receptors 4-6 (LGR4-6) as compared to wild type RSPO. In some embodiments, the E3 ligase binding domain binds a Zinc and Ring Finger 3 (ZNRF3) and/or a Ring Finger Protein 43 (RNF43). In particular embodiments, the E3 ligase binding domain is selected from the group consisting of: an scFv, a VHH/sdAb, a Fab fragment, a Fab′2 fragment, a diabody, and an Fv fragment. In various embodiments, the E3 ligase binding domain is fused to a C-terminus of an Fc fragment of an Fv-IgG, either directly or via a linker, optionally wherein the linker is a peptide linker of about 1 amino acid in length to about 30 amino acids in length, or about 5 amino acids in length to about 15 amino acids in length, or 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acids in length. In various embodiments, the E3 ligase binding domain is fused to a C-terminus of: a) a light chain or fragment thereof of a FZD binding domain; b) a heavy chain or fragment thereof of a FZD binding domain; c) a light chain or fragment thereof of a LRP5/6 binding domain; or d) a heavy chain or fragment thereof of a LRP5/6 binding domain, either directly or via a linker, optionally wherein the linker is a peptide linker of about 1 amino acid in length to about 30 amino acids in length, or about 5 amino acids in length to about 15 amino acids in length, or 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acids in length. In various embodiments, the binding domain that binds an E3 ubiquitin ligase is fused to a N-terminus of: a) a light chain or fragment thereof of a FZD binding domain; b) a heavy chain or fragment thereof of a FZD binding domain; c) a light chain or fragment thereof of a LRP5/6 binding domain; or d) a heavy chain or fragment thereof of a LRP5/6 binding domain, either directly or via a linker, optionally wherein the linker is a peptide linker of about 1 amino acid in length to about 30 amino acids in length, or about 5 amino acids in length to about 15 amino acids in length, or 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acids in length. In some embodiments, a WNT super agonist comprises a polypeptide having at least 90% or 95% sequence identity to a sequence provided in Table 3 or Table 4, or a combination of polypeptides, each having at least 90% or 95% sequence identity to a sequence provided in Table 3 or Table 4. 
     In a related embodiment, the disclosure provides a WNT enhancer molecule (e.g., an RSPO mimetic) comprising at least one binding domain that binds to at least one WNT receptor; and a WNT enhancer. In certain embodiments, an R-spondin (RSPO) mimetic comprises a first binding composition that binds a WNT receptor and a second binding composition that binds an E3 ubiquitin ligase. In some embodiments, the first binding composition binds a FZD receptor or an LRP receptor, optionally LRP5 and/or LRP6. In some embodiments, the first binding composition is selected from the group consisting of: an scFv, a VHH/sdAb, a Fab fragment, a Fab′2 fragment, a diabody, and an Fv fragment. In certain embodiments, the second binding composition is an RSPO protein, optionally a mutant RSPO protein, or an antibody or fragment thereof that binds an E3 ubiquitin ligase. In certain embodiments, the binding compositions are fused directly together or via a peptide linker. In some embodiments, the peptide linker is about 1 amino acid in length to about 30 amino acids in length, or about 5 amino acids in length to about 15 amino acids in length, optionally 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acids in length. In certain embodiments of WNT enhancer molecules, the peptide linker comprises one or more glycine and/or serine residues. In some embodiments, the WNT enhancer comprises a polypeptide having at least 90% or 95% sequence identity to a sequence provided in Table 3 or Table 4, or a combination of polypeptides, each having at least 90% or 95% sequence identity to a sequence provided in Table 3 or Table 4. 
     In yet a further embodiment, the disclosure provides a WNT surrogate molecule comprising at least one binding domain that binds a FZD receptor and at least one binding domain that binds an LRP receptor. In certain embodiments, a WNT surrogate comprises: a) a Frizzled (FZD) binding domain; and b) an LRP5/6 binding domain, wherein the super agonist molecule activates the canonical WNT signaling pathway in a cell. In certain embodiments: a) the FZD binding domain binds one or more FZD receptor; and b) the LRP5/6 binding domain binds LRP5 and/or LRP6. In some embodiments, the FZD binding domain is selected from the group consisting of: an scFv, a VHH/sdAb, a Fab fragment, a Fab′2 fragment, a diabody, and an Fv fragment. In some embodiments, the LRP5/6 binding domain is selected from the group consisting of: an scFv, a VHH/sdAb, a Fab fragment, a Fab′2 fragment, a diabody, and an Fv fragment. In some embodiments, the binding domains are fused directly together or via a peptide linker. In particular embodiments, the peptide linker is about 1 amino acid in length to about 30 amino acids in length, about 5 amino acids in length to about 15 amino acids in length, optionally 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acids in length. In particular embodiments, the peptide linker comprises one or more glycine and/or serine residues. In some embodiments, the WNT surrogate molecule comprises a polypeptide having at least 90% or 95% sequence identity to a sequence provided in Table 3 or Table 4, or a combination of polypeptides, each having at least 90% or 95% sequence identity to a sequence provided in Table 3 or Table 4. 
     In various embodiments of any of the molecules disclosed herein that comprise a WNT enhancer domain or an E3 ligase binding domain, the WNT enhancer is selected from the group consisting of: a wild-type RSPO protein, a mutant RSPO protein, and a binding domain that binds to an E3 ubiquitin ligase. In further embodiments, the mutant RSPO protein has reduced binding to Leucine-rich repeat-containing G-protein receptors 4-6 (LGR4-6) as compared to wild type RSPO. In yet further embodiments, the binding domain that binds a E3 ubiquitin ligase binds to a Zinc and Ring Finger 3 (ZNRF3) and/or a Ring Finger Protein 43 (RNF43). In yet a further embodiment, the binding domain that binds to an E3 ubiquitin ligase is selected from the group consisting of: an scFv, a VHH/sdAb, a Fab fragment, a Fab′2 fragment, a diabody, and an Fv fragment. In certain embodiments, the binding domain that binds an E3 ubiquitin ligase is fused to a C-terminus of an Fc fragment of the Fv-IgG. In other embodiments, the binding domain that binds an E3 ubiquitin ligase is fused to a C-terminus of: a) a light chain of a binding domain that binds to a FZD receptor; b) a heavy chain of a binding domain that binds to a FZD receptor; c) a light chain of a binding domain that binds to an LRP receptor; or b) a heavy chain of a binding domain that binds to an LRP receptor. In another embodiment, the binding domain that binds an E3 ubiquitin ligase is fused to a N-terminus of: a) a light chain of a binding domain that binds to a FZD receptor; b) a heavy chain of a binding domain that binds to a FZD receptor; c) a light chain of a binding domain that binds to an LRP receptor; or d) a heavy chain of a binding domain that binds to an LRP receptor. In certain embodiments, the super-agonist comprises a structure depicted in Table 3 or Table 4. 
     In various embodiments of any of the molecules disclosed herein, one or more of the polypeptides comprises an additional sequence, e.g., a tag, which may, e.g., be used to facilitate purification of the polypeptide. Examples of such tag molecules include, but are not limited to, His tags, Myc tags, and Flag tags. 
     In one embodiment, the present invention provides a method for treating a subject having a disease or disorder associated with reduced WNT signaling, comprising administering to the subject an effective amount of the WNT super agonist molecule, a WNT enhancer molecule, a WNT surrogate molecule, or a pharmaceutical composition comprising one or more of these molecules. In certain embodiments, the disease or disorder is selected from the group consisting of: oral mucositis, short bowel syndrome, inflammatory bowel diseases (IBD), other gastrointestinal disorders; treatment of metabolic syndrome, dyslipidemia, treatment of diabetes, treatment of pancreatitis, conditions where exocrine or endocrine pancreas tissues are damaged; conditions where enhanced epidermal regeneration is desired, e.g., epidermal wound healing, treatment of diabetic foot ulcers, syndromes involving tooth, nail, or dermal hypoplasia, etc., conditions where angiogenesis is beneficial; myocardial infarction, coronary artery disease, heart failure; immunodeficiencies, graft versus host diseases, acute kidney injuries, chronic kidney diseases, chronic obstructive pulmonary diseases (COPD), idiopathic pulmonary fibrosis (IPF), cirrhosis, acute liver failure, chronic liver diseases with hepatitis C or B virus infection or post-antiviral drug therapies, alcoholic liver diseases, alcoholic hepatitis, non-alcoholic liver diseases with steatosis or steatohepatitis, treatment of hearing loss, including internal and external loss of auditory hair cells, vestibular hypofunction, macular degeneration, treatment of vitreoretinopathy, diabetic retinopathy, other diseases of retinal degeneration, Fuchs&#39; dystrophy, other corneal diseases, stroke, traumatic brain injury, Alzheimer&#39;s disease, multiple sclerosis and other conditions affecting the blood brain barrier; spinal cord injuries, bone related diseases, other spinal cord diseases, and alopecia. 
     In one embodiment, the present invention provides a method of generating, culturing, or maintaining an organ tissue, cell, or an organoid culture, comprising contacting the organ tissue, cell, or an organoid culture with a WNT super agonist molecule, a WNT enhancer molecule, or a WNT surrogate molecule, or a pharmaceutical composition comprising the WNT super agonist molecule, WNT enhancer molecule, or WNT surrogate molecule. In a further embodiment, the organ tissue obtained is from a donor and contacted with the WNT super agonist molecule, WNT enhancer molecule, or WNT surrogate molecule, optionally by perfusing the organ tissue ex vivo with a composition comprising the WNT super agonist molecule, WNT enhancer molecule, or WNT surrogate molecule. In yet another embodiment, the viability of the organ tissue is maintained by contacting donor organ tissue in vivo, with a composition comprising the WNT super agonist or the WNT enhancer molecule. In another embodiment, the organoid culture is maintained by contacting the organoid culture with the WNT super agonist molecule, WNT enhancer molecule, or WNT surrogate molecule, optionally by culturing the organoid culture in a medium comprising the WNT super agonist or the WNT enhancer. 
     In a further related embodiment, the disclosure provides a method for inducing bone formation or increasing bone density in a subject, comprising administering to the subject an effective amount of a WNT super agonist molecule, WNT enhancer molecule, or WNT surrogate molecule, or a pharmaceutical composition comprising one or more of these molecules. In some embodiments, the method is performed using a WNT super agonist molecule that binds FZD5, FZD8, and FZD9. In some embodiments, the method is performed using a WNT surrogatet molecule that binds FZD5, FZD8, and FZD9. 
     In a further related embodiment, the disclosure provides a method for regenerating a salivary gland or inducing salivary gland growth in a subject, comprising administering to the subject an effective amount of a WNT super agonist molecule, WNT enhancer molecule, or WNT surrogate molecule, or a pharmaceutical composition comprising one or more of these molecules. In some embodiments, the methods is performed for treating hyposalivation in the subject. In some embodiments, the method is performed using a WNT super agonist molecule that binds FZD1, FZD2, and FZD7. In some embodiments, the method is performed using a WNT surrogate molecule that binds FZD1, FZD2, and FZD7. 
     In some embodiments, the present invention provides an RSPO mimetic comprising a first binding composition that binds one WNT receptor and a second binding composition that binds an E3 ubiquitin ligase. In some embodiments, the first binding composition binds a FZD receptor or an LRP receptor. In further embodiments, the first binding composition is selected from the group consisting of: an scFv, a VHH/sdAb, a Fab fragment, a Fab′2 fragment, a diabody, and an Fv fragment. In yet further embodiments, the second binding composition is an RSPO protein or an antibody or fragment thereof that binds an E3 ubiquitin ligase. 
     DETAILED DESCRIPTION 
     As used herein, including the appended claims, the singular forms of words such as “a,” “an,” and “the,” include their corresponding plural references unless the context clearly dictates otherwise. 
     Throughout this specification, unless the context requires otherwise, the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated element or integer or group of elements or integers but not the exclusion of any other element or integer or group of elements or integers. 
     Each embodiment in this specification is to be applied mutatis mutandis to every other embodiment unless expressly stated otherwise. 
     All references cited herein are incorporated by reference to the same extent as if each individual publication, patent application, or patent, was specifically and individually indicated to be incorporated by reference. 
     I. Definitions 
     “Activity” of a molecule may describe or refer to the binding of the molecule to a ligand or to a receptor, to catalytic activity, to the ability to stimulate gene expression, to antigenic activity, to the modulation of activities of other molecules, and the like. “Activity” of a molecule may also refer to activity in modulating or maintaining cell-to-cell interactions, e.g., adhesion, or activity in maintaining a structure of a cell, e.g., cell membranes or cytoskeleton. “Activity” may also mean specific activity, e.g., [catalytic activity]/[mg protein], or [immunological activity]/[mg protein], or the like. 
     The terms “administering” or “introducing” or “providing”, as used herein, refer to delivery of a composition to a cell, to cells, tissues and/or organs of a subject, or to a subject. Such administering or introducing may take place in vivo, in vitro or ex vivo. 
     As is well known in the art, an antibody is an immunoglobulin molecule capable of specific binding to a target, such as a carbohydrate, polynucleotide, lipid, polypeptide, etc., through at least one epitope recognition site, located in the variable region of the immunoglobulin molecule. As used herein, the term encompasses not only intact polyclonal or monoclonal antibodies, but also fragments thereof (such as dAb, Fab, Fab′, F(ab′)2, Fv), single chain (scFv), VHH, synthetic variants thereof, naturally occurring variants, fusion proteins comprising an antibody or an antigen-binding fragment thereof, humanized antibodies, chimeric antibodies, and any other modified configuration of the immunoglobulin molecule that comprises an antigen-binding site or fragment (epitope recognition site) of the required specificity. “Diabodies”, multivalent or multispecific fragments constructed by gene fusion (WO94/13804; P. Holliger et al (1993),  Proc. Natl. Acad. Sci. USA  90 6444-6448) are also a particular form of antibody contemplated herein. Minibodies comprising a scFv joined to a CH3 domain are also included herein (See e.g., S. Hu et al. (1996),  Cancer Res.,  56:3055-3061; Ward, E. S. et al. (1989)  Nature  341:544-546; Bird et al. (1988)  Science  242:423-426; Huston et al. (1988)  Proc. Natl. Acad. Sci. USA  85:5879-5883; PCT/US92/09965; WO94/13804; P. Holliger et al. (1993)  Proc. Natl. Acad. Sci. USA  90:6444-6448; and Y. Reiter et al. (1996)  Nature Biotech.  14:1239-1245). 
     The term “antigen-binding fragment” as used herein refers to a polypeptide fragment that contains at least one CDR of an immunoglobulin heavy and/or light chain, or of a VHH, that binds to the antigen of interest, in particular to one or more FZD receptor or LRP5 or LRP6 receptor. In this regard, an antigen-binding fragment of the herein described antibodies may comprise 1, 2, 3, 4, 5, or all 6 CDRs of a VH and VL sequence set forth herein from antibodies that bind one or more FZD receptor or LRP5 and/or LRP6. In particular embodiments, an antigen-binding fragment may comprise all three VH CDRs or all three VL CDRs. Similarly, an antigen binding fragment thereof may comprise all three CDRs of a VHH binding fragment. An antigen-binding fragment of a FZD-specific antibody is capable of binding to a FZD receptor. An antigen-binding fragment of a LRP5/6-specific antibody is capable of binding to a LRP5 and/or LRP6 receptor. As used herein, the term encompasses not only isolated fragments but also polypeptides comprising an antigen-binding fragment of an antibody disclosed herein, such as, for example, fusion proteins comprising an antigen-binding fragment of an antibody disclosed herein, such as, e.g., a fusion protein comprising a VHH that binds one or more FZD receptors and a VHH that binds LRP5 and/or LRP6. 
     The term “antigen” refers to a molecule or a portion of a molecule capable of being bound by a selective binding agent, such as an antibody, and additionally capable of being used in an animal to produce antibodies capable of binding to an epitope of that antigen. In certain embodiments, a binding agent (e.g., a WNT surrogate molecule or binding region thereof) is said to specifically bind an antigen when it preferentially recognizes its target antigen in a complex mixture of proteins and/or macromolecules. In certain embodiments, a WNT surrogate molecule or binding region thereof (e.g., an antibody or antigen-binding fragment thereof) is said to specifically bind an antigen when the equilibrium dissociation constant is ≤10 −7  or ≤10 −8  M. In some embodiments, the equilibrium dissociation constant may be ≤10 −9  M or ≤10 −10  M. 
     As used herein, the term “CDR” refers to at least one of the three hypervariable regions of a heavy or light chain variable (V) region. Proceeding from the N-terminus of a heavy or light chain, these regions are denoted as “CDR1,” “CDR2,” and “CDR3” respectively. An antigen-binding site, therefore, includes six CDRs, comprising the CDR set from each of a heavy and a light chain V region. A polypeptide comprising a single CDR, (e.g., a CDR1, CDR2 or CDR3) is referred to herein as a “molecular recognition unit.” Crystallographic analysis of a number of antigen-antibody complexes has demonstrated that the amino acid residues of CDRs form extensive contact with bound antigen, wherein the most extensive antigen contact is with the heavy chain CDR3. Thus, the molecular recognition units are primarily responsible for the specificity of an antigen-binding site. In certain embodiments, antibodies and antigen-binding fragments thereof as described herein include a heavy chain and a light chain CDRs, respectively interposed between a heavy chain and a light chain framework regions (FRs)which provide support to the CDRs and define the spatial relationship of the CDRs relative to each other. 
     As used herein, the term “FRs” refer to the four flanking amino acid sequences which frame the CDRs of a heavy or light chain V region. Some FR residues may contact bound antigen; however, FRs are primarily responsible for folding the V region into the antigen-binding site, particularly the FR residues directly adjacent to the CDRs. Within FRs, certain amino residues and certain structural features are very highly conserved. In this regard, all V region sequences contain an internal disulfide loop of around 90 amino acid residues. When the V regions fold into a binding-site, the CDRs are displayed as projecting loop motifs which form an antigen-binding surface. It is generally recognized that there are conserved structural regions of FRs which influence the folded shape of the CDR loops into certain “canonical” structures-regardless of the precise CDR amino acid sequence. Further, certain FR residues are known to participate in non-covalent interdomain contacts which stabilize the interaction of the antibody heavy and light chains. The structures and locations of immunoglobulin CDRs and variable domains may be determined by reference to Kabat, E. A. et al., Sequences of Proteins of Immunological Interest. 4th Edition. US Department of Health and Human Services. 1987, and updates thereof, now available on the Internet (immuno.bme.nwu.edu). 
     A “monoclonal antibody” refers to a homogeneous antibody population wherein the monoclonal antibody is comprised of amino acids (naturally occurring and non-naturally occurring) that are involved in the selective binding of an epitope. Monoclonal antibodies are highly specific, being directed against a single epitope. The term “monoclonal antibody” encompasses not only intact monoclonal antibodies and full-length monoclonal antibodies, but also fragments thereof (such as Fab, Fab′, F(ab′)2, Fv), single chain (scFv), VHH, variants thereof, fusion proteins comprising an antigen-binding fragment of a monoclonal antibody, humanized monoclonal antibodies, chimeric monoclonal antibodies, and any other modified configuration of the immunoglobulin molecule that comprises an antigen-binding fragment (epitope recognition site) of the required specificity and the ability to bind to an epitope, including WNT surrogate molecules disclosed herein. It is not intended to be limited as regards the source of the antibody or the manner in which it is made (e.g., by hybridoma, phage selection, recombinant expression, transgenic animals, etc.). The term includes whole immunoglobulins as well as the fragments etc. described above under the definition of “antibody.” 
     The term “co-receptor” refers to a first cell surface receptor that binds signaling molecule or ligand in conjunction with another receptor to facilitate ligand recognition and initiate a biological process, such as WNT pathway signaling. 
     The term “agonist activity” refers to the ability of an agonist to mimic the effect or activity of a naturally occurring protein. 
     As used herein “peptide linker” or “linker moiety” refers to a sequence of sometimes repeating amino acid residues, usually glycine and serine, that are used to join the various antigen binding domains described below. The length of the linker sequence determines the flexibility of the antigen binding domains in MsAbs, in particular, in the binding of epitopes on co-receptors such as FZD receptors, LRP5 and/or LRP6, and/or ZNRF3/RNF43. 
     As used herein, the term “enhances” refers to a measurable increase in the level of receptor signaling modulated by a ligand or ligand agonist compared with the level in the absence of the agonist, e.g., a WNT surrogate molecule. In particular embodiments, the increase in the level of receptor signaling is at least 10%, at least 20%, at least 50%, at least two-fold, at least five-fold, at least 10-fold, at least 20-fold, at least 50-fold, or at least 100-fold as compared to the level of receptor signaling in the absence of the agonist, e.g., in the same cell type. In certain embodiments, a WNT super agonist molecule increases the level of receptor signaling to a greater degree than a corresponding WNT surrogate molecule comprising the same FZD binding domain and LRP5/6 binding domain, but lacking the E3 ligase binding domain, e.g., by at least 10%, at least 20%, at least 50%, or at least two-fold. 
     An antigen or epitope that “specifically binds” or “preferentially binds” (used interchangeably herein) to an antibody or antigen-binding fragment thereof is a term well understood in the art, and methods to determine such specific or preferential binding are also well known in the art. A molecule, e.g., a WNT surrogate molecule or WNT super agonist molecule, is said to exhibit “specific binding” or “preferential binding” if it reacts or associates more frequently, more rapidly, with greater duration and/or with greater affinity with a particular cell or substance than it does with alternative cells or substances. A molecule or binding region thereof, e.g., a WNT surrogate molecule or binding region thereof, “specifically binds” or “preferentially binds” to a target antigen, e.g., a FZD receptor, if it binds with greater affinity, avidity, more readily, and/or with greater duration than it binds to other substances. It is also understood by reading this definition that, for example, a surrogate molecule or binding region thereof that specifically or preferentially binds to a first target may or may not specifically or preferentially bind to a second target. As such, “specific binding” or “preferential binding” does not necessarily require (although it can include) exclusive binding. Generally, but not necessarily, reference to binding means preferential binding. 
     The term “operably linked” means that the components to which the term is applied are in a relationship that allows them to carry out their inherent functions under suitable conditions. For example, a transcription control sequence “operably linked” to a protein coding sequence is ligated thereto so that expression of the protein coding sequence is achieved under conditions compatible with the transcriptional activity of the control sequences. 
     The term “control sequence” as used herein refers to polynucleotide sequences that can affect expression, processing or intracellular localization of coding sequences to which they are ligated or operably linked. The nature of such control sequences may depend upon the host organism. In particular embodiments, transcription control sequences for prokaryotes may include a promoter, ribosomal binding site, and transcription termination sequence. In other particular embodiments, transcription control sequences for eukaryotes may include promoters comprising one or a plurality of recognition sites for transcription factors, transcription enhancer sequences, transcription termination sequences and polyadenylation sequences. In certain embodiments, “control sequences” can include leader sequences and/or fusion partner sequences. 
     The term “polynucleotide” as referred to herein means single-stranded or double-stranded nucleic acid polymers. In certain embodiments, the nucleotides comprising the polynucleotide can be ribonucleotides or deoxyribonucleotides or a modified form of either type of nucleotide. Said modifications include base modifications such as bromouridine, ribose modifications such as arabinoside and 2′,3′-dideoxyribose and internucleotide linkage modifications such as phosphorothioate, phosphorodithioate, phosphoroselenoate, phosphorodiselenoate, phosphoroanilothioate, phoshoraniladate and phosphoroamidate. The term “polynucleotide” specifically includes single and double stranded forms of DNA. 
     The term “naturally occurring nucleotides” includes deoxyribonucleotides and ribonucleotides. The term “modified nucleotides” includes nucleotides with modified or substituted sugar groups and the like. The term “oligonucleotide linkages” includes oligonucleotide linkages such as phosphorothioate, phosphorodithioate, phosphoroselenoate, phosphorodiselenoate, phosphoroanilothioate, phoshoraniladate, phosphoroamidate, and the like. See, e.g., LaPlanche et al. (1986)  Nucl. Acids Res.  14:9081; Stec et al. (1984)  J. Am. Chem. Soc.  106:6077; Stein et al. (1988)  Nucl. Acids Res.  16:3209; Zon et al. (1991)  Anti -  Cancer Drug Design,  6:539; Zon et al. (1991) Oligonucleotides and Analogues: A Practical Approach, pp. 87-108 (F. Eckstein, Ed.), Oxford University Press, Oxford England; Stec et al., U.S. Pat. No. 5,151,510; Uhlmann and Peyman (1990)  Chem. Rev.  90:543, the disclosures of which are hereby incorporated by reference for any purpose. An oligonucleotide can include a detectable label to enable detection of the oligonucleotide or hybridization thereof. 
     The term “vector” is used to refer to any molecule (e.g., nucleic acid, plasmid, or virus) used to transfer coding information to a host cell. The term “expression vector” refers to a vector that is suitable for transformation of a host cell and contains nucleic acid sequences that direct and/or control expression of inserted heterologous nucleic acid sequences. Expression includes, but is not limited to, processes such as transcription, translation, and RNA splicing, if introns are present. 
     The term “host cell” is used to refer to a cell into which has been introduced, or which is capable of having introduced into it, a nucleic acid sequence encoding one or more of the herein described polypeptides, and which further expresses or is capable of expressing a selected gene of interest, such as a gene encoding any herein described polypeptide. The term includes the progeny of the parent cell, whether or not the progeny are identical in morphology or in genetic make-up to the original parent, so long as the selected gene is present. Accordingly there is also contemplated a method comprising introducing such nucleic acid into a host cell. The introduction may employ any available technique. For eukaryotic cells, suitable techniques may include calcium phosphate transfection, DEAE-Dextran, electroporation, liposome-mediated transfection and transduction using retrovirus or other virus, e.g. vaccinia or, for insect cells, baculovirus. 
     For bacterial cells, suitable techniques may include calcium chloride transformation, electroporation and transfection using bacteriophage. The introduction may be followed by causing or allowing expression from the nucleic acid, e.g. by culturing host cells under conditions for expression of the gene. In one embodiment, the nucleic acid is integrated into the genome (e.g. chromosome) of the host cell. Integration may be promoted by inclusion of sequences which promote recombination with the genome, in accordance-with standard techniques. 
     “Transduction” also refers to the acquisition and transfer of eukaryotic cellular sequences by retroviruses. The term “transfection” is used to refer to the uptake of foreign or exogenous DNA by a cell, and a cell has been “transfected” when the exogenous DNA has been introduced inside the cell membrane. A number of transfection techniques are well known in the art and are disclosed herein. See, e.g., Graham et al., 1973, Virology 52:456; Sambrook et al., 2001, MOLECULAR CLONING, A LABORATORY MANUAL, Cold Spring Harbor Laboratories; Davis et al., 1986, BASIC METHODS IN MOLECULAR BIOLOGY, Elsevier; and Chu et al., 1981, Gene 13:197. Such techniques can be used to introduce one or more exogenous DNA moieties into suitable host cells. 
     The term “transformation” as used herein refers to a change in a cell&#39;s genetic characteristics, and a cell has been transformed when it has been modified to contain a new DNA. For example, a cell is transformed where it is genetically modified from its native state. Following transfection or transduction, the transforming DNA may recombine with that of the cell by physically integrating into a chromosome of the cell, or may be maintained transiently as an episomal element without being replicated, or may replicate independently as a plasmid. A cell is considered to have been stably transformed when the DNA is replicated with the division of the cell. 
     The term “naturally occurring” or “native” when used in connection with biological materials such as nucleic acid molecules, polypeptides, host cells, and the like, refers to materials which are found in nature and are not manipulated by a human. Similarly, “non-naturally occurring” or “non-native” as used herein refers to a material that is not found in nature or that has been structurally modified or synthesized by a human. 
     The terms “polypeptide” “protein” and “peptide” and “glycoprotein” are used interchangeably and mean a polymer of amino acids not limited to any particular length. The term does not exclude modifications such as myristylation, sulfation, glycosylation, phosphorylation and addition or deletion of signal sequences. The terms “polypeptide” or “protein” means one or more chains of amino acids, wherein each chain comprises amino acids covalently linked by peptide bonds, and wherein said polypeptide or protein can comprise a plurality of chains non-covalently and/or covalently linked together by peptide bonds, having the sequence of native proteins, that is, proteins produced by naturally-occurring and specifically non-recombinant cells, or genetically-engineered or recombinant cells, and comprise molecules having the amino acid sequence of the native protein, or molecules having deletions from, additions to, and/or substitutions of one or more amino acids of the native sequence. The terms “polypeptide” and “protein” specifically encompass WNT surrogate molecules, FZD binding regions thereof, LRP5/6 binding regions thereof, antibodies and antigen-binding fragments thereof that bind to a FZD receptor or a LRP5 or LRP6 receptor disclosed herein, or sequences that have deletions from, additions to, and/or substitutions of one or more amino acid of any of these polypeptides. Thus, a “polypeptide” or a “protein” can comprise one (termed “a monomer”) or a plurality (termed “a multimer”) of amino acid chains. 
     The term “isolated protein,” “or “isolated antibody” referred to herein means that a subject protein, surrogate molecule, or antibody: (1) is free of at least some other proteins with which it would typically be found in nature; (2) is essentially free of other proteins from the same source, e.g., from the same species, (3) is expressed by a cell from a different species; (4) has been separated from at least about 50 percent of polynucleotides, lipids, carbohydrates, or other materials with which it is associated in nature; (5) is not associated (by covalent or noncovalent interaction) with portions of a protein with which the “isolated protein” is associated in nature; (6) is operably associated (by covalent or noncovalent interaction) with a polypeptide with which it is not associated in nature; or (7) does not occur in nature. Such an isolated protein can be encoded by genomic DNA, cDNA, mRNA or other RNA, or may be of synthetic origin, or any combination thereof. In certain embodiments, an isolated protein may comprise naturally-occurring and/or artificial polypeptide sequences. In certain embodiments, the isolated protein is substantially free from proteins or polypeptides or other contaminants that are found in its natural environment that would interfere with its use (therapeutic, diagnostic, prophylactic, research or otherwise). 
     A “WNT super agonist” is a molecule having enhanced WNT agonist activity. As used herein, the WNT super agonists have both WNT signaling and WNT signal enhancing activity. In some embodiments, the WNT super agonist molecule will bind both at least one FZD receptor and at least one LRP receptor, as well as binding and activating at least one E3 ubiquitin ligase receptor, thereby stabilizing the FZD and/or LRP receptors. 
     II. General 
     The present invention provides combinations of antigen binding molecules that act as WNT super agonist, WNT surrogate and WNT enhancing (RSPO mimetic) molecules by binding to and modulating co-receptor signaling, for example, antigen binding molecules that bind to one or more FZD receptor and one or more LRP5 or LRP6 receptor, and one or more ZNRF3/RNF43 E3 ubiquitin ligase molecules, which in turn modulate a downstream WNT signaling pathway, and methods of preparation and use thereof. In particular embodiments, the surrogate molecules activate or increase a signaling pathway associated with one or both of the co-receptors. 
     In particular embodiments, the WNT super agonist molecules disclosed herein comprise: (i) one or more antibodies or antigen-binding fragments thereof that specifically bind to one or more first co-receptor, including antibodies or antigen-binding fragments thereof having particular co-receptor specificity and/or functional properties; (ii) one or more antibodies or antigen-binding fragments thereof that specifically bind to one or more second co-receptors; and (iii) one or more polypeptides (e.g., a mutated R-spondin) that specifically bind to one or more E3 ligase, e.g., ZNRF3 and/or RNF43. Certain embodiments encompass specific structural formats or arrangements of the first and second co-receptor binding region(s) of the WNT super agonist molecules advantageous in increasing downstream signaling and related biological effects. 
     In particular embodiments, the WNT surrogate molecules disclosed herein comprise: (i) one or more antibodies or antigen-binding fragments thereof that specifically bind to one or more first co-receptor, including antibodies or antigen-binding fragments thereof having particular co-receptor specificity and/or functional properties; and (ii) one or more antibodies or antigen-binding fragments thereof that specifically bind to one or more second co-receptors. Certain embodiments encompass specific structural formats or arrangements of the first and second co-receptor binding region(s) of the WNT surrogate molecules advantageous in increasing downstream signaling and related biological effects. 
     In particular embodiments, the WNT enhancer molecules (also referred to as RSPO mimetics) disclosed herein comprise: (i) one or more antibodies or antigen-binding fragments thereof that specifically bind to one or more first co-receptor (either one or more FZD or LRP5/6), including antibodies or antigen-binding fragments thereof having particular co-receptor specificity and/or functional properties; (ii) one or more polypeptides (e.g., a mutated R-spondin) that specifically bind to one or more E3 ligase, e.g., ZNRF3 and/or RNF43. Certain embodiments encompass specific structural formats or arrangements of the first and second co-receptor binding region(s) of the WNT super agonist molecules advantageous in increasing downstream signaling and related biological effects. In particular embodiments, the WNT enhancer molecules do not bind to both a FZD receptor and an LRP5/6. 
     The practice of the present invention will employ, unless indicated specifically to the contrary, conventional methods of virology, immunology, microbiology, molecular biology and recombinant DNA techniques within the skill of the art, many of which are described below for the purpose of illustration. Such techniques are explained fully in the literature. See, e.g., Current Protocols in Molecular Biology or Current Protocols in Immunology, John Wiley &amp; Sons, New York, N.Y. (2009); Ausubel et al., Short Protocols in Molecular Biology, 3rd ed., Wiley &amp; Sons, 1995; Sambrook and Russell, Molecular Cloning: A Laboratory Manual (3rd Edition, 2001); Maniatis et al. Molecular Cloning: A Laboratory Manual (1982); DNA Cloning: A Practical Approach, vol. I &amp; II (D. Glover, ed.); Oligonucleotide Synthesis (N. Gait, ed., 1984); Nucleic Acid Hybridization (B. Hames &amp; S. Higgins, eds., 1985); Transcription and Translation (B. Hames &amp; S. Higgins, eds., 1984); Animal Cell Culture (R. Freshney, ed., 1986); Perbal, A Practical Guide to Molecular Cloning (1984) and other like references. 
     Sequences of illustrative antibodies, or antigen-binding fragments, or complementarity determining regions (CDRs) thereof, that bind to one or more FZD receptors, are set forth in WO2019126399. Sequences of illustrative LRP5 and/or LRP6 antibodies, or antigen-binding fragments, or complementarity determining regions (CDRs) thereof, are set forth in WO2019126401. Sequences of antigen binding molecules that bind one or more FZD receptor and LRP5 and/or LRP6 are set forth in U.S. Provisional application Nos. 62/607,875, 62/641,217, and 62/680,522, titled WNT Signaling Pathway Agonists, filed Dec. 19, 2017, Mar. 9, 2018, and Jun. 4, 2018, respectively. 
     Antibodies and antibody fragments thereof may be prepared by methods well known in the art. For example, the proteolytic enzyme papain preferentially cleaves IgG molecules to yield several fragments, two of which (the F(ab) fragments) each comprise a covalent heterodimer that includes an intact antigen-binding site. The enzyme pepsin is able to cleave IgG molecules to provide several fragments, including the F(ab′)2 fragment which comprises both antigen-binding sites. An Fv fragment for use according to certain embodiments of the present invention can be produced by preferential proteolytic cleavage of an IgM, and on rare occasions of an IgG or IgA immunoglobulin molecule. Fv fragments are, however, more commonly derived using recombinant techniques known in the art. The Fv fragment includes a non-covalent VH:VL heterodimer including an antigen-binding site which retains much of the antigen recognition and binding capabilities of the native antibody molecule. (See, e.g., Inbar et al. (1972)  Proc. Nat. Acad. Sci. USA  69:2659-2662; Hochman et al. (1976)  Biochem  15:2706-2710; and Ehrlich et al. (1980)  Biochem  19:4091-4096). 
     In certain embodiments, single chain Fv or scFV antibodies are contemplated. For example, Kappa bodies (Ill et al. (1997),  Prot. Eng.  10: 949-57; minibodies (Martin et al. (1994)  EMBO J  13: 5305-9; diabodies (Holliger et al. (1993)  PNAS  90: 6444-8; or janusins (Traunecker et al. (1991)  EMBO J  10: 3655-59; and Traunecker et al. (1992)  Int. J. Cancer  Suppl. 7: 51-52), may be prepared using standard molecular biology techniques following the teachings of the present application with regard to selecting antibodies having the desired specificity. In still other embodiments, bispecific or chimeric antibodies may be made that encompass the ligands of the present disclosure. For example, a chimeric antibody may comprise CDRs and framework regions from different antibodies, while bispecific antibodies may be generated that bind specifically to one or more FZD receptor through one binding domain and to a second molecule through a second binding domain. These antibodies may be produced through recombinant molecular biological techniques or may be physically conjugated together. 
     A single chain Fv (scFv) polypeptide is a covalently linked VH::VL heterodimer which is expressed from a gene fusion including VH- and VL-encoding genes linked by an encoded peptide linker. Huston et al. (1988)  Proc. Nat. Acad. Sci. USA  85(16):5879-5883. A number of methods have been described to discern chemical structures for converting the naturally aggregated—but chemically separated-light and heavy polypeptide chains from an antibody V region into an scFv molecule which will fold into a three dimensional structure substantially similar to the structure of an antigen-binding site. See, e.g., U.S. Pat. Nos. 5,091,513 and 5,132,405, to Huston et al.; and U.S. Pat. No. 4,946,778, to Ladner et al. 
     In certain embodiments, an antibody as described herein is in the form of a diabody. Diabodies are multimers of polypeptides, each polypeptide comprising a first domain comprising a binding region of an immunoglobulin light chain and a second domain comprising a binding region of an immunoglobulin heavy chain, the two domains being linked (e.g. by a peptide linker) but unable to associate with each other to form an antigen binding site: antigen binding sites are formed by the association of the first domain of one polypeptide within the multimer with the second domain of another polypeptide within the multimer (WO94/13804). A dAb fragment of an antibody consists of a VH domain (Ward, E. S. et al. (1989)  Nature  341:544-546). 
     Where bispecific antibodies are to be used, these may be conventional bispecific antibodies, which can be manufactured in a variety of ways (Holliger, P. and Winter G. (1993)  Curr. Op. Biotechnol.  4:446-449), e.g. prepared chemically or from hybrid hybridomas, or may be any of the bispecific antibody fragments mentioned above. Diabodies and scFv can be constructed without an Fc region, using only variable domains, potentially reducing the effects of anti-idiotypic reaction. 
     Bispecific diabodies, as opposed to bispecific whole antibodies, may also be particularly useful because they can be readily constructed and expressed in  E. coli . Diabodies (and many other polypeptides such as antibody fragments) of appropriate binding specificities can be readily selected using phage display (WO94/13804) from libraries. If one arm of the diabody is to be kept constant, for instance, with a specificity directed against antigen X, then a library can be made where the other arm is varied and an antibody of appropriate specificity selected. Bispecific whole antibodies may be made by knobs-into-holes engineering (J. B. B. Ridgeway et al. (1996)  Protein Eng.,  9:616-621). 
     In certain embodiments, the antibodies described herein may be provided in the form of a UniBody®. A UniBody® is an IgG4 antibody with the hinge region removed (see GenMab Utrecht, The Netherlands; see also, e.g., US20090226421). This proprietary antibody technology creates a stable, smaller antibody format with an anticipated longer therapeutic window than current small antibody formats. IgG4 antibodies are considered inert and thus do not interact with the immune system. Fully human IgG4 antibodies may be modified by eliminating the hinge region of the antibody to obtain half-molecule fragments having distinct stability properties relative to the corresponding intact IgG4 (GenMab, Utrecht). Halving the IgG4 molecule leaves only one area on the UniBody® that can bind to cognate antigens (e.g., disease targets) and the UniBody® therefore binds univalently to only one site on target cells. 
     In certain embodiments, the antibodies of the present disclosure may take the form of a single variable domain fragment known as a VHH. The VHH technology was originally developed following the discovery and identification that camelidae (e.g., camels and llamas) possess fully functional antibodies that consist of heavy chains only and therefore lack light chains. These heavy-chain only antibodies contain a single VHH domain and two constant domains (CH2, CH3). The cloned and isolated VHH domains have full antigen binding capacity and are very stable. These VHH domains are encoded by single genes and are efficiently produced in almost all prokaryotic and eukaryotic hosts e.g.  E. coli  (see e.g. U.S. Pat. No. 6,765,087), molds (for example  Aspergillus  or  Trichoderma ) and yeast (for example  Saccharomyces, Kluyvermyces, Hansenula  or Pichia (see e.g. U.S. Pat. No. 6,838,254). The production process is scalable and multi-kilogram quantities of VHHs have been produced. VHHs may be formulated as a ready-to-use solution having a long shelf life. The Nanoclone® method (see, e.g., WO 06/079372) is a proprietary method for generating VHHs against a desired target, based on automated high-throughput selection of B-cells. VHH antibodies typically have a small size of around 15 kDa. 
     In certain embodiments, the antibodies or antigen-binding fragments thereof as disclosed herein are humanized. This refers to a chimeric molecule, generally prepared using recombinant techniques, having an antigen-binding site derived from an immunoglobulin from a non-human species and the remaining immunoglobulin structure of the molecule based upon the structure and/or sequence of a human immunoglobulin. The antigen-binding site may comprise either complete variable domains fused onto constant domains or only the CDRs grafted onto appropriate framework regions in the variable domains. Epitope binding sites may be wild type or modified by one or more amino acid substitutions. This eliminates the constant region as an immunogen in human individuals, but the possibility of an immune response to the foreign variable region remains (LoBuglio, A. F. et al., (1989)  Proc Natl Acad Sci USA  86:4220-4224; Queen et al. (1988)  Proc Natl Acad Sci USA  86:10029-10033; and Riechmann et al. (1988)  Nature  332:323-327). Illustrative methods for humanization of the anti-FZD antibodies disclosed herein include the methods described in U.S. Pat. No. 7,462,697. 
     Another approach focuses not only on providing human-derived constant regions, but modifying the variable regions as well so as to reshape them as closely as possible to human form. It is known that the variable regions of both heavy and light chains contain three complementarity-determining regions (CDRs) which vary in response to the epitopes in question and determine binding capability, flanked by four framework regions (FRs) which are relatively conserved in a given species and which putatively provide a scaffolding for the CDRs. When nonhuman antibodies are prepared with respect to a particular epitope, the variable regions can be “reshaped” or “humanized” by grafting CDRs derived from nonhuman antibody on the FRs present in the human antibody to be modified. Application of this approach to various antibodies has been reported by Sato, K., et al., (1993)  Cancer Res  53:851-856. Riechmann, L., et al., (1988) supra; Verhoeyen, M., et al., (1988)  Science  239:1534-1536; Kettleborough, C. A., et al., (1991)  Protein Engg  4:773-3783; Maeda, H., et al., (1991)  Human Antibodies Hybridoma  2:124-134; Gorman, S. D., et al., (1991)  Proc Nat!AcadSci USA  88:4181-4185; Tempest, P. R., et al., (1991)  Bio Technol.  9:266-271; Co, M. S., et al., (1991)  Proc Natl Acad Sci USA  88:2869-2873; Carter, P., et al., (1992)  Proc Natd Acad Sci USA  89:4285-4289; and Co, M. S. et al., (1992)  J Immunol  148:1149-1154. In some embodiments, humanized antibodies preserve all CDR sequences (for example, a humanized mouse antibody which contains all six CDRs from the mouse antibodies). In other embodiments, humanized antibodies have one or more CDRs (one, two, three, four, five, six) which are altered with respect to the original antibody, which are also termed one or more CDRs “derived from” one or more CDRs from the original antibody. 
     In certain embodiments, the antibodies of the present disclosure may be chimeric antibodies. In this regard, a chimeric antibody is comprised of an antigen-binding fragment of an antibody operably linked or otherwise fused to a heterologous Fc portion of a different antibody. In certain embodiments, the heterologous Fc domain is of human origin. In other embodiments, the heterologous Fc domain may be from a different Ig class from the parent antibody, including IgA (including subclasses IgA1 and IgA2), IgD, IgE, IgG (including subclasses IgG1, IgG2, IgG3, and IgG4), and IgM. In further embodiments, the heterologous Fc domain may be comprised of CH2 and CH3 domains from one or more of the different Ig classes. As noted above with regard to humanized antibodies, the antigen-binding fragment of a chimeric antibody may comprise only one or more of the CDRs of the antibodies described herein (e.g., 1, 2, 3, 4, 5, or 6 CDRs of the antibodies described herein), or may comprise an entire variable domain (VL, VH or both). 
     III. Structures of Receptor Surrogate Ligands (WNT Surrogate Molecules) 
     The disclosure provides, in certain aspects, surrogate molecules that bind both one or more of a first receptor (e.g., FZD) and one or more of a second receptor (e.g., LRP5 and/or LRP6; also referred to as LRP5/6). For example, a WNT surrogate molecule can bind one or more human FZD receptors and one or both of a human LRP5 and/or a human LRP6. 
     In certain embodiments, a surrogate molecule is capable of modulating or modulates signaling events associated with at least one of the co-receptors that it binds, in a cell contacted with the surrogate molecule. In certain embodiments, the surrogate molecule increases receptor signaling. As an example, a WNT surrogate molecule specifically modulates the biological activity of a human WNT/β-catenin signaling pathway. 
     Surrogate molecules of the present invention are biologically active in binding to one or more of a first receptor and to one or more of a second receptor, and as an example, in the activation of WNT signaling, the WNT surrogate molecule is a WNT agonist. The term “agonist activity” refers to the ability of an agonist to mimic the effect or activity of a naturally occurring protein binding to a first and second receptor. The ability of the surrogate molecules and other receptor agonists disclosed herein to mimic the activity of the natural ligand can be confirmed by a number of assays. As an example, WNT surrogate molecules, some of which are disclosed herein activate, enhance or increase the canonical WNT/0-catenin signaling pathway. 
     In particular embodiments, the structures of the surrogate molecules disclosed herein are bispecific, i.e., they specifically bind to two or more different epitopes, e.g., one or more epitopes of a first receptor, and one or more epitopes of a second receptor. 
     In particular embodiments, WNT surrogate molecules disclosed herein are multivalent, e.g., they comprise two or more regions that each specifically bind to the same epitope, e.g., two or more regions that bind to an epitope within one or more first co-receptor and/or two or more regions that bind to an epitope within a second co-receptor. In particular embodiments, they comprise two or more regions that bind to an epitope within a first co-receptor and two or more regions that bind to an epitope within a second co-receptor. In certain embodiments, surrogate molecules comprise a ratio of the number of regions that bind one or more first co-receptor to the number of regions that a second co-receptor of or about: 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 2:3, 2:5, 2:7, 7:2, 5:2, 3:2, 3:4, 3:5, 3:7, 3:8, 8:3, 7:3, 5:3, 4:3, 4:5, 4:7, 4:9, 9:4, 7:4, 5:4, 6:7, 7:6, 1:2, 1:3, 1:4, 1:5, or 1:6. In certain embodiments, the surrogate molecules are bispecific and multivalent. 
     The structures of the WNT surrogate molecules disclosed herein may have any of a variety of different structural formats or configurations. The surrogate molecules may comprise polypeptides and/or non-polypeptide binding moieties, e.g., small molecules. In particular embodiments, the surrogate molecules comprise both a polypeptide region and a non-polypeptide binding moiety. In certain embodiments, the surrogate molecules may comprise a single polypeptide, or they may comprise two or more, three or more, or four or more polypeptides. In certain embodiments, one or more polypeptides of a surrogate molecule are antibodies or antigen-binding fragments thereof. In certain embodiments, surrogates comprise two antibodies or antigen binding fragments thereof, one that binds one or more first co-receptor and one that binds on or more second co-receptor. In certain embodiments, the surrogates comprises one, two, three, or four polypeptides, e.g., linked or bound to each other or fused to each other. Non-limiting examples of WNT surrogate structures contemplated by the disclosure are provided in  FIG.  7   . 
     When the surrogate molecules comprise a single polypeptide, they may be a fusion protein comprising one or more first co-receptor binding domain and one or more second co-receptor binding domain. The binding domains may be directly fused or they may be connected via a linker, e.g., a polypeptide linker, including but not limited to any of those disclosed herein. 
     When the surrogate molecules comprise two or more polypeptides, the polypeptides may be linked via covalent bonds, such as, e.g., disulfide bonds, and/or noncovalent interactions. For example, heavy chains of human immunoglobulin IgG interact at the level of their CH3 domains directly, whereas, at the level of their CH2 domains, they interact via the carbohydrate attached to the asparagine (Asn) N84.4 in the DE turn. In particular embodiments, the surrogate molecules comprise one or more regions derived from an antibody or antigen-binding fragment thereof, e.g., antibody heavy chains or antibody light chains or fragments thereof. In certain embodiments, a surrogate polypeptide comprises two antibody heavy chain regions (e.g., hinge regions) bound together via one or more disulfide bond. In certain embodiments, a surrogate polypeptide comprises an antibody light chain region (e.g., a CL region) and an antibody heavy chain region (e.g., a CH1 region) bound together via one or more disulfide bond. 
     Surrogate polypeptides may be engineered to facilitate binding between two polypeptides. For example, Knob-into-holes amino acid modifications may be introduced into two different polypeptides to facilitate their binding. Knobs-into-holes amino acid (AA) changes is a rational design strategy developed in antibody engineering, used for heterodimerization of the heavy chains, in the production of bispecific IgG antibodies. AA changes are engineered in order to create a knob on the CH3 of the heavy chains from a first antibody and a hole on the CH3 of the heavy chains of a second antibody. The knob may be represented by a tyrosine (Y) that belongs to the ‘very large’ IMGT volume class of AA, whereas the hole may be represented by a threonine (T) that belongs to the ‘small’ IMGT volume class. Other means of introducing modifications into polypeptides to facilitate their binding are known and available in the art. For example, specific amino acids may be introduced and used for cross-linking, such as Cysteine to form an intermolecular disulfide bond. 
     Surrogate molecules may have a variety of different structural formats, including but not limited to those as described in WO2019126398 and WO2020010308. 
     In one embodiment, a surrogate molecule comprises an scFv or antigen-binding fragment thereof fused to a VHH or antigen-binding fragment thereof. In certain embodiments, the scFv specifically binds one or more first receptor, and the VHH specifically binds to one or more second receptor. In certain embodiments, the scFv specifically binds LRP5 and/or LRP6, and the VHH specifically binds one or more FZD receptor. In particular embodiments, the scFv or antigen-binding fragment thereof is fused directly to the VHH or antigen-binding fragment thereof, whereas in other embodiments, the two binding regions are fused via a linker moiety. In particular embodiments, the VHH is fused or linked to the N-terminus of the scFV, while in other embodiments, the VHH is fused to the C-terminus of the scFv. 
     In various embodiments, including but not limited to those depicted in WO2019126398, WO2020010308, Table 3, Table 4, and  FIGS.  1 - 8   , a surrogate molecule comprises one or more Fab or antigen-binding fragment thereof and one or more VHH or antigen-binding fragment thereof (or alternatively, one or more scFv or antigen-binding fragment thereof). In certain embodiments, the Fab specifically binds one or more FZD receptor, and the VHH (or scFv) specifically binds LRP5 and/or LRP6. In certain embodiments, the Fab specifically binds LRP5 and/or LRP6, and the VHH (or scFv) specifically binds one or more FZD receptor. In certain embodiments, the VHH (or scFv) is fused to the N-terminus of the Fab, while in some embodiments, the VHH (or scFv) is fused to the C-terminus of the Fab. In particular embodiments, the Fab is present in a full IgG format, and the VHH (or scFv) is fused to the N-terminus and/or C-terminus of the IgG light chain. In particular embodiments, the Fab is present in a full IgG format, and the VHH (or scFv) is fused to the N-terminus and/or C-terminus of the IgG heavy chain. In particular embodiments, two or more VHHs (or scFvs) are fused to the IgG at any combination of these locations. 
     Fabs may be converted into a full IgG format that includes both the Fab and Fc fragments, for example, using genetic engineering to generate a fusion polypeptide comprising the Fab fused to an Fc region, i.e., the Fab is present in a full IgG format. The Fc region for the full IgG format may be derived from any of a variety of different Fcs, including but not limited to, a wild-type or modified IgG1, IgG2, IgG3, IgG4 or other isotype, e.g., wild-type or modified human IgG1, human IgG2, human IgG3, human IgG4, human IgG4Pro (comprising a mutation in core hinge region that prevents the formation of IgG4 half molecules), human IgA, human IgE, human IgM, or the modified IgG1 referred to as IgG1 LALAPG. The L235A, P329G (LALA-PG) variant has been shown to eliminate complement binding and fixation as well as Fc-7 dependent antibody-dependent cell-mediated cytotoxity (ADCC) in both murine IgG2a and human IgG1. These LALA-PG substitutions allow a more accurate translation of results generated with an “effectorless” antibody framework scaffold between mice and primates. In particular embodiments of any of the IgG disclosed herein, the IgG comprises one or more of the following amino acid substitutions: N297G, N297A, N297E, L234A, L235A, or P236G. 
     Non-limiting examples of bivalent and bispecific surrogate molecules of co-receptors that are bivalent towards both the one or more first receptor and one or more second receptor (e.g., FZD and LRP) are provided as the top four structures depicted in WO2019126398 and WO2020010308, where the VHH or scFv is depicted in white or grey, and the Fab or IgG is depicted in black. As shown, the VHH (or scFvs) may be fused to the N-termini of both light chains, to the N-termini of both heavy chains, to the C-termini of both light chains, or to the C-termini of both heavy chains. It is further contemplated, e.g., that VHH (or scFvs) could be fused to both the N-termini and C-termini of the heavy and/or light chains, to the N-termini of the light chains and the heavy chains, to the C-termini of the heavy and light chains, to the N-termini of the heavy chains and C-termini of the light chains, or to the C-termini of the heavy chains and the N-termini of the light chains. In other related embodiments, two or more VHH (or scFvs) may be fused together, optionally via a linker moiety, and fused to the Fab or IgG at one or more of these locations. In a related embodiment, the surrogate molecule has a Hetero-IgG format, whereas the Fab is present as a half antibody, and one or more VHH (or scFv) is fused to one or more of the N-terminus of the Fc, the N-terminus of the Fab, the C-terminus of the Fc, or the C-terminus of the Fab. A bispecific but monovalent to each receptor version of this format is depicted at  FIG.  6   . In certain embodiments, the Fab or antigen-binding fragment (or IgG) thereof is fused directly to the VHH (or scFv) or antigen-binding fragment thereof, whereas in other embodiments, the binding regions are fused via a linker moiety. In particular embodiments, the Fab is described herein or comprises any of the CDR sets described herein. 
     In various embodiments, including but not limited to those depicted in WO2019126398, WO2020010308, Table 3, Table 4, and  FIGS.  1 - 8   , an antigen binding molecule comprises one or more Fab or antigen-binding fragment thereof that binds one or more first receptor (e.g., FZD receptors) and one or more Fab or antigen-binding fragment thereof that binds to at least one or more second receptor (e.g., LRP5 and/or LRP6). In a particular embodiment, it comprises two Fab or antigen-binding fragments thereof that bind one or more first co-receptor and/or two Fab or antigen-binding fragments thereof that bind to one or more second co-receptor. In further embodiments, one or more of the Fab is present in a full IgG format, and in certain embodiments, both Fab are present in a full IgG format. In certain embodiments, the Fab in full IgG format specifically binds one or more first receptor (e.g., one or more FZD receptor), and the other Fab specifically binds at least one second receptor (e.g., LRP5 and/or LRP6). For example, the Fab specifically binds one or more FZD receptor, and the Fab in full IgG format specifically binds LRP5 and/or LRP6. In certain embodiments, the Fab specifically binds LRP5 and/or LRP6, and the Fab in full IgG format specifically binds one or more FZD receptor. In certain embodiments, the Fab is fused to the N-terminus of the IgG, e.g., to the heavy chain or light chain N-terminus, optionally via a linker. In certain embodiments, the Fab is fused to the N-terminus of the heavy chain of the IgG and not fused to the light chain. In particular embodiments, the two heavy chains can be fused together directly or via a linker. An example of such a bispecific and bivalent with respect to both receptors is shown in  FIG.  1 A . In other related embodiments, two or more VHHs may be fused together, optionally via a linker moiety, and fused to the Fab or IgG at one or more of these locations. In a related embodiment, the WNT surrogate molecule has a Hetero-IgG format, whereas one of the Fab is present as a half antibody, and the other Fab is fused to one or more of the N-terminus of the Fc, the N-terminus of the Fab, or the C-terminus of the Fc. A bispecific but monovalent to each receptor version of this format is depicted at  FIG.  6   . In certain embodiments, the Fab or antigen-binding fragment thereof is fused directly to the other Fab or IgG or antigen-binding fragment thereof, whereas in other embodiments, the binding regions are fused via a linker moiety. In particular embodiments, the one or both of the two Fabs are described herein or comprise any of the CDR sets described herein. 
     In certain embodiments, the antigen binding molecules have a format as described in PCT Application Publication No. WO2017/136820, e.g., a Fabs-in-tandem IgG (FIT-IG) format. Shiyong Gong, Fang Ren, Danqing Wu, Xuan Wu &amp; Chengbin Wu (2017). FIT-IG also include the formats disclosed in, e.g., Gong, et al (2017)  mAbs  9:118-1128. In certain embodiments, FIT-IGs combine the functions of two antibodies into one molecule by re-arranging the DNA sequences of two parental monoclonal antibodies into two or three constructs and co-expressing them in mammalian cells. Examples of FIT-IG formats and constructs are provided in  FIGS.  1 A and  1 B  and  FIGS.  2 A and  2 B  of PCT Application Publication No. WO2017/136820. In certain embodiments, FIT-IGs require no Fc mutation; no scFv elements; and no linker or peptide connector. The Fab-domains in each arm work “in tandem” forming a tetravalent bi-specific antibody with four active and independent antigen binding sites that retain the biological function of their parental antibodies In particular embodiments, WNT surrogates comprises a Fab and an IgG. In certain embodiments, the Fab binder LC is fused to the HC of the IgG, e.g., by a linker of various length in between. In various embodiment, the Fab binder HC can be fused or unfused to the LC of the IgG. A variation of this format has been called Fabs-in-tandem IgG (or FIT-Ig). 
     In certain embodiments, the WNT surrogate molecules have a format described in PCT Application Publication No. WO2009/080251 (Klein et al.), e.g. a CrossMab format. CrossMabs formats are also described in Schaefer et al. (2011)  Proc. Natl. Acad. Sci USA  108:11187-11192. The CrossMab format allows correct assembly of two heavy chains and two light chains derived from existing antibodies to form a bispecific, bivalent IgG antibodies. The technology is based on the cross over the antibody domain within one Fab-arm of a bispecific IgG antibody in order to enable correct chain association. Various portions of the Fab can be exchanged, e.g., the entire Fab, the variable heavy and light chains, or the CH1-CL chains can be exchanged. 
     In further embodiments of the present invention, the FiT-Ig and CrossMab technologies are combined to create a multispecific, multivalent antigen binding molecule, Cross-FiT, as depicted in  FIG.  1 A  and Table 2. Also contemplated is a linker between the crossed CL domain of the Fab and the Ig domains rather than between the CH1 and Ig domains. Additional antigen binding fragments, e.g., Fabs, VHH/sdAbs, and/or scFvs, can be appended to the Cross-FiT structure at various sites, e.g., the heavy or light chains and/or the C-terminus of the Fc domain to create multispecific antibodies. 
     In particular embodiments, surrogate molecules comprise two or more VHHs/sdAbs (or scFvs), including at least one that binds one or more first receptor and at least one that binds at least one second receptor. In certain embodiments, one of the binding regions is a VHH/sdAbs and the other is an scFv. Surrogate molecules comprising two or more VHH/sdAbs (or scFvs) may be formatted in a variety of configurations, including but not limited to those depicted in WO2019126398 and WO2020010308. In certain bispecific, bivalent formats, two or more VHH/sdAbs (or scFvs) are fused in tandem or fused to two different ends of an Fc, optionally via one or more linkers. Where linkers are present, the linker and its length may be the same or different between the VHH/sdAb (or scFv) and the other VHH/sdAb (or scFv), or between the VHH and Fc. For example, in certain embodiments, the VHH/sdAb is fused to the N-terminus, at either the heavy or light chain, and/or C-terminus of the IgG heavy chain. In particular embodiments, two or more VHH/sdAbs are fused to the IgG at any combination of these locations. In various embodiments, both VHH/sdAbs may be fused to the N-termini of the Fc, to the C-termini of the Fc, or one or more VHH/sdAb may be fused to either or both of an N-terminus or C-terminus of the Fc. In a related embodiment, the surrogate molecule has a Hetero-IgG format, whereas one VHH/sdAb is present as a half antibody, and the other is fused to the N-terminus of the Fc or the C-terminus of the Fc. In certain embodiments, the VHH/sdAb is fused directly to the other VHH/sdAb whereas in other embodiments, the binding regions are fused via a linker moiety. In particular embodiments, the VHH/sdAb are described herein or comprises any of the CDR sets described herein. In various embodiments, any of these formats may comprise one or more scFvs in place of one or more VHH/sdAbs. 
     In certain embodiments, a surrogate molecule is formatted as a diabody. The binders against the two co-receptors can also be linked together in a diabody (or DART) configuration. The diabody can also be in a single chain configuration. If the diabody is fused to an Fc, this will create a bivalent bispecific format. Without fusion to Fc, this would be a monovalent bispecific format. In certain embodiments, a diabody is a noncovalent dimer scFv fragment that consists of the heavy-chain variable (VH) and light-chain variable (VL) regions connected by a small peptide linker. Another form of diabody is a single-chain (Fv)2 in which two scFv fragments are covalently linked to each other. 
     As discussed, the surrogate molecules, in various embodiments, comprise one or more antibodies or antigen-binding fragments thereof disclosed herein. Thus, in particular embodiments, the surrogate comprises two polypeptides, wherein each polypeptide comprises an Nab or scFv that binds at least one first co-receptor and an Nab or scFv that binds at least one second co-receptor, optionally wherein one of the binding domains is an scFv and the other is an Nab. In certain embodiments, a surrogate comprises three polypeptides, wherein the first polypeptide comprises an antibody heavy chain and the second polypeptide comprises an antibody light chain, wherein the antibody heavy chain and light chain bind either receptor, and wherein the third polypeptide comprises a VHH/sdAb fused to a heavy chain Fc region or the light chain of the antibody, wherein the VHH/sdAb binds to either co-receptor. In other embodiments, the surrogates comprise four polypeptides, including two heavy chain polypeptides and two light chain polypeptides, wherein the two heavy chains and two light chains bind one or more first receptor, and further comprise one or more VHH/sdAb or scFv fused to one or more of the heavy chains and/or light chains, wherein the VHH/sdAb or scFv binds to one or more second co-receptor. In an illustrative embodiment, a WNT surrogate comprises at least four polypeptides, including two heavy chain polypeptides and two light chain polypeptides that bind either LRP5/6 or one or more FZDs, wherein the WNT surrogate further comprises a Fab that binds either LRP5/6 or one or more FZDs. For example, the Fab may comprise two polypeptides, each fused to one of the two heavy chain polypeptides, and two polypeptides, each fused to one of the two light chain polypeptides, or it may comprise two polypeptides each fused to one of the two heavy chain polypeptides and two additional polypeptides, each bound to one of the two polypeptides fused to the heavy chain polypeptides, thus making a second Fab. Other configurations disclosed herein may be used to produce different surrogate molecules. 
     Also contemplated are Ig molecules where the VL and VH domains of one Ig are appended with the VL and VH domains of a second antibody. This format is call Fv-Ig or 2Fv-Ig for a homodimer. The VL and VH domains from the second Ig are appended to the N-terminus of the VL and VH domains of the first Ig via short peptide linkers. This format preserves the natural antibody&#39;s avidity to cell surface receptors or to more than one receptor or co-receptor complexes (see, e.g., Wu, et al (2007)  Nature Biotechnol.  25:1290-1297) 
     In certain embodiments, the antigen binding formats are surrogate molecules that comprise one or more polypeptides comprising two or more binding regions. For illustrative purposes, the two or more binding regions may be a first receptor binding regions or a second receptor binding regions, or they may comprise one or more first receptor binding region and one or more second receptor binding region. The binding regions may be directly joined or contiguous, or may be separated by a linker, e.g. a polypeptide linker, or a non-peptidic linker, etc. The length of the linker, and therefore the spacing between the binding domains can be used to modulate the signal strength, and can be selected depending on the desired use of the surrogate molecule. The enforced distance between binding domains can vary, but in certain embodiments may be less than about 100 angstroms, less than about 90 angstroms, less than about 80 angstroms, less than about 70 angstroms, less than about 60 angstroms, or less than about 50 angstroms. In some embodiments the linker is a rigid linker, in other embodiments the linker is a flexible linker. In certain embodiments where the linker is a peptide linker, it may be from about 1-30 amino acids in length, about 5-15 amino acids in length, or about 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 or more amino acids in length, and is of sufficient length and amino acid composition to enforce the distance between binding domains. In some embodiments, the linker comprises or consists of one or more glycine and/or serine residues. 
     The surrogate molecule can be multimerized, e.g. through an Fc domain, by concatenation, coiled coils, polypeptide zippers, biotin/avidin or streptavidin multimerization, and the like. The surrogate molecules can also be joined to a moiety such as PEG, Fc, etc., as known in the art to enhance stability in vivo. 
     In certain embodiments, a surrogate molecule enhances or increases the co-receptors pathway signaling, e.g., in the case of WNT—β-catenin signaling, by at least 30%, 35%, 40%, 45%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 150%, 200%, 250%, 300%, 400% or 500%, as compared to the β-catenin signaling induced by a neutral substance or negative control as measured in an assay described above, for example as measured in the TOPFIash assay (see, e.g., Molinaar (1996)  Cell  86:391-399). A negative control may be included in these assays. By way of example, WNT surrogate molecules may enhance β-catenin signaling by a factor of 2×, 5×, 10×, 100×, 1000×, 10000× or more as compared to the activity in the absence of the WNT surrogate molecule when measured, for example when measured in the TOPFIash assay. 
     In certain embodiments, functional properties of the surrogate molecules (and WNT super agonists and WNT enhancers or RSPO mimetics) may be assessed using a variety of methods known to the skilled person, including e.g., affinity/binding assays (for example, surface plasmon resonance, competitive inhibition assays), cytotoxicity assays, cell viability assays, cell proliferation or differentiation assays in response to the native molecule/ligand, cancer cell and/or tumor growth inhibition using in vitro or in vivo models, including but not limited to any described herein. The surrogate molecules may also be tested for effects on one or both co-receptor internalization, in vitro and in vivo efficacy, etc. Such assays may be performed using well-established protocols known to the skilled person (see e.g., Current Protocols in Molecular Biology (Greene Publ. Assoc. Inc. &amp; John Wiley &amp; Sons, Inc., NY, NY); Current Protocols in Immunology (Edited by: John E. Coligan, Ada M. Kruisbeek, David H. Margulies, Ethan M. Shevach, Warren Strober 2001 John Wiley &amp; Sons, NY, NY); or commercially available kits. 
     In certain embodiments, a binding region of a surrogate molecule (e.g., an antigen-binding fragment of an anti-FZD antibody) comprises one or more of the CDRs of the anti-co-receptor antibodies. In this regard, it has been shown in some cases that the transfer of only the VHCDR3 of an antibody can be performed while still retaining desired specific binding (Barbas et al., PNAS (1995) 92: 2529-2533). See also, McLane et al., PNAS (1995) 92:5214-5218, Barbas et al., J. Am. Chem. Soc. (1994) 116:2161-2162). 
     Also disclosed herein is a method for obtaining an antibody or antigen binding domain specific for a co-receptor, the method comprising providing by way of addition, deletion, substitution or insertion of one or more amino acids in the amino acid sequence of a VH domain set out herein or a VH domain which is an amino acid sequence variant of the VH domain, optionally combining the VH domain thus provided with one or more VL domains, and testing the VH domain or VH/VL combination or combinations to identify a specific binding member or an antibody antigen binding domain specific for one or more co-receptors and optionally with one or more desired properties. The VL domains may have an amino acid sequence which is substantially as set out herein. An analogous method may be employed in which one or more sequence variants of a VL domain disclosed herein are combined with one or more VH domains. 
     Immunological binding generally refers to the non-covalent interactions of the type which occur between an immunoglobulin molecule and an antigen for which the immunoglobulin is specific, for example by way of illustration and not limitation, as a result of electrostatic, ionic, hydrophilic and/or hydrophobic attractions or repulsion, steric forces, hydrogen bonding, van der Waals forces, and other interactions. The strength, or affinity of immunological binding interactions can be expressed in terms of the dissociation constant (Kd) of the interaction, wherein a smaller Kd represents a greater affinity. Immunological binding properties of selected polypeptides can be quantified using methods well known in the art. One such method entails measuring the rates of antigen-binding site/antigen complex formation and dissociation, wherein those rates depend on the concentrations of the complex partners, the affinity of the interaction, and on geometric parameters that equally influence the rate in both directions. Thus, both the “on rate constant” (Kon) and the “off rate constant” (Koff) can be determined by calculation of the concentrations and the actual rates of association and dissociation. The ratio of Koff/Kon enables cancellation of all parameters not related to affinity, and is thus equal to the dissociation constant Kd. See, generally, Davies et al. (1990) Annual Rev. Biochem. 59:439-473. 
     In certain embodiments, the surrogate molecules or binding regions thereof described herein have an affinity of less than about 10,000 nM, less than about 1000 nM, less than about 100 nM, less than about 10 nM, less than about 1 nM, or less than about 0.1 nM, and in some embodiments, the antibodies may have even higher affinity for one or more co-receptors. 
     The constant regions of immunoglobulins show less sequence diversity than the variable regions, and are responsible for binding a number of natural proteins to elicit important biochemical events. In humans, there are five different classes of antibodies including IgA (which includes subclasses IgA1 and IgA2), IgD, IgE, IgG (which includes subclasses IgG1, IgG2, IgG3, and IgG4), and IgM. The distinguishing features between these antibody classes are their constant regions, although subtler differences may exist in the V region. Molecules disclosed herein may comprise an antibody constant region of any class, subclass, or isotype. 
     The Fc region of an antibody interacts with a number of Fc receptors and ligands, imparting an array of important functional capabilities referred to as effector functions. For IgG, the Fc region comprises Ig domains CH2 and CH3 and the N-terminal hinge leading into CH2. An important family of Fc receptors for the IgG class are the Fc gamma receptors (FcγRs). These receptors mediate communication between antibodies and the cellular arm of the immune system (Raghavan et al., 1996, Annu Rev Cell Dev Biol 12:181-220; Ravetch et al., 2001, Annu Rev Immunol 19:275-290). In humans this protein family includes FcγRI (CD64), including isoforms FcγRIa, FcγRIb, and FcγRIc; FcγRII (CD32), including isoforms FcγRIIa (including allotypes H131 and R131), FcγRIIb (including FcγRIIb-1 and FcγRIIb-2), and FcγRIIc; and FcγRIII (CD16), including isoforms FcγRIIIa (including allotypes V158 and F158) and FcγRIIIb (including allotypes FcγRIIIb-NA1 and FcγRIIIb-NA2) (Jefferis et al., 2002 , Immunol Lett  82:57-65). These receptors typically have an extracellular domain that mediates binding to Fc, a membrane spanning region, and an intracellular domain that may mediate some signaling event within the cell. These receptors are expressed in a variety of immune cells including monocytes, macrophages, neutrophils, dendritic cells, eosinophils, mast cells, platelets, B cells, large granular lymphocytes, Langerhans&#39; cells, natural killer (NK) cells, and T cells. Formation of the Fc/FcγR complex recruits these effector cells to sites of bound antigen, typically resulting in signaling events within the cells and important subsequent immune responses such as release of inflammation mediators, B cell activation, endocytosis, phagocytosis, and cytotoxic attack. 
     The ability to mediate cytotoxic and phagocytic effector functions is a potential mechanism by which antibodies destroy targeted cells. The cell-mediated reaction wherein nonspecific cytotoxic cells that express FcγRs recognize bound antibody on a target cell and subsequently cause lysis of the target cell is referred to as antibody dependent cell-mediated cytotoxicity (ADCC) (Raghavan et al., 1996, Annu Rev Cell Dev Biol 12:181-220; Ghetie et al., 2000, Annu Rev Immunol 18:739-766; Ravetch et al., 2001, Annu Rev Immunol 19:275-290). The cell-mediated reaction wherein nonspecific cytotoxic cells that express FcγRs recognize bound antibody on a target cell and subsequently cause phagocytosis of the target cell is referred to as antibody dependent cell-mediated phagocytosis (ADCP). All FcγRs bind the same region on Fc, at the N-terminal end of the Cg2 (CH2) domain and the preceding hinge. This interaction is well characterized structurally (Sondermann et al., 2001, J Mol Biol 309:737-749), and several structures of the human Fc bound to the extracellular domain of human FcγRIIIb have been solved (pdb accession code 1E4K) (Sondermann et al., 2000, Nature 406:267-273) (pdb accession codes 1IIS and IIIX) (Radaev et al., 2001, J Biol Chem 276:16469-16477.) 
     The different IgG subclasses have different affinities for the FcγRs, with IgG1 and IgG3 typically binding substantially better to the receptors than IgG2 and IgG4 (Jefferis et al., 2002 , Immunol Lett  82:57-65). All FcγRs bind the same region on IgG Fc, yet with different affinities: the high affinity binder FcγRI has a Kd for IgG1 of 10 −8  M −1 , whereas the low affinity receptors FcγRII and FcγRIII generally bind at 10 −6  and 10 −5  respectively. The extracellular domains of FcγRIIIa and FcγRIIIb are 96% identical; however, FcγRIIIb does not have an intracellular signaling domain. Furthermore, whereas FcγRI, FcγRIIa/c, and FcγRIIIa are positive regulators of immune complex-triggered activation, characterized by having an intracellular domain that has an immunoreceptor tyrosine-based activation motif (ITAM), FcγRIIb has an immunoreceptor tyrosine-based inhibition motif (ITIM) and is therefore inhibitory. Thus the former are referred to as activation receptors, and FcγRIIb is referred to as an inhibitory receptor. The receptors also differ in expression pattern and levels on different immune cells. Yet another level of complexity is the existence of a number of FcγR polymorphisms in the human proteome. A particularly relevant polymorphism with clinical significance is V158/F158 FcγRIIIa. Human IgG1 binds with greater affinity to the V158 allotype than to the F158 allotype. This difference in affinity, and presumably its effect on ADCC and/or ADCP, has been shown to be a significant determinant of the efficacy of the anti-CD20 antibody rituximab (Rituxan®, a registered trademark of IDEC Pharmaceuticals Corporation). Subjects with the V158 allotype respond favorably to rituximab treatment; however, subjects with the lower affinity F158 allotype respond poorly (Cartron et al., 2002, Blood 99:754-758). Approximately 10 −20 % of humans are V158/V158 homozygous, 45% are V158/F158 heterozygous, and 35-45% of humans are F158/F158 homozygous (Lehrnbecher et al., 1999 , Blood  94:4220-4232; Cartron et al., 2002 , Blood  99:754-758). Thus 80-90% of humans are poor responders, that is, they have at least one allele of the F158 FcγRIIIa. 
     The Fc region is also involved in activation of the complement cascade. In the classical complement pathway, C1 binds with its C1q subunits to Fc fragments of IgG or IgM, which has formed a complex with antigen(s). In certain embodiments of the invention, modifications to the Fc region comprise modifications that alter (either enhance or decrease) the ability of a FZD-specific antibody as described herein to activate the complement system (see e.g., U.S. Pat. No. 7,740,847). To assess complement activation, a complement-dependent cytotoxicity (CDC) assay may be performed (See, e.g., Gazzano-Santoro et al.,  J. Immunol . Methods, 202:163 (1996)). 
     Thus in certain embodiments, the present invention provides the surrogate molecules having a modified Fc region with altered functional properties, such as reduced or enhanced CDC, ADCC, or ADCP activity, or enhanced binding affinity for a specific FcγR or increased serum half-life. Other modified Fc regions contemplated herein are described, for example, in issued U.S. Pat. Nos. 7,317,091; 7,657,380; 7,662,925; 6,538,124; 6,528,624; 7,297,775; 7,364,731; Published U.S. Applications US2009092599; US20080131435; US20080138344; and published International Applications WO2006/105338; WO2004/063351; WO2006/088494; WO2007/024249. 
     Structurally, the Fc region can be important for proper assembly of the msAb. In particular, modifications to the CH3 domain such as knobs-in-hole (see, e.g., WO1996/027011; and WO1998/050431) or Azymetric mutations (see, e.g., WO2012/58768) can prevent heavy chain mispairing. The present invention utilizes these mutations in certain Fc embodiments. 
     The surrogate molecules disclosed herein may also be modified to include an epitope tag or label, e.g., for use in purification or diagnostic applications. There are many linking groups known in the art for making antibody conjugates, including, for example, those disclosed in U.S. Pat. No. 5,208,020 or EP Patent 0 425 235 B1, and Chari et al., Cancer Research 52:127-131 (1992). The linking groups include disulfide groups, thioether groups, acid labile groups, photolabile groups, peptidase labile groups, or esterase labile groups, as disclosed in the above-identified patents, disulfide and thioether groups being preferred. 
     In certain embodiments, and antigen-binding fragments thereof against one co-receptor and/or antibodies and antigen-binding fragments thereof against the other co-receptor present within a surrogate molecule are monoclonal. In certain embodiments, they are humanized. 
     IV. WNT Signal Enhancing Molecules (WNT Enhancers) 
     RSPOs are capable of amplifying WNT signals. The minimal functional unit of RSPO is composed of two Furin domains, Furin domain 1 that binds to ZNRF3/RNF43 E3 ligases, and Furin domain 2 that binds to LGR4-6, bringing together a ternary complex of RSPO, LGR, and the E3 ligases. This results in internalization of the whole complex and removal of ZNRF3/RNF43 away from their targets of destruction. Furin domain 1 alone is not functional, but it is capable of binding to both ZNRF3 and RNF43. In particular embodiments, when used in combination with a WNT or WNT surrogate molecule (e.g., to contact a cell), a WNT signal enhancing molecule increases signaling as compared to if only the WNT or WNT surrogate was used, e.g., by at least 10%, at least 20%, at least 30%, at least 50%, or at least two-fold, at least 3-fold, at least five-fold, or at least 10-fold. 
     The action module or E3 ligase binding domain responsible for enhancing WNT signaling described herein can be, but is not limited to, any functional moiety that can bind to the ZNRF3/RNF43 ligases, e.g., polypeptides, antibodies or fragments thereof, or organic chemicals. In particular embodiments, the action module, for example a polypeptide comprising the Furin domain 1 of an RSPO, either alone or together with a tissue specific targeting module (which may be substantially inactive in non-target tissues, so as to minimize potential off-target effects). The action module is fused to or bound to at least one WNT receptor or receptor binding domain, and when the E3 ligases ZNRF3/RNF43 are recruited to a ternary leading them to be relocated on the cell surface, sequestered, and/or cleared from the cell surface. 
     In certain embodiments, the action module or E3 ligase binding domain comprises a fragment or variant of an RSPO polypeptide (e.g., any of RSPOs 1-4), or a functional fragment or variant thereof. In particular embodiments, the action module comprises a fragment of a wild-type RSPO, and in other embodiments, the action module comprises a fragment of an RSPO comprising one or more amino acid modifications. The RSPO may be any RSPO known in the art or a homolog thereof, including RSPOs from any animal species, including but not limited to mammalian species, such as human RSPOs. RSPOs have been identified and described, and their polypeptide and encoding polynucleotide sequences are known and available in the art. In particular embodiments, the RSPO polypeptide is a human RSPO or a homolog found in other vertebrates or non-vertebrates, e.g., a mouse RSPO. Their homologues and variants are available from general database search, such as https://www.dot.ncbi.dot.nlm.dot.nih.dot.gov/protein/. The present invention includes (but is not limited to) action modules comprising or consisting of fragments and variants of any of these or other RSPOs, in particular, RSPO 2. In various embodiments, variants of any of the RSPO polypeptides and fragments thereof comprise one or more amino acid modifications, e.g., deletions, additions, or substitutions as compared to the wild-type RSPO polypeptide. The modification(s) may be present in any region of the variant of RSPO or a fragment thereof, including but not limited to a Furin domain 1 and/or a Furin domain 2. In particular embodiments, the RSPO is RSPO 2 containing mutations in the Furin domain 2, e.g., F105R and F109A, resulting in abrogated LGR4-6 binding. This mutant RSPO is known as “RSPO2RA”. It is understood that amino acid modifications outside of the Furin domain 1 or Furin domain 2 may alter the resulting variant such that the resulting variant has reduced LGR4-6 binding activity as compared to the wild-type RSPO or fragment thereof. 
     In certain embodiments, the action module comprises or consists of an RSPO sequence, e.g., a full length or wild-type RSPO-1, -2, -3 or -4, optionally a human RSPO-1, -2, -3, or -4, or a variant or fragment thereof. In particular embodiments, it is a variant of any of RSPOs-1-4 having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to the corresponding wild-type RSPO-1-4 sequence. In certain embodiments, the action module comprises or consists of a full length RSPO (e.g., any of RSPOs-1-4) comprising one or more amino acid modifications, including but not limited to any of those disclosed herein. In certain embodiments, the action module comprises or consists of a fragment of a wild-type or modified RSPO (e.g., any of RSPOs-1-4). In particular embodiments, the fragment is able to bind to ZNRF3 and/or RNF43. In certain embodiments, the action module comprises the Furin domain 1 of an RSPO protein, or fragments or variants of RSPO proteins. In certain embodiments, the action module comprises or consists of one or more (e.g., one, two or three or more Furin domain 1 of an RSPO protein (e.g., RSPO-1-4), or a variant thereof having at least 85%, at least 90%, at least 95%, at least 98% or at least 99% sequence identify to an RSPO Furin domain 1. In certain embodiments, the action module comprises an RSPO Furin 1 domain or variant or fragment thereof and an RSPO Furin 2 domain or variant or fragment thereof. In certain embodiments, the action module comprises an antibody, or antigen binding fragment thereof, that bind ZNRF3/RNF43. In particular embodiments, the action module specifically binds to either ZNRF3 or RNF43. Examples of ZNRF3/RNF43 binding molecules are described in WO2020014271. 
     In certain embodiments, the action module or E3 ligase binding domain comprises one or more Furin domain 1 of an RSPO, e.g., human RSPO 1 or human RSPO 2, or a variant thereof. In certain embodiments, the action module comprises one or more Furin domain 1 of an RSPO, but it does not comprise a Furin domain 2 of an RSPO. In certain embodiments, the action module comprises one or more Furin domain 1 of an RSPO, and it comprises a modified or variant Furin domain 2 of an RSPO, e.g., a Furin domain 2 with reduced activity as compared to the wild-type Furin domain 2. In certain embodiments, the action module comprises an RSPO protein having a modified or variant Furin domain 2 of an RSPO, e.g., a Furin domain 2 with reduced activity as compared to the wild-type Furin domain 2. In certain embodiments, an action module comprises two or more Furin domains 1, or variants thereof, or multimers of a Furin domain 1 or variant thereof. In certain embodiments, the action module comprises a variant RSPO Furin 1 domain comprising one or more point mutations, e.g., at amino acid residues corresponding to K58, H76, S77, R86, and/or N91 of human RSPO 2. In certain embodiments, the action module comprises a variant RSPO Furin 2 domain comprising one or more point mutations, e.g., at amino acid residues corresponding to F105, F109 (e.g., “RSPO2RA”), and/or K121 of human RSPO 2. In particular embodiments, the action module comprises a modified or variant Furin domain 1 of an RSPO that has increased activity, e.g., binding to ZNRF3/RNF43, as compared to the wild-type Furin domain 1. Action modules or E3 ligase binding domain may further comprise additional moieties or polypeptide sequences, e.g., additional amino acid residues to stabilize the structure of the WNT signal enhancing molecule in which it is present. In certain embodiments, an action module comprises a peptide or polypeptide without obvious/strong sequence homology to RSPOs but has binding affinity to ZNRF3/RNF43 comparable to or higher than the binding affinity of RSPOs to ZNRF3/RNF43. 
     In certain embodiments, the action module or E3 ligase binding domain comprises a Furin domain 1 of an RSPO polypeptide (e.g., a human RSPO), or a functional fragment or variant thereof, and a modified or variant Furin domain 2 of an RSPO polypeptide (e.g., a human RSPO), wherein the modified Furin domain 2 has reduced binding affinity to LGR4-6 as compared to the corresponding wild-type Furin domain 2. In certain embodiments, the Furin domain 2 comprises one or more point mutations, e.g., at amino acid residues corresponding to F105 and/or F109 of human RSPO 2. The skilled artisan can readily determine the corresponding amino acid residues in other RSPO polypeptides by comparing their amino acid sequences to human RSPO 2. In certain embodiments, the action module or E3 ligase binding domain comprises a Furin domain 1 or variant thereof and a Furin domain 2 or variant thereof, wherein the Furin domain 1 and/or Furin domain 2 comprises one or more point mutations. The one or more point mutations within the action module or E3 ligase binding domain (as compared to the corresponding wild-type RSPO sequence) may occur at any amino acid residues within the Furin domain 1 and/or Furin domain 2, including but not limited to, e.g., at amino acid residues K58, H76, S77, R86, N91, F105, F109, or K121 and other residues that can be modified to reduce the binding affinity to LGR4-6. Regions of the Furin domain 1 and Furin domain 2 of human RSPO 1 that are important for its functional activity have been identified, including conserved hydrophilic residues S48, N51, R66, R70 and Q71, and less conserved, hydrophobic residues, L46, L54, 162 and L64, which are important for binding to the E3 ligases. In addition, in the human RSPO 1 Furin domain 1, amino acid residues K59, S78, D85, R87, N88 and N92 form a hydrophilic interaction surface with LGR5, and the FSHNF amino acid sequence has been identified as a loop important for the hydrophobic surface. 
     In particular embodiments, action modules or E3 ligase binding domains comprising RSPO Furin domain 1 and/or Furin domain 2 may comprise one or more mutations within any of these regions, surfaces or amino acid residues. In particular embodiments, action modules comprising RSPO Furin domain 1 and/or Furin domain 2 may comprise one or more mutations or other alternations beyond these regions, surfaces or amino acid residues, which indirectly compromise LGR4-6 binding by affecting the structure and/or stability of the binding surface. In certain embodiments, action modules comprising RSPO Furin domain 1 and/or Furin domain 2 may comprise one or more mutations at any amino acid residues, including but not limited to any of those depicted in the accompanying Examples. In particular embodiments, the action module comprises a Furin 1 domain and a modified Furin domain 2 comprising amino acid substitutions at amino acid residues F105 and/or F109 (e.g., RSPO2RA). In particular embodiments, the action module comprises a modified Furin 1 domain and a modified Furin 2 domain, where in certain embodiments, the modified Furin 1 domain comprises one or more amino acid modifications at amino acids R65, R69 and/or Q70, and the modified Furin domain comprises one or more amino acid modification at amino acids F105 and/or F109. In particular embodiments, the modified Furin domain 2 has binding affinity to LGR4-6 less than 80%, less than 50%, less than 20%, or less than 10% the binding of the corresponding wild-type Furin domain 2, e.g., in the context of the full length RSPO protein. 
     In certain embodiments, the action module or E3 ligase binding domain comprises a Furin domain 1 of an RSPO polypeptide (e.g., a human RSPO), or a functional fragment or variant thereof, and an unmodified Furin domain 2 of an RSPO polypeptide (e.g., a human RSPO). While in certain embodiments, a modified Furin domain 2 having reduced binding affinity to LGR4-6 as compared to the corresponding wild-type Furin domain 2 is more desirable to increase the specificity of tissue targeting, in particular embodiments, the unmodified Furin domain 2 combined with the targeting module has improved tissue targeting over wild-type RSPO without targeting module, and has utility in certain contexts. 
     In certain embodiments, the action module or E3 ligase binding domain comprises a wild-type or modified RSPO Furin domain 1, e.g., from any of RSPO-1, -2, -3, -4, optionally human RSPOs-1, -2, -3 or -4. In particular embodiments, the action module comprises the RSPO Furin 1 domain and a wild-type or modified RSPO Furin 2 domain, e.g., from any of RSPO-1, -2, -3, -4, optionally human RSPOs-1, -2, -3 or -4. In particular embodiments, the action module comprises the first RSPO Furin 1 domain and a second wild-type or modified RSPO Furin 1 domain, e.g., from any of RSPO-1, -2, -3, -4, optionally human RSPOs-1, -2, -3 or -4. In particular embodiments, the modified Furin domain 2 has comparable binding affinity to LGR4-6 or a binding affinity to LGR4-6 of less than 80%, less than 50%, less than 20%, or less than 10% the binding of the corresponding wild-type Furin domain 2, e.g., in the context of the full length RSPO protein. In certain embodiments, the action module comprises an antibody or antigen-binding fragment thereof that specifically binds ZNRF3 and/or RNF43. In particular embodiments, the action module comprises an antibody or antigen-binding fragment thereof that binds to human RNF43 (hRNF43, NCBI reference sequence XP_011523257.1), or human ZNRF3 (hZNRF3; NCBI reference sequence NP_001193927.1). In particular embodiments, the action module is an antibody or an antigen-binding fragment thereof, comprising: a) CDRH1, CDRH2 and CDRH3 sequences set forth for any of the antibodies of WO2020014271 (e.g., see Table 2A); and/or b) CDRL1, CDRL2 and CDRL3 sequences set forth for any of the antibodies of WO2020014271 (e.g., see Table 2A), or a variant of said antibody, or antigen-binding fragment thereof, comprising one or more amino acid modifications, wherein said variant comprises less than 8 amino acid substitutions in said CDR sequences. 
     V. WNT Super Agonist Structures 
     The present invention encompasses WNT super agonist molecules, in particular, molecules containing a WNT surrogate (e.g., a FZD binder and an LRP binder) in combination with a WNT enhancer (e.g., an RSPO protein or E3 ligase binder). It was surprisingly found that molecules comprising both a WNT surrogate and a WNT enhancer acted as WNT super agonists, and induced a greater level of WNT signaling pathway activity than a WNT surrogate. In particular, it was expected that fusing an E3 ligase binding domain to a WNT surrogate would enhance ubiquitination of the target receptors of the WNT surrogate, and result in antagonism, based on previous studies of PROTAC, i.e., Deshaies, R. J., Nature, Vol 580, 16 Apr. 2020, p. 329). Similarly, it was previously shown that Disheveled binds to WNT receptors and serves as an adaptor to target the ZNRF3 and RNF43 E3 ubiquitin ligases to WNT receptors, leading to their degradation (Jiang, X. et al., 2015, Molecular Cell 58, 522-533). Thus, it was surprising and unexpected to find that the WNT enhancer (or RSPO mimetic, where the E3 ligase binding domain is fused to a FZD or LRP binding domain) and WNT super agonists disclosed herein resulted in increased levels of FZD protein on the cell surface and actually stimulated the WNT signaling pathway. 
     In certain embodiments, a WNT super agonist molecule enhances or increases the co-receptors pathway signaling, e.g., in the case of WNT—β-catenin signaling, by at least 30%, 35%, 40%, 45%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 150%, 200%, 250%, 300%, 400% or 500%, as compared to the β-catenin signaling induced by a neutral substance or negative control as measured in an assay described above, for example as measured in the TOPFlash assay (see, e.g., Molinaar (1996)  Cell  86:391-399). 
     In certain embodiments, a WNT super agonist molecule comprises a first binding domain that binds one or more FZD; a second binding domain that binds LRP5/6; and a third domain comprising a WNT enhancer, e.g., wherein the WNT enhancer comprises an E3 ligase binding domain. These domains may be present on one, two, three, or four polypeptides. When present on more than one polypeptide, the two or more polypeptides may be bound to each other to form the WNT super agonist. Non-limiting examples of various WNT super agonist structures contemplated by the disclosure are provided in Table 4 and  FIGS.  8 A- 8 B . 
     In certain embodiments, a WNT super agonist molecule comprises any of the structures disclosed herein for a WNT surrogate molecule, while further comprising a WNT enhancer domain and, optionally, a targeting module. In some embodiments, the WNT enhancer domain comprises an RSPO protein or functional variant or fragment thereof. In some embodiments, the WNT enhancer domain binds one or more E3 ligase. In particular embodiments, the WNT enhancer domain does not substantially bind to LGR. In particular embodiments, the WNT enhancer domain is a mutant RSPO that lacks an LGR binding region. 
     In some embodiments, the WNT super agonist molecule further comprises a targeting module, e.g., a targeting module that binds specific cell types or tissue types. In certain embodiments of WNT super agonists, one or more WNT enhancer domain is fused to either end of any polypeptide present within a WNT surrogate molecule. In particular embodiments, one, two, three, or four WNT enhancer domains are present within a WNT super agonist. 
     In certain embodiments, the WNT surrogates, WNT enhancers, or WNT super agonists comprise or have a structure including, but not limited to, a tandem scFv, scFv-IgG, Fv-IgG, Fab-IgG, VHH-IgG, or Fv-Fab (see, e.g., the general structures of  FIG.  1 A  and the specific structures of  FIGS.  2 A,  2 D,  2 E,  3 A,  3 J,  3 L,  3 M,  4 ,  7 ,  8 A,  8 B , and Tables 3 and 4). 
     Tandem scFv super agonists are generated and assembled by linking or directly fusing a first scFv to either the C- or N-terminus of a second scFv molecule. In one format, the first scFv can bind to one or more FZD receptors and the second scFv can bind to one or more LRP receptors. In an alternative format, the first scFv can bind to one or more LRP receptors, and the second scFv can bind to one or more FZD receptors. One of the scFv molecules can also be linked or directly fused at its C-terminus to the N-terminus of an Fc molecule. In certain embodiments of WNT super agonists, the WNT enhancer is linked or fused to the N-terminus of a first scFv, which in turn is linked or fused to the N-terminus of the second scFv, which is linked or fused to the N-terminus of the Fc molecule. In alternative embodiments, the WNT enhancer is linked or fused to the C-terminus of the Fc molecule, which in turn is linked or fused to the C-terminus of one scFv molecule, which is linked or fused at its N-terminus to the C-terminus of a second scFv molecule. 
     Fab-IgG molecules, where the FZD and LRP binders are both Fabs can be assembled in various approaches, such as charge pairing, knobs-in-holes, crossover of heavy and light chains of the Fabs, etc. In charge pairing the heavy chain (VH-CH1) domain of an anti-LRP6 Fab or an anti-FZD Fab (through direct fusion or a linker, e.g., a linker of 1-30 or 5-15 amino acid, e.g., 5, 10, or 15-mer amino acids) are fused in tandem with the N-terminus of the heavy chain (VH-CH1-CH2-CH3) of an anti-FZD or anti-LRP binder. In certain embodiments, also known as Fabs-in tandem (FiT), both VH-CH1 domains of anti-LRP6 and anti-FZD contain three amino acid mutations (Q39D, Q105D, S183K in the anti-LRP6 Fab; Q39K, Q105K, S183E in anti-FZD Fab) each for proper paring with their own partner light chains, which also contain three complementary amino acid mutations (Q38K, A/S43K, S176E in anti-LRP6 light chain; Q38D, A/S43D, S176K in the anti-FZD light chain). The order of the anti-LRP6 and anti-FZD Fabs could be reversed, where the anti-FZD binder is a Fab and is fused to anti-LRP binder which is in IgG format. In certain embodiments, the WNT enhancer can be attached to the Fab to the N-terminus of either the Vh or Vl the Fab furthest from the IgG domain. In other embodiments, the WNT enhancer is attached to C-terminus of the IgG domain. 
     HC-LC cross over approach for Fab-on-IgG format: The light chain (VL-CL) domains of anti-LRP6 binder is (through direct fusion or a linker, e.g., a linker of 1-30 or 5-15 amino acid, e.g., 5, 10, or 15-mer amino acids) fused in tandem with the N-terminus of the heavy chain (VH-CH1-CH2-CH3) of an anti-FZD binder. The second construct was VH-CH1 of the anti-LRP6 binder and the third construct was VL-CL of the anti-FZD binder. Similar to the example above, the order of the anti-LRP6 and the anti-FZD binders could be reversed, where anti-FZD binder Fab is fused to the N-terminus of the anti-LRP binder which is in IgG format. Also as above the WNT enhancer can be attached to N-terminus of the VH or VL of the crossover Fab furthest from the IgG domain, or attached to the C-terminus of the IgG domain. 
     In certain embodiments, the WNT surrogate region of the WNT super agonist is an Fv-IgG. Illustrative examples of various structural formats that may be used are provided in  FIG.  1 A , and  FIGS.  8 A and  8 B , as well as Table 4. In particular embodiments, the WNT super agonist is an Fv-IgG with the components including at least one binding domain that binds to at least one FZD receptor, at least one binding domain that binds to an LRP receptor, and either at least one RSPO protein (mutant or wild-type) or at least one binding domain that binds to an E3 ubiquitin ligase. In some embodiments, the LRP binding domain is a VHH or Fab fragment linked to the N-terminus of a Fab that binds to a FZD receptor, which is fused to an Fc domain at the C terminus of the FZD Fab (see, e.g.,  FIGS.  2 A,  2 D,  2 E,  3 A,  3 J,  3 L,  3 M,  4 A,  8 A,  8 B , and Table 4). In some embodiments, the FZD binding domain is a VHH or Fab fragment linked to the N-terminus of a Fab that binds to LRP5/6, which is fused to an Fc domain at the C terminus of the LRP5/6 Fab. In further embodiments, the Fv-IgG contains the LRP5/6 VHH and FZD Fab, with an RSPO protein or E3 ligase binder attached to the C-terminus of the Fc domain. Alternatively, the RSPO or E3 ligase binder can be attached to the C-terminus of the heavy or light chain of the Fab (see, e.g.,  FIG.  3 J ,  FIGS.  8 A and  8 B , and Table 4). 
     In certain embodiments, the WNT surrogate region of the WNT super agonist is an Fv-IgG comprising four linked polypeptides, e.g., as depicted in  FIG.  8 A  or  FIG.  8 B . In certain embodiments, the Fv-IgG comprises two heavy chain polypeptides and two light chain polypeptides. In certain embodiments, each heavy chain polypeptide comprises an Fc region, a variable region of an anti-FZD antibody, and a variable region of an anti-LRP5/6 antibody, wherein the two variable regions are present N-terminal to the Fc region, and wherein the two variable regions may be in either order. In one embodiment, the heavy chain comprises from N-terminus to C-terminus: an anti-LRP5/6 antibody variable region, an anti-FZD variable region, and an Fc region. In particular embodiments, one or both variable region is present within a Fab. The heavy chain may further comprise additional sequences, such as, e.g., a hinge region between the Fc region and the variable regions (or Fab). In particular embodiments, the two light chain polypeptides each comprise a variable region of an anti-FZD antibody, and a variable region of an anti-LRP5/6 antibody, wherein the two variable regions may be in either order, and wherein either or both variable region is present within a Fab. In particular embodiments, an E3 ligase binding domain is fused to the C-terminus or N-terminus of one or both heavy chains. In particular embodiments, an E3 ligase binding domain is fused to the C-terminus or N-terminus of one or both light chains (see, e.g.,  FIG.  8 B ). In particular embodiments, the two heavy chain polypeptides of the WNT super agonist molecule are the same, and bind to each other. In certain embodiments, the two heavy chain polypeptides of the WNT super agonist molecule are different, for example, when the WNT super agonist molecule includes only one E3 ligase binding domain. In order to properly combine a heavy chain without an E3 ligase domain with a heavy chain having an E3 ligase domain, the two different heavy chains may be engineered to selectively bind to each other to produce heterodimers, e.g., by introducing Knob-into-holes amino acid modifications into the two different polypeptides to facilitate their binding. 
     Additionally, the Fv-IgG or other format structure, can include a tissue or cell targeting domain, which can be attached at similar sites as the RSPO or E3 ligase binder or can be an full length antibody that binds a tissue/cell specific target with the WNT receptor binding domains and RSPO/E3 ligase binding domains attached at various sites as described above. 
     In particular embodiments, any of the domains present in the WNT super agonist are directly joined, or may be separated via a linker, e.g., a polypeptide linker, or a non-peptidic linker, etc. The length of the linker, and therefore the spacing between the binding domains can be used to modulate the signal strength, and can be selected depending on the desired use of the WNT super agonist molecule. The enforced distance between any of the various linked binding domains can vary, but in certain embodiments may be less than about 100 angstroms, less than about 90 angstroms, less than about 80 angstroms, less than about 70 angstroms, less than about 60 angstroms, or less than about 50 angstroms. In some embodiments, the linker is a rigid linker, in other embodiments the linker is a flexible linker. In certain embodiments where the linker is a peptide linker, it may be from about 1-30 amino acids in length, about 5-15 amino acids in length, or about 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 or more amino acids in length, and is of sufficient length and amino acid composition to enforce the distance between binding domains. In some embodiments, the linker comprises or consists of one or more glycine and/or serine residues. 
     In particular embodiments, the WNT super agonist comprises any of the ratios of FZD binding domains and LRP5/6 binding domains disclosed herein for WNT surrogate molecules. In particular embodiments, the WNT super agonist comprises any of the ratios of FZD binding domains and LRP5/6 binding domains disclosed herein for WNT surrogate molecules, and further comprises one or two E3 ligase binding domains. 
     In certain embodiments, the WNT super agonist molecules or one or more binding regions thereof described herein have an affinity of less than about 10,000 nM, less than about 1000 nM, less than about 100 nM, less than about 10 nM, less than about 1 nM, or less than about 0.1 nM, and in some embodiments, the antibodies may have even higher affinity for one or more co-receptors. 
     In particular embodiments, a WNT super agonist comprises one or more polypeptide sequence disclosed herein, e.g., in the Examples, or a functional variant or fragment thereof. 
     VI. Targeting Molecules 
     Any of the molecules disclosed herein, e.g., WNT super agonists, WNT surrogates, and WNT enhancers (RSPO mimetics) may further comprise a cell- or tissue-specific binding domain. 
     Specific cell types and cells within specific tissue may comprise one or more cell- or tissue-specific surface molecule, such as a cell surface receptor. As used herein, the molecule is said to be cell- or tissue-specific if a greater amount of the molecule is present on the specific cell or tissue type as compared to one or more other cell or tissue types, or any other cell or tissue type. In certain embodiments, the greater amount is at least two-fold, at least five-fold, at least 10-fold, at least 20-fold, at least 50-fold, or at least 100-fold as compared to the amount in the one or more other cell or tissue types, or any other cell or tissue type. In particular embodiments, the cell-specific surface molecule has increased or enhanced expression on a target organ, tissue or cell type, e.g., an organ, tissue or cell type in which it is desirous to enhance WNT signaling, e.g., to treat or prevent a disease or disorder, e.g., as compared to one or more other non-targeted organs, tissues or cell types. In certain embodiments, the cell-specific surface molecule is preferentially expressed on the surface of the target organ, tissue or cell type as compared to one or more other organ, tissue or cell types, respectively. For example, in particular embodiments, a cell surface receptor is considered to be a tissue-specific or cell-specific cell surface molecule if it is expressed at levels at least two-fold, at least five-fold, at least 10-fold, at least 20-fold, at least 30-fold, at least 40-fold, at least 50-fold, at least 100-fold, at least 500-fold, or at least 1000-fold higher in the target organ, tissue or cell than it is expressed in one or more, five or more, all other organs, tissues or cells, or an average of all other organs, tissue or cells, respectively. In certain embodiments, the tissue-specific or cell-specific cell surface molecule is a cell surface receptor, e.g., a polypeptide receptor comprising a region located within the cell surface membrane and an extracellular region to which the targeting module can bind. In various embodiments, the methods described herein may be practiced by specifically targeting cell surface molecules that are only expressed on the target tissue or a subset of tissues including the target tissue, or by specifically targeting cell surface molecules that have higher levels of expression on the target tissue as compared to all, most, or a substantial number of other tissues, e.g., higher expression on the target tissue than on at least two, at least five, at least ten, or at least twenty other tissues. 
     The targeted tissue may be bound by a targeting module, e.g., a binding domain that specifically binds to the tissue specific receptor. The targeted tissue may be any tissue, e.g., any mammalian tissue or cell type. In certain embodiments, the targeted tissue may be present in any organ. In certain embodiments, the target tissue is bone tissue, liver tissue, skin tissue, stomach tissue, intestine tissue, oral mucosa tissue, kidney tissue, central nervous system tissue, mammary gland tissue, taste bud tissue, ovary tissue, inner ear tissue (including cochlear and vestibular tissues), hair follicles, pancreas tissue, retina tissue, cornea tissue, heart tissue or lung tissue, and the targeting module binds to a tissue-specific cell surface molecule (e.g., a cell surface receptor) preferentially expressed on bone tissue, liver tissue, skin tissue, stomach tissue, intestine tissue, oral mucosa tissue, kidney tissue, central nervous system tissue, mammary gland tissue, taste bud tissue, ovary tissue, inner ear tissue (including cochlear and vestibular tissues), hair follicles, pancreas tissue, retina tissue, cornea tissue, heart tissue or lung tissue, respectively. 
     The targeting module may bind to any cell type, e.g., any cell within any tissue, organ or animal, including but not limited to mammals, such as humans. In certain embodiments, the tissue-specific WNT surrogate-signal enhancing combination molecule binds to specific cell types, e.g., specific cell types associated with a target tissue. For example, in liver tissue, the targeting module may bind to hepatocytes, precursors and stem cells of hepatocytes, biliary tract cells, and/or endothelial or other vascular cells. For example, in bone tissue, the targeting module may bind osteoblasts, precursors of osteoblasts, mesenchymal stem cells, stem cells and precursor cells that give rise to bone, cartilage and/or other cells present in bone tissue. Cell types present in various tissues, including but not limited to the tissues described herein, are known in the art, and in various embodiments, the tissue-specific WNT signal enhancing molecules described herein may bind any of them. 
     VII. WNT Enhancer Structures (RSPO Mimetics) 
     In some embodiments, an RSPO mimetic having the activities of RSPO is desirable. In certain embodiments, the disclosure provides RSPO mimetics, comprising: (i) either a FZD binding domain or an LRP5/6 binding domain (but not both); and an E3 ligase binding domain. The WNT enhancers can operate as RSPO mimetics. In certain embodiments, the RSPO mimetic can have the structures depicted in  FIG.  2 A,  2 D , or  2 E. In particular embodiments, an RSPO mimetic will have mutant RSPO (RSPO2RA) and at least one binding domain specific for a WNT receptor (e.g., FZD or LRP). The RSPO mimetic with a FZD binding domain can function as a tissue or cell specific RSPO mimetic if the FZD receptor expression is limited to a particular organ, tissue, or cell. 
     VIII. Linkers 
     In certain embodiments, the WNT surrogate, enhancer, and/or targeting modules are bound or fused directly to each other, whereas in other embodiments, they are separated by a linker, e.g., a polypeptide linker, or a non-peptidyl linker, etc. In particular embodiments, a linker is an Fc linker, e.g., a region of an antibody Fc domain capable of dimerizing with another Fc linker, e.g., via one or more disulfide bonds. In another particular embodiment, a linker is albumin, e.g., human serum albumin, where the targeting and action modules are on the N- and C-termini of albumin. 
     In certain embodiments, particularly when joining two polypeptides, the linker is made up of amino acids linked together by peptide bonds. In particular embodiments, the linker comprises, in length, from 1 up to about 40 amino acid residues, from 1 up to about 30 amino acid residues, from 1 up to about 20 amino acid residues, from 5 up to about 15 amino acid residues, or from 1 to about 10 amino acid residues, e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids. In certain embodiments, the amino acid residues in the linker are from among the twenty canonical amino acids, and in certain embodiments, selected from cysteine, glycine, alanine, proline, asparagine, glutamine, and/or serine. In certain embodiments, a linker comprises one or more non-natural amino acids. In some embodiments, a peptidyl linker is made up of a majority of amino acids that are sterically unhindered, such as glycine, serine, and alanine linked by a peptide bond. Certain linkers include polyglycines, polyserines, and polyalanines, or combinations of any of these. Some exemplary peptidyl linkers are poly(Gly)1-8, particularly (Gly)3, (Gly)4 (SEQ ID NO: 1), (Gly)5 (SEQ ID NO: 2), (Gly)6 (SEQ ID NO: 3), (Gly)7 (SEQ ID NO: 4), and (Gly)8 (SEQ ID NO: 5) as well as, poly(Gly)4 Ser (SEQ ID NO: 6), poly(Gly-Ala)2 (SEQ ID NO: 7), poly(Gly-Ala)3 (SEQ ID NO: 8), poly(Gly-Ala)4 (SEQ ID NO: 9) and poly(Ala)1-8 (SEQ ID NO: 10-14). Other specific examples of peptidyl linkers include (Gly)5Lys (SEQ ID NO: 15), and (Gly)5LysArg (SEQ ID NO: 16). To explain the above nomenclature, for example, (Gly)3Lys(Gly)4 means Gly-Gly-Gly-Lys-Gly-Gly-Gly-Gly (SEQ ID NO: 17). Other combinations of Gly and Ala are also useful. Additionally, a peptidyl linker can also comprise a non-peptidyl segment such as a 6 carbon aliphatic molecule of the formula —CH2-CH2-CH2-CH2-CH2-CH2-. The peptidyl linkers can be altered to form derivatives as described herein. 
     Illustrative non-peptidyl linkers include, for example, alkyl linkers such as —NH—(CH2) s-C(O)—, wherein s=2-20. These alkyl linkers may further be substituted by any non-sterically hindering group such as lower alkyl (e.g., C1-C6) lower acyl, halogen (e.g., Cl, Br), CN, NH2, phenyl, etc. Non-peptide portions of the inventive composition of matter, such as non-peptidyl linkers or non-peptide half-life extending moieties can be synthesized by conventional organic chemistry reactions. Chemical groups that find use in linking binding domains include carbamate; amide (amine plus carboxylic acid); ester (alcohol plus carboxylic acid), thioether (haloalkane plus sulfhydryl; maleimide plus sulfhydryl), Schiff s base (amine plus aldehyde), urea (amine plus isocyanate), thiourea (amine plus isothiocyanate), sulfonamide (amine plus sulfonyl chloride), disulfide; hydrazone, lipids, and the like, as known in the art. 
     The linkage between domains may comprise spacers, e.g. alkyl spacers, which may be linear or branched, usually linear, and may include one or more unsaturated bonds; usually having from one to about 300 carbon atoms; more usually from about one to 25 carbon atoms; and may be from about three to 12 carbon atoms. Spacers of this type may also comprise heteroatoms or functional groups, including amines, ethers, phosphodiesters, and the like. Specific structures of interest include: (CH 2 CH 2 O)n where n is from 1 to about 12; (CH 2 CH 2 NH)n, where n is from 1 to about 12; [(CH 2 )n(C═O)NH(CH 2 )m] z , where n and m are from 1 to about 6, and z is from 1 to about 10; [(CH 2 )nOPO 3 (CH 2 )m] z  where n and m are from 1 to about 6, and z is from 1 to about 10. Such linkers may include polyethylene glycol, which may be linear or branched. 
     In certain embodiments, the domains may be joined through a homo- or heterobifunctional linker. Illustrative entities include: azidobenzoyl hydrazide, N-[4-(p-azidosalicylamino)butyl]-3′-[2′-pyridyldithio]propionamide), bis-sulfosuccinimidyl suberate, dimethyladipimidate, disuccinimidyltartrate, N-γ-maleimidobutyryloxysuccinimide ester, N-hydroxy sulfosuccinimidyl-4-azidobenzoate, N-succinimidyl [4-azidophenyl]-1,3′-dithiopropionate, N-succinimidyl [4-iodoacetyl]aminobenzoate, glutaraldehyde, NHS-PEG-MAL; succinimidyl 4-[N-maleimidomethyl]cyclohexane-1-carboxylate; 3-(2-pyridyldithio)propionic acid N-hydroxysuccinimide ester (SPDP); N, N′-(1,3-phenylene) bismaleimide; N, N′-ethylene-bis-(iodoacetamide); or 4-(N-maleimidomethyl)-cyclohexane-1-carboxylic acid N-hydroxysuccinimide ester (SMCC); m-maleimidobenzoyl-N-hydroxysuccinimide ester (MBS), and succinimide 4-(p-maleimidophenyl)butyrate (SMPB), an extended chain analog of MBS. In certain embodiments, the succinimidyl group of these cross-linkers reacts with a primary amine, and the thiol-reactive maleimide forms a covalent bond with the thiol of a cysteine residue. 
     Other reagents useful include: homobifunctional cross-linking reagents including bismaleimidohexane (“BMH”); p,p′-difluoro-m,m′-dinitrodiphenylsulfone (which forms irreversible cross-linkages with amino and phenolic groups); dimethyl adipimidate (which is specific for amino groups); phenol-1,4-disulfonylchloride (which reacts principally with amino groups); hexamethylenediisocyanate or diisothiocyanate, or azophenyl-p-diisocyanate (which reacts principally with amino groups); disdiazobenzidine (which reacts primarily with tyrosine and histidine); O-benzotriazolyloxy tetramethuluronium hexafluorophosphate (HATU), dicyclohexyl carbodiimde, bromo-tris (pyrrolidino) phosphonium bromide (PyBroP); N,N-dimethylamino pyridine (DMAP); 4-pyrrolidino pyridine; N-hydroxy benzotriazole; and the like. 
     IX. Nucleic Acids and Polypeptides 
     The present invention further provides in certain embodiments an isolated nucleic acid encoding a polypeptide present in a molecule disclosed herein, e.g., a WNT surrogate, a WNT enhancer, or a WNT super agonist. Nucleic acids include DNA and RNA. These and related embodiments may include polynucleotides encoding antibody fragments that bind one or more co-receptors. The term “isolated polynucleotide” as used herein shall mean a polynucleotide of genomic, cDNA, or synthetic origin, or some combination thereof, which by virtue of its origin, the isolated polynucleotide: (1) is not associated with all or a portion of a polynucleotide in which the isolated polynucleotide is found in nature; (2) is linked to a polynucleotide to which it is not linked in nature, or (3) does not occur in nature as part of a larger sequence. An isolated polynucleotide may include naturally occurring and/or artificial sequences. 
     As will be understood by those skilled in the art, polynucleotides may include genomic sequences, extra-genomic and plasmid-encoded sequences and smaller engineered gene segments that express, or may be adapted to express, proteins, polypeptides, peptides and the like. Such segments may be naturally isolated, or modified synthetically by the skilled person. 
     As will be also recognized by the skilled artisan, polynucleotides may be single-stranded (coding or antisense) or double-stranded, and may be DNA (genomic, cDNA or synthetic) or RNA molecules. RNA molecules may include HnRNA molecules, which contain introns and correspond to a DNA molecule in a one-to-one manner, and mRNA molecules, which do not contain introns. Additional coding or non-coding sequences may, but need not, be present within a polynucleotide according to the present disclosure, and a polynucleotide may, but need not, be linked to other molecules and/or support materials. Polynucleotides may comprise a native sequence or may comprise a sequence that encodes a variant or derivative of such a sequence. 
     It will be appreciated by those of ordinary skill in the art that, as a result of the degeneracy of the genetic code, there are many nucleotide sequences that encodes an antibody as described herein. Some of these polynucleotides bear minimal sequence identity to the nucleotide sequence of the native or original polynucleotide sequence encoding a polypeptide within a WNT surrogate, a WNT enhancer, or a WNT super agonist. Nonetheless, polynucleotides that vary due to differences in codon usage are expressly contemplated by the present disclosure. In certain embodiments, sequences that have been codon-optimized for mammalian expression are specifically contemplated. 
     Therefore, in another embodiment of the invention, a mutagenesis approach, such as site-specific mutagenesis, may be employed for the preparation of variants and/or derivatives of the polypeptides described herein. By this approach, specific modifications in a polypeptide sequence can be made through mutagenesis of the underlying polynucleotides that encode them. These techniques provide a straightforward approach to prepare and test sequence variants, for example, incorporating one or more of the foregoing considerations, by introducing one or more nucleotide sequence changes into the polynucleotide. 
     Site-specific mutagenesis allows the production of mutants through the use of specific oligonucleotide sequences which encode the DNA sequence of the desired mutation, as well as a sufficient number of adjacent nucleotides, to provide a primer sequence of sufficient size and sequence complexity to form a stable duplex on both sides of the deletion junction being traversed. Mutations may be employed in a selected polynucleotide sequence to improve, alter, decrease, modify, or otherwise change the properties of the polynucleotide itself, and/or alter the properties, activity, composition, stability, or primary sequence of the encoded polypeptide. 
     In certain embodiments, the inventors contemplate the mutagenesis of the polynucleotide sequences that encode a polypeptide present in a molecule disclosed herein, e.g., a WNT surrogate, a WNT enhancer, or a WNT super agonist, to alter one or more properties of the encoded polypeptide, such as the binding affinity, or the function of a particular Fc region, or the affinity of the Fc region for a particular FcγR. The techniques of site-specific mutagenesis are well-known in the art, and are widely used to create variants of both polypeptides and polynucleotides. For example, site-specific mutagenesis is often used to alter a specific portion of a DNA molecule. In such embodiments, a primer comprising typically about 14 to about 25 nucleotides or so in length is employed, with about 5 to about 10 residues on both sides of the junction of the sequence being altered. 
     As will be appreciated by those of skill in the art, site-specific mutagenesis techniques have often employed a phage vector that exists in both a single stranded and double stranded form. Typical vectors useful in site-directed mutagenesis include vectors such as the M13 phage. These phages are readily commercially-available and their use is generally well-known to those skilled in the art. Double-stranded plasmids are also routinely employed in site directed mutagenesis that eliminates the step of transferring the gene of interest from a plasmid to a phage. 
     The preparation of sequence variants of the selected peptide-encoding DNA segments using site-directed mutagenesis provides a means of producing potentially useful species and is not meant to be limiting as there are other ways in which sequence variants of peptides and the DNA sequences encoding them may be obtained. For example, recombinant vectors encoding the desired peptide sequence may be treated with mutagenic agents, such as hydroxylamine, to obtain sequence variants. Specific details regarding these methods and protocols are found in the teachings of Maloy et al., 1994; Segal, 1976; Prokop and Bajpai, 1991; Kuby, 1994; and Maniatis et al., 1982, each incorporated herein by reference, for that purpose. 
     In many embodiments, one or more nucleic acids encoding a polypeptide of a molecule disclosed herein, e.g., a WNT surrogate, a WNT enhancer, or a WNT super agonist, are introduced directly into a host cell, and the cell incubated under conditions sufficient to induce expression of the encoded polypeptides. 
     The surrogate polypeptides of this disclosure may be prepared using standard techniques well known to those of skill in the art in combination with the polypeptide and nucleic acid sequences provided herein. The polypeptide sequences may be used to determine appropriate nucleic acid sequences encoding the particular polypeptide disclosed thereby. The nucleic acid sequence may be optimized to reflect particular codon “preferences” for various expression systems according to standard methods well known to those of skill in the art. 
     According to certain related embodiments there is provided a recombinant host cell that comprises one or more constructs as described herein, e.g., a vector comprising a nucleic acid encoding a surrogate molecule or polypeptide thereof, and a method of production of the encoded product, which method comprises expression from encoding nucleic acid therefor. Expression may conveniently be achieved by culturing under appropriate conditions recombinant host cells containing the nucleic acid. Following production by expression, an antibody or antigen-binding fragment thereof, may be isolated and/or purified using any suitable technique, and then used as desired. 
     Polypeptides, and encoding nucleic acid molecules and vectors, may be isolated and/or purified, e.g. from their natural environment, in substantially pure or homogeneous form, or, in the case of nucleic acid, free or substantially free of nucleic acid or genes of origin other than the sequence encoding a polypeptide with the desired function. Nucleic acid may comprise DNA or RNA and may be wholly or partially synthetic. Reference to a nucleotide sequence as set out herein encompasses a DNA molecule with the specified sequence, and encompasses a RNA molecule with the specified sequence in which U is substituted for T, unless context requires otherwise. 
     Systems for cloning and expression of a polypeptide in a variety of different host cells are well known. Suitable host cells include bacteria, mammalian cells, yeast and baculovirus systems. Mammalian cell lines available in the art for expression of a heterologous polypeptide include Chinese hamster ovary cells, HeLa cells, baby hamster kidney cells, NSO mouse melanoma cells and many others. A common, preferred bacterial host is  E. coli . Polypeptides present within a molecule disclosed herein, e.g., a WNT surrogate, a WNT enhancer, or a WNT super agonist, may be recombinantly produced in prokaryotic or eukaryotic cells. 
     The expression of polypeptides, e.g., antibodies and antigen-binding fragments thereof, in prokaryotic cells such as  E. coli  is well established in the art. For a review, see for example Pluckthun, A. Bio/Technology 9: 545-551 (1991). Expression in eukaryotic cells in culture is also available to those skilled in the art as an option for production of antibodies or antigen-binding fragments thereof, see recent reviews, for example Ref, M. E. (1993) Curr. Opinion Biotech. 4: 573-576; Trill J. J. et al. (1995) Curr. Opinion Biotech 6: 553-560. 
     Suitable vectors can be chosen or constructed, containing appropriate regulatory sequences, including promoter sequences, terminator sequences, polyadenylation sequences, enhancer sequences, marker genes and other sequences as appropriate. Vectors may be plasmids, viral e.g. phage, or phagemid, as appropriate. For further details see, for example, Molecular Cloning: a Laboratory Manual: 2nd edition, Sambrook et al., 1989, Cold Spring Harbor Laboratory Press. Many known techniques and protocols for manipulation of nucleic acid, for example in preparation of nucleic acid constructs, mutagenesis, sequencing, introduction of DNA into cells and gene expression, and analysis of proteins, are described in detail in Current Protocols in Molecular Biology, Second Edition, Ausubel et al. eds., John Wiley &amp; Sons, 1992, or subsequent updates thereto. 
     The present invention also provides, in certain embodiments, a method which comprises using a construct as stated above in an expression system in order to express a particular polypeptide present within a molecule disclosed herein, e.g., a WNT surrogate, a WNT enhancer, or a WNT super agonist. The term “transduction” is used to refer to the transfer of genes from one bacterium to another, usually by a phage. 
     Amino acid sequence modification(s) of any of the polypeptides described herein are contemplated. For example, it may be desirable to improve the binding affinity and/or other biological properties of the surrogate molecule. For example, amino acid sequence variants of a molecule disclosed herein, e.g., a WNT surrogate, a WNT enhancer, or a WNT super agonist, may be prepared by introducing appropriate nucleotide changes into a polynucleotide that encodes the antibody, or a chain thereof, or by peptide synthesis. Such modifications include, for example, deletions from, and/or insertions into and/or substitutions of, residues within the amino acid sequences of the antibody. Any combination of deletion, insertion, and substitution may be made to arrive at the final surrogate molecule, provided that the final construct possesses the desired characteristics (e.g., high affinity binding to one or more co-receptors). The amino acid changes also may alter post-translational processes of the antibody, such as changing the number or position of glycosylation sites. Any of the variations and modifications described above for polypeptides of the present invention may be included in antibodies of the present invention. 
     The present disclosure provides variants of any of the polypeptides (e.g., polypeptides of surrogate molecules, super agonists, or antibodies or antigen-binding fragments thereof) disclosed herein. In certain embodiments, a variant has at least 90%, at least 95%, at least 98%, or at least 99% identity to a polypeptide disclosed herein. In certain embodiments, such variant polypeptides bind to one or more first co-receptors, and/or to one or more second co-receptors, and/or to an E3 ligase at least about 50%, at least about 70%, and in certain embodiments, at least about 90% as well as a molecule specifically set forth herein. In further embodiments, such variant molecules bind to one or more first co-receptor, and/or to one or more second co-receptor, with greater affinity than the molecules set forth herein, for example, that bind quantitatively at least about 105%, 106%, 107%, 108%, 109%, or 110% as well as an antibody sequence specifically set forth herein. 
     In particular embodiments, a molecule disclosed herein, e.g., a WNT surrogate, a WNT enhancer, or a WNT super agonist, or a binding region thereof, e.g., a Fab, scFv, or VHH may comprise: a) a heavy chain variable region comprising: i. a CDR1 region that is identical in amino acid sequence to the heavy chain CDR1 region of a selected antibody described herein; ii. a CDR2 region that is identical in amino acid sequence to the heavy chain CDR2 region of the selected antibody; and iii. a CDR3 region that is identical in amino acid sequence to the heavy chain CDR3 region of the selected antibody; and/or b) a light chain variable domain comprising: i. a CDR1 region that is identical in amino acid sequence to the light chain CDR1 region of the selected antibody; ii. a CDR2 region that is identical in amino acid sequence to the light chain CDR2 region of the selected antibody; and iii. a CDR3 region that is identical in amino acid sequence to the light chain CDR3 region of the selected antibody; wherein the antibody specifically binds a selected target. In a further embodiment, the antibody, or antigen-binding fragment thereof, is a variant antibody or antigen-binding fragment thereof wherein the variant comprises a heavy and light chain identical to the selected antibody except for up to 8, 9, 10, 11, 12, 13, 14, 15, or more amino acid substitutions in the CDR regions of the VH and VL regions. In this regard, there may be 1, 2, 3, 4, 5, 6, 7, 8, or in certain embodiments, 9, 10, 11, 12, 13, 14, 15 more amino acid substitutions in the CDR regions of the selected antibody. Substitutions may be in CDRs either in the VH and/or the VL regions. (See e.g., Muller, 1998, Structure 6:1153-1167). 
     In particular embodiments, a molecule disclosed herein, e.g., a WNT surrogate, a WNT enhancer, or a WNT super agonist, or a binding region thereof, e.g., a Fab, scFv, or VHH/sdAb, may have: a) a heavy chain variable region having an amino acid sequence that is at least 80% identical, at least 95% identical, at least 90%, at least 95% or at least 98% or 99% identical, to the heavy chain variable region of an antibody or antigen-binding fragments thereof described herein; and/or b) a light chain variable region having an amino acid sequence that is at least 80% identical, at least 85%, at least 90%, at least 95% or at least 98% or 99% identical, to the light chain variable region of an antibody or antigen-binding fragments thereof described herein. 
     A polypeptide has a certain percent “sequence identity” to another polypeptide, meaning that, when aligned, that percentage of amino acids are the same when comparing the two sequences. Sequence similarity can be determined in a number of different manners. To determine sequence identity, sequences can be aligned using the methods and computer programs, including BLAST, available over the world wide web at ncbi.nlm.nih.gov/BLAST/. Another alignment algorithm is FASTA, available in the Genetics Computing Group (GCG) package, from Madison, Wis., USA, a wholly owned subsidiary of Oxford Molecular Group, Inc. Other techniques for alignment are described in Methods in Enzymology, vol. 266: Computer Methods for Macromolecular Sequence Analysis (1996), ed. Doolittle, Academic Press, Inc., a division of Harcourt Brace &amp; Co., San Diego, Calif., USA. Of particular interest are alignment programs that permit gaps in the sequence. The Smith-Waterman is one type of algorithm that permits gaps in sequence alignments. See Meth. Mol. Biol. 70: 173-187 (1997). Also, the GAP program using the Needleman and Wunsch alignment method can be utilized to align sequences. See J. Mol. Biol. 48: 443-453 (1970). 
     Of interest is the BestFit program using the local homology algorithm of Smith and Waterman (Advances in Applied Mathematics 2: 482-489 (1981) to determine sequence identity. The gap generation penalty will generally range from 1 to 5, usually 2 to 4 and in many embodiments will be 3. The gap extension penalty will generally range from about 0.01 to 0.20 and in many instances will be 0.10. The program has default parameters determined by the sequences inputted to be compared. Preferably, the sequence identity is determined using the default parameters determined by the program. This program is available also from Genetics Computing Group (GCG) package, from Madison, Wis., USA. 
     Another program of interest is the FastDB algorithm. FastDB is described in Current Methods in Sequence Comparison and Analysis, Macromolecule Sequencing and Synthesis, Selected Methods and Applications, pp. 127-149, 1988, Alan R. Liss, Inc. Percent sequence identity is calculated by FastDB based upon the following parameters: Mismatch Penalty: 1.00; Gap Penalty: 1.00; Gap Size Penalty: 0.33; and Joining Penalty: 30.0. 
     In particular embodiments, a molecule disclosed herein, e.g., a WNT surrogate, a WNT enhancer, or a WNT super agonist, or a binding region thereof, e.g., a Fab, scFv, or VHH may comprise: a) a heavy chain variable region comprising: i. a CDR1 region that is identical in amino acid sequence to the heavy chain CDR1 region of a selected antibody described herein; ii. a CDR2 region that is identical in amino acid sequence to the heavy chain CDR2 region of the selected antibody; and iii. a CDR3 region that is identical in amino acid sequence to the heavy chain CDR3 region of the selected antibody; and b) a light chain variable domain comprising: i. a CDR1 region that is identical in amino acid sequence to the light chain CDR1 region of the selected antibody; ii. a CDR2 region that is identical in amino acid sequence to the light chain CDR2 region of the selected antibody; and iii. a CDR3 region that is identical in amino acid sequence to the light chain CDR3 region of the selected antibody; wherein the antibody specifically binds a selected target (e.g., a FZD receptor, such as FZD1). In a further embodiment, the antibody, or antigen-binding fragment thereof, is a variant antibody wherein the variant comprises a heavy and light chain identical to the selected antibody except for up to 8, 9, 10, 11, 12, 13, 14, 15, or more amino acid substitutions in the CDR regions of the VH and VL regions. In this regard, there may be 1, 2, 3, 4, 5, 6, 7, 8, or in certain embodiments, 9, 10, 11, 12, 13, 14, 15 more amino acid substitutions in the CDR regions of the selected antibody. Substitutions may be in CDRs either in the VH and/or the VL regions. (See e.g., Muller, 1998, Structure 6:1153-1167). 
     Determination of the three-dimensional structures of representative polypeptides (e.g., variant FZD binding regions or LRP5/6 binding regions of WNT surrogate molecules as provided herein) may be made through routine methodologies such that substitution, addition, deletion or insertion of one or more amino acids with selected natural or non-natural amino acids can be virtually modeled for purposes of determining whether a so derived structural variant retains the space-filling properties of presently disclosed species. See, for instance, Donate et al., 1994 Prot. Sci. 3:2378; Bradley et al., Science 309: 1868-1871 (2005); Schueler-Furman et al., Science 310:638 (2005); Dietz et al., Proc. Nat. Acad. Sci. USA 103:1244 (2006); Dodson et al., Nature 450:176 (2007); Qian et al., Nature 450:259 (2007); Raman et al. Science 327:1014-1018 (2010). Some additional non-limiting examples of computer algorithms that may be used for these and related embodiments, such as for rational design of binding regions include VMD which is a molecular visualization program for displaying, animating, and analyzing large biomolecular systems using 3-D graphics and built-in scripting (see the website for the Theoretical and Computational Biophysics Group, University of Illinois at Urbana-Champagne, at ks.uiuc.edu/Research/vmd/. Many other computer programs are known in the art and available to the skilled person and which allow for determining atomic dimensions from space-filling models (van der Waals radii) of energy-minimized conformations; GRID, which seeks to determine regions of high affinity for different chemical groups, thereby enhancing binding, Monte Carlo searches, which calculate mathematical alignment, and CHARMM (Brooks et al. (1983) J. Comput. Chem. 4:187-217) and AMBER (Weiner et al (1981) J. Comput. Chem. 106: 765), which assess force field calculations, and analysis (see also, Eisenfield et al. (1991) Am. J. Physiol. 261: C376-386; Lybrand (1991) J. Pharm. Belg. 46:49-54; Froimowitz (1990) Biotechniques 8:640-644; Burbam et al. (1990) Proteins 7:99-111; Pedersen (1985) Environ. Health Perspect. 61:185-190; and Kini et al. (1991) J. Biomol. Struct. Dyn. 9:475-488). A variety of appropriate computational computer programs are also commercially available, such as from Schrödinger (Munich, Germany). 
     The accompanying Examples set forth a variety of polypeptide sequences that may be present within WNT surrogates, WNT super agonists, and WNT enhancers. In particular, Table 3 provides sequences of polypeptides present in illustrative WNT surrogates and WNT enhancers, and Table 4 provides sequences of polypeptides present in illustrative WNT super agonists and WNT enhancers. These tables also provide the structure of each of the molecules disclosed, which is listed or may be readily discerned from the name of the molecule. Illustrative binding domains present within the various molecules are provided in Table 2 with the full sequences shown in Tables 3 and 4. The various binding domains and molecules described in the Examples may be modified or combined in other orientations or configurations, including but not limited to any of the various configurations shown in the Examples or Figures. For example, the positions of the FZD binding domain and the LRP5/6 binding domain may be switched in any of the polypeptides present within the structures depicted. The disclosure further includes polypeptide variants of any of the polypeptides or binding domains thereof disclosed herein, such polypeptide variants having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to a polypeptide or binding domain thereof disclosed herein. 
     X. Compositions 
     Pharmaceutical compositions comprising a surrogate molecule described herein and one or more pharmaceutically acceptable diluent, carrier, or excipient are also disclosed. 
     In further embodiments, pharmaceutical compositions comprising a polynucleotide comprising a nucleic acid sequence encoding a surrogate molecule described herein and one or more pharmaceutically acceptable diluent, carrier, or excipient are also disclosed. In particular embodiments, the pharmaceutical composition further comprises one or more polynucleotides comprising a nucleic acid sequence encoding a naturally occurring co-receptor ligand polypeptide. In certain embodiments, the polynucleotides are DNA or mRNA, e.g., a modified mRNA. In particular embodiments, the polynucleotides are modified mRNAs further comprising a 5′ cap sequence and/or a 3′ tailing sequence, e.g., a polyA tail. In other embodiments, the polynucleotides are expression cassettes comprising a promoter operatively linked to the coding sequences. In certain embodiments, the nucleic acid sequence encoding the surrogate molecule and the nucleic acid sequence encoding naturally occurring co-receptor ligand polypeptide are present in the same polynucleotide. 
     In further embodiments, pharmaceutical compositions comprising an expression vector, e.g., a viral vector, comprising a polynucleotide comprising a nucleic acid sequence encoding a surrogate molecule described herein and one or more pharmaceutically acceptable diluent, carrier, or excipient are also disclosed. In particular embodiments, the pharmaceutical composition further comprises an expression vector, e.g., a viral vector, comprising a polynucleotide comprising a nucleic acid sequence encoding a naturally occurring co-receptor ligand polypeptide. In certain embodiments, the nucleic acid sequence encoding the surrogate molecule and the nucleic acid sequence encoding the naturally occurring co-receptor ligand polypeptide are present in the same polynucleotide, e.g., expression cassette. 
     The present invention further contemplates a pharmaceutical composition comprising a cell comprising an expression vector comprising a polynucleotide comprising a promoter operatively linked to a nucleic acid encoding a surrogate molecule and one or more pharmaceutically acceptable diluent, carrier, or excipient. In particular embodiments, the pharmaceutical composition further comprises a cell comprising an expression vector comprising a polynucleotide comprising a promoter operatively linked to a nucleic acid sequence encoding a polypeptide corresponding to the natural ligand of the receptors. In particular embodiments, the cell is a heterologous cell or an autologous cell obtained from the subject to be treated. In particular embodiments, the cell is a stem cell, e.g., an adipose-derived stem cell or a hematopoietic stem cell. 
     The subject molecules, alone or in combination, can be combined with pharmaceutically-acceptable carriers, diluents, excipients and reagents useful in preparing a formulation that is generally safe, non-toxic, and desirable, and includes excipients that are acceptable for mammalian, e.g., human or primate, use. Such excipients can be solid, liquid, semisolid, or, in the case of an aerosol composition, gaseous. Examples of such carriers, diluents and excipients include, but are not limited to, water, saline, Ringer&#39;s solutions, dextrose solution, and 5% human serum albumin. Supplementary active compounds can also be incorporated into the formulations. Solutions or suspensions used for the formulations can include a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial compounds such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating compounds such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates or phosphates; detergents such as Tween 20 to prevent aggregation; and compounds for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. In particular embodiments, the pharmaceutical compositions are sterile. 
     Pharmaceutical compositions may further include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, or phosphate buffered saline (PBS). In some cases, the composition is sterile and should be fluid such that it can be drawn into a syringe or delivered to a subject from a syringe. In certain embodiments, it is stable under the conditions of manufacture and storage and is preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be, e.g., a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the internal compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin. 
     Sterile solutions can be prepared by incorporating the surrogate molecule (or encoding polynucleotide or cell comprising the same) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. 
     In one embodiment, the pharmaceutical compositions are prepared with carriers that will protect the antibody or antigen-binding fragment thereof against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially. Liposomal suspensions can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art. 
     It may be advantageous to formulate the pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active antibody or antigen-binding fragment thereof calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms are dictated by and directly dependent on the unique characteristics of the antibody or antigen-binding fragment thereof and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active antibody or antigen-binding fragment thereof for the treatment of individuals. 
     The pharmaceutical compositions can be included in a container, pack, or dispenser, e.g. syringe, e.g. a prefilled syringe, together with instructions for administration. 
     The pharmaceutical compositions of the invention encompass any pharmaceutically acceptable salts, esters, or salts of such esters, or any other compound which, upon administration to an animal comprising a human, is capable of providing (directly or indirectly) the biologically active antibody or antigen-binding fragment thereof. 
     The present invention includes pharmaceutically acceptable salts of a WNT surrogate molecule described herein. The term “pharmaceutically acceptable salt” refers to physiologically and pharmaceutically acceptable salts of the compounds of the invention: i.e., salts that retain the desired biological activity of the parent compound and do not impart undesired toxicological effects thereto. A variety of pharmaceutically acceptable salts are known in the art and described, e.g., in “Remington&#39;s Pharmaceutical Sciences”, 17th edition, Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, Pa., USA, 1985 (and more recent editions thereof), in the “Encyclopaedia of Pharmaceutical Technology”, 3rd edition, James Swarbrick (Ed.), Informa Healthcare USA (Inc.), NY, USA, 2007, and in J. Pharm. Sci. 66: 2 (1977). Also, for a review on suitable salts, see “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, 2002). 
     Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Metals used as cations comprise sodium, potassium, magnesium, calcium, and the like. Amines comprise N—N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine (see, for example, Berge et al., “Pharmaceutical Salts,” J. Pharma Sci., 1977, 66, 119). The base addition salts of said acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. The free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid in the conventional manner. The free acid forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free acid for purposes of the present invention. 
     In some embodiments, the pharmaceutical composition provided herein comprise a therapeutically effective amount of a WNT surrogate molecule or pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable carrier, diluent and/or excipient, for example saline, phosphate buffered saline, phosphate and amino acids, polymers, polyols, sugar, buffers, preservatives and other proteins. Exemplary amino acids, polymers and sugars and the like are octylphenoxy polyethoxy ethanol compounds, polyethylene glycol monostearate compounds, polyoxyethylene sorbitan fatty acid esters, sucrose, fructose, dextrose, maltose, glucose, mannitol, dextran, sorbitol, inositol, galactitol, xylitol, lactose, trehalose, bovine or human serum albumin, citrate, acetate, Ringer&#39;s and Hank&#39;s solutions, cysteine, arginine, carnitine, alanine, glycine, lysine, valine, leucine, polyvinylpyrrolidone, polyethylene and glycol. Preferably, this formulation is stable for at least six months at 4° C. 
     In some embodiments, the pharmaceutical composition provided herein comprises a buffer, such as phosphate buffered saline (PBS) or sodium phosphate/sodium sulfate, tris buffer, glycine buffer, sterile water and other buffers known to the ordinarily skilled artisan such as those described by Good et al. (1966) Biochemistry 5:467. The pH of the buffer may be in the range of 6.5 to 7.75, preferably 7 to 7.5, and most preferably 7.2 to 7.4. 
     XI. Methods of Use 
     For illustrative purposes only, the WNT super agonist molecules, WNT surrogate molecules, and WNT enhancer molecules (RSPO mimetics), including those disclosed herein, can be used as to treat various diseases or disorders where tissue regeneration is necessary or beneficial. Subjects that may be treated include, but are not limited to, mammals, e.g., humans. Such diseases include, but are not limited to: increase bone growth or regeneration, bone grafting, healing of bone fractures, treatment of osteoporosis and osteoporotic fractures, vertebral compression fractures, spinal fusion, osseointegration of orthopedic devices, tendon-bone integration, tooth growth and regeneration, dental implantation, periodontal diseases, maxillofacial reconstruction, and osteonecrosis of the jaw. Also contemplated are: treatment of alopecia; enhancing regeneration of sensory organs, e.g. treatment of hearing loss, including internal and external auditory hair cells, treatment of vestibular hypofunction, treatment of macular degeneration, treatment of various retinopathies, including but not limited to vitreoretinopathy, diabetic retinopathy, other diseases of retinal degeneration, wet age-related macular degeneration (AMD), dry AMD, Fuchs&#39; dystrophy, other cornea disease, etc.; treatment of stroke, traumatic brain injury, Alzheimer&#39;s disease, multiple sclerosis and other conditions affecting the blood brain barrier; treatment of spinal cord injuries, other spinal cord diseases. The compositions of this invention may also be used in treatment of oral mucositis, treatment of short bowel syndrome, inflammatory bowel diseases (IBD), other gastrointestinal disorders; treatment of metabolic syndrome, dyslipidemia, treatment of diabetes, treatment of pancreatitis, conditions where exocrine or endocrine pancreas tissues are damaged; conditions where enhanced epidermal regeneration is desired, e.g., epidermal wound healing, treatment of diabetic foot ulcers, syndromes involving tooth, nail, or dermal hypoplasia, etc., conditions where angiogenesis is beneficial; treatment of myocardial infarction, coronary artery disease, heart failure; enhanced growth of hematopoietic cells, e.g. enhancement of hematopoietic stem cell transplants from bone marrow, mobilized peripheral blood, treatment of immunodeficiencies, graft versus host diseases, etc.; treatment of acute kidney injuries, chronic kidney diseases; treatment of lung diseases, chronic obstructive pulmonary diseases (COPD), idiopathic pulmonary fibrosis (IPF) enhanced regeneration of lung tissues. The compositions of the present invention may also be used in enhanced regeneration of liver cells, e.g. liver regeneration, treatment of cirrhosis, enhancement of liver transplantations, treatment of acute liver failure, treatment of chronic liver diseases with hepatitis C or B virus infection or post-antiviral drug therapies, alcoholic liver diseases, alcoholic hepatitis, non-alcoholic liver diseases with steatosis or steatohepatitis, and the like. The compositions of this invention may treat diseases and disorders including, without limitation, conditions in which regenerative cell growth is desired. 
     In particular embodiments, the WNT super agonist molecules, WNT surrogate molecules, and WNT enhancer molecules (RSPO mimetics), including those disclosed herein, may be used to induce bone formation or increase bone density in a subject. For example, the subject may be administered an effective amount of a WNT super agonist molecule, WNT surrogate molecule, or WNT enhancer molecule. In particular embodiments, the subject is administered a WNT super agonist molecule or a WNT surrogate molecule comprising a FZD binding domain that binds to FZD5, FZD8, and FZD9. 
     In certain embodiments, the WNT super agonist molecules, WNT surrogate molecules, and WNT enhancer molecules (RSPO mimetics), including those disclosed herein, may be used for regenerating a salivary gland, inducing salivary gland growth or salivary gland tissue growth in a subject. The method may be used to treat hyposalivation or dry mouth in a subject. For example, the subject may be administered an effective amount of a WNT super agonist molecule, WNT surrogate molecule, or WNT enhancer molecule. In particular embodiments, the subject is administered a WNT super agonist molecule or a WNT surrogate molecule comprising a FZD binding domain that binds to FZD1, FZD2, and FZD7. 
     In certain embodiments, the WNT super agonist molecules, WNT surrogate molecules, and WNT enhancer molecules (RSPO mimetics), including those disclosed herein, may be used to preserve cells, tissues, organs or organoids, e.g., tissue or organs for transplantation. For example, a cell, tissue, organ, or organoid may be contacted with a WNT super agonist molecule, WNT surrogate molecule, or WNT enhancer molecule in vivo or ex vivo. In the context of preserving cells, tissue, or organs for transplantation, the cell, tissue, organ, or organoid may be contacted with a WNT super agonist molecule, WNT surrogate molecule, or WNT enhancer molecule while still in the donor (i.e., before removal from the donor) and/or after removal from the donor. The methods may maintain or enhance viability of the cell, tissue, or organ, for example, during storage or prior to transplantation into a recipient. In particular embodiments, the cells, tissue, or organ is perfused in a composition or solution comprising the WNT super agonist molecule, WNT surrogate molecule, or WNT enhancer molecule. In certain embodiments, certain organ tissue is contacted with a WNT super agonist molecule to maintain viability of that tissue. In particular embodiments, the organ tissue is donor organ tissue to be transplanted to a recipient in need thereof. In certain embodiments, donor organ tissue is perfused in vivo with a solution comprising a WNT super agonist molecule disclosed here, e.g., before the organ tissue is removed from the donor. In certain embodiments, donor organ tissue is perfused ex vivo with a solution comprising a WNT super agonist molecule disclosed here, e.g., during storage or during transport from a donor to a recipient. In particular embodiment, the organ tissue contacted with a Wnt signal enhancing molecule remains viable for transplantation for at least 10%, at least 20%, at least 50%, or at least 100% longer than if it was not contacted with the Wnt signal enhancing molecule. In certain embodiments the organ tissue is liver tissue. 
     In certain embodiments, the WNT super agonist molecules, WNT surrogate molecules, and WNT enhancer molecules (RSPO mimetics), including those disclosed herein, may be used for the expansion and/or maintenance of ex vivo tissue, e.g., skin tissue. In particular embodiments, the tissue is isolated from a donor or a patient. The tissue may be contacted with (e.g., maintained or cultured in the presence of) a WNT super agonist molecule, WNT surrogate molecule, or WNT enhancer molecule in vivo or ex vivo. In certain embodiments, the tissue is contacted ex vivo, e.g., by perfusion with a composition comprising a WNT super agonist molecule, WNT surrogate molecule, or WNT enhancer molecule. 
     In another embodiments, the WNT super agonist molecules, WNT surrogate molecules, and WNT enhancer molecules (RSPO mimetics), including those disclosed herein, may be used to generate or maintain an organoid or organoid culture. For example, an organoid culture may be contacted with a WNT super agonist molecule, WNT surrogate molecule, or WNT enhancer molecule, for example, by culturing the organoid in a medium comprising a WNT super agonist molecule, WNT surrogate molecule, or WNT enhancer molecule. In certain embodiments, an organoid culture is generated, grown, or maintained by contacting it with one or more WNT super agonist molecules disclosed herein. In particular embodiments, the WNT super agonist molecule is present in the culture media used to grow or maintain the organoid tissue. 
     In particular embodiments, a pharmaceutical composition is administered parenterally, e.g., intravenously, orally, rectally, or by injection. In some embodiments, it is administered locally, e.g., topically or intramuscularly. In some embodiments, a composition is administered to target tissues, e.g., to bone, joints, ear tissue, eye tissue, gastrointestinal tract, skin, a wound site or spinal cord. 
     Methods of the invention may be practiced in vivo or ex vivo. In some embodiments, the contacting of a target cell or tissue with a surrogate molecule is performed ex vivo, with subsequent implantation of the cells or tissues, e.g., activated stem or progenitor cells, into the subject. The skilled artisan can determine an appropriate site of and route of administration based on the disease or disorder being treated. 
     The dose and dosage regimen may depend upon a variety of factors readily determined by a physician, such as the nature of the disease or disorder, the characteristics of the subject, and the subject&#39;s history. In particular embodiments, the amount of a surrogate molecule administered or provided to the subject is in the range of about 0.01 mg/kg to about 50 mg/kg, 0.1 mg/kg to about 500 mg/kg, or about 0.1 mg/kg to about 50 mg/kg of the subject&#39;s body weight. 
     All of the above U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the Application Data Sheet, are incorporated herein by reference, in their entirety. 
     From the foregoing it will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention. Accordingly, the invention is not limited except as by the appended claims. 
     EXAMPLES 
     The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention nor are they intended to represent that the experiments below are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g. amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric. 
     General methods in molecular biology, cell biology and biochemistry can be found in such standard textbooks as “Molecular Cloning: A Laboratory Manual, 3rd Ed.” (Sambrook et al., Harbor Laboratory Press 2001); “Short Protocols in Molecular Biology, 4th Ed.” (Ausubel et al. eds., John Wiley &amp; Sons 1999); “Protein Methods” (Bollag et al., John Wiley &amp; Sons 1996); “Nonviral Vectors for Gene Therapy” (Wagner et al. eds., Academic Press 1999); “Viral Vectors” (Kaplift &amp; Loewy eds., Academic Press 1995); “Immunology Methods Manual” (I. Lefkovits ed., Academic Press 1997); and “Cell and Tissue Culture: Laboratory Procedures in Biotechnology” (Doyle &amp; Griffiths, John Wiley &amp; Sons 1998), the disclosures of which are incorporated herein by reference. Reagents, cloning vectors, and kits for genetic manipulation referred to in this disclosure are available from commercial vendors such as BioRad, Stratagene, Invitrogen, Sigma-Aldrich, and ClonTech. 
     Recombinant molecules were generated that combine agonists for the WNT receptors, FZD and/or LRP co-receptors, together with agonists for the E3 ligase receptors, ZNRF3 or RNF43, to create WNT signaling ‘super agonists’ 
     Materials and methods employed in the following Examples include the following. 
     Protein Production 
     All recombinant proteins were produced in Expi293F cells (Thermo Fisher Scientific) by transient transfection. The FvFab proteins were first purified using cOmplete® His-tag purification resin (Sigma-Aldrich). The heterodimeric Fc-based proteins were first purified using MiniChrom MabSelect SuRe (Repligen), then polished by cOmplete® His-tag purification resin and anti-Flag M2 affinity gel (Sigma-Aldrich). Other proteins were first purified using MiniChrom MabSelect SuRe unless otherwise specified. All proteins were further polished with Superdex 200 Increase 10/300 GL (GE Healthcare Life Sciences) size-exclusion chromatography (SEC) using IxHBS buffer (20 mM HEPES pH 7.4, 150 mM NaCl). After that, the proteins were examined by SDS-polyacrylamide electrophoresis and estimated to be &gt;90% purity. 
     SuperTop Flash (STF) Assay 
     WNT signaling activity was measured using HEK293 cells containing a luciferase gene controlled by a WNT-responsive promoter (Super Top Flash reporter assay, STF) as previously reported ({Chen, 2020 #65}). In brief, cells were seeded at a density of 10,000 per well in 96-well plates 24 hours prior to treatment at the presence of 3 μM IWP2 to inhibit the production of endogenous WNTs. The recombinant proteins were then added to the cells with or without 20 nM Fc-RSPO2 overnight. Recombinant human WNT3A (R&amp;D systems) was used as a positive control. Cells were lysed with Luciferase Cell Culture Lysis Reagent (Promega) and luciferase activity was measured with Luciferase Assay System (Promega) using vendor suggested procedures. 
     Cell Flow Cytometry 
     HEK293 cells transiently transfected with a plasmid overexpressing ZNRF3 (Gen-Script OHu22977) were treated for 24 h with RSPO derivative molecules at 10 nM final concentration in DMEM supplemented with 10% FBS. Cells were dissociated using Gibco enzyme-free dissociation buffer, washed, and resuspended in FACS buffer (1× PBS with 1% BSA with 0.02% sodium azide). Cells were incubated with 1 nM F12578 IgG for 1 h. After washing, the cells were incubated with goat anti-human IgG Alexa Fluor 647 (Invitrogen, Carlsbad, Calif.) for 40 min. Cells were washed with FACS buffer and subjected to multi-channel analysis using a SONY SH800S flow cytometer (BD Biosciences. Data were processed with FlowJo software (FlowJo, Ashland, Oreg.) and fluorescence signals were displayed in histogram plots. 
     Primary Cells and Organoid Expansion 
     Mouse small intestinal organoids (#70931 STEMCELL Technologies) were maintained and expanded as described in Sato et al., 2009. In short, adapted expansion medium contained Advanced DMEM, 10 mM HEPES, 1× GlutaMAX, 1× Penicillin-Streptomycin, 1× B27, 1.25 mM N-acetylcysteine, 50 ng/mL recombinant human EGF, 50 ng/mL recombinant human Noggin and 500 ng/mL recombinant human R-Spondin 1 (see Table 1). 
     Human small intestinal organoids were a gift from the Calvin Kuo Lab at Stanford. Organoids were maintained and expanded as described in Sato et al., 2011 (Sato et al., 2011). In short, adapted expansion medium contained Advanced DMEM, 10 mM HEPES, 1× GlutaMAX, 1× Penicillin-Streptomycin, 1× B27, 1× N2, 1.25 mM N-acetylcysteine, 10 mM Nicotinamide, 50 ng/mL recombinant human EGF, 50 ng/mL recombinant human Noggin, 500 ng/mL recombinant human R-Spondin 1, 0.5 nM L6-F12578 surrogate Wnt, 10 nM recombinant Gastrin, 500 nM A83-01 and 10 M SB202190 (see Table 1). 
     Mouse hepatocyte organoids were grown from primary CD1 murine hepatocytes (#MSCP20 Thermo Fisher) and expanded as described in Hu et al., 2018. In short, adapted expansion medium contained Advanced DMEM, 10 mM HEPES, 1× GlutaMAX, 1× Penicillin-Streptomycin, 1× B27, 1.25 mM N-acetylcysteine, 50 ng/mL recombinant human EGF, 50 ng/mL recombinant human Noggin, 500 ng/mL recombinant human R-Spondin 1, 10 nM recombinant Gastrin, 3 μM CHIR99021, 25 ng/mL recombinant HGF, 50 ng/mL FGF7, 50 ng/mL FGF10, 10 mM Nicotinamide and 500 nM A83-01 (see Table 1). 
     Human kidney organoids were established from primary human renal proximal tubule epithelial cells (PCS-400-010) and maintained and expanded as described in Schutgens et al., 2019. In short, adapted expansion medium contained Advanced DMEM, 10 mM HEPES, 1× GlutaMAX, 1× Penicillin-Streptomycin, 1× B27, 50 ng/mL recombinant human EGF, 100 ng/mL recombinant human FGF10, 500 nM A83-01 and 500 ng/mL recombinant human R-Spondin 1 (see Table 1). 
     Outgrowth Efficiency Assay 
     For the outgrowth efficiency assay all organoid lines (mouse small intestine, human small intestine and human kidney) were digested to small, near single cell suspension, fragments using 1× TrypLE (12605010 GIBCO) for 10 minutes at 37° C. Mouse hepatocyte outgrowth efficiency was performed with primary single cells. For all cell types the base medium consisted of expansion medium without RSPO1, Surrogate Wnt and/or CHIR99021 and supplemented with 1 μM porcupine inhibitor Wnt-C59 (#5148 Tocris) and 10 μM Y-27632 (#5092280001 MilliporeSigma). Experimental conditions, as in  FIG.  3   , consisted of one or combination of 500 ng/mL RSPO1, 100 ng/mL recombinant human Wnt-3a, 1 nM Surrogate WNT L6-F12578 (0.1 nM for mouse small intestinal organoids) or 1 nM WNT super agonist L6-F12578-RSPO2RA (0.1 nM for mouse small intestinal organoids. All cells for all conditions were plated in 15 L Matrigel droplets in 96-well plates and submerged in 120 L of the experimental medium. Mouse small intestine, human small intestine and human kidney organoids were expanded for 7 days before measurement and mouse hepatocyte organoids for 14 days before measurements. The medium was changed approximately every 3 days. Each experiment consisted of three technical replicates per plate and was repeated three times. Outgrowth efficiency was quantified using cell viability assay CellTiter-Glo (G9683 Promega) measured on the SpectraMax Paradigm microplate reader (Molecular Devices) according to manufactures protocols. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Organoid Reagents 
               
               
                 Organoid reagents 
               
            
           
           
               
               
            
               
                 Component 
                 Catalog number 
               
               
                   
               
               
                 Advanced DMEM 
                 Thermo Scientific 12634-010 
               
               
                 HEPES 
                 Thermo Scientific 15630080 
               
               
                 GlutaMAX 
                 Thermo Scientific 35050061 
               
               
                 Penicillin-Streptomycin 
                 Thermo Scientific 15140122 
               
               
                 B27 
                 Thermo Scientific 17504044 
               
               
                 N2 
                 Thermo Scientific 17502048 
               
               
                 Nicotinamide 
                 Sigma-Aldrich N0636 
               
               
                 N-acetylcysteine 
                 Sigma-Aldrich A9165 
               
               
                 A83-01 
                 Tocris 2939 
               
               
                 CHIR99021 
                 Tocris 4423 
               
               
                 SB202190 
                 Tocris 126410 
               
               
                 Recombinant Human EGF 
                 Peprotech AF-100-15 
               
               
                 Recombinant Human FGF7 
                 Peprotech 100-19 
               
               
                 Recombinant Human FGF10 
                 Peprotech 100-26 
               
               
                 Recombinant Human Noggin 
                 Peprotech 120-10C 
               
               
                 Recombinant Human HGF 
                 Peprotech 100-39H 
               
               
                 Human Gastrin I 
                 Tocris 30061 
               
               
                 Recombinant Human R-Spondin 1 
                 R&amp;D 4645RS 
               
               
                 Recombinant Human Wnt-3a 
                 R&amp;D 5036WN 
               
               
                 Surrogate WNT L6-F12578 
                 In-house production 
               
               
                 WNT super agonist L6-F12578-RSPO2RA 
                 In-house production 
               
               
                 Matrigel ™ GFR Membrane Matrix 
                 Corning CB40230C 
               
               
                   
               
            
           
         
       
     
     Murine Studies and Dual Energy X-Ray Absorptiometry (DEXA): 
     All animal experiments were performed according to national ethical guidelines in addition to the guidance and approval by the Institutional Animal Care and Use Committee (IACUC) of Surrozen, Inc. Twelve-week-old C57Bl1/6J female mice were obtained from Jackson Laboratories (Bar Harbor, Me., USA) and were housed 4 per cage. Proteins treatments at 3 mg per kg were intraperitoneal dosed on day 0, 3, 7 and 10. Bone mineral density (BMD) and fat content of animals were measured via in vivo DEXA method using a Faxitron UltraFocus (Faxitron Bioptics, Tucson, Ariz.) on day 0, 7 and 13. Animals were anesthetized during imaging through isoflurane and sample ROI included the entire murine skeleton except material above the cervical spine due to increased radiographical intensity of the skull. BMD and fat content were calculated using the accompanying Vision DXA software. Animals were terminated on day 14, and liver, small intestine, and salivary glands were collected for histology. 
     Example 1 
     WNT Surrogate Formats 
     A new modular and flexible platform for potent, selective WNT surrogate generation was created (see, e.g., WO 2020/010308). A key feature of the platform was the requirement for multimerization of FZDs and LRPs, with optimal stoichiometry of two FZD and one or two LRP binders, for maximal WNT/β-catenin activation. This platform was built based on tandem scFv antibody fragment format (See Table 3). To understand whether additional multivalent antibody formats can produce active surrogate WNTs, Fv-IgG, Fab-IgG, scFv-IgG formats as shown in  FIG.  1 A ,  FIG.  4 A , and Table 3, were tested. These formats also offered different distances and geometries between the different binding arms on the antibody molecule, allowing the assessment of the contribution of format and geometry to activity. 
     Certain FZD and LRP binders were selected for each construct. Table 2 provides the nomenclature of components used. 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 WNT surrogate format components 
               
            
           
           
               
               
               
            
               
                 Component designation 
                 Clone name 
                 Specificity 
               
               
                   
               
               
                 F12578 
                 18R5 
                 FZD 1, 2, 7, 5, 8 
               
               
                 F127 
                 R2H1 
                 FZD 1, 2, 7 
               
               
                 F58 
                 2919 
                 FZD 5, 8 
               
               
                 F4 
                 5044 
                 FZD 4 
               
               
                 F4-2 
                 5063 
                 FZD 4 
               
               
                 F49 
                 3SC10 
                 FZD 4, 9 
               
               
                 F10 
                 hB9L9.3 
                 FZD 10 
               
               
                 F6 
                 R2M3 
                 FZD 1, 2, 7, 5, 8 
               
               
                 F7 
                 1791 
                 FZD 7 
               
               
                 F7B 
                 F7.B 
                 FZD1, 2, 7, 5, 8, 4 
               
               
                 F2I 
                 F2.I 
                 FZD1, 2, 7, 5, 8, 4 
               
               
                 L6 
                 YW211.31.57 
                 LRP6e3e4 
               
               
                 L2 
                 26 (009S-E04) 
                 LRP6e3e4 
               
               
                   
               
            
           
         
       
     
     An LRP6E3E4 binder, YW211.31.57 (see, e.g., U.S. Pat. No. 8,846,041; designated “L1”), and a FZD 1,2,7,5,8 binder, 18R5 (Gurney, et al. (2012)  Proc. Natl. Acad. Sci.  109:1171-11722; designated “F1”) were chosen to combine in the formats shown in  FIG.  1 A ,  FIG.  4 A , and Table 3 to generate the following constructs: L6F12578 (scFv-Fc), L6-F12578 (Fv-IgG), and L6-F12578 (Fab-IgG). As a negative control, anti-GFP binders were used. These proteins were purified via a Protein A-affinity column followed by size-exclusion chromatography (SEC) and tested in WNT responsive HEK293 Super TOP-FLASH (STF) reporter cells. 
     As shown in  FIG.  1 B , while all three formats yielded active surrogate WNTs, L6-F12578 (Fv-IgG) gave the highest Emax with EC50 of 0.81 nM, while L6-F12578 (Fab-IgG) gave the lowest Emax with EC50 of 0.39 nM. L6-F12578 (scFv-Fc) was the least potent with Emax similar to Fv-IgG. These surrogate WNTs responded to RSPO treatment, while preserving the relative range in potency and Emax; addition of RSPO increased both Emax and potency of all three surrogates ( FIG.  1 C ). 
     Since the Fv-IgG format produced the most active molecule, is easier to manufacture, and has more desirable biophysical properties, for example, being a much more stable format compared to tandem scFvs, which are less stable and have propensity for aggregation, we focused on Fv-IgG for additional WNT mimetic generation. To test the general applicability of this format, we chose additional FZD binders of different specificity for mimetic assembly with LRP binder, L6. These additional FZD binders, R2H1 (US 2016/0194394, FZD1,2,7 binder referred herein as F127), 2919 (WO 2017/127933, FZD5,8 binder referred herein as F58), 5044 (US 2016/0194394, FZD 4  binder referred herein as F4), 5063 (US 2016/0194394, FZD4 binder referred herein as F4-2), 3SC10 (WO 2019/126399, FZD 4,9  binder referred herein as F49), hB9L9.3 (US 2016/0194394, FZD 10  binder referred herein as F10), F7.B (Pavlovic, et al. (2018) mAbs 10(8): 1157-1167, FZD 1,2,4,5,7,8  binder referred herein as F7B), and F2.I (Pavlovic, et al. (2018) mAbs 10(8): 1157-1167, FZD 1,2,4,5,7,8  binder referred herein as F2I) covers the 8 FZDs that signals through β-catenin. The new WNT mimetics, L6-F127 (Fv-IgG), L6-F58 (Fv-IgG), L6-F7B (Fv-IgG), and L6-F2I (Fv-IgG) which binds FZD 1,2,7 , FZD 5,8 , FZD 1,2,4,5,7,8 , and FZD 1,2,4,5,7,8 , respectively, are highly active on the WNT responsive HEK293 STF cells ( FIG.  1 D,  1 L ). Since HEK293 cells does not express or expresses low levels of FZD 4 , FZD 9 , and FZD 10  (data not shown), the parental cells do not show significant response to L6-F4 (Fv-IgG), L6-F49 (Fv-IgG), and L6-F10 (Fv-IgG) ( FIG.  1 G,  1 I,  1 K ). However, L6-F4 (Fv-IgG), L6-F49 (Fv-IgG), L6-F10 (Fv-IgG), and L6-F4-2 (Fv-IgG) induced potent signaling in HEK293 STF cells over-expressing FZD 4 , FZD 9 , FZD 10 , and FZD 4 , respectively, consistent with their binding specificity toward these three receptors ( FIG.  1 F,  1 H,  1 J,  1 M ). These WNT mimetics are a valuable set of molecules that allows studies of β-catenin dependent FZDs. 
     We have shown previously that in tandem scFv format, multivalent binding to FZDs and LRPs are important for signaling, and bispecific tandem scFv molecules with one FZD and one LRP binding arms are either weak or inactive in inducing Wnt signaling (Chen et al., 2020). To assess the valency requirement in the Fv-IgG format, we generated this set of FZD/LRP binders in the bispecific Fv-Fab format where there is one each of FZD and LRP binding arms ( FIG.  1 A ). As shown in  FIG.  1 E- 1 K , none of these bispecific with monovalent binding to FZD and LRP induced significant activation of Wnt signaling, further confirming that the previously observed valency requirement in the tandem scFv, VHH-IgG formats also applies to other antibody formats. As the Fv-IgG molecules are studied further in the subsequent sections, the Fv-IgG designation will be removed from molecule names for brevity. 
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Formats and sequences of WNT surrogate molecules;    Italic underline    = linker;  Bold  = 
               
               
                 VH or VL. Formats are diagrammed in FIG. 7 
               
            
           
           
               
               
               
            
               
                   
                   
                 Polypeptide Sequence(s) Present in Structure 
               
               
                   
                   
                 (as depicted in the accompanying figures, WNT surrogate molecules 
               
               
                 Structure 
                 Structure 
                 typically comprises two of each polypeptide sequence shown for any 
               
               
                 Type 
                 Name 
                 particular structure) 
               
               
                   
               
               
                 Tandem 
                 L6-F12578 
                 SEQ ID NO: 18 
               
               
                 scFv 
                 (scFv-FC) 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWVRQAPGKGLEW 
                 
               
               
                   
                   
                 
                   VAEISPYSGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYY 
                 
               
               
                   
                   
                 
                   CALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GSAASGSSGGSSSGA 
                   
                   DIQ 
                 
               
               
                   
                   
                 
                   MTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSA 
                 
               
               
                   
                   
                 
                   SFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPTFGQ 
                 
               
               
                   
                   
                 
                   GTKVEIK 
                   
                     GSGSGGSGSGGSSGG 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASGF 
                 
               
               
                   
                   
                 
                   TFSHYTLSWVRQAPGKGLEWVSVISGDGSYTYYADSVKGRFTISSDNS 
                 
               
               
                   
                   
                 
                   KNTLYLQMNSLRAEDTAVYYCARNFIKYVFANWGQGTLVTVSS 
                   
                     GGG 
                   
                 
               
               
                   
                   
                 
                   
                     GSGGGGSGGGGS 
                   
                   DIELTQPPSVSVAPGQTARISCSGDNIGSFYVHWYQQ 
                 
               
               
                   
                   
                 
                   KPGQAPVLVIYDKSNRPSGIPERFSGSNSGNTATLTISGTQAEDEADYY 
                 
               
               
                   
                   
                   CQSYANTLSLVFGGGTKLTVL     GSGSG   DKTHTCPPCPAPEAAGGPSVFLFP 
               
               
                   
                   
                 PKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE 
               
               
                   
                   
                 EQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQ 
               
               
                   
                   
                 PREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK 
               
               
                   
                   
                 TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL 
               
               
                   
                   
                 SLSPGK 
               
               
                   
               
               
                 Fv-IgG 
                 L6-F12578 
                 Heavy Chain SEQ ID NO: 19 
               
               
                   
                 (Fv-IgG) 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWVRQAPGKGLEW 
                 
               
               
                   
                   
                 
                   VAEISPYSGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYY 
                 
               
               
                   
                   
                 
                   CALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GGGGSGGGGSGGGGS 
                   
                   E 
                 
               
               
                   
                   
                 
                   VQLVESGGGLVQPGGSLRLSCAASGFTFSHYTLSWVRQAPGKGLEW 
                 
               
               
                   
                   
                 
                   VSVISGDGSYTYYADSVKGRFTISSDNSKNTLYLQMNSLRAEDTAVYY 
                 
               
               
                   
                   
                   CARNFIKYVFANWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALG 
               
               
                   
                   
                 CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG 
               
               
                   
                   
                 TQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPP 
               
               
                   
                   
                 KPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE 
               
               
                   
                   
                 QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQP 
               
               
                   
                   
                 REPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT 
               
               
                   
                   
                 TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS 
               
               
                   
                   
                 LSPGK 
               
               
                   
                   
                 Light Chain SEQ ID NO: 20 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLI 
                 
               
               
                   
                   
                 
                   YSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPTF 
                 
               
               
                   
                   
                 
                   GQGTKVEIK 
                   
                     GGGGSGGGGSGGGGS 
                   
                   DIELTQPPSVSVAPGQTARISCSGD 
                 
               
               
                   
                   
                 
                   NIGSFYVHWYQQKPGQAPVLVIYDKSNRPSGIPERFSGSNSGNTATLTI 
                 
               
               
                   
                   
                   SGTQAEDEADYYCQSYANTLSLVFGGGTKLTVL GQPKAAPSVTLFPPSS 
               
               
                   
                   
                 EELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNK 
               
               
                   
                   
                 YAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 
               
               
                   
               
               
                 Fab(IgG) 
                 L6-F12578 
                 L6 Light Chain-F12578 Heavy Chain SEQ ID NO: 21 
               
               
                   
                 (Fab-IgG) 
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLI 
                 
               
               
                   
                   
                 
                   YSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPTF 
                 
               
               
                   
                   
                   GQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQW 
               
               
                   
                   
                 KVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVT 
               
               
                   
                   
                 HQGLSSPVTKSFNRGEC   GGGGSGGGGSGGGGS     EVQLVESGGGLVQPGG   
               
               
                   
                   
                 
                   SLRLSCAASGFTFSHYTLSWVRQAPGKGLEWVSVISGDGSYTYYADSV 
                 
               
               
                   
                   
                 
                   KGRFTISSDNSKNTLYLQMNSLRAEDTAVYYCARNFIKYVFANWGQG 
                 
               
               
                   
                   
                   TLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS 
               
               
                   
                   
                 GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV 
               
               
                   
                   
                 DKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCV 
               
               
                   
                   
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH 
               
               
                   
                   
                 QDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTK 
               
               
                   
                   
                 NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL 
               
               
                   
                   
                 TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
               
               
                   
                   
                 F12578 Light Chain SEQ ID NO: 22 
               
               
                   
                   
                 
                   DIELTQPPSVSVAPGQTARISCSGDNIGSFYVHWYQQKPGQAPVLVIY 
                 
               
               
                   
                   
                 
                   DKSNRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQSYANTLSLV 
                 
               
               
                   
                   
                   FGGGTKLTVL GQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTV 
               
               
                   
                   
                 AWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQV 
               
               
                   
                   
                 THEGSTVEKTVAPTECS 
               
               
                   
                   
                 L6Variable Heavy Chain - Constant Heavy Chain 1 SEQ ID NO: 23 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWVRQAPGKGLEW 
                 
               
               
                   
                   
                 
                   VAEISPYSGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYY 
                 
               
               
                   
                   
                   CALRARPPIRLHPRGSVMDYWGQGTLVTVSS ASTKGPSVFPLAPSSKST 
               
               
                   
                   
                 SGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSV 
               
               
                   
                   
                 VTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC 
               
               
                   
               
               
                 Fv-IgG 
                 L6-F127 
                 Heavy Chain SEQ ID NO: 24 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWVRQAPGKGLEWV 
                 
               
               
                   
                   
                 
                   AEISPYSGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCA 
                 
               
               
                   
                   
                 
                   LRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GGGGSGGGGSGGGGS 
                   
                   EVQL 
                 
               
               
                   
                   
                 
                   VESGGGLVQPGGSLRLSCAASGFNISSSYIHWVRQAPGKGLEWVAYIY 
                 
               
               
                   
                   
                 
                   SSYGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARAS 
                 
               
               
                   
                   
                   WYALDYWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY 
               
               
                   
                   
                 FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN 
               
               
                   
                   
                 VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLM 
               
               
                   
                   
                 ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
               
               
                   
                   
                 VSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLP 
               
               
                   
                   
                 PSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS 
               
               
                   
                   
                 FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
               
               
                   
                   
                 Light Chain SEQ ID NO: 25 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIY 
                 
               
               
                   
                   
                 
                   SASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPTFG 
                 
               
               
                   
                   
                 
                   QGTKVEIK 
                   
                     GGGGSGGGGSGGGGS 
                   
                   DIQMTQSPSSLSASVGDRVTITCRAS 
                 
               
               
                   
                   
                 
                   QSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTIS 
                 
               
               
                   
                   
                   SLQPEDFATYYCQQYWYGVAPITFGQGTKVEIK RTVAAPSVFIFPPSDEQ 
               
               
                   
                   
                 LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS 
               
               
                   
                   
                 LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 
               
               
                   
               
               
                 Fv-IgG 
                 L6-F58 
                 Heavy Chain SEQ ID NO: 26 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWVRQAPGKGLEWV 
                 
               
               
                   
                   
                 
                   AEISPYSGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCA 
                 
               
               
                   
                   
                 
                   LRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GGGGSGGGGSGGGGS 
                   
                   EVQL 
                 
               
               
                   
                   
                 
                   VESGGGLVQPGGSLRLSCAASGFNISYSYIHWVRQAPGKGLEWVASIY 
                 
               
               
                   
                   
                 
                   SSSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGAI 
                 
               
               
                   
                   
                   DYWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV 
               
               
                   
                   
                 TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHK 
               
               
                   
                   
                 PSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTP 
               
               
                   
                   
                 EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVL 
               
               
                   
                   
                 TVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREE 
               
               
                   
                   
                 MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS 
               
               
                   
                   
                 KLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
               
               
                   
                   
                 Light Chain SEQ ID NO: 27 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIY 
                 
               
               
                   
                   
                 
                   SASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPTFG 
                 
               
               
                   
                   
                 
                   QGTKVEIK 
                   
                     GGGGSGGGGSGGGGS 
                   
                   DIQMTQSPSSLSASVGDRVTITCRAS 
                 
               
               
                   
                   
                 
                   QSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTIS 
                 
               
               
                   
                   
                   SLQPEDFATYYCQQWYSSGHVLITFGQGTKVEIK RTVAAPSVFIFPPSDE 
               
               
                   
                   
                 QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST 
               
               
                   
                   
                 YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 
               
               
                   
               
               
                 Fv-IgG 
                 L6-F4-2 
                 Heavy Chain SEQ ID NO: 28 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWVRQAPGKGLEW 
                 
               
               
                   
                   
                 
                   VAEISPYSGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYY 
                 
               
               
                   
                   
                 
                   CALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GGGGSGGGGSGGGGS 
                   
                   E 
                 
               
               
                   
                   
                 
                   VQLVESGGGLVQPGGSLRLSCAASGFNISYYYIHWVRQAPGKGLEWV 
                 
               
               
                   
                   
                 
                   ASIYPSSGYTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                   
                   ARSSFYWAMDYWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALG 
               
               
                   
                   
                 CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG 
               
               
                   
                   
                 TQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPP 
               
               
                   
                   
                 KPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE 
               
               
                   
                   
                 QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQP 
               
               
                   
                   
                 REPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT 
               
               
                   
                   
                 TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS 
               
               
                   
                   
                 LSPGK 
               
               
                   
                   
                 Light Chain SEQ ID NO: 29 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLI 
                 
               
               
                   
                   
                 
                   YSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPTF 
                 
               
               
                   
                   
                 
                   GQGTKVEIK 
                   
                     GGGGSGGGGSGGGGS 
                   
                   DIQMTQSPSSLSASVGDRVTITCR 
                 
               
               
                   
                   
                 
                   ASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTL 
                 
               
               
                   
                   
                   TISSLQPEDFATYYCQQSYAAYLFTFGQGTKVEIK RTVAAPSVFIFPPSD 
               
               
                   
                   
                 EQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS 
               
               
                   
                   
                 TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 
               
               
                   
               
               
                 Fv-IgG 
                 L6-F10 
                 Heavy Chain SEQ ID NO: 30 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWVRQAPGKGLEW 
                 
               
               
                   
                   
                 
                   VAEISPYSGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYY 
                 
               
               
                   
                   
                 
                   CALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GGGGSGGGGSGGGGS 
                   
                   E 
                 
               
               
                   
                   
                 
                   VQLVESGGGLVQPGGSLRLSCAASGFTFSSFNMFWVRQAPGKGLEW 
                 
               
               
                   
                   
                 
                   VAGIDDDGSYPNYGSAVKGRATISRDNSKNTLYLQMNSLRAEDTAVY 
                 
               
               
                   
                   
                   YCAKSGYGGSWGGYIADDIDAWGQGTLVTVSS ASTKGPSVFPLAPSSK 
               
               
                   
                   
                 STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS 
               
               
                   
                   
                 SVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEA 
               
               
                   
                   
                 AGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV 
               
               
                   
                   
                 HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIE 
               
               
                   
                   
                 KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWES 
               
               
                   
                   
                 NGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL 
               
               
                   
                   
                 HNHYTQKSLSLSPGK 
               
               
                   
                   
                 Light Chain SEQ ID NO: 31 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLI 
                 
               
               
                   
                   
                 
                   YSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPTF 
                 
               
               
                   
                   
                 
                   GQGTKVEIK 
                   
                     GGGGSGGGGSGGGGS 
                   
                   ELTQPPSVSVSPGQTARITCSGDGS 
                 
               
               
                   
                   
                 
                   YAGSYYYGWYQQKPGQAPVTLIYYNNKRPSGIPERFSGSLSGSTNTLT 
                 
               
               
                   
                   
                   ISGVQAEDEADYYCGSADNSGAAFGGGTKLTVL RTVAAPSVFIFPPSDE 
               
               
                   
                   
                 QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST 
               
               
                   
                   
                 YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 
               
               
                   
               
               
                 Fv-IgG 
                 L6-F4 
                 Heavy Chain SEQ ID NO: 55 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWVRQAPGKGLEW 
                 
               
               
                   
                   
                 
                   VAEISPYSGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYY 
                 
               
               
                   
                   
                 
                   CALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GGGGSGGGGSGGGGS 
                   
                   E 
                 
               
               
                   
                   
                 
                   VQLVESGGGLVQPGGSLRLSCAASGFNLSSYSMHWVRQAPGKGLEW 
                 
               
               
                   
                   
                 
                   VAYISSYYGYTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYY 
                 
               
               
                   
                   
                   CARPAPGHWGFDYWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAA 
               
               
                   
                   
                 LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSS 
               
               
                   
                   
                 LGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFL 
               
               
                   
                   
                 FPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP 
               
               
                   
                   
                 REEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAK 
               
               
                   
                   
                 GQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENN 
               
               
                   
                   
                 YKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQK 
               
               
                   
                   
                 SLSLSPGK 
               
               
                   
                   
                 Light Chain SEQ ID NO: 56 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLI 
                 
               
               
                   
                   
                 
                   YSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPTF 
                 
               
               
                   
                   
                 
                   GQGTKVEIK 
                   
                     GGGGSGGGGSGGGGS 
                   
                   DIQMTQSPSSLSASVGDRVTITCR 
                 
               
               
                   
                   
                 
                   ASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTL 
                 
               
               
                   
                   
                   TISSLQPEDFATYYCQQWYYAPITFGQGTKVEIK RTVAAPSVFIFPPSDE 
               
               
                   
                   
                 QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST 
               
               
                   
                   
                 YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 
               
               
                   
               
               
                 Fv-IgG 
                 L6-F49 
                 Heavy Chain SEQ ID NO: 57 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWVRQAPGKGLEW 
                 
               
               
                   
                   
                 
                   VAEISPYSGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYY 
                 
               
               
                   
                   
                 
                   CALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GGGGSGGGGSGGGGS 
                   
                   E 
                 
               
               
                   
                   
                 
                   VQLVQSGAEVKKPGASVKVSCKASGGTFSSYAISWVRQAPGQGLEW 
                 
               
               
                   
                   
                 
                   MGWINAGNGNTTYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAV 
                 
               
               
                   
                   
                   YYCARHYYGSGSYPDWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTA 
               
               
                   
                   
                 ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS 
               
               
                   
                   
                 SSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSV 
               
               
                   
                   
                 FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT 
               
               
                   
                   
                 KPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISK 
               
               
                   
                   
                 AKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE 
               
               
                   
                   
                 NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT 
               
               
                   
                   
                 QKSLSLSPGK 
               
               
                   
                   
                 Light Chain SEQ ID NO: 58 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLI 
                 
               
               
                   
                   
                 
                   YSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPTF 
                 
               
               
                   
                   
                 
                   GQGTKVEIKR 
                   
                     GGGGSGGGGSGGGGS 
                   
                   DIQMTQSPSSPSASVGDRVTITCR 
                 
               
               
                   
                   
                 
                   ASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTL 
                 
               
               
                   
                   
                   TISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK RTVAAPSVFIFPPSDE 
               
               
                   
                   
                 QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST 
               
               
                   
                   
                 YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 
               
               
                   
               
               
                 Fv-IgG 
                 L6-F7B 
                 Heavy Chain SEQ ID NO: 59 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWVRQAPGKGLEW 
                 
               
               
                   
                   
                 
                   VAEISPYSGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYY 
                 
               
               
                   
                   
                 
                   CALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GGGGSGGGGSGGGGS 
                   
                   E 
                 
               
               
                   
                   
                 
                   VQLVESGGGLVQPGGSLRLSCAASGFNFSSSSIHWVRQAPGKGLEWV 
                 
               
               
                   
                   
                 
                   AYIYPSYDYTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                   
                   ARGYFYTWGGMDYWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAA 
               
               
                   
                   
                 LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSS 
               
               
                   
                   
                 LGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFL 
               
               
                   
                   
                 FPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP 
               
               
                   
                   
                 REEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAK 
               
               
                   
                   
                 GQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENN 
               
               
                   
                   
                 YKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQK 
               
               
                   
                   
                 SLSLSPGK 
               
               
                   
                   
                 Light Chain SEQ ID NO: 60 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLI 
                 
               
               
                   
                   
                 
                   YSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPTF 
                 
               
               
                   
                   
                 
                   GQGTKVEIKR 
                   
                     GGGGSGGGGSGGGGS 
                   
                   DIQMTQSPSSLSASVGDRVTITC 
                 
               
               
                   
                   
                 
                   RASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFT 
                 
               
               
                   
                   
                   LTISSLQPEDFATYYCQQYYSLFTFGQGTKVEIK RTVAAPSVFIFPPSDE 
               
               
                   
                   
                 QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST 
               
               
                   
                   
                 YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 
               
               
                   
               
               
                 Fv-IgG 
                 L6-F2I 
                 Heavy Chain SEQ ID NO: 61 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWVRQAPGKGLEW 
                 
               
               
                   
                   
                 
                   VAEISPYSGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYY 
                 
               
               
                   
                   
                 
                   CALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GGGGSGGGGSGGGGS 
                   
                   E 
                 
               
               
                   
                   
                 
                   VQLVESGGGLVQPGGSLRLSCAASGFNIHSSSIHWVRQAPGKGLEWV 
                 
               
               
                   
                   
                 
                   AATYSSFGSITYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                   
                   ARYHHPFGYALDYWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAAL 
               
               
                   
                   
                 GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL 
               
               
                   
                   
                 GTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLF 
               
               
                   
                   
                 PPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR 
               
               
                   
                   
                 EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKG 
               
               
                   
                   
                 QPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY 
               
               
                   
                   
                 KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS 
               
               
                   
                   
                 LSLSPGK 
               
               
                   
                   
                 Light Chain SEQ ID NO: 62 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLI 
                 
               
               
                   
                   
                 
                   YSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPTF 
                 
               
               
                   
                   
                 
                   GQGTKVEIKR 
                   
                     GGGGSGGGGSGGGGS 
                   
                   DIQMTQSPSSLSASVGDRVTITC 
                 
               
               
                   
                   
                 
                   RASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFT 
                 
               
               
                   
                   
                   LTISSLQPEDFATYYCQQGVYLFTFGQGTKVEIKR TVAAPSVFIFPPSDE 
               
               
                   
                   
                 QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST 
               
               
                   
                   
                 YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 
               
               
                 N-HC- 
                 L6-N-HC 
                 L6-N-HC appended ScFv-F12578-IgG HC SEQ ID NO: 63 
               
               
                 appended 
                 appended 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWVRQAPGKGLEW 
                 
               
               
                 ScFv-IgG 
                 ScFv- 
                 
                   VAEISPYSGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYY 
                 
               
               
                   
                 F12578-IgG 
                 
                   CALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GSAASGSSGGSSSGA 
                   
                   DIQ 
                 
               
               
                   
                   
                 
                   MTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSA 
                 
               
               
                   
                   
                 
                   SFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPTFGQ 
                 
               
               
                   
                   
                 
                   GTKVEIK 
                   
                     GGGGSGGGGSGGGGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASG 
                 
               
               
                   
                   
                 
                   FTFSHYTLSWVRQAPGKGLEWVSVISGDGSYTYYADSVKGRFTISSDN 
                 
               
               
                   
                   
                   SKNTLYLQMNSLRAEDTAVYYCARNFIKYVFANWGQGTLVTVSS AST 
               
               
                   
                   
                 KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP 
               
               
                   
                   
                 AVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCD 
               
               
                   
                   
                 KTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPE 
               
               
                   
                   
                 VKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY 
               
               
                   
                   
                 KCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV 
               
               
                   
                   
                 KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ 
               
               
                   
                   
                 GNVFSCSVMHEALHNHYTQKSLSLSPGK 
               
               
                   
                   
                 &gt;F12578 LC SEQ ID NO: 64 
               
               
                   
                   
                 
                   DIELTQPPSVSVAPGQTARISCSGDNIGSFYVHWYQQKPGQAPVLVIY 
                 
               
               
                   
                   
                 
                   DKSNRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQSYANTLSLV 
                 
               
               
                   
                   
                   FGGGTKLTVL GQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTV 
               
               
                   
                   
                 AWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQV 
               
               
                   
                   
                 THEGSTVEKTVAPTECS 
               
               
                   
               
               
                 N-HC- 
                 L6-N-HC 
                 L6-N-HC appended ScFv-F127-IgG HC SEQ ID NO: 65 
               
               
                 appended 
                 appended 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWVRQAPGKGLEW 
                 
               
               
                 ScFv-IgG 
                 ScFv-F127- 
                 
                   VAEISPYSGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYY 
                 
               
               
                   
                 IgG 
                 
                   CALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GSAASGSSGGSSSGA 
                   
                   DIQ 
                 
               
               
                   
                   
                 
                   MTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSA 
                 
               
               
                   
                   
                 
                   SFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPTFGQ 
                 
               
               
                   
                   
                 
                   GTKVEIK 
                   
                     GGGGSGGGGSGGGGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASG 
                 
               
               
                   
                   
                 
                   FNISSSYIHWVRQAPGKGLEWVAYIYSSYGSTYYADSVKGRFTISADTS 
                 
               
               
                   
                   
                   KNTAYLQMNSLRAEDTAVYYCARASWYALDYWGQGTLVTVSS ASTK 
               
               
                   
                   
                 GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA 
               
               
                   
                   
                 VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT 
               
               
                   
                   
                 HTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVK 
               
               
                   
                   
                 FNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC 
               
               
                   
                   
                 KVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGF 
               
               
                   
                   
                 YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN 
               
               
                   
                   
                 VFSCSVMHEALHNHYTQKSLSLSPGK 
               
               
                   
                   
                 &gt;F127 LC SEQ ID NO: 66 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLI 
                 
               
               
                   
                   
                 
                   YSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQYWYGVAP 
                 
               
               
                   
                   
                   ITFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKV 
               
               
                   
                   
                 QWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE 
               
               
                   
                   
                 VTHQGLSSPVTKSFNRGEC 
               
               
                   
               
               
                 N-HC- 
                 L6-N-HC 
                 L6-N-HC appended ScFv-F58-IgG HC SEQ ID NO: 67 
               
               
                 appended 
                 appended 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWVRQAPGKGLEW 
                 
               
               
                 ScFv-IgG 
                 ScFv-F58- 
                 
                   VAEISPYSGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYY 
                 
               
               
                   
                 IgG 
                 
                   CALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GSAASGSSGGSSSGA 
                   
                   DIQ 
                 
               
               
                   
                   
                 
                   MTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSA 
                 
               
               
                   
                   
                 
                   SFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPTFGQ 
                 
               
               
                   
                   
                 
                   GTKVEIK 
                   
                     GGGGSGGGGSGGGGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASG 
                 
               
               
                   
                   
                 
                   FNISYSYIHWVRQAPGKGLEWVASIYSSSGSTSYADSVKGRFTISADTS 
                 
               
               
                   
                   
                   KNTAYLQMNSLRAEDTAVYYCARGAIDYWGQGTLVTVSS ASTKGPSV 
               
               
                   
                   
                 FPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ 
               
               
                   
                   
                 SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTC 
               
               
                   
                   
                 PPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNW 
               
               
                   
                   
                 YVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN 
               
               
                   
                   
                 KALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD 
               
               
                   
                   
                 IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS 
               
               
                   
                   
                 VMHEALHNHYTQKSLSLSPGK 
               
               
                   
                   
                 &gt;F58 LC SEQ ID NO: 68 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLI 
                 
               
               
                   
                   
                 
                   YSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQWYSSGHV 
                 
               
               
                   
                   
                   LITFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAK 
               
               
                   
                   
                 VQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYAC 
               
               
                   
                   
                 EVTHQGLSSPVTKSFNRGEC 
               
               
                   
               
               
                 N-HC- 
                 L6-N-HC 
                 L6-N-HC appended ScFv-F4-2-IgG HC SEQ ID NO: 69 
               
               
                 appended 
                 appended 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWVRQAPGKGLEW 
                 
               
               
                 ScFv-IgG 
                 ScFv-F4-2- 
                 
                   VAEISPYSGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYY 
                 
               
               
                   
                 IgG 
                 
                   CALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GSAASGSSGGSSSGA 
                   
                   DIQ 
                 
               
               
                   
                   
                 
                   MTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSA 
                 
               
               
                   
                   
                 
                   SFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPTFGQ 
                 
               
               
                   
                   
                 
                   GTKVEIK 
                   
                     GGGGSGGGGSGGGGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASG 
                 
               
               
                   
                   
                 
                   FNISYYYIHWVRQAPGKGLEWVASIYPSSGYTYYADSVKGRFTISADT 
                 
               
               
                   
                   
                   SKNTAYLQMNSLRAEDTAVYYCARSSFYWAMDYWGQGTLVTVSS AS 
               
               
                   
                   
                 TKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHT 
               
               
                   
                   
                 FPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC 
               
               
                   
                   
                 DKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP 
               
               
                   
                   
                 EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE 
               
               
                   
                   
                 YKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCL 
               
               
                   
                   
                 VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ 
               
               
                   
                   
                 QGNVFSCSVMHEALHNHYTQKSLSLSPGK 
               
               
                   
                   
                 &gt;F4-2 LC SEQ ID NO: 70 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLI 
                 
               
               
                   
                   
                 
                   YSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQSYAAYLFT 
                 
               
               
                   
                   
                   FGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQ 
               
               
                   
                   
                 WKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEV 
               
               
                   
                   
                 THQGLSSPVTKSFNRGEC 
               
               
                   
               
               
                 N-HC- 
                 L6-N-HC 
                 L6-N-HC appended ScFv-F4-IgG HC SEQ ID NO: 71 
               
               
                 appended 
                 appended 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWVRQAPGKGLEW 
                 
               
               
                 ScFv-IgG 
                 ScFv-F4- 
                 
                   VAEISPYSGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYY 
                 
               
               
                   
                 IgG 
                 
                   CALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GSAASGSSGGSSSGA 
                   
                   DIQ 
                 
               
               
                   
                   
                 
                   MTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSA 
                 
               
               
                   
                   
                 
                   SFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPTFGQ 
                 
               
               
                   
                   
                 
                   GTKVEIK 
                   
                     GGGGSGGGGSGGGGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASG 
                 
               
               
                   
                   
                 
                   FNLSSYSMHWVRQAPGKGLEWVAYISSYYGYTYYADSVKGRFTISAD 
                 
               
               
                   
                   
                 
                   TSKNTAYLQMNSLRAEDTAVYYCARPAPGHWGFDYWGQGTLVTVSS 
                 
               
               
                   
                   
                 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGV 
               
               
                   
                   
                 HTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPK 
               
               
                   
                   
                 SCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE 
               
               
                   
                   
                 DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK 
               
               
                   
                   
                 EYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCL 
               
               
                   
                   
                 VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ 
               
               
                   
                   
                 QGNVFSCSVMHEALHNHYTQKSLSLSPGK 
               
               
                   
                   
                 &gt;F4 LC SEQ ID NO: 72 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLI 
                 
               
               
                   
                   
                 
                   YSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQWYYAPIT 
                 
               
               
                   
                   
                   FGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQ 
               
               
                   
                   
                 WKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEV 
               
               
                   
                   
                 THQGLSSPVTKSFNRGEC 
               
               
                   
               
               
                 N-HC- 
                 L6-N-HC 
                 L6-N-HC appended ScFv-F49-IgG SEQ ID NO: 73 
               
               
                 appended 
                 appended 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWVRQAPGKGLEW 
                 
               
               
                 ScFv-IgG 
                 ScFv-F49- 
                 
                   VAEISPYSGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYY 
                 
               
               
                   
                 IgG 
                 
                   CALRARPPIRIHPRGSVMDYWGQGTLVTVSS 
                   
                     GSAASGSSGGSSSGA 
                   
                   DIQ 
                 
               
               
                   
                   
                 
                   MTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSA 
                 
               
               
                   
                   
                 
                   SFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPTFGQ 
                 
               
               
                   
                   
                 
                   GTKVEIK 
                   
                     GGGGSGGGGSGGGGS 
                   
                   QVQLVQSGAEVKKPGASVKVSCKAS 
                 
               
               
                   
                   
                 
                   GGTFSSYAISWVRQAPGQGLEWMGWINAGNGNTTYAQKFQGRVTM 
                 
               
               
                   
                   
                 
                   TRQTSTSTVYMELSSLRSEDTAVYYCARHYYGSGSYPDWGQGTLVTV 
                 
               
               
                   
                   
                   SS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG 
               
               
                   
                   
                 VHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEP 
               
               
                   
                   
                 KSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH 
               
               
                   
                   
                 EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG 
               
               
                   
                   
                 KEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT 
               
               
                   
                   
                 CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR 
               
               
                   
                   
                 WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
               
               
                   
                   
                 &gt;F49 LC SEQ ID NO: 74 
               
               
                   
                   
                 
                   DIQMTQSPSSPSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIY 
                 
               
               
                   
                   
                 
                   AASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFG 
                 
               
               
                   
                   
                   GGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWK 
               
               
                   
                   
                 VDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH 
               
               
                   
                   
                 QGLSSPVTKSFNRGEC 
               
               
                   
               
               
                 N-HC- 
                 L6-N-HC 
                 L6-N-HC appended ScFv-F10-IgG HC SEQ ID NO: 75 
               
               
                 appended 
                 appended 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWVRQAPGKGLEW 
                 
               
               
                 ScFv-IgG 
                 ScFv-F10- 
                 
                   VAEISPYSGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYY 
                 
               
               
                   
                 IgG 
                 
                   CALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GSAASGSSGGSSSGA 
                   
                   DIQ 
                 
               
               
                   
                   
                 
                   MTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSA 
                 
               
               
                   
                   
                 
                   SFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPTFGQ 
                 
               
               
                   
                   
                 
                   GTKVEIK 
                   
                     GGGGSGGGGSGGGGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASG 
                 
               
               
                   
                   
                 
                   FTFSSFNMFWVRQAPGKGLEWVAGIDDDGSYPNYGSAVKGRATISRD 
                 
               
               
                   
                   
                 
                   NSKNTLYLQMNSLRAEDTAVYYCAKSGYGGSWGGYIADDIDAWGQG 
                 
               
               
                   
                   
                   TLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS 
               
               
                   
                   
                 GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV 
               
               
                   
                   
                 DKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCV 
               
               
                   
                   
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH 
               
               
                   
                   
                 QDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTK 
               
               
                   
                   
                 NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL 
               
               
                   
                   
                 TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
               
               
                   
                   
                 &gt;F10 LC SEQ ID NO: 76 
               
               
                   
                   
                 
                   ELTQPPSVSVSPGQTARITCSGDGSYAGSYYYGWYQQKPGQAPVTLIY 
                 
               
               
                   
                   
                 
                   YNNKRPSGIPERFSGSLSGSTNTLTISGVQAEDEADYYCGSADNSGAAF 
                 
               
               
                   
                   
                   GGGTKLTVL RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQ 
               
               
                   
                   
                 WKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEV 
               
               
                   
               
               
                   
                   
                 THQGLSSPVTKSFNRGEC 
               
               
                 N-HC- 
                 L6-N-HC- 
                 L6-N-HC appended ScFv-F7B-IgG HC SEQ ID NO: 189 
               
               
                 appended 
                 Appended 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWVRQAPGKGLEW 
                 
               
               
                 ScFv-IgG 
                 ScFv-F7B- 
                 
                   VAEISPYSGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYY 
                 
               
               
                   
                 IgG 
                 
                   CALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GSAASGSSGGSSSGA 
                   
                   DIQ 
                 
               
               
                   
                   
                 
                   MTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSA 
                 
               
               
                   
                   
                 
                   SFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPTFGQ 
                 
               
               
                   
                   
                 
                   GTKVEIK 
                   
                     GGGGSGGGGSGGGGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASG 
                 
               
               
                   
                   
                 
                   FNFSSSSIHWVRQAPGKGLEWVAYIYPSYDYTYYADSVKGRFTISADT 
                 
               
               
                   
                   
                 
                   SKNTAYLQMNSLRAEDTAVYYCARGYFYTWGGMDYWGQGTLVTVS 
                 
               
               
                   
                   
                   S ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGV 
               
               
                   
                   
                 HTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPK 
               
               
                   
                   
                 SCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE 
               
               
                   
                   
                 DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK 
               
               
                   
                   
                 EYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCL 
               
               
                   
                   
                 VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ 
               
               
                   
                   
                 QGNVFSCSVMHEALHNHYTQKSLSLSPGK 
               
               
                   
                   
                 F7B LC SEQ ID NO: 190 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLI 
                 
               
               
                   
                   
                 
                   YSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQYYSLFTFG 
                 
               
               
                   
                   
                   QGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWK 
               
               
                   
                   
                 VDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH 
               
               
                   
                   
                 QGLSSPVTKSFNRGEC 
               
               
                   
               
               
                 N-HC- 
                 L6-N-HC- 
                 L6-N-HC appended ScFv-F2I-IgG HC SEQ ID NO: 191 
               
               
                 appended 
                 Appended 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWVRQAPGKGLEW 
                 
               
               
                 ScFv-IgG 
                 ScFv-F2I- 
                 
                   VAEISPYSGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYY 
                 
               
               
                   
                 IgG 
                 
                   CALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GSAASGSSGGSSSGA 
                   
                   DIQ 
                 
               
               
                   
                   
                 
                   MTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSA 
                 
               
               
                   
                   
                 
                   SFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPTFGQ 
                 
               
               
                   
                   
                 
                   GTKVEIK 
                   
                     GGGGSGGGGSGGGGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASG 
                 
               
               
                   
                   
                 
                   FNIHSSSIHWVRQAPGKGLEWVAATYSSFGSITYADSVKGRFTISADTS 
                 
               
               
                   
                   
                   KNTAYLQMNSLRAEDTAVYYCARYHHPFGYALDYWGQGTLVTVSS A 
               
               
                   
                   
                 STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVH 
               
               
                   
                   
                 TFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKS 
               
               
                   
                   
                 CDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED 
               
               
                   
                   
                 PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE 
               
               
                   
                   
                 YKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCL 
               
               
                   
                   
                 VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ 
               
               
                   
                   
                 QGNVFSCSVMHEALHNHYTQKSLSLSPGK 
               
               
                   
                   
                 F2I LC SEQ ID NO: 192 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLI 
                 
               
               
                   
                   
                 
                   YSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQGVYLFTF 
                 
               
               
                   
                   
                   GQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQW 
               
               
                   
                   
                 KVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVT 
               
               
                   
                   
                 HQGLSSPVTKSFNRGEC 
               
               
                   
               
               
                 N-HC 
                 L6-N-HC 
                 L6-N-HC appended ScFv-F12578-IgG-Knob-His HC SEQ ID NO: 77 
               
               
                 appended 
                 appended 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWVRQAPGKGLEW 
                 
               
               
                 ScFv-IgG- 
                 ScFv- 
                 
                   VAEISPYSGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYY 
                 
               
               
                 Knob-his + 
                 F12578- 
                 
                   CALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GSAASGSSGGSSSGA 
                   
                   DIQ 
                 
               
               
                 IgG-Hole- 
                 IgG-Knob- 
                 
                   MTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSA 
                 
               
               
                 Flag 
                 his + 
                 
                   SFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPTFGQ 
                 
               
               
                   
                 F12578- 
                 
                   GTKVEIK 
                   
                     GGGGSGGGGSGGGGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASG 
                 
               
               
                   
                 IgG-Hole- 
                 
                   FTFSHYTLSWVRQAPGKGLEWVSVISGDGSYTYYADSVKGRFTISSDN 
                 
               
               
                   
                 Flag 
                   SKNTLYLQMNSLRAEDTAVYYCARNFIKYVFANWGQGTLVTVSS AST 
               
               
                   
                   
                 KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP 
               
               
                   
                   
                 AVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCD 
               
               
                   
                   
                 KTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPE 
               
               
                   
                   
                 VKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY 
               
               
                   
                   
                 KCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLWCLV 
               
               
                   
                   
                 KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ 
               
               
                   
                   
                 GNVFSCSVMHEALHNHYTQKSLSLSPGK   GSGSG   HHHHHH 
               
               
                   
                   
                 &gt; F12578-IgG-Hole Flag HC SEQ ID NO: 78 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFSHYTLSWVRQAPGKGLE 
                 
               
               
                   
                   
                 
                   WVSVISGDGSYTYYADSVKGRFTISSDNSKNTLYLQMNSLRAEDTAVY 
                 
               
               
                   
                   
                   YCARNFIKYVFANWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAAL 
               
               
                   
                   
                 GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL 
               
               
                   
                   
                 GTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLF 
               
               
                   
                   
                 PPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR 
               
               
                   
                   
                 EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKG 
               
               
                   
                   
                 QPREPQVYTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNY 
               
               
                   
                   
                 KTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS 
               
               
                   
                   
                 LSLSPGK   GSGSG   DYKDDDDK 
               
               
                   
                   
                 &gt;F12578 LC SEQ ID NO: 79 
               
               
                   
                   
                 
                   DIELTQPPSVSVAPGQTARISCSGDNIGSFYVHWYQQKPGQAPVLVIY 
                 
               
               
                   
                   
                 
                   DKSNRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQSYANTLSLV 
                 
               
               
                   
                   
                   FGGGTKLTVL GPPKAAPSVTLFPPSSEELPANKATLVCLISDFYPGAVTV 
               
               
                   
                   
                 AWKADSSPVKAGVETTTPSKPSNNKYAASSYLSLTPEPWKSHRSYSCPV 
               
               
                   
                   
                 THEGSTVEKTVAPTECS 
               
               
                   
               
               
                 N-HC 
                 L6-N-HC 
                 L6-N-HC appended ScFv-F127-IgG-Knob-His HC SEQ ID NO: 80 
               
               
                 appended 
                 appended 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWVRQAPGKGLEW 
                 
               
               
                 ScFv-IgG- 
                 ScFv-F127- 
                 
                   VAEISPYSGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYY 
                 
               
               
                 Knob-his + 
                 IgG-Knob- 
                 
                   CALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GSAASGSSGGSSSGA 
                   
                   DIQ 
                 
               
               
                 IgG-Hole- 
                 his + F127- 
                 
                   MTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSA 
                 
               
               
                 Flag 
                 IgG-Hole- 
                 
                   SFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPTFGQ 
                 
               
               
                   
                 Flag 
                 
                   GTKVEIK 
                   
                     GGGGSGGGGSGGGGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASG 
                 
               
               
                   
                   
                 
                   FNISSSYIHWVRQAPGKGLEWVAYIYSSYGSTYYADSVKGRFTISADTS 
                 
               
               
                   
                   
                   KNTAYLQMNSLRAEDTAVYYCARASWYALDYWGQGTLVTVSS ASTK 
               
               
                   
                   
                 GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA 
               
               
                   
                   
                 VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT 
               
               
                   
                   
                 HTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVK 
               
               
                   
                   
                 FNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC 
               
               
                   
                   
                 KVSNKALGAPIEKTISKAKGPPREPPVYTLPPSREEMTKNPVSLWCLVKG 
               
               
                   
                   
                 FYPSDIAVEWESNGPPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWPPGN 
               
               
                   
                   
                 VFSCSVMHEALHNHYTQKSLSLSPGK   GSGSG   HHHHHH 
               
               
                   
                   
                 &gt; F127-IgG-Hole Flag HC SEQ ID NO: 81 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFNISSSYIHWVRQAPGKGLEW 
                 
               
               
                   
                   
                 
                   VAYIYSSYGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYY 
                 
               
               
                   
                   
                   CARASWYALDYWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALG 
               
               
                   
                   
                 CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG 
               
               
                   
                   
                 TPTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPP 
               
               
                   
                   
                 KPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE 
               
               
                   
                   
                 QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQP 
               
               
                   
                   
                 REPQVYTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKT 
               
               
                   
                   
                 TPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS 
               
               
                   
                   
                 LSPGK   GSGSG   DYKDDDDK 
               
               
                   
                   
                 &gt;F127 LC SEQ ID NO: 82 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLI 
                 
               
               
                   
                   
                 
                   YSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQYWYGVAP 
                 
               
               
                   
                   
                   ITFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKV 
               
               
                   
                   
                 QWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE 
               
               
                   
                   
                 VTHQGLSSPVTKSFNRGEC 
               
               
                   
               
               
                 N-HC 
                 L6-N-HC 
                 L6-N-HC appended ScFv-F58-IgG-Knob-His HC SEQ ID NO: 83 
               
               
                 appended 
                 appended 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWVRQAPGKGLEW 
                 
               
               
                 ScFv-IgG- 
                 ScFv-F58- 
                 
                   VAEISPYSGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYY 
                 
               
               
                 Knob-his + 
                 IgG-Knob- 
                 
                   CALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GSAASGSSGGSSSGA 
                   
                   DIQ 
                 
               
               
                 IgG-Hole- 
                 his + F58- 
                 
                   MTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSA 
                 
               
               
                 Flag 
                 IgG-Hole- 
                 
                   SFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPTFGQ 
                 
               
               
                   
                 Flag 
                 
                   GTKVEIK 
                   
                     GGGGSGGGGSGGGGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASG 
                 
               
               
                   
                   
                 
                   FNISYSYIHWVRQAPGKGLEWVASIYSSSGSTSYADSVKGRFTISADTS 
                 
               
               
                   
                   
                   KNTAYLQMNSLRAEDTAVYYCARGAIDYWGQGTLVTVSS ASTKGPSV 
               
               
                   
                   
                 FPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ 
               
               
                   
                   
                 SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTC 
               
               
                   
                   
                 PPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNW 
               
               
                   
                   
                 YVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN 
               
               
                   
                   
                 KALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLWCLVKGFYPS 
               
               
                   
                   
                 DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC 
               
               
                   
                   
                 SVMHEALHNHYTQKSLSLSPGK   GSGSG   HHHHHH 
               
               
                   
                   
                 &gt; F58-IgG-Hole Flag HC SEQ ID NO: 84 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFNISYSYIHWVRQAPGKGLEW 
                 
               
               
                   
                   
                 
                   VASIYSSSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                   
                   ARGAIDYWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKD 
               
               
                   
                   
                 YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI 
               
               
                   
                   
                 CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKD 
               
               
                   
                   
                 TLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS 
               
               
                   
                   
                 TYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQ 
               
               
                   
                   
                 VYTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPV 
               
               
                   
                   
                 LDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 
               
               
                   
                   
                 K   GSGSG   DYKDDDDK 
               
               
                   
                   
                 &gt;F58 LC SEQ ID NO: 85 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLI 
                 
               
               
                   
                   
                 
                   YSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQWYSSGHV 
                 
               
               
                   
                   
                   LITFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAK 
               
               
                   
                   
                 VQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYAC 
               
               
                   
                   
                 EVTHQGLSSPVTKSFNRGEC 
               
               
                   
               
               
                 N-HC 
                 L6-N-HC 
                 L6-N-HC appended ScFv-F4-2-IgG-Knob-His HC SEQ ID NO: 86 
               
               
                 appended 
                 appended 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWVRQAPGKGLEW 
                 
               
               
                 ScFv-IgG- 
                 ScFv-F4-2- 
                 
                   VAEISPYSGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYY 
                 
               
               
                 Knob-his + 
                 IgG-Knob- 
                 
                   CALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GSAASGSSGGSSSGA 
                   
                   DIQ 
                 
               
               
                 IgG-Hole- 
                 his + F4-2- 
                 
                   MTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSA 
                 
               
               
                 Flag 
                 IgG-Hole- 
                 
                   SFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPTFGQ 
                 
               
               
                   
                 Flag 
                 
                   GTKVEIK 
                   
                     GGGGSGGGGSGGGGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASG 
                 
               
               
                   
                   
                 
                   FNISYYYIHWVRQAPGKGLEWVASIYPSSGYTYYADSVKGRFTISADT 
                 
               
               
                   
                   
                   SKNTAYLQMNSLRAEDTAVYYCARSSFYWAMDYWGQGTLVTVSS AS 
               
               
                   
                   
                 TKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHT 
               
               
                   
                   
                 FPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC 
               
               
                   
                   
                 DKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP 
               
               
                   
                   
                 EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE 
               
               
                   
                   
                 YKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLWCL 
               
               
                   
                   
                 VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ 
               
               
                   
                   
                 QGNVFSCSVMHEALHNHYTQKSLSLSPGK   GSGSG   HHHHHH 
               
               
                   
                   
                 &gt; F4-2-IgG-Hole Flag HC SEQ ID NO: 87 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFNISYYYIHWVRQAPGKGLEW 
                 
               
               
                   
                   
                 
                   VASIYPSSGYTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYY 
                 
               
               
                   
                   
                   CARSSFYWAMDYWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAAL 
               
               
                   
                   
                 GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL 
               
               
                   
                   
                 GTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLF 
               
               
                   
                   
                 PPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR 
               
               
                   
                   
                 EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKG 
               
               
                   
                   
                 QPREPQVYTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNY 
               
               
                   
                   
                 KTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS 
               
               
                   
                   
                 LSLSPGK   GSGSG   DYKDDDDK 
               
               
                   
                   
                 &gt;F4-2 LC SEQ ID NO: 88 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLI 
                 
               
               
                   
                   
                 
                   YSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQSYAAYLFT 
                 
               
               
                   
                   
                   FGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQ 
               
               
                   
                   
                 WKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEV 
               
               
                   
                   
                 THQGLSSPVTKSFNRGEC 
               
               
                   
               
               
                 N-HC 
                 L6-N-HC 
                 L6-N-HC appended ScFv-F4-IgG-Knob-His HC SEQ ID NO: 89 
               
               
                 appended 
                 appended 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWVRQAPGKGLEW 
                 
               
               
                 ScFv-IgG- 
                 ScFv-F4- 
                 
                   VAEISPYSGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYY 
                 
               
               
                 Knob-his + 
                 IgG-Knob- 
                 
                   CALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GSAASGSSGGSSSGA 
                   
                   DIQ 
                 
               
               
                 IgG-Hole- 
                 his + F4- 
                 
                   MTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSA 
                 
               
               
                 Flag 
                 IgG-Hole- 
                 
                   SFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPTFGQ 
                 
               
               
                   
                 Flag 
                 
                   GTKVEIK 
                   
                     GGGGSGGGGSGGGGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASG 
                 
               
               
                   
                   
                 
                   FNLSSYSMHWVRQAPGKGLEWVAYISSYYGYTYYADSVKGRFTISAD 
                 
               
               
                   
                   
                 
                   TSKNTAYLQMNSLRAEDTAVYYCARPAPGHWGFDYWGQGTLVTVSS 
                 
               
               
                   
                   
                 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGV 
               
               
                   
                   
                 HTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPK 
               
               
                   
                   
                 SCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE 
               
               
                   
                   
                 DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK 
               
               
                   
                   
                 EYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLWC 
               
               
                   
                   
                 LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW 
               
               
                   
                   
                 QQGNVFSCSVMHEALHNHYTQKSLSLSPGK   GSGSG   HHHHHH 
               
               
                   
                   
                 &gt; F4-IgG-Hole Flag HC SEQ ID NO: 90 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFNLSSYSMHWVRQAPGKGLE 
                 
               
               
                   
                   
                 
                   WVAYISSYYGYTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAV 
                 
               
               
                   
                   
                   YYCARPAPGHWGFDYWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGT 
               
               
                   
                   
                 AALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP 
               
               
                   
                   
                 SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPS 
               
               
                   
                   
                 VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK 
               
               
                   
                   
                 TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISK 
               
               
                   
                   
                 AKGQPREPQVYTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPE 
               
               
                   
                   
                 NNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYT 
               
               
                   
                   
                 QKSLSLSPGK   GSGSG   DYKDDDDK 
               
               
                   
                   
                 &gt;F4 LC SEQ ID NO: 91 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLI 
                 
               
               
                   
                   
                 
                   YSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQWYYAPIT 
                 
               
               
                   
                   
                   FGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQ 
               
               
                   
                   
                 WKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEV 
               
               
                   
                   
                 THQGLSSPVTKSFNRGEC 
               
               
                   
               
               
                 N-HC 
                 L6-N-HC 
                 L6-N-HC appended ScFv-F49-IgG-Knob-His HC SEQ ID NO: 92 
               
               
                 appended 
                 appended 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWVRQAPGKGLEW 
                 
               
               
                 ScFv-IgG- 
                 ScFv-F49- 
                 
                   VAEISPYSGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYY 
                 
               
               
                 Knob-his + 
                 IgG-Knob- 
                 
                   CALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GSAASGSSGGSSSGA 
                   
                   DIQ 
                 
               
               
                 IgG-Hole- 
                 his + F49- 
                 
                   MTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSA 
                 
               
               
                 Flag 
                 IgG-Hole- 
                 
                   SFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPTFGQ 
                 
               
               
                   
                 Flag 
                 
                   GTKVEIK 
                   
                     GGGGSGGGGSGGGGS 
                   
                   QVQLVQSGAEVKKPGASVKVSCKAS 
                 
               
               
                   
                   
                 
                   GGTFSSYAISWVRQAPGQGLEWMGWINAGNGNTTYAQKFQGRVTM 
                 
               
               
                   
                   
                 
                   TRDTSTSTVYMELSSLRSEDTAVYYCARHYYGSGSYPDWGQGTLVTV 
                 
               
               
                   
                   
                   SS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG 
               
               
                   
                   
                 VHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEP 
               
               
                   
                   
                 KSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH 
               
               
                   
                   
                 EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG 
               
               
                   
                   
                 KEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLW 
               
               
                   
                   
                 CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR 
               
               
                   
                   
                 WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK   GSGSG   HHHHHH 
               
               
                   
                   
                 &gt; F49-IgG-Hole Flag HC SEQ ID NO: 93 
               
               
                   
                   
                 
                   QVQLVQSGAEVKKPGASVKVSCKASGGTFSSYAISWVRQAPGQGLE 
                 
               
               
                   
                   
                 
                   WMGWINAGNGNTTYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTA 
                 
               
               
                   
                   
                   VYYCARHYYGSGSYPDWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGT 
               
               
                   
                   
                 AALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP 
               
               
                   
                   
                 SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPS 
               
               
                   
                   
                 VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK 
               
               
                   
                   
                 TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISK 
               
               
                   
                   
                 AKGQPREPQVYTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPE 
               
               
                   
                   
                 NNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYT 
               
               
                   
                   
                 QKSLSLSPGK   GSGSG   DYKDDDDK 
               
               
                   
                   
                 &gt;F49 LC SEQ ID NO: 94 
               
               
                   
                   
                 
                   DIQMTQSPSSPSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIY 
                 
               
               
                   
                   
                 
                   AASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFG 
                 
               
               
                   
                   
                   GGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWK 
               
               
                   
                   
                 VDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH 
               
               
                   
                   
                 QGLSSPVTKSFNRGEC 
               
               
                   
               
               
                 N-HC 
                 L6-N-HC 
                 L6-N-HC appended ScFv-F10-IgG-Knob-His HC SEQ ID NO: 95 
               
               
                 appended 
                 appended 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWVRQAPGKGLEW 
                 
               
               
                 ScFv-IgG- 
                 ScFv-F10- 
                 
                   VAEISPYSGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYY 
                 
               
               
                 Knob-his + 
                 IgG-Knob- 
                 
                   CALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GSAASGSSGGSSSGA 
                   
                   DIQ 
                 
               
               
                 IgG-Hole- 
                 his + F10- 
                 
                   MTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSA 
                 
               
               
                 Flag 
                 IgG-Hole- 
                 
                   SFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPTFGQ 
                 
               
               
                   
                 Flag 
                 
                   GTKVEIK 
                   
                     GGGGSGGGGSGGGGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASG 
                 
               
               
                   
                   
                 
                   FTFSSFNMFWVRQAPGKGLEWVAGIDDDGSYPNYGSAVKGRATISRD 
                 
               
               
                   
                   
                 
                   NSKNTLYLQMNSLRAEDTAVYYCAKSGYGGSWGGYIADDIDAWGQG 
                 
               
               
                   
                   
                   TLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS 
               
               
                   
                   
                 GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV 
               
               
                   
                   
                 DKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCV 
               
               
                   
                   
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH 
               
               
                   
                   
                 QDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTK 
               
               
                   
                   
                 NQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL 
               
               
                   
                   
                 TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK   GSGSG   HHHHHH 
               
               
                   
                   
                 &gt; F10-IgG-Hole Flag HC SEQ ID NO: 96 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFSSFNMFWVRQAPGKGLE 
                 
               
               
                   
                   
                 
                   WVAGIDDDGSYPNYGSAVKGRATISRDNSKNTLYLQMNSLRAEDTAV 
                 
               
               
                   
                   
                   YYCAKSGYGGSWGGYIADDIDAWGQGTLVTVSS ASTKGPSVFPLAPSS 
               
               
                   
                   
                 KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL 
               
               
                   
                   
                 SSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPE 
               
               
                   
                   
                 AAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVE 
               
               
                   
                   
                 VHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAP 
               
               
                   
                   
                 IEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWE 
               
               
                   
                   
                 SNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEA 
               
               
                   
                   
                 LHNHYTQKSLSLSPGK   GSGSG   DYKDDDDK 
               
               
                   
                   
                 &gt;F10 LC SEQ ID NO: 97 
               
               
                   
                   
                 
                   ELTQPPSVSVSPGQTARITCSGDGSYAGSYYYGWYQQKPGQAPVTLIY 
                 
               
               
                   
                   
                 
                   YNNKRPSGIPERFSGSLSGSTNTLTISGVQAEDEADYYCGSADNSGAAF 
                 
               
               
                   
                   
                   GGGTKLTVL RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQ 
               
               
                   
                   
                 WKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEV 
               
               
                   
                   
                 THQGLSSPVTKSFNRGEC 
               
               
                   
               
               
                 N-HC 
                 L6-N-HC 
                 L6-N-HC appended ScFv-F7B-IgG-Knob-His HC SEQ ID NO: 193 
               
               
                 appended 
                 appended 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWVRQAPGKGLEW 
                 
               
               
                 ScFv-IgG- 
                 ScFv-F7B- 
                 
                   VAEISPYSGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYY 
                 
               
               
                 Knob-his + 
                 IgG-Knob- 
                 
                   CALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GSAASGSSGGSSSGA 
                   
                   DIQ 
                 
               
               
                 IgG-Hole- 
                 his + F7B- 
                 
                   MTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSA 
                 
               
               
                 Flag 
                 IgG-Hole- 
                 
                   SFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPTFGQ 
                 
               
               
                   
                 Flag 
                 
                   GTKVEIK 
                   
                     GGGGSGGGGSGGGGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASG 
                 
               
               
                   
                   
                 
                   FNFSSSSIHWVRQAPGKGLEWVAYIYPSYDYTYYADSVKGRFTISADT 
                 
               
               
                   
                   
                 
                   SKNTAYLQMNSLRAEDTAVYYCARGYFYTWGGMDYWGQGTLVTVS 
                 
               
               
                   
                   
                   S ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGV 
               
               
                   
                   
                 HTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPK 
               
               
                   
                   
                 SCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE 
               
               
                   
                   
                 DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK 
               
               
                   
                   
                 EYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLWC 
               
               
                   
                   
                 LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW 
               
               
                   
                   
                 QQGNVFSCSVMHEALHNHYTQKSLSLSPGK   GSGSG   HHHHHH 
               
               
                   
                   
                 &gt; F7B-IgG-Hole Flag HC SEQ ID NO: 194 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFNFSSSSIHWVRQAPGKGLEW 
                 
               
               
                   
                   
                 
                   VAYIYPSYDYTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYY 
                 
               
               
                   
                   
                   CARGYFYTWGGMDYWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTA 
               
               
                   
                   
                 ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS 
               
               
                   
                   
                 SSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSV 
               
               
                   
                   
                 FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT 
               
               
                   
                   
                 KPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISK 
               
               
                   
                   
                 AKGQPREPQVYTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPE 
               
               
                   
                   
                 NNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYT 
               
               
                   
                   
                 QKSLSLSPGK   GSGSG   DYKDDDDK 
               
               
                   
                   
                 &gt;F7B LC SEQ ID NO: 195 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLI 
                 
               
               
                   
                   
                 
                   YSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQYYSLFTFG 
                 
               
               
                   
                   
                   QGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWK 
               
               
                   
                   
                 VDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH 
               
               
                   
                   
                 QGLSSPVTKSFNRGEC 
               
               
                   
               
               
                 N-HC 
                 L6-N-HC 
                 L6-N-HC appended ScFv-F2I-IgG-Knob-His HC SEQ ID NO: 196 
               
               
                 appended 
                 appended 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWVRQAPGKGLEW 
                 
               
               
                 ScFv-IgG- 
                 ScFv-F2I- 
                 
                   VAEISPYSGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYY 
                 
               
               
                 Knob-his + 
                 IgG-Knob- 
                 
                   CALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GSAASGSSGGSSSGA 
                   
                   DIQ 
                 
               
               
                 IgG-Hole- 
                 his + F2I- 
                 
                   MTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSA 
                 
               
               
                 Flag 
                 IgG-Hole- 
                 
                   SFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPTFGQ 
                 
               
               
                   
                 Flag 
                 
                   GTKVEIK 
                   
                     GGGGSGGGGSGGGGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASG 
                 
               
               
                   
                   
                 
                   FNIHSSSIHWVRQAPGKGLEWVAATYSSFGSITYADSVKGRFTISADTS 
                 
               
               
                   
                   
                   KNTAYLQMNSLRAEDTAVYYCARYHHPFGYALDYWGQGTLVTVSS A 
               
               
                   
                   
                 STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVH 
               
               
                   
                   
                 TFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKS 
               
               
                   
                   
                 CDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED 
               
               
                   
                   
                 PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE 
               
               
                   
                   
                 YKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLWCL 
               
               
                   
                   
                 VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ 
               
               
                   
                   
                 QGNVFSCSVMHEALHNHYTQKSLSLSPGK   GSGSG   HHHHHH 
               
               
                   
                   
                 &gt; F2I-IgG-Hole Flag HC SEQ ID NO: 197 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFNIHSSSIHWVRQAPGKGLEW 
                 
               
               
                   
                   
                 
                   VAATYSSFGSITYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYY 
                 
               
               
                   
                   
                   CARYHHPFGYALDYWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTA 
               
               
                   
                   
                 ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS 
               
               
                   
                   
                 SSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSV 
               
               
                   
                   
                 FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT 
               
               
                   
                   
                 KPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISK 
               
               
                   
                   
                 AKGQPREPQVYTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPE 
               
               
                   
                   
                 NNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYT 
               
               
                   
                   
                 QKSLSLSPGK   GSGSG   DYKDDDDK 
               
               
                   
                   
                 &gt;F2ILC SEQ ID NO: 198 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLI 
                 
               
               
                   
                   
                 
                   YSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQGVYLFTF 
                 
               
               
                   
                   
                   GQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQW 
               
               
                   
                   
                 KVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVT 
               
               
                   
                   
                 HQGLSSPVTKSFNRGEC 
               
               
                   
               
            
           
         
       
     
     Example 2 
     Generation of WNT Super Agonist Molecules 
     To complement the set of surrogate agonists, generation of a set of potent antagonist molecules to study WNT signaling through specific FZDs was also attempted. Previous studies have shown that antibodies that compete with WNT binding to FZD can serve as antagonists (Gurney, et al., supra), however, this approach required the continuous presence of the antibodies at relatively high concentrations. Additionally, not all FZD binding antibodies generated functioned as antagonists, e.g., if they did not compete with WNT binding to receptor. Therefore, a potent and FZD selective antagonist platform would be highly desirable for both research and therapeutic development. 
     ZNRF3 and RNF43 are membrane-bound E3 ligases that target WNT receptors (FZDs and LRPs) for degradation (Hao et al. (2012) Nature 485:195-200; and Koo et al. (2012)  Nature  488:665-669). Based on the activities of the E3 ligases, constructs were made to test if a fusion between FZD and E3 ligase binders would act as an antagonist of WNT signaling. 
     The E3 ligase binding activity of RSPO2 was utilized by fusing either a control GFP antibody or the FZD binding antibody, F12578, to a mutant RSPO2 fragment. The mutant RSPO2 fragment contained furin domains, Fu1Fu2, that harbor a double F105R/F109A mutation in the Fu2 domain ( FIG.  2 A , designated “RSPO2RA”). RSPO2RA fragment lost the ability to bind LGR (and therefore lost the WNT signal enhancing activity), but retained ability to bind E3 ligases (Xie et al. (2013)  EMBO Rep.  14:1120-1126). Compared to wild type RSPO2Fu1Fu2-Fc fusion (Fc-RSPO2), the RSPO2RA mutant fusion to a negative control anti-GFP antibody had significantly diminished WNT signal enhancing activity. Only modest activities were observed at the highest dose tested ( FIG.  2 B ). Surprisingly, while the fusion of the RSPO2RA mutant to F12578 (F12578-RSPO2RA) had no activity on its own, the fusion protein resulted in a biphasic curve in the presence of WNT3A, where at lower doses, it enhanced rather than inhibited WNT3A signaling ( FIG.  2 B ). To understand the mechanism leading to the enhanced signaling, we performed FACS analysis to assess the FZD receptor levels on cell surface. As shown in  FIG.  2 C , cell treated with F12578-RSPO2RA showed increased FZD levels as detected by anti-FZD antibody. These results suggest that, instead of acting as an inhibitor to reduce FZD levels, F12578-RSPO2RA acted at least in part in a RSPO mimetic fashion, increased receptor levels and enhanced Wnt signaling. 
     To understand the general applicability of this observation, additional fusion proteins between RSPO2RA with other FZD binders, R2M3 (“F6”) which binds FZD1,2,7,5,8 and 1791 (“F7”) which binds FZD7, were generated. In these cases, the RSPO2RA was fused to the N-terminus of the FZD binding antibody heavy chain. As shown in  FIG.  2 D , both RSPO2RA-F6 and RSPO2-F7 also behaved in a RSPO mimetic fashion and enhanced WNT3A activities at low doses. A fusion of RSPO2RA to the N-terminus of F6 Fab on its heavy chain, RSPO2RA-F6_Fab, was also generated. As shown in  FIG.  2 E , the monovalent fusion protein also enhanced WNT3A activity. These results surprisingly suggested that, instead of acting as a suppressor to reduce FZD levels, FZD binder fusions to RSPO2RA, or generally E3 ligase binders, acted in a RSPO mimetic fashion and enhanced WNT signaling. Structure and sequence of these novel RSPO mimetic molecules are shown in Table 4. 
     Since this approach yielded the surprising result of enhancers instead of predicted antagonists, it was further investigated whether the surrogate molecules of  FIG.  1   , in particular the Fv-Ig structure, in combination with the E3 ligase binders would result in a WNT super agonist. To that end, trispecific, hexavalent molecules were generated as shown in  FIG.  3 A . As shown in  FIG.  3 B , this type of molecule possesses both WNT surrogate and RSPO activities as exemplified by the construct L6-F12578-RSPO2RA. This WNT super agonist activity translated to different FZD binders, e.g., L6-F127-RSPO2RA, L6-F58-RSPO2RA, L6-F4-RSPO2RA, L6-F49-RSPO2RA, L6-F10-RSPO2RA, L6-F7B-RSPO2RA, L6-F2I-RSPO2RA, L6-F4-2-RSPO2RA ( FIG.  3 C- 3 K ). Additional formats where RSPO2RA was attached to different locations of the WNT mimetic molecule was also constructed as shown in  FIG.  3 J , with activities shown in 3K. Table 4 describes the different components/formats tested. 
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 WNT enhancers and WNT super agonist structures and sequences 
               
            
           
           
               
               
               
            
               
                   
                   
                 Sequences (as depicted in the accompanying 
               
               
                   
                   
                 figures, WNT enhancer molecules and WNT super 
               
               
                   
                   
                 agonist molecules typically comprises two of each 
               
               
                   
                   
                 polypeptide sequence shown for any particular 
               
               
                 Structure 
                 Components 
                 structure) 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Fc-RSPO2 
                 SEQ ID NO: 32 DKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCV VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS VLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREP QVYTLPPSREEMTKNQVSLTCLVNKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 F12578- RSPO2RA 
                 F12578 Light Chain SEQ ID NO: 22  DIELTQPPSVSVAPGQTARISCSGCNIGSFYVHWYQQKPGQA   PVLVIYDKSNRPSGIPERFSGSNSGNTATLTISGTQAEDEAD   YYCQSYANTLSLVFGGGTKLTVL GQPKAAPSVTLFPPSSEEL QANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQ SNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPT ECS F12578-RSPO2RA Heavy Chain SEQ ID NO: 34  EVGLVESGGGLVQPGGGSLTLSCAASGFTFSHTLSWVRQAPG   KGLEWVSVISGDGSYTYYADSVKGRFTISSDNSKNTLYLQMN   
               
               
                   
                   
                 S LRAEDTAVYYCARNFIKYVFANWGQGTLVTVSS ASTKGPSV 
               
               
                   
                   
                 FPLAPSSKSTSGGTAALGCLVKDYFPEVTVSWNSGALTSGV 
               
               
                   
                   
                 HTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICVNHKPSNT 
               
               
                   
                   
                 KVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTL 
               
               
                   
                   
                 MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE 
               
               
                   
                   
                 EQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKT 
               
               
                   
                   
                 ISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI 
               
               
                   
                   
                 AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ 
               
               
                   
                   
                 GNVFSCSVMHEALHNHYTQKSLSLSPGK   GGGGSGSGGSGGGG     
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 αGFP- RSPO2RA 
                 αGFP Light Chain SEQ ID NO: 35  DIELTQPPSVSVAPGQTARISCSGDNLGKKYVVWYQQKPGQA   PVLVIYGDDERPSGIPERFSGSNSGNTATLTISGTQAEDEAD   YYCASYDSSHILIVFGGGTKLTVL GQPKAAPSVTLFPPSSEE LQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSK QSNNKYAASSYLSLTPEQWKSHRESYSCQVTHEGSTVEKTVAP TECS αGFP Heavy Chain RSPO2RA SEQ ID NO: 36  QVQLVESGGGLVQPGGSLRLSCAASGFTFSRYGMHWVRQAPG   KGLEWVSGISSIGSNTYYADSVKGRFTISRDNSKNTLYLQMN   
               
               
                   
                   
                   SLRAEDTAVYYCARWYKTYIDVWGQGTLVTVSS ASTKGPSVF 
               
               
                   
                   
                 PLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVH 
               
               
                   
                   
                 TFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK 
               
               
                   
                   
                 VDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLM 
               
               
                   
                   
                 ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE 
               
               
                   
                   
                 QYNSTKYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTI 
               
               
                   
                   
                 SKAKGQPREPQVYTLPPSREEMTKNQVLTCLVKGFYPSIDA 
               
               
                   
                   
                 VEWESNQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG 
               
               
                   
                   
                 NVFSCSVMHEALHNHYTQKSLSLSPGK   GGGGSGSGGSGGGGS     
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 RSPO2RA-F6 
                 F6 Light Chain SEQ ID NO: 37  QAVVLQEPSLSVSPGGTVTLTCGLSSGSVSTNYYPSWYQQTP   GQAPRTLIYYTNTRSSDVPERFSGSIVGNKAALTITGAQPDD   ESVYFCLLYLGRGIWVFGGGTKLTVL GQPKAAPSVTLFPPSS EELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTP SKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTV APTECS RSPO2RA-F6 Heavy Chain SEQ ID NO: 38 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   VQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLE 
                 
               
               
                   
                   
                 
                   WMGWISAYNGNTNYAQKLQGRVTMTTDTSTSTAYMELRSLRS 
                 
               
               
                   
                   
                   DDTAVYYCASSKEKATYYYGMDVWGQGTTVTVSS ASTKGPSV 
               
               
                   
                   
                 FPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGV 
               
               
                   
                   
                 HTFPAVLSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNT 
               
               
                   
                   
                 KVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTL 
               
               
                   
                   
                 MISRTPEVTCVVVDVSHEDPEVKFNWYDGVEVHNAKTKPRE 
               
               
                   
                   
                 EQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKT 
               
               
                   
                   
                 ISKAKGQPREPQVYTLPPSREEMTKNWVSLTCLVKGFYPSDI 
               
               
                   
                   
                 AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ 
               
               
                   
                   
                 GNVFSCSVMHEALHNHYTQKSLSLSPGK 
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 RSPO2RA-F7 
                 F7 Light Chain SEQ ID NO: 39  DIVMTQSPKSMSMSVGERVTLRCKASENVLNYVSWYQQKPEQ   SPKLLIYGASNRYTGVPDRFTGSGSATDFTLTISSVQAEDLA  D YHCGQSYRYPTFGAGTKLELK RTVAAPSVFIFPPSDEQLKS GTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR GEC RSPO2RA-F7 Heavy Chain SEQ ID NO: 40 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   VESGGGLVQPKGSLKLSCAASGFTFNTYAMHWVRQAPGKGLE 
                 
               
               
                   
                   
                 
                   WVARIRSKSNNYAKNYDDSVKDRFTISRDDSQSMLYLQMNNL 
                 
               
               
                   
                   
                   KTEDTAMYYCVRENYGGRFDYWGQGTTLTVSS ASTKGPSVFP 
               
               
                   
                   
                 LAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHT 
               
               
                   
                   
                 FPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV 
               
               
                   
                   
                 DKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMI 
               
               
                   
                   
                 SRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ 
               
               
                   
                   
                 YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTIS 
               
               
                   
                   
                 KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV 
               
               
                   
                   
                 EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN 
               
               
                   
                   
                 VFSCSVMHEALHNHYTQKSLSLSPGK 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 RSPO2RA- αGFP 
                 αGFP Light Chain SEQ ID NO: 35 DIELTQPPSVSVAPGQTAISCSGDNLGKKYVYWYQQKPGQAPV LVIYGDDERPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCA SYDSSHILIVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKA TLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAA SSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS RSPO2RA-αGFP Heave Chain SEQ ID NO: 41                  
 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   LVQPGGSLRLSCAASGFTFSRYGMHWVRQAPGKGLEWVSGISSI 
                 
               
               
                   
                   
                 
                   GSNTYYADSVKGRFTISRDNSKNTLYLQUMNSLRAEDTAVYYCAR 
                 
               
               
                   
                   
                   WYKTYIDVWGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAA 
               
               
                   
                   
                 GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVV 
               
               
                   
                   
                 TVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPP 
               
               
                   
                   
                 VAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWY 
               
               
                   
                   
                 VDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCK 
               
               
                   
                   
                 VSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLT 
               
               
                   
                   
                 CLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKL 
               
               
                   
                   
                 TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 RSPO2RA-F6 Fab 
                 F6 Light Chain SEQ ID NO: 37  QAVVLQEPSLSVSPGGTVTLTCGLSSGSVSTNYYPSWYQQTPGQ   APRTLIYYTNTRSSDVPERFSGSIVGNKAALTITGAQPDDESVY   FCLLYLGRGIWVFGGGTKLTVL GQPKAAPSVTLFPPSSEELQAN KATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKY 
               
               
                   
                   
                 AASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 
               
               
                   
                   
                 RSPO2RA-F6-VH-CH1 SEQ ID NO: 42 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   VKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMGWISAY 
                 
               
               
                   
                   
                 
                   NGNTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCAS 
                 
               
               
                   
                   
                   SKEKATYYYGMDVWGQGTTVTVSS ASTKGPSVFPLAPSSKSTSG 
               
               
                   
                   
                 GTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS 
               
               
                   
                   
                 LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCGSGSG 
               
               
                   
                   
                 HHHHHH 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L6-F12578- RSPO2RA 
                 L6-F12578 Light Chain SEQ ID NO: 20  DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKA   PKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATY   YCQQSYTTPPTFGQGTKVEIKGGGGSGGGGSGGGGSDIELTQP   PSVSVAPGQTARISCSGDNIGSFYVHWYQQKPGQAPVLVIYDK   SNRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQSYANT  LSLVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCL ISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYL SLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS L6-F12478-RSPO2RA heavy Chain SEQ ID NO: 48  EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWVRQAPGK   
               
               
                   
                   
                 
                   GLEWVAEISPYSGSTYYADSVKGRFTISADTSKNTAYLQMNSL 
                 
               
               
                   
                   
                 
                   RAEDTAVYYCALRARPPIRLHPRGSVMDYWGQGTLVTVSSGGG 
                 
               
               
                   
                   
                 
                   GSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSH 
                 
               
               
                   
                   
                 
                   YTLSWVRQAPGKGLEWVSVISGDGSYTYYADSVKGRFTISSDN 
                 
               
               
                   
                   
                 
                   SKNTLYLQMNSLRAEDTAVYYCARFIKYVFANWGQGTLVTVS 
                 
               
               
                   
                   
                   S ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN 
               
               
                   
                   
                 SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV 
               
               
                   
                   
                 NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPP 
               
               
                   
                   
                 KPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK 
               
               
                   
                   
                 TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAP 
               
               
                   
                   
                 IEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP 
               
               
                   
                   
                 SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW 
               
               
                   
                   
                 QQGNVFSCSVMHEALHNHYTQKSLSLSPGK   GGGGSGSGGSGGG     
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 F127-RSPO2RA 
                 F127 Light Chain SEQ ID NO: 49  DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQ   KPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSL   QPEDFATYYCQQYWYGVAPITFGQGTKVEIK RTVAAP SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNA LQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYA CEVTHQGLSSPVTKSFNRGEC F127-RSPO2RA Heavy Chain SEQ ID NO: 50  EVQLVESGGGLVQPGGSLTLSCAASGFNISSSYIHWVR   QAPGKGLEWVAYIYSSYGSTYYADSVKGRFTISADTSK   
               
               
                   
                   
                 
                   NTAYLQMNSLRAEDTAVYYCARASWYALDYWGQGTL 
                 
               
               
                   
                   
                   VTVSS ASTKGPSASTKGPSVFPLAPSSKSTSGGTAALGCLV 
               
               
                   
                   
                 KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVV 
               
               
                   
                   
                 TVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTC 
               
               
                   
                   
                 PPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS 
               
               
                   
                   
                 HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV 
               
               
                   
                   
                 LTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPR 
               
               
                   
                   
                 EPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESN 
               
               
                   
                   
                 GQPENNYKTTPPVLDSDGSFFYSKLTVDKSRWQQGNVF 
               
               
                   
                   
                 SCSVMHEALHNHYTQKSLSLSPGK   GGGGSGSGGSGGGGS     
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L6-F127- RSPO2RA 
                 L6-F127 Light Chain SEQ ID NO: 25  DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYGGKPGKA   PKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATY   YCQQSYTTPPTFGQGTKVEIK G   GGGSGGGGSGGGGS   D IQMTQS   PSSLSASVGDRVTITCRASQSVSSAVAWYGGKPGKAPKLLIYS   ASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQYWY   GVAPITFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVC LLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSS TLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC L6-F127-RSPO2RA Heavy Chain DEQ ID NO: 51 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWVRQAPGK 
                 
               
               
                   
                   
                 
                   GLEWVAEISPYSGSTYYADSVKGRFTISADTSKNTAYLQMNSL 
                 
               
               
                   
                   
                 
                   RAEDTAVYYCALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GGG 
                   
                 
               
               
                   
                   
                 
                   
                     GSGGGGSGGGGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASGFNISS 
                 
               
               
                   
                   
                 
                   SYIHWRVQAPGKGLEWVAYIYSSYGSTYYADSVKGRFTISADT 
                 
               
               
                   
                   
                 
                   SKNTAYLQMNSLRAEDTAVYYCARASWYALDYWGQGTLVTVSS 
                 
               
               
                   
                   
                 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS 
               
               
                   
                   
                 GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVN 
               
               
                   
                   
                 HKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPK 
               
               
                   
                   
                 PKDTLMISRTPEVTCVVVDVSHEDPEVFKFNWYDGVEVHNAKT 
               
               
                   
                   
                 KPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPI 
               
               
                   
                   
                 EKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS 
               
               
                   
                   
                 DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDSRWQ 
               
               
                   
                   
                 QGNVFSCSVMHEALHNHYTQKSLSLSLSPGK   GGGGSGSGGSGGGG     
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 F58-RSPO2RA 
                 F58 Light Chain SEQ ID NO: 52  DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKA   PKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATY   YCQQWYSSGHVLITFGQGTKVEIK RTVAAPSVFIFPPSDEQLK SGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRG EC F8-RSPO2RA Heavy Chain SEQ ID NO: 53  EVQLESGGGLVQPGGSLRLSCAASGFNISYSIHVWVRQAPGK   GLEWVASIYSSSGSTSYADSVKGRFTISADTSKNTAYLQMNSL   
               
               
                   
                   
                   RAEDTAVYYCARGAIDYWGQGTLVTVSS ASTKGPSVFPLAPSS 
               
               
                   
                   
                 KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ 
               
               
                   
                   
                 SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPK 
               
               
                   
                   
                 SCDKTHTCPPCPAPEAAGGSVFLFPPKPKDTLMISRTPEVTC 
               
               
                   
                   
                 VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS 
               
               
                   
                   
                 VLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQ 
               
               
                   
                   
                 VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENN 
               
               
                   
                   
                 YKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L6-F58- RSPO2RA 
                 L6-F58 Light Chain SEQ ID NO: 27  DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKA   PKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATY   YCQQSYTTPPTFGQGTKVEIK     GGGGSGGGGSGGGGS     DIQMTQS   PSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYS   ASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQWYS  SGHVLITFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVV CLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLS STLTLSKADYEKHHVYACEVTHQGLSSPVTKSFVRGEC L6-58_RSPO2RA Heavy Chain SEQ ID NO: 54  EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWVRQAPGK   
               
               
                   
                   
                 
                   GLEWVAEISPYSGSTYYADSVKGRFTISADTSKNTAYLQMNSL 
                 
               
               
                   
                   
                 
                   RAEDTAVYYCALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GGG 
                   
                 
               
               
                   
                   
                 
                   
                     GSGGGGSGGGGS 
                   
                   EVQLESGGGLVQPGGSLRLSCAASGFNISY 
                 
               
               
                   
                   
                 
                   SYIHWVRQAPGKGLEWVASIYSSSGSTSYADSVKGRFTISADT 
                 
               
               
                   
                   
                   SKNTAYLQMNSLRAEDTAVYYCARGAIDYWGQGTLVTVSS AST 
               
               
                   
                   
                 KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGAL 
               
               
                   
                   
                 TSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP 
               
               
                   
                   
                 SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKD 
               
               
                   
                   
                 TLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR 
               
               
                   
                   
                 EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKT 
               
               
                   
                   
                 ISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA 
               
               
                   
                   
                 VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWGGGN 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L2-F6- RSPO2RA 
                 L2-F6 Light Chain SEQ ID: NO: 43                  
                  
                  
  QEPSLSVSPGGTVTLTCGLSSGSVSTNYYPSWYQQTPGQAPRT   LIYYTNTRSSDVPERFSGSIVGNKAALTITCAQPDDESVYFCL   LYLGRGIWVFGGGTKLTVL GQPKAAPSVTLFPPSSEELQANKA TLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYA ASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 
               
               
                   
                   
                 F6-RSPO2RA Heavy Chain SEQ ID: NO: 44 
               
               
                   
                   
                 
                   EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQ 
                 
               
               
                   
                   
                 
                   GLEWMGWISAYNGNTNYAQKLQGRVTMTTDTSTSTAYMELRSL 
                 
               
               
                   
                   
                   RSDDTAVYYCASSKEKATYYYGMDVWGQGTTVTVSS ASTKGPS 
               
               
                   
                   
                 VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGV 
               
               
                   
                   
                 HTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK 
               
               
                   
                   
                 VDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMI 
               
               
                   
                   
                 SRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY 
               
               
                   
                   
                 NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKA 
               
               
                   
                   
                 KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWE 
               
               
                   
                   
                 SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 F6-RSPO2RA 
                 F6 Light Chain SEQ ID NO: 37  QAVVLQEPSLSVSPGGTVTLTCGLSSGSVSTNYYPSWYQQTPG   QAPRTLIYYTNTRSSDVPERFSGSIVGNKAALTITGAQPDDES   VYFCLLYLGRGIWVFGGGTKLTVL GQPKAAPSVTLFPPSSEEL QANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQS NNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTEC S F6-RSPO2RA Heavy Chain SEQ ID NO: 44  EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQ   
               
               
                   
                   
                 
                   GLEWMGMISAYNGNTNYAQKLQGRVTMTTDTSTSTAYMELREL 
                 
               
               
                   
                   
                   RSDDTAVYYCASSKEKATYYYGMDVWGQGTTVTVSS ASTKGPS 
               
               
                   
                   
                 VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGV 
               
               
                   
                   
                 HTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK 
               
               
                   
                   
                 VDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMI 
               
               
                   
                   
                 SRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY 
               
               
                   
                   
                 NSTYRVVSVLTVLHQWLNGKEYKCKVSNKALGAPIEKTISKA 
               
               
                   
                   
                 KGQPREQVYTLPPSREEMTKNQSLTCLVKGFYPSIAVEWE 
               
               
                   
                   
                 SNQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L2-F6- RSPO2R@ CL 
                 L2-F6-FSPO2RA Light Chain SEQ ID NO: 45                  
                  
                  
                  
  SSGSVSTNYYPSWYQQTPGQAPRTLIYYTNTRSSDVP   
               
               
                   
                   
                 
                   ERFSGSIVGNKAALTITGAQPDDESVYFCLLYLGRGI 
                 
               
               
                   
                   
                   WVFGGGTKVTVL GQPKAAPSVTLFPPSSEELQANKAT 
               
               
                   
                   
                 LVCLISDFYPGAVTVAWKADSSPVKKAGVETTTPSKQS 
               
               
                   
                   
                 NNKYAASSYLSLTPEQWKSHRSYSCQVTHESGSTVEKT 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY 
               
               
                   
                   
                 SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEP 
               
               
                   
                   
                 KSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMIS 
               
               
                   
                   
                 RTPEVTCVVVDVSHEDPEKFNWYVDGVEVHNAKTKP 
               
               
                   
                   
                 REEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL 
               
               
                   
                   
                 GAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSL 
               
               
                   
                   
                 TCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG 
               
               
                   
                   
                 SFFLYSKLTVDKSRWQQGNFSCSVMHEALHNHYTQK 
               
               
                   
                   
                 SLSLSPGK 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 F6- RSO2RA@ CL 
                 F6-RSPO2RA Light Chain SEQ ID NO: 47  QAVVLQEPSLSVSPGGTVTLTCGLSSGSVSTNYYPSW   YQQTPGQAPRTLIYYTNTRSSDVPERFSGSIVGNKAA   LTITGAQPDDESVYFCLLYLGRGIWVFGGGTKLTVL G QPKAAPSVTLFPPSSEELQANKATLVCLISDFYGAV TVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLT PEQWKSHRSYSCQVTHEGSTVEKTVAPTECS   GGGGSG     
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 F6 Heavy Chain SEQ ID NO: 46 
               
               
                   
                   
                 
                   EVQLVQSGAEVKKPGASVKVSCKASGYTTSGISWV 
                 
               
               
                   
                   
                 
                   RQAPGQGLEWMGWISAYNGNTNYAQKLQGRVTMTTDT 
                 
               
               
                   
                   
                 
                   STSTAYMELRSLRSDDTAVYYCASSKEKATYYYGMDV 
                 
               
               
                   
                   
                   WGQGTTVTVSS ASTKGPSVFPLAPSSKSTSGGTAALG 
               
               
                   
                   
                 CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY 
               
               
                   
                   
                 SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEP 
               
               
                   
                   
                 KSCDTHTCPPCPAPEAAGGPSVFLFPPKPKDTIMIS 
               
               
                   
                   
                 RTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP 
               
               
                   
                   
                 REEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL 
               
               
                   
                   
                 GAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSL 
               
               
                   
                   
                 TCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG 
               
               
                   
                   
                 SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQK 
               
               
                   
                   
                 SLSLSPGK 
               
               
                   
                 
                   F4-2- 
                 
                 R4-2_LC SEQ ID NO: 98 
               
               
                   
                 
                   
                     RSPO2RA 
                   
                 
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQSVSSAV 
                 
               
               
                   
                   
                 
                   AWYQQKPGKAPKLLIYSASSLYSGVPSRFSGS 
                 
               
               
                   
                   
                 
                   RSGTDFTLTISSLQPEDFATYYCQQSYAAYLFT 
                 
               
               
                   
                   
                   FGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTAS 
               
               
                   
                   
                 VVCLLNNFYPREAKVQWKVDNALQSQNSQESV 
               
               
                   
                   
                 TEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVT 
               
               
                   
                   
                 HQGLSSVTKSFNRGEC 
               
               
                   
                   
                 &gt;F4-2_RSPO2RA_HC SEQ ID NO: 99 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRTSCAASGFNISYY 
                 
               
               
                   
                   
                 
                   YIHWVRQAPGKGLEWVASIYPSSGYTYYADSV 
                 
               
               
                   
                   
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                   
                   ARSSFYWAMDYWGQGTLVTVSS ASTKGPSVFP 
               
               
                   
                   
                 LAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSG 
               
               
                   
                   
                 ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSGTQ 
               
               
                   
                   
                 TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP 
               
               
                   
                   
                 APEAAGGPSVFLPPKPKDTLMISRTPEVTCVVV 
               
               
                   
                   
                 DVSHEDPEVKFNWYBDVEVHNAKTKREEQY 
               
               
                   
                   
                 NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL 
               
               
                   
                   
                 GAPIEKTISKAKGQPREPQVYTLPPSEEMTKNQ 
               
               
                   
                   
                 VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP 
               
               
                   
                   
                 VLDSDGFFLYSKLTVDKSRWQQGNVFSCSVMH 
               
               
                   
                   
                 EALHNHYTQKSLSLSPGK   GGGGSGSGGSGGGGS     
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                 
                   F10- 
                 
                 F10_LC SEQ ID NO: 100 
               
               
                   
                 
                   
                     RSPO2RA 
                   
                 
                 
                   ELTQPPSVSVSPGQTARITCSGDGSYAGSYYYG 
                 
               
               
                   
                   
                 
                   WYQQKPGQAPVTLIYNNKRPSGIPERFSGSL 
                 
               
               
                   
                   
                 
                   SGSTNTLTISGVQAEDEADYYCGSADNSGAAF 
                 
               
               
                   
                   
                   GGGTKLTVL RTVAAPSVFIFPPSDEQLKSGTASV 
               
               
                   
                   
                 VCLLNNFYPREAKVQWKVDNALQSGNSQESVTE 
               
               
                   
                   
                 QDKDSTYSLSSTLTLSKADYEKHKVYACEVTH 
               
               
                   
                   
                 QGLSSPVTKSFNRGEC 
               
               
                   
                   
                 &gt;F10_RSPO2RA_HC SEQ ID NO: 101 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFSSF 
                 
               
               
                   
                   
                 
                   NMFWVRQAPGKGLEWVAGIDDDGSYPNYGS 
                 
               
               
                   
                   
                 
                   AVKGRATISRDNSKNTLYLQMNSLRAEDTAVY 
                 
               
               
                   
                   
                 
                   YCAKSGYGGSWGGYIADDIDAWGQGTLVTVS 
                 
               
               
                   
                   
                   S ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYF 
               
               
                   
                   
                 PEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS 
               
               
                   
                   
                 VVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPK 
               
               
                   
                   
                 SCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMI 
               
               
                   
                   
                 SRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH 
               
               
                   
                   
                 NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK 
               
               
                   
                   
                 EYKCKVSNKALGAPIEKTISKAKGQPREPQVYTL 
               
               
                   
                   
                 PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNG 
               
               
                   
                   
                 QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ 
               
               
                   
                   
                 QGNVSCSYMHEALHNHYTQKSLSLSPGK   GGGG     
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                 
                   anti-GFP- 
                 
                 anti-GFP_LC SEQ ID NO NO: 102 
               
               
                   
                 
                   
                     RSPO2RA 
                   
                 
                 
                   DIELTQPPSVSVAPGQTARISCSGDNLGKKYVY 
                 
               
               
                   
                   
                 
                   WYQQKPGQAPVLVIYGDDERPSGIPERFSGSN 
                 
               
               
                   
                   
                 
                   SGNTATLTISGTQAEDEADYYCASYDSSHILIV 
                 
               
               
                   
                   
                   FGGGTKLTVL GQPKAAPSVTLFPPSSEELQANK 
               
               
                   
                   
                 ATLVCLISDFYPGAVTVAWKADSSPVKAGVETT 
               
               
                   
                   
                 TPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVT 
               
               
                   
                   
                 HEGSTVEKTVAPTECS 
               
               
                   
                   
                 &gt;anti-GFP_RSPO2RA_HC SEQ ID NO: 103 
               
               
                   
                   
                 
                   QVQLVESGGGLVQPGGSLRLSCAASGFTFSRY 
                 
               
               
                   
                   
                 
                   GMHWVRQAPGKGLEWVSGISSIGSNTYYADS 
                 
               
               
                   
                   
                 
                   VKGRFTISRDNSKNTLYLQMNSLRAEDTAVYY 
                 
               
               
                   
                   
                   CARWYKTYIDVWGQGTLVTVSS ASTKGPSVFP 
               
               
                   
                   
                 LAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSG 
               
               
                   
                   
                 ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ 
               
               
                   
                   
                 TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP 
               
               
                   
                   
                 APEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV 
               
               
                   
                   
                 DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY 
               
               
                   
                   
                 NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL 
               
               
                   
                   
                 GAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQ 
               
               
                   
                   
                 VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP 
               
               
                   
                   
                 VLDSDGSFFLYSKLTVDKSRWQQGNVFSCVMH 
               
               
                   
                   
                 EALHNHYTQKSLSLSPGKGGGGSGSGGSGGGGS 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                     Fv-IgG 
                   
                 
                 
                   L6-F2-2- 
                 
                 L6-F4-2-RSPO2RA_HC SEQ ID NO: 103 
               
               
                   
                 
                   
                     RSPO2RA 
                   
                 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSY 
                 
               
               
                   
                   
                 
                   YISWVRQAPGKGLEWVAEISPYSGSTYYADSV 
                 
               
               
                   
                   
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                   
                 
                   ALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     G 
                   
                 
               
               
                   
                   
                 
                   
                     GGGSGGGGSGGGGS 
                   
                   EVQLVESGGGLVQPGGSL 
                 
               
               
                   
                   
                 
                   RLSCAASGFNISYYYIHWVRQAPGKGLEWVAS 
                 
               
               
                   
                   
                 
                   IYPSSGYTYYADSVKGRFTISADTSKNTAYLQM 
                 
               
               
                   
                   
                 
                   NSLRAEDTAVYYCARSSFYWAMDYWGQGTL 
                 
               
               
                   
                   
                   VTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLV 
               
               
                   
                   
                 KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY 
               
               
                   
                   
                 SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKK 
               
               
                   
                   
                 VEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPK 
               
               
                   
                   
                 DTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG 
               
               
                   
                   
                 VEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW 
               
               
                   
                   
                 LNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQ 
               
               
                   
                   
                 VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEW 
               
               
                   
                   
                 ESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS 
               
               
                   
                   
                 RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 &gt;L6-F4-2_LC SEQ ID NO: 104 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQDVSTAV 
                 
               
               
                   
                   
                 
                   AWYQQKPGKAPKLLIYSASFLYSGVPSRFSGS 
                 
               
               
                   
                   
                 
                   GSGTDFTLTISSLQPEDFATYYCQQSYTTPPTF 
                 
               
               
                   
                   
                 
                   GQGTYKVEIK 
                   
                     GGGGSGGGGSGGGGS 
                   
                   DIQMTQSP 
                 
               
               
                   
                   
                 
                   SSLSASVGDRVTITCRASQSVSSAVAWYQQKP 
                 
               
               
                   
                   
                 
                   GKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTL 
                 
               
               
                   
                   
                 
                   TISSLQPEDFATYYCQQSYAAYLFTFGQGTKV 
                 
               
               
                   
                   
                   EIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNF 
               
               
                   
                   
                 YPREAKVQWKVDNALQSGNSQESVTEQDSKDST 
               
               
                   
                   
                 YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVT 
               
               
                   
                   
                 KSFNRGEC 
               
               
                 
                   
                     Fv-IgG 
                   
                 
                 
                   L6-F10- 
                 
                 L6-F10-RSPO2RA_HC SEQ ID NO: 105 
               
               
                   
                 
                   
                     RSPO2RA 
                   
                 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSY 
                 
               
               
                   
                   
                 
                   YISWVRQAPGKGLEWVAEISPYSGSTYYADSV 
                 
               
               
                   
                   
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                   
                 
                   ALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     G 
                   
                 
               
               
                   
                   
                 
                   
                     GGGSGGGGSGGGGS 
                   
                   EVQLVESGGGLVQPGGSL 
                 
               
               
                   
                   
                 
                   RLSCAASGFTFSSFNMFWVRQAPGKGLEWVA 
                 
               
               
                   
                   
                 
                   GIDDDGSYPNYGSAVKGRATISRDNSKNTLYL 
                 
               
               
                   
                   
                 
                   QMNSLRAEDTAVYYCAKSGYGGSWGGYIADD 
                 
               
               
                   
                   
                   IDAWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSG 
               
               
                   
                   
                 GTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF 
               
               
                   
                   
                 PAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH 
               
               
                   
                   
                 KPSNTKVDKKVEPKSCDEKTHTCPPCPAPEAAGGP 
               
               
                   
                   
                 SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPE 
               
               
                   
                   
                 VKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS 
               
               
                   
                   
                 VLTVLHQDWLNGKEYKCKVSNKALGAPIEKTIS 
               
               
                   
                   
                 KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK 
               
               
                   
                   
                 GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF 
               
               
                   
                   
                 FLYSKLTVDKSRWQQGNVFSCSBMHEALHNHY 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 &gt;L6-F10_LC SEQ ID NO: 106 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQDVSTAV 
                 
               
               
                   
                   
                 
                   AWYQQKPGKAPKLLIYSASFLYSGVPSRFSGS 
                 
               
               
                   
                   
                 
                   GSGTDFTLTISSLQPEDFATYYCQQSYTTPPTF 
                 
               
               
                   
                   
                 
                   GQGTKVEIK 
                   
                     GGGGSGGGGSGGGGS 
                   
                   ELTQPPSVS 
                 
               
               
                   
                   
                 
                   VSPGQTARITCSGDGSYAGSYYYGWYQQKPG 
                 
               
               
                   
                   
                 
                   QAPVTLIYYNNKRPSGIPERFSGSLSGSTNTLTI 
                 
               
               
                   
                   
                 
                   SGVQAEDEADYYCGSADNSGAAFGGGTKLTV 
                 
               
               
                   
                   
                   L RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYP 
               
               
                   
                   
                 REAKVQWKVDNALQSGNSQESVTEQDSKDSTYS 
               
               
                   
                   
                 LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS 
               
               
                   
                   
                 FNRGEC 
               
               
                 
                   
                     (F4)Fv-IvG 
                   
                 
                 
                   L6-F4- 
                 
                 
                   L6-F4-RSPO2RA HC SEQ ID NO: 107 
                 
               
               
                   
                 
                   
                     RSPO2RA 
                   
                 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWV 
                 
               
               
                   
                   
                 
                   RQAPGKGLEWVAEISPYSGSTYYADSVKGRFTISADT 
                 
               
               
                   
                   
                 
                   SKNTAYLQMNSLRAEDTAVYYCALRARPPIRLHPRGS 
                 
               
               
                   
                   
                 
                   VMDYWGQGTLVTVSS 
                   
                     GGGGSGGGGSGGGGS 
                   
                   EVQLVES 
                 
               
               
                   
                   
                 
                   GGGLVQPGGSLRLSCAASGFNLSSYSMHWVRQAPGKG 
                 
               
               
                   
                   
                 
                   LEWVAYISSYYGYTTYYADSVKGRFTISADTSKNTAYL 
                 
               
               
                   
                   
                 
                   QMNSLRAEDTAVYYCARPAPGHWGFDYWGQGTLVTVS 
                 
               
               
                   
                   
                   S ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP 
               
               
                   
                   
                 VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS 
               
               
                   
                   
                 SSLGTQTYICNVNHKPSNTKYVDKKVEPKSCDKTHTCP 
               
               
                   
                   
                 PCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV 
               
               
                   
                   
                 DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR 
               
               
                   
                   
                 VVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISK 
               
               
                   
                   
                 AKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS 
               
               
                   
                   
                 DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV 
               
               
                   
                   
                 DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK   GG     
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   L6-F4-RSPO2RA LC SEQ ID NO: 108 
                 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWQ 
                 
               
               
                   
                   
                 
                   QKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLT 
                 
               
               
                   
                   
                 
                   ISSLQPEDFATYYCQQSYTTPPTFGQGTKVEIK 
                   
                     GGGG 
                   
                 
               
               
                   
                   
                 
                   
                     SGGGGSGGGGS 
                   
                   DIQMTQSPSSLSASVGDRVTITCRAS 
                 
               
               
                   
                   
                 
                   QSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFS 
                 
               
               
                   
                   
                 
                   GSRSGTDFTLTISSLQPEDFATYYCQQWYYAPITFGQ 
                 
               
               
                   
                   
                   GTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLN 
               
               
                   
                   
                 NFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS 
               
               
                   
                   
                 LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR 
               
               
                   
                   
                 GEC 
               
               
                 
                   ( 
                   
                     F49) Fv-IgG 
                   
                 
                 
                   L6-F49- 
                 
                 
                   L6-F49-RSPO2RA HC SEQ ID NO: 109 
                 
               
               
                   
                 
                   
                     RSPO2RA 
                   
                 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWV 
                 
               
               
                   
                   
                 
                   RQAPGKGLEWVAEISPYSGSTYYADSVKGRFTISADT 
                 
               
               
                   
                   
                 
                   SKNTAYLQMNSLRAEDTAVYYCALRARPPIRLHPRGS 
                 
               
               
                   
                   
                 
                   VMDYWGQGTLVTVSS 
                   
                     GGGGSGGGGSGGGGS 
                   
                   EVQLVQS 
                 
               
               
                   
                   
                 
                   GAEVKKPGASVKVSCKASGGTFSSYAISWVRQAPGQG 
                 
               
               
                   
                   
                 
                   LEWMGWINAGNGNTTYAQKFQGRVTMTRDTSTSTVYM 
                 
               
               
                   
                   
                 
                   ELSSRLSEDTAVYYCARHYYGSGSYPDWGQGTLVTVS 
                 
               
               
                   
                   
                   S ASTKGPSVFPLAPSSKSTSGGTAALGCLVDEKYFPEP 
               
               
                   
                   
                 PCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV 
               
               
                   
                   
                 DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR 
               
               
                   
                   
                 VVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISK 
               
               
                   
                   
                 AKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS 
               
               
                   
                   
                 DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV 
               
               
                   
                   
                 DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK   GG     
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   L6-F49-RSPO2RA LC SEQ ID NO: 110 
                 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQ 
                 
               
               
                   
                   
                 
                   QKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLT 
                 
               
               
                   
                   
                 
                   ISSLQPEDFATYYCQQSYTTPPTFGQGTKVEIKR 
                   
                     GGG 
                   
                 
               
               
                   
                   
                 
                   
                     GSGGGGSGGGGS 
                   
                   DIQMTQSPSSPSASVGDRVTITCRA 
                 
               
               
                   
                   
                 
                   SQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF 
                 
               
               
                   
                   
                 
                   SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFG 
                 
               
               
                   
                   
                   GGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLL 
               
               
                   
                   
                 NNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTY 
               
               
                   
                   
                 SLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN 
               
               
                   
                   
                 RGEC 
               
               
                 
                   
                     (F10) Fv-IgG 
                   
                 
                 
                   L6-F10- 
                 
                 
                   L6-F10-RSPO2RA HC SEQ ID NO: 111 
                 
               
               
                   
                 
                   
                     RSPO2RA 
                   
                 
                 
                   EQQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWV 
                 
               
               
                   
                   
                 
                   RQAPGKGLEWVAEISPYSGSTYYADSVKGRFTISADY 
                 
               
               
                   
                   
                 
                   SKNTAYLQMNSLRAEDTAVYYCALRRPPIRLHPRGS 
                 
               
               
                   
                   
                 
                   VMDYWGQGTLVTVSS 
                   
                     GGGGSGGGGSGGGGS 
                   
                   EVQLVES 
                 
               
               
                   
                   
                 
                   GGGGLVQPGGSLRLSCAASGFTFSSFNMFWVRQAPGKG 
                 
               
               
                   
                   
                 
                   LEWVAGIDDDGSYPNYGSAVKGRATISRDNSKNTLYL 
                 
               
               
                   
                   
                 
                   QMNSLRAEDTAVYYCAKSGYGGSWGGYIADDIDAWGQ 
                 
               
               
                   
                   
                   GTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLV 
               
               
                   
                   
                 KDYFPEPVTVSWSGALTSGVHTFPAVLQSSGLYSLS 
               
               
                   
                   
                 SVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC 
               
               
                   
                   
                 DKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTP 
               
               
                   
                   
                 EVTCVVVDVSHEDPEVKFNWYDGVEVHNAKTKPREE 
               
               
                   
                   
                 QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAP 
               
               
                   
                   
                 IEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCL 
               
               
                   
                   
                 VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF 
               
               
                   
                   
                 LYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   L6-F10-FSPO2RA LC SEQ ID NO: 112 
                 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQ 
                 
               
               
                   
                   
                 
                   QKPGDAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLT 
                 
               
               
                   
                   
                 
                   ISSLQPEDFATYYCQQSYTTPPTFGQGTKVEIK 
                   
                     GGGG 
                   
                 
               
               
                   
                   
                 
                   
                     SGGGGSGGGGS 
                   
                   ELTQPPSVSVSPGQTARITCSGDGSY 
                 
               
               
                   
                   
                 
                   AGSYYYGWYQQKPGQAPVTLIYYNNKRPSGIPERFSG 
                 
               
               
                   
                   
                 
                   SLSGSTNTLTISGVQAEDEADYYCGSADNSGAAFGGG 
                 
               
               
                   
                   
                   TKLTVL RTVAAPSVFIFPPSDEQLKSGTASVVCLLNN 
               
               
                   
                   
                 FYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL 
               
               
                   
                   
                 SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRG 
               
               
                   
                   
                 EC 
               
               
                 
                   
                     Fv-IgG 
                   
                 
                 
                   L6-F7B- 
                 
                 
                   L6-F7B-RSPO2RA HC SEQ ID NO: 113 
                 
               
               
                   
                 
                   
                     RSPO2RA 
                   
                 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWV 
                 
               
               
                   
                   
                 
                   RQAPGKGLEWVAEISPYSGSTYYADSVKGRFTISADT 
                 
               
               
                   
                   
                 
                   SKNTAYLQMNSLRAEDTAVYYCALRARPPIRLHPRGS 
                 
               
               
                   
                   
                 
                   VMDYWGQGTLVTVSS 
                   
                     GGGGSGGGGSGGGGS 
                   
                   EVQLVES 
                 
               
               
                   
                   
                 
                   GGGLVQPGGSLRLSCAASGFNFSSSSIHWVRQAPGKG 
                 
               
               
                   
                   
                 
                   LEWVAYIYPSYDYTYYADSVKGRFTISADTSKNTAYL 
                 
               
               
                   
                   
                 
                   QMNSLRAEDTAVYYCARGYFYTWGGMDYWGQGTLVTV 
                 
               
               
                   
                   
                   SS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPE 
               
               
                   
                   
                 PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP 
               
               
                   
                   
                 SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTC 
               
               
                   
                   
                 PPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVV 
               
               
                   
                   
                 VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY 
               
               
                   
                   
                 RVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTIS 
               
               
                   
                   
                 KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP 
               
               
                   
                   
                 SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT 
               
               
                   
                   
                 VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK   G     
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   -L-6-F7B-RSPO2RA LC SEQ ID NO: 114 
                 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWQ 
                 
               
               
                   
                   
                 
                   QKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLT 
                 
               
               
                   
                   
                 
                   ISSLQPEDFATYYCQQSYTTPPTFGQGTKVEIKR 
                   
                     GGG 
                   
                 
               
               
                   
                   
                 
                   
                     GSGGGGSGGGGS 
                   
                   DIQMTQSPSSLSASVGDRVTITCRA 
                 
               
               
                   
                   
                 
                   SQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRF 
                 
               
               
                   
                   
                 
                   SGSRSGTDFTLTISSLQPEDFATYYCQQYYSLFTFGQ 
                 
               
               
                   
                   
                   GTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLN 
               
               
                   
                   
                 NFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS 
               
               
                   
                   
                 LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR 
               
               
                   
                   
                 GEC 
               
               
                 
                   
                     FV-IgG 
                   
                 
                 
                   L6-F2I- 
                 
                 
                   L6-F2I-RSPO2RA HC SEQ ID NO: 115 
                 
               
               
                   
                 
                   
                     RSPO2RA 
                   
                 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWV 
                 
               
               
                   
                   
                 
                   RQAPGKGLEWVAEISPYSGSTYYADSVKGRFTISADT 
                 
               
               
                   
                   
                 
                   SKNTAYLQMNSLRAEDTAVYYCALRARPPIRLHPRGS 
                 
               
               
                   
                   
                 
                   VMDYWGQGTLVTVSS 
                   
                     GGGGSGGGGSGGGGS 
                   
                   EVQLVES 
                 
               
               
                   
                   
                 
                   GGGLVQPGGSLRLSCAASGFNIHSSSIHWVRQAPGKG 
                 
               
               
                   
                   
                 
                   LEWVAATYSSFGSITYADSVKGRFTISADTSKNTAYL 
                 
               
               
                   
                   
                 
                   QMNSLRAEDTAVYYCARYHHPFGYALDYWGQGTLVTV 
                 
               
               
                   
                   
                   SS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPE 
               
               
                   
                   
                 PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP 
               
               
                   
                   
                 SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTC 
               
               
                   
                   
                 PPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVV 
               
               
                   
                   
                 VDVSHEDPEVKFNWYDGVEVHNAKTKPREEQYNSTY 
               
               
                   
                   
                 RVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTIS 
               
               
                   
                   
                 KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP 
               
               
                   
                   
                 SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT 
               
               
                   
                   
                 VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK   G     
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   -L6-F2I-RSPO2RA LC SEQ ID NO: 117 
                 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQ 
                 
               
               
                   
                   
                 
                   QKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLT 
                 
               
               
                   
                   
                 
                   ISSLQPEDFATYYCQQSYTTPPTFGQGTKVEIKR 
                   
                     GGG 
                   
                 
               
               
                   
                   
                 
                   
                     GSGGGGSGGGGS 
                   
                   DIQMTQSPSSLSASVGDRVTITCRA 
                 
               
               
                   
                   
                 
                   SQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRF 
                 
               
               
                   
                   
                 
                   SGSRSGTDFTLTISSLQPEDFATYYCQQGVYLFTFGQ 
                 
               
               
                   
                   
                   GTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLN 
               
               
                   
                   
                 NFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS 
               
               
                   
                   
                 LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR 
               
               
                   
                   
                 GEC 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   L6-N-HC 
                   appended 
                   ScFv- 
                   F12578-IgG- 
                   
                     RSPO2Ra 
                   
                 
                   L6-N-HC appended ScFv-F12578-IgG-RSPO2RA HC   SEQ ID NO: 118   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSY   YISWVRQAPGKGLEWVAEISPYSGSTYYADSV   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC  ALRARPPIRLHPRGSVMDYWGQGTLVTVSS   GS       AASGSSGGSSSGA   DIQMTQSPSSLSASVGDRVTIT  CRASQDVSTAVAWYQQKPGKAPKLLIYSASFL   YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY   CQQSYTTPPTFGQGTKVEIK     GGGGSGGGGSGG       GGS     EVQLVESGGGLVQPGGSLRLSCAASGFTF   SHYTLSWVRQAPGKGLEWVSVISGDGSYTYY   ADSVKGRFTISSDNSKNTLYLQMNSLRAEDTA   VYYCARNFIKYVFANWGQGTLVTVSS ASTKGP SVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS 
               
               
                   
                   
                 WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS 
               
               
                   
                   
                 SLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH 
               
               
                   
                   
                 TCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV 
               
               
                   
                   
                 TCVVVDVSHEDPEVKFNWYYVDGVEVHNAKTKP 
               
               
                   
                   
                 REEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV 
               
               
                   
                   
                 SNKALGAPIEKTISKAKGQPREPQVYTLPPSREEM 
               
               
                   
                   
                 TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY 
               
               
                   
                   
                 KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC 
               
               
                   
                   
                 SVMHEALHNHYTQKSLSLSPGK   GGGGSGSGGSG     
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   &gt;F12578 LC SEQ ID NO: 119 
                 
               
               
                   
                   
                 
                   DIELTQPPSVSVAPGQTARISCSGDNIGSFYVH 
                 
               
               
                   
                   
                 
                   WYQQKPGQAPVLVIYDKSNRPSGIPERFSGSN 
                 
               
               
                   
                   
                 
                   SGNTATLTISGTQAEDEADYYCQSYANTLSLV 
                 
               
               
                   
                   
                   FGGGTKLTVL GQPKAAPSVTLFPPSSEELQANK 
               
               
                   
                   
                 ATLVCLISDFYPGAVTVAWKADSSPVKAGVETT 
               
               
                   
                   
                 TPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVT 
               
               
                   
                   
                 HEGSTVEKTVAPTECS 
               
               
                 N-HC-appended scFv-IgG- 
                 
                   L6-HC 
                 
                 L6-N-HC appended ScFv-F127-IgG-RSPO2RA HC 
               
               
                 mutRspo2 
                 
                   appended 
                 
                 
                   SEQ ID NO: 120 
                 
               
               
                   
                 
                   ScFv-F127- 
                 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSY 
                 
               
               
                   
                 
                   IgG- 
                 
                 
                   YISWVRQAPGKGLEWVAEISPYSGSTYYADSV 
                 
               
               
                   
                 
                   
                     RSPO2RA 
                   
                 
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                   
                 
                   ALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GS 
                   
                 
               
               
                   
                   
                 
                   
                     AASGSSGGSSSGA 
                   
                   DIQMTQSPSSLSASVGDRVTIT 
                 
               
               
                   
                   
                 
                   CRASQDVSTAVAWYQQKPGKAPKLLIYSASFL 
                 
               
               
                   
                   
                 
                   YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY 
                 
               
               
                   
                   
                 
                   CQQSYTTPPTFGQGTKVEIK 
                   
                     GGGGSGGGGSGG 
                   
                 
               
               
                   
                   
                 
                   
                     GGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASGFNIS 
                 
               
               
                   
                   
                 
                   SSYIHWVRQAPGKGLEWVAYIYSSYGSTYYAD 
                 
               
               
                   
                   
                 
                   SVKGRFTISADTSKNTAYLQMNSLRAEDTAVY 
                 
               
               
                   
                   
                   YCARASWYALDYWGQGTLVTVSS ASTKGPSVF 
               
               
                   
                   
                 PLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS 
               
               
                   
                   
                 GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT 
               
               
                   
                   
                 QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP 
               
               
                   
                   
                 CPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVV 
               
               
                   
                   
                 VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ 
               
               
                   
                   
                 YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA 
               
               
                   
                   
                 LGAPIEKTISKAKGQPREPQVYTLPPSREEMTKN 
               
               
                   
                   
                 QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP 
               
               
                   
                   
                 PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM 
               
               
                   
                   
                 HEALHNHYTQKSLSLSPGK   GGGGSGSGGSGGGG     
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   &gt;F127LC SEQ ID NO: 121 
                 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQSVSSAV 
                 
               
               
                   
                   
                 
                   AWYQQKPGKAPKLLIYSASSLYSGVPSRFSGS 
                 
               
               
                   
                   
                 
                   RSGTDFTLTISSLQPEDFATYYCQQYWYGVAP 
                 
               
               
                   
                   
                   ITFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGT 
               
               
                   
                   
                 ASVVCLLNNFYPREAKVQWKVDNALQSGNSQE 
               
               
                   
                   
                 SVTEQDSKDSTYSLSSTLTLSKADYEKHKVTACE 
               
               
                   
                   
                 VTHQGLSSPVTKSFNRGEC 
               
               
                 N-HC-appended scFv-IgG- 
                 
                   L6-N-HC 
                 
                 L6-N-HC appended ScFv-F58-IgG-RSPO2RA HC 
               
               
                 mutRspo2 
                 
                   appended 
                 
                 
                   SEQ ID NO: 122 
                 
               
               
                   
                 
                   ScFv-F58- 
                 
                 
                   EVQLVESGGGLVQPGGGSLRLSCAASGFTFTSY 
                 
               
               
                   
                 
                   IgG- 
                 
                 
                   YISWVRQAPGKGLEWVAEISPYSGSTYYADSV 
                 
               
               
                   
                 
                   
                     RSPO2RA 
                   
                 
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                   
                 
                   ALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GS 
                   
                 
               
               
                   
                   
                     AASGSSGGSSSSGA   D IQMTQSPSSLSASVGDRVTIT   
               
               
                   
                   
                 
                   CRASQDVSTAVAWYQQKPGKAPKKLIYSASFL 
                 
               
               
                   
                   
                 
                   YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY 
                 
               
               
                   
                   
                 
                   CQQSYTTPPTFGQGTKVEIK 
                   
                     GGGGSGGGGSGG 
                   
                 
               
               
                   
                   
                 
                   
                     GGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASGFNIS 
                 
               
               
                   
                   
                 
                   YSYIHWVRQAPGKGLEWVASIYSSSGSTSYAD 
                 
               
               
                   
                   
                 
                   SVKGRFTISADTSKNTAYLQMNSLRAEDTAVY 
                 
               
               
                   
                   
                   YCARGAIDYWGQGTLVTVSS ASTKGPSVFPLAP 
               
               
                   
                   
                 SSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT 
               
               
                   
                   
                 SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI 
               
               
                   
                   
                 CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP 
               
               
                   
                   
                 EAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV 
               
               
                   
                   
                 SHEDPEVKFNWYCDGVEHNAKTKPREEQYNS 
               
               
                   
                   
                 TYRVVSVLTVLHQDWLNGKEYKCKVSNKALGA 
               
               
                   
                   
                 PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSL 
               
               
                   
                   
                 TCLVKGFYPSIAVEWESNGQPENNYKTTPPVLD 
               
               
                   
                   
                 SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   &gt;F58 LC SEQ ID NO: 123 
                 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQSVSSAV 
                 
               
               
                   
                   
                 
                   AWYQQKPGKAPKLLIYSASSLYSGVPSRFSGS 
                 
               
               
                   
                   
                 
                   RSGTDFTLTISSLQPEDFATYYCQQWYSSGHV 
                 
               
               
                   
                   
                   LITFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGT 
               
               
                   
                   
                 ASVVCLLNNFYPREAKVQWKVDNALQSGNSQE 
               
               
                   
                   
                 SVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE 
               
               
                   
                   
                 VTHQGLSSPVTKSFNRGEC 
               
               
                 N-HC-appended scFv-IgG- 
                 
                   L6-N-HC 
                 
                 L6-N-HC appended ScFv-F4-2-IgG-RSPO2RA HC 
               
               
                 mutRspo2 
                 
                   appended 
                 
                 
                   SEQ ID NO: 124 
                 
               
               
                   
                 
                   ScFv-F4-2- 
                 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSV 
                 
               
               
                   
                 
                   IgG- 
                 
                 
                   YISWVRQAPGKGLEWVAEISPYSGSTYYADSV 
                 
               
               
                   
                 
                   
                     RSPO2RA 
                   
                 
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                   
                 
                   ALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GS 
                   
                 
               
               
                   
                   
                 
                   
                     AASGSSGGSSSGA 
                   
                   DIQMTQSPSSLSASVGDRVTIT 
                 
               
               
                   
                   
                 
                   CRASQDVSTAVAWYQQKPGKAPKLLIYSASFL 
                 
               
               
                   
                   
                 
                   YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY 
                 
               
               
                   
                   
                 
                   CQQSYTTPPTFGQGTKVEIK 
                   
                     GGGGSGGGGSGG 
                   
                 
               
               
                   
                   
                 
                   
                     GGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASGFNIS 
                 
               
               
                   
                   
                 
                   YYYIHWVRQAPGKGLEWVASIYPSSGYTYYA 
                 
               
               
                   
                   
                 
                   DSVKGRFTISADTSKNTAYLQMNSLRAEDTAV 
                 
               
               
                   
                   
                   YYCARSSFYWAMDYWGQGTLVTVSS ASTKGP 
               
               
                   
                   
                 SVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS 
               
               
                   
                   
                 WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS 
               
               
                   
                   
                 SLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH 
               
               
                   
                   
                 TCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV 
               
               
                   
                   
                 TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP 
               
               
                   
                   
                 REEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV 
               
               
                   
                   
                 SNKALGAPIEKTISKAKGQPREPQVYTLPPSREEM 
               
               
                   
                   
                 TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY 
               
               
                   
                   
                 KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC 
               
               
                   
                   
                 SVMHEALHNHYTQKSLSLSPGK   GGGGSGSGGSG     
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   &gt;F4-2 LC SEQ ID NO: 125 
                 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQSVSSAV 
                 
               
               
                   
                   
                 
                   AWYQQKPGKAPKLLIYSASSLYSGVPSRFSGS 
                 
               
               
                   
                   
                 
                   RSGTDFTLTISSLQPEDFATYYCQQSYAAYLFT 
                 
               
               
                   
                   
                   FGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTAS 
               
               
                   
                   
                 VVCLLNNFYPREAKVQWKVDNALQSGNSQESV 
               
               
                   
                   
                 TEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVT 
               
               
                   
                   
                 HQGLSSPVTKSFNRGEC 
               
               
                 N-HC-appended scFv-IgG- 
                 
                   L6-N-HC 
                 
                 L6-N-HC appended ScFv-F4-IgG-RSPO2RA HC SEQ 
               
               
                 mutRspo2 
                 
                   appended 
                 
                 
                   ID NO: 126 
                 
               
               
                   
                 
                   ScFv-F4- 
                 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSY 
                 
               
               
                   
                 
                   IgG- 
                 
                 
                   YISWVRQAPGKGLEWVAEISPYSGSTYYADSV 
                 
               
               
                   
                 
                   
                     RSPO2RA 
                   
                 
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                   
                 
                   ALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GS 
                   
                 
               
               
                   
                   
                 
                   
                     AASGSSGGSSSGA 
                   
                   DIQMTQSPSSLSASVGDRVTIT 
                 
               
               
                   
                   
                 
                   CRASQDVSTAVAWYQQKPGKAPKLLIYSASFL 
                 
               
               
                   
                   
                 
                   YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY 
                 
               
               
                   
                   
                 
                   CQQSYTTPPTFGQGTKVEIK 
                   
                     GGGGSGGGGSGG 
                   
                 
               
               
                   
                   
                 
                   
                     GGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASGFNL 
                 
               
               
                   
                   
                 
                   SSYSMHWVRQAPGKGLEWVAYISSYYGYTYY 
                 
               
               
                   
                   
                 
                   ADSVKGRFTISADTSKNTAYLQMNSLRAEDTA 
                 
               
               
                   
                   
                   VYYCARPAPGHWGFDYWGQGTLVTVSS ASTK 
               
               
                   
                   
                 GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT 
               
               
                   
                   
                 VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP 
               
               
                   
                   
                 SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT 
               
               
                   
                   
                 HTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE 
               
               
                   
                   
                 VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK 
               
               
                   
                   
                 PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK 
               
               
                   
                   
                 VSNKALGAPIEKTISKAKGQPREPQVYTLPPSREE 
               
               
                   
                   
                 MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENN 
               
               
                   
                   
                 YKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVF 
               
               
                   
                   
                 SCSVMHEALHNHYTQKSLSLSPGK   GGGGSGSGG     
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   &gt;F4 LC SEQ ID NO: 127 
                 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQSVSSAV 
                 
               
               
                   
                   
                 
                   AWYQQKPGKAPKLLIYSASSLYSGVPSRFSGS 
                 
               
               
                   
                   
                 
                   RSGTDFTLTISSLQPEDFATYYCQQWYYAPITF 
                 
               
               
                   
                   
                   GQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASV 
               
               
                   
                   
                 VCLLNNFYPREAKVQWKVDNALQSGNSQESVTE 
               
               
                   
                   
                 QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH 
               
               
                   
                   
                 QGLSSPVTKSFNRGEC 
               
               
                 N-HC-appended scFv-IgG- 
                 
                   L6-N-HC 
                 
                 L6-N-HC appended ScFv-F49-IgG-RSPO2$A HC 
               
               
                 mutRspo2 
                 
                   appended 
                 
                 
                   SEQ ID NO: 128 
                 
               
               
                   
                 
                   ScFv-F49- 
                 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSY 
                 
               
               
                   
                 
                   IgG- 
                 
                 
                   YISWVRQAPGKGLEWVAEISPYSGSTYYADSV 
                 
               
               
                   
                 
                   
                     RSPO2RA 
                   
                 
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                   
                 
                   ALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GS 
                   
                 
               
               
                   
                   
                 
                   
                     AASGSSGGSSSGA 
                   
                   DIQMTQSPSSLSASVGDRVTIT 
                 
               
               
                   
                   
                 
                   CRASQDVSTAVAWYQQKPGKAPKLLIYSASFL 
                 
               
               
                   
                   
                 
                   YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY 
                 
               
               
                   
                   
                 
                   CQQSYTTPPTFGQGTKVEIK 
                   
                     GGGGSGGGGSGG 
                   
                 
               
               
                   
                   
                 
                   
                     GGS 
                   
                   QVQLVQSGAEVKKPGASVKVSCKASGGT 
                 
               
               
                   
                   
                 
                   FSSYAISWVRQAPGQGLEWMGWINAGNGNTT 
                 
               
               
                   
                   
                 
                   YAQKFQGRVTMTRDTSTSTVYMELSSLRSEDT 
                 
               
               
                   
                   
                   AVYYCARHYYGSGSYPDWGQGTLVTVSS AST 
               
               
                   
                   
                 KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV 
               
               
                   
                   
                 TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTV 
               
               
                   
                   
                 PSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK 
               
               
                   
                   
                 THTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTP 
               
               
                   
                   
                 EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT 
               
               
                   
                   
                 KPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC 
               
               
                   
                   
                 KVSNKALGAPIEKTISKAKGQPREPQVYTLPPSRE 
               
               
                   
                   
                 EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN 
               
               
                   
                   
                 NYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV 
               
               
                   
                   
                 FSCSVMHEALHNHYTQKSLSLSPGK   GGGGSGSG     
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   &gt;F49 LC SEQ ID NO: 129 
                 
               
               
                   
                   
                 
                   DIQMTQSPSSPSASVGDRVTITCRASQSISSYLN 
                 
               
               
                   
                   
                 
                   WYQQKPGKAPKLLIYAASSLQSGVPSRFSGSG 
                 
               
               
                   
                   
                 
                   SGTDFTLTISSLQPEDFATYYCQQSYSTPLTFG 
                 
               
               
                   
                   
                   GGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVV 
               
               
                   
                   
                 CLLNNFYPREAKVQWKVDNALQSGNSQESVTEQ 
               
               
                   
                   
                 DSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ 
               
               
                   
                   
                 GLSSPVTKSFNRGEC 
               
               
                 N-HC-appended scFv-IgG- 
                 
                   L6-N-HC 
                 
                 L6-N-HC appended ScFv-F10-IgG-RSPO2RA HC 
               
               
                 mutRspo2 
                 
                   appended 
                 
                 
                   SEQ ID NO: 130 
                 
               
               
                   
                 
                   ScFv-F10- 
                 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSY 
                 
               
               
                   
                 
                   IgG- 
                 
                 
                   YISWVRQAPGKGLEWVAEISPYSGSTYYADSV 
                 
               
               
                   
                 
                   
                     RSPO2RA 
                   
                 
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                   
                 
                   ALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   GS 
                 
               
               
                   
                   
                 
                   
                     AASGSSGGSSSGA 
                   
                   DIQMTQSPSSLSASVGDRVTIT 
                 
               
               
                   
                   
                 
                   CRASQDVSTAVAWYQQKPGKAPKLLIYSASFL 
                 
               
               
                   
                   
                 
                   YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY 
                 
               
               
                   
                   
                 
                   CQQSYTTPPTFGQGTKVEIK 
                   
                     GGGGSGGGGSGG 
                   
                 
               
               
                   
                   
                 
                   
                     GGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASGFTF 
                 
               
               
                   
                   
                 
                   SSFNMFWVRQAPGKGLEWVAGIDDDGSYPNY 
                 
               
               
                   
                   
                 
                   GSAVKGRATISRDNSKNTLYLQMNSLRAEDTA 
                 
               
               
                   
                   
                 
                   VYYCAKSGYGGSWGGYIADDIDAWGQGTLVT 
                 
               
               
                   
                   
                   VSS ASTKGSVFPLAPSSKSTSGGTAALGCLVKD 
               
               
                   
                   
                 YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL 
               
               
                   
                   
                 SSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVE 
               
               
                   
                   
                 PKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTL 
               
               
                   
                   
                 MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV 
               
               
                   
                   
                 HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG 
               
               
                   
                   
                 KEYKCKVSNKALGAPIEKTISKAKGQPREPQVYT 
               
               
                   
                   
                 LPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESN 
               
               
                   
                   
                 GQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW 
               
               
                   
                   
                 QQGNVFSVMHEALHNHYTQKSLSLSPGK   GGG     
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   &gt;F10 LC SEQ ID NO: 131 
                 
               
               
                   
                   
                 
                   ELTQPPSVSVSPGQTARITCSGDGSYAGSYYYG 
                 
               
               
                   
                   
                 
                   WYQQKPGQAPVTLIYYNNKRPSGIPERFSGSL 
                 
               
               
                   
                   
                 
                   SGSTNTLTISGVQAEDEADYYCGSADNSGAAF 
                 
               
               
                   
                   
                   GGGTKLTVL RTVAAPSVFIFPPSDEQLKSGTASV 
               
               
                   
                   
                 VCLLNNFYPREAKVQWKVDNALQSGNSQESVTE 
               
               
                   
                   
                 QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH 
               
               
                   
                   
                 QGLSSPVTKSFNRGEC 
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L6-N-Hc appended ScFv- F12578-IgG- RSPO2RA- Knob-his + F12578-IgG- RSPO2RA  Hole-Flag   
                 L6-N-HC appended ScFv-F12578-IgG-RSPO2RA-  Knob-His HC SEQ ID NO: 132   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSY   YISWVRQAPGKGLEWVAEISPYSGSTYYADSV   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC   ALRARPPIRLHPRGSVMDYWGQGTLVTVSS     GS       AASGSSGGSSSGA     DIQMTQSPSSLSASVGDRVTIT   CRASQDVSTAVAWYQQKPGKAPKLLIYSASFL   YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY   CQQSYTTPPTFGQGTKVEIK     GGGGSGGGGSGG       GGS     EVQLVESGGGLVQPGGSLRLSCAASGFTF   SHYTLSWVRQAPGKGLEWVSVISGDGSYTYY   ADSVKGRFTISSDNSKNTLYLQMNSLRAEDTA   VYYCARNFIKYVFANWGQGTLVTVSS ASTKGP SVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS 
               
               
                   
                   
                 SLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH 
               
               
                   
                   
                 TCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV 
               
               
                   
                   
                 TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP 
               
               
                   
                   
                 REEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV 
               
               
                   
                   
                 SNKALGAPIEKTISKAKGQPREPQVYTLPPSREEM 
               
               
                   
                   
                 TKNQVSLWCLVKGFYPSDIAVEWESNGQPENNY 
               
               
                   
                   
                 KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC 
               
               
                   
                   
                 SVMHEALHNHYTQKSLSLSPGK   GGGGSGGGGSG     
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 &gt;F12578-IgG-RSPO2RA-Hole Flag HC SEQ ID 
               
               
                   
                   
                 
                   NO: 133 
                 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFSHY 
                 
               
               
                   
                   
                 
                   TLSWVRQAPGKGLEWVSVISGDGSYTYYADS 
                 
               
               
                   
                   
                 
                   VKGRFTISSDNSKNTLYLQMNSLRAEDTAVYY 
                 
               
               
                   
                   
                   CARNFIKYYFANWGQGTLVTVSS ASTKGPSVFP 
               
               
                   
                   
                 LAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSG 
               
               
                   
                   
                 ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ 
               
               
                   
                   
                 TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP 
               
               
                   
                   
                 APEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV 
               
               
                   
                   
                 DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY 
               
               
                   
                   
                 NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL 
               
               
                   
                   
                 GAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQ 
               
               
                   
                   
                 VSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPP 
               
               
                   
                   
                 VLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMH 
               
               
                   
                   
                 EALHNHYTQKSLSLSPGK   GGGGSGGGGSGGGGS     
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   &gt;F12578 LC SEQ ID NO: 134 
                 
               
               
                   
                   
                 
                   DIELTQPPSVSVAPGQTARISCSGDNIGSFYVH 
                 
               
               
                   
                   
                 
                   WYQQKPGQAPVLVIYDKSNRPSGIPERFSGSN 
                 
               
               
                   
                   
                 
                   SGNTATLTISGTQAEDEADYYCQSYANTLSLV 
                 
               
               
                   
                   
                   FGGGTKLTVL GQPKAAPSVTLFPPSSEELQANK 
               
               
                   
                   
                 ATLVCLISDFYPGAVTVAWKADSSPVKAGVETT 
               
               
                   
                   
                 TPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVT 
               
               
                   
                   
                 HEGSTVEKTVAPTECS 
               
               
                 N-HC appended ScFv-IgG- 
                 
                   L6-N-HC 
                 
                 L6-N-HC appended ScFv-F127-IgG-RSPO2RA-Knob- 
               
               
                 mutRspo2-Knob + 
                 
                   appended 
                 
                 
                   His HC SEQ ID NO: 135 
                 
               
               
                 IgG-mutRspo2-Hole 
                 
                   ScFv-F127- 
                 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSY 
                 
               
               
                   
                 
                   IgG- 
                 
                 
                   YISWVRQAPGKGLEWVAEISPYSGSTYYADSV 
                 
               
               
                   
                 
                   RSPO2RA- 
                 
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                 
                   Knob-his + 
                 
                 
                   ALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GS 
                   
                 
               
               
                   
                 
                   F127-IgG- 
                 
                 
                   
                     AASGSSGGSSSGA 
                   
                   DIQMTQSPSSLSASVGDRVTIT 
                 
               
               
                   
                 
                   RSPO2RA 
                 
                 
                   CRASQDVSTAVAWYQQKPGKAPKLLIYSASFL 
                 
               
               
                   
                 
                   
                     Hole-Flag 
                   
                 
                 
                   YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY 
                 
               
               
                   
                   
                 
                   CQQSYTTPPTFGQGTKVEIK 
                   
                     GGGGSGGGGSGG 
                   
                 
               
               
                   
                   
                 
                   
                     GGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASGFNIS 
                 
               
               
                   
                   
                 
                   SSYIHWVRQAPGKGLEWVAYIYSSYGSTYYAD 
                 
               
               
                   
                   
                 
                   SVKGRFTISADTSKNTAYLQMNSLRAEDTAVY 
                 
               
               
                   
                   
                   YCARASWYALDYWGQGTLVTVSS ASTKGPSVF 
               
               
                   
                   
                 PLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS 
               
               
                   
                   
                 GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT 
               
               
                   
                   
                 QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP 
               
               
                   
                   
                 CPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVV 
               
               
                   
                   
                 VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ 
               
               
                   
                   
                 YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA 
               
               
                   
                   
                 LGAPIEKTISKAKGQPREPQVYTLPPSREEMTKN 
               
               
                   
                   
                 QVSLWCLVKGFYPSDIAVEWESNGQPENNYKTT 
               
               
                   
                   
                 PPVLDSDGSFFLYSKLTVDKSRWQQGNVFCSV 
               
               
                   
                   
                 MHEALHNHYTQKSLSLSPGK   GGGGSGGGGSGGG     
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 &gt;F127-IgG-RSPO2RA-Hole Flag HC SEQ ID 
               
               
                   
                   
                 
                   NO: 136 
                 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFNISSSY 
                 
               
               
                   
                   
                 
                   IHWVRQAPGKGLEWVAYIYSSYGSTYYADSV 
                 
               
               
                   
                   
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                   
                   ARASWYALDYWGQGTLVTVSS ASTKGPSVFPL 
               
               
                   
                   
                 APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSG 
               
               
                   
                   
                 ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ 
               
               
                   
                   
                 TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP 
               
               
                   
                   
                 APEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV 
               
               
                   
                   
                 DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY 
               
               
                   
                   
                 NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL 
               
               
                   
                   
                 GAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQ 
               
               
                   
                   
                 VSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPP 
               
               
                   
                   
                 VLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMH 
               
               
                   
                   
                 EALHNHYTQKSLSLSPGK   GGGGSGGGGSGGGGS     
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   &gt;F127 LC SEQ ID NO: 137 
                 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQSVSSAV 
                 
               
               
                   
                   
                 
                   AWYQQKPGKAPKLLIYSASSLYSGVPSRFSGS 
                 
               
               
                   
                   
                 
                   RSGTDFTLTISSLQPEDFATYYCQQYWYGVAP 
                 
               
               
                   
                   
                   ITFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGT 
               
               
                   
                   
                 ASVVCLLNNFYPREAKVQWKVDNALQSGNSQE 
               
               
                   
                   
                 SVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE 
               
               
                   
                   
                 VTHQGLSSPVTKSFNRGEC 
               
               
                 N-HC appended ScFv-IgG- 
                 
                   L6-N-HC 
                 
                 L6-N-HC appended ScFv-F58-IgG-RSPO2RA-Knob- 
               
               
                 mutRspo2-Knob + 
                 
                   appended 
                 
                 
                   His HC SEQ ID NO: 138 
                 
               
               
                 IgG-mutRspo2-Hole 
                 
                   ScFv-F58- 
                 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSY 
                 
               
               
                   
                 
                   IgG- 
                 
                 
                   YISWVRQAPGKGLEWVAEISPYSGSTYYADSV 
                 
               
               
                   
                 
                   RSPO2RA- 
                 
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                 
                   Knob-his + 
                 
                 
                   ALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GS 
                   
                 
               
               
                   
                 
                   F58-IgG- 
                 
                 
                   
                     AASGSSGGSSSGA 
                   
                   DIQMTQSPSSLSASVGDRVTIT 
                 
               
               
                   
                 
                   RSPO2RA 
                 
                 CRASQDVSTAVAWYQQKPGKAPKLLIYSASFL 
               
               
                   
                 
                   
                     Hole-Flag 
                   
                 
                 YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY 
               
               
                   
                   
                 
                   CQQSYTTPPTFGQGTKVEIK 
                   
                     GGGGSGGGGSGG 
                   
                 
               
               
                   
                   
                 
                   
                     GGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASGFNIS 
                 
               
               
                   
                   
                 
                   YSYIHWVRQAPGKGLEWVASIYSSSGSTSYAD 
                 
               
               
                   
                   
                 
                   SVKGRFTISADTSKNTATYLQMNSLRAEDTAVY 
                 
               
               
                   
                   
                   YCARGAIDYWGQGTLVTVSS ASTKGPSVFPLAP 
               
               
                   
                   
                 SSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT 
               
               
                   
                   
                 SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI 
               
               
                   
                   
                 CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP 
               
               
                   
                   
                 EAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV 
               
               
                   
                   
                 SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS 
               
               
                   
                   
                 TYRVVSVLTVLHQDWLNGKEYKCKVSNKALGA 
               
               
                   
                   
                 PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSL 
               
               
                   
                   
                 WCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL 
               
               
                   
                   
                 DSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   &gt;F58-IgG-RSPO2RA-Hole Flag HC SEQ ID NO: 139 
                 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFNISYS 
                 
               
               
                   
                   
                 
                   YIHWVRQAPGKGLEWVASIYSSSGSTSYADSV 
                 
               
               
                   
                   
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                   
                   ARGAIDYWGQGTLVTVSS ASTKGPSVFPLAPSS 
               
               
                   
                   
                 KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS 
               
               
                   
                   
                 GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC 
               
               
                   
                   
                 NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPE 
               
               
                   
                   
                 AAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS 
               
               
                   
                   
                 HEDPEVKFNWYVDGVEVHNAKTKPREEQYNST 
               
               
                   
                   
                 YRVVSVLTVLHQDWLNGKEYKCKVSNKALGAP 
               
               
                   
                   
                 IEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLS 
               
               
                   
                   
                 CAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS 
               
               
                   
                   
                 DGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALH 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   &gt;F58 LC SEQ ID NO: 140 
                 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQSVSSAV 
                 
               
               
                   
                   
                 
                   AWYQQKPGKAPKLLIYSASSLYSGVPSRFSGS 
                 
               
               
                   
                   
                 
                   RSGTDFTLTISSLQPEDFATYYCQQWYSSGHV 
                 
               
               
                   
                   
                   LITFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGT 
               
               
                   
                   
                 ASVVCLLNNFYPREAKVQWKVDNALQSGNSQE 
               
               
                   
                   
                 SVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE 
               
               
                   
                   
                 VTHQGLSSPVTKSFNRGEC 
               
               
                 N-HC appended ScFv-IgG- 
                 
                   L6-N-HC 
                 
                 L6-N-HC appended ScFv-F4-2-IgG-RSPO2RA-Knob- 
               
               
                 mutRspo2-Knob + 
                 
                   appended 
                 
                 
                   His HC SEQ ID NO: 141 
                 
               
               
                 IgG-mutRspo2-Hole 
                 
                   ScFv-F4-2- 
                 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSY 
                 
               
               
                   
                 
                   IgG- 
                 
                 
                   YISWVRQAPGKGLEWVAEISPYSGSTYYADSV 
                 
               
               
                   
                 
                   RSPO2RA- 
                 
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                 
                   Knob-his + 
                 
                 
                   ALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GS 
                   
                 
               
               
                   
                 
                   F4-2-IgG- 
                 
                 
                   
                     AASGSSGGSSSGA 
                   
                   DIQMTQSPSSLSASVGDRVTIT 
                 
               
               
                   
                 
                   RSPO2RA 
                 
                 
                   CRASQDVSTAVAWYQQKPGKAPKLLIYSASFL 
                 
               
               
                   
                 
                   
                     Hole-Flag 
                   
                 
                 
                   YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY 
                 
               
               
                   
                   
                 
                   CQQSYTTPPTFGQGTKVEIK 
                   
                     GGGGSGGGGSGG 
                   
                 
               
               
                   
                   
                 
                   
                     GGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASGFNIS 
                 
               
               
                   
                   
                 
                   YYYIHWVRQAPGKGLEWVASIYPSSGYTYYA 
                 
               
               
                   
                   
                 
                   DSVKGRFTISADTSKNTAYLQMNSLRAEDTAV 
                 
               
               
                   
                   
                   YYCARSSFYWAMDYWGQGTLVTVSS ASTKGP 
               
               
                   
                   
                 SVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS 
               
               
                   
                   
                 WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS 
               
               
                   
                   
                 SLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH 
               
               
                   
                   
                 TCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV 
               
               
                   
                   
                 TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP 
               
               
                   
                   
                 REEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV 
               
               
                   
                   
                 SNKALGAPIEKTISKAKGQPREPQVYTLPPSREEM 
               
               
                   
                   
                 TKNQVSLWCLVKGFYPSDIAVEWESNGQPENNY 
               
               
                   
                   
                 KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC 
               
               
                   
                   
                 SVMHEALHNHYTQKSLSLSPGK   GGGGSGGGGSG     
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 &gt;F4-2-IgG-RSPO2RA-Hole Flag HC SEQ ID 
               
               
                   
                   
                 
                   NO: 142 
                 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFNISYY 
                 
               
               
                   
                   
                 
                   YIHWVRQAPGKGLEWVASIYPSSGYTYYADSV 
                 
               
               
                   
                   
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                   
                   ARSSFYWAMDYWGQGTLVTVSS ASTKGPSVFP 
               
               
                   
                   
                 LAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSG 
               
               
                   
                   
                 ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ 
               
               
                   
                   
                 TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP 
               
               
                   
                   
                 APEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV 
               
               
                   
                   
                 DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY 
               
               
                   
                   
                 NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL 
               
               
                   
                   
                 GAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQ 
               
               
                   
                   
                 VSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPP 
               
               
                   
                   
                 VLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMH 
               
               
                   
                   
                 EALHNHYTQKSLSLSPGK   GGGGSGGGGSGGGGS     
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   &gt;F4-2 LC SEQ ID NO: 143 
                 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQSVSSAV 
                 
               
               
                   
                   
                 
                   AWYQQKPGKAPKLLIYSASSLYSGVPSRFSGS 
                 
               
               
                   
                   
                 
                   RSGTDFTLTISSLQPEDFATYYCQQSYAAYLFT 
                 
               
               
                   
                   
                   FGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTAS 
               
               
                   
                   
                 VVCLLNNFYPREAKVQWKVDNALQSGNSQESV 
               
               
                   
                   
                 TEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVT 
               
               
                   
                   
                 HQGLSSPVTKSFNRGEC 
               
               
                 N-HC appended ScFv-IgG- 
                 
                   L6-N-HC 
                 
                 L6-N-HC appended ScFv-F4-IgG-RSPO2RA-Knob- 
               
               
                 mutRspo2-Knob + 
                 
                   appended 
                 
                 
                   his HC SEQ ID NO: 144 
                 
               
               
                 IgG-mutRspo2-Hole 
                 
                   ScFv-F4- 
                 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSY 
                 
               
               
                   
                 
                   IgG- 
                 
                 
                   YISWVRQAPGKGLEWVAEISPYSGSTYYADSV 
                 
               
               
                   
                 
                   RSPO2RA- 
                 
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                 
                   Knob-his + 
                 
                 
                   ALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GS 
                   
                 
               
               
                   
                 
                   F4-IgG- 
                 
                 
                   
                     AASGSSGGSSSGA 
                   
                   DIQMTQSPSSLSASVGDRVTIT 
                 
               
               
                   
                 
                   RSPO2RA 
                 
                 
                   CRASQDVSTAVAWYQQKPGKAPKLLIYSASFL 
                 
               
               
                   
                 
                   
                     Hole-Flag 
                   
                 
                 
                   YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY 
                 
               
               
                   
                   
                 
                   CQQSYTTPPTFGQGTKVEIK 
                   
                     GGGGSGGGGSGG 
                   
                 
               
               
                   
                   
                 
                   
                     GGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASGFNL 
                 
               
               
                   
                   
                 
                   SSYSMHWVRQAPGKGLEWVAYISSYYGYTYY 
                 
               
               
                   
                   
                 
                   ADSVKGRFTISADTSKNTAYLQMNSLRAEDTA 
                 
               
               
                   
                   
                   VYYCARPAPGHWGFDYWGQGTLVTVSS ASTK 
               
               
                   
                   
                 GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT 
               
               
                   
                   
                 VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP 
               
               
                   
                   
                 SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT 
               
               
                   
                   
                 HTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE 
               
               
                   
                   
                 VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK 
               
               
                   
                   
                 PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK 
               
               
                   
                   
                 VSNKALGAPIEKTISKAKGQPREPQVYTLPPSREE 
               
               
                   
                   
                 MTKNQVSLWCLVKGFYPSDIAVEWESNGQPENN 
               
               
                   
                   
                 YKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVF 
               
               
                   
                   
                 SCSVMHEALHNHYTQKSLSLSPGK   GGGGSGGGG     
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   &gt;F4-IgG-RSPO2RA-Hole Flag HC SEQ ID NO: 145 
                 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFNLSSY 
                 
               
               
                   
                   
                 
                   SMHWVRQAPGKGLEWVAYISSYYGYTYYADS 
                 
               
               
                   
                   
                 
                   VKGRFTISADTSKNTAYLQMNSLRAEDTAVYY 
                 
               
               
                   
                   
                   CARPAPGHWGFDYWGQGTLVTVSS ASTKGPS 
               
               
                   
                   
                 VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW 
               
               
                   
                   
                 NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL 
               
               
                   
                   
                 GTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTC 
               
               
                   
                   
                 PPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTC 
               
               
                   
                   
                 VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE 
               
               
                   
                   
                 EQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN 
               
               
                   
                   
                 KALGAPIEKTISKAKGQPREPQVYTLPPSREEMT 
               
               
                   
                   
                 KNQVSLSCAVKGFYPSDIAVEWESNGQPENNYK 
               
               
                   
                   
                 TTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCS 
               
               
                   
                   
                 VMHEALHNHYTQKSLSLSPGK   GGGGSGGGGSGG     
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   &gt;F4 LC SEQ ID NO: 146 
                 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQSVSSAV 
                 
               
               
                   
                   
                 
                   AWYQQKPGKAPKLLIYSASSLYSGVPSRFSGS 
                 
               
               
                   
                   
                 
                   RSGTDFTLTISSLQPEDFATYYCQQWYYAPITF 
                 
               
               
                   
                   
                   GQGTKVEIK RTVAAPSVFIPPSDEQLKSGTASV 
               
               
                   
                   
                 VCLLNNFYPREAKVQWKVDNALQSGNSQESVTE 
               
               
                   
                   
                 QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH 
               
               
                   
                   
                 QGLSSPVTKSFNRGEC 
               
               
                 N-HC appended ScFv-IgG- 
                 
                   L6-N-HC 
                 
                 L6-N-HC appended ScFv-F49-IgG-RSPO2RA-Knob- 
               
               
                 mutRspo2-Knob + 
                 
                   appended 
                 
                 
                   His HC SEQ ID NO: 147 
                 
               
               
                 IgG-mutRspo2-Hole 
                 
                   ScFv-F49- 
                 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSY 
                 
               
               
                   
                 
                   IgG- 
                 
                 
                   YISWVRQAPGKGLEWVAEISPYSGSTYYADSV 
                 
               
               
                   
                 
                   RSPO2RA- 
                 
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                 
                   Knob-his + 
                 
                 
                   ALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GS 
                   
                 
               
               
                   
                 
                   F49-IgG- 
                 
                 
                   
                     AASGSSGGSSSGA 
                   
                   DIQMTQSPSSLSASVGDRVTIT 
                 
               
               
                   
                 
                   RSPO2RA 
                 
                 
                   CRASQDVSTAVAWYQQKPGKAPKLLIYSASFL 
                 
               
               
                   
                 
                   
                     Hole-Flag 
                   
                 
                 
                   YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY 
                 
               
               
                   
                   
                 
                   CQQSYTTPPTFGQGTKVEIK 
                   
                     GGGGSGGGGSGG 
                   
                 
               
               
                   
                   
                 
                   
                     GGS 
                   
                   QVQLVQSGAEVKKPGASVKVSCKASGGT 
                 
               
               
                   
                   
                 
                   FSSYAISWVRQAPGQGLEWMGWINAGNGNTT 
                 
               
               
                   
                   
                 
                   YAQKFQGRVTMTRDTSTSTVYMELSSLRSEDT 
                 
               
               
                   
                   
                   AVYYCARHYYGSGSYPDWGQGTLVTVSS AST 
               
               
                   
                   
                 KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV 
               
               
                   
                   
                 TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTV 
               
               
                   
                   
                 PSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK 
               
               
                   
                   
                 THTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTP 
               
               
                   
                   
                 EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT 
               
               
                   
                   
                 KPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC 
               
               
                   
                   
                 KVSNKALGAPIEKTISKAKGQPREPQVYTLPPSRE 
               
               
                   
                   
                 EMTKNQVSLWCLVKGFYPSDIAVEWESNGQPEN 
               
               
                   
                   
                 NYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV 
               
               
                   
                   
                 FSCSVMHEALHNHYTQKSLSLSPGK   GGGGSGGG     
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   &gt;F49-IgG-RSPO2RA-Hole Flag HC SEQ ID NO: 148 
                 
               
               
                   
                   
                 
                   QVQLVQSGAEVKKPGASVKVSCKASGGTFSSY 
                 
               
               
                   
                   
                 
                   AISWVRQAPGQGLEWMGWINAGNGNTTYAQ 
                 
               
               
                   
                   
                 
                   KFQGRVTMTRDTSTSTVYMELSSLRSEDTAVY 
                 
               
               
                   
                   
                   YCARHYYGSGSYPDWGQGTLVTVSS ASTKGPS 
               
               
                   
                   
                 VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW 
               
               
                   
                   
                 NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL 
               
               
                   
                   
                 GTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTC 
               
               
                   
                   
                 PPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTC 
               
               
                   
                   
                 VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE 
               
               
                   
                   
                 EQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN 
               
               
                   
                   
                 KALGAPIEKTISKAKGQPREPQVYTLPPSREEMT 
               
               
                   
                   
                 KNQVSLSCAVKGFYPSDIAVEWESNGQPENNYK 
               
               
                   
                   
                 TTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCS 
               
               
                   
                   
                 VMHEALHNHYTQKSLSLSPGK   GGGGSGGGGSGG     
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   &gt;F49 LC SEQ ID NO: 149 
                 
               
               
                   
                   
                 
                   DIQMTQSPSSPSASVGDRVTITCRASQSISSYLN 
                 
               
               
                   
                   
                 
                   WYQQKPGKAPKLLIYAASSLQSGVPSRFSGSG 
                 
               
               
                   
                   
                 
                   SGTDFTLTISSLQPEDFATYYCQQSYSTPLTFG 
                 
               
               
                   
                   
                   GGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVV 
               
               
                   
                   
                 CLLNNFYPREAKVQWKVDNALQSGNSQESVTEQ 
               
               
                   
                   
                 DSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ 
               
               
                   
                   
                 GLSSPVTKSFNRGEC 
               
               
                 N-HC appended ScFv-IgG- 
                 
                   L6-N-HC 
                 
                 L6-N-HC appended ScFv-F10-IgG-RSPO2RA-Knob- 
               
               
                 mutRspo2-Knob + 
                 
                   appended 
                 
                 
                   His HC SEQ ID NO: 150 
                 
               
               
                 IgG-mutRspo2-Hole 
                 
                   ScFv-F10- 
                 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSY 
                 
               
               
                   
                 
                   IgG- 
                 
                 
                   YISWVRQAPGKGLEWVAEISPYSGSTYYADSV 
                 
               
               
                   
                 
                   RSPO2RA- 
                 
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                 
                   Knob-his + 
                 
                 
                   ALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GS 
                   
                 
               
               
                   
                 
                   F10-IgG- 
                 
                 
                   
                     AASGSSGGSSSGA 
                   
                   DIQMTQSPSSLSASVGDRVTIT 
                 
               
               
                   
                 
                   RSPO2RA 
                 
                 
                   CRASQDVSTAVAWYQQKPGKAPKLLIYSASFL 
                 
               
               
                   
                 
                   
                     Hole-Flag 
                   
                 
                 
                   YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY 
                 
               
               
                   
                   
                 
                   CQQSYTTPPTFGQGTKVEIK 
                   
                     GGGGSGGGGSGG 
                   
                 
               
               
                   
                   
                 
                   
                     GGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASGFTF 
                 
               
               
                   
                   
                 
                   SSFNMFWVRQAPGKGLEWVAGIDDDGSYPNY 
                 
               
               
                   
                   
                 
                   GSAVKGRATISRDNSKNTLYLQMNSLRAEDTA 
                 
               
               
                   
                   
                 
                   VYYCAKSGYGGSWGGYIADDIDAWGQGTLVT 
                 
               
               
                   
                   
                   VSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKD 
               
               
                   
                   
                 YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL 
               
               
                   
                   
                 SSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVE 
               
               
                   
                   
                 PKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTL 
               
               
                   
                   
                 MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV 
               
               
                   
                   
                 HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG 
               
               
                   
                   
                 KEYKCKVSNKALGAPIEKTISKAKGQPREPQVYT 
               
               
                   
                   
                 LPPSREEMTKNQVSLWCLVKGFYPSDIAVEWES 
               
               
                   
                   
                 NGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR 
               
               
                   
                   
                 WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK   G     
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   &gt;F10-IgG-RSPO2RA-Hole Flag HC SEQ ID NO: 151 
                 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFSSF 
                 
               
               
                   
                   
                 
                   NMRWVRQAPGKGLEWVAGIDDDGSYPNYGS 
                 
               
               
                   
                   
                 
                   AVKGRATISRDNSKNTLYLQMNSLRAEDTAVY 
                 
               
               
                   
                   
                 
                   YCAKSGYGGSWGGYIADDIDAWGQGTLVTVS 
                 
               
               
                   
                   
                   S ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYF 
               
               
                   
                   
                 PEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS 
               
               
                   
                   
                 VVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPK 
               
               
                   
                   
                 SCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMI 
               
               
                   
                   
                 SRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH 
               
               
                   
                   
                 NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK 
               
               
                   
                   
                 EYKCKVSNKALGAPIEKTISDKAKGQPREPQVYTL 
               
               
                   
                   
                 PPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNG 
               
               
                   
                   
                 QPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQ 
               
               
                   
                   
                 QGNVFSCSVMHEALHNHYTQKSLSLSPGK   GGGG     
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   &gt;F10 LC SEQ ID NO: 152 
                 
               
               
                   
                   
                 
                   ELTQPPSVSVSPGQTARITCSGDGSYAGSYYYG 
                 
               
               
                   
                   
                 
                   WYQQKPGQAPVTLIYYNNKRPSGIPERFSGSL 
                 
               
               
                   
                   
                 
                   SGSTNTLTISGVQAEDEADYYCGSADNSGAAF 
                 
               
               
                   
                   
                   GGGTKLTVL RTVAAPSVFIFPPSDEQLKSGTASV 
               
               
                   
                   
                 VDLLNNFYPREAKVQWKVDNALQSGNSQESVTE 
               
               
                   
                   
                 QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH 
               
               
                   
                   
                 QGLSSPVTKSFNRGEC 
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   L6-N-HC 
                   appended 
                   ScFv- 
                   F12578-IgG- 
                   RSPO2RA- 
                   Knob-his + 
                   L6-N-HC 
                   appended 
                   ScFv- 
                   F12478-IgG- 
                   
                     Hole-Flag 
                   
                 
                 L6-N-HC appended Scfv-F12578-IgG-RSPO2RA-  Knob-His HC SEQ ID NO: 153   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSY   YISWVRQAPGKGLEWVAEISPYSGSTYYADSV   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC   ALRARPPIRLHPRGSVMDYWGQGTLVTVSS     GS       AASGSGGSSGA     DIQMTQSPSSLSASVGDRVTIT   CRASQDVSTAVAWYQQKPGKAPKLLIYSASFL   YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY   CQQSYTTPPTFGQGTKVEIK   GGGGSGGGGSGG     GGS     EVQLVESGGGLVQPGGSLRLSCAASGFTF   SHYTLSWVRQAPGKGLEWVSVISGDGSYTYY   ADSVKGRFTISSDNSKNTLYLQMNSLRAEDTA   VYYCARNFIKYVFANWGQGTLVTVSS ASTKGP SVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS SLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH TCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV TCVVVDVSHEDPEVKFNWYDGVEVHNAKTKP REEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV 
               
               
                   
                   
                 SNKALGAPIEKTISKAKGQPREPQVYTLPPSREEM 
               
               
                   
                   
                 TKNQVSLWCLVKGFYPSDIAVEWESNGQPENNY 
               
               
                   
                   
                 KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC 
               
               
                   
                   
                 SVMHEALHNHYTQKSLSLSPGK   GGGGSGGGGSG     
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 &gt;L6-N-HC appended ScFv-F12578-IgG-Hole Flag HC 
               
               
                   
                   
                 
                   SEQ ID NO: 154 
                 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSY 
                 
               
               
                   
                   
                 
                   YISWVRQAPGKGLEWVAEISPYSGSTYYADSV 
                 
               
               
                   
                   
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                   
                 
                   ALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GS 
                   
                 
               
               
                   
                   
                 
                   
                     AASGSSGGSSSGA 
                   
                   DIQMTQSPSSLSASVGDRVTIT 
                 
               
               
                   
                   
                 
                   CRASQDVSTAVAWYQQKPGKAPKLLIYSASFL 
                 
               
               
                   
                   
                 
                   YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY 
                 
               
               
                   
                   
                 
                   CQQSYTTPPTFGQGTKVEIK 
                   
                     GGGGSGGGGSGG 
                   
                 
               
               
                   
                   
                 
                   
                     GGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASGFTF 
                 
               
               
                   
                   
                 
                   SHYTLSWVRQAPGKGLEWVSVISGDGSYTYY 
                 
               
               
                   
                   
                 
                   ADSVKGRFTISSDNSKNTLYLQMNSLRAEDTA 
                 
               
               
                   
                   
                   VYYCARNFIKYVFANWGQGTLVTVSS ASTKGP 
               
               
                   
                   
                 SVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS 
               
               
                   
                   
                 WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS 
               
               
                   
                   
                 SLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH 
               
               
                   
                   
                 TCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV 
               
               
                   
                   
                 TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP 
               
               
                   
                   
                 REEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV 
               
               
                   
                   
                 SNKALGAPIEKTISKAKGQPREPQVYTLPPSREEM 
               
               
                   
                   
                 TKNWVSLSCAVKGFYPSDIAVEWESNGQPENNY 
               
               
                   
                   
                 KTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSC 
               
               
                   
                   
                 SVMHEALHNHYTQKSLSLSPGK   GSGSG   DYKDDD 
               
               
                   
                   
                 DK 
               
               
                   
                   
                 
                   &gt;F12578 LC SEQ ID NO: 155 
                 
               
               
                   
                   
                 
                   DIELTQPPSVSVAPGQTARISCSGDNIGSFYVH 
                 
               
               
                   
                   
                 
                   WYQQKPGQAPVLVIYDKSNRPSGIPERFSGSN 
                 
               
               
                   
                   
                 
                   SGNTATLTISGTQAEDEADYKYCQSYANTLSLV 
                 
               
               
                   
                   
                   FGGGTKLTVL GQPKAAPSVTLFPPSSEELQANK 
               
               
                   
                   
                 ATLVCLISDFYPGAVTVAWKADSSPVKAGVETT 
               
               
                   
                   
                 TPSKQSNNKYASSYLSLTPEQWKSHRSYSCQVT 
               
               
                   
                   
                 HEGSTVEKTVAPTECS 
               
               
                 N-HC appended ScFv-IgG- 
                 
                   L6-N-HC 
                 
                 L6-N-HC appended ScFv-F127-IgG-RSPO2RA-Knob- 
               
               
                 mutRspo2-Knob + 
                 
                   appended 
                 
                 
                   His HC SEQ ID NO: 156 
                 
               
               
                 N-HC appended ScFv-IgG- 
                 
                   ScFv-F127- 
                 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSY 
                 
               
               
                 Hole 
                 
                   IgG- 
                 
                 
                   YISWVRQAPGKGLEWVAEISPYSGSTYYADSV 
                 
               
               
                   
                 
                   RSPO2RA- 
                 
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                 
                   Knob-his + 
                 
                 
                   ALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GS 
                   
                 
               
               
                   
                 
                   L6-N-HC 
                 
                 
                   
                     AASGSSGGSSSGA 
                   
                   DIQMTQSPSSLSASVGDRVTIT 
                 
               
               
                   
                 
                   appended 
                 
                 
                   CRASQDVSTAVAWYQQKPGKAPKLLIYSASFL 
                 
               
               
                   
                 
                   ScFv-F127- 
                 
                 
                   YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY 
                 
               
               
                   
                 
                   IgG-Hole- 
                 
                 
                   CQQSYTTPPTFGQGTKVEIK 
                   
                     GGGGSGGGGSGG 
                   
                 
               
               
                   
                 
                   Flag 
                 
                 
                   
                     GGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASGFNIS 
                 
               
               
                   
                   
                 
                   SSYIHWVRQAPGKGLEWVAYIYSSYGSTYYAD 
                 
               
               
                   
                   
                 
                   SVKGRFTISADTSKNTAYLQMNSLRAEDTAVY 
                 
               
               
                   
                   
                   YCARASWYALDYWGQGTLVTVSS ASTKGPSVF 
               
               
                   
                   
                 PLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS 
               
               
                   
                   
                 GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT 
               
               
                   
                   
                 QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP 
               
               
                   
                   
                 CPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVV 
               
               
                   
                   
                 VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ 
               
               
                   
                   
                 YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA 
               
               
                   
                   
                 LGAPIEKTISKAKGQPREPQVYTLPPSREEMTKN 
               
               
                   
                   
                 QVSLWCLVKGFYPSDIAVEWESNGQGPENNYKTT 
               
               
                   
                   
                 MHEALHNHYTQKSLSLSPGK   GGGGSGGGGSGGG     
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 &gt;L6-N-HC appended ScFv-F127-IgG-Hole Flag HC 
               
               
                   
                   
                 
                   SEQ ID NO: 157 
                 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSY 
                 
               
               
                   
                   
                 
                   YISWVRQAPGKGLEWVAEISPYSGSTYYADSV 
                 
               
               
                   
                   
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                   
                 
                   ALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GS 
                   
                 
               
               
                   
                   
                 
                   
                     AASGSSGGSSSGA 
                   
                   DIQMTQSPSSLSASVGDRVTIT 
                 
               
               
                   
                   
                 
                   CRASQDVSTAVAWYQQKPGKAPKLLIYSASFL 
                 
               
               
                   
                   
                 
                   YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY 
                 
               
               
                   
                   
                 
                   CQQSYTTPPTFGQGTKVEIK 
                   
                     GGGGSGGGGSGG 
                   
                 
               
               
                   
                   
                 
                   
                     GGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASGFNIS 
                 
               
               
                   
                   
                 
                   SSYIHWVRQAPGKGLEWVAYIYSSYGSTYYAD 
                 
               
               
                   
                   
                 
                   SVKGRFTISADTSKNTAYLQMNSLRAEDTAVY 
                 
               
               
                   
                   
                   YCARASWYALDYWGQGTLVTVSS ASTKGPSVF 
               
               
                   
                   
                 PLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS 
               
               
                   
                   
                 GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT 
               
               
                   
                   
                 QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP 
               
               
                   
                   
                 CPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVV 
               
               
                   
                   
                 VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ 
               
               
                   
                   
                 YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA 
               
               
                   
                   
                 LGAPIEKTISKAKGQPREPQVYTLPPSREEMTKN 
               
               
                   
                   
                 QVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTP 
               
               
                   
                   
                 PVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVM 
               
               
                   
                   
                 HEALHNHYTQKSLSLSPGK   GSGSG   DYKDDDDK 
               
               
                   
                   
                 
                   &gt;F127 LC SEQ ID NO: 158 
                 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQSVSSAV 
                 
               
               
                   
                   
                 
                   AWYQQKPGKAPKLLIYSASSLYSGVPSRFSGS 
                 
               
               
                   
                   
                 
                   RSGTDFTLTISSLQPEDFATYYCQQYWYGVAP 
                 
               
               
                   
                   
                   ITFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGT 
               
               
                   
                   
                 ASVVCLLNNFYPREAKVQWKVDNALQSGNSQE 
               
               
                   
                   
                 SVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE 
               
               
                   
                   
                 VTHQGLSSPVTKSFNRGEC 
               
               
                 N-HC appended ScFc-IgG- 
                 
                   L6-N-HC 
                 
                 L6-N-HC appended ScFv-F58-IgG-RSPO2RA-Knob- 
               
               
                 mutRspo2-Knob + 
                 
                   appended 
                 
                 
                   his HC SEQ ID NO: 159 
                 
               
               
                 N-HC appended ScFv-IgG- 
                 
                   ScFv-F58 
                 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSY 
                 
               
               
                 Hole 
                 
                   IgG- 
                 
                 
                   YISWVRQAPGKGLEWVAEISPYSGSTYYADSV 
                 
               
               
                   
                 
                   RSPO2RA- 
                 
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                 
                   Knob-his + 
                 
                 
                   ALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GS 
                   
                 
               
               
                   
                 
                   L6-N-HC 
                 
                 
                   
                     AASGSSGGSSSGA 
                   
                   DIQMTQSPSSLSASVGDRVTIT 
                 
               
               
                   
                 
                   appended 
                 
                 
                   CRASQDVSTAVAWYQQKPGKAPKLLIYSASFL 
                 
               
               
                   
                 
                   ScFv-F58- 
                 
                 
                   YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY 
                 
               
               
                   
                 
                   IgG-Hole 
                 
                 
                   CQQSYTTPPTFGQGTKVEIK 
                   
                     GGGGSGGGGSGG 
                   
                 
               
               
                   
                 
                   
                     Flag 
                   
                 
                 
                   
                     GGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASGFNIS 
                 
               
               
                   
                   
                 
                   YSYIHWVRQAPGKGLEWVASIYSSSGSTSYAD 
                 
               
               
                   
                   
                 
                   SVKGRFTISADTSKNTAYLQMNSLRAEDTAVY 
                 
               
               
                   
                   
                   YCARGAIDYWGQGTLVTVSS ASTKGPSVFPLAP 
               
               
                   
                   
                 SSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT 
               
               
                   
                   
                 SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI 
               
               
                   
                   
                 CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP 
               
               
                   
                   
                 EAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV 
               
               
                   
                   
                 SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS 
               
               
                   
                   
                 TYRVVSVLTVLHQDWLNGKEYKCKVSNKALGA 
               
               
                   
                   
                 PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSL 
               
               
                   
                   
                 WCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL 
               
               
                   
                   
                 DSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 &gt;L6-N-HC appended ScFv-F58-IgG-Hole Flag HC 
               
               
                   
                   
                 
                   SEQ ID NO: 160 
                 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSY 
                 
               
               
                   
                   
                 
                   YISWVRQAPGKGLEWVAEISPYSGSTYYADSV 
                 
               
               
                   
                   
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                   
                 
                   ALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   GS 
                 
               
               
                   
                   
                 
                   
                     AASGSSGGSSSGA 
                   
                   DIQMTQSPSSLSASVGDRVTIT 
                 
               
               
                   
                   
                 
                   CRASQDVSTAVAWYQQKPGKAPKLLIYSASFL 
                 
               
               
                   
                   
                 
                   YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY 
                 
               
               
                   
                   
                 
                   CQQSYTTPPTFGQGTKVEIK 
                   
                     GGGGSGGGGSGG 
                   
                 
               
               
                   
                   
                 
                   
                     GGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASGFNIS 
                 
               
               
                   
                   
                 
                   YSYIHWVRQAPGKGLEWVASIYSSSGSTSYAD 
                 
               
               
                   
                   
                 
                   SVKGRFTISADTSKNTAYLQMNSLRAEDTAVY 
                 
               
               
                   
                   
                   YCARGAIDYWGQGTLVTVSS ASTKGPSVFPLAP 
               
               
                   
                   
                 SSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT 
               
               
                   
                   
                 SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI 
               
               
                   
                   
                 CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP 
               
               
                   
                   
                 EAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV 
               
               
                   
                   
                 SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS 
               
               
                   
                   
                 TYRVVSVLTVLHQDWLNGKEYKCKVSNKALGA 
               
               
                   
                   
                 PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSL 
               
               
                   
                   
                 SCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLD 
               
               
                   
                   
                 SDGSFFLVSKLTVDKSRWQQGNFSCSVMHEAL 
               
               
                   
                   
                 HNHYTQKSLSLSPGK   GSGSG   DYKDDDDK 
               
               
                   
                   
                 &gt;F58 LC SEQ ID NO: 161 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQSVSSAV 
                 
               
               
                   
                   
                 
                   AWYQQKPGKAPKLLIYSASSLYSGVPSRFSGS 
                 
               
               
                   
                   
                 
                   RSGTDFTLTISSLQPEDFATYYCQQWYSSGHV 
                 
               
               
                   
                   
                   LITFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGT 
               
               
                   
                   
                 ASVVCLLNNFYPREAKVQWKVDNALQSGANQE 
               
               
                   
                   
                 SVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE 
               
               
                   
                   
                 VTHQGLSSPVTKSFNRGEC 
               
               
                 N-HC appended ScFc-IgG- 
                 
                   L6-N-HC 
                 
                 L6-N-HC appended ScFv-F4-2-IgG-RSPO2RA-Knob- 
               
               
                 mutRspo2-Knob + 
                 
                   appended 
                 
                 
                   His HC SEQ ID NO: 162 
                 
               
               
                 N-HC appended ScFv-IgG- 
                 
                   ScFv-F4-2- 
                 
                 
                   EQVLVESGGGLVQPGGSLRLSCAASGFTFTSY 
                 
               
               
                 Hole 
                 
                   IgG- 
                 
                 
                   YISWVRQAPGKGLEWVAEISPYSGSTYYADSV 
                 
               
               
                   
                 
                   RSPO2RA- 
                 
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                 
                   Knob-his + 
                 
                 
                   ALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GS 
                   
                 
               
               
                   
                 
                   L6-N-HC 
                 
                 
                   
                     AASGSSGGSSSGA 
                   
                   DIQMTQSPSSLSASVGDRVTIT 
                 
               
               
                   
                 
                   appended 
                 
                 
                   CRASQDVSTAVAWYQQKPGKAPKLLIYSASFL 
                 
               
               
                   
                 
                   ScFv-F4-2- 
                 
                 
                   YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY 
                 
               
               
                   
                 
                   IgG-Hole- 
                 
                 
                   CQQSYTTPPTFGQGTKVEIK 
                   
                     GGGGSGGGGSGG 
                   
                 
               
               
                   
                 
                   
                     Flag 
                   
                 
                 
                   
                     GGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASGFNIS 
                 
               
               
                   
                   
                 
                   YYYIHWVRQAPGKGLEWVASIYPSSGYTYYA 
                 
               
               
                   
                   
                 
                   DSVKGRFTISADTSKNTAYLQMNSLRAEDTAV 
                 
               
               
                   
                   
                   YYCARSSFYWAMDYWGQGTLVTVSS ASTKGP 
               
               
                   
                   
                 SVFPLAPSSKSTSGGTAALGCLVDKYFPEPVTVS 
               
               
                   
                   
                 WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS 
               
               
                   
                   
                 SLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH 
               
               
                   
                   
                 TCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV 
               
               
                   
                   
                 TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP 
               
               
                   
                   
                 REEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV 
               
               
                   
                   
                 SNKALGAPIEKTISKAKGQPREPQVYTLPPSREEM 
               
               
                   
                   
                 TKNQVSLWCLVKGFYPSDIAVEWESNGQPENNY 
               
               
                   
                   
                 KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC 
               
               
                   
                   
                 SVMHEALHNHYTQKSLSLSPGK   GGGGSGGGGSG     
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 &gt;L6-N-HC appended ScFv-F4-2-IgG-Hole Flag HC 
               
               
                   
                   
                 
                   SEQ ID NO: 163 
                 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSY 
                 
               
               
                   
                   
                 
                   YISWVRQAPGKGLEWVAEISPYSGSTYYADSV 
                 
               
               
                   
                   
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                   
                 
                   ALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GS 
                   
                 
               
               
                   
                   
                 
                   
                     AASGSSGGSSSGA 
                   
                   DIQMTQSPSSLSASVGDRVTIT 
                 
               
               
                   
                   
                 
                   CRASQDVSTAVAWYQQKPKAPKLLIYSASFL 
                 
               
               
                   
                   
                 
                   YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY 
                 
               
               
                   
                   
                 
                   CQQSYTTPPTFGQGTKVEIK 
                   
                     GGGGSGGGGSGG 
                   
                 
               
               
                   
                   
                 
                   
                     GGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASGFNIS 
                 
               
               
                   
                   
                 
                   YYYIHWVRQAPGKGLEWVASIYPSSGYTYYA 
                 
               
               
                   
                   
                 
                   DSVKGRFTISADTSKNTAYLQMNSLRAEDTAV 
                 
               
               
                   
                   
                   YYCARSSFYWAMDYWGQGTLVTVSS ASTKGP 
               
               
                   
                   
                 SVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS 
               
               
                   
                   
                 WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS 
               
               
                   
                   
                 SLGTQTYICNVNHKPSNTKVDDVEPKSCDKTH 
               
               
                   
                   
                 TCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV 
               
               
                   
                   
                 TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP 
               
               
                   
                   
                 REEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV 
               
               
                   
                   
                 SNKALGQPIEKTISKAKGQPREPQVYTLPPSREEM 
               
               
                   
                   
                 TKNQVSLSCAVKGFYPSDIAVEWESNGQPENNY 
               
               
                   
                   
                 KTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSC 
               
               
                   
                   
                 SVMHEALHNHYTQKSLSLSPGK   GSGSG   DYKDDD 
               
               
                   
                   
                 DK 
               
               
                   
                   
                 &gt;F4-2 LC SEQ ID NO: 164 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQSVSSAV 
                 
               
               
                   
                   
                 
                   AWYQQKPGKAPKLLIYSASSLYSGVPSRFSGS 
                 
               
               
                   
                   
                 
                   RSGTDFTLTISSLQPEDFATYYCQQSYAAYLFT 
                 
               
               
                   
                   
                   FGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTAS 
               
               
                   
                   
                 VVCLLNNFYPREAKVQWKVDNALQSGNSQESV 
               
               
                   
                   
                 TEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVT 
               
               
                   
                   
                 HQGLSSPVTKSFNRGEC 
               
               
                 N-HC appended ScFv-IgG- 
                 
                   L6-N-HC 
                 
                 L6-N-HC appended ScFv-F4-IgG-RSPO2RA-Knob- 
               
               
                 mutRspo2-Knob + 
                 
                   appended 
                 
                 
                   His HC SEQ ID NO: 165 
                 
               
               
                 N-HC appended ScFv-IgG- 
                 
                   ScFv-F4- 
                 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYL 
                 
               
               
                 Hole 
                 
                   IgG- 
                 
                 
                   YISWVRQAPGKGLEWVAEISPYSGSTYYADSV 
                 
               
               
                   
                 
                   RSPO2RA- 
                 
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                 
                   Knob-his + 
                 
                 
                   ALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GS 
                   
                 
               
               
                   
                 
                   L6-N-HC 
                 
                 
                   
                     AASGSSGGSSSGA 
                   
                   DIQMTQSPSSLSASVGDRVTIT 
                 
               
               
                   
                 
                   appended 
                 
                 
                   CRASQDVSTAVAWYQQKPGKAPKLLIYSASFL 
                 
               
               
                   
                 
                   ScFv-F4- 
                 
                 
                   YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY 
                 
               
               
                   
                 
                   IgG-Hole 
                 
                 
                   CQQSYTTPPTFGQGTKVEIK 
                   
                     GGGGSGGGGSGG 
                   
                 
               
               
                   
                 
                   
                     Flag 
                   
                 
                 
                   
                     GGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASGFNL 
                 
               
               
                   
                   
                 
                   SSYSMHWVRQAPGKGLEWVAYISSYYGYTYY 
                 
               
               
                   
                   
                 
                   ADSVKGRFTISADTSKNTAYLQMNSLRAEDTA 
                 
               
               
                   
                   
                   VYYCARPAPGHWGFDYWGQGTLVTVSS ASTK 
               
               
                   
                   
                 GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT 
               
               
                   
                   
                 VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP 
               
               
                   
                   
                 SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT 
               
               
                   
                   
                 HTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE 
               
               
                   
                   
                 VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK 
               
               
                   
                   
                 PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK 
               
               
                   
                   
                 VSNKALGAPIEKTISKAKGQPREPQVYTLPPSREE 
               
               
                   
                   
                 MTKNQVSLWCLVKGFYPSDIAVEWESNGQPENN 
               
               
                   
                   
                 YKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVF 
               
               
                   
                   
                 SCSVMHEALHNHYTQKSLSLSPGK   GGGGSGGGG     
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 &gt;L6-N-HC appended ScFv-F4-IgG-Hole Flag HC 
               
               
                   
                   
                 
                   SEQ ID NO: 166 
                 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSY 
                 
               
               
                   
                   
                 
                   YISWVRQAPGKGLEWVAEISPYSGSTYYADSV 
                 
               
               
                   
                   
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                   
                 
                   ALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GS 
                   
                 
               
               
                   
                   
                 
                   
                     AASGSSGGSSSGA 
                   
                   DIQMTQSPSSLSASVGDRVTIT 
                 
               
               
                   
                   
                 
                   CRASQDVSTAVAWYQQKPGKAPKLLIYSASFL 
                 
               
               
                   
                   
                 
                   YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY 
                 
               
               
                   
                   
                 
                   CQQSYTTPPTFGQGTKVEIK 
                   
                     GGGGSGGGGSGG 
                   
                 
               
               
                   
                   
                 
                   
                     GGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASGFNL 
                 
               
               
                   
                   
                 
                   SSYSMHWVRQAPGKGLEWVAYISSYYGYTYY 
                 
               
               
                   
                   
                 
                   ADSVKGRFTISADTSKNTAYLQMNSLRAEDTA 
                 
               
               
                   
                   
                   VYYCARPAPGHWGFDYWGQGTLVTVSS ASTK 
               
               
                   
                   
                 GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT 
               
               
                   
                   
                 VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP 
               
               
                   
                   
                 SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT 
               
               
                   
                   
                 HTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE 
               
               
                   
                   
                 VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK 
               
               
                   
                   
                 PREEQYNSTYRVVSVLTVLGQDWLNGKEYKCK 
               
               
                   
                   
                 VSNKALGAPIEKTISKAKGQPREPQVYTLPPSREE 
               
               
                   
                   
                 MTKNQVSLSCAVKGFYPSDIAVEWESNGQPENN 
               
               
                   
                   
                 YKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVF 
               
               
                   
                   
                 SCSVMHEALHNHYTQKSLSLSPGK   GSGSG   DYKD 
               
               
                   
                   
                 DDDK 
               
               
                   
                   
                 
                   &gt;F4 LC SEQ ID NO: 167 
                 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQSVSSAV 
                 
               
               
                   
                   
                 
                   AWYQQKPGKAPKLLIYSASSLYSGVPSRFSGS 
                 
               
               
                   
                   
                 
                   RSGTDFTLTISSLQPEDFATYYCQQWYYAPITF 
                 
               
               
                   
                   
                   GQGTKVEIK RTVAPPSVFIFPPSDEQLKSGTASV 
               
               
                   
                   
                 VCLLNNFYPREAKVQWKVDNALQSGNSQESVTE 
               
               
                   
                   
                 QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH 
               
               
                   
                   
                 QGLSSPVTKSFNRGEC 
               
               
                 N-HC appended ScFv-IgG- 
                 
                   L6-N-HC 
                 
                 L6-N-HC appended ScFv-F49-IgG-RSPO2RA-Knob- 
               
               
                 mutRspo2-Inob + 
                 
                   appended 
                 
                 
                   His HC SEQ ID NO: 168 
                 
               
               
                 N-HC appended ScFv-IgG- 
                 
                   ScFv-F49- 
                 
                 
                   EQQLVESGGGLVQPGGSLRLSCAASGFTFTSY 
                 
               
               
                 Hole 
                 
                   IgG- 
                 
                 
                   YISWVRQAPGKGLEWVAEISPYSGSTYYADSV 
                 
               
               
                   
                 
                   RSPO2RA- 
                 
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                 
                   Knob-his + 
                 
                 
                   ALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GS 
                   
                 
               
               
                   
                 
                   L6-N-HC 
                 
                 
                   
                     AASGSSGGSSSGA 
                   
                   DIQMTQSPSSLSASVGDRVTIT 
                 
               
               
                   
                 
                   appended 
                 
                 
                   CRASQDVSTAVAWYQQKPGKAPKLLIYSASFL 
                 
               
               
                   
                 
                   ScFv-F49- 
                 
                 
                   YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY 
                 
               
               
                   
                 
                   IgG-Hole- 
                 
                 
                   CQQSYTTPPTFGQGTKVEIK 
                   
                     GGGGSGGGGSGG 
                   
                 
               
               
                   
                 
                   
                     Flag 
                   
                 
                 
                   
                     GGS 
                   
                   QVQLVQSGAEVKKPGASVKVSCKASGGT 
                 
               
               
                   
                   
                 
                   FSSYAISWVRQAPGQGLEWMGWINAGNGNTT 
                 
               
               
                   
                   
                 
                   YAQKFQGRVTMTRDTSTSTVYMELSSLRSEDT 
                 
               
               
                   
                   
                   AVYYCARHYYGSGSYPDWGQGTLVTVSS AST 
               
               
                   
                   
                 KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV 
               
               
                   
                   
                 TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTV 
               
               
                   
                   
                 PSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK 
               
               
                   
                   
                 THTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTP 
               
               
                   
                   
                 EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT 
               
               
                   
                   
                 KPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC 
               
               
                   
                   
                 KVSNKALGAPIEKTISKAKGQPREPQVYTLPPSRE 
               
               
                   
                   
                 EMTKNQVSLWCLVKGFYPSDIAVEWESNGQPEN 
               
               
                   
                   
                 NYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV 
               
               
                   
                   
                 FSCSVMHEALHNHYTQKSLSLSPGK   GGGGSGGG     
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 &gt;L6-N-HC appended ScFv-F49-IgG-Hole Flag HC 
               
               
                   
                   
                 
                   SEQ ID NO: 169 
                 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSY 
                 
               
               
                   
                   
                 
                   YISWVRQAPGKGLEWVAEISPYSGSTYYADSV 
                 
               
               
                   
                   
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                   
                 
                   ALRARPPIRLHPRQSVMDYWGQGTLVTVSS 
                   
                     GS 
                   
                 
               
               
                   
                   
                 
                   
                     AASGSSGGSSSGA 
                   
                   DIQMTQSPSSLSASVGDRVTIT 
                 
               
               
                   
                   
                 
                   CRASQDVSTAVAWYQQKPGKAPKLLIYSASFL 
                 
               
               
                   
                   
                 
                   YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY 
                 
               
               
                   
                   
                 
                   CQQSYTTPPTFGQGTKVEIK 
                   
                     GGGGSGGGGSGG 
                   
                 
               
               
                   
                   
                 
                   
                     GGS 
                   
                   QVQLVQSGAEVKKPGASVKVSCKASGGT 
                 
               
               
                   
                   
                 
                   FSSYAISWVRQAPGQGLEWMGWINAGNGNTT 
                 
               
               
                   
                   
                 
                   YAQKFQGRVTMTRDTSTSTVYMELSSLRSEDT 
                 
               
               
                   
                   
                   AVYYCARHYYGSGSYPDWGQGTLVTVSS AST 
               
               
                   
                   
                 KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV 
               
               
                   
                   
                 TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTV 
               
               
                   
                   
                 PSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK 
               
               
                   
                   
                 THTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTP 
               
               
                   
                   
                 EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT 
               
               
                   
                   
                 KPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC 
               
               
                   
                   
                 KVSNKALGAPIEKTISKAKGQPREPQVYTLPPSRE 
               
               
                   
                   
                 EMTKNQVSLSCAVKGFYPSDIAVEWESNGQPEN 
               
               
                   
                   
                 NYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNV 
               
               
                   
                   
                 FSCSVMHEALHNHYTQKSLSLSPGK   GSGSG   DYK 
               
               
                   
                   
                 DDDK 
               
               
                   
                   
                 
                   &gt;F49 LC SEQ ID NO: 170 
                 
               
               
                   
                   
                 
                   DIQMTQSPSSPSASVGDRVTITCRASQSISSYLN 
                 
               
               
                   
                   
                 
                   WYQQKPGKAPKLLIYAASSLQSGVPSRFSGSG 
                 
               
               
                   
                   
                 
                   SGTDFTLTISSLQPEDFATYYCQQSYSTPLTFG 
                 
               
               
                   
                   
                   GGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVV 
               
               
                   
                   
                 CLLNNFYPREAKVQWKVDNALQSGNSQESVTEQ 
               
               
                   
                   
                 DSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ 
               
               
                   
                   
                 GLSSPVTKSFNRGEC 
               
               
                 N-HC appended ScFv-IgG- 
                 
                   L6-N-HC 
                 
                 L6-N-HC appended ScFv-F10-IgG-RSPO2RA-Knob- 
               
               
                 mutRspo2-Knob + 
                 
                   appended 
                 
                 
                   His HC SEQ ID NO: 171 
                 
               
               
                 N-HC appended Scfv-IgG- 
                 
                   ScFv-F10- 
                 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSY 
                 
               
               
                 Hole 
                 
                   IgG- 
                 
                 
                   YISWVRQAPGKGLEWVAEISPYSGSTYYADSV 
                 
               
               
                   
                 
                   RSPO2RA- 
                 
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                 
                   Knob-his + 
                 
                 
                   ALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GS 
                   
                 
               
               
                   
                 
                   L6-N-HC 
                 
                 
                   
                     AASGSSGGSSSGA 
                   
                   DIQMTQSPSSLSASVGDRVTIT 
                 
               
               
                   
                 
                   appended 
                 
                 
                   CRASQDVSTAVAWYQQKPGKAPKLLIYSASFL 
                 
               
               
                   
                 
                   ScFv-F10- 
                 
                 
                   YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY 
                 
               
               
                   
                 
                   IgG-Hole- 
                 
                 
                   CQQSYTTPPTFGQGTKVEIK 
                   
                     GGGGSGGGGSGG 
                   
                 
               
               
                   
                 
                   
                     Flag 
                   
                 
                 
                   
                     GGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASGFTF 
                 
               
               
                   
                   
                 
                   SSFNMFWVRQAPGKGLEWVAGIDDDGSYPNY 
                 
               
               
                   
                   
                 
                   GSAVKGRATISRDNSKNTLYLQMNSLRAEDTA 
                 
               
               
                   
                   
                 
                   VYYCAKSGYGGSWGGYIADDIDAWGQGTLVT 
                 
               
               
                   
                   
                   VSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKD 
               
               
                   
                   
                 YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL 
               
               
                   
                   
                 SSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVE 
               
               
                   
                   
                 PKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTL 
               
               
                   
                   
                 MISRTPEVTCVVVDVSHEDPEVKFNWYDGVEV 
               
               
                   
                   
                 HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG 
               
               
                   
                   
                 KEYKCKVSNKALGAPIEKTISKAKGQPREPQVYT 
               
               
                   
                   
                 LPPSREEMTKNQVSLWCLVKGFYPSDIAVEWES 
               
               
                   
                   
                 NGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR 
               
               
                   
                   
                 WQQGNVFSCSVMHEALHNHYTQKSLSLSPGKG 
               
               
                   
                   
                 
                   
                     GGGSGGGGSGGGGS 
                   
                   NPICKGCLSCSKDNGCSRC 
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 &gt;L6-N-HC appended ScFv-F10-IgG-Hole Flag HC 
               
               
                   
                   
                 
                   SEQ ID NO: 172 
                 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSY 
                 
               
               
                   
                   
                 
                   YISWVRQAPGKGLEWVAEISPYSGSTYYADSV 
                 
               
               
                   
                   
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                   
                 
                   ALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GS 
                   
                 
               
               
                   
                   
                 
                   
                     AASGSSGGSSSGA 
                   
                   DIQMTQSPSSLSASVGDRVTIT 
                 
               
               
                   
                   
                 
                   CRASQDVSTAVAWYQQKPGKAPKLLIYSASFL 
                 
               
               
                   
                   
                 
                   YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY 
                 
               
               
                   
                   
                 
                   CQQSYTTPPTFGQGTKVEIK 
                   
                     GGGGSGGGGSGG 
                   
                 
               
               
                   
                   
                 
                   
                     GGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASGFTF 
                 
               
               
                   
                   
                 
                   SSFNMFWVRQAPGKGLEWVAGIDDDGSYPNY 
                 
               
               
                   
                   
                 
                   GSAVKGRATISRDNSKNTLYLQMNSLRAEDTA 
                 
               
               
                   
                   
                 
                   VYYCAKSGYGGSWGGYIADDIDAWGQGTLVT 
                 
               
               
                   
                   
                   VSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVDK 
               
               
                   
                   
                 YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL 
               
               
                   
                   
                 SSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVE 
               
               
                   
                   
                 PKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTL 
               
               
                   
                   
                 MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV 
               
               
                   
                   
                 HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG 
               
               
                   
                   
                 KEYKCKVSNKALGAPIEKTISKAKGQPREPQVYT 
               
               
                   
                   
                 LPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESN 
               
               
                   
                   
                 GQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRW 
               
               
                   
                   
                 QQGNVFSCSVMHEALHNHYTQKSLSLSPGK   GSG     
               
               
                   
                   
                     SG   DYKDDDDK 
               
               
                   
                   
                 
                   &gt;F10 LC SEQ ID NO: 173 
                 
               
               
                   
                   
                 
                   ELTQPPSVSVSPGQTARITCSGDGSYAGSYYYG 
                 
               
               
                   
                   
                 
                   WYQQKPGQAPVTLIYYNNKRPSGIPERFSGSL 
                 
               
               
                   
                   
                 
                   SGSTNTLTISGVQAEDEADYYCGSADNSGAAF 
                 
               
               
                   
                   
                   GGGTKLTVL RTVAAPSVFIPPSDEQLKSGTASV 
               
               
                   
                   
                 VCLLNNFYPREAKVQWKVDNALQSGNSQESVTE 
               
               
                   
                   
                 QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH 
               
               
                   
                   
                 QGLSSPVTKSFNRGEC 
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   L6-N-HC 
                   appended 
                   ScFv- 
                   F12578-IgG- 
                   RSPO2RA- 
                   Knob-his + 
                   F12578-IgG- 
                   
                     Hole-Flag 
                   
                 
                 L6-N-HC appended ScFv-F12578-IgG-RSPO2RA-  Knob-His HC SEQ ID NO: 174   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSY   YISWVRQAPGKGLEWVAEISPYSGSTYYADSV   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC   ALRARPPIRLHPRGSVMDYWGQGTLVTVSS     GS       AASGSSGGSSSGA     DIQMTQSPSSLSASVGDRVTIT   CRASQDVSTAVAWYQQKPGKAPKLLIYSASFL   YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY   CQQSYTTPPTFGQGTKVEIK     GGGGSGGGGSGG       GGS     EVQLVESGGGLVQPGGSLRLSCAASGFTF   SHYTLSWVRQAPGKGLEWVSVISGDGSYTYY   ADSVKGRFTISSDNSKNTLYLQMNSLRAEDTA   VYYCARNFIKYVFANWGQGTLVTVSS ASTKGP 
               
               
                   
                   
                 SVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS 
               
               
                   
                   
                 WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS 
               
               
                   
                   
                 SLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH 
               
               
                   
                   
                 TCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV 
               
               
                   
                   
                 TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP 
               
               
                   
                   
                 REEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV 
               
               
                   
                   
                 SNKALGAPIEKTISKAKGQPREPQVYTLPPSREEM 
               
               
                   
                   
                 TKNQVSLWCLVKGFYPSDIAVEWESNGQPENNY 
               
               
                   
                   
                 KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC 
               
               
                   
                   
                 SVMHEALHNHYTQKSLSLSPGK   GGGGSGGGGSG     
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   &gt;F12578-IgG-Hole Flag HC SEQ ID NO: 175 
                 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFSHY 
                 
               
               
                   
                   
                 
                   TLSWVRQAPGKGLEWVSVISGDGSYTYYADS 
                 
               
               
                   
                   
                 
                   VKGRFTISSDNSKNTLYLQMNSLRAEDTAVYY 
                 
               
               
                   
                   
                   CARNFIKYVFANWGQGTLVTVSS ASTKGPSVFP 
               
               
                   
                   
                 LAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSG 
               
               
                   
                   
                 ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ 
               
               
                   
                   
                 TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP 
               
               
                   
                   
                 APEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV 
               
               
                   
                   
                 DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY 
               
               
                   
                   
                 NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL 
               
               
                   
                   
                 GAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQ 
               
               
                   
                   
                 VSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPP 
               
               
                   
                   
                 VLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMH 
               
               
                   
                   
                 EALHNHYTQKSLSLSPGK   GSGSG   DYKDDDDK 
               
               
                   
                   
                 &gt;F12578 LC SEQ ID NO: 176 
               
               
                   
                   
                 
                   DIELTQPPSVSVAPGQTARISCSGDNIGSFYVH 
                 
               
               
                   
                   
                 
                   WYQQKPGQAPVLVIYDKSNRPSGIPERFSGSN 
                 
               
               
                   
                   
                 
                   SGNTATLTISGTQAEDEADYYCQSYANTLSLV 
                 
               
               
                   
                   
                   FGGGTKLTVL GQPKAAPSVTLFPPSSEELQANK 
               
               
                   
                   
                 ATLVCLISDFYPGAVTVAWKADSSPVKAGVETT 
               
               
                   
                   
                 TPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVT 
               
               
                   
                   
                 HEGSTVEKTVAPTECS 
               
               
                   
                 
                   L6-N-HC 
                 
                 L6-N-HC appended ScFv-F127-IgG-RSPO2RA-Knob- 
               
               
                   
                 
                   appended 
                 
                 
                   His HC SEQ ID NO: 1199 
                 
               
               
                   
                 
                   ScFv-F127- 
                 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSY 
                 
               
               
                   
                 
                   IgG- 
                 
                 
                   YISWVRQAPGKGLEWVAEISPYSGSTYYADSV 
                 
               
               
                   
                 
                   RSPO2RA- 
                 
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                 
                   Knob-his + 
                 
                 
                   ALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GS 
                   
                 
               
               
                   
                 
                   F127-IgG- 
                 
                 
                   
                     AASGSSGGSSSGA 
                   
                   DIQMTQSPSSLSASVGDRVTIT 
                 
               
               
                   
                 
                   
                     Hole-Flag 
                   
                 
                 
                   CRASQDVSTAVAWYQQKPGKAPKLLIYSASFL 
                 
               
               
                   
                   
                 
                   YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY 
                 
               
               
                   
                   
                 
                   CQQSYTTPPTFGQGTKVEIK 
                   
                     GGGGSGGGGSGG 
                   
                 
               
               
                   
                   
                 
                   
                     GGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASGFNIS 
                 
               
               
                   
                   
                 
                   SSYIHWVRQAPGKGLEWVAYIYSSYGSTYYAD 
                 
               
               
                   
                   
                 
                   SVKGRFTISADTSKNTAYLQMNSLRAEDTAVY 
                 
               
               
                   
                   
                   YCARASWYALDYWGQGTLVTVSS ASTKGPSVF 
               
               
                   
                   
                 PLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS 
               
               
                   
                   
                 GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT 
               
               
                   
                   
                 QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP 
               
               
                   
                   
                 CPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVV 
               
               
                   
                   
                 VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ 
               
               
                   
                   
                 YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA 
               
               
                   
                   
                 LGAPIEKTISKAKGQPREPQVYTLPPSREEMTKN 
               
               
                   
                   
                 QVSLWCLVKGFYPSDIAVEWESNGQPENNYKTT 
               
               
                   
                   
                 PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV 
               
               
                   
                   
                 MHEALHNHYTQKSLSLSPGK GGGGSGGGGSGGG   
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   &gt;F127-IgG-Hole Flag HC SEQ ID NO: 200 
                 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFNISSSY 
                 
               
               
                   
                   
                 
                   IHWVRQAPGKGLEWVAYIYSSYGSTYYADSV 
                 
               
               
                   
                   
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                   
                   ARASWYALDYWGQGTLVTVSS ASTKGPSVFPL 
               
               
                   
                   
                 APSSKSTSGGTAALGGLVKDYFPEPVTVSWNSG 
               
               
                   
                   
                 ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ 
               
               
                   
                   
                 TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP 
               
               
                   
                   
                 APEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV 
               
               
                   
                   
                 DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY 
               
               
                   
                   
                 NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL 
               
               
                   
                   
                 GAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQ 
               
               
                   
                   
                 VSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPP 
               
               
                   
                   
                 VLDSDGSFFLVSKLTVDKSRWQQGNFSCSVMH 
               
               
                   
                   
                 EALHNHYTQKSLSLSPGK   GSGS   DYKDDDDK 
               
               
                   
                   
                 
                   &gt;F127 LC SEQ ID NO: 201 
                 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQSVSSAV 
                 
               
               
                   
                   
                 
                   AWYQQKPGKAPKLLIYSASSLYSGVPSRFSGS 
                 
               
               
                   
                   
                 
                   RSGTDFTLTISSLQPEDFATYYCQQYWYGVAP 
                 
               
               
                   
                   
                   ITFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGT 
               
               
                   
                   
                 ASVVCLLNNFYPREAKVQWKVDNALQSGNSQE 
               
               
                   
                   
                 SVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE 
               
               
                   
                   
                 VTHQGLSSPVTKSFNRGEC 
               
               
                   
                 
                   L6-N-HC 
                 
                 L6-N-HC appended ScFv-F58-IgG-RSPO2RA-Inob- 
               
               
                   
                 
                   appended 
                 
                 
                   His HC SEQ ID NO: 202 
                 
               
               
                   
                 
                   ScFv-F58- 
                 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSY 
                 
               
               
                   
                 
                   IgG- 
                 
                 
                   YISWVRQAPGKGLEWVAEISPYSGSTYYADSV 
                 
               
               
                   
                 
                   RSPO2RA- 
                 
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                 
                   Knob-his + 
                 
                 
                   ALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GS 
                   
                 
               
               
                   
                 
                   F58-IgG- 
                 
                 
                   
                     AASGSSGGSSSGA 
                   
                   DIQMTQSPSSLSASVGDRVTIT 
                 
               
               
                   
                 
                   
                     Hole-Flag 
                   
                 
                 
                   CRASQDVSTAVAWYQQKPGKAPKLLIYSASFL 
                 
               
               
                   
                   
                 
                   YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY 
                 
               
               
                   
                   
                 
                   CQQSYTTPPTFGQGTKVEIK 
                   
                     GGGGSGGGGSGG 
                   
                 
               
               
                   
                   
                 
                   
                     GGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASGFNIS 
                 
               
               
                   
                   
                 
                   YSYIHWVRQAPGKGLEWVASIYSSSGSTSYAD 
                 
               
               
                   
                   
                 
                   SVKGRFTISADTSKNTAYLQMNSLRAEDTAVY 
                 
               
               
                   
                   
                   YCARGAIDYWGQGTLVTVSS ASTKGPSVFPLAP 
               
               
                   
                   
                 SSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT 
               
               
                   
                   
                 SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI 
               
               
                   
                   
                 CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP 
               
               
                   
                   
                 EAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV 
               
               
                   
                   
                 SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS 
               
               
                   
                   
                 TYRVVSVLTVLHQDWLNGKEYKCKVSNKALGA 
               
               
                   
                   
                 PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSL 
               
               
                   
                   
                 WCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL 
               
               
                   
                   
                 DSDGSFFLYSKLTVDKSRWQQGNFSCSVMHEA 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   &gt;F58-IgG-Hole Flag HC SEQ ID NO: 203 
                 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFNISYS 
                 
               
               
                   
                   
                 
                   YIHWVRQAPGKGLEWVASIYSSSGSTSYADSV 
                 
               
               
                   
                   
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                   
                   ARGAIDYWGAGTLVTVSS ASTKGPSVFPLAPSS 
               
               
                   
                   
                 KSTSGGTAALGCLVDKDYFPEVTVSWNSGALTS 
               
               
                   
                   
                 GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC 
               
               
                   
                   
                 NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPE 
               
               
                   
                   
                 AAGGSVFLFPPKPKDTLMISRTPEVTCVVVDVS 
               
               
                   
                   
                 HEDPEVKFNWYVDGVEVHNAKTKPREEQYNST 
               
               
                   
                   
                 YRVVSVLTVLHQDWLNGKEYKCKVSNKALGAP 
               
               
                   
                   
                 IEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLS 
               
               
                   
                   
                 CAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS 
               
               
                   
                   
                 DGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALH 
               
               
                   
                   
                 NHYTQKSLSLSPGK   GSGSG   DYKDDDDK 
               
               
                   
                   
                 
                   &gt;F58 LC SEQ ID NO: 204 
                 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQSVSSAV 
                 
               
               
                   
                   
                 
                   AWYQQKPGKAPKLLIYSASSLYSGVPSRFSGS 
                 
               
               
                   
                   
                 
                   RSGTDFTLTISSLQPEDFATYYCQQWYSSGHV 
                 
               
               
                   
                   
                   LITFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGT 
               
               
                   
                   
                 ASVVCLLNNFYPREAKVQWKVDNALQSQNSQE 
               
               
                   
                   
                 SVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE 
               
               
                   
                   
                 VTHQGLSSPVTKSFNRGEC 
               
               
                   
                 
                   L6-N-HC 
                 
                 L6-N-HC appended ScFv-F4-2-IgG-RSPO2RA-Knob- 
               
               
                   
                 
                   appended 
                 
                 
                   His HC SEQ ID NO: 177 
                 
               
               
                   
                 
                   ScFv-F4-2- 
                 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSY 
                 
               
               
                   
                 
                   IgG- 
                 
                 
                   YISWVRQAPGKGLEWVAEISPYSGSTYYADSV 
                 
               
               
                   
                 
                   RSPO2RA- 
                 
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                 
                   Knob-his + 
                 
                 
                   ALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GS 
                   
                 
               
               
                   
                 
                   F4-2-IgG- 
                 
                 
                   
                     AASGSSGGSSSGA 
                   
                   DIQMTQSPSSLSASVGDRVTIT 
                 
               
               
                   
                 
                   
                     Hole-Flag 
                   
                 
                 
                   CRASQDVSTAVAWYQQKPGKAPKLLIYSASFL 
                 
               
               
                   
                   
                 
                   YSTVPSRFSGSGSGTDFTLTISSLQPEDFATYY 
                 
               
               
                   
                   
                 
                   CQQSYTTPPTFGQGTKVEIK 
                   
                     GGGGSGGGGSGG 
                   
                 
               
               
                   
                   
                 
                   
                     GGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASGFNIS 
                 
               
               
                   
                   
                 
                   YYYIHWVRQAPGKGLEWVASIYPSSGYTYYA 
                 
               
               
                   
                   
                 
                   DSVKGRFTISADTSKNTAYLQMNSLRAEDTAV 
                 
               
               
                   
                   
                   YYCARSSFYWAMDYWGQGTLVTVSS ASTKGP 
               
               
                   
                   
                 SVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS 
               
               
                   
                   
                 WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS 
               
               
                   
                   
                 SLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH 
               
               
                   
                   
                 TCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV 
               
               
                   
                   
                 REEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV 
               
               
                   
                   
                 SNKALGAPIEKTIASKAKGQPREPQVYTLPPSREEM 
               
               
                   
                   
                 TKNQVSLWCLVKGFYPSDIAVEWESNGQPENNY 
               
               
                   
                   
                 KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC 
               
               
                   
                   
                 SVMHEALHNHYTQKSLSLSPGK   GGGGSGGGGSG     
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   &gt;F4-IgG-Hole Flag HC SEQ ID NO: 178 
                 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFNISYY 
                 
               
               
                   
                   
                 
                   YIHWVRQAPGKGLEWVASIYPSSGYTYYADSV 
                 
               
               
                   
                   
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                   
                   ARSSFYWAMDYWGQGTLVTVSS ASTKGPSVFP 
               
               
                   
                   
                 LAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSG 
               
               
                   
                   
                 ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ 
               
               
                   
                   
                 TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP 
               
               
                   
                   
                 APEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV 
               
               
                   
                   
                 DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY 
               
               
                   
                   
                 NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL 
               
               
                   
                   
                 GAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQ 
               
               
                   
                   
                 VSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPP 
               
               
                   
                   
                 VLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMH 
               
               
                   
                   
                 EALHNHYTQKSLSLSPGK   GSGSG   DYKDDDDK 
               
               
                   
                   
                 
                   &gt;F4-2 LC SEQ ID NO: 179 
                 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQSVSSAV 
                 
               
               
                   
                   
                 
                   AWYQQKPGKAPKLLIYSASSLYSGVPSRFSGS 
                 
               
               
                   
                   
                 
                   RSGTDFTLTISSLQPEDFATYYCQQSYAAYLFT 
                 
               
               
                   
                   
                   FGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTAS 
               
               
                   
                   
                 VVCLLNNFYPREAKVQWKVDNALQSGNSQESV 
               
               
                   
                   
                 TEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVT 
               
               
                   
                   
                 HQGLSSPVTKSFNRGEC 
               
               
                   
                 
                   L6-N-HC 
                 
                 L6-N-HC appended ScFv-F4-IgG-RSPO2RA-Knob- 
               
               
                   
                 
                   appended 
                 
                 
                   His HC SEQ ID NO: 180 
                 
               
               
                   
                 
                   ScFv-F4- 
                 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSY 
                 
               
               
                   
                 
                   IgG- 
                 
                 
                   YISWVRQAPGKGLEWVAEISPYSGSTYYADSV 
                 
               
               
                   
                 
                   RSPO2RA- 
                 
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                 
                   Knob-his + 
                 
                 
                   ALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GS 
                   
                 
               
               
                   
                 
                   F4-IgG- 
                 
                 
                   
                     AASGSSGGSSSGA 
                   
                   DIQMTQSPSSLSASVGDRVTIT 
                 
               
               
                   
                 
                   
                     Hole-Flag 
                   
                 
                 
                   CRASQDVSTAVAWYQQKPGKAPKLLIYSASFL 
                 
               
               
                   
                   
                 
                   YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY 
                 
               
               
                   
                   
                 
                   CQQSYTTPPTFGQGTKVEIK 
                   
                     GGGGSGGGGSGG 
                   
                 
               
               
                   
                   
                 
                   
                     GGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASGFNL 
                 
               
               
                   
                   
                 
                   SSYSMHWVRQAPGKGLEWVAYISSYYGYTYY 
                 
               
               
                   
                   
                 
                   ADSVKGRFTISADTSKNTAYLQMNSLRAEDTA 
                 
               
               
                   
                   
                   VYYCARPAPGHWGFDYWGQGTLVTVSS ASTK 
               
               
                   
                   
                 GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT 
               
               
                   
                   
                 VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP 
               
               
                   
                   
                 SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT 
               
               
                   
                   
                 HTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE 
               
               
                   
                   
                 VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK 
               
               
                   
                   
                 PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK 
               
               
                   
                   
                 VSNKALGAPIEKTISKAKGQPREPQVYTLPPSREE 
               
               
                   
                   
                 MTKNQVSLWCLVKGFYPSDIAVEWESNGQPENN 
               
               
                   
                   
                 YKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVF 
               
               
                   
                   
                 SCSVMHEALHNHYTQKSLSLSPGK   GGGGSGGGG     
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   &gt;F4-IgG-Hole Flag HC SEQ ID NO: 181 
                 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFNLSSY 
                 
               
               
                   
                   
                 
                   SMHWVRQAPGKGLEWVAYISSYYGYTYYADS 
                 
               
               
                   
                   
                 
                   VKGRFTISADTSKNTAYLQMNSLRAEDTAVYY 
                 
               
               
                   
                   
                   CARPAPGHWGFDYWGQGTLVTVSS ASTKGPS 
               
               
                   
                   
                 VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW 
               
               
                   
                   
                 NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL 
               
               
                   
                   
                 GTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTC 
               
               
                   
                   
                 PPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTC 
               
               
                   
                   
                 VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE 
               
               
                   
                   
                 EQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN 
               
               
                   
                   
                 KALGAPIEKTISKAKGQPREPQVYTLPPSREEMT 
               
               
                   
                   
                 KNQVSLSCAVKGFYPSDIAVEWESNGQPENNYK 
               
               
                   
                   
                 TTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCS 
               
               
                   
                   
                 VMHEALHNHYTQKSLSLSPGK   GSGSG   DYKDDDD 
               
               
                   
                   
                 K 
               
               
                   
                   
                 
                   &gt;F4 LC SEQ ID NO: 182 
                 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQSVSSAV 
                 
               
               
                   
                   
                 
                   AWYQQKPGKAPKLLIYSASSLYSGVPSRFSGS 
                 
               
               
                   
                   
                 
                   RSGTDFTLTISSLQPEDFATYYCQQWYYAPITF 
                 
               
               
                   
                   
                   GQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASV 
               
               
                   
                   
                 VDLLNNFYPREAKVQWKVDNALQSGNSQESVTE 
               
               
                   
                   
                 QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH 
               
               
                   
                   
                 QGLSSPVTKSFNRGEC 
               
               
                   
                 
                   L6-N-HC 
                 
                 L6-N-HC appended ScFv-F49-IgG-RSPO2RA-Knob- 
               
               
                   
                 
                   appended 
                 
                 
                   His HC SEQ ID NO: 183 
                 
               
               
                   
                 
                   ScFv-F49- 
                 
                 
                   EQVLVESGGGLVQPGGSLRLSCAASGFTFTSY 
                 
               
               
                   
                 
                   IgG- 
                 
                 
                   YISWVRQAPGKGLEWVAEISPYSGSTYYADSV 
                 
               
               
                   
                 
                   RSPO2RA- 
                 
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                 
                   Knob-his + 
                 
                 
                   ALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GS 
                   
                 
               
               
                   
                 
                   F49-IgG- 
                 
                 
                   
                     AASGSSGGSSSGA 
                   
                   DIQMTQSPSSLSASVGDRVTIT 
                 
               
               
                   
                 
                   
                     Hole-Flag 
                   
                 
                 
                   CRASQDVSTAVAWYQQKPGKAPKLLIYSASFL 
                 
               
               
                   
                   
                 
                   YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY 
                 
               
               
                   
                   
                 
                   CQQSYTTPPTFGQGTKVEIK 
                   
                     GGGGSGGGGSGG 
                   
                 
               
               
                   
                   
                 
                   
                     GGS 
                   
                   QVQLVQSGAEVKKPGASVKVSCKASGGT 
                 
               
               
                   
                   
                 
                   FSSYAISWVRQAPGQGLEWMGWINAGNGNTT 
                 
               
               
                   
                   
                 
                   YAQKFQGRVTMTRDTSTSTVYMELSSLRSEDT 
                 
               
               
                   
                   
                   AVYYCARHYYGSGSYPKDWGQGTLVTVSS AST 
               
               
                   
                   
                 KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV 
               
               
                   
                   
                 TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTV 
               
               
                   
                   
                 PSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK 
               
               
                   
                   
                 THTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTP 
               
               
                   
                   
                 EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT 
               
               
                   
                   
                 KPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC 
               
               
                   
                   
                 KVSNKALGAPIEKTISKAKGQPREPQVYTLPPSRE 
               
               
                   
                   
                 EMTKNQVSLWCLVKGFYPSIAVEWESNGQPEN 
               
               
                   
                   
                 NYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV 
               
               
                   
                   
                 FSCSVMHEALHNHYTQKSLSLSPGK   GGGGSGGG     
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   &gt;F49-IgG-Hole Flag HC SEQ ID NO: 184 
                 
               
               
                   
                   
                 QVQLVQSGAEVKKPGASVKVSCKASGGTFSSY 
               
               
                   
                   
                 AISWVRQAPGQGLEWMGWINAGNGNTTYAQ 
               
               
                   
                   
                 KFQGRVTMTRDTSTSTVYMELSSLRSEDTAVY 
               
               
                   
                   
                   YCARHYYGSGSYPDWGQGTLVTVSS ASTKGPS 
               
               
                   
                   
                 VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW 
               
               
                   
                   
                 NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL 
               
               
                   
                   
                 GTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTC 
               
               
                   
                   
                 PPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTC 
               
               
                   
                   
                 VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE 
               
               
                   
                   
                 EQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN 
               
               
                   
                   
                 KALGAPIEKTISKAKGQPREPQVYTLPPSREEMT 
               
               
                   
                   
                 KNQVSLSCAVKGFYPSDIAVEWESNGQPENNYK 
               
               
                   
                   
                 TTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCS 
               
               
                   
                   
                 VMHEALHNHYTQKSLSLSPGK   GSGSG   DYKDDDD 
               
               
                   
                   
                 K 
               
               
                   
                   
                 
                   &gt;F49 LC SEQ ID NO: 185 
                 
               
               
                   
                   
                 
                   DIQMTQSPSSPSASVGDRVTITCRASQSISSYLN 
                 
               
               
                   
                   
                 
                   WYQQKPGKAPKLLIYAASSLQSGVPSRFSGSG 
                 
               
               
                   
                   
                 
                   SGTDFTLTISSLQPEDFATYYCQQSYSTPLTFG 
                 
               
               
                   
                   
                   GGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVV 
               
               
                   
                   
                 CLLNNFYPREAKVQWKVDNALQSGNSQESVTEQ 
               
               
                   
                   
                 DSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ 
               
               
                   
                   
                 GLSSPVTKSFNRGEC 
               
               
                   
                 
                   L6-N-HC 
                 
                 &gt;L6-N-HC appended ScFv-F10-IgG-RSPO2RA- 
               
               
                   
                 
                   appended 
                 
                 
                   Knob-His HC SEQ ID NO: 186 
                 
               
               
                   
                 
                   ScFv-F10- 
                 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSY 
                 
               
               
                   
                 
                   IgG- 
                 
                 
                   YISWVRQAPGKGLEWVAEISPYSGSTYYADSV 
                 
               
               
                   
                 
                   RSPO2RA- 
                 
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                 
                   Knob-his + 
                 
                 
                   ALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GS 
                   
                 
               
               
                   
                 
                   F10-IgG- 
                 
                 
                   
                     AASGSSGGSSSGA 
                   
                   DIQMTQSPSSLSASVGDRVTIT 
                 
               
               
                   
                 
                   
                     Hole-Flag 
                   
                 
                 
                   CRASQDVSTAVAWYQQKPGKAPKLLIYSASFL 
                 
               
               
                   
                   
                 
                   YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY 
                 
               
               
                   
                   
                 
                   CQQSYTTPPTFGQGTKVEIK 
                   
                     GGGGSGGGGSGG 
                   
                 
               
               
                   
                   
                 
                   
                     GGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASGFTF 
                 
               
               
                   
                   
                 
                   SSFNMFWVRQAPGKGLEWVAGIDDDGSYPNY 
                 
               
               
                   
                   
                 
                   GSAVKGRATISRDNSKNTLYLQMNSLRAEDTA 
                 
               
               
                   
                   
                 
                   VYYCAKSGYGGSWGGYIADDIDAWGQGTLVT 
                 
               
               
                   
                   
                   VSS ASTKGPSVFPLAPSSKSTSGGTAALGSCLVKD 
               
               
                   
                   
                 YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL 
               
               
                   
                   
                 SSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVE 
               
               
                   
                   
                 PKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTL 
               
               
                   
                   
                 MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV 
               
               
                   
                   
                 HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG 
               
               
                   
                   
                 KEYKCKVSNKALGAPIEKTISKAKGQPREPQVYT 
               
               
                   
                   
                 LPPSREEMTKNQVSLWCLVKGFYPSDIAVEWES 
               
               
                   
                   
                 NGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR 
               
               
                   
                   
                 WQQGNFSCSVMHEALHNHYTQKSLSLSPGK   G     
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   &gt;F10-IgG-Hole Flag HC SEQ ID NO: 187 
                 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFSSF 
                 
               
               
                   
                   
                 
                   NMFWVRQAPGKGLEWVAGIDDDGSYPNYGS 
                 
               
               
                   
                   
                 
                   AVKGRATISRDKNSKNTLYLQMNSLRAEDTAVY 
                 
               
               
                   
                   
                 
                   YCAKSGYGGSWGGYIADDIDAWGQGTLVTVS 
                 
               
               
                   
                   
                   S ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYF 
               
               
                   
                   
                 PEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS 
               
               
                   
                   
                 VVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPK 
               
               
                   
                   
                 SCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMI 
               
               
                   
                   
                 SRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH 
               
               
                   
                   
                 NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK 
               
               
                   
                   
                 EYKCKVSNKALGAPIEKTISKAKGQPREPQVYTL 
               
               
                   
                   
                 PPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNG 
               
               
                   
                   
                 QPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQ 
               
               
                   
                   
                 QGNVFSCSVMHEALHNHYTQKSLSLSPGK GSGS   
               
               
                   
                   
                   G DYKDDDDK 
               
               
                   
                   
                 
                   &gt;F10 LC SEQ ID NO: 188 
                 
               
               
                   
                   
                 
                   ELTQPPSVSVSPGQTARITCSGDGSYAGSYYYG 
                 
               
               
                   
                   
                 
                   WYQQKPGQAPVITLIYYNNKRPSGIPERGSGSL 
                 
               
               
                   
                   
                 
                   SGSTNTLTISGVQAEDEADYYCGSADNSGAAF 
                 
               
               
                   
                   
                   GGGTKLTVL RTVAAPSVFIFPPSDEQLKSGTASV 
               
               
                   
                   
                 VCLLNNFYPREAKVQWKVDNALQSGNSQESVTE 
               
               
                   
                   
                 QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH 
               
               
                   
                   
                 QGLSSPVTKSFNRGEC 
               
               
                   
                 
                   L6-N-HC 
                 
                 L6-N-HC appended ScFv-F7B-IgG-RSPO2RA HC 
               
               
                   
                 
                   appended 
                 
                 
                   SEQ ID NO: 205 
                 
               
               
                   
                 
                   ScFv-F7B- 
                 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSY 
                 
               
               
                   
                 
                   IgG- 
                 
                 
                   YISWVRQAPGKGLEWVAEISPYSGSTYYADSV 
                 
               
               
                   
                 
                   RSPO2RA 
                 
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                   
                 
                   ALRARPPIRLHPRGSVMDYWGQGTLTVTVSS 
                   
                     GS 
                   
                 
               
               
                   
                   
                 
                   
                     AASGSSGGSSSGA 
                   
                   DIQMTQSPSSLSASVGDRVTIT 
                 
               
               
                   
                   
                 
                   CRASQDVSTAVAWYQQKPGKAPKLLIYSASFL 
                 
               
               
                   
                   
                 
                   YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY 
                 
               
               
                   
                   
                 
                   CQQSYTTPPTFGQGTKVEIK 
                   
                     GGGGSGGGGSGG 
                   
                 
               
               
                   
                   
                     GG   ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY 
               
               
                   
                   
                 FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS 
               
               
                   
                   
                 SVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEP 
               
               
                   
                   
                 KSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTL 
               
               
                   
                   
                 MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV 
               
               
                   
                   
                 HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG 
               
               
                   
                   
                 KEYKCKVSNKALGAPIEKTISDKAKGQPREPQVYT 
               
               
                   
                   
                 LPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESN 
               
               
                   
                   
                 GQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW 
               
               
                   
                   
                 QQGNVFSCSVMHEALHNHYTQKSLSLSPGK   GGG     
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 F7B LC SEQ ID NO: 206 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQSVSSAV 
                 
               
               
                   
                   
                 
                   AWYQQKPGKAPKLLIYSASSLYSGVPSRFSGS 
                 
               
               
                   
                   
                 
                   RSGTDTLTISSLQPEDFATYYCQQYYSLFTFG 
                 
               
               
                   
                   
                   QGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVV 
               
               
                   
                   
                 CLLNNFYPREAKVQWKVDNALQSGNSQESVTEQ 
               
               
                   
                   
                 DSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ 
               
               
                   
                   
                 GLSSPVTKSFNRGEC 
               
               
                   
                 
                   L6-N-HC 
                 
                 &gt;L6-N-HC appended ScFv-F21-IgG-RSPO2RA HC 
               
               
                   
                 
                   appended 
                 
                 
                   SEQ ID NO: 207 
                 
               
               
                   
                 
                   ScFv-F2I- 
                 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSY 
                 
               
               
                   
                 
                   IgG- 
                 
                 
                   YISWVRQAPGKGLEWVAEISPYSGSTYYADSV 
                 
               
               
                   
                 
                   RSPO2RA 
                 
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                   
                 
                   ALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GS 
                   
                 
               
               
                   
                   
                 
                   
                     AASGSSGGSSSGA 
                   
                   DIQMTQSPSSLSASVGDRVTIT 
                 
               
               
                   
                   
                 
                   CRASQDVSTAVAWYQQKPGKAPKLLIYSASFL 
                 
               
               
                   
                   
                 
                   YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY 
                 
               
               
                   
                   
                 
                   CQQSYTTPPTFGQGTKVEIK 
                   
                     GGGGSGGGGSGG 
                   
                 
               
               
                   
                   
                 
                   
                     GGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASGFNI 
                 
               
               
                   
                   
                 
                   HSSSIHWVRQAPGKGLEWVAATYSSFGSITYA 
                 
               
               
                   
                   
                 
                   DSVKGRFTISADTSKNTAYLQMNSLRAEDTAV 
                 
               
               
                   
                   
                   YYCARYHHPFGYALDYWGQGTLVTVSS ASTK 
               
               
                   
                   
                 GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT 
               
               
                   
                   
                 VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP 
               
               
                   
                   
                 SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT 
               
               
                   
                   
                 HTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE 
               
               
                   
                   
                 VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK 
               
               
                   
                   
                 PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK 
               
               
                   
                   
                 VSNKALGAPIEKTISKAKGQPREPQVYTLPPSREE 
               
               
                   
                   
                 MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENN 
               
               
                   
                   
                 YKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVF 
               
               
                   
                   
                 SCSVMHEALHNHYTQKSLSLSPGK   GGGGSGG     
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   &gt;F21 LC SEQ ID NO: 208 
                 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQSVSSAV 
                 
               
               
                   
                   
                 
                   AWYQQKPGKAPKLLIYSASSLYSGVPSRFSGS 
                 
               
               
                   
                   
                 
                   RSGTDFTLTISSLQPEDFATYYCQQGVYLFTFG 
                 
               
               
                   
                   
                   QGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVV 
               
               
                   
                   
                 CLLNNFYPREAKVQWKVDNALQSGNSQESVTEQ 
               
               
                   
                   
                 DSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ 
               
               
                   
                   
                 GLSSPVTKSFNRGEC 
               
               
                   
                 
                   L6-N-HC 
                 
                 &gt;L6-N-HC appended ScFv-F7B-IgG-RSPO2RA- 
               
               
                   
                 
                   appended 
                 
                 
                   Knob-His HC SEQ ID NO: 209 
                 
               
               
                   
                 
                   ScFv-F7B- 
                 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSY 
                 
               
               
                   
                 
                   IgG- 
                 
                 
                   YISWVRQAPGKGLEWVAEISPYSGSTYYADSV 
                 
               
               
                   
                 
                   RSPO2RA- 
                 
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                 
                   Knob-his + 
                 
                 
                   ALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GS 
                   
                 
               
               
                   
                 
                   F7B-IgG- 
                 
                 
                   
                     AASGSSGGSSGA 
                   
                   DIQMTQSPSSLSASVGDRVTIT 
                 
               
               
                   
                 
                   RSPO2RA 
                 
                 
                   CRASQDVSTAVAWYQQKPGKAPKLLIYSASFL 
                 
               
               
                   
                 
                   
                     Hole-Flag 
                   
                 
                 
                   YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY 
                 
               
               
                   
                   
                 
                   CQQSYTTPPTFGQGTKVEIK 
                   
                     GGGGSGGGGSGG 
                   
                 
               
               
                   
                   
                 
                   
                     GGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASGFNF 
                 
               
               
                   
                   
                 
                   SSSSIHWVRQAPGKGLEWVAYIYPSYDYTYYA 
                 
               
               
                   
                   
                 
                   DSVKGRFTISADTSKNTAYLQMNSLRAEDTAV 
                 
               
               
                   
                   
                   YYCARGYFYTWGGMDYWGQGTLVTVSS AST 
               
               
                   
                   
                 KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV 
               
               
                   
                   
                 TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTV 
               
               
                   
                   
                 PSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK 
               
               
                   
                   
                 THTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTP 
               
               
                   
                   
                 EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT 
               
               
                   
                   
                 KPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC 
               
               
                   
                   
                 KVSNKALGAPIEKTISKAKGQPREPQVYTLPPSRE 
               
               
                   
                   
                 EMTKNQVSLWCLVKGFYPSDIAVEWESNGQPEN 
               
               
                   
                   
                 NYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV 
               
               
                   
                   
                 FSCSVMHEALHNHYTQKSLSLSPGK   GGGGSGGG     
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   &gt;F7B-IgG-RSPO2RA-Hole Flag HC SEQ ID NO: 210 
                 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFNFSSSS 
                 
               
               
                   
                   
                 
                   IHWVRQAPGKGLEWVAYIYPSYDYTYYADSV 
                 
               
               
                   
                   
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                   
                   ARGYFYTWGGMDYWGQGTLVTVSS ASTKGPS 
               
               
                   
                   
                 VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW 
               
               
                   
                   
                 NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL 
               
               
                   
                   
                 GTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTC 
               
               
                   
                   
                 PPCPAPEAAGGPSVFLFPKKPKDTLMISRTPEVTC 
               
               
                   
                   
                 VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE 
               
               
                   
                   
                 EQYNSTYRVVSVLTVLHQDWWLNGKEYKCKVSN 
               
               
                   
                   
                 KALGAPIEKTISKAKGQPREPQVYTLPPSREEMT 
               
               
                   
                   
                 KNWVSLSCAVKGFYPSDIAVEWESNGQPENNYK 
               
               
                   
                   
                 TTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCS 
               
               
                   
                   
                 VMHEALHNHYTQKSLSLSPGK   GGGGSGGGGSGG     
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   &gt;F7B LC SEQ ID NO: 211 
                 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQSVSSAV 
                 
               
               
                   
                   
                 
                   AWYQQKPGKAPKLLIYSASSLYSGVPSRFSGS 
                 
               
               
                   
                   
                 
                   RSGTDFTLTISSLQPEDFATYYCQQYYSLFTFG 
                 
               
               
                   
                   
                   QGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVV 
               
               
                   
                   
                 CLLNNFYPREAKVQWKVDNALQSGNSQESVTEQ 
               
               
                   
                   
                 DSKDSTYSLSSTLTLSKADYEKHKVYCEVTHQ 
               
               
                   
                   
                 GLSSPVTKSFNRGEC 
               
               
                   
                 
                   L6-N-HC 
                 
                 &gt;L6-N-HC appended ScFv-F21-IgG-RSPO2RA-Knob- 
               
               
                   
                 
                   appended 
                 
                 
                   His HC SEQ ID NO: 212 
                 
               
               
                   
                 
                   ScFv-F2I- 
                 
                 
                   EVQLVESGGGLVQPGGGSLRLSCAASGFTFTSY 
                 
               
               
                   
                 
                   IgG- 
                 
                 
                   YIDWVRQAPGKGLEWVAEISPYSGSTYYADSV 
                 
               
               
                   
                 
                   RSPO2RA- 
                 
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                 
                   Knob-his + 
                 
                 A LRARPPIRLHPRGSVMDYWGQGTLVTVSS     GS     
               
               
                   
                 
                   F21-IgG- 
                 
                 
                   
                     AASGSSGGSSSGA 
                   
                   DIQMTQSPSSLSASVGDRVTIT 
                 
               
               
                   
                 
                   RSPO2RA 
                 
                 
                   CRASQDVSTAVAWYQQKPGKAPKLLIYSASFL 
                 
               
               
                   
                 
                   
                     Hole-Flag 
                   
                 
                 
                   YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY 
                 
               
               
                   
                   
                 
                   CQQSYTTPPTFGQGTKVEIK 
                   
                     GGGGSGGGGSGG 
                   
                 
               
               
                   
                   
                 
                   
                     GGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASGFNI 
                 
               
               
                   
                   
                 
                   HSSSIHWVRQAPGKGLEWVAATYSSFGSITYA 
                 
               
               
                   
                   
                 
                   DSVKGRFTISADTSKNTAYLQMNSLRAEDTAV 
                 
               
               
                   
                   
                   YYCARYHHPFGYALDYWGQGTLVTVSS ASTK 
               
               
                   
                   
                 GPSVFPLAPSSKSTSGGTAALGCLVDYFPEPVT 
               
               
                   
                   
                 VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP 
               
               
                   
                   
                 SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT 
               
               
                   
                   
                 HTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE 
               
               
                   
                   
                 VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK 
               
               
                   
                   
                 PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK 
               
               
                   
                   
                 VSNKALGAPIEKTISKAKGQPREPQVYTLPPSREE 
               
               
                   
                   
                 MTKNQVSLWCLVKGFYPSDIAVEWESNGQPENN 
               
               
                   
                   
                 YKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVF 
               
               
                   
                   
                 SCSVMHEALHNHYTQKSLSLSPGKGGGGSGGGG 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   &gt;F2I-IgG-RSPO2RA-Hole Flag HC SEQ ID NO: 213 
                 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFNIHSSS 
                 
               
               
                   
                   
                 
                   IHWVRQAPGKGLEWVAATYSSFGSITYADSVK 
                 
               
               
                   
                   
                 
                   GRFTISADTSKNTAYLQMNSLRAEDTAVYYCA 
                 
               
               
                   
                   
                   RYHHPFGYALDYWGQGTLVTVSS ASTKGPSVF 
               
               
                   
                   
                 PLAPSSKSTSGGTAALGCLVKDYFPEVTVSWNS 
               
               
                   
                   
                 GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT 
               
               
                   
                   
                 QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP 
               
               
                   
                   
                 CPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVV 
               
               
                   
                   
                 VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ 
               
               
                   
                   
                 YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA 
               
               
                   
                   
                 LGAPIEKTISDKAKGQPREPQVYTLPPSREEMTKN 
               
               
                   
                   
                 QVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTP 
               
               
                   
                   
                 PVLDSDGSFFLVSKLTVDKSRWQQGNFSCSVM 
               
               
                   
                   
                 HEALHNHYTQKSLSLSPGK   GGGGSGGGGSGGGG     
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   &gt;FI LC SEQ ID NO: 214 
                 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQSVSSAV 
                 
               
               
                   
                   
                 
                   AWYQQKPGKAPKLLIYSASSLYSGVPSRFSGS 
                 
               
               
                   
                   
                 
                   RSGTDFTLTISSLQPEDFATYYCQQGVYLFTFG 
                 
               
               
                   
                   
                   QGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVV 
               
               
                   
                   
                 CLLNNFYPREAKVQWKVDNALQSGNSQESVTEQ 
               
               
                   
                   
                 DSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ 
               
               
                   
                   
                 GLSSPVTKSFNRGEC 
               
               
                   
                 
                   L6-N-HC 
                 
                 &gt;L6-N-HC appended ScFv-F7B-IgG-RSPO2RA- 
               
               
                   
                 
                   appended 
                 
                 
                   Knob-His HC SEQ ID NO: 215 
                 
               
               
                   
                 
                   ScFv-F7B- 
                 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSY 
                 
               
               
                   
                 
                   IgG- 
                 
                 
                   YISWRQAPGKGLEWVAEISPYSGSTYYADSV 
                 
               
               
                   
                 
                   RSPO2RA- 
                 
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                 
                   Knob-his + 
                 
                 
                   ALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GS 
                   
                 
               
               
                   
                 
                   L6-N-HC 
                 
                 
                   
                     AASGSSGGSSSGA 
                   
                   DIQMTQSPSSLSASVGDRVTIT 
                 
               
               
                   
                 
                   appended 
                 
                 
                   CRASQDVSTAVAWYQQKPGKAPKLLIYSASFL 
                 
               
               
                   
                 
                   ScFv-F7B- 
                 
                 
                   YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY 
                 
               
               
                   
                 
                   IgG-Hole- 
                 
                 
                   CQQSYTTPPTFGQGTKVEIK 
                   
                     GGGGSGGGGSGG 
                   
                 
               
               
                   
                 
                   
                     Flag 
                   
                 
                     GGS   E VQLVESGGGLVQPGGSLRLSCAASGFNF   
               
               
                   
                   
                 
                   SSSSIHWVRQAPGKGLEWVAYIYPSYDYTYYA 
                 
               
               
                   
                   
                 
                   DSVKGRFTISADTSKNTAYLQMNSLRAEDTAV 
                 
               
               
                   
                   
                   YYCARGYFYTWGGMDYWGQGTLVTVSS AST 
               
               
                   
                   
                 KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV 
               
               
                   
                   
                 TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTV 
               
               
                   
                   
                 PSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK 
               
               
                   
                   
                 THTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTP 
               
               
                   
                   
                 EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT 
               
               
                   
                   
                 KPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC 
               
               
                   
                   
                 KVSNKALGAPIEKTISKAKGQPREPQVYTLPPSRE 
               
               
                   
                   
                 EMTKNQVSLWCLVKGFYPSDIAVEWESNGQPEN 
               
               
                   
                   
                 NYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV 
               
               
                   
                   
                 FSCSVMHEALHNHYTQKSLSLSPGKGGGGSGGG 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 &gt;L6-N-HC appended ScFv-F7B-IgG-Hole Flag HC 
               
               
                   
                   
                 
                   SEQ ID NO: 216 
                 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSY 
                 
               
               
                   
                   
                 
                   YISWVRQAPGKGLEWVAEISPYSGSTYYADSV 
                 
               
               
                   
                   
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                   
                 
                   ALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GS 
                   
                 
               
               
                   
                   
                 
                   
                     AASGSSGGSSSGA 
                   
                   DIQMTQSPSSLSASVGDRVTIT 
                 
               
               
                   
                   
                 
                   CRASQDVSTAVAWYQQKPGKAPKLLIYSASFL 
                 
               
               
                   
                   
                 
                   YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY 
                 
               
               
                   
                   
                 
                   CQQSYTTPPTFGQGKVEIK 
                   
                     GGGGSGGGGSGG 
                   
                 
               
               
                   
                   
                 
                   
                     GGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASGFNF 
                 
               
               
                   
                   
                 
                   SSSSIHWVRQAPGKGLEWVAYIYPSYDYTYYA 
                 
               
               
                   
                   
                 
                   DSVKGRFTISADTSKNTAYLQMNSLRAEDTAV 
                 
               
               
                   
                   
                   YYCARGYFYTWGGMDYWGQGTLVTVSS AST 
               
               
                   
                   
                 KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV 
               
               
                   
                   
                 TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTV 
               
               
                   
                   
                 PSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK 
               
               
                   
                   
                 THTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTP 
               
               
                   
                   
                 EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT 
               
               
                   
                   
                 KPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC 
               
               
                   
                   
                 KVSNKALGAPIEKTISKAKGQPREPQVYTLPPSRE 
               
               
                   
                   
                 EMTKNQVSLSCAVKGFYPSDIAVEWESNGQPEN 
               
               
                   
                   
                 NYKPPTTVLDSDGSFFLVSKLTVDKSRWQQGNV 
               
               
                   
                   
                 FSCSVMHEALHNHYTQKSLSLSPGK   GSGSG   DYK 
               
               
                   
                   
                 DDDDK 
               
               
                   
                   
                 
                   &gt;F7B LC SEQ ID NO: 217 
                 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQSVSSAV 
                 
               
               
                   
                   
                 
                   AWYQQKPGKAPKLLIYSASSLYSGVPSRFSGS 
                 
               
               
                   
                   
                 
                   RSGTDFTLTISSLQPEDFATYYCQQYYSLFTFG 
                 
               
               
                   
                   
                   QGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVV 
               
               
                   
                   
                 CLLNNFYPREAKVQWKVDNALQSGNSQESVTEQ 
               
               
                   
                   
                 DSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ 
               
               
                   
                   
                 GLSSPVTKSFNRGEC 
               
               
                   
                 
                   L6-N-HC 
                 
                 &gt;L6-N-HC appended ScFv-F2I-IgG-RSPO2RA-Knob- 
               
               
                   
                 
                   appended 
                 
                 
                   HIS HC SEQ ID NO: 218 
                 
               
               
                   
                 
                   ScFv-F2I- 
                 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSY 
                 
               
               
                   
                 
                   IgG- 
                 
                 
                   YISWVRQAPGKGLEWVAEISPYSGSTYYADSV 
                 
               
               
                   
                 
                   RSPO2RA- 
                 
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                 
                   Knob-hi + 
                 
                 
                   ALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GS 
                   
                 
               
               
                   
                 
                   L6-N-HC 
                 
                 
                   
                     AASGSSGGSSSGA 
                   
                   DIQMTQSPSSLSASVGDRVTIT 
                 
               
               
                   
                 
                   appended 
                 
                 
                   CRASQDVSTAVAWYQQKPGKAPKLLIYSASFL 
                 
               
               
                   
                 
                   ScFv-F2I- 
                 
                 
                   YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY 
                 
               
               
                   
                 
                   IgG-Hole- 
                 
                 
                   CQQSYTTPPTFGQGTKVEIK 
                   
                     GGGGSGGGGSGG 
                   
                 
               
               
                   
                 
                   
                     Flag 
                   
                 
                     GGS   E VQLVESGGGLVQPGGSLRLSCAASHGNI   
               
               
                   
                   
                 
                   HSSSIHWVRQAPGKGLEWVAATYSSFGSITYA 
                 
               
               
                   
                   
                 
                   DSVKGRFTISADTSKNTAYLQMNSLRAEDTAV 
                 
               
               
                   
                   
                   YYCARYHHPFGYALDYWGQGTLVTVSS ASTK 
               
               
                   
                   
                 GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT 
               
               
                   
                   
                 VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP 
               
               
                   
                   
                 SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT 
               
               
                   
                   
                 HTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE 
               
               
                   
                   
                 VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK 
               
               
                   
                   
                 PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK 
               
               
                   
                   
                 VSNKALGAPIEKTISKAKGQPREPQVYTLPPSREE 
               
               
                   
                   
                 MTKNQVSLWCLVKGFYPSIAVEWESNGQPENN 
               
               
                   
                   
                 YKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVF 
               
               
                   
                   
                 SCVMHEALHNHYTQKSLSLSPGKGGGGSGGGG 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 &gt;L6-N-HC appended ScFv-F2I-IgG-Hole Flag HC 
               
               
                   
                   
                 
                   SEQ ID NO: 219 
                 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSY 
                 
               
               
                   
                   
                 
                   YISWVRQAPGKGLEWVAEISPYSGSTYYADSV 
                 
               
               
                   
                   
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                   
                 
                   ALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GS 
                   
                 
               
               
                   
                   
                 
                   
                     AASGSSGGSSSGA 
                   
                   DIQMTQSPSSLSASVGDRVTIT 
                 
               
               
                   
                   
                 
                   CRASQDVSTAVAWYQQKPGKAPKLLIYSASFL 
                 
               
               
                   
                   
                 
                   YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY 
                 
               
               
                   
                   
                 
                   CQQSYTTPPTFGQGTKVEIK 
                   
                     GGGGSGGGGSGG 
                   
                 
               
               
                   
                   
                 
                   
                     GGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASGFNI 
                 
               
               
                   
                   
                 
                   HSSSIHWVRQAPGKGLEWVAATYSSFGSITYA 
                 
               
               
                   
                   
                 
                   DSVKGRFTISADTSKNTAYLQMNSLRAEDTAV 
                 
               
               
                   
                   
                   YYCARYHHPFGYALDYWGQGTLVTVSS ASTK 
               
               
                   
                   
                 GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT 
               
               
                   
                   
                 VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP 
               
               
                   
                   
                 SSSLGTQTYICNVHKPSNTKVDKKVEPKSCDKT 
               
               
                   
                   
                 HTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE 
               
               
                   
                   
                 VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK 
               
               
                   
                   
                 PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK 
               
               
                   
                   
                 VSNKALGAPIEKTISKAKGQPREPQVYTLPPSREE 
               
               
                   
                   
                 MTKNQVSLSCAVKGFYPSDIAVEWESNGQPENN 
               
               
                   
                   
                 YKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVF 
               
               
                   
                   
                 SCSVMHEALHNHYTQKSLSLSPGK   GSGSG   DYKD 
               
               
                   
                   
                 DDDK 
               
               
                   
                   
                 
                   &gt;F2I LC SEQ ID NO: 220 
                 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQSVSSAV 
                 
               
               
                   
                   
                 
                   AWYQQKPGKAPKLLIYSASSLYSGVPSRFSGS 
                 
               
               
                   
                   
                 
                   RSGTDFTLTISSLQPEDFATYYCQQGVVLFTFG 
                 
               
               
                   
                   
                   QGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVV 
               
               
                   
                   
                 CLLNNFYPREAKVQWKVDNALQSGNSQESVTEQ 
               
               
                   
                   
                 DSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ 
               
               
                   
                   
                 GLASSPVTKSFNRGEC 
               
               
                   
                 
                   L6-N-HC 
                 
                 &gt;L6-N-HC appended ScFv-F7B-IgG-RSPO2RA- 
               
               
                   
                 
                   appended 
                 
                 
                   Knob-His HC SEQ ID NO: 221 
                 
               
               
                   
                 
                   ScFv-F7B- 
                 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSY 
                 
               
               
                   
                 
                   IgG- 
                 
                 
                   YISWVRQAPGKGLEWVAEISPYSGSTYYADSV 
                 
               
               
                   
                 
                   RSPO2RA- 
                 
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                 
                   Knob-his + 
                 
                 
                   ALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GS 
                   
                 
               
               
                   
                 
                   F7B-IgG- 
                 
                 
                   
                     AASGSSGGSSSGA 
                   
                   DIQMTQSPSSLSASVGDRVTIT 
                 
               
               
                   
                 
                   
                     Hole-Flag 
                   
                 
                 
                   CRASQDVSTAVAWYQQKPGKAPKLLIYSASFL 
                 
               
               
                   
                   
                 
                   YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY 
                 
               
               
                   
                   
                 
                   CQQSYTTPPTFGQGTKVEIK 
                   
                     GGGGSGGGGSGG 
                   
                 
               
               
                   
                   
                 
                   
                     GGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASGFNF 
                 
               
               
                   
                   
                 
                   SSSSIHWVRQAPGKGLEWVAYIYPSYDYTYYA 
                 
               
               
                   
                   
                 
                   DSVKGRFTISADTSKNTAYLQMNSLRAEDTAV 
                 
               
               
                   
                   
                   YYCARGYFYTWGGMDYWGQGTLVTVSS AST 
               
               
                   
                   
                 KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV 
               
               
                   
                   
                 TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTV 
               
               
                   
                   
                 PSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK 
               
               
                   
                   
                 THTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTP 
               
               
                   
                   
                 EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT 
               
               
                   
                   
                 KPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC 
               
               
                   
                   
                 KVSNKALGAPIEKTISKAKGQPREPQVYTLPPSRE 
               
               
                   
                   
                 EMTKNQVSLWCLVKGFYPSDIAVEWESNGPQPEN 
               
               
                   
                   
                 NYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV 
               
               
                   
                   
                 FSCSVMHEALHNHYTQKSLSLSPGKGGGGSGGG 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   &gt;F7B-IgG-Hole Flag HC SEQ ID NO: 222 
                 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFNFSSSS 
                 
               
               
                   
                   
                 
                   IHWVRQAPGKGLEWVAYIYPSYDYTYYADSV 
                 
               
               
                   
                   
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                   
                   ARGYFYTWGGMDYWGQGTLVTVSS ASTKGPS 
               
               
                   
                   
                 VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW 
               
               
                   
                   
                 NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL 
               
               
                   
                   
                 GTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTC 
               
               
                   
                   
                 PPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTC 
               
               
                   
                   
                 VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE 
               
               
                   
                   
                 EQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN 
               
               
                   
                   
                 KALGAPIEKTISKAKGQPREPQVYTLPPSREEMT 
               
               
                   
                   
                 KNQVSLSCAVKGFYPSDIAVEWESNGQPENNYK 
               
               
                   
                   
                 TTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCS 
               
               
                   
                   
                 VMHEALHNHYTQKSLSLSPGKGSGSDYKDDDD 
               
               
                   
                   
                 K 
               
               
                   
                   
                 
                   &gt;F7B LC SEQ ID NO: 223 
                 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQSVSSAV 
                 
               
               
                   
                   
                 
                   AWYQQKPGKAPKLLIYSASSLYSGVPSRFSGS 
                 
               
               
                   
                   
                 
                   RSGTDFTLTISSLQPEDFATYYCQQYYSLFTFG 
                 
               
               
                   
                   
                   QGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVV 
               
               
                   
                   
                 CLLNNFYPREAKVQWKVDNALQSGNSQESVTEQ 
               
               
                   
                   
                 DSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ 
               
               
                   
                   
                 GLSSPVTKSFNRGEC 
               
               
                   
                 
                   L6-N-HC 
                 
                 &gt;L6-N-HC appended ScFv-F2I-IgG-RSPO2RA-Knob- 
               
               
                   
                 
                   appended 
                 
                 His HC SEQ ID NO: 224 
               
               
                   
                 
                   ScFv-F2I- 
                 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSY 
                 
               
               
                   
                 
                   IgG- 
                 
                 
                   YISWVRQAPGKGLEWVAEISPYSGSTYYADSV 
                 
               
               
                   
                 
                   RSPO2RA- 
                 
                 
                   KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC 
                 
               
               
                   
                 
                   Knob-his + 
                 
                 
                   ALRARPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GS 
                   
                 
               
               
                   
                 
                   F2I-IgG- 
                 
                 
                   
                     AASGSSGGSSSGA 
                   
                   DIQMTQSPSSLSASVGDRVTIT 
                 
               
               
                   
                 
                   
                     Hole-Flag 
                   
                 
                 
                   CRASQDVSTAVAWYQQKPGKAPKLLIYSASFL 
                 
               
               
                   
                   
                 
                   YSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY 
                 
               
               
                   
                   
                 
                   CQQSYTTPPTFGQGTKVEIK 
                   
                     GGGGSGGGGSGG 
                   
                 
               
               
                   
                   
                 
                   
                     GGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASGFNI 
                 
               
               
                   
                   
                 
                   HSSSIHWVRQAPGKGLEWVAATYSSFGSITYA 
                 
               
               
                   
                   
                 
                   DSVKGRFTISADTSKNTAYLQMNSLRAEDTAV 
                 
               
               
                   
                   
                   YYCARYHHPFGYALDYWGQGTLVTVSS ASTK 
               
               
                   
                   
                 GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT 
               
               
                   
                   
                 VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP 
               
               
                   
                   
                 SSSLGQGTYICNVNHKPSNTKVDKKVEPKSCDKT 
               
               
                   
                   
                 HTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE 
               
               
                   
                   
                 VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK 
               
               
                   
                   
                 PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK 
               
               
                   
                   
                 VSNKALGAPIEKTISKAKGQPREPQVYTLPPSREE 
               
               
                   
                   
                 MTKNQVSLWCLVKGFYPSDIAVEWESNGQPENN 
               
               
                   
                   
                 YKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVF 
               
               
                   
                   
                 SCSVMHEALHNHYTQKSLSLSPGKGGGGSGGGG 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   &gt;F2I-IgG-Hole Flag HC SEQ ID NO: 225 
                 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFNIHSSS 
                 
               
               
                   
                   
                 
                   IHWVRQAPGKGLEWVAATYSSFGSITYADSVK 
                 
               
               
                   
                   
                 
                   GRFTISADTSKNTAYLQMNSLRAEDTAVYYCA 
                 
               
               
                   
                   
                   RYHHPFGYALDYWGQGTLVTVSS ASTKGPSVF 
               
               
                   
                   
                 PLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS 
               
               
                   
                   
                 GALTSGVHTFPAVLQSSGLYSKSSVVTVPSSSLGT 
               
               
                   
                   
                 QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP 
               
               
                   
                   
                 CPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVV 
               
               
                   
                   
                 VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ 
               
               
                   
                   
                 YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA 
               
               
                   
                   
                 LGAPIEKTISKAKGQPREPQVYTLPPSREEMTKN 
               
               
                   
                   
                 QVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTP 
               
               
                   
                   
                 PVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVM 
               
               
                   
                   
                 HEALHNHYTQKSLSLSPGK   GSGSG   DYKDDDDK 
               
               
                   
                   
                 
                   &gt;F2I LC SEQ ID NO: 226 
                 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQSVSSAV 
                 
               
               
                   
                   
                 
                   AWYQQKPGKAPKLLIYSASSLYSGVPSRFSGS 
                 
               
               
                   
                   
                 
                   RSGTDFTLTISSLQPEDFATYYCQQBVYLFTFG 
                 
               
               
                   
                   
                   QGTKVEIK RTVAAPSVFIFPPSDEQLKGTASVV 
               
               
                   
                   
                 CLLNNFYPREAKVQWKVDNALQSGNSQESVTEQ 
               
               
                   
                   
                 DSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ 
               
               
                   
                   
                 GLSSVTKSFNRGEC 
               
               
                 
                   
                     RSPO2RA-N-LC-ScFv-IgG 
                   
                 
                 
                   RSPO2RA- 
                 
                 RSPO2RA-F12578 LC SEQ ID NO: 227 
               
               
                   
                 
                   
                     L6-F12578 
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     SGGGGSGGGGS 
                   
                   DIELTQPPSVSVAPGQTARISCSGDN 
                 
               
               
                   
                   
                 
                   IGSFYVHWYQQKPGQAPVLVIYDKSNRPSGIPERFSG 
                 
               
               
                   
                   
                 
                   SNSGNTATLTISGTQAEDEADYYCQSYANTLSLVFGG 
                 
               
               
                   
                   
                   GTKLTVL GQPKAAPSVTLFPPSSEELQANKATLVCLI 
               
               
                   
                   
                 SDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYA 
               
               
                   
                   
                 ASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTE 
               
               
                   
                   
                 CS 
               
               
                   
                   
                 
                   L6_F12578 HC SEQ ID NO: 228 
                 
               
               
                   
                   
                 
                   EVQLVESGGGGLVQPGGGSLRLSCAASGFTFTSYYISWV 
                 
               
               
                   
                   
                 
                   RQAPGKGLEWVAEISPYSGSTYYADSVKGRFTISADT 
                 
               
               
                   
                   
                 
                   SKNTAYLQMNSLRAEDTAVYYCALRARPPIRLHPRGS 
                 
               
               
                   
                   
                 
                   VMDYWGQGTLVTVSS 
                   
                     GSAASGSSGGSSSGA 
                   
                   DIQMTQS 
                 
               
               
                   
                   
                 
                   PSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAP 
                 
               
               
                   
                   
                 
                   KLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPE 
                 
               
               
                   
                   
                 
                   DFATYYCQQSYTTPPTFGQGTKVEIK 
                   
                     GGGGSGGGGSG 
                   
                 
               
               
                   
                   
                 
                   
                     GGGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFSHYT 
                 
               
               
                   
                   
                 
                   LSWVRQAPGKGLEWVSVISGDGSYTYYADSVKGRFTI 
                 
               
               
                   
                   
                 
                   SSDNSKNTLYLQMNSLRAEDTAVYYCARNFIKYVFAN 
                 
               
               
                   
                   
                   WGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALG 
               
               
                   
                   
                 CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY 
               
               
                   
                   
                 SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEP 
               
               
                   
                   
                 KSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMIS 
               
               
                   
                   
                 RTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP 
               
               
                   
                   
                 REEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL 
               
               
                   
                   
                 GAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSL 
               
               
                   
                   
                 TCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG 
               
               
                   
                   
                 SFFLYSKLTVDKSRWQQGNVSCSVMHEALHNHYTQK 
               
               
                   
                   
                 SLSLSPGK 
               
               
                 
                   
                     RSPO2RA-N-LC-ScFv-IgG 
                   
                 
                 
                   RSPO2RA- 
                 
                 
                   RSPO2RA-F127 LC SEQ ID NO: 229 
                 
               
               
                   
                 
                   
                     L6-F127 
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     SGGGGSGGGGS 
                   
                   DIQMTQSPSSLSASVGDRVTITCRAS 
                 
               
               
                   
                   
                 
                   QSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFS 
                 
               
               
                   
                   
                 
                   GSRSGTDFTLTISSLQPEDFATYYCQQYWYGVAPITF 
                 
               
               
                   
                   
                   GQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCL 
               
               
                   
                   
                 LNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST 
               
               
                   
                   
                 YSLSSTLTLSKADYEKHKVYACEVTHQGLGGPVTKSF 
               
               
                   
                   
                 NRGEC 
               
               
                   
                   
                 
                   L6_F127 HC SEQ ID NO: 230 
                 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWV 
                 
               
               
                   
                   
                 
                   RQAPGKGLEWVAEISPYSGSTYYADSVKGRFTISADT 
                 
               
               
                   
                   
                 
                   SKNTAYLQMNSLRAEDTAVYYCALRARPPIRLHPRGS 
                 
               
               
                   
                   
                 
                   VMDYWGQGTLVTVSS 
                   
                     GSAASGSSGGSSSGA 
                   
                   DIQMTQS 
                 
               
               
                   
                   
                 
                   PSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAP 
                 
               
               
                   
                   
                 
                   KLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPE 
                 
               
               
                   
                   
                 
                   DFATYYCQQSYTTPPTFGQGTKVEIK 
                   
                     GGGGSGGGGSG 
                   
                 
               
               
                   
                   
                 
                   
                     GGGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASGFNISSSY 
                 
               
               
                   
                   
                 
                   IHWVRQAPGKGLEWVAYIYSSYGSTYYADSVKGRFTI 
                 
               
               
                   
                   
                 
                   SADTSKNTAYLQMNSLRAEDTAVYYCARASWYALDYW 
                 
               
               
                   
                   
                   GQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGC 
               
               
                   
                   
                 LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS 
               
               
                   
                   
                 LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPK 
               
               
                   
                   
                 SCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISR 
               
               
                   
                   
                 TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR 
               
               
                   
                   
                 EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALG 
               
               
                   
                   
                 APIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT 
               
               
                   
                   
                 CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS 
               
               
                   
                   
                 FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS 
               
               
                   
                   
                 LSLSPGK 
               
               
                 
                   
                     RSPO2RA-N-LC-ScFv-IgG 
                   
                 
                 
                   RSPO2RA- 
                 
                 
                   RSPO2RA-F58 LC SEQ ID NO: 231 
                 
               
               
                   
                 
                   
                     L6-F58 
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     SGGGGSGGGGS 
                   
                   DIQMTQSPSSLSASVGDRVTITCRAS 
                 
               
               
                   
                   
                 
                   QSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFS 
                 
               
               
                   
                   
                 
                   GSRSGTDFTLTISSLQPEDFATYYCQQWYSSGHVLIT 
                 
               
               
                   
                   
                   FGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVC 
               
               
                   
                   
                 LLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS 
               
               
                   
                   
                 TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS 
               
               
                   
                   
                 FNREC 
               
               
                   
                   
                 
                   L6_F58 HC SEQ ID NO: 232 
                 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWV 
                 
               
               
                   
                   
                 
                   RQAPGKGLEWVAEISPYSGSTYYADSVKGRFTISADT 
                 
               
               
                   
                   
                 
                   SKNTAYLQMNSLRAEDTAVYYCALRARPPIRLHPRGS 
                 
               
               
                   
                   
                 
                   VMDYGQGTLVTVSS 
                   
                     GSAASGSSGGSSSGA 
                   
                   DIQMTQS 
                 
               
               
                   
                   
                 
                   PSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAP 
                 
               
               
                   
                   
                 
                   KLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPE 
                 
               
               
                   
                   
                 
                   DFATYYCQQSYTTPPTFGQGTKVEIK 
                   
                     GGGGSGGGGSG 
                   
                 
               
               
                   
                   
                 
                   
                     GGGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASGFNISYSY 
                 
               
               
                   
                   
                 
                   IHWVRQAPGKGLEWVASIYSSSGSTSYADSVKGRFTI 
                 
               
               
                   
                   
                 
                   SADTSKNTAYLQMNSLRAEDTAVYYCARGAIDYWGQG 
                 
               
               
                   
                   
                   TLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVK 
               
               
                   
                   
                 DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS 
               
               
                   
                   
                 VVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCD 
               
               
                   
                   
                 KTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE 
               
               
                   
                   
                 VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ 
               
               
                   
                   
                 YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPI 
               
               
                   
                   
                 EKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV 
               
               
                   
                   
                 KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL 
               
               
                   
                   
                 YSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL 
               
               
                   
                   
                 SPGK 
               
               
                 
                   
                     RSPO2RA-N-LC-ScFv-IgG 
                   
                 
                 
                   RSPO2RA- 
                 
                 
                   RSPO2RA-F4-2 LC SEQ ID NO: 233 
                 
               
               
                   
                 
                   
                     L6-F4-2 
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     SGGGGSGGGGS 
                   
                   DIQMTQSPSSLSASVGDRVTITCRAS 
                 
               
               
                   
                   
                 
                   QSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFS 
                 
               
               
                   
                   
                 
                   GSRSGTDFTLTISSLQPEDFATYYCQQSYAAYLFTFG 
                 
               
               
                   
                   
                   QGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLL 
               
               
                   
                   
                 NNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTY 
               
               
                   
                   
                 SLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN 
               
               
                   
                   
                 RGEC 
               
               
                   
                   
                 
                   L6-F4-2 HC SEQ ID NO: 234 
                 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWV 
                 
               
               
                   
                   
                 
                   RQAPGKGLEWVAEISPYSGSTYYADSVKGRFTISADT 
                 
               
               
                   
                   
                 
                   SKNTAYLQMNSLRAEDTAVYYCALRARPPIRLHPRGS 
                 
               
               
                   
                   
                 
                   VMDYWGQGTLVTVSS 
                   
                     GSAASGSSGGSSSGA 
                   
                   DIQMTQS 
                 
               
               
                   
                   
                 
                   PSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAP 
                 
               
               
                   
                   
                 
                   KLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPE 
                 
               
               
                   
                   
                 
                   DFATYYCQQSYTTPPTFGQGTKVEIK 
                   
                     GGGGSGGGGSG 
                   
                 
               
               
                   
                   
                 
                   
                     GGGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASGFNISYYY 
                 
               
               
                   
                   
                 
                   IHWVRQAPGKGLEWVASIYPSSGYTYYADSVKGRFTI 
                 
               
               
                   
                   
                 
                   SADTSKNTAYLQMNSLRAEDTAVYYCARSSFYWAMDY 
                 
               
               
                   
                   
                   WGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALG 
               
               
                   
                   
                 CLVDKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY 
               
               
                   
                   
                 SLSSVVTVPSSSLGTQTLYICNVNHKPSNTKVDKKVEP 
               
               
                   
                   
                 KSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMIS 
               
               
                   
                   
                 RTPEVTCVVVDVSHEDPEVKFNWYDGVEVHNAKTKP 
               
               
                   
                   
                 REEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL 
               
               
                   
                   
                 GAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSL 
               
               
                   
                   
                 TCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG 
               
               
                   
                   
                 SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQK 
               
               
                   
                   
                 SLSLSPGK 
               
               
                 
                   
                     RSPO2RA-N-LC-ScFv-IgG 
                   
                 
                 
                   RSPO2RA- 
                 
                 
                   RSPO2RA-F4 LC SEQ ID NO: 235 
                 
               
               
                   
                 
                   
                     L6-F4 
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     SGGGGSGGGGS 
                   
                   DIQMTQSPSSLSASVGDRVTITCRAS 
                 
               
               
                   
                   
                 
                   QSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFS 
                 
               
               
                   
                   
                 
                   GSRSGTDFTLTISSLQPEDFATYYCQQWYYAPITFGQ 
                 
               
               
                   
                   
                   GTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLN 
               
               
                   
                   
                 NFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS 
               
               
                   
                   
                 LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR 
               
               
                   
                   
                 GEC 
               
               
                   
                   
                 
                   L6-F4 HC SEQ ID NO: 236 
                 
               
               
                   
                   
                 
                   EVQLVESGGGGLVQPGGSL4LSCAASGFTFTSYYISWY 
                 
               
               
                   
                   
                 
                   RQAPGKGLEWVAEISPYSGSTYYADSVKGRFTISADT 
                 
               
               
                   
                   
                 
                   SKNTAYLQMNSLRAEDTAVYYCALRARPPIRLHPRGS 
                 
               
               
                   
                   
                 
                   VMDYWGQGTLVTVSS 
                   
                     GSAASGSSGGSSSGA 
                   
                   DIQMTQS 
                 
               
               
                   
                   
                 
                   PSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAP 
                 
               
               
                   
                   
                 
                   KLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPE 
                 
               
               
                   
                   
                 
                   DFATYYCQQSYTTPPTFGQGTKVEIK 
                   
                     GGGGSGGGGSG 
                   
                 
               
               
                   
                   
                 
                   
                     GGGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASGFNLSSYS 
                 
               
               
                   
                   
                 
                   MHWVRQAPGKGLEWVAYISSYYGYTYYADSVKGRFTI 
                 
               
               
                   
                   
                 
                   SADTSKNTAYLQMNSLRAEDTAVYYCARPAPGHWGFD 
                 
               
               
                   
                   
                   YWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAAL 
               
               
                   
                   
                 GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL 
               
               
                   
                   
                 YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVE 
               
               
                   
                   
                 PKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMI 
               
               
                   
                   
                 SRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK 
               
               
                   
                   
                 PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA 
               
               
                   
                   
                 LGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVS 
               
               
                   
                   
                 LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD 
               
               
                   
                   
                 GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ 
               
               
                   
                   
                 KSLSLSPGK 
               
               
                 RSPO2RA-N-LC-ScFv-IgG 
                 
                   RSPO2RA- 
                 
                 
                   RSPO2RA-F49 LC SEQ ID NO: 237 
                 
               
               
                   
                 
                   
                     L6-F49 
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     SGGGGSGGGGS 
                   
                   DIQMTQSPSSPSASVGDRVTITCRAS 
                 
               
               
                   
                   
                 
                   QSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFS 
                 
               
               
                   
                   
                 
                   GSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGG 
                 
               
               
                   
                   
                   GTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLN 
               
               
                   
                   
                 NFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS 
               
               
                   
                   
                 LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR 
               
               
                   
                   
                 GEC 
               
               
                   
                   
                 
                   L6-F49 HC SEQ ID NO: 238 
                 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWV 
                 
               
               
                   
                   
                 
                   RQAPGKGLEWVAEISPYSGSTYYADSVKGRFTISADT 
                 
               
               
                   
                   
                 
                   SKNTAYLQMNSLRAEDTAVYYCALRARPPIRLHPRGS 
                 
               
               
                   
                   
                 
                   VMDYWGQGTLVTVSS 
                   
                     GSAASGSSGGSSSGA 
                   
                   DIQMTQS 
                 
               
               
                   
                   
                 
                   PSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAP 
                 
               
               
                   
                   
                 
                   KLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPE 
                 
               
               
                   
                   
                 
                   DFATYYCQQSYTTPPTFGQGTKVEIK 
                   
                     GGGGSGGGGSG 
                   
                 
               
               
                   
                   
                 
                   
                     GGGS 
                   
                   QVQLVQSGAEVKKPGASVKVSCKASGGTFSSYA 
                 
               
               
                   
                   
                 
                   ISWVRQAPGQGLEWMGWINAGNGNTTYAQKFQGRVTM 
                 
               
               
                   
                   
                 
                   TRDTSTSTVYMELSSLRSEDTAVYYCARHYYGSGSYP 
                 
               
               
                   
                   
                   DWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAAL 
               
               
                   
                   
                 GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL 
               
               
                   
                   
                 YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVE 
               
               
                   
                   
                 PKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMI 
               
               
                   
                   
                 SRTPEVTCVVVDVSHEDPEVKFNWYDGVEVHNAKTK 
               
               
                   
                   
                 PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA 
               
               
                   
                   
                 LGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVS 
               
               
                   
                   
                 LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD 
               
               
                   
                   
                 GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ 
               
               
                   
                   
                 KSLSLSPGK 
               
               
                 
                   
                     RSPO2RA-N-LC-ScFv-IgG 
                   
                 
                 
                   RSPO2RA- 
                 
                 
                   RSPO2RA-F49 LC SEQ ID NO: 239 
                 
               
               
                   
                 
                   
                     L6-F49 
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     SGGGGSGGGGS 
                   
                   DIQMTQSPSSPSASVGDRVTITCRAS 
                 
               
               
                   
                   
                 
                   QSISSYLNWYLQQKPGKAPKLLIYAASSLQSGVPSRFS 
                 
               
               
                   
                   
                 
                   GSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGG 
                 
               
               
                   
                   
                   GTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLN 
               
               
                   
                   
                 NFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS 
               
               
                   
                   
                 LSSTLTLSKADYEKHVYACEVTHQGLSSPVTKSFNR 
               
               
                   
                   
                 GEC 
               
               
                   
                   
                 
                   L6-F49 HC SEQ ID NO: 240 
                 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWV 
                 
               
               
                   
                   
                 
                   RQAPGKGLEWVAEISPYSGSTYYADSVKGRFTISADT 
                 
               
               
                   
                   
                 
                   SKNTAYLQMNSLRAEDTAVYYCALRARPPIRLHPRGS 
                 
               
               
                   
                   
                 
                   VMDYWGQGTLVTVSS 
                   
                     GSAASGSSGGSSSSGA 
                   
                   DIQMTQS 
                 
               
               
                   
                   
                 
                   PSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAP 
                 
               
               
                   
                   
                 
                   KLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPE 
                 
               
               
                   
                   
                 
                   DFATYYCQQSYTTPPTFGQGTKVEIK 
                   
                     GGGGSGGGGSG 
                   
                 
               
               
                   
                   
                 
                   
                     GGGS 
                   
                   QVQLVQSGAEVKKPGASVKVSCKASGGTFSSYA 
                 
               
               
                   
                   
                 
                   ISWVRQAPGQGLEWMGWINAGNGNTTYAQKFQGRVTM 
                 
               
               
                   
                   
                 
                   TRDTSTSTVYMELSSLRSEDTAVYYCARGYYGSGSYP 
                 
               
               
                   
                   
                   DWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAAL 
               
               
                   
                   
                 GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL 
               
               
                   
                   
                 YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVE 
               
               
                   
                   
                 PKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMI 
               
               
                   
                   
                 SRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK 
               
               
                   
                   
                 PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA 
               
               
                   
                   
                 LGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVS 
               
               
                   
                   
                 LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD 
               
               
                   
                   
                 GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ 
               
               
                   
                   
                 KSLSLSPGK 
               
               
                 
                   
                     RSPO2RA-N-LC-ScFv-IgG 
                   
                 
                 
                   RSPO2RA- 
                 
                 
                   RSPO2RA-F49 LC SEQ ID NO: 241 
                 
               
               
                   
                 
                   
                     L6-F49 
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     SGGGGSGGGGS 
                   
                   DIQMTQSPSSPSASVGDRVTITCRAS 
                 
               
               
                   
                   
                 
                   QSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFS 
                 
               
               
                   
                   
                 
                   GSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGG 
                 
               
               
                   
                   
                   GTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLN 
               
               
                   
                   
                 NFYPREAKVQWKVDNALQSGNQESVTEQDSKDSTYS 
               
               
                   
                   
                 LSSTLTLSKADYEKHKVYACEVTHQGLGGPVTKSFNR 
               
               
                   
                   
                 GEC 
               
               
                   
                   
                 
                   L6-F49 HC SEQ ID NO: 242 
                 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWV 
                 
               
               
                   
                   
                 
                   RQAPGKGLEWVAEISPYSGSTYYADSVKGRFTISADT 
                 
               
               
                   
                   
                 
                   SKNTAYLQMNSLRAEDTAVYYCALRARPPIRLHPRGS 
                 
               
               
                   
                   
                 
                   VMDYWGQGTLVTVSS 
                   
                     GSAASGSSGGSSSGA 
                   
                   DIQMTQS 
                 
               
               
                   
                   
                 
                   PSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAP 
                 
               
               
                   
                   
                 
                   KLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPE 
                 
               
               
                   
                   
                 
                   DFATYYCQQSYTTPPTFGQGTKVEIK 
                   
                     GGGGSGGGGSG 
                   
                 
               
               
                   
                   
                 
                   
                     GGGS 
                   
                   QVQLVQSGAEVKKPGASVKVSCKASGGTFSSYA 
                 
               
               
                   
                   
                 
                   ISWVRQAPGQGLEWMGWINAGNGNTTYAQKFQGRVTM 
                 
               
               
                   
                   
                 
                   TRDTSTSTVYMELSSLRSEDTAVYYCARHYYGSGSYP 
                 
               
               
                   
                   
                   DWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAAL 
               
               
                   
                   
                 GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL 
               
               
                   
                   
                 YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVE 
               
               
                   
                   
                 PKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMI 
               
               
                   
                   
                 SRTPEVTCVVVDVSHEDPEVKFNWYDGVEVHNAKTK 
               
               
                   
                   
                 PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA 
               
               
                   
                   
                 LGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVS 
               
               
                   
                   
                 LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD 
               
               
                   
                   
                 GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ 
               
               
                   
                   
                 KSLSLSPGK 
               
               
                 
                   RSPO2RA-N-LC-ScFv-IgG 
                 
                 
                   RSPO2RA- 
                 
                 
                   RSPO2RA-F10 LC SEQ ID NO: 243 
                 
               
               
                   
                 
                   
                     L6-F10 
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     SGGGGSGGGGS 
                   
                   ELTQPPSVSVSPGQTARITCSGDGSY 
                 
               
               
                   
                   
                 
                   AGSYYYGWYQQKPGQAPVTLIYYNNKRPSGIPERFSG 
                 
               
               
                   
                   
                 
                   SLSGSTNTLTISGVQAEDEADYYCGSADNSGAAFGGG 
                 
               
               
                   
                   
                   TKLTVL RTVAAPSVFIFPPSDEQLKSGTASVVCLLNN 
               
               
                   
                   
                 FYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL 
               
               
                   
                   
                 SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRG 
               
               
                   
                   
                 EC 
               
               
                   
                   
                 
                   L6-F10 HC SEQ ID NO: 244 
                 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWV 
                 
               
               
                   
                   
                 
                   RQAPGKGLEWVAEISPYSGSTYYADSVKGRFTISADT 
                 
               
               
                   
                   
                 
                   SKNTAYLQMNSLRAEDTAVYYCALRARPPIRLHPRGS 
                 
               
               
                   
                   
                 
                   VMDYWGQGTLVTVSS 
                   
                     GSAASGSSGGSSSGA 
                   
                   DIQMTQS 
                 
               
               
                   
                   
                 
                   PSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAP 
                 
               
               
                   
                   
                 
                   KLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPE 
                 
               
               
                   
                   
                 
                   DFATYYCQQSYTTPPTFGQGTKVEIK 
                   GGGGSGGGGSG 
                 
               
               
                   
                   
                 
                   
                     GGGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFSSFN 
                 
               
               
                   
                   
                 
                   MFWVRQAPGKGLEWVAGIDDDGSYPNYGSAVKGRATI 
                 
               
               
                   
                   
                 
                   SRDNSKNTLYLQMNSLRAEDTAVYYCAKSGYGGSWGG 
                 
               
               
                   
                   
                   YIADDIDAWGQGTLVTVSS ASTKGPSVFPLAPSSKST 
               
               
                   
                   
                 SGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA 
               
               
                   
                   
                 VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNT 
               
               
                   
                   
                 KVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPK 
               
               
                   
                   
                 PKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYDGVE 
               
               
                   
                   
                 VHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK 
               
               
                   
                   
                 CKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREE 
               
               
                   
                   
                 MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT 
               
               
                   
                   
                 PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA 
               
               
                   
                   
                 LHNHTYQKSLSLSPGK 
               
               
                 
                   RSPO2RA-N-LC-ScFv-IgG 
                 
                 
                   RSPO2RA- 
                 
                 
                   RSPO2RA-F2I SEQ ID NO: 245 
                 
               
               
                   
                 
                   
                     L6-F2I 
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     SGGGGSGGGGS 
                   
                   DIQMTQSPSSLSASVGDRVTITCRAS 
                 
               
               
                   
                   
                 
                   QSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFS 
                 
               
               
                   
                   
                 
                   GSRSGTDFTLTISSLQPEDFATYYCQQGVYLFTFGQG 
                 
               
               
                   
                   
                   TKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNN 
               
               
                   
                   
                 FYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL 
               
               
                   
                   
                 SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRG 
               
               
                   
                   
                 EC 
               
               
                   
                   
                 
                   L6-F2I HC SEQ ID NO: 246 
                 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWV 
                 
               
               
                   
                   
                 
                   RQAPGKGLEWVAEISPYSGSTYYADSVKGRFTISADT 
                 
               
               
                   
                   
                 
                   SKNTAYLQMNSLRAEDTAVYYCALRARPPIRLHPRGS 
                 
               
               
                   
                   
                 
                   VMDYWGQGTLVTVSS 
                   
                     GSAASGSSGGSSSGA 
                   
                   DIQMTQS 
                 
               
               
                   
                   
                 
                   PSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAP 
                 
               
               
                   
                   
                 
                   KLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPE 
                 
               
               
                   
                   
                 
                   DFATYYCQQSYTTPPTFGQGTKVEIK 
                   
                     GGGGSGGGGSG 
                   
                 
               
               
                   
                   
                 
                   
                     GGGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASGFNIHSSS 
                 
               
               
                   
                   
                 
                   IHWVRQAPGKGLEWVAATYSSFGSITYADSVKGRFTI 
                 
               
               
                   
                   
                 
                   SADTSKNTAYLQMNSLRAEDTAVYYCARYHHPFGYAL 
                 
               
               
                   
                   
                   DYWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAA 
               
               
                   
                   
                 LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG 
               
               
                   
                   
                 LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKV 
               
               
                   
                   
                 EPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLM 
               
               
                   
                   
                 ISRTPEVTCVVVDVSHEDPEVKFNWYDGVEVHNAKT 
               
               
                   
                   
                 KPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK 
               
               
                   
                   
                 ALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQV 
               
               
                   
                   
                 SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS 
               
               
                   
                   
                 DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT 
               
               
                   
                   
                 QKSLSLSPGK 
               
               
                 
                   
                     RSPO2RA-N-LC-ScFv-IgG 
                   
                 
                 
                   RSPO2RA- 
                 
                 
                   RSPO2RA-F7B-LC SEQ ID NO: 247 
                 
               
               
                   
                 
                   
                     L6-F7B 
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     SGGGGSGGGGS 
                   
                   DIQMTQSPSSLSASVGDRVTITCRAS 
                 
               
               
                   
                   
                 
                   QSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFS 
                 
               
               
                   
                   
                 
                   GSRSGTDFTLTISSLQPEDFATYYCQQYYSLFTFGQG 
                 
               
               
                   
                   
                   TKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNN 
               
               
                   
                   
                 FYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL 
               
               
                   
                   
                 SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRG 
               
               
                   
                   
                 EC 
               
               
                   
                   
                 
                   L6-F7B HC SEQ ID NO: 248 
                 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWV 
                 
               
               
                   
                   
                 
                   RQAPGKGLEWVAEISPYSGSTYYADSVKGRFTISADT 
                 
               
               
                   
                   
                 
                   SKNTAYLQMNSLRAEDTAVYYCALRARPPIRLHPRGS 
                 
               
               
                   
                   
                 
                   VMDYWGQGTLVTVSS 
                   
                     GSAASGSSGGSSSSGA 
                   
                   DIQMTQS 
                 
               
               
                   
                   
                 
                   PSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAP 
                 
               
               
                   
                   
                 
                   KLLIYSASFLYSGVPSRFSGSGSGTYDFTLTISSLQPE 
                 
               
               
                   
                   
                 
                   DFATYYCQQSYTTPPTFGQGTKVEIK 
                   
                     GGGGSGGGGSG 
                   
                 
               
               
                   
                   
                 
                   
                     GGGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASGFNFSSSS 
                 
               
               
                   
                   
                 
                   IHWVRQAPGKGLEWVAYIYPSYDYTYYADSVKGRFTI 
                 
               
               
                   
                   
                 
                   SADTSKNTAYLQMNSLRAEDTAVYYCARGYFYTWGGM 
                 
               
               
                   
                   
                   DYWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAA 
               
               
                   
                   
                 LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG 
               
               
                   
                   
                 LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKV 
               
               
                   
                   
                 EPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLM 
               
               
                   
                   
                 ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT 
               
               
                   
                   
                 KPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK 
               
               
                   
                   
                 ALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQV 
               
               
                   
                   
                 SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS 
               
               
                   
                   
                 DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT 
               
               
                   
                   
                 QKSLSLSPGK 
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   RSPO2RA- 
                   
                     L6-F12578 
                   
                 
                   RSPO2RA-L6-F12578 HC SEQ ID NO: 249                    
                   
                   
    SGGGGSGGGGS     EVQLVESGGGLVQPGGSLRLSCAASG   FTFTSYYISWVRQAPGKGLEWVAEISPYSGSTYYADS   VKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCALRA   RPPIRLHPRGSVMDYWGQGTLVTVSS     GGGGSGGGGSG       GGGS     EVQLVESGGGLVQPGGGSLRLSCAASGFTFSHYT   LSWVRQAPGKGLEWVSVISGDGSYTYYADSVKGRFTI   SSDNDKNTLYLQMNSLRAEDTAVYYCARNFIKYVFAN   
               
               
                   
                   
                   WGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALG 
               
               
                   
                   
                 CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY 
               
               
                   
                   
                 SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEP 
               
               
                   
                   
                 KSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMIS 
               
               
                   
                   
                 RTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP 
               
               
                   
                   
                 REEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL 
               
               
                   
                   
                 GAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSL 
               
               
                   
                   
                 TCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG 
               
               
                   
                   
                 SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHTYQK 
               
               
                   
                   
                 SLSLSPGK 
               
               
                   
                   
                 
                   L6-F12578 LC SEQ ID NO: 250 
                 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQ 
                 
               
               
                   
                   
                 
                   QKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLT 
                 
               
               
                   
                   
                 
                   ISSLQPEDFATYYCQQSYTTPPTFGQGTKVEIK 
                   
                     GGGG 
                   
                 
               
               
                   
                   
                 
                   
                     SGGGGSGGGGS 
                   
                   DIELTQPPSVSVAPGQTARISCSGDN 
                 
               
               
                   
                   
                 
                   IGSFYVHWYQQKPGQAPVLVIYDKSNRPSGIPERFSG 
                 
               
               
                   
                   
                 
                   SNSGNTATLTISGTQAEDEADYYCQSYANTLSLVFGG 
                 
               
               
                   
                   
                   GTKLTVL GQPKAAPSVTLFPPSSEELQANKATLVCLI 
               
               
                   
                   
                 SDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYA 
               
               
                   
                   
                 ASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTE 
               
               
                   
                   
                 CS 
               
               
                 
                   
                     RSPO2RA-N-HC-Fv-IgG 
                   
                 
                 
                   RSPO2RA- 
                 
                 
                   RSPO2RA-L6-F127 HC SEQ ID NO: 251 
                 
               
               
                   
                 
                   
                     L6-F127 
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     SGGGGSGGGGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASG 
                 
               
               
                   
                   
                 
                   FTFTSYYISWVRQAPGKGLEWVAEISPYSGSTYYADS 
                 
               
               
                   
                   
                 
                   VKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCALRA 
                 
               
               
                   
                   
                 
                   RPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GGGGSGGGGSG 
                   
                 
               
               
                   
                   
                 
                   
                     GGGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASGFNISSSY 
                 
               
               
                   
                   
                 
                   IHWVRQAPGKGLEWVAYIYSSYGSTYYADSVKGRFTI 
                 
               
               
                   
                   
                 
                   SADTSKNTAYLQMNSLRAEDTAVYYCARASWYALDYW 
                 
               
               
                   
                   
                   GQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGC 
               
               
                   
                   
                 LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS 
               
               
                   
                   
                 LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPK 
               
               
                   
                   
                 SCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISR 
               
               
                   
                   
                 TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR 
               
               
                   
                   
                 EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALG 
               
               
                   
                   
                 APIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT 
               
               
                   
                   
                 CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS 
               
               
                   
                   
                 FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS 
               
               
                   
                   
                 LSLSPGK 
               
               
                   
                   
                 
                   L6-F127 LC SEQ ID NO: 252 
                 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQ 
                 
               
               
                   
                   
                 
                   QKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLT 
                 
               
               
                   
                   
                 
                   ISSLQPEDFATYYCQQSYTTPPTFGQGTKVEIK 
                   
                     GGGG 
                   
                 
               
               
                   
                   
                 
                   
                     SGGGGSGGGGS 
                   
                   DIQMTQSPSSLSASVGDRVTITCRAS 
                 
               
               
                   
                   
                 
                   QSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFS 
                 
               
               
                   
                   
                 
                   GSRSGTDFTLTISSLQPEDFATYYCQQYWYGVAPITF 
                 
               
               
                   
                   
                   GQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCL 
               
               
                   
                   
                 LNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST 
               
               
                   
                   
                 YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF 
               
               
                   
                   
                 NRGEC 
               
               
                 
                   
                     RSPO2RA-N-HC-Fv-IgG 
                   
                 
                 
                   RSPO2RA- 
                 
                 
                   RSPO2RA-L6-F58 HC SEQ ID NO: 253 
                 
               
               
                   
                 
                   
                     L6-F58 
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     SGGGGSGGGGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASG 
                 
               
               
                   
                   
                 
                   FTFTSYYISWVRQAPGKGLEWVAEISPYSGSTYYADS 
                 
               
               
                   
                   
                 
                   VKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCALRA 
                 
               
               
                   
                   
                 
                   RPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GGGGSGGGGSG 
                   
                 
               
               
                   
                   
                 
                   
                     GGGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASGFNISYSY 
                 
               
               
                   
                   
                 
                   IHWVRQAPGKGLEWVASIYSSSGSTSYADSVKGRFTI 
                 
               
               
                   
                   
                 
                   SADTSKNTAYLQMNSLRAEDTAVYYCARGAIDYWGQG 
                 
               
               
                   
                   
                   TLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVK 
               
               
                   
                   
                 DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS 
               
               
                   
                   
                 VVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCD 
               
               
                   
                   
                 KTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE 
               
               
                   
                   
                 VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTPREEQ 
               
               
                   
                   
                 YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPI 
               
               
                   
                   
                 EKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV 
               
               
                   
                   
                 KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL 
               
               
                   
                   
                 YSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL 
               
               
                   
                   
                 SPGK 
               
               
                   
                   
                 
                   L6-F58 LC SEQ ID NO: 254 
                 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQ 
                 
               
               
                   
                   
                 
                   QKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLT 
                 
               
               
                   
                   
                 
                   ISSLQPEDFATYYCQQSYTTPPTFGQGTKVEIK 
                   
                     GGGG 
                   
                 
               
               
                   
                   
                 
                   
                     SGGGGSGGGGS 
                   
                   DIQMTQSPSSLSASVGDRVTITCRAS 
                 
               
               
                   
                   
                 
                   QSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFS 
                 
               
               
                   
                   
                 
                   GSRSGTDFTLTISSLQPEDFATYYCQQWYSSGHVLIT 
                 
               
               
                   
                   
                   FGQGTKVEIK RTVAAPSVFIPPSDEQLKSGTASVVC 
               
               
                   
                   
                 LLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS 
               
               
                   
                   
                 TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS 
               
               
                   
                   
                 FNRGEC 
               
               
                 
                   
                     RSPO2RA-N-HC-Fv-IgG 
                   
                 
                 
                   RSPO2RA- 
                 
                 
                   RSPO2RA-L6-F4-2 HC SEQ ID NO: 255 
                 
               
               
                   
                 
                   
                     L6-F4-2 
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     SGGGGSGGGGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASG 
                 
               
               
                   
                   
                 
                   FTFTSYYISWVRQAPGKGLEWVAEISPYSGSTYYADS 
                 
               
               
                   
                   
                 
                   VKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCALRA 
                 
               
               
                   
                   
                 
                   RPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GGGGSGGGGSG 
                   
                 
               
               
                   
                   
                 
                   
                     GGGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASGFNISYYY 
                 
               
               
                   
                   
                 
                   IHWVRQAPGKGLEWVASIYPSSGYTYYADSVKGRFTI 
                 
               
               
                   
                   
                 
                   SADTSKNTAYLQMNSLRAEDTAVYYCARSSFYWAMDY 
                 
               
               
                   
                   
                   WGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALG 
               
               
                   
                   
                 CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY 
               
               
                   
                   
                 SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEP 
               
               
                   
                   
                 KSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMIS 
               
               
                   
                   
                 RTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP 
               
               
                   
                   
                 REEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL 
               
               
                   
                   
                 GAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSL 
               
               
                   
                   
                 TCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG 
               
               
                   
                   
                 SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHTYQK 
               
               
                   
                   
                 SLSLSPGK 
               
               
                   
                   
                 
                   L6-F4-2 LC SEQ ID NO: 256 
                 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQ 
                 
               
               
                   
                   
                 
                   QKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLT 
                 
               
               
                   
                   
                 
                   ISSLQPEDFATYYCQQSYTTPPTFGQGTKVEIK 
                   
                     GGGG 
                   
                 
               
               
                   
                   
                 
                   
                     SGGGGSGGGGS 
                   
                   DIQMTQSPSSLSASVGDRVTITCRAS 
                 
               
               
                   
                   
                 
                   QSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFS 
                 
               
               
                   
                   
                 
                   GSRSGTDFTLTISSLQPEDFATYYCQQSYAAYLFTFG 
                 
               
               
                   
                   
                   GTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLL 
               
               
                   
                   
                 NNFYPREAKVQWKVDNALQSGNQESVTEQDSKDSTY 
               
               
                   
                   
                 SLSSTLTLSKADYEKHDKVYACEVTHQGLSSPVTKSFN 
               
               
                   
                   
                 RGEC 
               
               
                 
                   
                     RSPO2RA-N-HC-Fv-IgG 
                   
                 
                 
                   RSPO2RA- 
                 
                 
                   RSPO2RA-L6-F4 HC SEQ ID NO: 257 
                 
               
               
                   
                 
                   
                     L6-F4 
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     SGGGGSGGGGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASG 
                 
               
               
                   
                   
                 
                   FTFTSYYISWVRQAPGKGLEWVAEISPYSGSTYYADS 
                 
               
               
                   
                   
                 
                   VKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCALRA 
                 
               
               
                   
                   
                 
                   RPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GGGGSGGGGSG 
                   
                 
               
               
                   
                   
                 
                   
                     GGGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASGFNLSSYS 
                 
               
               
                   
                   
                 
                   MHWVRQAPGKGLEWVAYISSYYGYTYYADSVKGRFTI 
                 
               
               
                   
                   
                 
                   SADTSKNTAYLQMNSLRAEDTAVYYCARPAPGHWGFD 
                 
               
               
                   
                   
                   YWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAAL 
               
               
                   
                   
                 GCLVKDYFPEPVTVSWNSGALTSGHTFPAVLQSSGL 
               
               
                   
                   
                 YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVE 
               
               
                   
                   
                 PKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMI 
               
               
                   
                   
                 SRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK 
               
               
                   
                   
                 PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA 
               
               
                   
                   
                 LGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVS 
               
               
                   
                   
                 LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD 
               
               
                   
                   
                 GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ 
               
               
                   
                   
                 KSLSLSPGK 
               
               
                   
                   
                 
                   L6-F4 LC SEQ ID NO: 258 
                 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQ 
                 
               
               
                   
                   
                 
                   QKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLT 
                 
               
               
                   
                   
                 
                   ISSLQPEDFATYYCQQSYTTPPTFGQGTKVEIK 
                   
                     GGGG 
                   
                 
               
               
                   
                   
                 
                   
                     SGGGGSGGGGS 
                   
                   DIQMTQSPSSLSASVGDRVTITCRAS 
                 
               
               
                   
                   
                 
                   QSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFS 
                 
               
               
                   
                   
                 
                   GSRSGTDFTLTISSLQPEDFATYYCQQWYYAPITFGQ 
                 
               
               
                   
                   
                   GTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLN 
               
               
                   
                   
                 NFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS 
               
               
                   
                   
                 LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR 
               
               
                   
                   
                 GEC 
               
               
                 
                   
                     RSPO2RA-N-HC-Fv-IgG 
                   
                 
                 
                   RSPO2RA- 
                 
                 
                   RSPO2RA-L6-F49 HC SEQ ID NO: 259 
                 
               
               
                   
                 
                   
                     L6-F49 
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     SGGGGSGGGGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASG 
                 
               
               
                   
                   
                 
                   FTFTSYYISWVRQAPGKGLEWVAEISPYSGSTYYADS 
                 
               
               
                   
                   
                 
                   VKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCALRA 
                 
               
               
                   
                   
                 
                   RPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GGGGSGGGGSG 
                   
                 
               
               
                   
                   
                 
                   
                     GGGS 
                   
                   EVQLVQSGAEVKKPGASVKVSCKASGGTFSSYA 
                 
               
               
                   
                   
                 
                   ISWVRQAPGQGLEWMGWINAGNGNTTYAQKFQGRVTM 
                 
               
               
                   
                   
                 
                   TRDTSTSTVYMELSSLRSEDTAVYYCARHYYGSGSYP 
                 
               
               
                   
                   
                   DWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAAL 
               
               
                   
                   
                 GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL 
               
               
                   
                   
                 YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVE 
               
               
                   
                   
                 PKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMI 
               
               
                   
                   
                 SRTPEVTCVVVDVSHEDPEVKFNWYDGVEVHNAKTK 
               
               
                   
                   
                 PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA 
               
               
                   
                   
                 LGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVS 
               
               
                   
                   
                 LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD 
               
               
                   
                   
                 GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ 
               
               
                   
                   
                 KSLSLSPGK 
               
               
                   
                   
                 
                   L6-F49 LC SEQ ID NO: 260 
                 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQ 
                 
               
               
                   
                   
                 
                   QKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLT 
                 
               
               
                   
                   
                   ISSLQPEDFATYYCQQSYTTPPTFGQGTKVEIK R GGG   
               
               
                   
                   
                 
                   
                     GSGGGGSGGGGS 
                   
                   DIQMTQSPSSPSASVGDRVTITCRA 
                 
               
               
                   
                   
                 
                   SQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF 
                 
               
               
                   
                   
                 
                   SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFG 
                 
               
               
                   
                   
                   GGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLL 
               
               
                   
                   
                 NNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTY 
               
               
                   
                   
                 SLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN 
               
               
                   
                   
                 RGEC 
               
               
                 
                   
                     RSPO2RA-N-HC-Fv-IgG 
                   
                 
                 
                   RSPO2RA- 
                 
                 
                   RSPO2RA-L6-F10 HC SEQ ID NO: 261 
                 
               
               
                   
                 
                   
                     L6-F10 
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     SGGGGSGGGGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASG 
                 
               
               
                   
                   
                 
                   FTFTSYYISWVRQAPKGLEWVAEISPYSGSTYYADS 
                 
               
               
                   
                   
                 
                   VKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCALRA 
                 
               
               
                   
                   
                 
                   RPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GGGGSGGGGSG 
                   
                 
               
               
                   
                   
                 
                   
                     GGGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFSSFN 
                 
               
               
                   
                   
                 
                   MFWVRQAPGKGLEWVAGIDDDGSYPNYGSAVKGRATI 
                 
               
               
                   
                   
                 
                   SRDNSKNTLYLQMNSLRAEDTAVYYCAKSGYGGSWGG 
                 
               
               
                   
                   
                   YIADDIDAWGQGTLVTVSS ASTKGPSVFPLAPSSKST 
               
               
                   
                   
                 SGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA 
               
               
                   
                   
                 VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNT 
               
               
                   
                   
                 KVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPK 
               
               
                   
                   
                 PKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVE 
               
               
                   
                   
                 VHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK 
               
               
                   
                   
                 CKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREE 
               
               
                   
                   
                 MTKNQVSLTCLVDKGFYPSDIAVEWESNGQPENNYKTT 
               
               
                   
                   
                 PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA 
               
               
                   
                   
                 LHNHYTQKSLSLSPGK 
               
               
                   
                   
                 
                   L6-F10 LC SEQ ID NO: 262 
                 
               
               
                   
                   
                 DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQ 
               
               
                   
                   
                 QKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLT 
               
               
                   
                   
                 ISSLQPEDFATYYCQQSYTTPPTFGQGTKVEIK   GGGG     
               
               
                   
                   
                 
                   
                     SGGGGSGGGGS 
                   
                   ELTQPPSVSVSPGQTARITCSGDGSY 
                 
               
               
                   
                   
                 
                   AGSYYYGWYQQKPGQAPVTLIYYNNKRPSGIPERFSG 
                 
               
               
                   
                   
                 
                   SLSGSTNTLTISGVQAEDEADYYCGSADNSGAAFGGG 
                 
               
               
                   
                   
                   TKLTVL RTVAAPSVFIFPPSDEQLKSGTASVVCLLNN 
               
               
                   
                   
                 FYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL 
               
               
                   
                   
                 SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRG 
               
               
                   
                   
                 EC 
               
               
                 
                   
                     RSPO2RA-N-HC-Fv-IgG 
                   
                 
                 
                   RSPO2RA- 
                 
                 
                   RSPO2RA-L6-F2I HC SEQ ID NO: 263 
                 
               
               
                   
                 
                   
                     L6-F2I 
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     SGGGGSGGGGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASG 
                 
               
               
                   
                   
                 
                   FTFTSYYISWVRQAPGKGLEWVAEISPYSGSTYYADS 
                 
               
               
                   
                   
                 
                   VKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCALRA 
                 
               
               
                   
                   
                 
                   RPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GGGGSGGGGSG 
                   
                 
               
               
                   
                   
                 
                   
                     GGGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASGFNIHSSS 
                 
               
               
                   
                   
                 
                   IHWVRQAPGKGLEWVAATYSSFGSITYADSVKGRFTI 
                 
               
               
                   
                   
                 
                   SADTSKNTAYLQMNSLRAEDTAVYYCARYHHHPFGYAL 
                 
               
               
                   
                   
                   DYWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAA 
               
               
                   
                   
                 LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG 
               
               
                   
                   
                 LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKV 
               
               
                   
                   
                 EPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLM 
               
               
                   
                   
                 ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT 
               
               
                   
                   
                 KPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK 
               
               
                   
                   
                 ALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQV 
               
               
                   
                   
                 SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS 
               
               
                   
                   
                 DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT 
               
               
                   
                   
                 QKSLSLSPGK 
               
               
                   
                   
                 
                   L6-F2I LC SEQ ID NO: 264 
                 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQ 
                 
               
               
                   
                   
                 
                   QKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLT 
                 
               
               
                   
                   
                   ISSLQPEDFATYYCQQSYTTPPTFGQGTKVEIK R   GGG     
               
               
                   
                   
                 
                   
                     GSGGGGSGGGGS 
                   
                   DIQMTQSPSSLSASVGDRVTITCRA 
                 
               
               
                   
                   
                 
                   SQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRF 
                 
               
               
                   
                   
                 
                   SGSRSGTDFTLTISSLQPEDFATYYCQQGVYLFTFGQ 
                 
               
               
                   
                   
                   GTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLN 
               
               
                   
                   
                 NFYPREAKVQWKVDNALQSGNASQESVTEQDSKDSTYS 
               
               
                   
                   
                 LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR 
               
               
                   
                   
                 GEC 
               
               
                 
                   
                     RSPO2RA-N-HC-Fv-IgG 
                   
                 
                 
                   RSPO2RA- 
                 
                 
                   RSPO2RA-L6-F7B HC SEQ ID NO: 265 
                 
               
               
                   
                 
                   
                     L6-F7B 
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     SGGGGSGGGGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASG 
                 
               
               
                   
                   
                 
                   FTFTSYYISWVRQAPGKGLEWVAEISPYSGSTYYADS 
                 
               
               
                   
                   
                 
                   VKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCALRA 
                 
               
               
                   
                   
                 
                   RPPIRLHPRGSVMDYWGQGTLVTVSS 
                   
                     GGGGSGGGGSG 
                   
                 
               
               
                   
                   
                 
                   
                     GGGS 
                   
                   EVQLVESGGGLVQPGGSLRLSCAASGFNFSSSS 
                 
               
               
                   
                   
                 
                   IHWVRQAPGKGLEWVAYIYPSYDYTYYADSVKGRFTI 
                 
               
               
                   
                   
                 
                   SADTSKNTAYLQMNSLRAEDTAVYYCARGYFYTWGGM 
                 
               
               
                   
                   
                   DYWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAA 
               
               
                   
                   
                 LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG 
               
               
                   
                   
                 LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKV 
               
               
                   
                   
                 EPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLM 
               
               
                   
                   
                 ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT 
               
               
                   
                   
                 KPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK 
               
               
                   
                   
                 ALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQV 
               
               
                   
                   
                 SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS 
               
               
                   
                   
                 DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT 
               
               
                   
                   
                 QKSLSLSPGK 
               
               
                   
                   
                 
                   L6-F7B LC SEQ ID NO: 266 
                 
               
               
                   
                   
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQ 
                 
               
               
                   
                   
                 
                   QKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLT 
                 
               
               
                   
                   
                   ISSLQPEDFATYYCQQSYTTPPTFGQGTKVEIK R   GGG     
               
               
                   
                   
                 
                   
                     GSGGGGSGGGGS 
                   
                   DIQMTQSPSSLSASVGDRVTITCRA 
                 
               
               
                   
                   
                 
                   SQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRF 
                 
               
               
                   
                   
                 
                   SGSRSGTDFTLTISSLQPEDFATYYCQQYYSLFTFGQ 
                 
               
               
                   
                   
                   GTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLN 
               
               
                   
                   
                 NFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS 
               
               
                   
                   
                 LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR 
               
               
                   
                   
                 GEC 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   RSPO2RA- 
                   
                     L6-F12578 
                   
                 
                 RSPO2RA-L6-F12578 LC SEQ ID NO: 267                  
                  
                  
    SGGGGSGGGGS     DIQMTQSPSSLSASVGDRVTITCRAS   QDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFS   GSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPTFGQ   GTKVEIK     GGGGSGGGGSGGGGS     DIELTQPPSVSVAPG   QTARISCSGDNIGSFYVHWYQQKPGQAPVLVIYDKSN   RPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQS   YANTLSLVFGGGTKLTVL GQPKAAPSVTLFPPSSEEL 
               
               
                   
                   
                 QANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETT 
               
               
                   
                   
                 TPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEG 
               
               
                   
                   
                 STVEKTVAPTECS 
               
               
                   
                   
                 
                   L6-F12578 HC SEQ ID NO: 268 
                 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWV 
                 
               
               
                   
                   
                 
                   RQAPGKGLEWVAEISPYSGSTYYADSVKGRFTISADT 
                 
               
               
                   
                   
                 
                   SKNTAYLQMNSLRAEDTAVYYCALRARPPIRLHPRGS 
                 
               
               
                   
                   
                 
                   VMDYWGQGTLVTVSS 
                   
                     GGGGSGGGGSGGGGS 
                   
                   EVQLVES 
                 
               
               
                   
                   
                 
                   GGGGLVQPGGSLRLSCAASGFTFSHYTLSWVRQAPGKG 
                 
               
               
                   
                   
                 
                   LEWVSVISGDGSYTYYADSVKGRFTISSDNSKNTLYL 
                 
               
               
                   
                   
                 
                   QMNSLRAEDTAVYYCARNFIKYVFANWGQGTLVTVSS 
                 
               
               
                   
                   
                 ASTKGPSVFPLAPSSKSTSGGTAALGCSLVKDYFPEPV 
               
               
                   
                   
                 TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS 
               
               
                   
                   
                 SLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP 
               
               
                   
                   
                 CPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVD 
               
               
                   
                   
                 VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
               
               
                   
                   
                 VSVLTVTLHQDWLNGKEYKCKVSNKALGAPIEKTISDKA 
               
               
                   
                   
                 KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD 
               
               
                   
                   
                 IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD 
               
               
                   
                   
                 KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
               
            
           
           
               
               
               
            
               
                 
                   
                     RSPO2RA-N-LC-Fv-IgG 
                   
                 
                 
                   LSPO2RA- 
                 
                 
                   RSPO2RA-L6-F127 LC SEQ ID NO: 269 
                 
               
               
                   
                 
                   
                     L6-F127 
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
            
           
           
               
               
               
            
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     SGGGGSGGGGS 
                   
                   DIQMTQSPSSLSASVGDRVTITCRAS 
                 
               
               
                   
                   
                 
                   QDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFS 
                 
               
               
                   
                   
                 
                   GSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPTFGQ 
                 
               
               
                   
                   
                 
                   GTKVEIK 
                   
                     GGGGSGGGGSGGGGS 
                   
                   DIQMTQSPSSLSASV 
                 
               
               
                   
                   
                 
                   GDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSAS 
                 
               
               
                   
                   
                 
                   SLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQ 
                 
               
               
                   
                   
                   QYWYGVAPITFGQGTKVEIK RTVAAPSVFIFPPSDEQ 
               
               
                   
                   
                 LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQE 
               
               
                   
                   
                 SVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH 
               
               
                   
                   
                 QGLSSPVTKSFNRGEC 
               
               
                   
                   
                 
                   L6-F127 HC SEQ ID NO: 270 
                 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWV 
                 
               
               
                   
                   
                 
                   RQAPGKGLEWVAEISPYSGSTYYADSVKGRFTISADT 
                 
               
               
                   
                   
                 
                   SKNTAYLQMNSLRAEDTAVYYCALRARPPIRLHPRGS 
                 
               
               
                   
                   
                 
                   VMDYWGQGTLVTVSS 
                   
                     GGGGSGGGGSGGGGS 
                   
                   EVQLVES 
                 
               
               
                   
                   
                 
                   GGGLVQPGGSLRLSCAASGFNISSSYIHWVRQAPGKG 
                 
               
               
                   
                   
                 
                   LEWVAYIYSSYGSTYYADSVKGRFTISADTSKNTAYL 
                 
               
               
                   
                   
                   QMNSLRAEDTAVYYCARASWYALDYWGQGTLVTVSS A 
               
               
                   
                   
                 STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT 
               
               
                   
                   
                 VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSS 
               
               
                   
                   
                 LGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC 
               
               
                   
                   
                 PAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV 
               
               
                   
                   
                 SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV 
               
               
                   
                   
                 SVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAK 
               
               
                   
                   
                 GQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI 
               
               
                   
                   
                 AVEWESNGQPENNYKTTPPVLDSDGSFFLYSLKLTVDK 
               
               
                   
                   
                 SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
               
               
                 
                   
                     RSPO2RA-N-LC-Fv-IgG 
                   
                 
                 
                   RSPO2RA- 
                 
                 
                   RSPO2RA-L6-F58 LC SEQ ID NO: 271 
                 
               
               
                   
                 
                   
                     L6-F58 
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     SGGGGSGGGGS 
                   
                   DIQMTQSPSSLSASVGDRVTITCRAS 
                 
               
               
                   
                   
                 
                   QDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFS 
                 
               
               
                   
                   
                 
                   GSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPTFGQ 
                 
               
               
                   
                   
                   GTKVEIK     GGGGSGGGGSGGGGS   D IQMTQSPSSLSASV   
               
               
                   
                   
                 
                   GDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSAS 
                 
               
               
                   
                   
                 
                   SLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQ 
                 
               
               
                   
                   
                   QWYSSGHVLITFGQGTKVEIK RTVAAPSVFIFPPSDE 
               
               
                   
                   
                 QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQ 
               
               
                   
                   
                 ESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVT 
               
               
                   
                   
                 HQGLSSPVTKSFNRGEC 
               
               
                   
                   
                 
                   L6-F58 HC SEQ ID NO: 272 
                 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWV 
                 
               
               
                   
                   
                 
                   RQAPGKGLEWVAEISPYSGSTYYADSVKGRFTISADT 
                 
               
               
                   
                   
                 
                   SKNTAYLQMNSLRAEDTAVYYCALRARPPIRLHPRGS 
                 
               
               
                   
                   
                 
                   VMDYWGQGTLVTVSS 
                   
                     GGGGSGGGGSGGGGS 
                   
                   EVQLVES 
                 
               
               
                   
                   
                 
                   GGGLVEQPGGSLRLSCAASGFNISYSYIHWVRQAPGKG 
                 
               
               
                   
                   
                 
                   LEWVASIYSSSGSTSYADSVKGRFTISADTSKNTAYL 
                 
               
               
                   
                   
                   QMNSLRAEDTAVYYCARGAIDYWGQGTLVTVSS ASTK 
               
               
                   
                   
                 GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW 
               
               
                   
                   
                 NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT 
               
               
                   
                   
                 QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP 
               
               
                   
                   
                 EAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE 
               
               
                   
                   
                 DPEVKFNWYDGVEVHNAKTKPREEQYNSTYRVVSVL 
               
               
                   
                   
                 TVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQP 
               
               
                   
                   
                 REPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE 
               
               
                   
                   
                 WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW 
               
               
                   
                   
                 QQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
               
               
                 
                   
                     RSPO2RA-N-LC-Fv-IgG 
                   
                 
                 
                   RSPO2RA- 
                 
                 
                   RSPO2RA-L6-F4-2 LC SEQ ID NO: 273 
                 
               
               
                   
                 
                   
                     L6-F4-2 
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     SGGGGSGGGG 
                   
                   DIQMTQSPSSLSASVGDRVTITCRASQ 
                 
               
               
                   
                   
                 
                   DVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSG 
                 
               
               
                   
                   
                 
                   SGSGTDFTLTISSLQPEDFATYYCQQSYTTPPTFGQG 
                 
               
               
                   
                   
                 
                   TKVEIK 
                   
                     GGGGSGGGGSGGGGS 
                   
                   DIQMTQSPSSLSASVG 
                 
               
               
                   
                   
                 
                   DRVTITCRASQSVSSAVAWYGGKPGKAPKLLIYSASS 
                 
               
               
                   
                   
                 
                   LYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQ 
                 
               
               
                   
                   
                   SYAAYLFTFGQGTKVEIK RTVAAPSVFIFPPSDEQLK 
               
               
                   
                   
                 SGTASVVCLLNNFYPREAKVQWKVDNALQSGANSQESV 
               
               
                   
                   
                 TEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQG 
               
               
                   
                   
                 LSSPVTKSFNRGEC 
               
               
                   
                   
                 
                   L6-F4-2 HC SEQ ID NO: 274 
                 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWV 
                 
               
               
                   
                   
                 
                   RQAPGKGLEWVAEISPYSGSTYYADSVKGRFTISADT 
                 
               
               
                   
                   
                 
                   SKNTAYLQMNSLRAEDTAVYYCALRARPPIRLHPRGS 
                 
               
               
                   
                   
                 
                   VMDYWGQGTLVTVSS 
                   
                     GGGGSGGGGSGGGGS 
                   
                   EVQLVES 
                 
               
               
                   
                   
                 
                   GGGLVQPGGSLRLSCAASGFNISYYYIHWVRQAPGKG 
                 
               
               
                   
                   
                 
                   LEWVASIYPSSGYTYYADSVKGRFTISADTSKNTAYL 
                 
               
               
                   
                   
                 
                   QMNSLRAEDTAVYYCARSSFYWAMDYWGQGTLVTVSS 
                 
               
               
                   
                   
                 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV 
               
               
                   
                   
                 TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS 
               
               
                   
                   
                 SLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP 
               
               
                   
                   
                 CPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVD 
               
               
                   
                   
                 VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
               
               
                   
                   
                 VSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKA 
               
               
                   
                   
                 KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD 
               
               
                   
                   
                 IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD 
               
               
                   
                   
                 KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
               
               
                 
                   
                     RSPO2RA-N-LC-Fv-IgG 
                   
                 
                 
                   RSPO2RA- 
                 
                 
                   RSPO2RA-L6-F4 LC SEQ ID NO: 275 
                 
               
               
                   
                 
                   
                     L6-F4 
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     SGGGGSGGGGS 
                   
                   DIQMTQSPSSLSASVGDRVTITCRAS 
                 
               
               
                   
                   
                 
                   QDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFS 
                 
               
               
                   
                   
                 
                   GSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPTFGQ 
                 
               
               
                   
                   
                 
                   GTKVEIK 
                   
                     GGGGSGGGGSGGGGS 
                   
                   DIQMTQSPSSLSASV 
                 
               
               
                   
                   
                 
                   GDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSAS 
                 
               
               
                   
                   
                 
                   SLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQ 
                 
               
               
                   
                   
                   QWYYAPITFGQGTKVEIK RTVAAPSVFIFPPSDEQLK 
               
               
                   
                   
                 SGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESV 
               
               
                   
                   
                 TEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQG 
               
               
                   
                   
                 LSSPVTKSFNRGEC 
               
               
                   
                   
                 
                   L6-F4 HC SEQ ID NO: 276 
                 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWV 
                 
               
               
                   
                   
                 
                   RQAPGKGLEWVAEISPYSGSTYYADSVKGRFTISADT 
                 
               
               
                   
                   
                 
                   SKNTAYLQMNSLRAEDTAVYYCALRARPPIRLHPRGS 
                 
               
               
                   
                   
                 
                   VMDYWGQGTLVTVSS 
                   
                     GGGGSGGGGSGGGGS 
                   
                   EVQLVES 
                 
               
               
                   
                   
                 
                   GGGLVQPGGSLRLSCAASGFNLSSYSMHWVRQAPGKG 
                 
               
               
                   
                   
                 
                   LEWVAYISSYYGYTYYADSVKGRFTISADTSKNTAYL 
                 
               
               
                   
                   
                 
                   QMNSLRAEDTAVYYCARPAPGHWGFDYWGQGTLVTVS 
                 
               
               
                   
                   
                   S ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP 
               
               
                   
                   
                 VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS 
               
               
                   
                   
                 SSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP 
               
               
                   
                   
                 PCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV 
               
               
                   
                   
                 DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR 
               
               
                   
                   
                 VVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISK 
               
               
                   
                   
                 AKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS 
               
               
                   
                   
                 DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV 
               
               
                   
                   
                 DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
               
               
                 
                   
                     RSPO2RA-N-LC-Fv-IgG 
                   
                 
                 
                   RSPO2RA- 
                 
                 
                   RSPO2RA-L6-F49 LC SEQ ID NO: 277 
                 
               
               
                   
                 
                   
                     L6-F49 
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     SGGGGSGGGGS 
                   
                   DIQMTQSPSSLSASVGDRVTITCRAS 
                 
               
               
                   
                   
                 
                   QDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFS 
                 
               
               
                   
                   
                 
                   GSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPTFGQ 
                 
               
               
                   
                   
                 
                   GTKVEIKR 
                   
                     GGGGSGGGGSGGGGS 
                   
                   DIQMTQSPSSPSAS 
                 
               
               
                   
                   
                 
                   VGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAA 
                 
               
               
                   
                   
                 
                   SSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC 
                 
               
               
                   
                   
                   QQSYSTPLTFGGGGTKVEIK RTVAAPSVFIFPPSDEQL 
               
               
                   
                   
                 KSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQES 
               
               
                   
                   
                 VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ 
               
               
                   
                   
                 GLSSPVTKSFNRGEC 
               
               
                   
                   
                 
                   L6-F49 HC SEQ ID NO: 278 
                 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWV 
                 
               
               
                   
                   
                 
                   RQAPGKGLEWVAEISPYSGSTYYADSVKGRFTISADT 
                 
               
               
                   
                   
                 
                   SKNTAYLQMNSLRAEDTAVYYCALRARPPIRLHPRGS 
                 
               
               
                   
                   
                 
                   VMDYWGQGTLVTVSS 
                   
                     GGGGSGGGGSGGGGS 
                   
                   EVQLVQS 
                 
               
               
                   
                   
                 
                   GAEVKKPGASVKVSCKASGGTFSSYAISWVRQAPGQG 
                 
               
               
                   
                   
                 
                   LEWMGWINAGNGNTTYAQKFQGRVTMTRDTSTSTVYM 
                 
               
               
                   
                   
                 
                   ELSSLRSEDTAVYYCARGYYGSGSYPDWGQGTLVTVS 
                 
               
               
                   
                   
                   S ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP 
               
               
                   
                   
                 VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS 
               
               
                   
                   
                 SSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP 
               
               
                   
                   
                 PCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV 
               
               
                   
                   
                 DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR 
               
               
                   
                   
                 VVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISK 
               
               
                   
                   
                 AKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS 
               
               
                   
                   
                 DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV 
               
               
                   
                   
                 DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
               
               
                 
                   
                     RSPO2RA-N-LC-Fv-IgG 
                   
                 
                 
                   RSPO2RA- 
                 
                 
                   RSPO2RA-L6-F10 LC SEQ ID NO: 279 
                 
               
               
                   
                 
                   
                     L6-F10 
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     SGGGGSGGGGS 
                   
                   DIQMTQSPSSLSASVGDRVTITCRAS 
                 
               
               
                   
                   
                 
                   QDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFS 
                 
               
               
                   
                   
                 
                   GSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPTFGQ 
                 
               
               
                   
                   
                 
                   GTKVEIK 
                   
                     GGGGSGGGGSGGGGS 
                   
                   ELTQPPSVSVSPGQT 
                 
               
               
                   
                   
                 
                   ARITCSGDGSYAGSYYYGWYQQKPGQAPVTLIYYNNK 
                 
               
               
                   
                   
                 
                   RPSGIPERFSGSLSGSTNTLTISGVQAEDEADYYCGS 
                 
               
               
                   
                   
                   ADNSGAAFGGGTKL TVLRTVAAPSVFIFPPSDEQLKS 
               
               
                   
                   
                 GTASVVCLLNNFYPREAKVQWKVDNALQSGNGQESVT 
               
               
                   
                   
                 EQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGL 
               
               
                   
                   
                 SSPVTKSFNRGEC 
               
               
                   
                   
                 
                   L6-F10 HC SEQ ID NO: 280 
                 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWV 
                 
               
               
                   
                   
                 
                   RQAPGKGLEWVAEISPYSGSTYYADSVKGRFTISADT 
                 
               
               
                   
                   
                 
                   SKNTAYLQMNSLRAEDTAVYYCALRARPPIRLHPRGS 
                 
               
               
                   
                   
                 
                   VMDYWGQGTLVTVSS 
                   
                     GGGGSGGGGSGGGGS 
                   
                   EVQLVES 
                 
               
               
                   
                   
                 
                   GGGLVQPGGSLRLSCAASGFTFSSFNMFWVRQAPGKG 
                 
               
               
                   
                   
                 
                   LEWVAGIDDDGSYPNYGSAVKGRATISRDNSKNTLYL 
                 
               
               
                   
                   
                 
                   QMNSLRAEDTAVYYCAKSGYSSSWGGYIADDIDAWGQ 
                 
               
               
                   
                   
                   GTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLV 
               
               
                   
                   
                 KDYFPEPVTVSWNSGALTSGVGTFPAVLQSSGLYSLS 
               
               
                   
                   
                 SVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC 
               
               
                   
                   
                 DKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTP 
               
               
                   
                   
                 EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE 
               
               
                   
                   
                 QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAP 
               
               
                   
                   
                 IEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCL 
               
               
                   
                   
                 VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF 
               
               
                   
                   
                 LYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS 
               
               
                   
                   
                 LSPGK 
               
               
                 
                   
                     RSPO2RA-N-LC-Fv-IgG 
                   
                 
                 
                   RSPO2RA- 
                 
                 
                   RSPO2RA-L6-F2I LC SEQ ID NO: 281 
                 
               
               
                   
                 
                   
                     L6-F7I 
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   SGGGGSGGGGS 
                   DIQMTQSPSSLSASVGDRVTITCRAS 
                 
               
               
                   
                   
                 
                   QDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFS 
                 
               
               
                   
                   
                 
                   GSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPTFGQ 
                 
               
               
                   
                   
                 
                   GTKVEIKR 
                   
                     GGGGSGGGGSGGGGS 
                   
                   DIQMTQSPSSLSAS 
                 
               
               
                   
                   
                 
                   VGDRVTITCRASQXVXXAVAWYQQKPGKAPKLLIYSA 
                 
               
               
                   
                   
                 
                   SSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYC 
                 
               
               
                   
                   
                   QQGVYLFTFGQGTKVEIK RTVAAPSVFIFPPSDEQLK 
               
               
                   
                   
                 SGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESV 
               
               
                   
                   
                 TEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQG 
               
               
                   
                   
                 LSSPVTKSFNRGEC 
               
               
                   
                   
                 
                   L6-F2I HC SEQ ID NO: 282 
                 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWV 
                 
               
               
                   
                   
                 
                   RQAPGKGLEWVAEISPYSGSTYYADSVKGRFTISADT 
                 
               
               
                   
                   
                 
                   SKNTAYLQMNSLRAEDTAVYYCALRARPPIRLHPRGS 
                 
               
               
                   
                   
                 
                   VMDYWGQGTLVTVSS 
                   
                     GGGGSGGGGSGGGGS 
                   
                   EVQLVES 
                 
               
               
                   
                   
                 
                   GGGLVQPGGSLRLSCAASGFNIHSSSIHWVRQAPGKG 
                 
               
               
                   
                   
                 
                   LEWVAATYSSFGSITYADSVKGRFTISADTSKNTAYL 
                 
               
               
                   
                   
                 
                   QMNSLRAEDTAVYYCARYHHPFGYALDYWGQGTLVTV 
                 
               
               
                   
                   
                   SS ASTKGPSVFPLAPSSKSTSGGTAALGCLVDKYFPE 
               
               
                   
                   
                 PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP 
               
               
                   
                   
                 SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTC 
               
               
                   
                   
                 PPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVV 
               
               
                   
                   
                 VDVSHEDPEVKFNWYDGVEVHNAKTKPREEQYNSTY 
               
               
                   
                   
                 RVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTIS 
               
               
                   
                   
                 KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP 
               
               
                   
                   
                 SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT 
               
               
                   
                   
                 VDKSRWQQGNVFSCSVMHEALHNHYTQSLSLSPGK 
               
               
                 
                   
                     RSPO2RA-N-LC-Fv-IgG 
                   
                 
                 
                   RSPO2RA- 
                 
                 
                   RSPO2RA-L6-F7B LC SEQ ID NO: 283 
                 
               
               
                   
                 
                   
                     L6-F7B 
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     SGGGGSGGGGS 
                   
                   DIQMTQSPSSLSASVGDRVTITCRAS 
                 
               
               
                   
                   
                 
                   QDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFS 
                 
               
               
                   
                   
                 
                   GSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPTFGQ 
                 
               
               
                   
                   
                 
                   GTKVEIKR 
                   
                     GGGGSGGGGSGGGGS 
                   
                   DIQMTQSPSSLSAS 
                 
               
               
                   
                   
                 
                   VGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSA 
                 
               
               
                   
                   
                 
                   SSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYC 
                 
               
               
                   
                   
                   QQYYSLFTFGQGTKVEIK RTVAAPSVFIFPPSDEQLK 
               
               
                   
                   
                 SGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESV 
               
               
                   
                   
                 TEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQG 
               
               
                   
                   
                 LSSPVTKSFNRGEC 
               
               
                   
                   
                 
                   L6-F7B HC SEQ ID NO: 284 
                 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWV 
                 
               
               
                   
                   
                 
                   RQAPGKGLEWVAEISPYSGSTYYADSVKGRFTISADT 
                 
               
               
                   
                   
                 
                   SKNTAYLQMNSLRAEDTAVYYCALRARPPIRLHPRGS 
                 
               
               
                   
                   
                 
                   VMDYWGQGTLVTVSS 
                   
                     GGGGSGGGGSGGGGS 
                   
                   EVQLVES 
                 
               
               
                   
                   
                 
                   GGGLVQPGGSLRLSCAASGFNFSSSSIHWVRQAPGKG 
                 
               
               
                   
                   
                 
                   LEWVAYIYPSYDTYYADSVKGRFTISADTSKNTAYL 
                 
               
               
                   
                   
                 
                   QMNSLRAEDTAVYYCARGYFYTWGGMDYWGQGTLVTV 
                 
               
               
                   
                   
                   SS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPE 
               
               
                   
                   
                 PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP 
               
               
                   
                   
                 SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTC 
               
               
                   
                   
                 PPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVV 
               
               
                   
                   
                 VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY 
               
               
                   
                   
                 RVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTIS 
               
               
                   
                   
                 KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP 
               
               
                   
                   
                 SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT 
               
               
                   
                   
                 VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   L6-F4-2- 
                   
                     RSPO2RA 
                   
                 
                   L6-F4-2-RSPORA LC SEQ ID NO: 285   DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQ   QKPGKAPLLIYSASFLYSGVPSRFSGSGSGTDFTLT   ISSLQPEDFATYYCQQSYTTPPTFGQGTKVEIKGGGG     SGGGGSGGGGS     DIQMTQSPSSLSASVGDRVTITCRAS   QSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFS  GSRSGTDFTLTISSLQPEDFATYYCQQSYAAYLFTFG  QGTKVDIK RTVAAPSVFIFPPSDEQLKSGTASVVCLL NNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTY SLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC   GGGGSGSGGSGGGGS     NPICKGCLSCSKDNGCSR   CQQKLFFFLRREGMRQYGECLHSCPSGYYGHRAPDMN  RCARCRIENCDSCRDKDACTKCKVGFYLHRGRCFDEC PDGFAPLEETMECVE 
               
               
                   
                   
                 
                   L6-F4-2-5063 HC SEQ ID NO: 286 
                 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWV 
                 
               
               
                   
                   
                 
                   RQAPGKGLEWVAEISPYSGSTYYADSVKGRFTISADT 
                 
               
               
                   
                   
                 
                   SKNTAYLQMNSLRAEDTAVYYCALRARPPIRLHPRGS 
                 
               
               
                   
                   
                 
                   VMDYWGQGTLVTVSS 
                   
                     GGGGSGGGGSGGGGS 
                   
                   EVQLVES 
                 
               
               
                   
                   
                 
                   GGGLVQPGGSLRLSCAASGFNISYYYIHWVRQAPGKG 
                 
               
               
                   
                   
                 
                   LEWVASIYPSSGYTYYADSVKGRFTISADTSKNTAYL 
                 
               
               
                   
                   
                 
                   QMNSLRAEDTAVYYCARSSFYWAMDYWGQGTLVTVSS 
                 
               
               
                   
                   
                 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV 
               
               
                   
                   
                 TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS 
               
               
                   
                   
                 SLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP 
               
               
                   
                   
                 CPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVD 
               
               
                   
                   
                 VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
               
               
                   
                   
                 VSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKA 
               
               
                   
                   
                 KGPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD 
               
               
                   
                   
                 IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD 
               
               
                   
                   
                 KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
               
               
                 
                   
                     RSPO2RA C-LC-Fv-IgG 
                   
                 
                 
                   L6-F4- 
                 
                 
                   L6 F4 RSPORA LC SEQ ID NO: 287 
                 
               
               
                   
                 
                   
                     RSPO2RA 
                   
                 
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQ 
                 
               
               
                   
                   
                 
                   QKPKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLT 
                 
               
               
                   
                   
                 
                   ISSLQPEDFATYYCQQSYTTPPTFGQGTKVEIK 
                   
                     GGGG 
                   
                 
               
               
                   
                   
                 
                   
                     SGGGGSGGGGS 
                   
                   DIQMTQSPSSLSASVGDRVTITCRAS 
                 
               
               
                   
                   
                 
                   QSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFS 
                 
               
               
                   
                   
                 
                   GSRSGTDFTLTISSLQPEDFATYYCQQWYYAPITFGQ 
                 
               
               
                   
                   
                   GTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLN 
               
               
                   
                   
                 NFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS 
               
               
                   
                   
                 LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNT 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
                 
                   L6-F4 HC SEQ ID NO: 288 
                 
               
               
                   
                   
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYYISWV 
                 
               
               
                   
                   
                 
                   RQAPGKGLEWVAEISPYSGSTYYADSVKGRFTISADT 
                 
               
               
                   
                   
                 
                   SKNTAYLQMNSLRAEDTAVYYCALRARPPIRLHPRGS 
                 
               
               
                   
                   
                 
                   VMDYWGQGTLVTVSS 
                   
                     GGGGSGGGGSGGGGS 
                   
                   EVQLVES 
                 
               
               
                   
                   
                 
                   GGGLVQPGGSLRLSCAASGFNLSSYSMHWVRQAPGKG 
                 
               
               
                   
                   
                 
                   LEWVAYISSYYGYTYYADSVKGRFTISADTSKNTAYL 
                 
               
               
                   
                   
                 
                   QMNSLRAEDTAVYYCARPAPGHWGFDYWGQGTLVTVS 
                 
               
               
                   
                   
                   S ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP 
               
               
                   
                   
                 VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS 
               
               
                   
                   
                 SSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP 
               
               
                   
                   
                 PCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV 
               
               
                   
                   
                 DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR 
               
               
                   
                   
                 VVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISK 
               
               
                   
                   
                 AKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS 
               
               
                   
                   
                 DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV 
               
               
                   
                   
                 DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                   
                     
                     
                         
                         
                     
                   
                   
                     Italic 
                       
                      underline: 
                       
                      linker 
                   
                 
               
               
                 
                   Bold: VH or VL 
                 
               
               
                 
                   “F” indicates Fzd binder and “aGFP” indicates anti-GFP antibody sequence 
                 
               
            
           
         
       
     
     Additional constructs with RSPO2RA fusions with other FZD and LRP binders (e.g., R2M3 (“F6) and 26 (“L2”)) were made having the RSPO2RA fusions at different locations on the IgG molecule. For example, the RSPO2RA protein was fused to C terminus of either the heavy or light chain of the IgG. As shown in  FIGS.  3 H and  31   , all of these FZD-RSPO2RA fusions resulted in RSPO mimetic activity, and additional fusion of a LRP binder resulted in super agonist activity. Therefore, these results demonstrated an approach to generate both RSPO mimetic as well as WNT super-agonists molecules that can target specific subsets of FZD receptors. 
     To further evaluate format and stoichiometry between different component, another set of molecules were generated between FZD and LRP binders and RSPO mutant as depicted in  FIG.  4 A ,  FIGS.  7  and  8   . The activities of these various molecules are shown in  FIGS.  4 B and  4 C . 
     Example 3 
     WNT Super Agonist Molecules Replace Both WNT and R-Spondin in Organoid Culture Expansion 
     Multiple tissues in the mammalian body are maintained by WNT-driven adult stem cells. Short-range Wnt signals are often further enhanced by local secretion of R-spondins. In this role, R-spondin acts as stem cell growth factor, but only in the presence of WNT. This pivotal interplay of WNT agonists in the stem cell niche is recapitulated in adult stem cell-derived organoid cultures. By providing niche signals in the culture medium, organoids can be maintained and expanded as self-organizing structures. Most of the media for epithelial organoid cultures is supplemented with R-spondin. The addition of R-spondin alone is sufficient if organoid cells secrete their own WNT proteins, such as, for example, Paneth cells in murine small intestinal organoids (Sato et al., 2009). Organoid cultures without endogenous WNT source, such as human intestinal organoids, require the addition of WNT&#39;s or WNT mimetics (Sato et al., 2011, Janda et al., 2017). Obtaining high quality WNT proteins and/or R-spondins for organoid medium can be laborious and costly. To test whether a single WNT super agonist molecule can replace both WNT and R-spondin in organoid medium, we tested the outgrowth efficiency of several different organoid cultures in the presence of L6-F12578-RSPO2RA. 
     We first examined the applicability of WNT super agonist in the expansion of mouse small intestinal organoids. Murine cells were grown in the presence of porcupine inhibitor C59 to block any endogenous WNT secretion. The addition of RSPO1, WNT3A or L6-F12578 alone had little to no effect on the growth of these cells ( FIG.  5 A,  5 B ). As expected, WNT3A plus RSPO1 and L6-F12578 plus RSPO1 stimulated the outgrowth of large cystic organoids in seven days. As shown in  FIG.  5 A-B , the WNT super agonist L6-F12578-RSPO2RA alone at 0.1 nM was enough to stimulate maximal outgrowth. The addition of recombinant RSPO1 did not further enhance proliferation. Next, we looked at human small intestinal organoids, which require both exogenous WNT and RSPO1 in their expansion medium. While human small intestinal organoids had no response to recombinant WNT3A, a slight increase in outgrowth was observed with L6-F12578 alone ( FIG.  5 C,  5 D ). Similar as in mouse, the addition of L6-F12578-RSPO2RA alone at 1 nM displayed an activity level that is equivalent to L6-F12578 and RSPO1 combination ( FIG.  5 C-D ). To further investigate the applicability of WNT super agonist in other cell types and tissues, we tested the expansion of mouse hepatocytes and human tubuloids, two culture systems that depend on the presence of R-spondin in their medium (Hu et al., 2018, Schutgens et al., 2019). Similar to the experimental setup for mouse and human intestine, porcupine inhibitor C59 was added to block any endogenous WNT signal and for mouse hepatocytes we additionally removed GSK3 inhibitor CHIR99021 from the base medium. Over the course of 14 days, murine hepatocytes cultured in L6-F12578-RSPO2RA expanded at a higher rate compared to L6-F12578 alone. The addition of recombinant RSPO1 to both conditions further enhanced outgrowth ( FIG.  5 E,  5 F ). The added effect of RSPO1 to L6-F12578-RSPO2RA can be due to a differential sensitivity to RSPO1 and RSPO2 but needs further investigation. Human kidney tubuloids cultured in L6-F12578-RSPO2RA alone rapidly expanded within one week to similar levels of the L6-F12578 and RSPO1 combination and outperforming recombinant WNT3A plus RSPO1 or surrogate WNT alone ( FIG.  5 G,  5 H ). Taken together, WNT super agonist can replace WNT3A and RSPO in organoids cultures from intestine, liver and kidney for both mouse and human. We expect L6-F12578-RSPO2RA and other WNT super agonists to outperform recombinant WNT, RSPO and WNT- and RSPO-conditioned media for a wide variety of other organoid models. 
     Example 4 
     In Vivo Effects of WNT Mimetic Molecules 
     The effects of WNT mimetic of different FZD specificity has not been fully explored previously. To test the in vivo effect of WNT mimetics with different FZD specificity, the panel of WNT mimetics described in  FIG.  1    were dosed at 3 mg per kg intraperitoneally on day 0, 3, 7 and 10 in C57Bl/6J mice. Since we have previously established the effects of FZD1,2,7 WNT mimetics on bone formation in vivo (PCT Publication WO 2019/126398), we tested whether other FZD specificity could also impact bone formation. Compared to baseline at day 0, the whole-body bone mineral densities (BMD) were increased by 39%, 38%, 29% and 11% in the groups of L6-F12578, L6-F127, L6-F58, and L6-F4 at day 13 (P&lt;0.001), respectively ( FIG.  6 A ). Similarly, the BMDs of femur and lumbar were increased up to 60% in the groups of L6-F12578, L6-F127, L6-F58, and L6-F4 at day 13 (P&lt;0.001) ( FIG.  6 B , C). These data not only confirmed our previous finding that FZD 1,2,7  specific WNT mimetics induce bone formation, but also suggest that FZD 5,8  specific WNT mimetics and FZD 4  specific WNT mimetics can also induce bone formation. 
     The body weights of the various treatment groups were also evaluated, and animals treated with L6-F12578 and L6-F127 groups showed significant reduction ( FIG.  6 D ). This weight reduction may be predominately contributed by decreased body fat content as seen on day 7 and 13 by DEXA analysis ( FIG.  6 E ). The other significant changes observed in the treated animals were the significant increases in salivary gland weight in the groups of L6-F12578, L6-F127, L6-F4, and L6-F10 compared with Vehicle group on day 14, by 101% (P&lt;0.001), 114% (P&lt;0.001), 29% (p&lt;0.01) and 22% (P&lt;0.05) respectively ( FIG.  6 F ), where the effects of L6-F12578 and L6-F127 being the most pronounced. We observed wet fur and fur color change (brown) during day 7-14 of the mice in the groups of L6-F12578, L6-F127. Significant increase in liver and intestine weights have also been observed in several treatment groups ( FIG.  6 G,  6 H ). The liver weight increased by 28% (P&lt;0.001) in L6-F12578 group and by 48% (P&lt;0.001) in L6-F4 group, and the small intestine weight increased by 21% (P&lt;0.05), 31% (P&lt;0.001), 30% (p&lt;0.01) and 24% (P&lt;0.05) in the group of L6-F12578, L6-F58, L6-F4, and L6-F49, respectively. 
     All of the above U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the Application Data Sheet, are incorporated herein by reference, in their entirety. 
     From the foregoing it will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention, and the various embodiments described above can be combined to provide further embodiments. Accordingly, the invention is not limited except as by the appended claims. Aspects of the embodiments can be modified, if necessary to employ concepts of the various patents, applications and publications disclosed herein to provide yet further embodiments. These and other changes can be made to the embodiments in light of the above-detailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims, but should be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure. 
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