TRISPECIFIC COMPOSITIONS COMPRISING IL-2, VEGF BINDING DOMAINS, AND PD-1 BINDING DOMAINS

[0001] This application is continuation of claims the benefit of U.S. patent application Ser. No. 19/359,286, filed Oct. 15, 2025, which claims the benefit of U.S. Provisional Application No. 63/708,077, filed Oct. 16, 2024, and U.S. Provisional Application No. 63/739,330, filed Dec. 27, 2024, which applications are incorporated by reference in their entirety.

[0002] The instant application contains a Sequence Listing which has been submitted electronically in XML file format and is hereby incorporated by reference in its entirety. Said XML copy, created on Mar. 16, 2026, is named 56146-746_301_SL.xml and is 764,075 bytes in size.

[0003] Described herein are multifunctional immunocytokine compositions which comprise a PD-1 binding domain, a VEGFA binding domain, and a cytokine. In some embodiments, the cytokine is an IL-2 polypeptide. Such compositions are useful in the treatment of diseases and disorders such as cancer.

[0004] In some embodiments of a multifunctional immunocytokine composition, the VEGFA binding domain and PD-1 binding domain and/or IL-2 polypeptide exhibit cooperative behavior such that binding of the VEGFA binding domain to VEGFA (e.g., VEGF dimers) results in enhanced anti-PD-1 activity and/or enhanced IL-2 activity. In some embodiments, this cooperative behavior results from a non-covalent multimerization of the immunocytokine composition when the VEGFA binding domain binds to VEGFA. For example, in some embodiments, a first molecule of the multifunctional immunocytokine can bind to a monomer of a VEGF dimer in situ and a second molecule of the multifunctional immunocytokine can bind to the other monomer of the VEGF dimer, thus forming, in essence, a non-covalent multimer of the multifunctional immunocytokine. Once formed, the multimer can exhibit enhanced anti-PD-1 and/or enhanced IL-2 activity (e.g., by avidity-like effects) compared to the multifunctional immunocytokine without the presence of VEGFA. Thus, in some embodiments, multifunctional immunocytokines of the instant disclosure can provide for delivery of PD-1 and/or IL-2 to a subject with increased therapeutic index by optimizing the activity in tumor microenvironments where VEGFA is present.

[0005] In some embodiments, a multifunctional immunocytokine of the instant disclosure utilizes an IL-2 polypeptide with reduced activity compared to wild type IL-2 (SEQ ID NO: 701, human IL-2). In some embodiments, use of such an IL-2 polypeptide allows for reduced off-target effects as the IL-2 can be sufficiently active due to the targeting nature of the other components of the immunocytokine and/or the multimerization effects described supra, yet will be less active outside of target tissue, thereby enhancing therapeutic index.

[0006] In some embodiments, an IL-2 polypeptide of the instant disclosure exhibits reduced binding to heparin compared to other IL-2 polypeptides or to wild type IL-2. In some embodiments, the reduced binding to heparin can impart favorable characteristics to the immunocytokine composition, such as enhanced PK, half-life, bioavailability, and biodistribution due to the prevention of accumulation of the immunocytokine composition in heparin rich tissues.

[0007] Also described herein are novel anti-VEGFA and PD-1 binding domains with certain advantages over those otherwise known. Such binding domains in some instances have optimal properties for inclusion in an immunocytokine composition of the instant disclosure.

[0008] Further provided herein are methods of treating cancer and other disease with the aforementioned compositions, as well as pharmaceutical compositions comprising the same.

[0009] In an aspect, the present disclosure provides a composition, comprising: a) a first binding domain targeting programmed cell death protein 1 (PD-1); b) a second binding domain targeting vascular endothelial growth factor A (VEGFA); and c) a cytokine, wherein each of the first binding domain, the second binding domain, and the cytokine are in covalent association.

[0010] In an aspect, the present disclosure provides a multifunctional immunocytokine composition, comprising: a) a first binding domain targeting programmed cell death protein 1 (PD-1); b) a second binding domain targeting vascular endothelial growth factor A (VEGFA); and c) a cytokine, wherein each of the first binding domain, the second binding domain, and the cytokine are in covalent association. In some embodiments, the cytokine is selected from an interleukin, a TNF family cytokine, an interferon, a TGF-b family cytokine, and a chemokine.

[0011] In some embodiments, the cytokine is an IL-2 polypeptide. In some embodiments, the IL-2 polypeptide comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% a sequence identity to wild type IL-2 (SEQ ID NO: 701). In some embodiments, the IL-2 polypeptide has reduced affinity for the IL-2 receptor beta subunit compared to the IL-2 of SEQ ID NO: 701. In some embodiments, the IL-2 polypeptide exhibits a reduced ability to signal through the IL-2 receptor beta/gamma complex compared to the IL-2 of SEQ ID NO: 701. In some embodiments, the IL-2 polypeptide retains the ability to bind to the IL-2 receptor alpha subunit and exhibits a diminished ability to bind to the IL-2 receptor beta or gamma subunits relative to SEQ ID NO: 701. In some embodiments, the IL-2 polypeptide has reduced affinity for heparin compared to the IL-2 of SEQ ID NO: 701. In some embodiments, the IL-2 polypeptide comprises a modified B′C′ loop region, wherein the modified B′C′ loop region comprises a deletion of one or more amino acids of the B′C′ loop region between amino acids 73 and 84 of the IL-2 polypeptide and insertion of an exogenous peptide into the B′C′ loop region, wherein residue position numbering is based on SEQ ID NO: 701 as a reference sequence. In some embodiments, the inserted peptide comprises the sequence GDGSIN (SE ID NO: 700). In some embodiments, the inserted peptide consists of the sequence GDGSIN. In some embodiments, the deletion of one or more amino acids of the B′C′ loop region comprises a deletion of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acids between amino acids 73 and 84 of the IL-2 polypeptide. In some embodiments, the deletion of one or more amino acids of the B′C′ loop region comprises a deletion of each of amino acids 74-83 of the IL-2 polypeptide. In some embodiments, the IL-2 polypeptide comprises a peptide sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to amino acids 1-73 of SEQ ID NO: 701 and a peptide sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to amino acids 84-133 of SEQ ID NO: 501. In some embodiments, the IL-2 polypeptide comprises a peptide sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 783. In some embodiments, the IL-2 polypeptide comprises a K76A or R81S substitution, or both. In some embodiments, the IL-2 polypeptide comprises polypeptide comprises an amino acid substitution at residue N88. In some embodiments, the IL-2 polypeptide comprises an N88D substitution. In some embodiments, the IL-2 polypeptide comprises a substitution at any one of residues L12, E15, L19, T123, Q126, or I129. In some embodiments, the IL-2 polypeptide comprises one or more substitutions selected from L12A, L12Y, E15D, E15S, L19A, L19D, T123A, Q126T, I129A, and I129K. In some embodiments, the IL-2 polypeptide comprises any one of the following sets of substitutions: Q126T; I129K; I129A, E15S, T123A; E15D; L12A, L19A, E15S; L12Y, L19D; L12A, L19A; or L19D. In some embodiments, the IL-2 polypeptide comprises an E15D or an L19D substitution. In some embodiments, the IL-2 polypeptide comprises a T3A substitution. In some embodiments, the IL-2 polypeptide comprises a C125S substitution. In some embodiments, the composition comprises the sequence set forth in any one of SEQ ID NOs: 702-783. In some embodiments, the IL-2 polypeptide is in covalent association via a fusion of the IL-2 polypeptide to the portion of the composition to which it is attached. In some embodiments, the IL-2 polypeptide is fused via its C-terminus.

[0012] In some embodiments, the first binding domain targeting programmed cell death protein 1 (PD-1) is capable of disrupting the interaction of PD-1 with programmed cell death ligand 1 (PD-L1). In some embodiments, the first binding domain is an antigen binding fragment derived from an antibody. In some embodiments, the first binding domain comprises a heavy chain variable domain (VH) comprising a heavy chain first complementary determining region (VH CDR1), a heavy chain second complementary determining region (VH CDR2), and a heavy chain third complementary determining region (VH CDR3). In some embodiments, the VH is comprised in a Fab, a Fab′, F(ab′)₂, a bispecific F(ab′)₂, a variable fragment (Fv), a single chain variable fragment (scFv), a bispecific scFv, disulfide stabilized Fv (dsFv), a minibody, a diabody, a bispecific diabody, triabody, a tetrabody, a maxibody, a camelid, a VHH, a Fab-Fc, a scFv-Fc, or a bispecific antibody. In some embodiments, the VH comprises a set of VH CDR1, VH CDR2, and VH CDR3 derived from an antibody in Table 1A, 1B, or 1C. In some embodiments, the VH comprise an amino acid sequence of a VH set forth in Table 1A, 1B, or 1C.

[0013] In some embodiments, the first binding domain is a VHH. In some embodiments, the first binding domain comprises: a) a VH CDR1 sequence of SEQ ID NO: 2; a VH CDR2 sequence of SEQ ID NO: 3; and a VH CDR3 sequence of SEQ ID NO: 4; b) a VH CDR1 sequence of SEQ ID NO: 6; a VH CDR2 sequence of SEQ ID NO: 7; and a VH CDR3 sequence of SEQ ID NO: 8; c) a VH CDR1 sequence of SEQ ID NO: 14; a VH CDR2 sequence of SEQ ID NO: 15; and a VH CDR3 sequence of CDR3 SEQ ID NO: 16; d) a VH CDR1 sequence of SEQ ID NO: 18; a VH CDR2 sequence of SEQ ID NO: 19; and a VH CDR3 sequence of CDR 3 of SEQ ID NO: 20; e) a VH CDR1 sequence of SEQ ID NO: 288, a VH CDR2 sequence of SEQ ID NO: 289, and a VH CDR3 sequence of SEQ ID NO: 290, or f) a VH CDR1, VH CDR2, and VHCDR3 of a VHH provided in Table 1C. In some embodiments, the VHH comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to any one of SEQ ID NOs: 1, 5, 13, 17, 287, or that of a VHH provided in Table 1C.

[0014] In some embodiments, the VH comprises: a) a VH CDR1 sequence of NYYMY (SEQ ID NO: 80), a VH CDR2 sequence of GINPSNGGTNFNEKFKN (SEQ ID NO: 81), and a VH CDR3 sequence of RDYRFDMGFDY (SEQ ID NO: 82); b) a VH CDR1 sequence of NSGMH (SEQ ID NO:86), a VH CDR2 sequence of VIWYDGSKRYYADSVKG (SEQ ID NO: 87), and a VH CDR3 sequence of NDDY (SEQ ID NO: 88); or c) a VH CDR1 sequence of GYTFTSYYMY (SEQ ID NO: 113), a VH CDR2 sequence of GVNPSNGGTNFNEKFKS (SEQ ID NO: 114), and a VH CDR3 sequence of RDYRYDMGFDY (SEQ ID NO: 115). In some embodiments, the VH comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to any one of SEQ ID NOs: 48, 50, or 76.

[0015] In some embodiments, the first binding domain comprises a light chain variable domain (VL) comprising a light chain first complementary determining region (VL CDR1), a light chain second complementary determining region (VL CDR2), and a light chain third complementary determining region (VL CDR3). In some embodiments, the VL is comprised in the Fab, Fab′, F(ab′)₂, bispecific F(ab′)₂, variable fragment (Fv), single chain variable fragment (scFv), bispecific scFv, disulfide stabilized Fv (dsFv), minibody, diabody, bispecific diabody, triabody, tetrabody, maxibody, Fab-Fc, scFv-Fc, or bispecific antibody in which the VH of the first binding domain is comprised. In some embodiments, the VL comprises a set of VL CDR1, VL CDR2, and VL CDR3 derived from an antibody in Table 1A or 1B. In some embodiments, the VL comprises: a) a VL CDR1 sequence of RASKGVSTSGYSYLH (SEQ ID NO: 83), a VL CDR2 sequence of LASYLES (SEQ ID NO: 84), and a VL CDR3 sequence of QHSRDLPLT (SEQ ID NO: 85); b) a VL CDR1 sequence of RASQSVSSYLA (SEQ ID NO: 89), a VL CDR2 sequence of DASNRAT (SEQ ID NO: 90), and a VL CDR3 sequence of QQSSNWPRT (SEQ ID NO: 91); or c) a VL CDR1 sequence of RASKGVSTSGYSYLH (SEQ ID NO: 83), a VL CDR2 sequence of LASYLE (SEQ ID NO: 117), and a VL CDR3 sequence of QHSRELPLT (SEQ ID NO: 118). In some embodiments, the VL comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to any one of SEQ ID NOs: 49, 51, or 77.

[0016] In some embodiments, the first binding domain comprises: a) a VH having a VH CDR1 sequence of NYYMY (SEQ ID NO: 80), a VH CDR2 sequence of GINPSNGGTNFNEKFKN (SEQ ID NO: 81), and a VH CDR3 sequence of RDYRFDMGFDY (SEQ ID NO: 82), and a VL having a VL CDR1 sequence of RASKGVSTSGYSYLH (SEQ ID NO: 83), a VL CDR2 sequence of LASYLES (SEQ ID NO: 84), and a VL CDR3 sequence of QHSRDLPLT (SEQ ID NO: 85); or b) a VH having a VH CDR1 sequence of NSGMH (SEQ ID NO: 86), a VH CDR2 sequence of VIWYDGSKRYYADSVKG (SEQ ID NO: 87), and a VH CDR3 sequence of NDDY (SEQ ID NO: 88), and a VL having a VL CDR1 sequence of RASQSVSSYLA (SEQ ID NO: 89), a VL CDR2 sequence of DASNRAT (SEQ ID NO: 90), and a VL CDR3 sequence of QQSSNWPRT (SEQ ID NO: 91; or c) a VH having a VH CDR1 sequence of GYTFTSYYMY (SEQ ID NO: 113), a VH CDR2 sequence of GVNPSNGGTNFNEKFKS (SEQ ID NO: 114), and a VH CDR3 sequence of RDYRYDMGFDY (SEQ ID NO: 115), and a VL having a VL CDR1 sequence of RASKGVSTSGYSYLH (SEQ ID NO: 83), a VL CDR2 sequence of LASYLE (SEQ ID NO: 117), and a VL CDR3 sequence of QHSRELPLT (SEQ ID NO: 118). In some embodiments, the first binding domain comprises: a) a VH comprising an amino acid sequence amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 48 and a VL comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 49; b) a VH comprising an amino acid sequence amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 50 and a VL comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 51; or c) a VH comprising an amino acid sequence amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 76 and a VL comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 77.

[0017] In some embodiments, the first binding domain is an scFv. In some embodiments, the first binding domain is a Fab.

[0018] In some embodiments, the second binding domain targeting VEGFA is capable of disrupting the interaction of VEGFA with one or more of its receptors. In some embodiments, the second binding domain is comprised in an antigen binding fragment derived from an antibody.

[0019] In some embodiments, the second binding domain comprises a heavy chain variable domain (VH) comprising a heavy chain first complementary determining region (VH CDR1), a heavy chain second complementary determining region (VH CDR2), and a heavy chain third complementary determining region (VH CDR3). In some embodiments, the VH is comprised in a Fab, a Fab′, F(ab′)₂, a bispecific F(ab′)₂, a variable fragment (Fv), a single chain variable fragment (scFv), a bispecific scFv, disulfide stabilized Fv (dsFv), a minibody, a diabody, a bispecific diabody, triabody, a tetrabody, a maxibody, a camelid, a VHH, a Fab-Fc, a scFv-Fc, or a bispecific antibody. In some embodiments, the VH comprises a set of VH CDR1, VH CDR2, and VH CDR3 derived from an antibody in Table 2A or 2B. In some embodiments, the VH comprises an amino acid sequence of a VH set forth in Table 2A, 2B, or 2C. In some embodiments, the VH comprises a VH CDR1 having a sequence GYTFTNYGMN (SEQ ID NO: 123), a VH CDR2 having a sequence WINTYTGEPTYAADFK (SEQ ID NO: 124), and a VH CDR3 having a sequence YPHYYGSSHWYFDV (SEQ ID NO: 125). In some embodiments, the VH comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 122. In some embodiments, the second binding domain comprises a light chain variable domain (VL) comprising a light chain first complementary determining region (VL CDR1), a light chain second complementary determining region (VL CDR2), and a light chain third complementary determining region (VL CDR3). In some embodiments, the VL is comprised in the Fab, Fab′, F(ab′)₂, bispecific F(ab′)₂, variable fragment (Fv), single chain variable fragment (scFv), bispecific scFv, disulfide stabilized Fv (dsFv), minibody, diabody, bispecific diabody, triabody, tetrabody, maxibody, Fab-Fc, scFv-Fc, or bispecific antibody in which the VH of the second binding domain is comprised. In some embodiments, the VL comprises a set of VL CDR1, VL CDR2, and VL CDR3 derived from an antibody in Table 2A or 2B. In some embodiments, the VL comprises a VL CDR1 having a sequence SASQDISNYLN (SEQ ID NO: 128), a VL CDR2 having a sequence FTSSLHS (SEQ ID NO: 129), and a VL CDR3 having a sequence QQYSTVPWT (SEQ ID NO: 130). In some embodiments, the VL comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 127. In some embodiments, the second binding domain comprises a VH having a VH CDR1 having a sequence GYTFTNYGMN (SEQ ID NO: 123), a VH CDR2 having a sequence WINTYTGEPTYAADFK (SEQ ID NO: 124), and a VH CDR3 having a sequence YPHYYGSSHWYFDV (SEQ ID NO: 125), and a VL having a VL CDR1 having a sequence SASQDISNYLN (SEQ ID NO: 128), a VL CDR2 having a sequence FTSSLHS (SEQ ID NO: 129), and a VL CDR3 having a sequence QQYSTVPWT (SEQ ID NO: 130). In some embodiments, the second binding domain comprises a VH comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 122 and a VL comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 127.

[0020] In some embodiments, the second binding domain is an scFv. In some embodiments, the second binding domain is a Fab.

[0021] In some embodiments, the second binding domain is a single domain antibody. In some embodiments, the second binding domain is a single domain heavy chain antibody (VHH). In some embodiments, the second binding domain comprises: a) a VH CDR1 sequence of AYPMM (SEQ ID NO: 202), a VH CDR2 sequence of EISPSGSYTYYADSVRG (SEQ ID NO: 203), and a VH CDR3 sequence of DPRKLDY (SEQ ID NO: 204); b) a VH CDR1 sequence of LYDMM (SEQ ID NO: 206), a VH CDR2 sequence of FIGGDGLNTYYADSVKG (SEQ ID NO: 207), and a VH CDR3 sequence of AGTQFDY (SEQ ID NO: 208); c) a VH CDR1 sequence of WYPMW (SEQ ID NO: 210), a VH CDR2 sequence of LIEGQGDRTYYADSVKG (SEQ ID NO: 211), and a VH CDR3 sequence of AGDRTAGSRGNSFDY (SEQ ID NO: 212); d) a VH CDR1 sequence of AYPMM (SEQ ID NO: 202), a VH CDR2 sequence of EISPSGSYTYYADSVKG (SEQ ID NO: 215), and a VH CDR3 sequence of DPRKFDY (SEQ ID NO: 216); or e) a VH CDR1 having the sequence SYSMG (SEQ ID NO: 218), a VH CDR2 having the sequence AISKGGYKYDAVSLEG (SEQ ID NO: 219) or the sequence of SEQ ID NO: 279, and a VH CDR3 having the sequence SRAYGSSRLRLADTYEY (SEQ ID NO: 220). In some embodiments, the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to any one of SEQ ID NOs: 200, 201, 205, 209, 213, 217, 221, or 280-284. In some embodiments, the second binding domain comprises a light chain single domain antibody. In some embodiments, the second binding domain comprises a VL CDR1 having the sequence RASQWIGPELS (SEQ ID NO: 223), a VL CDR2 having the sequence HTSILQS (SEQ ID NO: 224), and a VL CDR3 having the sequence QQYMFQPRT (SEQ ID NO: 225). In some embodiments, the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95&, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 222.

[0022] In some embodiments, the second binding domain is an anti-VEGFA anticalin. In some embodiments, the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 226.

[0023] In some embodiments, the composition comprises multiple copies of the first binding domain, the second binding domain, or both. In some embodiments, the composition comprises multiple copies of the second binding domain. In some embodiments, the composition comprises two copies of the second binding domain. In some embodiments, one of the copies of the second binding domain contains an extension of one or more amino acids on the second binding domain relative to the other copy. In some embodiments, the multiple copies of the second binding domain are present on the same polypeptide chain. In some embodiments, the multiple copies of the second binding domain are present on different polypeptide chains.

[0024] In some embodiments, the composition comprises an Fc domain comprising first CH2 and CH3 domains on a first polypeptide chain and second CH2 and CH3 domains on a second polypeptide chain. In some embodiments, the Fc domain is derived from an IgG. In some embodiments, the Fc domain is derived from an IgG1 or IgG4. In some embodiments, the composition comprises a structure of the formula:

wherein: Y is the first CH2 and CH3 domains; Y′ is the second CH2 and CH3 domains; X and X′ are each independently the first binding domain, the second binding domain, a copy of the first binding domain, a copy of the second binding domain, the cytokine, a copy of the cytokine, a masking polypeptide for the cytokine, or absent; Z and Z′ are each independently the first binding domain, the second binding domain, a copy of the first binding domain, a copy of the second binding domain, the cytokine, a copy of the cytokine, a third binding domain targeting PD-1, or a fourth binding domain targeting VEGFA, a masking polypeptide for the cytokine, or absent. C and C′ are each independently the cytokine, a copy of the cytokine, or absent, wherein C and C′, if present, are attached to a side chain of a residue of the Fc domain via a linker; wherein X, Y, and Z and X′, Y′ and Z′ are depicted in an N-terminal to C-terminal direction; and wherein each of X, X′, Z, and Z′ are independently and optionally connected to Y or Y′ via a peptide linker.

[0025] In some embodiments, X is the first binding domain; X′ is a copy of the first binding domain, the cytokine, or absent; one of Z or Z′ is the second binding domain and the other is absent, the cytokine, or a copy of the second binding domain; and one of C or C′ is the cytokine and the other is absent, or both C and C′ are absent. In some embodiments, X′ is the cytokine and C and C′ are both absent. In some embodiments, X′ is the copy of the first binding domain and one of C or C′ is the cytokine. In some embodiments, X′ is the copy of the first binding domain, one of Z or Z′ is the second binding domain and the other is the cytokine, and both C and C′ are absent. In some embodiments: Z is the second binding domain and Z′ is a copy of the second binding domain; Z is the second binding domain and Z′ is absent; or Z is absent and Z′ is the second binding domain. In some embodiments, X is the second binding domain, X′ is a copy of the second binding domain, the cytokine, or absent; one of Z or Z′ is the first binding domain and the other is absent, the cytokine, or a copy of the first binding domain; and one of C or C′ is the cytokine and the other is absent, or both C and C′ are absent. In some embodiments, X′ is the cytokine and C and C′ are both absent. In some embodiments, X′ is a copy of the second binding domain one of C or C′ is the cytokine. In some embodiments, X′ is the copy of the second binding domain, one of Z or Z′ is the second binding domain and the other is the cytokine, and both C and C′ are absent. In some embodiments: Z is the first binding domain and Z′ is a copy of the first binding domain; Z is the first binding domain and Z′ is absent; or Z is absent and Z′ is the first binding domain. In some embodiments, X is the first binding domain, X′ is the second binding domain, one of C or C′ is the cytokine and the other is absent, Z is absent or the third binding domain, and Z′ is absent or the fourth binding domain. In some embodiments: Z is the third binding domain and Z′ is absent; Z is absent and Z′ is the fourth binding domain; or both Z and Z′ are absent. In some embodiments, X is the first binding domain, X′ is the second binding domain, one of Z or Z′ is the cytokine and the other is the masking polypeptide for the cytokine, and both C and C′ are absent. In some embodiments, the masking polypeptide for the cytokine is attached to the Y or Y′ to which it is connected via a cleavable peptide linker. In some embodiments, if the third binding domain is present, the first binding domain comprises a Fab and the third binding domain comprises an scFv, and wherein the Fab and the scFv comprise the same VH and VL. In some embodiments, if the fourth binding domain is present, the second binding domain comprises a Fab and the fourth binding domain comprises an scFv, and wherein the Fab and the scFv comprise the same VH and VL. In some embodiments, X is one of the first or second binding domains and is a Fab, VHH, or scFv. In some embodiments, X is one of the first or second binding domains and is a Fab. In some embodiments, X′ is a copy of X. In some embodiments, one Z or Z′ is one of the first or second binding domains and is an scFv or a VHH, wherein if X is the first binding domain then Z or Z′ is the second binding domain and if X is the second binding domain then Z or Z′ is the first binding domain.

[0026] In some embodiments: X is a Fab and the first binding domain, X′ is a copy of the first binding domain, Z is an scFv or VHH and is the second binding domain, Z′ is a copy of the second binding domain, C is the cytokine, and C′ is absent; or X is a Fab and the second binding domain, X′ is a copy of the second binding domain, Z is an scFv or VHH and is the first binding domain, Z′ is a copy of the first binding domain, C is the cytokine, and C′ is absent; or X is a Fab and is the first binding domain, X′ is a Fab and is the second binding domain, Z and Z′ are absent, and C or C′ is the cytokine and the other is absent; X is a Fab and is the first binding domain, X′ is a Fab and is the second binding domain; Z is an scFv or VHH and is the third binding domain, Z′ is absent, and C or C′ is the cytokine and the other is absent; or X is a Fab and is the second binding domain, X′ is a Fab and is the first binding domain, Z is an scFv or VHH and is the fourth binding domain, Z′ is absent, and C or C′ is the cytokine and the other is absent; or X is a Fab and is the first binding domain, X′ is the cytokine, Z is an scFv or VHH and is the second binding domain, Z′ is a copy of the second binding domain, and C and C′ are both absent; or X is a Fab and is the second binding domain, X′ is the cytokine, Z is an scFv or VHH and is the first binding domain, Z′ is a copy of the first binding domain, and C and C′ are both absent; or X is a Fab and is the first binding domain, X′ is an scFv and is the second binding domain; Z and Z′ are both absent, and C or C′ is the cytokine and the other is absent; or X is a Fab and is the second binding domain, X′ is an scFv and is the first binding domain, Z and Z′ are both absent, and C or C′ is the cytokine and the other is absent; or X is a Fab and is the first binding domain, X′ is Fab or ScFv and is the second binding domain, one of Z or Z′ is the cytokine and the other is the masking polypeptide for the cytokine, and C and C′ are both absent; or X is a Fab and is the second binding domain, X′ is a Fab or scFv and is the first binding domain, one of Z or Z′ is the cytokine and the other is the masking polypeptide for the cytokine, and C and C′ are both absent.

[0027] In some embodiments, the first binding domain comprises a Fab, and wherein the composition comprises: a) a first polypeptide chain comprising the VL of the first binding domain; b) a second polypeptide chain comprising the VH of the first binding domain; and c) a third polypeptide chain comprising the IL-2 polypeptide.

[0028] In some embodiments, the first binding domain comprises: a) a VH having a VH CDR1 sequence of NYYMY (SEQ ID NO: 80), a VH CDR2 sequence of GINPSNGGTNFNEKFKN (SEQ ID NO: 81), and a VH CDR3 sequence of RDYRFDMGFDY (SEQ ID NO: 82), and a VL having a VL CDR1 sequence of RASKGVSTSGYSYLH (SEQ ID NO: 83), a VL CDR2 sequence of LASYLES (SEQ ID NO: 84), and a VL CDR3 sequence of QHSRDLPLT (SEQ ID NO: 85); or b) a VH having a VH CDR1 sequence of NSGMH (SEQ ID NO: 86), a VH CDR2 sequence of VIWYDGSKRYYADSVKG (SEQ ID NO: 87), and a VH CDR3 sequence of NDDY (SEQ ID NO: 88), and a VL having a VL CDR1 sequence of RASQSVSSYLA (SEQ ID NO: 89), a VL CDR2 sequence of DASNRAT (SEQ ID NO: 90), and a VL CDR3 sequence of QQSSNWPRT (SEQ ID NO: 91); or c) a VH having a VH CDR1 sequence of GYTFTSYYMY (SEQ ID NO: 113), a VH CDR2 sequence of GVNPSNGGTNFNEKFKS (SEQ ID NO: 114), and a VH CDR3 sequence of RDYRYDMGFDY (SEQ ID NO: 115), and a VL having a VL CDR1 sequence of RASKGVSTSGYSYLH (SEQ ID NO: 83), a VL CDR2 sequence of LASYLE (SEQ ID NO: 117), and a VL CDR3 sequence of QHSRELPLT (SEQ ID NO: 118). In some embodiments, the first binding domain comprises: a) a VH comprising an amino acid sequence amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 48 and a VL comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 49; b) a VH comprising an amino acid sequence amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 50 and a VL comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 51; or c) a VH comprising an amino acid sequence amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 76 and a VL comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 77. In some embodiments, the first polypeptide chain comprises, in N- to C-terminal direction, the VL and light chain constant region. In some embodiments, the light chain constant region comprises an amino acid having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 276. In some embodiments, the first polypeptide chain comprises the sequence

(SEQ ID NO: 47)

EIVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRL

LIYLASYLESGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPL

TFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKV

QWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEV

THQGLSSPVTKSFNRGEC.

[0029] In some embodiments, the second polypeptide chain comprises, in an N-terminal to C-terminal direction, the VH of the Fab of the first binding domain and an antibody constant region. In some embodiments, the antibody constant region is an IgG1 or IgG4 constant region. In some embodiments, the antibody constant region comprises, in an N-terminal to C-terminal direction, a CH1 domain, a hinge region, a CH2 domain, and a CH3 domain. In some embodiments: a) the CH1 domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to any one of SEQ ID NOs: 272-275; b) the hinge region comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to any one of SEQ ID NOs 265-271; and/or c) the CH2 and CH3 domains together comprise an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to any one of SEQ ID NOs 229-234. In some embodiments, the second polypeptide chain comprises, in an N-terminal to C-terminal direction, the VH of the Fab, the antibody constant region, an optional peptide linker, and the second binding domain. In some embodiments, the optional peptide linker is present and has a sequence (GS)_n (SEQ ID NO: 23), (GGS)_n (SEQ ID NO: 24), (GGGS)_n (SEQ ID NO: 25), (GGSG)_n (SEQ ID NO: 26), (GGSGG)_n (SEQ ID NO: 27), (GGGGS)_n (SEQ ID NO: 28), wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or a sequence GGGGS (SEQ ID NO: 21), (GGGGS)₂ (SEQ ID NO: 22), (GGGGS)₃ (SEQ ID NO: 29), or (GGGGS)₄ (SEQ ID NO: 30). In some embodiments, the second binding domain is a VHH. In some embodiments, the VHH comprises a two proline peptide on its C-terminus. In some embodiments, the VHH comprises a) a VH CDR1 sequence of AYPMM (SEQ ID NO: 202), a VH CDR2 sequence of EISPSGSYTYYADSVRG (SEQ ID NO: 203), and a VH CDR3 sequence of DPRKLDY (SEQ ID NO: 204); b) a VH CDR1 sequence of LYDMM (SEQ ID NO: 206), a VH CDR2 sequence of FIGGDGLNTYYADSVKG (SEQ ID NO: 207), and a VH CDR3 sequence of AGTQFDY (SEQ ID NO: 208); c) a VH CDR1 sequence of WYPMW (SEQ ID NO: 210), a VH CDR2 sequence of LIEGQGDRTYYADSVKG (SEQ ID NO: 211), and a VH CDR3 sequence of AGDRTAGSRGNSFDY (SEQ ID NO: 212); d) a VH CDR1 sequence of AYPMM (SEQ ID NO: 202), a VH CDR2 sequence of EISPSGSYTYYADSVKG (SEQ ID NO: 215), and a VH CDR3 sequence of DPRKFDY (SEQ ID NO: 216); or e) a VH CDR1 having the sequence SYSMG (SEQ ID NO: 218), a VH CDR2 having the sequence AISKGGYKYDAVSLEG (SEQ ID NO: 219) or the sequence of SEQ ID NO: 279, and a VH CDR3 having the sequence SRAYGSSRLRLADTYEY (SEQ ID NO: 220). In some embodiments, the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to any one of SEQ ID NOs: 200, 201, 205, 209, 213, 217, 221, or 280-284. In some embodiments, the VHH comprises a VH CDR1 having the sequence SYSMG (SEQ ID NO: 218), a VH CDR2 having the sequence AISKGGYKYDAVSLEG (SEQ ID NO: 219) or the sequence of SEQ ID NO: 279, and a VH CDR3 having the sequence SRAYGSSRLRLADTYEY (SEQ ID NO: 220). In some embodiments, the second binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO:200, 217, or 221. In some embodiments, the second polypeptide chain further comprises an additional binding domain targeting VEGFA. In some embodiments, the additional binding domain targeting VEGFA is a VHH. In some embodiments, both the second binding domain and the additional binding domain targeting VEGFA are both VHHs comprising an identical amino acid sequence, or wherein the VHH positioned C-terminal to the other VHH comprises an additional two proline peptide on its C-terminus as compared to the other VHH, optionally wherein the VHH comprises a two proline peptide on its C-terminus. In some embodiments, the additional binding domain targeting VEGFA comprises a VH CDR1 having the sequence SYSMG (SEQ ID NO: 218), a VH CDR2 having the sequence AISKGGYKYDAVSLEG (SEQ ID NO: 219) or the sequence of SEQ ID NO: 279, and a VH CDR3 having the sequence SRAYGSSRLRLADTYEY (SEQ ID NO: 220). In some embodiments, the additional binding domain targeting VEGFA an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 200, 217, or 221. In some embodiments, the second polypeptide chain comprises, in an N-terminal to C-terminal direction, the VH of the Fab, an antibody constant region, an optional peptide linker, the second binding domain, a second optional peptide linker, and the additional binding domain targeting VEGFA. In some embodiments, the second optional peptide linker is present and has a sequence (GS)_n (SEQ ID NO: 23), (GGS)_n (SEQ ID NO: 24), (GGGS)_n (SEQ ID NO: 25), (GGSG)_n (SEQ ID NO: 26), (GGSGG)_n (SEQ ID NO: 27), (GGGGS)_n (SEQ ID NO: 28), wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or a sequence (GGGGS)₂ (SEQ ID NO: 22), (GGGGS)₃ (SEQ ID NO: 29), or (GGGGS)₄ (SEQ ID NO: 30). In some embodiments, the second polypeptide chain comprises the sequence set forth in any one of SEQ ID NOs: 163, 164, 169, or 171.

[0030] In some embodiments, the third polypeptide chain comprises, in an N-terminal to C-terminal direction, the IL-2 polypeptide, an optional peptide linker, and an antibody constant region. In some embodiments, the optional peptide linker is present and has a sequence (GS)_n (SEQ ID NO: 23), (GGS)_n (SEQ ID NO: 24), (GGGS)_n (SEQ ID NO: 25), (GGSG)_n (SEQ ID NO: 26), (GGSGG)_n (SEQ ID NO: 27), (GGGGS)_n (SEQ ID NO: 28), wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or a sequence GGGGS (SEQ ID NO: 21), (GGGGS)₂ (SEQ ID NO: 22), (GGGGS)₃ (SEQ ID NO: 29), or (GGGGS)₄ (SEQ ID NO: 30). In some embodiments, the third polypeptide chain comprises, in an N-terminal to C-terminal direction, the IL-2 polypeptide, the optional peptide linker, an antibody constant region, a second optional peptide linker, and the second binding domain or an additional binding domain targeting VEGFA, wherein the additional binding domain targeting VEGFA is present if the second binding is present on the second polypeptide chain or if the second binding domain is also present on the third polypeptide chain. In some embodiments, the second optional peptide linker is present and has a sequence (GS)_n (SEQ ID NO: 23), (GGS)_n (SEQ ID NO: 24), (GGGS)_n (SEQ ID NO: 25), (GGSG)_n (SEQ ID NO: 26), (GGSGG)_n (SEQ ID NO: 27), (GGGGS)_n (SEQ ID NO: 28), wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or a sequence GGGGS (SEQ ID NO: 21), (GGGGS)₂ (SEQ ID NO: 22), (GGGGS)₃ (SEQ ID NO: 29), or (GGGGS)₄ (SEQ ID NO: 30). In some embodiments, the second binding domain or the additional binding domain targeting VEGFA is a VHH. In some embodiments, the VHH comprises a two proline peptide on its C-terminus. In some embodiments, the second binding domain or the additional binding domain targeting VEGFA comprises a VH CDR1 having the sequence SYSMG (SEQ ID NO: 218), a VH CDR2 having the sequence AISKGGYKYDAVSLEG (SEQ ID NO: 219) or the sequence of SEQ ID NO: 279, and a VH CDR3 having the sequence SRAYGSSRLRLADTYEY (SEQ ID NO: 220). In some embodiments, the second binding domain or the additional binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 200, 217 or 221. In some embodiments, the third polypeptide comprises the second binding domain and the additional binding domain targeting VEGFA separated by an optional peptide linker. In some embodiments, the optional peptide linker is present and has a sequence (GS)_n (SEQ ID NO: 23), (GGS)_n (SEQ ID NO: 24), (GGGS)_n (SEQ ID NO: 25), (GGSG)_n (SEQ ID NO: 26), (GGSGG)_n (SEQ ID NO: 27), (GGGGS)_n (SEQ ID NO: 28), wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or a sequence GGGGS (SEQ ID NO: 21), (GGGGS)₂ (SEQ ID NO: 22), (GGGGS)₃ (SEQ ID NO: 29), or (GGGGS)₄ (SEQ ID NO: 30). In some embodiments, both the second binding domain and the additional binding domain targeting VEGFA are both VHHs comprising an identical amino acid sequence, or wherein the VHH positioned C-terminal to the other VHH comprises an additional two proline peptide on its C-terminus as compared to the other VHH. In some embodiments, the antibody constant region is an IgG1 or IgG4 constant region, or a portion thereof. In some embodiments, the antibody constant region comprises, in an N-terminal to C-terminal direction, a hinge region, a CH2 domain, and a CH3 domain. In some embodiments, the antibody constant region comprises, in an N-terminal to C-terminal direction, a hinge region portion, a CH2 domain, and a CH3 domain. In some embodiments: a) the hinge region portion comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to any one of SEQ ID NOs: 265-271; and/or b) the CH2 and CH3 domains together comprise an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to any one of SEQ ID NOs: 229-234. In some embodiments, the third polypeptide chain comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 802, 803, 806, or 807. In some embodiments: the first polypeptide chain comprises the amino acid sequence set forth in SEQ ID NO: 47; the second polypeptide chain comprises the amino acid sequence of any one of SEQ ID NOs: 163, 164, 169, or 171; and the third polypeptide chain comprises the amino acid sequence of any one of SEQ ID NOs: 802, 803, 806, or 807. In some embodiments, the first polypeptide chain, the second polypeptide chain, and the third polypeptide chain comprise, respectively, the amino acid sequences set forth in: SEQ ID NOs: 47, 163, and 802; SEQ ID NOs: 47, 163, and 803; SEQ ID NOs: 47, 164, and 806; SEQ ID NOs: 47, 164, and 807; SEQ ID NOs: 47, 169, and 802; SEQ ID NOs: 47, 169, and 803; SEQ ID NOs: 47, 172, and 802; SEQ ID NOs: 47, 172, and 803; SEQ ID NOs: 47, 163, and 806; SEQ ID NOs: 47, 163, and 807; SEQ ID NOs: 47, 169, and 806; SEQ ID NOs: 47, 169, and 807; SEQ ID NOs: 47, 171, and 809; or SEQ ID NOs: 47, 171, and 810.

[0031] In some embodiments, the second binding domain is a Fab having a VH and a VL, wherein the composition comprises a) a first polypeptide chain comprising the VL of the first binding domain; b) a second polypeptide chain comprising the VH of the first binding domain; and c) a third polypeptide chain comprising the IL-2 polypeptide.

[0032] In some embodiments, second binding domain Fab comprises a VH having a VH CD1, VH CDR2, and VH CDR3 and a VL having a VL CDR1, CDR2, and CDR3 of any one of the anti-VEGFA antibodies in Table 2A, optionally wherein the VH comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the corresponding VL. In some embodiments, the VH CDR1, VH CDR2, and VH CDR3 are SEQ ID NOs: 123, 124, and 125, respectively and the VL CDR1, VL CDR2, and VL CDR3 are SEQ ID NOs: 128, 129, and 130, respectively. In some embodiments, the VH and VL each have a sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NOs: 122 and 126, respectively. In some embodiments, the first polypeptide chain comprises, in N- to C-terminal direction, the VL and a light chain constant region. In some embodiments, the light chain constant region comprises an amino acid having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 276, 277, or 278.

[0033] In some embodiments, the second polypeptide chain comprises, in an N-terminal to C-terminal direction, the VH of the Fab of the second binding domain and an antibody constant region. In some embodiments, the antibody constant region is an IgG1 or an IgG4. In some embodiments, the antibody constant region comprises, in an N-terminal to C-terminal direction, a CH1 domain, a hinge region, a CH2 domain, and a CH3 domain. In some embodiments, the CH1 domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to any one of SEQ ID NOs: 272-275, the hinge region comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to any one of SEQ ID NOs 265-271, and/or the CH2 and CH3 domains together comprise an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to any one of SEQ ID NOs 229-234. In some embodiments, the second polypeptide chain comprises, in an N-terminal to C-terminal direction, the VH of the Fab, the antibody constant region, an optional peptide linker, and the first binding domain specific for PD-1. In some embodiments, the optional peptide linker is present and comprises a sequence of any one of SEQ ID NOs: 21-30. In some embodiments, the first binding domain is a VHH. In some embodiments, the VHH comprises a VH CDR1, VH CDR2, and VH CDR3 of any one of the anti-PD-1 VHH in Table 1B or Table 1C. In some embodiments, the anti-PD-1 binding domain comprises the CDRS of VHH47, VHH62, VHH70, VHH76, VHH84, or VHH178. In some embodiments, the first binding domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to any one of VHH47, VHH62, VHH70, VHH76, VHH84, or VHH178. In some embodiments, the first binding domain is VHH47. In some embodiments, the second polypeptide chain further comprises an additional binding domain targeting PD-1. In some embodiments, the additional binding domain VHH comprises an identical amino acid sequence compared to the first binding domain. In some embodiments, the first binding domain and the additional binding domain are separated by a peptide linker, optionally wherein the peptide linker comprises a sequence of any one of SEQ ID NOs: 22-30.

[0034] In some embodiments, the third polypeptide chain comprises, in an N-terminal to C-terminal direction, a VH of a second Fab specific for VEGFA, an antibody constant region, an optional peptide linker, and the IL-2 polypeptide. In some embodiments, the second Fab is the same as the Fab of the second binding domain. In some embodiments, the antibody constant region of the third polypeptide is an IgG1 or an IgG4. In some embodiments, the antibody constant region of the third polypeptide comprises, in an N-terminal to C-terminal direction, a CH1 domain, a hinge region, a CH2 domain, and a CH3 domain. In some embodiments, the CH1 domain comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to any one of SEQ ID NOs: 272-275, the hinge region comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to any one of SEQ ID NOs 265-271, and/or the CH2 and CH3 domains together comprise an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to any one of SEQ ID NOs 229-234. In some embodiments, the optional peptide linker of the third polypeptide is present and comprises a sequence of any one of SEQ ID NOs: 21-30.

[0035] In some embodiments, the IL-2 polypeptide comprises the sequence set forth in SEQ ID NO: 751, 753, 754, or 758.

[0036] In some embodiments, the composition comprises only one cytokine.

[0037] In an aspect, the present disclosure provides one or more polynucleotides encoding the composition of any one of the embodiments disclosed herein, or a portion thereof.

[0038] In an aspect, the present disclosure provides a host cell comprising the composition of any one of the embodiments disclosed herein or the one or more polynucleotides of any of the embodiments disclosed herein.

[0039] In an aspect, the present disclosure provides a pharmaceutical composition comprising the composition of any one of the embodiments disclosed herein, and a pharmaceutically acceptable carrier or excipient.

[0040] In an aspect, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject at therapeutically effective amount of the composition of any one of the embodiments disclosed herein or the pharmaceutical composition of any one of the embodiments disclosed herein.

[0041] In an aspect, the present disclosure provides an IL-2 polypeptide comprising a modified B′C′ loop region, wherein the modified B′C′ loop region comprises a deletion of one or more amino acids of the B′C′ loop region between amino acids 73 and 84 of the IL-2 polypeptide, wherein residue position numbering is based on SEQ ID NO: 701 as a reference sequence, and an insertion of a peptide comprising the sequence GDGSIN into the deleted portion of the B′C′ loop region. In some embodiments, the deletion of one or more amino acids of the B′C′ loop region comprises a deletion of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acids between amino acids 73 and 84 of the IL-2 polypeptide. In some embodiments, the deletion of one or more amino acids of the B′C′ loop region comprises a deletion of each of amino acids 74-83 of the IL-2 polypeptide. In some embodiments, the inserted peptide consists of the sequence GDGSIN. In some embodiments, the IL-2 polypeptide comprises a peptide sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to amino acids 1-73 of SEQ ID NO: 701 and a peptide sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to amino acids 84-133 of SEQ ID NO: 701. In some embodiments, the IL-2 polypeptide comprises a peptide sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 783. An IL-2 polypeptide comprising the amino acid substitutions K76A and R81S, wherein residue position numbering is based on SEQ ID NO: 1 as a reference sequence. In some embodiments, the IL-2 polypeptide exhibits reduced binding to heparin compared to the IL-2 polypeptide of SEQ ID NO: 701. In some embodiments, the IL-2 polypeptide exhibits reduced binding to the IL-2 receptor beta subunit compared to the IL-2 of SEQ ID NO: 1. In some embodiments, the IL-2 polypeptide comprises an amino acid substitution at residue N88. In some embodiments, the IL-2 polypeptide comprises an N88D substitution. In some embodiments, the IL-2 polypeptide exhibits reduced binding to the IL-2 receptor gamma subunit. In some embodiments, the IL-2 polypeptide comprises a substitution at any one of residues L12, E15, L19, T123, Q126, or I129. In some embodiments, the IL-2 polypeptide comprises one or more substitutions selected from L12A, L12Y, E15D, E15S, L19A, L19D, T123A, Q126T, or I129A, I129K. In some embodiments, the IL-2 polypeptide comprises any one of the following sets of substitutions: Q126T; I129K; I129A, E15S, T123A; E15D; L12A, L19A, E15S; L12Y, L19D; L12A, L19A; or L19D. In some embodiments, the IL-2 polypeptide comprises an E15D or an L19D substitution. In some embodiments, the IL-2 polypeptide comprises a T3A substitution. In some embodiments, the IL-2 polypeptide comprises a C125S substitution. In some embodiments, the IL-2 polypeptide binds to the IL-2 receptor alpha subunit. In some embodiments, the IL-2 polypeptide comprises the sequence set forth in any one of SEQ ID NOs: 703-774.

[0042] In an aspect, the present disclosure provides a fusion polypeptide comprising the IL-2 polypeptide of any one of the embodiments disclosed herein and an additional polypeptide. In some embodiments, the IL-2 polypeptide is fused to the additional polypeptide at its C-terminus. In some embodiments, the additional polypeptide comprises an Fc domain. In some embodiments, the IL-2 polypeptide is connected to the Fc domain via a peptide linker.

[0043] Additional aspects and advantages of the present disclosure will become readily apparent to those skilled in this art from the following detailed description, wherein only illustrative embodiments of the present disclosure are shown and described. As will be realized, the present disclosure is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, all without departing from the disclosure. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive.

[0044] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and/or take precedence over any such contradictory material.

[0064] While certain figures discussed supra include immunocytokine compositions or Fc domain contains scaffolds depicted as having various modifications to the Fc domain, compositions with alternative Fc domains or modifications thereof are also within the scope of the instant disclosure. The depiction of the formats with the indicated Fc modifications is not limiting.

[0065] The following description and examples illustrate embodiments of the present disclosure in detail. It is to be understood that this present disclosure is not limited to the particular embodiments described herein and as such can vary. Those of skill in the art will recognize that there are numerous variations and modifications of this present disclosure, which are encompassed within its scope.

[0066] Although various features of the present disclosure may be described in the context of a single embodiment, the features may also be provided separately or in any suitable combination. Conversely, although the present disclosure may be described herein in the context of separate embodiments for clarity, the present disclosure may also be implemented in a single embodiment.

[0067] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0068] Provided herein in an aspect are multifunctional immunocytokines. In some embodiments, the multifunctional immunocytokines comprise a PD-1 binding domain, a VEGFA binding domain, and a cytokine, such as IL-2.

[0069] An immunocytokine composition described herein comprises one or more binding domains which specifically target one of PD-1 or VEGFA. In some preferred embodiments, an immunocytokine composition comprises both PD-1 and VEGFA binding domains.

[0070] A binding domain selectively binds or preferentially binds to a target if it binds with greater affinity, avidity, more readily, and/or with greater duration than it binds to other substances. As such, “specific binding” or “preferential binding” does not necessarily require (although it can include) exclusive binding. Generally, but not necessarily, reference to specific binding means preferential binding where the affinity of the binding domain is at least at least 2-fold greater, at least 3-fold greater, at least 4-fold greater, at least 5-fold greater, at least 6-fold greater, at least 7-fold greater, at least 8-fold greater, at least 9-fold greater, at least 10-fold greater, at least 20-fold greater, at least 30-fold greater, at least 40-fold greater, at least 50-fold greater, at least 60-fold greater, at least 70-fold greater, at least 80-fold greater, at least 90-fold greater, at least 100-fold greater, or at least 1000-fold greater than the affinity of the binding domain for unrelated amino acid sequences.

[0071] In some embodiments, a binding domain of the disclosure can inhibit the action/activity of the substance to which it binds (e.g., by disruption an interaction of PD-1 with its receptor (e.g., PD-L1) and/or by disruption of VEGFA with one or more of its receptors (e.g., VEGFR1, VEGFR2, VEGFR3).

[0072] The binding domains of the instant disclosure can be of any desired format which binds specifically to the intended target. As such, the nature of the binding domains is not necessarily limited and can encompass, for example, polypeptides (e.g., antigen binding fragments derived from antibodies or other peptides which bind specifically for the target, such as variants of receptors of the targets or other polypeptides), aptamers (e.g., nucleic acid aptamers), small molecules, and the like. In some embodiments, a binding domain of the instant disclosure is a polypeptide.

[0073] In some embodiments, a binding domain of the instant disclosure comprises an antigen binding fragment derived from an antibody, or a variant thereof. Antigen binding fragments of antibodies, including any of the antibodies herein (e.g., the anti-PD-1 antibodies or anti-VEGFA antibodies described below), are contemplated as being used as binding domains in immunocytokine compositions described herein. The terms “antigen binding portion of an antibody,” “antigen binding domain,” “antibody fragment,” or a “functional fragment of an antibody” are used interchangeably herein to refer to one or more fragments of an antibody that retain the ability to specifically bind to an antigen. In some embodiments, such regions refer to the VH and/or the VL of the antibody, or a derivative or portion thereof. Representative antigen binding fragments include, but are not limited to, a Fab, a Fab′, a F(ab′)₂, a bispecific F(ab′)₂, a trispecific F(ab′)₂, a variable fragment (Fv), a single chain variable fragment (scFv), a dsFv, a bispecific scFv, a variable heavy domain, a variable light domain, a variable NAR domain, bispecific scFv, an AVIMER®, a minibody, a diabody, a bispecific diabody, triabody, a tetrabody, a minibody, a maxibody, a camelid, a VHH, a minibody, an intrabody, fusion proteins comprising an antibody portion (e.g., a domain antibody), a single chain binding polypeptide, a scFv-Fc, a Fab-Fc, a bispecific T cell engager (BiTE; two scFvs produced as a single polypeptide chain, where each scFv comprises an amino acid sequences a combination of CDRs or a combination of VL/VL described herein), a tetravalent tandem diabody (TandAb; an antibody fragment that is produced as a non-covalent homodimer folder in a head-to-tail arrangement, e.g., a TandAb comprising an scFv, where the scFv comprises an amino acid sequences a combination of CDRs or a combination of VL/VL described herein), a Dual-Affinity Re-targeting Antibody (DART; different scFvs joined by a stabilizing interchain disulphide bond), a bispecific antibody (bscAb; two single-chain Fv fragments joined via a glycine-serine linker), a single domain antibody (sdAb), a fusion protein, a bispecific disulfide-stabilized Fv antibody fragment (dsFv-dsFv′; two different disulfide-stabilized Fv antibody fragments connected by flexible linker peptides).

[0074] In some embodiments, a binding domain of the instant disclosure is a Fab, a Fab′, F(ab′)₂, a bispecific F(ab′)₂, a variable fragment (Fv), a single chain variable fragment (scFv), a bispecific scFv, disulfide stabilized Fv (dsFv), a minibody, a diabody, a bispecific diabody, triabody, a tetrabody, a maxibody, a camelid, a single domain antibody (e.g., a VHH), a Fab-Fc, a scFv-Fc, or a bispecific antibody. In some embodiments, a binding domain of the instant disclosure is Fab, a Fab′, F(ab′)₂, a bispecific F(ab′)₂, a variable fragment (Fv), a single chain variable fragment (scFv), a bispecific scFv, disulfide stabilized Fv (dsFv), a minibody, a diabody, a bispecific diabody, triabody, a tetrabody, a maxibody, a camelid, a single domain antibody (e.g., a VHH), a Fab-Fc, or a scFv-Fc. In some embodiments, a binding domain of the instant disclosure is Fab, a Fab′, F(ab′)₂, a bispecific F(ab′)₂, a variable fragment (Fv), a single chain variable fragment (scFv), disulfide stabilized Fv (dsFv), a camelid, or a VHH. In some embodiments, a binding domain of the instant disclosure is Fab, a Fab′, F(ab′)₂, a variable fragment (Fv), a single chain variable fragment (scFv), disulfide stabilized Fv (dsFv), a camelid, or a single domain antibody (e.g., a VHH). In some embodiments, a binding domain of the instant disclosure is Fab, a Fab′, a variable fragment (Fv), a single chain variable fragment (scFv), disulfide stabilized Fv (dsFv), or a single domain antibody (e.g., a VHH). In some embodiments, a binding domain of the instant disclosure is Fab, a single chain variable fragment (scFv), or a single domain antibody (e.g., a VHH). In some embodiments, each binding domain of an immunocytokine composition is independently one of those described above. In some embodiments, each binding domain of an immunocytokine composition described herein is independently a Fab, an scFv, or a single domain antibody (e.g., a VHH).

[0075] In some embodiments, a binding domain of the instant disclosure comprises a VH derived from an antibody, or a derivative thereof. In some embodiments, the VH retains the CDRs of the VH of the antibody from which the VH of the immunocytokine composition is derived (e.g., a heavy chain first complementary determining region (VH CDR1), a heavy chain second complementary determining region (VH CDR2), and a heavy chain third complementary determining region (VH CDR3)). In some embodiments, the VH retains the CDRS of the VH of the antibody from which it is derived and comprises one or more mutations in the framework region. In some embodiments, the VH retains the CDRs of the VH of the antibody from which it is derived and comprises up to 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 mutations in the framework region. In some embodiments, each mutation is a conservative mutation. In some embodiments, the binding domain comprises a VH of a corresponding antibody (e.g., with no mutations to the framework region). In some embodiments, the VH is comprises in a Fab, a Fab′, F(ab′)₂, a bispecific F(ab′)₂, a variable fragment (Fv), a single chain variable fragment (scFv), a bispecific scFv, disulfide stabilized Fv (dsFv), a minibody, a diabody, a bispecific diabody, triabody, a tetrabody, a maxibody, a camelid, a VHH, a Fab-Fc, a scFv-Fc, or a bispecific antibody. In some embodiments, the VH is comprised in a Fab, a Fab′, an scFv, or a VHH. In some embodiments, the VH is comprised in a Fab, an scFv, or a VHH. In some embodiments, the VH is comprised in a Fab or an scFv. In some embodiments, the VH is a VHH.

[0076] In some embodiments, a VHH of the instant disclosure can comprise one or more modifications which improve immunogenicity or reduce binding of pre-existing antibodies to the VHH. Examples of such modifications are described in, for example, U.S. Patent Publication Nos. US20180009888A9 (e.g., extension peptides of 1 to 5 extending beyond the C-terminal “SS” of the VHH, such as those consisting of the amino acids Ala and Gly), US20160207981A1 (e.g., substitutions of the C-terminal “SS” of the VHH, such as with an amino acid or peptide of a sequence E, SE, EG, SEG, EP, EPG, DP, DPG, K, SK, KP, KPG, RP, or RPG and/or substitutions of Leu 11 of the VHH, such as an L11K, L11R, L11D, or L11E substitution), US20140161796A1 (e.g., deletions of certain sequences from the VHH), US20170121399A1 (e.g., substitutions of Leu 11 of the VHH (e.g., L11K or L11V) and/or Leu 89 (e.g., L89T), and Lin et al., “A structure-based engineering approach to abrogate pre-existing antibody binding to biotherapeutics,” PLoS ONE 16(7): e0254944. doi.org/10.1371/journal.pone.0254944 (e.g., the addition of 1, 2, or 3 prolines beyond the C-terminal “SS” of the VHH, such as a two-proline peptide). In some embodiments, a VHH described herein comprises a C-terminal modification of the addition of 1, 2 or 3 prolines to the C-terminus of the VHH (e.g., to the C-terminus of any of the VHHs described herein). In some embodiments, a VHH described herein comprises a C-terminal modification of the addition of 2 prolines to the C-terminus of the VHH. In embodiments where two VHHs are linked in series (e.g., by a flexible peptide linker), in some instance only the C-terminal VHH will comprise the modification (e.g., only the C-terminal VHH comprises the sequence “PP” after the C-terminal “SS” of the VHH). In some instances, both VHHs linked in series will contain the modification (e.g., both will comprise the sequence “PP” after the C-terminal “SS” of each VHH).

[0077] In some embodiments, a binding domain of the instant disclosure comprises a VL derived from an antibody, or a derivative thereof. In some embodiments, the VL retains the CDRs of the VL of the antibody from which the VL of the immunocytokine composition is derived (e.g., a light chain first complementary determining region (VL CDR1), a light chain second complementary determining region (VL CDR2), and a light chain third complementary determining region (VL CDR3)). In some embodiments, the VL retains the CDRS of the VL of the antibody from which it is derived and comprises one or more mutations in the framework region. In some embodiments, the VL retains the CDRs of the VL of the antibody from which it is derived and comprises up to 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 mutations in the framework region. In some embodiments, each mutation is a conservative mutation. In some embodiments, the binding domain comprises a VL of a corresponding antibody (e.g., with no mutations to the framework region). In some embodiments, the VL is comprised in a Fab, a Fab′, F(ab′)₂, a bispecific F(ab′)₂, a variable fragment (Fv), a single chain variable fragment (scFv), a bispecific scFv, disulfide stabilized Fv (dsFv), a minibody, a diabody, a bispecific diabody, triabody, a tetrabody, a maxibody, a Fab-Fc, a scFv-Fc, or a bispecific antibody. In some embodiments, the VL is comprised in a Fab, a Fab′, or an scFv. In some embodiments, the VL is comprised in a Fab or an scFv. In some embodiments, the VL is comprised in the same Fab, Fab′, F(ab′)₂, bispecific F(ab′)₂, scFv, bispecific scFv, dsFv, minibody, diabody, bispecific diabody, triabody, tetrabody, maxibody, Fab-Fc, scFv-Fc, or bispecific antibody as the corresponding VH. In some embodiments, the VL is comprised in the same Fab, Fab′, or scFv as the corresponding VH. In some embodiments, the VL is comprised in the same Fab or scFv as the corresponding VH.

[0078] In some embodiments, a binding domain of the instant disclosure is a light chain single domain antibody.

[0079] In some embodiments, a binding domain specifically binds to one or more epitopes on one or more target antigens. In some embodiments, a binding domain selectively binds to an epitope on a single antigen.

[0080] In some embodiments, an immunocytokine composition of the instant disclosure comprise one or more binding domains which target programmed cell death protein 1 (PD-1). In some embodiments, a binding domain incorporated into an immunocytokine composition of the disclosure specifically binds to PD-1. In some embodiments, the anti-PD-1 binding domain is capable of disrupting and/or preventing the interaction of PD-1 with programmed cell death ligand 1 (PD-L1).

[0081] Programmed cell death protein 1 (also known as PD-1 and CD279), is a cell surface receptor that plays a role in down-regulating the immune system and promoting self-tolerance by suppressing T cell inflammatory activity. PD-1 is an immune cell inhibitory molecule that is expressed on activated B cells, T cells, and myeloid cells. PD-1 represents an immune checkpoint and guards against autoimmunity via a dual mechanism of promoting apoptosis (programmed cell death) in antigen-specific T-cells in lymph nodes while reducing apoptosis in regulatory T cells. PD-1 is a member of the CD28/CTLA-4/ICOS costimulatory receptor family that delivers negative signals that affect T and B cell immunity. PD-1 is monomeric both in solution as well as on cell surface, in contrast to CTLA-4 and other family members that are all disulfide-linked homodimers. Signaling through the PD-1 inhibitory receptor upon binding its ligand, PD-L1, suppresses immune responses against autoantigens and tumors and plays a role in the maintenance of peripheral immune tolerance. The interaction between PD-1 and PD-L1 results in a decrease in tumor infiltrating lymphocytes, a decrease in T cell receptor mediated proliferation, and immune evasion by the cancerous cells. A non-limiting, exemplary, human PD-1 amino acid sequence is

(SEQ ID NO: 31)

MQIPQAPWPVVWAVLQLGWRPGWFLDSPDRPWNPPTFSPALLVVTEGDNA

TFTCSFSNTSESFVLNWYRMSPSNQTDKLAAFPEDRSQPGQDCRFRVTQL

PNGRDFHMSVVRARRNDSGTYLCGAISLAPKAQIKESLRAELRVTERRAE

VPTAHPSPSPRPAGQFQTLVVGVVGGLLGSLVLLVWVLAVICSRAARGTI

GARRTGQPLKEDPSAVPVFSVDYGELDFQWREKTPEPPVPCVPEQTEYAT

IVFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWPL.

[0082] In some embodiments, the anti-PD-1 binding domain is comprised in an antigen binding fragment derived from an antibody. For example, the anti-PD-1 binding domain can be derived from any anti-PD-1 antibody known in the art or which can be made according to well understood methods. In some embodiments, the antibody or antigen binding fragment thereof of an immunocytokine composition described herein is derived from an anti-PD-1 antibody or antigen binding fragment.

[0083] In one embodiment, an anti-PD-1 binding domain of an immunocytokine composition comprises and antigen binding fragment. In some embodiments, the anti-PD-1 binding domain of the disclosure comprises a combination of a heavy chain variable region (VH) and a light chain variable region (VL) described herein, or of other anti-PD-1 antibodies or antigen binding fragments known in the art. In another embodiment, an anti-PD-1 antibody or an anti-PD-1 antigen binding fragment of the disclosure comprises a combination of complementarity determining regions (VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3) described herein or of other anti-PD-1 antibodies or antigen binding fragments known in the art.

[0084] In one embodiment, an anti-PD-1 binding domain of the disclosure comprises the CDRs of an antibody selected from Tislelizumab, Baizean, 0KVO4111B3N, BGB-A317, hu317-1/IgG4mt2, Sintilimab, Tyvyt, IBI-308, Toripalimab, TeRuiPuLi, Terepril, Tuoyi, JS-001, TAB-001, Camrelizumab, HR-301210, INCSHR-01210, SHR-1210, Cemiplimab, Cemiplimab-rwlc, LIBTAYO®, 6QVL057INT, H4H7798N, REGN-2810, SAR-439684, Avelumab, BAVENCIO®, 451238, KXG2PJ551I, MSB-0010682, MSB-0010718C, PF-06834635, Durvalumab, IMFINZI®, 28X28X9OKV, MEDI-4736, Lambrolizumab, Pembrolizumab, KEYTRUDA®, MK-3475, SCH-900475, h409AI1, Nivolumab, Nivolumab BMS, OPDIVO®, BMS-936558, MDX-1106, ONO-4538, Prolgolimab, Forteca, BCD-100, Penpulimab, AK-105, Zimberelimab, AB-122, GLS-010, WBP-3055, Balstilimab, 1Q2QT5M7EO, AGEN-2034, AGEN-2034w, Genolimzumab, Geptanolimab, APL-501, CBT-501, GB-226, Dostarlimab, ANB-011, GSK-4057190A, P0GVQ9A4S5, TSR-042, WBP-285, Serplulimab, HLX-10, CS-1003, Retifanlimab, 2Y3T5IF01Z, INCMGA-00012, INCMGA-0012, MGA-012, Sasanlimab, LZZ0IC2EWP, PF-06801591, RN-888, Spartalizumab, NVP-LZV-184, PDR-001, QOG25L6Z8Z, Relatlimab/nivolumab, BMS-986213, Cetrelimab, JNJ-3283, JNJ-63723283, LYK98WP91F, Tebotelimab, MGD-013, BCD-217, BAT-1306, HX-008, MEDI-5752, JTX-4014, Cadonilimab, AK-104, BI-754091, Pidilizumab, CT-011, MDV-9300, YBL-006, AMG-256, RG-6279, RO-7284755, BH-2950, IBI-315, RG-6139, RO-7247669, ONO-4685, AK-112, 609-A, LY-3434172, T-3011, MAX-10181, AMG-404, IBI-318, MGD-019, INCB-086550, ONCR-177, LY-3462817, RG-7769, RO-7121661, F-520, XmAb-23104, Pd-1-pik, SG-001, 5-95016, Sym-021, LZM-009 (a.k.a., Lipustobart), Budigalimab, 6VDO4TY300, ABBV-181, PR-1648817, CC-90006, XmAb-20717, 2661380, AMP-224, B7-DCIg, EMB-02, ANB-030, PRS-332, [89Zr]Deferoxamide-pembrolizumab, 89Zr-Df-Pembrolizumab, [89Zr]Df-Pembrolizumab, STI-1110, STI-A1110, CX-188, mPD-1 Pb-Tx, MCLA-134, 244C8, ENUM 224C8, ENUM C8, 388D4, ENUM 388D4, ENUM D4, MEDIO680, or AMP-514 incorporated into a VH and VL. In some embodiments, the anti-PD-1 binding domain comprises the VH and VL of any one of these antibodies. In some embodiments, the anti-PD-1 binding domain comprises the VH and VL of any one of these antibodies or the VH and VL which include the CDRs of these antibodies in one of the following formats: a Fab, a Fab′, F(ab′)₂, a bispecific F(ab′)₂, a variable fragment (Fv), a single chain variable fragment (scFv), a bispecific scFv, disulfide stabilized Fv (dsFv), a minibody, a diabody, a bispecific diabody, triabody, a tetrabody, a maxibody, a Fab-Fc, a scFv-Fc, or a bispecific antibody. In some embodiments, the VH and VL of any one of these antibodies or the VH and VL which include the CDRs of these antibodies is comprised in a Fab, a Fab′, or an scFv. In some embodiments, the VH and VL any one of these antibodies or of the VH and VL which include the CDRs of these antibodies is comprised in a Fab or an scFv. In some embodiments, the VH and VL of any of these antibodies or the VH and VL which include the CDRs of these antibodies is comprised in a Fab. In some embodiments, the VH and VL of any of these antibodies or the VH and VL which include the CDRs of these antibodies is comprised in an scFv.

[0085] In some embodiments, an anti-PD-1 binding domain of the disclosure comprises the CDRs (e.g., VH and VL CDRs) of Tislelizumab, Sintilimab, Toripalimab, Terepril, Camrelizumab, Cemiplimab, Pembrolizumab Nivolumab, Prolgolimab, Penpulimab, Zimberelimab, Balstilimab, Genolimzumab, Geptanolimab, Dostarlimab, Serplulimab, Retifanlimab, Sasanlimab, Spartalizumab, Cetrelimab, Tebotelimab, Cadonilimab, Pidilizumab, LZM-009 (a.k.a. Lipustobart), or Budigalimab incorporated into a VH and VL. In one embodiment, an anti-PD-1 binding domain of the disclosure comprises the VH and VL of Tislelizumab, Sintilimab, Toripalimab, Terepril, Camrelizumab, Cemiplimab, Pembrolizumab, Nivolumab, Prolgolimab, Penpulimab, Zimberelimab, Balstilimab, Genolimzumab, Geptanolimab, Dostarlimab, Serplulimab, Retifanlimab, Sasanlimab, Spartalizumab, Cetrelimab, Tebotelimab, Cadonilimab, Pidilizumab, LZM-009 (a.k.a. Lipustobart), or Budigalimab. In some embodiments, the anti-PD-1 binding domain comprises the VH and VL of any one of these antibodies or the VH and VL which include the CDRs of these antibodies in one of the following formats: a Fab, a Fab′, F(ab′)₂, a bispecific F(ab′)₂, a variable fragment (Fv), a single chain variable fragment (scFv), a bispecific scFv, disulfide stabilized Fv (dsFv), a minibody, a diabody, a bispecific diabody, triabody, a tetrabody, a maxibody, a Fab-Fc, a scFv-Fc, or a bispecific antibody. In some embodiments, the VH and VL of any one of these antibodies or the VH and VL which include the CDRs of these antibodies is comprised in a Fab, a Fab′, or an scFv. In some embodiments, the VH and VL any one of these antibodies or of the VH and VL which include the CDRs of these antibodies is comprised in a Fab or an scFv. In some embodiments, the VH and VL of any of these antibodies or the VH and VL which include the CDRs of these antibodies is comprised in a Fab. In some embodiments, the VH and VL of any of these antibodies or the VH and VL which include the CDRs of these antibodies is comprised in an scFv.

[0086] An anti-PD-1 binding domain can comprise a heavy chain, a VH, or a VH-CH1 domain (e.g., as in a Fab) having an amino acid sequence of any one of those set forth in Table 1A, or a portion corresponding to a VH thereof (e.g., the portion depicted in bold). An anti-PD-1 binding domain can comprise (or further comprise) a light chain (e.g., as in a Fab) or VL having an amino acid sequence of any one of those described in Table 1A, or a portion corresponding to a VL thereof. In preferred embodiments, the heavy chain, VH, or VH-CH1 domain and VL or light chain are from the same antibody or antigen binding fragment described in Table 1A.

[0087] In some embodiments, the anti-PD-1 binding domain comprises the VH and VL of Nivolumab, Pembrolizumab, LZM-009, Dostarlimab, Sintilimab, Spartalizumab, Tislelizumab, or Cemiplimab. In some embodiment, the anti-PD-1 binding domain comprises the VH and VL of Dostarlimab, Sintilimab, Spartalizumab, or Tislelizumab. In some embodiments, the anti-PD-1 binding domain comprises the VH and VL of Nivolumab, Pembrolizumab, LZM-009 (a.k.a. Lipustobart), or Cemiplimab. In some embodiments, the anti-PD-1 binding domain comprises the VH and VL of Nivolumab. In some embodiments, the anti-PD-1 binding domain comprises the VH and VL of Nivolumab in a Fab or scFv format. In some embodiments, the anti-PD-1 binding domain comprises the VH and VL of LZM-009 (a.k.a. Lipustobart). In some embodiments, the anti-PD-1 binding domain comprises the VH and VL of LZM-009 (a.k.a. Lipustobart) in a Fab or scFv format.

[0088] TABLES 1A and 1B provide the sequences of exemplary anti-PD-1 antibodies and anti-PD-1 antigen binding fragments which contain sets of CDRs which can be incorporated into VHs and/or VLs and used as anti-PD-1 binding domains as described herein. In some embodiments, the VHs and VLs of the antibodies in Table 1A are incorporated into anti-PD-1 binding domains (e.g., in a Fab or scFv format). In some embodiments, CDRs of a VH described in Table 1A or 1B are incorporated into a binding domain as a VHH. In some embodiments, a VH as described in Table 1A or 1B is incorporated into a binding domain as a VHH.

[0089] In some instances, the SEQ ID NOs listed in Table 1A contain full-length heavy or light chains of the indicated antibodies with the VH or VL respectively indicated in bold. Where there is a reference herein to a VH or VL of a SEQ ID NO in Table 1A which contains a full-length heavy or light chain, it is intended to reference the bolded portion of the sequence. For example, reference to “a VH having an amino acid sequence shown in SEQ ID NO: 32” refers to the bolded portion of SEQ ID NO: 32 in Table 1A.

[0090] An anti-PD-1 binding domain can comprise a VH having an amino acid sequence of any one of SEQ ID NOS: 32, 34, 36, 38, 40, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 372, 74, 76, and 78. An anti-PD-1 binding domain can comprise (or further comprise) a VL having an amino acid sequence of any one of SEQ ID NOS: 33, 35, 37, 39, 41, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, and 79.

[0091] An anti-PD-1 binding domain can comprise a heavy chain or VH having an amino acid sequence of any one of SEQ ID NOS: 32, 34, 36, 38, 40, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, and 78, or a portion corresponding to a VH thereof (e.g., the portion depicted in bold). An anti-PD-1 binding domain can comprise (or further comprise) a light chain or VL having an amino acid sequence of any one of SEQ ID NOS: 33, 35, 37, 39, 41, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, and 79, or a portion corresponding to a VL thereof.

[0092] In one instance, an anti-PD-1 binding domain comprises a VH having an amino acid sequence shown in SEQ ID NO: 32, and a VL having an amino acid sequence shown in SEQ ID NO: 33. In another instance, an anti-PD-1 binding domain comprises a VH having an amino acid sequence shown in SEQ ID NO: 34, and a VL having an amino acid sequence shown in SEQ ID NO: 35. In another instance, an anti-PD-1 binding domain comprises a VH having an amino acid sequence shown in SEQ ID NO:36, and a VL having an amino acid sequence shown in SEQ ID NO: 37. In another instance, an anti-PD-1 binding domain comprises a VH having an amino acid sequence shown in SEQ ID NO: 38, and a VL having an amino acid sequence shown in SEQ ID NO: 39. In another instance, an anti-PD-1 binding domain comprises a VH having an amino acid sequence shown in SEQ ID NO: 40, and a VL having an amino acid sequence shown in SEQ ID NO: 41. In another instance, an anti-PD-1 binding domain comprises a VH having an amino acid sequence shown in SEQ ID NO: 46, and a VL having an amino acid sequence shown in SEQ ID NO: 47. In another instance, an anti-PD-1 binding domain comprises a VH having an amino acid sequence shown in SEQ ID NO: 48, and a VL having an amino acid sequence shown in SEQ ID NO: 49. In another instance, an anti-PD-1 binding domain comprises a VH having an amino acid sequence shown in SEQ ID NO: 50, and a VL having an amino acid sequence shown in SEQ ID NO: 51. In another instance, an anti-PD-1 binding domain comprises a VH having an amino acid sequence shown in SEQ ID NO: 52, and a VL having an amino acid sequence shown in SEQ ID NO: 53. In another instance, an anti-PD-1 binding domain comprises a VH having an amino acid sequence shown in SEQ ID NO: 54, and a VL having an amino acid sequence shown in SEQ ID NO: 55. In another instance, an anti-PD-1 binding domain comprises a VH having an amino acid sequence shown in SEQ ID NO: 56, and a VL having an amino acid sequence shown in SEQ ID NO: 57. In another instance, an anti-PD-1 binding domain comprises a VH having an amino acid sequence shown in SEQ ID NO: 58, and a VL having an amino acid sequence shown in SEQ ID NO: 59. In another instance, an anti-PD-1 binding domain comprises a VH having an amino acid sequence shown in SEQ ID NO: 60, and a VL having an amino acid sequence shown in SEQ ID NO: 61. In another instance, an anti-PD-1 binding domain comprises a VH having an amino acid sequence shown in SEQ ID NO: 62, and a VL having an amino acid sequence shown in SEQ ID NO: 63. In another instance, an anti-PD-1 binding domain comprises a VH having an amino acid sequence shown in SEQ ID NO: 64, and a VL having an amino acid sequence shown in SEQ ID NO: 65. In another instance, an anti-PD-1 binding domain comprises a VH having an amino acid sequence shown in SEQ ID NO: 66, and a VL having an amino acid sequence shown in SEQ ID NO: 67. In another instance, an anti-PD-1 binding domain comprises a VH having an amino acid sequence shown in SEQ ID NO: 68, and a VL having an amino acid sequence shown in SEQ ID NO: 69. In another instance, an anti-PD-1 binding domain comprises a VH having an amino acid sequence shown in SEQ ID NO: 70, and a VL having an amino acid sequence shown in SEQ ID NO: 71. In another instance, an anti-PD-1 binding domain comprises a VH having an amino acid sequence shown in SEQ ID NO: 72, and a VL having an amino acid sequence shown in SEQ ID NO: 73. In another instance, an anti-PD-1 binding domain comprises a VH having an amino acid sequence shown in SEQ ID NO: 74, and a VL having an amino acid sequence shown in SEQ ID NO: 75. In another instance, an anti-PD-1 binding domain comprises a VH having an amino acid sequence shown in SEQ ID NO: 76, and a VL having an amino acid sequence shown in SEQ ID NO: 77. In another instance, an anti-PD-1 binding domain comprises a VH having an amino acid sequence shown in SEQ ID NO: 78, and a VL having an amino acid sequence shown in SEQ ID NO: 79. In another instance, an anti-PD-1 binding domain comprises a VH having an amino acid sequence shown in SEQ ID NO: 9, and a VL having an amino acid sequence shown in SEQ ID NO: 10. In another instance, an anti-PD-1 binding domain comprises a VH having an amino acid sequence shown in SEQ ID NO: 11, and a VL having an amino acid sequence shown in SEQ ID NO: 12.

[0093] In one instance, an anti-PD-1 binding domain comprises a VH CDR1 having an amino acid sequence of SEQ ID NO: 80, a VH CDR2 having an amino acid sequence of SEQ ID NO: 81, a VH CDR3 having an amino acid sequence of SEQ ID NO: 82, VL CDR1 having an amino acid sequence of SEQ ID NO: 83, a VL CDR2 having an amino acid sequence of SEQ ID NO: 84, and a VL CDR3 having an amino acid sequence of SEQ ID NO: 85. In some embodiments, the anti-PD-1 binding domain comprises a corresponding VH and VL having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the VH and VL of the parent antibody (e.g., contains the indicated CDRs and the VH and VL each comprise the indicated sequence identity overall).

[0094] In one instance, an anti-PD-1 binding domain comprises a VH CDR1 having an amino acid sequence of SEQ ID NO: 86, a VH CDR2 having an amino acid sequence of SEQ ID NO: 87, a VH CDR3 having an amino acid sequence of SEQ ID NO: 88, VL CDR1 having an amino acid sequence of SEQ ID NO: 89, a VL CDR2 having an amino acid sequence of SEQ ID NO: 90, and a VL CDR3 having an amino acid sequence of SEQ ID NO: 91. In some embodiments, the anti-PD-1 binding domain comprises a corresponding VH and VL having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the VH and VL of the parent antibody (e.g., contains the indicated CDRs and the VH and VL each comprise the indicated sequence identity overall).

[0095] In one instance, an anti-PD-1 binding domain comprises a VH CDR1 having an amino acid sequence of SEQ ID NO: 92, a VH CDR2 having an amino acid sequence of SEQ ID NO: 93, a VH CDR3 having an amino acid sequence of SEQ ID NO: 94, VL CDR1 having an amino acid sequence of SEQ ID NO: 95, a VL CDR2 having an amino acid sequence of SEQ ID NO: 96, and a VL CDR3 having an amino acid sequence of SEQ ID NO: 97. In some embodiments, the anti-PD-1 binding domain comprises a corresponding VH and VL having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the VH and VL of the parent antibody (e.g., contains the indicated CDRs and the VH and VL each comprise the indicated sequence identity overall).

[0096] In one instance, an anti-PD-1 binding domain comprises a VH CDR1 having an amino acid sequence of SEQ ID NO: 98, a VH CDR2 having an amino acid sequence of SEQ ID NO: 99, a VH CDR3 having an amino acid sequence of SEQ ID NO: 100, VL CDR1 having an amino acid sequence of SEQ ID NO: 89, a VL CDR2 having an amino acid sequence of SEQ ID NO: 102, and a VL CDR3 having an amino acid sequence of SEQ ID NO: 103. In some embodiments, the anti-PD-1 binding domain comprises a corresponding VH and VL having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the VH and VL of the parent antibody (e.g., contains the indicated CDRs and the VH and VL each comprise the indicated sequence identity overall).

[0097] In one instance, an anti-PD-1 binding domain comprises a VH CDR1 having an amino acid sequence of SEQ ID NO: 113, a VH CDR2 having an amino acid sequence of SEQ ID NO: 114, a VH CDR3 having an amino acid sequence of SEQ ID NO: 115, VL CDR1 having an amino acid sequence of SEQ ID NO: 83, a VL CDR2 having an amino acid sequence of SEQ ID NO: 117, and a VL CDR3 having an amino acid sequence of SEQ ID NO: 118. In some embodiments, the anti-PD-1 binding domain comprises a corresponding VH and VL having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the VH and VL of the parent antibody (i.e., SEQ ID NOs: 76 and 77, respectively) (e.g., contains the indicated CDRs and the VH and VL each comprise the indicated sequence identity overall).

[0098] In some embodiments, an immunocytokine composition comprises one of the antibodies described in Table 1A or 1B below (optionally comprising one or more modifications to the Fc domain, hinge region, or other modification described herein) fused to a binding domain specific for VEGFA (e.g., any of the VEGFA binding domains described herein). In some embodiments, the binding domain specific for VEGFA is fused to the C-terminus of the heavy chain of the antibody described in Table 1A or 1B. In some embodiments, the binding domain specific for VEGFA fused to the antibody of Table 1A or 1B is an anti-VEGFA single-domain antibody as described herein.

[0099] In some embodiments, an anti-PD-1 binding domain comprises a single domain antibody. In some embodiments, the anti-PD-1 binding domain of a dual binding composition is a single domain antibody described in Table 1A or 1, or a variant thereof.

[0100] In some embodiments, the anti-PD-1 binding domain is a single domain antibody comprising a CDR1 as set forth in SEQ ID NO: 2, a CDR2 as set forth in SEQ ID NO: 3, and a CDR3 as set forth in SEQ ID NO: 4. In some embodiments, the CDRs are comprised in a VHH. In some embodiments, the anti-PD-1 binding domain comprises an amino acid sequence having 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% to the sequence set forth in SEQ ID NO: 1 (e.g., the anti-PD-1 binding domain comprises the indicated sequence identity to SEQ ID NO: 1 and retains the CDRs).

[0101] In some embodiments, the anti-PD-1 binding domain is a single domain antibody comprising a CDR1 as set forth in SEQ ID NO: 6, a CDR2 as set forth in SEQ ID NO: 7, and a CDR3 as set forth in SEQ ID NO: 8. In some embodiments, the CDRs are comprised in a VHH. In some embodiments, the anti-PD-1 binding domain comprises an amino acid sequence having 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% to the sequence set forth in SEQ ID NO: 5 (e.g., the anti-PD-1 binding domain comprises the indicated sequence identity to SEQ ID NO: 5 and retains the CDRs).

[0102] In some embodiments, the anti-PD-1 binding domain is a single domain antibody comprising a CDR1 as set forth in SEQ ID NO: 14, a CDR2 as set forth in SEQ ID NO: 15, and a CDR3 as set forth in SEQ ID NO: 16. In some embodiments, the CDRs are comprised in a VHH. In some embodiments, the anti-PD-1 binding domain comprises an amino acid sequence having 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% to the sequence set forth in SEQ ID NO: 13 (e.g., the anti-PD-1 binding domain comprises the indicated sequence identity to SEQ ID NO: 13 and retains the CDRs).

[0103] In some embodiments, the anti-PD-1 binding domain is a single domain antibody comprising a CDR1 as set forth in SEQ ID NO: 18, a CDR2 as set forth in SEQ ID NO: 19, and a CDR3 as set forth in SEQ ID NO: 20. In some embodiments, the CDRs are comprised in a VHH. In some embodiments, the anti-PD-1 binding domain comprises an amino acid sequence having 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% to the sequence set forth in SEQ ID NO: 17 (e.g., the anti-PD-1 binding domain comprises the indicated sequence identity to SEQ ID NO: 17 and retains the CDRs).

[0104] In some embodiments, the anti-PD-1 binding domain is a single domain antibody comprising a CDR1 as set forth in SEQ ID NO: 288, a CDR2 as set forth in SEQ ID NO: 289, and a CDR3 as set forth in SEQ ID NO: 290. In some embodiments, the CDRs are comprised in a VHH. In some embodiments, the anti-PD-1 binding domain comprises an amino acid sequence having 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% to the sequence set forth in SEQ ID NO: 287 (e.g., the anti-PD-1 binding domain comprises the indicated sequence identity to SEQ ID NO: 287 and retains the CDRs).

[0105] In some embodiments, an immunocytokine composition comprises one or two anti-PD-binding domains. In some embodiments, the immunocytokine composition comprises one anti-PD-1 binding domain. In some embodiments, the immunocytokine composition comprises two anti-PD-1 binding domains. In some embodiments, each anti-PD-1 binding domain is a Fab or scFv. In some embodiments, each anti-PD-1 binding domain is a single domain antibody. In some embodiments, the immunocytokine composition comprises two copies of the same anti-PD-1 binding domain. In some embodiments, the immunocytokine composition comprises two anti-PD-1 Fabs. In some embodiments, the immunocytokine composition comprises one anti-PD-1 Fab and one anti-Pd-1 scFv. In some embodiments, the anti-PD-1 Fab and the anti-PD-1 scFv comprise the same VH and VL. In some embodiments, the immunocytokine composition comprises one anti-PD-1 Fab and one anti-PD-1 single domain antibody.

TABLE 1A
Exemplary Antibodies Targeting PD-1 From Which anti-PD-1 binding
domains can be derived
Antibody
or Ag-
binding	Antigen		SEQ
fragment	Bound	Sequence	ID NO
Tislelizumab,	PD-1	QVQLQESGPGLVKPSETLSLTCTVSGFSLTSYGVHWIRQPPGK	32
Baizean,		GLEWIGVIYADGSTNYNPSLKSRVTISKDTSKNQVSLKLSSVT
0KVO411B3N,		AADTAVYYCARAYGNYWYIDVWGQGTTVTVSSASTKGPSVFP
BGB-A317,		LAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA
hu317-		VLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVES
1/IgG4mt2		KYGPPCPPCPAPPVAGGPSVFLFPPKPKDTLMISRTPEVTCVVVAV
Heavy		SQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVV
Chain (VH		HQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPS
in Bold)		QEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL
		DSDGSFFLYSKLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLS
		LSLGK
Tislelizumab,	PD-1	DIVMTQSPDSLAVSLGERATINCKSSESVSNDVAWYQQKPGQP	33
Baizean,		PKLLINYAFHRFTGVPDRFSGSGYGTDFTLTISSLQAEDVAVY
0KVO411B3N,		YCHQAYSSPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTAS
BGB-A317,		VVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS
hu317-		LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
1/IgG4mt2
Light Chain
(VL in
Bold)
Sintilimab,	PD-1	QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPG	34
Tyvyt, IBI-		QGLEWMGLIIPMEDTAGYAQKFQGRVAITVDESTSTAYMELS
308 Heavy		SLRSEDTAVYYCARAEHSSTGTFDYWGQGTLVTVSSASTKGPS
Chain (VH		VFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHT
in Bold)		FPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKR
		VESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVV
		VDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVL
		TVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYT
		LPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP
		PVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQK
		SLSLSLGK
Sintilimab,	PD-1	DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGK	35
Tyvyt, IBI-		APKLLISAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY
308 Light		CQQANHLPFTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTAS
Chain (VL		VVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS
in Bold)		LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
Toripalimab,	PD-1	QGQLVQSGAEVKKPGASVKVSCKASGYTFTDYEMHWVRQA	36
TeRuiPuLi,		PIHGLEWIGVIESETGGTAYNQKFKGRVTITADKSTSTAYMEL
Terepril,		SSLRSEDTAVYYCAREGITTVATTYYWYFDVWGQGTTVTVSS
Tuoyi, JS-		ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGA
001, TAB-		LTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPS
001 Heavy		NTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRT
Chain (VH		PEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNST
in Bold)		YRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQP
		REPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
		NNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEAL
		HNHYTQKSLSLSLGK
Toripalimab,	PD-1	DVVMTQSPLSLPVTLGQPASISCRSSQSIVHSNGNTYLEWYLQ	37
TeRuiPuLi,		KPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAED
Terepril,		VGVYYCFQGSHVPLTFGQGTKLEIKRTVAAPSVFIFPPSDEQLK
Tuoyi, JS-		SGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK
001, TAB-		DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
001 Light
Chain (VL
in Bold)
Camrelizumab,	PD-1	EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYMMSWVRQAP	38
HR-		GKGLEWVATISGGGANTYYPDSVKGRFTISRDNAKNSLYLQM
301210,		NSLRAEDTAVYYCARQLYYFDYWGQGTTVTVSSASTKGPSVF
INCSHR-		PLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP
01210,		AVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVE
SHR-1210		SKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD
Heavy		VSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTV
Chain (VH		LHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPP
in Bold)		SQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV
		LDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSL
		SLSLGK
Camrelizumab,	PD-1	DIQMTQSPSSLSASVGDRVTITCLASQTIGTWLTWYQQKPGK	39
HR-		APKLLIYTATSLADGVPSRFSGSGSGTDFTLTISSLQPEDFATY
301210,		YCQQVYSIPWTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTA
INCSHR-		SVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS
01210,		LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SHR-1210
Light Chain
(Light
Chain in
Bold)
Cemiplimab,	PD-1	EVQLLESGGVLVQPGGSLRLSCAASGFTFSNFGMTWVRQAPG	40
Cemiplimab-		KGLEWVSGISGGGRDTYFADSVKGRFTISRDNSKNTLYLQMN
rwlc,		SLKGEDTAVYYCVKWGNIYFDYWGQGTLVTVSSASTKGPSVF
LIBTAYO ®,		PLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP
6QVL057INT,		AVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVE
H4H7798N,		SKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD
REGN-		VSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTV
2810, SAR-		LHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPP
439684		SQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV
Heavy		LDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSL
Chain (VH		SLSLGK
in Bold)
Cemiplimab,	PD-1	DIQMTQSPSSLSASVGDSITITCRASLSINTFLNWYQQKPGKAP	41
Cemiplimab-		NLLIYAASSLHGGVPSRFSGSGSGTDFTLTIRTLQPEDFATYYC
rwlc,		QQSSNTPFTFGPGTVVDFRRTVAAPSVFIFPPSDEQLKSGTASVV
LIBTAYO ®,		CLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSS
6QVL057INT,		TLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
H4H7798N,
REGN-
2810, SAR-
439684
Light Chain
(VL in
Bold)
Lambrolizumab,	PD-1	QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAP	46
Pembrolizumab,		GQGLEWMGGINPSNGGTNFNEKFKNRVTLTTDSSTTTAYME
KEYTRUDA ®,		LKSLQFDDTAVYYCARRDYRFDMGFDYWGQGTTVTVSSAST
MK-		KGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTS
3475, SCH-		GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTK
900475,		VDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEV
h409A11		TCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRV
Heavy		VSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQ
Chain (VH		VYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY
in Bold)		KTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNH
		YTQKSLSLSLGK
		VH CDR1: NYYMY (SEQ ID NO: 80)
		VH CDR2: GINPSNGGTNFNEKFKN (SEQ ID NO: 81)
		VH CDR3: RDYRFDMGFDY (SEQ ID NO: 82)
Lambrolizumab,	PD-1	EIVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQK	47
Pembrolizumab,		PGQAPRLLIYLASYLESGVPARFSGSGSGTDFTLTISSLEPEDF
KEYTRUDA ®,		AVYYCQHSRDLPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKS
MK-		GTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD
3475, SCH-		STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
900475,		VL CDR1: RASKGVSTSGYSYLH (SEQ ID NO: 83)
h409A11		VL CDR2: LASYLES (SEQ ID NO: 84)
Light		VL CDR3: QHSRDLPLT (SEQ ID NO: 85)
Chain (VL
in Bold)
Lambrolizumab,	PD-1	QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPG	48
Pembrolizumab,		QGLEWMGGFPSNGGTNFNEKFKNRVTLTTDSSTTTAYMELKSLQ
KEYTRUDA ®,		FDDTAVYYCARRDYRFDMGFDYWGQGTTVTVSS
MK-		VH CDR1: NYYMY (SEQ ID NO: 80)
3475, SCH-		VH CDR2: GINPSNGGTNFNEKFKN (SEQ ID NO: 81)
900475,		VH CDR3: RDYRFDMGFDY (SEQ ID NO: 82)
h409A11
VH
Lambrolizumab,	PD-1	EIVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPG	49
Pembrolizumab,		QAPRLLIYLASYLESGVPARFSGSGSGTDFTLTISSLEPEDFAVYYC
KEYTRUDA ®,		QHSRDLPLTFGGGTKVEIK
MK-		VL CDR1: RASKGVSTSGYSYLH (SEQ ID NO: 83)
3475, SCH-		VL CDR2: LASYLES (SEQ ID NO: 84)
900475,		VL CDR3: QHSRDLPLT (SEQ ID NO: 85)
h409A11
VL
Nivolumab,	PD-1	QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGK	50
Nivolumab		GLEWVAVIWYDGSKRYYADSVKGRFTISRDNSKNTLFLQMNSLR
BMS,		AEDTAVYYCATNDDYWGQGTLVTVSS
OPDIVO ®,		VH CDR1: NSGMH (SEQ ID NO: 86)
BMS-		VH CDR2: VIWYDGSKRYYADSVKG (SEQ ID NO: 87)
936558,		VH CDR3: NDDY (SEQ ID NO: 88)
MDX-1106,
ONO-4538
VH
Nivolumab,	PD-1	EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPR	51
Nivolumab		LLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSS
BMS,		NWPRTFGQGTKVEIK
OPDIVO ®,		VL CDR1: RASQSVSSYLA (SEQ ID NO: 89)
BMS-		VL CDR2: DASNRAT (SEQ ID NO: 90)
936558,		VL CDR3: QQSSNWPRT (SEQ ID NO: 91)
MDX-1106,
ONO-4538
VL
Prolgolimab,	PD-1	QVQLVQSGGGLVQPGGSLRLSCAASGFTFSSYWMYWVRQVP	52
Forteca,		GKGLEWVSAIDTGGGRTYYADSVKGRFAISRVNAKNTMYLQ
BCD-100		MNSLRAEDTAVYYCARDEGGGTGWGVLKDWPYGLDAWGQ
Heavy		GTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV
Chain (VH		TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC
in Bold)		NVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPP
		KPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK
		TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPI
		EKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI
		AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN
		VFSCSVMHEALHNHYTQKSLSLSPGK
Prolgolimab,	PD-1	QPVLTQPLSVSVALGQTARITCGGNNIGSKNVHWYQQKPGQ	53
Forteca,		APVLVIYRDSNRPSGIPERFSGSNSGNTATLTISRAQAGDEADY
BCD-100		YCQVWDSSTAVFGTGTKLTVLQRTVAAPSVFIFPPSDEQLKSGT
Light Chain		ASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST
(VL in		YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
Bold)
Balstilimab,	PD-1	QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAP	54
1Q2QT5M7EO,		GKGLEWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQ
AGEN-		MNSLRAEDTAVYYCASNGDHWGQGTLVTVSSASTKGPSVFPL
2034,		APCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV
AGEN-		LQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESK
2034w		YGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS
Heavy		QEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLH
Chain (VH		QDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ
in Bold)		EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD
		SDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSL
		SLG
Balstilimab,	PD-1	EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQ	55
1Q2QT5M7EO,		APRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYY
AGEN-		CQQYNNWPRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTAS
2034,		VVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS
AGEN-		LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
2034w
Light Chain
(VL in
Bold)
Dostarlimab,	PD-1	EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQAPG	56
ANB-011,		KGLEWVSTISGGGSYTYYQDSVKGRFTISRDNSKNTLYLQMN
GSK-		SLRAEDTAVYYCASPYYAMDYWGQGTTVTVSSASTKGPSVFP
4057190A,		LAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA
P0GVQ9A4S5,		VLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVES
TSR-		KYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV
042, WBP-		SQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVL
285 Heavy		HQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPS
Chain (VH		QEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL
in Bold)		DSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLS
		LSLGK
Dostarlimab,	PD-1	DIQLTQSPSFLSAYVGDRVTITCKASQDVGTAVAWYQQKPGK	57
ANB-011,		APKLLIYWASTLHTGVPSRFSGSGSGTEFTLTISSLQPEDFATY
GSK-		YCQHYSSYPWTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTA
4057190A,		SVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS
P0GVQ9A4S5,		LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
TSR-
042, WBP-
285 Light
Chain (VL
in Bold)
Serplulimab,	PD-1	QVQLVESGGGLVKPGGSLRLSCAASGFTFSNYGMSWIRQAPG	58
HLX-10		KGLEWSTISGGGSNIYYADSVKGRFTISRDNAKNSLYLQMNSL
Heavy		RAEDTAVYYCVSYYYGIDFWGQGTSVTVSSASKYGPSVFPLAP
Chain (VH		CSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ
in Bold)		SSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYG
		PPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQE
		DPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVVLTVLHQ
		DWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQE
		EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS
		DGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLS
		LGK
		VH CDR1: FTFSNYGMS (SEQ ID NO: 92)
		VH CDR2: TISGGGSNIY (SEQ ID NO: 93)
		VH CDR3: VSYYYGIDF (SEQ ID NO: 94)
Serplulimab,	PD-1	DIQMTQSPSSLSASVGDRVTITCKASQDVTTAVAWYQQKPGK	59
HLX-10		APKLLIYWASTRHTGVPSRFSGSGSGTDFTLTISSLQPEDFATY
Light Chain		YCQQHYTIPWTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTA
(VL in		SVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS
Bold)		LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
		VL CDR1: KASQDVTTAVA (SEQ ID NO: 95)
		VL CDR2: WASTRHT (SEQ ID NO: 96)
		VL CDR3: QQHYTIPWT (SEQ ID NO: 97)
Retifanlimab,	PD-1	QVQLVQSGAEVKKPGASVKVSCKASGYSFTSYWMNWVRQAP	60
2Y3T5IF01Z,		GQGLEWIGVIHPSDSETWLDQKFKDRVTITVDKSTSTAYMEL
INCMGA-		SSLRSEDTAVYYCAREHYGTSPFAYWGQGTLVTVSSASTKGPS
00012,		VFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHT
INCMGA-		FPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKR
0012, MGA-		VESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVV
012 Heavy		VDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVL
Chain (VH		TVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYT
in Bold)		LPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP
		PVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQK
		SLSLSLG
Retifanlimab,	PD-1	EIVLTQSPATLSLSPGERATLSCRASESVDNYGMSFMNWFQQ	61
2Y3T5IF01Z,		KPGQPPKLLIHAASNQGSGVPSRFSGSGSGTDFTLTISSLEPED
INCMGA-		FAVYFCQQSKEVPYTFGGGTKVEIKRTVAAPSVFIFPPSDEQLK
00012,		SGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK
INCMGA-		DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
0012, MGA-
012 Light
Chain (VL
in Bold)
Sasanlimab,	PD-1	QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWINWVRQAP	62
LZZ0IC2EWP,		GQGLEWMGNIYPGSSLTNYNEKFKNRVTMTRDTSTSTVYME
PF-		LSSLRSEDTAVYYCARLSTGTFAYWGQGTLVTVSSASTKGPSV
06801591,		FPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF
RN-888		PAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRV
Heavy		ESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVV
Chain (VH		DVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLT
in Bold)		VLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLP
		PSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP
		VLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKS
		LSLSLGK
Sasanlimab,	PD-1	DIVMTQSPDSLAVSLGERATINCKSSQSLWDSGNQKNFLTWY	63
LZZ0IC2EWP,		QQKPGQPPKLLIYWTSYRESGVPDRFSGSGSGTDFTLTISSLQ
PF-		AEDVAVYYCQNDYFYPHTFGGGTKVEIKRTVAAPSVFIFPPSDE
06801591,		QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQ
RN-888		DSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR
Light		GEC
Chain (VL
in Bold)
Spartalizumab,	PD-1	EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQAT	64
NVP-		GQGLEWMGNIYPGTGGSNFDEKFKNRVTITADKSTSTAYME
LZV-184,		LSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSSASTKGPS
PDR-001,		VFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHT
QOG25L6Z8Z		FPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKR
Heavy		VESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVV
Chain (VH		VDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVL
in Bold)		TVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYT
		LPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP
		PVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQK
		SLSLSLG
Spartalizumab,	PD-1	EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTWYQ	65
NVP-		QKPGQAPRLLIYWASTRESGVPSRFSGSGSGTDFTFTISSLEAE
LZV-184,		DAATYYCQNDYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQL
PDR-001,		KSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDS
QOG25L6Z8Z		KDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGE
Light		C
Chain (VL
in Bold)
Cetrelimab,	PD-1	QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPG	66
JNJ-3283,		QGLEWMGGIIPIFDTANYAQKFQGRVTITADESTSTAYMELSS
JNJ-		LRSEDTAVYYCARPGLAAAYDTGSLDYWGQGTLVTVSSASTK
63723283,		GPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSG
LYK98WP91F		VHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKV
Heavy		DKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVT
Chain (VH		CVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVV
in Bold)		SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQV
		YTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK
		TTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHY
		TQKSLSLSLGK
Cetrelimab,	PD-1	EIVLTQSPATLSLSPGERATLSCRASQSVRSYLAWYQQKPGQA	67
JNJ-3283,		PRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYC
JNJ-		QQRNYWPLTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASV
63723283,		VCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLS
LYK98WP91F		STLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
Light
Chain (VL
in Bold)
Tebotelimab	PD-1	DIQMTQSPSSLSASVGDRVTITCRASQDVSSVVAWYQQKPGK	68
MGD-013		APKLLIYSASYRYTGVPSRFSGSGSGTDFTLTISSLQPEDFATY
Heavy		YCQQHYSTPWTFGGGTKLEIKGGGSGGGGQVQLVQSGAEVKK
Chain (VH		PGASVKVSCKASGYSFTSYWMNWVRQAPGQGLEWIGVIHPSDSE
in Bold)		TWLDQKFKDRVTITVDKSTSTAYMELSSLRSEDTAVYYCAREHY
		GTSPFAYWGQGTLVTVSSGGCGGGEVAACEKEVAALEKEVAAL
		EKEVAALEKESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLYITR
		EPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNS
		TYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQ
		PREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP
		ENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEA
		LHNHYTQKSLSLSLG
Tebotelimab,	PD-1	EIVLTQSPATLSLSPGERATLSCRASESVDNYGMSFMNWFQQ	69
MGD-013		KPGQPPKLLIHAASNQGSGVPSRFSGSGSGTDFTLTISSLEPED
Light Chain		FAVYFCQQSKEVPYTFGGGTKVEIKGGGSGGGGQVQLVQSGA
(VL in		EVKKPGASVKVSCKASGYTFTDYNMDWVRQAPGQGLEWMGDI
Bold)		NPDNGVTIYNQKFEGRVTMTTDTSTSTAYMELRSLRSDDTAVYY
		CAREADYFYFDYWGQGTTLTVSSGGGGGKVAACKEKVAALKE
		KVAALKEKVAALKE
Pidilizumab,	PD-1	QVQLVQSGSELKKPGASVKISCKASGYTFTNYGMNWVRQAP	70
CT-011,		GQGLQWMGWINTDSGESTYAEEFKGRFVFSLDTSVNTAYLQI
MDV-9300		TSLTAEDTGMYFCVRVGYDALDYWGQGTLVTVSSASTKGPSV
Heavy		FPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF
Chain (VH		PAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRV
in Bold)		EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
		VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS
		VLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV
		YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK
		TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHY
		TQKSLSLSPGK
Pidilizumab,	PD-1	EIVLTQSPSSLSASVGDRVTITCSARSSVSYMHWFQQKPGKAP	71
CT-011,		KLWIYRTSNLASGVPSRFSGSGSGTSYCLTINSLQPEDFATYYC
MDV-9300		QQRSSFPLTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVV
Light Chain		CLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSS
(VL in		TLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
Bold)
SG-001 VH	PD-1	QVQLVESGGGVVQPGRSLRLTCKASGLTFSSSGMHWVRQAPGK	72
		GLEWVAVIWYDGSKRYYADSVKGRFTISRDNSKNTLFLQMNSLR
		AEDTAVYYCATNNDYWGQGTLVTVSS
		VH CDR1: GLTFSSSG (SEQ ID NO: 98)
		VH CDR2: IWYDGSKR (SEQ ID NO: 99)
		VH CDR3: ATNNDY (SEQ ID NO: 100)
SG-001 VL	PD-1	EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPR	73
		LLIYTASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQYS
		NWPRTFGQGTKVEIK
		VL CDR1: RASQSVSSYLA (SEQ ID NO: 89)
		VL CDR2: TASNRAT (SEQ ID NO: 102)
		VL CDR3: QQYSNWPRT (SEQ ID NO: 103)
mpLZM-	PD-1	EVQLQQSGPVLVKPGASVKMSCKASGYTFTSYYMYWVKQSHGK	74
009 VH		SLEWIGGVNPSNGGTNFNEKFKSKATLTVDKSSSTAYMELNSLTS
(Murine		EDSAVYYCARRDYRYDMGFDYWGQGTTLTVSS
Precursor of
LZM-009)
mpLZM-	PD-1	QIVLTQSPAIMSASPGEKVTMTCRASKGVSTSGYSYLHWYQQKP	75
009 VL		GSSPRLLIYLASYLESGVPVRFSGSGSGTSYSLTISRMEAEDAATY
(Murine		YCQHSRELPLTFGTGTRLEIK
Precursor of
LZM-009)
LZM-009	PD-1	QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMYWVRQAPG	76
VH		QGLEWMGGVNPSNGGTNFNEKFKSRVTITADKSTSTAYMELSSL
		RSEDTAVYYCARRDYRYDMGFDYWGQGTTVTVSS
		VH CDR1: GYTFTSYYMY (SEQ ID NO: 113)
		VH CDR2: GVNPSNGGTNFNEKFKS (SEQ ID NO: 114)
		VH CDR3: RDYRYDMGFDY (SEQ ID NO: 115)
LZM-009	PD-1	EIVLTQSPATLSLSPGERATISCRASKGVSTSGYSYLHWYQQKPG	77
VL		QAPRLLIYLASYLESGVPARFSGSGSGTDFTLTISSLEPEDFATYYC
		QHSRELPLTFGTGTKVEIK
		VL CDR1: RASKGVSTSGYSYLH (SEQ ID NO: 83)
		VL CDR2: LASYLE (SEQ ID NO: 117)
		VL CDR3: QHSRELPLT (SEQ ID NO: 118)
Budigalimab,	PD-1	EIQLVQSGAEVKKPGSSVKVSCKASGYTFTHYGMNWVRQAP	78
6VDO4TY3OO,		GQGLEWVGWVNTYTGEPTYADDFKGRLTFTLDTSTSTAYME
ABBV-		LSSLRSEDTAVYYCTREGEGLGFGDWGQGTTVTVSSASTKGP
181, PR-		SVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVH
1648817		TFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDK
Heavy		KVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV
Chain (VH		TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV
in Bold)		VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREP
		QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENN
		YKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN
		HYTQKSLSLSPGK
Budigalimab,	PD-1	DVVMTQSPLSLPVTPGEPASISCRSSQSIVHSHGDTYLEWYLQ	79
6VDO4TY3OO,		KPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAED
ABBV-		VGVYYCFQGSHIPVTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKS
181, PR-		GTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD
1648817		STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
Light Chain
(VL in
Bold)
PD-1-Fc-	PD-1	MQIPQAPWPWWAVLQLGWRPGWFLDSPDRPWNPPTFSPALLVV	104
OX40L		TEGDNATFTCSFSNTSESFVLNWYRMSPSNQTDKLAAFPEDRSQP
(Code), SL-		GQDCRFRVTQLPNGRDFHMSVVRARRNDSGTYLCGAISLAPKAQ
279252		IKESLRAELRVTERRAEVPTAHPSPSPRPAGQFQSKYGPPCPSCPA
(Code),		PEFLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNW
TAK-252		YVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLSGKEYK
(Code)		CKVSSKGLPSSIEKTISNATGQPREPQVYTLPPSQEEMTKNQVSLT
		CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLT
		VDKSSWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKIEGRMDQ
		VSHRYPRIQSIKVQFTEYKKEKGFILTSQKEDEIMKVQNNSVIINC
		DGFYLISLKGYFSQEVNISLHYQKDEEPLFQLKKVRSVNSLMVAS
		LTYKDKVYLNVTTDNTSLDDFHVNGGELILIHQNPGEFCVLMQIP
		QAPWPWWAVLQLGWRPGWFLDSPDRPWNPPTFSPALLVVTEGD
		NATFTCSFSNTSESFVLNWYRMSPSNQTDKLAAFPEDRSQPGQDC
		RFRVTQLPNGRDFHMSVVRARRNDSGTYLCGAISLAPKAQIKESL
		RAELRVTERRAEVPTAHPSPSPRPAGQFQQVSHRYPRIQSIKVQFT
		EYKKEKGFILTSQKEDEIMKVQNNSVIINCDGFYLISLKGYFSQEV
		NISLHYQKDEEPLFQLKKVRSVNSLMVASLTYKDKVYLNVTTDN
		TSLDDFHVNGGELILIHQNPGEFCVL
Anti-PD-1	PD-1	DVQLVESGGG VVQPGGSLRL SCAASGSIAS	1
VHH 1		IHAMGWFRQA PGKEREFVAV ITWSGGITYY ADSVKGRFTI
		SRDNSKNTVY LQMNSLRPED TALYYCAGDK HQSSWYDYWG
		QGTLVTVSS (SEQ ID NO: 1)
		VH CDR1: GSIASIHA (SEQ ID NO: 2)
		VH CDR2: ITWSGGIT (SEQ ID NO: 3)
		VH CDR3: AGDKHQSSWYDY (SEQ ID NO: 4)
Anti-PD-1	PD-1	EVQLVESGGGLVKPGGSLRLSCAASGFTFSDESMTWMRQAPGKG	5
VHH 2		LEWVSYISSGGGVKFYADSVKGRFTISRDNAKNSLYLQMNSLRA
		EDTAVYYCAREAPLRLGESPHDAFDISGQGTMVTVSS (SEQ ID
		NO: 5)
		VH CDR1: DESMT (SEQ ID NO: 6)
		VH CDR2: YISSGGGVKFYADSVKG (SEQ ID NO: 7)
		VH CDR3: EAPLRLGESPHDAFDI (SEQ ID NO: 8)
Anti-PD-1	PD-1	QVQLQESGGGSVQAGGSLRLSCVASQYTYNTVGWFRQAPGKER	13
VHH 3		EGVAGIYNGGDQTYYSESAKGRFTISQDNAKRTVYLQMNSLKPE
		DTAMYYCAAGRLIVSGRWSMTKEEYQYWGQGTQVTVSS (SEQ
		ID NO: 13)
		VH CDR1: QYTYNT (SEQ ID NO: 14)
		VH CDR2: IYNGGDQT (SEQ ID NO: 15)
		VH CDR3: AAGRLIVSGRWSMTKEEYQY (SEQ ID NO: 16)
Anti-PD-1	PD-1	EVQLVESGGGEVQPGGSLRLSCAASGSITGANTMGWYRQAPGK	17
VHH 4		QRDLVALIGNYVTHYAESVKGRFTISRDNAKNTVYLQMSSLRAE
		DTAVYYCYLYTDNLGTSWGQGTLVTVKP (SEQ ID NO: 17)
		VH CDR1: ANTMG (SEQ ID NO: 18)
		VH CDR2: LIGNYVTHYAESVKG (SEQ ID NO: 19)
		VH CDR3: YTDNLGTS (SEQ ID NO: 20)
Anti-PD-1	PD-1	EVQLVESGGGLVQPGGSLRLSCAASGFAFSSYDMSWVRQAPG	105
scFv from		KGLDWVATISGGGRYTYYPDSVKGRFTISRDNSKNNLYLQMN
Ivonescimab		SLRAEDTALYYCANRYGEAWFAYWGQGTLVTVSSGGGGSGG
(VH in bold,		GGSGGGGSGGGGSDIQMTQSPSSMSASVGDRVTFTCRASQDINT
VL in		YLSWFQQKPGKSPKTLIYRANRLVSGVPSRFSGSGSGQDYTLTISS
bold + italics)		LQPEDMATYYCLQYDEFPLTFGAGTKLELKR
Flipped	PD-1	EVQLVESGGGLVQPGGSLRLSCAASGFAFSSYDMSWVRQAPG	106
Ivonescimab		KGLDWVATISGGGRYTYYPDSVKGRFTISRDNSKNNLYLQMN
HC, no scFv		SLRAEDTALYYCANRYGEAWFAYWGQGTLVTVSSASTKGPSV
targeting		FPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF
VEGF (VH		PAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKV
in bold)		EPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTC
		VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS
		VLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV
		YTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
		TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT
		QKSLSLSPGK
Flipped	PD-1	EIVLTQSPATLSLSPGERATISCRASKGVSTSGYSYLHWYQQK	107
Ivonescimab		PGQAPRLLIYLASYLESGVPARFSGSGSGTDFTLTISSLEPEDF
LC (VL in		ATYYCQHSRELPLTFGTGTKVEIKRTVAAPSVFIFPPSDEQLKS
bold)		GTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD
		STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
pembrolizumab	PD-1	QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAP	108
scFv		GQGLEWMGGINPSNGGTNFNEKFKNRVTLTTDSSTTTAYME
VH-VL		LKSLQFDDTAVYYCARRDYRFDMGFDYWGQGTTVTVSSGGG
(VH in bold,		GSGGGGSGGGGSGGGGSEIVLTQSPATLSLSPGERATLSCRASKG
VL in		VSTSGYSYLHWYQQKPGQAPRLLIYLASYLESGVPARFSGSGSGT
bold + italics)		DFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIK
pembrolizumab	PD-1	EIVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQ	109
scFv		APRLLIYLASYLESGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQ
VL-VH		HSRDLPLTFGGGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLV
(VH in bold,		QSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLE
VL in		WMGGINPSNGGTNFNEKFKNRVTLTTDSSTTTAYMELKSLQF
bold + italics)		DDTAVYYCARRDYRFDMGFDYWGQGTTVTVSS
LZM009	PD-1	QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMYWVRQAP	110
scFv VH-		GQGLEWMGGVNPSNGGTNFNEKFKSRVTITADKSTSTAYME
VL		LSSLRSEDTAVYYCARRDYRYDMGFDYWGQGTTVTVSSGGG
(VH in bold,		GSGGGGSGGGGSGGGGSEIVLTQSPATLSLSPGERATISCRASKG
VL in		VSTSGYSYLHWYQQKPGQAPRLLIYLASYLESGVPARFSGSGSGT
bold + italics)		DFTLTISSLEPEDFATYYCQHSRELPLTFGTGTKVEI
LZM009	PD-1	EIVLTQSPATLSLSPGERATISCRASKGVSTSGYSYLHWYQQKPGQ	111
scFv VL-		APRLLIYLASYLESGVPARFSGSGSGTDFTLTISSLEPEDFATYYCQ
VH		HSRELPLTFGTGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLV
(VH in bold,		QSGAEVKKPGASVKVSCKASGYTFTSYYMYWVRQAPGQGLE
VL in		WMGGVNPSNGGTNFNEKFKSRVTITADKSTSTAYMELSSLRS
bold + italics)		EDTAVYYCARRDYRYDMGFDYWGQGTTVTVSS

TABLE 1B
Antibody
or Ag-			SEQ
binding	Antigen		ID
fragment	Bound	Sequence	NO
Anti PD1	PD-1	EVQLVESGGGLVQPGGSLRLSCAVSGNIYNRNFMGWFRQAPGK
VHH5		GLEGVSAIYTGTSRTYYADSVKGRFTISRDNSKNTVYLQMNSLRA
		EDTAVYYCAADLREGFWDTGVWNTWGQGTLVTVSS (SEQ ID
		NO: 287)
		VH CDR1: RNFMG (SEQ ID NO: 288)
		VH CDR2: AIYTGTSRTYYADSVKG (SEQ ID NO: 289)
		VH CDR3: DLREGFWDTGVWNT (SEQ ID NO: 290)
Anti-PD1 X	PD-1	EVQLVESGGGLVQPGGSLRLSCAASGFAFSNYYMYWVRQAPGK
VH		GLEWMGGINPSNGGTNFNEKFKNRVTISRDNSKNNLYLQMNSLR
		AEDTALYYCARRDYRFDMGFDYWGQGTLVTVSS (SEQ ID NO: 9)
Anti-PD1 X	PD-1	DIQMTQSPSSMSASVGDRVTFTCRASKGVSTSGYSYLHWFQQKP
VL		GKSPKTLIYLASYLESGVPSRFSGSGSGQDYTLTISSLQPEDMATY
		YCQHSRDLPLTFGAGTKLELKR (SEQ ID NO: 10)
Anti-PD1 Y	PD-1	EVQLVESGGGLVQPGGSLRLSCAASGFAFSSYYMYWVRQAPGK
VH		GLEWMGGVNPSNGGTNFNEKFKSRVTISRDNSKNNLYLQMNSL
		RAEDTALYYCARRDYRYDMGFDYWGQGTLVTVSS (SEQ ID NO:
		11)
Anti-PD1 Y	PD-1	DIQMTQSPSSMSASVGDRVTFTCRASKGVSTSGYSYLHWFQQKP
VL		GKSPKTLIYLASYLESGVPSRFSGSGSGQDYTLTISSLQPEDMATY
		YCQHSRELPLTFGAGTKLELKR (SEQ ID NO: 12)

[0106] In some embodiments, the anti-PD-1 binding domain is one provided in Table 1C, or a derivative thereof. In some embodiments, the anti-PD-1 binding domain is one which comprises the CDRs of a VHH provided in Table 1C (e.g., those of VHH 74, 62, 70, 76, 84, or 178). In some embodiments, the anti-PD-1 binding domain is one which comprises the CDRs of a VHH provided in Table 1C and comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the corresponding full-length VHH sequence (e.g., VHH 74, 62, 70, 76, 84, or 178). In some embodiments, the anti-PD-1 binding domain is one of the VHHs provided in Table 1C. sequence (e.g., VHH 74, 62, 70, 76, 84, or 178).

TABLE 1C
Exemplary anti-PD-1 VHH binding domains
		Full
		Length
anti		VHH		CDR1		CDR2		CDR3
PD-1		SEQ		SEQ		SEQ		SEQ
VHH No.	Sequence	ID NO	CDR1	ID NO	CDR2	ID NO	CDR3	ID NO
VH	EVQLVESGGGLV	501	GFDF	502	INAP	503	ARDEAV	504
H45	QPGGSLRLSCAAS		STTW		GSET		AGYHW
	GFDFSTTWMGWL						WFDP
	RQAPGKEREFVA
	AINAPGSETYYAD
	SVKGRFTISRDNS
	KNTLYLQMNSLR
	PEDTAVYYCARD
	EAVAGYHWWFD
	PWGQGTLVTVSS
VH	EVQLVESGGGLV	505	GFTV	506	INDE	507	ARVVSG	508
H46	QPGGSLRLSCAAS		SDYD		GTTT		QQLVFP
	GFTVSDYDMAWY						LDY
	RQAPGKGRELVA
	GINDEGTTTSYAD
	SVKGRFTISRDNA
	KNTLYLQMNSLR
	PEDTAVYYCARV
	VSGQQLVFPLDY
	WGQGSLVTVSS
VH	DVQLVESGGGLV	509	GLPF	510	ISGSS	511	ATSGYS	512
H47	QPGGSLRLSCAAS		SDYS		ITT		YVAGG
	GLPFSDYSMGWF						MDV
	RQAPGKEREFVA
	GISGSSITTYYADS
	VKGRFTISRDNSK
	NTLYLQMNSLRPE
	DTAVYYCATSGY
	SYVAGGMDVWG
	QGTTVTVSS
VH	EVQLVESGGGLV	513	GFVF	514	ISAP	515	AREDSS	516
H48	QPGGSLRLSCAAS		SDHA		VGVT		GYLDWF
	GFVFSDHAMGWF						DP
	RQAPGKGRELVA
	AISAPVGVTYYPD
	SVEGRFTISRDNA
	KRMVYLQMNSLR
	AEDTAVYYCARE
	DSSGYLDWFDPW
	GQGTLVTVSS
VH	DVQLVESGGGLV	517	GLSF	518	ISGSS	511	ASLGPT	520
H49	QPGGSLRLSCAAS		SDYS		ITT		YYYDSS
	GLSFSDYSMGWF						GDDY
	RQAPGKEREFVA
	GISGSSITTYYADS
	VKGRFTISRDNSK
	NTVYLQMNSLRP
	EDTAVYYCASLG
	PTYYYDSSGDDY
	WGQGTLVTVSS
VH	EVQLVESGGGLV	521	GFTV	522	IDAS	523	ARHVW	524
H50	QPGGSLRLSCAAS		NDY		GTKT		GDHGG
	GFTVNDYDMAW		D				WYPLDY
	YRQAPGKGRELV
	AGIDASGTKTSYA
	DSVKGRFTISRDN
	AKNTLYLQMNSL
	RPEDTAVYYCAR
	HVWGDHGGWYP
	LDYWGQGTLVTV
	SS
VH	EVQLVESGGGLV	525	GFSV	526	LTES	527	ARVVVS	528
H51	QPGGSLRLSCAAS		NDY		GGST		DSSGYY
	GFSVNDYDMAW		D				YPLDY
	YRQAPGKGRELV
	AGLTESGGSTSYA
	DSVKGRFTISRDN
	AKNTLYLQMNSL
	RPEDTAVYYCAR
	VVVSDSSGYYYPL
	DYWGQGTLVTVS
	S
VH	EVQLVESGGGLV	529	GISFS	530	ISSK	531	VGGEQ	532
H52	QPGGSLRLSCAAS		DYG		GGAT		WLEDN
	GISFSDYGMGWF
	RQAPGKGRELVA
	AISSKGGATYYPD
	SVEGRFTISRDNA
	KRMVYLQMNSLR
	AEDTAVYYCVGG
	EQWLEDNWGQG
	TLVTVSS
VH	EVQLVESGGGLV	533	GFTF	534	ISGP	535	AKEEPA	536
H53	QPGGSLRLSCAAS		SDYT		GGIT		GYSSGW
	GFTFSDYTMGWF						YGFDY
	RQAPGKGRELVA
	AISGPGGITYYPDS
	VEGRFTISRDNAK
	RMVYLQMNSLRA
	EDTAVYYCAKEE
	PAGYSSGWYGFD
	YWGQGTLVTVSS
VH	EVQLVESGGGLV	537	GFTF	538	IGSS	539	ARDELIS	540
H54	QPGGSLRLSCAAS		GDT		GSDT		GYAWY
	GFTFGDTWMGWL		W				FDN
	RQAPGKEREFVA
	AIGSSGSDTYYAD
	SVKGRFTISRDNS
	KNTLYLQMNSLR
	PEDTAVYYCARD
	ELISGYAWYFDN
	WGQGTLVTVSS
VH	EVQLVESGGGLV	541	GLDF	542	ISAP	543	AALGDY	544
H55	QPGGSLRLSCAAS		HNY		GGAT		DDY
	GLDFHNYAMGWF		A
	RQAPGKGRELVA
	AISAPGGATYYPD
	SVEGRFTISRDNA
	KRMVYLQMNSLR
	AEDTAVYYCAAL
	GDYDDYWGQGT
	LVTVSS
VH	DVQLVESGGGLV	545	GFTF	546	IMGS	547	ASQYSY	548
H56	QPGGSLRLSCAAS		SDYD		GGTT		GLSYFD
	GFTFSDYDMGWF						Y
	RQAPGKEREFVA
	AIMGSGGTTYYA
	DSVKGRFTISRDN
	SKNTVYLQMNSL
	RPEDTAVYYCAS
	QYSYGLSYFDYW
	GQGTLVTVSS
VH	DVQLVESGGGLV	549	GIPFS	550	ISGSS	511	ASLGYS	552
H57	QPGGSLRLSCAAS		DYS		ITT		YGYGGF
	GIPFSDYSMGWFR						DY
	QAPGKEREFVAGI
	SGSSITTYYADSV
	KGRFTISRDNSKN
	TVYLQMNSLRPE
	DTAVYYCASLGY
	SYGYGGFDYWGQ
	GTLVTVSS
VH	EVQLVESGGGLV	553	GFKF	554	ISNK	555	AGGSG	556
H58	QPGGSLRLSCAAS		EEYA		GGAT		WLTDY
	GFKFEEYAMGWF
	RQAPGKGRELVA
	AISNKGGATYYPD
	SVEGRFTISRDNA
	KRMVYLQMNSLR
	AEDTAVYYCAGG
	SGWLTDYWGRGT
	LVTVSS
VH	EVQLVESGGGLV	557	GFAF	558	ISAP	543	TTGEQW	560
H59	QPGGSLRLSCAAS		GDY		GGAT		LDDY
	GFAFGDYAMGWF		A
	RQAPGKGRELVA
	AISAPGGATYYPD
	SVEGRFTISRDNA
	KRMVYLQMNSLR
	AEDTAVYYCTTG
	EQWLDDYWGQG
	TLVTVSS
VH	EVQLVESGGGLV	561	GFDF	562	ISGY	563	AGGSG	564
H60	QPGGSLRLSCAAS		DNY		GGAT		WLSDS
	GFDFDNYGMGWF		G
	RQAPGKGRELVA
	AISGYGGATYYPD
	SVEGRFTISRDNA
	KRMVYLQMNSLR
	AEDTAVYYCAGG
	SGWLSDSWGQGT
	MVTVSS
VH	EVQLVESGGGLV	565	GGTF	566	ISGP	567	AGGQG	568
H61	QPGGSLRLSCAAS		SDYA		GGAT		WLTDY
	GGTFSDYAMGWF
	RQAPGKGRELVA
	AISGPGGATYYPD
	SVEGRFTISRDNA
	KRMVYLQMNSLR
	AEDTAVYYCAGG
	QGWLTDYWGQG
	TLVTVSS
VH	DVQLVESGGGLV	569	GLSF	570	ISGSS	511	ASLGLT	572
H62	QPGGSLRLSCAAS		SEYS		ITT		YGDSDQ
	GLSFSEYSMGWF						FDY
	RQAPGKEREFVA
	GISGSSITTYYADS
	VKGRFTISRDNSK
	NTVYLQMNSLRP
	EDTAVYYCASLG
	LTYGDSDQFDYW
	GQGTLVTVSS
VH	EVQLVESGGGLV	573	GLTIS	574	ISGP	567	TTGFYS	576
H63	QPGGSLRLSCAAS		DYA		GGAT		LEDY
	GLTISDYAMGWF
	RQAPGKGRELVA
	AISGPGGATYYPD
	SVEGRFTISRDNA
	KRMVYLQMNSLR
	AEDTAVYYCTTG
	FYSLEDYWGQGT
	LVTVSS
VH	EVQLVESGGGLV	577	GFPF	578	ISGH	579	AGLGDY	580
H64	QPGGSLRLSCAAS		SDYA		GGAT		EDY
	GFPFSDYAMGWF
	RQAPGKGRELVA
	AISGHGGATYYPD
	SVEGRFTISRDNA
	KRMVYLQMNSLR
	AEDTAVYYCAGL
	GDYEDYWGQGTL
	VTVSS
VH	EVQLVESGGGLV	581	GFDF	582	ISNK	555	AGGSYL	584
H65	QPGGSLRLSCAAS		SNYG		GGAT		EDY
	GFDFSNYGMGWF
	RQAPGKGRELVA
	AISNKGGATYYPD
	SVEGRFTISRDNA
	KRMVYLQMNSLR
	AEDTAVYYCAGG
	SYLEDYWGQGTL
	VTVSS
VH	EVQLVESGGGLV	585	GLNF	586	ISAG	587	AGGSG	588
H66	QPGGSLRLSCAAS		DNY		SGAT		WLTDS
	GLNFDNYGMGWF		G
	RQAPGKGRELVA
	AISAGSGATYYPD
	SVEGRFTISRDNA
	KRMVYLQMNSLR
	AEDTAVYYCAGG
	SGWLTDSWGQGS
	LVTVSS
VH	EVQLVESGGGLV	589	GFSF	590	ISAP	591	AREDSS	592
H67	QPGGSLRLSCAAS		SDAA		GGVT		GWINWF
	GFSFSDAAMGWF						DP
	RQAPGKGRELVA
	AISAPGGVTYYPD
	SVEGRFTISRDNA
	KRMVYLQMNSLR
	AEDTAVYYCARE
	DSSGWINWFDPW
	GQGTLVTVSS
VH	EVQLVESGGGLV	593	GFDF	594	ISNK	555	ARLEDT	596
H68	QPGGSLRLSCAAS		NDH		GGAT		ATT
	GFDFNDHAMGWF		A
	RQAPGKGRELVA
	AISNKGGATYYPD
	SVEGRFTISRDNA
	KRMVYLQMNSLR
	AEDTAVYYCARL
	EDTATTWGQGTL
	VTVSS
VH	EVQLVESGGGLV	597	GFPF	578	ISGL	599	AGGEDY	600
H69	QPGGSLRLSCAAS		SDYA		GGAT		IIDH
	GFPFSDYAMGWF
	RQAPGKGRELVA
	AISGLGGATYYPD
	SVEGRFTISRDNA
	KRMVYLQMNSLR
	AEDTAVYYCAGG
	EDYIIDHWGQGVL
	VTVSS
VH	DVQLVESGGGLV	601	GITFS	602	ISGSS	511	ATAGLS	604
H70	QPGGSLRLSCAAS		DYS		ITT		GSYGGL
	GITFSDYSMGWFR						DY
	QAPGKEREFVAGI
	SGSSITTYYADSV
	KGRFTISRDNSKN
	TVYLQMNSLRPE
	DTAVYYCATAGL
	SGSYGGLDYWGQ
	GTLVTVSS
VH	EVQLVESGGGLV	605	GFDF	606	ISGP	567	AKLPVT	608
H71	QPGGSLRLSCAAS		NDFA		GGAT		TEGPGD
	GFDFNDFAMGWF						AFDI
	RQAPGKGRELVA
	AISGPGGATYYPD
	SVEGRFTISRDNA
	KRMVYLQMNSLR
	AEDTAVYYCAKL
	PVTTEGPGDAFDI
	WGQGTMVTVSS
VH	DVQLVESGGGLV	609	GFDF	610	ISAP	591	TTDFVS	612
H72	QPGGSLRLSCAAS		SDAA		GGVT		GYLDY
	GFDFSDAAMGWF
	RQAPGKGRELVA
	AISAPGGVTYYPD
	SVEGRFTISRDNA
	KRMVYLQMNSLR
	PEDTAVYYCTTDF
	VSGYLDYWGQGI
	LVTVSS
VH	EVQLVESGGGLV	613	GVDF	614	ISSY	615	AVLGDY	616
H73	QPGGSLRLSCAAS		SNYA		GGAT		EDY
	GVDFSNYAMGWF
	RQAPGKGRELVA
	AISSYGGATYYPD
	SVEGRFTISRDNA
	KRMVYLQMNSLR
	AEDTAVYYCAVL
	GDYEDYWGQGTL
	VTVSS
VH	EVQLVESGGGLV	617	GSAF	618	ISGP	567	AALGDY	620
H74	QPGGSLRLSCAAS		GTYA		GGAT		FDY
	GSAFGTYAMGWF
	RQAPGKGRELVA
	AISGPGGATYYPD
	SVEGRFTISRDNA
	KRMVYLQMNSLR
	AEDTAVYYCAAL
	GDYFDYWGQGTL
	VTVSS
VH	EVQLVESGGGLV	621	GLTF	622	ISGP	567	AALPDN	624
H75	QPGGSLRLSCAAS		SDYG		GGAT		DYGDYL
	GLTFSDYGMGWF
	RQAPGKGRELVA
	AISGPGGATYYPD
	SVEGRFTISRDNA
	KRMVYLQMNSLR
	AEDTAVYYCAAL
	PDNDYGDYLWGQ
	GTMVTVSS
VH	DVQLVESGGGLV	625	GISFS	626	ISGSS	511	ASLGLS	628
H76	QPGGSLRLSCAAS		DYS		ITT		QYSGYD
	GISFSDYSMGWFR						EDY
	QAPGKEREFVAGI
	SGSSITTYYADSV
	KGRFTISRDNSKN
	TVYLQMNSLRPE
	DTAVYYCASLGL
	SQYSGYDEDYWG
	QGTLVTVSS
VH	EVQLVESGGGLV	629	GFNF	630	ISGY	563	AGGSSS	632
H77	QPGGSLRLSCAAS		DEFG		GGAT		VEDY
	GFNFDEFGMGWF
	RQAPGKGRELVA
	AISGYGGATYYPD
	SVEGRFTISRDNA
	KRMVYLQMNSLR
	AEDTAVYYCAGG
	SSSVEDYWGQGT
	LVTVSS
VH	EVQLVESGGGLV	633	GFDF	634	ISGL	599	ATLGEY	636
H78	QPGGSLRLSCAAS		EDYG		GGAT		GDYDY
	GFDFEDYGMGWF
	RQAPGKGRELVA
	AISGLGGATYYPD
	SVEGRFTISRDNA
	KRMVYLQMNSLR
	AEDTAVYYCATL
	GEYGDYDYWGQ
	GTLVTVSS
VH	EVQLVESGGGLV	637	GLNF	638	ISNK	555	ATLEWE	640
H79	QPGGSLRLSCAAS		GDY		GGAT		LDY
	GLNFGDYAMGWF		A
	RQAPGKGRELVA
	AISNKGGATYYPD
	SVEGRFTISRDNA
	KRMVYLQMNSLR
	AEDTAVYYCATL
	EWELDYWGQGTL
	VTVSS
VH	EVQLVESGGGLV	641	GFKF	642	ISGP	567	AGGAG	644
H80	QPGGSLRLSCAAS		GDY		GGAT		WLTDY
	GFKFGDYAMGWF		A
	RQAPGKGRELVA
	AISGPGGATYYPD
	SVEGRFTISRDNA
	KRMVYLQMNSLR
	AEDTAVYYCAGG
	AGWLTDYWGQG
	TLVTVSS
VH	DVQLVESGGGLV	645	GISLS	646	ISGSS	511	ASLGFT	648
H81	QPGGSLRLSCAAS		DYS		ITT		MIVGGI
	GISLSDYSMGWFR						DY
	QAPGKEREFVAGI
	SGSSITTYYADSV
	KGRFTISRDNSKN
	TVYLQMNSLRPE
	DTAVYYCASLGF
	TMIVGGIDYWGQ
	GTLVTVSS
VH	EVQLVESGGGLV	649	GFDF	650	ISAP	515	VYLGDA	652
H82	QPGGSLRLSCAAS		SGFS		VGVT		FDI
	GFDFSGFSMGWF
	RQAPGKGRELVA
	AISAPVGVTYYPD
	SVEGRFTISRDNA
	KRMVYLQMNSLR
	AEDTAVYYCVYL
	GDAFDIWGQGTM
	VTVSS
VH	DVQLVESGGGLV	653	GFTIS	654	IMGS	547	AKQPPD	656
H83	QPGGSLRLSCAAS		GND		GGTT		WYFDL
	GFTISGNDMGWF
	RQAPGKEREFVA
	AIMGSGGTTYYA
	DSVKGRFTISRDN
	SKNTVYLQMNSL
	RPEDTAVYYCAK
	QPPDWYFDLWGR
	GTLVTVSS
VH	EVQLVESGGGLV	657	GFAF	658	INAA	659	ARDEQIS	660
H84	QPGGSLRLSCAAS		SDTW		GSDT		GYAWY
	GFAFSDTWMGWL						FDL
	RQAPGKEREFVA
	AINAAGSDTYYA
	DSVKGRFTISRDN
	SKNTLYLQMNSL
	RPEDTAVYYCAR
	DEQISGYAWYFD
	LWGRGTLVTVSS
VH	EVQLVESGGGLV	661	GLAL	662	ISAG	663	ARNFEIR	664
H85	QPGGSLRLSCAAS		SSYD		GEHT		YFNP
	GLALSSYDMAWY
	RQAPGKGRELVA
	GISAGGEHTSYAD
	SVKGRFTISRDNA
	KNTLYLQMNSLR
	PEDTAVYYCARN
	FEIRYFNPWGQGT
	LVTVSS
VH	EVQLVESGGGLV	665	GFNF	421	ISAP	591	ARVADY	668
H86	QPGGSLRLSCAAS		EEYG		GGVT		GSGSYS
	GFNFEEYGMGWF						SNWFDP
	RQAPGKGRELVA
	AISAPGGVTYYPD
	SVEGRFTISRDNA
	KRMVYLQMNSLK
	SEDTAVYYCARV
	ADYGSGSYSSNW
	FDPWGQGTLVTV
	SS
VH	EVQLVESGGGLV	669	GLVF	670	ISAP	591	ARVCSE	672
H87	QPGGSLRLSCAAS		SDYS		GGVT		YCGGD
	GLVFSDYSMGWF						WLSAGY
	RQAPGKGRELVA						WYFDL
	AISAPGGVTYYPD
	SVEGRFTISRDNA
	KRMVYLQMNSLR
	AEDTAVYYCARV
	CSEYCGGDWLSA
	GYWYFDLWGRG
	TLVTVSS
VH	EVQLVESGGGLV	673	GFSV	674	ISGS	675	TRVVSG	676
H88	QPGGSLRLSCAAS		SDYD		ASHT		QQLVFP
	GFSVSDYDMAWY						LDY
	RQAPGKGRELVA
	GISGSASHTSYAD
	SVKGRFTISRDNA
	KNTLYLQMNSLR
	PEDTAVYYCTRV
	VSGQQLVFPLDY
	WGQGSLVTVSS
VH	EVQLVESGGGLV	677	GFDF	678	ISSH	679	ASLGSD	680
H89	QPGGSLRLSCAAS		GGY		GGAT		YGEGDD
	GFDFGGYGMGWF		G				Y
	RQAPGKGRELVA
	AISSHGGATYYPD
	SVEGRFTISRDNA
	KRMVYLQMNSLR
	AEDTAVYYCASL
	GSDYGEGDDYWG
	QGTLVTVSS
VH	EVQLVESGGGLV	681	GITL	682	ISGL	599	VGGSG	684
H90	QPGGSLRLSCAAS		EDYA		GGAT		WLSDY
	GITLEDYAMGWF
	RQAPGKGRELVA
	AISGLGGATYYPD
	SVEGRFTISRDNA
	KRMVYLQMNSLR
	AEDTAVYYCVGG
	SGWLSDYWGHGT
	LVTVSS
VH	DVQLVESGGGLV	685	GFPV	686	IMGS	547	ASQPED	688
H91	QPGGSLRLSCAAS		SNYD		GGTT		WYFDL
	GFPVSNYDMGWF
	RQAPGKEREFVA
	AIMGSGGTTYYA
	DSVKGRFTISRDN
	SKNTVYLQMNSL
	RPEDTAVYYCAS
	QPEDWYFDLWGR
	GTLVTVSS
VH	EVQLVESGGGLV	689	GFNF	690	ISSGS	691	ARLPVV	692
H92	QPGGSLRLSCAAS		GDH		GAT		VTGDGA
	GFNFGDHAMGWF		A				FDI
	RQAPGKGRELVA
	AISSGSGATYYPD
	SVEGRFTISRDNA
	KRMVYLQMNSLK
	SEDTAVYYCARLP
	VVVTGDGAFDIW
	GQGTMVTVSS
VH	DVQLVESGGGLV	693	GLPF	510	ISGSS	511	ATSGYS	512
H178	QPGGSLRLSCAAS		SDYS		ITT		YSAGGM
	GLPFSDYSMGWF						DV
	RQAPGKEREFVA
	GISGSSITTYYADS
	VKGRFTISRDNSK
	NTLYLQMNSLRPE
	DTAVYYCATSGY
	SYSAGGMDVWG
	QGTTVTVSSPP
VH	DVQLVESGGGLV	694	GLPF	510	ISGSS	511	ATSGYS	512
H179	QPGGSLRLSCAAS		SDYS		ITT		YVAGG
	GLPFSDYSMGWF						MDV
	RQAPGKEREFVA
	GISGSSITTYYADS
	VKGRFTISRDNSK
	NTLYLQMNSLRPE
	DTAVYYCATSGY
	SYVAGGMDVWG
	QGTTVTVSSPP
VH	DVQLVESGGGEV	695	GLPF	510	ISGSS	511	ATSGYS	512
H180	QPGGSLRLSCAAS		SDYS		ITT		YVAGG
	GLPFSDYSMGWF						MDV
	RQAPGKEREFVA
	GISGSSITTYYADS
	VKGRFTISRDNSK
	NTLYLQMNSLRPE
	DTAVYYCATSGY
	SYVAGGMDVWG
	QGTTVTVSS
VH	DVQLVESGGGEV	696	GLPF	510	ISGSS	511	ATSGYS	512
H181	QPGGSLRLSCAAS		SDYS		ITT		YVAGG
	GLPFSDYSMGWF						MDV
	RQAPGKEREFVA
	GISGSSITTYYADS
	VKGRFTISRDNSK
	NTLYLQMNSLRPE
	DTAVYYCATSGY
	SYVAGGMDVWG
	QGTTVTVSSPP
VH	DVQLVESGGGEV	697	GLPF	510	ISGSS	699	ATSGYS	512
H182	QPGGSLRLSCAAS		SDYS		STT		YVAGG
	GLPFSDYSMGWF						MDV
	RQAPGKEREFVA
	GISGSSSTTYYAD
	SVKGRFTISRDNS
	KNTLYLQMNSLR
	PEDTAVYYCATS
	GYSYVAGGMDV
	WGQGTTVTVSSPP
VH	DVQLVESGGGEV	698	GLPF	510	ISGSS	511	ATSGYS	512
H183	QPGGSLRLSCAAS		SDYS		ITT		YSAGGM
	GLPFSDYSMGWF						DV
	RQAPGKEREFVA
	GISGSSITTYYADS
	VKGRFTISRDNSK
	NTLYLQMNSLRPE
	DTAVYYCATSGY
	SYSAGGMDVWG
	QGTTVTVSSPP
VH	EVQLLESGGGLV	175
H103	QPGGSLRLSCAAS
	GSTFSSYTVSWFR
	QAPGKEREFVSAII
	GSSGHTYYSDSVK
	GRFTISRDNSKNT
	LYLQMNSLKPED
	TAVYYCAADRVY
	DHEEYGITEDYAY
	GQGTLVTVSS
VH	EVQLLESGGGLV	176
H104	QPGGSLRLSCAAS
	GFTFSSYFIGWFR
	QAPGKEREFVSAII
	GSGGSTYYDDAV
	KGRFTISRDNSKN
	TLYLQMNSLKPE
	DTAVYYCAVKRH
	AYYGRDRSYNYD
	YWGQGTLVTVSS
VH	EVQLLESGGGLV	177
H105	QPGGSLRLSCAAS
	GGTFSIYGIGWFR
	QAPGKEREFVSGII
	LTGGSTYYADSV
	KGRFTISRDNSKN
	TLYLQMNSLKPE
	DTAVYYCYVDVP
	LYDTGYHTYWGQ
	GTLVTVSS
VH	EVQLLESGGGLV	178
H106	QPGGSLRLSCAAS
	GSSFSSYDLGWFR
	QAPGKEREFVSAY
	ILSGGSTYYEDSV
	KGRFTISRDNSKN
	TLYLQMNSLKPE
	DTAVYYCYADYT
	VERDRYSYWGQG
	TLVTVSS
VH	EVQLLESGGGLV	179
H107	QPGGSLRLSCAAS
	GFIFSSYHLAWFR
	QAPGKEREFVSAS
	IGSSEDTEYADSV
	KGRFTISRDNSKN
	TLYLQMNSLKPE
	DTAVYYCYADHG
	VKYYEYWGRGTL
	VTVSS
VH	EVQLLESGGGLV	180
H108	QPGGSLRLSCAAS
	GRTYEIYGMGWF
	RQAPGKEREFVSG
	SISSEGSTFYADSV
	KGRFTISRDNSKN
	TLYLQMNSLKPE
	DTAVYYCYADQS
	YPYGYTTYWGQG
	TLVTVSS
VH	EVQLLESGGGLV	181
H109	QPGGSLRLSCAAS
	GSSFSIYDMGWFR
	QAPGKEREFVSAY
	ITSGGDTYYEDSV
	KGRFTISRDNSKN
	TLYLQMNSLKPE
	DTAVYYCYAGVP
	QDEDYWGQGTLV
	TVSS
VH	EVQLLESGGGLV	182
H110	QPGGSLRLSCAAS
	GRIFSILDVGWFR
	QAPGKEREFVSAI
	SGSSGGRYYADS
	VKGRFTISRDNSK
	NTLYLQMNSLKP
	EDTAVYYCSVLES
	EYQLYDYWGQGT
	LVTVSS
VH	EVQLLESGGGLV	183
H111	QPGGSLRLSCAAS
	GRTLSSYDMGWF
	RQAPGKEREFVSA
	FITSGGSTFYEDSV
	KGRFTISRDNSKN
	TLYLQMNSLKPE
	DTAVYYCYADYV
	HDRGYWGQGTLV
	TVSS
VH	EVQLLESGGGLV	184
H112	QPGGSLRLSCAAS
	GSTFSSYTMAWF
	RQAPGKEREFVSA
	NITSGGDTYYADS
	VKGRFTISRDNSK
	NTLYLQMNSLKP
	EDTAVYYCAADV
	VYDEDYWGLSTH
	YTVSS
VH	EVQLLESGGGLV	185
H113	QPGGSLRLSCAAS
	GFEFSIYDLGWFR
	QAPGEEREFVSAY
	ITSEGSTYYVDSV
	KGRFTISRDNSKN
	TLYLQMNSLKPE
	DTAVYYCYADRG
	LHYSYWGQGTLV
	TVSS
VH	EVQLLESGGGLV	186
H114	QPGGSLRLSCAAS
	GIIFSIYDMGWFR
	QAPGKEREFVSAF
	ITSGGSTYYPDSV
	KGRFTISRDNSKN
	TLYLQMNSLKPE
	DTAVYYCYAEEG
	VGLEGYWGQGTL
	VTVSS
VH	EVQLLESGGGLV	187
H115	QPGGSLRLSCAAS
	GSPEREYGVGWF
	RQAPGKEREFVSG
	VISSGGSTYYADS
	VKGRFTISRDNSK
	NTLYLQMNSLKP
	EDTAVYYCYADH
	GTDQGSYTYWGQ
	GTLVTVSS
VH	EVQLLESGGGLV	188
H116	QPGGSLRLSCAAS
	GSFFSSYSVGWFR
	QAPGKEREFVSAI
	VIRTGSTYYGDSV
	KGRFTISRDNSKN
	TLYLQMNSLKPE
	DTAVYYCYADES
	FDQESNWGQGTL
	VTVSS
VH	EVQLLESGGGLV	189
H117	QPGGSLRLSCAAS
	GSSFSSYIMGWFR
	QAPGKEREFVSAV
	IGSGGDTYYADSV
	KGRFTISRDNSKN
	TLYLQMNSLKPE
	DTAVYYCYVDAD
	TPVTTSHWGQGT
	LVTVSS
VH	EVQLLESGGGLV	190
H118	QPGGSLRLSCAAS
	GSIFSSYAMGWFR
	QAPGKEREFVSAI
	VGSSGSTYYADSV
	KGRFTISRDNSKN
	TLYLQMNSLKPE
	DTAVYYCAVQRG
	IDYSFDFWGQGTL
	VTVSS
VH	EVQLLESGGGLV	191
H119	QPGGSLRLSCAAS
	GSIFSIYAMGWFR
	QAPGKEREFVSAS
	VISSGSTYYADSV
	KGRFTISRDNSKN
	TLYLQMNSLKPE
	DTAVYYCSAHTD
	YSLYDYWGQGTL
	VTVSS
VH	EVQLLESGGGLV	192
H120	QPGGSLRLSCAAS
	GFIFSFYHLAWFR
	QAPGKEREFVSAS
	IGSSEDTEYADSV
	KGRFTISRDNSKN
	TLYLQMNSLKPE
	DTAVYYCYAVHG
	VKYYEYWGQGTL
	VTVSS
VH	EVQLLESGGGLV	193
H121	QPGGSLRLSCAAS
	GSIFEFYAVGWFR
	QAPGKEREFVSAT
	ISSTGSKYYEDSV
	KGRFTISRDNSKN
	TLYLQMNSLKPE
	DTAVYYCAVDIG
	EGFDYWGQGTLV
	TVSS
VH	EVQLLESGGGLV	194
H122	QPGGSLRLSCAAS
	GSIFSYYGMGWF
	RQAPGKEREFVSG
	IISSGGSTYYADSV
	KGRFTISRDNSKN
	TLYLQMNSLKPE
	DTAVYYCYADTY
	TQRYTYWGQGTL
	VTVSS
VH	EVQLLESGGGLV	195
H123	QPGGSLRLSCAAS
	GSIFSSYAVGWFR
	QAPGKEREFVSAQ
	IISSGSTYYEDSVK
	GRFTISRDNSKNT
	LYLQMNSLKPED
	TAVYYCAAEEYY
	GYFDYWGQGTLV
	TVSS
VH	EVQLLESGGGLV	196
H124	QPGGSLRLSCAAS
	GSIFSIYAMSWFR
	QAPGKEREFVSAL
	IGSGGSTFYADSV
	KGRFTISRDNSKN
	TLYLQMNSLKPE
	DTAVYYCYATVG
	DHPQFQYDYWGQ
	GTLVTVSS
VH	EVQLLESGGGLV	197
H125	QPGGSLRLSCAAS
	GRIFSRYAMGWF
	RQAPGKEREFVSA
	YIATSGSRYYGDS
	VKGRFTISRDNSK
	NTLYLQMNSLKP
	EDTAVYYCGVSL
	PQGTGQGYDLYD
	TWGQGTLVTVSS
VH	EVQLLESGGGLV	198
H126	QPGGSLRLSCAAS
	GFEFSIYHLGWFR
	QAPGEEREFVSAY
	ITSEGSTYYVDSV
	KGRFTISRDNSKN
	TLYLQMNSLKPE
	DTAVYYCYADRG
	LHYSYWGQGTLV
	TVSS