Heterodimeric antigen-binding molecules that bind to viral particles and uses thereof

Abstract

The present disclosure provides a heterodimeric antibody, or antigen-binding fragment thereof, comprising two heavy chains with different amino acid sequences and a binding polypeptide. The heterodimer antibody, or the antigen-binding fragment thereof, include a first heavy chain comprising none or one or more modifications and the second heavy chain comprises one or more modifications and is fused to a binding polypeptide, which can form a isopeptide bond with a binding peptide. The present disclosure further provides systems and methods for purifying such heterodimeric antibodies, and antigen-binding fragments thereof.

Description

135975-91820REGN 11918HETERODIMERIC ANTIGEN-BINDING MOLECULES THAT BIND TO VIRAL PARTICLES AND USES THEREOFRELATED APPLICATIONS

[0001] This application claims priority to U.S. Application Serial No. 63 / 723,206, filed November 21, 2024, the entire contents of which are expressly incorporated by reference herein.SEQUENCE LISTING

[0002] The application contains a Sequence Listing which has been submitted electronically in .XML format and is hereby incorporated by reference in its entirety. Said .XML copy, created on November 3, 2025, is named “135975-91820.xml” and is 851,838 bytes in size. The sequence listing contained in this .XML file is part of the specification and is hereby incorporated by reference herein in its entirety.FIELD OF INVENTION

[0003] The present disclosure provides heterodimeric antigen-binding molecules that bind to viral particles, and methods of purifying such molecules from a heterogeneous mixture of homodimer antigen-binding molecules.BACKGROUND

[0004] Viral particles have emerged as vectors for gene therapy and the treatment of disease. Viral vectors, such as those based on the genome of adeno-associated virus (AAV), offer promising platforms for gene delivery. Despite advances providing the ability to direct AAV infection, retargeted AAV as a gene delivery vehicle remains less than ideal, at least in part, due to limited success from the efforts to redirect vector tropism. The efficiency of AAV vector-mediated gene delivery to different cell types also varies greatly. One possible mechanism for inefficient AAV transduction of certain cells may be low expression cellular receptor(s) to mediate virus binding and entry. There remains a need for selective and restrictive targeting of AAVs with enhanced cellular binding and transduction capabilities.SUMMARY

[0005] In general, the present disclosure provides heterodimeric antibodies, and antigen-binding fragments thereof, that bind to a capsid of an adeno-associated virus (AAV) particle and a molecule (i.e., a target molecule) on a cell surface, and methods of use thereof. By binding to both a capsid of an AAV and a target cell surface molecule, the heterodimeric antibodies, and antigen-binding fragments thereof, described herein can bridge the virus to target cell surfaces that are not naturally targeted by the virus, thereby redirecting virus delivery and transduction.135975-91820REGN 11918

[0006] In one aspect, provided herein is a heterodimeric antibody, or an antigen-binding fragment thereof, comprising: a) a first heavy chain comprising a first heavy chain variable region and a first heavy chain constant region, wherein the first heavy chain constant region comprises a first CH3 domain of a human IgG, wherein the human IgG is IgGl, IgG2, or IgG4; b) a second heavy chain comprising a second heavy chain variable region and a second heavy chain constant region, wherein the second heavy chain constant region comprises 1) a second CH3 domain of a human IgG, wherein the human IgG is IgGl, IgG2, or IgG4; and 2) one or more modifications in the second CH3 domain that reduces or eliminates binding of the second CH3 domain to Protein A; and c) a binding polypeptide fused to the C-terminus of the second heavy chain, wherein the binding polypeptide forms an isopeptide bond with a binding peptide not attached to the heterodimeric antibody.

[0007] In another aspect, provided herein is the heterodimeric antibody, or an antigen-binding fragment thereof, comprising: a) a first heavy chain comprising a first heavy chain variable region and a first heavy chain constant region that comprises a first CH3 region of a human IgG, wherein the human IgG is IgGl, IgG2, or IgG4; b) a second heavy chain comprising a second heavy chain variable region and a second heavy chain constant region that comprises a second CH3 region of a human IgG, wherein the human IgG is IgGl, IgG2, or IgG4; and c) a binding polypeptide fused to the C-terminus of the second heavy chain, wherein the binding polypeptide can form an isopeptide bond with a peptide not attached to the heterodimeric antibody.

[0008] In some embodiments, the second heavy chain further comprises one or more modifications in the second CH3 region that reduces or eliminates binding of the second CH3 region to Protein A.

[0009] In some embodiments, the first heavy chain further comprises one or more modifications in a first hinge domain; and / or the second heavy chain further comprises one or more modifications in a second hinge domain.

[0010] In some embodiments, the first heavy chain constant region comprises from N-terminal to C- terminal the first hinge domain, a first CH2 domain, and the first CH3 domain; and / or wherein the second heavy chain constant region comprises from N-terminal to C-terminal the second hinge domain, a second CH2 domain, and the second CH3 domain.

[0011] In some embodiments, the first heavy chain constant region comprises from N-terminal to C- terminal a first CHI domain, the first hinge domain, the first CH2 domain, and the first CH3 domain; and / or wherein the second heavy chain constant region comprises from N-terminal to C-terminal a second CHI domain, the second hinge domain, the second CH2 domain, and the second CH3 domain.

[0012] In some embodiments, the first CHI domain, the first hinge domain, the first CH2 domain, and the first CH3 domain of the first heavy chain constant region are the same human isotype; and / or wherein the second CHI domain, the second hinge domain, the second CH2 domain, and the second CH3 domain of the second heavy chain constant region are the same human isotype.

[0013] In some embodiments, the first CHI domain, the first hinge domain, the first CH2 domain, and the first CH3 domain of the first heavy chain constant region are different human isotypes; and / or135975-91820REGN 11918 wherein the second CHI domain, the second hinge domain, the second CH2 domain, and the second CH3 domain of the second heavy chain constant region are different human isotypes.

[0014] In some embodiments, the first CHI domain, the first hinge domain, the first CH2 domain, and the first CH3 domain of the first heavy chain constant region are each selected from IgGl, IgG2, and IgG4; and / or wherein the second CHI domain, the second hinge domain, the second CH2 domain, and the second CH3 domain of the second heavy chain constant region are each selected from IgGl, IgG2, and IgG4.

[0015] In some embodiments, the first CHI domain, the first hinge domain, the first CH2 domain, and the first CH3 domain of the first heavy chain constant region are human IgGl ; and / or wherein the second CHI domain, the second hinge domain, the second CH2 domain, and the second CH3 domain of the second heavy chain constant region are human IgGl.

[0016] In some embodiments, the first CHI domain, the first hinge domain, the first CH2 domain, and the first CH3 domain of the first heavy chain constant region are human IgG2; and / or wherein the second CHI domain, the second hinge domain, the second CH2 domain, and the second CH3 domain of the second heavy chain constant region are human IgG2.

[0017] In some embodiments, the first CHI domain, the first hinge domain, the first CH2 domain, and the first CH3 domain of the first heavy chain constant region are human IgG4; and / or wherein the second CHI domain, the second hinge domain, the CH2 domain, and the CH3 domain of the second heavy chain constant region are human IgG4.

[0018] In some embodiments, the first hinge domain and / or the second hinge domain are a chimera of two or more IgG isotypes.

[0019] In some embodiments, the first hinge domain chimera and / or the second hinge domain chimera is IgG2 / IgG4.

[0020] In some embodiments, the one or more modifications in the second CH3 domain are selected from the group consisting of (a) 95R, and (b) 95R and 96F in the IMGT exon numbering system, or (a’) 435R, and (b’) 435R and 436F in the EU numbering system.

[0021] In some embodiments, the second CH3 domain further comprises one to five modifications selected from the group consisting of 16E, 18M, 44S, 52N, 57M, and 821 in the IMGT exon numbering system, or 356E, 358M, 384S, 392N, 397M, and 4221 in the EU numbering system.

[0022] In some embodiments, the second CH3 domain is non-immunogenic or substantially non- immunogenic in a human.

[0023] In some embodiments, the first hinge domain comprises one or more modifications at positions 233-236 and the second hinge domain comprises one or more modifications at positions 233-236; optionally wherein the one or more modifications in the first hinge domain and / or the second hinge domain are G, G, G, and unoccupied; G, G, unoccupied, and unoccupied; G, unoccupied, unoccupied, and unoccupied; or all unoccupied, with positions numbered by EU numbering.135975-91820REGN 11918

[0024] In some embodiments, positions 226-229 of the first hinge domain and the second hinge domain are CPPC.

[0025] In some embodiments, the first hinge domain amino acid sequence and / or the second hinge domain amino acid sequence comprises CPPCPAPGGG-GPSVF (SEQ ID NO: 167), CPPCPAPGG- GPSVF (SEQ ID NO: 168), CPPCPAPG— GPSVF (SEQ ID NO: 169), or CPPCPAP— -GPSVF (SEQ ID NO: 170).

[0026] In some embodiments, the first heavy chain constant region has an amino acid sequence comprising SEQ ID NOs: 174-177, 182-188, 193-196, 201, or 203 or a variant thereof having up to five insertions, deletions, substitutions, or insertions.

[0027] In some embodiments, the first heavy chain constant region comprises SEQ ID NOs: 174- 177, 182-188, 193-196, 201, or 203.

[0028] In some embodiments, the first heavy chain constant region consists of SEQ ID NOs: 174- 177, 182-188, 193-196, 201, or 203.

[0029] In some embodiments, the second heavy chain constant region has an amino acid sequence comprising SEQ ID NOs: 178-181, 189-192, 197-200, 202, and 204 or a variant thereof having up to five insertions deletions, substitutions, or insertions.

[0030] In some embodiments, the second heavy chain constant region comprises SEQ ID NOs: 178- 181, 189-192, 197-200, 202, and 204.

[0031] In some embodiments, the second heavy chain constant region consists of SEQ ID NOs: 178- 181, 189-192, 197-200, 202, and 204.

[0032] In some embodiments, the heterodimeric antibody, or antigen-binding fragment thereof further comprises an immunoglobulin light chain.

[0033] In some embodiments, the immunoglobulin light chain is a human immunoglobulin light chain.

[0034] In some embodiments, the immunoglobulin light chain comprises a light chain variable region and a light chain constant region.

[0035] In some embodiments, the first heavy chain variable region selectively binds a first epitope and the second heavy chain variable region selectively binds a second epitope.

[0036] In some embodiments, the first epitope and the second epitope are on the same target molecule.

[0037] In some embodiments, the first epitope and the second epitope are on different target molecules.

[0038] In some embodiments, the binding polypeptide is linked via a first linker to the C-terminus of the second heavy chain.

[0039] In some embodiments, the first linker comprises the amino acid sequence selected from the group consisting of SEQ ID NO: 213 (GLSG), SEQ ID NO: 214 (GLSGSG), SEQ ID NO: 215135975-91820REGN 11918(GLSGLSGS), SEQ ID NO: 216 (GLSGLSGLSG), SEQ ID NO: 217 (GLSGGSGLSG), and SEQ ID NO: 219 (GSGESG).

[0040] In some embodiments, the first linker comprises the amino acid sequence of SEQ ID NO: 219 (GSGESG).

[0041] In some embodiments, the binding polypeptide comprises the amino acid sequence of any one of SEQ ID NOs: 55-70; and the binding peptide comprises the amino acid sequence of any one of SEQ ID NOs: 71-85.

[0042] In some embodiments, the binding polypeptide and binding peptide form a binding pair, and wherein the binding pair is selected from the group consisting of (i) Spy Catcher: Spy Tag, (ii) KTag: SpyTag, (iii) pilin-C: Isopeptag, (iv) SnoopCatcher: SnoopTag, and (v) SpyCatcher002:SpyTag002.

[0043] In some embodiments, the binding polypeptide is SpyCatcher.

[0044] In some embodiments, the binding peptide is SpyTag.

[0045] In some embodiments, the binding polypeptide is KTag and the binding peptide is SpyTag.

[0046] In some embodiments, the binding polypeptide is pilin-C and the binding peptide is isopeptag.

[0047] In some embodiments, the binding polypeptide is SnoopCatcher and the binding peptide is SnoopTag.

[0048] In some embodiments, the binding polypeptide is SpyCatcher002 and the binding peptide is SpyTag002.

[0049] In some embodiments, the target molecule is a cell surface molecule, wherein the cell surface molecule is calcium voltage-gated channel auxiliary subunit gamma 1 (CACNG1), asialoglycoprotein receptor 1 (ASGR1), Fel d 1, ENTPD3, PTPRA, CD20, CD63, Her2, GABA, transferrin receptor, CD3, CD34, integrin, adipophilin, AIM-2, ALDH1A1, alpha-actinin-4, alpha-fetoprotein (AFP), ARTCI, B-RAF, BAGE-1, BCLX (L), BCR-ABL fusion protein b3a2, beta-catenin, BING-4, CA- 125, CALCA, carcinoembryonic antigen (CEA), CASP-5, CASP-8, CD274, CD45, Cdc27, CDK12, CDK4, CDKN2A, CEA, CLPP, COA-1, CPSF, CSNK1A1, CTAG1, CTAG2, cyclin DI, Cyclin-Al, dek-can fusion protein, DKK1, EFTUD2, Elongation factor 2, ENAH (hMena), Ep-CAM, EpCAM, EphA3, epithelial tumor antigen (ETA), ETV6-AML1 fusion protein, EZH2, E6, E7, FGF5, FLT3- ITD, FN1, G250 / MN / CAIX, GAGE-1,2,8, GAGE- 3, 4, 5, 6, 7, GAS7, glypican-3, GnTV, gplOO / Pmel 17, GPNMB, HAUS3, Hepsin, HER-2 / neu, HERV-K-MEL, HLA-A11, HLA-A2, HLA-DOB, hsp70- 2, IDO1, IGF2B3, IL13Ralpha2, intestinal carboxyl esterase, K-ras, Kallikrein 4, KIF20A, KK-LC-1, KKLC1, KM-HN-1, KMHN1 also known as CCDC110, LAGE-1, LDLR-fucosyltransferase AS fusion protein, Lengsin, M-CSF, MAGE-A1, MAGE- A 10, MAGE-A12, MAGE-A2, MAGE- A3, MAGE-A4, MAGE-A6, MAGE-A9, MAGE-CI, MAGE-C2, malic enzyme, mammaglobin-A, MART2, MATN, MC1R, MCSP, mdm-2, MEI, Melan-A / MART-1, Meloe, Midkine, MMP-2, MMP- 7, MUC1, MUC5AC, mucin, MUM-1, MUM-2, MUM-3, Myosin, Myosin class I, N-raw, NA88- A, neo-PAP, NFYC, NY-BR-1, NY-ESO-l / LAGE-2, OA1, OGT, OS-9, P polypeptide, p53, PAP, PAX5, PBF, pml-RARalpha fusion protein, polymorphic epithelial mucin (PEM), PPP1R3B, PRAME,135975-91820REGN 11918PRDX5, PSA, PSMA, PTPRK, RAB 38 / N Y-MEL-1, RAGE-1, RBAF600, RGS5, RhoC, R F43, RU2AS, SAGE, secernin 1, SIRT2, SNRPD1, SOXIO, Spl7, SPA17, SSX-2, SSX-4, STEAP1, survivin, SYT-SSX1 or SYT-SSX2 fusion protein, TAG-1, TAG-2, Telomerase, TGF-betaRII, TPBG, TRAG-3, Triosephosphate isomerase, TRP-l / gp75, TRP-2, TRP2-INT2, tyrosinase, VEGF, WT1, XAGE-lb / GAGED2a, Kras, NY-ESO1, MAGE-A3, HPV E2, HPV E6, HPV E7, WT-1 antigen, ErbB receptors, Melan A (MARTI), gp 100, tyrosinase, TRP-l / gp 75, and TRP-2; MAGE-1 and MAGE-3; HPV EG and E7 proteins; Mucin-1 (MUC-1); prostate-specific antigen (PSA); carcinoembryonic antigen (CEA), MAGE-2, MAGE-4, MAGE-6, MAGE-10, MAGE-12, BAGE-1, CAGE-1,2,8, CAGE-3 to 7, LAGE-1, NY-ESO-l / LAGE-2, NA-88, GnTV, TRP2-INT2, E6, E7, human glucagon receptor (hGCGR) or ectonucleoside triphosphate diphosphohydrolase 3 (hENTPD3).

[0050] In some embodiments, the cell surface molecule is CACNG1.

[0051] In some embodiments, the first heavy chain is encoded by a nucleotide sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to the nucleotide sequence of SEQ ID NO: 154; and / or wherein the second heavy chain is encoded by a nucleotide sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to the nucleotide sequence of SEQ ID NO: 156.

[0052] In some embodiments, the first heavy chain comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 155; and / or wherein the second heavy chain comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 157.

[0053] In some embodiments, the first heavy chain comprises or consists of the amino acid sequence of SEQ ID NO: 155; and / or wherein the second heavy chain comprises or consists of the amino acid sequence of SEQ ID NO: 157.

[0054] In some embodiments, the light chain is encoded by a nucleotide sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to the nucleotide sequence of SEQ ID NO: 158.

[0055] In some embodiments, the light chain comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 159.

[0056] In another aspect, provided herein is a composition comprising (a) the heterodimeric antibody, or antigen-binding fragment thereof as any of the above-described heterodimeric antibodies or antigen-binding fragments, and (b) a pharmaceutically acceptable carrier.

[0057] In another aspect, provided herein is a system to deliver a nucleic acid to a cell, the system comprising 1) the heterodimeric antibody, or antigen-binding fragment thereof as any of the abovedescribed heterodimeric antibodies or antigen-binding fragments, or the composition as any or the above-described compositions; and 2) a viral particle, wherein the viral particle comprises one or more recombinant viral capsid proteins, wherein the one or more recombinant viral capsid proteins comprises a heterologous amino acid sequence, wherein the heterologous amino acid sequence is the binding peptide, and wherein the nucleic acid is encapsulated in the viral particle.135975-91820REGN 11918

[0058] In some embodiments, the binding peptide is linked to the one or more recombinant viral capsid proteins via a second linker.

[0059] In some embodiments, the second linker comprises the amino acid sequence selected from the group consisting of SEQ ID NO: 213 (GLSG), SEQ ID NO: 214 (GLSGSG), SEQ ID NO: 215 (GLSGLSGS), SEQ ID NO: 216 (GLSGLSGLSG), SEQ ID NO: 217 (GLSGGSGLSG), and SEQ ID NO: 219 (GSGESG).

[0060] In some embodiments, the second linker comprises the amino acid sequence of SEQ ID NO: 219 (GSGESG).

[0061] In some embodiments, the first linker and second linker are identical.

[0062] In some embodiments, the first linker and second linker are not identical.

[0063] In some embodiments, the one or more recombinant viral capsid proteins comprise one or more mutations in comparison to the corresponding wild type capsid protein.

[0064] In some embodiments, the recombinant viral capsid protein is derived from: (i) a capsid gene of an adeno-associated virus (AAV), wherein the capsid gene encodes an AAV VP1, VP2, and / or VP3 capsid protein.

[0065] In some embodiments, the viral particle is an adeno-associated virus (AAV) particle.

[0066] In some embodiments, the AAV particle is selected from the group consisting of AAV1, AAV2, AAV2quad(Y-F), AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAV13, rhlO, rh39, rh43, and rh74, or any variant thereof.

[0067] In some embodiments, the adeno-associated virus is AAV2.

[0068] In some embodiments, the adeno-associated virus is AAV9.

[0069] In some embodiments, the nucleic acid encodes a gene.

[0070] In some embodiments, the gene is selected from the group consisting of non-translated RNAs / non-coding RNAs, receptors, fusion proteins, agonists, antagonists, activators, inhibitors, enzymes, factors and co-factors, repressors, activators, ligands, protein hormones, therapeutic proteins, suicide proteins, structural proteins, storage proteins, transport proteins, signal proteins, neurotransmitters, contractile proteins, and any variant thereof.In another aspect, provided herein is a method of making a heterodimeric antibody, or antigen-binding fragment thereof comprising: a) loading an affinity matrix with a mixture of multimeric proteins comprising (i) a first homodimer comprising two copies of a first heavy chain comprising a first heavy chain variable region and a first heavy chain constant region, wherein the first heavy chain constant region comprises 1) a first CH3 domain of a human IgG selected from IgGl, IgG2, and IgG4; (ii) a second homodimer comprising two copies of the second heavy chain comprising a second heavy chain variable region and a second heavy chain constant region, wherein the second heavy chain constant region comprises 1) a second CH3 domain of a human IgG selected from IgGl, IgG2, and IgG4; 2) one or more modifications in the second CH3 domain that reduces or eliminates binding of the second CH3 domain to Protein A; and 3) one or more modifications within a second hinge135975-91820REGN 11918 domain, and wherein a binding polypeptide is fused to the C-terminus of the second heavy chain, wherein the binding polypeptide forms an isopeptide bond with a binding peptide not attached to the second heavy chain; and (iii) a heterodimer comprising the first heavy chain and the second heavy chain, wherein the first heavy chain has greater affinity for the affinity matrix than does the second heavy chain; and b) el uting and col leering the heterodimer from the affinity matrix in a buffer comprising a salt, an anion, and having a first pH range, wherein the first homodimer elutes from the affinity matrix in the buffer at a second pH range and the second homodimer elutes from the affinity matrix in the buffer at a third pH range, wherein the third pH range comprises a higher pH than the first pH range, and wherein the first pH range comprises a higher pH than the second pH range.

[0071] In some embodiments, the first heavy chain constant region further comprises one or more modifications within a first hinge domain.

[0072] In some embodiments, the affinity matrix comprises a Protein A ligand affixed to a substrate.

[0073] In some embodiments, the Protein A ligand is an engineered Protein A comprising a Z- domain tetramer or a Y-domain tetramer.

[0074] In some embodiments, the substrate comprises any one or more of agarose, polystyrene divinylbenzene), polymethacrylate, cellulose, controlled pore glass, and spherical silica.

[0075] In some embodiments, the substrate is a particle and the affinity matrix comprises a multiplicity of the particles having a mean diameter of 25 pm to 100 pm.

[0076] In some embodiments, the particles have a mean diameter of 45 pm and comprise pores having a mean diameter of 1100 A.

[0077] In some embodiments, 5 to 50 grams of protein are loaded per liter of affinity matrix.

[0078] In some embodiments, the method comprising applying a pH gradient to the loaded affinity matrix of step (a).

[0079] In some embodiments, further comprising washing the loaded affinity matrix of step (a) with a solution at pH 6-8 prior to applying the pH gradient.

[0080] In some embodiments, the pH gradient is run between pH 6 and pH 3.

[0081] In some embodiments, the first pH range is selected from a range within pH 5.5 and pH 3.6.

[0082] In some embodiments, the anion is acetate.

[0083] In some embodiments, the buffer comprises 40 mM acetate.

[0084] In some embodiments, the salt is sodium chloride.

[0085] In some embodiments, the salt comprises about 250 to about 500 mM sodium chloride.

[0086] In some embodiments, the first heavy chain comprises a first CH3 domain that is capable of binding to Protein A and the second heavy chain comprises a second CH3 domain that is not capable of binding to Protein A.

[0087] In some embodiments, the second heavy chain comprises a HY to RF substitution in the second CH3 domain.135975-91820REGN 11918

[0088] In some embodiments, the heterodimer comprises a heterodimeric antibody, or antigenbinding fragment thereof.

[0089] In some embodiments, the mixture of multimeric proteins is produced by a plurality of eukaryotic cells in a cell culture.

[0090] In some embodiments, the eukaryotic cells comprise Chinese hamster ovary (CHO) cells or derivatives thereof.

[0091] In some embodiments, the method further comprising (c) loading a second affinity matrix with a mixture comprising the first homodimer and the heterodimer collected at step (b); (d) eluting and collecting the heterodimer from the affinity matrix in a buffer having a first pH range, wherein, the first homodimer elutes from the affinity matrix in the buffer at a second pH range.

[0092] In some embodiments, the first heavy chain constant region comprises from N-terminal to C- terminal the first hinge domain, a first CH2 domain, and the first CH3 domain; and / or wherein the second heavy chain constant region comprises from N-terminal to C-terminal the second hinge domain, a second CH2 domain, and the second CH3 domain.

[0093] In some embodiments, the first heavy chain constant further comprises a first CHI domain, and / or the second heavy chain constant further comprises a second CHI domain.In some embodiments, the first CHI domain, the first hinge domain, the first CH2 domain, and / or the first CH3 domain of the first heavy chain constant region are derived from human IgGl, human IgG2, and / or human IgG4; and / or the second CHI domain, the second hinge domain, the second CH2 domain, and / or the second CH3 domain of the second heavy chain constant region are derived from human IgGl, human IgG2, and / or human IgG4.

[0094] In some embodiments, the first hinge domain and / or the second hinge domain are a chimera of two or more IgG isotypes, optionally wherein first hinge domain chimera and / or the second hinge domain chimera is IgG2 / IgG4.

[0095] In some embodiments, the one or more modifications in the second CH3 domain are selected from the group consisting of (a) 95R, and (b) 95R and 96F in the IMGT exon numbering system, or (a’) 435R, and (b’) 435R and 436F in the EU numbering system.

[0096] In some embodiments, the second CH3 domain further comprises one to five modifications selected from the group consisting of 16E, 18M, 44S, 52N, 57M, and 821 in the IMGT exon numbering system, or 356E, 358M, 384S, 392N, 397M, and 4221 in the EU numbering system.

[0097] In some embodiments, the one or more modifications in the first hinge domain and the one or more modifications at in the second hinge domain are at positions 233-236, and are G, G, G, and unoccupied; G, G, unoccupied, and unoccupied; G, unoccupied, unoccupied, and unoccupied; or all unoccupied, with positions numbered by EU numbering.

[0098] In some embodiments, the first hinge domain amino acid sequence and / or the second hinge domain amino acid sequence comprises CPPCPAPGGG-GPSVF (SEQ ID NO: 167), CPPCPAPGG-135975-91820REGN 11918GPSVF (SEQ ID NO: 168), CPPCPAPG— GPSVF (SEQ ID NO: 169), or CPPCPAP— -GPSVF (SEQ ID NO: 170).

[0099] In some embodiments, the first heavy chain constant region has an amino acid sequence comprising SEQ ID NOs: 174-177, 182-188, 193-196, 201, or 203 or a variant thereof having up to five insertions deletions, substitutions, or insertions.

[0100] In some embodiments, the second heavy chain constant region has an amino acid sequence comprising SEQ ID NOs: 178-181, 189-192, 197-200, 202, and 204 or a variant thereof having up to five insertions deletions, substitutions, or insertions.

[0101] In some embodiments, the heterodimer further comprises an immunoglobulin light chain, optionally wherein the immunoglobulin light chain is human.

[0102] In some embodiments, the binding polypeptide is linked via a first linker to the C-terminus of the second heavy chain, wherein the first linker comprises the amino acid sequence selected from the group consisting of SEQ ID NO: 219 (GSGESG).

[0103] In some embodiments, the binding polypeptide comprises the amino acid sequence of any one of SEQ ID NOs: 55-70; and the binding peptide comprises the amino acid sequence of any one of SEQ ID NOs: 71-85.

[0104] In some embodiments, the binding polypeptide and binding peptide form a binding pair, and wherein the binding pair is selected from the group consisting of (i) Spy Catcher: Spy Tag, (ii) KTag: SpyTag, (iii) pilin-C: Isopeptag, (iv) SnoopCatcher: SnoopTag, and (v) SpyCatcher002:SpyTag002.

[0105] In some embodiments, the binding polypeptide is SpyCatcher and the binding peptide is SpyTag.

[0106] In some embodiments, the first heavy chain is encoded by a nucleotide sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to the nucleotide sequence of SEQ ID NO: 154; and / or wherein the second heavy chain is encoded by a nucleotide sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to the nucleotide sequence of SEQ ID NO: 156.

[0107] In some embodiments, the first heavy chain comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 155; and / or wherein the second heavy chain comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 157.

[0108] In some embodiments, the first heavy chain comprises or consists of the amino acid sequence of SEQ ID NO: 155; and / or wherein the second heavy chain comprises or consists of the amino acid sequence of SEQ ID NO: 157.

[0109] In some embodiments, the light chain is encoded by a nucleotide sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to the nucleotide sequence of SEQ ID NO: 158.

[0110] In some embodiments, the light chain comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 159.135975-91820REGN 11918

[0111] In another aspect, provided herein is a heterodimeric antibody, or antigen-binding fragment thereof made according to the method as any of the above-described methods.

[0112] In another aspect, provided herein is a composition comprising the heterodimeric antibody, or antigen-binding fragment thereof as any of the above-described heterodimeric antibodies or antigenbinding fragments, and a pharmaceutically acceptable carrier.

[0113] In another aspect, provided herein is a method of delivering a nucleic acid molecule to a target cell, the method comprising: 1) combining the heterodimeric antibody, or antigen-binding fragment thereof as any of the above-described heterodimeric antibodies or antigen-binding fragments, or the composition as any of the above-described compositions, with a recombinant viral particle comprising a binding peptide, wherein the binding peptide forms an isopeptide bond with the binding polypeptide fused to the second heavy chain of the heterodimeric antibody, or antigenbinding fragment thereof; 2) contacting the target cell with the mixture of step (1), wherein the heterodimeric antibody, or antigen-binding fragment thereof specifically binds to a cell surface molecule on the target cell.

[0114] In some embodiments, the target cell is in vitro.

[0115] In some embodiments, the target cell is in vivo in a subject.

[0116] In some embodiments, the subject is a human.

[0117] In some embodiments, the target cell is a human target cell.

[0118] In some embodiments, targeting ligand binds calcium channel, voltage-dependent, gamma subunit 1 (CACNG1).

[0119] In some embodiments, the nucleic acid molecule is encapsulated by the recombinant viral particle.

[0120] In some embodiments, the nucleic acid molecule is under the control of a promoter selected from the group consisting of a viral promoter, a bacterial promoter, a mammalian promoter, an avian promoter, a fish promoter, an insect promoter, and any combination thereof.

[0121] In some embodiments, the recombinant viral particle is an adeno-associated virus (AAV) particle or a lenti virus particle.

[0122] In some embodiments, the recombinant viral particle is selected from the group consisting of AAV1, AAV2, AAV2quad(Y-F), AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAV13, rhlO, rh39, rh43, rh74, and any variant thereof.

[0123] In some embodiments, the recombinant viral particle comprises one or more recombinant viral capsid proteins.

[0124] In some embodiments, the one or more recombinant viral capsid proteins are derived from: (i) a capsid gene of an adeno-associated virus (AAV) , wherein the capsid gene encodes an AAV VP1, VP2, and / or VP3 capsid proteins; or (ii) a lentivirus.

[0125] In some embodiments, the binding peptide is fused to the one or more recombinant viral capsid proteins.135975-91820REGN 11918

[0126] In some embodiments, the heterodimeric antibody, or antigen-binding fragment thereof and the recombinant viral particle bind via the binding polypeptide and binding peptide isopeptide bond.BRIEF DESCRIPTION OF FIGURES

[0127] Figure 1 (FIG. 1) shows a schematic representation of the different antibody species generated by expression of two heavy chain molecules with different amino acid sequences and a light chain. The schematic on the left depicts a homodimer (homodimer A) where both the heavy chains comprise a mutation in the CH3 domain (“star”) and are fused to a polypeptide at the C-terminus. The schematic on the right depicts a second homodimer (homodimer B) where both heavy chains do not comprise either a CH3 domain mutation or a polypeptide fused at the C-terminal end. The schematic in the center depicts an example of a heterodimer antibody as described herein, which comprises one heavy chain with a CH3 domain mutation and a polypeptide fused to the C-terminal end, and a second heavy chain without either of the modifications of the first heavy chain.

[0128] Figures 2A-2D (FIGs. 2A-2D) show mRNA expression across four skeletal muscle tissues: diaphragm (Figure 2A), tibialis anterior (Figure 2B), gastrocnemius (Figure 2C), and quadriceps (Figure 2D). Quantification determined by quantitative polymerase chain reaction (qPCR). Legend: WT AAV9 (control, without antibody); homodimeric mAb (homodimeric monoclonal antibody (“homodimeric mAb”) comprising identical heavy chains, wherein each heavy chain is operably linked at its C-terminus to SpyCatcher); and heterodimeric mAb (heterodimer monoclonal antibody (“heterodimeric antibody” as described herein).

[0129] Figures 3A-3D (FIGs. 3A-3D) show mRNA expression across four skeletal muscle tissues: diaphragm (Figure 3A), tibialis anterior (Figure 3B), gastrocnemius (Figure 3C), and quadriceps (Figure 3D). Quantification determined by digital polymerase chain reaction (dPCR). Legend: WT AAV9 (control, without antibody); homodimeric mAb (homodimeric monoclonal antibody (“homodimeric mAb”) comprising identical heavy chains, wherein each heavy chain is operably linked at its C-terminus to SpyCatcher); and heterodimeric mAb (heterodimer monoclonal antibody (“heterodimeric antibody” as described herein).DETAILED DESCRIPTION

[0130] Before the present disclosure is described, it is to be understood that this disclosure is not limited to particular methods and experimental conditions described, as such methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims.

[0131] Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. All patents, applications and non-patent publications mentioned in this specification are135975-91820REGN 11918 incorporated herein by reference in their entireties All publications mentioned are hereby incorporated by reference.Definitions

[0132] The term “about” in the context of numerical values and ranges refers to values or ranges that approximate or are close to the recited values or ranges such that the compositions and methods can perform as intended, such as having a desired rate, amount, density, degree, increase, decrease, percentage, ratio, number, value, purity, pH, concentration, presence of a form or variant, temperature or amount of time, as is apparent from the teachings contained herein. For example, “about” can signify values either above or below the stated value in a range of approx. + / - 10% or more or less depending on the ability to perform. Thus, this term encompasses values beyond those simply resulting from systematic error.

[0133] As used herein , the terms “antibodies” (also referred to as “immunoglobulins”), “antibody molecules” are examples of proteins having multiple polypeptide chains and extensive post- translational modifications. The canonical immunoglobulin protein (for example, IgG) comprises four polypeptide chains - two light chains and two heavy chains. Each light chain is linked to one heavy chain via a cysteine disulfide bond, and the two heavy chains are bound to each other via two cysteine disulfide bonds. Immunoglobulins produced in mammalian systems are also glycosylated at various residues (for example, at asparagine residues) with various polysaccharides, and can differ from species to species, which may affect antigenicity for therapeutic antibodies. Butler and Spearman, “The choice of mammalian cell host and possibilities for glycosylation engineering,” Curr. Opin. Biotech. 30:107-112 (2014).

[0134] The phrase “antigen-binding fragments” include, but are not limited to: antibody fragments (for example, Fab, ScFv-Fc, dAB-Fc, half antibodies, and other combinations of heavy and / or light chains), multispecifics (for example, bispecific, IgG-ScFv, IgG-dab, ScFV-Fc-ScFV, trispecifics).

[0135] The phrase “heavy chain,” or “immunoglobulin heavy chain” includes an immunoglobulin heavy chain constant region sequence from any organism, and unless otherwise specified includes a heavy chain variable domain. Heavy chains are classified as Y, mu, alpha, delta, or epsilon, and define the antibody’s isotype as IgG, IgM, IgA, IgD, and IgE, respectively. Heavy chain variable domains include three heavy chain CDRs and four FR regions, unless otherwise specified. Fragments of heavy chains include CDRs, CDRs, and FRs, and combinations thereof. A typical heavy chain has, following the variable domain (from N-terminal to C-terminal), a CHI domain, a hinge, a CH2 domain, and a CH3 domain. A functional fragment of a heavy chain includes a fragment that is capable of specifically recognizing an antigen (e.g., recognizing the antigen with a KD in the micromolar, nanomolar, or picomolar range), that is capable of expressing and secreting from a cell, and that comprises at least one CDR.135975-91820REGN 11918

[0136] The phrase “variable domain” includes an amino acid sequence of an immunoglobulin light or heavy chain (modified as desired) that comprises the following amino acid regions, in sequence from N-terminal to C-terminal (unless otherwise indicated): FR1, HCDR1, FR2, HCDR2, FR3, HCDR3, FR4 for a heavy chain variable domain, and FR1, LCDR1, FR2, LCDR2, FR3, LCDR3, FR4 for a light chain variable domain. A “variable domain” includes an amino acid sequence capable of folding into a canonical domain (VH or VL) having a dual beta sheet structure wherein the beta sheets are connected by a disulfide bond between a residue of a first beta sheet and a second beta sheet.

[0137] The phrase “complementarity determining region,” or the term “CDR,” includes an amino acid sequence encoded by a nucleic acid sequence of an organism’s immunoglobulin genes that normally (i.e. , in a wild-type animal) appears between two framework regions in a variable region of a light or a heavy chain of an immunoglobulin molecule (e.g., an antibody or a T cell receptor). A CDR can be encoded by, for example, a germline sequence or a rearranged or unrearranged sequence, and, for example, by a naive or a mature B cell or a T cell. In some circumstances (e.g., for a CDR3), CDRs can be encoded by two or more sequences (e.g., germline sequences) that are not contiguous (e.g., in an unrearranged nucleic acid sequence) but are contiguous in a B cell nucleic acid sequence, e.g., as the result of splicing or connecting the sequences (e.g., V-D-J recombination to form a heavy chain CDR3).

[0138] The phrase “light chain” includes an immunoglobulin light chain constant region sequence from any organism, and unless otherwise specified includes human kappa and lambda light chains. Light chain variable (VL) domains typically include three light chain CDRs and four framework (FR) regions, unless otherwise specified. Generally, a full-length light chain includes, from amino terminus to carboxyl terminus, a VL domain that includes FR1-LCDR1-FR2-LCDR2-FR3-LCDR3-FR4, and a light chain constant domain. Light chains that can be used with this heterodimeric antibody, and antigen-binding fragment thereof, as described herein, include those, e.g., that do not selectively bind either the first or second antigen selectively bound by the antigen-binding protein. Suitable light chains include those that can be identified by screening for the most commonly employed light chains in existing antibody libraries (wet libraries or in silico), where the light chains do not substantially interfere with the affinity and / or selectivity of the antigen-binding domains of the antigen-binding proteins. Suitable light chains include those that can bind one or both epitopes that are bound by the antigen-binding regions of the antigen-binding protein.

[0139] Within light and heavy chains, the variable and constant regions are joined by a “J” segment of about 12 or more amino acids, with the heavy chain also including a “D” segment of about 10 or more amino acids. (See generally, Fundamental Immunology (Paul, W., ed., 2nd ed. Raven Press, N.Y., 1989), Ch. 7) (incorporated by reference in its entirety for all purposes).

[0140] The phrase “Fc-containing protein” includes antibodies and antigen-binding fragments thereof, multispecific antibodies, bispecific antibodies, immunoadhesins, and other binding proteins that comprise at least a functional portion of an immunoglobulin CH2 and CH3 region. A “functional135975-91820REGN 11918 portion” refers to a CH2 and CH3 region that can bind a Fc receptor (e.g., an FcyR; or an FcRn, i.e., a neonatal Fc receptor), and / or that can participate in the activation of complement. If the CH2 and CH3 region contains deletions, substitutions, and / or insertions or other modifications that render it unable to bind any Fc receptor and also unable to activate complement, the CH2 and CH3 region is not functional. “Fc-fusion proteins” comprise part or all of two or more proteins, one of which is an Fc portion of an immunoglobulin molecule that are not fused in their natural state. Fc-fusion proteins include Fc-fusion (N-terminal), Fc-fusion (C-terminal), monospecific Fc-fusion and bispecific Fc- fusion or multi-specific Fc-fusion.

[0141] Several antibody effector functions are mediated at least in part by Fc receptors (FcRs), which bind the Fc region of an antibody in the constant domain (specifically, the CH2 and CH3 domain) of a typical immunoglobulin. There are a number of Fc receptors which are specific for the different classes of immunoglobulins, i.e., IgG, IgE, IgA, IgM, and IgD. The human IgG Fc receptor family is divided into three groups: FcyR! (CD64), which is capable of binding IgG with high affinity, FcyRII (CD32) and FcyRIII (CD 16) both of which are low affinity receptors. Each FcyR subclass is encoded by two or three genes, and alternative RNA splicing leads to multiple transcripts, hence, a broad diversity in FcyR isoforms exists (e.g. FcyRIA (CD64; FCGR1A, Swiss Prot P12314), FcyRIB (CD64; FCRG1B), FcyRIIA (CD32; FCGR2A, Swiss Prot P12318), FcyRIIB (CD32; FCGR2B, Swiss Prot P31994), FcyRIIC (CD32; FCGR2C), FcyRIIIA (CD16a; FCGR3A, Swiss Prot P08637), and FcyRIIIB (CD16b; FCGR3B)). Furthermore, Fc receptors are expressed on a variety of cells, including, e.g., B cells, monocytes, dendritic cells, neutrophils, and certain lymphocytes. For example, U937 cells, a human monocyte cell line, express both FcyRI and FcyRIIA (see e.g., Jones, et al. J Immunol 135(5):3348-53 (1985); and Brooks, et al. J Exp Med 170:1369-85 (October 1989)).

[0142] The phrase “hinge” or “hinge domain” refers to a region of consecutive amino acid residues that connect the C-terminus of the CHI to the N-terminus of the CH2 domain of an immunoglobulin. In human IgGl, lgG2, and lgG4, the hinge region runs from residue 216 to 236 by EU numbering. Residues 231-236 form a lower hinge and residues 216 to 230 form an upper and middle (or core) hinge. The demarcation between upper and middle varies by isotype. The upper and middle hinges of IgGl, lgG2 and lgG4 are 12-15 consecutive amino acids encoded by a distinct hinge exon. The lower hinge includes several N-terminal amino acids of the CH2 domain (encoded by the CH2 exon) (Brekkeet al. Immunology Today 16(2):85-90 (1995)). lgG3 comprises a hinge region consisting of four segments: one upper segment resembling the hinge region of IgGl, and 3 segments that are identical amino acid repeats unique to lgG3.

[0143] The amino-terminal portion of each chain includes a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition. This variable region is initially expressed linked to a cleavable signal peptide. The variable region without the signal peptide is sometimes referred to as a mature variable region. Thus, for example, a light chain mature variable region means a light chain variable region without the light chain signal peptide. However, reference135975-91820REGN 11918 to a variable region does not mean that a signal sequence is necessarily present; and in fact, signal sequences are cleaved once the heterodimeric antibodies, or antigen-binding fragments thereof as described herein have been expressed and secreted.

[0144] The mature variable regions of each light / heavy chain pair form the antibody binding site. Thus, an intact antibody has two binding sites, i.e., is divalent. In natural antibodies, the binding sites are the same. However, heterodimeric antibodies, or antigen-binding fragments thereof as described herein can be made in which the two binding sites are different (e.g., bispecific antibody) (see, e.g., Songsivilai and Lachmann, Clin. Exp. Immunol., 79:315-321 (1990); Kostelny et al., J. Immunol., 148:1547-53 (1992)). The CDRs from the two chains of each pair are aligned by the framework regions, enabling binding to a specific epitope. From N-terminal to C -terminal, both light and heavy chains comprise the domains FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The assignment of amino acids to each domain is in accordance with the definitions of Kabat, Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, MD, 1987 and 1991), or Chothia & Eesk, 7. Mol. Biol. 196:901-917 (1987); Chothia et al., Nature 342:878-883 (1989). Kabat also provides a widely used numbering convention (Kabat numbering) in which corresponding residues between different heavy chain variable regions or between different light chain variable regions are assigned the same number. Although Kabat numbering can be used for antibody constant regions, the EU index is more commonly used.

[0145] The term “heterodimer” or “heterodimeric” or any grammatical variations thereof refers to a protein complex composed of two polypeptides which differ in amino acid sequence. In some embodiments, the antibody is heterodimeric based on a first heavy chain and a second heavy chain of different amino acid sequences. In some embodiments, the first heavy chain and second heavy chain are heterodimeric at one or more domains within a heavy chain, or a functional fragment thereof, e.g., HCDR1, HCDR2, HCDR3, CHI, hinge, CH2, CH3, or any combination thereof.

[0146] Antibodies, antigen-binding fragments thereof, or fusion proteins thereof are typically provided in isolated form. This means that a heterodimeric antibody, or antigen-binding fragment thereof disclosed herein is typically at least 50% w / w pure of interfering proteins and other contaminants arising from its production or purification but does not exclude the possibility that a heterodimeric antibody, or antigen-binding fragment thereof is combined with an excess of pharmaceutical acceptable carrier(s) or other vehicle intended to facilitate its use. Sometimes heterodimeric antibodies, or antigen-binding fragments thereof disclosed herein are at least 60, 70, 80, 90, 95, or 99% w / w pure of interfering proteins and contaminants from production or purification. Often a heterodimeric antibody, or antigen-binding fragment thereof is the predominant macromolecular species remaining after its purification.

[0147] In some embodiments, the antibody includes any form of antibody with at least one binding region including monovalent fragments, divalent tetrameric units of two heavy chains and light chains, antigen-binding fragments thereof and higher order complexes of any of these. An antibody135975-91820REGN 11918 can be mono-specific in which case all binding regions have the same specificity (e.g., same antigen) or multi-specific in which the binding sites have at least two specificities (e.g., different antigens). In some embodiments, the antigen-binding fragment includes a heavy chain variable region (the binding region) and a heavy chain constant region and no light chain (i.e., a Dab or nanobody).

[0148] A “monoclonal antibody” refers to a preparation of antibody molecules resulting from propagation of a single clone consisting essentially of the same antibody molecules Minor differences resulting from spontaneous mutations arising in culture or posttranslational processing may be present. A monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope. Accordingly, the term “mouse or murine monoclonal antibody” refers to antibodies displaying a single binding specificity which have variable and constant regions derived from murine or mouse germline immunoglobulin sequences.

[0149] A “multispecific antibody” typically comprises multiple different variable domains (two in the case of bispecific antibody), wherein each variable domain is capable of specifically binding to a separate antigen or to a different epitope on the same antigen. Example bispecific formats that can be used with disclosed constant regions include e.g., scFv-based bispecific formats, IgG-scFv fusions, dual variable domain (DVD)-lg, Quadroma, knobs-into- holes, common light chain (e.g., common light chain with knobs-into-holes, etc.), CrossMab, CrossFab, (SEED)body, dual acting Fab (DAF)- IgG, and Mab2 bispecific formats (see, e.g., Klein et al. 2012, mAbs 4:6, 1-11 , and references cited therein, for a review of the foregoing formats). Bispecific antibodies can also be constructed using peptide / nucleic acid conjugation, e.g., wherein unnatural amino acids with orthogonal chemical reactivity are used to generate site- specific antibody-oligonucleotide conjugates which then selfassemble into multimeric complexes with defined composition, valency, and geometry. (See, e.g., Kazane et al. 2013, J. Am. Chem. Soc. 9; 135(1 ):340-6 [Epub: Dec. 21 , 2012]). Another example multispecific format that can be used with the disclosed constant regions includes a first antigenbinding domain that specifically binds a target molecule, and a second antigen-binding domain that specifically binds an internalizing effector protein, wherein such second antigen-binding domains are capable of activating and internalizing the effector protein, e.g., a receptor. (See US 2013 / 0243775A1).

[0150] In some embodiments, a multispecific antibody, or antigen-binding fragment thereof, includes one or modifications in the heavy chain constant domains, e.g., CHI, hinge, CH2, and / or CH3. In some embodiments, the multispecific antibody, or antigen-binding fragment thereof, comprises one or more modifications in the heavy chain constant domain, is heterodimeric as to the constant region, e.g., one of the two heavy chains comprises one or more modifications in the heavy chain constant domain, e.g., CHI, hinge, CH2, and / or CH3. In some embodiments, the multispecific antibody, or antigen-binding fragment thereof, comprises one or more modifications in the hinge domain of one or both heavy chains, and is heterodimeric as to the constant region. In some embodiments, the135975-91820REGN 11918 multispecific antibody, or antigen-binding fragment thereof, comprises one or more modifications in the CH3 domain of one or both heavy chains, and is heterodimeric as to the constant region.

[0151] In some embodiments, the multispecific antibody, or antigen-binding fragment thereof, comprises a first heavy chain with one or more modifications in the CH3 domain and a second heavy chain with one or more modifications in the hinge domain and fused to a binding polypeptide, and is heterodimeric as to the constant regions of the first and second heavy chains. In some embodiments, the multispecific antibody, or antigen-binding fragment thereof, comprises a first heavy chain and a second heavy chain with one or more modifications in the hinge domain, one or more modifications in the CH3 domain, and fused to a binding polypeptide, and is heterodimeric as to the constant regions of the first and second heavy chains. In some embodiments, the multispecific antibody, or antigenbinding fragment thereof, comprises a first heavy chain and a second heavy chain with one or more modifications in the CH3 domain, and fused to a binding polypeptide, and is heterodimeric as to the constant regions of the first and second heavy chains. In some embodiments, the multispecific antibody, or antigen-binding fragment thereof, comprises a first heavy chain with one or more modification in the hinge domain, one or more modifications in the CH3 domain, and a second heavy chain with one or more modifications in the hinge domain, and fused to a binding polypeptide, and is heterodimeric as to the constant regions of the first and second heavy chains. In some embodiments, the multispecific antibody, or antigen-binding fragment thereof, comprises a first heavy chain with one or more modification in the hinge domain, one or more modifications in the CH3 domain, and a second heavy chain and fused to a binding polypeptide, and is heterodimeric as to the constant regions of the first and second heavy chains.

[0152] The phrase “bispecific antibody” includes an antibody capable of selectively binding two or more epitopes. Bispecific antibodies generally comprise two different heavy chains, with each heavy chain specifically binding a different epitope — either on two different molecules (e.g., antigens) or on the same molecule (e.g., on the same antigen). If a bispecific antibody is capable of selectively binding two different epitopes (a first epitope and a second epitope), the affinity of the first heavy chain for the first epitope will generally be at least one to two or three or four orders of magnitude lower than the affinity of the first heavy chain for the second epitope, and vice versa. The epitopes recognized by the bispecific antibody can be on the same or a different target (e.g., on the same or a different protein). Bispecific antibodies can be made, for example, by combining heavy chains that recognize different epitopes of the same antigen. For example, nucleic acid sequences encoding heavy chain variable sequences that recognize different epitopes of the same antigen can be fused to nucleic acid sequences encoding different heavy chain constant regions, and such sequences can be expressed in a cell that expresses an immunoglobulin light chain. The predominant form of a bispecific antibody has two heavy chains each having three heavy chain CDRs, followed by (N-terminal to C -terminal) a CHI domain, a hinge, a CH2 domain, and a CH3 domain, and an immunoglobulin light chain that either does not confer antigen-binding specificity but that can associate with each heavy chain, or that135975-91820REGN 11918 can associate with each heavy chain and that can bind one or more of the epitopes bound by the heavy chain antigen-binding regions, or that can associate with each heavy chain and enable binding or one or both of the heavy chains to one or both epitopes.

[0153] In some embodiments, the heterodimeric antibodies, or antigen-binding fragments thereof disclosed herein includes one or modifications in the heavy chain constant domains, e.g., CHI, hinge, CH2, and / or CH3. In some embodiments, the heterodimeric antibodies, or antigen-binding fragments thereof disclosed herein comprising one or more modifications in the heavy chain constant domain, is heterodimeric as to the constant region, e.g., one of the two heavy chains comprises one or more modifications in the heavy chain constant domain, e.g., CHI, hinge, CH2, and / or CH3, and the other heavy chain constant region is wildtype or alternatively modified at the one or more modifications of its constant region.

[0154] An “epitope” is an antigenic determinant capable of specific binding to an antibody. Epitopes usually consist of surface groupings of molecules such as amino acids or sugar side chains and usually have specific three dimensional structural characteristics, as well as specific charge characteristics. Conformational and nonconformational epitopes are distinguished in that the binding to the former, but not the latter, is lost in the presence of denaturing solvents. The epitope may comprise amino acid residues directly involved in the binding (also called immunodominant component of the epitope) and other amino acid residues, which are not directly involved in the binding, such as amino acid residues which are effectively blocked by the specific antigen binding peptide (in other words, the amino acid residue is within the footprint of the specific antigen binding peptide).

[0155] As used herein, the term “binding” refers to an interaction between at least two entities, or molecular structures, such as an antibody-antigen interaction, or an Fc-containing protein to an FcvR (wherein the Fc-containing protein is an antibody, Ig, antibody-binding fragment, or Fc-fusion protein, e.g., receptor-Fc fusion). For instance, binding affinity typically corresponds to a KD value of about 10~7 M or less, such as about 10~8 M or less, such as about 10~9 M or less when determined by, for instance, surface plasmon resonance (SPR) technology in a BIAcore 3000™ instrument using the antigen or FcR as the ligand and the antibody, Ig, antibody-binding fragment, or Fc-containing protein as the analyte (or anti -ligand). Accordingly, a heterodimeric antibody, or antigen-binding fragment thereof binds to a target antigen or receptor with an affinity corresponding to a KD value that is at least ten-fold lower, such as at least 100 fold lower, for instance at least 1,000 fold lower, such as at least 10,000 fold lower, for instance at least 100,000 fold lower than its affinity for binding to a non-specific antigen (e.g., BSA, casein). There is an inverse relationship between KD and binding affinity, therefore the smaller the KD value, the higher the affinity. Thus, the term “lower affinity” relates to a lower ability to form an interaction, and therefore a larger KD value. The term “high affinity” antibody refers to those antibodies having a binding affinity to their target of at least 10'9M, at least 1010M; at least 1011M; or at least 1012M, as measured by surface plasmon resonance, for example, BIACORE™ or solution-affinity EEISA.135975-91820REGN 11918

[0156] A humanized antibody is a genetically engineered antibody in which the CDRs from a nonhuman “donor” antibody are grafted into human “acceptor” antibody sequences (see, e.g., Queen, US 5,530,101 and 5,585,089; Winter, US 5,225,539, Carter, US 6,407,213, Adair, US 5,859,2056,881,557, Foote, US 6,881,557). The acceptor antibody sequences can be, for example, a mature human antibody sequence, a composite of such sequences, a consensus sequence of human antibody sequences, or a germline region sequence. Thus, a humanized antibody is an antibody having some or all CDRs entirely or substantially from a donor antibody and variable region framework sequences and constant regions, if present, entirely or substantially from human antibody sequences. Similarly, a humanized heavy chain has at least one, two and usually all three CDRs entirely or substantially from a donor antibody heavy chain, and a heavy chain variable region framework sequence and heavy chain constant region, if present, substantially from human heavy chain variable region framework and constant region sequences. Similarly, a humanized light chain has at least one, two and usually all three CDRs entirely or substantially from a donor antibody light chain, and a light chain variable region framework sequence and light chain constant region, if present, substantial ly from human light chain variable region framework and constant region sequences. Other than nanobodies and dAbs, a humanized antibody comprises a humanized heavy chain and a humanized light chain. A CDR in a humanized antibody is substantially from a corresponding CDR in a nonhuman antibody when at least 85%, 90%, 95% or 100% of corresponding residues (as defined by Kabat) are identical between the respective CDRs. The variable region framework sequences of an antibody chain or the constant region of an antibody chain are substantially from a human variable region framework sequence or human constant region respectively when at least 85, 90, 95 or 100% of corresponding residues defined by Kabat are identical.

[0157] Although humanized antibodies often incorporate all six CDRs (preferably as defined by Kabat) from a mouse antibody, they can also be made with less than all CDRs (e.g., at least 3, 4, or 5 CDRs from a mouse antibody) (e.g., Pascalis et al., J. Immunol. 169:3076, 2002; Vajdos et al., Journal of Molecular Biology, 320: 415-428, 2002; Iwahashi et al., Mol. Immunol. 36:1079- 1091, 1999; Tamura et al, Journal of Immunology, 164:1432-1441, 2000).

[0158] A chimeric antibody is an antibody in which the mature variable regions of light and heavy chains of a non-human antibody (e.g., a mouse) are combined with human light and heavy chain constant regions. Such antibodies substantially or entirely retain the binding specificity of the mouse antibody, and are about two-thirds human sequence.

[0159] A veneered antibody is a type of humanized antibody that retains some and usually all of the CDRs and some of the non-human variable region framework residues of a non- human antibody but replaces other variable region framework residues that may contribute to B- or T-cell epitopes, for example exposed residues (Padlan, Mol. Immunol. 28:489, 1991) with residues from the corresponding positions of a human antibody sequence. The result is an antibody in which the CDRs135975-91820REGN 11918 are entirely or substantially from a non-human antibody and the variable region frameworks of the non-human antibody are made more human-like by the substitutions.

[0160] A human antibody refers to antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Such an antibody can be one produced by a human or human B-cells, or a transgenic mouse bearing human immunoglobulin genes, or by from a phage display, retroviral display, ribosomal display, and the like (see for instance Hoogenboom et al., J. Mol. Biol. 227, 381 (1991 ) (phage display), Vaughan et al., Nature Biotech 14, 309 (1996) (phage display), Hanes and Plucthau, PNAS USA 94, 4937-4942 (1997) (ribosomal display), Parmley and Smith, Gene 73, 305-318 (1988) (phage display), Scott TIBS 17, 241-245 (1992), Cwirla et al., PNAS USA 87, 6378-6382 (1990), Russell et al., Nucl. Acids Research 21, 1081-1085 (1993), Hogenboom et al., Immunol. Reviews 130, 43-68 (1992), Chiswell and McCafferty, TIBTECH 10, 80-84 (1992), and US 5,733,743). Human antibodies can include amino acid residues not encoded by human germline immunoglobulin introduced by maturation in vivo, such as by somatic mutation or gene rearrangement in vivo. Human antibodies can also include a small number of mutations (e.g., up to 10 per heavy or light chain) introduced by random or site- specific mutagenesis in vitro).

[0161] The term “components” refers to the constituent molecules needed to produce a recombinant AAV, including covalently surface modified adeno-associated viruses and includes, but is not limited to, promoters, polyadenylation signals, transgenes, polynucleotides encoding retargeting molecules, AAV cap genes, AAV rep genes, ITRs, helper polynucleotide sequence(s), polynucleotides encoding a first member of a specific binding pair and a second cognate member of a specific binding pair (for covalently surface modified AAV), as well as peptides encoded by the genes and sequences. Optional components include detargeting mutation sequences, introns, IRESs, RRSs, operators and enhancers.

[0162] The phrase “assembly of components” refers to components that assemble together by way of bonds, forces, interactions, and / or attractions. Examples include the assembly of heavy and light chains to form antibodies, capsid proteins and isopeptide bonds formed during conjugation of specific binding pairs.

[0163] The term “cell” includes any cell that is suitable for expressing a recombinant nucleic acid sequence. Cells include those of prokaryotes and eukaryotes (single-cell or multiple- cell), bacterial cells (e.g., strains of E. coli, Bacillus spp., Streptomyces spp., etc.), mycobacteria cells, fungal cells, yeast cells (e.g., S. cerevisiae, S. pombe, P. pastoris, P. methanolica, etc.), plant cells, insect cells (e.g., SF-9, SF-21, baculovirus-infected insect cells, Trichoplusia ni, etc.), non-human animal cells, human cells, or cell fusions such as, for example, hybridomas or quadromas. In some embodiments, the cell is a human, monkey, ape, hamster, rat, or mouse cell. In some embodiments, the cell is eukaryotic and is selected from the following cells: CHO (e.g., CHO KI, DXB-11 CHO, Veggie- CHO), COS (e.g., COS-7), retinal cell, Vero, CV1, kidney (e.g., HEK293, 293 EBNA, MSR 293, MDCK, HaK, BHK), HeLa, HepG2, WI38, MRC 5, Colo205, HB 8065, HL-60, (e.g., BHK21), Jurkat, Daudi, A431 (epidermal), CV-1, U937, 3T3, L cell, C127 cell, SP2 / 0, NS-0, MMT 060562,135975-91820REGN 11918Sertoli cell, BRL 3A cell, HT1080 cell, myeloma cell, tumor cell, and a cell line derived from an aforementioned cell. In some embodiments, the cell comprises one or more viral genes, e.g., a retinal cell that expresses a viral gene (e.g., a PER.C6™ cell).

[0164] As used herein, “affinity chromatography” is a chromatographic method that makes use of the specific, reversible interactions between biomolecules rather than general properties of the biomolecule such as isoelectric point, hydrophobicity, or size, to effect chromatographic separation. “Protein A affinity chromatography” or “Protein A chromatography” refers to a specific affinity chromatographic method that makes use of the affinity of the IgG binding domains of Protein A for the Fc portion of an immunoglobulin molecule. This Fc portion comprises human or animal immunoglobulin constant domains, CH2 and CH3, or immunoglobulin domains substantially similar to these. Protein A encompasses native protein from the cell wall of Staphylococcus aureus, Protein A produced by recombinant or synthetic methods, and variants that retain the ability to bind to an Fc region. In practice, Protein A chromatography involves using Protein A immobilized to a solid support. See Gagnon, Protein A Affinity Chromatography, Purification Tools for Monoclonal Antibodies, pp. 155-198, Validated Biosystems, 1996. Protein G and Protein L may also be used for affinity chromatography. The solid support is a non-aqueous matrix onto which Protein A adheres. Such supports include agarose, sepharose, glass, silica, polystyrene, nitrocellulose, charcoal, sand, cellulose, and any other suitable material. Such materials are well known in the art. Any suitable method can be used to affix the second protein to the solid support. Methods for affixing proteins to suitable solid supports are well known in the art. See e.g., Ostrove, in Guide to Protein Purification, Methods in Enzymology, 182: 357-371, 1990. Such solid supports, with and without immobilized Protein A, are readily available from many commercial sources including such as Vector Laboratory (Burlingame, Calif), Santa Cruz Biotechnology (Santa Cruz, Calif), BioRad (Hercules, Calif), Amersham Biosciences (part of GE Healthcare, Uppsala, Sweden), Pall (Port Washington, NY) and EMD-Millipore (Billerica, Mass.). Protein A immobilized to a pore glass matrix is commercially available as PROSEPO-A (Millipore). The solid phase may also be an agarose-based matrix. Protein A immobilized on an agarose matrix is commercially available as MAB SELECT™ (Amersham Biosciences).

[0165] Affinity chromatography also includes media that can be used to selectively bind and thus purify antibodies, fragments of antibodies, or chimeric fusion proteins that contain immunoglobulin domains and / or sequences. Antibodies include IgG, IgA, IgM, IgY, IgD, and IgE types. Antibodies also include single chain antibodies such as camelid antibodies, engineered camelid antibodies, single chain antibodies, single-domain antibodies, nanobodies, and the like. Antibody fragments include VH, VL, CL, CH sequences. Antibody fragments and fusion proteins containing antibody sequences include for example F(ab’)3, F(ab’)2, Fab, Fc, Fv, dsFv, (scFv)2, scFv, scAb, minibody, diabody, triabody, tetrabody, Fc-fusion proteins, trap molecules, and the like (see Ayyar et al, Methods 56 (2012): 116-129). Such affinity chromatography media may contain ligands that selectively bind135975-91820REGN 11918 antibodies, their fragments, and fusion proteins contains those fragments. Such ligands include antibody binding proteins, bacterially derived receptors, antigens, lectins, or anti- antibodies directed to the target molecule, the antibody requiring purification. For example, camelid-derived affinity ligands directed against any one or more of IgG-CHl, IgG-Fc, IgG- CH3, IgGl, LC-kappa, LC- lambda, IgG3 / 4, IgA, IgM, and the like may be used as affinity ligands (commercially available as CAPTURESELECT™ chromatography resins, Life Technologies, Inc., Carlsbad, Calif.)

[0166] The phrase “ionic modifier” includes moieties that reduce the effect of, or disrupt, nonspecific (i.e., non-affinity) ionic interactions between proteins. “Ionic modifiers” include, for example, salts, ionic combinations of Group I and Group II metals with acetate, bicarbonate, carbonate, a halogen (e.g., chloride or fluoride), nitrate, phosphate, or sulfate. A non-limiting illustrative list of “ionic modifiers” includes beryllium, lithium, sodium, and potassium salts of acetate; sodium and potassium bicarbonates; lithium, sodium, potassium, and cesium carbonates; lithium, sodium, potassium, cesium, and magnesium chlorides; sodium and potassium fluorides; sodium, potassium, and calcium nitrates; sodium and potassium phosphates; and calcium and magnesium sulfates. “Ionic modifiers” include those moieties that affect ionic interactions that, upon addition to a pH gradient or step, or upon equilibration of a Protein A support in an “ionic modifier” and application of a pH step or gradient, results in a broadening of pH unit distance between el ution of a homodimeric IgG and a heterodimeric IgG (e.g., a wild-type human IgG and the same IgG but bearing one or more modifications of its CH3 domain as described herein). A suitable concentration of an “ionic modifier” can be determined by its concentration employing the same column, pH step or gradient, with increasing concentration of “ionic modifier” until a maximal pH distance is reached at a given pH step or pH gradient.

[0167] The term “subject” includes human and other mammalian subjects that receive either prophylactic or therapeutic treatment.

[0168] Compositions or methods “comprising” one or more recited elements may include other elements not specifically recited. For example, a composition that comprises antibody may contain the antibody alone or in combination with other ingredients.

[0169] “Polynucleotide” includes a sequence of nucleotides covalently joined, and includes RNA and DNA. Oligonucleotides are considered shorter polynucleotides. Genes are DNA polynucleotides (polydeoxyribonucleic acid) that ultimately encode polypeptides, which are translated from RNA (polyribonucleic acid) that was typically transcribed from DNA. DNA polynucleotides also can encode RNA polynucleotides that is not translated, but rather function as RNA “products”. The type of polynucleotide (that is, DNA or RNA) is apparent from the context of the usage of the term. A polynucleotide referred to or identified by the polypeptide it encodes sets forth and covers all suitable sequences in accordance with codon degeneracy. Polynucleotides, including those disclosed herein, include percent identity sequences and homologous sequences when indicated.135975-91820REGN 11918

[0170] “Polypeptide” or “peptide” refers to sequence(s) of amino acids covalently joined. Polypeptides include natural, semi-synthetic and synthetic proteins and protein fragments. “Polypeptide” and “protein” can be used interchangeably. Oligopeptides are considered shorter polypeptides.

[0171] A “gene of interest” (GOI) encodes a “protein of interest” or “polypeptide of interest” and optionally can include other associated sequences. The sequences can be natural, semi-synthetic or synthetic. Native sequences, mutant sequences and degenerate sequences can be GOIs. A gene of interest also can be referred to as a “transgene.”

[0172] A “nucleotide of interest” includes GOIs and sequences encoding non-translated RNAs / non- coding RNAs (such as, but not limited to, antisense RNA, micro RNA, small interfering RNA, catalytic RNA, and ribozymes). NOIs and GOIs also can be referred to as “payloads.”

[0173] “Protein of interest” or “polypeptide of interest” (POI) can have any amino acid sequence, and includes any protein, polypeptide, or peptide that is desired to be expressed, typically for gene therapy purposes. Protein types can include, but are not limited to, receptors, fusion proteins, agonists, antagonists, activators, inhibitors, enzymes (such as those used in enzyme replacement therapy), factors and co-factors, repressors, activators, ligands, protein hormones, therapeutic proteins, suicide proteins, structural proteins, storage proteins, transport proteins, signal proteins, neurotransmitters, and contractile proteins. Derivatives, components, domains, chains, and fragments of the above also are included. The sequences can be natural, semi-synthetic or synthetic.

[0174] “Purification” in its various grammatical forms includes, but is not limited to, the use of one or more procedures such as depth filtration, tangential flow filtration, affinity capture, ionic exchange, and the like.

[0175] The term “target cells” includes any cells in which expression of a nucleotide of interest is desired or tolerated. Preferably, target cells exhibit a “target,” such as a receptor, ligand, protein, including glycoproteins, and / or antigen, including complexes thereof, on their surface that allows the cell to be targeted. Example targets are calcium voltage-gated channel auxiliary subunit gamma 1 (CACNG1), asialoglycoprotein receptor 1 (ASGR1), Feldl, ENTPD3, PTPRA, CD20, CD63, and Her2. Additional targets include GABA, transferrin receptor, CD3, CD34, integrin, adipophilin, AIM- 2, ALDH1A1, alpha-actinin-4, alpha-fetoprotein (“AFP”), ARTCI, B-RAF, BAGE-1, BCEX (E), BCR-ABL fusion protein b3a2, beta-catenin, BING-4, CA-125, CALC A, carcinoembryonic antigen (“CEA”), C ASP-5, CASP-8, CD274, CD45, Cdc27, CDK12, CDK4, CDKN2A, CEA, CLPP, COA-1, CPSF, CSNK1A1, CTAG1, CTAG2, cyclin DI, Cyclin-Al, dek-can fusion protein, DKK1, EFTUD2, Elongation factor 2, ENAH (hMena), Ep-CAM, EpCAM, EphA3, epithelial tumor antigen (“ETA”), ETV6-AML1 fusion protein, EZH2, E6, E7, FGF5, FLT3-ITD, FN1, G250 / MN / CAIX, GAGE-1,2,8, GAGE- 3, 4, 5, 6, 7, GAS7, glypican-3, GnTV, gplOO / Pmel 17, GPNMB, HAUS3, Hepsin, HER-2 / neu, HERV-K-MEL, HLA-A11, HLA-A2, HLA-DOB, hsp70-2, IDO1, IGF2B3, IL13Ralpha2, Intestinal carboxyl esterase, K-ras, Kallikrein 4, KIF20A, KK-LC-1, KKLC1, KM-HN-1, KMHN1 also known135975-91820REGN 11918 as CCDC110, LAGE-1, LDLR-fucosyltransferase AS fusion protein, Lengsin, M-CSF, MAGE-A1, MAGE- A 10, MAGE-A12, MAGE-A2, MAGE- A3, MAGE-A4, MAGE-A6, MAGE-A9, MAGECI, MAGE-C2, malic enzyme, mammaglobin-A, MART2, MATN, MC1R, MCSP, mdm-2, MEI, Mel an- A / MART-1 , Meloe, Midkine, MMP-2, MMP-7, MUC1, MUC5AC, mucin, MUM-1, MUM- 2, MUM-3, Myosin, Myosin class I, N-raw, NA88- A, neo-PAP, NFYC, NY-BR-1, NY-ESO- l / LAGE-2, OA1, OGT, OS-9, P polypeptide, p53, PAP, PAX5, PBF, pml-RARalpha fusion protein, polymorphic epithelial mucin (“PEM”), PPP1R3B, PRAME, PRDX5, PSA, PSMA, PTPRK, RAB 38 / N Y-MEL- 1 , RAGE-1, RBAF600, RGS5, RhoC, R F43, RU2AS, SAGE, secernin 1, SIRT2, SNRPD1, SOXIO, Spl7, SPA17, SSX-2, SSX-4, STEAP1, survivin, SYT-SSX1 or -SSX2 fusion protein, TAG-1, TAG-2, Telomerase, TGF-betaRII, TPBG, TRAG-3, Triosephosphate isomerase, TRP-l / gp75, TRP-2, TRP2-INT2, tyrosinase, tyrosinase (“TYR”), VEGF, WT1, XAGE-lb / GAGED2a, Kras, NY- ESO1, MAGE- A3, HPV E2, HPV E6, HPV E7, WT-1 antigen (in lymphoma and other solid tumors), ErbB receptors, Melan A [MARTI], gp 100, tyrosinase, TRP-l / gp 75, and TRP-2 (in melanoma); MAGE-1 and MAGE-3 (in bladder, head and neck, and non-small cell carcinoma); HPV EG and E7 proteins (in cervical cancer); Mucin [MUC-1] (in breast, pancreas, colon, and prostate cancers); prostate-specific antigen [PSA] (in prostate cancer); carcinoembryonic antigen [CEA] (in colon, breast, and gastrointestinal cancers), and such shared tumor-specific antigens as MAGE-2, MAGE-4, MAGE-6, MAGE- 10, MAGE- 12, BAGE-1, CAGE-1,2,8, CAGE-3 TO 7, LAGE-1, NY-ESO-l / LAGE-2, NA-88, GnTV, TRP2-INT2, E6, E7, human glucagon receptor (hGCGR), and human ectonucleoside triphosphate diphosphohydrolase 3 (hENTPD3). Other targets can be selected by the person skilled in the art. See WO 2019 / 006046.

[0176] Other techniques and components can be referenced in International Patent Publication Nos. W02010151792, WO2014047231, W02016018740, W02016161010, and W02019006046 and U.S. Patent No. 8,586,713.Heterodimeric Antibodies, and Antigen-binding Fragments thereof

[0177] The present disclosure provides an antibody, or an antigen-binding fragment thereof, format that combines two or more modifications in one or more heavy chains fused to a binding pol y peptide that can be used with human antibody components.

[0178] The present disclosure provides heterodimeric antibodies, or antigen-binding fragments thereof, comprising two heavy chains with different amino acid sequences and a binding polypeptide. In some embodiments, the first heavy chain comprises one or more modifications and the second heavy chain comprises one or more modifications and is fused to a binding polypeptide. In some embodiments, the first heavy chain may include one or more modifications in the hinge domain (e.g., the first hinge domain). In some embodiments, the second heavy chain includes a mutation in the hinge domain (e.g., the second hinge domain). In some embodiments, the second heavy chain also comprises one or more modifications in the CH3 domain (e.g., the second CH3 domain), wherein the135975-91820REGN 11918 equivalent positions in the first heavy chain (e.g., first CH3 domain) do not comprise the same one or more modifications. In some embodiments, the second heavy chain is fused at the C-terminal end to a polypeptide (e.g., a binding polypeptide), which can form an isopeptide bond with a peptide (e.g., binding peptide) which is not attached to the heterodimeric antibody.

[0179] Modifications in a heavy chain and / or a light chain of a heterodimeric antibody, or antigenbinding fragment thereof disclosed herein are optional. Modification in a heavy chain variable region, a light chain variable region, a CHI domain, a CH2 domain, a CH3 domain, and / or a hinge domain of a heterodimeric antibody, or antigen-binding fragment thereof disclosed herein are illustrative and can be selected by a skilled person in view of the teachings contained herein.

[0180] An example of a heterodimeric antibody, or antigen-binding fragment thereof comprises (1) a first heavy chain comprising one or more modifications in the hinge domain, (2) a second heavy chain comprising (i) one or more modifications in the hinge domains, (ii) one or more modifications in the CH3 domain; and (iii) a binding polypeptide fused to the C-terminal end of the second heavy chain, where the binding polypeptide can form an isopeptide bond with a peptide which is not attached to the heterodimeric antibody, and (3) a light chain.

[0181] In another aspect, an example of a heterodimeric antibody, or antigen-binding fragment thereof comprises (1) a first heavy chain, (2) a second heavy chain comprising (i) one or more modifications in the hinge domains, (ii) one or more modifications in the CH3 domain; and (iii) a binding polypeptide fused to the C-terminal end of the second heavy chain, where the binding polypeptide can form an isopeptide bond with a peptide which is not attached to the heterodimeric antibody, and (3) a light chain.

[0182] A heavy chain, e.g., an immunoglobulin heavy chain, includes a variable domain and a constant domain. The variable domain includes three CDRs and four framework regions, e.g., FR1- HCDR1-FR2-HCDR2-FR3-HCDR3-FR4. The constant domain includes a CHI domain followed by a hinge domain and CH2 and CH3 domains. The one of more modifications in the first and second heavy chains may be found in the constant domain, e.g., the hinge and CH3 domains.

[0183] In some embodiments, the heterodimeric antibody, or antigen-binding fragment thereof, comprises a first heavy chain with one or more modifications in the CH3 domain and a second heavy chain with one or more modifications in the hinge domain and fused to a binding polypeptide, and is heterodimeric as to the constant regions of the first and second heavy chains. In some embodiments, the heterodimeric antibody, or antigen-binding fragment thereof, comprises a first heavy chain and a second heavy chain with one or more modifications in the hinge domain, one or more modifications in the CH3 domain, and fused to a binding polypeptide, and is heterodimeric as to the constant regions of the first and second heavy chains. In some embodiments, the heterodimeric antibody, or antigenbinding fragment thereof, comprises a first heavy chain and a second heavy chain with one or more modifications in the CH3 domain, and fused to a binding polypeptide, and is heterodimeric as to the constant regions of the first and second heavy chains. In some embodiments, the heterodimeric135975-91820REGN 11918 antibody, or antigen-binding fragment thereof, comprises a first heavy chain with one or more modification in the hinge domain, one or more modifications in the CH3 domain, and a second heavy chain with one or more modifications in the hinge domain, and fused to a binding polypeptide, and is heterodimeric as to the constant regions of the first and second heavy chains. In some embodiments, the heterodimeric antibody, or antigen-binding fragment thereof, comprises a first heavy chain with one or more modification in the hinge domain, one or more modifications in the CH3 domain, and a second heavy chain and fused to a binding polypeptide, and is heterodimeric as to the constant regions of the first and second heavy chains.

[0184] The disclosure provides modified immunoglobulin heavy chain regions in which each of positions 233-236 by EU number is occupied by G or is unoccupied. Position 236 is unoccupied in canonical human lgG2 but is occupied by in other canonical human IgG isotypes. Positions 233-235 are occupied by residues other than G in all four human isotypes. Posidon 233 is not believed to interact directly with Fey receptors but was included in the mutagenesis because removing replacing the wildtype Glu residue in IgGl and lgG4 or Pro residue in lgG2 in combination with the other mutations would reduce immunogenicity. In four example modified constant regions, positions 233- 236 are Gly, Gly, Gly, unoccupied; Gly, Gly, unoccupied, unoccupied; Gly, unoccupied, unoccupied, unoccupied; and all unoccupied (see Table 1). These segments can be represented as GGG-, GG-, G- - or — with representing an unoccupied position.

[0185] The hinge modification within positions 233-236 can be combined with position 228 being occupied by P. Position 228 is naturally occupied by P in human IgGl and lgG2 but is occupied by S in human lgG4 and R in human lgG3. An S228P mutation in an lgG4 antibody is advantageous in stabilizing an lgG4 antibody and reducing exchange of heavy chain light chain pairs between exogenous and endogenous antibodies.

[0186] Preferably positions 226-229 are occupied by C, P, P, and C, respectively.

[0187] Example hinge regions have residues 226-236, sometimes referred to as middle (or core) and lower hinge, occupied by the modified hinge sequences designated GGG-(233-236), GG-(233-236), G— (233-236) and no G(233-236). See Table 1 below.Table 1: Hinge modifications135975-91820REGN 11918

[0188] The modified hinge regions described above can be incorporated into a heavy chain constant region, which typically include CH2 and CH3 domains, and which may have an additional hinge segment (e.g., an upper hinge) flanking the designated region, and a CHI region. Such additional constant region segments present are typically of the same isotype, preferably a human isotype, although can be hybrids of different isotypes, e.g., IgG2 / IgG4. The isotype of such additional human constant regions segments is preferably human lgG4 but can also be human IgGl, lgG2, or lgG3 or hybrids thereof in which domains are of different isotypes. Example sequences of human IgGl, lgG2, and lgG4 are SEQ ID NOs: 182-184. A constant region is considered to be of a designated isotype if the constant region differs from that isotype by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substitutions, deletions, or internal insertions, except however, that the CHI domain can be omitted entirely as can the upper hinge region. CHI, CH2, and CH3 domains are considered to be of IgGl, lgG2 or lgG4 isotype if differing from the CHI, CH2, and CH3 region of the exemplified sequence by no more than 1, 2, 3, 4, or 5 substitutions, deletions, or internal insertions. The remainder of a hinge outside the 226-236 region sequences presented above is considered to be of IgGl, lgG2 or lgG4 isotype if it differs from the corresponding part of the hinge region of the exemplified hinge sequences by no more than 1 or 2 substitutions, deletions, or internal insertions.

[0189] Some preferred heavy chain constant regions have amino acid sequences consisting of or comprising SEQ ID NOs: 174-177. These heavy chain constant regions incorporate SEQ ID NO: 167, SEQ ID NO: 168, SEQ ID NO: 169, and SEQ ID NO: 170 at residues 226-236 shown above in an otherwise-human lgG4 isotype. Other preferred constant regions differ from the designated SEQ ID NO: at up to 1, 2, 3 ,4 ,5, 6, 7, 8, 9, or 10 positions but retain at least GGG-, GG-, G— or at EU positions 232-236, and P at position 228, and preferably retain of residues 226-236 shown above for SEQ ID NO: 167, SEQ ID NO: 168, SEQ ID NO: 169, and SEQ ID NO: 170. Variations from the designated SEQ ID NOs. can represent one or several natural allotypic or isoallotypic variations, variations to increase or reduce an effector function such as complement-mediated cytotoxicity or ADCC (see, e.g., Winter et al., US Patent No. 5,624,821; Tso et al., US Patent No. 5,834,597; and Lazar et al., Proc. Natl. Acad. Sci. USA 103:4005, 2006), or to prolong half-life in humans (see, e.g., Hinton et al., J. Biol. Chem. 279:6213, 2004), for which example substitutions include a Gin at position 250 and / or a Leu at position 428 (EU numbering. Other variations can add or remove sites of post-translational modification, such as N-linked glycosylation at N-X-S / T motifs. Variations can also include introduction of knobs (i.e., replacement of one or more amino acids with larger amino acids) or holes (i.e., replacement of one or more amino acids with smaller amino acids) to promote formation of heterodimers between different heavy chains for production of heterodimeric antibodies, or antigen-binding fragments thereof disclosed herein. Example substitutions to form a knob and hole135975-91820REGN 11918 pair are T336Y and Y407T, respectively (Ridgeway et al., Protein Engineering vol.9 no.7 pp. 617- 621, 1996). Variations can also include mutations that reduce protein A interaction (e.g., H435R and Y436F) in the EU numbering system. The heterodimeric antibodies, or antigen-binding fragments thereof disclosed herein in which one heavy chain has such a variation, and another does not, can be separated from their parental antibodies by protein-A affinity chromatography. For example, SEQ ID NOs.: 178-181 are the same as SEQ ID NOs: 174-177 except for the presence of H435R and Y436F mutations. One or more residues from the C-terminus of constant regions, particularly a C- terminal lysine on the heavy chain, can be lost as a result of post-translational modification.

[0190] Other heavy chain constant regions comprise or consist of SEQ ID NOs: 185-188 and 189- 192, which correspond to SEQ ID NOs: 174-177 and 178-181 respectively except that the former are of human IgGl rather than lgG4 isotype. Other heavy chain constant regions comprise or consist of SEQ ID NOS. 193-196 and 197-200, which correspond to SEQ ID NOs: 174-177 and 178-181 respectively except the former are of human lgG2 rather than lgG4 isotype. See Table 2 below.Table 2: IgG isotypes135975-91820REGN 11918135975-91820REGN 11918135975-91820REGN 11918135975-91820REGN 11918

[0191] Other preferred constant regions differ from any of the above designated SEQ ID NOs. at up to 1, 2, 3, 4 ,5, 6, 7, 8, 9, or 10 positions but retain at least GGG-, GG-, G — or at EU positions 232- 236 and P at position 228 and preferably retain residues 226-236 shown above for SEQ ID NO: 167, SEQ ID NO: 168, SEQ ID NO: 169, and SEQ ID NO: 170 in the same manner as was discussed for lgG4 isotype constant regions.

[0192] Additional preferred constant regions comprise one or more IgG subclasses, e.g., IgGl, IgG2, and / or IgG4. For example, the hinge domain, CHI, CH2, and / or CH3 may be hybrids of two or more IgG subclasses, e.g, IgGl / IgG2, IgG4 / IgGl, IgG4 / IgG2, or any other combination of IgGl, IgG2, and / or IgG4. Example sequences are shown in Table 3.Table 3: Hybrid IgG constant regions135975-91820REGN 11918

[0193] Modified constant regions and heterodimeric antibodies, or antigen-binding fragments thereof disclosed herein incorporating such constant regions are characterized by reduced affinity for Fey receptors compared with isotype matched controls (wildtype constant regions or heterodimeric antibodies, or antigen-binding fragments thereof incorporating the same), and / or affect one or more effector function of the binding protein (e.g., modifications that affect FcyR binding, FcRn binding and thus half-life, and / or CDC activity). Such modifications include, but are not limited to, the following modifications and combinations thereof, with reference to EU numbering of an immunoglobulin constant region: 238, 239, 248, 249, 250, 252, 254, 255, 256, 258, 265, 267, 268, 269, 270, 272, 276, 278, 280, 283, 285, 286, 289, 290, 292, 293, 294, 295, 296, 297, 298, 301, 303,305, 307, 308, 309, 31 1, 312, 315, 318, 320, 322, 324, 326, 327, 328, 329, 330, 331, 332, 333, 334,335, 337, 338, 339, 340, 342, 344, 356, 358, 359, 360, 361, 362, 373, 375, 376, 378, 380, 382, 383,384, 386, 388, 389, 398, 414, 416, 419, 428, 430, 433, 434, 435, 437, 438, and 439.

[0194] For example, and not by way of limitation, the antibody, or antigen-binding fragment thereof disclosed herein exhibits enhanced serum half-life (as compared with the same heterodimeric antibody, or antigen-binding fragment thereof without the recited modification s)) and has a modification at position 250 (e.g., E or Q); 250 and 428 (e.g., L or F); 252 (e.g., L / Y / F / W or T), 254 (e.g., S or T), and 256 (e.g., S / R / Q / E / D or T); or a modification at 428 and / or 433 (e.g., L / R / SI / P / Q or K) and / or 434 (e.g., H / F or Y); or a modification at 250 and / or 428; or a modification at 307 or 308 (e.g., 308F, V308F), and 434. In another example, the modification can comprise a 428L (e.g., M428L) and 434S (e.g., N434S) modification; a 428L, 2591 (e.g., V259I), and a 308F (e.g., V308F) modification; a 433K (e.g., H433K) and a 434 (e.g., 434Y) modification; a 252, 254, and 256 (e.g., 252Y1, 254T, and 256E) modification; a 250Q and 428L modification (e.g., T250Q and M428L); a 307 and / or 308 modification (e.g., 308F or 308P).

[0195] Binding affinity (Ka) of the antibody, or antigen-binding fragment thereof disclosed herein to Fey receptors is preferably reduced at least 90, 95, or 99% compared with the isotype matched controls. Preferably binding affinity is reduced to background levels (i.e., same signal within experimental error as in a control reaction with an sc-Fv fragment lacking any constant region or in135975-91820REGN 11918 which an irrelevant receptor is used in place of Fey) . Preferably, affinity is reduced to a background level or at least 90, 95, or 99% for each of human Fey receptors, yRI, yRIIA, yRIIB, and yRIIIA.

[0196] Likewise, effector functions dependent on Fey receptor binding, such as ADCC or ADCP are reduced, preferably by at least 90, 95, or 99% or more preferably to background level. Such functions include cell killing or phagocytosis, B-cell activation, and release of inflammatory mediators, such as cytokines. Some such effects can be quantified by measurement of EC50, which refers to the half maximal effective concentration of an antibody which induces a response halfway between the baseline and maximum after a specified exposure time. The EC50 essentially represents the concentration of an antibody where 50% of its maximal effect is observed. Some heterodimeric antibodies, or antigen-binding fragments thereof disclosed herein including a modified heavy chain constant region show cytotoxicity of less than 20% cytolysis (i.e. % cytotoxicity), or less than 10%, or 5%, 4%, 3%, 2%, or even 0% or undetectable cytolysis (cytotoxicity), as measured in an in vitro or ex vivo cell killing assay compared with suitable isotype-matched control antibodies with a wildtype constant region, optionally, measured at a heterodimeric antibody, or antigen-binding fragment thereof concentration of 10 nM.

[0197] However, binding affinity of an antibody, or antigen-binding fragment thereof or fusion protein incorporating such a heavy chain constant region is preferably not substantially affected by the modified constant region. That is, the binding affinity is typically the same within experimental error or at least within a factor of 2 or 3 of a suitable control antibody with a isotype-matched wild type constant region. The same is the case for functional properties not dependent on FcyR binding, such as ability to inhibit receptor-ligand binding (e.g., EC50), or ability to agonize a receptor.

[0198] Immunogenicity of modified constant regions or heterodimeric antibodies, or antigen-binding fragments thereof disclosed herein incorporated modified constant regions compared with isotype matched controls can be assessed in vitro from dendrocyte maturation or T-cell proliferation on challenge (Gaitonde et al., Methods Mol. Biol. 2011 ;716:267-80) or in vivo by comparing incidence of reactive antibodies against administered antibodies between populations. The immunogenicity of modified constant regions or heterodimeric antibodies, or antigen-binding fragments thereof disclosed herein incorporating the modified constant regions is preferably not significantly different from the isotype matched controls or not worse than 2, 3, or 5 fold greater than the isotype matched control. Likewise, pharmacokinetic parameters such as Cmax, Caverage, area under the curve and half-life are preferably not significantly different or at least not lower by a factor of no more than 2, 3 or 5 that isotype matched controls. Such parameters can be measured in a mouse such as described in the Examples, in other animal model or a human. Substantial retendon of such PK parameters provides an indication that modified constant regions or heterodimeric antibodies, or antigen-binding fragments thereof disclosed herein incorporating them have not undergone substantial conformational changes triggering enhanced removal mechanisms.135975-91820REGN 11918

[0199] It has been previously noted (Lindhofer, H. et al. (1995) J. Immunol. 155:219-225)) that because human lgG3 does not to bind to Protein A, it can potentially be used together with any of the other three human IgG subclasses in a purification strategy similar to the one used for mouse-rat hybrids. However, although the sequences of all four human IgG subclasses are highly homologous, it is not known how readily the Fc portions of IgGl, lgG2, and lgG4 form heterodimers with lgG3; even merely preferential formation of homodimers would have a negative impact on total yields of the desired heterodimers under certain circumstances (e.g., isolation from quadromas). Additional modifications may also be necessary to compensate for the difference between the hinge region of lgG3 and those of the other subclasses. It would also be preferable, in some circumstances, not to require the presence of the full lgG3 Fc, because of potential impact on effector functions.

[0200] It has been reported (Jendeberg, L. et al. (1997) J. Immunological Meth. 201 :25-34)) that the inability of lgG3 to bind Protein A is determined by a single amino acid residue, Arg435 (EU numbering; Arg95 by IMGT), which corresponding position in the other IgG subclasses is occupied by a histidine residue. It is therefore possible, instead of lgG3, to use an IgGl sequence in which His435 is mutated to Arg. Thus, a single point mutation in IgGl should be sufficient to create the different binding affinities amenable to a new purification scheme.

[0201] However, the specified point mutation introduces a novel peptide sequence across the mutation, which could potentially be immunogenic. The point mutation could, in theory, be loaded onto an MHC class II molecule and presented to T cells, and consequently elicit an immune response. To avoid this pitfall, a dipeptide mutation, H435R / Y436F (EU numbering; H95R / Y96F by IMGT) can be used. See Table 4. The resulting sequence in the vicinity of the alteration is identical to that of lgG3, and would therefore be expected to be immunologically “invisible,” because there would be no non-native short peptides available for presentation to T cells. It has been reported that this double mutant still does not bind Protein A (Jendeberg, L. et al. (1997) J. Immunological Meth. 201 :25-34). Finally, the dipeptide mutation does not include any of the residues that form the Fc dimer interface, so it is unlikely to interfere with the formation of heterodimers. This dipeptide mutation is designated as “IgGl AAdp” (and, similarly, lgG2AAdp, lgG4AAdp, and FcAAdp). This dipeptide mutation is also designated as “Fc(modified)” and denotes its inability to bind Protein A. For example, SEQ ID NOs: 178-181 are the same as SEQ ID NOs: 174-177 except for the presence of H435R and Y436F mutations (see Table 2).Table 4: CH3 domains135975-91820REGN 11918

[0202] The FcAAdp modification does not include any of the residues believed to form the Fc dimer interface, so the FcAAdp modification is unlikely to interfere with the formation of heterodimers. Because the FcAAdp is so minimal, it can likely be incorporated into other engineered Fc forms as well. lgG2AAdp and lgG4AAdp may be advantageous in situations in which the effector functions (or lack thereof) associated with each of the latter are desired.

[0203] As used herein, “binding polypeptide” and “binding peptide”, also referred to a “proteimprotein binding pair” or “specific binding pairs” and the like include two proteins (that is, a binding polypeptide, and a binding peptide) that interact to form a covalent isopeptide bond under conditions that enable or facilitate isopeptide bond formation, wherein the term “cognate” refers to components that function together by to reacting together to form an isopeptide bond. Thus, the binding polypeptide and binding peptide react together efficiently to form an isopeptide bond under conditions that enable or facilitate isopeptide bond formation can also be referred to as being a “complementary” pair of polypeptide / peptide linkers. Specific binding pairs capable of interacting to form a covalent isopeptide bond are reviewed in Veggiani et al. (2014) Trends Biotechnol. 32:506, and include, for example, peptide:peptide binding pairs such as SpyTag: SpyCatcher, SpyTag002:SpyCatcher002, SpyTag:KTag, isopeptag:pilin C, SnoopTag: SnoopCatcher, and others. Spy Tag002:SpyCatcher002 and SpyTag003:SpyCatcher003 are different iterations of Spy Tag:Spy Catcher.

[0204] The term “isopeptide bond” refers to an amide bond between a carboxyl or carboxamide group and an amino group at least one of which is not derived from a protein main chain or alternatively viewed is not part of the protein backbone. An isopeptide bond may form within a single protein or may occur between two peptides or a peptide and a protein. Thus, an isopeptide bond may form intramolecularly within a single protein or intermolecularly, that is between two peptide / protein molecules, such as between two peptide linkers. Typically, an isopeptide bond may occur between a lysine residue and an asparagine, aspartic acid, glutamine, or glutamic acid residue or the terminal135975-91820 REGN 11918 carboxyl group of the protein or peptide chain or may occur between the alpha-amino terminus of the protein or peptide chain and an asparagine, aspartic acid, glutamine, or glutamic acid. Each residue of the pair involved in the isopeptide bond is referred to herein as a reactive residue. An isopeptide bond may form between a lysine residue and an asparagine residue or between a lysine residue and an aspartic acid residue. Particularly, isopeptide bonds can occur between the side chain amine of lysine and carboxamide group of asparagine or carboxyl group of an aspartate.

[0205] In some embodiments, the heterodimeric antibody, or antigen-binding fragment thereof, is fused to a polypeptide or peptide (e.g., a binding polypeptide or binding peptide). The polypeptide or peptide (e.g., a binding polypeptide or binding peptide) is fused to the C-terminus of the first heavy chain or the second heavy chain, or both. For example, the first heavy chain includes a wildtype hinge domain at positions 232-236 (EU numbering), or a modified hinge domain at positions 232-236 (EU numbering) as shown above for SEQ ID NOs: 167-170. The second heavy chain includes a wildtype hinge domain at positions 232-236 (EU numbering), or a modified hinge domain at positions 232-236 (EU numbering) as shown above for SEQ ID NOs: 167-170 as the first heavy chain. The second heavy chain also includes one or more modifications in the second CH3 region that reduces or eliminates binding of the second CH3 region to Protein A, e.g., H435R / Y436F (EU numbering;H95R / Y96F by IMGT). Additionally, the second heavy chain is fused at the C-terminus to a binding polypeptide, e.g., SpyCatcher (binds to SpyTag), SpyCatcher002 (binds to SpyTag002), SpyCatcher003 (binds to SpyTag003), KTag (binds to SpyTag), pilin C (binds to isopeptag), SnoopCatcher (binds SnoopTag), and others. Spy Tag002:SpyCatcher002 and SpyTag003:SpyCatcher003 are different iterations of Spy Tag: Spy Catcher.

[0206] Examples heterodimeric antibodies, or antigen-binding fragments thereof, as described herein are shown in Table 5.Table 5: Example Heterodimer Antibodies135975-91820REGN 11918135975-91820REGN 11918

[0207] The heterodimeric antibodies, or antigen-binding fragments thereof, as described herein, may be directed to any number of cellular target proteins. The heterodimeric antibodies, or antigen-binding fragments thereof disclosed herein are particularly useful for surface-bound target proteins. The desired response can be, for example, clearing of a target or cell or virus bearing the same, signal transduction through a receptor, e.g., inducing apoptosis, inhibiting a receptor binding to a ligand or counterreceptor, or internalization of a heterodimeric antibody, or antigen-binding fragment thereof conjugated to a toxic agent. Heterodimeric antibodies, or antigen-binding fragments thereof disclosed herein can be made to the same targets as existing commercial antibodies or fusion proteins or can be135975-91820REGN 11918 derivatized versions of commercial antibodies or fusion proteins in which the existing constant region has been replaced by a modified constant region of the present disclosure.

[0208] Targets of interest include growth factor receptors (e.g., FGFR, HGFR, PDGFR, EFGR, NGFR, and VEGFR) and their ligands. Other targets are G-protein receptors and include substance K receptor, the angiotensin receptor, a and [3 adrenergic receptors, the serotonin receptors, and PAF receptor. See, e.g., Gilman, Ann. Rev. Biochem. 56:625 649 (1987). Other targets are CD (cluster of differentiation markers). Other targets include ion channels (e.g., calcium, sodium, and potassium channels), muscarinic receptors, acetylcholine receptors, GABA receptors, glutamate receptors, and dopamine receptors (see Harpold, U.S. Pat. No. 5,401,629 and U.S. Pat. No. 5,436,128). Other targets are adhesion proteins such as integrins, selectins, and immunoglobulin superfamily members (see Springer, Nature 346:425 433 (1990). Osborn, Cell 62:3 (1990); Hynes, Cell 69:11 (1992)). Other targets are cytokines, such as interleukins IL-1 through about IL-37 to-date, tumor necrosis factors, interferon, and tumor growth factor beta, colony stimulating factor (CSF), and granulocyte monocyte colony stimulating factor (GM-CSF). See Human Cytokines: Handbook for Basic & Clinical Research (Aggrawal et al. eds., Blackwell Scientific, Boston, Mass. 1991). Other targets are amyloidogenic peptides, such as Abeta, alpha-synuclein or prion peptide. Other targets are hormones, enzymes, and intracellular and intercellular messengers, such as, adenyl cyclase, guanyl cyclase, and phospholipase C. Target molecules can be human, mammalian or bacterial. Other targets are antigens, such as proteins, glycoproteins, and carbohydrates from microbial pathogens, both viral and bacterial, and tumors.

[0209] Example targets are calcium voltage-gated channel auxiliary subunit gamma 1 (CACNG1), asialoglycoprotein receptor 1 (ASGR1), Feldl, ENTPD3, PTPRA, CD20, CD63, and Her2. Additional targets include GABA, transferrin receptor, CD3, CD34, integrin, adipophilin, AIM-2, ALDH1A1, alpha-actinin-4, alpha-fetoprotein (“AFP”), ARTCI, B-RAF, BAGE-1, BCLX (L), BCR- ABL fusion protein b3a2, beta-catenin, BING-4, CA-125, CALCA, carcinoembryonic antigen (“CEA”), C ASP-5, CASP-8, CD274, CD45, Cdc27, CDK12, CDK4, CDKN2A, CEA, CLPP, COA-1, CPSF, CSNK1A1, CTAG1, CTAG2, cyclin DI, Cyclin-Al, dek-can fusion protein, DKK1, EFTUD2, Elongation factor 2, ENAH (hMena), Ep-CAM, EpCAM, EphA3, epithelial tumor antigen (“ETA”), ETV6-AML1 fusion protein, EZH2, E6, E7, FGF5, FLT3-ITD, FN1, G250 / MN / CAIX, GAGE-1,2,8, GAGE- 3, 4, 5, 6, 7, GAS7, glypican-3, GnTV, gplOO / Pmel 17, GPNMB, HAUS3, Hepsin, HER-2 / neu, HERV-K-MEL, HLA-A11, HLA-A2, HLA-DOB, hsp70-2, IDO1, IGF2B3, IL13Ralpha2, Intestinal carboxyl esterase, K-ras, Kallikrein 4, KIF20A, KK-LC-1, KKLC1, KM-HN-1, KMHN1 also known as CCDC110, LAGE-1, LDLR-fucosyltransferase AS fusion protein, Lengsin, M-CSF, MAGE-A1, MAGE- A 10, MAGE-A12, MAGE-A2, MAGE- A3, MAGE-A4, MAGE-A6, MAGE-A9, MAGECI, MAGE-C2, malic enzyme, mammaglobin-A, MART2, MATN, MC1R, MCSP, mdm-2, MEI, Mel an- A / MART-1 , Meloe, Midkine, MMP-2, MMP-7, MUC1, MUC5AC, mucin, MUM-1, MUM- 2, MUM-3, Myosin, Myosin class I, N-raw, NA88- A, neo-PAP, NFYC, NY-BR-1, NY-ESO-135975-91820REGN 11918 l / LAGE-2, OA1, OGT, OS-9, P polypeptide, p53, PAP, PAX5, PBF, pml-RARalpha fusion protein, polymorphic epithelial mucin (“PEM”), PPP1R3B, PRAME, PRDX5, PSA, PSMA, PTPRK, RAB 38 / N Y-MEL- 1, RAGE-1, RBAF600, RGS5, RhoC, R F43, RU2AS, SAGE, secernin 1, SIRT2, SNRPD1, SOXIO, Spl7, SPA17, SSX-2, SSX-4, STEAP1, survivin, SYT-SSX1 or -SSX2 fusion protein, TAG-1, TAG-2, Telomerase, TGF-betaRII, TPBG, TRAG-3, Triosephosphate isomerase, TRP-l / gp75, TRP-2, TRP2-INT2, tyrosinase, tyrosinase (“TYR”), VEGF, WT1, XAGE-lb / GAGED2a, Kras, NY- ESO1, MAGE- A3, HPV E2, HPV E6, HPV E7, WT-1 antigen (in lymphoma and other solid tumors), ErbB receptors, Melan A [MARTI], gp 100, tyrosinase, TRP-l / gp 75, and TRP-2 (in melanoma); MAGE-1 and MAGE-3 (in bladder, head and neck, and non-small cell carcinoma); HPV EG and E7 proteins (in cervical cancer); Mucin [MUC-1] (in breast, pancreas, colon, and prostate cancers); prostate-specific antigen [PSA] (in prostate cancer); carcinoembryonic antigen [CEA] (in colon, breast, and gastrointestinal cancers), and such shared tumor-specific antigens as MAGE-2, MAGE-4, MAGE-6, MAGE- 10, MAGE- 12, BAGE-1, CAGE-1,2,8, CAGE-3 TO 7, LAGE-1, NY-ESO-l / LAGE-2, NA-88, GnTV, TRP2-INT2, E6, E7, human glucagon receptor (hGCGR) and, human ectonucleoside triphosphate diphosphohydrolase 3 (hENTPD3). Other targets can be selected by the person skilled in the art. See WO 2019 / 006046.

[0210] Some examples of commercial antibodies and their targets include alemtuzumab (CD52); rituximab (CD20); trastuzumab (Her / neu); nimotuzumab, cetuximab (EGFR); bevacizumab (VEGF); palivizumab (RSV); abciximab (Gpllb / llla); infliximab, adalimumab, certolizumab, golimumab (TNF- alpha); baciliximab, daclizumab (IL-2); omalizumab (IgE); gemtuzumab (CD33); nataliz umab (VLA- 4); vedolizumab (alpha4beta7); belimumab (BAFF); otelixizumab, teplizumab (CD3); ofatumumab, ocrelizumab (CD20); epratuzumab (CD22); alemtuzumumab (CD52); eculizumab (C5); canakimumab (IL-lbeta); mepolizumab (IL-5); reslizumab, tocilizumab (IL-6R); ustekinumab, briakinumab (IL- 12, 23). Examples of commercial fusion proteins include etanercept which binds TNF-alpha, alefacept (LFA3-Fc fusion which binds CD2), TACI-Fc fusion which binds BAFF and APRIL, abatacept (CTLA-4-Fc which binds CD80 and CD86), and romiplostim (a peptide analog of thrombopoietin fused to Fc). Any of the commercial antibodies or fusion proteins can be modified to replace the existing heavy chain constant region with a modified heavy chain constant region, comprising one or modification in the sequence and is fused to a heterologous polypeptide, e.g., a binding polypeptide, as described herein. Alternatively, a modified heavy chain constant region(s) can be linked to other antibodies with the same target specificity (e.g., as determined by a competition assay) as any of the above commercial antibodies or fusion proteins.

[0211] In summary, the heterodimeric antibody, or antigen-binding fragment thereof, described above includes two heavy chains of different amino acid sequence that use the same light chain, wherein the constant region of one of the heavy chains is modified to the FcAAdp format, in the hinge domain, and fused to a binding polypeptide as described herein, and the other heavy chain may be modified in the hinge domain. Its configuration is that of a natural human antibody, and should135975-91820REGN 11918 therefore share its favorable properties, including a low propensity to aggregate, in vivo stability, minimal immunogenicity, biodistribution properties similar to those of antibodies, good pharmacokinetics, and, optionally, effector functions. Methods for isolating such heterodimeric antibodies, or antigen-binding fragments thereof as described herein are provided that are relatively rapid and simple in execution.Immunogenicity

[0212] One advantage of many embodiments of the disclosure is the ability to employ the modification(s) to make a heterodimeric antibody, or antigen-binding fragment thereof that is both readily isolable based on differential binding to Protein A and is also non-immunogenic or substantially non-immunogenic in a human. This feature makes such embodiments particularly useful in making heterodimeric antibodies, or antigen-binding fragments thereof disclosed herein for human therapeutic use, and in making immunoadhesins, e.g., that are non- immunogenic or substantially non- immunogenic (employing human binding moieties, i.e., human receptor components and / or human ligands). This feature is associated with heterodimeric antibodies, or antigen-binding fragments thereof disclosed herein having CH3 domains with the H95R / Y96F (IMGT numbering) modifications of IgGl , lgG2, and lgG3, and those CH3 domains that contain further modifications that result in the position being modified reflecting a wild-type sequence of a different IgG isotype. Thus, although the modification is not found in nature associated with the particular IgG isotype, the modified sequence is locally identical with a wild-type sequence of a different IgG isotype, and the modification is not expected to be immunogenic or substantially immunogenic. It is also possible that a modification is non-immunogenic even if its sequence is not locally identical to any native sequence; such modifications would be equally useful. The minimal point mutation H95R (IMGT numbering), if non- immunogenic, would therefore be a suitable embodiment of the disclosure.

[0213] Thus, heterodimeric antibodies, or antigen-binding fragments thereof disclosed herein are provided that are non-immunogenic or substantially non-immunogenic in a human, with respect to their heavy chain constant domains, but nonetheless bear one or more differential modifications of the heavy chain constant domain, including a modification that results in a differential affinity of the heavy chain constant domains with respect to an affinity reagent (e.g., Protein A). The modifications comprise those disclosed herein. In a specific embodiment, the heterodimeric antibody, or antigenbinding fragment thereof that is non- immunogenic or substantially non-immunogenic in a human with respect to its CH3 domain, yet having differentially modified heavy chains is a human IgGl , lgG2, or lgG4 comprising a CH3 domain that comprises one of the following modifications (or, in another embodiment, consists essentially of one of the following modifications): H95R, or H95R and Y96F (IMGT numbering).

[0214] The heterodimeric antibodies, or antigen-binding fragments thereof disclosed herein are expected to be non-immunogenic, or substantially non- immunogenic, with respect to humans in135975-91820REGN 11918 whom tolerance to human IgGl, lgG2, and lgG4 isoforms has not been broken to any significant degree.

[0215] In particular, the FcAAdp modification is expected to be immunologically “invisible” because the binding groove of MHC class II molecules accommodates a 9-mer that comprises the major determinant recognized by variable loops of the T cell receptor, so that peptides lacking any native 9- mer subsequence would appear unlikely to elicit an immune response. However, peptides longer than 9-mers (usually about 13- to 17mer) are bound by MHC class II, and it is possible that protruding segments may potentially influence binding. Therefore, additional modifications (over the FcAAdp modification) that eliminate longer non- native sequences may further reduce potential for immunogenicity. One specific example is the modification V422I (EU; V82I by IMGT numbering), which extends the length of the minimal non-native peptide from 14 to 39 residues in IgGl AAdp, and to 43 residues in the analogously defined lgG2AAdp. Another example is the modification L445P (EU; L105P by IMGT numbering) in lgG4AAdp, which extends the length from 10 to 14 residues.

[0216] Modifications in a heavy chain and / or a light chain of a heterodimeric antibody, or antigenbinding fragment thereof disclosed herein are optional. Modification in a heavy chain variable region, a light chain variable region, a CHI domain, a CH2 domain, a CH3 domain, and / or a hinge domain of a heterodimeric antibody, or antigen-binding fragment thereof disclosed herein are illustrative and can be selected by a skilled person in view of the teachings contained herein.Pharmacokinetics

[0217] The binding site for Protein A overlaps with the binding site for the neonatal Fc receptor, FcRN, which is thought to be responsible for conferring a prolonged serum half-life to immunoglobulins. Modifications in the vicinity of the Protein A binding site, therefore, raise the possibility that the format proposed here could have a shorter serum half-life than those of IgGl, 2, and 4, given that human lgG3 has a shorter serum half-life (about 7 days) than the other IgG subclasses (about 21 days). Some Fc mutants affecting His435 have been shown not to bind FcRN, and have a shorter half-life in mice. However, pharmacokinetic analysis has shown that the serum half-life of the IgGl AA / lgGl heterodimer is not appreciably different from that of the IgGl homodimer (incorporate by reference W02010151792A1). Thus, the IgGl AAdp mutation has the advantage of ablating Protein A binding while still preserving the longer half-life of IgGl.

[0218] Accordingly, in one embodiment, the heterodimeric antibodies, or antigen-binding fragments thereof disclosed herein fused to a binding polypeptide is provided that comprises a modification of a CH3 domain as described herein, wherein the antigen-binding protein displays a pharmacokinetic profile equivalent to the same heterodimeric antibodies, or anti gen -binding fragments thereof disclosed herein fused to a binding polypeptide that lacks the modification at the CH3 domain. In one embodiment, the heterodimeric antibodies, or antigen-binding fragments thereof is provided herein that comprises an IgGl AA / lgGl heterodimeric Fc, wherein the heterodimeric antibodies, or antigen-135975-91820REGN 11918 binding fragments thereof disclosed herein have a serum half-life that is about 1.5 -fold, about 2-fold, about 2.5-fold, or about 3 fold higher than a heterodimeric antibody, or antigen-binding fragment thereof that is otherwise identical but comprises an lgG3 CH3 domain, or that is otherwise identical but comprises at least one lgG3 heavy chain. In one embodiment, a heterodimeric antibody, or antigen-binding fragment thereof is provided comprising an IgGl AA / lgGl heterodimeric Fc, wherein the heterodimeric antibody, or antigen-binding fragment thereof exhibits a serum half-life that is about the same as that of the heterodimeric antibody, or antigen-binding fragment thereof without the IgGlAA modification (i.e., an IgGl homodimeric antibody).Engineering Heterodimeric Antibodies

[0219] Immunoglobulin heavy chain variable regions that can be used to generate heterodimeric antibodies, or antigen-binding fragments thereof disclosed herein, with desired characteristics (e.g., desired specificities, desired affinities, desired functionalities, e.g., blocking, non-blocking, inhibiting, activating, etc.) can be generated using any method known in the art. The desired heavy chains can then be constructed by cloning nucleic acid sequences containing the variable regions in constructs having the desired heavy chain constant regions described herein.

[0220] In one embodiment, the first heavy chain comprises a variable region that is encoded by a nucleic acid that is derived from the genome of a mature B cell of a first animal that has been immunized with a first antigen, and the first heavy chain specifically recognizes the first antigen. In a specific embodiment, the second heavy chain comprises a variable region that is encoded by a nucleic acid that is derived from the genome of a mature B cell of a second animal that has been immunized with a second antigen, and the second heavy chain specifically recognizes the second antigen.

[0221] In one embodiment, the first animal and / or the second animal is a genetically modified animal comprising an unrearranged human immunoglobulin heavy chain variable region. In one embodiment, the first animal and / or the second animal is a genetically modified animal comprising an unrearranged human immunoglobulin heavy chain variable region and a human immunoglobulin constant region. In one embodiment, the first animal and / or the second animal is a genetically modified mouse that comprises an unrearranged human immunoglobulin heavy chain variable region.

[0222] Immunoglobulin heavy chain variable region sequences can be obtained by any other method known in the art, e.g., by phage display, and sequences obtained thereby can be employed to make nucleic acid constructs to be joined to nucleic acids encoding any suitable heavy chain, e.g., heavy chains with modified CH3 domains as described herein, and placed in an expression construct and transferred to a cell that is capable of making the heavy chain, e.g., in the presence of a suitable light chain.

[0223] The heterodimeric antibodies, or antigen-binding fragments thereof disclosed herein, comprising two heavy chains comprising different amino acid sequences, e.g. a monovalent antibody that recognizes the same epitope and comprises different constant regions, or a bispecific antibody135975-91820REGN 11918 that recognizes two different epitopes (or two different antigens), are more easily isolated where they can pair with the same light chain (i.e., light chains having identical variable and constant domains). A variety of methods are known in the art for generating light chains that can pair with two heavy chains of differing specificity, while not interfering or not substantially interfering with the selectivity and / or affinity of the heavy chain variable domain with its target antigen.

[0224] In this approach, a light chain can be selected by surveying usage statistics for all light chain variable domains, identifying the most frequently employed light chain in human antibodies, and pairing that light chain with the two heavy chains of differing specificity.

[0225] In another approach, a light chain can be selected by observing light chain sequences in a phage display library (e.g., a phage display library comprising human light chain variable region sequences, e.g., a human ScFv library) and selecting the most commonly used light chain variable region from the library.

[0226] In another approach, a light chain can be selected by assaying a phage display library of light chain variable sequences using the heavy chain variable sequences of both heavy chains as probes. A light chain that associates with both heavy chain variable sequences is selected as a light chain for the heavy chains, and allows binding and / or activation with respect to both epitopes.

[0227] In another approach, a light chain can be selected by combining known light chains with desired heavy chains and assaying the resulting heterodimeric antibody, or antigen-binding fragment thereof, for binding specificity, affinity, and / or activation ability.

[0228] To the extent that a difficulty is encountered in any of the approaches for selecting a light chain (e.g., the light chain interferes with the binding of one or both of the heavy chains with its antigen, or the light chain fails to associate satisfactorily with one or both of the heavy chains), the light chain can be aligned with the heavy chains’ cognate light chains, and modifications are made in the light chain to more closely match sequence characteristics common to the cognate light chains of both heavy chains. If the chances of immunogenicity need to be minimized, the modifications preferably result in sequences that are present in known human light chain sequences, such that proteolytic processing is unlikely to generate a T cell epitope based on parameters and methods known in the art for assessing the likelihood of immunogenicity (i.e., in silico as well as wet assays).

[0229] The compositions and methods are particularly useful in making human heterodimeric antibodies, i.e., heterodimeric antibodies comprising human constant and variable domains. In some embodiments human antibodies include those having heavy chain variable and heavy chain constant domains derived from human germline immunoglobulin sequences, in some embodiments derived from somatically mutated human immunoglobulin sequences (generated, e.g., in an animal that comprises human immunoglobulin gene sequences). In some embodiments the human variable and / or constant regions may include amino acid residues not encoded by human germline immunoglobulin sequences or encoded as the result of recombination and / or splicing for example in the CDRs and in particular CDR3. Human antibodies are not intended to include antibodies in which CDR sequences135975-91820REGN 11918 derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences. Those antibodies are referred to as humanized or chimeric antibodies. Human antibodies do include those comprising mutations, e.g., introduced in vitro by random or sitespecific mutagenesis, but the mutations are preferably non-immunogenic in a human.

[0230] The methods and compositions can be used to make chimeric antibodies, preferably non- immunogenic in a human, or of low immunogenicity. Chimeric antibodies are antibodies in which one of a heavy chain variable region or framework or CDR or heavy chain constant region or domain are from different species (e.g., human and mouse, or human and primate). In some embodiments, chimeric antibodies include antibodies having a heavy chain variable region of non-human origin (e.g., mouse) and a heavy chain constant region of human origin. In some embodiments, chimeric antibodies include antibodies having a heavy chain variable region of human origin and a heavy chain constant region of non-human (e.g., mouse) origin. In various embodiments, regions of mouse origin are identical or substantially identical to a mouse immunoglobulin germline sequence with or without somatic hypermutations. Chimeric antibodies also include antibodies having a light chain constant region that is identical or substantially identical to a human immunoglobulin germline sequence and a non-human (e.g., mouse) heavy chain or chimeric human / nonhuman heavy chain. Chimeric antibodies include antibodies having a light chain constant domain that is identical or substantially identical to a non-human (e.g., mouse) immunoglobulin germline sequence and a human or chimeric nonhuman / human heavy chain.

[0231] In some embodiments, the compositions and methods are for making an affinity-matured antibody. In some embodiments, an affinity-matured antibody comprises one or more alterations in one or more CDRs that result in higher affinity (e.g., KO in the nanomolar or picomolar range) of the antibody for its target antigen as compared to a substantially identical antibody that lacks the alteration(s). Affinity-matured antibodies can be made by any suitable method known in the art, e.g., by random or site-directed mutagenesis of CDRs and / or framework regions followed by affinity screening, VH domain shuffling, etc.

[0232] In some embodiments, the antibodies disclosed herein are neutralizing antibodies.

[0233] Neutralizing antibodies include antibodies capable of neutralizing, inhibiting, or preventing an antigen’s biological activity. Neutralizing antibodies include those that, upon binding an antigen, prevent or reduce the antigen’s ability to act on a natural target of the antigen in vivo and in vitro. Examples of neutralizing antibodies include an antibody to a protein ligand of a biological receptor that prevents the ligand from binding the receptor, or an antibody to a biological receptor that prevents the receptor from binding its ligand, where ligand binding in the absence of the antibody causes the receptor to effect a change inside of a cell. Determining whether an antibody is a neutralizing antibody generally entails conducting a functional assay wherein the antibody’s effect on the biological activity of the antigen is measured.135975-91820REGN 11918

[0234] The methods and compositions of the disclosure are also useful in a variety of applications for antibodies and other binding proteins. A short description of some useful applications are provided here.

[0235] The heterodimeric antibodies, or antigen-binding fragments thereof disclosed herein that comprise binding specificity toward a tumor antigen and a T-cell antigen can be made that target an antigen on a cell, e.g., CD20, and also target an antigen on a T-cell, e.g., CD3. In this way, the heterodimeric antibody, or antigen-binding fragment thereof targets both a cell of interest in a patient (e.g., B cell in a lymphoma patient, via CD20 binding) as well as a T-cell of the patient. The heterodimeric antibody, or antigen-binding fragment thereof, in various embodiments, can be designed so as to activate the T-cell upon binding CD3, thus coupling T-cell activation to a specific, selected tumor cell.

[0236] The heterodimeric antibodies, or antigen-binding fragments thereof disclosed herein, that comprise two binding moieties that are each directed to a target (e.g., an antigen) on the surface of the same cell can also be made. This design is particularly suited to targeting specific cells or cell types that express both targets on the surface of the same cell. Although targets might appear individually on other cells, the binding moieties of these binding proteins are selected such that each binding moiety binds its target with a relatively low affinity (e.g., low micromolar, or high nanomolar — e.g., over a hundred nanomolar KD, e.g., 500, 600, 700, 800 nanomolar). In this way, prolonged target binding is favored only in situations where the two targets are in proximity on the same cell.

[0237] Heterodimeric antibodies, or antigen-binding fragments thereof disclosed herein, that comprise two binding moieties that bind the same target, each at a different epitope of the same target, can be made. This design is particularly suited for maximizing the probability of successfully blocking a target with the heterodimeric antibodies, or antigen-binding fragments thereof. Multiple extracellular loops, e.g., of a transmembrane channel or a cell surface receptor, can be targeted by the same heterodimeric antibodies, or antigen-binding fragments thereof disclosed herein.

[0238] The heterodimeric antibodies, or antigen-binding fragments thereof disclosed herein, that comprise two binding moieties that cluster and activate negative regulators of immune signaling to result in immune suppression can be made. Repression in cis can be achieved where the targets are on the same cell; repression in trans can be achieved where the targets are on different cells. Repression in cis, e.g., can be achieved with a heterodimeric antibody, or antigen-binding fragment thereof, having an anti-IgGRIIb binding moiety and an anti-FelDl binding moiety, such that the IgGRIIb is clustered only in the presence of FelDl, in order to down-regulate an immune response to FelDl. Repression in trans, e.g., can be achieved with a heterodimeric antibody, or antigen-binding fragment thereof, having an anti-BTLA binding moiety and a binding moiety that specifically binds a tissuespecific antigen of interest, such that clustering of the inhibitory BTLA molecule occurs only in the selected target tissue, which potentially addresses auto-immune diseases.135975-91820REGN 11918

[0239] The heterodimeric antibodies, or antigen-binding fragments thereof disclosed herein, that activate multi-component receptors can be made. In this design, two binding moieties directed to two components of a receptor bind, cross-link the receptor, and activate signaling from the receptor. This can be done, e.g., using a heterodimeric antibody, or antigen-binding fragment thereof, with a binding moiety that binds IFNAR1 and a binding moiety that binds IFNAR2, where binding cross-links the receptor. Such a heterodimeric antibody, or antigen-binding fragment thereof, can provide an alternative to interferon treatment.

[0240] The heterodimeric antibodies, or antigen-binding fragments thereof disclosed herein, that transport binding moieties across a semipermeable barrier, e.g., the blood-brain barrier, can be made. In this design, one binding moiety binds a target that can transit a particular selective barrier; the other binding moiety targets a molecule with a therapeutic activity, wherein the target molecule with therapeutic activity cannot normally traverse the barrier. This kind of heterodimeric antibody, or antigen-binding fragment thereof, is useful for bringing therapeutics to tissues that the therapeutic would not otherwise reach. Some examples include targeting the pIGR receptor to transport a therapeutic into the gut or lung, or targeting the transferrin receptor to transport a therapeutic across the blood-brain barrier.

[0241] The heterodimeric antibodies, or antigen-binding fragments thereof disclosed herein, that transport binding moieties into specific cells or cell types can be made. In this design, one binding moiety targets a cell surface protein (e.g., a receptor) that is readily internalized into the cell. The other binding moiety targets an intracellular protein, where binding of the intracellular protein results in a therapeutic effect.

[0242] The heterodimeric antibodies, or antigen-binding fragments thereof disclosed herein, that bind a surface receptor of a phagocytic immune cell and a surface molecule of an infectious pathogen (e.g., a yeast or bacterium), to bring the infectious pathogen in the vicinity of a phagocytic immune cell to facilitate phagocytosis of the pathogen. An example of such a design would be a heterodimeric antibody, or antigen-binding fragment thereof, that targets a CD64 or CD89 molecule and also a pathogen.

[0243] The heterodimeric antibodies, or antigen-binding fragments thereof disclosed herein, that have an antibody variable region as one binding moiety and a non-lg moiety as a second binding moiety. The antibody variable region achieves targeting, whereas the non-lg moiety is an effector or a toxin linked to an Fc. In this way, the ligand (e.g., an effector or toxin) is delivered to the target bound by the antibody variable region.

[0244] The heterodimeric antibodies, or antigen-binding fragments thereof disclosed herein, that have two moieties each bound to an Ig region (e.g., an Ig sequence containing a CH2 and CH3 region) such that any two protein moieties can be brought in each other’s vicinity in the context of the Fc. Examples of this design include traps, e.g., homo- or heterodimeric trap molecules.135975-91820REGN 11918Nucleic Acids

[0245] Nucleic acid sequences encoding monoclonal antibodies can be obtained by any suitable method known in the art. Examples of suitable methods for obtaining monoclonal antibodies (and their nucleic acid sequences) include, for example, by a hybridoma method (see, e.g., Kohler et al. (1975) Nature 256:495-497) or a phage antibody library (see, e.g., see Clackson et al. (1991) Nature 352:624-628).

[0246] In various embodiments, the immunoglobulin heavy chain variable domains are derived from nucleic acid sequences of a genetically modified animal or a transgenic animal. In some embodiments, the regions are derived from an animal that comprises a human immunoglobulin minilocus. In some embodiments, the regions are derived from mice comprising one or more extrachromosomal nucleic acids that comprise one or more nucleic acids encoding immunoglobulin sequences. In various embodiments, the animal can have one or more unrearranged human immunoglobulin nucleic acid sequences. In some embodiments, the animal comprises human light chain variable regions nucleic acid sequences, in some embodiments human heavy chain variable sequences, in some embodiments both heavy and light chain variable sequences, and in some embodiments further comprises human constant region sequences. In a specific embodiment, the nucleic acid sequences are derived from a mouse in which endogenous mouse heavy chain variable gene segments and light chain variable gene segments have been replaced with human heavy chain variable gene segments and light chain variable gene segments.

[0247] In some embodiments, the nucleic acid sequences are derived from naive B or T cells of such an animal. In other embodiments, the nucleic acid sequences are derived from B or T cells of an animal that has been immunized with an antigen of interest.

[0248] In various embodiments, the nucleic acid sequences are derived from cells by amplifying them with primers, including for example sets of degenerate primers that comprise one or more FR, joining, or constant sequences.

[0249] In various embodiments, the immunoglobulin heavy chain variable domains are derived from nucleic acids of an animal that has been immunized with an antigen of interest. For example, a nonhuman transgenic or genetically modified animal is immunized with the antigen of interest (by, e.g., exposing the animal to the antigen or a cell bearing the antigen or a nucleic acid encoding an expressible form of the antigen), allowing the animal to undergo an immune response, isolating immune cells (e.g., B cells) from the animal, optionally immortalizing the cells, and screening the cells to identify reactivity with the antigen, and / or identifying and / or isolating a nucleic acid sequences that encode an immunoglobulin variable region that is capable of recognizing the antigen when placed in the context of an antibody. In some embodiments, the cell is a B cell. In some embodiments, a B cell of the immunized animal is used to make a hybridoma, and a B cell expressing an antibody that specifically recognizes an epitope of the antigen is identified and nucleic acid135975-91820REGN 11918 sequences that encode a variable region amino acid sequence that recognizes the epitope is identified and / or isolated.

[0250] In some embodiments, the nucleic acids are derived from humans, non- human primates (e.g., apes such as chimpanzees), monkeys (e.g., cynomologous or rhesus), rodents (e.g., mice, rats, hamsters), donkeys, goats, sheep, etc.

[0251] In some embodiments, the heavy chains comprise sequences that are derived from human cells. For example, human fetal cells exposed in vitro to an antigen and placed in a suitable host animal (e.g., a SCID mouse).

[0252] In some embodiments, the nucleic acids are introduced into a cell using a vector. Vectors include, for example, plasmids, cosmids, retroviruses, adenoviruses, adeno- associated viruses, plant viruses, YACs, BACs, EBV-derived episomes.

[0253] In some embodiments, the nucleic acids are present in an expression vector or expression construct. In some embodiments, the expression vector or construct is a vector that contains a promoter operably linked to the nucleic acid sequence of interest such that the nucleic acid sequence of interest is capable of being expressed under suitable conditions in a suitable cell. Expression vectors or constructs can include leader sequences, enhancers, promoter elements that enhance transcription or translation, transcription stop sequences, splicing sequences, transcription-enhancing introns, IRES elements, marker genes, selection sequences, recombinase recognition sites, homology arms, viral sequences, operators (e.g., prokaryotic operators) etc. In some embodiments, the expression vectors comprise elements that allow inducible expression, for example, a prokaryotic operator operably linked to a eukaryotic promoter. In some embodiments, expression is induced upon addition of an expression inducer. In other embodiments, expression is induced upon removal of an expression inhibitor. In some embodiments, expression is induced by a temperature change.

[0254] In some embodiments, one or more heavy chain nucleotide sequences are on the same vector. In some embodiments, a heavy chain nucleic acid sequence and a light chain nucleic acid sequence herein are on the same vector. In one embodiment, two heavy chain nucleic acid sequences and a light chain nucleic acid sequence are on the same vector.

[0255] In some embodiments, the nucleic acids are expressed in a cell that comprises one or more nucleic acids from a virus. In specific embodiments, the virus is selected from adenovirus, adeno- associated virus, SV-40, Epstein-Barr virus, a retrovirus, a lentivirus, baculovirus, coronavirus, herpes simplex virus, poliovirus, Semliki Forest virus, Sindbis virus, and Vaccinia virus.

[0256] Host cells are cells that can be transformed to express a nucleic acid of interest. In various embodiments, transformation includes changing the nucleic acid content of a cell such that it contains exogenous nucleic acids (e.g., a nucleic acid not found in the cell in nature, or one or more additional copies of a nucleic acid corresponding to a nucleic acid sequence found in the cell in nature). The nucleic acid content of a cell can be changed by any suitable method known in the art, e.g., by integrating the nucleic acid into the cell’s genome or by placing it in the cell in an extra-chromosomal135975-91820REGN 11918 or extra-genomic form. In some embodiments the nucleic acid content of the cell can be changed such that the cell transiently expresses the nucleic acid of interest, or the nucleic acid content can be changed such that the cell stably expresses the nucleic acid of interest. In some embodiments, the change in genetic content of the cell is inherited when the cell divides.Isolating the Heterodimeric Antibody, or Antigen-binding Fragment Thereof

[0257] Heterodimeric proteins, including multi- or bi-specific antibodies, can be formatted for purification using affinity chromatography. One such format is based upon a standard fully human IgG antibody having an improved pharmacokinetic profile and minimal immunogenicity (see US Patent No. 8,586,713). A single common light chain and two distinct heavy chains combine to form the heterodimer antibody. One of the heavy chains contains a substituted Fc sequence (hereinafter “Fc(modified)”) that reduces or eliminates binding of the Fc(modified)* to Protein A. For example, one such Fc(modified) sequence contains H435R / Y436F (by EU numbering system; H95R / Y96F by IMGT exon numbering system) substitutions in the CH3 domain. Co-expression of the two heavy chains and the common light chain, results in three products: two of which are homodimeric for the heavy chains and one of which is the desired heterodimeric bispecific product. The Fc(modified) sequence allows selective purification of the Fc Fc(modified) heterodimer product on commercially available affinity columns, due to intermediate binding affinity for Protein A compared to the high avidity FcFc heavy chain homodimer, or the weakly binding Fc(modified) Fc(modified) homodimer.

[0258] Among the heterodimeric proteins (e.g., multi- or bi-specific antibodies) that can be purified using such affinity chromatography techniques are those including heavy chain constant regions modified to reduce binding to Fey receptors. The modification occurs within positions 233-236 by replacement of natural residues by glycine(s) and / or deletion(s). In various embodiments, the heavy chain constant region includes a hinge domain in which positions 233-236 within the hinge domain may be G, G, G and unoccupied; G, G, unoccupied, and unoccupied; G, unoccupied, unoccupied, and unoccupied; or all unoccupied, with positions numbered by EU numbering. These modifications can reduce binding of such heterodimeric proteins to Fey receptors, and particularly can reduce binding to background levels for any or all of FcyRI, FcyRIIA, FcyRIIB, and FcyRIIIA. In some cases, the immunoglobulin heavy chain is human IgGl or IgG4 isotype, and positions 226-229 may be CPPC (see WO 2016 / 161010).

[0259] For some chromatographic runs the addition of 0.5 molar to 1.0 molar ionic modifier (e.g., NaCl) drastically and unexpectedly improved separation of homodimeric IgGl and heterodimeric IgGl. Ionic modifier addition broadened the pH range for elution (1.2 pH units with ionic modifier, but 0.2 pH unit without ionic modifier) such that a pH step gradient could successfully separate the two species. In other runs, however, satisfactory separation was achieved with NaCl concentration of only about 150 mM (see Example 4). In order to ensure that satisfactory separation can be achieved,135975-91820REGN 11918 in one embodiment isolation of the heterodimeric antibody, or antigen-binding fragment thereof, is made in the presence of about 0.5 to about 1.0 molar ionic modifier.

[0260] Accordingly, in one embodiment a method for separating a heterodimeric antibody, or antigen-binding fragment thereof, comprising a heterodimeric IgG with one chain comprising a modification as described herein, comprises a step of employing a pH gradient in the presence of an ionic modifier. In one embodiment, the ionic modifier is present at a concentration sufficient to maximize the pH difference between elution from a Protein A support of an IgG homodimer and an IgG heterodimer as described herein (i.e., with CH3 modificationis)). In a specific embodiment, the ionic modifier is present at a concentration of about 0.5 to about 1.0 molar. In another specific embodiment, the ionic modifier is present at a concentration of about 0.15 to about 0.5 molar.

[0261] In one embodiment, the ionic modifier is a salt. In one embodiment, the ionic modifier is a salt of an alkaline metal or an alkaline earth metal and a halogen. In a specific embodiment, the salt is a chloride salt of an alkaline metal or an alkaline earth metal, e.g., NaCl, KC1, LiCl, CaCU, MgCb. In a specific embodiment, the salt is present at a molarity of about 0.5, 0.6, 0.7, 0.8, 0.9, or 1.0.

[0262] In one embodiment, the pH gradient is from about pH 3.9 to about pH 4.5, in another embodiment from about pH 4.0 to about pH 4.4., and in another embodiment about pH 4.1 to about pH 4.3. In a specific embodiment, the gradient is a linear gradient.

[0263] In one embodiment, the pH gradient is a step gradient. In one embodiment, the method comprises applying to an equilibrated Protein A column (equilibrated, e.g., in PBS or another suitable buffer or liquid) a step of about pH 3.9, about pH 4.0, about pH 4.1 , about pH 4.2, about pH 4.3, or about pH 4.4. In a specific embodiment, the step is about pH 4.2.

[0264] In one embodiment, the heterodimeric antibody, or antigen-binding fragment thereof, comprising the heterodimeric IgG CH3 domain elutes from the Protein A support in one or more fractions substantially free of non-heterodimeric IgG. In a specific embodiment, the eluted heterodimeric antibody, or antigen-binding fragment thereof, fraction(s) comprise less than about 1 %, 0.5%, or 0.1 % of total protein by weight that is non- heterodimeric antibody.

[0265] The heterodimeric antibodies, or antigen-binding fragments thereof, as described herein, can also be chemically modified by covalent conjugation to a polymer to, for instance, further increase their circulating half-life. Example polymers, and methods to attach them to peptides, are illustrated in for instance US 4,766,106, US 4,179,337, US 4,495,285, and US 4,609,546. Additional illustrative polymers include polyoxyethylated polyols and polyethylene glycol (PEG) (e.g., a PEG with a molecular weight of between about 1,000 and about 40,000, such as between about 2,000 and about 20,000, e.g., about 3,000-12,000 g / mol).

[0266] The heterodimeric antibodies, or antigen-binding fragments thereof disclosed herein can be radiolabeled antibody for either diagnostic or therapeutic purposes. Examples of radioisotopes include 3H, 14C, 15N, 35S, 90Y, "mTc, and 1251, 1311, 186Re, and 225Ac. Methods for preparing radiolabeled amino acids and heterodimeric antibodies, or antigen-binding fragments thereof135975-91820REGN 11918 disclosed herein containing them are known (see for instance Junghans et al., in Cancer Chemotherapy and Biotherapy 655-686 (2nd edition, Chafner and Longo, eds., Lippincott Raven (1996)) and US 4,681 ,581 , US 4,735,210, US 5,101,827, US 5,102,990 (US RE35,500), US 5,648,471 and US 5,697,902. For example, a radioisotope may be conjugated by a chloramine T method. Other detectable markers include an enzyme, a chromophore, or a fluorescent label.

[0267] The heterodimeric antibodies, or antigen-binding fragments thereof disclosed herein can be conjugated to a toxic agent. Toxic agents can be cytotoxic or cytostatic. Some example of toxic agents include antitubulin agents, auristatins, DNA minor groove binders, DNA replication inhibitors, alkylating agents (e.g., platinum complexes such as cis-platin, mono(platinum), bis(platinum) and tri- nuclear platinum complexes and carboplatin), anthracyclines, antibiotics, antifolates, antimetabolites, chemotherapy sensitizers, duocarmycins, camptothecins, etoposides, fluorinated pyrimidines, ionophores, lexitropsins, nitrosoureas, platinols, pre-forming compounds, purine antimetabolites, puromycins, radiation sensitizers, steroids, taxanes, topoisomerase inhibitors, vinca alkaloids, or the like.Viral Particles

[0268] Generally, the recombinant viral capsid proteins described herein may be derived from a capsid gene of a non-enveloped virus, e.g., is encoded by a cap gene modified to express a genetically modified capsid protein of a non-enveloped virus, wherein the non-enveloped virus infects human cells, or serotypes of non-enveloped viruses that generally infect human cells, e.g., adenovirus, adeno- associated virus, etc. In some embodiments, a recombinant viral capsid protein described herein is derived from a herpes simplex virus (HSV), lenti virus, human papillomavirus (HPV), baculovirus, bacovirus, or adeno-associated virus (AAV).

[0269] In some embodiments, a recombinant viral capsid protein described herein is derived from an AAV capsid gene that encodes the VP1, VP2, and / or VP3 capsid proteins of the AAV (or portions of the VP1, VP2, and / or VP3 capsid proteins), e.g., is encoded by a cap gene modified to encode a genetically modified adeno-associated virus (AAV) VP1, VP2, and / or VP3 capsid protein, e.g., a genetically modified capsid protein of a AAV serotype that infects humans selected from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, and AAV9. In some embodiments, the recombinant viral capsid protein is derived from an AAV2 or AAV9 capsid gene that respectively encodes an AAV2 VP1, VP2, and / or VP3 capsid protein or AAV9 VP1, VP2, and / or VP3 capsid protein e.g., is encoded by an AAV2 or AAV9 cap gene modified to respectively encode a genetically modified AAV2 VP1, VP2, and / or VP3 capsid protein or a genetically modified AAV9 VP1, VP2, and / or VP3 capsid protein. In some embodiments, the recombinant viral capsid protein is a derived from an AAV6 capsid gene, e.g., is encoded by an AAV6 cap gene modified to encode a genetically modified AAV6 VP1, VP2, and / or VP3 capsid protein, the wildtype amino acid sequence of which AAV6 VP1 capsid protein is set forth respectively as SEQ ID NO: 220. In some135975-91820REGN 11918 embodiments, the recombinant viral capsid protein is a derived from an AAV2 capsid gene, e.g., is encoded by an AAV2 cap gene modified to encode a genetically modified AAV2 VP1, VP2, and / or VP3 capsid protein, the wildtype amino acid sequence of which AAV2 VP1 capsid protein is set forth respectively as SEQ ID NO: 221. In some embodiments the recombinant viral capsid protein is derived from an AAV9 capsid gene, e.g., is encoded by an AAV9 cap gene modified to encode a genetically modified AAV9 VP1, VP2, and / or VP3 capsid protein, the wildtype amino acid sequence of which AAV9 VP1 capsid protein is set forth respectively as SEQ ID NO: 222.

[0270] In some embodiments, the recombinant viral capsid protein is derived from (encoded by) a chimeric AAV capsid gene, wherein the chimeric capsid gene comprises a plurality of nucleic acid sequences, wherein each of the plurality of nucleic acid sequences encodes a portion of a capsid protein of a different AAV serotype, and wherein the plurality of nucleic acid sequences together encodes a chimeric AAV capsid protein. In some embodiments, the recombinant viral capsid protein is derived from a chimeric AAV2 capsid gene. In some embodiments, the recombinant viral capsid protein is derived from a chimeric AAV6 capsid gene. In some embodiments, the recombinant viral capsid protein is derived from a chimeric AAV9 capsid gene.

[0271] Generally, a recombinant viral capsid protein as described herein is modified to comprise a peptide tag (first member of a protein: protein binding pair) operably linked (e.g., inserted into and / or displayed by), optionally via a linker, to the recombinant capsid protein such that the peptide tag (first member of a protein: protein binding pair), and optional linker itself reduces and / or abolishes the natural tropism of the recombinant capsid protein or capsid comprising same, as compared to a reference capsid protein lacking the peptide tag (first member of a protein: protein binding pair), and optional linker or capsid comprising the reference capsid, respectively. In some embodiments, the peptide tag (first member of a protein: protein binding pair) is operably linked (e.g., inserted into and / or displayed by), optional I y via a linker, to a region of the capsid protein involved with the natural tropism of the wildtype reference capsid protein, e.g., a region of the capsid protein involved with cell targeting. In some embodiments, the peptide tag (first member of a protein: protein binding pair), and optional linker is operably linked (e.g., inserted into and / or displayed by), optionally via a linker, to a knob domain of an Ad fiber protein. In some embodiments, the peptide tag (first member of a protein: protein binding pair) is operably linked (e.g., inserted into and / or displayed by), optionally via a linker, to the HI loop of an Ad fiber protein. In some embodiments, the peptide tag (first member of a protein: protein binding pair) is operably linked (e.g., inserted into and / or displayed by), optionally via a linker, to an exposed variable loop in an AAV capsid protein. In some embodiments, the peptide tag (first member of a protein: protein binding pair) is operably linked (e.g., inserted into and / or displayed by), optionally via a linker, to an exposed variable loop of an AAV2 capsid protein. In some embodiments, the peptide tag (first member of a protein: protein binding pair) is operably linked (e.g., inserted into and / or displayed by), optionally via a linker, to an exposed variable loop of an AAV9 capsid protein.135975-91820REGN 11918

[0272] In some embodiments (i) the viral capsid protein is derived from an AAV2 capsid gene that encodes an AAV2 VP1, VP2, and / or VP3 capsid protein and the peptide tag is operably linked to (e.g., inserted into and / or displayed by), optionally via a linker, an amino acid at position 1453 or 1587 of the AAV2 VP1 capsid protein (or corresponding positions of the VP2 and / or VP3 capsid proteins encoded from the same capsid gene, or the corresponding amino acids of VP1, VP2, and / or VP3 capsid proteins of a different AAV that infects humans, e.g., AAV1, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, and AAV9); (ii) the viral capsid protein is derived from an AAV6 capsid gene and the peptide tag (first member of a protein: protein binding pair) is operably linked to (e.g., inserted into and / or displayed by), optionally via a linker, an amino acid at position 1585 of the AAV6 VP1 capsid protein (or corresponding positions of the VP2 and / or VP3 capsid proteins encoded from the same capsid gene, or the corresponding amino acids of VP1, VP2, and / or VP3 capsid proteins of a different AAV that infects humans, e.g., AAV1, AAV2, AAV3, AAV4, AAV5, AAV7, AAV8, and AAV9); or (iii) the viral capsid protein is derived from an AAV9 capsid gene that encodes an AAV9 VP1, VP2, and / or VP3 capsid protein and the peptide tag is operably linked to (e.g., inserted into and / or displayed by), optionally via a linker, an amino acid at position 1453 or 1589 AAV9 VP1 capsid (or corresponding positions of the VP2 and / or VP3 capsid proteins encoded from the same capsid gene, or the corresponding amino acids of VP1, VP2, and / or VP3 capsid proteins of a different AAV that infects humans, e.g., AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, and AAV8).

[0273] In some embodiments, the peptide tag (first member of a protein: protein binding pair) is operably linked, optionally via a linker, to an amino acid a position selected from the group consisting of 453 of AAV2 capsid protein VP1, 587 of AAV2 capsid protein VP1, 585 of AAV6 capsid protein VP1, 453 of AAV9 capsid protein VP1, and 589 of AAV9 capsid protein VP1 (or corresponding positions of the VP2 and / or VP3 capsid proteins encoded from the same capsid gene, or the corresponding amino acids of VP1, VP2, and / or VP3 capsid proteins of a different AAV that infects humans, e.g., AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, and AAV9), e.g., is fused to the C-terminus of an amino acid at a position selected from the group consisting of 453 of AAV2 capsid protein VP1, 587 of AAV2 capsid protein VP1, 585 of AAV6 capsid protein VP 1, 453 of AAV9 capsid protein VP1, and 589 of AAV9 capsid protein VP1 (or corresponding positions of the VP2 and / or VP3 capsid proteins encoded from the same capsid gene, or the corresponding amino acids of VP1 , VP2, and / or VP3 capsid proteins of a different AAV that infects humans, e.g. , AAV 1 , AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, and AAV9). In some embodiments, the peptide tag (first member of a protein: protein binding pair), and optional linker is inserted immediately after (e.g., is fused to the C-terminus of) an amino acid at position 453 of AAV2 capsid protein VP1 (or corresponding positions of the VP2 and / or VP3 capsid proteins encoded from the same capsid gene, or the corresponding amino acids of VP1, VP2, and / or VP3 capsid proteins of a different AAV that infects humans, e.g., AAV1, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, and AAV9). In some embodiments, the peptide tag (first member of a protein: protein binding pair) and135975-91820REGN 11918 optional linker is inserted immediately after (e.g., is fused to the C-terminus of) an amino acid at position 587 of AAV2 capsid protein VP1 (or corresponding positions of the VP2 and / or VP3 capsid proteins encoded from the same capsid gene, or the corresponding amino acids of VP1, VP2, and / or VP3 capsid proteins of a different AAV that infects humans, e.g., AAV1, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, and AAV9). In some embodiments, the peptide tag (first member of a protein: protein binding pair), and optional linker is inserted immediately after (e.g., is fused to the C-terminus of) an amino acid at position 585 of AAV6 capsid protein VP1 (or corresponding positions of the VP2 and / or VP3 capsid proteins encoded from the same capsid gene, or the corresponding amino acids of VP1, VP2, and / or VP3 capsid proteins of a different AAV that infects humans, e.g., AAV1, AAV2, AAV3, AAV4, AAV5, AAV7, AAV8, and AAV9). In some embodiments, the peptide tag (first member of a protein: protein binding pair), and optional linker is inserted immediately after (e.g., is fused to the C-terminus of) an amino acid at position 453 of AAV9 capsid protein VP1 (or corresponding positions of the VP2 and / or VP3 capsid proteins encoded from the same capsid gene, or the corresponding amino acids of VP1, VP2, and / or VP3 capsid proteins of a different AAV that infects humans, e.g., AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, and AAV8). In some embodiments, the peptide tag (first member of a protein: protein binding pair), and optional linker is inserted immediately after (e.g., is fused to the C-terminus of) an amino acid at position 589 of AAV9 capsid protein VP1 (or corresponding positions of the VP2 and / or VP3 capsid proteins encoded from the same capsid gene, or the corresponding amino acids of VP1, VP2, and / or VP3 capsid proteins of a different AAV that infects humans, e.g., AAV1, AAV2 AAV3, AAV4, AAV5, AAV6, AAV7, and AAV8). In some embodiments, the peptide tag (first member of a protein: protein binding pair), and optional linker is inserted and / or displayed between positions 587 and 588 of an AAV2 VP1 capsid protein (or corresponding positions of the VP2 and / or VP3 capsid proteins encoded from the same capsid gene, or the corresponding amino acids of VP1, VP2, and / or VP3 capsid proteins of a different AAV that infects humans, e.g., AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, and AAV8).

[0274] In some embodiments, a recombinant capsid protein as described herein comprises a (second and different) mutation, which may be in addition to the peptide tag (first member of a protein: protein binding pair), and optional linker. In some embodiments, the (second and different mutation) comprises an insertion of a heterologous peptide into the capsid protein, substitution of one or more amino acids of the capsid protein with one or more heterologous amino acids, deletion of one or more amino acids of the capsid protein, or a combination thereof. For example, in some embodiment, a recombinant viral capsid protein as described herein may be derived from an AAV2 capsid gene (e.g., is a genetically modified AAV2 VP1, VP2, and / or VP3 capsid protein), comprises a peptide tag (first member of a protein: protein binding pair) and optional linker, and may further comprise a mutation, e.g., a R585A and / or R588A mutation in the AAV2 VP1 capsid protein (or corresponding mutation in the VP2 and / or VP3 capsid proteins encoded from the same AAV2 capsid gene). In some embodiments, a recombinant viral capsid protein is derived from a AAV2 capsid gene, e.g., is a135975-91820REGN 11918 genetically modified AAV2 VP1, VP2, and / or VP3 capsid protein, comprises a peptide tag (first member of a protein: protein binding pair) ,and optional linker inserted immediately after (e.g., fused to the C -terminus of) an amino acid at position 453 of the AAV2 VP1 protein (or amino acids at corresponding positions of the AAV2 VP2 and / or VP3 capsid proteins encoded by the AAV2 capsid gene), and further comprises a mutation selected from the group consisting of R585A and / or R588A (or corresponding mutations in the VP2 and / or VP3 capsid proteins encoded from the same AAV2 capsid gene). In some embodiments, a recombinant viral capsid protein is derived from an AAV2 capsid gene, e.g., is a genetically modified AAV2 VP1, VP2, and / or VP3 capsid protein, comprises a peptide tag (first member of a proteimprotein binding pair), and optional linker inserted immediately after (e.g., fused to the C-terminus of) an amino acid at position 587 of the AAV2 VP1 capsid protein (or amino acids at corresponding positions of the AAV2 VP2 and / or VP3 capsid proteins encoded from the same AAV2 capsid gene), and further comprises a mutation selected from the group consisting of R585A, R588A and / or corresponding mutations in the VP2 and / or VP3 capsid proteins encoded from the same AAV2 capsid gene.

[0275] In some embodiments, a recombinant viral capsid protein is derived from an AAV9 capsid gene, e.g., is a genetically modified AAV9 VP1, VP2, and / or VP3 capsid protein, comprises a peptide tag (first member of a protein: protein binding pair), and optional linker inserted immediately after (e.g., fused to the C-terminus of) an amino acid at position 453 of the AAV9 VP1 protein (or the amino acid at corresponding positions of the AAV9 VP2 or VP3 capsid proteins encoded from the same AAV9 capsid gene), and further comprises a W503A mutation (or a corresponding mutation in the VP2 and / or VP3 capsid proteins encoded from the same AAV2 capsid gene). In some embodiments, a recombinant viral capsid protein is derived from an AAV9 capsid gene, e.g., is a genetically modified AAV9 VP1, VP2, and / or VP3 capsid protein, comprises a peptide tag (first member of a protein: protein binding pair), and optional linker inserted immediately after (e.g., fused to the C-terminus of) an amino acid at position 589 of the AAV9 VP1 protein (or the amino acids at corresponding positions of the AAV9 VP2 and / or VP3 capsid proteins encoded from the same AAV9 capsid gene), and further comprises a W503A mutation (or a corresponding mutation in the VP2 and / or VP3 capsid proteins encoded from the same AAV2 capsid gene).

[0276] In some embodiments, a Cap protein, e.g., a VP1 capsid protein as described herein, a VP2 capsid protein as described herein, and / or a VP3 capsid protein as described herein, can be modified to comprise any number of various capsid modifications, e.g., one or more of a point mutation (e.g., amino acid substitutions, deletions, and / or insertions), a detectable label, a member of a proteimprotein binding pair, etc.

[0277] In some embodiments, the one or more point mutation(s) in a capsid protein (e.g., a VP1, VP2, and / or VP3 capsid protein) described herein can result in detargeting a viral particle comprising the mutant capsid protein from its natural target cell. Detargeting of a viral particle from its natural target cell can be important especially if systemic versus local or loco-regional administration of the135975-91820REGN 11918 viral particles is intended, as uptake of the viral particles by the natural target cell can limit the effective dose of the viral particles. Accordingly, a point mutation disclosed herein can be a point mutation that can reduce the transduction of a viral particle, which is mediated by the natural receptor of the viral particle, by at least 50%, preferably at least 80%, especially at least 95%. In some embodiments, a detargeting mutation disclosed herein can involve deletion or replacement of one or more an amino acids in the viral capsid that can be involved in binding of the respective viral particle to its natural receptor. Such point mutations can allow for efficient detargeting of the viral particle from cells expressing the natural receptor or, for targeting purposes, can increase specificity of the respective mutant viral particle for a new target cell.

[0278] In some embodiments, a capsid protein (e.g., a VP1, VP2, and / or VP3 capsid protein) of the present disclosure can be modified to comprise an inserted heterologous amino acid sequence (e.g., a peptide insertion described herein or an additional peptide insertion, such as a peptide comprising, consisting essentially of, or consisting of any of various targeting molecules described herein) capable of retargeting or redirecting a viral particle described herein. “Retargeting” or “redirecting” may include a scenario in which a wild-type viral particle targets several cells within a tissue and / or several organs within an organism, and general targeting of the cells, tissues, and / or organs is reduced or abolished by insertion of a heterologous amino acid sequence, and retargeting the viral particle to more a specific cell in the tissue or a specific organ in the organism is achieved with the inserted heterologous amino acid sequence, which can, e.g., bind a marker expressed by a specific cell. Such retargeting or redirecting may also include a scenario in which the wild-type viral particle targets a tissue, and targeting of the tissue is reduced or abolished by insertion of the heterologous amino acid sequence, and retargeting to a completely different tissue is achieved with the inserted heterologous amino acid sequence.

[0279] One or more of the detargeting mutation is) and / or insertion(s) can be introduced into a capsid protein of any of the AAV serotypes disclosed herein. Such detargeting and / or retargeting mutation(s) and / or insertion(s) can result in detargeting and / or retargeting of an AAV particle comprising a mutant capsid protein from or to specific cells within a tissue and / or organs within an organism. For example, cells, tissues, and / or organs, which may be detargeted and / or detargeted by AAV particles comprising mutant capsids, may include or be derived from, without limitation, liver, skeletal muscle, vascular and / or smooth muscle, cardiac muscle, nervous system (e.g., brain, spinal cord, neurons, glia, ependymal cells), eye (e.g., retina and retinal cells including photoreceptors such as rods and cones, RPE, etc.), lung, heart, pancreas, kidney, and epithelium.

[0280] In various embodiments, an AAV2 serotype is preferred for use in the compositions and / or methods of the present disclosure. In some embodiments the capsid of the AAV2 particle can comprise one or more amino acid mutations within a heparan sulfate proteoglycan (HSPG) binding domain of the AAV2 capsid. In some embodiments, the capsid of the AAV2 particle can comprise one or more amino acid mutations within a laminin receptor (LamR) binding domain, e.g., a 37 / 67-135975-91820REGN 11918 kDa LamR binding domain, of the AAV2 capsid. In some embodiments, the capsid of the AAV2 particle can comprise one or more mutations at an amino acid position(s) selected from amino acid position(s) R484, R487, R585, R588, and K532 (VP1 numbering), or a combination thereof, relative to a wild-type AAV2 capsid. In certain embodiments, the capsid of the AAV2 particle comprises a mutation at amino acid position R585 and / or R588. In some embodiments, the capsid of the AAV2 particle comprises one or more amino acid substitutions at an amino acid position(s) selected from R484A, R487A, R487G, K532A, K532D, R585A, R585S, R585Q, R588A, and R588T, or any combination thereof, relative to a wild-type AAV2 capsid. In some embodiments, the capsid of the AAV2 particle comprises an amino acid substitution R585A and / or R588A. AAV2 R585 corresponds to AAV9 S586, and AAV8 Q588 and AAV2 R588 corresponds to AAV9 A589 and AAV8 T591, respectively. Thus, when AAV9 is used, the capsid of the AAV9 particle can comprise a mutation at amino acid position S586 and / or A589. Similarly, when AAV8 is used, the capsid of the AAV8 particle can comprise a mutation at amino acid position Q588 and / or T591. In some embodiments, the capsid of the AAV2 particle comprises one or more insertion(s) at amino acid position G453 or N587, or a combination thereof.

[0281] In some embodiments, an AAV9 serotype is used in the compositions and / or methods of the present disclosure. In some embodiments, the capsid of the AAV9 particle can comprise one or more amino acid mutations within a galactose binding domain of the AAV9 capsid. In some embodiments, the capsid of the AAV9 particle can comprise one or more mutations at an amino acid position(s) selected from amino acid position(s) D271, N272, Y446, S469, N470, A742, V473, W503, E500, P504 and Q590 (VP1 numbering), and a combination thereof, relative to a wild-type AAV9 capsid. In certain embodiments, the capsid of the AAV9 particle comprises a mutation at amino acid position N272 and / or W503. In some embodiments, the capsid of the AAV9 particle comprises one or more amino acid substitutions selected from K532A, K532D, R484A, R487A, R585A, R585S, R585Q, R487G, R588A, and R588T, and any combination thereof, relative to a wild-type AAV9 capsid. In some embodiments, the capsid of the AAV9 particle comprises an amino acid substitution N272A and / or W503A, relative to a wild-type AAV9 capsid. In some embodiments, the capsid of the AAV9 particle comprises one or more insertion(s) at amino acid position G453, A587, or A589, or a combination thereof.

[0282] In some embodiments, an AAV 1 serotype is used in the compositions and / or methods of the present disclosure. In some embodiments, the capsid of the AAV1 particle can comprise one or more amino acid mutations within a sialic acid binding domain, e.g., an N-linked sialic acid binding domain, of the AAV1 capsid. In some embodiments, the capsid of the AAV1 particle can comprise one or more amino acid mutations within a binding domain of the AAV 1 capsid essential for binding adeno-associated virus receptor (AAVR). In some embodiments, the capsid of the AAV1 particle can comprise one or more mutations at an amino acid position(s) selected from amino acid position(s) N500 (which corresponds to AAV2 E499 and AAV9 E500), K531, and K531 (VP1 numbering), and a135975-91820REGN 11918 combination thereof, relative to a wild-type AAV1 capsid. In some embodiments, the capsid of the AAV1 particle comprises one or more amino acid substitutions selected from N500E, K531A and K531E, and any combination thereof, relative to a wild-type AAV1 capsid.

[0283] In some embodiments, an AAV6 serotype is used in the compositions and / or methods of the present disclosure. In some embodiments, the capsid of the AAV6 particle can comprise one or more amino acid mutations within a sialic acid binding domain, e.g., an N-linked sialic acid binding domain, of the AAV6 capsid. In some embodiments, the capsid of the AAV6 particle can comprise one or more amino acid mutations within a heparan sulfate proteoglycan (HSPG) binding domain of the AAV6 capsid. In some embodiments, the capsid of the AAV6 particle can comprise one or more amino acid mutations within an epidermal growth factor receptor (EGFR) binding domain of the AAV6 capsid. In some embodiments, the capsid of the AAV6 particle can comprise an amino acid mutation at amino acid position N500 (which corresponds to AAV2 E499 and AAV9 E500) (VP1 numbering), relative to a wild-type AAV6 capsid. In some embodiments, the capsid of the AAV6 particle comprises amino acid substitution N500E relative to a wild-type AAV6 capsid. In some embodiments, the capsid of the AAV6 particle comprises an insertion at amino acid position Q585.

[0284] In some embodiments, an AAV8 serotype is used in the compositions and / or methods of the present disclosure. In some embodiments, the capsid of the AAV8 particle can comprise one or more amino acid mutations within a laminin receptor (LamR) binding domain, e.g., a 37 / 67-kDa LamR binding domain, of the AAV8 capsid. In some embodiments, the capsid of the AAV8 particle comprises an insertion at amino acid position N590 (VP1 numbering).

[0285] In some embodiments, an AAV5 serotype is used in the compositions and / or methods of the present disclosure. In some embodiments, the capsid of the AAV5 particle can comprise one or more amino acid mutations within a sialic acid binding domain, e.g., an N-linked sialic acid binding domain, of the AAV5 capsid. In some embodiments, the capsid of the AAV5 particle can comprise one or more amino acid mutations within a platelet-derived growth factor receptor (PDGFR) of the AAV5 capsid. In some embodiments, the capsid of the AAV5 particle can comprise a mutation at amino acid position T571 (VP1 numbering) relative to a wild-type AAV5 capsid. In some embodiments, the capsid of the AAV5 particle comprises an amino acid substitution T571S relative to a wild-type AAV5 capsid.

[0286] In some embodiments, an avian AAV is used in the compositions and / or methods of the present disclosure. In some embodiments, the capsid of the avian AAV particle comprises an insertion at amino acid position is) G444 or K580 (VP1 numbering), or a combination thereof.

[0287] In some embodiments, a bearded dragon AAV is used in the compositions and / or methods of the present disclosure. In some embodiments, the capsid of the bearded dragon AAV particle comprises an insertion at amino acid position(s) G436 or T573 (VP1 numbering), or a combination thereof.135975-91820REGN 11918Table 6: Example AAV detargeting mutations135975-91820REGN 11918Anti-CACNGl antibodies

[0288] In another aspect, provided herein are amino acid molecules of the CDR, HCVR, LCVR, HC, or LC sequences of the anti-AAV / anti-CACNGl multispecific antigen-binding molecules disclosed herein, or variants thereof, including amino acid molecules comprising any of the polypeptide sequences as set forth in Table 7 herein, in any combination thereof. In some embodiments, the acid molecules described herein may comprise one or more polypeptide sequence(s) from Table 7. In some embodiments, the amino acid molecules described herein may comprise one or more polypeptide sequence(s) selected from Table 7 that are a set of six CDRs (i.e., HCDR1-HCDR2- HCDR3-LCDR1-LCDR2-LCDR3).

[0289] In another aspect, provided herein are nucleic acid molecules encoding any of the CDR, HCVR, LCVR, HC, or LC sequences of the anti-AAV / anti-CACNGl multispecific antigen-binding molecules disclosed herein, or variants thereof, including nucleic acid molecules comprising any of the polynucleotide sequences as set forth in Table 8 herein, in any combination thereof. In some embodiments, the nucleic acid molecules described herein may comprise one or more polynucleotide sequence(s) from Table 8 that encode a pair of HCVR / LCVR amino acid sequences. In some embodiments, the nucleic acid molecules described herein may comprise one or more polynucleotide sequence(s) selected from Table 8 that encode a set of six CDRs (i.e., HCDR1-HCDR2-HCDR3- LCDR 1 -LCDR2-LCDR3) .Table 7. Amino Acid Sequence Identifiers for Anti-CACNGl Antibodies135975-91820REGN 11918Table 8. Nucleic Acid Sequence Identifiers for Anti-CACNGl Antibodies135975-91820REGN 11918H2aM31929N / REGN10728HCVR DNA SequenceCAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACT CTCCTGTACAGCGTCTGGAATCACCTTCAGAAATTATGGCATGCACTGGGTCCGCCAGGC TCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATGTGGTATGATGGAAGTAATAAGTACT ATGCAGACTCCGTGAAGGGCCGTTTCACCATCTCCGGAGACAATTCCAAGGTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTATATTACTGTGCGAGAAGGGGCACT ATAAGAACAGCTGCCCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCCTCA (SEQ ID NO: 614)135975-91820REGN 11918HCVR Amino Acid SequenceQVQLVESGGGVVQPGRSLRLSCTASGITFRNYGMHWVRQAPGKGLEWVAVMWYDGSNKYYADSVKGRFTISGDNSKVYLQMNSLRAEDTAVYYCARRGTIRTAAPFDYWGQGTLVTVSS (SEQ ID NO: 615)HCDR1 DNA SequenceGGAATCACCTTCAGAAATTATGGC (SEQ ID NO: 616)HCDR1 Amino Acid SequenceGITFRNYG (SEQ ID NO: 617)HCDR2 DNA SequenceATGTGGTATGATGGAAGTAATAAG (SEQ ID NO: 618)HCDR2 Amino Acid SequenceMWYDGSNK (SEQ ID NO: 619)HCDR3 DNA SequenceGCGAGAAGGGGCACTATAAGAACAGCTGCCCCTTTTGACTAC (SEQ ID NO: 620)HCDR3 Amino Acid SequenceARRGTIRTAAPFDY (SEQ ID NO: 621)LCVR DNA SequenceGACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCGTC AAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACC TGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCACCTTCGG CCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 622)LCVR Amino Acid SequenceDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 623)LCDR1 DNA SequenceCAGAGCATTAGCAGCTAT (SEQ ID NO: 624)LCDR1 Amino Acid SequenceQSISSY (SEQ ID NO: 625)LCDR2 DNA SequenceGCTGCATCCLCDR2 Amino Acid SequenceAASLCDR3 DNA SequenceCAACAGAGTTACAGTACCCCTCCGATCACC (SEQ ID NO: 628)LCDR3 Amino Acid SequenceQQSYSTPPIT (SEQ ID NO: 629)HC DNA SequenceCAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACT135975-91820REGN 11918CTCCTGTACAGCGTCTGGAATCACCTTCAGAAATTATGGCATGCACTGGGTCCGCCAGGC TCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATGTGGTATGATGGAAGTAATAAGTACT ATGCAGACTCCGTGAAGGGCCGTTTCACCATCTCCGGAGACAATTCCAAGGTGTATCTGC AAATGAACAGCCTGAGAGCCGAGGACACGGCTGTATATTACTGTGCGAGAAGGGGCACTATAAGAACAGCTGCCCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCCTCA GCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAG AGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTC GTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAG TCCAAATATGGTCCCCCATGCCCACCGTGCCCAGCACCAGGCGGTGGCGGACCATCAGTC TTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACG TGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGC CAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGA CCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCC GTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCA GGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACA GAAGTCCCTCTCCCTGTCTCTGGGTAAATGA (SEQ ID NO: 630)HC Amino Acid SequenceQVQLVESGGGVVQPGRSLRLSCTASGITFRNYGMHWVRQAPGKGLEWVAVMWYDGSNKYYADSVKGRFTISGDNSKVYLQMNSLRAEDTAVYYCARRGTIRTAAPFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPGGGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVL HQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKG FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALH NHYTQKSLSLSLGK (SEQ ID NO: 631)LC DNA SequenceGACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCGTC AAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACC TGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCACCTTCGG CCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTT CTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACT CCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCAC CCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG (SEQ ID NO: 632)LC Amino Acid SequenceDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGT ASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK VYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 633)H2AM31944N135975-91820REGN 11918HCVR DNA SequenceCAGGTGCAGTTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACT CTCCTGTGAAGCGTCTGGAATCACCTTCAGAAACTATGGCATGCACTGGGTCCGCCAGGC TCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATGTGGTATGATGGAAGTAATAAATACT ACGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGGTGTATCTGCAAATGAACAGCCTGAGAGCCGAAGACACGGCTGTGTATTACTGTGCGAGACG GGGTCATATAGCAACAGCTGCTCCCTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGT CTCCTCA (SEQ ID NO: 634)HCVR Amino Acid SequenceQVQLVESGGGVVQPGRSLRLSCEASGITFRNYGMHWVRQAPGKGLEWVAVMWYDGSNKYYADSVKGRFTISRDNSKNTVYLQMNSLRAEDTAVYYCARRGHIATAAPFDYWGQGTLVTVSS (SEQ ID NO: 635)HCDR1 DNA SequenceGGAATCACCTTCAGAAACTATGGC (SEQ ID NO: 636)HCDR1 Amino Acid SequenceGITFRNYG (SEQ ID NO: 637)HCDR2 DNA SequenceATGTGGTATGATGGAAGTAATAAA (SEQ ID NO: 638)HCDR2 Amino Acid SequenceMWYDGSNK (SEQ ID NO: 639)HCDR3 DNA SequenceGCGAGACGGGGTCATATAGCAACAGCTGCTCCCTTTGACTAC (SEQ ID NO: 640)HCDR3 Amino Acid SequenceARRGHIATAAPFDY (SEQ ID NO: 641)LCVR DNA SequenceGACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCCGTAGGAGACAGAGTCACC ATCAGTTGCCGGGCAAGTCAGAGCATTAGTAGTTATTTAAATTGGTATCAGCAGAAACCA GGGAAAGCCCCTAAGGTCCTGATGTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCA AGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAGGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCACCTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 642)LCVR Amino Acid SequenceDIQMTQSPSSLSASVGDRVTISCRASQSISSYLNWYQQKPGKAPKVLMYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 643)LCDR1 DNA SequenceCAGAGCATTAGTAGTTAT (SEQ ID NO: 644)LCDR1 Amino Acid SequenceQSISSY (SEQ ID NO: 645)LCDR2 DNA SequenceGCTGCATCCLCDR2 Amino Acid SequenceAAS135975-91820REGN 11918LCDR3 DNA SequenceCAACAGAGTTACAGTACCCCTCCGATCACC (SEQ ID NO: 648)LCDR3 Amino Acid SequenceQQSYSTPPIT (SEQ ID NO: 649)HC DNA SequenceCAGGTGCAGTTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACT CTCCTGTGAAGCGTCTGGAATCACCTTCAGAAACTATGGCATGCACTGGGTCCGCCAGGC TCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATGTGGTATGATGGAAGTAATAAATACT ACGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGGTG TATCTGCAAATGAACAGCCTGAGAGCCGAAGACACGGCTGTGTATTACTGTGCGAGACG GGGTCATATAGCAACAGCTGCTCCCTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGT CTCCTCAGCCAAAACAACAGCCCCATCGGTCTATCCACTGGCCCCTGTGTGTGGAGATACAACTGGCTCCTCGGTGACTCTAGGATGCCTGGTCAAGGGTTATTTCCCTGAGCCAGTGAC CTTGACCTGGAACTCTGGATCCCTGTCCAGTGGTGTGCACACCTTCCCAGCTGTCCTGCA GTCTGACCTCTACACCCTCAGCAGCTCAGTGACTGTAACCTCGAGCACCTGGCCCAGCCA GTCCATCACCTGCAATGTGGCCCACCCGGCAAGCAGCACCAAGGTGGACAAGAAAATTG AGCCCAGAGGGCCCACAATCAAGCCCTGTCCTCCATGCAAATGCCCAGCACCTAACCTCT TGGGTGGACCATCCGTCTTCATCTTCCCTCCAAAGATCAAGGATGTACTCATGATCTCCCT GAGCCCCATAGTCACATGTGTGGTGGTGGATGTGAGCGAGGATGACCCAGATGTCCAGA TCAGCTGGTTTGTGAACAACGTGGAAGTACACACAGCTCAGACACAAACCCATAGAGAG GATTACAACAGTACTCTCCGGGTGGTCAGTGCCCTCCCCATCCAGCACCAGGACTGGATG AGTGGCAAGGAGTTCAAATGCAAGGTCAACAACAAAGACCTCCCAGCGCCCATCGAGAG AACCATCTCAAAACCCAAAGGGTCAGTAAGAGCTCCACAGGTATATGTCTTGCCTCCACC AGAAGAAGAGATGACTAAGAAACAGGTCACTCTGACCTGCATGGTCACAGACTTCATGCCTGAAGACATTTACGTGGAGTGGACCAACAACGGGAAAACAGAGCTAAACTACAAGAA CACTGAACCAGTCCTGGACTCTGATGGTTCTTACTTCATGTACAGCAAGCTGAGAGTGGA AAAGAAGAACTGGGTGGAAAGAAATAGCTACTCCTGTTCAGTGGTCCACGAGGGTCTGC ACAATCACCACACGACTAAGAGCTTCTCCCGGACTCCGGGTAAATGA (SEQ ID NO: 650)HC Amino Acid SequenceQVQLVESGGGVVQPGRSLRLSCEASGITFRNYGMHWVRQAPGKGLEWVAVMWYDGSNKY YADSVKGRFTISRDNSKNTVYLQMNSLRAEDTAVYYCARRGHIATAAPFDYWGQGTLVTVS SAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLY TLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPP KIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPI QHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMV TDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK (SEQ ID NO: 651)LC DNA SequenceGACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCCGTAGGAGACAGAGTCACC ATCAGTTGCCGGGCAAGTCAGAGCATTAGTAGTTATTTAAATTGGTATCAGCAGAAACCA GGGAAAGCCCCTAAGGTCCTGATGTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCA AGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCT GAGGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCACCTTCGGC CAAGGGACACGACTGGAGATTAAACGAGCTGATGCTGCACCAACTGTATCCATCTTCCC ACCATCCAGTGAGCAGTTAACATCTGGAGGTGCCTCAGTCGTGTGCTTCTTGAACAACTTCTACCCCAAAGACATCAATGTCAAGTGGAAGATTGATGGCAGTGAACGACAAAATGGCG TCCTGAACAGTTGGACTGATCAGGACAGCAAAGACAGCACCTACAGCATGAGCAGCACC CTCACGTTGACCAAGGACGAGTATGAACGACATAACAGCTATACCTGTGAGGCCACTCA CAAGACATCAACTTCACCCATTGTCAAGAGCTTCAACAGGGGAGAGTGTTGA (SEQ ID NO: 652)135975-91820REGN 11918LC Amino Acid SequenceDIQMTQSPSSLSASVGDRVTISCRASQSISSYLNWYQQKPGKAPKVLMYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRADAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRGEC (SEQ ID NO: 653)H4H31265P2 / REGN5972HCVR DNA SequenceCAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTACAGCGTCTGGATTCACCTTCCGTTCCTATGGCATGCACTGGGTCCGCCAGGCT CCAGGCAAGGGGCTGGAGTGGGTGTCAGTTATTTGGATTGATGGAAATAATATATACTAT GCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGGACAGCCTGAGAGCCGAGGACACGGCTGTTTATTACTGTGCGAGAAGAC TGGCTATAACATCAGCTGCCCCCTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCT CCTCA (SEQ ID NO: 654)HCVR Amino Acid SequenceQVQLVESGGGVVQPGRSLRLSCTASGFTFRSYGMHWVRQAPGKGLEWVSVIWIDGNNIYYADSVKGRFTISRDNSKNTLYLQMDSLRAEDTAVYYCARRLAITSAAPFDYWGQGTLVTVSS (SEQ ID NO: 655)HCDR1 DNA SequenceGGATTCACCTTCCGTTCCTATGGC (SEQ ID NO: 656)HCDR1 Amino Acid SequenceGFTFRSYG (SEQ ID NO: 657)HCDR2 DNA SequenceATTTGGATTGATGGAAATAATATA (SEQ ID NO: 658)HCDR2 Amino Acid SequenceIWIDGNNI (SEQ ID NO: 659)HCDR3 DNA SequenceGCGAGAAGACTGGCTATAACATCAGCTGCCCCCTTTGACTAC (SEQ ID NO: 660)HCDR3 Amino Acid SequenceARRLAITSAAPFDY (SEQ ID NO: 661)LCVR DNA SequenceGACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACC ATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACC AGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACC TGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCACCTTCGG CCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 662)LCVR Amino Acid SequenceDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 663)LCDR1 DNA SequenceCAGAGCATTAGCAGCTAT (SEQ ID NO: 664)135975-91820REGN 11918LCDR1 Amino Acid SequenceQSISSY (SEQ ID NO: 665)LCDR2 DNA SequenceGCTGCATCCLCDR2 Amino Acid SequenceAASLCDR3 DNA SequenceCAACAGAGTTACAGTACCCCTCCGATCACC (SEQ ID NO: 668)LCDR3 Amino Acid SequenceQQSYSTPPIT (SEQ ID NO: 669)HC DNA SequenceCAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTACAGCGTCTGGATTCACCTTCCGTTCCTATGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGTCAGTTATTTGGATTGATGGAAATAATATATACTAT GCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTA TCTGCAAATGGACAGCCTGAGAGCCGAGGACACGGCTGTTTATTACTGTGCGAGAAGAC TGGCTATAACATCAGCTGCCCCCTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCT CCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACG GTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACG AAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGT TGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCCTGGGGGGACC ATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGT ACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAA CAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCA AGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGA GGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCG ACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCC TCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCCCTGTCTCTGGGTAAATGA (SEQ ID NO: 670)HC Amino Acid SequenceQVQLVESGGGVVQPGRSLRLSCTASGFTFRSYGMHWVRQAPGKGLEWVSVIWIDGNNIYYADSVKGRFTISRDNSKNTLYLQMDSLRAEDTAVYYCARRLAITSAAPFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVL HQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKG FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALH NHYTQKSLSLSLGK* (SEQ ID NO: 671)LC DNA SequenceGACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACC ATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACC AGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCGTC135975-91820REGN 11918AAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACC TGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCACCTTCGG CCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCC GCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACT CCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCAC CCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCC ATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG (SEQ IDNO: 672)LC Amino Acid SequenceDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC* (SEQ ID NO: 673)H2aM31941NHCVR DNA SequenceCAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGT CTCCTGCAAGGCTTCTGGTTACGCCTTCACCACCTATGGTATCACCTGGGTGCGACAGGC CCCTGGACAAGGACTTGAGTGGATGGGATGGATCAGCGCTTACAATGGAAATACAAACT ATGCAGAGAAGGTCCAGGGCAGATTCACCATGACCACAGACACATCCACGAATACAGCCTACATGGAGCTGAGGAGCCTGAGATCCGACGACACGGCCGTGTATTTCTGTGCGAGAAA GGGTCACTATGGTTCGGGGACTTATTATAACCCCTTTGGTTTTGATTTTTGGGGCCAAGG GACAATGGTCACCGTCTCTTCA (SEQ ID NO: 674)HCVR Amino Acid SequenceQVQLVQSGAEVKKPGASVKVSCKASGYAFTTYGITWVRQAPGQGLEWMGWISAYNGNTNYAEKVQGRFTMTTDTSTNTAYMELRSLRSDDTAVYFCARKGHYGSGTYYNPFGFDFWGQG TMVTVSS (SEQ ID NO: 675)HCDR1 DNA SequenceGGTTACGCCTTCACCACCTATGGT (SEQ ID NO: 676)HCDR1 Amino Acid SequenceGYAFTTYG (SEQ ID NO: 677)HCDR2 DNA SequenceATCAGCGCTTACAATGGAAATACA (SEQ ID NO: 678)HCDR2 Amino Acid SequenceISAYNGNT (SEQ ID NO: 679)HCDR3 DNA SequenceGCGAGAAAGGGTCACTATGGTTCGGGGACTTATTATAACCCCTTTGGTTTTGATTTT (SEQID NO: 680)HCDR3 Amino Acid SequenceARKGHYGSGTYYNPFGFDF (SEQ ID NO: 681)LCVR DNA SequenceGAAATTATGTTGATGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACC CTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAGCTACTTAGCCTGGTACCAACAGAA ACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAGCAGGGCCACTGACATCCC135975-91820REGN 11918AGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGG AGCCTGAAGATTTTGCAGTTTATTTCTGTCAGCAGTATTATGGCTCACCTTGGACGTTCGG CCAAGGGACCAAGGTGGAAATCAAGCG (SEQ ID NO: 682)LCVR Amino Acid SequenceEIMLMQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATDIPDRFSGSGSGTDFTLTISRLEPEDFAVYFCQQYYGSPWTFGQGTKVEIK (SEQ ID NO: 683)LCDR1 DNA SequenceCAGAGTGTTAGCAGCAGCTAC (SEQ ID NO: 684)LCDR1 Amino Acid SequenceQSVSSSY (SEQ ID NO: 685)LCDR2 DNA SequenceGGTGCATCCLCDR2 Amino Acid SequenceGASLCDR3 DNA SequenceCAGCAGTATTATGGCTCACCTTGGACG (SEQ ID NO: 688)LCDR3 Amino Acid SequenceQQYYGSPWT (SEQ ID NO: 689)HC DNA SequenceCAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGT CTCCTGCAAGGCTTCTGGTTACGCCTTCACCACCTATGGTATCACCTGGGTGCGACAGGC CCCTGGACAAGGACTTGAGTGGATGGGATGGATCAGCGCTTACAATGGAAATACAAACTATGCAGAGAAGGTCCAGGGCAGATTCACCATGACCACAGACACATCCACGAATACAGCC TACATGGAGCTGAGGAGCCTGAGATCCGACGACACGGCCGTGTATTTCTGTGCGAGAAA GGGTCACTATGGTTCGGGGACTTATTATAACCCCTTTGGTTTTGATTTTTGGGGCCAAGG GACAATGGTCACCGTCTCTTCAGCCAAAACGACACCCCCATCTGTCTATCCACTGGCCCC TGGATCTGCTGCCCAAACTAACTCCATGGTGACCCTGGGATGCCTGGTCAAGGGCTATTTCCCTGAGCCAGTGACAGTGACCTGGAACTCTGGATCCCTGTCCAGCGGTGTGCACACCTT CCCAGCTGTCCTGCAGTCTGACCTCTACACTCTGAGCAGCTCAGTGACTGTCCCCTCCAG CACCTGGCCCAGCGAGACCGTCACCTGCAACGTTGCCCACCCGGCCAGCAGCACCAAGGTGGACAAGAAAATTGTGCCCAGGGATTGTGGTTGTAAGCCTTGCATATGTACAGTCCCAG AAGTATCATCTGTCTTCATCTTCCCCCCAAAGCCCAAGGATGTGCTCACCATTACTCTGAC TCCTAAGGTCACGTGTGTTGTGGTAGACATCAGCAAGGATGATCCCGAGGTCCAGTTCAG CTGGTTTGTAGATGATGTGGAGGTGCACACAGCTCAGACGCAACCCCGGGAGGAGCAGT TCAACAGCACTTTCCGCTCAGTCAGTGAACTTCCCATCATGCACCAGGACTGGCTCAATGGCAAGGAGTTCAAATGCAGGGTCAACAGTGCAGCTTTCCCTGCCCCCATCGAGAAAACC ATCTCCAAAACCAAAGGCAGACCGAAGGCTCCACAGGTGTACACCATTCCACCTCCCAA GGAGCAGATGGCCAAGGATAAAGTCAGTCTGACCTGCATGATAACAGACTTCTTCCCTGAAGACATTACTGTGGAGTGGCAGTGGAATGGGCAGCCAGCGGAGAACTACAAGAACACT CAGCCCATCATGGACACAGATGGCTCTTACTTCGTCTACAGCAAGCTCAATGTGCAGAAG TCCAACTGGGAGGCAGGAAATACTTTCACCTGCTCTGTGTTACATGAGGGCCTGCACAAC CACCATACTGAGAAGTCCCTCTCCCACTCTCCTGGTAAATGA (SEQ ID NO: 690)HC Amino Acid SequenceQVQLVQSGAEVKKPGASVKVSCKASGYAFTTYGITWVRQAPGQGLEWMGWISAYNGNTN YAEKVQGRFTMTTDTSTNTAYMELRSLRSDDTAVYFCARKGHYGSGTYYNPFGFDFWGQG TMVTVSSAKTTPPSVYPLAPGSAAQTNSMVTLGCLVKGYFPEPVTVTWNSGSLSSGVHTFPA135975-91820REGN 11918VLQSDLYTLSSSVTVPSSTWPSETVTCNVAHPASSTKVDKKIVPRDCGCKPCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCVVVDISKDDPEVQFSWFVDDVEVHTAQTQPREEQFNSTFRSVSELPIMHQDWLNGKEFKCRVNSAAFPAPIEKTISKTKGRPKAPQVYTIPPPKEQMAKDKVSLTC MITDFFPEDITVEWQWNGQPAENYKNTQPIMDTDGSYFVYSKLNVQKSNWEAGNTFTCSVL HEGLHNHHTEKSLSHSPGK (SEQ ID NO: 691)LC DNA SequenceGAAATTATGTTGATGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACC CTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAGCTACTTAGCCTGGTACCAACAGAA ACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAGCAGGGCCACTGACATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGG AGCCTGAAGATTTTGCAGTTTATTTCTGTCAGCAGTATTATGGCTCACCTTGGACGTTCGG CCAAGGGACCAAGGTGGAAATCAAGCGAGCTGATGCTGCACCAACTGTATCCATCTTCC CACCATCCAGTGAGCAGTTAACATCTGGAGGTGCCTCAGTCGTGTGCTTCTTGAACAACT TCTACCCCAAAGACATCAATGTCAAGTGGAAGATTGATGGCAGTGAACGACAAAATGGC GTCCTGAACAGTTGGACTGATCAGGACAGCAAAGACAGCACCTACAGCATGAGCAGCACCCTCACGTTGACCAAGGACGAGTATGAACGACATAACAGCTATACCTGTGAGGCCACTC ACAAGACATCAACTTCACCCATTGTCAAGAGCTTCAACAGGGGAGAGTGTTGA (SEQ ID NO: 692)LC Amino Acid SequenceEIMLMQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATDIPDRFSGSGSGTDFTLTISRLEPEDFAVYFCQQYYGSPWTFGQGTKVEIKRADAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRGEC (SEQ ID NO: 693)REGN7660HCVR DNA SequenceGAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCGGGGGGGTCCCTGAAACT CTCCTGTACAGCCTCTGGGTTGACCCTCAGTGACTCTGCTATGCACTGGGTCCGCCAGGC TTCCGGGAAAGGGCTGGAGTGGGTTGGCCGTATAAGAAATAAGGCTAATAGGTACGCGACAGAATATGCTGCGTCGGTGAAAGGCAGGTTCACCATTTCAAGAGATGATTCAAAGAACACGGCGTATCTACAAATGAACAGCCTGAAAACCGAGGACACGGCCGTGTATTATTGTAC TAGAAACTGGAAGATTTTCCTCTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTC CTCA (SEQ ID NO: 694)HCVR Amino Acid SequenceEVQLVESGGGLVQPGGSLKLSCTASGLTLSDSAMHWVRQASGKGLEWVGRIRNKANRYATEYAASVKGRFTISRDDSKNTAYLQMNSLKTEDTAVYYCTRNWKIFLFDYWGQGTLVTVSS (SEQ ID NO: 695)HCDR1 DNA SequenceGGGTTGACCCTCAGTGACTCTGCT (SEQ ID NO: 696)HCDR1 Amino Acid SequenceGLTLSDSA (SEQ ID NO: 697)HCDR2 DNA SequenceATAAGAAATAAGGCTAATAGGTACGCGACA (SEQ ID NO: 698)HCDR2 Amino Acid SequenceIRNKANRYAT (SEQ ID NO: 699)HCDR3 DNA Sequence135975-91820REGN 11918ACTAGAAACTGGAAGATTTTCCTCTTTGACTAC (SEQ ID NO: 700)HCDR3 Amino Acid SequenceTRNWKIFLFDY (SEQ ID NO: 701)LCVR DNA SequenceGAAATTGTGTTGACGCAGTCTCCAGGCACCCTGACTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTGGCAGCAAATACTTAGCCTGGTTCCAGCAGAAACGTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAGCAGGACCAGTGGCATCCCCGACAGGATCAGTGGCAGTGGGTCAGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATGGAAGTTCACCCTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA (SEQ ID NO: 702)LCVR Amino Acid SequenceEIVLTQSPGTLTLSPGERATLSCRASQSVGSKYLAWFQQKRGQAPRLLIYGASSRTSGIPDRISGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIK (SEQ ID NO: 703)LCDR1 DNA SequenceCAGAGTGTTGGCAGCAAATAC (SEQ ID NO: 704)LCDR1 Amino Acid SequenceQSVGSKY (SEQ ID NO: 705)LCDR2 DNA SequenceGGTGCATCCLCDR2 Amino Acid SequenceGASLCDR3 DNA SequenceCAGCAGTATGGAAGTTCACCCTGGACG (SEQ ID NO: 708)LCDR3 Amino Acid SequenceQQYGSSPWT (SEQ ID NO: 709)HC DNA SequenceGAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCGGGGGGGTCCCTGAAACTCTCCTGTACAGCCTCTGGGTTGACCCTCAGTGACTCTGCTATGCACTGGGTCCGCCAGGCTTCCGGGAAAGGGCTGGAGTGGGTTGGCCGTATAAGAAATAAGGCTAATAGGTACGCGACAGAATATGCTGCGTCGGTGAAAGGCAGGTTCACCATTTCAAGAGATGATTCAAAGAACACGGCGTATCTACAAATGAACAGCCTGAAAACCGAGGACACGGCCGTGTATTATTGTACTAGAAACTGGAAGATTTTCCTCTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGA135975-91820REGN 11918CATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTC CCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCA GGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCCCTGTCTCTGGGTAAATGA (SEQ ID NO: 710)HC Amino Acid SequenceEVQLVESGGGLVQPGGSLKLSCTASGLTLSDSAMHWVRQASGKGLEWVGRIRNKANRYATEYAASVKGRFTISRDDSKNTAYLQMNSLKTEDTAVYYCTRNWKIFLFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS LSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALH NHYTQKSLSLSLGK (SEQ ID NO: 711)LC DNA SequenceGAAATTGTGTTGACGCAGTCTCCAGGCACCCTGACTTTGTCTCCAGGGGAAAGAGCCACC CTCTCCTGCAGGGCCAGTCAGAGTGTTGGCAGCAAATACTTAGCCTGGTTCCAGCAGAAA CGTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAGCAGGACCAGTGGCATCCCCGACAGGATCAGTGGCAGTGGGTCAGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATGGAAGTTCACCCTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACT CCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCAC CCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG (SEQ ID NO: 712)LC Amino Acid SequenceEIVLTQSPGTLTLSPGERATLSCRASQSVGSKYLAWFQQKRGQAPRLLIYGASSRTSGIPDRISGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 713)REGN9909HCVR DNA SequenceGAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCGGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAACAACTATGGCATGAGCTGGGTCCGCCAGGGTCCAGGGAAGGGGCTGGAGTGGGTCTCATCTATTAGTGGTAGTGGTGGTACCACATTCTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGT ATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGGCAAAGGA GGATATTGTAGTAGTAGCGGCTGCCGTCACTACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA (SEQ ID NO: 714)HCVR Amino Acid SequenceEVQLLESGGGLVQPGGSLRLSCAASGFTFNNYGMSWVRQGPGKGLEWVSSISGSGGTTFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCGKGGYCSSSGCRHYGMDVWGQGTTVTVSS (SEQ ID NO: 715)HCDR1 DNA SequenceGGATTCACCTTTAACAACTATGGC (SEQ ID NO: 716)HCDR1 Amino Acid Sequence135975-91820REGN 11918GFTFNNYG (SEQ ID NO: 717)HCDR2 DNA SequenceATTAGTGGTAGTGGTGGTACCACA (SEQ ID NO: 718)HCDR2 Amino Acid SequenceISGSGGTT (SEQ ID NO: 719)HCDR3 DNA SequenceGGCAAAGGAGGATATTGTAGTAGTAGCGGCTGCCGTCACTACGGTATGGACGTC (SEQ IDNO: 720)HCDR3 Amino Acid SequenceGKGGYCSSSGCRHYGMDV (SEQ ID NO: 721)LCVR DNA SequenceCAGTCTGTGCTGACTCAGCCACCCTCAGCGTCTGGGACCCCCGGGCAGAGGGTCACCATCTCTTGTTCTGGAAGCAGCTCCAACATCGGAAATAATTATATATACTGGTACCAGCGGCTCCCAGGAACGACCCCCAAACTCCTCATCTATAGGAATAATCAGCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCAGTGGGCTCCGGTCCGAGGATGAGGCTGATTATTACTGTGCAGCATGGGATGACACCCTGAGTGGGTATGTCTTCGGAACTGGGACCAAGGTCACCGTCCTA (SEQ ID NO: 722)LCVR Amino Acid SequenceQSVLTQPPSASGTPGQRVTISCSGSSSNIGNNYIYWYQRLPGTTPKLLIYRNNQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCAAWDDTLSGYVFGTGTKVTVL (SEQ ID NO: 723)LCDR1 DNA SequenceAGCTCCAACATCGGAAATAATTAT (SEQ ID NO: 724)LCDR1 Amino Acid SequenceSSNIGNNY (SEQ ID NO: 725)LCDR2 DNA SequenceAGGAATAATLCDR2 Amino Acid SequenceRNNLCDR3 DNA SequenceGCAGCATGGGATGACACCCTGAGTGGGTATGTC (SEQ ID NO: 728)LCDR3 Amino Acid SequenceAAWDDTLSGYV (SEQ ID NO: 729)HC DNA SequenceGAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCGGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAACAACTATGGCATGAGCTGGGTCCGCCAGGGTCCAGGGAAGGGGCTGGAGTGGGTCTCATCTATTAGTGGTAGTGGTGGTACCACATTCTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGGCAAAGGAGGATATTGTAGTAGTAGCGGCTGCCGTCACTACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGCCAAAACAACAGCCCCATCGGTCTATCCACTGGCCCCTGTGTGTGGAGATACAACTGGCTCCTCGGTGACTCTAGGATGCCTGGTCAAGGGTTATTTCCCTGAGCCAGTGACCTTGACCTGGAACTCTGGATCCCTGTCCAGTGGTGTGCACACCTTCCC135975-91820REGN 11918AGCTGTCCTGCAGTCTGACCTCTACACCCTCAGCAGCTCAGTGACTGTAACCTCGAGCAC CTGGCCCAGCCAGTCCATCACCTGCAATGTGGCCCACCCGGCAAGCAGCACCAAGGTGG ACAAGAAAATTGAGCCCAGAGGGCCCACAATCAAGCCCTGTCCTCCATGCAAATGCCCA GCACCTAACCTCTTGGGTGGACCATCCGTCTTCATCTTCCCTCCAAAGATCAAGGATGTA CTCATGATCTCCCTGAGCCCCATAGTCACATGTGTGGTGGTGGATGTGAGCGAGGATGAC CCAGATGTCCAGATCAGCTGGTTTGTGAACAACGTGGAAGTACACACAGCTCAGACACA AACCCATAGAGAGGATTACAACAGTACTCTCCGGGTGGTCAGTGCCCTCCCCATCCAGCACCAGGACTGGATGAGTGGCAAGGAGTTCAAATGCAAGGTCAACAACAAAGACCTCCCAG CGCCCATCGAGAGAACCATCTCAAAACCCAAAGGGTCAGTAAGAGCTCCACAGGTATAT GTCTTGCCTCCACCAGAAGAAGAGATGACTAAGAAACAGGTCACTCTGACCTGCATGGTCACAGACTTCATGCCTGAAGACATTTACGTGGAGTGGACCAACAACGGGAAAACAGAGC TAAACTACAAGAACACTGAACCAGTCCTGGACTCTGATGGTTCTTACTTCATGTACAGCA AGCTGAGAGTGGAAAAGAAGAACTGGGTGGAAAGAAATAGCTACTCCTGTTCAGTGGTCCACGAGGGTCTGCACAATCACCACACGACTAAGAGCTTCTCCCGGACTCCGGGTAAATG A (SEQ ID NO: 730)HC Amino Acid SequenceEVQLLESGGGLVQPGGSLRLSCAASGFTFNNYGMSWVRQGPGKGLEWVSSISGSGGTTFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCGKGGYCSSSGCRHYGMDVWGQGTTVTVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLT CMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCS VVHEGLHNHHTTKSFSRTPGK (SEQ ID NO: 731)LC DNA SequenceCAGTCTGTGCTGACTCAGCCACCCTCAGCGTCTGGGACCCCCGGGCAGAGGGTCACCATC TCTTGTTCTGGAAGCAGCTCCAACATCGGAAATAATTATATATACTGGTACCAGCGGCTC CCAGGAACGACCCCCAAACTCCTCATCTATAGGAATAATCAGCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCAGTGGGCTCCGG TCCGAGGATGAGGCTGATTATTACTGTGCAGCATGGGATGACACCCTGAGTGGGTATGTC TTCGGAACTGGGACCAAGGTCACCGTCCTACGAGCTGATGCTGCACCAACTGTATCCATCTTCCCACCATCCAGTGAGCAGTTAACATCTGGAGGTGCCTCAGTCGTGTGCTTCTTGAAC AACTTCTACCCCAAAGACATCAATGTCAAGTGGAAGATTGATGGCAGTGAACGACAAAA TGGCGTCCTGAACAGTTGGACTGATCAGGACAGCAAAGACAGCACCTACAGCATGAGCAGCACCCTCACGTTGACCAAGGACGAGTATGAACGACATAACAGCTATACCTGTGAGGCC ACTCACAAGACATCAACTTCACCCATTGTCAAGAGCTTCAACAGGGGAGAGTGTTGA (SEQ ID NO: 732)LC Amino Acid SequenceQSVLTQPPSASGTPGQRVTISCSGSSSNIGNNYIYWYQRLPGTTPKLLIYRNNQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCAAWDDTLSGYVFGTGTKVTVLRADAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDE YERHNSYTCEATHKTSTSPIVKSFNRGEC (SEQ ID NO: 733)REGN10713HCVR DNA SequenceGAGGTGCAGCTGGTGGAGTCTGGGGGAAACTTGGTACAGCCTGGGGGGTCCCTGAGACT CTCCTGTGCAGCCTCTGGATTCACCTTTACCAGCCATGCCATGAACTGGGTCCGCCAGGC TCCAGGGAAGGGGCTGGAGTGGGTCTCAGTTATTACTGGTAGAGGTTTTGACACACACTACGCTGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACATTTCCAAAAACACGCTGTA TCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTTTATTACTGTGCGAAAGGTC TCTATGATTCGGGGAATTATTATATCGATTACTGGGGCCAGGGAACCCTGGTCACCGTCT135975-91820REGN 11918CCTCA (SEQ ID NO: 734)HCVR Amino Acid SequenceEVQLVESGGNLVQPGGSLRLSCAASGFTFTSHAMNWVRQAPGKGLEWVSVITGRGFDTHYADSVKGRFTISRDISKNTLYLQMNSLRAEDTAVYYCAKGLYDSGNYYIDYWGQGTLVTVSS (SEQ ID NO: 735)HCDR1 DNA SequenceGGATTCACCTTTACCAGCCATGCC (SEQ ID NO: 736)HCDR1 Amino Acid SequenceGFTFTSHA (SEQ ID NO: 737)HCDR2 DNA SequenceATTACTGGTAGAGGTTTTGACACA (SEQ ID NO: 738)HCDR2 Amino Acid SequenceITGRGFDT (SEQ ID NO: 739)HCDR3 DNA SequenceGCGAAAGGTCTCTATGATTCGGGGAATTATTATATCGATTAC (SEQ ID NO: 740)HCDR3 Amino Acid SequenceAKGLYDSGNYYIDY (SEQ ID NO: 741)LCVR DNA SequenceCAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGACAGAAGGTCACCATCTCCTGCTCTGGAAGCAGCTCCAACATTGGGAATAATTATGTTTCCTGGTACCAGCAGCTCCCAGGAACAGCCCCCAAACTCCTCATTTATGACAATAATAAGCGACCCTCAGGGATTCCT GACCGATTCTCTGGCTCCAAGTCTGGCACGTCAGCCACCCTGGGCATCACCGGACTCCAG ACTGGGGACGAGGCCGATTATTACTGCGGAACATGGGATCTCAGCCTGAGTTTCAATTGGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTA (SEQ ID NO: 742)LCVR Amino Acid SequenceQSVLTQPPSVSAAPGQKVTISCSGSSSNIGNNYVSWYQQLPGTAPKLLIYDNNKRPSGIPDRFSGSKSGTSATLGITGLQTGDEADYYCGTWDLSLSFNWVFGGGTKLTVL (SEQ ID NO: 743)LCDR1 DNA SequenceAGCTCCAACATTGGGAATAATTAT (SEQ ID NO: 744)LCDR1 Amino Acid SequenceSSNIGNNY (SEQ ID NO: 745)LCDR2 DNA SequenceGACAATAATLCDR2 Amino Acid SequenceDNNLCDR3 DNA SequenceGGAACATGGGATCTCAGCCTGAGTTTCAATTGGGTG (SEQ ID NO: 748)LCDR3 Amino Acid SequenceGTWDLSLSFNWV (SEQ ID NO: 749)135975-91820REGN 11918HC DNA SequenceGAGGTGCAGCTGGTGGAGTCTGGGGGAAACTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTACCAGCCATGCCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGTTATTACTGGTAGAGGTTTTGACACACACTACGCTGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACATTTCCAAAAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTTTATTACTGTGCGAAAGGTCTCTATGATTCGGGGAATTATTATATCGATTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCCCTGTCTCTGGGTAAATGA (SEQ ID NO: 750)HC Amino Acid SequenceEVQLVESGGNLVQPGGSLRLSCAASGFTFTSHAMNWVRQAPGKGLEWVSVITGRGFDTHYADSVKGRFTISRDISKNTLYLQMNSLRAEDTAVYYCAKGLYDSGNYYIDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK* (SEQ ID NO: 751)LC DNA SequenceCAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGACAGAAGGTCACCATCTCCTGCTCTGGAAGCAGCTCCAACATTGGGAATAATTATGTTTCCTGGTACCAGCAGCTCCCAGGAACAGCCCCCAAACTCCTCATTTATGACAATAATAAGCGACCCTCAGGGATTCCTGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAGCCACCCTGGGCATCACCGGACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGAACATGGGATCTCAGCCTGAGTTTCAATTGGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTAGGCCAGCCCAAGGCCGCCCCCTCCGTGACCCTGTTCCCCCCCTCCTCCGAGGAGCTGCAGGCCAACAAGGCCACCCTGGTGTGCCTGATCTCCGACTTCTACCCCGGCGCCGTGACCGTGGCCTGGAAGGCCGACTCCTCCCCCGTGAAGGCCGGCGTGGAGACCACCACCCCCTCCAAGCAGTCCAACAACAAGTACGCCGCCTCCTCCTACCTGTCCCTGACCCCCGAGCAGTGGAAGTCCCACCGGTCCTACTCCTGCCAGGTGACCCACGAGGGCTCCACCGTGGAGAAGACCGTGGCCCCCACCGAGTGCTCCTGA (SEQID NO: 752)LC Amino Acid SequenceQSVLTQPPSVSAAPGQKVTISCSGSSSNIGNNYVSWYQQLPGTAPKLLIYDNNKRPSGIPDRFSGSKSGTSATLGITGLQTGDEADYYCGTWDLSLSFNWVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS* (SEQ ID NO: 753)135975-91820REGN 11918REGN10715HCVR DNA SequenceCAGGTGCAGCTACAGCAGTGGGGCGCAGGACTGTTGAAGCCTTCGGCGACCCTGTCCCGCACCTGCGCTGTCTATGGTGGGTCCTTCAGTGGTTACTACTGGAACTGGATCCGCCAGTCCCCAGGGAAGGGGCTGGAATGGATTGGGGAAATCCTTCATAGTGGAAGAACCAACTACA ACCCGTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGTCCAAGAACCAGTTCTCCC TGAAGCTGACCTCTGTGACCGCCGCGGACACGGCTGTATATTACTGTGCGGGAAGGATAGCAGCTCGTCACGGCTGGTTCGACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA (SEQ ID NO: 754)HCVR Amino Acid SequenceQVQLQQWGAGLLKPSATLSRTCAVYGGSFSGYYWNWIRQSPGKGLEWIGEILHSGRTNYNP SLKSRVTISVDTSKNQFSLKLTSVTAADTAVYYCAGRIAARHGWFDPWGQGTLVTVSS (SEQ ID NO: 755)HCDR1 DNA SequenceGGTGGGTCCTTCAGTGGTTACTAC (SEQ ID NO: 756)HCDR1 Amino Acid SequenceGGSFSGYY (SEQ ID NO: 757)HCDR2 DNA SequenceATCCTTCATAGTGGAAGAACC (SEQ ID NO: 758)HCDR2 Amino Acid SequenceILHSGRT (SEQ ID NO: 759)HCDR3 DNA SequenceGCGGGAAGGATAGCAGCTCGTCACGGCTGGTTCGACCCC (SEQ ID NO: 760)HCDR3 Amino Acid SequenceAGRIAARHGWFDP (SEQ ID NO: 761)LCVR DNA SequenceGACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTACATCTGTAGGAGACAGAGTCACCATCTCTTGTCGGGCGAGTCAGGATATTCGCAAGTGGTTAGCCTGGTATCAACAGAAACCA GGAAAAGCCCCTAAACTCCTGATCTATGCTACATCCAGTTTGCAAAGTGGGGTCCCTTCA AGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCT GAGGATTTTGCAACTTACTTTTGTCAACAGGCTAACAGTTTCCCGTTCACTTTTGGCCAGG GGACCAAGCTGGAGATCAAA (SEQ ID NO: 762)LCVR Amino Acid SequenceDIQMTQSPSSVSTSVGDRVTISCRASQDIRKWLAWYQQKPGKAPKLLIYATSSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQANSFPFTFGQGTKLEIK (SEQ ID NO: 763)LCDR1 DNA SequenceCAGGATATTCGCAAGTGG (SEQ ID NO: 764)LCDR1 Amino Acid SequenceQDIRKW (SEQ ID NO: 765)LCDR2 DNA SequenceGCTACATCC135975-91820REGN 11918LCDR2 Amino Acid SequenceATSLCDR3 DNA SequenceCAACAGGCTAACAGTTTCCCGTTCACT (SEQ ID NO: 768)LCDR3 Amino Acid SequenceQQANSFPFT (SEQ ID NO: 769)HC DNA SequenceCAGGTGCAGCTACAGCAGTGGGGCGCAGGACTGTTGAAGCCTTCGGCGACCCTGTCCCG CACCTGCGCTGTCTATGGTGGGTCCTTCAGTGGTTACTACTGGAACTGGATCCGCCAGTCCCCAGGGAAGGGGCTGGAATGGATTGGGGAAATCCTTCATAGTGGAAGAACCAACTACA ACCCGTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGTCCAAGAACCAGTTCTCCC TGAAGCTGACCTCTGTGACCGCCGCGGACACGGCTGTATATTACTGTGCGGGAAGGATAGCAGCTCGTCACGGCTGGTTCGACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA GCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAG AGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTC AGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAG TCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCCTGGGGGGACCATCA GTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGT GGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGA GTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAG ATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCC GTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTAC ACACAGAAGTCCCTCTCCCTGTCTCTGGGTAAATGA (SEQ ID NO: 770)HC Amino Acid SequenceQVQLQQWGAGLLKPSATLSRTCAVYGGSFSGYYWNWIRQSPGKGLEWIGEILHSGRTNYNPSLKSRVTISVDTSKNQFSLKLTSVTAADTAVYYCAGRIAARHGWFDPWGQGTLVTVSSASTK GPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS VVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQ DWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNH YTQKSLSLSLGK* (SEQ ID NO: 771)LC DNA SequenceGACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTACATCTGTAGGAGACAGAGTCACC ATCTCTTGTCGGGCGAGTCAGGATATTCGCAAGTGGTTAGCCTGGTATCAACAGAAACCA GGAAAAGCCCCTAAACTCCTGATCTATGCTACATCCAGTTTGCAAAGTGGGGTCCCTTCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCT GAGGATTTTGCAACTTACTTTTGTCAACAGGCTAACAGTTTCCCGTTCACTTTTGGCCAGG GGACCAAGCTGGAGATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCAT CTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATC CCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGAC GCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGG135975-91820REGN 11918GCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG (SEQ ID NO: 772)LC Amino Acid SequenceDIQMTQSPSSVSTSVGDRVTISCRASQDIRKWLAWYQQKPGKAPKLLIYATSSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQANSFPFTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKH KVYACEVTHQGESSPVTKSFNRGEC* (SEQ ID NO: 773)REGN10716HCVR DNA SequenceCAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCCCT CACCTGCACTGTCTCTGGTGACTCCATCAATAATTACTACTGGACCTGGCTCCGGCAGCC CCCAGGGAAGGGACTGGAGTGGATTGGTTATATCTATTACAGTGGGAGCGCCAACTACA ACCCCTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGTCCAAGAACCAGTTCTCCCTGAAGCTAAATTCTGTGACCGCTGCGGACACGGCCGTGTATTACTGTGCGAGAGGGGCG GTCAAGTACTTCCGGCATTGGGGCCAGGGCACCCTGGTCACCGTCTCCTCA (SEQ ID NO: 774)HCVR Amino Acid SequenceQVQLQESGPGLVKPSETLSLTCTVSGDSINNYYWTWLRQPPGKGLEWIGYIYYSGSANYNPS LKSRVTISVDTSKNQFSLKLNSVTAADTAVYYCARGAVKYFRHWGQGTLVTVSS (SEQ ID NO: 775)HCDR1 DNA SequenceGGTGACTCCATCAATAATTACTAC (SEQ ID NO: 776)HCDR1 Amino Acid SequenceGDSINNYY (SEQ ID NO: 777)HCDR2 DNA SequenceATCTATTACAGTGGGAGCGCC (SEQ ID NO: 778)HCDR2 Amino Acid SequenceIYYSGSA (SEQ ID NO: 779)HCDR3 DNA SequenceGCGAGAGGGGCGGTCAAGTACTTCCGGCAT (SEQ ID NO: 780)HCDR3 Amino Acid SequenceARGAVKYFRH (SEQ ID NO: 781)LCVR DNA SequenceGAAATTGTGTTGACGCAGTCTCCGGGCACCCTCTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGACTATTAACCACAACAACTTAGCCTGGTACCAGCAGAGACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAACAGGGCCACTGCCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGG AGCCTGAAGATTTTGAAGTGTATTCTTGTCAGCAGTATGGTAGCTTGCCGCTCACTTTCG GCGGAGGGACCAAGGTGGAGATCAAA (SEQ ID NO: 782)LCVR Amino Acid SequenceEIVLTQSPGTLSLSPGERATLSCRASQTINHNNLAWYQQRPGQAPRLLIYGASNRATAIPDRFSGSGSGTDFTLTISRLEPEDFEVYSCQQYGSLPLTFGGGTKVEIK (SEQ ID NO: 783)LCDR1 DNA Sequence135975-91820REGN 11918CAGACTATTAACCACAACAAC (SEQ ID NO: 784)LCDR1 Amino Acid SequenceQTINHNN (SEQ ID NO: 785)LCDR2 DNA SequenceGGTGCATCCLCDR2 Amino Acid SequenceGASLCDR3 DNA SequenceCAGCAGTATGGTAGCTTGCCGCTCACT (SEQ ID NO: 788)LCDR3 Amino Acid SequenceQQYGSLPLT (SEQ ID NO: 789)HC DNA SequenceCAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCCCT CACCTGCACTGTCTCTGGTGACTCCATCAATAATTACTACTGGACCTGGCTCCGGCAGCC CCCAGGGAAGGGACTGGAGTGGATTGGTTATATCTATTACAGTGGGAGCGCCAACTACA ACCCCTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGTCCAAGAACCAGTTCTCCCTGAAGCTAAATTCTGTGACCGCTGCGGACACGGCCGTGTATTACTGTGCGAGAGGGGCG GTCAAGTACTTCCGGCATTGGGGCCAGGGCACCCTGGTCACCGTCTCCTCAGCCTCCACC AAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCC GCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTAC TCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGC AACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGG TCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGT GGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGG AGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTG GTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGC AGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAAC CAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGA CGGCTCCTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGA ATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCC TCTCCCTGTCTCTGGGTAAATGA (SEQ ID NO: 790)HC Amino Acid SequenceQVQLQESGPGLVKPSETLSLTCTVSGDSINNYYWTWLRQPPGKGLEWIGYIYYSGSANYNPSLKSRVTISVDTSKNQFSLKLNSVTAADTAVYYCARGAVKYFRHWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT VPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMIS RTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWL NGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQ KSLSLSLGK* (SEQ ID NO: 791)LC DNA SequenceGAAATTGTGTTGACGCAGTCTCCGGGCACCCTCTCTTTGTCTCCAGGGGAAAGAGCCACC CTCTCCTGCAGGGCCAGTCAGACTATTAACCACAACAACTTAGCCTGGTACCAGCAGAG135975-91820REGN 11918ACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAACAGGGCCACTGCCATCCC AGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGG AGCCTGAAGATTTTGAAGTGTATTCTTGTCAGCAGTATGGTAGCTTGCCGCTCACTTTCG GCGGAGGGACCAAGGTGGAGATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCC CGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACT TCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCAC CCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCC ATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG (SEQ IDNO: 792)LC Amino Acid SequenceEIVLTQSPGTLSLSPGERATLSCRASQTINHNNLAWYQQRPGQAPRLLIYGASNRATAIPDRFSGSGSGTDFTLTISRLEPEDFEVYSCQQYGSLPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKH KVYACEVTHQGLSSPVTKSFNRGEC* (SEQ ID NO: 793)REGN10717HCVR DNA SequenceCAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACT CTCCTGTGCAGCGTCTGGATTCACCTTCAGTACATATGGCATGCACTGGGTCCGCCAGGC TCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATTTGGCATGATGGAAGTGATAAATATT ATGTAGACTCCGTGAAGGGCCGATTCTCCATCGCCAGAGACAATTCCAAGAACACGCTTT ATCTGCAAATGAATAGTCTGAGAGTCGAGGACACGGGTATATATTACTGTGCGAGAAGG GGTATACGTGGAACCGTTTTTGACCACTGGGGCCTGGGAACCCTGGTCACCGTCTCCTCA (SEQ ID NO: 794)HCVR Amino Acid SequenceQVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWHDGSDKYYVDSVKGRFSIARDNSKNTLYLQMNSLRVEDTGIYYCARRGIRGTVFDHWGLGTLVTVSS (SEQ ID NO: 795)HCDR1 DNA SequenceGGATTCACCTTCAGTACATATGGC (SEQ ID NO: 796)HCDR1 Amino Acid SequenceGFTFSTYG (SEQ ID NO: 797)HCDR2 DNA SequenceATTTGGCATGATGGAAGTGATAAA (SEQ ID NO: 798)HCDR2 Amino Acid SequenceIWHDGSDK (SEQ ID NO: 799)HCDR3 DNA SequenceGCGAGAAGGGGTATACGTGGAACCGTTTTTGACCAC (SEQ ID NO: 800)HCDR3 Amino Acid SequenceARRGIRGTVFDH (SEQ ID NO: 801)LCVR DNA SequenceGACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACC CTCACTTGTCGGGCCAGTCAGAGTATTAGTAACAAGTTGGCCTGGTATCAGCAGAAACCA GGGAAAGCCCCTAACCTCCTGATCTATAAGGCGTCTAATTTAGAAAGTGGGGTCCCATCA135975-91820REGN 11918AGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCT GATGATTTTGCAACTTATTACTGCCAACAGTATAATAGTTATTCGTGGACGTTCGGCCAA GGGACCAAGGTGGAAATCAAA (SEQ ID NO: 802)LCVR Amino Acid SequenceDIQMTQSPSTLSASVGDRVTLTCRASQSISNKLAWYQQKPGKAPNLLIYKASNLESGVPSRFS GSGSGTEFTLTISSLQPDDFATYYCQQYNSYSWTFGQGTKVEIK (SEQ ID NO: 803)LCDR1 DNA SequenceCAGAGTATTAGTAACAAG (SEQ ID NO: 804)LCDR1 Amino Acid SequenceQSISNK (SEQ ID NO: 805)LCDR2 DNA SequenceAAGGCGTCTLCDR2 Amino Acid SequenceKASLCDR3 DNA SequenceCAACAGTATAATAGTTATTCGTGGACG (SEQ ID NO: 808)LCDR3 Amino Acid SequenceQQYNSYSWT (SEQ ID NO: 809)LC Constant Light (CL) Domain DNA SequenceCGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCT GGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAG TGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACG AGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACA AAGAGCTTCAACAGGGGAGAGTGTTAG (SEQ ID NO: 1170)LC Constant Light (CL) Domain Amino Acid SequenceRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1147)HC DNA SequenceCAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACT CTCCTGTGCAGCGTCTGGATTCACCTTCAGTACATATGGCATGCACTGGGTCCGCCAGGC TCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATTTGGCATGATGGAAGTGATAAATATTATGTAGACTCCGTGAAGGGCCGATTCTCCATCGCCAGAGACAATTCCAAGAACACGCTTT ATCTGCAAATGAATAGTCTGAGAGTCGAGGACACGGGTATATATTACTGTGCGAGAAGG GGTATACGTGGAACCGTTTTTGACCACTGGGGCCTGGGAACCCTGGTCACCGTCTCCTCA GCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAG AGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTC GTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTC AGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGA CCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCCTGGGGGGACCATCA GTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTC ACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGC ACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGA135975-91820REGN 11918GTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCA AAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAG ATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACAT CGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGG TGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTAC ACACAGAAGTCCCTCTCCCTGTCTCTGGGTAAATGA (SEQ ID NO: 810), orCAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACT CTCCTGTGCAGCGTCTGGATTCACCTTCAGTACATATGGCATGCACTGGGTCCGCCAGGC TCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATTTGGCATGATGGAAGTGATAAATATT ATGTAGACTCCGTGAAGGGCCGATTCTCCATCGCCAGAGACAATTCCAAGAACACGCTTTATCTGCAAATGAATAGTCTGAGAGTCGAGGACACGGGTATATATTACTGTGCGAGAAGG GGTATACGTGGAACCGTTTTTGACCACTGGGGCCTGGGAACCCTGGTCACCGTCTCCTCA GCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGG GGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTC AGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGAC CTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGC CCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCC CTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAAC TGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGT ACGGCAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACC ATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCG GGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCA GCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAA GAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACA ACCACTACACGCAGAAGTCCCTCTCCCTGTCTCCGGGTAAA (SEQ ID NO: 1172)HC Amino Acid SequenceQVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWHDGSDKYYVDSVKGRFSIARDNSKNTLYLQMNSLRVEDTGIYYCARRGIRGTVFDHWGLGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS SVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHN HYTQKSESESEGK* (SEQ ID NO: 811),OrQVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWHDGSDKYYVDSVKGRFSIARDNSKNTLYLQMNSLRVEDTGIYYCARRGIRGTVFDHWGLGTLVTVSSAST KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS SVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKP KDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL HNHYTQKSESESPGK (SEQ ID NO: 1173)135975-91820REGN 11918LC DNA SequenceGACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACC CTCACTTGTCGGGCCAGTCAGAGTATTAGTAACAAGTTGGCCTGGTATCAGCAGAAACCA GGGAAAGCCCCTAACCTCCTGATCTATAAGGCGTCTAATTTAGAAAGTGGGGTCCCATCA AGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCT GATGATTTTGCAACTTATTACTGCCAACAGTATAATAGTTATTCGTGGACGTTCGGCCAA GGGACCAAGGTGGAAATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATC CCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAG GAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGAC GCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGG GCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG (SEQ ID NO: 812)LC Amino Acid SequenceDIQMTQSPSTLSASVGDRVTLTCRASQSISNKLAWYQQKPGKAPNLLIYKASNLESGVPSRFS GSGSGTEFTLTISSLQPDDFATYYCQQYNSYSWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKS GTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK HKVYACEVTHQGLSSPVTKSFNRGEC* (SEQ ID NO: 813)REGN10783HCVR DNA SequenceCAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGACGTCCCTGAGACT CTCCTGTGCAGCGTCAGGATTCACCTTCAGTAGCTATGGCATGCACTGGGTCCGCCAGGC TCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATGGATTGATGGAAGTAATAAATATT ATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTG TATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAAG GGGGGGTATAGTAGTAGCTGCCCCCTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA (SEQ ID NO: 814)HCVR Amino Acid SequenceQVQLVESGGGVVQPGTSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWIDGSNKYY ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRGGIVVAAPFDYWGQGTLVTVSS (SEQ ID NO: 815)HCDR1 DNA SequenceGGATTCACCTTCAGTAGCTATGGC (SEQ ID NO: 816)HCDR1 Amino Acid SequenceGFTFSSYG (SEQ ID NO: 817)HCDR2 DNA SequenceATATGGATTGATGGAAGTAATAAA (SEQ ID NO: 818)HCDR2 Amino Acid SequenceIWIDGSNK (SEQ ID NO: 819)HCDR3 DNA SequenceGCGAGAAGGGGGGGTATAGTAGTAGCTGCCCCCTTTGACTAC (SEQ ID NO: 820)HCDR3 Amino Acid SequenceARRGGIVVAAPFDY (SEQ ID NO: 821)LCVR DNA SequenceGACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACC135975-91820REGN 11918ATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCACCTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 822)LCVR Amino Acid SequenceDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 823)LCDR1 DNA SequenceCAGAGCATTAGCAGCTAT (SEQ ID NO: 824)LCDR1 Amino Acid SequenceQSISSY (SEQ ID NO: 825)LCDR2 DNA SequenceGCTGCATCCLCDR2 Amino Acid SequenceAAS (LCDR3 DNA SequenceCAACAGAGTTACAGTACCCCTCCGATCACC (SEQ ID NO: 828)LCDR3 Amino Acid SequenceQQSYSTPPIT (SEQ ID NO: 829)HC DNA SequenceCAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGACGTCCCTGAGACTCTCCTGTGCAGCGTCAGGATTCACCTTCAGTAGCTATGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATGGATTGATGGAAGTAATAAATATTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAAGGGGGGGTATAGTAGTAGCTGCCCCCTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCCCTGTCTCTGGGTAAATGA (SEQ ID NO: 830)HC Amino Acid SequenceQVQLVESGGGVVQPGTSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWIDGSNKYY135975-91820REGN 11918ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRGGIVVAAPFDYWGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY SLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKP KDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEAL HNHYTQKSLSLSLGK* (SEQ ID NO: 831)LC DNA SequenceGACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCGTC AAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACC TGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCACCTTCGG CCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTT CTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACT CCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCAC CCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG (SEQ ID NO: 832)LC Amino Acid SequenceDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGT ASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK VYACEVTHQGLSSPVTKSFNRGEC* (SEQ ID NO: 833)REGN7854HCVR DNA SequenceCAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGT CTCCTGCAAGGCTTCTGGTTACGCCTTCACCACCTATGGTATCACCTGGGTGCGACAGGC CCCTGGACAAGGACTTGAGTGGATGGGATGGATCAGCGCTTACAATGGAAATACAAACT ATGCAGAGAAGGTCCAGGGCAGATTCACCATGACCACAGACACATCCACGAATACAGCCTACATGGAGCTGAGGAGCCTGAGATCCGACGACACGGCCGTGTATTTCTGTGCGAGAAA GGGTCACTATGGTTCGGGGACTTATTATAACCCCTTTGGTTTTGATTTTTGGGGCCAAGG GACAATGGTCACCGTCTCTTCA (SEQ ID NO: 834)HCVR Amino Acid SequenceQVQLVQSGAEVKKPGASVKVSCKASGYAFTTYGITWVRQAPGQGLEWMGWISAYNGNTN YAEKVQGRFTMTTDTSTNTAYMELRSLRSDDTAVYFCARKGHYGSGTYYNPFGFDFWGQG TMVTVSS (SEQ ID NO: 835)HCDR1 DNA SequenceGGTTACGCCTTCACCACCTATGGT (SEQ ID NO: 836)HCDR1 Amino Acid SequenceGYAFTTYG (SEQ ID NO: 837)HCDR2 DNA SequenceATCAGCGCTTACAATGGAAATACA (SEQ ID NO: 838)HCDR2 Amino Acid SequenceISAYNGNT (SEQ ID NO: 839)135975-91820REGN 11918HCDR3 DNA SequenceGCGAGAAAGGGTCACTATGGTTCGGGGACTTATTATAACCCCTTTGGTTTTGATTTT (SEQID NO: 840)HCDR3 Amino Acid SequenceARKGHYGSGTYYNPFGFDF (SEQ ID NO: 841)LCVR DNA SequenceGAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAGCTACTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAGCAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGG AGCCTGAAGATTTTGCTTTGTATTTCTGTCAGCAGTATTATGGCTCACCTTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA (SEQ ID NO: 842)LCVR Amino Acid SequenceEIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFALYFCQQYYGSPWTFGQGTKVEIK (SEQ ID NO: 843)LCDR1 DNA SequenceCAGAGTGTTAGCAGCAGCTAC (SEQ ID NO: 844)LCDR1 Amino Acid SequenceQSVSSSY (SEQ ID NO: 845)LCDR2 DNA SequenceGGTGCATCCLCDR2 Amino Acid SequenceGASLCDR3 DNA SequenceCAGCAGTATTATGGCTCACCTTGGACG (SEQ ID NO: 848)LCDR3 Amino Acid SequenceQQYYGSPWT (SEQ ID NO: 849)HC DNA SequenceCAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGTTACGCCTTCACCACCTATGGTATCACCTGGGTGCGACAGGCCCCTGGACAAGGACTTGAGTGGATGGGATGGATCAGCGCTTACAATGGAAATACAAACTATGCAGAGAAGGTCCAGGGCAGATTCACCATGACCACAGACACATCCACGAATACAGCCTACATGGAGCTGAGGAGCCTGAGATCCGACGACACGGCCGTGTATTTCTGTGCGAGAAAGGGTCACTATGGTTCGGGGACTTATTATAACCCCTTTGGTTTTGATTTTTGGGGCCAAGGGACAATGGTCACCGTCTCTTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCG AGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCG CGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCA135975-91820REGN 11918GGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCT CCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACC CTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAA AGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACA ACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGC TCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCAT GAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCCCTGTCTCTGGGTAAATGA (SEQ ID NO: 850)HC Amino Acid SequenceQVQLVQSGAEVKKPGASVKVSCKASGYAFTTYGITWVRQAPGQGLEWMGWISAYNGNTN YAEKVQGRFTMTTDTSTNTAYMELRSLRSDDTAVYFCARKGHYGSGTYYNPFGFDFWGQG TMVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV LQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYR VVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQV SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSC SVMHEAEHNHYTQKSESESEGK (SEQ ID NO: 851)LC DNA SequenceGAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACC CTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAGCTACTTAGCCTGGTACCAACAGAA ACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAGCAGGGCCACTGGCATCCC AGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGG AGCCTGAAGATTTTGCTTTGTATTTCTGTCAGCAGTATTATGGCTCACCTTGGACGTTCGG CCAAGGGACCAAGGTGGAAATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCC GCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTT CTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACT CCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCAC CCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCC ATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG (SEQ IDNO: 852)LC Amino Acid SequenceEIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFS GSGSGTDFTLTISRLEPEDFALYFCQQYYGSPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKS GTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK HKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 853)REGN14570HCVR DNA SequenceCAGGTGCAGCTACAGCAGTGGGGCGCAGGACTGTTGAAGCCTTCGGCGACCCTGTCCCG CACCTGCGCTGTCTATGGTGGGTCCTTCAGTGGTTACTACTGGAACTGGATCCGCCAGTC CCCAGGGAAGGGGCTGGAATGGATTGGGGAAATCCTTCATAGTGGAAGAACCAACTACA ACCCGTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGTCCAAGAACCAGTTCTCCC TGAAGCTGACCTCTGTGACCGCCGCGGACACGGCTGTATATTACTGTGCGGGAAGGATA GCAGCTCGTCACGGCTGGTTCGACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA (SEQ ID NO: 854)HCVR Amino Acid SequenceQVQLQQWGAGLLKPSATLSRTCAVYGGSFSGYYWNWIRQSPGKGLEWIGEILHSGRTNYNP SLKSRVTISVDTSKNQFSLKLTSVTAADTAVYYCAGRIAARHGWFDPWGQGTLVTVSS (SEQ ID NO: 855)135975-91820REGN 11918HCDR1 DNA SequenceGGTGGGTCCTTCAGTGGTTACTAC (SEQ ID NO: 856)HCDR1 Amino Acid SequenceGGSFSGYY (SEQ ID NO: 857)HCDR2 DNA SequenceATCCTTCATAGTGGAAGAACC (SEQ ID NO: 858)HCDR2 Amino Acid SequenceILHSGRT (SEQ ID NO: 859)HCDR3 DNA SequenceGCGGGAAGGATAGCAGCTCGTCACGGCTGGTTCGACCCC (SEQ ID NO: 860)HCDR3 Amino Acid SequenceAGRIAARHGWFDP (SEQ ID NO: 861)LCVR DNA SequenceGACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTACATCTGTAGGAGACAGAGTCACCATCTCTTGTCGGGCGAGTCAGGATATTCGCAAGTGGTTAGCCTGGTATCAACAGAAACCAGGAAAAGCCCCTAAACTCCTGATCTATGCTACATCCAGTTTGCAAAGTGGGGTCCCTTCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAGGATTTTGCAACTTACTTTTGTCAACAGGCTAACAGTTTCCCGTTCACTTTTGGCCAGGGGACCAAGCTGGAGATCAAA (SEQ ID NO: 862)LCVR Amino Acid SequenceDIQMTQSPSSVSTSVGDRVTISCRASQDIRKWLAWYQQKPGKAPKLLIYATSSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQANSFPFTFGQGTKLEIK (SEQ ID NO: 863)LCDR1 DNA SequenceCAGGATATTCGCAAGTGG (SEQ ID NO: 864)LCDR1 Amino Acid SequenceQDIRKW (SEQ ID NO: 865)LCDR2 DNA SequenceGCTACATCCLCDR2 Amino Acid SequenceATSLCDR3 DNA SequenceCAACAGGCTAACAGTTTCCCGTTCACT (SEQ ID NO: 868)LCDR3 Amino Acid SequenceQQANSFPFT (SEQ ID NO: 869)HC DNA SequenceCAGGTGCAGCTACAGCAGTGGGGCGCAGGACTGTTGAAGCCTTCGGCGACCCTGTCCCGCACCTGCGCTGTCTATGGTGGGTCCTTCAGTGGTTACTACTGGAACTGGATCCGCCAGTCCCCAGGGAAGGGGCTGGAATGGATTGGGGAAATCCTTCATAGTGGAAGAACCAACTACAACCCGTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGTCCAAGAACCAGTTCTCCCTGAAGCTGACCTCTGTGACCGCCGCGGACACGGCTGTATATTACTGTGCGGGAAGGATAGCAGCTCGTCACGGCTGGTTCGACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA135975-91820REGN 11918GCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGG GGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTC GTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTC AGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGAC CTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGC CCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGG GACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCC CTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAAC TGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGT ACCAAAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATG GCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACC ATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCG GGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCA GCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCAC GCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAA GAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGTCCCTCTCCCTGTCTCCGGGTAAATGA (SEQ ID NO: 870)HC Amino Acid Sequence (N297Q is indicated in bold)QVQLQQWGAGLLKPSATLSRTCAVYGGSFSGYYWNWIRQSPGKGLEWIGEILHSGRTNYNP SLKSRVTISVDTSKNQFSLKLTSVTAADTAVYYCAGRIAARHGWFDPWGQGTLVTVSSASTK GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS VVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKP KDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYQSTYRVVSVLTV LHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL HNHYTQKSLSLSPGK (SEQ ID NO: 871)LC DNA SequenceGACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTACATCTGTAGGAGACAGAGTCACC ATCTCTTGTCGGGCGAGTCAGGATATTCGCAAGTGGTTAGCCTGGTATCAACAGAAACCA GGAAAAGCCCCTAAACTCCTGATCTATGCTACATCCAGTTTGCAAAGTGGGGTCCCTTCA AGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCT GAGGATTTTGCAACTTACTTTTGTCAACAGGCTAACAGTTTCCCGTTCACTTTTGGCCAGG GGACCAAGCTGGAGATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCAT CTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATC CCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAG GAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGAC GCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG (SEQ ID NO: 872)LC Amino Acid SequenceDIQMTQSPSSVSTSVGDRVTISCRASQDIRKWLAWYQQKPGKAPKLLIYATSSLQSGVPSRFS GSGSGTDFTLTISSLQPEDFATYFCQQANSFPFTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSG TASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKH KVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 873)REGN14571HCVR DNA SequenceCAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCCCT CACCTGCACTGTCTCTGGTGACTCCATCAATAATTACTACTGGACCTGGCTCCGGCAGCC CCCAGGGAAGGGACTGGAGTGGATTGGTTATATCTATTACAGTGGGAGCGCCAACTACA ACCCCTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGTCCAAGAACCAGTTCTCCC TGAAGCTAAATTCTGTGACCGCTGCGGACACGGCCGTGTATTACTGTGCGAGAGGGGCG135975-91820REGN 11918GTCAAGTACTTCCGGCATTGGGGCCAGGGCACCCTGGTCACCGTCTCCTCA (SEQ ID NO: 874)HCVR Amino Acid SequenceQVQLQESGPGLVKPSETLSLTCTVSGDSINNYYWTWLRQPPGKGLEWIGYIYYSGSANYNPS LKSRVTISVDTSKNQFSLKLNSVTAADTAVYYCARGAVKYFRHWGQGTLVTVSS (SEQ ID NO: 875)HCDR1 DNA SequenceGGTGACTCCATCAATAATTACTAC (SEQ ID NO: 876)HCDR1 Amino Acid SequenceGDSINNYY (SEQ ID NO: 877)HCDR2 DNA SequenceATCTATTACAGTGGGAGCGCC (SEQ ID NO: 878)HCDR2 Amino Acid SequenceIYYSGSA (SEQ ID NO: 879)HCDR3 DNA SequenceGCGAGAGGGGCGGTCAAGTACTTCCGGCAT (SEQ ID NO: 880)HCDR3 Amino Acid SequenceARGAVKYFRH (SEQ ID NO: 881)LCVR DNA SequenceGAAATTGTGTTGACGCAGTCTCCGGGCACCCTCTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGACTATTAACCACAACAACTTAGCCTGGTACCAGCAGAGACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAACAGGGCCACTGCCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGG AGCCTGAAGATTTTGAAGTGTATTCTTGTCAGCAGTATGGTAGCTTGCCGCTCACTTTCG GCGGAGGGACCAAGGTGGAGATCAAA (SEQ ID NO: 882)LCVR Amino Acid SequenceEIVLTQSPGTLSLSPGERATLSCRASQTINHNNLAWYQQRPGQAPRLLIYGASNRATAIPDRFSGSGSGTDFTLTISRLEPEDFEVYSCQQYGSLPLTFGGGTKVEIK (SEQ ID NO: 883)LCDR1 DNA SequenceCAGACTATTAACCACAACAAC (SEQ ID NO: 884)LCDR1 Amino Acid SequenceQTINHNN (SEQ ID NO: 885)LCDR2 DNA SequenceGGTGCATCCLCDR2 Amino Acid SequenceGASLCDR3 DNA SequenceCAGCAGTATGGTAGCTTGCCGCTCACT (SEQ ID NO: 888)LCDR3 Amino Acid SequenceQQYGSLPLT (SEQ ID NO: 889)135975-91820REGN 11918HC DNA SequenceCAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCCCT CACCTGCACTGTCTCTGGTGACTCCATCAATAATTACTACTGGACCTGGCTCCGGCAGCC CCCAGGGAAGGGACTGGAGTGGATTGGTTATATCTATTACAGTGGGAGCGCCAACTACA ACCCCTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGTCCAAGAACCAGTTCTCCC TGAAGCTAAATTCTGTGACCGCTGCGGACACGGCCGTGTATTACTGTGCGAGAGGGGCG GTCAAGTACTTCCGGCATTGGGGCCAGGGCACCCTGGTCACCGTCTCCTCAGCCTCCACC AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCG GCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCA GGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTAC TCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGC AACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTG TGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAG TCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCA CATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTG GACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACCAAAGCA CGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGT ACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCT GACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCG CCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTG CTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGG CAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACG CAGAAGTCCCTCTCCCTGTCTCCGGGTAAATGA (SEQ ID NO: 890)HC Amino Acid Sequence (N297Q is indicated in bold)QVQLQESGPGLVKPSETLSLTCTVSGDSINNYYWTWLRQPPGKGLEWIGYIYYSGSANYNPS LKSRVTISVDTSKNQFSLKLNSVTAADTAVYYCARGAVKYFRHWGQGTLVTVSSASTKGPS VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYQSTYRVVSVLTVLHQ DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPGK (SEQ ID NO: 891)LC DNA SequenceGAAATTGTGTTGACGCAGTCTCCGGGCACCCTCTCTTTGTCTCCAGGGGAAAGAGCCACC CTCTCCTGCAGGGCCAGTCAGACTATTAACCACAACAACTTAGCCTGGTACCAGCAGAG ACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAACAGGGCCACTGCCATCCC AGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGG AGCCTGAAGATTTTGAAGTGTATTCTTGTCAGCAGTATGGTAGCTTGCCGCTCACTTTCG GCGGAGGGACCAAGGTGGAGATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCC CGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACT TCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAAC TCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCAC CCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCC ATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG (SEQ ID NO: 892)LC Amino Acid SequenceEIVLTQSPGTLSLSPGERATLSCRASQTINHNNLAWYQQRPGQAPRLLIYGASNRATAIPDRFS GSGSGTDFTLTISRLEPEDFEVYSCQQYGSLPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSG TASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKH KVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 893)135975-91820REGN 11918REGN14572HCVR DNA SequenceCAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACT CTCCTGTGCAGCGTCTGGATTCACCTTCAGTACATATGGCATGCACTGGGTCCGCCAGGC TCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATTTGGCATGATGGAAGTGATAAATATT ATGTAGACTCCGTGAAGGGCCGATTCTCCATCGCCAGAGACAATTCCAAGAACACGCTTTATCTGCAAATGAATAGTCTGAGAGTCGAGGACACGGGTATATATTACTGTGCGAGAAGG GGTATACGTGGAACCGTTTTTGACCACTGGGGCCTGGGAACCCTGGTCACCGTCTCCTCA (SEQ ID NO: 894)HCVR Amino Acid SequenceQVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWHDGSDKYYVDSVKGRFSIARDNSKNTLYLQMNSLRVEDTGIYYCARRGIRGTVFDHWGLGTLVTVSS (SEQ ID NO: 895)HCDR1 DNA SequenceGGATTCACCTTCAGTACATATGGC (SEQ ID NO: 896)HCDR1 Amino Acid SequenceGFTFSTYG (SEQ ID NO: 897)HCDR2 DNA SequenceATTTGGCATGATGGAAGTGATAAA (SEQ ID NO: 898)HCDR2 Amino Acid SequenceIWHDGSDK (SEQ ID NO: 899)HCDR3 DNA SequenceGCGAGAAGGGGTATACGTGGAACCGTTTTTGACCAC (SEQ ID NO: 900)HCDR3 Amino Acid SequenceARRGIRGTVFDH (SEQ ID NO: 901)LCVR DNA SequenceGACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACC CTCACTTGTCGGGCCAGTCAGAGTATTAGTAACAAGTTGGCCTGGTATCAGCAGAAACCA GGGAAAGCCCCTAACCTCCTGATCTATAAGGCGTCTAATTTAGAAAGTGGGGTCCCATCA AGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAACAGTATAATAGTTATTCGTGGACGTTCGGCCAA GGGACCAAGGTGGAAATCAAA (SEQ ID NO: 902)LCVR Amino Acid SequenceDIQMTQSPSTLSASVGDRVTLTCRASQSISNKLAWYQQKPGKAPNLLIYKASNLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYSWTFGQGTKVEIK (SEQ ID NO: 903)LCDR1 DNA SequenceCAGAGTATTAGTAACAAG (SEQ ID NO: 904)LCDR1 Amino Acid SequenceQSISNK (SEQ ID NO: 905)LCDR2 DNA SequenceAAGGCGTCT135975-91820REGN 11918LCDR2 Amino Acid SequenceKASLCDR3 DNA SequenceCAACAGTATAATAGTTATTCGTGGACG (SEQ ID NO: 908)LCDR3 Amino Acid SequenceQQYNSYSWT (SEQ ID NO: 909)HC DNA SequenceCAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTACATATGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATTTGGCATGATGGAAGTGATAAATATTATGTAGACTCCGTGAAGGGCCGATTCTCCATCGCCAGAGACAATTCCAAGAACACGCTTTATCTGCAAATGAATAGTCTGAGAGTCGAGGACACGGGTATATATTACTGTGCGAGAAGGGGTATACGTGGAACCGTTTTTGACCACTGGGGCCTGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACCAAAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGTCCCTCTCCCTGTCTCCGGGTAAATGA (SEQ ID NO: 910)HC Amino Acid Sequence (N297Q is indicated in bold)QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWHDGSDKYYVDSVKGRFSIARDNSKNTLYLQMNSLRVEDTGIYYCARRGIRGTVFDHWGLGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYQSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 911)LC DNA SequenceGACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCCTCACTTGTCGGGCCAGTCAGAGTATTAGTAACAAGTTGGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAACCTCCTGATCTATAAGGCGTCTAATTTAGAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAACAGTATAATAGTTATTCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAG GAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGAC135975-91820REGN 11918GCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG (SEQ ID NO: 912)LC Amino Acid SequenceDIQMTQSPSTLSASVGDRVTLTCRASQSISNKLAWYQQKPGKAPNLLIYKASNLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYSWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 913)REGN14573HCVR DNA SequenceGAGGTGCAGCTGGTGGAGTCTGGGGGAAACTTGGTACAGCCTGGGGGGTCCCTGAGACT CTCCTGTGCAGCCTCTGGATTCACCTTTACCAGCCATGCCATGAACTGGGTCCGCCAGGC TCCAGGGAAGGGGCTGGAGTGGGTCTCAGTTATTACTGGTAGAGGTTTTGACACACACTACGCTGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACATTTCCAAAAACACGCTGTA TCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTTTATTACTGTGCGAAAGGTC TCTATGATTCGGGGAATTATTATATCGATTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA (SEQ ID NO: 914)HCVR Amino Acid SequenceEVQLVESGGNLVQPGGSLRLSCAASGFTFTSHAMNWVRQAPGKGLEWVSVITGRGFDTHYADSVKGRFTISRDISKNTLYLQMNSLRAEDTAVYYCAKGLYDSGNYYIDYWGQGTLVTVSS (SEQ ID NO: 915)HCDR1 DNA SequenceGGATTCACCTTTACCAGCCATGCC (SEQ ID NO: 916)HCDR1 Amino Acid SequenceGFTFTSHA (SEQ ID NO: 917)HCDR2 DNA SequenceATTACTGGTAGAGGTTTTGACACA (SEQ ID NO: 918)HCDR2 Amino Acid SequenceITGRGFDT (SEQ ID NO: 919)HCDR3 DNA SequenceGCGAAAGGTCTCTATGATTCGGGGAATTATTATATCGATTAC (SEQ ID NO: 920)HCDR3 Amino Acid SequenceAKGLYDSGNYYIDY (SEQ ID NO: 921)LCVR DNA SequenceCAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGACAGAAGGTCACCATCTCCTGCTCTGGAAGCAGCTCCAACATTGGGAATAATTATGTTTCCTGGTACCAGCAGCTCCCAGGAACAGCCCCCAAACTCCTCATTTATGACAATAATAAGCGACCCTCAGGGATTCCT GACCGATTCTCTGGCTCCAAGTCTGGCACGTCAGCCACCCTGGGCATCACCGGACTCCAG ACTGGGGACGAGGCCGATTATTACTGCGGAACATGGGATCTCAGCCTGAGTTTCAATTGGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTA (SEQ ID NO: 922)LCVR Amino Acid SequenceQSVLTQPPSVSAAPGQKVTISCSGSSSNIGNNYVSWYQQLPGTAPKLLIYDNNKRPSGIPDRFSGSKSGTSATLGITGLQTGDEADYYCGTWDLSLSFNWVFGGGTKLTVL (SEQ ID NO: 923)135975-91820REGN 11918LCDR1 DNA SequenceAGCTCCAACATTGGGAATAATTAT (SEQ ID NO: 924)LCDR1 Amino Acid SequenceSSNIGNNY (SEQ ID NO: 925)LCDR2 DNA SequenceGACAATAATLCDR2 Amino Acid SequenceDNNLCDR3 DNA SequenceGGAACATGGGATCTCAGCCTGAGTTTCAATTGGGTG (SEQ ID NO: 928)LCDR3 Amino Acid SequenceGTWDLSLSFNWV (SEQ ID NO: 929)HC DNA SequenceGAGGTGCAGCTGGTGGAGTCTGGGGGAAACTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTACCAGCCATGCCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGTTATTACTGGTAGAGGTTTTGACACACACTACGCTGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACATTTCCAAAAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTTTATTACTGTGCGAAAGGTCTCTATGATTCGGGGAATTATTATATCGATTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACCAAAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGTCCCTCTCCCTGTCTCCGGGTAAATGA (SEQ ID NO: 930)HC Amino Acid Sequence (N297Q is indicated in bold)EVQLVESGGNLVQPGGSLRLSCAASGFTFTSHAMNWVRQAPGKGLEWVSVITGRGFDTHYADSVKGRFTISRDISKNTLYLQMNSLRAEDTAVYYCAKGLYDSGNYYIDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYQSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 931)LC DNA SequenceCAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGACAGAAGGTCACCATC135975-91820REGN 11918TCCTGCTCTGGAAGCAGCTCCAACATTGGGAATAATTATGTTTCCTGGTACCAGCAGCTC CCAGGAACAGCCCCCAAACTCCTCATTTATGACAATAATAAGCGACCCTCAGGGATTCCT GACCGATTCTCTGGCTCCAAGTCTGGCACGTCAGCCACCCTGGGCATCACCGGACTCCAG ACTGGGGACGAGGCCGATTATTACTGCGGAACATGGGATCTCAGCCTGAGTTTCAATTGGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTAGGCCAGCCCAAGGCCGCCCCCTCCGTGACCCTGTTCCCCCCCTCCTCCGAGGAGCTGCAGGCCAACAAGGCCACCCTGGTGTGCCTGATCTCCGACTTCTACCCCGGCGCCGTGACCGTGGCCTGGAAGGCCGACTCCTCCCCCGT GAAGGCCGGCGTGGAGACCACCACCCCCTCCAAGCAGTCCAACAACAAGTACGCCGCCT CCTCCTACCTGTCCCTGACCCCCGAGCAGTGGAAGTCCCACCGGTCCTACTCCTGCCAGG TGACCCACGAGGGCTCCACCGTGGAGAAGACCGTGGCCCCCACCGAGTGCTCCTGA (SEQID NO: 932)LC Amino Acid SequenceQSVLTQPPSVSAAPGQKVTISCSGSSSNIGNNYVSWYQQLPGTAPKLLIYDNNKRPSGIPDRFSGSKSGTSATLGITGLQTGDEADYYCGTWDLSLSFNWVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPE QWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 933)REGN14574HCVR DNA SequenceCAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGACGTCCCTGAGACT CTCCTGTGCAGCGTCAGGATTCACCTTCAGTAGCTATGGCATGCACTGGGTCCGCCAGGC TCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATGGATTGATGGAAGTAATAAATATTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTG TATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAAG GGGGGGTATAGTAGTAGCTGCCCCCTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA (SEQ ID NO: 934)HCVR Amino Acid SequenceQVQLVESGGGVVQPGTSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWIDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRGGIVVAAPFDYWGQGTLVTVSS (SEQ ID NO: 935)HCDR1 DNA SequenceGGATTCACCTTCAGTAGCTATGGC (SEQ ID NO: 936)HCDR1 Amino Acid SequenceGFTFSSYG (SEQ ID NO: 937)HCDR2 DNA SequenceATATGGATTGATGGAAGTAATAAA (SEQ ID NO: 938)HCDR2 Amino Acid SequenceIWIDGSNK (SEQ ID NO: 939)HCDR3 DNA SequenceGCGAGAAGGGGGGGTATAGTAGTAGCTGCCCCCTTTGACTAC (SEQ ID NO: 940)HCDR3 Amino Acid SequenceARRGGIVVAAPFDY (SEQ ID NO: 941)LCVR DNA SequenceGACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACC ATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACC135975-91820REGN 11918AGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCACCTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 942)LCVR Amino Acid SequenceDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 943)LCDR1 DNA SequenceCAGAGCATTAGCAGCTAT (SEQ ID NO: 944)LCDR1 Amino Acid SequenceQSISSY (SEQ ID NO: 945)LCDR2 DNA SequenceGCTGCATCCLCDR2 Amino Acid SequenceAASLCDR3 DNA SequenceCAACAGAGTTACAGTACCCCTCCGATCACC (SEQ ID NO: 948)LCDR3 Amino Acid SequenceQQSYSTPPIT (SEQ ID NO: 949)HC DNA SequenceCAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGACGTCCCTGAGACTCTCCTGTGCAGCGTCAGGATTCACCTTCAGTAGCTATGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATGGATTGATGGAAGTAATAAATATTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAAGGGGGGGTATAGTAGTAGCTGCCCCCTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACCAAAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGTCCCTCTCCCTGTCTCCGGGTAAATGA (SEQ ID NO: 950)HC Amino Acid Sequence (N297Q is indicated in bold)QVQLVESGGGVVQPGTSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWIDGSNKYY135975-91820REGN 11918ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRGGIVVAAPFDYWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFP PKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYQSTYRVVSV LTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTC LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 951)LC DNA SequenceGACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACC ATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACC AGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCGTC AAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACC TGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCACCTTCGG CCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTT CTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACT CCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCAC CCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCC ATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG (SEQ ID NO: 952)LC Amino Acid SequenceDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGT ASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK VYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 953)REGN14647HCVR DNA SequenceCAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACT CTCCTGTACAGCGTCTGGAATCACCTTCAGAAATTATGGCATGCACTGGGTCCGCCAGGC TCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATGTGGTATGATGGAAGTAATAAGTACT ATGCAGACTCCGTGAAGGGCCGTTTCACCATCTCCGGAGACAATTCCAAGGTGTATCTGC AAATGAACAGCCTGAGAGCCGAGGACACGGCTGTATATTACTGTGCGAGAAGGGGCACT ATAAGAACAGCTGCCCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCCTCA (SEQ ID NO: 954)HCVR Amino Acid SequenceQVQLVESGGGVVQPGRSLRLSCTASGITFRNYGMHWVRQAPGKGLEWVAVMWYDGSNKY YADSVKGRFTISGDNSKVYLQMNSLRAEDTAVYYCARRGTIRTAAPFDYWGQGTLVTVSS (SEQ ID NO: 955)HCDR1 DNA SequenceGGAATCACCTTCAGAAATTATGGC (SEQ ID NO: 956)HCDR1 Amino Acid SequenceGITFRNYG (SEQ ID NO: 957)HCDR2 DNA SequenceATGTGGTATGATGGAAGTAATAAG (SEQ ID NO: 958)HCDR2 Amino Acid SequenceMWYDGSNK (SEQ ID NO: 959)135975-91820REGN 11918HCDR3 DNA SequenceGCGAGAAGGGGCACTATAAGAACAGCTGCCCCTTTTGACTAC (SEQ ID NO: 960)HCDR3 Amino Acid SequenceARRGTIRTAAPFDY (SEQ ID NO: 961)LCVR DNA SequenceGACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCACCTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 962)LCVR Amino Acid SequenceDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 963)LCDR1 DNA SequenceCAGAGCATTAGCAGCTAT (SEQ ID NO: 964)LCDR1 Amino Acid SequenceQSISSY (SEQ ID NO: 965)LCDR2 DNA SequenceGCTGCATCCLCDR2 Amino Acid SequenceAASLCDR3 DNA SequenceCAACAGAGTTACAGTACCCCTCCGATCACC (SEQ ID NO: 968)LCDR3 Amino Acid SequenceQQSYSTPPIT (SEQ ID NO: 969)HC DNA SequenceCAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTACAGCGTCTGGAATCACCTTCAGAAATTATGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATGTGGTATGATGGAAGTAATAAGTACTATGCAGACTCCGTGAAGGGCCGTTTCACCATCTCCGGAGACAATTCCAAGGTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTATATTACTGTGCGAGAAGGGGCACTATAAGAACAGCTGCCCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACCAAAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACC135975-91820REGN 11918ATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCG GGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCA GCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCAC GCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAA GAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACA ACCACTACACGCAGAAGTCCCTCTCCCTGTCTCCGGGTAAATGA (SEQ ID NO: 970)HC Amino Acid SequenceQVQLVESGGGVVQPGRSLRLSCTASGITFRNYGMHWVRQAPGKGLEWVAVMWYDGSNKY YADSVKGRFTISGDNSKVYLQMNSLRAEDTAVYYCARRGTIRTAAPFDYWGQGTLVTVSSA STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPP KPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYQSTYRVVSVL TVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 971)LC DNA SequenceGACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACC ATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACC AGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCGTC AAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACC TGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCACCTTCGG CCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCC GCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTT CTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACT CCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCAC CCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG (SEQ ID NO: 972)LC Amino Acid SequenceDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGT ASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK VYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 973)REGN10712HCVR DNA SequenceCAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACT CTCCTGTGCAGCCTCTGGATTCACATTCAGTACCTATGGCATGTACTGGGTCCGCCAGAC TCCAGGCAAGGGGCTGGAGTGGGTGACAGTTATATCATTTGATGGAAATAAAAAATACT ATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAAAACACGCTG TTTCTGCAAATGAACAGCCTGAAAACTGAGGACACGGCTGTATATTACTGTGCGAAATCT TCTAACTGGAACTACGGTTCTTTTGATATATGGGGCCAAGGGACAATGGTCACCGTCTCT TCA (SEQ ID NO: 1180)HCVR Amino Acid SequenceQVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMYWVRQTPGKGLEWVTVISFDGNKKYY ADSVKGRFTISRDNSKNTLFLQMNSLKTEDTAVYYCAKSSNWNYGSFDIWGQGTMVTVSS (SEQ ID NO: 1181)HCDR1 DNA SequenceGGATTCACATTCAGTACCTATGGC (SEQ ID NO: 1182)135975-91820REGN 11918HCDR1 Amino Acid SequenceGFTFSTYG (SEQ ID NO: 1183)HCDR2 DNA SequenceATATCATTTGATGGAAATAAAAAA (SEQ ID NO: 1184)HCDR2 Amino Acid SequenceISFDGNKK (SEQ ID NO: 1185)HCDR3 DNA SequenceGCGAAATCTTCTAACTGGAACTACGGTTCTTTTGATATA (SEQ ID NO: 1186)HCDR3 Amino Acid SequenceAKSSNWNYGSFDI (SEQ ID NO: 1187)LCVR DNA SequenceCAGTCTGTGCTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGAGGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAGGTTATGATGTACACTGGTACCAGCAGCTTCCAGGCACAGCCCCCAGACTCCTCATCTCTTATAACAGCAATCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCTGAGGATGAGGCTGACTATTACTGCCAGTCCTATGACAGAAGCCTGAGTGGTTCTGTGTTCGGAGGAGGCACCCAGCTGACCGTCCTC (SEQ ID NO: 1188)LCVR Amino Acid SequenceQSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPRLLISYNSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRSLSGSVFGGGTQLTVL (SEQ ID NO: 1189)LCDR1 DNA SequenceAGCTCCAACATCGGGGCAGGTTATGAT (SEQ ID NO: 1190)LCDR1 Amino Acid SequenceSSNIGAGYD (SEQ ID NO: 1191)LCDR2 DNA SequenceTATAACAGCLCDR2 Amino Acid SequenceYNSLCDR3 DNA SequenceCAGTCCTATGACAGAAGCCTGAGTGGTTCTGTG (SEQ ID NO: 1194)LCDR3 Amino Acid SequenceQSYDRSLSGSV (SEQ ID NO: 1195)HC DNA SequenceCAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACATTCAGTACCTATGGCATGTACTGGGTCCGCCAGACTCCAGGCAAGGGGCTGGAGTGGGTGACAGTTATATCATTTGATGGAAATAAAAAATACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAAAACACGCTGTTTCTGCAAATGAACAGCCTGAAAACTGAGGACACGGCTGTATATTACTGTGCGAAATCTTCTAACTGGAACTACGGTTCTTTTGATATATGGGGCCAAGGGACAATGGTCACCGTCTCTTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGT135975-91820REGN 11918GTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTC CTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAA GACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTG AGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCCTGGGGGGACCAT CAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGG TCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTAC GTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACA GCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAG GAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTC CAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGG AGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGAC ATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCC CGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAG GTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCCCTGTCTCTGGGTAAATGA (SEQ ID NO: 1196)HC Amino Acid SequenceQVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMYWVRQTPGKGLEWVTVISFDGNKKYY ADSVKGRFTISRDNSKNTLFLQMNSLKTEDTAVYYCAKSSNWNYGSFDIWGQGTMVTVSSA STKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS LSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPK DTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVL HQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKG FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALH NHYTQKSLSLSLGK (SEQ ID NO: 1197)HC constant, hlgG4 (S108P) DNA SequenceGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAG AGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTC GTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTC AGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGA CCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAG TCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCCTGGGGGGACCATCA GTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTC ACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGT GGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGC ACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGA GTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCA AAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAG ATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACAT CGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCC GTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGG TGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCCCTGTCTCTGGGTAAATGA (SEQ ID NO: 1198)HC constant, hlgG4 (S108P) Amino Acid SequenceASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY SLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKP KDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTV LHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEAL HNHYTQKSLSLSLGK (SEQ ID NO: 1199)LC DNA SequenceCAGTCTGTGCTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGAGGGTCACCAT135975-91820REGN 11918CTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAGGTTATGATGTACACTGGTACCAGCAGCTTCCAGGCACAGCCCCCAGACTCCTCATCTCTTATAACAGCAATCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCTGAGGATGAGGCTGACTATTACTGCCAGTCCTATGACAGAAGCCTGAGTGGTTCTGTGTTCGGAGGAGGCACCCAGCTGACCGTCCTCGGCCAGCCCAAGGCCGCCCCCTCCGTGACCCTGTTCCCCCCCTCCTCCGAGGAGCTGCAGGCCAACAAGGCCACCCTGGTGTGCCTGATCTCCGACTTCTACCCCGGCGCCGTGACCGTGGCCTGGAAGGCCGACTCCTCCCCCGTGAAGGCCGGCGTGGAGACCACCACCCCCTCCAAGCAGTCCAACAACAAGTACGCCGCCTCCTCCTACCTGTCCCTGACCCCCGAGCAGTGGAAGTCCCACCGGTCCTACTCCTGCCAGGTGACCCACGAGGGCTCCACCGTGGAGAAGACCGTGGCCCCCACCGAGTGCTCCTGA (SEQID NO: 1200)LC Amino Acid SequenceQSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPRLLISYNSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRSLSGSVFGGGTQLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 1201)LC constant, hLamda DNA SequenceGGCCAGCCCAAGGCCGCCCCCTCCGTGACCCTGTTCCCCCCCTCCTCCGAGGAGCTGCAGGCCAACAAGGCCACCCTGGTGTGCCTGATCTCCGACTTCTACCCCGGCGCCGTGACCGTGGCCTGGAAGGCCGACTCCTCCCCCGTGAAGGCCGGCGTGGAGACCACCACCCCCTCCAAGCAGTCCAACAACAAGTACGCCGCCTCCTCCTACCTGTCCCTGACCCCCGAGCAGTGGAAGTCCCACCGGTCCTACTCCTGCCAGGTGACCCACGAGGGCTCCACCGTGGAGAAGACCGTGGCCCCCACCGAGTGCTCCTGA (SEQ ID NO: 1202)LC constant, hLamda Amino Acid SequenceGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 1203)REGN9908HCVR DNA SequenceGAGGTGCAGTTGTTGGAGTCTGGGGGAGGCTTGGCACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGCAGTTATGCCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCATCTGTTAGTGGTAGTGGTGGTACCACATATTATGCAGCCTCCGTGAAGGGCCGGTTCACCGTCTCCAGAGACAATTCCAAGAAGACGCTCTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGGGAAAGGAGGATATTGTAGTAGTAGTGGTTGCCGTCACTACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCGCA (SEQ ID NO: 1204)HCVR Amino Acid SequenceEVQLLESGGGLAQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSVSGSGGTTYYAASVKGRFTVSRDNSKKTLYLQMNSLRAEDTAVYYCGKGGYCSSSGCRHYGMDVWGQGTTVTVSA (SEQ ID NO: 1205)HCDR1 DNA SequenceGGATTCACCTTTAGCAGTTATGCC (SEQ ID NO: 1206)HCDR1 Amino Acid SequenceGFTFSSYA (SEQ ID NO: 1207)HCDR2 DNA SequenceGTTAGTGGTAGTGGTGGTACCACA (SEQ ID NO: 1208)135975-91820REGN 11918HCDR2 Amino Acid SequenceVSGSGGTT (SEQ ID NO: 1209)HCDR3 DNA SequenceGGGAAAGGAGGATATTGTAGTAGTAGTGGTTGCCGTCACTACGGTATGGACGTC (SEQ IDNO: 1210)HCDR3 Amino Acid SequenceGKGGYCSSSGCRHYGMDV (SEQ ID NO: 1211)LCVR DNA SequenceCAGTCTGTGCTGACTCAGCCACCCTCAGCGTCTGGGACCCCCGGGCAGAGGGTCGCCATTTCTTGTTCTGGAAGCAACTCCAACATCGGAAATAATTACTTATACTGGTACCAGCAGATCCCAGGAACGACCCCCAAACTCCTCATCTATAGAAATAATCAGCGGCCCTCAGGGGTCCCTGACCGATTCTCTGCCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCAGTGGGCTCCGGTCCGGGGATGAGGCTGATTATTACTGTGCAGCATGGGATGACAGCCTGAGTGGGTATGTCTTCGGAACTGGGACCAAGGTCACCGTCCTA (SEQ ID NO: 1212)LCVR Amino Acid SequenceQSVLTQPPSASGTPGQRVAISCSGSNSNIGNNYLYWYQQIPGTTPKLLIYRNNQRPSGVPDRFSASKSGTSASLAISGLRSGDEADYYCAAWDDSLSGYVFGTGTKVTVL (SEQ ID NO: 1213)LCDR1 DNA SequenceAACTCCAACATCGGAAATAATTA (SEQ ID NO: 1214)LCDR1 Amino Acid SequenceNSNIGNN (SEQ ID NO: 1215)LCDR2 DNA SequenceAGAAATAATLCDR2 Amino Acid SequenceRNNLCDR3 DNA SequenceGCAGCATGGGATGACAGCCTGAGTGGGTATGTC (SEQ ID NO: 1218)LCDR3 Amino Acid SequenceAAWDDSLSGYV (SEQ ID NO: 1219)HC DNA SequenceGAGGTGCAGTTGTTGGAGTCTGGGGGAGGCTTGGCACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGCAGTTATGCCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCATCTGTTAGTGGTAGTGGTGGTACCACATATTATGCAGCCTCCGTGAAGGGCCGGTTCACCGTCTCCAGAGACAATTCCAAGAAGACGCTCTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGGGAAAGGAGGATATTGTAGTAGTAGTGGTTGCCGTCACTACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCGCAGCCAAGACAACACCTCCTTCTGTGTATCCTCTGGCTCCTGGATGTGGAGATACAACAGGATCTTCTGTGACACTGGGATGTCTGGTGAAGGGATATTTTCCTGAATCTGTGACAGTGACATGGAACTCTGGATCTCTGTCTTCTTCTGTGCATACATTTCCTGCTCTGCTGCAGTCTGGACTGTATACAATGTCTTCTTCTGTGACAGTGCCTTCTTCTACATGGCCTTCTCAGACAGTGACATGTTCTGTGGCTCATCCTGCTTCTTCTACAACAGTGGATAAGAAGCTGGAACCTTCTGGACCTATCTCTACAATCAATCCTTGTCCTCCTTGTAAGGAATGTCATAAGTGTCCTGCTCCTAATCTGGAAGGAGGACCTTCTGTGTTTATCTTTCCTCCTAATATCAAGGATGTGCTGATGATCTCTCTGACACCTAAGGTGACATGTGTGGTGGTGGATGT135975-91820REGN 11918GTCTGAAGATGATCCTGATGTGCAGATCTCTTGGTTTGTGAATAATGTGGAAGTGCATAC AGCTCAGACACAGACACATAGAGAAGATTATAATTCTACAATCAGAGTGGTGTCTACAC TGCCTATCCAGCATCAGGATTGGATGTCTGGAAAGGAATTTAAGTGTAAGGTGAATAAT AAGGATCTGCCTTCTCCTATCGAAAGAACAATCTCTAAGATCAAGGGACTGGTGAGAGC TCCTCAGGTGTATATCCTGCCTCCTCCTGCTGAACAGCTGTCCAGAAAGGATGTGTCTCT GACATGTCTGGTGGTGGGATTTAATCCTGGAGATATCTCTGTGGAATGGACATCTAATGG ACATACAGAAGAAAATTATAAGGATACAGCTCCTGTGCTGGATTCTGATGGATCTTATTT TATCTATTCTAAGCTGAATATGAAGACATCTAAGTGGGAAAAGACAGATTCTTTTTCTTGTAATGTGAGACATGAAGGACTGAAGAATTATTATCTGAAGAAGACAATCTCCAGATCTCCTGGAAAGTGA (SEQ ID NO: 1220)HC Amino Acid SequenceEVQLLESGGGLAQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSVSGSGGTTYYAASVKGRFTVSRDNSKKTLYLQMNSLRAEDTAVYYCGKGGYCSSSGCRHYGMDVWGQGTTVTVSAAKTTPPSVYPLAPGCGDTTGSSVTLGCLVKGYFPESVTVTWNSGSLSSSVHTFPALLQSGLYTMSSSVTVPSSTWPSQTVTCSVAHPASSTTVDKKLEPSGPISTINPCPPCKECHKCPAPNLEGGPSVFIFPPNIKDVLMISLTPKVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTIRVVSTLPIQHQDWMSGKEFKCKVNNKDLPSPIERTISKIKGLVRAPQVYILPPPAEQLSR KDVSLTCLVVGFNPGDISVEWTSNGHTEENYKDTAPVLDSDGSYFIYSKLNMKTSKWEKTDS FSCNVRHEGLKNYYLKKTISRSPGK (SEQ ID NO: 1221)HC constant, m!gG2b DNA SequenceGCCAAGACAACACCTCCTTCTGTGTATCCTCTGGCTCCTGGATGTGGAGATACAACAGGATCTTCTGTGACACTGGGATGTCTGGTGAAGGGATATTTTCCTGAATCTGTGACAGTGACATGGAACTCTGGATCTCTGTCTTCTTCTGTGCATACATTTCCTGCTCTGCTGCAGTCTGGACTGTATACAATGTCTTCTTCTGTGACAGTGCCTTCTTCTACATGGCCTTCTCAGACAGTGACATGTTCTGTGGCTCATCCTGCTTCTTCTACAACAGTGGATAAGAAGCTGGAACCTTCTGGACCTATCTCTACAATCAATCCTTGTCCTCCTTGTAAGGAATGTCATAAGTGTCCTGCTCCTAATCTGGAAGGAGGACCTTCTGTGTTTATCTTTCCTCCTAATATCAAGGATGTGCTGATGATCTCTCTGACACCTAAGGTGACATGTGTGGTGGTGGATGTGTCTGAAGATGATCCTGAT GTGCAGATCTCTTGGTTTGTGAATAATGTGGAAGTGCATACAGCTCAGACACAGACACAT AGAGAAGATTATAATTCTACAATCAGAGTGGTGTCTACACTGCCTATCCAGCATCAGGATTGGATGTCTGGAAAGGAATTTAAGTGTAAGGTGAATAATAAGGATCTGCCTTCTCCTATC GAAAGAACAATCTCTAAGATCAAGGGACTGGTGAGAGCTCCTCAGGTGTATATCCTGCC TCCTCCTGCTGAACAGCTGTCCAGAAAGGATGTGTCTCTGACATGTCTGGTGGTGGGATT TAATCCTGGAGATATCTCTGTGGAATGGACATCTAATGGACATACAGAAGAAAATTATA AGGATACAGCTCCTGTGCTGGATTCTGATGGATCTTATTTTATCTATTCTAAGCTGAATAT GAAGACATCTAAGTGGGAAAAGACAGATTCTTTTTCTTGTAATGTGAGACATGAAGGAC TGAAGAATTATTATCTGAAGAAGACAATCTCCAGATCTCCTGGAAAGTGA (SEQ ID NO: 1222)HC constant, m!gG2b Amino Acid SequenceAKTTPPSVYPLAPGCGDTTGSSVTLGCLVKGYFPESVTVTWNSGSLSSSVHTFPALLQSGLYTMSSSVTVPSSTWPSQTVTCSVAHPASSTTVDKKLEPSGPISTINPCPPCKECHKCPAPNLEGGPSVFIFPPNIKDVLMISLTPKVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTIRVVSTLPIQHQDWMSGKEFKCKVNNKDLPSPIERTISKIKGLVRAPQVYILPPPAEQLSRKDVSL TCLVVGFNPGDISVEWTSNGHTEENYKDTAPVLDSDGSYFIYSKLNMKTSKWEKTDSFSCNV RHEGLKNYYLKKTISRSPGK (SEQ ID NO: 1223)LC DNA SequenceCAGTCTGTGCTGACTCAGCCACCCTCAGCGTCTGGGACCCCCGGGCAGAGGGTCGCCATTTCTTGTTCTGGAAGCAACTCCAACATCGGAAATAATTACTTATACTGGTACCAGCAGATC CCAGGAACGACCCCCAAACTCCTCATCTATAGAAATAATCAGCGGCCCTCAGGGGTCCCT GACCGATTCTCTGCCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCAGTGGGCTCCGG TCCGGGGATGAGGCTGATTATTACTGTGCAGCATGGGATGACAGCCTGAGTGGGTATGTC135975-91820REGN 11918TTCGGAACTGGGACCAAGGTCACCGTCCTAGGCCAACCTAAATCATCTCCATCCGTTACT CTCTTCCCCCCATCTTCAGAAGAACTCGAAACCAATAAAGCCACACTCGTTTGCACCATT ACAGATTTCTATCCAGGAGTAGTTACAGTCGATTGGAAAGTAGACGGAACACCAGTTAC ACAGGGTATGGAAACCACACAACCATCTAAGCAGTCTAATAACAAATACATGGCCTCAT CATACCTCACTCTTACCGCCCGCGCATGGGAAAGACATTCATCATATTCTTGCCAGGTAA CCCACGAAGGACACACAGTTGAAAAATCTTTGAGTAGAGCAGATTGTAGTTGA (SEQ ID NO: 1224)LC Amino Acid SequenceQSVLTQPPSASGTPGQRVAISCSGSNSNIGNNYLYWYQQIPGTTPKLLIYRNNQRPSGVPDRFS ASKSGTSASLAISGLRSGDEADYYCAAWDDSLSGYVFGTGTKVTVLGQPKSSPSVTLFPPSSE ELETNKATLVCTITDFYPGVVTVDWKVDGTPVTQGMETTQPSKQSNNKYMASSYLTLTARA WERHSSYSCQVTHEGHTVEKSLSRADCS (SEQ ID NO: 1225)LC constant, mLambda DNA SequenceGGCCAACCTAAATCATCTCCATCCGTTACTCTCTTCCCCCCATCTTCAGAAGAACTCGAA ACCAATAAAGCCACACTCGTTTGCACCATTACAGATTTCTATCCAGGAGTAGTTACAGTC GATTGGAAAGTAGACGGAACACCAGTTACACAGGGTATGGAAACCACACAACCATCTAA GCAGTCTAATAACAAATACATGGCCTCATCATACCTCACTCTTACCGCCCGCGCATGGGA AAGACATTCATCATATTCTTGCCAGGTAACCCACGAAGGACACACAGTTGAAAAATCTTT GAGTAGAGCAGATTGTAGTTGA (SEQ ID NO: 1226)LC constant, mLambda Amino Acid SequenceGQPKSSPSVTLFPPSSEELETNKATLVCTITDFYPGVVTVDWKVDGTPVTQGMETTQPSKQSN NKYMASSYLTLTARA WERHSSYSCQVTHEGHTVEKSLSRADCS (SEQ ID NO: 1227)

[0290] According to certain example embodiments, provided herein are anti-CACNGl heterodimeric antibodies, or anti gen -binding fragments thereof, wherein an antigen-binding domain that binds to CACNG1 comprises a heavy chain variable region (HCVR) having an amino acid sequence selected from SEQ ID NOs: 615, 635, 655, 675, 695, 715, 735, 755, 775, 795, 815, 835, 855, 875, 895, 915, 935, 955, 1181, or 1205 or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.

[0291] In some embodiments, provided herein are anti-CACNGl heterodimeric antibodies, or antigen-binding fragments thereof, wherein an antigen-binding domain that binds to CACNG1 comprises a light chain variable region (LCVR) having an amino acid sequence selected from SEQ ID NOs: 623, 643, 663, 683, 703, 723, 743, 763, 783, 803, 823, 843, 863, 883, 903, 923, 943, 963, 1189, or 1213 or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.

[0292] In some embodiments, provided herein are anti-CACNGl heterodimeric antibodies, or antigen-binding fragments thereof, wherein an antigen-binding domain that binds to CACNG1 comprises a HCVR and LCVR (HCVR / LCVR) amino acid sequence pair selected from SEQ ID NOs: 615 / 623 (e.g., H2aM31929N / REGN10728), SEQ ID NOs: 635 / 643 (e.g., H2aM31944N), SEQ ID NOs: 655 / 663 (e.g., H4H31265P2 / REGN5972), SEQ ID NOs: 675 / 683 (e.g., H2aM31941N), SEQ ID NOs: 695 / 703 (e.g., REGN7660), SEQ ID NOs: 715 / 723 (e.g., REGN9909), SEQ ID NOs: 735 / 743 (e.g., REGN10713), SEQ ID NOs: 755 / 763 (e.g., REGN10715), SEQ ID NOs: 775 / 783 (e.g.,135975-91820REGN 11918REGN10716), SEQ ID NOs: 795 / 803 (e.g., REGN10717), SEQ ID NOs: 815 / 823 (e.g., REGN10783), SEQ ID NOs: 835 / 843 (e.g., REGN7854), SEQ ID NOs: 855 / 863 (e.g., REGN14570), SEQ ID NOs: 875 / 883 (e.g., REGN14571), SEQ ID NOs: 895 / 903 (e.g., REGN14572), SEQ ID NOs: 915 / 923 (e.g., REGN14573), SEQ ID NOs: 935 / 943 (e.g., REGN14574), SEQ ID NOs: 955 / 963 (e.g., REGN14647), SEQ ID NOs: 1181 / 1189 (e.g., REGN10712), and SEQ ID NOs: 1205 / 1213 (e.g., REGN9908).

[0293] In some embodiments, provided herein are anti-CACNGl heterodimeric antibodies, or antigen-binding fragments thereof, wherein an antigen-binding domain that binds to CACNG1 comprises a heavy chain CDR1 (HCDR1) domain having an amino acid sequence selected from SEQ ID NOs: 617, 637, 657, 677, 697, 717, 737, 757, 777, 797, 817, 837, 857, 877, 897, 917, 937, 957, 1183, or 1207 or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity; a heavy chain CDR2 (HCDR2) domain having an amino acid sequence selected from SEQ ID NOs: 619, 639, 659, 679, 699, 719, 739, 759, 779, 799, 819, 839, 859, 879, 899, 919, 939, 959, 1185, or 1209 or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity; a heavy chain CDR3 (HCDR3) domain having an amino acid sequence selected from SEQ ID NOs: 621, 641, 661, 681, 701, 721, 741, 761, 781, 801, 821, 841, 861, 881, 901, 921, 941, 961, 1187, or 1211 or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity; a light chain CDR1 (LCDR1) domain having an amino acid sequence of SEQ ID NOs: 625, 645, 665, 685, 705, 725, 745, 765, 785, 805, 825, 845, 865, 885, 905, 925, 945, 965, 1191, or 1215 or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity; a light chain CDR2 (LCDR2) domain having an amino acid sequence of A AS, GAS, RNN, DNN, ATS, KAS, or YNS a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity; and a light chain CDR3 (LCDR3) domain having an amino acid sequence of SEQ ID NOs: 629, 649, 669, 689, 709, 729, 749, 769, 789, 809, 829, 849, 869, 889, 909, 929, 949, 969, 1195, or 1219 or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.

[0294] Certain non-limiting, example anti-CACNGl heterodimeric antibodies, or antigen-binding fragments thereof disclosed herein, wherein an antigen-binding domain that binds to CACNG1 comprising a set of six CDRs (i.e., HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3), respectively, having the amino acid sequences selected from SEQ ID NOs: 617- 619- 621- 625- AAS - 629 (e.g., H2aM31929N / REGN10728), SEQ ID NOs: 637- 639- 641- 645- AAS - 649 (e.g., H2aM31944N), SEQ ID NOs: 657- 659- 661- 665- AAS - 669 (e.g., H4H31265P2 / REGN5972), SEQ ID NOs: 677- 679- 681- 685- GAS - 689 (e.g., H2aM31941N), SEQ ID NOs: 697- 699- 701- 705- GAS - 709 (e.g., REGN7660), SEQ ID NOs: 717- 719- 721- 725- RNN - 729 (e.g., REGN9909), SEQ ID NOs: 737- 739- 741- 745- DNN - 749 (e.g., REGN10713), SEQ ID NOs: 757- 759- 761- 765- ATS - 769 (e.g., REGN10715), SEQ ID NOs: 777- 779- 781- 785- GAS - 789 (e.g., REGN10716), SEQ ID NOs: 797-135975-91820REGN 11918799- 801- 805- KAS - 809 (e.g., REGN10717), SEQ ID NOs: 817- 819- 821- 825- AAS - 829 (e.g., REGN10783), SEQ ID NOs: 837- 839- 841- 845- GAS - 849 (e.g., REGN7854), SEQ ID NOs: 857- 859- 861- 865- ATS - 869 (e.g., REGN14570), SEQ ID NOs: 877- 879- 881- 885- GAS - 889 (e.g., REGN14571), SEQ ID NOs: 897- 899- 901- 905- KAS - 909 (e.g., REGN14572), SEQ ID NOs: 917- 919- 921- 925- DNN - 929 (e.g., REGN14573), SEQ ID NOs: 937- 939- 941- 945- AAS - 949 (e.g., REGN14574), SEQ ID NOs: 957- 959- 961- 965- AAS - 969 (e.g., REGN14647), SEQ ID NOs: 1183- 1185- 1187- 1191- YNS - 1195 (e.g., REGN10712), and SEQ ID NOs: 1207- 1209- 1211- 1215- RNN - 1219 (e.g., REGN9908).

[0295] In an embodiment provided herein, an anti-CACNGl heterodimeric antibody, or an antigenbinding fragment thereof, wherein an antigen-binding domain that binds to CACNG1 herein can comprise an anti-CACNGl antibody, or antigen-binding fragment thereof, wherein the anti-C ACNG I antibody or anti gen -binding fragment thereof can include: a) a heavy chain variable region (HCVR) that comprises a HCDR1, HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 615, and / or a light chain variable region (LCVR) that comprises a LCDR1, LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 623; b) a heavy chain variable region (HCVR) that comprises a HCDR1, HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 635, and / or a light chain variable region (LCVR) that comprises a LCDR1, LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 643; c) a heavy chain variable region (HCVR) that comprises a HCDR1, HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 655, and / or a light chain variable region (LCVR) that comprises a LCDR1, LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 663; d) a heavy chain variable region (HCVR) that comprises a HCDR1, HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 675, and / or a light chain variable region (LCVR) that comprises a LCDR1, LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 683; e) a heavy chain variable region (HCVR) that comprises a HCDR1, HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 695, and / or a light chain variable region (LCVR) that comprises a LCDR1, LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 703; f) a heavy chain variable region (HCVR) that comprises a HCDR1, HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 715, and / or a light chain variable region (LCVR) that comprises a LCDR1, LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 723; g) a heavy chain variable region (HCVR) that comprises a HCDR1, HCDR2, and HCDR3135975-91820REGN 11918 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 735, and / or a light chain variable region (LCVR) that comprises a LCDR1, LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 743; h) a heavy chain variable region (HCVR) that comprises a HCDR1, HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 755, and / or a light chain variable region (LCVR) that comprises a LCDR1, LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 763; i) a heavy chain variable region (HCVR) that comprises a HCDR1, HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 775, and / or a light chain variable region (LCVR) that comprises a LCDR1, LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 783; j) a heavy chain variable region (HCVR) that comprises a HCDR1, HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 795, and / or a light chain variable region (LCVR) that comprises a LCDR1, LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 803; k) a heavy chain variable region (HCVR) that comprises a HCDR1, HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 815, and / or a light chain variable region (LCVR) that comprises a LCDR1, LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 823; l) a heavy chain variable region (HCVR) that comprises a HCDR1, HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 835, and / or a light chain variable region (LCVR) that comprises a LCDR1, LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 843; m) a heavy chain variable region (HCVR) that comprises a HCDR1, HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 855, and / or a light chain variable region (LCVR) that comprises a LCDR1, LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 863; n) a heavy chain variable region (HCVR) that comprises a HCDR1, HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 875, and / or a light chain variable region (LCVR) that comprises a LCDR1, LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 883; o) a heavy chain variable region (HCVR) that comprises a HCDR1, HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 895, and / or a light chain variable region (LCVR) that comprises a LCDR1, LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 903; p) a heavy chain variable region (HCVR) that comprises a HCDR1, HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 915, and / or a light135975-91820REGN 11918 chain variable region (LCVR) that comprises a LCDR1, LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 923; q) a heavy chain variable region (HCVR) that comprises a HCDR1, HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 935, and / or a light chain variable region (LCVR) that comprises a LCDR1, LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 943; r) a heavy chain variable region (HCVR) that comprises a HCDR1, HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 955, and / or a light chain variable region (LCVR) that comprises a LCDR1, LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 963; s) a heavy chain variable region (HCVR) that comprises a HCDR1, HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 1181, and / or a light chain variable region (LCVR) that comprises a LCDR1, LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1189; and / or t) a heavy chain variable region (HCVR) that comprises a HCDR1, HCDR2, and HCDR3 contained within a HCVR comprising the amino acid sequence of SEQ ID NO: 1205, and / or a light chain variable region (LCVR) that comprises a LCDR1, LCDR2, and LCDR3 contained within a LCVR comprising the amino acid sequence of SEQ ID NO: 1213.

[0296] In an embodiment provided herein, an anti-CACNGl heterodimeric antibody, or an antigenbinding fragment thereof, wherein an antigen-binding domain that binds to CACNG1 herein can comprise an anti-CACNGl antibody, or antigen-binding fragment thereof, wherein the anti-C ACNG I antibody or anti gen -binding fragment thereof can include: a) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 617, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 619, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 621; and / or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 625, a LCDR2 comprising the amino acid sequence of AAS, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 629; b) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 637, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 639, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 641 ; and / or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 645, a LCDR2 comprising the amino acid sequence of AAS, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 649; c) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 657, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 659, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 661; and / or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 665, a LCDR2 comprising the amino acid sequence of AAS, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 669;135975-91820REGN 11918 d) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 677, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 679, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 681; and / or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 685, a LCDR2 comprising the amino acid sequence of GAS, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 689; e) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 697, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 699, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 701; and / or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 705, a LCDR2 comprising the amino acid sequence of GAS, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 709; f) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 717, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 719, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 721; and / or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 725, a LCDR2 comprising the amino acid sequence of RNN, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 729; g) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 737, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 739, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 741 ; and / or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 745, a LCDR2 comprising the amino acid sequence of DNN, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 749; h) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 757, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 759, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 761; and / or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 765, a LCDR2 comprising the amino acid sequence of ATS, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 769; i) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 777, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 779, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 781; and / or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 785, a LCDR2 comprising the amino acid sequence of GAS, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 789; j) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 797, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 799, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 801; and / or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 805, a LCDR2 comprising the amino acid sequence of KAS, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 809; k) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 817, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 819, and a HCDR3 comprising the amino acid sequence of135975-91820REGN 11918SEQ ID NO: 821; and / or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 825, a LCDR2 comprising the amino acid sequence of AAS, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 829; l) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 837, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 839, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 841 ; and / or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 845, a LCDR2 comprising the amino acid sequence of GAS, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 849; m) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 857, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 859, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 861; and / or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 865, a LCDR2 comprising the amino acid sequence of ATS, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 869; n) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 877, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 879, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 881; and / or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 885, a LCDR2 comprising the amino acid sequence of GAS, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 889; o) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 897, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 899, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 901 ; and / or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 905, a LCDR2 comprising the amino acid sequence of KAS, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 909; p) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 917, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 919, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 921; and / or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 925, a LCDR2 comprising the amino acid sequence of DNN, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 929; q) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 937, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 939, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 941 ; and / or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 945, a LCDR2 comprising the amino acid sequence of AAS, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 949; r) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 957, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 959, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 961; and / or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 965, a LCDR2 comprising the amino acid sequence of AAS, and a LCDR3 comprising the amino acid135975-91820REGN 11918 sequence of SEQ ID NO: 969; s) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1183, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1185, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 1187; and / or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1191, a LCDR2 comprising the amino acid sequence of YNS, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1195; and / or t) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1207, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 1209, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 1211; and / or a LCDR1 comprising the amino acid sequence of SEQ ID NO: 1215, a LCDR2 comprising the amino acid sequence of RNN, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 1219.

[0297] In an embodiment provided herein, an anti-CACNGl heterodimeric antibody, or an antigenbinding fragment thereof, wherein an antigen-binding domain that binds to CACNG1 herein can comprise an anti-CACNGl antibody, or antigen-binding fragment thereof, wherein the anti-C ACNG I antibody or anti gen -binding fragment thereof can include: a) a HCVR comprising the amino acid sequence of SEQ ID NO: 615, and / or a LCVR comprising the amino acid sequence of SEQ ID NO: 623; b) a HCVR comprising the amino acid sequence of SEQ ID NO: 635, and / or a LCVR comprising the amino acid sequence of SEQ ID NO: 643; c) a HCVR comprising the amino acid sequence of SEQ ID NO: 655, and / or a LCVR comprising the amino acid sequence of SEQ ID NO: 663; d) a HCVR comprising the amino acid sequence of SEQ ID NO: 675, and / or a LCVR comprising the amino acid sequence of SEQ ID NO: 683; e) a HCVR comprising the amino acid sequence of SEQ ID NO: 695, and / or a LCVR comprising the amino acid sequence of SEQ ID NO: 703; f) a HCVR comprising the amino acid sequence of SEQ ID NO: 715, and / or a LCVR comprising the amino acid sequence of SEQ ID NO: 723; g) a HCVR comprising the amino acid sequence of SEQ ID NO: 735, and / or a LCVR comprising the amino acid sequence of SEQ ID NO: 743; h) a HCVR comprising the amino acid sequence of SEQ ID NO: 755, and / or a LCVR comprising the amino acid sequence of SEQ ID NO: 763; i) a HCVR comprising the amino acid sequence of SEQ ID NO: 775, and / or a LCVR comprising the amino acid sequence of SEQ ID NO: 783; j) a HCVR comprising the amino acid sequence of SEQ ID NO: 795, and / or a LCVR comprising the amino acid sequence of SEQ ID NO: 803; k) a HCVR comprising the amino acid sequence of SEQ ID NO: 815, and / or a LCVR comprising the amino acid sequence of SEQ ID NO: 823;135975-91820REGN 11918 l) a HCVR comprising the amino acid sequence of SEQ ID NO: 835, and / or a LCVR comprising the amino acid sequence of SEQ ID NO: 843; m) a HCVR comprising the amino acid sequence of SEQ ID NO: 855, and / or a LCVR comprising the amino acid sequence of SEQ ID NO: 863; n) a HCVR comprising the amino acid sequence of SEQ ID NO: 875, and / or a LCVR comprising the amino acid sequence of SEQ ID NO: 883; o) a HCVR comprising the amino acid sequence of SEQ ID NO: 895, and / or a LCVR comprising the amino acid sequence of SEQ ID NO: 903; p) a HCVR comprising the amino acid sequence of SEQ ID NO: 915, and / or a LCVR comprising the amino acid sequence of SEQ ID NO: 923; q) a HCVR comprising the amino acid sequence of SEQ ID NO: 935, and / or a LCVR comprising the amino acid sequence of SEQ ID NO: 943; r) a HCVR comprising the amino acid sequence of SEQ ID NO: 955, and / or a LCVR comprising the amino acid sequence of SEQ ID NO: 963; s) a HCVR comprising the amino acid sequence of SEQ ID NO: 1181, and / or a LCVR comprising the amino acid sequence of SEQ ID NO: 1189; and / or t) a HCVR comprising the amino acid sequence of SEQ ID NO: 1205, and / or a LCVR comprising the amino acid sequence of SEQ ID NO: 1213.

[0298] In an embodiment provided herein, an anti-CACNGl heterodimeric antibody, or an antigenbinding fragment thereof, wherein an antigen-binding domain that binds to CACNG1 herein can comprise an anti-CACNGl antibody, or antigen-binding fragment thereof, wherein the anti-C ACNG I antibody or anti gen -binding fragment thereof can include: a) a HC region that comprises the amino acid sequence of SEQ ID NO: 63...

Claims

135975-91820REGN 11918WHAT IS CLAIMED:

1. A heterodimeric antibody, or an antigen-binding fragment thereof, comprising: a) a first heavy chain comprising a first heavy chain variable region and a first heavy chain constant region, wherein the first heavy chain constant region comprises a first CH3 domain of a human IgG, wherein the human IgG is IgGl, IgG2, or IgG4; b) a second heavy chain comprising a second heavy chain variable region and a second heavy chain constant region, wherein the second heavy chain constant region comprises 1) a second CH3 domain of a human IgG, wherein the human IgG is IgGl, IgG2, or IgG4; and 2) one or more modifications in the second CH3 domain that reduces or eliminates binding of the second CH3 domain to Protein A; and c) a binding polypeptide fused to the C-terminus of the second heavy chain, wherein the binding polypeptide forms an isopeptide bond with a binding peptide not attached to the heterodimeric antibody.

2. The heterodimeric antibody, or the antigen-binding fragment thereof of claim 1 , wherein the first heavy chain further comprises one or more modifications in a first hinge domain; and / or the second heavy chain further comprises one or more modifications in a second hinge domain.

3. The heterodimeric antibody, or antigen-binding fragment thereof of claim 2, wherein the first heavy chain constant region comprises from N-terminal to C-terminal the first hinge domain, a first CH2 domain, and the first CH3 domain; and / or wherein the second heavy chain constant region comprises from N-terminal to C-terminal the second hinge domain, a second CH2 domain, and the second CH3 domain.

4. The heterodimeric antibody, or antigen-binding fragment thereof of claim 3, wherein the first heavy chain constant region comprises from N-terminal to C-terminal a first CHI domain, the first hinge domain, the first CH2 domain, and the first CH3 domain; and / or wherein the second heavy chain constant region comprises from N-terminal to C-terminal a second CHI domain, the second hinge domain, the second CH2 domain, and the second CH3 domain.

5. The heterodimeric antibody, or antigen-binding fragment thereof of claim 4, wherein the first CHI domain, the first hinge domain, the first CH2 domain, and the first CH3 domain of the first heavy chain constant region are the same human isotype; and / or wherein the second CHI domain, the135975-91820REGN 11918 second hinge domain, the second CH2 domain, and the second CH3 domain of the second heavy chain constant region are the same human isotype.

6. The heterodimeric antibody, or antigen-binding fragment thereof of claim 4, wherein the first CHI domain, the first hinge domain, the first CH2 domain, and the first CH3 domain of the first heavy chain constant region are different human isotypes; and / or wherein the second CHI domain, the second hinge domain, the second CH2 domain, and the second CH3 domain of the second heavy chain constant region are different human isotypes.

7. The heterodimeric antibody, or antigen-binding fragment thereof of claim 5 or 6, wherein the first CHI domain, the first hinge domain, the first CH2 domain, and the first CH3 domain of the first heavy chain constant region are each selected from IgGl, IgG2, and IgG4; and / or wherein the second CHI domain, the second hinge domain, the second CH2 domain, and the second CH3 domain of the second heavy chain constant region are each selected from IgGl, IgG2, and IgG4.

8. The heterodimeric antibody, or antigen-binding fragment thereof of any one of claims 5-7, wherein the first CHI domain, the first hinge domain, the first CH2 domain, and the first CH3 domain of the first heavy chain constant region are human IgGl ; and / or wherein the second CHI domain, the second hinge domain, the second CH2 domain, and the second CH3 domain of the second heavy chain constant region are human IgGl.

9. The heterodimeric antibody, or antigen-binding fragment thereof of any one of claims 5-7, wherein the first CHI domain, the first hinge domain, the first CH2 domain, and the first CH3 domain of the first heavy chain constant region are human IgG2; and / or wherein the second CHI domain, the second hinge domain, the second CH2 domain, and the second CH3 domain of the second heavy chain constant region are human IgG2.

10. The heterodimeric antibody, or antigen-binding fragment thereof of any one of claims 5-7, wherein the first CHI domain, the first hinge domain, the first CH2 domain, and the first CH3 domain of the first heavy chain constant region are human IgG4; and / or wherein the second CHI domain, the second hinge domain, the CH2 domain, and the CH3 domain of the second heavy chain constant region are human IgG4.

11. The heterodimeric antibody, or antigen-binding fragment thereof of claim 6 or 7, wherein the first hinge domain and / or the second hinge domain are a chimera of two or more IgG isotypes.135975-91820REGN 1191812. The heterodimeric antibody, or antigen-binding fragment thereof of claim 11, wherein the first hinge domain chimera and / or the second hinge domain chimera is IgG2 / IgG4.

13. The heterodimeric antibody, or antigen-binding fragment thereof of any one of claims 1-10, wherein the one or more modifications in the second CH3 domain are selected from the group consisting of (a) 95R, and (b) 95R and 96F in the IMGT exon numbering system, or (a’) 435R, and (b’) 435R and 436F in the EU numbering system.

14. The heterodimeric antibody, or antigen-binding fragment thereof of claim 13, wherein the second CH3 domain further comprises one to five modifications selected from the group consisting of 16E, 18M, 44S, 52N, 57M, and 821 in the IMGT exon numbering system, or 356E, 358M, 384S, 392N, 397M, and 4221 in the EU numbering system.

15. The heterodimeric antibody, or antigen-binding fragment thereof of claim 13 or 14, wherein the second CH3 domain is non-immunogenic or substantially non-immunogenic in a human.

16. The heterodimeric antibody, or antigen-binding fragment thereof of any one of claims 2-15, wherein the first hinge domain comprises one or more modifications at positions 233-236 and the second hinge domain comprises one or more modifications at positions 233-236; optionally wherein the one or more modifications in the first hinge domain and / or the second hinge domain are G, G, G, and unoccupied; G, G, unoccupied, and unoccupied; G, unoccupied, unoccupied, and unoccupied; or all unoccupied, with positions numbered by EU numbering.

17. The heterodimeric antibody, or antigen-binding fragment thereof of claim 16, wherein positions 226-229 of the first hinge domain and the second hinge domain are CPPC.

18. The heterodimeric antibody, or antigen-binding fragment thereof of claim 17, wherein the first hinge domain amino acid sequence and / or the second hinge domain amino acid sequence comprises CPPCPAPGGG-GPSVF (SEQ ID NO: 167), CPPCPAPGG-GPSVF (SEQ ID NO: 168), CPPCPAPG— GPSVF (SEQ ID NO: 169), or CPPCPAP— -GPSVF (SEQ ID NO: 170).

19. The heterodimeric antibody, or antigen-binding fragment thereof of any one of the preceding claims, wherein the first heavy chain constant region has an amino acid sequence comprising SEQ ID NOs: 174-177, 182-188, 193-196, 201, or 203 or a variant thereof having up to five insertions, deletions, substitutions, or insertions.135975-91820REGN 1191820. The heterodimeric antibody, or antigen-binding fragment thereof of any one of the preceding claims, wherein the first heavy chain constant region comprises SEQ ID NOs: 174-177, 182-188, 193- 196, 201, or 203.

21. The heterodimeric antibody, or antigen-binding fragment thereof of any one of the preceding claims, wherein the first heavy chain constant region consists of SEQ ID NOs: 174-177, 182-188, 193-196, 201, or 203.

22. The heterodimeric antibody, or antigen-binding fragment thereof of any one of the preceding claims, wherein the second heavy chain constant region has an amino acid sequence comprising SEQ ID NOs: 178-181, 189-192, 197-200, 202, and 204 or a variant thereof having up to five insertions deletions, substitutions, or insertions.

23. The heterodimeric antibody, or antigen-binding fragment thereof of any one of the preceding claims, wherein the second heavy chain constant region comprises SEQ ID NOs: 178-181, 189-192, 197-200, 202, and 204.

24. The heterodimeric antibody, or antigen-binding fragment thereof of any one of the preceding claims, wherein the second heavy chain constant region consists of SEQ ID NOs: 178-181, 189-192, 197-200, 202, and 204.

25. The heterodimeric antibody, or antigen-binding fragment thereof of any one of claims 1-24, further comprising an immunoglobulin light chain.

26. The heterodimeric antibody, or antigen-binding fragment thereof of claim 25, wherein the immunoglobulin light chain is a human immunoglobulin light chain.

27. The heterodimeric antibody, or antigen-binding fragment thereof of claim 25 or 26, wherein the immunoglobulin light chain comprises a light chain variable region and a light chain constant region.

28. The heterodimeric antibody, or antigen-binding fragment thereof of any one of the preceding claims, wherein the first heavy chain variable region selectively binds a first epitope and the second heavy chain variable region selectively binds a second epitope.

29. The heterodimeric antibody, or antigen-binding fragment thereof of claim 28, wherein the first epitope and the second epitope are on the same target molecule.135975-91820REGN 1191830. The heterodimeric antibody, or antigen-binding fragment thereof of claim 28, wherein the first epitope and the second epitope are on different target molecules.

31. The heterodimeric antibody, or antigen-binding fragment thereof of any one of the preceding claims, wherein the binding polypeptide is linked via a first linker to the C-terminus of the second heavy chain.

32. The heterodimeric antibody, or antigen-binding fragment thereof of claim 31 , wherein the first linker comprises the amino acid sequence selected from the group consisting of SEQ ID NO: 213 (GLSG), SEQ ID NO: 214 (GLSGSG), SEQ ID NO: 215 (GLSGLSGS), SEQ ID NO: 216 (GLSGLSGLSG), SEQ ID NO: 217 (GLSGGSGLSG), and SEQ ID NO: 219 (GSGESG).

33. The heterodimeric antibody, or antigen-binding fragment thereof of claim 32, wherein the first linker comprises the amino acid sequence of SEQ ID NO: 219 (GSGESG).

34. The heterodimeric antibody, or antigen-binding fragment thereof of any one of the preceding claims, wherein the binding polypeptide comprises the amino acid sequence of any one of SEQ ID NOs: 55-70; and the binding peptide comprises the amino acid sequence of any one of SEQ ID NOs: 71-85.

35. The heterodimeric antibody, or antigen-binding fragment thereof of any one of the preceding claims, wherein the binding polypeptide and binding peptide form a binding pair, and wherein the binding pair is selected from the group consisting of(i) Spy Catcher: Spy Tag,(ii) KTag: SpyTag,(iii) pilin-C: Isopeptag,(iv) SnoopCatcher: SnoopTag, and(v) SpyCatcher002:SpyTag002.

36. The heterodimeric antibody, or antigen-binding fragment thereof of any one of the preceding claims, wherein the binding polypeptide is SpyCatcher.

37. The heterodimeric antibody, or antigen-binding fragment thereof of any one of the preceding claims, wherein the binding peptide is SpyTag.135975-91820REGN 1191838. The heterodimeric antibody, or antigen-binding fragment thereof of any one of claims 1-35, wherein the binding polypeptide is KTag and the binding peptide is SpyTag.

39. The heterodimeric antibody, or antigen-binding fragment thereof of any one of claims 1-35, wherein the binding polypeptide is pilin-C and the binding peptide is isopeptag.

40. The heterodimeric antibody, or antigen-binding fragment thereof of any one of claims 1-35, wherein the binding polypeptide is SnoopCatcher and the binding peptide is SnoopTag.

41. The heterodimeric antibody, or antigen-binding fragment thereof of any one of claims 1-35, wherein the binding polypeptide is SpyCatcher002 and the binding peptide is SpyTag002.

42. The heterodimeric antibody, or antigen-binding fragment thereof of any one of claims 29-41, wherein the target molecule is a cell surface molecule, wherein the cell surface molecule is calcium voltage-gated channel auxiliary subunit gamma 1 (CACNG1), asialoglycoprotein receptor 1 (ASGR1), Fel d 1, ENTPD3, PTPRA, CD20, CD63, Her2, GABA, transferrin receptor, CD3, CD34, integrin, adipophilin, AIM-2, ALDH1A1, alpha-actinin-4, alpha-fetoprotein (AFP), ARTCI, B-RAF, BAGE-1, BCLX (L), BCR-ABL fusion protein b3a2, beta-catenin, BING-4, CA-125, CALCA, carcinoembryonic antigen (CEA), CASP-5, CASP-8, CD274, CD45, Cdc27, CDK12, CDK4, CDKN2A, CEA, CLPP, COA-1, CPSF, CSNK1A1, CTAG1, CTAG2, cyclin DI, Cyclin-Al, dek-can fusion protein, DKK1, EFTUD2, Elongation factor 2, ENAH (hMena), Ep-CAM, EpCAM, EphA3, epithelial tumor antigen (ETA), ETV6-AML1 fusion protein, EZH2, E6, E7, FGF5, FLT3-ITD, FN1, G250 / MN / CAIX, GAGE-1,2,8, GAGE- 3, 4, 5, 6, 7, GAS7, glypican-3, GnTV, gplOO / Pmel 17, GPNMB, HAUS3, Hepsin, HER-2 / neu, HERV-K-MEL, HLA-A11, HLA-A2, HLA-DOB, hsp70-2, IDO1, IGF2B3, IL13Ralpha2, intestinal carboxyl esterase, K-ras, Kallikrein 4, KIF20A, KK-LC-1, KKLC1, KM-HN-1, KMHN1 also known as CCDC110, LAGE-1, LDLR-fucosyltransferase AS fusion protein, Lengsin, M-CSF, MAGE-A1, MAGE-A10, MAGE-A12, MAGE-A2, MAGE-A3, MAGE-A4, MAGE-A6, MAGE-A9, MAGE-CI, MAGE-C2, malic enzyme, mammaglobin-A, MART2, MATN, MC1R, MCSP, mdm-2, MEI, Melan-A / MART-1, Meloe, Midkine, MMP-2, MMP- 7, MUC1, MUC5AC, mucin, MUM-1, MUM-2, MUM-3, Myosin, Myosin class I, N-raw, NA88- A, neo-PAP, NFYC, NY-BR-1, NY-ESO-l / LAGE-2, OA1, OGT, OS-9, P polypeptide, p53, PAP, PAX5, PBF, pml-RARalpha fusion protein, polymorphic epithelial mucin (PEM), PPP1R3B, PRAME, PRDX5, PSA, PSMA, PTPRK, RAB 38 / N Y-MEL-1, RAGE-1, RBAF600, RGS5, RhoC, R F43, RU2AS, SAGE, secernin 1, SIRT2, SNRPD1, SOXIO, Spl7, SPA17, SSX-2, SSX-4, STEAP1, survivin, SYT-SSX1 or SYT-SSX2 fusion protein, TAG-1, TAG-2, Telomerase, TGF-betaRII, TPBG, TRAG-3, Triosephosphate isomerase, TRP-l / gp75, TRP-2, TRP2-INT2, tyrosinase, VEGF, WT1, XAGE-lb / GAGED2a, Kras, NY- ESO1, MAGE- A3, HPV E2, HPV E6, HPV E7, WT-1 antigen,135975-91820REGN 11918ErbB receptors, Melan A (MARTI), gp 100, tyrosinase, TRP-l / gp 75, and TRP-2; MAGE-1 and MAGE-3; HPV EG and E7 proteins; Mucin-1 (MUC-1); prostate-specific antigen (PSA); carcinoembryonic antigen (CEA), MAGE-2, MAGE-4, MAGE-6, MAGE-10, MAGE-12, BAGE-1, CAGE- 1,2, 8, CAGE-3 to 7, LAGE-1, NY-ESO-l / LAGE-2, NA-88, GnTV, TRP2-INT2, E6, E7, human glucagon receptor (hGCGR) or ectonucleoside triphosphate diphosphohydrolase 3 (hENTPD3).

43. The heterodimeric antibody, or antigen-binding fragment thereof of claim 42, wherein the cell surface molecule is CACNG1.

44. The heterodimeric antibody, or antigen-binding fragment thereof of any one of the preceding claims, wherein the first heavy chain is encoded by a nucleotide sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to the nucleotide sequence of SEQ ID NO: 154; and / or wherein the second heavy chain is encoded by a nucleotide sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to the nucleotide sequence of SEQ ID NO: 156.

45. The heterodimeric antibody, or antigen-binding fragment thereof of any one of the preceding claims, wherein the first heavy chain comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 155; and / or wherein the second heavy chain comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 157.

46. The heterodimeric antibody, or antigen-binding fragment thereof of any one of the preceding claims, wherein the first heavy chain comprises or consists of the amino acid sequence of SEQ ID NO: 155; and / or wherein the second heavy chain comprises or consists of the amino acid sequence of SEQ ID NO: 157.

47. The heterodimeric antibody, or antigen-binding fragment thereof of any one of claims 25-46, wherein the light chain is encoded by a nucleotide sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to the nucleotide sequence of SEQ ID NO: 158.

48. The heterodimeric antibody, or antigen-binding fragment thereof of any one of claim 25-47, wherein the light chain comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 159.135975-91820REGN 1191849. A composition comprising (a) the heterodimeric antibody, or antigen-binding fragment thereof of any one of claims 1-48, and (b) a pharmaceutically acceptable carrier.

50. A system to deliver a nucleic acid to a cell, the system comprising1) the heterodimeric antibody, or antigen-binding fragment thereof, of any one of claims 1-48, or the composition of claim 49; and2) a viral particle, wherein the viral particle comprises one or more recombinant viral capsid proteins, wherein the one or more recombinant viral capsid proteins comprises a heterologous amino acid sequence, wherein the heterologous amino acid sequence is the binding peptide, and wherein the nucleic acid is encapsulated in the viral particle.

51. The system of claim 50, wherein the binding peptide is linked to the one or more recombinant viral capsid proteins via a second linker.

52. The system of claim 51, wherein the second linker comprises the amino acid sequence selected from the group consisting of SEQ ID NO: 213 (GLSG), SEQ ID NO: 214 (GLSGSG), SEQ ID NO: 215 (GLSGLSGS), SEQ ID NO: 216 (GLSGLSGLSG), SEQ ID NO: 217 (GLSGGSGLSG), and SEQ ID NO: 219 (GSGESG).

53. The system of claim 51 or 52, wherein the second linker comprises the amino acid sequence of SEQ ID NO: 219 (GSGESG).

54. The system of any one of claims 51-53, wherein the first linker and second linker are identical.

55. The system of any one of claims 51-53, wherein the first linker and second linker are not identical.

56. The system of any one of claims 50-55, wherein the one or more recombinant viral capsid proteins comprise one or more mutations in comparison to the corresponding wild type capsid protein.

57. The system of any one of claims 50-56, wherein the recombinant viral capsid protein is derived from: (i) a capsid gene of an adeno-associated virus (AAV), wherein the capsid gene encodes an AAV VP1, VP2, and / or VP3 capsid protein.

58. The system of any one of claims 50-57, wherein the viral particle is an adeno-associated virus (AAV) particle.135975-91820REGN 1191859. The system of claim 57 or 58, wherein the AAV particle is selected from the group consisting of AAV1, AAV2, AAV2quad(Y-F), AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAV13, rhlO, rh39, rh43, and rh74, or any variant thereof.

60. The system of claim 59, wherein the adeno-associated virus is AAV2.

61. The system of claim 59, wherein the adeno-associated virus is AAV9.

62. The system of any one of claims 50-61, wherein the nucleic acid encodes a gene.

63. The system of claim 62, wherein the gene is selected from the group consisting of nontranslated RNAs / non-coding RNAs, receptors, fusion proteins, agonists, antagonists, activators, inhibitors, enzymes, factors and co-factors, repressors, activators, ligands, protein hormones, therapeutic proteins, suicide proteins, structural proteins, storage proteins, transport proteins, signal proteins, neurotransmitters, contractile proteins, and any variant thereof.

64. A method of making a heterodimeric antibody, or antigen-binding fragment thereof comprising: a) loading an affinity matrix with a mixture of multimeric proteins comprising(i) a first homodimer comprising two copies of a first heavy chain comprising a first heavy chain variable region and a first heavy chain constant region, wherein the first heavy chain constant region comprises 1) a first CH3 domain of a human IgG selected from IgGl, IgG2, and IgG4;(ii) a second homodimer comprising two copies of the second heavy chain comprising a second heavy chain variable region and a second heavy chain constant region, wherein the second heavy chain constant region comprises 1) a second CH3 domain of a human IgG selected from IgGl, IgG2, and IgG4; 2) one or more modifications in the second CH3 domain that reduces or eliminates binding of the second CH3 domain to Protein A; and 3) one or more modifications within a second hinge domain, and wherein a binding polypeptide is fused to the C-terminus of the second heavy chain, wherein the binding polypeptide forms an isopeptide bond with a binding peptide not attached to the second heavy chain; and(iii) a heterodimer comprising the first heavy chain and the second heavy chain, wherein the first heavy chain has greater affinity for the affinity matrix than does the second heavy chain; and b) el uting and collecting the heterodimer from the affinity matrix in a buffer comprising a salt, an anion, and having a first pH range, wherein the first homodimer elutes from the affinity matrix in135975-91820REGN 11918 the buffer at a second pH range and the second homodimer elutes from the affinity matrix in the buffer at a third pH range, wherein the third pH range comprises a higher pH than the first pH range, and wherein the first pH range comprises a higher pH than the second pH range.

65. The method of claim 64, wherein the first heavy chain constant region further comprises one or more modifications within a first hinge domain.

66. The method according claim 64 or 65, wherein the affinity matrix comprises a Protein A ligand affixed to a substrate.

67. The method according to claim 66, wherein the Protein A ligand is an engineered Protein A comprising a Z-domain tetramer or a Y-domain tetramer.

68. The method according to claim 67, wherein the substrate comprises any one or more of agarose, poly( styrene divinylbenzene), polymethacrylate, cellulose, controlled pore glass, and spherical silica.

69. The method according to claim 68, wherein the substrate is a particle and the affinity matrix comprises a multiplicity of the particles having a mean diameter of 25 pm to 100 pm.

70. The method according to claim 69, wherein the particles have a mean diameter of 45 pm and comprise pores having a mean diameter of 1100 A.

71. The method according to any one of claims 64-70, wherein 5 to 50 grams of protein are loaded per liter of affinity matrix.

72. The method according to claim 64, comprising applying a pH gradient to the loaded affinity matrix of step (a).

73. The method according to claim 72, further comprising washing the loaded affinity matrix of step (a) with a solution at pH 6-8 prior to applying the pH gradient.

74. The method according to claim 72, wherein the pH gradient is run between pH 6 and pH 3.

75. The method according to any one of claims 72-74, wherein the first pH range is selected from a range within pH 5.5 and pH 3.6.135975-91820REGN 1191876. The method according to claim 75, wherein the anion is acetate.

77. The method according to claim 76, wherein the buffer comprises 40 mM acetate.

78. The method according to any one of claims 64-77, wherein the salt is sodium chloride.

79. The method according to claim 78, wherein the salt comprises about 250 to about 500 mM sodium chloride.

80. The method according to any one of claims 64-77, wherein the first heavy chain comprises a first CH3 domain that is capable of binding to Protein A and the second heavy chain comprises a second CH3 domain that is not capable of binding to Protein A.

81. The method according to claim 80, wherein the second heavy chain comprises a HY to RF substitution in the second CH3 domain.

82. The method according to claim 80 or claim 81, wherein the heterodimer comprises a heterodimeric antibody, or antigen-binding fragment thereof.

83. The method according to any one of claims 64-82, wherein the mixture of multimeric proteins is produced by a plurality of eukaryotic cells in a cell culture.

84. The method according to claim 83, wherein the eukaryotic cells comprise Chinese hamster ovary (CHO) cells or derivatives thereof.

85. The method according to any one of claims 64-84, further comprising(c) loading a second affinity matrix with a mixture comprising the first homodimer and the heterodimer collected at step (b);(d) eluting and col lecti ng the heterodimer from the affinity matrix in a buffer having a first pH range, wherein the first homodimer elutes from the affinity matrix in the buffer at a second pH range.

86. The method of any one of claims 65-85, wherein the first heavy chain constant region comprises from N-terminal to C-terminal the first hinge domain, a first CH2 domain, and the first CH3 domain; and / or wherein the second heavy chain constant region comprises from N-terminal to C-terminal the second hinge domain, a second CH2 domain, and the second CH3 domain.135975-91820REGN 1191887. The method of claim 86, wherein the first heavy chain constant further comprises a first CHI domain, and / or the second heavy chain constant further comprises a second CHI domain.

88. The method of claim 87, wherein the first CHI domain, the first hinge domain, the first CH2 domain, and / or the first CH3 domain of the first heavy chain constant region are derived from human IgGl, human IgG2, and / or human IgG4; and / or the second CHI domain, the second hinge domain, the second CH2 domain, and / or the second CH3 domain of the second heavy chain constant region are derived from human IgGl, human IgG2, and / or human IgG4.

89. The method of any one of claims 86-88, wherein the first hinge domain and / or the second hinge domain are a chimera of two or more IgG isotypes, optionally wherein first hinge domain chimera and / or the second hinge domain chimera is IgG2 / IgG4.

90. The method of any one of claims 64-89, wherein the one or more modifications in the second CH3 domain are selected from the group consisting of (a) 95R, and (b) 95R and 96F in the IMGT exon numbering system, or (a’) 435R, and (b’) 435R and 436F in the EU numbering system.

91. The method of claim 90, wherein the second CH3 domain further comprises one to five modifications selected from the group consisting of 16E, 18M, 44S, 52N, 57M, and 821 in the IMGT exon numbering system, or 356E, 358M, 384S, 392N, 397M, and 4221 in the EU numbering system.

92. The method of any one of claims 64-91, wherein the one or more modifications in the first hinge domain and the one or more modifications in the second hinge domain are at positions 233-236, and wherein positions 233-236 are G, G, G, and unoccupied; G, G, unoccupied, and unoccupied; G, unoccupied, unoccupied, and unoccupied; or all unoccupied, with positions numbered by EU numbering.

93. The method of claim 92, wherein the first hinge domain amino acid sequence and / or the second hinge domain amino acid sequence comprises CPPCPAPGGG-GPSVF (SEQ ID NO: 167), CPPCPAPGG— GPSVF (SEQ ID NO: 168), CPPCPAPG— GPSVF (SEQ ID NO: 169), or CPPCPAP- — GPSVF (SEQ ID NO: 170).

94. The method of any one of claims 64-93, wherein the first heavy chain constant region has an amino acid sequence comprising SEQ ID NOs: 174-177, 182-188, 193-196, 201, or 203 or a variant thereof having up to five insertions deletions, substitutions or insertions.135975-91820REGN 1191895. The method of any one of claims 64-94, wherein the second heavy chain constant region has an amino acid sequence comprising SEQ ID NOs: 178-181, 189-192, 197-200, 202, and 204 or a variant thereof having up to five insertions deletions, substitutions or insertions.

96. The method of any one of claims 64-95, wherein the heterodimer further comprises an immunoglobulin light chain, optionally wherein the immunoglobulin light chain is human.

97. The method of any one of claims 64-96, wherein the binding polypeptide is linked via a first linker to the C-terminus of the second heavy chain, wherein the first linker comprises the amino acid sequence selected from the group consisting of SEQ ID NO: 219 (GSGESG).

98. The method of claim 64-97, wherein the binding polypeptide comprises the amino acid sequence of any one of SEQ ID NOs: 55-70; and the binding peptide comprises the amino acid sequence of any one of SEQ ID NOs: 71-85.

99. The method of any one of claims 64-98, wherein the binding polypeptide and binding peptide form a binding pair, and wherein the binding pair is selected from the group consisting of(i) Spy Catcher: Spy Tag,(ii) KTag: SpyTag,(iii) pilin-C: Isopeptag,(iv) SnoopCatcher: SnoopTag, and(v) SpyCatcher002:SpyTag002.

100. The method of claim 98 or 99, wherein the binding polypeptide is SpyCatcher and the binding peptide is SpyTag.

101. The method of any one of claims 64-100, wherein the first heavy chain is encoded by a nucleotide sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to the nucleotide sequence of SEQ ID NO: 154; and / or wherein the second heavy chain is encoded by a nucleotide sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to the nucleotide sequence of SEQ ID NO: 156.

102. The method of any one of claims 64-101, wherein the first heavy chain comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 155; and / or135975-91820REGN 11918 wherein the second heavy chain comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 157.

103. The method of any one of claims 64-102, wherein the first heavy chain comprises or consists of the amino acid sequence of SEQ ID NO: 155; and / or wherein the second heavy chain comprises or consists of the amino acid sequence of SEQ ID NO: 157.

104. The method of any one of claims 96-103, wherein the light chain is encoded by a nucleotide sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to the nucleotide sequence of SEQ ID NO: 158.

105. The method of any one of claims 96-104, wherein the light chain comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 159.

106. A heterodimeric antibody, or antigen-binding fragment thereof made according to the method of any one of claims 64-105.

107. A composition comprising the heterodimeric antibody, or antigen-binding fragment thereof of claim 106, and a pharmaceutically acceptable carrier.

108. A method of delivering a nucleic acid molecule to a target cell, the method comprising:1) combining the heterodimeric antibody, or antigen-binding fragment thereof of any one of claims 1-48 and 106, or the composition of claim 49 or 107, with a recombinant viral particle comprising a binding peptide, wherein the binding peptide forms an isopeptide bond with the binding polypeptide fused to the second heavy chain of the heterodimeric antibody, or antigen-binding fragment thereof;2) contacting the target cell with the mixture of step (1), wherein the heterodimeric antibody, or antigen-binding fragment thereof specifically binds to a cell surface molecule on the target cell.

109. The method of claim 108, wherein the target cell is in vitro.

110. The method of claim 108, wherein the target cell is in vivo in a subject.

111. The method of claim 108, wherein the subject is a human.135975-91820REGN 11918112. The method of any one of claims 108-111, wherein the target cell is a human target cell.

113. The method of claim 112, wherein the target cell is a human muscle cell, and wherein the targeting ligand binds calcium channel, voltage-dependent, gamma subunit 1 (CACNG1).

114. The method of any one of claims 108-113, wherein the nucleic acid molecule is encapsulated by the recombinant viral particle.

115. The method of claim 114, wherein the nucleic acid molecule is under the control of a promoter selected from the group consisting of a viral promoter, a bacterial promoter, a mammalian promoter, an avian promoter, a fish promoter, an insect promoter, and any combination thereof.

116. The method of any one of claims 108-115, wherein the recombinant viral particle is an adeno- associated virus (AAV) particle or a lentivirus particle.

117. The method of claim 116, wherein the recombinant viral particle is selected from the group consisting of AAV1, AAV2, AAV2quad(Y-F), AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAV13, rhlO, rh39, rh43, rh74, and any variant thereof.

118. The method of any one of claims 108-117, wherein the recombinant viral particle comprises one or more recombinant viral capsid proteins.

119. The method of claim 118, wherein the one or more recombinant viral capsid proteins are derived from: (i) a capsid gene of an adeno-associated virus (AAV) , wherein the capsid gene encodes an AAV VP1, VP2, and / or VP3 capsid proteins; or (ii) a lentivirus.

120. The method of claim 118 or 119, wherein the binding peptide is fused to the one or more recombinant viral capsid proteins.

121. The method of any one of claims 108-120, wherein the heterodimeric antibody, or antigenbinding fragment thereof and the recombinant viral particle bind via the binding polypeptide and binding peptide isopeptide bond.