Antibody molecule and its use against C5AR1

Abstract

Providing an antibody molecule against C5aR1 and its use. [Solution] An antibody molecule that specifically binds to C5aR1 is disclosed. The antibody molecule can be used to treat, prevent, and / or diagnose disorders such as ANCA vasculitis. The present invention particularly provides an anti-C5aR1 antibody with increased specificity to C5aR1, and therapeutic uses of the antibody in the effective treatment of diseases or disorders related to C5a and its receptor, such as ANCA vasculitis, COVID-19, acute respiratory distress syndrome (ARDS), influenza A, typical hemolytic uremic syndrome, age-related macular degeneration, rheumatoid arthritis, sepsis, severe burns, antiphospholipid syndrome, asthma, lupus nephritis, Goodpasture syndrome, and chronic obstructive pulmonary disease.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 62 / 960,544, filed on 13 January 2020, the disclosures of which are incorporated herein by reference in their entirety. [Background technology]

[0002] Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) is an autoimmune disease characterized by inflammation and destruction of small and medium-sized blood vessels, as well as the presence of circulating antibodies against myeloperoxidase (MPO-ANCA) or proteinase 3 (PR3-ANCA). AAV affects various organs, but the kidneys are the most common, with over 75% of patients exhibiting rapidly progressing glomerulonephritis. Complement component 5a (C5a), a potent anaphylatoxin, promotes neutrophil chemotaxis and activation, which are important triggers in inflammatory diseases induced by type III hypersensitivity, such as ANCA-vasculitis.

[0003] C5 and its receptors, such as the complement 5 receptor 1 (C5aR1), are involved in ANCA vasculitis and other disorders that share similar disease mechanisms. There is a need to develop new methods for treating, preventing, and diagnosing various disorders related to receptor 1). [Overview of the project] [Means for solving the problem]

[0004] The present invention particularly provides an anti-C5aR1 antibody with increased specificity to C5aR1, and therapeutic uses of said antibody in the effective treatment of diseases or disorders related to C5a and its receptor, such as ANCA vasculitis, COVID-19, acute respiratory distress syndrome (ARDS), influenza A, typical hemolytic uremic syndrome, age-related macular degeneration, rheumatoid arthritis, sepsis, severe burns, antiphospholipid syndrome, asthma, lupus nephritis, Goodpasture syndrome, and chronic obstructive pulmonary disease. As described herein, the present invention is in part based on the identification of a novel anti-C5aR1-specific antibody that binds to specific regions on site I and / or site II of C5aR1 and exhibits significantly reduced cross-reactivity to C5aR2 or any other G protein-coupled receptor. In particular, the anti-C5aR1 antibody of the present invention exhibits high binding affinity to C5aR1 (e.g., less than 50 nM K) D The present invention is characterized by having a site I and exhibiting minimal cross-reactivity with C5aR2. The C5aR1 antibody of the present invention is highly significant because it can potently inhibit C5aR1 signaling in the presence of high concentrations of C5a. As a result, it is possible to achieve therapeutic effects using the C5aR1 antibody of the present invention at lower doses compared to other anti-C5aR1 antibodies or C5a antibodies. This is demonstrated by the observation of remarkably high efficacy in functional assays compared to prior art antibodies, as described herein. Furthermore, the highly potent site I C5aR1 antibody of the present invention competes with each other for site I, and the highly potent site II C5aR1 antibody of the present invention competes with each other for site II. Furthermore, the present invention provides methods and compositions for inhibiting C5aR1 and / or C5a signaling by targeting both site I and site II of C5aR1. By simultaneously targeting site I and site II, the inhibitory activity is significantly enhanced. For example, a combination of a site I antibody and a site II antibody, or a bispecific antibody (e.g., biparatope), rather than two site II antibodies or a combination of two site II antibodies, significantly enhances activity. The anti-C5aR1 antibody of the present invention is a promising and potent therapeutic agent, particularly for complement-mediated diseases or disorders such as ANCA vasculitis.

[0005] The C5a-C5aR1 system is of great interest for therapeutic interventions to inhibit neutrophil attraction to local sites, inhibit neutrophil activation, and inhibit vascular destruction. The compositions and methods disclosed herein may include the step of administering a C5aR1 antagonist, and may also include methods for treating subjects in need of such treatment.

[0006] In one embodiment, an antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is described herein, comprising a heavy chain variable region (VH) having the sequence disclosed herein and / or a light chain variable region (VL) having the sequence disclosed herein.

[0007] In one embodiment, an antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1), comprising a heavy chain variable region (VH) and / or a light chain variable region (VL), wherein the VH comprises HCDR1, HCDR2, and HCDR3, each differing from the HCDR1, HCDR2, and HCDR3 of the VH described in Table 2A by one, two, or three or fewer amino acid residues, or having at least 85%, 90%, 95%, 99%, or 100% identity, and / or the VL comprises LCDR1, LCDR2, and LCDR3, each differing from the LCDR1, LCDR2, and LCDR3 of the VL described in Table 2B by one, two, or three or fewer amino acid residues, or having at least 85%, 90%, 95%, 99%, or 100% identity.

[0008] In some embodiments, VH includes HCDR1, HCDR2, and HCDR3, each differing from the HCDR1, HCDR2, and HCDR3 of VH described in Table 1A by one, two, or three or fewer amino acid residues, or having at least 85%, 90%, 95%, 99%, or 100% identity.

[0009] In some embodiments, VH comprises HCDR1, HCDR2, and HCDR3, each differing from the HCDR1, HCDR2, and HCDR3 of VH described in Table 3A by one, two, or three or fewer amino acid residues, or having at least 85%, 90%, 95%, 99%, or 100% identity.

[0010] In some embodiments, the VL includes LCDR1, LCDR2, and LCDR3, each differing from the LCDR1, LCDR2, and LCDR3 of the VL described in Table 1B by one, two, or three or fewer amino acid residues, or having at least 85%, 90%, 95%, 99%, or 100% identity.

[0011] In some embodiments, the VL includes LCDR1, LCDR2, and LCDR3, each differing from the LCDR1, LCDR2, and LCDR3 of the VL described in Table 3B by one, two, or three or fewer amino acid residues, or having at least 85%, 90%, 95%, 99%, or 100% identity.

[0012] In one embodiment, an antibody molecule capable of binding to C5aR1 (e.g., human C5aR1), comprising VH and / or VL, is described herein, wherein VH comprises (i) HCDR1, which has an amino acid sequence that differs by one, two, or three or fewer amino acid residues from any of the amino acid sequences of SEQ ID NOs. 601-661, or has at least 85%, 90%, 95%, 99%, or 100% identity; (ii) HCDR2, which has an amino acid sequence that differs by one, two, or three or fewer amino acid residues from any of the amino acid sequences of SEQ ID NOs. 721-781, or has at least 85%, 90%, 95%, 99%, or 100% identity; and / or (iii) HCDR1, which has an amino acid sequence that differs by one, two, or three or fewer amino acid residues from any of the amino acid sequences of SEQ ID NOs. 841-901, or has at least 85%, 90%, 95%, 99% identity. or comprising HCDR3 containing an amino acid sequence having 100% identity, and / or in this case, the VL comprises (i) LCDR1 containing an amino acid sequence that differs by one, two, or three or fewer amino acid residues from any of the amino acid sequences of SEQ ID NOs. 662 to 720, or has at least 85%, 90%, 95%, 99%, or 100% identity, (ii) LCDR2 containing an amino acid sequence that differs by one, two, or three or fewer amino acid residues from any of the amino acid sequences of SEQ ID NOs. 782 to 840, or has at least 85%, 90%, 95%, 99%, or 100% identity, and / or (iii) LCDR3 containing an amino acid sequence that differs by one, two, or three or fewer amino acid residues from any of the amino acid sequences of SEQ ID NOs. 902 to 960, or has at least 85%, 90%, 95%, 99%, or 100% identity.

[0013] In one embodiment, an antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is described herein, in which case the antibody molecule competes with C5aR1 antibody molecules comprising HCDR1 containing the amino acid sequence of SEQ ID NO: 656, HCDR2 containing the amino acid sequence of SEQ ID NO: 776, and HCDR3 containing the amino acid sequence of SEQ ID NO: 896, LCDR1 containing the amino acid sequence of SEQ ID NO: 715, LCDR2 containing the amino acid sequence of SEQ ID NO: 835, and LCDR3 containing the amino acid sequence of SEQ ID NO: 955.

[0014] In one embodiment, the present invention provides an antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1), wherein the antibody molecule comprises VH and / or VH, wherein the VH comprises HCDR1 comprising the amino acid sequence of SEQ ID NO: 1456, HCDR2 comprising the amino acid sequence of SEQ ID NO: 1457, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 1458, LCDR1 comprising the amino acid sequence of SEQ ID NO: 1459, LCDR2 comprising the amino acid sequence of SEQ ID NO: 1460, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 1461.

[0015] In some embodiments, antibody molecules capable of binding to complement component 5a receptor 1 (C5aR1) compete with C5aR1 antibody molecules including HCDR1 containing the amino acid sequence of SEQ ID NO: 656, HCDR2 containing the amino acid sequence of SEQ ID NO: 776, and HCDR3 containing the amino acid sequence of SEQ ID NO: 896.

[0016] In some embodiments, antibody molecules capable of binding to complement component 5a receptor 1 (C5aR1) compete with C5aR1 antibody molecules comprising LCDR1 containing the amino acid sequence of SEQ ID NO: 715, LCDR2 containing the amino acid sequence of SEQ ID NO: 835, and LCDR3 containing the amino acid sequence of SEQ ID NO: 955.

[0017] In one embodiment, an antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is described herein, wherein the antibody molecule binds to an epitope on site I of C5aR1, and the epitope on site I comprises the amino acid residue of SEQ ID NO: 1449 or SEQ ID NO: 1452.

[0018] In some embodiments, the antibody molecule binds to amino acid residues T8-D18 in SEQ ID NO: 1449 or SEQ ID NO: 1452.

[0019] In some embodiments, the antibody molecule binds to the amino acid residue T8-G12 in SEQ ID NO: 1449 or SEQ ID NO: 1452.

[0020] In some embodiments, the antibody molecule binds to amino acid residues T8, D10, Y11, Y14, and / or D15 in SEQ ID NO: 1449 or SEQ ID NO: 1452.

[0021] In one embodiment, an antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1), comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH has at least 80% identity with the amino acid sequence of any of SEQ ID NOs. 481 to 541, and the VL has at least 70% identity with the amino acid sequence of any of SEQ ID NOs. 542 to 600.

[0022] In some embodiments, the antibody molecule includes a heavy chain variable region (VH) and has at least 75% identity with the amino acid sequence of any of SEQ ID NOs. 481 to 541. In some embodiments, the antibody molecule includes a heavy chain variable region (VH) and has at least 78% identity with the amino acid sequence of any of SEQ ID NOs. 481 to 541. In some embodiments, the antibody molecule includes a heavy chain variable region (VH) and has at least 80% identity with the amino acid sequence of any of SEQ ID NOs. 481 to 541. In some embodiments, the antibody molecule includes a heavy chain variable region (VH) and has at least 82% identity with the amino acid sequence of any of SEQ ID NOs. 481 to 541. In some embodiments, the antibody molecule includes a heavy chain variable region (VH) and has at least 85% identity with the amino acid sequence of any of SEQ ID NOs. 481 to 541. In some embodiments, the antibody molecule includes a heavy chain variable region (VH) and has at least 87% identity with the amino acid sequence of any of SEQ ID NOs. 481 to 541. In some embodiments, the antibody molecule includes a heavy chain variable region (VH) and has at least 90% identity with the amino acid sequence of any of SEQ ID NOs. 481 to 541. In some embodiments, the antibody molecule includes a heavy chain variable region (VH) and has at least 92% identity with the amino acid sequence of any of SEQ ID NOs. 481 to 541. In some embodiments, the antibody molecule includes a heavy chain variable region (VH) and has at least 95% identity with the amino acid sequence of any of SEQ ID NOs. 481 to 541. In some embodiments, the antibody molecule includes a heavy chain variable region (VH) and has at least 97% identity with the amino acid sequence of any of SEQ ID NOs. 481 to 541. In some embodiments, the antibody molecule includes a heavy chain variable region (VH) and has at least 98% identity with the amino acid sequence of any of SEQ ID NOs. 481 to 541. In some embodiments, the antibody molecule includes a heavy chain variable region (VH) and has at least 99% identity with the amino acid sequence of any of SEQ ID NOs. 481 to 541. In some embodiments, the antibody molecule includes a heavy chain variable region (VH) that has 100% identity with any of the amino acid sequences of SEQ ID NOs. 481 to 541.

[0023] In some embodiments, the antibody molecule includes a light chain variable region (VH) and has at least 68% identity with any of the amino acid sequences of SEQ ID NOs. 542-600. In some embodiments, the antibody molecule includes a light chain variable region (VH) and has at least 70% identity with any of the amino acid sequences of SEQ ID NOs. 542-600. In some embodiments, the antibody molecule includes a light chain variable region (VH) and has at least 72% identity with any of the amino acid sequences of SEQ ID NOs. 542-600. In some embodiments, the antibody molecule includes a light chain variable region (VH) and has at least 75% identity with any of the amino acid sequences of SEQ ID NOs. 542-600. In some embodiments, the antibody molecule includes a light chain variable region (VL) and has at least 78% identity with any of the amino acid sequences of SEQ ID NOs. 542-600. In some embodiments, the antibody molecule includes a light chain variable region (VL) and has at least 80% identity with any of the amino acid sequences of SEQ ID NOs. 542-600. In some embodiments, the antibody molecule includes a light chain variable region (VL) and has at least 82% identity with any of the amino acid sequences of SEQ ID NOs. 542-600. In some embodiments, the antibody molecule includes a light chain variable region (VL) and has at least 85% identity with any of the amino acid sequences of SEQ ID NOs. 542-600. In some embodiments, the antibody molecule includes a light chain variable region (VL) and has at least 87% identity with any of the amino acid sequences of SEQ ID NOs. 542-600. In some embodiments, the antibody molecule includes a light chain variable region (VL) and has at least 90% identity with any of the amino acid sequences of SEQ ID NOs. 542-600. In some embodiments, the antibody molecule includes a light chain variable region (VL) and has at least 92% identity with any of the amino acid sequences of SEQ ID NOs. 542-600. In some embodiments, the antibody molecule includes a light chain variable region (VL) and has at least 95% identity with any of the amino acid sequences of SEQ ID NOs. 542-600. In some embodiments, the antibody molecule includes a light chain variable region (VL) that has at least 97% identity with any of the amino acid sequences of SEQ ID NOs. 542 to 600. In some embodiments, the antibody molecule includes a light chain variable region (VL) that has at least 98% identity with any of the amino acid sequences of SEQ ID NOs. 542 to 600.In some embodiments, the antibody molecule includes a light chain variable region (VL) that has at least 99% identity with any of the amino acid sequences of SEQ ID NOs. 542 to 600. In some embodiments, the antibody molecule includes a light chain variable region (VL) that has 100% identity with any of the amino acid sequences of SEQ ID NOs. 542 to 600.

[0024] In one embodiment, an antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1), comprising VH and / or VL, wherein VH comprises HCDR1 comprising the amino acid sequence of SEQ ID NO: 656, HCDR2 comprising the amino acid sequence of SEQ ID NO: 776, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 896, and wherein VL comprises LCDR1 comprising the amino acid sequence of SEQ ID NO: 715, LCDR2 comprising the amino acid sequence of SEQ ID NO: 835, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 955.

[0025] In one embodiment, an antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1), comprising VH and / or VL, wherein VH comprises an amino acid sequence having at least 80% identity with the amino acid sequence of SEQ ID NO: 536, and VL comprises an amino acid sequence having at least 70% identity with the amino acid sequence of SEQ ID NO: 595.

[0026] In one embodiment, the antibody molecule comprises VH, which contains the amino acid sequence of SEQ ID NO: 536, and VL, which contains the amino acid sequence of SEQ ID NO: 595.

[0027] In one embodiment, the present invention provides an antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1), wherein the antibody molecule comprises VH and / or VH, wherein the VH comprises HCDR1 comprising the amino acid sequence of SEQ ID NO: 1462, HCDR2 comprising the amino acid sequence of SEQ ID NO: 1463, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 1464, LCDR1 comprising the amino acid sequence of SEQ ID NO: 1465, LCDR2 comprising the amino acid sequence of SEQ ID NO: 672, LCDR2 comprising the amino acid sequence of SEQ ID NO: 792, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 912.

[0028] In one embodiment, an antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1), comprising VH and / or VL, wherein VH comprises HCDR1 comprising the amino acid sequence of SEQ ID NO: 603, HCDR2 comprising the amino acid sequence of SEQ ID NO: 723, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 843, and wherein VL comprises LCDR1 comprising the amino acid sequence of SEQ ID NO: 663, LCDR2 comprising the amino acid sequence of SEQ ID NO: 783, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 903.

[0029] In one embodiment, the antibody molecule comprises VH containing the amino acid sequence of SEQ ID NO: 483, and VL containing the amino acid sequence of SEQ ID NO: 543.

[0030] In one embodiment, an antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1), comprising VH and / or VL, wherein VH comprises HCDR1 comprising the amino acid sequence of SEQ ID NO: 611, HCDR2 comprising the amino acid sequence of SEQ ID NO: 731, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 851, and wherein VL comprises LCDR1 comprising the amino acid sequence of SEQ ID NO: 671, LCDR2 comprising the amino acid sequence of SEQ ID NO: 792, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 911.

[0031] In some embodiments, the antibody molecule comprises VH containing the amino acid sequence of SEQ ID NO: 491, and VL containing the amino acid sequence of SEQ ID NO: 551.

[0032] In one embodiment, an antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is described herein, in which case the antibody molecule competes with C5aR1 antibody molecules comprising HCDR1 containing the amino acid sequence of SEQ ID NO: 612, HCDR2 containing the amino acid sequence of SEQ ID NO: 732, and HCDR3 containing the amino acid sequence of SEQ ID NO: 852, LCDR1 containing the amino acid sequence of SEQ ID NO: 672, LCDR2 containing the amino acid sequence of SEQ ID NO: 792, and LCDR3 containing the amino acid sequence of SEQ ID NO: 912.

[0033] In one embodiment, an antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is described herein, wherein the antibody molecule binds to an epitope on site II of C5aR1, and the epitope on site II comprises the amino acid residue of SEQ ID NO: 1450.

[0034] In some embodiments, the antibody molecule binds to amino acid residues R175-G189 in SEQ ID NO: 1448.

[0035] In some embodiments, the antibody molecule binds to amino acid residues E180-P183 in SEQ ID NO: 1448.

[0036] In some embodiments, the antibody molecule binds to amino acid residues E180-P184 in SEQ ID NO: 1448.

[0037] In some embodiments, the antibody molecule binds to amino acid residues E178-P183 in SEQ ID NO: 1448.

[0038] In one embodiment, an antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1), comprising VH and / or VL, wherein VH comprises HCDR1 comprising the amino acid sequence of SEQ ID NO: 612, HCDR2 comprising the amino acid sequence of SEQ ID NO: 732, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 852, and wherein VL comprises LCDR1 comprising the amino acid sequence of SEQ ID NO: 672, LCDR2 comprising the amino acid sequence of SEQ ID NO: 792, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 912.

[0039] In one embodiment, the Specified Description describes an antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1), comprising VH and / or VL, wherein VH comprises HCDR1 having an amino acid sequence different from SEQ ID NO: 612 by one or two amino acid residues or less, HCDR2 having an amino acid sequence different from SEQ ID NO: 732 by one or two amino acid residues or less, and HCDR3 having an amino acid sequence different from SEQ ID NO: 852 by one or two amino acid residues or less; and VL comprises LCDR1 having an amino acid sequence different from SEQ ID NO: 672 by one or two amino acid residues or less, LCDR2 having an amino acid sequence different from SEQ ID NO: 792 by one or two amino acid residues or less, and LCDR3 having an amino acid sequence different from SEQ ID NO: 912 by one or two amino acid residues or less.

[0040] In one embodiment, an antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1), comprising VH and / or VL, wherein VH comprises an amino acid sequence having at least 80% identity with the amino acid sequence of SEQ ID NO: 492, and VL comprises an amino acid sequence having at least 70% identity with the amino acid sequence of SEQ ID NO: 552.

[0041] In some embodiments, the antibody molecule comprises VH containing the amino acid sequence of SEQ ID NO: 492, and VL containing the amino acid sequence of SEQ ID NO: 552.

[0042] In one embodiment, an antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1), comprising VH and / or VL, wherein VH comprises HCDR1 comprising the amino acid sequence of SEQ ID NO: 602, HCDR2 comprising the amino acid sequence of SEQ ID NO: 722, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 842, and wherein VL comprises LCDR1 comprising the amino acid sequence of SEQ ID NO: 662, LCDR2 comprising the amino acid sequence of SEQ ID NO: 782, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 902.

[0043] In some embodiments, the antibody molecule comprises VH containing the amino acid sequence of SEQ ID NO: 482, and VL containing the amino acid sequence of SEQ ID NO: 542.

[0044] In one embodiment, an antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1), comprising VH and / or VL, wherein VH comprises HCDR1 comprising the amino acid sequence of SEQ ID NO: 617, HCDR2 comprising the amino acid sequence of SEQ ID NO: 737, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 857, and wherein VL comprises LCDR1 comprising the amino acid sequence of SEQ ID NO: 677, LCDR2 comprising the amino acid sequence of SEQ ID NO: 797, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 917.

[0045] In some embodiments, the antibody molecule comprises VH containing the amino acid sequence of SEQ ID NO: 497, and VL containing the amino acid sequence of SEQ ID NO: 557.

[0046] In some embodiments, the antibody molecule reduces (e.g., inhibits or interferes with) the local enrichment of C5a relative to C5aR1.

[0047] In some embodiments, the antibody molecule has a dissociation constant (K) of less than approximately 100 nM. D) binds to C5aR1. In some embodiments, the antibody molecule has a dissociation constant (K D ) that binds to C5aR1. In some embodiments, the antibody molecule has a dissociation constant (K D ) that binds to C5aR1. In some embodiments, the antibody molecule has a dissociation constant (K D ) that binds to C5aR1. In some embodiments, the antibody molecule has a dissociation constant (K D ) that binds to C5aR1. In some embodiments, the antibody molecule has a dissociation constant (K D ) that binds to C5aR1. In some embodiments, the antibody molecule has a dissociation constant (K D ) that binds to C5aR1. In some embodiments, the antibody molecule has a dissociation constant (K D ) that binds to C5aR1. In some embodiments, the antibody molecule has a dissociation constant (K D ) that binds to C5aR1. In some embodiments, the antibody molecule has a dissociation constant (K D ) that binds to C5aR1. In some embodiments, the antibody molecule has a dissociation constant (K D ) that binds to C5aR1. In some embodiments, the antibody molecule has a dissociation constant (K D ) that binds to C5aR1. In some embodiments, the antibody molecule has a dissociation constant (K D ) that binds to C5aR1. In some embodiments, the antibody molecule has a dissociation constant (K D ) that binds to C5aR1. In some embodiments, the antibody molecule has a dissociation constant (K D ) that binds to C5aR1. In some embodiments, the antibody molecule has a dissociation constant (K D ) that binds to C5aR1. In some embodiments, the antibody molecule has a dissociation constant (K D ) that binds to C5aR1. In some embodiments, the antibody molecule has a dissociation constant (K D ) that binds to C5aR1. In some embodiments, the antibody molecule has a dissociation constant (KD ) binds to C5aR1. In some embodiments, the antibody molecule has a dissociation constant (K) of less than approximately 5 nM. D ) binds to C5aR1. In some embodiments, the antibody molecule has a dissociation constant (K) of less than approximately 3 nM. D ) binds to C5aR1. In some embodiments, the antibody molecule has a dissociation constant (K) of less than approximately 1 nM. D ) binds to C5aR1. In some embodiments, the antibody molecule has a dissociation constant (K) of less than approximately 0.5 nM. D ) binds to C5aR1. In some embodiments, the antibody molecule has a dissociation constant (K) of less than approximately 0.1 nM. D ) binds to C5aR1. In some embodiments, the antibody molecule has a dissociation constant (K) of less than approximately 100 pM. D ) binds to C5aR1. In some embodiments, the antibody molecule has a dissociation constant (K) of less than approximately 80 pM. D ) binds to C5aR1. In some embodiments, the antibody molecule has a dissociation constant (K) of less than approximately 50 pM. D ) binds to C5aR1. In some embodiments, the antibody molecule has a dissociation constant (K) of less than approximately 25 pM. D ) binds to C5aR1. In some embodiments, the antibody molecule has a dissociation constant (K) of less than approximately 10 pM. D It binds to C5aR1.

[0048] In some embodiments, the antibody molecule has a dissociation constant (K) of 1 pM to 500 nM. D ) binds to C5aR1. In some embodiments, the antibody molecule has a dissociation constant (K) of 5 pM to 100 nM. D ) binds to C5aR1. In some embodiments, the antibody molecule has a dissociation constant (K) of 10 pM to 50 nM. D ) binds to C5aR1. In some embodiments, the antibody molecule has a dissociation constant (K) of 500 pM to 10 nM. D ) binds to C5aR1. In some embodiments, the antibody molecule has a dissociation constant (K) of 1 nM to 10 nM. D ) binds to C5aR1. In some embodiments, the antibody molecule has a dissociation constant (K) of 1 nM to 50 nM. D) binds to C5aR1. In some embodiments, the antibody molecule has a dissociation constant (K) of 10 nM to 50 nM. D It binds to C5aR1.

[0049] In some embodiments, the antibody molecule reduces C5a-inducible chemotaxis.

[0050] In some embodiments, antibody molecules can bind to neutrophils.

[0051] In some embodiments, the antibody molecule does not bind to C5aR2 or other GPCRs, or does not bind substantially.

[0052] In one embodiment, an antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is described herein, wherein the antibody molecule comprises a first immunoglobulin variable region that binds to a first epitope and a second immunoglobulin variable region that binds to a second epitope, wherein the first epitope is located at site II of C5aR1 and comprises the amino acid residue of SEQ ID NO: 1450, and the second epitope is located at site I of C5aR1 and comprises the amino acid residue of SEQ ID NO: 1449 or SEQ ID NO: 1452.

[0053] In some embodiments, the polyspecific antibody molecule includes a first immunoglobulin variable region that binds to amino acid residues R175-G189 in SEQ ID NO: 1450.

[0054] In some embodiments, the polyspecific antibody molecule includes a second immunoglobulin variable region that binds to amino acid residues T8-D18 in SEQ ID NO: 1449 or SEQ ID NO: 1452.

[0055] In some embodiments, the polyspecific antibody molecule includes a first immunoglobulin variable region that competes with the C5aR1 antibody molecule, comprising HCDR1 comprising the amino acid sequence of SEQ ID NO: 612, HCDR2 comprising the amino acid sequence of SEQ ID NO: 732, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 852, LCDR1 comprising the amino acid sequence of SEQ ID NO: 672, LCDR2 comprising the amino acid sequence of SEQ ID NO: 792, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 912, and in this case, the second immunoglobulin variable region competes with the C5aR1 antibody molecule, comprising HCDR1 comprising the amino acid sequence of SEQ ID NO: 656, HCDR2 comprising the amino acid sequence of SEQ ID NO: 776, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 896, LCDR1 comprising the amino acid sequence of SEQ ID NO: 715, LCDR2 comprising the amino acid sequence of SEQ ID NO: 835, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 955.

[0056] In one embodiment, the present invention provides a polyspecific antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1), wherein the antibody molecule comprises a first immunoglobulin variable region that binds to a first epitope and a second immunoglobulin variable region that binds to a second epitope, wherein the first epitope is located on site II of C5aR1, and wherein the first immunoglobulin variable region comprises HCDR1 containing the amino acid sequence of SEQ ID NO: 612, HCDR2 containing the amino acid sequence of SEQ ID NO: 732, HCDR3 containing the amino acid sequence of SEQ ID NO: 852, and SEQ ID NO: 67 The second immunoglobulin variable region includes LCDR1 containing the amino acid sequence of 2, LCDR2 containing the amino acid sequence of SEQ ID NO: 792, and LCDR3 containing the amino acid sequence of SEQ ID NO: 912, wherein the second epitope is located on site I of C5aR, and wherein the second immunoglobulin variable region includes HCDR1 containing the amino acid sequence of SEQ ID NO: 656, HCDR2 containing the amino acid sequence of SEQ ID NO: 776, and HCDR3 containing the amino acid sequence of SEQ ID NO: 896, LCDR1 containing the amino acid sequence of SEQ ID NO: 715, LCDR2 containing the amino acid sequence of SEQ ID NO: 835, and LCDR3 containing the amino acid sequence of SEQ ID NO: 955.

[0057] A polyspecific antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) comprises a first immunoglobulin variable region that binds to a first epitope and a second immunoglobulin variable region that binds to a second epitope, wherein the first epitope is located on site II of C5aR1, and the first immunoglobulin variable region comprises HCDR1 containing the amino acid sequence of SEQ ID NO: 1462, HCDR2 containing the amino acid sequence of SEQ ID NO: 1463, HCDR3 containing the amino acid sequence of SEQ ID NO: 1464, LCDR1 containing the amino acid sequence of SEQ ID NO: 1465, SEQ ID NO: The second immunoglobulin variable region includes LCDR2 containing the amino acid sequence of 792, and LCDR3 containing the amino acid sequence of SEQ ID NO: 912, wherein the second epitope is located on site I of C5aR, and wherein the second immunoglobulin variable region includes HCDR1 containing the amino acid sequence of SEQ ID NO: 1456, HCDR2 containing the amino acid sequence of SEQ ID NO: 1457, and HCDR3 containing the amino acid sequence of SEQ ID NO: 1458, LCDR1 containing the amino acid sequence of SEQ ID NO: 1459, LCDR2 containing the amino acid sequence of SEQ ID NO: 1460, and LCDR3 containing the amino acid sequence of SEQ ID NO: 1461.

[0058] In some embodiments, the polyspecific antibody molecule is a bispecific antibody or a biparatope antibody.

[0059] In some embodiments, the polyspecific antibody is a bispecific antibody molecule, or a biparatope antibody molecule, comprising a semi-antibody or fragment thereof having binding specificity to a first epitope, and a semi-antibody or fragment thereof having binding specificity to a second epitope.

[0060] In some embodiments, the polyspecific antibody is a bispecific antibody molecule or a biparatope antibody molecule comprising an scFv or a fragment thereof having binding specificity to a first epitope.

[0061] In some embodiments, the polyspecific antibody is a bispecific antibody molecule or a biparatope antibody molecule comprising an scFv or a fragment thereof having binding specificity to a second epitope.

[0062] In some embodiments, the polyspecific antibody molecule reduces C5a-induced chemotaxis.

[0063] In some embodiments, the polyspecific antibody molecule can bind to neutrophils.

[0064] In some embodiments, the polyspecific antibody molecule does not bind to C5aR2 or other GPCRs, or does not bind substantially.

[0065] In one embodiment, a pharmaceutical composition is described herein that comprises an antibody molecule disclosed herein and optionally further comprises a pharmaceutically acceptable carrier or excipient.

[0066] In one embodiment, a combination comprising the antibody molecule of the present invention and a second therapeutic agent is described herein.

[0067] In some embodiments, the combination includes an antibody molecule that can bind to site I on C5aR1 and an antibody molecule that can bind to site II on C5aR1.

[0068] In some embodiments, the combination includes antibody Ab 329 and antibody Ab 583.

[0069] In some embodiments, the combination includes a second therapeutic agent, in which case the second therapeutic agent includes a low molecular weight (e.g., abacopan).

[0070] In some embodiments, the combination includes a second antibody molecule.

[0071] In some embodiments, the combination includes a second antibody molecule, which is an antibody molecule described herein.

[0072] In some embodiments, the combination includes a second antibody molecule, which is the 3C5, 7F3, or 7h3 of the antibody.

[0073] In one embodiment, a nucleic acid molecule comprising a nucleotide sequence encoding an antibody molecule described herein is described.

[0074] In one embodiment, a vector comprising a nucleic acid antibody molecule described herein is described herein.

[0075] In one embodiment, a host cell containing a nucleic acid molecule described herein is described herein.

[0076] In one embodiment, a method for producing an anti-C5aR1 antibody molecule is described herein, which includes culturing host cells under conditions that enable the production of an antibody molecule, thereby producing the antibody molecule.

[0077] In one embodiment, the method further includes isolating an antibody molecule.

[0078] In one embodiment, the method is a method for treating a disease or disorder, the method comprising administering an effective amount of an antibody molecule, a pharmaceutical composition, or a combination described herein to a subject in need thereof, thereby treating the disorder.

[0079] In some embodiments, the failure is related to C5aR1 (for example, a failure related to the activation of C5aR1).

[0080] In some embodiments, the disorder is an autoimmune disorder.

[0081] In some embodiments, the disorder is rheumatoid arthritis.

[0082] In some embodiments, the disorder is kidney disorder.

[0083] In some embodiments, the disorder is ANCA vasculitis or lupus erythematosus.

[0084] In some embodiments, the disorder is cancer.

[0085] In some embodiments, the method further includes administering a second therapeutic agent to the subject.

[0086] In one embodiment, a method for modulating (e.g., reducing) C5aR1 activity is described herein, which comprises contacting a cell or subject in need with an effective amount of an antibody molecule, a pharmaceutical composition, or a combination thereof as described herein, thereby modulating (e.g., reducing) C5aR1 activity.

[0087] In some embodiments, C5aR1 activity is regulated in vitro, in vitro, or in vivo.

[0088] In one embodiment, an antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is described herein, wherein the antibody molecule binds to an epitope on site I of C5aR1, wherein the epitope on site I comprises the amino acid residue of SEQ ID NO: 1449 or SEQ ID NO: 1452, and wherein the antibody molecule reduces C5a-inducible chemotaxis.

[0089] In one embodiment, an antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is described herein, wherein the antibody molecule binds to an epitope on site I of C5aR1, wherein the epitope on site I comprises the amino acid residue of SEQ ID NO: 1449 or SEQ ID NO: 1452, and wherein the antibody molecule reduces C5a-induced calcium release.

[0090] In one embodiment, an antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is described herein, wherein the antibody molecule binds to an epitope on site I of C5aR1, wherein the epitope on site I comprises the amino acid residue of SEQ ID NO: 1449 or SEQ ID NO: 1452, and wherein the antibody molecule reduces C5a-inducible CD11b expression.

[0091] In one embodiment, an antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is described herein, wherein the antibody molecule binds to an epitope on site I of C5aR1, wherein the epitope on site I comprises the amino acid residue of SEQ ID NO: 1449 or SEQ ID NO: 1452, and wherein the antibody molecule binds to C5aR1 on human neutrophils.

[0092] In one embodiment, an antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is described herein, wherein the antibody molecule binds to an epitope on site I of C5aR1, wherein the epitope on site I comprises the amino acid residue of SEQ ID NO: 1449 or SEQ ID NO: 1452, and wherein the antibody molecule does not substantially bind to C5aR2 or other GPCRs.

[0093] In one embodiment, an antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is described herein, wherein the antibody molecule binds to an epitope on site II of C5aR1, wherein the epitope on site II comprises the amino acid residue of SEQ ID NO: 1450, and wherein the antibody molecule reduces C5a-inducible chemotaxis.

[0094] In one embodiment, an antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is described herein, wherein the antibody molecule binds to an epitope on site II of C5aR1, wherein the epitope on site II comprises the amino acid residue of SEQ ID NO: 1450, and wherein the antibody molecule reduces C5a-induced calcium release.

[0095] In one embodiment, an antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is described herein, wherein the antibody molecule binds to an epitope on site II of C5aR1, wherein the epitope on site II comprises the amino acid residue of SEQ ID NO: 1450, and wherein the antibody molecule reduces C5a-inducible CD11b expression.

[0096] In one embodiment, an antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is described herein, wherein the antibody molecule binds to an epitope on site II of C5aR1, wherein the epitope on site II comprises the amino acid residue of SEQ ID NO: 1450, and wherein the antibody molecule binds to C5aR1 on human neutrophils.

[0097] In one embodiment, an antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is described herein, wherein the antibody molecule binds to an epitope on site II of C5aR1, wherein the epitope on site II comprises the amino acid residue of SEQ ID NO: 1450, and wherein the antibody molecule does not substantially bind to C5aR2 or other GPCRs.

[0098] In one embodiment, an antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is described herein, wherein the antibody molecule binds to epitopes on sites I and II of C5aR1, wherein the epitopes on sites I and II comprise the amino acid residues of SEQ ID NOs. 1449, 1452, and 1450, and wherein the antibody molecule reduces C5a-inducible chemotaxis.

[0099] In one embodiment, an antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is described herein, wherein the antibody molecule binds to epitopes on sites I and II of C5aR1, wherein the epitopes on sites I and II comprise the amino acid residues of SEQ ID NOs. 1449, 1452, and 1450, and wherein the antibody molecule reduces C5a-induced calcium release.

[0100] In one embodiment, an antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is described herein, wherein the antibody molecule binds to epitopes on sites I and II of C5aR1, wherein the epitopes on sites I and II comprise the amino acid residues of SEQ ID NOs. 1449, 1452, and 1450, and wherein the antibody molecule reduces C5a-inducible CD11b expression.

[0101] In one embodiment, an antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is described herein, wherein the antibody molecule binds to epitopes on sites I and II of C5aR1, wherein the epitopes on sites I and II comprise the amino acid residues of SEQ ID NOs: 1449, 1452, and 1450, and wherein the antibody molecule binds to C5aR1 on human neutrophils.

[0102] In one embodiment, an antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is described herein, wherein the antibody molecule binds to epitopes on sites I and II of C5aR1, wherein the epitopes on sites I and II comprise the amino acid residues of SEQ ID NOs. 1449, 1452, and 1450, and wherein the antibody molecule does not substantially bind to C5aR2 or other GPCRs. In embodiments of the present invention, for example, the following items are provided. (Item 1) An antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1), wherein the antibody molecule is Antibody molecules that compete with C5aR1 antibody molecules, including HCDR1 containing SEQ ID NO: 656, HCDR2 containing SEQ ID NO: 776, HCDR3 containing SEQ ID NO: 896, LCDR1 containing SEQ ID NO: 715, LCDR2 containing SEQ ID NO: 835, and LCDR3 containing SEQ ID NO: 955. (Item 2) An antibody molecule capable of binding to C5aR1, wherein the antibody molecule binds to an epitope on site I of C5aR1, and the epitope on site I contains SEQ ID NO: 1449 or SEQ ID NO: 1452. (Item 3) The antibody molecule described in item 2, wherein the antibody molecule is bound to residues T8-D18 of SEQ ID NO: 1449 or SEQ ID NO: 1452. (Item 4) The antibody molecule described in item 3, wherein the antibody molecule is bound to residues T8-G12 of SEQ ID NO: 1449 or SEQ ID NO: 1452. (Item 5) The antibody molecule described in item 3, wherein the antibody molecule is bound to residues T8, D10, Y11, Y14 and / or D15 of SEQ ID NO: 1449 or SEQ ID NO: 1452. (Item 6) An antibody molecule capable of binding to C5aR1, comprising a heavy chain variable region (VH) and a light chain variable region (VL), The aforementioned VH has at least 80% identity with any of sequence numbers 481 to 541, An antibody molecule in which the aforementioned VL has at least 70% identity with any of the sequence numbers 542 to 600. (Item 7) An antibody molecule capable of binding to complement C5aR1, comprising VH and / or VL, The aforementioned VH is, i. HCDR1 containing sequence number 656, ii. HCDR2 including sequence number 776, and iii. Contains HCDR3 including sequence number 896, and The aforementioned VL is, i. LCDR1 containing sequence number 715, ii. LCDR2 including sequence number 835, and iii. An antibody molecule containing LCDR3, which contains SEQ ID NO: 955. (Item 8) An antibody molecule capable of binding to C5aR1, comprising VH and / or VL, The aforementioned VH is, i. HCDR1 containing sequence number 1456, ii. HCDR2 including sequence number 1457, and iii. Containing HCDR3 including sequence number 1458, The aforementioned VL is, i. LCDR1 containing sequence number 1459, ii. LCDR2 including sequence number 1460, and iii. An antibody molecule containing LCDR3, including sequence number 1461. (Item 9) An antibody molecule capable of binding to C5aR1, comprising VH and / or VL, The aforementioned VH has at least 80% identity with SEQ ID NO: 536, and The aforementioned VL is an antibody molecule that contains at least 70% identity with SEQ ID NO: 595. (Item 10) The antibody molecule according to any one of items 7 to 9, wherein VH contains SEQ ID NO: 536 and VL contains SEQ ID NO: 595. (Item 11) An antibody molecule capable of binding to complement C5aR1, comprising VH and / or VL, The aforementioned VH is, i. HCDR1 containing sequence number 603, ii. HCDR2 including sequence number 723, and iii. Contains HCDR3 including sequence number 843, The aforementioned VL is, i. LCDR1 containing sequence number 663, ii. LCDR2 including sequence number 783, and iii. An antibody molecule containing LCDR3, including SEQ ID NO: 903. (Item 12) The antibody molecule according to item 11, wherein VH contains SEQ ID NO: 483 and VL contains SEQ ID NO: 543. (Item 13) An antibody molecule capable of binding to C5aR1, comprising VH and / or VL, The aforementioned VH is, i. HCDR1 containing sequence number 611, ii. HCDR2 including sequence number 731, and iii. Containing HCDR3 containing sequence number 851, The aforementioned VL is, i. LCDR1 containing sequence number 671, ii. LCDR2 including sequence number 792, and iii. An antibody molecule containing LCDR3, including sequence number 911. (Item 14) The antibody molecule according to item 13, wherein VH contains SEQ ID NO: 491 and VL contains SEQ ID NO: 551. (Item 15) An antibody molecule that can bind to C5aR1, wherein the antibody molecule is Antibody molecules that compete with C5aR1 antibody molecules, including HCDR1 containing SEQ ID NO: 612, HCDR2 containing SEQ ID NO: 732, HCDR3 containing SEQ ID NO: 852, LCDR1 containing SEQ ID NO: 672, LCDR2 containing SEQ ID NO: 792, and LCDR3 containing SEQ ID NO: 912. (Item 16) An antibody molecule capable of binding to C5aR1, wherein the antibody molecule binds to an epitope on site II of C5aR1, and the epitope on site II contains SEQ ID NO: 1450. (Item 17) The antibody molecule described in item 16, wherein the antibody molecule is bound to amino acid residues R175-G189 of sequence number 1448. (Item 18) The antibody molecule described in item 17, wherein the antibody molecule is bound to amino acid residues E180-P183 of sequence number 1448. (Item 19) The antibody molecule described in item 17, wherein the antibody molecule is bound to amino acid residues E180-P184 of sequence number 1448. (Item 20) The antibody molecule described in item 17, wherein the antibody molecule is bound to amino acid residues E178-P183 of sequence number 1448. (Item 21) An antibody molecule capable of binding to C5aR1, comprising VH and / or VL, The aforementioned VH is, i. HCDR1 containing sequence number 612, ii. HCDR2 including sequence number 732, and iii. Contains HCDR3 including sequence number 852, The aforementioned VL is, i. LCDR1 containing sequence number 672, ii. LCDR2 including sequence number 792, and iii. An antibody molecule containing LCDR3, including sequence number 912. (Item 22) An antibody molecule capable of binding to C5aR1, comprising VH and / or VL, The aforementioned VH is, i. HCDR1 containing sequence number 1462, ii. HCDR2 including sequence number 1463, and iii. Containing HCDR3 including sequence number 1464, The aforementioned VL is, i. LCDR1 containing sequence number 1465, ii. LCDR2 including sequence number 1466, and iii. An antibody molecule containing LCDR3, including SEQ ID NO: 1467. (Item 23) An antibody molecule capable of binding to C5aR1, comprising VH and / or VL, The aforementioned VH is, i. Sequence ID 612 refers to HCDR1 with one or two or fewer amino acid residues that differ. ii. Sequence ID 732 refers to HCDR2 with one or two or fewer amino acid residues that are different, and iii. Sequence ID 852 contains HCDR3 with one or fewer amino acid residues that differ from the original, The aforementioned VL is, i. Sequence ID 672 refers to LCDR1 with one or fewer amino acid residues that differ. ii. Sequence ID 792 refers to LCDR2 with one or two or fewer amino acid residues different, and iii. Sequence ID 912 is an antibody molecule containing LCDR3 with one or fewer amino acid residues that differ. (Item 24) An antibody molecule capable of binding to C5aR1, comprising VH and / or VL, The aforementioned VH has at least 80% identity with sequence number 492, and The aforementioned VL is an antibody molecule that contains at least 70% identity with SEQ ID NO: 552. (Item 25) The antibody molecule according to any one of items 21 to 24, wherein VH contains SEQ ID NO: 492 and VL contains SEQ ID NO: 552. (Item 26) An antibody molecule capable of binding to C5aR1, comprising VH and / or VL, The aforementioned VH is, i. HCDR1 containing sequence number 602, ii. HCDR2 including sequence number 722, and iii. Contains HCDR3 including sequence number 842, The aforementioned VL is, i. LCDR1 containing sequence number 662, ii. LCDR2 including sequence number 782, and iii. An antibody molecule containing LCDR3, including sequence number 902. (Item 27) The antibody molecule according to item 26, wherein VH contains SEQ ID NO: 482 and VL contains SEQ ID NO: 542. (Item 28) An antibody molecule capable of binding to C5aR1, comprising VH and / or VL, The aforementioned VH is, i. HCDR1 containing sequence number 617, ii. HCDR2 including sequence number 737, and iii. Contains HCDR3 including sequence number 857, The aforementioned VL is, i. LCDR1 containing sequence number 677, ii. LCDR2 including sequence number 797, and iii. An antibody molecule containing LCDR3, including SEQ ID NO: 917. (Item 29) The antibody molecule according to item 28, wherein VH contains sequence number 497 and VL contains sequence number 557. (Item 30) The antibody molecule described in any one of items 1 to 29 reduces (e.g., inhibits or prevents) the local enrichment of C5a relative to C5aR1. (Item 31) The aforementioned antibody molecule has a dissociation constant (K) less than approximately 100 nM. D An antibody molecule that binds to C5aR1, as described in any one of items 1 to 30. (Item 32) The antibody molecule has a K content of 10 pM to 50 nM. D The antibody molecule described in item 31, which binds to C5aR1. (Item 33) The antibody molecule described in any one of items 1 to 32 reduces C5a-inducible chemotaxis. (Item 34) The antibody molecule described in any one of items 1 to 33, wherein the antibody molecule is capable of binding to neutrophils. (Item 35) The antibody molecule described in any one of items 1 to 34, wherein the antibody molecule does not bind to C5aR2 or other GPCRs, or does not bind substantially to them. (Item 36) A polyspecific antibody molecule that can bind to C5aR1, wherein the antibody molecule is It comprises a first immunoglobulin variable region that binds to a first epitope, and a second immunoglobulin variable region that binds to a second epitope, The first epitope is located at site II of C5aR1, including sequence number 1450, and A polyspecific antibody molecule in which the second epitope is located at site I of C5aR1, including SEQ ID NO: 1449 or SEQ ID NO: 1452. (Item 37) The first immunoglobulin variable region is a multispecific antibody molecule described in item 36, which binds to amino acid residues R175-G189 of SEQ ID NO: 1450. (Item 38) The second immunoglobulin variable region is a multispecific antibody molecule as described in item 36, which binds to amino acid residues T8-D18 of SEQ ID NO: 1449 or SEQ ID NO: 1452. (Item 39) The first immunoglobulin variable region is, Competing with C5aR1 antibody molecules, including HCDR1 containing SEQ ID NO: 612, HCDR2 containing SEQ ID NO: 732, HCDR3 containing the amino acid sequence of SEQ ID NO: 852, LCDR1 containing SEQ ID NO: 672, LCDR2 containing SEQ ID NO: 792, and LCDR3 containing SEQ ID NO: 912, The second immunoglobulin variable region is A polyspecific antibody molecule that competes with the C5aR1 antibody molecule, as described in item 36, comprising HCDR1 containing SEQ ID NO: 656, HCDR2 containing SEQ ID NO: 776, HCDR3 containing SEQ ID NO: 896, LCDR1 containing SEQ ID NO: 715, LCDR2 containing SEQ ID NO: 835, and LCDR3 containing SEQ ID NO: 955. (Item 40) It was a multispecific antibody molecule that could bind to complement component 5a receptor 1 (C5aR1). And the antibody molecule, It comprises a first immunoglobulin variable region that binds to a first epitope, and a second immunoglobulin variable region that binds to a second epitope, The aforementioned first epitope is located at site II of C5aR1. The first immunoglobulin variable region includes HCDR1 containing SEQ ID NO: 612, HCDR2 containing SEQ ID NO: 732, and HCDR3 containing SEQ ID NO: 852, LCDR1 containing SEQ ID NO: 672, LCDR2 containing SEQ ID NO: 792, and LCDR3 containing SEQ ID NO: 912. The aforementioned second epitope is located at site I of C5aR, and A polyspecific antibody molecule in which the second immunoglobulin variable region comprises HCDR1 containing SEQ ID NO: 656, HCDR2 containing SEQ ID NO: 776, HCDR3 containing SEQ ID NO: 896, LCDR1 containing the amino acid sequence of SEQ ID NO: 715, LCDR2 containing SEQ ID NO: 835, and LCDR3 containing SEQ ID NO: 955. (Item 41) A polyspecific antibody molecule capable of binding to complement C5aR1, wherein the antibody molecule is It comprises a first immunoglobulin variable region that binds to a first epitope, and a second immunoglobulin variable region that binds to a second epitope, The aforementioned first epitope is located at site II of C5aR1. The first immunoglobulin variable region includes HCDR1 containing SEQ ID NO: 1462, HCDR2 containing SEQ ID NO: 1463, HCDR3 containing SEQ ID NO: 1464, LCDR1 containing SEQ ID NO: 1465, LCDR2 containing the amino acid sequence of SEQ ID NO: 1466, and LCDR3 containing SEQ ID NO: 1467. The aforementioned second epitope is located at site I of C5aR, and A polyspecific antibody molecule in which the second immunoglobulin variable region comprises HCDR1 containing SEQ ID NO: 1456, HCDR2 containing SEQ ID NO: 1457, HCDR3 containing SEQ ID NO: 1458, LCDR1 containing SEQ ID NO: 1459, LCDR2 containing SEQ ID NO: 1460, and LCDR3 containing SEQ ID NO: 1461. (Item 42) A polyspecific antibody molecule according to any one of items 36 to 41, wherein the antibody is a bispecific antibody or a biparatope antibody. (Item 43) The polyspecific antibody molecule according to item 42, wherein the bispecific antibody molecule or biparatope antibody molecule comprises a semi-antibody or fragment thereof having binding specificity to the first epitope, and a semi-antibody or fragment thereof having binding specificity to the second epitope. (Item 44) The polyspecific antibody according to item 43, wherein the bispecific antibody molecule or biparatope antibody molecule comprises an scFv or a fragment thereof having binding specificity to the first epitope. (Item 45) The polyspecific antibody according to item 43, wherein the bispecific antibody molecule or biparatope antibody molecule comprises an scFv or a fragment thereof having binding specificity to the second epitope. (Item 46) The aforementioned antibody molecule is a polyspecific antibody molecule according to any one of items 36 to 45, which reduces C5a-inducible chemotaxis. (Item 47) The aforementioned antibody molecule is a polyspecific antibody molecule according to any one of items 36 to 46, which can bind to neutrophils. (Item 48) The antibody molecule does not bind to C5aR2 or other GPCRs, or is substantially bound to them. No, a polyspecific antibody molecule as described in any one of items 36-47. (Item 49) A pharmaceutical composition comprising an antibody molecule described in any one of items 1 to 48, and further comprising optionally pharmaceutically acceptable carriers or excipients. (Item 50) A combination comprising an antibody molecule described in any of items 1-48 and a second therapeutic agent. (Item 51) The combination described in item 50, wherein the second therapeutic agent includes a low molecular weight (e.g., abacopan). (Item 52) The combination described in item 50, wherein the second therapeutic agent includes a second antibody molecule. (Item 53) The combination described in item 52, wherein the second antibody molecule is an antibody molecule described in any one of items 1 to 48. (Item 54) The combinations described in item 53, wherein the second antibody molecule is antibody 3C5, 7F3, or 7h3. (Item 55) A nucleic acid molecule containing a nucleotide sequence that encodes an antibody molecule as described in any one of items 1 to 48. (Item 56) A vector containing the nucleic acid molecule described in item 55. (Item 57) A host cell containing the nucleic acid molecule described in item 55, or the vector described in item 56. (Item 58) A method for producing an anti-C5aR1 antibody molecule, comprising culturing host cells described in item 57 under conditions that enable the production of an antibody molecule, thereby producing the antibody molecule. (Item 59) The method according to item 58, further comprising isolating the antibody molecule. (Item 60) A method for treating a disease or disorder, comprising administering an effective amount of an antibody molecule described in any of items 1 to 48, a pharmaceutical composition described in item 49, or a combination described in any of items 50 to 54 to a subject in need thereof, thereby treating the disorder. (Item 61) The method according to item 60, wherein the disorder is related to C5aR1 (for example, related to C5aR1 activation). (Item 62) The method according to item 60 or 61, wherein the disorder is an autoimmune disorder. (Item 63) The method according to item 62, wherein the disorder is rheumatoid arthritis. (Item 64) The method according to item 60 or 61, wherein the impairment is renal impairment. (Item 65) The method according to item 60 or 61, wherein the disorder is ANCA vasculitis or lupus erythematosus. (Item 66) The method according to item 60 or 61, wherein the disease or disorder is cancer. (Item 67) The method according to any one of items 60 to 66, further comprising administering a second therapeutic agent to the subject. (Item 68) A method for regulating (e.g., reducing) C5aR1 activity, comprising contacting a cell or subject in need of such regulation with an effective amount of an antibody molecule described in any of items 1 to 48, a pharmaceutical composition described in item 49, or a combination described in any of items 50 to 54, thereby regulating (e.g., reducing) the C5aR1 activity. (Item 69) The method according to item 68, wherein the C5aR1 activity is regulated in vitro, in vitro, or in vivo. [Brief explanation of the drawing]

[0103] [Figure 1] Figure 1 shows that a combination of site I and site II antibodies, or a diparatope antibody, that binds to sites I and II on C5aR1, enables the formation of large clusters that would not be formed by equivalent monospecific antibodies.

[0104] [Figure 2]Figures 2A–2D are a series of graphs showing the functionality of exemplary anti-C5aR1 antibodies quantified by the GeneBLAzer assay (clone 66 (Figure 2A), clone 11-v2 (Figure 2B), clone 583 (Figure 2C), and clone 329 (Figure 2D)). The concentration of C5a was plotted on the x-axis, and the activation rate of C5aR1 was plotted on the y-axis. The dose response of C5a in the absence of an antagonist is plotted in black, and the dose response in the presence of various antibody concentrations is plotted in gray shading.

[0105] [Figure 3] Figures 3A–3C are a series of graphs showing exemplary combinations of site I and site II antibodies (clones 66 and 79, respectively) (Figure 3C), which were more effective in the GeneBLAzer assay than either antibody alone (clone 66 (Figure 3A) and clone 79 (Figure 3B)).

[0106] [Figure 4-1] Figure 4A shows a superposition model of mAb 329 interacting with ECL2 of C5aR1. Figure 4B shows the residues of LCDR1 and 3 interacting with ECL2 of C5aR1. [Figure 4-2] Figure 4C is an exemplary cartoon diagram of the crystal structure of the 329-Fab-peptide complex (left panel). VH and VL are shown in ribbon representation, and the ECL2 cyclic peptide is shown as a sphere. The center panel shows the primary structure of the cyclic peptide and its 3D structure as seen in the Fab-peptide complex, with the highlighted residue (REEYFPPKVL) derived from ECL2 of human C5aR1. The peptide exists in a hairpin loop structure, similar to that found in the C5aR1 receptor molecule. The right panel shows the binding and molecular interactions of the cyclic peptide with the Fab domain. Hydrogen bonds are shown by dotted lines, and the relevant residues are labeled. The Fab-peptide interaction is primarily with the CDR residue of the VL domain, with the E180 residue appearing to be responsible for the majority of the interaction with the antibody.

[0107] [Figure 5-1] Figure 5A shows the results of alanine scanning mutations related to the interaction between mab583 and site I. The N-terminal amino acid sequence of C5aR1 is listed at the top of the figure. Glycosylation sites are indicated by rectangular boxes. The only naturally occurring glycosylation site is at position N5. Other sites were introduced by mutation induction. Mutations that eliminated binding of clone 583 are circled. Sulfated tyrosines at positions 11 and 14 are indicated by asterisks. Figure 5B shows the results of alanine scanning mutations related to the interaction between mab66 and site I. Mutations that eliminated binding of clone 66 are circled. Sulfated tyrosines at positions 11 and 14 are indicated by asterisks. [Figure 5-2] Figure 5C shows the results of Ala scanning mutations in ECL1. Figure 5D shows the results of Ala scanning mutations in ECL3. Figure 5E shows the structural positions of ECL1 and ECL3 relative to ECL2. [Figure 5-3] Figure 5F shows ala scanning mutations in C5aR1 ECL2 in clones 11, 336, and 329. Mutations that eliminated the binding are circled.

[0108] [Figure 6] Figure 6 is a graph showing the binding of an exemplary anti-C5aR1 antibody to human neutrophils.

[0109] [Figure 7] Figure 7 is a graph showing C5aR1 antagonism by exemplary anti-C5aR1 antibodies in the GeneBLAzer assay, compared to isotype control (HYHEL-10), non-antagonist control, several reference anti-C5aR1 antibodies (i.e., antibodies 3C5, 7F3, and 7h3), and the small molecule inhibitor avacopan.

[0110] [Figure 8]Figures 8A–8F are a series of graphs showing cell chemotaxis induced by exemplary anti-C5aR1 antibodies at various concentrations: 11v2 (Figure 8A), 66 (Figure 8B), 322 (Figure 8C), 329 (Figure 8D), 336v2-1 (Figure 8E), and 583 (Figure 8F).

[0111] [Figure 9] Figures 9A–9D are a series of graphs showing the chemotaxis of neutrophils induced by exemplary anti-C5aR1 antibodies 11v2 (Figure 9A), 66 (Figure 9B), 329 (Figure 9C), and 583 (Figure 9D) at various concentrations.

[0112] [Figure 10] Figures 10A to 10I are a series of graphs showing the inhibition of C5aR1 chemotaxis using different anti-C5aR1 antibody clone combinations, namely clone 11 + clone 66 (Figure 10A), clone 66 + clone 329 (Figure 10B), clone 66 + clone 336v2 (Figure 10C), clone 11 + clone 583 (Figure 10D), clone 583 + clone 329 (Figure 10E), clone 583 + clone 336v2 (Figure 10F), clone 11 + clone 322 (Figure 10G), clone 322 + clone 329 (Figure 10H), and clone 322 + clone 336v2 (Figure 10I).

[0113] [Figure 11] Figures 11A–11C are a series of graphs showing C5aR1 inhibition of C5a-induced calcium efflux in U937 cells by C5aR1 antibodies, namely clone 11v2 (Figure 11A), clone 329 (Figure 11B), and clone 583 (Figure 11C).

[0114] [Figure 12] Figures 12A-12C are a series of graphs showing C5aR1 inhibition of C5a-induced calcium efflux in human neutrophil cells by C5aR1 antibody clones 11v2 (Figure 12A), 329 (Figure 12B), and 583 (Figure 12C).

[0115] [Figure 13] Figures 13A–13B are a series of graphs showing inhibition of C5aR1 signaling by exemplary anti-C5aR1 antibodies in the GeneBLAzer assay (Figure 13A), and inhibition of C5a-induced calcium flow in C5aR1-U937 cells by the same exemplary anti-C5aR1 antibody (Figure 13B). -9.5, -9, -8.5, and -8 correspond to concentrations of antibody 329 of 10⁻⁹ M, 10⁻⁹ M, 10⁻⁹ M, 10⁻⁹ M, and 10⁻⁹ M, respectively.

[0116] [Figure 14] Figures 14A–14C are a series of graphs showing the inhibition of C5aR1 signaling in the GeneBLAzer assay by antibody 329 (Figure 14A), avacopan (Figure 14B), or a combination of antibody 329 and avacopan (Figure 14C).

[0117] [Figure 15] Figures 15A-15C are a series of graphs showing the inhibition of C5aR1 signaling in the GeneBLAzer assay by antibody 329 (Figure 15A), antibody 66 (Figure 15B), or a combination of antibody 329 and antibody 66 (Figure 15C).

[0118] [Figure 16] Figures 16A–16B are a series of graphs showing the binding of site II antibody 329 alone, or in combination with site I antibody (either clone 66 (Figure 16A) or clone 583 (Figure 16B)), to cells expressing C5aR1 on their surface. HYHEL10 isotype controls are included for comparison.

[0119] [Figure 17] Figures 17A-17C are a series of graphs showing the inhibition of calcium saturation in C5aR1-U937 cells by antibody 66 (Figure 17A), antibody 329 (Figure 17B), or a combination of antibody 66 and antibody 329 (Figure 17C).

[0120] [Figure 18] Figures 18A-18C are a series of graphs showing the inhibition of chemotaxis by antibody 583 (Figure 18A), antibody 329 (Figure 18B), or a combination of antibody 583 and antibody 329 (Figure 18C).

[0121] [Figure 19] Figures 19A-19E are a series of graphs showing C5aR1-mediated Gα signaling when two paratope antibodies are used, specifically clone 329 IgG4 with 583scFv linked to the light chain (Figure 19A), clone 336 IgG4 with 583scFv linked to the light chain (Figure 19B), clone 11 IgG4 with 583scFv linked to the heavy chain (Figure 19C), clone 329 IgG4 with 583scFv linked to the heavy chain (Figure 19D), and clone 336 IgG4 with 583scFv linked to the heavy chain (Figure 19E).

[0122] [Figure 20-1] Figures 20A–20G are a series of graphs showing C5aR1-mediated inhibition of C5aR1-mediated Gα signaling in the presence of C5-alpha for two paratope antibodies targeting both site I and site II, including clone 329 IgG4 with clone 583scFv linked to the heavy chain (Figure 20A), clone 329 IgG4 with clone 583scFv linked to the light chain (Figure 20B), clone 336 IgG4 with clone 583scFv linked to the heavy chain (Figure 20C), clone 11 IgG4 with clone 583scFv linked to the heavy chain (Figure 20D), as well as two IgG4 antibodies, clone 329 and clone 583 (Figure 20E), IgG-clone 329 only (Figure 20F), and clone 583 only (Figure 20G). [Figure 20-2] Same as above. [Figure 20-3] Same as above.

[0123] [Figure 21-1]Figures 21A-21C are a series of graphs showing C5aR1-mediated inhibition of CD11b expression in C5aR1 mice (Jackson Laboratories). Bp = diparatope antibody. Figure 21A shows blood samples taken 10 minutes before, 1 minute after, 5 minutes after, and 2 hours after injection, after injecting clone 329, clone 583, or diparatope antibody 5 hours after treatment with avacopan. Figure 21B shows blood samples taken 5 minutes before, 1 minute after, 5 minutes after, and 2 hours after injection, after injecting clone 329, clone 583, or diparatope antibody 5 hours after treatment with avacopan. Figure 21C shows blood samples taken 1 hour after treatment with avacopan, after injection of clone 329, clone 583, or diparatope antibody, at 5 minutes before, 1 minute after, 5 minutes after, and 2 hours after injection. [Figure 21-2] Same as above. [Figure 21-3] Same as above.

[0124] [Figure 22] Figures 22A-22D are a series of graphs showing the inhibition of C5aR1 signaling in the GeneBLAzer assay by site I-targeted antibody 3c5 (Figure 22A), site II-targeted antibody shc7 (Figure 22B), a combination of the two antibodies (Figure 22C), or a biparatope antibody containing one antigen-binding domain from 3c5 and one antigen-binding domain from shc7 (Figure 22D). [Modes for carrying out the invention]

[0125] In particular, the present invention provides an anti-C5aR1 antibody that can efficiently inhibit C5a-C5aR inhibition and block C5a signaling in the presence of high concentrations of C5a. Furthermore, the present invention provides a method and composition for inhibiting C5aR1 and / or C5a signaling by targeting both site I and site II of C5aR1. Simultaneous targeting of site I and site II significantly enhances the inhibitory activity.

[0126] The disclosures herein are, at least in part, based on the identification of antagonistic antibody molecules that inhibit soluble C5a from binding to and / or signaling C5aR1. While we do not wish to be bound by theory, in some embodiments, the antibody molecules described herein have one or more of the following properties: targeting an epitope on C5aR1 to sterically interfere with C5a binding and allosterically inhibit C5aR1 from fitting into the signaling structure; inhibiting competition and substitution by C5a with strong binding affinity / avidity and a slow dissociation rate; having virtually no cross-reactivity with structurally homologous C5aR2 or other GPCRs; lacking Fc effector function and inhibiting C5aR1-expressing cells from exerting cytotoxic effects; or having beneficial biophysical, pharmacokinetic, and / or biodistribution properties that enable long-term therapeutic effects compared to small molecule antagonists.

[0127] C5a / C5aR1 interaction The binding of C5a to C5aR1 is the final event in the complement pathway and can have multifaceted effects. One major consequence is the migration, transport, and / or activation of leukocytes, including neutrophils, though not limited to these. By targeting the final stage of C5aR1 signaling, the rest of the complement system can continue to function fully. Inhibition of C5aR1 with the small molecule allosteric antagonist CCX168 (avacopan) has been clinically demonstrated and is in a Phase III clinical trial in patients with ANCA vasculitis. The antibody molecules described herein can reduce abnormal inflammation and / or tissue damage by inhibiting (e.g., blocking) C5aR1 signaling and the subsequent chemotaxis and activation of leukocytes at the site of inflammation, at least in part. Antibody therapies targeting C5aR1 offer an approach to specific inhibition of C5a / C5aR1 signaling (e.g., blocking C5a signaling in the presence of high concentrations of C5a). Furthermore, the biophysical properties, biodistribution, and / or PK properties of antibody molecules are often superior to those of small molecule drugs, such as a long serum half-life, reduced administration frequency, high specificity and / or affinity, and / or a favorable development potential profile. Moreover, many small molecules that target GPCRs often exhibit reactivity to multiple GPCRs due to their conserved normative structure and a small number of contact residues. By engaging with multiple contact sites throughout the structural landscape, antibodies can offer improved specificity.

[0128] Due to the diparatope nature of C5a, which allows it to independently bind to two distinct regions of C5aR1, antagonistic behavior can be mimicked by engaging C5aR1 with diparatope antibodies targeting binding site I and binding site II, providing a potent strategy to inhibit C5a signaling. For example, engaging sites I and II can orthosterically disrupt both C5a binding sites, providing the strongest antagonistic effect and potentially increasing avidity and / or cross-linking receptors. While we do not wish to be constrained by theory, in some embodiments, intramolecular or intermolecular engagement of sites I and II by a single diparatope antibody could mask multiple (e.g., all) C5a binding sites, while simultaneously enhancing the dissociation rate and residence time of the antibody molecule. The lifespan of neutrophils is estimated to be less than 24 hours. Therefore, in some embodiments, antibody molecules with long residence times could potentially occupy C5aR1 for the entire lifespan of the cell. While we do not wish to be constrained by theory, in some embodiments, the antibody molecules described herein are thought to be able to improve their properties in terms of pharmacodynamic (PD) enhancement by improving residence time compared to small molecule antagonists (e.g., improved target engagement, improved pharmacokinetics (PK), and improved efficiency).

[0129] This specification discloses antibody molecules that bind to C5aR1, such as human C5aR1, with high affinity and specificity. Some of the antibody molecules described herein have been beneficially improved in their ability to reduce (e.g., inhibit, block, or neutralize) one or more biological activities of C5aR1. Nucleic acid molecules encoding antibody molecules, expression vectors, host cells, compositions (e.g., pharmaceutical compositions), kits, and methods for producing antibody molecules are also provided. The antibody molecules and pharmaceutical compositions disclosed herein can be used (alone or in combination with other agents or therapeutic modalities) to treat, prevent and / or diagnose disorders and conditions associated with C5aR1, such as ANCA vasculitis.

[0130] definition As used herein, the articles "a" and "an" refer to one or more (i.e., at least one) grammatical objects of the article.

[0131] Unless the context clearly indicates otherwise, the term “or” is used herein to mean the term “and / or” and is interchangeable with the term “and / or”.

[0132] "Approximately" and "about" generally mean an acceptable degree of error in the measured quantity, taking into account the nature or precision of the scale. Exemplary degrees of error are within 20 percent (%) of a given value or range of values, typically within 10 percent, and more typically within 5 percent.

[0133] The compositions and methods disclosed herein include polypeptides and nucleic acids having a specified sequence, or a sequence substantially identical or similar to such sequence, for example, a sequence that is at least 85%, 90%, 95% or more identical to the specified sequence.

[0134] In the context of amino acid sequences, the term “substantially identical” is used herein to mean that the first and second amino acid sequences may have a common structural domain and / or common functional activity, such that the first amino acid sequence contains, in sufficient or minimal numbers, amino acid residues that are identical to those in the second amino acid sequence, or ii) amino acid residues that are conserved substitutions of aligned amino acid residues in the second amino acid sequence. For example, an amino acid sequence containing a common structural domain that has at least about 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to a reference sequence such as the sequence provided herein.

[0135] In the context of nucleotide sequences, the term “substantially identical” is used herein to mean that the first nucleic acid sequence contains a sufficient or minimum number of nucleotides identical to the aligned nucleotides in the second nucleic acid sequence, such that the first and second nucleotide sequences encode a polypeptide having common functional activity, or a common structural polypeptide domain, or a common functional polypeptide activity. For example, a nucleotide sequence having at least about 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to a reference sequence such as the sequence provided herein.

[0136] The term "functional variant" refers to a polypeptide that has an amino acid sequence substantially identical to the natural sequence, or is encoded by a nucleotide sequence substantially identical to the natural sequence, and is capable of having one or more activities of the natural sequence.

[0137] The calculation of homology or sequence identity between sequences (these terms are used interchangeably herein) is carried out as follows:

[0138] To determine the percentage of identity between two nucleic acid sequences or between two nucleic acid sequences, the sequences are aligned for optimal comparison (for example, gaps may be introduced in one or both of the first and second amino acid sequences or nucleic acid sequences for optimal alignment, and non-homologous sequences may be ignored for comparison purposes). In a typical embodiment, the length of the reference sequence aligned for comparison purposes is at least 30%, e.g., at least 40%, 50%, 60%, e.g., at least 70%, 80%, 90%, 100% of the length of the reference sequence. Then, amino acid residues or nucleotides at the corresponding amino acid or nucleotide positions are compared. The molecules are identical at the position when the position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence.

[0139] The percentage of identity between two sequences is a function of the number of identical positions shared by those sequences, taking into account the number of gaps that need to be introduced for optimal alignment of the two sequences, and the length of each gap.

[0140] The comparison of sequences and the determination of the percentage of identity between two sequences may be performed using mathematical algorithms. In one embodiment, the percentage of identity between two amino acid sequences is determined using the algorithm of Needleman and Wunsch ((1970) J.Mol.Biol.48:444-453), incorporated into the GAP program of the GCG software package (available at www.gcg.com), using either a Blossum 62 matrix or a PAM250 matrix, and gap weights of 16, 14, 12, 10, 8, 6, or 4, and length weights of 1, 2, 3, 4, 5, or 6. In a particular embodiment, the percentage of identity between two nucleotide sequences is determined using the GAP program of the GCG software package (available at www.gcg.com), using the NWSgapdna.CMP matrix, and gap weights of 40, 50, 60, 70, or 80, and length weights of 1, 2, 3, 4, 5, or 6. One suitable parameter set (and the one that should be used unless otherwise specified) is the Blossum 62 scoring matrix with 12 gap penalties, 4 gap extension penalties, and 5 frame shift gap penalties.

[0141] The percentage of identity between two amino acid or nucleotide sequences may be determined using the algorithm of E. Meyers and W. Miller ((1989) CABIOS, 4:11-17), incorporated into the ALIGN program (version 2.0), using the PAM120 weight residue table, a gap length penalty of 12, and a gap length penalty of 4.

[0142] The nucleic acid and protein sequences described herein may be used, for example, as “query sequences” for conducting searches against public databases for the purpose of identifying other family species or related sequences. Such searches are performed by Altschul, et al. The NBLAST and XBLAST programs (version 2.0) from al. (1990) J. Mol. Biol. 215:403-10 may be used. A BLAST nucleotide search may be performed using the NBLAST program, score=100, and word length=12 to obtain nucleotide sequences homologous to the nucleic acids described herein. A BLAST protein search may be performed using the XBLAST program, score=50, and word length=3 to obtain amino acid sequences homologous to the protein molecules described herein. To obtain gapped alignment for comparative purposes, Gapped BLAST may be used as described in Altschul et al., (1997) Nucleic Acids Res. 25:3389-3402. When using the BLAST and gapped BLAST programs, the default parameters for each program (e.g., XBLAST and NBLAST) may be used. See www.ncbi.nlm.nih.gov.

[0143] As used herein, the term "hybridizes under low stringency, medium stringency, high stringency, or very high stringency conditions" describes the conditions of hybridization and washing. Guidance for performing the hybridization reactions can be found in Current Protocols in Molecular Biology, John Wiley & Sons, N.Y. (1989), 6.3.1-6.3.6, which is incorporated by reference. Both aqueous and non-aqueous methods are described in that reference and either can be used. The specific hybridization conditions referred to herein are as follows: 1) Low stringency hybridization conditions in 6X sodium chloride / sodium citrate (SSC) at about 45°C, followed by two washes in 0.2X SSC, 0.1% SDS at at least 50°C (the wash temperature can be raised to 55°C for low stringency conditions); 2) Medium stringency hybridization conditions in 6X SSC at about 45°C, followed by one or more washes in 0.2X SSC, 0.1% SDS at 60°C; 3) High stringency hybridization conditions in 6X SSC at 45°C, followed by one or more washes in 0.2X SSC, 0.1% SDS at 65°C; and preferably, 4) Very high stringency hybridization conditions in 0.5M sodium phosphate, 7% SDS at 65°C, followed by one or more washes in 0.2X SSC, 1% SDS at 65°C. Condition 4) of very high stringency conditions is the appropriate condition and should be used unless otherwise specified.

[0144] The molecules described herein may have additional conservative substitutions or non-essential amino acid substitutions that do not substantially affect their function.

[0145] The term "amino acid" is intended to encompass all molecules that contain both an amino functionality and an acid functionality, whether natural or synthetic, and that can be included in a natural amino acid polymer. Exemplary amino acids include natural amino acids, analogs, derivatives and conjugates thereof, amino acid analogs having variant side chains, and all stereoisomers of any of these. As used herein, the term "amino acid" includes both D- or L-optical isomers, and peptidomimetics.

[0146] A "conservative amino acid substitution" is a substitution in which an amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains are defined in the art. These families include amino acids having basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), β-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine).

[0147] The terms "polypeptide", "peptide", and "protein" (when single chain) are used interchangeably herein and refer to an amino acid polymer of any length. The polymer may be linear or branched, may contain modified amino acids, and non-amino acids may interrupt. Further the term includes modified amino acid polymers, e.g., amino acid polymers modified by formation of disulfide bonds, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation such as conjugation with a label component. A polypeptide may be isolated from a natural source, produced by recombinant techniques from a eukaryotic or prokaryotic host, or be a product of synthetic methods.

[0148] The terms “nucleic acid,” “nucleic acid sequence,” “nucleotide sequence,” or “polynucleotide sequence,” and “polynucleotide” are interchangeable. These terms refer to polymeric forms of nucleotides of any length, either deoxyribonucleotides, ribonucleotides, or their analogues. Polynucleotides may be single-stranded or double-stranded, and the single-stranded portion may be a coding strand or a non-coding (antisense) strand. Polynucleotides may include modified nucleotides, such as methylated nucleotides and nucleotide analogs. Nucleotide sequences may be interrupted by non-nucleotide components. Polynucleotides may be further modified after polymerization, for example, by conjugation with labeling components. Nucleic acids may be recombinant polynucleotides, or polynucleotides of genomic, cDNA, semi-synthetic, or synthetic origin that do not exist in nature or are linked to other polynucleotides in unnatural configurations.

[0149] As used herein, the term “isolated” refers to a substance that has been removed from its original or natural environment (e.g., the natural environment, if it is natural). For example, a naturally occurring polynucleotide or polypeptide present in a living animal is not isolated, but the same polynucleotide or polypeptide separated by human intervention from some or all of the substances present together in a natural system is isolated. Such a polynucleotide may be part of a vector, and / or such a polynucleotide or polypeptide may be part of a composition, but such a vector or composition is isolated in that it is not part of the environment in which it existed in nature.

[0150] As used herein, the term “treat” a disorder (e.g., a disorder as described herein) means, in some embodiments, that a subject (e.g., a human) having a disorder such as, for example, a disorder as described herein, and / or experiencing symptoms of such a disorder, suffers less severe symptoms and / or recovers faster when an antibody molecule is administered than when no antibody molecule is administered. After treatment of the disorder in the subject, the patient’s recovery may be monitored or the presence of symptoms of the disorder may be detected, for example, by using other assays such as urinalysis, blood tests, yotharamic acid clearance tests, or imaging (e.g., ultrasound, X-ray, or cystoscopy), for example, by detecting a decrease in the presence (or absence) of symptoms. Treatment may, for example, partially or completely, reduce, improve, alleviate, inhibit, or reduce the severity of a disorder such as a disorder as described herein, and / or reduce its incidence, and optionally delay its onset, or delay the manifestation of one or more of the effects or symptoms, characteristics and / or causes. In some embodiments, treatment is the treatment of a subject who does not exhibit specific signs of a disorder, such as a disorder described herein, and / or a subject who exhibits only early signs of a disorder, such as a disorder described herein. In some embodiments, treatment is the treatment of a subject who exhibits one or more established signs of a disorder, such as a disorder described herein. In some embodiments, treatment is the treatment of a subject who has been diagnosed with a disorder, such as a disorder described herein.

[0151] As used herein, the term “prevents” a disorder, such as those described herein, means that a subject (e.g., a human) is less likely to have a disorder, such as those described herein, when administered with an antibody molecule.

[0152] Various embodiments of the compositions and methods described herein are described in further detail below. Additional definitions are provided throughout this specification.

[0153] C5aR1 C5aR1 (complement component 5a receptor 1), also known as complement 5a receptor 1, C5a receptor, cluster of differentiation 88 (CD88), or C5a anaphylatoxin chemotactic receptor 1, is a G protein-coupled receptor encoded by the Complement C5a Receptor 1 (C5AR1) gene. Most GPCR molecules are randomly distributed on the cell surface, and most class A GPCRs are monomers. C5aR1 belongs to class A GPCRs, but is likely to exist as an oligomer. Oligomerous GPCR molecules can become monomers when each of their respective antagonists bind to them. This suggests that oligomerization is likely due to nonspecific interactions. C5aR1 is a receptor for complement component 5a (C5a) and plays a role in many biological processes, such as regulating inflammatory responses, obesity, development, and cancer. C5aR1 is widely expressed in granulocytes (e.g., neutrophils, eosinophils, basophils, and mast cells) and immature dendritic cells, as well as in the brain, lungs, heart, kidneys, liver, ovaries, and testes. C5aR1 is also present on the cell membrane. The number of C5 receptors per cell is very large, reaching up to approximately 200,000 sites per white blood cell.

[0154] C5a exhibits high affinity for C5aR1, with measured values ​​ranging from low nanomolar to low picomolar. Due to its small molecular weight, the binding rate is fast (approximately 4.8e8M). -1 minutes -1The Kd of C5aR1 on neutrophils typically ranges from low nanomolar to high picomolar (depending on the assay format and the presence of G proteins). Typically, G protein signaling requires engagement for only 1–2 seconds. This underscores the importance of C5aR1 inhibitors (e.g., antibody molecules described herein) having long residence times. GPCRs can have multiple conformational states that alter the level of activity (e.g., not binary). While we do not wish to be constrained by theory, in some embodiments, the antibody molecules described herein may be able to shift their energy state to prefer an inactive state upon engagement.

[0155] C5aR1 is a class 1 G protein-coupled receptor (GPCR) with a normative GPCR structure comprising seven transmembrane helices, four extracellular domains, and four intracellular domains. C5aR1 includes two regions exposed to the extracellular environment, which are involved in interaction with the C5a ligand. One region referred to herein as “site I” typically comprises the N-terminal residues of C5aR1 (e.g., the N-terminal 37 residues). Site I generally forms a flexible random coil structure. In some embodiments, site I comprises or consists of the amino acid sequence MNSFNYTTPDYGHYDDKDTLDLNTPVDKTSNTLRVPD (SEQ ID NO: 1449). In one embodiment, the antibody molecule bound to site I binds to an amino acid sequence containing or consisting of sequence number 1449, or to a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with the sequence, or to a sequence containing 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or fewer amino acid differences with respect to the sequence. In one embodiment, site I contains or consists of the amino acid sequence MDSFNYTTPDYGHYDDKDTLDLNTPVDKTSNTLRVPD (sequence number 1452). In some embodiments, the antibody molecule that binds to site I binds to an amino acid sequence containing or consisting of sequence number 1452, or to a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with respect to that sequence, or to a sequence containing 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or fewer amino acid differences with respect to that sequence. The antibody molecule that binds to site I can typically bind to all residues in site I or a subset thereof. For example, the antibody molecule that binds to site I comes into contact with one or more residues in site I. In some embodiments, site I generally contains a large number of sulfated residues (e.g., sulfated tyrosine residues) and a large number of Asp residues.While we do not wish to be constrained by theory, in some embodiments, site I is thought to recruit C5a to the receptor by binding to C5a as a flexible extension from other parts of the C5aR1 protein, thereby increasing the local concentration of C5a around C5aR1-expressing cells.

[0156] C5aR1 comprises three extracellular loops (ECLs), referred to herein as extracellular loop 1 (ECL1), extracellular loop 2 (ECL2), and extracellular loop 3 (ECL3). ECL1 comprises residues 94-110 of C5aR1 and is defined by the amino acid sequence of SEQ ID NO: 1453. ECL2 comprises residues 175-200 of C5aR1 and is defined by the amino acid sequence of SEQ ID NO: 1450. ECL3 comprises residues 266-282 of C5aR1 and is defined by the amino acid sequence of SEQ ID NO: 1454. Certain amino acids of C5aR1 have native variants, such as N2D and N279K.

[0157] The second region, referred to herein as “site II,” may include three extracellular loops (e.g., ECL1, ECL2, and ECL3) and transmembrane residues that form the C5aR1 vestibule. Site II typically includes ECL2, which contains the amino acid sequence of SEQ ID NO: 1450, and optionally transmembrane residues that form the C5aR1 vestibule. An antibody molecule that binds to site II can typically bind to all residues in site II or a subset thereof. For example, an antibody molecule that binds to site II will come into contact with one or more residues in site II. Similarly, an antibody molecule that binds to ECL1, ECL2, and / or ECL3 will come into contact with one or more residues in ECL1, ECL2, and / or ECL3. In some embodiments, an antibody molecule that binds to site II binds to ECL2. In some embodiments, an antibody molecule that binds to site II binds to ECL1. In some embodiments, an antibody molecule that binds to site II binds to ECL3. In some embodiments, an antibody molecule that binds to site II binds to both ECL1 and ECL2. In one embodiment, the antibody molecule that binds to site II binds to ECL2 and ECL3. In another embodiment, the antibody molecule that binds to site II binds to ECL1 and ECL3. In another embodiment, the antibody molecule that binds to site II binds to ECL1, ECL2, and ECL3. In another embodiment, the antibody molecule that binds to site II binds to ECL2 but not to ECL1 and / or ECL3, or does not bind substantially to them. In another embodiment, the antibody molecule that binds to site II binds to ECL1 but not to ECL2 and / or ECL3, or does not bind substantially to them. In another embodiment, the antibody molecule that binds to site II binds to ECL2 but not to ECL1 and / or ECL3, or does not bind substantially to them. In another embodiment, the antibody molecule that binds to site II binds to ECL2 and also to one or more residues in ECL1 and / or ECL3. In another embodiment, the antibody molecule that binds to site II binds to ECL1 and ECL2 but not to ECL3, or does not bind substantially to it.In some embodiments, an antibody molecule that binds to site II binds to ECL1 and ECL3, but not to ECL2, or does not bind substantially to it. In some embodiments, an antibody molecule that binds to site II binds to ECL2 and ECL3, but not to ECL1, or does not bind substantially to it. In some embodiments, an antibody molecule that binds to site II further binds to one or more transmembrane residues (e.g., transmembrane residues that form the vestibule region). In some embodiments, an antibody molecule that binds to site II does not bind to one or more transmembrane residues (e.g., transmembrane residues that form the vestibule region), or does not bind substantially to it. ECL2 generally contains Phe and Tyr residues that are exposed to the solvent. While we do not wish to be constrained by theory, in some embodiments, the binding of C5a to site II is considered important for the activation of downstream signaling by C5aR1.

[0158] The energy of agonist binding to the extracellular domain transmits allosteric structural changes to the transmembrane and intracellular domains, leading to G protein binding and signal transduction. Two agonists are known for C5aR1: C5a and C5a desArg C5a is a C-terminal arginine molecule that is rapidly cleaved by carboxypeptidase N, which then binds to C5aR1 with low affinity, resulting in biased signaling. desArg Because it forms a compound, it has a short serum half-life. C5a desArg Unlike C5a, it does not signal via the Gα pathway and does not stimulate granulocyte release. However, C5a desArg C5a stimulates neutrophil chemotaxis, desArg Inhibiting binding and thus inhibiting neutrophil migration to the site of inflammation is also a subject of interest. C5a desArg Signal transduction works to favor chemotaxis and is difficult to desensitize (for example, neutrophils use C5a desArg (Instead, C5a continues to migrate until it reaches a high concentration). In one embodiment, an orthosteric antagonist that blocks C5a binding (e.g., an antibody molecule described herein) is used to block C5a desArgIt also inhibits (e.g., blocks) the binding. Inhibition of C5a binding is required at the site of inflammation in some embodiments. desArg Inhibition of this pathway is needed in the periphery and can hinder the migration of neutrophils to the site of inflammation. Targeting C5aR1 often leaves the cell membrane toxic complex pathway (C5b) intact.

[0159] C5a / C5aR1 signaling generally involves the following steps: receptor recognition, activation, and signal transduction. Engagement between C5aR1 and C5a involves binding to two sites (sometimes referred to herein as site I and site II) in a stepwise manner. Initially, C5a engages with site I on the N-terminal domain of C5aR1; this interaction is primarily induced by basic residues on C5a and sulfated tyrosine and acidic residues at the N-terminus. Additional contact occurs, for example, with basic residues on site II located on the second extracellular loop (ECL2) of C5aR1 and acidic residues on C5a. Upon full engagement, the C-terminus of C5a promotes activation, which is primarily induced by aspartic acid at position 282 of C5aR1 and terminal arginine at the C-terminus of C5a. C5a binding site II is essential for C5aR1 signaling, while site I may not be essential. Upon engagement, activation is initiated by reconstitution of the contact established between transmembrane helices 3, 6, and 7, inducing an allosteric conformational change of C5aR1 toward the intracellular side, which is necessary for G-protein binding. Functional verification of the importance of sites I and II to C5a engagement and signaling is revealed by the presence of orthosteric antagonists targeting either site I or site II.

[0160] An exemplary amino acid sequence of human C5aR1 (SEQ ID NO: 1448) is provided below. Human NP_001727.1 C5a Anaphylatoxin Chemotactic Receptor 1 [Homo sapiens] MNSFNYTTPDYGHYDDKDTLDLNTPVDKTSNTLRVPDILALVIFAVVFLVGVLGNALVVWVTAFEAKRTINAIWFLNLAVADFLSCLALPILFTSIVQHHHWPFGGAACSILPSLILLNMYASILLLATISADRFLLVFKPIWCQNFRGAGLAWIACAVAWGLALLLTIPSFLYRVVREEYFPPKVLCGVDYSHDKRRERAVAIVRLVLGFLWPLLTLTICYTFILLRTWSRRATRSTKTLKVVVAVVASFFIFWLPYQVTGIMMSFLEPSSPTFLLLNKLDSLCVSFAYINCCINPIIYVVAGQGFQGRLRKSLPSLLRNVLTEESVVRESKSFTRSTVDTMAQKTQAV (Sequence ID 1448)

[0161] The domains and major regions of the exemplary human C5aR1 sequence of Sequence ID No. 1448 are illustrated in the annotated sequence provided below. The N-terminal peptide (residues 1-37) is shown in bold and italics. Transmembrane helix residues (residues 38-64, 70-93, 111-132, 154-174, 201-226, 243-265, and 283-303) are underlined. ECL1 (residues 94-110), ECL2 (residues 175-200), and ECL3 (residues 266-282) are shown in bold, not italics. Certain amino acids have native variants (N2D and N279K), which are shown in lowercase below. [ka]

[0162] When used herein, an anti-C5aR1 antibody molecule binds to or substantially binds to human C5aR1, meaning it binds to or substantially binds to one or more isoforms of human C5aR1, for example, one or more isoforms of human C5aR1 described herein. In one embodiment, the antibody molecule binds to or substantially binds to human C5aR1 having the amino acid sequence of SEQ ID NO: 1448.

[0163] In one embodiment, the antibody molecule binds to site I of C5aR1 (e.g., human C5aR1). An exemplary human C5aR1 site I includes or consists of the following amino acid sequence:MNSFNYT TPDYGHYD DKDTLDLNTPVDKTSNTLRVPD (SEQ ID NO: 1449). In one embodiment, the antibody molecule binds to the amino acid sequence of SEQ ID NO: 1449, or to a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with the sequence, or to a sequence containing 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or fewer amino acid differences with respect to the sequence. In one embodiment, the antibody molecule binds to a region containing at least five (e.g., at least 5, 10, 15, 20, 25, 30, 31, 32, 33, 34, 35, 36, or 37) amino acids (e.g., consecutive amino acids) of SEQ ID NO: 1449. Another exemplary human C5aR1 site I includes, or consists of, the following amino acid sequence: MDSFNYT TPDYGHYD DKDTLDLNTPVDKTSNTLRVPD (SEQ ID NO: 1452). In one embodiment, the antibody molecule binds to the amino acid sequence of SEQ ID NO: 1452, or to a sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to said sequence, or to a sequence that contains 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or fewer amino acid differences from said sequence. In one embodiment, the antibody molecule binds to a region containing at least five (e.g., at least 5, 10, 15, 20, 25, 30, 31, 32, 33, 34, 35, 36, or 37) amino acids of SEQ ID NO: 1452 (e.g., consecutive amino acids).

[0164] In one embodiment, the antibody molecule binds to the ECL2 of site II of C5aR1 (e.g., human C5aR1). An exemplary human C5aR1 ECL2 includes or consists of: RVVREEYFPPKVLCGVDYSHDKRRER (SEQ ID NO: 1450) (underlined part is the core epitope region). In certain embodiments, the antibody molecule binds to the amino acid sequence of SEQ ID NO: 1450, or binds to a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity to that sequence, or binds to a sequence containing 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or fewer amino acid differences from that sequence. In certain embodiments, the antibody molecule binds to a region containing at least 5 (e.g., at least 5, 10, 15, 20, 25, 26, or 27) amino acids of SEQ ID NO: 1450 (e.g., contiguous amino acids). In certain embodiments, the antibody molecule binds to a region containing at least 5 (e.g., at least 5, 10, 15, 16, 17, 18, or 19) amino acids of the underlined part of SEQ ID NO: 1450 (e.g., contiguous amino acids).

[0165] In certain embodiments, the antibody molecule binds to ECL1 of site II of C5aR1 (e.g., human C5aR1). Exemplary human C5aR1 ECL1 comprises or consists of: TSIVQHHHWPFGGAACS (SEQ ID NO: 1453). In certain embodiments, the antibody molecule binds to the amino acid sequence of SEQ ID NO: 1453, or binds to a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity to that sequence, or binds to a sequence containing 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or fewer amino acid differences from that sequence. In certain embodiments, the antibody molecule binds to a region containing at least 5 (e.g., at least 5, 10, 15, 16, or 17) amino acids of SEQ ID NO: 1453 (e.g., contiguous amino acids).

[0166] In one embodiment, the antibody molecule binds to the ECL3 of site II of C5aR1 (e.g., human C5aR1). An exemplary human C5aR1 ECL3 includes: SFLEPSSPTFLLLNKLD (SEQ ID NO: 1454). In one embodiment, the antibody molecule binds to the amino acid sequence of SEQ ID NO: 1454, or to a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with that sequence, or to a sequence containing 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or fewer amino acid differences with respect to that sequence. In one embodiment, the antibody molecule binds to a region containing at least 5 (e.g., at least 5, 10, 15, 16, or 17) amino acids (e.g., consecutive amino acids) of SEQ ID NO: 1454. Another exemplary human C5aR1 ECL3 includes or consists of: SFLEPSSPTFLLLKKLD (SEQ ID NO: 1455). In one embodiment, the antibody molecule binds to the amino acid sequence of SEQ ID NO: 1455, or to a sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to said sequence, or to a sequence that contains 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or fewer amino acid differences from said sequence. In another embodiment, the antibody molecule binds to a region containing at least five (e.g., at least 5, 10, 15, 16, or 17) amino acids (e.g., consecutive amino acids) of SEQ ID NO: 1455.

[0167] An example amino acid sequence for mouse C5aR1 (SEQ ID NO: 1451) is provided below. Mouse C5aR1 (SEQ ID NO: 1451) MDPIDNSSFEINYDHYGTMDPNIPADGIHLPKRQPGDVAALIIYSVVFLVGVPGNLVVWVTAFEARRAVNAIWFLNLAVADLSCLALPVLFTTVLNHNYWYFDATACIVLPSLILLNMYASILLLATISADRFLLVFKPIWCQKVRGTGLAWMACGVAWVLALLLTIPSFVYR EAYKDFYSEHTVCGINYGGGSFPKEKAVAILRLMVGFVLPLLTLNICYTFLLLRTWSRKATRSTKTLKVVMAVVICFFIFWLPYQVTGVMIAWLPPSSPTLKRVEKLNSLCVSLAYINCCVNPIIYVMAGQGFHGRLLRSLPSIIRNALSEDSVGRDSKTFTPSTTDTSTRKSQAV

[0168] When used herein, an anti-C5aR1 antibody molecule binds to or substantially binds to C5aR1, meaning it binds to or substantially binds to one or more isoforms of C5aR1, for example, one or more isoforms of C5aR1 described herein. In one embodiment, the antibody molecule binds to or substantially binds to C5aR1 having the amino acid sequence of SEQ ID NO: 1451.

[0169] When used herein, an anti-C5aR1 antibody molecule does not bind to or substantially binds to C5aR1, meaning it does not bind to or substantially binds to one or more isoforms of C5aR1, such as one or more isoforms of C5aR1 described herein. In one embodiment, the antibody molecule does not bind to or substantially binds to C5aR1 having the amino acid sequence of SEQ ID NO: 1451.

[0170] Epitope The antibody molecules described herein can bind to epitopes on C5aR1 (e.g., human C5aR1). For example, the epitopes bound to the antibody molecules described herein may include one or more epitope contact sites.

[0171] The antibody molecules described herein can bind to one or more residues on C5aR1. The amino acids to which the antibody molecules described herein bind are defined as “epitopes” or “epitope contact sites”.

[0172] In some embodiments, the antibody molecules described herein are designed to target the sulfated N-terminal peptide or site I of C5aR1, as defined by SEQ ID NO: 1449 or SEQ ID NO: 1452. In some embodiments, the site I residue targeted by the antibody molecules described herein is sulfated. In some embodiments, one or more of the amino acid residues T8 (threonine 8), D10 (aspartic acid 10), Y11 (tyrosine 11), Y14 (tyrosine 14), and / or D15 (aspartic acid 15) are essential site I epitope contact sites. In some embodiments, all of the amino acid residues T8 (threonine 8), D10 (aspartic acid 10), Y11 (tyrosine 11), Y14 (tyrosine 14), and / or D15 (aspartic acid 15) are essential site I epitope contact sites. In some embodiments, sulfation at Y11 and / or Y14 is essential for the binding of the site I antibody molecule described herein. In some embodiments, with respect to the binding of the site I antibody molecule described herein, the core epitope extends to 12 amino acids from T7 to D18 of SEQ ID NO: 1448. In some embodiments, with respect to the binding of the site I antibody molecule described herein, the core epitope extends to amino acids from T8 to D18 of SEQ ID NO: 1448.

[0173] The initial engagement site for C5a binding; the Staphylococcus aureus CHIPS protein binds to the N-terminal peptide. This contacts both sulfated tyrosines, strongly blocking C5a-mediated C5aR1 signaling; and by mutating the tyrosines at positions 11 and 14 to phenylalanine, the functionality of C5a-mediated C5aR1 signaling is significantly reduced; and the sulfated group can provide strong binding energy for producing high-affinity antibodies.

[0174] In some embodiments, the antibody molecules described herein are designed to target site II, as defined by the amino acids in SEQ ID NO: 1450. In some embodiments, the amino acids encompassing R175 to G189 in SEQ ID NO: 1448 are the core epitopes for binding to the site II antibody molecules described herein. In some embodiments, the amino acids encompassing E180 to P183 in SEQ ID NO: 1448 are the core epitopes for binding to the site II antibody molecules described herein. In some embodiments, the amino acids encompassing E180 to P184 in SEQ ID NO: 1448 are the core epitopes for binding to the site II antibody molecules described herein. In some embodiments, the amino acids encompassing E178 to P183 in SEQ ID NO: 1448 are the core epitopes for binding to the site II antibody molecules described herein. In some embodiments, R35, H101, V176, V177, R178, E179, E180, Y181, F182, P183, P184, K185, L187 of sequence number 1448, One or more of the D191, S193, H194, E266, P267, S268, F272, L273, and / or K276 residues are important for the binding of the site II antibodies described herein. In some embodiments, one or more of the E180, Y181, F182, and / or P183 residues of SEQ ID NO: 1448 are essential epitopes for the binding of the site II antibodies described herein. In one embodiment, the amino acid residue W102 of SEQ ID NO: 1448 is essential for the binding of the site II antibodies described herein. While we do not wish to be bound by theory, in some embodiments, the antibody molecules described herein are orthosteric inhibitors that inhibit docking into the binding pocket of the C5a C-terminus, which contributes to C5aR1 signaling, and therefore are considered to be designed to target site II of C5aR1, at least partially.

[0175] In some embodiments, the antibody molecule described herein is designed to target both site I and site II of C5aR1. In some embodiments, the antibody molecule described herein is designed to target both the sulfated N-terminal peptide within site I of C5aR1 and ECL2 within site II of C5aR1.

[0176] In some embodiments, the antibody molecule contacts (e.g., binds to or substantially binds to) one or more residues or regions of site I and / or site II of C5aR1 (e.g., human C5aR1). In some embodiments, the antibody molecule binds to an epitope or a portion of it (e.g., site II epitope) containing ECL2 of C5aR1. In some embodiments, the antibody molecule binds to an epitope or a portion of it (e.g., site II epitope) containing ECL1 of C5aR1. In some embodiments, the antibody molecule binds to an epitope or a portion of it (e.g., site II epitope) containing ECL3 of C5aR1. In some embodiments, the antibody molecule binds to an epitope (e.g., site II epitope) containing a sulfated N-terminal region. In some embodiments, the antibody molecule binds to an epitope (e.g., sulfated site I epitope). In some embodiments, the antibody molecule binds to an epitope (e.g., non-sulfated site I epitope) containing a non-sulfated N-terminal region.

[0177] In one embodiment, the antibody molecule binds to one or more epitopes described herein. In one embodiment, the antibody molecule binds to one or more residues (e.g., consecutive residues) within a region of the human C5aR1 site I sequence, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36 or all of them (e.g., consecutive residues), including, for example, SEQ ID NO: 1449 or 1452, or substantially binds to. In one embodiment, the antibody molecule binds to or substantially binds to one or more residues (e.g., consecutive residues) within the region of the human C5aR1 site II sequence, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or all of them (e.g., consecutive residues), including, for example, any of SEQ ID NOs. 1450, 1453, 1454, or 1455. In another embodiment, the antibody molecule binds to or substantially binds to one or more residues (e.g., consecutive residues) within the core epitope region of the human C5aR1 site II sequence, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or more residues (e.g., consecutive residues), including, for example, amino acids 1-20 of SEQ ID NO. 1450. In one embodiment, the antibody molecule is one or more residues within the region of the human C5aR1 site I sequence, including, for example, SEQ ID NOs. 1449 or 1452, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36 or all of the residues (for example, consecutive It binds to, or substantially binds to, one or more residues (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or all of) within the region of the human C5aR1 site II sequence, including, for example, any of sequence numbers 1450, 1453, 1454 or 1455 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or all of) (e.g., consecutive residues).In one embodiment, an antibody molecule binds to or substantially binds to one or more residues (e.g., consecutive residues) within the region of the human C5aR1 site I sequence, such as SEQ ID NO: 1449 or 1452, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36 or all of them (e.g., consecutive residues); and to one or more residues (e.g., consecutive residues) within the core epitope region of the human C5aR1 site II sequence, such as amino acids 1-20 of SEQ ID NO: 1450, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more residues (e.g., consecutive residues).

[0178] antibody molecule This specification discloses antibody molecules or antigen-binding fragments that bind to C5aR1. As described above, the antibodies of this disclosure inhibit C5a from binding to C5aR1 and inhibit diseases associated with dysfunction of the C5a / C5aR1 pathway, such as ANCA-associated vasculitis.

[0179] As used herein, the term “antibody molecule” refers to a protein such as an immunoglobulin chain or a fragment thereof containing at least one immunoglobulin variable domain sequence. The term “antibody molecule” includes, for example, full-length antibodies, mature antibodies, and antigen-binding fragments of antibodies. For example, an antibody molecule may contain a heavy chain (H) variable domain sequence (abbreviated herein as VH) and a light chain (L) variable domain sequence (abbreviated herein as VL). In another example, an antibody molecule may contain two heavy chain (H) variable domain sequences and two light chain (L) variable domain sequences, thereby forming two antigen-binding sites such as Fab, Fab', F(ab')2, Fc, Fd, Fd', Fv, single-chain antibodies (e.g., scFv), single-variable domain antibodies, diabody (Dab) (bivalent and bispecific), and chimeric (e.g., humanized) antibodies. These may be produced by modifying whole antibodies or newly synthesized using recombinant DNA technology. These functional antibody fragments retain the ability to selectively bind to their respective antigens or receptors. Antibodies and antibody fragments may originate from any class of antibody, including but not limited to IgG, IgA, IgM, IgD, and IgE, and from any subclass of antibody (e.g., IgG1, IgG2, IgG3, and IgG4). Antibody molecules may be monoclonal or polyclonal. Antibody molecules may be human antibodies, humanized antibodies, CDR-transplant antibodies, or antibodies produced in vitro. Antibody molecules may have a heavy chain constant region selected from, for example, IgG1, IgG2 (e.g., for SEQ ID NOs. 1444, 1445, 1446, and 1447), IgG3, or IgG4. Antibody molecules may have a light chain selected from, for example, kappa or lambda. The term “immunoglobulin” (Ig) is used interchangeably with the term “antibody” herein.

[0180] Examples of antigen-binding fragments include: (i) Fab fragments, which are monovalent fragments consisting of VL, VH, CL, and CH1 domains; (ii) F(ab')2 fragments, which are bivalent fragments containing two Fab fragments linked by a disulfide bond in the hinge region; (iii) Fd fragments, which consist of VH and CH1 domains; (iv) Fv fragments, which consist of the VL and VH domains of one arm of the antibody; (v) diabody (dAb) fragments, which consist of the VH domain; (vi) camelid variable domains or camelid variable domains; (vii) single-stranded Fv (scFv), see, for example, Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883); and (viii) single-domain antibodies. These antibody fragments may be obtained using any suitable method, including some conventional techniques known to those skilled in the art, and the fragments can be screened for usefulness in the same manner as complete antibodies.

[0181] The term "antibody" includes complete molecules as well as their functional fragments. The properties of an antibody can be modified by altering its constant region, for example, through mutation (e.g., increasing or decreasing one or more of the following: Fc receptor binding, antibody glycosylation, cysteine ​​residue count, effector cell function, or complement function).

[0182] The antibody molecule may be a single-chain antibody. Single-chain antibodies (scFv) may be manipulated (see, for example, Colcher, D. et al. (1999) Ann NY Acad Sci 880:263-80; and Reiter, Y. (1996) Clin Cancer Res 2:245-52). Single-chain antibodies can be dimerized or multimerized to produce polyvalent antibodies with specificity for different epitopes of the same target protein.

[0183] The antibody molecules disclosed herein may be single-domain antibodies. Single-domain antibodies may include antibodies whose complementary determining region is part of a single-domain polypeptide. Examples, but not limited to, include heavy-chain antibodies, naturally light-chain-deficient antibodies, single-domain antibodies derived from conventional four-chain antibodies, engineered antibodies, and single-domain scaffolds other than those derived from antibodies. Single-domain antibodies may be any of the present or future single-domain antibodies. Single-domain antibodies may originate from any species, including, but not limited to, mice, humans, camels, llamas, fish, sharks, goats, rabbits, and cattle. According to some embodiments, a single-domain antibody is a naturally occurring single-domain antibody known as a light-chain-deficient heavy-chain antibody. Such a single-domain antibody is disclosed, for example, in WO94 / 04678. For clarity, the variable domain derived from a naturally light-chain-deficient heavy-chain antibody is referred to herein as VHH or nanobody and is distinguished from the VH of conventional four-chain immunoglobulins. Such VHH molecules may originate from antibodies elicited by camelid species such as camels, llamas, dromedaries, alpacas, and guanacos. Other non-camelid species may naturally produce heavy-chain antibodies lacking light chains. Such VHHs are also expected.

[0184] The VH and VL regions can be further subdivided into highly variable regions called "complementarity-determining regions" (CDRs), which contain more conserved regions called "framework regions" (FR or FW). As used herein, the terms "complementarity-determining regions" and "CDRs" refer to the amino acid sequences within the antibody variable regions that confer antigen specificity and binding affinity. As used herein, the terms "framework," "FW," and "FR" are interchangeable.

[0185] The scope of the framework area and CDR has been precisely defined by numerous methods (Kabat, EA, et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, USD Department of Health and Human). See Services, NIH Publication No. 91-3242; Chothia, C. et al. (1987) J. Mol. Biol. 196:901-917; and the AbM definition used by Oxford Molecular's AbM antibody modeling software. For a complete overview, see, for example, Protein Sequence and Structure Analysis of Antibody Variable Domains. In: Antibody Engineering. See Lab Manual (Ed.: Duebel, S. and Kontermann, R., Springer-Verlag, Heidelberg). In some embodiments, the following definitions are used: AbM definition for the heavy chain variable domain CDR1, and Kabat definition for the other CDRs. In some embodiments, the Kabat definition is used for all CDRs. Furthermore, embodiments described with respect to Kabat or AbM CDRs may be carried out using Chothia hypervariable loops. Each VH and VL typically comprises three CDRs and four FRs, arranged from the amino terminus to the carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.

[0186] As used herein, “immunoglobulin variable domain sequence” refers to an amino acid sequence capable of forming the structure of an immunoglobulin variable domain. For example, the sequence may include all or part of the amino acid sequence of a native variable domain. For example, the sequence may include, or not include, one, two, or more N-terminal or C-terminal amino acids, or may include other modifications that are compatible with the formation of a protein structure.

[0187] The term "antigen-binding region" refers to the portion of an antibody molecule that contains determinants that form an interface for binding to an antigen or its epitope, such as C5aR1. For proteins (or protein mimes), the antigen-binding region typically includes one or more loops (at least, for example, four amino acids or amino acid mimetic loops) that form an interface for binding to an antigen, such as C5aR1. Typically, the antigen-binding region of an antibody molecule includes at least one or two CDRs and / or hypervariable loops, or more typically, at least three, four, five, or six CDRs and / or hypervariable loops.

[0188] The terms “competitive” or “cross-competitive” are used interchangeably herein and refer to the ability of an antibody molecule to interfere with the binding of an anti-C5aR1 antibody molecule, such as the anti-C5aR1 antibody molecule provided herein, to a target such as C5aR1. Interference with binding may be direct or indirect (e.g., through allosteric modulation of the antibody molecule or the target). The extent to which an antibody molecule can interfere with the binding of another antibody molecule to its target, i.e., whether this constitutes competition, can be determined using a competitive binding assay, such as a FACS assay, ELISA assay, or BIACORE assay. In some embodiments, the competitive binding assay is a quantitative competitive assay. In one embodiment, a first anti-C5aR1 antibody molecule is said to compete with a second anti-C5aR1 antibody molecule in terms of binding to the target when, in a competitive binding assay (e.g., a competitive assay as described herein), the binding of the first antibody molecule to the target decreases by 10% or more, for example, 20% or more, 30% or more, 40% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more.

[0189] As used herein, the terms “monoclonal antibody” or “monoclonal antibody composition” refer to an antibody molecular preparation having a single molecular composition. A monoclonal antibody composition exhibits a single binding specificity and affinity to a particular epitope. Monoclonal antibodies may be prepared by hybridoma technology or by methods that do not utilize hybridoma technology (e.g., recombinant methods).

[0190] A "effectively human" protein is one that does not induce neutralizing antibody responses, such as the human anti-mouse antibody (HAMA) response. HAMA can be problematic in many situations, such as when antibody molecules are repeatedly administered in the treatment of chronic or relapsing disease conditions. The HAMA response can potentially neutralize repeated antibody administration by increasing antibody clearance from serum (see, e.g., Saleh et al., Cancer Immunol. Immunother., 32:180-190 (1990)) and by a potential allergic reaction (see LoBuglio et al., Hybridoma, 5:5117-5123 (1986)).

[0191] The antibody molecule may be a polyclonal antibody or a monoclonal antibody. In some embodiments, the antibody may be recombinantly produced, for example, by any suitable phage display or combinatorial method.

[0192] Various phage display and combinatorial methods for antibody production are known in this field (e.g., Ladner et al. U.S. Patent No. 5,223,409; Kang et al. International Patent Application Publication WO92 / 18619; Dower et al. International Patent Application Publication WO91 / 17271; Winter et al. International Patent Application Publication WO92 / 20791; Markland et al. International Patent Application Publication WO92 / 15679; Breitling et al. International Patent Application Publication WO93 / 01288; McCafferty et al. International Patent Application Publication WO92 / 01047; Garrard et al. International Patent Application Publication WO92 / 09690; Ladner et al. International Patent Application Publication WO90 / 02809; Fuchs et al. (1991) Bio / Technology 9:1370-1372; Hay et al. al.(1992)Hum Antibod Hybridomas 3:81-85;Huse et al.(1989)Science 246:1275-1281;Griffths et al.(1993)EMBO J 12:725-734;Hawkins et al.(1992)J Mol Biol 226:889-896;Clackson et al. al. (1991) Nature 352:624-628; Gram et al. (1992) PNAS 89:3576-3580; Garrad et al. (1991) Bio / Technology 9:1373-1377; Hoogenboom et al. (1991) Nuc Acid Res 19:4133-4137; and Barbas et al. al.(1991)PNAS This is described in 88:7978-7982. All of their contents are incorporated herein by reference.

[0193] In some embodiments, the antibody molecule may be a fully human antibody (e.g., an antibody produced in a mouse genetically engineered to produce antibodies from a human immunoglobulin sequence), or a non-human antibody, such as an antibody from a rodent (mouse or rat), goat, primate (e.g., monkey), or camel. In some embodiments, the non-human antibody is a rodent antibody (mouse or rat antibody). Methods for producing rodent antibodies are known in the art.

[0194] Human monoclonal antibodies can be produced using transgenic mice that carry human immunoglobulin genes, rather than those derived from mice. Splenocytes derived from these transgenic mice, immunized with the target antigen, are used to create hybridomas that secrete human mAbs with specific affinity for human protein-derived epitopes (e.g., Wood et al. International Patent Application Publication WO91 / 00906; Kucherlapati et al. International Patent Application Publication WO91 / 10741; Lonberg et al. International Patent Application Publication WO92 / 03918; Kay et al. International Patent Application 92 / 03917; Lonberg, N et al. 1994 Nature). 368:856-859;Green,LLet al.1994 Nature Genet.7:13-21;Morrison,SLet al.1994 Proc.Natl.Acad.Sci.USA 81:6851-6855;Bruggeman et al.1993 Year Immunol 7:33-40;Tuaillon et al.1993 PNAS 90:3720-3724;Bruggeman et al.1991 Eur J Immunol 21:1323-1326).

[0195] Antibodies may have variable regions or parts thereof, such as CDRs, produced in non-human organisms such as rats or mice. Chimeric antibodies, CDR-transplanted antibodies, and humanized antibodies are within the scope of the present invention. Antibodies produced in non-human organisms such as rats or mice, and subsequently modified, for example, in the variable framework or constant region, to reduce their antigenicity in humans, are also within the scope of the present invention.

[0196] Chimeric antibodies may be produced by any suitable recombinant DNA technology. Several methods are known in this field (Robinson et al. International Patent Application Publication WO1987 / 002671; Akira et al. European Patent Application Publication 184,187; Taniguchi, M. European Patent Application Publication 171,496; Morrison et al. European Patent Application Publication 173,494; Neuberger et al. International Patent Application Publication WO86 / 01533; Cabilly et al. U.S. Patent No. 4,816,567; Cabilly et al. European Patent Application Publication 125,023; Better et al. (1988 Science 240:1041-1043); Liu et al. (1987) PNAS 84:3439-3443; Liu et al. 1987, J. Immunol. 139:3521-3526; Sun et al. (1987) PNAS See 84:214-218; Nishimura et al. 1987, Canc. Res. 47:999-1005; Wood et al. (1985) Nature 314:446-449; and Shaw et al. 1988, J. Natl Cancer Inst. 80:1553-1559).

[0197] Humanized antibodies or CDR-transplanting antibodies replace donor CDRs and at least one, two, and most often all three, recipient CDRs. The antibody may replace at least a portion of the non-human CDRs, or only a portion of the CDRs may be replaced with non-human CDRs. Only the number of CDRs required for the humanized antibody to bind to lipopolysaccharides needs to be replaced. In some embodiments, the donor is a rodent antibody, e.g., a rat or mouse antibody, and the recipient is a human framework or human consensus framework. Typically, the immunoglobulin providing the CDRs is referred to as the “donor,” and the immunoglobulin providing the framework is referred to as the “acceptor.” In some embodiments, the donor immunoglobulin is non-human (e.g., rodent). The acceptor framework is typically a natural (e.g., human) framework or consensus framework, or a sequence that is approximately 85% or more identical to them, e.g., 90%, 95%, or 99% or more.

[0198] As used herein, the term “consensus sequence” refers to a sequence formed from the most frequently occurring amino acids (or nucleotides) in a family of related sequences (see, for example, Winnaker, From Genes to Clones (Verlagsgesellschaft, Weinheim, Germany 1987)). In a family of proteins, each position in the consensus sequence is occupied by the most frequently occurring amino acid at that position in the family. If two amino acids are equally frequent, either one may be included in the consensus sequence. “Consensus framework” refers to the framework region in a consensus immunoglobulin sequence.

[0199] As described above, an antibody molecule or its antigen-binding fragment can bind to C5aR1 at a specific residue. For example, in some embodiments, an antibody molecule or its antigen-binding fragment can bind to C5aR1 at site I (SEQ ID NO: 1449 or SEQ ID NO: 1452) and / or site II (SEQ ID NO: 1448).

[0200] In some embodiments, the C5aR1 antibodies disclosed herein exhibit antagonistic activity against C5a-mediated C5aR1 signaling, resulting in, for example, inhibition of neutrophil calcium translocation and chemotaxis in the presence of C5a. Both antibodies against site I and site II were identified and selected for their ability to inhibit the binding of C5a to C5aR1. Approximately 61 C5aR1 antagonist antibodies were evaluated and sequence-analyzed. The sequences are summarized in Tables 1, 2, and 3.

[0201] In some embodiments, the antibodies presented herein include AYAMS (SEQ ID NO: 1456), SISTGGNTY (SEQ ID NO: 1457), and GYQRFSGFAY (SEQ ID NO: 1458) or their variants. In some examples, SEQ ID NOs. 1456-1458 are referred to as CDRs. In some embodiments, antibody variants contain sequences that differ by five, four, three, two, or one or fewer amino acids from SEQ ID NOs. 1456, 1457, and / or 1458. In some embodiments, antibodies containing SEQ ID NOs. 1456, 1457, and / or 1458 bind to site I as defined by SEQ ID NO: 1449 or SEQ ID NO: 1452. In some embodiments, SEQ ID NOs. 1456, 1457, and / or 1458 are part of an HCDR.

[0202] In some embodiments, the antibodies presented herein include RSSQSLVHSNGNTYLN (SEQ ID NO: 1459), KVSNRLS (SEQ ID NO: 1460), and SQSTHVPYT (SEQ ID NO: 1461). In some examples, SEQ ID NOs. 1459-1461 are referred to as CDR. In some embodiments, the antibody variants contain sequences that differ by 5, 4, 3, 2, or 1 or fewer amino acids from SEQ ID NOs. 1459, 1460, and / or 1461. In some embodiments, antibodies containing SEQ ID NOs. 1459, 1460, and / or 1461 bind to site II as defined by SEQ ID NO: 1449 or SEQ ID NO: 1452. In some embodiments, SEQ ID NOs. 1459, 1460, and / or 1461 are part of LCDR.

[0203] In some embodiments, the antibodies presented herein include NYWMH (SEQ ID NO: 1462), YLNPSSGYTKY (SEQ ID NO: 1463), and SGGDNYGNPYYFDR (SEQ ID NO: 1464) or variants thereof. In some examples, SEQ ID NOs. 1462-1464 are referred to as CDRs. In some embodiments, antibody variants contain sequences that differ from SEQ ID NOs. 1462, 1463, and / or 1464 by 5, 4, 3, 2, or 1 or fewer amino acids. In some embodiments, antibodies containing SEQ ID NOs. 1462, 1463, and / or 1464 bind to site II as defined by SEQ ID NO: 1450 or SEQ ID NO: 1452. In some embodiments, SEQ ID NOs. 1462, 1463, and / or 1464 are part of HCDRs.

[0204] In some embodiments, the antibodies presented herein include VHSNGNTYLH (SEQ ID NO: 1465), KVSNRFS (SEQ ID NO: 792), and SQSTLVPLT (SEQ ID NO: 912) or variants thereof. In some examples, SEQ ID NOs. 1465, 792, and 912 are referred to as CDRs. In some embodiments, antibody variants contain sequences that differ from SEQ ID NOs. 1465, 792, and / or 912 by 5, 4, 3, 2, or 1 or fewer amino acids. In some embodiments, antibodies containing SEQ ID NOs. 1465, 792, and / or 912 bind to site II as defined by SEQ ID NO: 1450 or SEQ ID NO: 1452. In some embodiments, SEQ ID NOs. 1465, 792, and / or 912 are part of an LCDR.

[0205] In some embodiments, the anti-C5aR1 antibody comprises a Fab linked to an Fc domain, and includes two heavy chains and two light chains. Each heavy chain and light chain includes a heavy chain variable region (HCVR or VH) and a light chain variable region (LCVR or VL). The heavy chain and light chain also include three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3).

[0206] In some embodiments, the antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is Ab583 and includes HCDR1 containing the amino acid sequence of SEQ ID NO: 656, HCDR2 containing the amino acid sequence of SEQ ID NO: 776, and HCDR3 containing the amino acid sequence of SEQ ID NO: 896, as well as LCDR1 containing the amino acid sequence of SEQ ID NO: 715, LCDR2 containing the amino acid sequence of SEQ ID NO: 835, and LCDR3 containing the amino acid sequence of SEQ ID NO: 955, or includes sequences that differ from the amino acids of SEQ ID NOs: 656, 776, 896, 715, 955 and / or 835 by 5, 4, 3, 2, or 1 or fewer amino acids. In some embodiments, the antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is Ab583 and includes a variable heavy chain containing the amino acid sequence of SEQ ID NO: 536, or a variable heavy chain having at least 70, 80, 90, 95, 96, 97, 98, 99, or 100% identity with the amino acid sequence of SEQ ID NO: 536. In some embodiments, the antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is Ab583, which includes a variable light chain containing the amino acid sequence of SEQ ID NO: 595, or a variable light chain having at least 70, 80, 90, 95, 96, 97, 98, 99, or 100% identity with the amino acid sequence of SEQ ID NO: 595. In some embodiments, Ab583 can bind to C5aR1 at site I (SEQ ID NO: 1449 or SEQ ID NO: 1452).

[0207] In some embodiments, the antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is antibody Ab66, comprising HCDR1 containing the amino acid sequence of SEQ ID NO: 603, HCDR2 containing the amino acid sequence of SEQ ID NO: 723, and HCDR3 containing the amino acid sequence of SEQ ID NO: 843, as well as LCDR1 containing the amino acid sequence of SEQ ID NO: 663, LCDR2 containing the amino acid sequence of SEQ ID NO: 783, and LCDR3 containing the amino acid sequence of SEQ ID NO: 903, or comprising a sequence that differs from the amino acids of SEQ ID NOs: 603, 723, 843, 663, 783, and / or 903 by 5, 4, 3, 2, or 1 or fewer amino acids. In some embodiments, the antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is Ab66, comprising a variable heavy chain containing the amino acid sequence of SEQ ID NO: 483, or a variable heavy chain having at least 70, 80, 90, 95, 96, 97, 98, 99, or 100% identity with the amino acid sequence of SEQ ID NO: 483. In some embodiments, the antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is Ab66, which includes a variable light chain containing the amino acid sequence of SEQ ID NO: 543, or a variable light chain having at least 70, 80, 90, 95, 96, 97, 98, 99, or 100% identity with the amino acid sequence of SEQ ID NO: 543. In some embodiments, Ab66 can bind to C5aR1 at site I (SEQ ID NO: 1449 or SEQ ID NO: 1452).

[0208] In some embodiments, the antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is antibody Ab322, comprising HCDR1 containing the amino acid sequence of SEQ ID NO: 611, HCDR2 containing the amino acid sequence of SEQ ID NO: 731, and HCDR3 containing the amino acid sequence of SEQ ID NO: 851, as well as LCDR1 containing the amino acid sequence of SEQ ID NO: 671, LCDR2 containing the amino acid sequence of SEQ ID NO: 791, and LCDR3 containing the amino acid sequence of SEQ ID NO: 911, or comprising sequences that differ from the amino acids of SEQ ID NOs: 611, 731, 851, 671, 791, and / or 911 by 5, 4, 3, 2, or 1 or fewer amino acids. In some embodiments, the antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is Ab322, comprising a variable heavy chain containing the amino acid sequence of SEQ ID NO: 491, or a variable heavy chain having at least 70, 80, 90, 95, 96, 97, 98, 99, or 100% identity with the amino acid sequence of SEQ ID NO: 491. In some embodiments, the antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is Ab322, which includes a variable light chain containing the amino acid sequence of SEQ ID NO: 551, or a variable light chain having at least 70, 80, 90, 95, 96, 97, 98, 99, or 100% identity with the amino acid sequence of SEQ ID NO: 551. In some embodiments, Ab322 can bind to C5aR1 at site I (SEQ ID NO: 1449 or SEQ ID NO: 1452).

[0209] In some embodiments, the antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is antibody Ab329, comprising HCDR1 containing the amino acid sequence of SEQ ID NO: 612, HCDR2 containing the amino acid sequence of SEQ ID NO: 732, and HCDR3 containing the amino acid sequence of SEQ ID NO: 852, as well as LCDR1 containing the amino acid sequence of SEQ ID NO: 672, LCDR2 containing the amino acid sequence of SEQ ID NO: 792, and LCDR3 containing the amino acid sequence of SEQ ID NO: 912, or comprising sequences that differ from the amino acids of SEQ ID NOs: 612, 732, 852, 672, 792, and / or 912 by 5, 4, 3, 2, or 1 or fewer amino acids. In some embodiments, the antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is Ab329, comprising a variable heavy chain containing the amino acid sequence of SEQ ID NO: 492, or a variable heavy chain having at least 70, 80, 90, 95, 96, 97, 98, 99, or 100% identity with the amino acid sequence of SEQ ID NO: 492. In some embodiments, the antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is Ab329, which includes a variable light chain containing the amino acid sequence of SEQ ID NO: 552, or a variable light chain having at least 70, 80, 90, 95, 96, 97, 98, 99, or 100% identity with the amino acid sequence of SEQ ID NO: 552. In some embodiments, Ab329 can bind to C5aR1 at site II (SEQ ID NO: 1450).

[0210] In some embodiments, the antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is the antibody Ab336v2, comprising HCDR1 containing the amino acid sequence of SEQ ID NO: 617, HCDR2 containing the amino acid sequence of SEQ ID NO: 737, and HCDR3 containing the amino acid sequence of SEQ ID NO: 857, as well as LCDR1 containing the amino acid sequence of SEQ ID NO: 677, LCDR2 containing the amino acid sequence of SEQ ID NO: 797, and LCDR3 containing the amino acid sequence of SEQ ID NO: 917, or comprising sequences that differ from the amino acids of SEQ ID NOs: 617, 737, 857, 677, 797, and / or 917 by 5, 4, 3, 2, or 1 or fewer amino acids. In some embodiments, the antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is Ab336v2, comprising a variable heavy chain containing the amino acid sequence of SEQ ID NO: 497, or a variable heavy chain having at least 70, 80, 90, 95, 96, 97, 98, 99, or 100% identity with the amino acid sequence of SEQ ID NO: 497. In some embodiments, the antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is Ab336v2, comprising a variable light chain containing the amino acid sequence of SEQ ID NO: 557, or a variable light chain having at least 70, 80, 90, 95, 96, 97, 98, 99, or 100% identity with the amino acid sequence of SEQ ID NO: 557. In some embodiments, Ab336v2 can bind to C5aR1 at site II (SEQ ID NO: 1450).

[0211] In some embodiments, an antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is the antibody Ab11v2, comprising HCDR1 containing the amino acid sequence of SEQ ID NO: 602, HCDR2 containing the amino acid sequence of SEQ ID NO: 722, and HCDR3 containing the amino acid sequence of SEQ ID NO: 842, as well as LCDR1 containing the amino acid sequence of SEQ ID NO: 662, LCDR2 containing the amino acid sequence of SEQ ID NO: 782, and LCDR3 containing the amino acid sequence of SEQ ID NO: 902, or comprising sequences that differ from the amino acids of SEQ ID NOs: 602, 722, 842, 662, 782, and / or 902 by 5, 4, 3, 2, or 1 or fewer amino acids. In some embodiments, the antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is Ab11v2, which includes a variable heavy chain containing the amino acid sequence of SEQ ID NO: 482, or a variable heavy chain having at least 70, 80, 90, 95, 96, 97, 98, 99, or 100% identity with the amino acid sequence of SEQ ID NO: 482. In some embodiments, the antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is Ab11v2, which includes a variable light chain containing the amino acid sequence of SEQ ID NO: 542, or a variable light chain having at least 70, 80, 90, 95, 96, 97, 98, 99, or 100% identity with the amino acid sequence of SEQ ID NO: 542. In some embodiments, Ab11v2 can bind to C5aR1 at site II (SEQ ID NO: 1450).

[0212] In some embodiments, the antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is Ab583 and includes HCDR1 containing the amino acid sequence of SEQ ID NO: 176, HCDR2 containing the amino acid sequence of SEQ ID NO: 296, and HCDR3 containing the amino acid sequence of SEQ ID NO: 416, as well as LCDR1 containing the amino acid sequence of SEQ ID NO: 235, LCDR2 containing the amino acid sequence of SEQ ID NO: 355, and LCDR3 containing the amino acid sequence of SEQ ID NO: 475, or includes sequences that differ from the amino acids of SEQ ID NOs: 176, 296, 416, 235, 355, and / or 475 by 5, 4, 3, 2, or 1 or fewer amino acids. In some embodiments, the antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is Ab583 and includes a variable heavy chain containing the amino acid sequence of SEQ ID NO: 56, or a variable heavy chain having at least 70, 80, 90, 95, 96, 97, 98, 99, or 100% identity with the amino acid sequence of SEQ ID NO: 56. In some embodiments, the antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is Ab583, which includes a variable light chain containing the amino acid sequence of SEQ ID NO: 115, or a variable light chain having at least 70, 80, 90, 95, 96, 97, 98, 99, or 100% identity with the amino acid sequence of SEQ ID NO: 115. In some embodiments, Ab583 can bind to C5aR1 at site I (SEQ ID NO: 1449 or SEQ ID NO: 1452).

[0213] In some embodiments, the antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is antibody Ab66, comprising HCDR1 containing the amino acid sequence of SEQ ID NO: 123, HCDR2 containing the amino acid sequence of SEQ ID NO: 243, and HCDR3 containing the amino acid sequence of SEQ ID NO: 363, as well as LCDR1 containing the amino acid sequence of SEQ ID NO: 183, LCDR2 containing the amino acid sequence of SEQ ID NO: 303, and LCDR3 containing the amino acid sequence of SEQ ID NO: 423, or comprising sequences that differ from the amino acids of SEQ ID NO: 123, 243, 363, 183, 303, and / or 423 by 5, 4, 3, 2, or 1 or fewer amino acids. In some embodiments, the antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is Ab66, comprising a variable heavy chain containing the amino acid sequence of SEQ ID NO: 3, or a variable heavy chain having at least 70, 80, 90, 95, 96, 97, 98, 99, or 100% identity with the amino acid sequence of SEQ ID NO: 3. In some embodiments, the antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is Ab66, which includes a variable light chain containing the amino acid sequence of SEQ ID NO: 63, or a variable light chain having at least 70, 80, 90, 95, 96, 97, 98, 99, or 100% identity with the amino acid sequence of SEQ ID NO: 63. In some embodiments, Ab66 can bind to C5aR1 at site I (SEQ ID NO: 1449 or SEQ ID NO: 1452).

[0214] In some embodiments, the antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is antibody Ab322, comprising HCDR1 containing the amino acid sequence of SEQ ID NO: 131, HCDR2 containing the amino acid sequence of SEQ ID NO: 251, and HCDR3 containing the amino acid sequence of SEQ ID NO: 371, as well as LCDR1 containing the amino acid sequence of SEQ ID NO: 191, LCDR2 containing the amino acid sequence of SEQ ID NO: 311, and LCDR3 containing the amino acid sequence of SEQ ID NO: 431, or comprising sequences that differ from the amino acids of SEQ ID NOs: 131, 251, 371, 191, 311, and / or 431 by 5, 4, 3, 2, or 1 or fewer amino acids. In some embodiments, the antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is Ab322, comprising a variable heavy chain containing the amino acid sequence of SEQ ID NO: 11, or a variable heavy chain having at least 70, 80, 90, 95, 96, 97, 98, 99, or 100% identity with the amino acid sequence of SEQ ID NO: 11. In some embodiments, the antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is Ab322, which includes a variable light chain containing the amino acid sequence of SEQ ID NO: 71, or a variable light chain having at least 70, 80, 90, 95, 96, 97, 98, 99, or 100% identity with the amino acid sequence of SEQ ID NO: 71. In some embodiments, Ab322 can bind to C5aR1 at site I (SEQ ID NO: 1449 or SEQ ID NO: 1452).

[0215] In some embodiments, the antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is antibody Ab329, comprising HCDR1 containing the amino acid sequence of SEQ ID NO: 132, HCDR2 containing the amino acid sequence of SEQ ID NO: 252, and HCDR3 containing the amino acid sequence of SEQ ID NO: 372, as well as LCDR1 containing the amino acid sequence of SEQ ID NO: 192, LCDR2 containing the amino acid sequence of SEQ ID NO: 312, and LCDR3 containing the amino acid sequence of SEQ ID NO: 432, or comprising sequences that differ from the amino acids of SEQ ID NOs: 132, 252, 372, 192, 312, and / or 432 by 5, 4, 3, 2, or 1 or fewer amino acids. In some embodiments, the antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is Ab329, comprising a variable heavy chain containing the amino acid sequence of SEQ ID NO: 12, or a variable heavy chain having at least 70, 80, 90, 95, 96, 97, 98, 99, or 100% identity with the amino acid sequence of SEQ ID NO: 12. In some embodiments, the antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is Ab329, which includes a variable light chain containing the amino acid sequence of SEQ ID NO: 72, or a variable light chain having at least 70, 80, 90, 95, 96, 97, 98, 99, or 100% identity with the amino acid sequence of SEQ ID NO: 72. In some embodiments, Ab329 can bind to C5aR1 at site II (SEQ ID NO: 1450).

[0216] In some embodiments, the antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is the antibody Ab336v2, comprising HCDR1 containing the amino acid sequence of SEQ ID NO: 137, HCDR2 containing the amino acid sequence of SEQ ID NO: 257, and HCDR3 containing the amino acid sequence of SEQ ID NO: 377, as well as LCDR1 containing the amino acid sequence of SEQ ID NO: 197, LCDR2 containing the amino acid sequence of SEQ ID NO: 317, and LCDR3 containing the amino acid sequence of SEQ ID NO: 437, or comprising sequences that differ from the amino acids of SEQ ID NOs: 137, 257, 377, 197, 317, and / or 437 by 5, 4, 3, 2, or 1 or fewer amino acids. In some embodiments, the antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is Ab336v2, comprising a variable heavy chain containing the amino acid sequence of SEQ ID NO: 17, or a variable heavy chain having at least 70, 80, 90, 95, 96, 97, 98, 99, or 100% identity with the amino acid sequence of SEQ ID NO: 17. In some embodiments, the antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is Ab336v2, comprising a variable light chain containing the amino acid sequence of SEQ ID NO: 77, or a variable light chain having at least 70, 80, 90, 95, 96, 97, 98, 99, or 100% identity with the amino acid sequence of SEQ ID NO: 77. In some embodiments, Ab336v2 can bind to C5aR1 at site II (SEQ ID NO: 1450).

[0217] In some embodiments, the antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is the antibody Ab11v2, comprising HCDR1 containing the amino acid sequence of SEQ ID NO: 122, HCDR2 containing the amino acid sequence of SEQ ID NO: 242, and HCDR3 containing the amino acid sequence of SEQ ID NO: 362, as well as LCDR1 containing the amino acid sequence of SEQ ID NO: 182, LCDR2 containing the amino acid sequence of SEQ ID NO: 302, and LCDR3 containing the amino acid sequence of SEQ ID NO: 422, or comprising sequences that differ from the amino acids of SEQ ID NOs: 122, 242, 362, 182, 302, and / or 422 by 5, 4, 3, 2, or 1 or fewer amino acids. In some embodiments, the antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is the antibody Ab11v2, comprising a variable heavy chain containing the amino acid sequence of SEQ ID NO: 2, or a variable heavy chain having at least 70, 80, 90, 95, 96, 97, 98, 99, or 100% identity with the amino acid sequence of SEQ ID NO: 2. In some embodiments, the antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is Ab11v2, which includes a variable light chain containing the amino acid sequence of SEQ ID NO: 62, or a variable light chain having at least 70, 80, 90, 95, 96, 97, 98, 99, or 100% identity with the amino acid sequence of SEQ ID NO: 62. In some embodiments, Ab11v2 can bind to C5aR1 at site II (SEQ ID NO: 1450).

[0218] In some embodiments, the antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is Ab583, comprising HCDR1 containing the amino acid sequence of SEQ ID NO: 1136, HCDR2 containing the amino acid sequence of SEQ ID NO: 1256, and HCDR3 containing the amino acid sequence of SEQ ID NO: 1376, as well as LCDR1 containing the amino acid sequence of SEQ ID NO: 1195, LCDR2 containing the amino acid sequence of SEQ ID NO: 1315, and LCDR3 containing the amino acid sequence of SEQ ID NO: 1435, or comprising sequences that differ from the amino acids of SEQ ID NOs: 1136, 1256, 1376, 1195, 1315, and / or 1435 by 5, 4, 3, 2, or 1 or fewer amino acids. In some embodiments, the antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is Ab583, comprising a variable heavy chain containing the amino acid sequence of SEQ ID NO: 1016, or a variable heavy chain having at least 70, 80, 90, 95, 96, 97, 98, 99, or 100% identity with the amino acid sequence of SEQ ID NO: 1016. In some embodiments, the antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is Ab583, comprising a variable light chain containing the amino acid sequence of SEQ ID NO: 1075, or a variable light chain having at least 70, 80, 90, 95, 96, 97, 98, 99, or 100% identity with the amino acid sequence of SEQ ID NO: 1075. In some embodiments, Ab583 can bind to C5aR1 at site I (SEQ ID NO: 1449 or SEQ ID NO: 1452).

[0219] In some embodiments, an antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is antibody Ab66, comprising HCDR1 containing the amino acid sequence of SEQ ID NO: 1082, HCDR2 containing the amino acid sequence of SEQ ID NO: 1202, and HCDR3 containing the amino acid sequence of SEQ ID NO: 1322, as well as LCDR1 containing the amino acid sequence of SEQ ID NO: 1143, LCDR2 containing the amino acid sequence of SEQ ID NO: 1263, and LCDR3 containing the amino acid sequence of SEQ ID NO: 1383, or comprising sequences that differ from the amino acids of SEQ ID NOs: 1082, 1202, 1322, 1143, 1263, and / or 1383 by 5, 4, 3, 2, or 1 or fewer amino acids. In some embodiments, the antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is Ab66, comprising a variable heavy chain containing the amino acid sequence of SEQ ID NO: 962, or a variable heavy chain having at least 70, 80, 90, 95, 96, 97, 98, 99, or 100% identity with the amino acid sequence of SEQ ID NO: 962. In some embodiments, the antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is Ab66, comprising a variable light chain containing the amino acid sequence of SEQ ID NO: 1023, or a variable light chain having at least 70, 80, 90, 95, 96, 97, 98, 99, or 100% identity with the amino acid sequence of SEQ ID NO: 1023. In some embodiments, Ab66 can bind to C5aR1 at site I (SEQ ID NO: 1449 or SEQ ID NO: 1452).

[0220] In some embodiments, an antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is antibody Ab322, comprising HCDR1 containing the amino acid sequence of SEQ ID NO: 1091, HCDR2 containing the amino acid sequence of SEQ ID NO: 1211, and HCDR3 containing the amino acid sequence of SEQ ID NO: 1331, as well as LCDR1 containing the amino acid sequence of SEQ ID NO: 1151, LCDR2 containing the amino acid sequence of SEQ ID NO: 1271, and LCDR3 containing the amino acid sequence of SEQ ID NO: 1391, or comprising sequences that differ from the amino acids of SEQ ID NOs: 1091, 1211, 1331, 1151, 1271, and / or 1391 by 5, 4, 3, 2, or 1 or fewer amino acids. In some embodiments, the antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is Ab322, comprising a variable heavy chain containing the amino acid sequence of SEQ ID NO: 971, or a variable heavy chain having at least 70, 80, 90, 95, 96, 97, 98, 99, or 100% identity with the amino acid sequence of SEQ ID NO: 971. In some embodiments, the antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is Ab322, comprising a variable light chain containing the amino acid sequence of SEQ ID NO: 1031, or a variable light chain having at least 70, 80, 90, 95, 96, 97, 98, 99, or 100% identity with the amino acid sequence of SEQ ID NO: 1031. In some embodiments, Ab322 can bind to C5aR1 at site I (SEQ ID NO: 1449 or SEQ ID NO: 1452).

[0221] In some embodiments, an antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is antibody Ab329, comprising HCDR1 containing the amino acid sequence of SEQ ID NO: 1092, HCDR2 containing the amino acid sequence of SEQ ID NO: 1212, and HCDR3 containing the amino acid sequence of SEQ ID NO: 1332, as well as LCDR1 containing the amino acid sequence of SEQ ID NO: 1152, LCDR2 containing the amino acid sequence of SEQ ID NO: 1272, and LCDR3 containing the amino acid sequence of SEQ ID NO: 1392, or comprising sequences that differ from the amino acids of SEQ ID NOs: 1092, 1212, 1332, 1152, 1272, and / or 1392 by 5, 4, 3, 2, or 1 or fewer amino acids. In some embodiments, the antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is Ab329, comprising a variable heavy chain containing the amino acid sequence of SEQ ID NO: 972, or a variable heavy chain having at least 70, 80, 90, 95, 96, 97, 98, 99, or 100% identity with the amino acid sequence of SEQ ID NO: 972. In some embodiments, the antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is Ab329, comprising a variable light chain containing the amino acid sequence of SEQ ID NO: 1032, or a variable light chain having at least 70, 80, 90, 95, 96, 97, 98, 99, or 100% identity with the amino acid sequence of SEQ ID NO: 1032. In some embodiments, Ab329 can bind to C5aR1 at site II (SEQ ID NO: 1450).

[0222] In some embodiments, the antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is the antibody Ab336v2, comprising HCDR1 containing the amino acid sequence of SEQ ID NO: 1097, HCDR2 containing the amino acid sequence of SEQ ID NO: 1217, and HCDR3 containing the amino acid sequence of SEQ ID NO: 1337, as well as LCDR1 containing the amino acid sequence of SEQ ID NO: 1157, LCDR2 containing the amino acid sequence of SEQ ID NO: 1277, and LCDR3 containing the amino acid sequence of SEQ ID NO: 1397, or comprising sequences that differ from the amino acids of SEQ ID NOs: 1097, 1217, 1337, 1157, 1277, and / or 1397 by 5, 4, 3, 2, or 1 or fewer amino acids. In some embodiments, the antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is Ab336v2, comprising a variable heavy chain containing the amino acid sequence of SEQ ID NO: 977, or a variable heavy chain having at least 70, 80, 90, 95, 96, 97, 98, 99, or 100% identity with the amino acid sequence of SEQ ID NO: 977. In some embodiments, the antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is Ab336v2, comprising a variable light chain containing the amino acid sequence of SEQ ID NO: 1037, or a variable light chain having at least 70, 80, 90, 95, 96, 97, 98, 99, or 100% identity with the amino acid sequence of SEQ ID NO: 1037. In some embodiments, Ab336v2 can bind to C5aR1 at site II (SEQ ID NO: 1450).

[0223] In some embodiments, an antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is the antibody Ab11v2, comprising HCDR1 containing the amino acid sequence of SEQ ID NO: 1082, HCDR2 containing the amino acid sequence of SEQ ID NO: 1202, and HCDR3 containing the amino acid sequence of SEQ ID NO: 1322, as well as LCDR1 containing the amino acid sequence of SEQ ID NO: 1142, LCDR2 containing the amino acid sequence of SEQ ID NO: 1262, and LCDR3 containing the amino acid sequence of SEQ ID NO: 1382, or comprising sequences that differ from the amino acids of SEQ ID NOs: 1082, 1202, 1322, 1142, 1262, and / or 1382 by 5, 4, 3, 2, or 1 or fewer amino acids. In some embodiments, the antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is Ab11v2, which includes a variable heavy chain containing the amino acid sequence of SEQ ID NO: 962, or a variable heavy chain having at least 70, 80, 90, 95, 96, 97, 98, 99, or 100% identity with the amino acid sequence of SEQ ID NO: 962. In some embodiments, the antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1) is Ab11v2, which includes a variable light chain containing the amino acid sequence of SEQ ID NO: 1022, or a variable light chain having at least 70, 80, 90, 95, 96, 97, 98, 99, or 100% identity with the amino acid sequence of SEQ ID NO: 1022. In some embodiments, Ab11v2 can bind to C5aR1 at site II (SEQ ID NO: 1450).

[0224] In one embodiment, the antibody molecule is defined using, for example, the IMGT, Kabat, or Chothia definitions for CDR, as shown in Table 1A, 2A, or 3A (e.g., VH-11, VH-11v2, VH-66, VH-79, VH-184, VH-216, VH-272, VH-308, VH-317, VH-317v2, VH-322, VH-329, VH-330, VH-332, VH-335, VH-336v1, VH-336v2, VH-336v3, VH-338, VH-341v1, VH-341v2, VH-343, VH-399, VH-402, VH-416, VH-429, VH-430, VH-4 40, VH-453, VH-454, VH-465, VH-475, VH-481, VH-497, VH-502, VH-503, VH-504, VH- 507, VH-508, VH-510, VH-511, VH-521, VH-530, VH-536, VH-541, VH-547, VH-549, VH This includes one, two, or three CD-Rs of VH as described herein, such as VH-550, VH-553, VH-556, VH-557, VH-567, VH-568, VH-570, VH-573, VH-583, VH-584, VH-585, VH-586, VH-588, or VH-592.

[0225] In one embodiment, the antibody molecule is, for example, defined using the IMGT, Kabat, or Chothia definitions for CDR, as shown in Tables 1B, 2B, or 3B (e.g., VK-11, VK-66, VK-79, VK-184, VK-184_C_Y, VK-216_272, VK-308, VK-317, VK-317v2, VK-322, VK-329, VK-330, VK-332, VK-335, VK-336v1, VK-336v2, VK-338v1, VK-338v2, VK-341v1, VK-341v2, VK-343, VK-399, VK-402, VK-416, VK-429, VK-43 0, VK-440, VK-453, VK-454, VK-465, VK-475, VK-481, VK-497, VK-502, VK-503, VK- 504, VK-507, VK-508, VK-510, VK-511, VK-518, VK-528, VK-521, VK-530, VK-541, V This includes one, two, or three CD-Rs of the VLs listed herein, such as K-547, VK-549, VK-550, VK-553, VK-556, VK-557, VK-567, VK-568, VK-583, VK-584, VK-585, VK-586, VK-588, and VK-592.

[0226] In one embodiment, the antibody molecule includes one, two, or three CDRs of the VH of the antibody molecule described herein, such as any of 11v2, 322, 329, 330, 336v2-1, 402, 429, 430, 440, 453, 454, 465, 475, 507, 510, 511, 518, 528, 541, 547, 549, 550, 553, 556, 567, 568, 570, 573, 583, 584, 585, 586, 588, or 592 of the antibody, using the definitions of IMGT, Kabat, or Chothia for CDRs, for example.

[0227] In one embodiment, the antibody molecule includes one, two, or three CDRs of the VL region of the antibody molecule described herein, such as any of 11v2, 322, 329, 330, 336v2-1, 402, 429, 430, 440, 453, 454, 465, 475, 507, 510, 511, 518, 528, 541, 547, 549, 550, 553, 556, 567, 568, 570, 573, 583, 584, 585, 586, 588, or 592 of the antibody, using the definitions of IMGT, Kabat, or Chothia for CDRs.

[0228] In some embodiments, the antibody molecule can bind to, or substantially bind to, human C5aR1. In some embodiments, the antibody molecule binds to C5aR1 with high affinity, such as a strength of, for example, less than about 100 nM, typically about 10 nM, more typically about 10 to 0.001 nM, about 10 to 0.01 nM, about 5 to 0.01 nM, about 3 to 0.05 nM, about 1 to less than 0.1 nM, or greater, such as a dissociation constant (KD) of about 80, 70, 60, 50, 40, 30, 20, 10, 8, 6, 4, 3, 2, 1, 0.5, 0.2, 0.1, 0.05, 0.01, 0.005, or less than 0.001 nM. In some embodiments, the antibody molecule binds to C5aR1 with high affinity, such as 1 × 10 -4 , 1 x 10 -5 or 1 × 10 -5 s -1 Slower than K off It binds to C5aR1. In one embodiment, the antibody molecule is 1 × 10 4 , 5×10 4 , 1 x 10 5 , or 5×10 5 M -1 s -1 Faster than K on It then binds to C5aR1.

[0229] In some embodiments, the antibody molecule can bind to, or substantially bind to, human C5aR1. In some embodiments, the antibody molecule has a strength of, for example, less than about 100 nM, typically about 10 nM, more typically about 10 to 0.001 nM, about 10 to 0.01 nM, about 5 to 0.01 nM, about 3 to 0.05 nM, about 1 to less than 0.1 nM, or greater, for example, about 80, 70, 60, 50, 40, 30, 20, 10, 8, 6, 4, 3, 2, 1, 0.5, 0.2, 0.1, 0.05, 0.01, 0.005, or a dissociation constant (K) less than 0.001 nM. D ) and other factors bind to C5aR1 with high affinity. In one embodiment, the antibody molecule is 1 × 10 -4 , 5×10 -5 , or 1 × 10 -5 s -1 Slower than K off It binds to C5aR1. In one embodiment, the antibody molecule is 1 × 10 4 , 5×10 4 , 1 x 10 5 , or 5×10 5 M -1 s -1 Faster than K on It then binds to C5aR1.

[0230] In some embodiments, as determined by the methods described herein (e.g., normalized against an antibody-free control), the antibody molecule inhibits the binding of human C5aR1 to human C5a by 50% or more, for example, 60% or more, 70% or more, 80% or more, 85% or more, 90% or more, 95% or more, 96% or more, 97% or more, 98% or more, 99% or more, or 100%.

[0231] Antibodies can be humanized by any suitable method, and several such methods are known in this field (e.g., Morrison, SL 1985, Science 229:1202-1207, Oi et al. 1986, BioTechniques). See 4:214, and Queen et al. US5,585,089, US5,693,761, and US5,693,762. (All content of those works is incorporated herein by reference.)

[0232] Humanized antibodies or CDR-transplant antibodies can be prepared by CDR transplantation or CDR substitution, in which case one, two, or all CDRs of the immunoglobulin chain can be substituted. See, for example, U.S. Patent No. 5,225,539; Jones et al. 1986 Nature 321:552-525; Verhoeyan et al. 1988 Science 239:1534; Beidler et al. 1988 J.Immunol. 141:4053-4060; Winter U.S. 5,225,539. All content of those documents is expressly incorporated herein by reference. Winter has reported a CDR transplantation method that can be used to prepare humanized antibodies (UK Patent Application GB 2188638A, filed March 26, 1987; Winter U.S. 5,225,539). The content of that document is expressly incorporated herein by reference.

[0233] Humanized antibodies in which specific amino acids are substituted, deleted, or added are also provided. Criteria for selecting amino acids from a donor are described in US5,585,089, for example, rows 12-16 of US5,585,089, and the contents of that document are incorporated herein by reference. Other techniques for humanizing antibodies are described in Padlan et al. EP519596A1, published December 23, 1992.

[0234] In one embodiment, the antibody molecule has a heavy chain constant region selected from among the heavy chain constant regions of IgG1, IgG2 (e.g., IgG2a), IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE, particularly the (e.g., human) heavy chain constant regions of IgG1, IgG2, IgG3, and IgG4. In another embodiment, the antibody molecule has a light chain constant region selected from among the (e.g., human) light chain constant regions of kappa or lambda. The properties of the antibody molecule can be modified by altering the constant regions, for example, by mutation (e.g., increasing or decreasing one or more of the following: Fc receptor binding, antibody glycosylation, cysteine ​​residue count, effector cell function, and / or complement function). In one embodiment, the antibody molecule has effector function and can immobilize complement. In another embodiment, the antibody molecule does not recruit effector cells or immobilize complement. In certain embodiments, the antibody molecule has little to no ability to bind to the Fc receptor. For example, the antibody molecule may be an isotype or subtype, fragment, or other variant that does not support binding to the Fc receptor, for example, having a mutated or deleted Fc receptor binding region.

[0235] In some embodiments, the constant region of an antibody molecule is modified. Methods for modifying the constant region of an antibody are known in the art. Antibody molecules with modified function, such as those with modified affinity for effector ligands like FcR on cells, or for the C1 component of complement, can be prepared by substituting at least one amino acid residue in the constant region of the antibody with another residue (see, for example, EP 388,151 A1, U.S. Patent No. 5,624,821, and U.S. Patent No. 5,648,260; all of the contents of those publications are incorporated herein by reference). In human IgG4, amino acid mutations that stabilize the antibody structure, such as S228P (EU system, S241P in the Kabat system), are also expected. Similar types of modifications may also be described in which immunoglobulins, when applied to mice or other species, reduce or eliminate these functions.

[0236] In some embodiments, the amino acids in the antibody molecule are standard amino acids only. In some embodiments, the antibody molecule comprises native amino acids, their analogues, derivatives and congeners, amino acid analogues having variant side chains, and / or all stereoisomers of any of these. The antibody molecule may also comprise D-optical isomers or L-optical isomers of amino acids and peptide mimetic molecules.

[0237] The polypeptides of antibody molecules described herein may be linear or branched, may contain modified amino acids, and may have non-amino acid intercalations. The antibody molecules may be modified by any other operation, such as the formation of disulfide bonds, glycosylation, lipidation, acetylation, phosphorylation, or conjugate with labeling components, for example. The polypeptides may be isolated from natural sources, produced from eukaryotic or prokaryotic hosts by recombinant technology, or are products of synthetic methods.

[0238] The antibody molecules described herein may be used alone in a non-conjugated form, or conjugated to substances such as toxins or parts (e.g., therapeutic agents), radioactive compounds, molecules of plant, fungal or bacterial origin, or biological proteins (e.g., protein toxins) or particles (e.g., recombinant viral particles via viral coat proteins). For example, an anti-C5aR1 antibody may be conjugated to an α-, β-, or γ-emitter, or to a radioactive isotope such as a β- and γ-emitter.

[0239] Antibody molecules may be derivatized or linked to other functional molecules (e.g., other peptides or proteins). As used herein, a “derivativeized” antibody molecule is a modified antibody molecule. Methods of derivatization include, but are not limited to, the addition of a fluorescent moiety, radionucleotide, toxin, enzyme, or affinity ligand such as biotin. Thus, antibody molecules are intended to include derivatized and otherwise modified forms of antibodies described herein, including immunoadhesion molecules. For example, an antibody molecule may be functionally linked (by chemical coupling, genetic fusion, non-covalent bonding, or otherwise) to one or more other molecular entities, such as another antibody (e.g., a bispecific antibody or diabody), a detectable agent, a toxin, a drug, and / or a protein or peptide that can mediate the binding of an antibody or antibody moiety to another molecule (e.g., a streptavidin core region or polyhistidine tag).

[0240] Some types of derivatized antibody molecules are produced by crosslinking two or more antibodies (antibodies of the same type, or different types of antibodies to produce, for example, bispecific antibodies). Suitable crosslinkers include heterobifunctional crosslinkers having two distinct reactive groups separated by a suitable spacer (e.g., m-maleimidobenzoyl-N-hydroxysuccinimidyl), or homobifunctional crosslinkers (e.g., disuccinimidyl suberate). Such linkers are available from Pierce Chemical Company, Rockford, Ill.

[0241] Useful detection agents in which anti-dengue antibody molecules can be derivatized (or labeled) to include fluorescent compounds, various enzymes, prosthetic groups, luminescent substances, bioluminescent substances, fluorescent-emitting metal atoms such as europium (Eu) and other lanthanides, and radioactive substances (described below). Exemplary fluorescent detection agents include fluorescein, fluorescein isothiocyanate, rhodamine, 5-dimethylamine-1-naphthalenesulfonyl chloride, and phycoerythrin. Antibodies may be derivatized using detectable enzymes such as alkaline phosphatase, horseradish peroxidase, β-galactosidase, acetylcholinesterase, and glucose oxidase. When antibodies are derivatized with detectable enzymes, the antibodies are detected by adding additional reagents that the enzyme uses to produce a detectable reaction product. For example, in the presence of horseradish peroxidase as a detection agent, a detectable colored reaction product is produced by adding hydrogen peroxide and diaminobenzidine. Antibody molecules may be derivatized with prosthetic groups (e.g., streptavidin / biotin and avidin / biotin). For example, an antibody may be derivatized with biotin and detected by indirectly measuring the binding of avidin or streptavidin. Suitable fluorescent substances include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride, or phycoerythrin. An example of a luminescent substance is luminol. Examples of bioluminescent substances include luciferase, luciferin, and aequorin.

[0242] Labeled antibody molecules can be used diagnostically and / or experimentally in many situations, including (i) isolation of a specified antigen by standard techniques such as affinity chromatography or immunoprecipitation, (ii) detection of a specified antigen (in cell lysates or cell supernatants) to assess the abundance and expression pattern of a protein, and (iii) monitoring of protein levels in tissues as part of a clinical laboratory procedure to determine the effectiveness of a given therapeutic regimen.

[0243] Antibody molecules may typically be conjugated to another molecular entity such as a label or a therapeutic (e.g., for antimicrobial use (e.g., antibacterial or bactericidal), immunomodulatory, immunostimulatory, cytocidal, or cytostatic) agent or moiety. Radioisotopes can be used for diagnostic or therapeutic applications. Radioisotopes that can be bound to antibody molecules include, but are not limited to, α-, β-, or γ-emitters, or β- and γ-emitters. Such radioisotopes include, but are not limited to, iodine ( 131 I or 125 I), yttrium ( 90 Y), lutetium ( 177 Lu), actinium ( 225 Ac), praseodymium, astatine ( 211 At), rhenium ( 186 Re), bismuth ( 212 Bi or 213 Bi), indium ( 111 In), technetium ( 99 mTc), phosphorus ( 32 P), rhodium ( 188 Rh), sulfur ( 35 S), carbon ( 14 C), tritium ( 3 H), chromium ( 51 Cr), chlorine ( 36 Cl), cobalt ( 57 Co or 58 Co), iron ( 59 Fe), selenium ( 75 Se), or gallium ( 67 Ga). Radioisotopes useful as therapeutic agents include yttrium ( 90 Y), lutetium ( 177 Lu), actinium ( 225 Ac), praseodymium, astatine ( 211 At), rhenium ( 186 Re), bismuth ( 212 Bi or 213 Bi), and rhodium ( 188 Rh). For example, radioisotopes useful as labels for diagnostic applications include iodine (131 I or 125 I), Indium ( 111 In), technetium ( 99 mTc), phosphorus ( 32 P), carbon ( 14 C), and tritium (3 H), or one or more of the therapeutic isotopes mentioned above.

[0244] This disclosure provides radiolabeled antibody molecules and methods for labeling them. In one embodiment, a method for labeling an antibody molecule is disclosed. The method includes contacting an antibody molecule with a chelating agent to produce a conjugated antibody. The conjugated antibody is, for example, 111 indium, 90 Yttrium, and 177 Radioactive labeling with radioactive isotopes such as lutetium is used to generate labeled antibody molecules.

[0245] In another aspect, the Disclosure provides a method for producing antibody molecules disclosed herein. The method includes, for example, providing an antigen or a fragment thereof such as C5aR1; obtaining an antibody molecule that specifically binds to the antigen; and evaluating the effectiveness of the antibody molecule in modulating the activity of an antigen such as C5aR1 and / or in an organism expressing the antigen. The method may further include administering the antibody molecule, including its derivative (e.g., a humanized antibody molecule), to a subject such as a human.

[0246] This disclosure provides isolated nucleic acid molecules encoding the antibody molecules described above, their vectors, and host cells. The nucleic acid molecules include, but are not limited to, RNA, genomic DNA, and cDNA.

[0247] The amino acid sequences of exemplary antibody molecules are listed in Tables 1A, 1B, 2A, 2B, 3A, and 3B. Tables 1A, 2A, and 3A list exemplary heavy chain variable region sequences and their complementarity-determining regions (CDRs). Tables 1B, 2B, and 3B list exemplary light chain variable region sequences and their complementarity-determining regions (CDRs). Table 1C lists matched pairs of heavy chain variable regions and light chain variable regions of exemplary antibody molecules described herein. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 2-1] [Table 2-2] [Table 2-3] Table 2-4 Table 2-5 Table 2-6 Table 2-7 Table 2-8 Table 2-9 Table 2-10 Table 3-1 Table 3-2 Table 3-3 Table 3-4 Table 4-1 Table 4-2 Table 4-3 Table 4-4 Table 4-5 Table 4-6 Table 4-7 Table 4-8 Table 4-9 Table 4-10 Table 4-11 Table 4-12 Table 5-1 Table 5-2 Table 5-3 Table 5-4 Table 5-5 Table 5-6 Table 5-7 Table 5-8 Table 5-9 Table 5-10 Table 6-1 Table 6-2 Table 6-3 Table 6-4 Table 6-5 Table 6-6 Table 6-7 Table 6-8 Table 6-9 Table 6-10 Table 6-11 Table 6-12 Table 7-1 Table 7-2 Table 7-3 Table 7-4 Table 7-5 Table 7-6 [Table 7-7] [Table 7-8] [Table 7-9] [Table 7-10] [Table 7-11]

[0248] In one embodiment, the antibody molecule is defined using, for example, the IMGT, Kabat, or Chothia definitions for CDR, as shown in Table 1A, 2A, or 3A (e.g., VH-11, VH-11v2, VH-66, VH-79, VH-184, VH-216, VH-272, VH-308, VH-317, VH-317v2, VH-322, VH-329, VH-330, VH-332, VH-335, VH-336v1, VH-336v2, VH-336v3, VH-338, VH-341v1, VH-341v2, VH-343, VH-399, VH-402, VH-416, VH-429, VH-430, VH-4 40, VH-453, VH-454, VH-465, VH-475, VH-481, VH-497, VH-502, VH-503, VH-504, VH- 507, VH-508, VH-510, VH-511, VH-521, VH-530, VH-536, VH-541, VH-547, VH-549, VH This includes one, two, or three CD-Rs of VH as described herein, such as VH-550, VH-553, VH-556, VH-557, VH-567, VH-568, VH-570, VH-573, VH-583, VH-584, VH-585, VH-586, VH-588, or VH-592.

[0249] In one embodiment, the antibody molecule is, for example, defined using the IMGT, Kabat, or Chothia definitions for CDR, as shown in Tables 1B, 2B, or 3B (e.g., VK-11, VK-66, VK-79, VK-184, VK-184_C_Y, VK-216_272, VK-308, VK-317, VK-317v2, VK-322, VK-329, VK-330, VK-332, VK-335, VK-336v1, VK-336v2, VK-338v1, VK-338v2, VK-341v1, VK-341v2, VK-343, VK-399, VK-402, VK-416, VK-429, VK-43 0, VK-440, VK-453, VK-454, VK-465, VK-475, VK-481, VK-497, VK-502, VK-503, VK- 504, VK-507, VK-508, VK-510, VK-511, VK-518, VK-528, VK-521, VK-530, VK-541, V This includes one, two, or three CD-Rs of the VLs listed herein, such as K-547, VK-549, VK-550, VK-553, VK-556, VK-557, VK-567, VK-568, VK-583, VK-584, VK-585, VK-586, VK-588, and VK-592.

[0250] In one embodiment, the antibody molecule includes one, two, or three CDRs of the VH of the antibody molecule described herein, such as any of 11v2, 322, 329, 330, 336v2-1, 402, 429, 430, 440, 453, 454, 465, 475, 507, 510, 511, 518, 528, 541, 547, 549, 550, 553, 556, 567, 568, 570, 573, 583, 584, 585, 586, 588, or 592 of the antibody, using the definitions of IMGT, Kabat, or Chothia for CDRs, for example. In one embodiment, the antibody molecule includes one, two, or three CDRs of the VH of the antibody molecule described herein, such as any of 11v2, 322, 329, 330, 336v2-1, 402, 429, 430, 440, 453, 454, 465, 475, 507, 510, 511, 518, 528, 541, 547, 549, 550, 553, 556, 567, 568, 570, 573, 583, 584, 585, 586, 588, or 592 of the antibody, using the definitions of IMGT, Kabat, or Chothia for CDRs, for example.

[0251] In one embodiment, the antibody molecule includes one, two, or three CDRs of the VL region of the antibody molecule described herein, such as any of 11v2, 322, 329, 330, 336v2-1, 402, 429, 430, 440, 453, 454, 465, 475, 507, 510, 511, 518, 528, 541, 547, 549, 550, 553, 556, 567, 568, 570, 573, 583, 584, 585, 586, 588, or 592 of the antibody, using the definitions of IMGT, Kabat, or Chothia for CDRs.

[0252] In one embodiment, the antibody molecule is, for example, defined using the IMGT, Kabat, or Chothia definitions for CDRs, as shown in Table 1A, 2A, or 3A (e.g., VH-11, VH-11v2, VH-66, VH-79, VH-184, VH-216, VH-272, VH-308, VH-317, VH-317v2, VH-322, VH-329, VH-330, VH-332, VH-335, VH-336v1, VH-336v2, VH-336v3, VH-338, VH-341v1, VH-341v2, VH-343, VH-399, VH-40 2, VH-416, VH-429, VH-430, VH-440, VH-453, VH-454, VH-465, VH-475, VH-4 81, VH-497, VH-502, VH-503, VH-504, VH-507, VH-508, VH-510, VH-511, VH- 521, VH-530, VH-536, VH-541, VH-547, VH-549, VH-550, VH-553, VH-556, VH -557, VH-567, VH-568, VH-570, VH-573, VH-583, VH-584, VH-585, VH-586, VH This includes one, two, or three VH CDRs as described herein, such as VK-588 or VH-592, and Tables 1B, 2B, or 3B (e.g., VK-11, VK-66, VK-79, VK-184, VK-184_C_Y, VK-216_272, VK-308, VK-317, VK-317v2, VK-322, VK-329, VK-330, VK-332, VK-335, VK-336v1, VK-336v2, VK-338v1, VK-588v2 -338v2, VK-341v1, VK-341v2, VK-343, VK-399, VK-402, VK-416, VK-429, VK -430, VK-440, VK-453, VK-454, VK-465, VK-475, VK-481, VK-497, VK-502, V K-503, VK-504, VK-507, VK-508, VK-510, VK-511, VK-518, VK-528, VK-521, VK-530, VK-541, VK-547, VK-549, VK-550, VK-553, VK-556, VK-557, VK-567,This includes one, two, or three CD-Rs of the VLs listed herein, such as VK-568, VK-583, VK-584, VK-585, VK-586, VK-588, or VK-592.

[0253] In one embodiment, the antibody molecule is one, two, or three of the VHs of the antibody molecules described herein, such as 11v2, 322, 329, 330, 336v2-1, 402, 429, 430, 440, 453, 454, 465, 475, 507, 510, 511, 518, 528, 541, 547, 549, 550, 553, 556, 567, 568, 570, 573, 583, 584, 585, 586, 588, or 592, using the definitions of IMGT, Kabat, or Chothia for CDR (for example, any of 11v2, 322, 329, 330, 336v2-1, 402, 429, 430, 440, 453, 454, 465, 475, 507, 510, 511, 518, 528, 541, 547, 549, 550, 553, 556, 567, 568, 570, 573, 583, 584, 585, 586, 588, or 592, as listed in Table 1C). Including CDRs and using the definitions of IMGT, Kabat, or Chothia for CDRs, including one, two, or three CDRs of the VL regions of antibody molecules described herein, such as (if listed in Table 1C) any of 11v2, 322, 329, 330, 336v2-1, 402, 429, 430, 440, 453, 454, 465, 475, 507, 510, 511, 518, 528, 541, 547, 549, 550, 553, 556, 567, 568, 570, 573, 583, 584, 585, 586, 588, or 592 of the antibody.

[0254] In one embodiment, the antibody molecule comprises one, two, or three HCDRs listed in Table 1A, 2A, or 3A. In another embodiment, the antibody molecule comprises one, two, or three LCDRs listed in Table 1B, 2B, or 3B. In yet another embodiment, the antibody molecule comprises one, two, or three HCDRs listed in Table 1A, 2A, or 3A, and one, two, or three LCDRs listed in Table 1B, 2B, or 3B.

[0255] In one embodiment, the antibody molecule includes one, two, or three CDRs of the VL region of the antibody molecule described herein, such as any of 11v2, 322, 329, 330, 336v2-1, 402, 429, 430, 440, 453, 454, 465, 475, 507, 510, 511, 518, 528, 541, 547, 549, 550, 553, 556, 567, 568, 570, 573, 583, 584, 585, 586, 588, or 592 of the antibody, using the definitions of IMGT, Kabat, or Chothia for CDRs.

[0256] In one embodiment, the antibody molecule is, for example, defined using the IMGT, Kabat, or Chothia definitions for CDRs, as shown in Table 1A, 2A, or 3A (e.g., VH-11, VH-11v2, VH-66, VH-79, VH-184, VH-216, VH-272, VH-308, VH-317, VH-317v2, VH-322, VH-329, VH-330, VH-332, VH-335, VH-336v1, VH-336v2, VH-336v3, VH-338, VH-341v1, VH-341v2, VH-343, VH-399, VH-40 2, VH-416, VH-429, VH-430, VH-440, VH-453, VH-454, VH-465, VH-475, VH-4 81, VH-497, VH-502, VH-503, VH-504, VH-507, VH-508, VH-510, VH-511, VH- 521, VH-530, VH-536, VH-541, VH-547, VH-549, VH-550, VH-553, VH-556, VH -557, VH-567, VH-568, VH-570, VH-573, VH-583, VH-584, VH-585, VH-586, VH This includes one, two, or three VH CDRs as described herein, such as VK-588 or VH-592, and Tables 1B, 2B, or 3B (e.g., VK-11, VK-66, VK-79, VK-184, VK-184_C_Y, VK-216_272, VK-308, VK-317, VK-317v2, VK-322, VK-329, VK-330, VK-332, VK-335, VK-336v1, VK-336v2, VK-338v1, VK-588v2 -338v2, VK-341v1, VK-341v2, VK-343, VK-399, VK-402, VK-416, VK-429, VK -430, VK-440, VK-453, VK-454, VK-465, VK-475, VK-481, VK-497, VK-502, V K-503, VK-504, VK-507, VK-508, VK-510, VK-511, VK-518, VK-528, VK-521, VK-530, VK-541, VK-547, VK-549, VK-550, VK-553, VK-556, VK-557, VK-567,This includes one, two, or three CD-Rs of the VLs listed herein, such as VK-568, VK-583, VK-584, VK-585, VK-586, VK-588, or VK-592.

[0257] In one embodiment, the antibody molecule is one, two, or three of the VHs of the antibody molecules described herein, such as 11v2, 322, 329, 330, 336v2-1, 402, 429, 430, 440, 453, 454, 465, 475, 507, 510, 511, 518, 528, 541, 547, 549, 550, 553, 556, 567, 568, 570, 573, 583, 584, 585, 586, 588, or 592, using the definitions of IMGT, Kabat, or Chothia for CDR (for example, any of 11v2, 322, 329, 330, 336v2-1, 402, 429, 430, 440, 453, 454, 465, 475, 507, 510, 511, 518, 528, 541, 547, 549, 550, 553, 556, 567, 568, 570, 573, 583, 584, 585, 586, 588, or 592, as listed in Table 1C). Including CDRs and using the definitions of IMGT, Kabat, or Chothia for CDRs, including one, two, or three CDRs of the VL regions of antibody molecules described herein, such as (if listed in Table 1C) any of 11v2, 322, 329, 330, 336v2-1, 402, 429, 430, 440, 453, 454, 465, 475, 507, 510, 511, 518, 528, 541, 547, 549, 550, 553, 556, 567, 568, 570, 573, 583, 584, 585, 586, 588, or 592 of the antibody.

[0258] In one embodiment, the antibody molecule comprises one, two, or three HCDRs listed in Table 1A, 2A, or 3A. In another embodiment, the antibody molecule comprises one, two, or three LCDRs listed in Table 1B, 2B, or 3B. In yet another embodiment, the antibody molecule comprises one, two, or three HCDRs listed in Table 1A, 2A, or 3A, and one, two, or three LCDRs listed in Table 1B, 2B, or 3B.

[0259] In one embodiment, the antibody molecule comprises HCDR1, HCDR2, and HCDR3 as listed in the same row in Table 1A, 2A, or 3A. In another embodiment, the antibody molecule comprises LCDR1, LCDR2, and LCDR3 as listed in the same row in Table 1B, 2B, or 3B. In yet another embodiment, the antibody molecule comprises HCDR1, HCDR2, and HCDR3 as listed in the same row in Table 1A, 2A, or 3A, and LCDR1, LCDR2, and LCDR3 as listed in the same row in Table 1B, 2B, or 3B.

[0260] In one embodiment, the antibody molecule is, for example, defined using the IMGT, Kabat, or Chothia definitions for CDRs, as shown in Table 1A, 2A, or 3A (e.g., VH-11, VH-11v2, VH-66, VH-79, VH-184, VH-216, VH-272, VH-308, VH-317, VH-317v2, VH-322, VH-329, VH-330, VH-332, VH-335, VH-336v1, VH-336v2, VH-336v3, VH-338, VH-341v1, VH-341v2, VH-343, VH-399, VH-402, VH-416, VH-429, VH-430, VH-440, VH-453, VH-454, VH-465, VH-475, VH-481, VH-497, VH-502, VH-503, VH-504, VH-507, VH-508, VH-510, VH-511, VH-521, VH-530, VH-536, VH-541, VH-547, VH-549, VH-550, This includes one, two, three, or four frameworks of VH as described herein, such as VH-553, VH-556, VH-557, VH-567, VH-568, VH-570, VH-573, VH-583, VH-584, VH-585, VH-586, VH-588, or VH-592.

[0261] In one embodiment, the antibody molecule comprises one, two, three, or four frameworks of VH of the antibody molecule described herein, such as Table 1A, 2A, or 3A (for example, any of 11v2, 322, 329, 330, 336v2-1, 402, 429, 430, 440, 453, 454, 465, 475, 507, 510, 511, 518, 528, 541, 547, 549, 550, 553, 556, 567, 568, 570, 573, 583, 584, 585, 586, 588, or 592 of the antibody, as listed in Table 1C). In one embodiment, the antibody molecule comprises one, two, three, or four frameworks of VH of the antibody molecule described herein, such as Table 1A, 2A, or 3A (for example, any of 11v2, 322, 329, 330, 336v2-1, 402, 429, 430, 440, 453, 454, 465, 475, 507, 510, 511, 518, 528, 541, 547, 549, 550, 553, 556, 567, 568, 570, 573, 583, 584, 585, 586, 588, or 592 of the antibody, as listed in Table 1C).In one embodiment, the antibody molecule is, for example, defined using the IMGT, Kabat, or Chothia definitions for CDR, as shown in Table 1B, 2B, or 3B (e.g., VK-11, VK-66, VK-79, VK-184, VK-184_C_Y, VK-216_272, VK-308, VK-317, VK-317v2, VK-322, VK-329, VK-330, VK-332, VK-335, VK-336v1, VK-336v2, VK-338v1, VK-338v2, VK-341v1, VK-341v2, VK-343, VK-399, VK-402, VK-416, VK-429, VK-430, V K-440, VK-453, VK-454, VK-465, VK-475, VK-481, VK-497, VK-502, VK-503, VK-504, VK-507, VK-508, VK-510, VK-511, VK-518, VK-528, VK-521, VK-530, VK-541, VK-547 This includes one, two, three, or four frameworks of the VLs described herein, such as VK-549, VK-550, VK-553, VK-556, VK-557, VK-567, VK-568, VK-583, VK-584, VK-585, VK-586, VK-588, or VK-592.

[0262] In one embodiment, the antibody molecule comprises one, two, three, or four frameworks of the VL regions of the antibody molecule described herein, such as any of the following, if listed in Table 1C: 11v2, 322, 329, 330, 336v2-1, 402, 429, 430, 440, 453, 454, 465, 475, 507, 510, 511, 518, 528, 541, 547, 549, 550, 553, 556, 567, 568, 570, 573, 583, 584, 585, 586, 588, or 592 of the antibody molecule, using the definitions of IMGT, Kabat, or Chothia for CDR.

[0263] In one embodiment, the antibody molecule is, for example, defined using the IMGT, Kabat, or Chothia definitions for CDRs, as shown in Table 1A, 2A, or 3A (e.g., VH-11, VH-11v2, VH-66, VH-79, VH-184, VH-216, VH-272, VH-308, VH-317, VH-317v2, VH-322, VH-329, VH-330, VH-332, VH-335, VH-336v1, VH-336v2, VH-336v3, VH-338, VH-341v1, VH-341v2, VH-343, VH-399, VH-40 2, VH-416, VH-429, VH-430, VH-440, VH-453, VH-454, VH-465, VH-475, VH-4 81, VH-497, VH-502, VH-503, VH-504, VH-507, VH-508, VH-510, VH-511, VH- 521, VH-530, VH-536, VH-541, VH-547, VH-549, VH-550, VH-553, VH-556, VH -557, VH-567, VH-568, VH-570, VH-573, VH-583, VH-584, VH-585, VH-586, VH This includes one, two, three or four frameworks of VH as described herein, such as VK-588 or VH-592, and Tables 1B, 2B, or 3B (e.g., VK-11, VK-66, VK-79, VK-184, VK-184_C_Y, VK-216_272, VK-308, VK-317, VK-317v2, VK-322, VK-329, VK-330, VK-332, VK-335, VK-336v1, VK-336v2, VK-3 38v1, VK-338v2, VK-341v1, VK-341v2, VK-343, VK-399, VK-402, VK-416, VK -429, VK-430, VK-440, VK-453, VK-454, VK-465, VK-475, VK-481, VK-497, V K-502, VK-503, VK-504, VK-507, VK-508, VK-510, VK-511, VK-518, VK-528, VK-521, VK-530, VK-541, VK-547, VK-549, VK-550, VK-553, VK-556, VK-557,This includes one, two, three, or four frameworks of the VLs described herein, such as VK-567, VK-568, VK-583, VK-584, VK-585, VK-586, VK-588, or VK-592.

[0264] In one embodiment, the antibody molecule is one, two, three, or four frames of VH of the antibody molecule described herein, such as 11v2, 322, 329, 330, 336v2-1, 402, 429, 430, 440, 453, 454, 465, 475, 507, 510, 511, 518, 528, 541, 547, 549, 550, 553, 556, 567, 568, 570, 573, 583, 584, 585, 586, 588, or 592, using the definitions of IMGT, Kabat, or Chothia for CDR, as shown in Tables 1A, 2A, or 3A (for example, any of 11v2, 322, 329, 330, 336v2-1, 402, 429, 430, 440, 453, 454, 465, 475, 507, 510, 511, 518, 528, 541, 547, 549, 550, 553, 556, 567, 568, 570, 573, 583, 584, 585, 586, 588, or 592, as listed in Table 1C). Including the work and using the definitions of IMGT, Kabat, or Chothia for CDR, the framework includes one, two, three, or four VL regions of antibody molecules described herein, such as Table 1B, 2B, or 3B ((if listed in Table 1C) for example, any of the antibody 11v2, 322, 329, 330, 336v2-1, 402, 429, 430, 440, 453, 454, 465, 475, 507, 510, 511, 518, 528, 541, 547, 549, 550, 553, 556, 567, 568, 570, 573, 583, 584, 585, 586, 588, or 592). In one embodiment, the antibody molecule comprises one, two, three, or four frameworks of the VL regions of the antibody molecule described herein, such as any of the following, if listed in Table 1C: 11v2, 322, 329, 330, 336v2-1, 402, 429, 430, 440, 453, 454, 465, 475, 507, 510, 511, 518, 528, 541, 547, 549, 550, 553, 556, 567, 568, 570, 573, 583, 584, 585, 586, 588, or 592 of the antibody molecule, using the definitions of IMGT, Kabat, or Chothia for CDR.

[0265] In one embodiment, the antibody molecule is, for example, defined using the IMGT, Kabat, or Chothia definitions for CDRs, as shown in Table 1A, 2A, or 3A (e.g., VH-11, VH-11v2, VH-66, VH-79, VH-184, VH-216, VH-272, VH-308, VH-317, VH-317v2, VH-322, VH-329, VH-330, VH-332, VH-335, VH-336v1, VH-336v2, VH-336v3, VH-338, VH-341v1, VH-341v2, VH-343, VH-399, VH-40 2, VH-416, VH-429, VH-430, VH-440, VH-453, VH-454, VH-465, VH-475, VH-4 81, VH-497, VH-502, VH-503, VH-504, VH-507, VH-508, VH-510, VH-511, VH- 521, VH-530, VH-536, VH-541, VH-547, VH-549, VH-550, VH-553, VH-556, VH -557, VH-567, VH-568, VH-570, VH-573, VH-583, VH-584, VH-585, VH-586, VH This includes one, two, three or four frameworks of VH as described herein, such as VK-588 or VH-592, and Tables 1B, 2B, or 3B (e.g., VK-11, VK-66, VK-79, VK-184, VK-184_C_Y, VK-216_272, VK-308, VK-317, VK-317v2, VK-322, VK-329, VK-330, VK-332, VK-335, VK-336v1, VK-336v2, VK-3 38v1, VK-338v2, VK-341v1, VK-341v2, VK-343, VK-399, VK-402, VK-416, VK -429, VK-430, VK-440, VK-453, VK-454, VK-465, VK-475, VK-481, VK-497, V K-502, VK-503, VK-504, VK-507, VK-508, VK-510, VK-511, VK-518, VK-528, VK-521, VK-530, VK-541, VK-547, VK-549, VK-550, VK-553, VK-556, VK-557,This includes one, two, three, or four frameworks of the VLs described herein, such as VK-567, VK-568, VK-583, VK-584, VK-585, VK-586, VK-588, or VK-592.

[0266] In one embodiment, the antibody molecule is one, two, three, or four frames of VH of the antibody molecule described herein, such as 11v2, 322, 329, 330, 336v2-1, 402, 429, 430, 440, 453, 454, 465, 475, 507, 510, 511, 518, 528, 541, 547, 549, 550, 553, 556, 567, 568, 570, 573, 583, 584, 585, 586, 588, or 592, using the definitions of IMGT, Kabat, or Chothia for CDR, as shown in Tables 1A, 2A, or 3A (for example, any of 11v2, 322, 329, 330, 336v2-1, 402, 429, 430, 440, 453, 454, 465, 475, 507, 510, 511, 518, 528, 541, 547, 549, 550, 553, 556, 567, 568, 570, 573, 583, 584, 585, 586, 588, or 592, as listed in Table 1C). The antibody molecule includes one, two, three, or four VL region frameworks of the antibody molecule described herein, including workpieces and using the definitions of IMGT, Kabat, or Chothia for CDR, as shown in Tables 1B, 2B, or 3B (for example, any of the antibody 11v2, 322, 329, 330, 336v2-1, 402, 429, 430, 440, 453, 454, 465, 475, 507, 510, 511, 518, 528, 541, 547, 549, 550, 553, 556, 567, 568, 570, 573, 583, 584, 585, 586, 588, or 592, if listed in Table 1C). In some embodiments, the antibody molecule includes all heavy chain frameworks listed in the same row of Tables 1A, 2A, or 3A. In one embodiment, the antibody molecule includes all light chain frameworks listed in the same row of Table 1B, 2B, or 3B. In another embodiment, the antibody molecule includes all heavy chain frameworks listed in the same row of Table 1A, 2A, or 3A, and all light chain frameworks listed in the same row of Table 1B, 2B, or 3B.

[0267] In one embodiment, the antibody molecule is a VH (e.g., VH-11, VH-11v2, VH-66, VH-79, VH-184, VH-216, VH-272, VH-308, VH-317, VH-317v2, VH-322, VH-329, VH-330, VH-332, VH-335, VH-336v1, VH-336v2, VH-336v3, VH-338, VH-341v1, VH-341v2, VH-343, VH-399, VH-402, VH-416, VH-429, VH-430, VH-440, VH-4 53, VH-454, VH-465, VH-475, VH-481, VH-497, VH-502, VH-503, VH-504, VH-507, VH-508, VH-510, VH-511, VH-521, VH-530, VH-536, VH-541, VH-547, VH-549, VH-550, VH-553, VH-556, VH-557, VH-567, VH-568, VH-570, VH-573, VH-583, VH-584, VH-585, VH-586, VH-588, or VH-592), or an amino acid sequence substantially identical thereto.In one embodiment, the antibody molecule is a VL containing the amino acid sequence listed in Table 1B, 2B, or 3B (e.g., VK-11, VK-66, VK-79, VK-184, VK-184_C_Y, VK-216_272, VK-308, VK-317, VK-317v2, VK-322, VK-329, VK-330, VK-332, VK-335, VK-336v1, VK-336v2, VK-338v1, VK-338v2, VK-341v1, VK-341v2, VK-343, VK-399, VK-402, VK-416, VK-429, VK-430, VK-44 Contains any of the following amino acid sequences: 0, VK-453, VK-454, VK-465, VK-475, VK-481, VK-497, VK-502, VK-503, VK-504, VK-507, VK-508, VK-510, VK-511, VK-518, VK-528, VK-521, VK-530, VK-541, VK-547, VK-549, VK-550, VK-553, VK-556, VK-557, VK-567, VK-568, VK-583, VK-584, VK-585, VK-586, VK-588, VK-592, or substantially identical thereto.

[0268] In one embodiment, the antibody molecule is a VH (e.g., VH-11, VH-11v2, VH-66, VH-79, VH-184, VH-216, VH-272, VH-308, VH-317, VH-317v2, VH-322, VH-329, VH-330, VH-332, VH-335, VH-336v1, VH-336v2, VH-336v3, VH-338, VH-341v1, VH-341v2, VH-343, VH-399, VH-402, VH-416, VH-429, VH-430, VH-440, VH-453, VH-454, VH-465, VH-475, VH-481, VH-497, VH-502, VH-503 , VH-504, VH-507, VH-508, VH-510, VH-511, VH-521, VH-530, VH-536, VH-54 1, VH-547, VH-549, VH-550, VH-553, VH-556, VH-557, VH-567, VH-568, VH-5 70, VH-573, VH-583, VH-584, VH-585, VH-586, VH-588, or VH-592), or These include amino acid sequences that are substantially identical to those, and VLs that include amino acid sequences listed in Table 1B, 2B, or 3B (e.g., VK-11, VK-66, VK-79, VK-184, VK-184_C_Y, VK-216_272, VK-308, VK-317, VK-317v2, VK-322, VK-329, VK-330, VK-332, VK-335, VK-336v1, VK-336v2, VK-338v1, VK-338v2, VK-341v1, VK-341v2, VK-343, VK-399, VK-402, VK-416, VK -429, VK-430, VK-440, VK-453, VK-454, VK-465, VK-475, VK-481, VK-497, V K-502, VK-503, VK-504, VK-507, VK-508, VK-510, VK-511, VK-518, VK-528, VK-521, VK-530, VK-541, VK-547, VK-549, VK-550, VK-553, VK-556, VK-557 , VK-567, VK-568, VK-583, VK-584, VK-585, VK-586, VK-588, VK-592),or contain amino acid sequences substantially identical thereto. In one embodiment, the antibody molecule contains VH (e.g., VH-11, VH-11v2, VH-66, VH-79, VH-184, VH-216, VH-272, VH-308, VH-317, VH-317v2, VH-322, VH-329, VH-330, VH-332, VH-335, VH-336v1, VH-336v2, VH-336v3, VH-338, VH-341v1, VH-341v2, VH-343, VH-399, VH-402, VH-416, VH-429, VH -430, VH-440, VH-453, VH-454, VH-465, VH-475, VH-481, VH-497, VH-502, VH-503, VH-504, VH-507, VH-508, VH-510, VH-511, VH-521, VH-530, VH-53 6, VH-541, VH-547, VH-549, VH-550, VH-553, VH-556, VH-557, VH-567, VH- 568, VH-570, VH-573, VH-583, VH-584, VH-585, VH-586, VH-588, or VH-59 VL (e.g., VK-11, VK-66, VK-79, VK-184, VK-184_C_Y, VK-216_272, VK-308, VK-317, VK-317v2, VK-322, VK-329, VK-330, VK-332, VK-335, VK-336v1, VK-336v2, VK-338v1, VK-338v2, VK-341v1, VK-341v2, VK-343, VK-399, V K-402, VK-416, VK-429, VK-430, VK-440, VK-453, VK-454, VK-465, VK-475 , VK-481, VK-497, VK-502, VK-503, VK-504, VK-507, VK-508, VK-510, VK-5 11, VK-518, VK-528, VK-521, VK-530, VK-541, VK-547, VK-549, VK-550, VK -553, VK-556, VK-557, VK-567, VK-568, VK-583, VK-584, VK-585, VK-586,The antibody molecule contains either VK-588 or VK-592, or an amino acid sequence substantially identical thereto. In some embodiments, the antibody molecule contains the VH of an antibody molecule described herein, such as those listed in Table 1A, 2A, or 3A (for example, any of 11v2, 322, 329, 330, 336v2-1, 402, 429, 430, 440, 453, 454, 465, 475, 507, 510, 511, 518, 528, 541, 547, 549, 550, 553, 556, 567, 568, 570, 573, 583, 584, 585, 586, 588, or 592, as listed in Table 1C). In one embodiment, the antibody molecule includes the VL of an antibody molecule described herein, such as those listed in Table 1B, 2B, or 3B (for example, any of the antibodies listed in Table 1C, such as 11v2, 322, 329, 330, 336v2-1, 402, 429, 430, 440, 453, 454, 465, 475, 507, 510, 511, 518, 528, 541, 547, 549, 550, 553, 556, 567, 568, 570, 573, 583, 584, 585, 586, 588, or 592). In one embodiment, the antibody molecule is any of the antibody molecules described herein, such as those listed in Table 1A, 2A, or 3A (for example, 11v2, 322, 329, 330, 336v2-1, 402, 429, 430, 440, 453, 454, 465, 475, 507, 510, 511, 518, 528, 541, 547, 549, 550, 553, 556, 567, 568, 570, 573, 583, 584, 585, 586, 588, or 592, if listed in Table 1C). It includes VH and VL of the antibody molecules described herein, such as those listed in Table 1B, 2B, or 3B (for example, any of the antibodies listed in Table 1C, such as 11v2, 322, 329, 330, 336v2-1, 402, 429, 430, 440, 453, 454, 465, 475, 507, 510, 511, 518, 528, 541, 547, 549, 550, 553, 556, 567, 568, 570, 573, 583, 584, 585, 586, 588, or 592).

[0269] In some embodiments, the antibody molecule further comprises a heavy chain constant region. In some embodiments, the heavy chain constant region is an IgG1 constant region, such as any of SEQ ID NOs: 1441-1443 or their functional moieties. In other embodiments, the heavy chain constant region is an IgG2 constant region, such as any of SEQ ID NOs: 1444-1447 or their functional moieties. In some embodiments, the antibody molecule further comprises a light chain constant region. In some embodiments, the antibody molecule further comprises a heavy chain constant region and a light chain constant region. In certain embodiments, the antibody molecule comprises a variable region containing a heavy chain constant region, a light chain constant region, and 1, 2, 3, 4, 5, or 6 CDRs of VH and / or VL as listed in Tables 1A, 2A, or 3A. In certain embodiments, the antibody molecule comprises a heavy chain constant region, a light chain constant region, and a variable region containing 1, 2, 3, 4, 5, or 6 CDRs of the antibody molecule as listed in Table 1C. In one embodiment, the antibody molecule comprises a heavy chain constant region, a light chain constant region, a VH as described in Table 1A, 2A, or 3A, and a VL as described in Table 1B, 2B, or 3B.

[0270] An example of a heavy chain constant region is described below. Exemplary IgG1 constant region >IGHG1*01 STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP (Sequence ID 1441) >IGHG1*03 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP (Sequence ID 1442) >IGHG1*04 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNIFSCSVMHEALHNHYTQKSLSLSP (Sequence ID 1443) Exemplary IgG2 constant region >IGHG2*01 STKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP (Sequence ID 1444) >IGHG2*02 STKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVTSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGMEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP (Sequence ID 1445) >IGHG2*04 STKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP (Sequence ID 1446) >IGHG2*06 STKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDISVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP (Sequence ID 1447)

[0271] In some embodiments, the antibody molecule can bind to, or substantially bind to, human C5aR1. In some embodiments, the antibody molecule has strengths such as less than about 100 nM, less than about 80 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 25 nM, about 10 nM, and more typically about 10 to 0.001 nM, about 10 to 0.01 nM, about 10 to 0.01 nM, about 5 to 0.01 nM, about 3 to 0.05 nM, less than about 1 to 0.1 nM, or greater, for example, about 80, 70, 60, 50, 40, 30, 20, 10, 8, 6, 4, 3, 2, 1, 0.5, 0.2, 0.1, 0.05, 0.01, 0.005, or a dissociation constant (K) less than 0.001 nM. D ) and other factors bind to C5aR1 with high affinity. In one embodiment, the antibody molecule is 1 × 10 -4 , 5×10 -5 , or 1 × 10 -5 s -1 Slower than K off It binds to C5aR1. In one embodiment, the antibody molecule is 1 × 10 4 , 5×10 4 , 1 x 10 5 , or 5×10 5 M -1 s -1 Faster than K on It then binds to C5aR1.

[0272] In some embodiments, as determined by the methods described herein (e.g., normalized against an antibody-free control), the antibody molecule inhibits the binding of human C5aR1 to human C5a by 50% or more, for example, 60% or more, 70% or more, 80% or more, 85% or more, 90% or more, 95% or more, 96% or more, 97% or more, 98% or more, 99% or more, or 100%.

[0273] In some embodiments, the antibody molecule binds to a linear or structural epitope on C5aR1. In some embodiments, the antibody molecule binds to an epitope conserved between human and mouse C5aR1. In some embodiments, the antibody molecule binds to an epitope described herein. In some embodiments, the antibody molecule binds to, or substantially binds to, the same, similar, or overlapping epitope on C5aR1 as a second antibody molecule (e.g., an antibody molecule listed in Table 1C). In some embodiments, the antibody molecule competes with a second antibody molecule (e.g., an antibody molecule listed in Table 1C) for binding to C5aR1.

[0274] In some embodiments, the epitope is a linear epitope. In other embodiments, the epitope is a structural epitope.

[0275] In one embodiment, the antibody molecule binds to an epitope of an antibody molecule listed in Table 1C. In one embodiment, the epitope of the antibody molecule in Table 1C includes a cyclic ECL2 region (e.g., included in site II) and / or a sulfated N-terminus (e.g., included in site I) and / or a non-sulfated N-terminus (e.g., included in site I).

[0276] In one embodiment, the antibody molecule comprises VH, in which case VH comprises three HCDRs (HCDR1, HCDR2, and HCDR3), in which case VH comprises one, two, or all of the following: (i) an HCDR1 having an amino acid sequence that differs from the amino acid sequence of HCDR1 of antibody 11v2 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 of antibody 11v2; (ii) the HC of antibody 11v2 (iii) The amino acid sequence of DR2 is an HCDR2 that includes an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR2 of antibody 11v2, or (iii) the amino acid sequence of HCDR3 of antibody 11v2 is an HCDR3 that includes an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of antibody 11v2.

[0277] In one embodiment, the antibody molecule comprises VH, in which case VH comprises three HCDRs (HCDR1, HCDR2, and HCDR3), in which case VH comprises one, two, or all of the following: (i) an HCDR1 having an amino acid sequence that differs from the amino acid sequence of HCDR1 of antibody 322 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR1 of antibody 322; (ii) the HC of antibody 322 (iii) The amino acid sequence of DR2 is an HCDR2 that includes an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR2 of antibody 322, or (iii) the amino acid sequence of HCDR3 of antibody 322 is an HCDR3 that includes an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of antibody 322.

[0278] In one embodiment, the antibody molecule comprises VH, in which case VH comprises three HCDRs (HCDR1, HCDR2, and HCDR3), in which case VH comprises one, two, or all of the following: (i) an HCDR1 having an amino acid sequence that differs from the amino acid sequence of HCDR1 of antibody 329 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR1 of antibody 329; (ii) the HC of antibody 329 (iii) The amino acid sequence of DR2 is an HCDR2 that has an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an HCDR3 that has an amino acid sequence with at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR2 of antibody 329.

[0279] In one embodiment, the antibody molecule comprises VH, in which case VH comprises three HCDRs (HCDR1, HCDR2, and HCDR3), in which case VH comprises one, two, or all of the following: (i) an HCDR1 having an amino acid sequence that differs from the amino acid sequence of HCDR1 of antibody 330 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 of antibody 330; (ii) the HC of antibody 330 (iii) The amino acid sequence of DR2 is an HCDR2 that has an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an HCDR3 that has an amino acid sequence with at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR2 of antibody 330, or (iii) the amino acid sequence of HCDR3 of antibody 330 is an HCDR3 that has an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an HCDR3 that has an amino acid sequence with at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR3 of antibody 330.

[0280] In one embodiment, the antibody molecule comprises VH, in which case VH comprises three HCDRs (HCDR1, HCDR2, and HCDR3), in which case VH comprises one, two, or all of the following: (i) an HCDR1 having an amino acid sequence that differs from the amino acid sequence of HCDR1 of antibody 336v2-1 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR1 of antibody 336v2-1; (ii) the HC of antibody 336v2-1 (iii) The amino acid sequence of DR2 is an HCDR2 containing an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR2 of antibody 336v2-1, or (iii) the amino acid sequence of HCDR3 of antibody 336v2-1 is an HCDR3 containing an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of antibody 336v2-1.

[0281] In one embodiment, the antibody molecule comprises VH, in which case VH comprises three HCDRs (HCDR1, HCDR2, and HCDR3), in which case VH comprises one, two, or all of the following: (i) an HCDR1 having an amino acid sequence that differs from the amino acid sequence of HCDR1 of antibody 402 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 of antibody 402; (ii) the HC of antibody 402 (iii) The amino acid sequence of DR2 is an HCDR2 that includes an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR2 of antibody 402, or (iii) the amino acid sequence of HCDR3 of antibody 402 is an HCDR3 that includes an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of antibody 402.

[0282] In one embodiment, the antibody molecule comprises VH, in which case the VH comprises three HCDRs (HCDR1, HCDR2, and HCDR3), in which case the VH comprises one, two, or all of the following: (i) an HCDR1 having an amino acid sequence that differs from the amino acid sequence of HCDR1 of antibody 429 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR1 of antibody 429; (ii) the HC of antibody 429 (iii) The amino acid sequence of DR2 is an HCDR2 that has an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an HCDR3 that has an amino acid sequence with at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR2 of antibody 429.

[0283] In one embodiment, the antibody molecule comprises VH, in which case VH comprises three HCDRs (HCDR1, HCDR2, and HCDR3), in which case VH comprises one, two, or all of the following: (i) an HCDR1 having an amino acid sequence that differs from the amino acid sequence of HCDR1 of antibody 430 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR1 of antibody 430; (ii) the HC of antibody 430 (iii) The amino acid sequence of DR2 is an HCDR2 that has an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an HCDR3 that has an amino acid sequence with at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR2 of antibody 430, or (iii) the amino acid sequence of HCDR3 of antibody 430 is an HCDR3 that has an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an HCDR3 that has an amino acid sequence with at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR3 of antibody 430.

[0284] In one embodiment, the antibody molecule comprises VH, in which case VH comprises three HCDRs (HCDR1, HCDR2, and HCDR3), in which case VH comprises one, two, or all of the following: (i) an HCDR1 having an amino acid sequence that differs from the amino acid sequence of HCDR1 of antibody 440 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 of antibody 440; (ii) the HC of antibody 440 (iii) The amino acid sequence of DR2 is an HCDR2 that has an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an HCDR3 that has an amino acid sequence with at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR2 of antibody 440, or (iii) the amino acid sequence of HCDR3 of antibody 440 is an HCDR3 that has an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an HCDR3 that has an amino acid sequence with at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR3 of antibody 440.

[0285] In one embodiment, the antibody molecule comprises VH, in which case VH comprises three HCDRs (HCDR1, HCDR2, and HCDR3), in which case VH comprises one, two, or all of the following: (i) an HCDR1 having an amino acid sequence that differs from the amino acid sequence of HCDR1 of antibody 453 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR1 of antibody 453; (ii) the HC of antibody 453 (iii) The amino acid sequence of DR2 is an HCDR2 that has an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an HCDR3 that has an amino acid sequence with at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR2 of antibody 453, or (iii) the amino acid sequence of HCDR3 of antibody 453 is an HCDR3 that has an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an HCDR3 that has an amino acid sequence with at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR3 of antibody 453.

[0286] In one embodiment, the antibody molecule comprises VH, in which case the VH comprises three HCDRs (HCDR1, HCDR2, and HCDR3), in which case the VH comprises one, two, or all of the following: (i) an HCDR1 having an amino acid sequence that differs from the amino acid sequence of HCDR1 of antibody 454 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR1 of antibody 454; (ii) the HC of antibody 454 (iii) The amino acid sequence of DR2 is an HCDR2 that includes an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR2 of antibody 454, or (iii) the amino acid sequence of HCDR3 of antibody 454 is an HCDR3 that includes an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of antibody 454.

[0287] In one embodiment, the antibody molecule comprises VH, in which case VH comprises three HCDRs (HCDR1, HCDR2, and HCDR3), in which case VH comprises one, two, or all of the following: (i) an HCDR1 having an amino acid sequence that differs from the amino acid sequence of HCDR1 of antibody 465 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR1 of antibody 465; (ii) the HC of antibody 465 (iii) The amino acid sequence of DR2 is an HCDR2 that includes an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR2 of antibody 465, or (iii) the amino acid sequence of HCDR3 of antibody 465 is an HCDR3 that includes an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of antibody 465.

[0288] In one embodiment, the antibody molecule comprises VH, in which case VH comprises three HCDRs (HCDR1, HCDR2, and HCDR3), in which case VH comprises one, two, or all of the following: (i) an HCDR1 having an amino acid sequence that differs from the amino acid sequence of HCDR1 of antibody 475 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR1 of antibody 475; (ii) the HC of antibody 475 (iii) The amino acid sequence of DR2 is an HCDR2 that has an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an HCDR3 that has an amino acid sequence with at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR2 of antibody 475, or (iii) the amino acid sequence of HCDR3 of antibody 475 is an HCDR3 that has an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an HCDR3 that has an amino acid sequence with at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR3 of antibody 475.

[0289] In one embodiment, the antibody molecule comprises VH, in which case VH comprises three HCDRs (HCDR1, HCDR2, and HCDR3), in which case VH comprises one, two, or all of the following: (i) an HCDR1 having an amino acid sequence that differs from the amino acid sequence of HCDR1 of antibody 507 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR1 of antibody 507; (ii) the HC of antibody 507 (iii) The amino acid sequence of DR2 is an HCDR2 that includes an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR2 of antibody 507, or (iii) the amino acid sequence of HCDR3 of antibody 507 is an HCDR3 that includes an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of antibody 507.

[0290] In one embodiment, the antibody molecule comprises VH, in which case VH comprises three HCDRs (HCDR1, HCDR2, and HCDR3), in which case VH comprises one, two, or all of the following: (i) an HCDR1 having an amino acid sequence that differs from the amino acid sequence of HCDR1 of antibody 510 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR1 of antibody 510; (ii) the HC of antibody 510 (iii) The amino acid sequence of DR2 is an HCDR2 containing an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR2 of antibody 510, or (iii) the amino acid sequence of HCDR3 of antibody 510 is an HCDR3 containing an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of antibody 510.

[0291] In one embodiment, the antibody molecule comprises VH, in which case VH comprises three HCDRs (HCDR1, HCDR2, and HCDR3), in which case VH comprises one, two, or all of the following: (i) an HCDR1 having an amino acid sequence that differs from the amino acid sequence of HCDR1 of antibody 511 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR1 of antibody 511; (ii) the HC of antibody 511 (iii) The amino acid sequence of DR2 is an HCDR2 that includes an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR2 of antibody 511, or (iii) the amino acid sequence of HCDR3 of antibody 511 is an HCDR3 that includes an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of antibody 511.

[0292] In one embodiment, the antibody molecule comprises VH, in which case VH comprises three HCDRs (HCDR1, HCDR2, and HCDR3), in which case VH comprises one, two, or all of the following: (i) an HCDR1 having an amino acid sequence that differs from the amino acid sequence of HCDR1 of antibody 518 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR1 of antibody 518; (ii) the HC of antibody 518 (iii) The amino acid sequence of DR2 is an HCDR2 that has an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an HCDR3 that has an amino acid sequence with at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR2 of antibody 518, or (iii) the amino acid sequence of HCDR3 of antibody 518 is an HCDR3 that has an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an HCDR3 that has an amino acid sequence with at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR3 of antibody 518.

[0293] In one embodiment, the antibody molecule comprises VH, in which case VH comprises three HCDRs (HCDR1, HCDR2, and HCDR3), in which case VH comprises one, two, or all of the following: (i) an HCDR1 having an amino acid sequence that differs from the amino acid sequence of HCDR1 of antibody 528 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR1 of antibody 528; (ii) the HC of antibody 528 (iii) The amino acid sequence of DR2 is an HCDR2 that includes an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR2 of antibody 528, or (iii) the amino acid sequence of HCDR3 of antibody 528 is an HCDR3 that includes an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of antibody 528.

[0294] In one embodiment, the antibody molecule comprises VH, in which case the VH comprises three HCDRs (HCDR1, HCDR2, and HCDR3), in which case the VH comprises one, two, or all of the following: (i) an HCDR1 having an amino acid sequence that differs from the amino acid sequence of HCDR1 of antibody 541 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR1 of antibody 541; (ii) the HC of antibody 541 (iii) The amino acid sequence of DR2 is an HCDR2 that includes an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR2 of antibody 541, or (iii) the amino acid sequence of HCDR3 of antibody 541 is an HCDR3 that includes an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of antibody 541.

[0295] In one embodiment, the antibody molecule comprises VH, in which case VH comprises three HCDRs (HCDR1, HCDR2, and HCDR3), in which case VH comprises one, two, or all of the following: (i) an HCDR1 having an amino acid sequence that differs from the amino acid sequence of HCDR1 of antibody 547 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR1 of antibody 547; (ii) the HC of antibody 547 (iii) The amino acid sequence of DR2 is an HCDR2 that has an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an HCDR3 that has an amino acid sequence with at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR2 of antibody 547, or (iii) the amino acid sequence of HCDR3 of antibody 547 is an HCDR3 that has an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an HCDR3 that has an amino acid sequence with at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR3 of antibody 547.

[0296] In one embodiment, the antibody molecule comprises VH, in which case VH comprises three HCDRs (HCDR1, HCDR2, and HCDR3), in which case VH comprises one, two, or all of the following: (i) an HCDR1 having an amino acid sequence that differs from the amino acid sequence of HCDR1 of antibody 549 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR1 of antibody 549; (ii) the HC of antibody 549 (iii) The amino acid sequence of DR2 is an HCDR2 that has an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an HCDR3 that has an amino acid sequence with at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR2 of antibody 549, or (iii) the amino acid sequence of HCDR3 of antibody 549 is an HCDR3 that has an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an HCDR3 that has an amino acid sequence with at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR3 of antibody 549.

[0297] In one embodiment, the antibody molecule comprises VH, in which case VH comprises three HCDRs (HCDR1, HCDR2, and HCDR3), in which case VH comprises one, two, or all of the following: (i) an HCDR1 having an amino acid sequence that differs from the amino acid sequence of HCDR1 of antibody 550 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 of antibody 550; (ii) the HC of antibody 550 (iii) The amino acid sequence of DR2 is an HCDR2 containing an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR2 of antibody 550, or (iii) the amino acid sequence of HCDR3 of antibody 550 is an HCDR3 containing an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of antibody 550.

[0298] In one embodiment, the antibody molecule comprises VH, in which case VH comprises three HCDRs (HCDR1, HCDR2, and HCDR3), in which case VH comprises one, two, or all of the following: (i) an HCDR1 having an amino acid sequence that differs from the amino acid sequence of HCDR1 of antibody 553 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR1 of antibody 553; (ii) the HC of antibody 553 (iii) The amino acid sequence of DR2 is an HCDR2 that includes an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR2 of antibody 553, or (iii) the amino acid sequence of HCDR3 of antibody 553 is an HCDR3 that includes an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of antibody 553.

[0299] In one embodiment, the antibody molecule comprises VH, in which case VH comprises three HCDRs (HCDR1, HCDR2, and HCDR3), in which case VH comprises one, two, or all of the following: (i) an HCDR1 having an amino acid sequence that differs from the amino acid sequence of HCDR1 of antibody 556 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR1 of antibody 556; (ii) the HC of antibody 556 (iii) The amino acid sequence of DR2 is an HCDR2 that includes an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 556's HCDR2, or (iii) the amino acid sequence of antibody 556's HCDR3 is an HCDR3 that includes an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 556's HCDR3.

[0300] In one embodiment, the antibody molecule comprises VH, in which case VH comprises three HCDRs (HCDR1, HCDR2, and HCDR3), in which case VH comprises one, two, or all of the following: (i) an HCDR1 having an amino acid sequence that differs from the amino acid sequence of HCDR1 of antibody 567 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR1 of antibody 567; (ii) the HC of antibody 567 (iii) The amino acid sequence of DR2 is an HCDR2 that includes an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 567, or (iii) the amino acid sequence of antibody 567's HCDR3 is an HCDR3 that includes an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 567's HCDR3.

[0301] In one embodiment, the antibody molecule comprises VH, in which case VH comprises three HCDRs (HCDR1, HCDR2, and HCDR3), in which case VH comprises one, two, or all of the following: (i) an HCDR1 having an amino acid sequence that differs from the amino acid sequence of HCDR1 of antibody 568 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR1 of antibody 568; (ii) the HC of antibody 568 (iii) The amino acid sequence of DR2 is an HCDR2 that has an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an HCDR3 that has an amino acid sequence with at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR2 of antibody 568, or (iii) the amino acid sequence of HCDR3 of antibody 568 is an HCDR3 that has an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an HCDR3 that has an amino acid sequence with at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR3 of antibody 568.

[0302] In one embodiment, the antibody molecule comprises VH, in which case VH comprises three HCDRs (HCDR1, HCDR2, and HCDR3), in which case VH comprises one, two, or all of the following: (i) an HCDR1 having an amino acid sequence that differs from the amino acid sequence of HCDR1 of antibody 570 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR1 of antibody 570; (ii) the HC of antibody 570 (iii) The amino acid sequence of DR2 is an HCDR2 that includes an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR2 of antibody 570, or (iii) the amino acid sequence of HCDR3 of antibody 570 is an HCDR3 that includes an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of antibody 570.

[0303] In one embodiment, the antibody molecule comprises VH, in which case VH comprises three HCDRs (HCDR1, HCDR2, and HCDR3), in which case VH comprises one, two, or all of the following: (i) an HCDR1 having an amino acid sequence that differs from the amino acid sequence of HCDR1 of antibody 573 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR1 of antibody 573; (ii) the HC of antibody 573 (iii) The amino acid sequence of DR2 is an HCDR2 that has an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an HCDR3 that has an amino acid sequence with at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR2 of antibody 573, or (iii) the amino acid sequence of HCDR3 of antibody 573 is an HCDR3 that has an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an HCDR3 that has an amino acid sequence with at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR3 of antibody 573.

[0304] In one embodiment, the antibody molecule comprises VH, in which case VH comprises three HCDRs (HCDR1, HCDR2, and HCDR3), in which case VH comprises one, two, or all of the following: (i) an HCDR1 having an amino acid sequence that differs from the amino acid sequence of HCDR1 of antibody 583 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR1 of antibody 583; (ii) the HC of antibody 583 (iii) The amino acid sequence of DR2 is an HCDR2 containing an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR2 of antibody 583, or (iii) the amino acid sequence of HCDR3 of antibody 583 is an HCDR3 containing an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of antibody 583.

[0305] In one embodiment, the antibody molecule comprises VH, in which case VH comprises three HCDRs (HCDR1, HCDR2, and HCDR3), in which case VH comprises one, two, or all of the following: (i) an HCDR1 having an amino acid sequence that differs from the amino acid sequence of HCDR1 of antibody 584 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR1 of antibody 584; (ii) the HC of antibody 584 (iii) The amino acid sequence of DR2 is an HCDR2 containing an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR2 of antibody 584, or (iii) the amino acid sequence of HCDR3 of antibody 584 is an HCDR3 containing an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of antibody 584.

[0306] In one embodiment, the antibody molecule comprises VH, in which case VH comprises three HCDRs (HCDR1, HCDR2, and HCDR3), in which case VH comprises one, two, or all of the following: (i) an HCDR1 having an amino acid sequence that differs from the amino acid sequence of HCDR1 of antibody 585 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR1 of antibody 585; (ii) the HC of antibody 585 (iii) The amino acid sequence of DR2 is an HCDR2 that includes an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR2 of antibody 585, or (iii) the amino acid sequence of HCDR3 of antibody 585 is an HCDR3 that includes an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of antibody 585.

[0307] In one embodiment, the antibody molecule comprises VH, in which case VH comprises three HCDRs (HCDR1, HCDR2, and HCDR3), in which case VH comprises one, two, or all of the following: (i) an HCDR1 having an amino acid sequence that differs from the amino acid sequence of HCDR1 of antibody 586 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR1 of antibody 586; (ii) the HC of antibody 586 (iii) The amino acid sequence of DR2 is an HCDR2 containing an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 586's HCDR2, or (iii) the amino acid sequence of antibody 586's HCDR3 is an HCDR3 containing an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 586's HCDR3.

[0308] In one embodiment, the antibody molecule comprises VH, in which case VH comprises three HCDRs (HCDR1, HCDR2, and HCDR3), in which case VH comprises one, two, or all of the following: (i) an HCDR1 having an amino acid sequence that differs from the amino acid sequence of HCDR1 of antibody 588 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR1 of antibody 588; (ii) the HC of antibody 588 (iii) The amino acid sequence of DR2 is an HCDR2 containing an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR2 of antibody 588, or (iii) the amino acid sequence of HCDR3 of antibody 588 is an HCDR3 containing an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of antibody 588.

[0309] In one embodiment, the antibody molecule comprises VH, in which case VH comprises three HCDRs (HCDR1, HCDR2, and HCDR3), in which case VH comprises one, two, or all of the following: (i) an HCDR1 having an amino acid sequence that differs from the amino acid sequence of HCDR1 of antibody 592 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of HCDR1 of antibody 592; (ii) the HC of antibody 592 (iii) The amino acid sequence of DR2 is an HCDR2 that includes an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR2 of antibody 592, or (iii) the amino acid sequence of HCDR3 of antibody 592 is an HCDR3 that includes an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of antibody 592.

[0310] In one embodiment, the antibody molecule comprises a VL, in which the VL comprises three LCDRs (LCDR1, LCDR2, and LCDR3), in which the VL comprises one, two, or all of the following: (i) an LCDR1 having an amino acid sequence that differs from the amino acid sequence of LCDR1 of antibody 11v2 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR1 of antibody 11v2; (ii) the LCD of antibody 11v2 (iii) The amino acid sequence of DR2 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR2 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR2 of antibody 11v2, or (iii) the amino acid sequence of LCDR3 of antibody 11v2 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR3 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR3 of antibody 11v2.

[0311] In one embodiment, the antibody molecule comprises a VL, in which the VL comprises three LCDRs (LCDR1, LCDR2, and LCDR3), in which the VL comprises one, two, or all of the following: (i) an LCDR1 having an amino acid sequence that differs from the amino acid sequence of LCDR1 of antibody 322 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR1 of antibody 322; (ii) the LC of antibody 322 (iii) The amino acid sequence of DR2 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR2 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 322's LCDR2, or (iii) the amino acid sequence of antibody 322's LCDR3 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR3 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 322's LCDR3.

[0312] In one embodiment, the antibody molecule comprises a VL, in which the VL comprises three LCDRs (LCDR1, LCDR2, and LCDR3), in which the VL comprises one, two, or all of the following: (i) an LCDR1 having an amino acid sequence that differs from the amino acid sequence of LCDR1 of antibody 329 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of LCDR1 of antibody 329; (ii) the LCD of antibody 329 (iii) The amino acid sequence of DR2 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR2 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 329's LCDR2, or (iii) the amino acid sequence of antibody 329's LCDR3 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR3 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 329's LCDR3.

[0313] In one embodiment, the antibody molecule comprises a VL, in which the VL comprises three LCDRs (LCDR1, LCDR2, and LCDR3), in which the VL comprises one, two, or all of the following: (i) an LCDR1 having an amino acid sequence that differs from the amino acid sequence of LCDR1 of antibody 330 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR1 of antibody 330; (ii) the LC of antibody 330 (iii) The amino acid sequence of DR2 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR2 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR2 of antibody 330, or (iii) the amino acid sequence of LCDR3 of antibody 330 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR3 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR3 of antibody 330.

[0314] In one embodiment, the antibody molecule comprises a VL, in which the VL comprises three LCDRs (LCDR1, LCDR2, and LCDR3), in which the VL comprises one, two, or all of the following: (i) an LCDR1 having an amino acid sequence that differs from the amino acid sequence of LCDR1 of antibody 336v2-1 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of LCDR1 of antibody 336v2-1; (ii) the LC of antibody 336v2-1 (iii) The amino acid sequence of DR2 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR2 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR2 of antibody 336v2-1, or (iii) the amino acid sequence of LCDR3 of antibody 336v2-1 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR3 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR3 of antibody 336v2-1.

[0315] In one embodiment, the antibody molecule comprises a VL, in which the VL comprises three LCDRs (LCDR1, LCDR2, and LCDR3), in which the VL comprises one, two, or all of the following: (i) an LCDR1 having an amino acid sequence that differs from the amino acid sequence of LCDR1 of antibody 402 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR1 of antibody 402; (ii) the LC of antibody 402 (iii) The amino acid sequence of DR2 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR2 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 402's LCDR2, or (iii) the amino acid sequence of antibody 402's LCDR3 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR3 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 402's LCDR3.

[0316] In one embodiment, the antibody molecule comprises a VL, in which the VL comprises three LCDRs (LCDR1, LCDR2, and LCDR3), in which the VL comprises one, two, or all of the following: (i) an LCDR1 having an amino acid sequence that differs from the amino acid sequence of LCDR1 of antibody 429 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of LCDR1 of antibody 429; (ii) the LC of antibody 429 (iii) The amino acid sequence of DR2 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR2 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 429's LCDR2, or (iii) the amino acid sequence of antibody 429's LCDR3 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR3 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 429's LCDR3.

[0317] In one embodiment, the antibody molecule comprises a VL, in which the VL comprises three LCDRs (LCDR1, LCDR2, and LCDR3), in which the VL comprises one, two, or all of the following: (i) an LCDR1 having an amino acid sequence that differs from the amino acid sequence of LCDR1 of antibody 430 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of LCDR1 of antibody 430; (ii) the LC of antibody 430 (iii) The amino acid sequence of DR2 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR2 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 430's LCDR2, or (iii) the amino acid sequence of antibody 430's LCDR3 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR3 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 430's LCDR3.

[0318] In one embodiment, the antibody molecule comprises a VL, in which the VL comprises three LCDRs (LCDR1, LCDR2, and LCDR3), in which the VL comprises one, two, or all of the following: (i) an LCDR1 having an amino acid sequence that differs from the amino acid sequence of LCDR1 of antibody 440 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of LCDR1 of antibody 440; (ii) the LC of antibody 440 (iii) The amino acid sequence of DR2 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR2 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR2 of antibody 440, or (iii) the amino acid sequence of LCDR3 of antibody 440 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR3 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR3 of antibody 440.

[0319] In one embodiment, the antibody molecule comprises a VL, in which the VL comprises three LCDRs (LCDR1, LCDR2, and LCDR3), in which the VL comprises one, two, or all of the following: (i) an LCDR1 having an amino acid sequence that differs from the amino acid sequence of LCDR1 of antibody 453 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of LCDR1 of antibody 453; (ii) the LC of antibody 453 (iii) The amino acid sequence of DR2 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR2 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 453's LCDR2, or (iii) the amino acid sequence of antibody 453's LCDR3 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR3 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 453's LCDR3.

[0320] In one embodiment, the antibody molecule comprises a VL, in which the VL comprises three LCDRs (LCDR1, LCDR2, and LCDR3), in which the VL comprises one, two, or all of the following: (i) an LCDR1 having an amino acid sequence that differs from the amino acid sequence of antibody 454 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of antibody 454; (ii) the LC of antibody 454 (iii) The amino acid sequence of DR2 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR2 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 454's LCDR2, or (iii) the amino acid sequence of antibody 454's LCDR3 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR3 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 454's LCDR3.

[0321] In one embodiment, the antibody molecule comprises a VL, in which the VL comprises three LCDRs (LCDR1, LCDR2, and LCDR3), in which the VL comprises one, two, or all of the following: (i) an LCDR1 having an amino acid sequence that differs from the amino acid sequence of LCDR1 of antibody 465 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of LCDR1 of antibody 465; (ii) the LC of antibody 465 (iii) The amino acid sequence of DR2 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR2 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 465's LCDR2, or (iii) the amino acid sequence of antibody 465's LCDR3 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR3 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 465's LCDR3.

[0322] In one embodiment, the antibody molecule comprises a VL, in which the VL comprises three LCDRs (LCDR1, LCDR2, and LCDR3), in which the VL comprises one, two, or all of the following: (i) an LCDR1 having an amino acid sequence that differs from the amino acid sequence of LCDR1 of antibody 475 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of LCDR1 of antibody 475; (ii) the LC of antibody 475 (iii) The amino acid sequence of DR2 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR2 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 475's LCDR2, or (iii) the amino acid sequence of antibody 475's LCDR3 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR3 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 475's LCDR3.

[0323] In one embodiment, the antibody molecule comprises a VL, in which the VL comprises three LCDRs (LCDR1, LCDR2, and LCDR3), in which the VL comprises one, two, or all of the following: (i) an LCDR1 having an amino acid sequence that differs from the amino acid sequence of LCDR1 of antibody 507 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR1 of antibody 507; (ii) the LC of antibody 507 (iii) The amino acid sequence of DR2 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR2 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 507's LCDR2, or (iii) the amino acid sequence of antibody 507's LCDR3 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR3 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 507's LCDR3.

[0324] In one embodiment, the antibody molecule comprises a VL, in which the VL comprises three LCDRs (LCDR1, LCDR2, and LCDR3), in which the VL comprises one, two, or all of the following: (i) an LCDR1 having an amino acid sequence that differs from the amino acid sequence of LCDR1 of antibody 510 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of LCDR1 of antibody 510; (ii) the LCD of antibody 510 (iii) The amino acid sequence of DR2 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR2 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR2 of antibody 510, or (iii) the amino acid sequence of LCDR3 of antibody 510 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR3 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR3 of antibody 510.

[0325] In one embodiment, the antibody molecule comprises a VL, in which the VL comprises three LCDRs (LCDR1, LCDR2, and LCDR3), in which the VL comprises one, two, or all of the following: (i) an LCDR1 having an amino acid sequence that differs from the amino acid sequence of LCDR1 of antibody 511 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of LCDR1 of antibody 511; (ii) the LC of antibody 511 (iii) The amino acid sequence of DR2 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR2 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR2 of antibody 511, or (iii) the amino acid sequence of LCDR3 of antibody 511 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR3 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR3 of antibody 511.

[0326] In one embodiment, the antibody molecule comprises a VL, in which the VL comprises three LCDRs (LCDR1, LCDR2, and LCDR3), in which the VL comprises one, two, or all of the following: (i) an LCDR1 having an amino acid sequence that differs from the amino acid sequence of LCDR1 of antibody 518 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of LCDR1 of antibody 518; (ii) the LC of antibody 518 (iii) The amino acid sequence of DR2 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR2 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 518's LCDR2, or (iii) the amino acid sequence of antibody 518's LCDR3 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR3 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 518's LCDR3.

[0327] In one embodiment, the antibody molecule comprises a VL, in which the VL comprises three LCDRs (LCDR1, LCDR2, and LCDR3), in which the VL comprises one, two, or all of the following: (i) an LCDR1 having an amino acid sequence that differs from the amino acid sequence of LCDR1 of antibody 528 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of LCDR1 of antibody 528; (ii) the LC of antibody 528 (iii) The amino acid sequence of DR2 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR2 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 528's LCDR2, or (iii) the amino acid sequence of antibody 528's LCDR3 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR3 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 528's LCDR3.

[0328] In one embodiment, the antibody molecule comprises a VL, in which the VL comprises three LCDRs (LCDR1, LCDR2, and LCDR3), in which the VL comprises one, two, or all of the following: (i) an LCDR1 having an amino acid sequence that differs from the amino acid sequence of LCDR1 of antibody 541 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of LCDR1 of antibody 541; (ii) the LC of antibody 541 (iii) The amino acid sequence of DR2 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR2 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 541's LCDR2, or (iii) the amino acid sequence of antibody 541's LCDR3 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR3 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 541's LCDR3.

[0329] In one embodiment, the antibody molecule comprises a VL, in which the VL comprises three LCDRs (LCDR1, LCDR2, and LCDR3), in which the VL comprises one, two, or all of the following: (i) an LCDR1 having an amino acid sequence that differs from the amino acid sequence of LCDR1 of antibody 547 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of LCDR1 of antibody 547; (ii) the LC of antibody 547 (iii) The amino acid sequence of DR2 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR2 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 547's LCDR2, or (iii) the amino acid sequence of antibody 547's LCDR3 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR3 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 547's LCDR3.

[0330] In one embodiment, the antibody molecule comprises a VL, in which the VL comprises three LCDRs (LCDR1, LCDR2, and LCDR3), in which the VL comprises one, two, or all of the following: (i) an LCDR1 having an amino acid sequence that differs from the amino acid sequence of LCDR1 of antibody 549 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of LCDR1 of antibody 549; (ii) the LC of antibody 549 (iii) The amino acid sequence of DR2 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR2 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 549's LCDR2, or (iii) the amino acid sequence of antibody 549's LCDR3 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR3 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 549's LCDR3.

[0331] In one embodiment, the antibody molecule comprises a VL, in which the VL comprises three LCDRs (LCDR1, LCDR2, and LCDR3), in which the VL comprises one, two, or all of the following: (i) an LCDR1 having an amino acid sequence that differs from the amino acid sequence of LCDR1 of antibody 550 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR1 of antibody 550; (ii) the LC of antibody 550 (iii) The amino acid sequence of DR2 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR2 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 550's LCDR2, or (iii) the amino acid sequence of antibody 550's LCDR3 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR3 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 550's LCDR3.

[0332] In one embodiment, the antibody molecule comprises a VL, in which the VL comprises three LCDRs (LCDR1, LCDR2, and LCDR3), in which the VL comprises one, two, or all of the following: (i) an LCDR1 having an amino acid sequence that differs from the amino acid sequence of LCDR1 of antibody 553 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR1 of antibody 553; (ii) the LCD of antibody 553 (iii) The amino acid sequence of DR2 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR2 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 553's LCDR2, or (iii) the amino acid sequence of antibody 553's LCDR3 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR3 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 553's LCDR3.

[0333] In one embodiment, the antibody molecule comprises a VL, in which the VL comprises three LCDRs (LCDR1, LCDR2, and LCDR3), in which the VL comprises one, two, or all of the following: (i) an LCDR1 having an amino acid sequence that differs from the amino acid sequence of LCDR1 of antibody 556 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of LCDR1 of antibody 556; (ii) the LCD of antibody 556 (iii) The amino acid sequence of DR2 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR2 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 556's LCDR2, or (iii) the amino acid sequence of antibody 556's LCDR3 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR3 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 556's LCDR3.

[0334] In one embodiment, the antibody molecule comprises a VL, in which the VL comprises three LCDRs (LCDR1, LCDR2, and LCDR3), in which the VL comprises one, two, or all of the following: (i) an LCDR1 having an amino acid sequence that differs from the amino acid sequence of LCDR1 of antibody 567 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR1 of antibody 567; (ii) the LC of antibody 567 (iii) The amino acid sequence of DR2 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR2 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 567's LCDR2, or (iii) the amino acid sequence of antibody 567's LCDR3 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR3 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 567's LCDR3.

[0335] In one embodiment, the antibody molecule comprises a VL, in which the VL comprises three LCDRs (LCDR1, LCDR2, and LCDR3), in which the VL comprises one, two, or all of the following: (i) an LCDR1 having an amino acid sequence that differs from the amino acid sequence of LCDR1 of antibody 568 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of LCDR1 of antibody 568; (ii) the LC of antibody 568 (iii) The amino acid sequence of DR2 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR2 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 568's LCDR2, or (iii) the amino acid sequence of antibody 568's LCDR3 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR3 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 568's LCDR3.

[0336] In one embodiment, the antibody molecule comprises a VL, in which the VL comprises three LCDRs (LCDR1, LCDR2, and LCDR3), in which the VL comprises one, two, or all of the following: (i) an LCDR1 having an amino acid sequence that differs from the amino acid sequence of LCDR1 of antibody 570 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR1 of antibody 570; (ii) the LC of antibody 570 (iii) The amino acid sequence of DR2 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR2 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 570's LCDR2, or (iii) the amino acid sequence of antibody 570's LCDR3 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR3 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 570's LCDR3.

[0337] In one embodiment, the antibody molecule comprises a VL, in which the VL comprises three LCDRs (LCDR1, LCDR2, and LCDR3), in which the VL comprises one, two, or all of the following: (i) an LCDR1 having an amino acid sequence that differs from the amino acid sequence of LCDR1 of antibody 573 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of LCDR1 of antibody 573; (ii) the LC of antibody 573 (iii) The amino acid sequence of DR2 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR2 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 573's LCDR2, or (iii) the amino acid sequence of antibody 573's LCDR3 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR3 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 573's LCDR3.

[0338] In one embodiment, the antibody molecule comprises a VL, in which the VL comprises three LCDRs (LCDR1, LCDR2, and LCDR3), in which the VL comprises one, two, or all of the following: (i) an LCDR1 having an amino acid sequence that differs from the amino acid sequence of LCDR1 of antibody 583 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR1 of antibody 583; (ii) the LCD of antibody 583 (iii) The amino acid sequence of DR2 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR2 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 583, or (iii) the amino acid sequence of antibody 583 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR3 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 583.

[0339] In one embodiment, the antibody molecule comprises a VL, in which the VL comprises three LCDRs (LCDR1, LCDR2, and LCDR3), in which the VL comprises one, two, or all of the following: (i) an LCDR1 having an amino acid sequence that differs from the amino acid sequence of LCDR1 of antibody 584 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR1 of antibody 584; (ii) the LC of antibody 584 (iii) The amino acid sequence of DR2 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR2 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 584's LCDR2, or (iii) the amino acid sequence of antibody 584's LCDR3 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR3 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 584's LCDR3.

[0340] In one embodiment, the antibody molecule comprises a VL, in which the VL comprises three LCDRs (LCDR1, LCDR2, and LCDR3), in which the VL comprises one, two, or all of the following: (i) an LCDR1 having an amino acid sequence that differs from the amino acid sequence of LCDR1 of antibody 585 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR1 of antibody 585; (ii) the LCD of antibody 585 (iii) The amino acid sequence of DR2 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR2 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 585's LCDR2, or (iii) the amino acid sequence of antibody 585's LCDR3 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR3 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 585's LCDR3.

[0341] In one embodiment, the antibody molecule comprises a VL, in which the VL comprises three LCDRs (LCDR1, LCDR2, and LCDR3), in which the VL comprises one, two, or all of the following: (i) an LCDR1 having an amino acid sequence that differs from the amino acid sequence of LCDR1 of antibody 586 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of LCDR1 of antibody 586; (ii) the LC of antibody 586 (iii) The amino acid sequence of DR2 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR2 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 586's LCDR2, or (iii) the amino acid sequence of antibody 586's LCDR3 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR3 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 586's LCDR3.

[0342] In one embodiment, the antibody molecule comprises a VL, in which the VL comprises three LCDRs (LCDR1, LCDR2, and LCDR3), in which the VL comprises one, two, or all of the following: (i) an LCDR1 having an amino acid sequence that differs from the amino acid sequence of antibody 588 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of antibody 588's LCDR1; (ii) the LC of antibody 588 (iii) The amino acid sequence of DR2 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR2 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 588's LCDR2, or (iii) the amino acid sequence of antibody 588's LCDR3 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR3 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 588's LCDR3.

[0343] In one embodiment, the antibody molecule comprises a VL, in which the VL comprises three LCDRs (LCDR1, LCDR2, and LCDR3), in which the VL comprises one, two, or all of the following: (i) an LCDR1 having an amino acid sequence that differs from the amino acid sequence of LCDR1 of antibody 592 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR1 of antibody 592; (ii) the LC of antibody 592 (iii) The amino acid sequence of DR2 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR2 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 592's LCDR2, or (iii) the amino acid sequence of antibody 592's LCDR3 is an amino acid sequence that differs by one, two, or three or fewer amino acid residues, or an LCDR3 that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of antibody 592's LCDR3.

[0344] In one embodiment, the antibody molecule comprises (i) one, two, or all of the following VH: HCDR1, which comprises an amino acid sequence that differs from the amino acid sequence of HCDR1 of antibody 11v2 by 1, 2, or 3 or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 of antibody 11v2; HCDR2, which comprises an amino acid sequence that differs from the amino acid sequence of HCDR2 of antibody 11v2 by 1, 2, or 3 or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR2 of antibody 11v2; or HC, which comprises an amino acid sequence that differs from the amino acid sequence of HCDR3 of antibody 11v2 by 1, 2, or 3 or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of antibody 11v2. VL comprising DR3, and (ii) one, two, or all of the following: LCDR1 comprising an amino acid sequence that differs from the amino acid sequence of LCDR1 of antibody 11v2 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR1 of antibody 11v2; LCDR2 comprising an amino acid sequence that differs from the amino acid sequence of LCDR2 of antibody 11v2 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR2 of antibody 11v2; or LCDR3 comprising an amino acid sequence that differs from the amino acid sequence of LCDR3 of antibody 11v2 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR3 of antibody 11v2.

[0345] In one embodiment, the antibody molecule comprises (i) one, two, or all of the following VH: HCDR1 comprising an amino acid sequence that differs from the amino acid sequence of HCDR1 of antibody 322 by 1, 2, or 3 or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 of antibody 322; HCDR2 comprising an amino acid sequence that differs from the amino acid sequence of HCDR2 of antibody 322 by 1, 2, or 3 or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR2 of antibody 322; or HC comprising an amino acid sequence that differs from the amino acid sequence of HCDR3 of antibody 322 by 1, 2, or 3 or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of antibody 322. VL comprising DR3 and (ii) one, two, or all of the following: LCDR1 comprising an amino acid sequence that differs from the amino acid sequence of LCDR1 of antibody 322 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR1 of antibody 322; LCDR2 comprising an amino acid sequence that differs from the amino acid sequence of LCDR2 of antibody 322 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR2 of antibody 322; or LCDR3 comprising an amino acid sequence that differs from the amino acid sequence of LCDR3 of antibody 322 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR3 of antibody 322.

[0346] In one embodiment, the antibody molecule comprises (i) one, two, or all of the following VH: HCDR1 comprising an amino acid sequence that differs from the amino acid sequence of HCDR1 of antibody 329 by 1, 2, or 3 or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 of antibody 329; HCDR2 comprising an amino acid sequence that differs from the amino acid sequence of HCDR2 of antibody 329 by 1, 2, or 3 or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR2 of antibody 329; or HC comprising an amino acid sequence that differs from the amino acid sequence of HCDR3 of antibody 329 by 1, 2, or 3 or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of antibody 329. VL comprising DR3, and (ii) one, two, or all of the following: LCDR1 comprising an amino acid sequence that differs from the amino acid sequence of LCDR1 of antibody 329 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR1 of antibody 329; LCDR2 comprising an amino acid sequence that differs from the amino acid sequence of LCDR2 of antibody 329 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR2 of antibody 329; or LCDR3 comprising an amino acid sequence that differs from the amino acid sequence of LCDR3 of antibody 329 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR3 of antibody 329.

[0347] In one embodiment, the antibody molecule comprises (i) one, two, or all of the following VH: HCDR1 comprising an amino acid sequence that differs from the amino acid sequence of HCDR1 of antibody 330 by 1, 2, or 3 or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 of antibody 330; HCDR2 comprising an amino acid sequence that differs from the amino acid sequence of HCDR2 of antibody 330 by 1, 2, or 3 or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR2 of antibody 330; or HC comprising an amino acid sequence that differs from the amino acid sequence of HCDR3 of antibody 330 by 1, 2, or 3 or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of antibody 330. VL comprising DR3 and (ii) one, two, or all of the following: LCDR1 comprising an amino acid sequence that differs from the amino acid sequence of LCDR1 of antibody 330 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR1 of antibody 330; LCDR2 comprising an amino acid sequence that differs from the amino acid sequence of LCDR2 of antibody 330 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR2 of antibody 330; or LCDR3 comprising an amino acid sequence that differs from the amino acid sequence of LCDR3 of antibody 330 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR3 of antibody 330.

[0348] In one embodiment, the antibody molecule comprises (i) one, two, or all of the following: VH: an amino acid sequence that differs from the amino acid sequence of HCDR1 of antibody 336v2-1 by 1, 2, or 3 or fewer amino acid residues, or HCDR1 having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 of antibody 336v2-1; and HCDR2: an amino acid sequence that differs from the amino acid sequence of HCDR2 of antibody 336v2-1 by 1, 2, or 3 or fewer amino acid residues. HCDR2 containing an amino acid sequence with a different base, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR2 of antibody 336v2-1; or an amino acid sequence containing an amino acid sequence that differs from the amino acid sequence of HCDR3 of antibody 336v2-1 by 1, 2, or 3 or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of antibody 336v2-1 VL containing DR3 and (ii) one, two or all of the following: an amino acid sequence that differs from the amino acid sequence of LCDR1 of antibody 336v2-1 by 1, 2 or 3 or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99 or 100% homology to the amino acid sequence of LCDR1 of antibody 336v2-1; an amino acid sequence that differs from the amino acid sequence of LCDR2 of antibody 336v2-1 by 1, 2 or 3 or fewer amino acid residues LCDR2 includes an acid sequence, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR2 of antibody 336v2-1; or LCDR3 includes an amino acid sequence that differs from the amino acid sequence of LCDR3 of antibody 336v2-1 by 1, 2, or 3 or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR3 of antibody 336v2-1.

[0349] In one embodiment, the antibody molecule comprises (i) one, two, or all of the following VH: HCDR1, which comprises an amino acid sequence that differs from the amino acid sequence of HCDR1 of antibody 402 by 1, 2, or 3 or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 of antibody 402; HCDR2, which comprises an amino acid sequence that differs from the amino acid sequence of HCDR2 of antibody 402 by 1, 2, or 3 or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR2 of antibody 402; or HC, which comprises an amino acid sequence that differs from the amino acid sequence of HCDR3 of antibody 402 by 1, 2, or 3 or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of antibody 402. VL comprising DR3, and (ii) one, two, or all of the following: LCDR1 comprising an amino acid sequence that differs from the amino acid sequence of LCDR1 of antibody 402 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR1 of antibody 402; LCDR2 comprising an amino acid sequence that differs from the amino acid sequence of LCDR2 of antibody 402 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR2 of antibody 402; or LCDR3 comprising an amino acid sequence that differs from the amino acid sequence of LCDR3 of antibody 402 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR3 of antibody 402.

[0350] In one embodiment, the antibody molecule comprises (i) one, two, or all of the following VH: HCDR1 comprising an amino acid sequence that differs from the amino acid sequence of HCDR1 of antibody 429 by 1, 2, or 3 or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 of antibody 429; HCDR2 comprising an amino acid sequence that differs from the amino acid sequence of HCDR2 of antibody 429 by 1, 2, or 3 or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR2 of antibody 429; or HC comprising an amino acid sequence that differs from the amino acid sequence of HCDR3 of antibody 429 by 1, 2, or 3 or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of antibody 429. VL comprising DR3 and (ii) one, two, or all of the following: LCDR1 comprising an amino acid sequence that differs from the amino acid sequence of LCDR1 of antibody 429 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR1 of antibody 429; LCDR2 comprising an amino acid sequence that differs from the amino acid sequence of LCDR2 of antibody 429 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR2 of antibody 429; or LCDR3 comprising an amino acid sequence that differs from the amino acid sequence of LCDR3 of antibody 429 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR3 of antibody 429.

[0351] In one embodiment, the antibody molecule comprises (i) one, two, or all of the following VH: HCDR1, which comprises an amino acid sequence that differs from the amino acid sequence of HCDR1 of antibody 430 by 1, 2, or 3 or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 of antibody 430; HCDR2, which comprises an amino acid sequence that differs from the amino acid sequence of HCDR2 of antibody 430 by 1, 2, or 3 or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR2 of antibody 430; or HC, which comprises an amino acid sequence that differs from the amino acid sequence of HCDR3 of antibody 430 by 1, 2, or 3 or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of antibody 430. VL comprising DR3 and (ii) one, two, or all of the following: LCDR1 comprising an amino acid sequence that differs from the amino acid sequence of LCDR1 of antibody 430 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR1 of antibody 430; LCDR2 comprising an amino acid sequence that differs from the amino acid sequence of LCDR2 of antibody 430 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR2 of antibody 430; or LCDR3 comprising an amino acid sequence that differs from the amino acid sequence of LCDR3 of antibody 430 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR3 of antibody 430.

[0352] In one embodiment, the antibody molecule comprises (i) one, two, or all of the following VH: HCDR1 comprising an amino acid sequence that differs from the amino acid sequence of HCDR1 of antibody 440 by 1, 2, or 3 or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR1 of antibody 440; HCDR2 comprising an amino acid sequence that differs from the amino acid sequence of HCDR2 of antibody 440 by 1, 2, or 3 or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR2 of antibody 440; or HC comprising an amino acid sequence that differs from the amino acid sequence of HCDR3 of antibody 440 by 1, 2, or 3 or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of HCDR3 of antibody 440. VL comprising DR3 and (ii) one, two, or all of the following: LCDR1 comprising an amino acid sequence that differs from the amino acid sequence of LCDR1 of antibody 440 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR1 of antibody 440; LCDR2 comprising an amino acid sequence that differs from the amino acid sequence of LCDR2 of antibody 440 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR2 of antibody 440; or LCDR3 comprising an amino acid sequence that differs from the amino acid sequence of LCDR3 of antibody 440 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR3 of antibody 440.

[0353] In one embodiment, the antibody molecule comprises (i) one, two, or all of the following VH: HCDR1 comprising an amino acid sequence that differs from the amino acid sequence of antibody 453 by 1, 2, or 3 or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of antibody 453 HCDR1; HCDR2 comprising an amino acid sequence that differs from the amino acid sequence of antibody 453 HCDR2 by 1, 2, or 3 or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of antibody 453 HCDR2; or HC comprising an amino acid sequence that differs from the amino acid sequence of antibody 453 HCDR3 by 1, 2, or 3 or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of antibody 453 HCDR3 VL comprising DR3 and (ii) one, two, or all of the following: LCDR1 comprising an amino acid sequence that differs from the amino acid sequence of LCDR1 of antibody 453 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR1 of antibody 453; LCDR2 comprising an amino acid sequence that differs from the amino acid sequence of LCDR2 of antibody 453 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR2 of antibody 453; or LCDR3 comprising an amino acid sequence that differs from the amino acid sequence of LCDR3 of antibody 453 by one, two, or three or fewer amino acid residues, or an amino acid sequence having at least 85, 90, 95, 99, or 100% homology with the amino acid sequence of LCDR3 of antibody 453.

[0354] In one embodiment, the antibody molecule comprises (i) one, two, or all of the following VH: HCDR1, which comprises an amino acid sequence that differs from the amino acid sequence of antibody 454 by 1, 2, or 3 or fewer amino acid residues, or an amino acid sequence that has at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of antibody 454; HCDR2, which comprises an amino acid sequence that differs from the amino acid sequence of antibody 454 by 1, 2, or 3 or fewer ami...

Claims

[Claim 1] The invention described in the specification.

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