Molecules for controlling autoimmune responses

Abstract

The present disclosure provides, inter alia, molecules comprising an autoantibody binding domain and at least one modified Fc domain. The present disclosure also provides methods and compositions that allow for selective depletion and / or neutralization of pathogenic autoantibodies.

Description

[0001] Cross-reference to related applications This application claims the benefit of U.S. Provisional Application No. 63 / 517,101, filed August 1, 2023. The contents of the above application are hereby incorporated herein by reference in their entirety. Background Technology

[0002] Autoimmune diseases develop when the body's immune system attacks its own healthy cells. Various types of autoimmune diseases exist, such as Graves' disease, type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, preeclampsia, multiple sclerosis, and vasculitis. Autoantibodies are antibodies that target both self-antigens and healthy cells, and are produced by pathogenic plasma cells. Autoantibodies are considered biomarkers of autoimmune diseases, and methods for targeting and depleting autoantibodies in patients with autoimmune diseases have been explored. However, treatments for autoimmune diseases often do not selectively deplete pathogenic autoantibodies, leading to the depletion of antibodies that provide an appropriate immune response against invading pathogens. Summary of the Invention

[0003] In some embodiments, this disclosure provides, in particular, a molecule that selectively targets and neutralizes and / or depletes pathogenic autoantibodies in a subject.

[0004] The molecules described herein comprise a first polypeptide and a second polypeptide, wherein the first polypeptide comprises an autoantibody-binding domain and a first Fc domain, and the second polypeptide comprises a second Fc domain. As described herein, such molecules neutralize and deplete specific pathogenic autoantibodies. In some embodiments, the targeting and depletion of autoantibodies is achieved through a mechanism that targets lysosomes of cells with immune complexes containing autoantibodies for degradation.

[0005] The molecules described herein can be used to treat autoimmune diseases such as Graves' disease, thyroid eye disease, and / or other autoimmune diseases associated with autoantibodies targeting the thyroid-stimulating hormone receptor (TSHR). In some embodiments, the molecules include an autoantigen domain, which is a TSHR autoantigen domain or a fragment or variant thereof.

[0006] In addition to containing an autoantibody-binding domain that targets the autoantibody, the molecules described herein may also contain modifications that target specific internalization receptors. In some embodiments, the molecules described herein contain an Fc domain that binds to a receptor on a cell, which induces internalization of the bound molecule. Such molecules allow binding of anti-TSHR autoantibodies via an autoantigen domain and targeting of lysosomes for degradation via binding to an internalization receptor. In some embodiments, the molecule may contain modifications in its first and / or second Fc domains that increase its binding affinity for Fc-γ-RIIB (FcγRIIB). In some embodiments, the first and / or second Fc domains of the molecule may contain modifications that increase its binding affinity for the human neonatal Fc receptor (FcRn).

[0007] In some embodiments, the molecule described herein includes an antigen-binding domain, wherein the antigen-binding domain binds to a receptor on a cell, the receptor causing the bound molecule to internalize (e.g., see...). Figure 3 In some implementations, the antigen-binding domain binds to internalizing receptors such as FcγRIIB, ASPGR, and / or FcRn. Molecules targeting internalizing receptors such as FcγRIIB can inhibit / deplete self-antigen-specific B cells on the surface of said cells (e.g., as in Chu et al.). Mol Immunol As described in 45:3926-3933 (2008), the references are incorporated herein by reference in their entirety.

[0008] All such strategies aim to deplete certain autoantibodies associated with autoimmune diseases. In some implementations, the autoantibody is an anti-TSHR autoantibody, and the disease is Graves' disease, Graves' orbital disease (thyroid eye disease), or another autoimmune disease caused by an anti-TSHR autoantibody. The molecule may contain a TSHR autoantigen domain that targets the anti-TSHR autoantibody, as well as an Fc domain and / or an antigen-binding domain that enables the complex (molecule and autoantibody) to target the lysosomes of the cell for selective degradation.

[0009] In one aspect, this disclosure provides a molecule comprising: a first polypeptide including a first Fc domain and an autoantibody-binding domain for binding to an anti-TSHR autoantibody; and a second polypeptide including a second Fc domain; wherein the first Fc domain and the second Fc domain form a homodimer or heterodimer of the first polypeptide and the second polypeptide. In some embodiments, the second polypeptide further includes an autoantibody-binding domain for binding to an anti-TSHR autoantibody, and the molecule is a homodimer. In some embodiments, the second polypeptide further includes an autoantibody-binding domain for binding to an anti-TSHR autoantibody, and the molecule is a heterodimer. In some embodiments, the second polypeptide does not include an autoantibody-binding domain for binding to an anti-TSHR autoantibody, and the molecule is a heterodimer.

[0010] In some embodiments, the autoantibody-binding domain is covalently linked to the first Fc domain. In some embodiments, the C-terminus of the autoantibody-binding domain is covalently linked to the N-terminus of the first Fc domain. In some embodiments, the N-terminus of the autoantibody-binding domain is covalently linked to the C-terminus of the first Fc domain.

[0011] In some embodiments, the first and second Fc domains form heterodimers due to a knocks-in-holes (KIH) mutation. In some embodiments, the KIH mutation comprises Y349T and T394F, according to the EU numbering scheme. In some embodiments, the first Fc domain comprises the Y349T mutation, and the second Fc domain comprises the T394F mutation. In some embodiments, the KIH mutation comprises T366W, S354C, T366S, L368A, Y407V, and Y349C, according to the EU numbering scheme. In some embodiments, the first Fc domain comprises the T366W and S354C mutations, and the second Fc domain comprises the T366S, L368A, Y407V, and Y349C mutations, according to the EU numbering scheme.

[0012] In some embodiments, the first and / or second Fc domains comprise the IgG1 isotype. In some embodiments, the first and / or second Fc domains comprise the human IgG1 isotype.

[0013] In some embodiments, the first and / or second Fc domains comprise one or more mutant amino acid residues that increase the half-life. In some embodiments, according to the EU numbering scheme, the first and / or second Fc domains comprise one of the following mutant amino acid residues: M252Y, S254T, and T256E. In some embodiments, according to the EU numbering scheme, the first and / or second Fc domains comprise a combination of the following mutant amino acid residues: M252Y, S254T, and T256E. In some embodiments, according to the EU numbering scheme, the first and / or second Fc domains comprise one of the following mutant amino acid residues: M428L and N434S. In some embodiments, according to the EU numbering scheme, the first and / or second Fc domains comprise a combination of the following mutant amino acid residues: M428L and N434S.

[0014] In some embodiments, the first and / or second Fc domains contain one or more mutated amino acid residues that alter their binding to an internalization receptor on the cell, wherein the internalization receptor is capable of shuttling its cargo to the lysosome of the cell, thereby causing degradation. In some embodiments, the altered binding to the internalization receptor includes increased binding to the internalization receptor. In some embodiments, a molecule that binds to an autoantibody via an autoantibody-binding domain binds to an internalization receptor on the cell, the internalization receptor internalizes the molecule, and the autoantibody is shuttled to the lysosome of the cell for degradation. In some embodiments, the internalization receptor includes one of the following: FcγRIIB, FcRn, ASGPR, CD38, or BCMA.

[0015] In some implementations, the first and / or second Fc domains contain one or more mutant amino acid residues that increase the binding of FcγRIIB relative to the corresponding wild-type Fc domain.

[0016] In some embodiments, the first and / or second Fc domains containing one or more mutant amino acid residues do not have increased binding affinity for FcγRI, FcγRIIA167H, FcγRIIA167R, FcγRIIIA176F, FcγRIIIA176V, FcγRIIIB, FcγRIIIB, and / or FcRn relative to the corresponding wild-type Fc domains. In some embodiments, the first and / or second Fc domains containing one or more mutant amino acid residues have decreased binding affinity for FcγRI, FcγRIIA167H, FcγRIIA167R, FcγRIIIA176F, FcγRIIIA176V, FcγRIIIB, FcγRIIIB, and / or FcRn relative to the corresponding wild-type Fc domains. In some embodiments, the first and / or second Fc domains containing one or more mutant amino acid residues have substantially no binding affinity for the corresponding wild-type Fc domains to FcγRI, FcγRIIA167H, FcγRIIA167R, FcγRIIIA176F, FcγRIIIA176V, FcγRIIIB, FcγRIIIB and / or FcRn.

[0017] In some embodiments, after the two molecules bind to the anti-TSHR autoantibody, an immune complex with enhanced binding kinetics to FcγRIIB is formed relative to an immune complex comprising the anti-TSHR autoantibody and two corresponding molecules having a wild-type Fc domain. In some embodiments, after the two molecules bind to the anti-TSHR autoantibody, an immune complex with enhanced binding kinetics to FcγRIIB is formed relative to an immune complex comprising an anti-TSHR autoantibody that binds only to a single molecule. In some embodiments, after the two molecules bind to the anti-TSHR autoantibody, an immune complex with enhanced binding kinetics to FcγRIIB is formed relative to the anti-TSHR autoantibody alone. In some embodiments, the enhanced binding kinetics include an increase in association rate, a decrease in dissociation rate, and / or a change in the equilibrium dissociation constant. In some embodiments, the enhanced binding kinetics result in an increase in the affinity, stability, strength, frequency, and / or duration of the binding between the immune complex and FcγRIIB.

[0018] In some embodiments, enhanced binding kinetics includes an immune complex binding affinity to FcγRIIB that is at least 10% higher. In some embodiments, a binding affinity that is at least 10% higher includes binding affinity of at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% or higher. In some embodiments, the molecule binds to FcγRIIB with an affinity in the range of about 1 µM to 0.001 µM. In some embodiments, the molecule binds to FcγRIIB with an affinity in the range of about 1 µM to 0.001 µM. In some embodiments, the molecule binds to FcγRIIB with an affinity in the range of about 0.1 µM to 0.01 µM. In some embodiments, binding affinity includes binding affinity to cell lines overexpressing FcγRIIB (e.g., CHO cell lines) as measured by flow cytometry.

[0019] In some implementations, the molecule does not bind to complement (C1q).

[0020] In some embodiments, the molecule preferentially binds to immune cells expressing FcγRIIB, relative to immune cells expressing FcγRIIA. In some embodiments, the molecule substantially contains no binding affinity for cells that do not express FcγRIIB. In some embodiments, immune cells expressing FcγRIIB include B cells, monocytes, and / or basophils. In some embodiments, immune cells that do not express FcγRIIB include T cells, NK cells, neutrophils, and / or eosinophils.

[0021] In some implementations, the molecule does not activate immune cells (e.g., it does not activate immune cells to secrete pro-inflammatory cytokines, such as IL-6).

[0022] In some embodiments, the molecule inhibits B cells by cross-linking FcγRIIB with B cell receptors. In some embodiments, the molecule cross-links FcγRIIB with B cell receptors. In some embodiments, one or two molecules, together with an immune complex of an anti-TSHR autoantibody, cross-link FcγRIIB with B cell receptors.

[0023] In some implementations, according to the EU numbering scheme, the one or more mutated amino acid residues that add binding to FcγRIIB include one or more of the following amino acid mutations: E233V, L234D, L235F, G236R, G237D, S239L, S267D, H268P, S298G, T299A, A327L, L328A, A330H, E333I R292Q, E233P, P238D, H268D, P271G, A330R, L234Y, T250V, V264I, T307P, Q311R, A330K, P343R, M428L, N434A, Y436T, Q438R, S440E, G236N, S267E, L235R, D270E, E233D, and G237D.

[0024] In some implementations, according to the EU numbering scheme, the one or more mutant amino acid residues that add binding to FcγRIIB comprise one or more of the following sets of amino acid mutations: (i) E233V, L234D, L235F, G236R, G237D, S239L, S267D, H268P, S298G, T299A, A327L, L328A, A330H, and E333I; (ii) E233V, L234D, L235F, G236R, G237D, S239L, S267D, R292Q, H268P, S298G, T299A, A327L, L328A, A330H, and E333I; (iii) E233V, L234D, L235F, G236R, G237D, S239L, H268P, R292Q, S298G, T299A, A327L, L328A, A330H, and E333I; (iv) E233P, G237D, P238D, H268D, P271G, and A330R; (v) L234Y, P238D, T250V, V264I, T307P, Q311R, A330K, P343R, M428L, N434A, Y436T, Q438R, and S440E; (vi) L234D, G236N, and S267E; (vii) L235R; (viii) G236N and S267E; (ix) P238D and D270E; (x) P238D and P271G; (xi) P238D, D270E, and P271G; (xii) G237D, P238D, P271G, and A330R; (xiii) G237D, P238D, D270E, P271G, and A330R; (xiv) E233D, G237D, P238D, H268D, P271G, and A330R; and (xv) P238D. In some embodiments, according to the EU numbering scheme, one or more mutant amino acid residues include the mutant amino acid residue P238D. In some embodiments, according to the EU numbering scheme, one or more mutant amino acid residues do not include the following mutant amino acid residues: S267E and L328F.

[0025] In some embodiments, according to the EU numbering scheme, the first and / or second Fc domains contain the following mutant amino acid residues: L234A, L235A, and P238D. In some embodiments, according to the EU numbering scheme, the first and / or second Fc domains contain the following mutant amino acid residues: L234A, L235A, P238D, and P329G.

[0026] In some implementations, according to the EU numbering scheme, the first and / or second Fc domains contain the following mutant amino acid residues: M428L, N434S, and P238D.

[0027] In some embodiments, according to the EU numbering scheme, the first and / or second Fc domains comprise at least one of the following mutant amino acid residues: S267E and L328F. In some embodiments, according to the EU numbering scheme, the first and / or second Fc domains comprise a combination of the following mutant amino acid residues: S267E and L328F.

[0028] In some embodiments, the first and / or second Fc domains contain one or more mutant amino acid residues that enhance binding to FcRn. In some embodiments, the first and / or second Fc domains contain one or more mutant amino acid residues that enhance binding to FcRn at neutral or near-neutral pH (e.g., between about 6.8 and 7.5).

[0029] In some embodiments, the first and second Fc domains comprise human IgG1 isotypes and remain bound to FcRn upon entry into environments with acidic pH and / or low calcium concentrations (e.g., endosomes within cells). In some embodiments, according to the EU numbering scheme, the first and / or second Fc domains comprise at least one of the following mutant amino acid residues: M252Y, S254T, T256E, H433K, and N434F. In some embodiments, according to the EU numbering scheme, the first and / or second Fc domains comprise a combination of the following mutant amino acid residues: M252Y, S254T, T256E, H433K, and N434F.

[0030] In some embodiments, the first and / or second Fc domains comprise at least one mutant amino acid sequence that reduces binding to one or more Fc-γ receptors (FcγRs). In some embodiments, according to the EU numbering scheme, the first and / or second Fc domains comprise at least one of the following mutant amino acid residues: G236R and L328R.

[0031] In some embodiments, the first Fc domain comprises a sequence or fragment or variant thereof selected from SEQ ID NO: 103, 105, 107, 109, 111-113, 115, 117, 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139-149, 163-164, 374-376, 378 (e.g., a sequence selected from SEQ ID NO: 107, 109, 113, 115, 119, 131, 139, 140, 142, 148, 374 or 378). In some embodiments, the second Fc domain comprises a sequence or fragment or variant thereof selected from SEQ ID NO: 104, 106, 108, 110, 111, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 139-149, 163-164, 374-375, 377, 379 (e.g., a sequence selected from SEQ ID NO: 108, 110, 114, 116, 120, 132, 139, 140, 142, 148, 374, or 379).

[0032] In some implementations, the autoantibody-binding domain is covalently linked to the first Fc domain via a linker. In some embodiments, the adapter comprises the amino acid sequence of SEQ ID NO: 150 (GGGGS), SEQ ID NO: 151 (GGGGSGGGGS), SEQ ID NO: 152 (GGGGSGGGGSGGGGS), SEQ ID NO: 153 (VDGGGGSGGGGSGGGGSG), SEQ ID NO: 154 (GGGGSGGGGSGGGGSGGGSGGGS), SEQ ID NO: 155 (GGGGSGGGGSGGGGSGGGSSGGGGS), SEQ ID NO: 156 (GSGGS), SEQ ID NO: 157 (GGSG), SEQ ID NO: 158 (GGSGG), SEQ ID NO: 159 (GSGSG), SEQ ID NO: 160 (GSGGG), SEQ ID NO: 161 (GGGSG), or SEQ ID NO: 162 (GSSSG).

[0033] In some embodiments, the autoantibody-binding domain comprises an autoantigen or a fragment or variant thereof. In some embodiments, the autoantigen comprises a TSHR autoantigen domain or a fragment or variant thereof. In some embodiments, the TSHR autoantigen domain comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 5. In some embodiments, the TSHR autoantigen domain comprises the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 5. In some embodiments, the autoantibody-binding domain comprises a variant of the TSHR autoantigen domain, which comprises one or more of the following mutations relative to the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 5: R112P, D143P, V169R, I253R, H63S, or any combination thereof. In some embodiments, the autoantibody-binding domain comprises a variant of the TSHR autoantigen domain, which comprises the following mutations relative to the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 5: R112P and D143P. In some embodiments, the autoantibody-binding domain comprises a TSHR autoantigen domain variant, wherein the TSHR autoantigen domain variant contains the following mutations relative to the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 5: R112P, D143P, V169R, and I253R. In some embodiments, the autoantibody-binding domain comprises a TSHR autoantigen domain variant, wherein the TSHR autoantigen domain variant contains the following mutations relative to the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 5: R112P, D143P, and H63S. In some embodiments, the autoantibody-binding domain comprises a TSHR autoantigen domain variant, wherein the TSHR autoantigen domain variant contains the sequence of any one of SEQ ID NO: 1-8. In some embodiments, the autoantibody-binding domain comprises a TSHR autoantigen domain variant, wherein the TSHR autoantigen domain variant contains the sequence of any one of SEQ ID NO: 307-317.

[0034] In some embodiments, the first polypeptide comprises: an amino acid sequence that is at least 90% identical to SEQ ID NO: 1 and an amino acid sequence that is at least 90% identical to SEQ ID NO: 103; an amino acid sequence that is at least 90% identical to SEQ ID NO: 2 and an amino acid sequence that is at least 90% identical to SEQ ID NO: 103; an amino acid sequence that is at least 90% identical to SEQ ID NO: 3 and an amino acid sequence that is at least 90% identical to SEQ ID NO: 103; an amino acid sequence that is at least 90% identical to SEQ ID NO: 4 and an amino acid sequence that is at least 90% identical to SEQ ID NO: 103; an amino acid sequence that is at least 90% identical to SEQ ID NO: 5 and an amino acid sequence that is at least 90% identical to SEQ ID NO: 103; an amino acid sequence that is at least 90% identical to SEQ ID NO: 6 and an amino acid sequence that is at least 90% identical to SEQ ID NO: 103; an amino acid sequence that is at least 90% identical to SEQ ID NO: 7 and an amino acid sequence that is at least 90% identical to SEQ ID NO: 103; an amino acid sequence that is at least 90% identical to SEQ ID NO: 103 ... SEQ ID NO: 103 has an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 8 and at least 90% identical to the amino acid sequence of SEQ ID NO: 103; SEQ ID NO: 307 has an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 103; SEQ ID NO: 308 has an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 103; SEQ ID NO: 309 has an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 103; SEQ ID NO: 310 has an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 103; SEQ ID NO: 311 has an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 103; SEQ ID NO: 312 has an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 103 and at least 90% identical to the amino acid sequence of SEQ ID NO: 103; SEQ ID NO: 312 has an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 103 and at least 90% identical to the amino acid sequence of SEQ ID NO: 103. The amino acid sequence is at least 90% identical to SEQ ID NO: 103; the amino acid sequence is at least 90% identical to SEQ ID NO: 313 and at least 90% identical to SEQ ID NO: 103; the amino acid sequence is at least 90% identical to SEQ ID NO: 314 and at least 90% identical to SEQ ID NO: 103; the amino acid sequence is at least 90% identical to SEQ ID NO: 315 and at least 90% identical to SEQ ID NO: 103;Amino acid sequences that are at least 90% identical to SEQ ID NO: 316 and at least 90% identical to SEQ ID NO: 103; amino acid sequences that are at least 90% identical to SEQ ID NO: 317 and at least 90% identical to SEQ ID NO: 103; amino acid sequences that are at least 90% identical to SEQ ID NO: 1 and at least 90% identical to SEQ ID NO: 105; amino acid sequences that are at least 90% identical to SEQ ID NO: 2 and at least 90% identical to SEQ ID NO: 105; amino acid sequences that are at least 90% identical to SEQ ID NO: 3 and at least 90% identical to SEQ ID NO: 105; amino acid sequences that are at least 90% identical to SEQ ID NO: 4 and at least 90% identical to SEQ ID NO: 105; amino acid sequences that are at least 90% identical to SEQ ID NO: 5 and at least 90% identical to SEQ ID NO: 105; amino acid sequences that are at least 90% identical to SEQ ID NO: 316 ... The amino acid sequence that is at least 90% identical to SEQ ID NO: 6 and at least 90% identical to SEQ ID NO: 105; the amino acid sequence that is at least 90% identical to SEQ ID NO: 7 and at least 90% identical to SEQ ID NO: 105; the amino acid sequence that is at least 90% identical to SEQ ID NO: 8 and at least 90% identical to SEQ ID NO: 105; the amino acid sequence that is at least 90% identical to SEQ ID NO: 307 and at least 90% identical to SEQ ID NO: 105; the amino acid sequence that is at least 90% identical to SEQ ID NO: 308 and at least 90% identical to SEQ ID NO: 105; the amino acid sequence that is at least 90% identical to SEQ ID NO: 309 and at least 90% identical to SEQ ID NO: 105; the amino acid sequence that is at least 90% identical to SEQ ID NO: 310 and at least 90% identical to SEQ ID NO: 105; and the amino acid sequence that is at least 90% identical to SEQ ID NO: 105. The amino acid sequence that is at least 90% identical to SEQ ID NO: 311 and at least 90% identical to SEQ ID NO: 105; the amino acid sequence that is at least 90% identical to SEQ ID NO: 312 and at least 90% identical to SEQ ID NO: 105; the amino acid sequence that is at least 90% identical to SEQ ID NO: 313 and at least 90% identical to SEQ ID NO: 105;Amino acid sequences that are at least 90% identical to SEQ ID NO: 314 and at least 90% identical to SEQ ID NO: 105; amino acid sequences that are at least 90% identical to SEQ ID NO: 315 and at least 90% identical to SEQ ID NO: 105; amino acid sequences that are at least 90% identical to SEQ ID NO: 316 and at least 90% identical to SEQ ID NO: 105; amino acid sequences that are at least 90% identical to SEQ ID NO: 317 and at least 90% identical to SEQ ID NO: 105; amino acid sequences that are at least 90% identical to SEQ ID NO: 4, at least 90% identical to SEQ ID NO: 209, at least 90% identical to SEQ ID NO: 210 and at least 90% identical to SEQ ID NO: 105; or amino acid sequences that are at least 90% identical to SEQ ID NO: 1 and at least 90% identical to SEQ ID NO: 1 and at least 90% identical to SEQ ID NO: 1. The amino acid sequence that is at least 90% identical to SEQ ID NO: 107; the amino acid sequence that is at least 90% identical to SEQ ID NO: 2 and the amino acid sequence that is at least 90% identical to SEQ ID NO: 107; the amino acid sequence that is at least 90% identical to SEQ ID NO: 3 and the amino acid sequence that is at least 90% identical to SEQ ID NO: 107; the amino acid sequence that is at least 90% identical to SEQ ID NO: 4 and the amino acid sequence that is at least 90% identical to SEQ ID NO: 107; the amino acid sequence that is at least 90% identical to SEQ ID NO: 5 and the amino acid sequence that is at least 90% identical to SEQ ID NO: 107; the amino acid sequence that is at least 90% identical to SEQ ID NO: 6 and the amino acid sequence that is at least 90% identical to SEQ ID NO: 107; the amino acid sequence that is at least 90% identical to SEQ ID NO: 7 and the amino acid sequence that is at least 90% identical to SEQ ID NO: 107; the amino acid sequence that is at least 90% identical to SEQ ID NO: 8 and the amino acid sequence that is at least 90% identical to SEQ ID NO: 107; ... Amino acid sequences that are at least 90% identical to SEQ ID NO: 307; amino acid sequences that are at least 90% identical to SEQ ID NO: 107; amino acid sequences that are at least 90% identical to SEQ ID NO: 308; amino acid sequences that are at least 90% identical to SEQ ID NO: 107; amino acid sequences that are at least 90% identical to SEQ ID NO: 309; amino acid sequences that are at least 90% identical to SEQ ID NO: 107.The amino acid sequences that are at least 90% identical to SEQ ID NO: 310 and at least 90% identical to SEQ ID NO: 107; the amino acid sequences that are at least 90% identical to SEQ ID NO: 311 and at least 90% identical to SEQ ID NO: 107; the amino acid sequences that are at least 90% identical to SEQ ID NO: 312 and at least 90% identical to SEQ ID NO: 107; the amino acid sequences that are at least 90% identical to SEQ ID NO: 313 and at least 90% identical to SEQ ID NO: 107; the amino acid sequences that are at least 90% identical to SEQ ID NO: 314 and at least 90% identical to SEQ ID NO: 107; the amino acid sequences that are at least 90% identical to SEQ ID NO: 315 and at least 90% identical to SEQ ID NO: 107; the amino acid sequences that are at least 90% identical to SEQ ID NO: 316 ...0 and at least 90% identical to SEQ ID NO: 107; the amino acid sequences that are at least 90% identical to SEQ ID NO: 311 and at least 90% identical to SEQ ID NO: 107; the amino acid sequences that are at least 90% identical to SEQ ID NO: 312 and at least 90% identical to SEQ ID NO: 107; the amino acid sequences that are at least 90% identical to SEQ ID NO: 313 and at least 90% identical to SEQ ID NO: 107; the amino acid sequences that are at SEQ ID NO: 107 has an amino acid sequence that is at least 90% identical to SEQ ID NO: 317; amino acid sequences that are at least 90% identical to SEQ ID NO: 107; amino acid sequences that are at least 90% identical to SEQ ID NO: 1 and at least 90% identical to SEQ ID NO: 109; amino acid sequences that are at least 90% identical to SEQ ID NO: 2 and at least 90% identical to SEQ ID NO: 109; amino acid sequences that are at least 90% identical to SEQ ID NO: 3 and at least 90% identical to SEQ ID NO: 109; amino acid sequences that are at least 90% identical to SEQ ID NO: 4 and at least 90% identical to SEQ ID NO: 109; amino acid sequences that are at least 90% identical to SEQ ID NO: 5 and at least 90% identical to SEQ ID NO: 109; amino acid sequences that are at least 90% identical to SEQ ID NO: 6 and at least 90% identical to SEQ ID NO: 109. Amino acid sequences that are at least 90% identical to SEQ ID NO: 7; amino acid sequences that are at least 90% identical to SEQ ID NO: 109; amino acid sequences that are at least 90% identical to SEQ ID NO: 8; amino acid sequences that are at least 90% identical to SEQ ID NO: 109; amino acid sequences that are at least 90% identical to SEQ ID NO: 307; amino acid sequences that are at least 90% identical to SEQ ID NO: 109.The amino acid sequences that are at least 90% identical to SEQ ID NO: 308 and at least 90% identical to SEQ ID NO: 109; the amino acid sequences that are at least 90% identical to SEQ ID NO: 309 and at least 90% identical to SEQ ID NO: 109; the amino acid sequences that are at least 90% identical to SEQ ID NO: 310 and at least 90% identical to SEQ ID NO: 109; the amino acid sequences that are at least 90% identical to SEQ ID NO: 311 and at least 90% identical to SEQ ID NO: 109; the amino acid sequences that are at least 90% identical to SEQ ID NO: 312 and at least 90% identical to SEQ ID NO: 109; the amino acid sequences that are at least 90% identical to SEQ ID NO: 313 and at least 90% identical to SEQ ID NO: 109; the amino acid sequences that are at least 90% identical to SEQ ID NO: 314 ... The amino acid sequence is at least 90% identical to SEQ ID NO: 109; the amino acid sequence is at least 90% identical to SEQ ID NO: 315 and at least 90% identical to SEQ ID NO: 109; the amino acid sequence is at least 90% identical to SEQ ID NO: 316 and at least 90% identical to SEQ ID NO: 109; the amino acid sequence is at least 90% identical to SEQ ID NO: 317 and at least 90% identical to SEQ ID NO: 109; the amino acid sequence is at least 90% identical to SEQ ID NO: 1 and at least 90% identical to SEQ ID NO: 113; the amino acid sequence is at least 90% identical to SEQ ID NO: 2 and at least 90% identical to SEQ ID NO: 113; the amino acid sequence is at least 90% identical to SEQ ID NO: 3 and at least 90% identical to SEQ ID NO: 113; the amino acid sequence is at least 90% identical to SEQ ID NO: 4 and at least 90% identical to SEQ ID NO: 113; the amino acid sequence is ... 113 contains at least 90% identical amino acid sequences; amino acid sequences that are at least 90% identical to SEQ ID NO: 5 and at least 90% identical to SEQ ID NO: 113; amino acid sequences that are at least 90% identical to SEQ ID NO: 6 and at least 90% identical to SEQ ID NO: 113; amino acid sequences that are at least 90% identical to SEQ ID NO: 7 and at least 90% identical to SEQ ID NO: 113;The amino acid sequences that are at least 90% identical to SEQ ID NO: 8 and at least 90% identical to SEQ ID NO: 113; the amino acid sequences that are at least 90% identical to SEQ ID NO: 307 and at least 90% identical to SEQ ID NO: 113; the amino acid sequences that are at least 90% identical to SEQ ID NO: 308 and at least 90% identical to SEQ ID NO: 113; the amino acid sequences that are at least 90% identical to SEQ ID NO: 309 and at least 90% identical to SEQ ID NO: 113; the amino acid sequences that are at least 90% identical to SEQ ID NO: 310 and at least 90% identical to SEQ ID NO: 113; the amino acid sequences that are at least 90% identical to SEQ ID NO: 311 and at least 90% identical to SEQ ID NO: 113; the amino acid sequences that are at least 90% identical to SEQ ID NO: 312 and at least 90% identical to SEQ ID NO: 113; the amino acid sequences that are ... SEQ ID NO: 113 has an amino acid sequence that is at least 90% identical to SEQ ID NO: 313; SEQ ID NO: 314 has an amino acid sequence that is at least 90% identical to SEQ ID NO: 113; SEQ ID NO: 315 has an amino acid sequence that is at least 90% identical to SEQ ID NO: 113; SEQ ID NO: 316 has an amino acid sequence that is at least 90% identical to SEQ ID NO: 113; SEQ ID NO: 317 has an amino acid sequence that is at least 90% identical to SEQ ID NO: 113; SEQ ID NO: 1 has an amino acid sequence that is at least 90% identical to SEQ ID NO: 1; SEQ ID NO: 15 has an amino acid sequence that is at least 90% identical to SEQ ID NO: 115; SEQ ID NO: 2 has an amino acid sequence that is at least 90% identical to SEQ ID NO: 113; SEQ ID NO: 317 has an amino acid sequence that is at least 90% identical to SEQ ID NO: 113; SEQ ID NO: 1 has an amino acid sequence that is at least 90% identical to SEQ ID NO: 115; SEQ ID NO: 2 has an amino acid sequence that is at least 90% identical to SEQ ID NO: 113; SEQ ID NO: 314 has an amino acid sequence that is at least 90% identical to SEQ ID NO: 113; SEQ ID NO: 315 has an amino acid sequence that is at least 90% identical to SEQ ID NO: 115; SEQ ID NO: 315 has an amino acid sequence that is at least 90% identical to SEQ ID NO: 113; SEQ ID NO: 316 has an amino acid sequence that is at least 90% identical to SEQ ID NO: 113; SEQ ID NO: 317 has an amino The amino acid sequence that is at least 90% identical to SEQ ID NO: 115; the amino acid sequence that is at least 90% identical to SEQ ID NO: 3 and the amino acid sequence that is at least 90% identical to SEQ ID NO: 115; the amino acid sequence that is at least 90% identical to SEQ ID NO: 4 and the amino acid sequence that is at least 90% identical to SEQ ID NO: 115; the amino acid sequence that is at least 90% identical to SEQ ID NO: 5 and the amino acid sequence that is at least 90% identical to SEQ ID NO: 115;The amino acid sequences that are at least 90% identical to SEQ ID NO: 6 and at least 90% identical to SEQ ID NO: 115; the amino acid sequences that are at least 90% identical to SEQ ID NO: 7 and at least 90% identical to SEQ ID NO: 115; the amino acid sequences that are at least 90% identical to SEQ ID NO: 8 and at least 90% identical to SEQ ID NO: 115; the amino acid sequences that are at least 90% identical to SEQ ID NO: 307 and at least 90% identical to SEQ ID NO: 115; the amino acid sequences that are at least 90% identical to SEQ ID NO: 308 and at least 90% identical to SEQ ID NO: 115; the amino acid sequences that are at least 90% identical to SEQ ID NO: 309 and at least 90% identical to SEQ ID NO: 115; the amino acid sequences that are at least 90% identical to SEQ ID NO: 310 and at least 90% identical to SEQ ID NO: 115; the amino acid sequences that are at least 90% identical to SEQ ID NO: 310 and at least 90% identical to SEQ ID NO: 115; the amino acid sequences that are at least 90% identical to SEQ ID NO: 6 and at least 90% identical to SEQ ID NO: 115; the amino acid sequences that are at least 90% identical to SEQ ID NO: 310 and at least 90% identical to SEQ ID NO: 115; the amino acid sequences that are ... The amino acid sequence that is at least 90% identical to SEQ ID NO: 115; the amino acid sequence that is at least 90% identical to SEQ ID NO: 311 and at least 90% identical to SEQ ID NO: 115; the amino acid sequence that is at least 90% identical to SEQ ID NO: 312 and at least 90% identical to SEQ ID NO: 115; the amino acid sequence that is at least 90% identical to SEQ ID NO: 313 and at least 90% identical to SEQ ID NO: 115; the amino acid sequence that is at least 90% identical to SEQ ID NO: 314 and at least 90% identical to SEQ ID NO: 115; the amino acid sequence that is at least 90% identical to SEQ ID NO: 315 and at least 90% identical to SEQ ID NO: 115; the amino acid sequence that is at least 90% identical to SEQ ID NO: 316 and at least 90% identical to SEQ ID NO: 115; the amino acid sequence that is ... 317 contains at least 90% identical amino acid sequences and amino acid sequences that are at least 90% identical to SEQ ID NO: 115; amino acid sequences that are at least 90% identical to SEQ ID NO: 1 and amino acid sequences that are at least 90% identical to SEQ ID NO: 117; amino acid sequences that are at least 90% identical to SEQ ID NO: 2 and amino acid sequences that are at least 90% identical to SEQ ID NO: 117; amino acid sequences that are at least 90% identical to SEQ ID NO: 3 and amino acid sequences that are at least 90% identical to SEQ ID NO: 117.Amino acid sequences that are at least 90% identical to SEQ ID NO: 4 and at least 90% identical to SEQ ID NO: 117; amino acid sequences that are at least 90% identical to SEQ ID NO: 5 and at least 90% identical to SEQ ID NO: 117; amino acid sequences that are at least 90% identical to SEQ ID NO: 6 and at least 90% identical to SEQ ID NO: 117; amino acid sequences that are at least 90% identical to SEQ ID NO: 7 and at least 90% identical to SEQ ID NO: 117; amino acid sequences that are at least 90% identical to SEQ ID NO: 8 and at least 90% identical to SEQ ID NO: 117; amino acid sequences that are at least 90% identical to SEQ ID NO: 307 and at least 90% identical to SEQ ID NO: 117; amino acid sequences that are at least 90% identical to SEQ ID NO: 308 and at least 90% identical to SEQ ID NO: 117; amino acid sequences that are at least 90% identical to SEQ ID NO: 4 ... The amino acid sequence that is at least 90% identical to SEQ ID NO: 309 and at least 90% identical to SEQ ID NO: 117; the amino acid sequence that is at least 90% identical to SEQ ID NO: 310 and at least 90% identical to SEQ ID NO: 117; the amino acid sequence that is at least 90% identical to SEQ ID NO: 311 and at least 90% identical to SEQ ID NO: 117; the amino acid sequence that is at least 90% identical to SEQ ID NO: 312 and at least 90% identical to SEQ ID NO: 117; the amino acid sequence that is at least 90% identical to SEQ ID NO: 313 and at least 90% identical to SEQ ID NO: 117; the amino acid sequence that is at least 90% identical to SEQ ID NO: 314 and at least 90% identical to SEQ ID NO: 117; the amino acid sequence that is at least 90% identical to SEQ ID NO: 315 and at least 90% identical to SEQ ID NO: 117; the amino acid sequence that is at least 90% identical to SEQ ID NO: 315 and at least 90% identical to SEQ ID NO: 117; the amino acid sequence that is at least 90% identical to SEQ ID NO: 319 ... Amino acid sequences that are at least 90% identical to SEQ ID NO: 316; amino acid sequences that are at least 90% identical to SEQ ID NO: 117; amino acid sequences that are at least 90% identical to SEQ ID NO: 317; amino acid sequences that are at least 90% identical to SEQ ID NO: 117; amino acid sequences that are at least 90% identical to SEQ ID NO: 1 and amino acid sequences that are at least 90% identical to SEQ ID NO: 119;Amino acid sequences that are at least 90% identical to SEQ ID NO: 2 and at least 90% identical to SEQ ID NO: 119; amino acid sequences that are at least 90% identical to SEQ ID NO: 3 and at least 90% identical to SEQ ID NO: 119; amino acid sequences that are at least 90% identical to SEQ ID NO: 4 and at least 90% identical to SEQ ID NO: 119; amino acid sequences that are at least 90% identical to SEQ ID NO: 5 and at least 90% identical to SEQ ID NO: 119; amino acid sequences that are at least 90% identical to SEQ ID NO: 6 and at least 90% identical to SEQ ID NO: 119; amino acid sequences that are at least 90% identical to SEQ ID NO: 7 and at least 90% identical to SEQ ID NO: 119; amino acid sequences that are at least 90% identical to SEQ ID NO: 8 and at least 90% identical to SEQ ID NO: 119; amino acid sequences that are ... SEQ ID NO: 307 has an amino acid sequence that is at least 90% identical to SEQ ID NO: 119; SEQ ID NO: 308 has an amino acid sequence that is at least 90% identical to SEQ ID NO: 119; SEQ ID NO: 309 has an amino acid sequence that is at least 90% identical to SEQ ID NO: 119; SEQ ID NO: 310 has an amino acid sequence that is at least 90% identical to SEQ ID NO: 119; SEQ ID NO: 311 has an amino acid sequence that is at least 90% identical to SEQ ID NO: 119; SEQ ID NO: 312 has an amino acid sequence that is at least 90% identical to SEQ ID NO: 119; SEQ ID NO: 313 has an amino acid sequence that is at least 90% identical to SEQ ID NO: 119; SEQ ID NO: 313 has an amino acid sequence that is at least 90% identical to SEQ ID NO: 119; SEQ ID NO: 319 ... SEQ ID NO: 119 has an amino acid sequence that is at least 90% identical to the ...Amino acid sequences that are at least 90% identical to SEQ ID NO: 317 and at least 90% identical to SEQ ID NO: 119; amino acid sequences that are at least 90% identical to SEQ ID NO: 1 and at least 90% identical to SEQ ID NO: 121; amino acid sequences that are at least 90% identical to SEQ ID NO: 2 and at least 90% identical to SEQ ID NO: 121; amino acid sequences that are at least 90% identical to SEQ ID NO: 3 and at least 90% identical to SEQ ID NO: 121; amino acid sequences that are at least 90% identical to SEQ ID NO: 4 and at least 90% identical to SEQ ID NO: 121; amino acid sequences that are at least 90% identical to SEQ ID NO: 5 and at least 90% identical to SEQ ID NO: 121; amino acid sequences that are at least 90% identical to SEQ ID NO: 6 and at least 90% identical to SEQ ID NO: 121; amino acid sequences that are at least 90% identical to SEQ ID NO: 119 ... 7. Amino acid sequences that are at least 90% identical to SEQ ID NO: 121; amino acid sequences that are at least 90% identical to SEQ ID NO: 8 and at least 90% identical to SEQ ID NO: 121; amino acid sequences that are at least 90% identical to SEQ ID NO: 307 and at least 90% identical to SEQ ID NO: 121; amino acid sequences that are at least 90% identical to SEQ ID NO: 308 and at least 90% identical to SEQ ID NO: 121; amino acid sequences that are at least 90% identical to SEQ ID NO: 309 and at least 90% identical to SEQ ID NO: 121; amino acid sequences that are at least 90% identical to SEQ ID NO: 310 and at least 90% identical to SEQ ID NO: 121; amino acid sequences that are at least 90% identical to SEQ ID NO: 311 and at least 90% identical to SEQ ID NO: 121; amino acid sequences that are at least 90% identical to SEQ ID NO: 121; amino acid sequences that are at least 90% identical to SEQ ID NO: 311; amino acid sequences that are at least 90% identical to SEQ ID NO: 12 ... The amino acid sequence that is at least 90% identical to SEQ ID NO: 312 and at least 90% identical to SEQ ID NO: 121; the amino acid sequence that is at least 90% identical to SEQ ID NO: 313 and at least 90% identical to SEQ ID NO: 121; the amino acid sequence that is at least 90% identical to SEQ ID NO: 314 and at least 90% identical to SEQ ID NO: 121;The amino acid sequences that are at least 90% identical to SEQ ID NO: 315 and at least 90% identical to SEQ ID NO: 121; the amino acid sequences that are at least 90% identical to SEQ ID NO: 316 and at least 90% identical to SEQ ID NO: 121; the amino acid sequences that are at least 90% identical to SEQ ID NO: 317 and at least 90% identical to SEQ ID NO: 121; the amino acid sequences that are at least 90% identical to SEQ ID NO: 1 and at least 90% identical to SEQ ID NO: 123; the amino acid sequences that are at least 90% identical to SEQ ID NO: 2 and at least 90% identical to SEQ ID NO: 123; the amino acid sequences that are at least 90% identical to SEQ ID NO: 3 and at least 90% identical to SEQ ID NO: 123; the amino acid sequences that are at least 90% identical to SEQ ID NO: 4 and at least 90% identical to SEQ ID NO: 123; the amino acid sequences that are at least 90% identical to SEQ ID NO: 315 and at least 90% identical to SEQ ID NO: 121; the amino acid sequences that are at least 90% identical to SEQ ID NO: 316 and at least 90% identical to SEQ ID NO: 123; the amino acid sequences that are at least 90% identical to SEQ ID NO: 317 and at least 90% identical to SEQ ID NO: 121; the amino acid sequences that are at least 90% identical to SEQ ID NO: 316 and at least 90% identical to SEQ ID NO: 123; the amino acid sequences that are at least 90% identical to SEQ ID NO: 123; the amino acid sequences that are at least 90% identical to SEQ ID NO: 123; the amino acid sequences that are at least Amino acid sequences that are at least 90% identical to SEQ ID NO: 123; amino acid sequences that are at least 90% identical to SEQ ID NO: 5 and at least 90% identical to SEQ ID NO: 123; amino acid sequences that are at least 90% identical to SEQ ID NO: 6 and at least 90% identical to SEQ ID NO: 123; amino acid sequences that are at least 90% identical to SEQ ID NO: 7 and at least 90% identical to SEQ ID NO: 123; amino acid sequences that are at least 90% identical to SEQ ID NO: 8 and at least 90% identical to SEQ ID NO: 123; amino acid sequences that are at least 90% identical to SEQ ID NO: 307 and at least 90% identical to SEQ ID NO: 123; amino acid sequences that are at least 90% identical to SEQ ID NO: 308 and at least 90% identical to SEQ ID NO: 123; amino acid sequences that are at least 90% identical to SEQ ID NO: 309 and at least 90% identical to SEQ ID NO: 123; amino acid sequences that are ... Amino acid sequences that are at least 90% identical to SEQ ID NO: 310 and at least 90% identical to SEQ ID NO: 123; amino acid sequences that are at least 90% identical to SEQ ID NO: 311 and at least 90% identical to SEQ ID NO: 123; amino acid sequences that are at least 90% identical to SEQ ID NO: 312 and at least 90% identical to SEQ ID NO: 123;Amino acid sequences that are at least 90% identical to SEQ ID NO: 313 and at least 90% identical to SEQ ID NO: 123; amino acid sequences that are at least 90% identical to SEQ ID NO: 314 and at least 90% identical to SEQ ID NO: 123; amino acid sequences that are at least 90% identical to SEQ ID NO: 315 and at least 90% identical to SEQ ID NO: 123; amino acid sequences that are at least 90% identical to SEQ ID NO: 316 and at least 90% identical to SEQ ID NO: 123; amino acid sequences that are at least 90% identical to SEQ ID NO: 317 and at least 90% identical to SEQ ID NO: 123; amino acid sequences that are at least 90% identical to SEQ ID NO: 1 and at least 90% identical to SEQ ID NO: 125; amino acid sequences that are at least 90% identical to SEQ ID NO: 2 and at least 90% identical to SEQ ID NO: 123; amino acid sequences that are at least 90% identical to SEQ ID NO: 125; amino acid sequences that are at least 90% identical to SEQ ID NO: 125; amino acid sequences that are at least 90% identical to SEQ ID NO: 123 ... The amino acid sequence is at least 90% identical to SEQ ID NO: 125; the amino acid sequence is at least 90% identical to SEQ ID NO: 3 and at least 90% identical to SEQ ID NO: 125; the amino acid sequence is at least 90% identical to SEQ ID NO: 4 and at least 90% identical to SEQ ID NO: 125; the amino acid sequence is at least 90% identical to SEQ ID NO: 5 and at least 90% identical to SEQ ID NO: 125; the amino acid sequence is at least 90% identical to SEQ ID NO: 6 and at least 90% identical to SEQ ID NO: 125; the amino acid sequence is at least 90% identical to SEQ ID NO: 7 and at least 90% identical to SEQ ID NO: 125; the amino acid sequence is at least 90% identical to SEQ ID NO: 8 and at least 90% identical to SEQ ID NO: 125; the amino acid sequence is at least 90% identical to SEQ ID NO: 307 and at least 90% identical to SEQ ID NO: 125. The amino acid sequence that is at least 90% identical to SEQ ID NO: 125; the amino acid sequence that is at least 90% identical to SEQ ID NO: 308 and the amino acid sequence that is at least 90% identical to SEQ ID NO: 125; the amino acid sequence that is at least 90% identical to SEQ ID NO: 309 and the amino acid sequence that is at least 90% identical to SEQ ID NO: 125; the amino acid sequence that is at least 90% identical to SEQ ID NO: 310 and the amino acid sequence that is at least 90% identical to SEQ ID NO: 125;The amino acid sequences that are at least 90% identical to SEQ ID NO: 311 and at least 90% identical to SEQ ID NO: 125; the amino acid sequences that are at least 90% identical to SEQ ID NO: 312 and at least 90% identical to SEQ ID NO: 125; the amino acid sequences that are at least 90% identical to SEQ ID NO: 313 and at least 90% identical to SEQ ID NO: 125; the amino acid sequences that are at least 90% identical to SEQ ID NO: 314 and at least 90% identical to SEQ ID NO: 125; the amino acid sequences that are at least 90% identical to SEQ ID NO: 315 and at least 90% identical to SEQ ID NO: 125; the amino acid sequences that are at least 90% identical to SEQ ID NO: 316 and at least 90% identical to SEQ ID NO: 125; the amino acid sequences that are at least 90% identical to SEQ ID NO: 317 and at least 90% identical to SEQ ID NO: 125; the amino acid sequences that are at least 90% identical to SEQ ID NO: 317 and at least 90% identical to SEQ ID NO: 125; the amino acid sequences that are at least 90% identical to SEQ ID NO: 312 ...125; the amino acid sequences that are at least 90% identical to SEQ ID NO: 125; the SEQ ID NO: 125 has an amino acid sequence that is at least 90% identical to SEQ ID NO: 1; an amino acid sequence that is at least 90% identical to SEQ ID NO: 1 and at least 90% identical to SEQ ID NO: 127; an amino acid sequence that is at least 90% identical to SEQ ID NO: 2 and at least 90% identical to SEQ ID NO: 127; an amino acid sequence that is at least 90% identical to SEQ ID NO: 3 and at least 90% identical to SEQ ID NO: 127; an amino acid sequence that is at least 90% identical to SEQ ID NO: 4 and at least 90% identical to SEQ ID NO: 127; an amino acid sequence that is at least 90% identical to SEQ ID NO: 5 and at least 90% identical to SEQ ID NO: 127; an amino acid sequence that is at least 90% identical to SEQ ID NO: 6 and at least 90% identical to SEQ ID NO: 127; an amino acid sequence that is at least 90% identical to SEQ ID NO: 7 and at least 90% identical to SEQ ID NO: 127. Amino acid sequences that are at least 90% identical to SEQ ID NO: 127; amino acid sequences that are at least 90% identical to SEQ ID NO: 8 and at least 90% identical to SEQ ID NO: 127; amino acid sequences that are at least 90% identical to SEQ ID NO: 307 and at least 90% identical to SEQ ID NO: 127; amino acid sequences that are at least 90% identical to SEQ ID NO: 308 and at least 90% identical to SEQ ID NO: 127;The amino acid sequences that are at least 90% identical to SEQ ID NO: 309 and at least 90% identical to SEQ ID NO: 127; the amino acid sequences that are at least 90% identical to SEQ ID NO: 310 and at least 90% identical to SEQ ID NO: 127; the amino acid sequences that are at least 90% identical to SEQ ID NO: 311 and at least 90% identical to SEQ ID NO: 127; the amino acid sequences that are at least 90% identical to SEQ ID NO: 312 and at least 90% identical to SEQ ID NO: 127; the amino acid sequences that are at least 90% identical to SEQ ID NO: 313 and at least 90% identical to SEQ ID NO: 127; the amino acid sequences that are at least 90% identical to SEQ ID NO: 314 and at least 90% identical to SEQ ID NO: 127; the amino acid sequences that are at least 90% identical to SEQ ID NO: 315 and at least 90% identical to SEQ ID NO: 127; the amino acid sequences that are at least 90% identical to SEQ ID NO: 315 and at least 90% identical to SEQ ID NO: 127; the amino acid sequences that are at least 90% identical to SEQ ID NO: 319 ...127; the amino acid sequences that are at least 90% identical to SEQ ID NO: 127; the The amino acid sequence is at least 90% identical to SEQ ID NO: 127; the amino acid sequence is at least 90% identical to SEQ ID NO: 316 and at least 90% identical to SEQ ID NO: 127; the amino acid sequence is at least 90% identical to SEQ ID NO: 317 and at least 90% identical to SEQ ID NO: 127; the amino acid sequence is at least 90% identical to SEQ ID NO: 1 and at least 90% identical to SEQ ID NO: 129; the amino acid sequence is at least 90% identical to SEQ ID NO: 2 and at least 90% identical to SEQ ID NO: 129; the amino acid sequence is at least 90% identical to SEQ ID NO: 3 and at least 90% identical to SEQ ID NO: 129; the amino acid sequence is at least 90% identical to SEQ ID NO: 4 and at least 90% identical to SEQ ID NO: 129; the amino acid sequence is at least 90% identical to SEQ ID NO: 5 and at least 90% identical to SEQ ID NO: 129. 129 has an amino acid sequence that is at least 90% identical to SEQ ID NO: 6; an amino acid sequence that is at least 90% identical to SEQ ID NO: 7; an amino acid sequence that is at least 90% identical to SEQ ID NO: 129; an amino acid sequence that is at least 90% identical to SEQ ID NO: 8; and an amino acid sequence that is at least 90% identical to SEQ ID NO: 129.The amino acid sequences that are at least 90% identical to SEQ ID NO: 307 and at least 90% identical to SEQ ID NO: 129; the amino acid sequences that are at least 90% identical to SEQ ID NO: 308 and at least 90% identical to SEQ ID NO: 129; the amino acid sequences that are at least 90% identical to SEQ ID NO: 309 and at least 90% identical to SEQ ID NO: 129; the amino acid sequences that are at least 90% identical to SEQ ID NO: 310 and at least 90% identical to SEQ ID NO: 129; the amino acid sequences that are at least 90% identical to SEQ ID NO: 311 and at least 90% identical to SEQ ID NO: 129; the amino acid sequences that are at least 90% identical to SEQ ID NO: 312 and at least 90% identical to SEQ ID NO: 129; the amino acid sequences that are at least 90% identical to SEQ ID NO: 313 and at least 90% identical to SEQ ID NO: 129; the amino acid sequences that are at least 90% identical to SEQ ID NO: 313 and at least 90% identical to SEQ ID NO: 129; the amino acid sequences that are at least 90% identical to SEQ ID NO: 307 and at least 90% identical to SEQ ID NO: 129; the amino acid sequences that are at least 90% identical to SEQ ID NO: 313 and at least 90% identical to SEQ ID NO: 129; the amino acid sequences that are ... The amino acid sequence that is at least 90% identical to SEQ ID NO: 129; the amino acid sequence that is at least 90% identical to SEQ ID NO: 314 and at least 90% identical to SEQ ID NO: 129; the amino acid sequence that is at least 90% identical to SEQ ID NO: 315 and at least 90% identical to SEQ ID NO: 129; the amino acid sequence that is at least 90% identical to SEQ ID NO: 316 and at least 90% identical to SEQ ID NO: 129; the amino acid sequence that is at least 90% identical to SEQ ID NO: 317 and at least 90% identical to SEQ ID NO: 129; the amino acid sequence that is at least 90% identical to SEQ ID NO: 1 and at least 90% identical to SEQ ID NO: 131; the amino acid sequence that is at least 90% identical to SEQ ID NO: 2 and at least 90% identical to SEQ ID NO: 131; the amino acid sequence that is at least 90% identical to SEQ ID NO: 3 and at least 90% identical to SEQ ID NO: 129; the amino acid sequence that is at least 90% identical to SEQ ID NO: 314 and at least 90% identical to SEQ ID NO: 129; the amino acid sequence that is at least 90% identical to SEQ ID NO: 315 and at least 90% identical to SEQ ID NO: 129; the amino acid sequence that is at least 90% identical to SEQ ID NO: 316 and at least 90% identical to SEQ ID NO: 129; the amino acid sequence that is at least 90% identical to SEQ ID NO: 317 and at least 90% identical to SEQ ID NO: 129; the amino acid sequence that is at least 90% identical to SEQ ID NO: 131; the amino acid sequence that is at The amino acid sequence that is at least 90% identical to SEQ ID NO: 131; the amino acid sequence that is at least 90% identical to SEQ ID NO: 4 and the amino acid sequence that is at least 90% identical to SEQ ID NO: 131; the amino acid sequence that is at least 90% identical to SEQ ID NO: 5 and the amino acid sequence that is at least 90% identical to SEQ ID NO: 131; the amino acid sequence that is at least 90% identical to SEQ ID NO: 6 and the amino acid sequence that is at least 90% identical to SEQ ID NO: 131;Amino acid sequences that are at least 90% identical to SEQ ID NO: 7 and at least 90% identical to SEQ ID NO: 131; amino acid sequences that are at least 90% identical to SEQ ID NO: 8 and at least 90% identical to SEQ ID NO: 131; amino acid sequences that are at least 90% identical to SEQ ID NO: 307 and at least 90% identical to SEQ ID NO: 131; amino acid sequences that are at least 90% identical to SEQ ID NO: 308 and at least 90% identical to SEQ ID NO: 131; amino acid sequences that are at least 90% identical to SEQ ID NO: 309 and at least 90% identical to SEQ ID NO: 131; amino acid sequences that are at least 90% identical to SEQ ID NO: 310 and at least 90% identical to SEQ ID NO: 131; amino acid sequences that are at least 90% identical to SEQ ID NO: 311 and at least 90% identical to SEQ ID NO: 131; amino acid sequences that are ... SEQ ID NO: 131 has an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 312 and at least 90% identical to the amino acid sequence of SEQ ID NO: 131; SEQ ID NO: 313 has an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 131; SEQ ID NO: 314 has an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 131; SEQ ID NO: 315 has an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 131; SEQ ID NO: 316 has an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 131; SEQ ID NO: 317 has an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 131; SEQ ID NO: 1 has an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 1 and ... The amino acid sequence that is at least 90% identical to SEQ ID NO: 133; the amino acid sequence that is at least 90% identical to SEQ ID NO: 2 and the amino acid sequence that is at least 90% identical to SEQ ID NO: 133; the amino acid sequence that is at least 90% identical to SEQ ID NO: 3 and the amino acid sequence that is at least 90% identical to SEQ ID NO: 133; the amino acid sequence that is at least 90% identical to SEQ ID NO: 4 and the amino acid sequence that is at least 90% identical to SEQ ID NO: 133;The amino acid sequences that are at least 90% identical to SEQ ID NO: 5 and at least 90% identical to SEQ ID NO: 133; the amino acid sequences that are at least 90% identical to SEQ ID NO: 6 and at least 90% identical to SEQ ID NO: 133; the amino acid sequences that are at least 90% identical to SEQ ID NO: 7 and at least 90% identical to SEQ ID NO: 133; the amino acid sequences that are at least 90% identical to SEQ ID NO: 8 and at least 90% identical to SEQ ID NO: 133; the amino acid sequences that are at least 90% identical to SEQ ID NO: 307 and at least 90% identical to SEQ ID NO: 133; the amino acid sequences that are at least 90% identical to SEQ ID NO: 308 and at least 90% identical to SEQ ID NO: 133; the amino acid sequences that are at least 90% identical to SEQ ID NO: 309 and at least 90% identical to SEQ ID NO: 133; the amino acid sequences that are ... SEQ ID NO: 133 has an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 310 and at least 90% identical to the amino acid sequence of SEQ ID NO: 133; SEQ ID NO: 311 has an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 133; SEQ ID NO: 312 has an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 133; SEQ ID NO: 313 has an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 133; SEQ ID NO: 314 has an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 133; SEQ ID NO: 315 has an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 133; SEQ ID NO: 316 has an amino acid sequence that is at least 90% identical to SEQ ID NO: 133; 317 has an amino acid sequence that is at least 90% identical to SEQ ID NO: 133; 1 has an amino acid sequence that is at least 90% identical to SEQ ID NO: 1 and SEQ ID NO: 135; 2 has an amino acid sequence that is at least 90% identical to SEQ ID NO: 2 and SEQ ID NO: 135.Amino acid sequences that are at least 90% identical to SEQ ID NO: 3 and at least 90% identical to SEQ ID NO: 135; amino acid sequences that are at least 90% identical to SEQ ID NO: 4 and at least 90% identical to SEQ ID NO: 135; amino acid sequences that are at least 90% identical to SEQ ID NO: 5 and at least 90% identical to SEQ ID NO: 135; amino acid sequences that are at least 90% identical to SEQ ID NO: 6 and at least 90% identical to SEQ ID NO: 135; amino acid sequences that are at least 90% identical to SEQ ID NO: 7 and at least 90% identical to SEQ ID NO: 135; amino acid sequences that are at least 90% identical to SEQ ID NO: 8 and at least 90% identical to SEQ ID NO: 135; amino acid sequences that are at least 90% identical to SEQ ID NO: 307 and at least 90% identical to SEQ ID NO: 135; amino acid sequences that are at least 90% identical to SEQ ID NO: 13 ... SEQ ID NO: 308 has an amino acid sequence that is at least 90% identical to SEQ ID NO: 135; SEQ ID NO: 309 has an amino acid sequence that is at least 90% identical to SEQ ID NO: 135; SEQ ID NO: 310 has an amino acid sequence that is at least 90% identical to SEQ ID NO: 135; SEQ ID NO: 311 has an amino acid sequence that is at least 90% identical to SEQ ID NO: 135; SEQ ID NO: 312 has an amino acid sequence that is at least 90% identical to SEQ ID NO: 135; SEQ ID NO: 313 has an amino acid sequence that is at least 90% identical to SEQ ID NO: 135; SEQ ID NO: 314 has an amino acid sequence that is at least 90% identical to SEQ ID NO: 135; SEQ ID NO: 315 ... Amino acid sequences that are at least 90% identical to SEQ ID NO: 315; amino acid sequences that are at least 90% identical to SEQ ID NO: 135; amino acid sequences that are at least 90% identical to SEQ ID NO: 316; amino acid sequences that are at least 90% identical to SEQ ID NO: 135; amino acid sequences that are at least 90% identical to SEQ ID NO: 317; amino acid sequences that are at least 90% identical to SEQ ID NO: 135.Amino acid sequences that are at least 90% identical to SEQ ID NO: 1 and at least 90% identical to SEQ ID NO: 137; amino acid sequences that are at least 90% identical to SEQ ID NO: 2 and at least 90% identical to SEQ ID NO: 137; amino acid sequences that are at least 90% identical to SEQ ID NO: 3 and at least 90% identical to SEQ ID NO: 137; amino acid sequences that are at least 90% identical to SEQ ID NO: 4 and at least 90% identical to SEQ ID NO: 137; amino acid sequences that are at least 90% identical to SEQ ID NO: 5 and at least 90% identical to SEQ ID NO: 137; amino acid sequences that are at least 90% identical to SEQ ID NO: 6 and at least 90% identical to SEQ ID NO: 137; amino acid sequences that are at least 90% identical to SEQ ID NO: 7 and at least 90% identical to SEQ ID NO: 137; amino acid sequences that are ... 8. Amino acid sequences that are at least 90% identical to SEQ ID NO: 137; amino acid sequences that are at least 90% identical to SEQ ID NO: 307; amino acid sequences that are at least 90% identical to SEQ ID NO: 137; amino acid sequences that are at least 90% identical to SEQ ID NO: 308; amino acid sequences that are at least 90% identical to SEQ ID NO: 137; amino acid sequences that are at least 90% identical to SEQ ID NO: 309; amino acid sequences that are at least 90% identical to SEQ ID NO: 137; amino acid sequences that are at least 90% identical to SEQ ID NO: 310; amino acid sequences that are at least 90% identical to SEQ ID NO: 137; amino acid sequences that are at least 90% identical to SEQ ID NO: 311; amino acid sequences that are at least 90% identical to SEQ ID NO: 137; amino acid sequences that are at least 90% identical to SEQ ID NO: 312; amino acid sequences that are at least 90% identical to SEQ ID NO: 137 ... The amino acid sequence is at least 90% identical to that of SEQ ID NO: 313 and at least 90% identical to that of SEQ ID NO: 137; the amino acid sequence is at least 90% identical to that of SEQ ID NO: 314 and at least 90% identical to that of SEQ ID NO: 137; the amino acid sequence is at least 90% identical to that of SEQ ID NO: 315 and at least 90% identical to that of SEQ ID NO: 137.Amino acid sequences that are at least 90% identical to SEQ ID NO: 316 and at least 90% identical to SEQ ID NO: 137; amino acid sequences that are at least 90% identical to SEQ ID NO: 317 and at least 90% identical to SEQ ID NO: 137; amino acid sequences that are at least 90% identical to SEQ ID NO: 1 and at least 90% identical to SEQ ID NO: 376; amino acid sequences that are at least 90% identical to SEQ ID NO: 2 and at least 90% identical to SEQ ID NO: 376; amino acid sequences that are at least 90% identical to SEQ ID NO: 3 and at least 90% identical to SEQ ID NO: 376; amino acid sequences that are at least 90% identical to SEQ ID NO: 4 and at least 90% identical to SEQ ID NO: 376; amino acid sequences that are at least 90% identical to SEQ ID NO: 5 ...316 and at least 90% identical to SEQ ID NO: 137; amino acid sequences that are at least 90% identical to SEQ ID NO: 317 and at least 90% identical to SEQ ID NO: 137; amino acid sequences that are at least 90% identical to SEQ ID NO: 137 and at least 90% identical to SEQ ID NO: 376; amino acid sequences that are at least 90% identical to SEQ ID NO: 316 and at least 90% identical to SEQ ID NO: 137; amino acid sequences that are at least 90% identical to SEQ ID NO: 316 and at least 90% identical The amino acid sequence that is at least 90% identical to SEQ ID NO: 6 and at least 90% identical to SEQ ID NO: 376; the amino acid sequence that is at least 90% identical to SEQ ID NO: 7 and at least 90% identical to SEQ ID NO: 376; the amino acid sequence that is at least 90% identical to SEQ ID NO: 8 and at least 90% identical to SEQ ID NO: 376; the amino acid sequence that is at least 90% identical to SEQ ID NO: 307 and at least 90% identical to SEQ ID NO: 376; the amino acid sequence that is at least 90% identical to SEQ ID NO: 308 and at least 90% identical to SEQ ID NO: 376; the amino acid sequence that is at least 90% identical to SEQ ID NO: 309 and at least 90% identical to SEQ ID NO: 376; the amino acid sequence that is at least 90% identical to SEQ ID NO: 310 and at least 90% identical to SEQ ID NO: 376; and the amino acid sequence that is at least 90% identical to SEQ ID NO: 376. The amino acid sequence that is at least 90% identical to SEQ ID NO: 311 and at least 90% identical to SEQ ID NO: 376; the amino acid sequence that is at least 90% identical to SEQ ID NO: 312 and at least 90% identical to SEQ ID NO: 376; the amino acid sequence that is at least 90% identical to SEQ ID NO: 313 and at least 90% identical to SEQ ID NO: 376;Amino acid sequences that are at least 90% identical to SEQ ID NO: 314 and at least 90% identical to SEQ ID NO: 376; amino acid sequences that are at least 90% identical to SEQ ID NO: 315 and at least 90% identical to SEQ ID NO: 376; amino acid sequences that are at least 90% identical to SEQ ID NO: 316 and at least 90% identical to SEQ ID NO: 376; amino acid sequences that are at least 90% identical to SEQ ID NO: 317 and at least 90% identical to SEQ ID NO: 376; amino acid sequences that are at least 90% identical to SEQ ID NO: 1 and at least 90% identical to SEQ ID NO: 378; amino acid sequences that are at least 90% identical to SEQ ID NO: 2 and at least 90% identical to SEQ ID NO: 378; amino acid sequences that are at least 90% identical to SEQ ID NO: 3 and at least 90% identical to SEQ ID NO: 378; amino acid sequences that are at least 90% identical to SEQ ID NO: 3 and at least 90% identical to SEQ ID NO: 378. SEQ ID NO: 378 has an amino acid sequence that is at least 90% identical to SEQ ID NO: 4; an amino acid sequence that is at least 90% identical to SEQ ID NO: 5; an amino acid sequence that is at least 90% identical to SEQ ID NO: 378; an amino acid sequence that is at least 90% identical to SEQ ID NO: 6; an amino acid sequence that is at least 90% identical to SEQ ID NO: 7; an amino acid sequence that is at least 90% identical to SEQ ID NO: 378; an amino acid sequence that is at least 90% identical to SEQ ID NO: 8; an amino acid sequence that is at least 90% identical to SEQ ID NO: 378; an amino acid sequence that is at least 90% identical to SEQ ID NO: 307; an amino acid sequence that is at least 90% identical to SEQ ID NO: 378; an amino acid sequence that is at least 90% identical to SEQ ID NO: 308; and an amino acid sequence that is at least 90% identical to SEQ ID NO: 378. Amino acid sequences that are at least 90% identical to SEQ ID NO: 378; amino acid sequences that are at least 90% identical to SEQ ID NO: 309 and at least 90% identical to SEQ ID NO: 378; amino acid sequences that are at least 90% identical to SEQ ID NO: 310 and at least 90% identical to SEQ ID NO: 378; amino acid sequences that are at least 90% identical to SEQ ID NO: 311 and at least 90% identical to SEQ ID NO: 378;Amino acid sequences that are at least 90% identical to SEQ ID NO: 312 and at least 90% identical to SEQ ID NO: 378; amino acid sequences that are at least 90% identical to SEQ ID NO: 313 and at least 90% identical to SEQ ID NO: 378; amino acid sequences that are at least 90% identical to SEQ ID NO: 314 and at least 90% identical to SEQ ID NO: 378; amino acid sequences that are at least 90% identical to SEQ ID NO: 315 and at least 90% identical to SEQ ID NO: 378; amino acid sequences that are at least 90% identical to SEQ ID NO: 316 and at least 90% identical to SEQ ID NO: 378; amino acid sequences that are at least 90% identical to SEQ ID NO: 317 and at least 90% identical to SEQ ID NO: 378.

[0035] In some embodiments, the first polypeptide comprises: the amino acid sequence of SEQ ID NO: 1 and the amino acid sequence of SEQ ID NO: 103; the amino acid sequence of SEQ ID NO: 2 and the amino acid sequence of SEQ ID NO: 103; the amino acid sequence of SEQ ID NO: 3 and the amino acid sequence of SEQ ID NO: 103; the amino acid sequence of SEQ ID NO: 4 and the amino acid sequence of SEQ ID NO: 103; the amino acid sequence of SEQ ID NO: 5 and the amino acid sequence of SEQ ID NO: 103; the amino acid sequence of SEQ ID NO: 6 and the amino acid sequence of SEQ ID NO: 103; the amino acid sequence of SEQ ID NO: 7 and the amino acid sequence of SEQ ID NO: 103; the amino acid sequence of SEQ ID NO: 8 and the amino acid sequence of SEQ ID NO: 103; the amino acid sequence of SEQ ID NO: 307 and the amino acid sequence of SEQ ID NO: 103; the amino acid sequence of SEQ ID NO: 308 and the amino acid sequence of SEQ ID NO: 103; and the amino acid sequence of SEQ ID NO: 309 and the amino acid sequence of SEQ ID NO: 103. The amino acid sequences of SEQ ID NO: 103; SEQ ID NO: 310 and SEQ ID NO: 103; SEQ ID NO: 311 and SEQ ID NO: 103; SEQ ID NO: 312 and SEQ ID NO: 103; SEQ ID NO: 313 and SEQ ID NO: 103; SEQ ID NO: 314 and SEQ ID NO: 103; SEQ ID NO: 315 and SEQ ID NO: 103; SEQ ID NO: 316 and SEQ ID NO: 103; SEQ ID NO: 317 and SEQ ID NO: 103; SEQ ID NO: 1 and SEQ ID NO: 105; SEQ ID NO: 2 and SEQ ID NO: 105; SEQ ID The amino acid sequences of SEQ ID NO: 3 and SEQ ID NO: 105; the amino acid sequences of SEQ ID NO: 4 and SEQ ID NO: 105; the amino acid sequences of SEQ ID NO: 5 and SEQ ID NO: 105;The amino acid sequences of SEQ ID NO: 6 and SEQ ID NO: 105; the amino acid sequences of SEQ ID NO: 7 and SEQ ID NO: 105; the amino acid sequences of SEQ ID NO: 8 and SEQ ID NO: 105; the amino acid sequences of SEQ ID NO: 307 and SEQ ID NO: 105; the amino acid sequences of SEQ ID NO: 308 and SEQ ID NO: 105; the amino acid sequences of SEQ ID NO: 309 and SEQ ID NO: 105; the amino acid sequences of SEQ ID NO: 310 and SEQ ID NO: 105; the amino acid sequences of SEQ ID NO: 311 and SEQ ID NO: 105; the amino acid sequences of SEQ ID NO: 312 and SEQ ID NO: 105; the amino acid sequences of SEQ ID NO: 313 and SEQ ID NO: 105; SEQ ID NO: The amino acid sequences of SEQ ID NO: 314 and SEQ ID NO: 105; the amino acid sequences of SEQ ID NO: 315 and SEQ ID NO: 105; the amino acid sequences of SEQ ID NO: 316 and SEQ ID NO: 105; the amino acid sequences of SEQ ID NO: 317 and SEQ ID NO: 105; the amino acid sequences of SEQ ID NO: 4, SEQ ID NO: 209, SEQ ID NO: 210 and SEQ ID NO: 105; the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 107; the amino acid sequences of SEQ ID NO: 2 and SEQ ID NO: 107; the amino acid sequences of SEQ ID NO: 3 and SEQ ID NO: 107; the amino acid sequences of SEQ ID NO: 4 and SEQ ID NO: 107; the amino acid sequences of SEQ ID NO: 5 and SEQ ID NO: 107; the amino acid sequences of SEQ ID NO: 314 and SEQ ID NO: 105; the amino acid sequences of SEQ ID NO: 316 and SEQ ID NO: 105; the amino acid sequences of SEQ ID NO: 317 and SEQ ID NO: 105; the amino acid sequences of SEQ ID NO: 4, SEQ ID NO: 209, SEQ ID NO: 210 and SEQ ID NO: 105; the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 107; the amino acid sequences of SEQ ID NO: 210 and SEQ ID NO: 107; the amino acid sequences of SEQ ID NO: 314 and SEQ ID NO: 105; the amino acid sequences of SEQ ID NO: 314 and SEQ ID NO: 105; the amino acid sequences of SEQ ID NO: 315 and SEQ ID NO: 105; the amino acid sequences of SEQ ID NO: 3 The amino acid sequences of SEQ ID NO: 107; SEQ ID NO: 6 and SEQ ID NO: 107; SEQ ID NO: 7 and SEQ ID NO: 107; SEQ ID NO: 8 and SEQ ID NO: 107.The amino acid sequences of SEQ ID NO: 307 and SEQ ID NO: 107; the amino acid sequences of SEQ ID NO: 308 and SEQ ID NO: 107; the amino acid sequences of SEQ ID NO: 309 and SEQ ID NO: 107; the amino acid sequences of SEQ ID NO: 310 and SEQ ID NO: 107; the amino acid sequences of SEQ ID NO: 311 and SEQ ID NO: 107; the amino acid sequences of SEQ ID NO: 312 and SEQ ID NO: 107; the amino acid sequences of SEQ ID NO: 313 and SEQ ID NO: 107; the amino acid sequences of SEQ ID NO: 314 and SEQ ID NO: 107; the amino acid sequences of SEQ ID NO: 315 and SEQ ID NO: 107; the amino acid sequences of SEQ ID NO: 316 and SEQ ID NO: 107; SEQ ID NO: The amino acid sequences of SEQ ID NO: 317 and SEQ ID NO: 107; the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 109; the amino acid sequences of SEQ ID NO: 2 and SEQ ID NO: 109; the amino acid sequences of SEQ ID NO: 3 and SEQ ID NO: 109; the amino acid sequences of SEQ ID NO: 4 and SEQ ID NO: 109; the amino acid sequences of SEQ ID NO: 5 and SEQ ID NO: 109; the amino acid sequences of SEQ ID NO: 6 and SEQ ID NO: 109; the amino acid sequences of SEQ ID NO: 7 and SEQ ID NO: 109; the amino acid sequences of SEQ ID NO: 8 and SEQ ID NO: 109; the amino acid sequences of SEQ ID NO: 307 and SEQ ID NO: 109; the amino acid sequences of SEQ ID NO: 308 and SEQ ID NO: 109; SEQ ID NO: The amino acid sequences of SEQ ID NO: 309 and SEQ ID NO: 109; the amino acid sequences of SEQ ID NO: 310 and SEQ ID NO: 109; the amino acid sequences of SEQ ID NO: 311 and SEQ ID NO: 109;The amino acid sequences of SEQ ID NO: 312 and SEQ ID NO: 109; the amino acid sequences of SEQ ID NO: 313 and SEQ ID NO: 109; the amino acid sequences of SEQ ID NO: 314 and SEQ ID NO: 109; the amino acid sequences of SEQ ID NO: 315 and SEQ ID NO: 109; the amino acid sequences of SEQ ID NO: 316 and SEQ ID NO: 109; the amino acid sequences of SEQ ID NO: 317 and SEQ ID NO: 109; the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 113; the amino acid sequences of SEQ ID NO: 2 and SEQ ID NO: 113; the amino acid sequences of SEQ ID NO: 3 and SEQ ID NO: 113; the amino acid sequences of SEQ ID NO: 4 and SEQ ID NO: 113; the amino acid sequences of SEQ ID NO: 5 and SEQ ID NO: 113; the amino acid sequences of ... The amino acid sequences of SEQ ID NO: 113; SEQ ID NO: 6 and SEQ ID NO: 113; SEQ ID NO: 7 and SEQ ID NO: 113; SEQ ID NO: 8 and SEQ ID NO: 113; SEQ ID NO: 307 and SEQ ID NO: 113; SEQ ID NO: 308 and SEQ ID NO: 113; SEQ ID NO: 309 and SEQ ID NO: 113; SEQ ID NO: 310 and SEQ ID NO: 113; SEQ ID NO: 311 and SEQ ID NO: 113; SEQ ID NO: 312 and SEQ ID NO: 113; SEQ ID NO: 313 and SEQ ID NO: 113; SEQ ID NO: The amino acid sequences of SEQ ID NO: 314 and SEQ ID NO: 113; the amino acid sequences of SEQ ID NO: 315 and SEQ ID NO: 113; the amino acid sequences of SEQ ID NO: 316 and SEQ ID NO: 113;The amino acid sequences of SEQ ID NO: 317 and SEQ ID NO: 113; the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 115; the amino acid sequences of SEQ ID NO: 2 and SEQ ID NO: 115; the amino acid sequences of SEQ ID NO: 3 and SEQ ID NO: 115; the amino acid sequences of SEQ ID NO: 4 and SEQ ID NO: 115; the amino acid sequences of SEQ ID NO: 5 and SEQ ID NO: 115; the amino acid sequences of SEQ ID NO: 6 and SEQ ID NO: 115; the amino acid sequences of SEQ ID NO: 7 and SEQ ID NO: 115; the amino acid sequences of SEQ ID NO: 8 and SEQ ID NO: 115; the amino acid sequences of SEQ ID NO: 307 and SEQ ID NO: 115; the amino acid sequences of SEQ ID NO: 308 and SEQ ID NO: 115; and the amino acid sequences of SEQ ID NO: 115 and SEQ ID NO: 115. The amino acid sequences of SEQ ID NO: 115; SEQ ID NO: 309 and SEQ ID NO: 115; SEQ ID NO: 310 and SEQ ID NO: 115; SEQ ID NO: 311 and SEQ ID NO: 115; SEQ ID NO: 312 and SEQ ID NO: 115; SEQ ID NO: 313 and SEQ ID NO: 115; SEQ ID NO: 314 and SEQ ID NO: 115; SEQ ID NO: 315 and SEQ ID NO: 115; SEQ ID NO: 316 and SEQ ID NO: 115; SEQ ID NO: 317 and SEQ ID NO: 115; SEQ ID NO: 1 and SEQ ID NO: 117; SEQ ID NO: The amino acid sequences of SEQ ID NO: 2 and SEQ ID NO: 117; the amino acid sequences of SEQ ID NO: 3 and SEQ ID NO: 117; the amino acid sequences of SEQ ID NO: 4 and SEQ ID NO: 117;The amino acid sequences of SEQ ID NO: 5 and SEQ ID NO: 117; the amino acid sequences of SEQ ID NO: 6 and SEQ ID NO: 117; the amino acid sequences of SEQ ID NO: 7 and SEQ ID NO: 117; the amino acid sequences of SEQ ID NO: 8 and SEQ ID NO: 117; the amino acid sequences of SEQ ID NO: 307 and SEQ ID NO: 117; the amino acid sequences of SEQ ID NO: 308 and SEQ ID NO: 117; the amino acid sequences of SEQ ID NO: 309 and SEQ ID NO: 117; the amino acid sequences of SEQ ID NO: 310 and SEQ ID NO: 117; the amino acid sequences of SEQ ID NO: 311 and SEQ ID NO: 117; the amino acid sequences of SEQ ID NO: 312 and SEQ ID NO: 117; the amino acid sequences of SEQ ID NO: 313 and SEQ ID NO: 117; and the amino acid sequences of SEQ ID NO: 117 and SEQ ID NO: 117. The amino acid sequences of SEQ ID NO: 117; SEQ ID NO: 314 and SEQ ID NO: 117; SEQ ID NO: 315 and SEQ ID NO: 117; SEQ ID NO: 316 and SEQ ID NO: 117; SEQ ID NO: 317 and SEQ ID NO: 117; SEQ ID NO: 1 and SEQ ID NO: 119; SEQ ID NO: 2 and SEQ ID NO: 119; SEQ ID NO: 3 and SEQ ID NO: 119; SEQ ID NO: 4 and SEQ ID NO: 119; SEQ ID NO: 5 and SEQ ID NO: 119; SEQ ID NO: 6 and SEQ ID NO: 119; SEQ ID NO: The amino acid sequences of SEQ ID NO: 7 and SEQ ID NO: 119; the amino acid sequences of SEQ ID NO: 8 and SEQ ID NO: 119; the amino acid sequences of SEQ ID NO: 307 and SEQ ID NO: 119;The amino acid sequences of SEQ ID NO: 308 and SEQ ID NO: 119; the amino acid sequences of SEQ ID NO: 309 and SEQ ID NO: 119; the amino acid sequences of SEQ ID NO: 310 and SEQ ID NO: 119; the amino acid sequences of SEQ ID NO: 311 and SEQ ID NO: 119; the amino acid sequences of SEQ ID NO: 312 and SEQ ID NO: 119; the amino acid sequences of SEQ ID NO: 313 and SEQ ID NO: 119; the amino acid sequences of SEQ ID NO: 314 and SEQ ID NO: 119; the amino acid sequences of SEQ ID NO: 315 and SEQ ID NO: 119; the amino acid sequences of SEQ ID NO: 316 and SEQ ID NO: 119; the amino acid sequences of SEQ ID NO: 317 and SEQ ID NO: 119; SEQ ID NO: The amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 121; the amino acid sequences of SEQ ID NO: 2 and SEQ ID NO: 121; the amino acid sequences of SEQ ID NO: 3 and SEQ ID NO: 121; the amino acid sequences of SEQ ID NO: 4 and SEQ ID NO: 121; the amino acid sequences of SEQ ID NO: 5 and SEQ ID NO: 121; the amino acid sequences of SEQ ID NO: 6 and SEQ ID NO: 121; the amino acid sequences of SEQ ID NO: 7 and SEQ ID NO: 121; the amino acid sequences of SEQ ID NO: 8 and SEQ ID NO: 121; the amino acid sequences of SEQ ID NO: 307 and SEQ ID NO: 121; the amino acid sequences of SEQ ID NO: 308 and SEQ ID NO: 121; the amino acid sequences of SEQ ID NO: 309 and SEQ ID NO: 121; SEQ ID The amino acid sequences of SEQ ID NO: 310 and SEQ ID NO: 121; the amino acid sequences of SEQ ID NO: 311 and SEQ ID NO: 121; the amino acid sequences of SEQ ID NO: 312 and SEQ ID NO: 121;The amino acid sequences of SEQ ID NO: 313 and SEQ ID NO: 121; the amino acid sequences of SEQ ID NO: 314 and SEQ ID NO: 121; the amino acid sequences of SEQ ID NO: 315 and SEQ ID NO: 121; the amino acid sequences of SEQ ID NO: 316 and SEQ ID NO: 121; the amino acid sequences of SEQ ID NO: 317 and SEQ ID NO: 121; the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 123; the amino acid sequences of SEQ ID NO: 2 and SEQ ID NO: 123; the amino acid sequences of SEQ ID NO: 3 and SEQ ID NO: 123; the amino acid sequences of SEQ ID NO: 4 and SEQ ID NO: 123; the amino acid sequences of SEQ ID NO: 5 and SEQ ID NO: 123; the amino acid sequences of SEQ ID NO: 6 and SEQ ID NO: 123; the amino acid sequences of SEQ ID NO: 314 and SEQ ID NO: 121; the amino acid sequences of SEQ ID NO: 315 and SEQ ID NO: 121; the amino acid sequences of SEQ ID NO: 316 and SEQ ID NO: 121; the amino acid sequences of SEQ ID NO: 317 and SEQ ID NO: 121; the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 123; the amino acid sequences of SEQ ID NO: 314 and SEQ ID NO: 121; the amino acid sequences of SEQ ID NO: 315 and SEQ ID NO: 121; the amino acid sequences of SEQ ID NO: 316 and SEQ ID NO: 123; the amino acid sequences of SEQ ID NO: 317 and SEQ ID NO: 121; the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 123; the amino Amino acid sequences of SEQ ID NO: 123; amino acid sequences of SEQ ID NO: 7 and SEQ ID NO: 123; amino acid sequences of SEQ ID NO: 8 and SEQ ID NO: 123; amino acid sequences of SEQ ID NO: 307 and SEQ ID NO: 123; amino acid sequences of SEQ ID NO: 308 and SEQ ID NO: 123; amino acid sequences of SEQ ID NO: 309 and SEQ ID NO: 123; amino acid sequences of SEQ ID NO: 310 and SEQ ID NO: 123; amino acid sequences of SEQ ID NO: 311 and SEQ ID NO: 123; amino acid sequences of SEQ ID NO: 312 and SEQ ID NO: 123; amino acid sequences of SEQ ID NO: 313 and SEQ ID NO: 123; amino acid sequences of SEQ ID NO: 314 and SEQ ID NO: 123; SEQ ID The amino acid sequences of SEQ ID NO: 315 and SEQ ID NO: 123; the amino acid sequences of SEQ ID NO: 316 and SEQ ID NO: 123; the amino acid sequences of SEQ ID NO: 317 and SEQ ID NO: 123;The amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 125; the amino acid sequences of SEQ ID NO: 2 and SEQ ID NO: 125; the amino acid sequences of SEQ ID NO: 3 and SEQ ID NO: 125; the amino acid sequences of SEQ ID NO: 4 and SEQ ID NO: 125; the amino acid sequences of SEQ ID NO: 5 and SEQ ID NO: 125; the amino acid sequences of SEQ ID NO: 6 and SEQ ID NO: 125; the amino acid sequences of SEQ ID NO: 7 and SEQ ID NO: 125; the amino acid sequences of SEQ ID NO: 8 and SEQ ID NO: 125; the amino acid sequences of SEQ ID NO: 307 and SEQ ID NO: 125; the amino acid sequences of SEQ ID NO: 308 and SEQ ID NO: 125; the amino acid sequences of SEQ ID NO: 309 and SEQ ID NO: 125; and the amino acid sequences of SEQ ID NO: 125 and SEQ ID NO: 125. The amino acid sequences of SEQ ID NO: 310 and SEQ ID NO: 125; SEQ ID NO: 311 and SEQ ID NO: 125; SEQ ID NO: 312 and SEQ ID NO: 125; SEQ ID NO: 313 and SEQ ID NO: 125; SEQ ID NO: 314 and SEQ ID NO: 125; SEQ ID NO: 315 and SEQ ID NO: 125; SEQ ID NO: 316 and SEQ ID NO: 125; SEQ ID NO: 317 and SEQ ID NO: 125; SEQ ID NO: 1 and SEQ ID NO: 127; SEQ ID NO: 2 and SEQ ID NO: 127; SEQ ID NO: 127; SEQ ID NO: 125 ... The amino acid sequences of SEQ ID NO: 3 and SEQ ID NO: 127; the amino acid sequences of SEQ ID NO: 4 and SEQ ID NO: 127; the amino acid sequences of SEQ ID NO: 5 and SEQ ID NO: 127;The amino acid sequences of SEQ ID NO: 6 and SEQ ID NO: 127; the amino acid sequences of SEQ ID NO: 7 and SEQ ID NO: 127; the amino acid sequences of SEQ ID NO: 8 and SEQ ID NO: 127; the amino acid sequences of SEQ ID NO: 307 and SEQ ID NO: 127; the amino acid sequences of SEQ ID NO: 308 and SEQ ID NO: 127; the amino acid sequences of SEQ ID NO: 309 and SEQ ID NO: 127; the amino acid sequences of SEQ ID NO: 310 and SEQ ID NO: 127; the amino acid sequences of SEQ ID NO: 311 and SEQ ID NO: 127; the amino acid sequences of SEQ ID NO: 312 and SEQ ID NO: 127; the amino acid sequences of SEQ ID NO: 313 and SEQ ID NO: 127; the amino acid sequences of SEQ ID NO: 314 and SEQ ID NO: 127; the amino acid sequences of SEQ ID NO: 314 and SEQ ID NO: 127; the amino acid sequences of SEQ ID NO: 315 and SEQ ID NO: 127; the amino acid sequences of SEQ ID NO: 316 and SEQ ID NO: 127; the amino acid sequences of SEQ ID NO: 317 ... The amino acid sequences of SEQ ID NO: 127; SEQ ID NO: 315 and SEQ ID NO: 127; SEQ ID NO: 316 and SEQ ID NO: 127; SEQ ID NO: 317 and SEQ ID NO: 127; SEQ ID NO: 1 and SEQ ID NO: 129; SEQ ID NO: 2 and SEQ ID NO: 129; SEQ ID NO: 3 and SEQ ID NO: 129; SEQ ID NO: 4 and SEQ ID NO: 129; SEQ ID NO: 5 and SEQ ID NO: 129; SEQ ID NO: 6 and SEQ ID NO: 129; SEQ ID NO: 7 and SEQ ID NO: 129; SEQ ID NO: The amino acid sequences of SEQ ID NO: 8 and SEQ ID NO: 129; the amino acid sequences of SEQ ID NO: 307 and SEQ ID NO: 129; the amino acid sequences of SEQ ID NO: 308 and SEQ ID NO: 129;The amino acid sequences of SEQ ID NO: 309 and SEQ ID NO: 129; the amino acid sequences of SEQ ID NO: 310 and SEQ ID NO: 129; the amino acid sequences of SEQ ID NO: 311 and SEQ ID NO: 129; the amino acid sequences of SEQ ID NO: 312 and SEQ ID NO: 129; the amino acid sequences of SEQ ID NO: 313 and SEQ ID NO: 129; the amino acid sequences of SEQ ID NO: 314 and SEQ ID NO: 129; the amino acid sequences of SEQ ID NO: 315 and SEQ ID NO: 129; the amino acid sequences of SEQ ID NO: 316 and SEQ ID NO: 129; the amino acid sequences of SEQ ID NO: 317 and SEQ ID NO: 129; the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 131; SEQ ID NO: The amino acid sequences of SEQ ID NO: 2 and SEQ ID NO: 131; the amino acid sequences of SEQ ID NO: 3 and SEQ ID NO: 131; the amino acid sequences of SEQ ID NO: 4 and SEQ ID NO: 131; the amino acid sequences of SEQ ID NO: 5 and SEQ ID NO: 131; the amino acid sequences of SEQ ID NO: 6 and SEQ ID NO: 131; the amino acid sequences of SEQ ID NO: 7 and SEQ ID NO: 131; the amino acid sequences of SEQ ID NO: 8 and SEQ ID NO: 131; the amino acid sequences of SEQ ID NO: 307 and SEQ ID NO: 131; the amino acid sequences of SEQ ID NO: 308 and SEQ ID NO: 131; the amino acid sequences of SEQ ID NO: 309 and SEQ ID NO: 131; the amino acid sequences of SEQ ID NO: 310 and SEQ ID NO: 131; SEQ The amino acid sequences of SEQ ID NO: 311 and SEQ ID NO: 131; the amino acid sequences of SEQ ID NO: 312 and SEQ ID NO: 131; the amino acid sequences of SEQ ID NO: 313 and SEQ ID NO: 131;The amino acid sequences of SEQ ID NO: 314 and SEQ ID NO: 131; the amino acid sequences of SEQ ID NO: 315 and SEQ ID NO: 131; the amino acid sequences of SEQ ID NO: 316 and SEQ ID NO: 131; the amino acid sequences of SEQ ID NO: 317 and SEQ ID NO: 131; the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 133; the amino acid sequences of SEQ ID NO: 2 and SEQ ID NO: 133; the amino acid sequences of SEQ ID NO: 3 and SEQ ID NO: 133; the amino acid sequences of SEQ ID NO: 4 and SEQ ID NO: 133; the amino acid sequences of SEQ ID NO: 5 and SEQ ID NO: 133; the amino acid sequences of SEQ ID NO: 6 and SEQ ID NO: 133; the amino acid sequences of SEQ ID NO: 7 and SEQ ID NO: 133; the amino acid sequences of SEQ ID NO: 13 ... Amino acid sequence of SEQ ID NO: 133; amino acid sequences of SEQ ID NO: 8 and SEQ ID NO: 133; amino acid sequences of SEQ ID NO: 307 and SEQ ID NO: 133; amino acid sequences of SEQ ID NO: 308 and SEQ ID NO: 133; amino acid sequences of SEQ ID NO: 309 and SEQ ID NO: 133; amino acid sequences of SEQ ID NO: 310 and SEQ ID NO: 133; amino acid sequences of SEQ ID NO: 311 and SEQ ID NO: 133; amino acid sequences of SEQ ID NO: 312 and SEQ ID NO: 133; amino acid sequences of SEQ ID NO: 313 and SEQ ID NO: 133; amino acid sequences of SEQ ID NO: 314 and SEQ ID NO: 133; amino acid sequences of SEQ ID NO: 315 and SEQ ID NO: 133; SEQ The amino acid sequences of SEQ ID NO: 316 and SEQ ID NO: 133; the amino acid sequences of SEQ ID NO: 317 and SEQ ID NO: 133; the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 135;The amino acid sequences of SEQ ID NO: 2 and SEQ ID NO: 135; the amino acid sequences of SEQ ID NO: 3 and SEQ ID NO: 135; the amino acid sequences of SEQ ID NO: 4 and SEQ ID NO: 135; the amino acid sequences of SEQ ID NO: 5 and SEQ ID NO: 135; the amino acid sequences of SEQ ID NO: 6 and SEQ ID NO: 135; the amino acid sequences of SEQ ID NO: 7 and SEQ ID NO: 135; the amino acid sequences of SEQ ID NO: 8 and SEQ ID NO: 135; the amino acid sequences of SEQ ID NO: 307 and SEQ ID NO: 135; the amino acid sequences of SEQ ID NO: 308 and SEQ ID NO: 135; the amino acid sequences of SEQ ID NO: 309 and SEQ ID NO: 135; the amino acid sequences of SEQ ID NO: 310 and SEQ ID NO: 135; the amino acid sequences of ... The amino acid sequences of SEQ ID NO: 135; SEQ ID NO: 311 and SEQ ID NO: 135; SEQ ID NO: 312 and SEQ ID NO: 135; SEQ ID NO: 313 and SEQ ID NO: 135; SEQ ID NO: 314 and SEQ ID NO: 135; SEQ ID NO: 315 and SEQ ID NO: 135; SEQ ID NO: 316 and SEQ ID NO: 135; SEQ ID NO: 317 and SEQ ID NO: 135; SEQ ID NO: 1 and SEQ ID NO: 137; SEQ ID NO: 2 and SEQ ID NO: 137; SEQ ID NO: 3 and SEQ ID NO: 137; SEQ ID NO: 137; SEQ ID NO: 3 The amino acid sequences of NO:4 and SEQ ID NO:137; the amino acid sequences of SEQ ID NO:5 and SEQ ID NO:137; the amino acid sequences of SEQ ID NO:6 and SEQ ID NO:137;The amino acid sequences of SEQ ID NO: 7 and SEQ ID NO: 137; the amino acid sequences of SEQ ID NO: 8 and SEQ ID NO: 137; the amino acid sequences of SEQ ID NO: 307 and SEQ ID NO: 137; the amino acid sequences of SEQ ID NO: 308 and SEQ ID NO: 137; the amino acid sequences of SEQ ID NO: 309 and SEQ ID NO: 137; the amino acid sequences of SEQ ID NO: 310 and SEQ ID NO: 137; the amino acid sequences of SEQ ID NO: 311 and SEQ ID NO: 137; the amino acid sequences of SEQ ID NO: 312 and SEQ ID NO: 137; the amino acid sequences of SEQ ID NO: 313 and SEQ ID NO: 137; the amino acid sequences of SEQ ID NO: 314 and SEQ ID NO: 137; SEQ ID NO: The amino acid sequences of SEQ ID NO: 315 and SEQ ID NO: 137; the amino acid sequences of SEQ ID NO: 316 and SEQ ID NO: 137; the amino acid sequences of SEQ ID NO: 317 and SEQ ID NO: 137; the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 376; the amino acid sequences of SEQ ID NO: 2 and SEQ ID NO: 376; the amino acid sequences of SEQ ID NO: 3 and SEQ ID NO: 376; the amino acid sequences of SEQ ID NO: 4 and SEQ ID NO: 376; the amino acid sequences of SEQ ID NO: 5 and SEQ ID NO: 376; the amino acid sequences of SEQ ID NO: 6 and SEQ ID NO: 376; the amino acid sequences of SEQ ID NO: 7 and SEQ ID NO: 376; the amino acid sequences of SEQ ID NO: 8 and SEQ ID NO: 376; SEQ ID The amino acid sequences of SEQ ID NO: 307 and SEQ ID NO: 376; the amino acid sequences of SEQ ID NO: 308 and SEQ ID NO: 376; the amino acid sequences of SEQ ID NO: 309 and SEQ ID NO: 376;The amino acid sequences of SEQ ID NO: 310 and SEQ ID NO: 376; the amino acid sequences of SEQ ID NO: 311 and SEQ ID NO: 376; the amino acid sequences of SEQ ID NO: 312 and SEQ ID NO: 376; the amino acid sequences of SEQ ID NO: 313 and SEQ ID NO: 376; the amino acid sequences of SEQ ID NO: 314 and SEQ ID NO: 376; the amino acid sequences of SEQ ID NO: 315 and SEQ ID NO: 376; the amino acid sequences of SEQ ID NO: 316 and SEQ ID NO: 376; the amino acid sequences of SEQ ID NO: 317 and SEQ ID NO: 376; the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 378; the amino acid sequences of SEQ ID NO: 2 and SEQ ID NO: 378; SEQ ID NO: The amino acid sequences of SEQ ID NO: 3 and SEQ ID NO: 378; SEQ ID NO: 4 and SEQ ID NO: 378; SEQ ID NO: 5 and SEQ ID NO: 378; SEQ ID NO: 6 and SEQ ID NO: 378; SEQ ID NO: 7 and SEQ ID NO: 378; SEQ ID NO: 8 and SEQ ID NO: 378; SEQ ID NO: 307 and SEQ ID NO: 378; SEQ ID NO: 308 and SEQ ID NO: 378; SEQ ID NO: 309 and SEQ ID NO: 378; SEQ ID NO: 310 and SEQ ID NO: 378; SEQ ID NO: 311 and SEQ ID NO: The amino acid sequences of SEQ ID NO: 378; SEQ ID NO: 312 and SEQ ID NO: 378; SEQ ID NO: 313 and SEQ ID NO: 378; SEQ ID NO: 314 and SEQ ID NO: 378;The amino acid sequences of SEQ ID NO: 315 and SEQ ID NO: 378; the amino acid sequences of SEQ ID NO: 316 and SEQ ID NO: 378; the amino acid sequences of SEQ ID NO: 317 and SEQ ID NO: 378.

[0036] In some embodiments, the second polypeptide comprises: (i) an amino acid sequence that is at least 90% identical to SEQ ID NO: 104; (ii) an amino acid sequence that is at least 90% identical to SEQ ID NO: 106; (iii) an amino acid sequence that is at least 90% identical to SEQ ID NO: 108; (iv) an amino acid sequence that is at least 90% identical to SEQ ID NO: 110; (v) an amino acid sequence that is at least 90% identical to SEQ ID NO: 209, at least 90% identical to SEQ ID NO: 210, and at least 90% identical to SEQ ID NO: 106; (vi) an amino acid sequence that is at least 90% identical to SEQ ID NO: 114; (vii) an amino acid sequence that is at least 90% identical to SEQ ID NO: 116; (viii) an amino acid sequence that is at least 90% identical to SEQ ID NO: 118; (ix) an amino acid sequence that is at least 90% identical to SEQ ID NO: 120; (x) an amino acid sequence that is at least 90% identical to SEQ ID NO: 104 ...06; (viii) an amino acid sequence that is at least 90% identical to SEQ ID NO: 118; (ix) an amino acid sequence that is at least 90% identical to SEQ ID NO: 120; (viii) an amino acid sequence that is at least 90% identical to SEQ ID NO: 114; The amino acid sequence that is at least 90% identical to SEQ ID NO: 122; (xi) the amino acid sequence that is at least 90% identical to SEQ ID NO: 124; (xii) the amino acid sequence that is at least 90% identical to SEQ ID NO: 126; (xiii) the amino acid sequence that is at least 90% identical to SEQ ID NO: 128; (xiv) the amino acid sequence that is at least 90% identical to SEQ ID NO: 130; (xv) the amino acid sequence that is at least 90% identical to SEQ ID NO: 132; (xvi) the amino acid sequence that is at least 90% identical to SEQ ID NO: 134; (xvii) the amino acid sequence that is at least 90% identical to SEQ ID NO: 136; (xviii) the amino acid sequence that is at least 90% identical to SEQ ID NO: 138; (xix) the amino acid sequence that is at least 90% identical to SEQ ID NO: 377; or (xx) the amino acid sequence that is at least 90% identical to SEQ ID NO: 379.

[0037] In some embodiments, the second polypeptide comprises: (i) the amino acid sequence of SEQ ID NO: 104; (ii) the amino acid sequence of SEQ ID NO: 106; (iii) the amino acid sequence of SEQ ID NO: 108; (iv) the amino acid sequence of SEQ ID NO: 110; (v) the amino acid sequences of SEQ ID NO: 209, SEQ ID NO: 210, and SEQ ID NO: 106; (vi) the amino acid sequence of SEQ ID NO: 114; (vii) the amino acid sequence of SEQ ID NO: 116; (viii) the amino acid sequence of SEQ ID NO: 118; (ix) the amino acid sequence of SEQ ID NO: 120; (x) the amino acid sequence of SEQ ID NO: 122; (xi) the amino acid sequence of SEQ ID NO: 124; (xii) the amino acid sequence of SEQ ID NO: 126; (xiii) the amino acid sequence of SEQ ID NO: Amino acid sequence of SEQ ID NO: 128; (xiv) amino acid sequence of SEQ ID NO: 130; (xv) amino acid sequence of SEQ ID NO: 132; (xvi) amino acid sequence of SEQ ID NO: 134; (xvii) amino acid sequence of SEQ ID NO: 136; (xviii) amino acid sequence of SEQ ID NO: 138; (xix) amino acid sequence of SEQ ID NO: 377; or (xx) amino acid sequence of SEQ ID NO: 379.

[0038] In some embodiments, (i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 211, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 218; (ii) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 212, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 219; (iii) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 213, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 220; (iv) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 214, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 221; (v) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 215, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 222; (vi) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 216, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 223; (vii) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 217, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 218. (viii) The first polypeptide contains the amino acid sequence of SEQ ID NO: 225, and the second polypeptide contains the amino acid sequence of SEQ ID NO: 228; (ix) The first polypeptide contains the amino acid sequence of SEQ ID NO: 226, and the second polypeptide contains the amino acid sequence of SEQ ID NO: 229; (x) The first polypeptide contains the amino acid sequence of SEQ ID NO: 227, and the second polypeptide contains the amino acid sequence of SEQ ID NO: 230; (xi) The first polypeptide contains the amino acid sequence of SEQ ID NO: 231, and the second polypeptide contains the amino acid sequence of SEQ ID NO: 238; (xii) The first polypeptide contains the amino acid sequence of SEQ ID NO: 232, and the second polypeptide contains the amino acid sequence of SEQ ID NO: 239; (xiiii) The first polypeptide contains the amino acid sequence of SEQ ID NO: 233, and the second polypeptide contains the amino acid sequence of SEQ ID NO: 240; (xiv) The first polypeptide contains the amino acid sequence of SEQ ID NO: 234, and the second polypeptide contains the amino acid sequence of SEQ ID NO: 229. (xv) The first polypeptide contains the amino acid sequence of SEQ ID NO: 235, and the second polypeptide contains the amino acid sequence of SEQ ID NO: 242; (xvi) The first polypeptide contains the amino acid sequence of SEQ ID NO: 236, and the second polypeptide contains the amino acid sequence of SEQ ID NO: 243.(xvii) The first polypeptide contains the amino acid sequence of SEQ ID NO: 237, and the second polypeptide contains the amino acid sequence of SEQ ID NO: 244; (xviii) The first polypeptide contains the amino acid sequence of SEQ ID NO: 245, and the second polypeptide contains the amino acid sequence of SEQ ID NO: 248; (xix) The first polypeptide contains the amino acid sequence of SEQ ID NO: 246, and the second polypeptide contains the amino acid sequence of SEQ ID NO: 249; (xx) The first polypeptide contains the amino acid sequence of SEQ ID NO: 247, and the second polypeptide contains the amino acid sequence of SEQ ID NO: 250; (xxi) The first polypeptide contains the amino acid sequence of SEQ ID NO: 318, and the second polypeptide contains the amino acid sequence of SEQ ID NO: 332; (xxi) The first polypeptide contains the amino acid sequence of SEQ ID NO: 319, and the second polypeptide contains the amino acid sequence of SEQ ID NO: 333; (xxii) The first polypeptide contains the amino acid sequence of SEQ ID NO: 320, and the second polypeptide contains the amino acid sequence of SEQ ID NO: 244. (xxii) The first polypeptide contains the amino acid sequence of SEQ ID NO: 321, and the second polypeptide contains the amino acid sequence of SEQ ID NO: 335; (xxiv) The first polypeptide contains the amino acid sequence of SEQ ID NO: 322, and the second polypeptide contains the amino acid sequence of SEQ ID NO: 336; (xxv) The first polypeptide contains the amino acid sequence of SEQ ID NO: 323, and the second polypeptide contains the amino acid sequence of SEQ ID NO: 337; (xxvi) The first polypeptide contains the amino acid sequence of SEQ ID NO: 324, and the second polypeptide contains the amino acid sequence of SEQ ID NO: 338; (xxvii) The first polypeptide contains the amino acid sequence of SEQ ID NO: 325, and the second polypeptide contains the amino acid sequence of SEQ ID NO: 339; (xxviii) The first polypeptide contains the amino acid sequence of SEQ ID NO: 326, and the second polypeptide contains the amino acid sequence of SEQ ID NO: 340; (xxix) The first polypeptide contains the amino acid sequence of SEQ ID NO: 327, and the second polypeptide contains the amino acid sequence of SEQ ID NO: 339. The amino acid sequence of SEQ ID NO: 341; (xxx) the first polypeptide contains the amino acid sequence of SEQ ID NO: 329 and the second polypeptide contains the amino acid sequence of SEQ ID NO: 343; (xxxi) the first polypeptide contains the amino acid sequence of SEQ ID NO: 330 and the second polypeptide contains the amino acid sequence of SEQ ID NO: 344;(xxxii) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 331, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 345; (xxxiii) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 346, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 360; (xxxiv) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 347, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 361; (xxxv) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 348, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 362; (xxxvi) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 349, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 363; (xxxvii) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 350, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 364; (xxxviii) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 351, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 364. The amino acid sequence of SEQ ID NO: 365; (xxxix) the first polypeptide contains the amino acid sequence of SEQ ID NO: 352 and the second polypeptide contains the amino acid sequence of SEQ ID NO: 366; (xl) the first polypeptide contains the amino acid sequence of SEQ ID NO: 353 and the second polypeptide contains the amino acid sequence of SEQ ID NO: 367; (xli) the first polypeptide contains the amino acid sequence of SEQ ID NO: 350 and the second polypeptide contains the amino acid sequence of SEQ ID NO: 368; (xlii) the first polypeptide contains the amino acid sequence of SEQ ID NO: 355 and the second polypeptide contains the amino acid sequence of SEQ ID NO: 369; (xliii) the first polypeptide contains the amino acid sequence of SEQ ID NO: 356 and the second polypeptide contains the amino acid sequence of SEQ ID NO: 370; (xliv) the first polypeptide contains the amino acid sequence of SEQ ID NO: 357 and the second polypeptide contains the amino acid sequence of SEQ ID NO: 371; (xlv) the first polypeptide contains the amino acid sequence of SEQ ID NO: 358 and the second polypeptide contains the amino acid sequence of SEQ ID NO: 369. The amino acid sequence of SEQ ID NO: 372; or (xlvi) the first polypeptide contains the amino acid sequence of SEQ ID NO: 359, and the second polypeptide contains the amino acid sequence of SEQ ID NO: 373.

[0039] In some embodiments, the molecule further comprises an antigen-binding domain. In some embodiments, the antigen-binding domain is covalently linked to a second Fc domain. In some embodiments, the C-terminus of the antigen-binding domain is covalently linked to the N-terminus of the second Fc domain. In some embodiments, the N-terminus of the antigen-binding domain is covalently linked to the C-terminus of the second Fc domain. In some embodiments, the antigen-binding domain is covalently linked to a first Fc domain. In some embodiments, the C-terminus of the antigen-binding domain is covalently linked to the N-terminus of the first Fc domain. In some embodiments, the N-terminus of the antigen-binding domain is covalently linked to the C-terminus of the first Fc domain. In some embodiments, the antigen-binding domain is selected from the group consisting of: Fab, Fab', Fab'2, Fab2, Fab3, F(ab')2, Fd, Fv, sdAb, scFv, SMIP, biantibody, triantibody, tetraantibody, microantibody, nanobody, macrobody, tandab, DVD, BiTe, TandAb, or any combination thereof. In some embodiments, the antigen-binding domain binds to an internalization receptor expressed on the cell surface. In some embodiments, the internalization receptor is selected from the group consisting of FcγRIIB, FcRn, ASGPR, CD38, SLAMF7, GPCR5D, and BCMA. In some embodiments, the internalization receptor is ASGPR. In some embodiments, the antigen-binding domain comprises Fab. In some embodiments, Fab comprises an antibody heavy chain sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 209 and an antibody light chain sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 210. In some embodiments, Fab comprises the antibody heavy chain sequence of SEQ ID NO: 209 and the antibody light chain sequence of SEQ ID NO: 210.

[0040] In some embodiments, the second Fc domain further includes a second autoantibody-binding domain. In some embodiments, the N-terminus of the second Fc domain is covalently linked to the C-terminus of the second autoantibody-binding domain. In some embodiments, the C-terminus of the second Fc domain is covalently linked to the C-terminus of the second autoantibody-binding domain. In some embodiments, the second autoantibody-binding domain binds to an anti-TSHR autoantibody.

[0041] In some embodiments, when administered to a subject, the molecule is able to selectively deplete anti-TSHR autoantibodies bound to the autoantibody-binding domain. In some embodiments, anti-TSHR autoantibodies bound to the autoantibody-binding domain are selectively depleted by uptake into cells and shuttle transport of the autoantibody to lysosomes for degradation.

[0042] In some implementations, the second polypeptide does not contain an autoantibody-binding domain that binds to the anti-TSHR autoantibody.

[0043] In another aspect, this disclosure provides a nucleic acid comprising a nucleotide sequence encoding a molecule of this disclosure.

[0044] In another aspect, this disclosure provides a host cell containing nucleic acids, said nucleic acids comprising nucleotide sequences encoding molecules of the present disclosure.

[0045] In another aspect, this disclosure provides a vector comprising nucleic acid containing a nucleotide sequence encoding a molecule of the present disclosure. In some embodiments, the vector comprises a viral vector. In some embodiments, the viral vector includes a retroviral vector, a lentiviral vector, an adeno-associated virus (AAV) vector, or an adenovirus vector.

[0046] In another aspect, this disclosure provides a pharmaceutical composition comprising a nucleic acid of a molecule or encoding molecule of this disclosure and a pharmaceutically acceptable carrier.

[0047] In another aspect, this disclosure provides a method for preparing the molecules of this disclosure, the method comprising expressing a nucleic acid comprising a nucleotide sequence encoding a molecule in a host cell, and recovering the molecule.

[0048] In another aspect, this disclosure provides a method for treating a subject who has or is susceptible to an autoimmune disease, the method comprising administering to the subject a pharmaceutical composition comprising a molecule of this disclosure or a nucleic acid encoding said molecule. In some embodiments, the autoimmune disease is Graves' disease (GD), thyroid ophthalmopathy, or another autoimmune disease involving anti-TSHR autoantibodies.

[0049] In another aspect, this disclosure provides a method of treating a subject suffering from or susceptible to an autoimmune disease, the method comprising: administering to the subject a first pharmaceutical composition comprising a molecule of this disclosure or a nucleic acid encoding said molecule; and administering to the subject a second pharmaceutical composition, the second pharmaceutical composition selectively depleting plasma cells generating autoantibodies targeted by an autoantibody-binding domain. In some embodiments, the autoimmune disease is Graves' disease (GD), thyroid ophthalmopathy, or another autoimmune disease involving anti-TSHR autoantibodies. In some embodiments, the first pharmaceutical composition is administered before the second pharmaceutical composition. In some embodiments, the first pharmaceutical composition is administered after the second pharmaceutical composition. In some embodiments, the first pharmaceutical composition and the second pharmaceutical composition are administered together.

[0050] In some embodiments, the level of anti-TSHR autoantibodies in the subject or in a biological sample from the subject is reduced relative to the pre-administration level after administration. In some embodiments, the level of anti-TSHR autoantibodies is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% relative to the pre-administration level. In some embodiments, the reduced anti-TSHR autoantibody level persists over time. In some embodiments, the duration of persistence includes at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 10 weeks, 12 weeks, or longer. In some embodiments, the pharmaceutical composition is administered to the subject intravenously, intramuscularly, or subcutaneously. In some embodiments, the subject is a human being.

[0051] In another aspect, this disclosure provides a method for selectively depleting anti-TSHR autoantibodies in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a molecule of this disclosure or a nucleic acid encoding the molecule.

[0052] In another aspect, this disclosure provides a method for treating a human subject who has or is susceptible to Graves' disease (GD), thyroid eye disease, or another autoimmune disease involving anti-TSHR autoantibodies, the method comprising administering to the subject a pharmaceutical composition comprising a molecule of this disclosure or a nucleic acid encoding the molecule.

[0053] In another aspect, this disclosure provides a pharmaceutical composition comprising: a molecule of this disclosure or a nucleic acid encoding the molecule; a molecule of plasma cells that selectively depletes autoantibodies targeted by an autoantibody-binding domain or a nucleic acid encoding the molecule; and a pharmaceutically acceptable carrier.

[0054] In another aspect, this disclosure provides a composition for reducing the titer of anti-TSHR autoantibodies in the serum of a subject in need, the composition comprising: a plurality of molecules, each molecule comprising (a) a first polypeptide comprising a first Fc domain and an autoantibody-binding domain that binds to an anti-TSHR autoantibody; and (b) a second polypeptide comprising a second Fc domain, wherein the first Fc domain and the second Fc domain form a homodimer or heterodimer of the first polypeptide and the second polypeptide; wherein the first and / or second Fc domain comprises one or more mutant amino acid residues. Furthermore, it exhibits increased binding affinity for FcγRIIB relative to the corresponding wild-type Fc domain, and wherein, upon administration of the plurality of molecules, the molecules bind to anti-TSHR autoantibodies to form an immune complex comprising two molecules bound to the anti-TSHR autoantibody; and wherein the immune complex binds to and is internalized by FcγRIIB expressed on the surface of hepatic sinusoidal endothelial cells (LSEC) with higher affinity, thereby reducing the titer of anti-TSHR autoantibodies in the subject's serum; wherein the higher affinity is relative to the immune complex comprising two corresponding molecules having wild-type Fc domains.

[0055] In another aspect, this disclosure provides an immune complex comprising an anti-TSHR autoantibody and two molecules of this disclosure, wherein the immune complex has enhanced binding kinetics with FcγRIIB relative to an immune complex comprising an anti-TSHR autoantibody that binds to two corresponding molecules having a wild-type Fc domain.

[0056] In another aspect, this disclosure provides an immune complex comprising: (i) an anti-TSHR autoantibody; and (ii) two molecules, each molecule comprising: a first polypeptide comprising a first Fc domain and an autoantibody-binding domain that binds to the anti-TSHR autoantibody; and a second polypeptide comprising a second Fc domain; wherein the first Fc domain and the second Fc domain form a homodimer or heterodimer of the first polypeptide and the second polypeptide; wherein the first and / or second Fc domain comprises one or more mutant amino acid residues and has increased binding affinity for FcγRIIB relative to the corresponding wild-type Fc domain; and wherein the immune complex has enhanced binding kinetics with FcγRIIB relative to an immune complex comprising an anti-TSHR autoantibody that binds to two corresponding molecules having a wild-type Fc domain. In some embodiments, the immune complex has enhanced binding kinetics with FcγRIIB relative to an immune complex comprising an anti-TSHR autoantibody and only a single molecule. In some embodiments, the immune complex has enhanced binding kinetics with FcγRIIB relative to an anti-TSHR autoantibody alone. In some implementations, the autoantibody-binding domain of each of the two molecules binds to the anti-TSHR autoantibody.

[0057] In some implementations, enhanced binding kinetics include an increase in association rate, a decrease in dissociation rate, and / or a change in the equilibrium dissociation constant.

[0058] In some implementations, enhanced binding kinetics result in increased affinity, stability, strength, frequency, and / or duration of the binding between the immune complex and FcγRIIB.

[0059] In some embodiments, the first and / or second Fc domains containing one or more mutant amino acid residues do not have increased binding affinity for FcγRI, FcγRIIA167H, FcγRIIA167R, FcγRIIIA176F, FcγRIIIA176V, FcγRIIIB, FcγRIIIB, and / or FcRn relative to the corresponding wild-type Fc domains. In some embodiments, the first and / or second Fc domains containing one or more mutant amino acid residues have decreased binding affinity for FcγRI, FcγRIIA167H, FcγRIIA167R, FcγRIIIA176F, FcγRIIIA176V, FcγRIIIB, FcγRIIIB, and / or FcRn relative to the corresponding wild-type Fc domains. In some embodiments, the first and / or second Fc domains containing one or more mutant amino acid residues have negligible or no binding affinity for the corresponding wild-type Fc domains to FcγRI, FcγRIIA167H, FcγRIIA167R, FcγRIIIA176F, FcγRIIIA176V, FcγRIIIB, FcγRIIIB and / or FcRn.

[0060] In some embodiments, enhanced binding kinetics includes an immune complex binding affinity to FcγRIIB that is at least 10% higher. In some embodiments, a binding affinity that is at least 10% higher includes binding affinity of at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% or higher.

[0061] In some embodiments, binding affinity includes binding affinity to cell lines overexpressing FcγRIIB (e.g., CHO cell lines), measured by flow cytometry. In some embodiments, the immune complex preferentially binds to immune cells expressing FcγRIIB relative to immune cells expressing FcγRIIA. In some embodiments, the immune complex crosslinks FcγRIIB with B cell receptors on B cells. Attached Figure Description

[0062] Figure 1 This diagram illustrates an exemplary molecule described herein for selectively depleting autoantibodies targeted by an autoantibody-binding domain.

[0063] Figure 2 The exemplary molecular forms described herein are shown.

[0064] Figure 3 The exemplary molecular forms described herein are shown.

[0065] Figure 4 The exemplary molecular forms described herein are shown.

[0066] Figure 5 The exemplary molecular forms described herein are shown.

[0067] Figure 6 A- Figure 6 B shows the results from the binding assay using anti-TSHR autoantibodies M22 and K1-70 in Fab fragment form. Figure 6 A shows that using single-cycle kinetics at pH 7.4, M22 binds to TSHR260 variants 2P, 2P2R, and 2P1S. Figure 6 A shows that using single-cycle kinetics at pH 7.4, K1-70 binds to TSHR260 variants 2P, 2P2R, and 2P1S.

[0068] Figure 7 Results from binding assays using anti-TSHR autoantibodies M22, K1-70, CS-17, and K1-18 in full-length IgG form are shown. The results indicate that, using multi-cycle kinetics at pH 7.4, M22, K1-70, CS-17, and K1-18 bind to the TSHR260 variants 2P2R (variants D3 and E3) fused to various Fc domains.

[0069] Figure 8 A illustrates an exemplary mechanism by which anti-TSHR autoantibodies stimulate cAMP production in cells.

[0070] Figure 8 B shows the results from cAMP assays after adding increasing concentrations of agonists (M22, K1-18, and TSH).

[0071] Figure 9 Results from cAMP assays are shown after administration of an exemplary molecule (variant D3) alone, with anti-TSHR autoantibody (M22), or with TSH.

[0072] Figure 10 Results from cAMP assays are shown after administration of the exemplary molecule (variant D3) alone or in combination with anti-TSHR autoantibodies (M22 or K1-18).

[0073] Figure 11 Results from cAMP assays are shown using healthy donor serum or patient serum samples containing anti-TSHR autoantibodies, with and without the exemplary molecule (variant D3).

[0074] Figure 12 A- Figure 12B shows results from a cAMP assay, where the exemplary molecule (variant D3) reduced serum levels in a single patient sample. Figure 12 A) and combined patient serum samples ( Figure 12 TSHR activity in B) (measured via downstream cAMP activity).

[0075] Figure 13 A- Figure 13 D illustrates some exemplary mechanisms of action of molecules described herein that contain mutations in the Fc domain to increase affinity for FcγRIIB, including neutralization of autoantibodies ( Figure 13 A) Clearing autoantibodies by targeting FcγRIIB isotype 2 on hepatic sinusoidal endothelial cells. Figure 13 B) Targeting pathogenic B cells that produce target autoantibodies (e.g., anti-TSHR autoantibodies) by directing FcγRIIB isotype 1 to the B cell receptor (BCR) (which leads to B cell apoptosis and inhibition). Figure 13 C) and bind to FcγRIIB on T cells and prevent T cell activation ( Figure 13 D).

[0076] Figure 14 A- Figure 14 D shows the results from a binding assay that measures trastuzumab control (when the exemplary molecule is captured onto the SPR sensor chip and FcγR is used as the analyte). Figure 14 A) Variant B3 ( Figure 14 B) Variant D3 ( Figure 14 C) and variant E3 ( Figure 14 D) Binding activity with the activating receptor FcγRIIA167H.

[0077] Figure 15 A- Figure 15 D shows the results from a binding assay that measures trastuzumab control (when the exemplary molecule is captured onto the SPR sensor chip and FcγR is used as the analyte). Figure 15 A) Variant B3 ( Figure 15 B) Variant D3 ( Figure 15 C) and variant E3 ( Figure 15 D) Binding activity with the activating receptor FcγRIIA167R.

[0078] Figure 16 A- Figure 16 D shows the results from a binding assay that measures trastuzumab control (when the exemplary molecule is captured onto the SPR sensor chip and FcγR is used as the analyte). Figure 16 A) Variant B3 ( Figure 16 B) Variant D3 ( Figure 16 C) and variant E3 ( Figure 16 D) Binding activity with the inhibitory receptor FcγRIIB.

[0079] Figure 17 A- Figure 17 D shows the results from a binding assay that measures trastuzumab control (when His-labeled FcγR is captured onto the SPR sensor chip and the exemplary molecule is used as the analyte) Figure 17 A) Variant B3 ( Figure 17 B) Variant D3 ( Figure 17 C) and variant E3 ( Figure 17 D) Binding activity with the activating receptor FcγRIIA167H.

[0080] Figure 18 A- Figure 18 D shows the results from a binding assay that measures trastuzumab control (when His-labeled FcγR is captured onto the SPR sensor chip and the exemplary molecule is used as the analyte) Figure 18 A) Variant B3 ( Figure 18 B) Variant D3 ( Figure 18 C) and variant E3 ( Figure 18 D) Binding activity with the activating receptor FcγRIIA167R.

[0081] Figure 19 A- Figure 19 D shows the results from a binding assay that measures trastuzumab control (when His-labeled FcγR is captured onto the SPR sensor chip and the exemplary molecule is used as the analyte) Figure 19 A) Variant B3 ( Figure 19 B) Variant D3 ( Figure 19 C) and variant E3 ( Figure 19 D) Binding activity with the inhibitory receptor FcγRIIB.

[0082] Figure 20 A- Figure 20 B shows the results from ELISA, which demonstrates the binding of an exemplary molecule to C1q.

[0083] Figure 21Results from a binding assay are shown, which measures the binding of the TSHR autoantibody (M22) to CHO cells expressing FcγRIIB when M22 is pre-complexed with exemplary molecules such that most of M22 binds to two molecules (when molecules are added at a 4:1 molecule:M22 molar ratio) compared to when M22 primarily binds to one molecule (when molecules are added at a 1:1 molecule:M22 molar ratio). Results when anti-FcγRIIB blocking antibody 2B6 is included in the 4:1 assay are also shown.

[0084] Figure 22 A- Figure 22 B involves the expression of FcγRIIB protein in various immune cell types. Figure 22 A is adapted from Kerntke et al., (2020) Frontiers in immunology. 11: 489401, which is incorporated in this paper by reference and shows that B cells have high expression of FcγRIIB. Figure 22 B cells show that the immune complexes of M22 and the exemplary molecule bind most strongly to B cells and unlabeled cells. Unlabeled cells represent cells that are negative for CD16, CD19, CD56, and CD3 and therefore cannot be classified as monocytes, B cells, NK cells, or T cells. These cells can be non-classical monocytes or basophils.

[0085] Figure 23 A- Figure 23 B illustrates the binding of M22 pre-complexed with the exemplary molecule to cells expressing FcγRIIB: B cells ( Figure 23 A) and monocytes ( Figure 23 B). Results were also shown when anti-FcγRIIB blocking antibody 2B6 was included in the experiment.

[0086] Figure 24 A- Figure 24 B illustrates M22 and NK cells pre-complexed with an exemplary molecule ( Figure 24 A) and unlabeled cells ( Figure 24 The binding of B) is also shown. Results were also shown when anti-FcγRIIB blocking antibody 2B6 was included in the experiment.

[0087] Figure 25 Variant D3 did not bind strongly to CHO-FcγRIIB+ cells. In contrast, variant B3 bound to CHO-FcγRIIB+ cells at concentrations as low as 1 nM. Binding of variant D3 to CHO-FcγRIIB+ cells was only evident at 1 uM. Binding of variants B3 and D3 was completely blocked by 2B6 (an anti-FcγRIIB blocking antibody).

[0088] Figure 26 The illustration shows the binding of an exemplary molecule to a B cell.

[0089] Figure 27 A- Figure 27 B shows an exemplary molecule compared to a classic cell (CD14+). Figure 27 A) and unlabeled cells ( Figure 27 B) binding. Unlabeled cells represent cells that are negative for CD16, CD19, CD56, and CD3 and therefore cannot be classified as monocytes, B cells, NK cells, or T cells. These cells can be non-classical monocytes or basophils.

[0090] Figure 28 A- Figure 28 B illustrates the exemplary in vivo activity of the exemplary molecule described herein. Figure 28 A shows a schematic diagram of the administration of the exemplary molecule in wild-type BALB / c mice (M22 antibody was administered 1 day prior to administration of the exemplary molecule). Figure 28 B- Figure 28 C shows the serum concentration (ng / mL) of the M22 antibody as measured over time when different exemplary molecules were administered at t=0.

[0091] Figure 29 A- Figure 29 B illustrates the exemplary in vivo activity of the exemplary molecule described herein. Figure 29 A shows a schematic diagram of the administration of the exemplary molecule in wild-type BALB / c mice (M22 antibody was administered 1 day prior to administration of the exemplary molecule). Figure 29 B- Figure 29 C shows the serum concentration (ng / mL) of the exemplary molecule (“ASP”) measured over time when different exemplary molecules were administered at t=0.

[0092] Figure 30 A- Figure 30 B shows the results from the pK experiment, which measured the concentration (ng / mL) of the molecule (“ASP”) in serum over time. Figure 30 A) and the mean half-life of the molecule, where each point represents the median of 5 mice (wild-type BALB / c mice), and the bars represent SEM ( Figure 30 B).

[0093] Figure 31 A- Figure 31 C illustrates the exemplary in vivo activity of the exemplary molecule described herein. Figure 31 A shows a schematic diagram of the administration of an exemplary molecule in B-hFcRn mice (mice containing the human FcRn gene) (M22 antibody was administered 1 day prior to administration of the exemplary molecule). Figure 31 B- Figure 31 C shows the serum concentration (ng / mL) of the M22 antibody as measured over time when different exemplary molecules were administered at t=0.

[0094] Figure 32 A- Figure 32 C illustrates the exemplary in vivo activity of the exemplary molecule described herein. Figure 32 A shows a schematic diagram of the administration of an exemplary molecule in B-hFcRn mice (mice containing the human FcRn gene) (M22 antibody was administered 1 day prior to administration of the exemplary molecule). Figure 32 B- Figure 32 C shows the serum concentration (ng / mL) of the exemplary molecule (“ASP”) measured over time when different exemplary molecules were administered at t=0.

[0095] Figure 33 A- Figure 33 B shows the results from the pK experiment, which measured the concentration (ng / mL) of the molecule (“ASP”) in serum over time. Figure 33 A) and the mean half-life of the molecule, where each point represents the median of 5 mice (B-hFcRn), and the bars represent SEM ( Figure 33 B).

[0096] Figure 34 A- Figure 34 C illustrates the exemplary in vivo activity of the exemplary molecule described herein. Figure 34 A shows a schematic diagram of the administration of the exemplary molecule in huFcγR-huFcRn mice (mice containing the human FcRn and FcγR genes) (M22 antibody was administered 1 day prior to administration of the exemplary molecule). Figure 35 B- Figure 35 C shows the serum concentration (ng / mL) of the M22 antibody as measured over time when different exemplary molecules were administered at t=0.

[0097] Figure 35 A- Figure 35 C illustrates the exemplary in vivo activity of the exemplary molecule described herein. Figure 35 A shows a schematic diagram of the administration of the exemplary molecule in huFcγR-huFcRn mice (mice containing the human FcRn and FcγR genes) (M22 antibody was administered 1 day prior to administration of the exemplary molecule). Figure 35 B- Figure 35 C shows the serum concentration (ng / mL) of the exemplary molecule (“ASP”) measured over time when different exemplary molecules were administered at t=0.

[0098] Figure 36 A- Figure 36B shows the results from the pK experiment, which measured the concentration (ng / mL) of the molecule (“ASP”) in serum over time. Figure 36 A) and the average half-life of the molecules, where each point represents the median of 5 mice (huFcγR-huFcRn mice), and the bars represent SEM ( Figure 36 B).

[0099] Figure 37 Exemplary results from an experiment investigating the formation of immune complexes between an exemplary molecule (variant D3) and an M22 antibody are shown. The M22 antibody and the exemplary molecule were mixed in various proportions, and complex formation was evaluated by HPLC-SEC.

[0100] Figure 38 Exemplary results from an experiment investigating the formation of immune complexes between exemplary molecules and M22 antibodies are shown. Patient serum samples were incubated with fluorescently labeled molecules, and the molecules were shown to complex in 2:1 and 1:1 (molecule: autoantibody) complexes (indicated by characteristic peaks).

[0101] Figure 39 A- Figure 39 B shows the results of an ELISA assay that measures inflammatory cytokines to assess an immune response to an exemplary molecule. Figure 39 A shows the level of IL-6 secreted into the supernatant of human PBMCs cultured with the exemplary molecule and the M22 antibody. Figure 39 B shows the level of MCP-1 secreted into the supernatant of human PBMCs cultured with the exemplary molecule and the M22 antibody.

[0102] Figure 40 A- Figure 40 B shows measurements taken from monocytes after culturing with the exemplary molecule and M22 antibody. Figure 40 A) and NK cells ( Figure 40 The results of the activation experiment of B).

[0103] Figure 41 A- Figure 41 B shows the results of an experiment measuring the activation of TH-P immune cells cultured with an exemplary molecule-M22 immune complex (molecule:M22 ratio of 4:1).

[0104] Figure 42 The results are shown from experiments using AC-SINS (Affinity-Capture Self-Interacting Nanoparticle Spectroscopy) to identify the self-association tendency of exemplary molecules.

[0105] Figure 43 A- Figure 43B shows the results of measuring the exemplary molecular variant D3 using DSC. Figure 43 A) and variant E3 ( Figure 43 B) The results of the thermal stability experiment.

[0106] Figure 44 The results of Western blot analysis measuring phosphorylation of FcγRIIB in B cells incubated with exemplary molecules (pre-complexed with M22 (4:1) or as a free drug) in the presence of activated anti-IgG / IgM F(ab)2 or anti-IgM F(ab)2 are shown.

[0107] Figure 45 Results from a binding assay are shown, which measures the binding activity of trastuzumab control, variants G1, G2, G3, G6, G7, and G8 to the activating receptor FcγRIIA167R when the molecule is captured onto an SPR sensor chip and FcγR is used as the analyte.

[0108] Figure 46 The results are shown from a binding assay that measures the binding activity of variants G9, G10, G11, G12, G13, G14 and G4 with the activating receptor FcγRIIA167R when the molecule is captured onto the SPR sensor chip and FcγR is used as the analyte.

[0109] Figure 47 Results from a binding assay are shown, which measures the binding activity of trastuzumab control, variant G1, variant G2, variant G3, variant G6, variant G7, and variant G8 to the activating receptor FcγRIIA167H when the molecule is captured onto an SPR sensor chip and FcγR is used as the analyte.

[0110] Figure 48 Results from a binding assay are shown, which measures the binding activity of variants G9, G10, G11, G12, G13, G14 and G4 with the activating receptor FcγRIIA167H when the molecule is captured onto the SPR sensor chip and FcγR is used as the analyte.

[0111] Figure 49 Results from a binding assay are shown, which measures the binding activity of trastuzumab control, variants G1, G2, G3, G6, G7, and G8 to the inhibitory receptor FcγRIIB when the molecule is captured onto an SPR sensor chip and FcγR is used as the analyte.

[0112] Figure 50Results from a binding assay are shown, which measures the binding activity of variants G9, G10, G11, G12, G13, G14 and G4 to the inhibitory receptor FcγRIIB when the molecules are captured onto an SPR sensor chip and FcγR is used as an analyte.

[0113] Figure 51 A bar graph showing the mean fluorescence intensity (MFI) of an Alexa Fluor 647-labeled M22 autoantibody, the binding of which was detected by flow cytometry to increasing concentrations of the free molecule and ectopically expressed FcγRIIB (CHO-FcγRIIB) in a genetically engineered CHO-K1 cell line. Pretreatment of CHO-FcγRIIB cells with 10 µg / mL of the anti-FcγRIIB blocking antibody clone 2B6 was used to evaluate the FcγRIIB-dependent binding of the exemplary molecule. MFI values ​​were calculated from live single cells. Each condition was evaluated individually.

[0114] Figure 52 The flow cytometry half-shifted histogram shows the fluorescence signal of the Alexa Fluor 647-labeled M22 autoantibody, representing the detection of increasing concentrations of the free molecule binding to ectopically expressed FcγRIIB (CHO-FcγRIIB) in the genetically engineered CHO-K1 cell line. Pretreatment of CHO-FcγRIIB cells with 10 µg / mL of the anti-FcγRIIB blocking antibody clone 2B6 was used to evaluate the FcγRIIB-dependent binding of the exemplary molecule. The signal was calculated from a single peak in live cells. Each condition was evaluated individually.

[0115] Figure 53 Bar graph showing the mean fluorescence intensity (MFI) of the Alexa Fluor 647-labeled M22 autoantibody, which was used by flow cytometry to detect the binding of increasing concentrations of the free molecule to FcγRIIA167R (CHO-FcγRIIA167R) ectopically expressed in the genetically engineered CHO-K1 cell line. CHO-FcγRIIA167R cells were pretreated with 10 µg / mL of the anti-FcγRIIA blocking antibody clone IV.3 to evaluate the FcγRIIA-dependent binding of the molecule. MFI values ​​were calculated from live single cells. Each condition was evaluated individually. Data represent n=2 biological replicates and mean ± sd.

[0116] Figure 54The flow cytometry half-shifted histogram shows the fluorescence signal of the Alexa Fluor 647-labeled M22 autoantibody, representing the detection of increasing concentrations of the free molecule binding to FcγRIIA167R (CHO-FcγRIIA167R) ectopically expressed in the genetically engineered CHO-K1 cell line. CHO-FcγRIIA167R cells were pretreated with 10 µg / mL of the anti-FcγRIIA blocking antibody clone IV.3 to evaluate the FcγRIIA-dependent binding of the molecule. The signal was calculated from a single peak in live cells. Representative data are from one of two independent experiments.

[0117] definition To facilitate understanding of this disclosure, certain terms are defined below. The following terms, and other alternative definitions, are set forth throughout the specification. Publications and other references cited herein for the purpose of describing background and providing additional details regarding their practice are hereby incorporated by reference.

[0118] The article “a / an” is used in this text to refer to one or more (i.e., at least one) grammatical objects of the article. For example, “an element” means one element or more elements.

[0119] Application: As used herein, generally refers to the administration of the composition to a subject or system. Those skilled in the art will recognize the many routes of administration that may be used to administer the composition to a subject (e.g., a person) where appropriate. For example, in some embodiments, administration may be ocular, oral, parenteral, topical, etc. In some specific embodiments, administration may be bronchial (e.g., via bronchial infusion), buccal, dermal (which may be or include, for example, one or more of the following: topical application to the dermis, intradermal, interdermal, transdermal, etc.), enteric, intra-arterial, intradermal, gastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrasheath, intravenous, intravenous, intracardiac, intra-organ (e.g., intrahepatic), mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (e.g., via tracheal infusion), vaginal, vitreous, etc. In some specific embodiments, administration may be parenteral (e.g., via intravenous injection). In some embodiments, administration may involve intermittent (e.g., multiple doses separated by time) dosing and / or periodic (e.g., individual doses separated by the same time period) dosing. In some embodiments, administration may involve continuous dosing (e.g., infusion) for at least a selected time period.

[0120] Affinity:As is known in the art, “affinity” is a measure of the tightness with which two or more binding partners associate with each other (e.g., antibody and target antigen). Those skilled in the art understand the various assays that can be used to assess affinity, and will also understand appropriate controls for such assays. In some embodiments, affinity is assessed in a quantitative assay. In some embodiments, affinity is assessed at multiple concentrations (e.g., concentration of one binding partner at a time). In some embodiments, affinity is assessed in the presence of one or more potential competitor entities (e.g., possibly present in a relevant – e.g., physiological – environment). In some embodiments, affinity is assessed relative to a reference (e.g., a known affinity with a specific threshold – a “positive control” reference – or a known affinity with a specific threshold – a “negative control” reference). In some embodiments, affinity may be assessed relative to a contemporaneous reference. In some embodiments, affinity may be assessed relative to a historical reference. Generally, when affinity is assessed relative to a reference, affinity is assessed under comparable conditions.

[0121] Approximately or about: As used herein and when applied to one or more values ​​of interest, "about" refers to a value similar to the stated reference value. In some embodiments, unless otherwise stated or otherwise apparent from the context (other than where such a value would exceed 100% of a possible reference value), the terms "about" or "approximately" refer to a range of values ​​falling within 20% (greater or less) in either direction of the stated reference value.

[0122] Antibody:As used herein, a term refers to a polypeptide comprising a canonical immunoglobulin sequence element sufficient to confer specific binding to a particular target antigen. As is known in the art, intact antibodies, such as those produced in nature, are tetramers comprising two identical heavy-chain polypeptides and two identical light-chain polypeptides that associate with each other to form a structure commonly referred to as a “Y-shape.” Each heavy chain contains at least four domains—an amino-terminal variable (VH) domain (located at the apex of the Y structure), followed by three constant domains: CH1, CH2, and a carboxyl-terminal CH3 (located at the base of the stem of the Y). A short region called a “switch” connects the heavy-chain variable and constant regions. A “hinge” connects the CH2 and CH3 domains to the remainder of the antibody. Two disulfide bonds in this hinge region link the two heavy-chain polypeptides in the intact antibody together. Each light chain contains two domains—an amino-terminal variable (VL) domain, followed by a carboxyl-terminal constant (CL) domain—separated from each other by another “switch.” A complete antibody tetramer comprises two heavy-chain-light-chain dimers, with the heavy and light chains linked together by a single disulfide bond; two additional disulfide bonds link the heavy-chain hinge regions together, causing the dimers to link together and form a tetramer. Naturally occurring antibodies are typically also glycosylated at the CH2 domain. Each domain in a natural antibody has a structure characterized by an “immunoglobulin fold,” formed by two β-sheets (e.g., 3-chain, 4-chain, or 5-chain folds) packaged opposite each other into compressed antiparallel β-barrels. Each variable domain contains three hypervariable loops called “complementarity-determining regions” or “CDRs” (CDR1, CDR2, and CDR3) and four slightly invariant “framework” regions (FR1, FR2, FR3, and FR4). When a natural antibody folds, the FR regions form β-sheets that provide the structural framework for the domain, and the CDR loop regions from both the heavy and light chains aggregate in three-dimensional space to create a single hypervariable antigen-binding site at the apex of the Y-structure. Naturally occurring antibodies have an Fc region located at the base of the Y structure that binds to elements of the complement system and also to receptors on effector cells, including, for example, effector cells mediating cytotoxicity. The affinity and / or other binding properties of the Fc region to Fc receptors can be modulated by glycosylation or other modifications. In some embodiments, antibodies generated and / or utilized according to this disclosure comprise glycosylated Fc domains, including modified or engineered glycosylated Fc domains. In some embodiments, any polypeptide or polypeptide complex containing sufficient immunoglobulin domain sequences as found in natural antibodies can be referred to as and / or used as an "antibody," regardless of whether such polypeptide is naturally occurring (e.g., generated by an organism's response to an antigen) or produced by recombinant engineering, chemical synthesis, or other artificial systems or methods. In some embodiments, the antibody is polyclonal. In some embodiments, the antibody is monoclonal.In some embodiments, the antibody has a constant region sequence specific to mouse, rabbit, primate, or human antibodies. In some embodiments, as known in the art, the antibody sequence element is humanized, primate-based, chimeric, etc. Furthermore, as used herein, the term "antibody" in appropriate embodiments (unless otherwise stated or obvious from the context) may refer to any of the constructs or forms known or developed in the art for utilizing the structural and functional characteristics of an antibody in alternative presentations. For example, in some embodiments, the antibodies utilized according to this disclosure are presented in forms selected from, but not limited to: intact IgA, IgG, IgE, or IgM antibodies; bispecific or multispecific antibodies; antibody fragments, as used herein in the broadest sense, and encompassing a variety of antibody structures (preferably those fragments exhibiting the desired antigen-binding activity). For example, the antibodies described herein may be immunoglobulins, heavy chain antibodies, light chain antibodies, LRR-based antibodies, or other protein scaffolds with antibody-like properties, as well as any other immune-binding motifs known in the art, including, for example, Fab, Fab', Fab'2, Fab2, Fab3, F(ab')2, Fd, Fv, sdAb, scFv, SMIP, biantibodies, triantibodies, tetraantibodies, microantibodies, nanoantibodies, large antibodies, tandab, DVD, BiTe, TandAb, etc., or any combination thereof. The subunit structures and three-dimensional configurations of different types of antibodies are known in the art. In some embodiments, the antibody may lack the covalent modifications (e.g., glycan linkages) that it would have naturally. In some embodiments, the antibody may contain covalent modifications, such as glycans, cargo portions (e.g., detectable portions, therapeutic portions, catalytic portions, etc.) or attachments to other side groups (e.g., polyethylene glycol, etc.). 。

[0123] Antigen-binding domain:An "antigen-binding domain" refers to a portion of an antibody that binds the antigen bound by the intact antibody. Antigen-binding domains of antibodies include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. Exemplary antigen-binding domains include, but are not limited to, Fab, Fab', Fab'2, Fab2, Fab3, F(ab')2, Fd, Fv, sdAb, scFv, SMIP, biantibodies, triantibodies, tetraantibodies, microantibodies, nanoantibodies, large antibodies, tandab, DVD, BiTe, TandAb, and any combination thereof. In some embodiments, the antigen-binding domain of the antibody described herein is scFv. In some embodiments, the antigen-binding domain of the antibody described herein is a VHH-only domain. Like whole antibody molecules, antigen-binding domains can be monospecific or multispecific (e.g., bispecific). A multispecific antigen-binding domain of an antibody may contain at least two distinct variable domains, each of which is capable of specifically binding to a single antigen or different epitopes of the same antigen.

[0124] Antibody heavy chain: As used in this article, it refers to the larger of the two types of polypeptide chains present in naturally occurring intact antibodies.

[0125] Antibody light chain: As used in this article, it refers to the smaller of the two types of polypeptide chains present in naturally occurring intact antibodies.

[0126] Synthetic antibodies: As used herein, this refers to antibodies produced using recombinant DNA technology. The term should also be interpreted as meaning antibodies generated by synthesizing a DNA molecule encoding an antibody (which expresses an antibody protein) or specifying an amino acid sequence of an antibody, wherein the DNA or amino acid sequence is obtained using synthetic DNA or amino acid sequence techniques available and well-known in the art.

[0127] antigenAs used herein, the term "antigen" refers to a molecule (e.g., peptide, polypeptide, or polysaccharide) that elicits a specific immune response. Antigen-specific immune responses, also known as adaptive immune responses, are mediated by lymphocytes (e.g., T cells, B cells, NK cells) that express antigen receptors (e.g., T cell receptors, B cell receptors). In some embodiments, the antigen is a T cell antigen and elicits a cellular immune response. In some embodiments, the antigen is a B cell antigen and elicits a humoral (i.e., antibody) response. In some embodiments, the antigen is both a T cell antigen and a B cell antigen. As used herein, the term "antigen" encompasses a full-length polypeptide and portions or immunogenic fragments of said polypeptide, as well as peptide epitopes within said polypeptide (e.g., peptide epitopes that bind to major histocompatibility complex (MHC) molecules (e.g., MHC class I or MHC class II). In some embodiments, the antigen is an autoantigen. In some embodiments, the antigen is tissue-specific or non-specific, for example, identified from cells or tissues that are targets of an autoimmune response or from healthy cells or tissues.

[0128] Autoantigen As used in this article, "autoantigen" refers to an antigen that triggers an autoimmune response. An autoantigen is an endogenous (self) antigen recognized by the immune system as non-self (i.e., foreign pathogen). Autoantigens can be proteins or immunogenic fragments of proteins, or complexes of proteins recognized by the immune system of a subject with or susceptible to an autoimmune disease.

[0129] Autoimmune diseases As used in this article, "autoimmune disease" refers to an immune response against self-antigens or autoantigens.

[0130] Related: Two events or entities are “related” to each other if the presence, level, extent, type, and / or form of one is associated with the presence, level, extent, type, and / or form of the other. For example, a particular entity (e.g., peptide, genetic marker, metabolite, microorganism, etc.) is considered to be related to a particular disease, condition, or disorder if its presence, level, and / or form are associated with the incidence, susceptibility, severity, stage, etc., of that disease, condition, or disorder (e.g., in a relevant population).

[0131] Combined structural domainAs used herein, "binding domain" refers to a portion or entity that specifically binds to a target moiety or entity. Typically, the interaction between the binding domain and its target is non-covalent. In some embodiments, the binding domain can be or comprises a moiety or entity of any chemical class, including, for example, carbohydrates, lipids, nucleic acids, metals, peptides, and small molecules. In some embodiments, the binding domain can be or comprises a peptide (or a complex thereof). In some embodiments, the binding domain can be or comprises a target-binding moiety of an antibody, cytokine, ligand (e.g., a receptor ligand), receptor, toxin, etc. In some embodiments, the binding domain can be or comprises an aptamer. In some embodiments, the binding domain can be or comprises a peptide nucleic acid (PNA). In some embodiments, the binding domain can be an antigen (e.g., an autoantigen). In some embodiments, the binding domain binds to an antibody (i.e., a "target antibody").

[0132] Effective dosage: As used herein with respect to dosage, it refers to a dose sufficient to prevent or treat the target disease or condition of the subject. The effective amount for therapeutic or preventative use will depend, for example, on the stage and severity of the disease or condition being treated, the subject's age, weight, and general health condition, as well as the judgment of the prescribing physician. The dosage will also be determined by the chosen agent, the method of administration, the time and frequency of administration, the presence, nature, and extent of any adverse side effects that may accompany the administration of the particular agent, and the desired physiological effect. Those skilled in the art will understand that various diseases or conditions may require long-term treatment involving multiple administrations, possibly using the molecules of the present invention in each or multiple rounds of administration.

[0133] coding: As used herein, “encoding” refers to the inherent property of a specific nucleotide sequence in a polynucleotide (such as a gene, cDNA, or mRNA) as a template for the synthesis of other polymers and macromolecules (having defined nucleotide sequences (i.e., rRNA, tRNA, and mRNA) or defined amino acid sequences) in biological processes, and the resulting biological properties. Therefore, if the transcription and translation of the mRNA corresponding to a gene produces a protein in a cell or other biological system, then the gene encodes that protein. Both the coding strand, whose nucleotide sequence is identical to the mRNA sequence and is typically provided in the sequence listing, and the non-coding strand, which serves as a transcription template for a gene or cDNA, can be referred to as the protein or other product encoding that gene or cDNA.

[0134] Epitope:As used herein, an epitope refers to a portion specifically recognized by an immunoglobulin (e.g., antibody) binding component. In some embodiments, an epitope consists of multiple chemical atoms or groups on the antigen. In some embodiments, such chemical atoms or groups are surface-exposed when the antigen adopts an associated three-dimensional conformation. In some embodiments, such chemical atoms or groups are physically close to each other in space when the antigen adopts such a conformation. In some embodiments, at least some of such chemical atoms or groups are physically separated from each other when the antigen adopts an alternative conformation (e.g., linearization or denaturation).

[0135] Express: As used herein, the term “expression” of a nucleic acid sequence refers to the generation of any gene product from the nucleic acid sequence. In some embodiments, the gene product may be a transcript. In some embodiments, the gene product may be a polypeptide. In some embodiments, the expression of a nucleic acid sequence involves one or more of the following: (1) generating an RNA template from a DNA sequence (e.g., by transcription); (2) processing of the RNA transcript (e.g., by splicing, editing, 5' cap formation, and / or 3' end formation); (3) translating RNA into a polypeptide or protein; and (4) post-translational modifications of the polypeptide or protein.

[0136] Excerpt:As used herein, the terms "fragment" or "part" refer to a structure that comprises a discrete portion of the whole but lacks one or more parts found throughout the whole structure. In some embodiments, a fragment consists of such discrete portions. In some embodiments, a fragment consists of or contains a characteristic structural element or part found throughout the whole. In some embodiments, the nucleotide fragment comprises or is composed of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500 or more monomeric units (e.g., nucleic acids) found in the whole nucleotide sequence. In some embodiments, the nucleotide fragment contains or is composed of at least about 5%, 10%, 15%, 20%, 25%, 30%, 25%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more of monomeric units (e.g., nucleic acids) found in the whole nucleotide. In some embodiments, the polypeptide or protein fragment comprises or is composed of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500 or more monomeric units (e.g., amino acids) found in the whole polypeptide or protein. In some embodiments, the polypeptide or protein fragment comprises or is composed of at least about 5%, 10%, 15%, 20%, 25%, 30%, 25%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more of monomeric units (e.g., amino acids) found in the whole polypeptide or protein. In some embodiments, the whole material or entity may be referred to as the "parent" of the fragment.

[0137] identityAs used herein, the term "identity" refers to the overall relevance between polymer molecules, such as nucleic acid molecules (e.g., DNA molecules and / or RNA molecules) and / or polypeptide molecules. In some embodiments, polymer molecules are considered "substantially identical" to each other if their sequences are at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical. For example, the percentage of identity between two nucleic acid or polypeptide sequences can be calculated by comparing the two sequences for optimal comparison purposes (e.g., vacancies can be introduced in one or both of the first and second sequences to achieve optimal alignment, and dissimilar sequences can be ignored for comparison purposes). In some embodiments, the length of the sequence compared for comparison purposes is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or substantially 100% of the length of the reference sequence. Nucleotides at corresponding positions are then compared. The molecules are considered identical at a position in the first sequence when that position is occupied by the same residue (e.g., a nucleotide or amino acid) as the corresponding position in the second sequence. The percentage of identity between two sequences is a function of the number of common positions shared by the sequences, taking into account the number of vacancies introduced for optimal alignment and the length of each vacancies. Sequence comparisons and the determination of the percentage of identity between two sequences can be accomplished using mathematical algorithms. For example, the percentage of identity between two nucleotide sequences can be determined using the algorithm of Meyers and Miller (CABIOS, 1989, 4: 11-17), which has been incorporated into the ALIGN program (version 2.0). In some exemplary embodiments, nucleic acid sequence comparisons using the ALIGN program employ a PAM120 weighted residue table, a vacancy length penalty of 12, and a vacancy penalty of 4. Alternatively, the percentage of identity between two nucleotide sequences can be determined using the GAP program in the GCG software package with an NWSgapdna.CMP matrix.

[0138] Human antibodies: As used herein, it is intended to include antibodies having variable and constant regions generated (or assembled) from human immunoglobulin sequences. In some embodiments, although the amino acid sequence of the antibody (or antibody component) contains residues or elements not encoded by human germline immunoglobulin sequences (e.g., containing sequence variations that may have been introduced (initially) through in vitro random or site-specific mutagenesis or in vivo somatic mutations), such as in one or more CDRs and particularly CDR3, the antibody (or antibody component) may be considered " human ".

[0139] immune cellsAs used herein, the term "immune cell" refers to a cell that participates in an immune response (e.g., promotes an immune response). Examples of immune cells include, but are not limited to, T lymphocytes, natural killer (NK) cells, macrophages, monocytes, dendritic cells, neutrophils, eosinophils, mast cells, platelets, large granular lymphocytes, Langerhans cells, plasma cells, or B lymphocytes. The source of immune cells (e.g., T lymphocytes) may be obtained from the subject.

[0140] immune mediators As used herein, the term "immune mediator" refers to any molecule that affects the cells and processes involved in an immune response. Immune mediators include cytokines, chemokines, soluble proteins, enzymes, and cell surface markers.

[0141] Immune response: As used herein, it refers to the cellular and / or systemic response to an antigen that occurs when immune cells identify an antigen molecule as foreign and induce antibody formation and / or activate autologous or other immune cells to remove the antigen.

[0142] Immunoglobulins or Ig: As used in this article, "antibody" refers to a class of proteins that function as antibodies. Antibodies expressed by B cells are sometimes called BCRs (B cell receptors) or antigen receptors. This class of proteins includes five members: IgA, IgG, IgM, IgD, and IgE. IgA is a primary antibody found in bodily secretions such as saliva, tears, breast milk, gastrointestinal secretions, and mucus secretions from the respiratory and genitourinary tracts. IgG is the most common circulating antibody. IgM is the major immunoglobulin produced in the primary immune response of most subjects. It is the most effective immunoglobulin in agglutination, complement fixation, and other antibody responses, and is important in the defense against bacteria and viruses. IgD is an immunoglobulin that does not have known antibody functions but can act as an antigen receptor. IgE is an immunoglobulin that mediates immediate-type hypersensitivity reactions by inducing the release of mediators from mast cells and basophils upon exposure to allergens.

[0143] improve , Increase or reduce:As used herein, the terms “improvement,” “increase,” or “decrease,” or grammatically equivalent comparative terms, refer to a value relative to an equivalent reference measurement. For example, in some embodiments, an assessment value obtained with the target agent may be “improved” relative to an assessment value obtained with an equivalent reference agent. Alternatively or additionally, in some embodiments, an assessment value obtained in the target subject or system may be “improved” relative to an assessment value obtained in the same subject or system under different conditions (e.g., before or after an event such as administration of the target agent) or in different comparable subjects (e.g., in the presence of one or more indicators of a specific target disease, condition, or ailment, or in prior exposure to the ailment or agent, etc., in an equivalent subject or system different from the target subject or system). In some embodiments, comparative terms refer to statistically relevant differences (e.g., whose prevalence and / or magnitude are sufficient to achieve statistical relevance). In the given context, those skilled in the art will recognize or will be able to readily determine the degree and / or prevalence of the difference required or sufficient to achieve such statistical significance.

[0144] Separate: As used herein, "isolated" refers to substances that have been altered or removed from their natural state. For example, nucleic acids or polypeptides naturally present in living organisms are not "isolated," but the same nucleic acids or polypeptides that are partially or completely separated from their natural coexisting substances are "isolated." Isolated nucleic acids or polypeptides may exist in substantially purified forms or may exist in non-natural environments such as host cells.

[0145] K D： As used herein, it refers to the dissociation constant of a conjugate (e.g., an antibody or its binding component) from a complex with its partner (e.g., an epitope to which the antibody or its binding component is bound).

[0146] K off： As used herein, it refers to the dissociation rate constant of a conjugate (e.g., an antibody or its conjugated component) from a complex with its partner (e.g., an epitope to which the antibody or its conjugated component is bound).

[0147] K on： As used herein, it refers to the association rate constant of the association between a binder (e.g., an antibody or a binding component thereof) and its partner (e.g., an epitope bound to an antibody or a binding component thereof).

[0148] adjust:As used herein, the term "modulation" refers to a detectable increase or decrease in the level of response and / or a change in the nature of response in a subject compared to the level and / or nature of response in untreated subjects and / or compared to the level and / or nature of response in otherwise identical but untreated subjects. This term encompasses the disruption and / or influence of natural signals or responses, thereby mediating a beneficial therapeutic response in subjects, preferably humans.

[0149] Nucleic acid As used herein, "nucleic acid" refers to a polymer of at least three nucleotides. In some embodiments, the nucleic acid includes DNA. In some embodiments, the nucleic acid includes RNA. In some embodiments, the nucleic acid is single-stranded. In some embodiments, the nucleic acid is double-stranded. In some embodiments, the nucleic acid comprises both single-stranded and double-stranded portions. In some embodiments, the nucleic acid comprises a backbone containing one or more phosphodiester-linked bonds. In some embodiments, the nucleic acid comprises a backbone containing both phosphodiester-linked and non-phosphodiester-linked bonds. For example, in some embodiments, the nucleic acid may comprise a backbone containing one or more thiophosphate or 5'-N-phosphamide bonds and / or one or more peptide bonds, such as those found in "peptide nucleic acid". In some embodiments, the nucleic acid comprises one or more or all of the natural residues ( like,Adenine, cytosine, deoxyadenosine, deoxycytidine, deoxyguanosine, deoxythymidine, guanine, thymine, uracil). In some embodiments, the nucleic acid contains one or more or all of the non-natural residues. In some embodiments, the non-natural residues include nucleoside analogs (e.g., 2-aminoadenosine, 2-thiothymidine, inosine, pyrrolopyrimidine, 3-methyladenosine, 5-methylcytidine, C-5-propynyl-cytidine, C-5-propynyl-uridine, 2-aminoadenosine, C5-bromouridine, C5-fluorouridine, C5-iodouridine, C5-propynyl-uridine, C5-propynyl-cytidine, C5-methylcytidine, 2-aminoadenosine, 7-deazoadenosine, 7-deazoguanosine, 8-oxoadenosine, 8-oxoguanosine, O(6)-methylguanine, 2-thiocytidine, methylated bases, intercalated bases, and combinations thereof). In some embodiments, the non-natural residues contain one or more modified sugars (e.g., 2'-fluororibose, ribose, 2'-deoxyribose, arabinose, and hexose) compared to the sugars in the natural residues. In some embodiments, the nucleic acid has a nucleotide sequence encoding a functional gene product such as RNA or a polypeptide. In some embodiments, the nucleic acid has a nucleotide sequence containing one or more introns. In some embodiments, the nucleic acid can be prepared by isolating from a natural source, enzymatically synthesizing (e.g., by polymerase based on a complementary template, e.g., in vivo or in vitro), replicating in a recombinant cell or system, or chemically synthesizing. In some implementations, the length of the nucleic acid is at least 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 20, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000 or more residues.

[0150] Operable connection: As used herein, this refers to, for example, a functional link between a regulatory sequence and a heterologous nucleic acid sequence that enables the latter to be expressed. For example, the first and second nucleic acid sequences are operatively linked when they are functionally related. Similarly, if a promoter affects the transcription or expression of a coding sequence, the promoter is operatively linked to the coding sequence. Typically, the operatively linked DNA sequences are contiguous and, when two protein-coding regions need to be linked, are within the same reading frame.

[0151] Pharmaceutical CompositionAs used herein, "active agent" refers to an active agent formulated with one or more pharmaceutically acceptable carriers. In some embodiments, the active agent of interest is present at a unit dose suitable for administration in a treatment regimen that, when administered to the relevant population, shows a statistically significant probability of achieving the intended therapeutic effect. In some embodiments, the pharmaceutical composition may be specifically formulated for administration in solid or liquid form, including those suitable for: oral administration, such as drench (aqueous or non-aqueous solution or suspension), tablets (e.g., those tablets targeted for absorption via buccal, sublingual, and systemic administration), pellets, powders, granules, pastes for application to the tongue; parenteral administration, such as by subcutaneous, intramuscular, intravenous, or epidural injection, as, for example, a sterile solution or suspension or sustained-release formulation; topical administration, such as as a cream, ointment, controlled-release patch, or spray to the skin, lungs, or mouth; intravaginal or rectal administration, such as as a vaginal suppository, cream, or foam; sublingual; ocular; transdermal; or nasal, pulmonary administration, and application to other mucosal surfaces.

[0152] Polynucleotides: As used herein, "nucleotide chain" refers to a nucleotide chain. Furthermore, nucleic acids are polymers of nucleotides. Therefore, nucleic acids and polynucleotides, as used herein, are interchangeable. Those skilled in the art will generally know that nucleic acids are polynucleotides that can be hydrolyzed into monomeric "nucleotides." Monomeric nucleotides can be hydrolyzed into nucleosides. As used herein, polynucleotides include, but are not limited to, all nucleic acid sequences obtained by any means available in the art, including, but not limited to, recombinant methods (i.e., cloning nucleic acid sequences from recombinant libraries or cell genomes using common cloning techniques and PCR, etc.) and synthetic methods.

[0153] protein:As used herein, a polypeptide (i.e., a string of at least two amino acids linked together by peptide bonds) is used. Therefore, protein and polypeptide are used interchangeably as used herein. A protein may include portions other than amino acids (e.g., it may be a glycoprotein, proteoglycan, etc.) and / or may be otherwise processed or modified. Those skilled in the art will understand that a “protein” can be a complete polypeptide produced by a cell (with or without a signal sequence) or can be its characteristic portion. Those skilled in the art will understand that a protein may sometimes include, for example, more than one polypeptide linked by one or more disulfide bonds or associated by other covalent or non-covalent means. A polypeptide may contain L-amino acids, D-amino acids, or both, and may contain any of a variety of amino acid modifications or analogs known in the art. Useful modifications include, for example, terminal acetylation, amidation, methylation, etc. In some embodiments, a protein may contain native amino acids, non-native amino acids, synthetic amino acids, and combinations thereof. The term “peptide” is generally used to refer to polypeptides with a length of less than about 100 amino acids, less than about 50 amino acids, less than 20 amino acids, or less than 10 amino acids. In some implementations, the protein is an antibody, an antibody fragment, its biologically active portion, and / or its characteristic portion.

[0154] Specific binding: As used herein, the term "specific binding" for antigen-binding domains (such as those found in antibodies) refers to an antigen-binding domain that recognizes a specific antigen but substantially does not recognize or bind to other molecules in a sample. For example, an antigen-binding domain that specifically binds to an antigen from one species may also bind to antigens from one or more other species. However, this cross-species reactivity itself does not change the classification of the antigen-binding domain as specific. In another instance, an antigen-specific antigen-binding domain may also bind to different allelic forms of an antigen. However, this cross-reactivity itself does not change the classification of the antigen-binding domain as specific. In some cases, the terms "specific binding" or "specific binding" may be used with respect to the interaction of an antigen-binding domain with a second chemical substance, meaning that the interaction depends on the presence of a specific structure (e.g., an antigenic determinant or epitope) on the chemical substance; for example, the antigen-binding domain recognizes and binds to a specific protein structure rather than a typical protein. If the antigen-binding domain is specific to epitope "A", then in a reaction containing labeled "A" and the antigen-binding domain, the presence of a molecule containing epitope A (or free unlabeled A) will reduce the amount of labeled A binding to the antigen-binding domain.

[0155] Subjects:As used herein, "organism" refers to an organism, such as a mammal (e.g., a human, a non-human mammal, a non-human primate, a primate, a laboratory animal, a mouse, a rat, a hamster, a gerbil, a cat, or a dog). In some embodiments, the human subject is an adult, adolescent, or pediatric subject. In some embodiments, the subject has a disease, condition, or disorder, such as a disease, condition, or disorder that can be treated as provided herein, such as an autoimmune disease. In some embodiments, the subject is susceptible to a disease, condition, or disorder; in some embodiments, susceptible subjects tend to and / or show an increased risk of developing the disease, condition, or disorder (compared to the average risk observed in a reference subject or population). In some embodiments, the subject exhibits one or more symptoms of a disease, condition, or disorder. In some embodiments, the subject does not exhibit a specific symptom (e.g., clinical manifestations of a disease) or characteristic of a disease, condition, or disorder. In some embodiments, the subject does not exhibit any symptoms or characteristic of a disease, condition, or disorder. In some embodiments, the subject is a patient. In some embodiments, the subject is an individual who is receiving and / or has received a diagnostic and / or therapeutic treatment.

[0156] Target: As used herein, refers to cells, tissues, organs, or sites in the body of a subject who is a recipient of the provided methods, systems, and / or compositions, such as cells, tissues, organs, or sites in the body that require treatment or are preferentially bound to molecules such as those described herein.

[0157] treat: As used herein, the term "treat" (or "treatment") refers to a partial or complete reduction, improvement, delayed onset, suppression, prevention, relief, and / or decrease in morbidity and / or severity of one or more symptoms or features of a disease, condition, and / or disorder. In some embodiments, treatment may be administered to a subject who does not exhibit signs or features of a disease, condition, and / or disorder (e.g., it may be prophylactic). In some embodiments, treatment may be administered to a subject who exhibits only early or mild signs or features of a disease, condition, and / or disorder, for example, for the purpose of reducing the risk of developing a pathology associated with the disease, condition, and / or disorder. In some embodiments, treatment may be administered to a subject exhibiting identified, severe, and / or late signs of a disease, condition, or disorder. As used herein, "therapeutic agent" is any agent used to treat a subject.

[0158] Carrier:As used herein, the term "vector" refers to a composition of substances containing isolated nucleic acids and capable of being used to deliver the isolated nucleic acids into the cell. Many vectors are known in the art, including, but not limited to, linear polynucleotides, polynucleotides associated with ionic or amphoteric compounds, plasmids, and viruses. Therefore, the term "vector" includes autonomously replicating plasmids or viruses. The term should also be interpreted to include non-plasmid and non-viral components that facilitate the transfer of nucleic acids into cells, such as, for example, polylysine compounds, liposomes, etc. Examples of viral vectors include, but are not limited to, adenovirus vectors, adeno-associated virus vectors, retroviral vectors, lentiviral vectors, etc.

[0159] Throughout this disclosure, all aspects may be presented in range format. It should be understood that the range format is merely for convenience and brevity and should not be construed as a rigid limitation on the range. Therefore, a range description should be considered to have all possible subranges of the specific disclosure, as well as individual numerical values ​​within that range. For example, a range such as 1 to 6 should be considered to have specific subranges of the disclosure (such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc.) and individual numerical values ​​within that range (e.g., 1, 2, 2.7, 3, 4, 5, 5.3, and 6). This applies regardless of the width of the range. Detailed Implementation

[0160] Some autoimmune diseases are driven by autoantibodies that produce an immune response to self-antigens (i.e., self-antigens). Although certain autoantibody-antigen pairs and their effects in autoimmune diseases (e.g., TSHR and Graves' disease) have been identified, many are poorly controlled with current treatments. Current standard of care involves suppressing the autoimmune response by inhibiting or depleting intact immune components or cell populations, including those necessary for a healthy immune response to foreign pathogens. Current treatments include glucocorticoids, antibodies targeting plasma cells, antibodies targeting FcRn (“FcRn inhibitors”), and plasmapheresis. FcRn inhibitors lead to pan-IgG depletion and often result in incomplete depletion of autoantibodies.

[0161] This disclosure covers molecules for selectively depleting autoantibodies (i.e., anti-TSHR autoantibodies) to treat autoimmune diseases (e.g., Graves' disease and thyroid ophthalmopathy). In some embodiments, the molecules described herein comprise a first polypeptide comprising a first Fc domain and an autoantibody-binding domain that binds to the autoantibody (i.e., anti-TSHR autoantibody); and a second polypeptide comprising a second Fc domain; wherein the first Fc domain and the second Fc domain form a homodimer or heterodimer of the first polypeptide and the second polypeptide. In some embodiments, the second polypeptide further comprises an autoantibody-binding domain that binds to the autoantibody (i.e., anti-TSHR autoantibody). In some embodiments, the autoantibody-binding domains in the first polypeptide and the second polypeptide are identical, and the molecule is a homodimer. In some embodiments, the autoantibody-binding domains in the first polypeptide and the second polypeptide are different, and the molecule is a heterodimer. In some embodiments, the second polypeptide does not further comprise an autoantibody-binding domain that binds to the autoantibody (i.e., anti-TSHR autoantibody), and the molecule is a heterodimer.

[0162] This disclosure particularly provides molecules that selectively target and deplete autoantibodies, for example, by directing the autoantibody to an internalization receptor, which binds to the cell and internalizes the complex into the cell for lysosomal degradation. In some embodiments, the autoantibody-binding domain comprises an autoantigen. For example, if the specific autoantibody to be targeted is an anti-TSHR autoantibody (e.g., for treating Graves' disease and thyroid ophthalmopathy), the autoantigen domain may comprise a TSHR autoantigen domain. In addition to comprising an autoantibody-binding domain, the molecule may also include modifications in its first and / or second Fc domains that increase its binding to an internalization receptor or endocytic receptor on the cell surface (e.g., internalizing the ligand and targeting the ligand to a lysosome). In some embodiments, the molecule may comprise an antigen-binding domain that binds to an internalization receptor or endocytic receptor on the cell surface (e.g., internalizing the ligand and targeting the ligand to a lysosome).

[0163] Graves' disease, thyroid eye disease and TSHR In some implementations, the molecules described herein can be used to treat Graves' disease, thyroid eye disease, and other autoimmune diseases associated with autoantibodies targeting the thyroid-stimulating hormone receptor (TSHR), achieved by including an autoantibody-binding domain comprising a TSHR autoantigen domain or a fragment or variant thereof.

[0164] Graves' disease is an autoimmune thyroid disorder caused by antibodies that stimulate thyrotropin or thyroid-stimulating hormone (TSH) receptors (TSHR) located on thyroid follicular cells or thyroid cells. These antibodies can bind to TSH receptors in the retro-orbital tissue and cause Graves' orbital disease or thyroid eye disease (see Burch and Cooper). JAMA 314(23): 2544 (2015)). Therefore, stimulatory thyroid-stimulating hormone receptor antibodies are a major cause of Graves' disease and GO, and are an important indicator for diagnosis and prediction of clinical severity.

[0165] Graves' disease is common, affecting 20-30 people per 100,000 (see Burch and Cooper). JAMA 314(23): 2544 (2015)). Graves' disease is predominantly seen in women. Approximately 3% of women and 0.5% of men will develop Graves' disease in their lifetime, and about 25%–50% of people with Graves' disease will develop Graves' orbital disease (GO) (see Burch and Cooper, JAMA 314(23): 2544 (2015); and George et al., Front Endocrinol , 11: 629925 (2021), the cited reference is incorporated herein by reference in its entirety. Current treatments for Graves' disease and GO aim to alleviate symptoms but do not target the underlying causes of the disease.

[0166] The thyroid-stimulating hormone receptor (TSHR) is the primary autoantigen responsible for Graves' hyperthyroidism and related eye disease (Graves' ophthalmopathy or thyroid eye disease). TSHR peptides are recognized by the immune system through uptake and displayed on antigen-presenting cells (APCs) via MHC class II. T helper cells recognize the TSHR autoantigen domain by binding to fragments of the TSHR autoantigen domain on APCs. T helper cells are activated and bind to B cells, leading to the maturation of B cells into plasma cells that secrete TSHR antibodies via the inflammatory cytokines interleukin II and interferon-gamma. The synthesized TSHR antibodies bind to TSH-R expressed on thyroid cells and orbital target cells (fibroblasts, preadipocytes). This activates pathways such as the Gαs adenylate cyclase (AC) pathway and stimulates protein kinase A, including gene activation induced by cAMP response element-binding (CREB) proteins. Other pathways, including Gαq protein kinase C (PKC), are also activated, leading to activation of protein kinase B (Akt) and induction of the mammalian target of rapamycin (mTOR). This induction of gene expression results in differentiation into preadipocytes and the synthesis of glycosaminoglycans in the orbital space, and can cause edema and subsequent fibrosis, a clinical phenotype of thyroid ophthalmopathy (see George et al.). Front Endocrinol , 11: 629925 (2021); and Hansen et al., International Journal of Molecular Sciences 24.7: 6835 (2023)).

[0167] Graves' disease can be diagnosed by clinical features, elevated levels of thyroxine (T4) and triiodothyronine (T3), and undetectable levels of TSH. The level of TSHR antibodies is also an important indicator (see Burch and Cooper). JAMA 314(23): 2544 (2015)). Standard care for treating hyperthyroidism due to Graves' disease includes antithyroid medication to normalize thyroid hormone production, use of RAI to destroy the thyroid gland, or surgical removal of the thyroid gland (see Burch and Cooper, JAMA 314(23): 2544 (2015)). However, these therapies do not target stimulating TSHR antibodies, which are associated with the disease.

[0168] Thyroid ophthalmopathy (also known as Graves' orbital disease) presents with bulging eyes, upper eyelid retraction, diplopia, and irritation of the periorbital tissues and conjunctiva (see George et al.). Front Endocrinol, 11: 629925 (2021)). Since most people with Graves' disease have hyperthyroidism, characteristic symptoms of Graves' disease include palpitations, tremors, heat intolerance, weight loss, and anxiety.

[0169] Other recently developed treatments for Graves' disease and other autoimmune diseases involving pathogenic plasma cells that produce autoantibodies include antibodies targeting B-cell / plasma cell markers such as anti-CD20 antibodies (e.g., rituximab), anti-CD19 antibodies, anti-CD38 antibodies (e.g., daratumumab), FcRn inhibitors, and plasmapheresis. However, such strategies target all B cells or plasma cells, not just those producing pathogenic autoantibodies. In the case of CD38, targeting this marker also depletes other CD38+ cells, including monocytes, T cells, and NK cells. FcRn inhibitors lead to pan-IgG depletion and often result in incomplete depletion of autoantibodies.

[0170] This disclosure recognizes that further selective introduction can be made to maintain basic immunity and enhance the efficacy of antibodies, for example, targeting foreign pathogens such as viral antigens. The molecules described herein include further selectivity for target autoantibodies involved in autoimmune diseases. In some embodiments, this strategy includes utilizing the TSHR autoantigen domain or fragments or variants thereof to target and destroy anti-TSHR autoantibodies, thereby eliminating autoimmune responses involved in Graves' disease and thyroid ophthalmopathy.

[0171] Exemplary molecule This disclosure provides molecules for selectively depleting and / or neutralizing autoantibodies (i.e., anti-TSHR autoantibodies) to treat autoimmune diseases (e.g., Graves' disease). In some embodiments, the molecules described herein comprise a first polypeptide comprising a first Fc domain and an autoantibody-binding domain that binds to the autoantibody (i.e., anti-TSHR autoantibody); and a second polypeptide comprising a second Fc domain; wherein the first Fc domain and the second Fc domain form a homodimer or heterodimer of the first polypeptide and the second polypeptide. In some embodiments, the second polypeptide further comprises an autoantibody-binding domain that binds to the anti-TSHR autoantibody, and the molecule is a homodimer. In some embodiments, the second polypeptide further comprises an autoantibody-binding domain that binds to the anti-TSHR autoantibody, and the molecule is a heterodimer. In some embodiments, the second polypeptide does not comprise an autoantibody-binding domain that binds to the anti-TSHR autoantibody, and the molecule is a heterodimer.

[0172] In some implementations, the first and / or second polypeptide also includes an antigen-binding domain (e.g., a Fab domain).

[0173] In some embodiments, the first and second polypeptides of the molecule described herein may be in the form of a fusion protein. In some embodiments, the first and second polypeptides of the molecule described herein may be in the form of a chemically conjugated molecule.

[0174] In some embodiments, the first and / or second Fc domains contain one or more mutant amino acid residues and have increased binding affinity for internalizing receptors (e.g., FcγRIIB) relative to the corresponding wild-type Fc domains.

[0175] In some embodiments, an immune complex is formed upon binding of one or two molecules to an autoantibody (i.e., an anti-TSHR autoantibody). In some embodiments, the immune complex formed with one molecule described herein and an autoantibody (i.e., an anti-TSHR autoantibody) exhibits enhanced binding kinetics with FcγRIIB, relative to an immune complex comprising an autoantibody (i.e., an anti-TSHR autoantibody) that binds to one corresponding molecule having a wild-type Fc domain. In some embodiments, the immune complex formed with two molecules described herein and an autoantibody (i.e., an anti-TSHR autoantibody) exhibits enhanced binding kinetics with FcγRIIB, relative to an immune complex comprising two corresponding molecules having a wild-type Fc domain. Such enhanced binding kinetics increase the clearance of the immune complex.

[0176] Autoantibody binding domain This disclosure provides molecules comprising an autoantibody-binding domain. The autoantibody-binding domain may comprise any domain that binds to an autoantibody driving an autoimmune disease (e.g., an anti-TSHR antibody). In some embodiments, the autoantibody-binding domain comprises an autoantigen or a fragment or variant thereof (e.g., a TSHR autoantigen domain or a fragment or variant thereof). In some embodiments, the autoantibody-binding domain comprises a binding domain that targets any portion or region or epitope on the autoantibody. In some embodiments, the autoantibody-binding domain comprises a Fab domain, scFv domain, VHH, Fc domain, peptide sequence, mimic epitope, and / or any portion of the autoantigen domain targeted by the autoantibody.

[0177] In some implementations, the autoantibody binding domain described herein prevents autoantibodies from binding to their homologous autoantigens (e.g., autoantibodies against TSHR autoantigens).

[0178] Autoantigen In some embodiments, the molecule includes an autoantibody-binding domain containing an autoantigen or a fragment or variant thereof. Such autoantigen domains target autoantibodies associated with various autoimmune diseases. For example, the TSHR autoantigen domain (or a fragment or variant thereof) can be used in a molecule to target anti-TSHR autoantibodies known to cause autoimmune diseases such as Graves' disease and thyroid ophthalmopathy.

[0179] TSHR belongs to the class A family of G protein-coupled receptors containing leucine-rich repeat sequences, including follicle-stimulating hormone (FSH). The first 21 amino acids (as shown in SEQ ID NO: 9) are a signal peptide that is eventually cleaved. The remaining amino acid sequence contains an N-terminal leucine-rich repeat domain (LRD, amino acids 22-281), a hinge or cleavage domain (CD, amino acids 282-409), and a transmembrane domain (TMD, amino acids 410-764). TSHR-stimulating autoantibodies (which cause Graves' disease and hyperthyroidism) bind to the LRD (see Miller-Gallacher et al., Journal of Molecular Endocrinology 62(3): 117 (2019), which is cited in full in this article.

[0180] In some embodiments, the autoantigen domain includes a thyroid-stimulating hormone receptor (TSHR) or a fragment or variant thereof. In some embodiments, the TSHR autoantigen domain comprises a fragment or variant of SEQ ID NO: 9. In some embodiments, the TSHR autoantigen domain comprises a leucine-rich repeating sequence domain of TSHR corresponding to amino acids 22-260 of SEQ ID NO: 9 or as indicated in SEQ ID NO: 1, "TSHR260". Such domains are known to interact with certain stimulating antibodies, including an autoantibody called M22 (see Miller-Gallacher et al.). Journal of Molecular Endocrinology 62(3): 117-128 (2019)). It is also known that such domains interact with antagonistic antibodies such as K1-70 (see Miller-Gallacher et al., Journal of Molecular Endocrinology62(3): 117-128 (2019)). In some embodiments, the TSHR self-antigen domain comprises a fragment of TSHR corresponding to amino acids 22-289 of SEQ ID NO: 9 (human wild-type TSHR) or "TSHR289" as indicated in SEQ ID NO: 5. In some embodiments, the self-antigen domain comprises an amino acid sequence or a fragment thereof that is at least 90% identical to the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 5. In some embodiments, the self-antigen domain comprises the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 5 or a fragment thereof.

[0181] In some implementations, the TSHR autoantigen domain contains one or more mutations that increase stability while retaining binding to either stimulating anti-TSHR autoantibodies (e.g., M22) or TSH-blocking anti-TSHR autoantibodies (e.g., K1-70). Certain mutations introduced in TSHR260 have been shown to produce TSHR260 mutants with approximately 900-fold greater thermostability than wild-type TSHR and TSHR260 (see Miller-Gallacher et al.). Journal of Molecular Endocrinology 62(3): 117-128 (2019)).

[0182] In some embodiments, the self-antigen domain comprises a human TSHR self-antigen domain variant that contains one or more of the following mutations relative to the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 5: R112P, D143P, V169R, I253R, H63S, or any combination thereof. In some embodiments, the self-antigen domain comprises a human TSHR self-antigen domain variant that contains the following mutations relative to the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 5: R112P and D143P (see, for example, SEQ ID NO: 2 and 6). In some embodiments, the self-antigen domain comprises a human TSHR self-antigen domain variant that contains the following mutations relative to the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 5: R112P, D143P, V169R, and I253R (see, for example, SEQ ID NO: 3 and 7). In some embodiments, the self-antigen domain comprises a human TSHR self-antigen domain variant that contains the following mutations relative to the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 5: R112P, D143P, and H63S (see, for example, SEQ ID NO: 4 and 8).

[0183] In some embodiments, the self-antigen domain comprises a human TSHR self-antigen domain variant that contains one or more of the following mutations relative to the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 5: S94, G194P, K218P, V87P, G137P, G188P, or any combination thereof. In some embodiments, the self-antigen domain comprises a human TSHR self-antigen domain variant that contains the mutation S94P relative to the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 5 (see, for example, SEQ ID NO: 307). In some embodiments, the self-antigen domain comprises a human TSHR self-antigen domain variant that contains the following mutations relative to the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 5: S94P and G194P (see, for example, SEQ ID NO: 308). In some embodiments, the self-antigen domain comprises a human TSHR self-antigen domain variant containing the following mutations relative to the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 5: S94P, G194P, and K218P (see, for example, SEQ ID NO: 309). In some embodiments, the self-antigen domain comprises a human TSHR self-antigen domain variant containing the following mutations relative to the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 5: V87P, S94P, G194P, and K218P (see, for example, SEQ ID NO: 310). In some embodiments, the self-antigen domain comprises a human TSHR self-antigen domain variant containing the following mutations relative to the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 5: V87P, S94P, and G194P (see, for example, SEQ ID NO: 311). In some embodiments, the self-antigen domain comprises a human TSHR self-antigen domain variant that contains the following mutations relative to the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 5: V87P, G194P, and K218P (see, for example, SEQ ID NO: 312).In some embodiments, the self-antigen domain comprises a human TSHR self-antigen domain variant containing the following mutations relative to the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 5: V87P and G194P (see, for example, SEQ ID NO: 313). In some embodiments, the self-antigen domain comprises a human TSHR self-antigen domain variant containing the mutation G194P relative to the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 5 (see, for example, SEQ ID NO: 314). In some embodiments, the self-antigen domain comprises a human TSHR self-antigen domain variant containing the following mutations relative to the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 5: G194P and K218P (see, for example, SEQ ID NO: 315). In some embodiments, the self-antigen domain comprises a human TSHR self-antigen domain variant containing the following mutations relative to the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 5: V87P, S94P, G137P, G194P, and K218P (see, for example, SEQ ID NO: 316). In some embodiments, the self-antigen domain comprises a human TSHR self-antigen domain variant containing the following mutations relative to the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 5: V87P, S94P, G137P, G188P, G194P, and K218P (see, for example, SEQ ID NO: 317).

[0184] In some embodiments, the self-antigen domain comprises a human TSHR self-antigen domain variant comprising a sequence at least 90% identical to any one of SEQ ID NOs: 1-8 and 307-317 (shown in Table 1 below). In some embodiments, the self-antigen domain comprises a human TSHR self-antigen domain variant comprising a sequence selected from SEQ ID NOs: 1-8 and 307-317 (shown in Table 1 below).

[0185] Table 1: Exemplary TSHR antigen sequences Antigen-binding domain In some embodiments, the molecules provided herein comprise one or more antigen-binding domains (e.g., as shown in the image). Figure 3 (As shown). In some embodiments, the antigen-binding domain binds to an internalized receptor (e.g., FcγRIIB, FcRn, ASGPR, BCMA, CD38, SLAMF7, GPCR5D, and / or CD138).

[0186] The antigen-binding domain can include, but is not limited to, monoclonal antibodies, synthetic antibodies, human antibodies, humanized antibodies, non-human antibodies, and any fragment thereof. Thus, in one embodiment, the antigen-binding domain portion comprises a mammalian antibody or a fragment thereof. In some embodiments, the antigen-binding domain contained in the molecule can be any binding polypeptide, such as, but not limited to, a protein scaffold having antibody-like properties (e.g., an antibody variable domain), and any other immune-binding motif known in the art, including, for example, Fab, Fab', Fab'2, Fab2, Fab3, F(ab')2, Fd, Fv, sdAb, scFv, SMIP, biantibodies, triantibodies, tetraantibodies, microantibodies, nanobodies, large antibodies, tandab, DVD, BiTe, TandAb, VHH, peptide sequences or mimic epitopes, or any combination thereof.

[0187] In some embodiments, the antigen-binding domain binds to an autoantibody (e.g., an anti-TSHR autoantibody). In some embodiments, the antigen-binding domain binds to an internalization receptor (e.g., FcγRIIB, FcRn, ASGPR, BCMA, CD38, SLAMF7, GPCR5D, and / or CD138).

[0188] In some embodiments, the molecules described herein comprise antigen-binding domains that target two or more targets. In some embodiments, the antigen-binding domain is a bispecific antigen-binding domain. In some embodiments, the antigen-binding domain comprises a trispecific antigen-binding domain. In some embodiments, the antigen-binding domain targets two non-overlapping epitopes on the same target (e.g., two non-overlapping epitopes on FcγRIIB, FcRn, ASGPR, BCMA, CD38, SLAMF7, GPCR5D, and / or CD138 in the case of targeting an antigen-binding domain of an internalizing receptor, or two non-overlapping epitopes of an autoantibody).

[0189] In some embodiments, the molecule may include a first antigen-binding domain and a second antigen-binding domain, such that each antigen-binding domain is capable of binding to the same or different target antigens. In some embodiments, the first antigen-binding domain targets an autoantibody (e.g., an anti-TSHR autoantibody), and the second antigen-binding domain targets an internalization receptor (e.g., FcγRIIB, FcRn, ASGPR, BCMA, CD38, SLAMF7, GPCR5D, and / or CD138).

[0190] In some embodiments, the antigen-binding domain comprises a Fab, which contains heavy and light chain antibody components. In some embodiments, the antigen-binding domain comprises a Fab containing any of the following specific heavy and light chain antibody sequences shown in Table 2.

[0191] In some embodiments, the antigen-binding domain is a Fab comprising an antibody heavy chain sequence that is at least 90% identical to that of SEQ ID NO: 209 and / or an antibody light chain sequence that is at least 90% identical to that of SEQ ID NO: 210. In some embodiments, the antigen-binding domain is a Fab comprising the antibody heavy chain sequence of SEQ ID NO: 209 and / or the antibody light chain sequence of SEQ ID NO: 210.

[0192] Table 2: Other exemplary antigen-binding domain sequences Fc structural domain In some embodiments, the molecule described herein comprises a first polypeptide containing an autoantigen domain linked to a first Fc domain, the autoantigen domain containing a TSHR autoantigen domain or a fragment or variant thereof; and a second polypeptide containing a second Fc domain. The TSHR autoantigen domain or a fragment or variant thereof targets an anti-TSHR autoantibody, and upon binding, causes the complex to target and internalize the receptor and shuttle to the lysosome to degrade the anti-TSHR autoantibody.

[0193] In some embodiments, the Fc domain described herein contains one or more mutations that alter its binding affinity to certain Fc receptors (e.g., FcγRIIB, FcγRI, FcγRIIA167H, FcγRIIA167R, FcγRIIIA176F, FcγRIIIA176V, FcγRIIIB and / or FcRn).

[0194] In some embodiments, the first Fc domain and the second Fc domain are identical (e.g., in the case of homodimer molecules). In some embodiments, the first Fc domain and the second Fc domain are different (e.g., in the case of heterodimer molecules).

[0195] In some embodiments, the Fc domain comprises one or more mutant amino acid residues and has reduced binding affinity for FcγRI, FcγRIIA167H, FcγRIIA167R, FcγRIIIA176F, FcγRIIIA176V, FcγRIIIB, FcγRIIIB, and / or FcRn relative to the corresponding wild-type Fc domain. In some embodiments, the Fc domain comprises one or more mutant amino acid residues and has substantially no binding affinity for FcγRI, FcγRIIA167H, FcγRIIA167R, FcγRIIIA176F, FcγRIIIA176V, FcγRIIIB, FcγRIIIB, and / or FcRn relative to the corresponding wild-type Fc domain.

[0196] In some embodiments, the first and / or second Fc domains of the molecule contain modifications (e.g., one or more mutations) that enhance binding to internalized receptors. In some embodiments, the first and / or second Fc domains of the molecule contain modifications (e.g., one or more mutations) that reduce binding to certain Fc receptors. In some embodiments, the first and / or second Fc domains of the molecule contain modifications (e.g., one or more mutations) that enhance other characteristics of the molecule described herein (e.g., increased half-life, heterodimerization, etc.).

[0197] The Fc domain contained in the molecule may comprise any of the five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM. In some embodiments, the conventional antibody comprises an IgG antibody. In some embodiments, the Fc domain described herein comprises a specific isotype selected from the group of IgG isotypes: IgG1, IgG2, IgG3, and IgG4. In some embodiments, the molecule comprises a first and / or second Fc domain as an IgG1 isotype. In some embodiments, the molecule comprises a first and / or second Fc domain as a human IgG1 isotype. Additionally, in some embodiments, the Fc domain may comprise any specific heavy chain constant domain corresponding to different classes of immunoglobulins (including α, δ, ε, γ, and μ). In some embodiments, the conventional antibody is a complete IgG1 antibody or other antibody classes or isotypes as described herein (see, for example, Hudson et al.). Nat. Med 9:129 (2003); Pluckthun, The Pharmacology of Monoclonal Antibodies, 113:269 (1994); Hollinger et al., Proc. Natl. Acad. Sci. USA 90: 6444(1993); WO 1993 / 01161; and U.S. Patent Nos. 5,571,894, 5,869,046, 6,248,516 and 5,587,458, each incorporated herein by reference.

[0198] The Fc region of the antibody contained in the molecules described herein can bind to elements of the complement system and also to receptors on effector cells, including, for example, effector cells mediating cytotoxicity. As is known in the art, the affinity and / or other binding properties of the Fc region to Fc receptors can be modulated by glycosylation or other modifications. In some embodiments, the molecules described herein comprise glycosylated Fc domains, including modified or engineered glycosylated Fc domains. In some embodiments, the molecules are naturally occurring (e.g., produced by an organism that responds to an antigen) or generated through recombinant engineering, chemical synthesis, or other artificial systems or methods.

[0199] In some embodiments, one or more modifications to the Fc domain increase the clearance of immune complexes formed by one or more molecules described herein that bind to an autoantibody (e.g., an anti-TSHR autoantibody). In some embodiments, one or more modifications to the Fc domain can induce selective targeting and / or clearance of immune complexes formed by one or more molecules described herein that bind to a target antibody. For example, in some embodiments, an immune complex with enhanced binding kinetics to one or more Fc receptors (e.g., FcγRIIB) is formed relative to an immune complex containing two corresponding molecules having a wild-type Fc domain (e.g., an anti-TSHR autoantibody) after the binding of two molecules to an autoantibody (e.g., an anti-TSHR autoantibody). The binding kinetics may be characterized by, for example, an increase in association rate, a decrease in dissociation rate, and / or a change in the equilibrium dissociation constant. In some embodiments, the Fc domain preferentially binds to immune cells expressing FcγRIIB relative to immune cells expressing FcγRIIA. In some embodiments, the Fc domain has essentially no binding affinity for cells that do not express FcγRIIB (e.g., T cells, NK cells, neutrophils, and / or eosinophils). In some embodiments, the immune cells expressing FcγRIIB are B cells, monocytes, and / or basophils.

[0200] In some embodiments, enhanced binding kinetics includes an immune complex binding affinity to one or more Fc receptors (e.g., FcγRIIB) that is at least 10% higher. In some embodiments, enhanced binding kinetics includes binding affinity of at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% or higher.

[0201] In some embodiments, the molecule binds to FcγRIIB with an affinity in the range of about 1 µM to 0.001 µM. In some embodiments, the molecule binds to FcγRIIB with an affinity in the range of about 1 µM to 0.01 µM. In some embodiments, the molecule binds to FcγRIIB with an affinity in the range of about 0.1 µM to 0.01 µM.

[0202] In some embodiments, the Fc domain described herein contains one or more modifications such that the molecule described herein does not activate immune cells (e.g., does not activate immune cells to secrete pro-inflammatory cytokines, such as IL-6).

[0203] Exemplary Fc domain sequences used according to this disclosure are shown in Table 3 below. It should be understood that any of these Fc domain sequences can be used in the first or second polypeptide of the molecules of this disclosure. It should also be understood that any of the exemplary Fc domain sequences having a club-shaped mutation (identified by the reference symbol “club”) can be used together with any of the exemplary Fc domain sequences having a mortar-shaped mutation (identified by the reference symbol “mortar”) to prepare heterodimeric molecules. In some embodiments, the Fc domain sequences shown in Table 3 can be used in pairs to prepare heterodimeric molecules, for example, but not limited to, based on the numerical references in Table 3 (e.g., human IgG1 Fc 1.1 club-shaped can be used with human IgG1 Fc 1.1 mortar-shaped, human IgG1 Fc 1.2 club-shaped can be used with human IgG1 Fc 1.2 mortar-shaped, etc.). It should also be understood that the Fc domain sequences mentioned in Table 3 that can be used for "antigen arms for Ag depletion" (i.e., in peptides that also contain an autoantibody binding domain) or "free arms for Ag depletion" (i.e., in peptides that do not contain an autoantibody binding domain) are intended to be exemplary and non-limiting only. That is, the Fc domain sequences in Table 3 that are identified as being usable for "antigen arms for Ag depletion" may be used for "free arms for Ag depletion" in some embodiments, and the Fc domain sequences in Table 3 that are marked as being usable for "free arms for Ag depletion" may be used for "antigen arms for Ag depletion" in some embodiments.

[0204] Table 3: Exemplary Fc domain sequences In some embodiments, the first Fc domain comprises a sequence selected from SEQ ID NO: 103, SEQ ID NO: 105, SEQ ID NO: 107, SEQ ID NO: 109, SEQ ID NO: 113, SEQ ID NO: 115, SEQ ID NO: 117, SEQ ID NO: 119, SEQ ID NO: 121, SEQ ID NO: 123, SEQ ID NO: 125, SEQ ID NO: 127, SEQ ID NO: 129, SEQ ID NO: 131, SEQ ID NO: 133, SEQ ID NO: 135, SEQ ID NO: 137, SEQ ID NO: 376, and SEQ ID NO: 378, and the second Fc domain comprises a sequence selected from SEQ ID NO: 104, SEQ ID NO: 106, SEQ ID NO: 108, SEQ ID NO: 110, SEQ ID NO: 114 ... 116. SEQ ID NO: 118, SEQ ID NO: 120, SEQ ID NO: 122, SEQ ID NO: 124, SEQ ID NO: 126, SEQ ID NO: 128, SEQ ID NO: 130, SEQ ID NO: 132, SEQ ID NO: 134, SEQ ID NO: 136, SEQ ID NO: 138, SEQ The sequence of ID NO: 377 and SEQ ID NO: 379.

[0205] In some embodiments, the first Fc domain comprises a sequence selected from SEQ ID NO: 103, SEQ ID NO: 105, SEQ ID NO: 113, SEQ ID NO: 115, SEQ ID NO: 117, SEQ ID NO: 121, SEQ ID NO: 123, SEQ ID NO: 125, SEQ ID NO: 376, and SEQ ID NO: 378, and the second Fc domain comprises a sequence selected from SEQ ID NO: 104, SEQ ID NO: 106, SEQ ID NO: 114, SEQ ID NO: 116, SEQ ID NO: 118, SEQ ID NO: 122, SEQ ID NO: 124, SEQ ID NO: 126, SEQ ID NO: 377, and SEQ ID NO: 379.

[0206] In some embodiments, the first Fc domain comprises a sequence selected from SEQ ID NO: 107, SEQ ID NO: 109, SEQ ID NO: 119, SEQ ID NO: 127, SEQ ID NO: 129, SEQ ID NO: 131, SEQ ID NO: 133, SEQ ID NO: 135, and SEQ ID NO: 137, and the second Fc domain comprises a sequence selected from SEQ ID NO: 108, SEQ ID NO: 110, SEQ ID NO: 120, SEQ ID NO: 128, SEQ ID NO: 130, SEQ ID NO: 132, SEQ ID NO: 134, SEQ ID NO: 136, and SEQ ID NO: 138.

[0207] In some embodiments, the first Fc domain contains the sequence of SEQ ID NO: 103, and the second Fc domain contains the sequence of SEQ ID NO: 104. In some embodiments, the first Fc domain contains the sequence of SEQ ID NO: 105, and the second Fc domain contains the sequence of SEQ ID NO: 106. In some embodiments, the first Fc domain contains the sequence of SEQ ID NO: 107, and the second Fc domain contains the sequence of SEQ ID NO: 108. In some embodiments, the first Fc domain contains the sequence of SEQ ID NO: 109, and the second Fc domain contains the sequence of SEQ ID NO: 110. In some embodiments, the first Fc domain contains the sequence of SEQ ID NO: 113, and the second Fc domain contains the sequence of SEQ ID NO: 114. In some embodiments, the first Fc domain contains the sequence of SEQ ID NO: 115, and the second Fc domain contains the sequence of SEQ ID NO: 116. In some embodiments, the first Fc domain contains the sequence of SEQ ID NO: 117, and the second Fc domain contains the sequence of SEQ ID NO: 118. In some embodiments, the first Fc domain contains the sequence of SEQ ID NO: 119, and the second Fc domain contains the sequence of SEQ ID NO: 120. In some embodiments, the first Fc domain contains the sequence of SEQ ID NO: 121, and the second Fc domain contains the sequence of SEQ ID NO: 122. In some embodiments, the first Fc domain contains the sequence of SEQ ID NO: 123, and the second Fc domain contains the sequence of SEQ ID NO: 124. In some embodiments, the first Fc domain contains the sequence of SEQ ID NO: 125, and the second Fc domain contains the sequence of SEQ ID NO: 126. In some embodiments, the first Fc domain contains the sequence of SEQ ID NO: 127, and the second Fc domain contains the sequence of SEQ ID NO: 128. In some embodiments, the first Fc domain contains the sequence of SEQ ID NO: 129, and the second Fc domain contains the sequence of SEQ ID NO: 130. In some embodiments, the first Fc domain contains the sequence of SEQ ID NO: 131, and the second Fc domain contains the sequence of SEQ ID NO: 132. In some embodiments, the first Fc domain contains the sequence of SEQ ID NO: 133, and the second Fc domain contains the sequence of SEQ ID NO: 134.In some embodiments, the first Fc domain contains the sequence of SEQ ID NO: 135, and the second Fc domain contains the sequence of SEQ ID NO: 136. In some embodiments, the first Fc domain contains the sequence of SEQ ID NO: 137, and the second Fc domain contains the sequence of SEQ ID NO: 138. In some embodiments, the first Fc domain contains the sequence of SEQ ID NO: 376, and the second Fc domain contains the sequence of SEQ ID NO: 377. In some embodiments, the first Fc domain contains the sequence of SEQ ID NO: 378, and the second Fc domain contains the sequence of SEQ ID NO: 379. In some embodiments, the first Fc domain contains the sequence of SEQ ID NO: 111, and the second Fc domain contains the sequence of SEQ ID NO: 111. In some embodiments, the first Fc domain contains the sequence of SEQ ID NO: 139, and the second Fc domain contains the sequence of SEQ ID NO: 139. In some embodiments, the first Fc domain contains the sequence of SEQ ID NO: 140, and the second Fc domain contains the sequence of SEQ ID NO: 140. In some embodiments, the first Fc domain contains the sequence of SEQ ID NO: 141, and the second Fc domain contains the sequence of SEQ ID NO: 141. In some embodiments, the first Fc domain contains the sequence of SEQ ID NO: 142, and the second Fc domain contains the sequence of SEQ ID NO: 142. In some embodiments, the first Fc domain contains the sequence of SEQ ID NO: 143, and the second Fc domain contains the sequence of SEQ ID NO: 143. In some embodiments, the first Fc domain contains the sequence of SEQ ID NO: 144, and the second Fc domain contains the sequence of SEQ ID NO: 144. In some embodiments, the first Fc domain contains the sequence of SEQ ID NO: 145, and the second Fc domain contains the sequence of SEQ ID NO: 145. In some embodiments, the first Fc domain contains the sequence of SEQ ID NO: 146, and the second Fc domain contains the sequence of SEQ ID NO: 146. In some embodiments, the first Fc domain contains the sequence of SEQ ID NO: 147, and the second Fc domain contains the sequence of SEQ ID NO: 147. In some embodiments, the first Fc domain contains the sequence of SEQ ID NO: 148, and the second Fc domain contains the sequence of SEQ ID NO: 148.In some embodiments, the first Fc domain contains the sequence of SEQ ID NO: 149, and the second Fc domain contains the sequence of SEQ ID NO: 149. In some embodiments, the first Fc domain contains the sequence of SEQ ID NO: 163, and the second Fc domain contains the sequence of SEQ ID NO: 163. In some embodiments, the first Fc domain contains the sequence of SEQ ID NO: 164, and the second Fc domain contains the sequence of SEQ ID NO: 164. In some embodiments, the first Fc domain contains the sequence of SEQ ID NO: 374, and the second Fc domain contains the sequence of SEQ ID NO: 374. In some embodiments, the first Fc domain contains the sequence of SEQ ID NO: 375, and the second Fc domain contains the sequence of SEQ ID NO: 375.

[0208] Hinge sequence In some embodiments, the Fc domain comprises a hinge sequence. In some embodiments, the Fc domain comprises the amino acid sequence of SEQ ID NO: 299 (DKTHTCPPCP). In some embodiments, the Fc domain comprises the amino acid sequence of SEQ ID NO: 300 (EPKSSDKTHTCPPCP). In some embodiments, the Fc domain comprises the amino acid sequence of SEQ ID NO: 301 (ERKCCVECPPCP). In some embodiments, the Fc domain comprises the amino acid sequence of SEQ ID NO: 302 (ELKTRPLGDTTHTCPPCP). In some embodiments, the Fc domain comprises the amino acid sequence of SEQ ID NO: 303 (ELKTRPLGDTTHTCPRCP(EPKSCDTPPPCPRCP)3). In some embodiments, the Fc domain comprises the amino acid sequence of SEQ ID NO: 304 (ESKYGPPCPPCP).

[0209] In this context, it should be understood that any of the exemplary Fc domain sequences provided in Table 3 can be modified by replacing the hinge sequence of SEQ ID NO: 299 (DKTHTCPPCP) or SEQ ID NO: 300 (EPKSSDKTHTCPPCP) with the hinge sequence of SEQ ID NO: 301 (ERKCCVECPPCP), SEQ ID NO: 302 (ELKTRPLGDTTHTCPPCP), SEQ ID NO: 303 (ELKTRPLGDTTHTCPRCP(EPKSCDTPPPCPRCP)3), SEQ ID NO: 304 (ESKYGPPCPPCP), or any other suitable hinge sequence (including variants of the hinge sequence of SEQ ID NO: 299-304 containing 1, 2, 3, 4, 5 or more mutations).

[0210] Mutations that increase binding to internalization receptors In some embodiments, additional mutations are introduced into the Fc domain of the molecule described herein to target and internalize ligands and to target the ligands to lysosomal cell surface receptors (i.e., internalization receptors or endocytic receptors). By modifying the Fc domain to increase binding to internalization receptors, the molecule described herein and its bound autoantibodies are targeted for internalization and lysosomal degradation.

[0211] In some embodiments, the molecule includes a first and / or a second Fc domain containing one or more mutant amino acid residues that alter its binding to an internalization receptor on a cell, wherein the internalization receptor is capable of shuttling its cargo to the lysosomes of the cell, thereby leading to degradation. In some embodiments, the altered binding to the internalization receptor includes an increased binding to the internalization receptor. Without wishing to be bound by any theory, once the molecule binding to the autoantibody binds to the internalization receptor on the cell, the internalization receptor internalizes the molecule and the autoantibody is shuttled to the lysosomes of the cell for degradation.

[0212] Exemplary internalizing receptors include, but are not limited to, FcγRIIB, FcRn, ASGPR, BCMA, CD38, SLAMF7, GPCR5D, or CD138.

[0213] In some embodiments, the first and / or second Fc domains comprise one or more mutant amino acid residues that enhance binding to human FcγR (particularly FcγRIIB). In some embodiments, according to the EU numbering scheme, such mutations comprise at least one of the following mutant amino acid residues: S267E and L328F. In some embodiments, according to the EU numbering scheme, the first and / or second Fc domains comprise a combination of the following mutant amino acid residues: S267E and L328F. In some embodiments, according to the EU numbering scheme, the first and / or second Fc domains comprise the mutant amino acid residue P238D. In some embodiments, according to the EU numbering scheme, the first and / or second Fc domains comprise at least one of the following mutant amino acid residues: L234A, L235A, and P238D. In some embodiments, according to the EU numbering scheme, the first and / or second Fc domains comprise the following mutant amino acid residues: L234A, L235A, and P238D. In some embodiments, according to the EU numbering scheme, the first and / or second Fc domains comprise at least one of the following mutant amino acid residues: L234A, L235A, P238D, and P329G. In some embodiments, according to the EU numbering scheme, the first and / or second Fc domains comprise at least one of the following mutant amino acid residues: L234A, L235A, and P238D. In some embodiments, according to the EU numbering scheme, the first and / or second Fc domains comprise at least one of the following mutant amino acid residues: L234A, L235A, and P238D. In some embodiments, according to the EU numbering scheme, the first and / or second Fc domains comprise at least one of the following mutant amino acid residues: N297A and P238D. In some implementations, according to the EU numbering scheme, the first and / or second Fc domains contain the following mutant amino acid residues: N297A and P238D.

[0214] In some embodiments, one or more Fc mutations are introduced to increase binding to the human neonatal receptor (FcRn). In some embodiments, the Fc domain is the IgG1 Fc domain. Human IgG1 naturally binds to FcRn at acidic pH, which allows it to be recycled back to the cell surface after binding to FcRn and internalization into the cell without being degraded in lysosomes. In some embodiments, the Fc mutations include mutations that increase binding to FcRn in a neutral pH environment (e.g., the extracellular environment). Without wishing to be bound by any theory, such mutations are included in the molecules described herein to increase the binding of the Fc domain to FcRn on the cell surface in a neutral pH environment, thereby increasing the receptor-mediated internalization into the cell and the shuttle transport of (molecule-bound) autoantibodies to lysosomes.

[0215] In some embodiments, the first and / or second Fc domains contain one or more mutant amino acid residues that increase binding to FcRn at neutral or near-neutral pH (e.g., between about 6.8 and 7.5). In some embodiments, the first and / or second Fc domains contain a human IgG1 isotype and remain bound to FcRn upon entry into an environment with an acidic pH and / or a low calcium concentration (e.g., endosomes within a cell). In some embodiments, according to the EU numbering scheme, the first and / or second Fc domains contain at least one of the following mutant amino acid residues: M252Y, S254T, T256E, H433K, and N434F. In some embodiments, according to the EU numbering scheme, such mutations include combinations containing the following mutations: M252Y, S254T, T256E, H433K, and N434F (i.e., "MST-HN"). In some implementations, according to the EU numbering scheme, the first and / or second Fc domains contain a combination of the following mutant amino acid residues: M252Y, S254T, T256E, H433K, and N434F (i.e., "MST-HN").

[0216] In some embodiments, the first and / or second Fc domains comprise at least one mutant amino acid sequence that reduces binding to one or more Fc-γ receptors (FcγRs). Such modifications can prevent immune cross-linking leading to an inflammatory response (i.e., immune cross-linking of the molecule, autoantibodies, and FcγRs). Such mutations can focus the molecule's primary mechanism of action on (i.e.) the targeted internalization and subsequent degradation of autoantibodies. In some embodiments, according to the EU numbering scheme, the first and / or second Fc domains comprise at least one of the following mutant amino acid residues: G236R and L328R.

[0217] In some embodiments, the molecule described herein may comprise any combination of the aforementioned Fc mutations that alter the binding to the internalizing receptor or Fc receptor. In some embodiments, the molecule described herein comprises an Fc domain comprising a combination of the “MST-HN” modification and the “RR” mutation described herein. In some embodiments, the molecule described herein comprises an Fc domain comprising a combination of the “MST-HN” modification and the “P238D” mutation described herein. In some embodiments, the molecule described herein comprises an Fc domain comprising a combination of the “MST-HN” modification and the “RR” and “P238D” mutations described herein.

[0218] i. Exemplary FcγRIIB mutation In some embodiments, the Fc domain contains one or more amino acid mutations that increase affinity for FcγRIIB. In some embodiments, FcγRIIB is human FcγRIIB. In some embodiments, FcγRIIB is mouse FcγRIIB.

[0219] In some embodiments, the Fc domain is used in the molecule described herein, which contains one or more mutations that enhance the binding kinetics of an immune complex comprising one or more molecules binding to a target antibody to FcγRIIB. In some embodiments, enhanced binding kinetics include a binding affinity of at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% or higher. In some embodiments, enhanced binding kinetics include an increase in the affinity, stability, strength, frequency, and / or duration of the binding between the immune complex and FcγRIIB. In some embodiments, enhanced binding kinetics include an increase in the association rate, a decrease in the dissociation rate, and / or a change in the equilibrium dissociation constant.

[0220] In some embodiments, the molecules described herein having first and second Fc domains contain one or more mutations in the first and / or second Fc domains to increase binding to FcγRIIB, wherein, after the two molecules bind to the target antibody, an immune complex with enhanced binding kinetics to FcγRIIB is formed relative to an immune complex containing the target antibody that binds to the two corresponding molecules having wild-type Fc domains. Not wishing to be bound by any theory, the molecules described herein may have one or more mutations that increase binding affinity to FcγRIIB, but the binding affinity of the individual molecule to FcγRIIB is moderate. In some embodiments, the molecule binds to FcγRIIB with an affinity in the range of about 1 µM to 0.001 µM. In some embodiments, the molecule binds to FcγRIIB with an affinity in the range of about 1 µM to 0.01 µM. In some embodiments, the molecule binds to FcγRIIB with an affinity in the range of about 0.1 µM to 0.01 µM. In some embodiments, when two or more molecules are present in an immune complex containing a target antibody, such mutations, when introduced into the Fc domain of the molecule described herein, confer an affinity-mediated binding effect to FcγRIIB. In some embodiments, the molecule described herein has increased binding to FcγRIIB when the immune complex contains two molecules that bind to the target antibody, compared to an immune complex containing only one molecule that binds to the target antibody. While not wishing to be bound by any theory, this affinity-mediated effect allows for selective binding and depletion of the immune complex, and allows for weaker binding (and therefore depletion) of the molecule when it is not part of the immune complex. These characteristics allow the molecule described herein to circulate in the subject's bloodstream for a longer period before being cleared by FcγRIIB-mediated internalization and degradation.

[0221] Furthermore, this disclosure provides Fc domain mutations that achieve binding affinity for FcγRIIB to confer affinity-mediated effects, thereby utilizing the benefits and additional selectivity described herein. In some embodiments, exemplary Fc domain mutations that can be used to achieve these binding kinetics with FcγRIIB, according to the EU numbering scheme, include one or more of the following mutations: E233V, L234D, L235F, G236R, G237D, S239L, S267D, H268P, S298G, T299A, A327L, L328A, A330H, E3 33I, R292Q, E233P, P238D, H268D, P271G, A330R, L234Y, T250V, V264I, T307P, Q311R, A330K, P343R, M428L, N434A, Y436T, Q438R, S440E, G236N, S267E, L235R, D270E, E233D, and G237D.

[0222] In some embodiments, the Fc domain mutation includes one or more of the following mutations: E233V, L234D, L235F, G236R, G237D, S239L, S267D, H268P, S298G, T299A, A327L, L328A, A330H, or E333I. In some embodiments, according to the EU numbering scheme, the Fc domain contains the following mutation set: E233V, L234D, L235F, G236R, G237D, S239L, S267D, H268P, S298G, T299A, A327L, L328A, A330H, and E333I (e.g., see SEQ ID NO: 113, 114, and 139).

[0223] In some embodiments, according to the EU numbering scheme, the Fc domain mutation includes one or more of the following mutations: E233V, L234D, L235F, G236R, G237D, S239L, S267D, R292Q, H268P, S298G, T299A, A327L, L328A, A330H, or E333I. In some embodiments, according to the EU numbering scheme, the Fc domain contains the following mutation set: E233V, L234D, L235F, G236R, G237D, S239L, S267D, R292Q, H268P, S298G, T299A, A327L, L328A, A330H, and E333I (e.g., see SEQ ID NO: 115, 116, and 140).

[0224] In some embodiments, according to the EU numbering scheme, the Fc domain mutation includes one or more of the following mutations: E233V, L234D, L235F, G236R, G237D, S239L, H268P, R292Q, S298G, T299A, A327L, L328A, A330H, or E333I. In some embodiments, according to the EU numbering scheme, the Fc domain contains the following mutation set: E233V, L234D, L235F, G236R, G237D, S239L, H268P, R292Q, S298G, T299A, A327L, L328A, A330H, and E333I (e.g., see SEQ ID NO: 117, 118, and 141).

[0225] In some embodiments, according to the EU numbering scheme, Fc domain mutations include one or more of the following mutations: L234Y, P238D, T250V, V264I, T307P, Q311R, A330K, P343R, M428L, N434A, Y436T, Q438R, or S440E. In some embodiments, according to the EU numbering scheme, the Fc domain contains the following mutation set: L234Y, P238D, T250V, V264I, T307P, Q311R, A330K, P343R, M428L, N434A, Y436T, Q438R, and S440E (e.g., see SEQ ID NO: 119, 120, and 142).

[0226] In some embodiments, according to the EU numbering scheme, the Fc domain mutation includes one or more of the following mutations: L234D, G236N, or S267E. In some embodiments, according to the EU numbering scheme, the Fc domain contains the following mutation set: L234D, G236N, and S267E (see, for example, SEQ ID NO: 121, 122, and 143).

[0227] In some implementations, according to the EU numbering scheme, Fc domain mutations include L235R (e.g., see SEQ ID NO: 123, 124 and 144).

[0228] In some embodiments, according to the EU numbering scheme, the Fc domain mutation includes one or both of the following mutations: G236N and S267E. In some embodiments, according to the EU numbering scheme, the Fc domain contains the following mutation set: G236N and S267E (e.g., see SEQ ID NO: 125, 126, and 145).

[0229] In some embodiments, according to the EU numbering scheme, the Fc domain mutation includes one or both of the following mutations: P238D and D270E. In some embodiments, according to the EU numbering scheme, the Fc domain contains the following mutation set: P238D and D270E (e.g., see SEQ ID NO: 127, 128 and 146).

[0230] In some embodiments, according to the EU numbering scheme, the Fc domain mutation includes one or both of the following mutations: P238D and P271G. In some embodiments, according to the EU numbering scheme, the Fc domain contains the following mutation set: P238D and P271G (see, for example, SEQ ID NO: 129, 130 and 147).

[0231] In some embodiments, according to the EU numbering scheme, the Fc domain mutation includes one or more of the following mutations: P238D, D270E, or P271G. In some embodiments, according to the EU numbering scheme, the Fc domain contains the following mutation set: P238D, D270E, and P271G (see, for example, SEQ ID NO: 131, 132, and 148).

[0232] In some embodiments, according to the EU numbering scheme, the Fc domain mutation includes one or more of the following mutations: G237D, P238D, P271G, or A330R. In some embodiments, according to the EU numbering scheme, the Fc domain contains the following mutation set: G237D, P238D, P271G, and A330R (see, for example, SEQ ID NO: 133, 134, and 149).

[0233] In some embodiments, according to the EU numbering scheme, the Fc domain mutation includes one or more of the following mutations: G237D, P238D, D270E, P271G, or A330R. In some embodiments, according to the EU numbering scheme, the Fc domain contains the following mutation set: G237D, P238D, D270E, P271G, and A330R (see, for example, SEQ ID NO: 135, 136, and 163).

[0234] In some embodiments, according to the EU numbering scheme, the Fc domain mutation includes one or more of the following mutations: E233D, G237D, P238D, H268D, P271G, or A330R. In some embodiments, according to the EU numbering scheme, the Fc domain contains the following mutation set: E233D, G237D, P238D, H268D, P271G, and A330R (see, for example, SEQ ID NO: 137, 138, and 164).

[0235] In some implementations, according to the EU numbering scheme, the Fc domain mutation includes P238D (e.g., see SEQ ID NO: 107 and 108).

[0236] In some embodiments, the mutated Fc domain having increased binding affinity for FcγRIIB also has reduced or undetectable binding to certain activating Fc receptors. In some embodiments, activating Fc receptors include one or more of FcγRI, FcγRIIA167H, FcγRIIA167R, FcγRIIIA176F, FcγRIIIA176V, FcγRIIIB, and / or FcRn. Such binding properties bring additional beneficial properties to the molecules described herein, including, for example, a low risk of toxicity because the risk of activating an innate immune response (by activating Fc receptors) in response to the introduced molecule is less.

[0237] In some embodiments, the Fc domain described herein contains one or more modifications such that the molecule described herein does not activate immune cells (e.g., does not activate immune cells to secrete pro-inflammatory cytokines, such as IL-6).

[0238] Mutations for heterodimerization In some implementations, an Fc mutation is introduced to promote heterodimerization of two peptides, wherein each peptide contains an Fc domain, and the first and second Fc domains heterodimerize to produce the complete molecule.

[0239] Obtaining heterodimerized Fc domains of two distinct peptides from a single composition is challenging, particularly because random pairing of different peptides can produce undesirable species. Complex purification procedures are required in those cases to isolate the desired antibody agent due to the presence of mismatch byproducts and significantly reduced production yields. Generally, the same problem of mismatch byproducts persists even when recombinant expression techniques are used. One approach to addressing the problem of mismatch byproducts is called the "mortar and pestle structure technique" (KIH), which aims to force pairing of two distinct peptides containing Fc domains by modifying the contact interface by introducing a mutation into the CH3 region of the Fc domain. In one CH3 region, a bulky amino acid is replaced with an amino acid with a short side chain to produce a "mortar," and an amino acid with a large side chain is introduced into the other CH3 region to produce a "pestle." For example, co-expressing the two heavy chains of an antibody with this modification with the two light chains resulted in observed high yields of heterodimer formation compared to homodimers (see Ridgway et al.). Protein Eng.9:617 (1996); and WO 1996 / 027011, which is incorporated herein by reference. In some embodiments, the molecules described herein utilize KIH technology as described, for example, WO 1998 / 050431 (which is incorporated herein by reference in its entirety).

[0240] As described herein, the molecule comprises a first Fc domain and a second Fc domain. In some embodiments, the first Fc domain and / or the second Fc domain comprises CH2 variants and / or CH3 variants, wherein each of such variants independently comprises at least one different amino acid substitution, resulting in heterodimeric domain pairs, such that heterodimerization of the first and second Fc domains of the molecule of the present invention is preferred over homodimerization.

[0241] As described herein, the first and / or second Fc domains in the molecule may contain certain mutations utilizing KIH technology, including but not limited to CH3 modification. In some embodiments, the molecule contains first and second Fc domains modified using a kidney-and-honeypot (KIH) structure to form a heterodimer. In some embodiments, according to the EU numbering scheme, the KIH mutations include Y349T and T394F. In some embodiments, the first Fc domain contains the Y349T mutation, and the second Fc domain contains the T394F mutation. In some embodiments, the first Fc domain contains the T394F mutation, and the second Fc domain contains the Y349T mutation. In some embodiments, according to the EU numbering scheme, the KIH mutations include T366W, S354C, T366S, L368A, Y407V, and Y349C. In some embodiments, the first Fc domain contains the T366W and S354C mutations, and the second Fc domain contains the T366S, L368A, Y407V, and Y349C mutations.

[0242] Those skilled in the art will understand that other known KIH mutations or other Fc modifications are known in the art to promote heterodimerization and can be used in the molecules described herein, such as charge-charge exchange designs (e.g., “DD-KK” mutant pairs) and isotype chain exchange designs (e.g., “SEED Fc”) (see Ha et al., Frontiers in Immunology 7:394 (2016), which is incorporated herein by reference in its entirety.

[0243] Mutations for extending half-life In some embodiments, the first and / or second Fc domains of the molecule contain one or more mutant amino acid residues that increase the half-life. In some embodiments, according to the EU numbering scheme, the first and / or second Fc domains contain one of the following mutant amino acid residues: M252Y, S254T, and T256E (“MST” or “YTE”) to increase the half-life. In some embodiments, according to the EU numbering scheme, the first and / or second Fc domains contain a combination of the following mutant amino acid residues: M252Y, S254T, and T256E to increase the half-life. In some embodiments, according to the EU numbering scheme, the first and / or second Fc domains contain one of the following mutant amino acid residues: M428L and N434S (“L / S”). In some embodiments, according to the EU numbering scheme, the first and / or second Fc domains contain a combination of the following mutant amino acid residues: M428L and N434S.

[0244] In some embodiments, according to the EU numbering scheme, the first and / or second Fc domains contain one of the following mutant amino acid residues: T250Q and M428L (“QL”) to increase the half-life. In some embodiments, according to the EU numbering scheme, the first and / or second Fc domains contain one of the following mutant amino acid residues: H433K and N434F (“KF”) to increase the half-life. In some embodiments, according to the EU numbering scheme, the first and / or second Fc domains contain one of the following mutant amino acid residues: T307A, E380A, and N434A (“AAA”) to increase the half-life. In some embodiments, according to the EU numbering scheme, the first and / or second Fc domains contain the following mutant amino acid residue: V308P to increase the half-life. In some embodiments, according to the EU numbering scheme, the first and / or second Fc domains contain one of the following mutated amino acid residues: M252Y, V308P, and N434Y (“YPY”) to increase the half-life. In some embodiments, according to the EU numbering scheme, the first and / or second Fc domains contain one of the following mutated amino acid residues: H285D, T307Q, and A378V (“DQV”) to increase the half-life. In some embodiments, according to the EU numbering scheme, the first and / or second Fc domains contain one of the following mutated amino acid residues: L309D, Q311H, and N434S (“DHS”) to increase the half-life. Exemplary Fc mutations are described, for example, by Liu et al. Antibodies In 9(4): 64 (2020), it is hereby incorporated in its entirety by reference.

[0245] connector The molecules described herein include an Fc domain linked to an autoantibody-binding domain. In some embodiments, the autoantibody-binding domain is directly linked to the Fc domain. In some embodiments, the autoantibody-binding domain is linked to the Fc domain via a linker. Various linkers are intended for use in the molecules described herein. While linkers may be located between the autoantibody-binding domain and the Fc domain, they may also be located between other domains of the molecule, such as linking one or more self-antigen domains within the autoantibody-binding domain.

[0246] In some embodiments, the linker includes a flexible linker to provide flexibility within the molecule (e.g., between the self-antigen domain and the Fc domain). In some embodiments, the flexible linker contains at least one flexible amino acid (e.g., Gly).

[0247] An exemplary flexible connector includes a glycine polymer (G). n Glycine-serine polymers (including, for example, (GS)) n (GSGGS: SEQ ID NO: 156) n and (GGGS: SEQ ID NO: 151) n (where n is an integer of at least 1), glycine-alanine polymers, alanine-serine polymers, and other flexible linkers known in the art. Glycine and glycine-serine polymers are relatively unstructured and therefore may be able to act as neutral linkers between components. Glycine even gains significantly more phi-psi space than alanine and is much less restricted than residues with longer side chains (see Scheraga, where n is an integer of at least 1), glycine-alanine polymers, alanine-serine polymers, and other flexible linkers known in the art. Rev. Computational Chem. 11:173-142 (1992)). In some embodiments, the adapter comprises the amino acid sequence of SEQ ID NO: 150 (GGGGS), SEQ ID NO: 151 (GGGGSGGGGS), SEQ ID NO: 152 (GGGGSGGGGSGGGGS) or SEQ ID NO: 153 (VDGGGGSGGGGSGGGGSG).

[0248] Other exemplary flexible joints include, but are not limited to, SEQ ID NO: 157 (GGSG), SEQ ID NO: 158 (GGSGG), SEQ ID NO: 159 (GSGSG), SEQ ID NO: 160 (GSGGG), SEQ ID NO: 161 (GGGSG), and SEQ ID NO: 162 (GSSSG). Other exemplary joints also include the following: GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 154) and GGGGSGGGGSGGGGSGGGSSGGGGS (SEQ ID NO: 155).

[0249] Those skilled in the art will recognize that the design of the molecules described herein may include wholly or partially flexible joints, such that the joints may include flexible joints and one or more portions that impart a lower flexibility structure to provide the desired molecular structure.

[0250] Suitable linkers can be readily selected and can have various lengths, such as 1 amino acid (e.g., Gly) to 20 amino acids or more, 2 amino acids to 15 amino acids, 3 amino acids to 12 amino acids, including 4 amino acids to 10 amino acids, 5 amino acids to 9 amino acids, 6 amino acids to 8 amino acids, or 7 amino acids to 8 amino acids (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 amino acids).

[0251] In some embodiments, the linker may be or include an amino acid-free synthetic linker, such as a polyethylene (PEG) linker or other known synthetic linkers, which are commonly used for chemical conjugation, for example, in antibody-drug conjugates. In this context, it should also be understood that the molecules described herein encompass molecules in which components of the first or second polypeptide (i.e., the self-antigen domain, antigen-binding domain, Fc domain) are linked via chemical conjugation (e.g., “click” or other chemistry), optionally linked with intercalated amino acids or synthetic linkers.

[0252] In some embodiments, the molecules described herein are fusion proteins, wherein the first and second polypeptides may be encoded by a single nucleic acid sequence. In some embodiments, the molecules described herein are chemically conjugated molecules comprising components using synthetic chemical conjugation.

[0253] Exemplary configuration Various configurations of the molecules described herein are considered. Such configurations include various elements of the molecules described herein, including a first polypeptide comprising an autoantibody-binding domain linked to a first Fc domain and a second polypeptide comprising a second Fc domain. Exemplary autoantibody-binding domains, antigen-binding domains, Fc domains, and linkers are described. These components can be assembled in different configurations to produce the molecules described herein.

[0254] Exemplary combinations of specific self-antigen domains, antigen-binding domains, Fc domains, and linkers are provided in Table 4 below. In some embodiments, any combination in Table 4 may be included, for example... Figure 2 In the molecular configuration shown, the C-terminus of the self-antigen domain (A) is connected to the N-terminus of the first Fc domain (Fc1) (the first polypeptide) via an optional linker (L), and forms a heterodimer with the second Fc domain (Fc2) of the second polypeptide.

[0255] In some implementations, any combination of the options in Table 4 can be included, for example... Figure 3 In the molecular configuration shown, the C-terminus of the self-antigen domain (A) is connected to the N-terminus of the first Fc domain (Fc1) (first polypeptide) via an optional linker (L), and the molecule also includes an antigen-binding domain, wherein the C-terminus of the antigen-binding domain (HC / LC Fab) is connected to the N-terminus of the second Fc domain (Fc2) (second polypeptide). In some embodiments (not shown), the N-terminus of the antigen-binding domain (HC / LC Fab) is alternatively connected to the C-terminus of the second Fc domain (Fc2) (second polypeptide). In some embodiments (not shown), the C-terminus of the first Fc domain (Fc1) is alternatively connected to the N-terminus of the first self-antigen domain (A) (first polypeptide) via an optional linker (L). In some embodiments (not shown), the C-terminus of the first Fc domain (Fc1) is alternatively linked to the N-terminus of the first self-antigen domain (A) (first polypeptide) via an optional linker (L), and the N-terminus of the antigen-binding domain (HC / LC Fab) is alternatively linked to the C-terminus of the second Fc domain (Fc2) (second polypeptide).

[0256] In some implementations, any combination of the options in Table 4 can be included, for example... Figure 4 In the molecular configuration shown, the C-terminus of the first Fc domain (Fc1) is connected to the N-terminus of the self-antigen domain (A) (the first polypeptide) via an optional linker (L), and forms a heterodimer with the second Fc domain (Fc2) of the second polypeptide.

[0257] In some implementations, any combination of the options in Table 4 can be included, for example... Figure 5 In the molecular configuration shown in A, the molecule comprises two self-antigen domains, wherein the C-terminus of a first Fc domain (Fc1) is connected via an optional linker (L') to the N-terminus of a first self-antigen domain (A') (a first polypeptide), and the C-terminus of a second Fc domain (Fc2) is connected via an optional linker (L') to the N-terminus of a second self-antigen domain (A') (a second polypeptide). In some embodiments, the two self-antigen domains are identical (e.g., in the homodimeric molecule of this disclosure). In some embodiments, the two self-antigen domains are different (e.g., in the heterodimeric molecule of this disclosure).

[0258] In some implementations, any combination of the options in Table 4 can be included, for example... Figure 5 In the molecular configuration shown in B, the molecule comprises two self-antigen domains, wherein the C-terminus of the first self-antigen domain (A) is connected via an optional linker (L) to the N-terminus of the first Fc domain (Fc1) (a first polypeptide), and the C-terminus of the second self-antigen domain (A) is connected via an optional linker (L) to the N-terminus of the second Fc domain (Fc2) (a second polypeptide). In some embodiments, the two self-antigen domains are identical (e.g., in the homodimeric molecule of this disclosure). In some embodiments, the two self-antigen domains are different (e.g., in the heterodimeric molecule of this disclosure).

[0259] in Figures 2-5 The "A" or "A'" is designated as an antigen (e.g., any antigen described herein), and this disclosure also covers any domains that target autoantibodies against that component in the molecules described herein.

[0260] Alternatively or concurrently, in some embodiments, the molecule may comprise a first antigen-binding domain and a second antigen-binding domain, such that each antigen-binding domain is capable of binding to the same or different target antigens. In some embodiments, the first and / or second polypeptide of the molecule comprises an antigen-binding domain. In some embodiments, the first polypeptide of the molecule comprises an antigen-binding domain. In some embodiments, the second polypeptide of the molecule comprises an antigen-binding domain. In some embodiments, both the first and second polypeptides of the molecule comprise antigen-binding domains. In some embodiments, the first antigen-binding domain targets an anti-TSHR autoantibody, and the second antigen-binding domain targets an internalization receptor (e.g., ASPGR).

[0261] Table 4: Exemplary TSHR antibody depletion combinations In some embodiments, the molecule comprises an amino acid sequence comprising any combination of the sequences shown in Table 4. In some embodiments, the molecule comprises an amino acid sequence comprising any combination of the sequences shown in Table 4, and includes a linker (L) between the self-antigen domain and the Fc domain (e.g., as shown in Table 4). Figures 2-5 (As shown in any of the configurations).

[0262] In some embodiments, the molecule comprises a first polypeptide, wherein the first polypeptide comprises: (i) an amino acid sequence that is at least 90% identical to SEQ ID NO: 1 and an amino acid sequence that is at least 90% identical to SEQ ID NO: 103; (ii) an amino acid sequence that is at least 90% identical to SEQ ID NO: 2 and an amino acid sequence that is at least 90% identical to SEQ ID NO: 103; (iii) an amino acid sequence that is at least 90% identical to SEQ ID NO: 3 and an amino acid sequence that is at least 90% identical to SEQ ID NO: 103; (iv) an amino acid sequence that is at least 90% identical to SEQ ID NO: 4 and an amino acid sequence that is at least 90% identical to SEQ ID NO: 103; (v) an amino acid sequence that is at least 90% identical to SEQ ID NO: 1 and an amino acid sequence that is at least 90% identical to SEQ ID NO: 105; (vi) an amino acid sequence that is at least 90% identical to SEQ ID NO: 2 and an amino acid sequence that is at least 90% identical to SEQ ID NO: 105; (vii) an amino acid sequence that is at least 90% identical to SEQ ID NO: 105; and (vii) an amino acid sequence that is at least 90% identical to SEQ ID NO: 103. 3. An amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 105; (viii) An amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 4 and an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 105; or (ix) An amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 4, an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 209, an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 210 and an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 105.In some embodiments, the molecule comprises a first polypeptide, wherein the first polypeptide comprises: (i) the amino acid sequence of SEQ ID NO: 1 and the amino acid sequence of SEQ ID NO: 103; (ii) the amino acid sequence of SEQ ID NO: 2 and the amino acid sequence of SEQ ID NO: 103; (iii) the amino acid sequence of SEQ ID NO: 3 and the amino acid sequence of SEQ ID NO: 103; (iv) the amino acid sequence of SEQ ID NO: 4 and the amino acid sequence of SEQ ID NO: 103; (v) the amino acid sequence of SEQ ID NO: 1 and the amino acid sequence of SEQ ID NO: 105; (vi) the amino acid sequence of SEQ ID NO: 2 and the amino acid sequence of SEQ ID NO: 105; (vii) the amino acid sequence of SEQ ID NO: 3 and the amino acid sequence of SEQ ID NO: 105; (viii) the amino acid sequence of SEQ ID NO: 4 and the amino acid sequence of SEQ ID NO: 105; or (ix) the amino acid sequence of SEQ ID NO: 4, SEQ ID NO: 103, SEQ ID NO: 104, SEQ ID NO: 105 ... The amino acid sequences of SEQ ID NO: 209, SEQ ID NO: 210, and SEQ ID NO: 105; (x) the amino acid sequences of SEQ ID NO: 5 and SEQ ID NO: 103; and (xi) the amino acid sequences of SEQ ID NO: 6 and SEQ ID NO: 103.

[0263] In some embodiments, the molecule comprises a second polypeptide, wherein the second polypeptide comprises: (i) an amino acid sequence that is at least 90% identical to SEQ ID NO: 104; (ii) an amino acid sequence that is at least 90% identical to SEQ ID NO: 106; (iii) an amino acid sequence that is at least 90% identical to SEQ ID NO: 108; (iv) an amino acid sequence that is at least 90% identical to SEQ ID NO: 110; or (v) an amino acid sequence that is at least 90% identical to SEQ ID NO: 209, an amino acid sequence that is at least 90% identical to SEQ ID NO: 210, and an amino acid sequence that is at least 90% identical to SEQ ID NO: 106. In some embodiments, the second polypeptide comprises: (i) the amino acid sequence of SEQ ID NO: 104, (ii) the amino acid sequence of SEQ ID NO: 106, (iii) the amino acid sequence of SEQ ID NO: 108, (iv) the amino acid sequence of SEQ ID NO: 110, or (v) the amino acid sequence of SEQ ID NO: 209, the amino acid sequence of SEQ ID NO: 210, and the amino acid sequence of SEQ ID NO: 106.

[0264] In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 1 and SEQ ID NO: 103, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 104; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 1 and SEQ ID NO: 104, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 103. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 2 and SEQ ID NO: 103, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 104; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 2 and SEQ ID NO: 104, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 103. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 3 and SEQ ID NO: 103, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 104; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 3 and SEQ ID NO: 104, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 103. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 4 and SEQ ID NO: 103, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 104; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 4 and SEQ ID NO: 104, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 103. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises an amino acid sequence containing SEQ ID NO: 5 and SEQ ID NO: 103, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO: 104; or (ii) the first polypeptide comprises an amino acid sequence containing SEQ ID NO: 5 and SEQ ID NO: 104, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO: 103.In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 6 and SEQ ID NO: 103, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 104; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 6 and SEQ ID NO: 104, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 103. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 7 and SEQ ID NO: 103, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 104; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 7 and SEQ ID NO: 104, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 103. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 8 and SEQ ID NO: 103, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 104; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 8 and SEQ ID NO: 104, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 103. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 307 and SEQ ID NO: 103, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 104; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 307 and SEQ ID NO: 104, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 103. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises an amino acid sequence containing SEQ ID NO: 308 and SEQ ID NO: 103, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO: 104; or (ii) the first polypeptide comprises an amino acid sequence containing SEQ ID NO: 308 and SEQ ID NO: 104, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO: 103.In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 309 and SEQ ID NO: 103, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 104; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 309 and SEQ ID NO: 104, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 103. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 310 and SEQ ID NO: 103, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 104; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 310 and SEQ ID NO: 104, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 103. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 311 and SEQ ID NO: 103, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 104; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 311 and SEQ ID NO: 104, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 103. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 312 and SEQ ID NO: 103, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 104; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 312 and SEQ ID NO: 104, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 103. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises an amino acid sequence containing SEQ ID NO: 313 and SEQ ID NO: 103, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO: 104; or (ii) the first polypeptide comprises an amino acid sequence containing SEQ ID NO: 313 and SEQ ID NO: 104, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO: 103.In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 314 and SEQ ID NO: 103, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 104; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 314 and SEQ ID NO: 104, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 103. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 315 and SEQ ID NO: 103, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 104; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 315 and SEQ ID NO: 104, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 103. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 316 and SEQ ID NO: 103, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 104; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 316 and SEQ ID NO: 104, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 103. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 317 and SEQ ID NO: 103, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 104; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 317 and SEQ ID NO: 104, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 103.

[0265] In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 1 and SEQ ID NO: 105, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 106; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 1 and SEQ ID NO: 106, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 105. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 2 and SEQ ID NO: 105, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 106; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 2 and SEQ ID NO: 106, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 105. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 3 and SEQ ID NO: 105, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 106; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 3 and SEQ ID NO: 106, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 105. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 4 and SEQ ID NO: 105, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 106; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 4 and SEQ ID NO: 106, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 105. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises an amino acid sequence containing SEQ ID NO: 5 and SEQ ID NO: 105, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO: 106; or (ii) the first polypeptide comprises an amino acid sequence containing SEQ ID NO: 5 and SEQ ID NO: 106, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO: 105.In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 6 and SEQ ID NO: 105, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 106; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 6 and SEQ ID NO: 106, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 105. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 7 and SEQ ID NO: 105, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 106; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 7 and SEQ ID NO: 106, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 105. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 8 and SEQ ID NO: 105, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 106; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 8 and SEQ ID NO: 106, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 105. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 307 and SEQ ID NO: 105, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 106; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 307 and SEQ ID NO: 106, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 105. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises an amino acid sequence containing SEQ ID NO: 308 and SEQ ID NO: 105, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO: 106; or (ii) the first polypeptide comprises an amino acid sequence containing SEQ ID NO: 308 and SEQ ID NO: 106, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO: 105.In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 309 and SEQ ID NO: 105, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 106; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 309 and SEQ ID NO: 106, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 105. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 310 and SEQ ID NO: 105, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 106; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 310 and SEQ ID NO: 106, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 105. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 311 and SEQ ID NO: 105, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 106; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 311 and SEQ ID NO: 106, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 105. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 312 and SEQ ID NO: 105, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 106; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 312 and SEQ ID NO: 106, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 105. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises an amino acid sequence containing SEQ ID NO: 313 and SEQ ID NO: 105, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO: 106; or (ii) the first polypeptide comprises an amino acid sequence containing SEQ ID NO: 313 and SEQ ID NO: 106, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO: 105.In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 314 and SEQ ID NO: 105, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 106; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 314 and SEQ ID NO: 106, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 105. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 315 and SEQ ID NO: 105, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 106; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 315 and SEQ ID NO: 106, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 105. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 316 and SEQ ID NO: 105, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 106; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 316 and SEQ ID NO: 106, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 105. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 317 and SEQ ID NO: 105, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 106; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 317 and SEQ ID NO: 106, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 105.

[0266] In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 1 and SEQ ID NO: 107, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 108; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 1 and SEQ ID NO: 108, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 107. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 2 and SEQ ID NO: 107, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 108; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 2 and SEQ ID NO: 108, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 107. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 3 and SEQ ID NO: 107, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 108; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 3 and SEQ ID NO: 108, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 107. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 4 and SEQ ID NO: 107, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 108; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 4 and SEQ ID NO: 108, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 107. In some embodiments, the molecule comprises a first and a second polypeptide, wherein (i) the first polypeptide comprises an amino acid sequence containing SEQ ID NO: 5 and SEQ ID NO: 107, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO: 108; or (ii) the first polypeptide comprises an amino acid sequence containing SEQ ID NO: 5 and SEQ ID NO: 108, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO: 107.In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 6 and SEQ ID NO: 107, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 108; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 6 and SEQ ID NO: 108, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 107. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 7 and SEQ ID NO: 107, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 108; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 7 and SEQ ID NO: 108, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 107. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 8 and SEQ ID NO: 107, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 108; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 8 and SEQ ID NO: 108, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 107. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 307 and SEQ ID NO: 107, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 108; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 307 and SEQ ID NO: 108, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 107. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises an amino acid sequence containing SEQ ID NO: 308 and SEQ ID NO: 107, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO: 108; or (ii) the first polypeptide comprises an amino acid sequence containing SEQ ID NO: 308 and SEQ ID NO: 108, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO: 107.In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 309 and SEQ ID NO: 107, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 108; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 309 and SEQ ID NO: 108, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 107. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 310 and SEQ ID NO: 107, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 108; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 310 and SEQ ID NO: 108, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 107. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 311 and SEQ ID NO: 107, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 108; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 311 and SEQ ID NO: 108, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 107. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 312 and SEQ ID NO: 107, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 108; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 312 and SEQ ID NO: 108, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 107. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises an amino acid sequence containing SEQ ID NO: 313 and SEQ ID NO: 107, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO: 108; or (ii) the first polypeptide comprises an amino acid sequence containing SEQ ID NO: 313 and SEQ ID NO: 108, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO: 107.In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 314 and SEQ ID NO: 107, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 108; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 314 and SEQ ID NO: 108, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 107. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 315 and SEQ ID NO: 107, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 108; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 315 and SEQ ID NO: 108, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 107. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 316 and SEQ ID NO: 107, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 108; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 316 and SEQ ID NO: 108, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 107. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 317 and SEQ ID NO: 107, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 108; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 317 and SEQ ID NO: 108, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 107.

[0267] In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 1 and SEQ ID NO: 109, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 110; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 1 and SEQ ID NO: 110, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 109. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 2 and SEQ ID NO: 109, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 110; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 2 and SEQ ID NO: 110, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 109. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 3 and SEQ ID NO: 109, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 110; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 3 and SEQ ID NO: 110, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 109. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 4 and SEQ ID NO: 109, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 110; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 4 and SEQ ID NO: 110, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 109. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises an amino acid sequence containing SEQ ID NO: 5 and SEQ ID NO: 109, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO: 110; or (ii) the first polypeptide comprises an amino acid sequence containing SEQ ID NO: 5 and SEQ ID NO: 110, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO: 109.In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 6 and SEQ ID NO: 109, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 110; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 6 and SEQ ID NO: 110, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 109. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 7 and SEQ ID NO: 109, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 110; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 7 and SEQ ID NO: 110, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 109. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 8 and SEQ ID NO: 109, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 110; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 8 and SEQ ID NO: 110, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 109. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 307 and SEQ ID NO: 109, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 110; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 307 and SEQ ID NO: 110, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 109. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises an amino acid sequence containing SEQ ID NO: 308 and SEQ ID NO: 109, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO: 110; or (ii) the first polypeptide comprises an amino acid sequence containing SEQ ID NO: 308 and SEQ ID NO: 110, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO: 109.In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 309 and SEQ ID NO: 109, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 110; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 309 and SEQ ID NO: 110, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 109. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 310 and SEQ ID NO: 109, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 110; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 310 and SEQ ID NO: 110, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 109. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 311 and SEQ ID NO: 109, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 110; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 311 and SEQ ID NO: 110, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 109. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 312 and SEQ ID NO: 109, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 110; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 312 and SEQ ID NO: 110, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 109. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises an amino acid sequence containing SEQ ID NO: 313 and SEQ ID NO: 109, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO: 110; or (ii) the first polypeptide comprises an amino acid sequence containing SEQ ID NO: 313 and SEQ ID NO: 110, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO: 109.In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 314 and SEQ ID NO: 109, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 110; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 314 and SEQ ID NO: 110, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 109. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 315 and SEQ ID NO: 109, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 110; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 315 and SEQ ID NO: 110, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 109. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 316 and SEQ ID NO: 109, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 110; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 316 and SEQ ID NO: 110, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 109. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 317 and SEQ ID NO: 109, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 110; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 317 and SEQ ID NO: 110, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 109.

[0268] In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 1 and SEQ ID NO: 113, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 114; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 1 and SEQ ID NO: 114, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 113. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 2 and SEQ ID NO: 113, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 114; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 2 and SEQ ID NO: 114, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 113. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 3 and SEQ ID NO: 113, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 114; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 3 and SEQ ID NO: 114, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 113. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 4 and SEQ ID NO: 113, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 114; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 4 and SEQ ID NO: 114, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 113. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises an amino acid sequence containing SEQ ID NO: 5 and SEQ ID NO: 113, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO: 114; or (ii) the first polypeptide comprises an amino acid sequence containing SEQ ID NO: 5 and SEQ ID NO: 114, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO: 113.In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 6 and SEQ ID NO: 113, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 114; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 6 and SEQ ID NO: 114, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 113. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 7 and SEQ ID NO: 113, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 114; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 7 and SEQ ID NO: 114, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 113. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 8 and SEQ ID NO: 113, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 114; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 8 and SEQ ID NO: 114, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 113. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 307 and SEQ ID NO: 113, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 114; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 307 and SEQ ID NO: 114, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 113. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises an amino acid sequence containing SEQ ID NO: 308 and SEQ ID NO: 113, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO: 114; or (ii) the first polypeptide comprises an amino acid sequence containing SEQ ID NO: 308 and SEQ ID NO: 114, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO: 113.In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 309 and SEQ ID NO: 113, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 114; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 309 and SEQ ID NO: 114, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 113. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 310 and SEQ ID NO: 113, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 114; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 310 and SEQ ID NO: 114, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 113. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 311 and SEQ ID NO: 113, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 114; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 311 and SEQ ID NO: 114, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 113. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 312 and SEQ ID NO: 113, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 114; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 312 and SEQ ID NO: 114, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 113. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises an amino acid sequence containing SEQ ID NO: 313 and SEQ ID NO: 113, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO: 114; or (ii) the first polypeptide comprises an amino acid sequence containing SEQ ID NO: 313 and SEQ ID NO: 114, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO: 113.In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 314 and SEQ ID NO: 113, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 114; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 314 and SEQ ID NO: 114, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 113. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 315 and SEQ ID NO: 113, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 114; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 315 and SEQ ID NO: 114, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 113. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 316 and SEQ ID NO: 113, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 114; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 316 and SEQ ID NO: 114, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 113. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 317 and SEQ ID NO: 113, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 114; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 317 and SEQ ID NO: 114, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 113.

[0269] In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 1 and SEQ ID NO: 115, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 116; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 1 and SEQ ID NO: 116, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 115. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 2 and SEQ ID NO: 115, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 116; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 2 and SEQ ID NO: 116, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 115. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 3 and SEQ ID NO: 115, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 116; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 3 and SEQ ID NO: 116, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 115. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 4 and SEQ ID NO: 115, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 116; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 4 and SEQ ID NO: 116, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 115. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises an amino acid sequence containing SEQ ID NO: 5 and SEQ ID NO: 115, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO: 116; or (ii) the first polypeptide comprises an amino acid sequence containing SEQ ID NO: 5 and SEQ ID NO: 116, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO: 115.In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 6 and SEQ ID NO: 115, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 116; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 6 and SEQ ID NO: 116, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 115. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 7 and SEQ ID NO: 115, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 116; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 7 and SEQ ID NO: 116, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 115. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 8 and SEQ ID NO: 115, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 116; or (ii) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 8 and SEQ ID NO: 116, and the second polypeptide comprises amino acid sequence containing SEQ ID NO: 115. In some embodiments, the molecule comprises first and second polypeptides, wherein (i) the first polypeptide comprises amino acid sequences containing SEQ ID NO: 307 and SEQ ID NO: 115, and the second polypeptide comprises amino a...

Claims

1. A molecule comprising: A first polypeptide, the first polypeptide comprising a first Fc domain and an autoantibody-binding domain that binds to an anti-TSHR autoantibody; and A second polypeptide, wherein the second polypeptide contains a second Fc domain; The first Fc domain and the second Fc domain form a homodimer or heterodimer of the first polypeptide and the second polypeptide.

2. The molecule of claim 1, wherein the second polypeptide further comprises an autoantibody-binding domain that binds to the anti-TSHR autoantibody, and the molecule is a homodimer.

3. The molecule of claim 1, wherein the second polypeptide further comprises an autoantibody-binding domain that binds to the anti-TSHR autoantibody, and the molecule is a heterodimer.

4. The molecule of claim 1, wherein the second polypeptide does not contain an autoantibody-binding domain that binds to the anti-TSHR autoantibody, and the molecule is a heterodimer.

5. The molecule of any one of claims 1-4, wherein the autoantibody binding domain is covalently linked to the first Fc domain.

6. The molecule of claim 5, wherein the C-terminus of the autoantibody-binding domain is covalently linked to the N-terminus of the first Fc domain.

7. The molecule of claim 5, wherein the N-terminus of the autoantibody-binding domain is covalently linked to the C-terminus of the first Fc domain.

8. The molecule according to any one of claims 1-7, wherein the first Fc domain and the second Fc domain form a heterodimer due to a kilometre structure (KIH) mutation.

9. The molecule of claim 8, wherein, according to the EU numbering scheme, the KIH mutation comprises Y349T and T394F.

10. The molecule of claim 9, wherein the first Fc domain contains the Y349T mutation, and the second Fc domain contains the T394F mutation.

11. The molecule of claim 8, wherein the KIH mutation comprises T366W, S354C, T366S, L368A, Y407V, and Y349C according to the EU numbering scheme.

12. The molecule of claim 11, wherein, according to the EU numbering scheme, the first Fc domain comprises the T366W and S354C mutations, and the second Fc domain comprises the T366S, L368A, Y407V, and Y349C mutations.

13. The molecule of any one of claims 1-12, wherein the first Fc domain and / or the second Fc domain comprises the IgG1 isotype.

14. The molecule of claim 13, wherein the first Fc domain and / or the second Fc domain comprises human IgG1 isotype.

15. The molecule of any one of claims 1-14, wherein the first Fc domain and / or the second Fc domain comprises one or more mutant amino acid residues that increase the half-life.

16. The molecule of claim 15, wherein, according to the EU numbering scheme, the first Fc domain and / or the second Fc domain comprises one of the following mutant amino acid residues: M252Y, S254T, and T256E.

17. The molecule of claim 15 or 16, wherein, according to the EU numbering scheme, the first Fc domain and / or the second Fc domain comprises a combination of the following mutant amino acid residues: M252Y, S254T, and T256E.

18. The molecule of claim 15, wherein, according to the EU numbering scheme, the first Fc domain and / or the second Fc domain comprises one or more of the following mutant amino acid residues: M428L and N434S.

19. The molecule of claim 15 or 18, wherein, according to the EU numbering scheme, the first Fc domain and / or the second Fc domain comprises a combination of the following mutant amino acid residues: M428L and N434S.

20. The molecule of any one of claims 1-19, wherein the first Fc domain and / or the second Fc domain comprises one or more mutant amino acid residues that alter their binding to an internalization receptor on a cell, wherein the internalization receptor is capable of shuttling its cargo to the lysosome of the cell, thereby causing degradation.

21. The molecule of claim 20, wherein the alteration of binding to the internalization receptor comprises an increase in binding to the internalization receptor.

22. The molecule of claim 20 or 21, wherein when the molecule, which binds to an autoantibody via the autoantibody-binding domain, binds to the internalization receptor on a cell, the internalization receptor internalizes the molecule, and the autoantibody is shuttled to the lysosomes of the cell for degradation.

23. The molecule of any one of claims 20-22, wherein the internalizing receptor comprises one of the following: FcγRIIB, FcRn, ASGPR, CD38, or BCMA.

24. The molecule of any one of claims 1-23, wherein the first Fc domain and / or the second Fc domain comprises one or more mutant amino acid residues that increase the binding of FcγRIIB relative to the corresponding wild-type Fc domain.

25. The molecule of claim 24, wherein the first Fc domain and / or the second Fc domain comprising one or more mutant amino acid residues does not have increased binding affinity for FcγRI, FcγRIIA167H, FcγRIIA167R, FcγRIIIA176F, FcγRIIIA176V, FcγRIIIB and / or FcRn relative to the corresponding wild-type Fc domain.

26. The molecule of claim 24 or 25, wherein the first Fc domain and / or the second Fc domain comprising one or more mutant amino acid residues have reduced binding affinity to FcγRI, FcγRIIA167H, FcγRIIA167R, FcγRIIIA176F, FcγRIIIA176V, FcγRIIIB and / or FcRn relative to the corresponding wild-type Fc domain.

27. The molecule of any one of claims 24-26, wherein the first Fc domain and / or the second Fc domain comprising one or more mutant amino acid residues have substantially no binding affinity for FcγRI, FcγRIIA167H, FcγRIIA167R, FcγRIIIA176F, FcγRIIIA176V, FcγRIIIB and / or FcRn relative to the corresponding wild-type Fc domain.

28. The molecule of any one of claims 24-27, wherein, upon binding of the two molecules to the anti-TSHR autoantibody, an immune complex with enhanced binding kinetics to FcγRIIB is formed relative to the immune complex comprising the anti-TSHR autoantibody and the two corresponding molecules having a wild-type Fc domain.

29. The molecule of any one of claims 24-28, wherein after the two molecules bind to the anti-TSHR autoantibody, an immune complex with enhanced binding kinetics to FcγRIIB is formed relative to an immune complex comprising the anti-TSHR autoantibody that binds only to a single molecule.

30. The molecule of any one of claims 24-29, wherein after the two molecules bind to the anti-TSHR autoantibody, an immune complex with enhanced binding kinetics to FcγRIIB is formed relative to the anti-TSHR autoantibody alone.

31. The molecule of any one of claims 28-30, wherein the enhanced binding kinetics comprises an increase in association rate, a decrease in dissociation rate, and / or a change in equilibrium dissociation constant.

32. The molecule of any one of claims 28-31, wherein the enhanced binding kinetics result in an increase in the affinity, stability, strength, frequency, and / or duration of the binding between the immune complex and FcγRIIB.

33. The molecule of any one of claims 28-32, wherein the enhanced binding kinetics comprises that the binding affinity of the immune complex to FcγRIIB is at least 10% higher.

34. The molecule of claim 33, wherein the binding affinity of at least 10% comprises at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% or higher.

35. The molecule of claim 33, wherein the molecule binds to FcγRIIB with an affinity in the range of about 1 µM to 0.001 µM.

36. The molecule of claim 35, wherein the molecule binds to FcγRIIB with an affinity in the range of about 1 µM to 0.001 µM.

37. The molecule of claim 36, wherein the molecule binds to FcγRIIB with an affinity in the range of about 0.1 µM to 0.01 µM.

38. The molecule of claim 33 or 34, wherein the binding affinity comprises the binding affinity to a cell line (e.g., CHO cell line) overexpressing FcγRIIB, as measured by flow cytometry.

39. The molecule according to any one of claims 24-38, wherein the molecule does not bind to complement (C1q).

40. The molecule of any one of claims 24-39, wherein the molecule preferentially binds to immune cells expressing FcγRIIB relative to immune cells expressing FcγRIIA.

41. The molecule of claim 40, wherein the molecule substantially does not contain binding affinity for cells that do not express FcγRIIB.

42. The molecule of claim 40 or 41, wherein the immune cells expressing FcγRIIB include B cells, monocytes, and / or basophils.

43. The molecule of claim 41 or 42, wherein the immune cells that do not express FcγRIIB include T cells, NK cells, neutrophils and / or eosinophils.

44. The molecule of any one of claims 24-43, wherein the molecule does not activate immune cells (e.g., does not activate immune cells to secrete pro-inflammatory cytokines, such as IL-6).

45. The molecule of any one of claims 24-44, wherein the molecule inhibits B cells by crosslinking FcγRIIB with B cell receptors.

46. ​​The molecule of claim 45, wherein the molecule crosslinks FcγRIIB with the B cell receptor.

47. The molecule of claim 45, wherein one or both molecules, together with an immune complex of an anti-TSHR autoantibody, crosslink FcγRIIB with a B cell receptor.

48. The molecule according to any one of claims 24-47, wherein, according to the EU numbering scheme, the one or more mutant amino acid residues that increase the binding to FcγRIIB comprise one or more of the following amino acid mutations: E233V, L234D, L235F, G236R, G237D, S239L, S267D, H268P, S298G, T299A, A327L, L328A, A 330H, E333I, R292Q, E233P, P238D, H268D, P271G, A330R, L234Y, T250V, V264I, T307P, Q311R, A330K, P343R, M428L, N434A, Y436T, Q438R, S440E, G236N, S267E, L235R, D270E, E233D, and G237D.

49. The molecule of claim 48, wherein, according to the EU numbering scheme, the one or more mutant amino acid residues that increase the binding to FcγRIIB comprise one or more of the following amino acid mutation sets: (i) E233V, L234D, L235F, G236R, G237D, S239L, S267D, H268P, S298G, T299A, A327L, L328A, A330H and E333I; (ii) E233V, L234D, L235F, G236R, G237D, S239L, S267D, R292Q, H268P, S298G, T299A, A327L, L328A, A330H and E333I; (iii) E233V, L234D, L235F, G236R, G237D, S239L, H268P, R292Q, S298G, T299A, A327L, L328A, A330H and E333I; (iv) E233P, G237D, P238D, H268D, P271G and A330R; (v) L234Y, P238D, T250V, V264I, T307P, Q311R, A330K, P343R, M428L, N434A, Y436T, Q438R and S440E; (vi) L234D, G236N and S267E; (vii) L235R; (viii) G236N and S267E; (ix) P238D and D270E; (x) P238D and P271G; (xi) P238D, D270E and P271G; (xii) G237D, P238D, P271G and A330R; (xiii) G237D, P238D, D270E, P271G and A330R (xiv) E233D, G237D, P238D, H268D, P271G, and A330R; and (xv) P238D.

50. The molecule of any one of claims 24-49, wherein, according to the EU numbering scheme, the one or more mutant amino acid residues comprise the mutant amino acid residue P238D.

51. The molecule according to any one of claims 24-50, wherein, according to the EU numbering scheme, the one or more mutant amino acid residues do not contain the following mutant amino acid residues: S267E and L328F.

52. The molecule according to any one of claims 24-51, wherein, according to the EU numbering scheme, the first Fc domain and / or the second Fc domain comprises the following mutant amino acid residues: L234A, L235A, and P238D.

53. The molecule of claim 52, wherein, according to the EU numbering scheme, the first Fc domain and / or the second Fc domain comprises the following mutant amino acid residues: L234A, L235A, P238D, and P329G.

54. The molecule of claims 24-53, wherein, according to the EU numbering scheme, the first Fc domain and / or the second Fc domain comprises the following mutant amino acid residues: M428L, N434S, and P238D.

55. The molecule according to any one of claims 24-50 or 52-54, wherein, according to the EU numbering scheme, the first Fc domain and / or the second Fc domain comprises at least one of the following mutant amino acid residues: S267E and L328F.

56. The molecule of claim 55, wherein, according to the EU numbering scheme, the first Fc domain and / or the second Fc domain comprises a combination of the following mutant amino acid residues: S267E and L328F.

57. The molecule of any one of claims 1-23, wherein the first Fc domain and / or the second Fc domain comprises one or more mutant amino acid residues that increase binding to FcRn.

58. The molecule of claim 57, wherein the first Fc domain and / or the second Fc domain comprises one or more mutant amino acid residues that increase binding to FcRn at neutral or near-neutral pH (e.g., between about 6.8 and 7.5).

59. The molecule of claim 57 or 58, wherein the first Fc domain and the second Fc domain comprise a human IgG1 isotype and remain bound to FcRn upon entry into an environment having an acidic pH and / or a low calcium concentration (e.g., entering the endosome of a cell).

60. The molecule according to any one of claims 57-59, wherein, according to the EU numbering scheme, the first Fc domain and / or the second Fc domain comprises at least one of the following mutant amino acid residues: M252Y, S254T, T256E, H433K, and N434F.

61. The molecule of claim 60, wherein, according to the EU numbering scheme, the first Fc domain and / or the second Fc domain comprises a combination of the following mutant amino acid residues: M252Y, S254T, T256E, H433K, and N434F.

62. The molecule of any one of claims 1-61, wherein the first Fc domain and / or the second Fc domain comprises at least one mutant amino acid sequence that reduces binding to one or more Fc-γ receptors (FcγR).

63. The molecule of claim 62, wherein, according to the EU numbering scheme, the first Fc domain and / or the second Fc domain comprises at least one of the following mutant amino acid residues: G236R and L328R.

64. The molecule of claim 63, wherein, according to the EU numbering scheme, the first Fc domain and / or the second Fc domain comprises one of the following mutant amino acid residues: G236R and L328R.

65. The molecule of any one of claims 1-64, wherein the first Fc domain comprises a sequence selected from SEQ ID NO: 103, 105, 107, 109, 111-113, 115, 117, 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139-149, 163-164, 374-376, 378, or a fragment or variant thereof (e.g., a sequence selected from SEQ ID NO: 107, 109, 113, 115, 119, 131, 139, 140, 142, 148, 374, or 378).

66. The molecule of any one of claims 1-65, wherein the second Fc domain comprises a sequence selected from SEQ ID NO: 104, 106, 108, 110, 111, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 139-149, 163-164, 374-375, 377, 379, or a fragment or variant thereof (e.g., a sequence selected from SEQ ID NO: 108, 110, 114, 116, 120, 132, 139, 140, 142, 148, 374, or 379).

67. The molecule of any one of claims 1-66, wherein the autoantibody binding domain is covalently linked to the first Fc domain via a linker.

68. The molecule of claim 67, wherein the linker comprises the amino acid sequence of SEQ ID NO: 150 (GGGGS), SEQ ID NO: 151 (GGGGSGGGGS), SEQ ID NO: 152 (GGGGSGGGGSGGGGS), SEQ ID NO: 153 (VDGGGGSGGGGSGGGGSG), SEQ ID NO: 154 (GGGGSGGGGSGGGGSGGGSGGGS), SEQ ID NO: 155 (GGGGSGGGGSGGGGSGGGSSGGGGS), SEQ ID NO: 156 (GSGGS), SEQ ID NO: 157 (GGSG), SEQ ID NO: 158 (GGSGG), SEQ ID NO: 159 (GSGSG), SEQ ID NO: 160 (GSGGG), SEQ ID NO: 161 (GGGSG), or SEQ ID NO: 162 (GSSSG).

69. The molecule of any one of claims 1-68, wherein the autoantibody binding domain comprises an autoantigen or a fragment or variant thereof.

70. The molecule of claim 69, wherein the self-antigen comprises a TSHR self-antigen domain or a fragment or variant thereof.

71. The molecule of claim 70, wherein the TSHR self-antigen domain comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO:

5.

72. The molecule of claim 71, wherein the TSHR self-antigen domain comprises the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO:

5.

73. The molecule of any one of claims 1-71, wherein the autoantibody binding domain comprises a TSHR autoantigen domain variant, the TSHR autoantigen domain variant comprising one or more of the following mutations relative to the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 5: R112P, D143P, V169R, I253R, H63S or any combination thereof.

74. The molecule of any one of claims 1-71, wherein the autoantibody binding domain comprises a TSHR autoantigen domain variant, the TSHR autoantigen domain variant comprising the following mutations relative to the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 5: R112P and D143P.

75. The molecule of any one of claims 1-71, wherein the autoantibody binding domain comprises a TSHR autoantigen domain variant, the TSHR autoantigen domain variant comprising the following mutations relative to the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 5: R112P, D143P, V169R, and I253R.

76. The molecule of any one of claims 1-71, wherein the autoantibody binding domain comprises a TSHR autoantigen domain variant, the TSHR autoantigen domain variant comprising the following mutations relative to the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 5: R112P, D143P, and H63S.

77. The molecule of any one of claims 1-71, wherein the autoantibody binding domain comprises a variant of the TSHR autoantigen domain, the variant of the TSHR autoantigen domain comprising a sequence of any one of SEQ ID NO: 1-8.

78. The molecule of any one of claims 1-71, wherein the autoantibody binding domain comprises a variant of the TSHR autoantigen domain, the variant of the TSHR autoantigen domain comprising a sequence of any one of SEQ ID NO: 307-317.

79. The molecule of any one of claims 1-78, wherein the first polypeptide comprises: The amino acid sequence is at least 90% identical to that of SEQ ID NO: 1 and at least 90% identical to that of SEQ ID NO: 103; The amino acid sequence is at least 90% identical to SEQ ID NO: 2 and at least 90% identical to SEQ ID NO: 103; The amino acid sequence is at least 90% identical to SEQ ID NO: 3 and at least 90% identical to SEQ ID NO: 103; The amino acid sequence is at least 90% identical to SEQ ID NO: 4 and at least 90% identical to SEQ ID NO: 103; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 5 and at least 90% identical to that of SEQ ID NO: 103; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 6 and at least 90% identical to that of SEQ ID NO: 103; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 7 and at least 90% identical to that of SEQ ID NO: 103; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 8 and at least 90% identical to that of SEQ ID NO: 103; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 307 and at least 90% identical to that of SEQ ID NO: 103; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 308 and at least 90% identical to that of SEQ ID NO: 103; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 309 and at least 90% identical to that of SEQ ID NO: 103; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 310 and at least 90% identical to that of SEQ ID NO: 103; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 311 and at least 90% identical to that of SEQ ID NO: 103; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 312 and at least 90% identical to that of SEQ ID NO: 103; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 313 and at least 90% identical to that of SEQ ID NO: 103; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 314 and at least 90% identical to that of SEQ ID NO: 103; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 315 and at least 90% identical to that of SEQ ID NO: 103; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 316 and at least 90% identical to that of SEQ ID NO: 103; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 317 and at least 90% identical to that of SEQ ID NO: 103; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 1 and at least 90% identical to that of SEQ ID NO: 105; The amino acid sequence is at least 90% identical to SEQ ID NO: 2 and at least 90% identical to SEQ ID NO: 105; The amino acid sequence is at least 90% identical to SEQ ID NO: 3 and at least 90% identical to SEQ ID NO: 105; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 4 and at least 90% identical to that of SEQ ID NO: 105; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 5 and at least 90% identical to that of SEQ ID NO: 105; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 6 and at least 90% identical to that of SEQ ID NO: 105; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 7 and at least 90% identical to that of SEQ ID NO: 105; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 8 and at least 90% identical to that of SEQ ID NO: 105; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 307 and at least 90% identical to that of SEQ ID NO: 105; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 308 and at least 90% identical to that of SEQ ID NO: 105; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 309 and at least 90% identical to that of SEQ ID NO: 105; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 310 and at least 90% identical to that of SEQ ID NO: 105; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 311 and at least 90% identical to that of SEQ ID NO: 105; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 312 and at least 90% identical to that of SEQ ID NO: 105; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 313 and at least 90% identical to that of SEQ ID NO: 105; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 314 and at least 90% identical to that of SEQ ID NO: 105; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 315 and at least 90% identical to that of SEQ ID NO: 105; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 316 and at least 90% identical to that of SEQ ID NO: 105; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 317 and at least 90% identical to that of SEQ ID NO: 105; Amino acid sequences that are at least 90% identical to SEQ ID NO: 4, at least 90% identical to SEQ ID NO: 209, at least 90% identical to SEQ ID NO: 210, and at least 90% identical to SEQ ID NO: 105; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 1 and at least 90% identical to that of SEQ ID NO: 107; The amino acid sequence is at least 90% identical to SEQ ID NO: 2 and at least 90% identical to SEQ ID NO: 107; The amino acid sequence is at least 90% identical to SEQ ID NO: 3 and at least 90% identical to SEQ ID NO: 107; The amino acid sequence is at least 90% identical to SEQ ID NO: 4 and at least 90% identical to SEQ ID NO: 107; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 5 and at least 90% identical to that of SEQ ID NO: 107; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 6 and at least 90% identical to that of SEQ ID NO: 107; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 7 and at least 90% identical to that of SEQ ID NO: 107; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 8 and at least 90% identical to that of SEQ ID NO: 107; The amino acid sequence is at least 90% identical to SEQ ID NO: 307 and at least 90% identical to SEQ ID NO: 107; The amino acid sequence is at least 90% identical to SEQ ID NO: 308 and at least 90% identical to SEQ ID NO: 107; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 309 and at least 90% identical to that of SEQ ID NO: 107; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 310 and at least 90% identical to that of SEQ ID NO: 107; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 311 and at least 90% identical to that of SEQ ID NO: 107; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 312 and at least 90% identical to that of SEQ ID NO: 107; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 313 and at least 90% identical to that of SEQ ID NO: 107; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 314 and at least 90% identical to that of SEQ ID NO: 107; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 315 and at least 90% identical to that of SEQ ID NO: 107; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 316 and at least 90% identical to that of SEQ ID NO: 107; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 317 and at least 90% identical to that of SEQ ID NO: 107; The amino acid sequence is at least 90% identical to SEQ ID NO: 1 and at least 90% identical to SEQ ID NO: 109; The amino acid sequence is at least 90% identical to SEQ ID NO: 2 and at least 90% identical to SEQ ID NO: 109; The amino acid sequence is at least 90% identical to SEQ ID NO: 3 and at least 90% identical to SEQ ID NO: 109; The amino acid sequence is at least 90% identical to SEQ ID NO: 4 and at least 90% identical to SEQ ID NO: 109; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 5 and at least 90% identical to that of SEQ ID NO: 109; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 6 and at least 90% identical to that of SEQ ID NO: 109; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 7 and at least 90% identical to that of SEQ ID NO: 109; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 8 and at least 90% identical to that of SEQ ID NO: 109; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 307 and at least 90% identical to that of SEQ ID NO: 109; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 308 and at least 90% identical to that of SEQ ID NO: 109; The amino acid sequence is at least 90% identical to SEQ ID NO: 309 and at least 90% identical to SEQ ID NO: 109; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 310 and at least 90% identical to that of SEQ ID NO: 109; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 311 and at least 90% identical to that of SEQ ID NO: 109; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 312 and at least 90% identical to that of SEQ ID NO: 109; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 313 and at least 90% identical to that of SEQ ID NO: 109; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 314 and at least 90% identical to that of SEQ ID NO: 109; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 315 and at least 90% identical to that of SEQ ID NO: 109; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 316 and at least 90% identical to that of SEQ ID NO: 109; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 317 and at least 90% identical to that of SEQ ID NO: 109; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 1 and at least 90% identical to that of SEQ ID NO: 113; The amino acid sequence is at least 90% identical to SEQ ID NO: 2 and at least 90% identical to SEQ ID NO: 113; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 3 and at least 90% identical to that of SEQ ID NO: 113; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 4 and at least 90% identical to that of SEQ ID NO: 113; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 5 and at least 90% identical to that of SEQ ID NO: 113; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 6 and at least 90% identical to that of SEQ ID NO: 113; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 7 and at least 90% identical to that of SEQ ID NO: 113; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 8 and at least 90% identical to that of SEQ ID NO: 113; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 307 and at least 90% identical to that of SEQ ID NO: 113; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 308 and at least 90% identical to that of SEQ ID NO: 113; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 309 and at least 90% identical to that of SEQ ID NO: 113; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 310 and at least 90% identical to that of SEQ ID NO: 113; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 311 and at least 90% identical to that of SEQ ID NO: 113; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 312 and at least 90% identical to that of SEQ ID NO: 113; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 313 and at least 90% identical to that of SEQ ID NO: 113; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 314 and at least 90% identical to that of SEQ ID NO: 113; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 315 and at least 90% identical to that of SEQ ID NO: 113; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 316 and at least 90% identical to that of SEQ ID NO: 113; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 317 and at least 90% identical to that of SEQ ID NO: 113; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 1 and at least 90% identical to that of SEQ ID NO: 115; The amino acid sequence is at least 90% identical to SEQ ID NO: 2 and at least 90% identical to SEQ ID NO: 115; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 3 and at least 90% identical to that of SEQ ID NO: 115; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 4 and at least 90% identical to that of SEQ ID NO: 115; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 5 and at least 90% identical to that of SEQ ID NO: 115; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 6 and at least 90% identical to that of SEQ ID NO: 115; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 7 and at least 90% identical to that of SEQ ID NO: 115; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 8 and at least 90% identical to that of SEQ ID NO: 115; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 307 and at least 90% identical to that of SEQ ID NO: 115; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 308 and at least 90% identical to that of SEQ ID NO: 115; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 309 and at least 90% identical to that of SEQ ID NO: 115; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 310 and at least 90% identical to that of SEQ ID NO: 115; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 311 and at least 90% identical to that of SEQ ID NO: 115; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 312 and at least 90% identical to that of SEQ ID NO: 115; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 313 and at least 90% identical to that of SEQ ID NO: 115; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 314 and at least 90% identical to that of SEQ ID NO: 115; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 315 and at least 90% identical to that of SEQ ID NO: 115; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 316 and at least 90% identical to that of SEQ ID NO: 115; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 317 and at least 90% identical to that of SEQ ID NO: 115; The amino acid sequence is at least 90% identical to SEQ ID NO: 1 and at least 90% identical to SEQ ID NO: 117; The amino acid sequence is at least 90% identical to SEQ ID NO: 2 and at least 90% identical to SEQ ID NO: 117; The amino acid sequence is at least 90% identical to SEQ ID NO: 3 and at least 90% identical to SEQ ID NO: 117; The amino acid sequence is at least 90% identical to SEQ ID NO: 4 and at least 90% identical to SEQ ID NO: 117; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 5 and at least 90% identical to that of SEQ ID NO: 117; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 6 and at least 90% identical to that of SEQ ID NO: 117; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 7 and at least 90% identical to that of SEQ ID NO: 117; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 8 and at least 90% identical to that of SEQ ID NO: 117; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 307 and at least 90% identical to that of SEQ ID NO: 117; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 308 and at least 90% identical to that of SEQ ID NO: 117; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 309 and at least 90% identical to that of SEQ ID NO: 117; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 310 and at least 90% identical to that of SEQ ID NO: 117; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 311 and at least 90% identical to that of SEQ ID NO: 117; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 312 and at least 90% identical to that of SEQ ID NO: 117; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 313 and at least 90% identical to that of SEQ ID NO: 117; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 314 and at least 90% identical to that of SEQ ID NO: 117; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 315 and at least 90% identical to that of SEQ ID NO: 117; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 316 and at least 90% identical to that of SEQ ID NO: 117; The amino acid sequence is at least 90% identical to SEQ ID NO: 317 and at least 90% identical to SEQ ID NO: 117; The amino acid sequence is at least 90% identical to SEQ ID NO: 1 and at least 90% identical to SEQ ID NO: 119; The amino acid sequence is at least 90% identical to SEQ ID NO: 2 and at least 90% identical to SEQ ID NO: 119; The amino acid sequence is at least 90% identical to SEQ ID NO: 3 and at least 90% identical to SEQ ID NO: 119; The amino acid sequence is at least 90% identical to SEQ ID NO: 4 and at least 90% identical to SEQ ID NO: 119; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 5 and at least 90% identical to that of SEQ ID NO: 119; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 6 and at least 90% identical to that of SEQ ID NO: 119; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 7 and at least 90% identical to that of SEQ ID NO: 119; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 8 and at least 90% identical to that of SEQ ID NO: 119; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 307 and at least 90% identical to that of SEQ ID NO: 119; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 308 and at least 90% identical to that of SEQ ID NO: 119; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 309 and at least 90% identical to that of SEQ ID NO: 119; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 310 and at least 90% identical to that of SEQ ID NO: 119; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 311 and at least 90% identical to that of SEQ ID NO: 119; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 312 and at least 90% identical to that of SEQ ID NO: 119; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 313 and at least 90% identical to that of SEQ ID NO: 119; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 314 and at least 90% identical to that of SEQ ID NO: 119; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 315 and at least 90% identical to that of SEQ ID NO: 119; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 316 and at least 90% identical to that of SEQ ID NO: 119; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 317 and at least 90% identical to that of SEQ ID NO: 119; The amino acid sequence is at least 90% identical to SEQ ID NO: 1 and at least 90% identical to SEQ ID NO: 121; The amino acid sequence is at least 90% identical to SEQ ID NO: 2 and at least 90% identical to SEQ ID NO: 121; The amino acid sequence is at least 90% identical to SEQ ID NO: 3 and at least 90% identical to SEQ ID NO: 121; The amino acid sequence is at least 90% identical to SEQ ID NO: 4 and at least 90% identical to SEQ ID NO: 121; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 5 and at least 90% identical to that of SEQ ID NO: 121; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 6 and at least 90% identical to that of SEQ ID NO: 121; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 7 and at least 90% identical to that of SEQ ID NO: 121; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 8 and at least 90% identical to that of SEQ ID NO: 121; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 307 and at least 90% identical to that of SEQ ID NO: 121; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 308 and at least 90% identical to that of SEQ ID NO: 121; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 309 and at least 90% identical to that of SEQ ID NO: 121; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 310 and at least 90% identical to that of SEQ ID NO: 121; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 311 and at least 90% identical to that of SEQ ID NO: 121; The amino acid sequence is at least 90% identical to SEQ ID NO: 312 and at least 90% identical to SEQ ID NO: 121; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 313 and at least 90% identical to that of SEQ ID NO: 121; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 314 and at least 90% identical to that of SEQ ID NO: 121; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 315 and at least 90% identical to that of SEQ ID NO: 121; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 316 and at least 90% identical to that of SEQ ID NO: 121; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 317 and at least 90% identical to that of SEQ ID NO: 121; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 1 and at least 90% identical to that of SEQ ID NO: 123; The amino acid sequence is at least 90% identical to SEQ ID NO: 2 and at least 90% identical to SEQ ID NO: 123; The amino acid sequence is at least 90% identical to SEQ ID NO: 3 and at least 90% identical to SEQ ID NO: 123; The amino acid sequence is at least 90% identical to SEQ ID NO: 4 and at least 90% identical to SEQ ID NO: 123; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 5 and at least 90% identical to that of SEQ ID NO: 123; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 6 and at least 90% identical to that of SEQ ID NO: 123; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 7 and at least 90% identical to that of SEQ ID NO: 123; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 8 and at least 90% identical to that of SEQ ID NO: 123; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 307 and at least 90% identical to that of SEQ ID NO: 123; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 308 and at least 90% identical to that of SEQ ID NO: 123; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 309 and at least 90% identical to that of SEQ ID NO: 123; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 310 and at least 90% identical to that of SEQ ID NO: 123; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 311 and at least 90% identical to that of SEQ ID NO: 123; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 312 and at least 90% identical to that of SEQ ID NO: 123; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 313 and at least 90% identical to that of SEQ ID NO: 123; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 314 and at least 90% identical to that of SEQ ID NO: 123; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 315 and at least 90% identical to that of SEQ ID NO: 123; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 316 and at least 90% identical to that of SEQ ID NO: 123; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 317 and at least 90% identical to that of SEQ ID NO: 123; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 1 and at least 90% identical to that of SEQ ID NO: 125; The amino acid sequence is at least 90% identical to SEQ ID NO: 2 and at least 90% identical to SEQ ID NO: 125; The amino acid sequence is at least 90% identical to SEQ ID NO: 3 and at least 90% identical to SEQ ID NO: 125; The amino acid sequence is at least 90% identical to SEQ ID NO: 4 and at least 90% identical to SEQ ID NO: 125; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 5 and at least 90% identical to that of SEQ ID NO: 125; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 6 and at least 90% identical to that of SEQ ID NO: 125; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 7 and at least 90% identical to that of SEQ ID NO: 125; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 8 and at least 90% identical to that of SEQ ID NO: 125; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 307 and at least 90% identical to that of SEQ ID NO: 125; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 308 and at least 90% identical to that of SEQ ID NO: 125; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 309 and at least 90% identical to that of SEQ ID NO: 125; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 310 and at least 90% identical to that of SEQ ID NO: 125; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 311 and at least 90% identical to that of SEQ ID NO: 125; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 312 and at least 90% identical to that of SEQ ID NO: 125; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 313 and at least 90% identical to that of SEQ ID NO: 125; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 314 and at least 90% identical to that of SEQ ID NO: 125; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 315 and at least 90% identical to that of SEQ ID NO: 125; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 316 and at least 90% identical to that of SEQ ID NO: 125; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 317 and at least 90% identical to that of SEQ ID NO: 125; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 1 and at least 90% identical to that of SEQ ID NO: 127; The amino acid sequence is at least 90% identical to SEQ ID NO: 2 and at least 90% identical to SEQ ID NO: 127; The amino acid sequence is at least 90% identical to SEQ ID NO: 3 and at least 90% identical to SEQ ID NO: 127; The amino acid sequence is at least 90% identical to SEQ ID NO: 4 and at least 90% identical to SEQ ID NO: 127; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 5 and at least 90% identical to that of SEQ ID NO: 127; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 6 and at least 90% identical to that of SEQ ID NO: 127; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 7 and at least 90% identical to that of SEQ ID NO: 127; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 8 and at least 90% identical to that of SEQ ID NO: 127; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 307 and at least 90% identical to that of SEQ ID NO: 127; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 308 and at least 90% identical to that of SEQ ID NO: 127; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 309 and at least 90% identical to that of SEQ ID NO: 127; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 310 and at least 90% identical to that of SEQ ID NO: 127; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 311 and at least 90% identical to that of SEQ ID NO: 127; The amino acid sequence is at least 90% identical to SEQ ID NO: 312 and at least 90% identical to SEQ ID NO: 127; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 313 and at least 90% identical to that of SEQ ID NO: 127; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 314 and at least 90% identical to that of SEQ ID NO: 127; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 315 and at least 90% identical to that of SEQ ID NO: 127; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 316 and at least 90% identical to that of SEQ ID NO: 127; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 317 and at least 90% identical to that of SEQ ID NO: 127; The amino acid sequence is at least 90% identical to SEQ ID NO: 1 and at least 90% identical to SEQ ID NO: 129; The amino acid sequence is at least 90% identical to SEQ ID NO: 2 and at least 90% identical to SEQ ID NO: 129; The amino acid sequence is at least 90% identical to SEQ ID NO: 3 and at least 90% identical to SEQ ID NO: 129; The amino acid sequence is at least 90% identical to SEQ ID NO: 4 and at least 90% identical to SEQ ID NO: 129; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 5 and at least 90% identical to that of SEQ ID NO: 129; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 6 and at least 90% identical to that of SEQ ID NO: 129; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 7 and at least 90% identical to that of SEQ ID NO: 129; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 8 and at least 90% identical to that of SEQ ID NO: 129; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 307 and at least 90% identical to that of SEQ ID NO: 129; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 308 and at least 90% identical to that of SEQ ID NO: 129; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 309 and at least 90% identical to that of SEQ ID NO: 129; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 310 and at least 90% identical to that of SEQ ID NO: 129; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 311 and at least 90% identical to that of SEQ ID NO: 129; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 312 and at least 90% identical to that of SEQ ID NO: 129; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 313 and at least 90% identical to that of SEQ ID NO: 129; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 314 and at least 90% identical to that of SEQ ID NO: 129; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 315 and at least 90% identical to that of SEQ ID NO: 129; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 316 and at least 90% identical to that of SEQ ID NO: 129; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 317 and at least 90% identical to that of SEQ ID NO: 129; The amino acid sequence is at least 90% identical to SEQ ID NO: 1 and at least 90% identical to SEQ ID NO: 131; The amino acid sequence is at least 90% identical to SEQ ID NO: 2 and at least 90% identical to SEQ ID NO: 131; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 3 and at least 90% identical to that of SEQ ID NO: 131; The amino acid sequence is at least 90% identical to SEQ ID NO: 4 and at least 90% identical to SEQ ID NO: 131; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 5 and at least 90% identical to that of SEQ ID NO: 131; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 6 and at least 90% identical to that of SEQ ID NO: 131; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 7 and at least 90% identical to that of SEQ ID NO: 131; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 8 and at least 90% identical to that of SEQ ID NO: 131; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 307 and at least 90% identical to that of SEQ ID NO: 131; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 308 and at least 90% identical to that of SEQ ID NO: 131; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 309 and at least 90% identical to that of SEQ ID NO: 131; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 310 and at least 90% identical to that of SEQ ID NO: 131; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 311 and at least 90% identical to that of SEQ ID NO: 131; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 312 and at least 90% identical to that of SEQ ID NO: 131; The amino acid sequence is at least 90% identical to SEQ ID NO: 313 and at least 90% identical to SEQ ID NO: 131; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 314 and at least 90% identical to that of SEQ ID NO: 131; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 315 and at least 90% identical to that of SEQ ID NO: 131; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 316 and at least 90% identical to that of SEQ ID NO: 131; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 317 and at least 90% identical to that of SEQ ID NO: 131; The amino acid sequence is at least 90% identical to SEQ ID NO: 1 and at least 90% identical to SEQ ID NO: 133; The amino acid sequence is at least 90% identical to SEQ ID NO: 2 and at least 90% identical to SEQ ID NO: 133; The amino acid sequence is at least 90% identical to SEQ ID NO: 3 and at least 90% identical to SEQ ID NO: 133; The amino acid sequence is at least 90% identical to SEQ ID NO: 4 and at least 90% identical to SEQ ID NO: 133; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 5 and at least 90% identical to that of SEQ ID NO: 133; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 6 and at least 90% identical to that of SEQ ID NO: 133; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 7 and at least 90% identical to that of SEQ ID NO: 133; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 8 and at least 90% identical to that of SEQ ID NO: 133; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 307 and at least 90% identical to that of SEQ ID NO: 133; The amino acid sequence is at least 90% identical to SEQ ID NO: 308 and at least 90% identical to SEQ ID NO: 133; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 309 and at least 90% identical to that of SEQ ID NO: 133; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 310 and at least 90% identical to that of SEQ ID NO: 133; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 311 and at least 90% identical to that of SEQ ID NO: 133; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 312 and at least 90% identical to that of SEQ ID NO: 133; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 313 and at least 90% identical to that of SEQ ID NO: 133; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 314 and at least 90% identical to that of SEQ ID NO: 133; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 315 and at least 90% identical to that of SEQ ID NO: 133; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 316 and at least 90% identical to that of SEQ ID NO: 133; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 317 and at least 90% identical to that of SEQ ID NO: 133; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 1 and at least 90% identical to that of SEQ ID NO: 135; The amino acid sequence is at least 90% identical to SEQ ID NO: 2 and at least 90% identical to SEQ ID NO: 135; The amino acid sequence is at least 90% identical to SEQ ID NO: 3 and at least 90% identical to SEQ ID NO: 135; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 4 and at least 90% identical to that of SEQ ID NO: 135; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 5 and at least 90% identical to that of SEQ ID NO: 135; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 6 and at least 90% identical to that of SEQ ID NO: 135; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 7 and at least 90% identical to that of SEQ ID NO: 135; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 8 and at least 90% identical to that of SEQ ID NO: 135; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 307 and at least 90% identical to that of SEQ ID NO: 135; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 308 and at least 90% identical to that of SEQ ID NO: 135; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 309 and at least 90% identical to that of SEQ ID NO: 135; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 310 and at least 90% identical to that of SEQ ID NO: 135; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 311 and at least 90% identical to that of SEQ ID NO: 135; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 312 and at least 90% identical to that of SEQ ID NO: 135; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 313 and at least 90% identical to that of SEQ ID NO: 135; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 314 and at least 90% identical to that of SEQ ID NO: 135; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 315 and at least 90% identical to that of SEQ ID NO: 135; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 316 and at least 90% identical to that of SEQ ID NO: 135; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 317 and at least 90% identical to that of SEQ ID NO: 135; The amino acid sequence is at least 90% identical to SEQ ID NO: 1 and at least 90% identical to SEQ ID NO: 137; The amino acid sequence is at least 90% identical to SEQ ID NO: 2 and at least 90% identical to SEQ ID NO: 137; The amino acid sequence is at least 90% identical to SEQ ID NO: 3 and at least 90% identical to SEQ ID NO: 137; The amino acid sequence is at least 90% identical to SEQ ID NO: 4 and at least 90% identical to SEQ ID NO: 137; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 5 and at least 90% identical to that of SEQ ID NO: 137; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 6 and at least 90% identical to that of SEQ ID NO: 137; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 7 and at least 90% identical to that of SEQ ID NO: 137; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 8 and at least 90% identical to that of SEQ ID NO: 137; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 307 and at least 90% identical to that of SEQ ID NO: 137; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 308 and at least 90% identical to that of SEQ ID NO: 137; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 309 and at least 90% identical to that of SEQ ID NO: 137; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 310 and at least 90% identical to that of SEQ ID NO: 137; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 311 and at least 90% identical to that of SEQ ID NO: 137; The amino acid sequence is at least 90% identical to SEQ ID NO: 312 and at least 90% identical to SEQ ID NO: 137; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 313 and at least 90% identical to that of SEQ ID NO: 137; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 314 and at least 90% identical to that of SEQ ID NO: 137; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 315 and at least 90% identical to that of SEQ ID NO: 137; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 316 and at least 90% identical to that of SEQ ID NO: 137; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 317 and at least 90% identical to that of SEQ ID NO: 137; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 1 and at least 90% identical to that of SEQ ID NO: 376; The amino acid sequence is at least 90% identical to SEQ ID NO: 2 and at least 90% identical to SEQ ID NO: 376; The amino acid sequence is at least 90% identical to SEQ ID NO: 3 and at least 90% identical to SEQ ID NO: 376; The amino acid sequence is at least 90% identical to SEQ ID NO: 4 and at least 90% identical to SEQ ID NO: 376; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 5 and at least 90% identical to that of SEQ ID NO: 376; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 6 and at least 90% identical to that of SEQ ID NO: 376; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 7 and at least 90% identical to that of SEQ ID NO: 376; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 8 and at least 90% identical to that of SEQ ID NO: 376; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 307 and at least 90% identical to that of SEQ ID NO: 376; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 308 and at least 90% identical to that of SEQ ID NO: 376; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 309 and at least 90% identical to that of SEQ ID NO: 376; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 310 and at least 90% identical to that of SEQ ID NO: 376; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 311 and at least 90% identical to that of SEQ ID NO: 376; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 312 and at least 90% identical to that of SEQ ID NO: 376; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 313 and at least 90% identical to that of SEQ ID NO: 376; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 314 and at least 90% identical to that of SEQ ID NO: 376; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 315 and at least 90% identical to that of SEQ ID NO: 376; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 316 and at least 90% identical to that of SEQ ID NO: 376; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 317 and at least 90% identical to that of SEQ ID NO: 376; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 1 and at least 90% identical to that of SEQ ID NO: 378; The amino acid sequence is at least 90% identical to SEQ ID NO: 2 and at least 90% identical to SEQ ID NO: 378; The amino acid sequence is at least 90% identical to SEQ ID NO: 3 and at least 90% identical to SEQ ID NO: 378; The amino acid sequence is at least 90% identical to SEQ ID NO: 4 and at least 90% identical to SEQ ID NO: 378; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 5 and at least 90% identical to that of SEQ ID NO: 378; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 6 and at least 90% identical to that of SEQ ID NO: 378; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 7 and at least 90% identical to that of SEQ ID NO: 378; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 8 and at least 90% identical to that of SEQ ID NO: 378; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 307 and at least 90% identical to that of SEQ ID NO: 378; The amino acid sequence is at least 90% identical to SEQ ID NO: 308 and at least 90% identical to SEQ ID NO: 378; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 309 and at least 90% identical to that of SEQ ID NO: 378; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 310 and at least 90% identical to that of SEQ ID NO: 378; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 311 and at least 90% identical to that of SEQ ID NO: 378; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 312 and at least 90% identical to that of SEQ ID NO: 378; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 313 and at least 90% identical to that of SEQ ID NO: 378; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 314 and at least 90% identical to that of SEQ ID NO: 378; The amino acid sequence is at least 90% identical to that of SEQ ID NO: 315 and at least 90% identical to that of SEQ ID NO: 378; An amino acid sequence that is at least 90% identical to SEQ ID NO: 316 and an amino acid sequence that is at least 90% identical to SEQ ID NO: 378; or The amino acid sequence is at least 90% identical to that of SEQ ID NO: 317 and at least 90% identical to that of SEQ ID NO:

378.

80. The molecule of claim 79, wherein the first polypeptide comprises: The amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 103; the amino acid sequences of SEQ ID NO: 2 and SEQ ID NO: 103; the amino acid sequences of SEQ ID NO: 3 and SEQ ID NO: 103; the amino acid sequences of SEQ ID NO: 4 and SEQ ID NO: 103; the amino acid sequences of SEQ ID NO: 5 and SEQ ID NO: 103; the amino acid sequences of SEQ ID NO: 6 and SEQ ID NO: 103; the amino acid sequences of SEQ ID NO: 7 and SEQ ID NO: 103; the amino acid sequences of SEQ ID NO: 8 and SEQ ID NO: 103; the amino acid sequences of SEQ ID NO: 307 and SEQ ID NO: 103; the amino acid sequences of SEQ ID NO: 308 and SEQ ID NO: 103; the amino acid sequences of SEQ ID NO: 309 and SEQ ID NO: 103; the amino acid sequences of SEQ ID NO: 103 ... The amino acid sequences of SEQ ID NO: 103; SEQ ID NO: 310 and SEQ ID NO: 103; SEQ ID NO: 311 and SEQ ID NO: 103; SEQ ID NO: 312 and SEQ ID NO: 103; SEQ ID NO: 313 and SEQ ID NO: 103; SEQ ID NO: 314 and SEQ ID NO: 103; SEQ ID NO: 315 and SEQ ID NO: 103; SEQ ID NO: 316 and SEQ ID NO: 103; SEQ ID NO: 317 and SEQ ID NO: 103; SEQ ID NO: 1 and SEQ ID NO: 105; SEQ ID NO: 2 and SEQ ID NO: 105; SEQ ID NO: The amino acid sequences of SEQ ID NO: 3 and SEQ ID NO: 105; the amino acid sequences of SEQ ID NO: 4 and SEQ ID NO: 105; the amino acid sequences of SEQ ID NO: 5 and SEQ ID NO: 105;The amino acid sequences of SEQ ID NO: 6 and SEQ ID NO: 105; the amino acid sequences of SEQ ID NO: 7 and SEQ ID NO: 105; the amino acid sequences of SEQ ID NO: 8 and SEQ ID NO: 105; the amino acid sequences of SEQ ID NO: 307 and SEQ ID NO: 105; the amino acid sequences of SEQ ID NO: 308 and SEQ ID NO: 105; the amino acid sequences of SEQ ID NO: 309 and SEQ ID NO: 105; the amino acid sequences of SEQ ID NO: 310 and SEQ ID NO: 105; the amino acid sequences of SEQ ID NO: 311 and SEQ ID NO: 105; the amino acid sequences of SEQ ID NO: 312 and SEQ ID NO: 105; the amino acid sequences of SEQ ID NO: 313 and SEQ ID NO: 105; SEQ ID NO: The amino acid sequences of SEQ ID NO: 314 and SEQ ID NO: 105; the amino acid sequences of SEQ ID NO: 315 and SEQ ID NO: 105; the amino acid sequences of SEQ ID NO: 316 and SEQ ID NO: 105; the amino acid sequences of SEQ ID NO: 317 and SEQ ID NO: 105; the amino acid sequences of SEQ ID NO: 4, SEQ ID NO: 209, SEQ ID NO: 210 and SEQ ID NO: 105; the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 107; the amino acid sequences of SEQ ID NO: 2 and SEQ ID NO: 107; the amino acid sequences of SEQ ID NO: 3 and SEQ ID NO: 107; the amino acid sequences of SEQ ID NO: 4 and SEQ ID NO: 107; the amino acid sequences of SEQ ID NO: 5 and SEQ ID NO: 107; the amino acid sequences of SEQ ID NO: 107 and SEQ ID NO: 107; the amino acid sequences of SEQ ID NO: 314 and SEQ ID NO: 105; the amino acid sequences of SEQ ID NO: 316 and SEQ ID NO: 105; the amino acid sequences of SEQ ID NO: 317 and SEQ ID NO: 105; the amino acid sequences of SEQ ID NO: 4 and SEQ ID NO: 107; the amino acid sequences of SEQ ID NO: 314 and SEQ ID NO: 105; the amino acid sequences of SEQ ID NO: 317 and SEQ ID NO: 105; the amino acid sequences of SEQ ID NO: 314 and SEQ ID NO: 105; the amino acid sequences of SEQ ID NO: 315 and SEQ ID NO: 105; the amino acid sequences of SEQ ID NO: 316 and SEQ ID NO: 105; the amino acid sequences of The amino acid sequence of SEQ ID NO: 107; the amino acid sequences of SEQ ID NO: 6 and SEQ ID NO: 107; the amino acid sequences of SEQ ID NO: 7 and SEQ ID NO: 107; the amino acid sequences of SEQ ID NO: 8 and SEQ ID NO: 107;The amino acid sequences of SEQ ID NO: 307 and SEQ ID NO: 107; the amino acid sequences of SEQ ID NO: 308 and SEQ ID NO: 107; the amino acid sequences of SEQ ID NO: 309 and SEQ ID NO: 107; the amino acid sequences of SEQ ID NO: 310 and SEQ ID NO: 107; the amino acid sequences of SEQ ID NO: 311 and SEQ ID NO: 107; the amino acid sequences of SEQ ID NO: 312 and SEQ ID NO: 107; the amino acid sequences of SEQ ID NO: 313 and SEQ ID NO: 107; the amino acid sequences of SEQ ID NO: 314 and SEQ ID NO: 107; the amino acid sequences of SEQ ID NO: 315 and SEQ ID NO: 107; the amino acid sequences of SEQ ID NO: 316 and SEQ ID NO: 107; SEQ ID NO: The amino acid sequences of SEQ ID NO: 317 and SEQ ID NO: 107; the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 109; the amino acid sequences of SEQ ID NO: 2 and SEQ ID NO: 109; the amino acid sequences of SEQ ID NO: 3 and SEQ ID NO: 109; the amino acid sequences of SEQ ID NO: 4 and SEQ ID NO: 109; the amino acid sequences of SEQ ID NO: 5 and SEQ ID NO: 109; the amino acid sequences of SEQ ID NO: 6 and SEQ ID NO: 109; the amino acid sequences of SEQ ID NO: 7 and SEQ ID NO: 109; the amino acid sequences of SEQ ID NO: 8 and SEQ ID NO: 109; the amino acid sequences of SEQ ID NO: 307 and SEQ ID NO: 109; the amino acid sequences of SEQ ID NO: 308 and SEQ ID NO: 109; SEQ ID The amino acid sequences of SEQ ID NO: 309 and SEQ ID NO: 109; the amino acid sequences of SEQ ID NO: 310 and SEQ ID NO: 109; the amino acid sequences of SEQ ID NO: 311 and SEQ ID NO: 109;The amino acid sequences of SEQ ID NO: 312 and SEQ ID NO: 109; the amino acid sequences of SEQ ID NO: 313 and SEQ ID NO: 109; the amino acid sequences of SEQ ID NO: 314 and SEQ ID NO: 109; the amino acid sequences of SEQ ID NO: 315 and SEQ ID NO: 109; the amino acid sequences of SEQ ID NO: 316 and SEQ ID NO: 109; the amino acid sequences of SEQ ID NO: 317 and SEQ ID NO: 109; the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 113; the amino acid sequences of SEQ ID NO: 2 and SEQ ID NO: 113; the amino acid sequences of SEQ ID NO: 3 and SEQ ID NO: 113; the amino acid sequences of SEQ ID NO: 4 and SEQ ID NO: 113; the amino acid sequences of SEQ ID NO: 5 and SEQ ID NO: 113; the amino acid sequences of ... The amino acid sequences of SEQ ID NO: 113; SEQ ID NO: 6 and SEQ ID NO: 113; SEQ ID NO: 7 and SEQ ID NO: 113; SEQ ID NO: 8 and SEQ ID NO: 113; SEQ ID NO: 307 and SEQ ID NO: 113; SEQ ID NO: 308 and SEQ ID NO: 113; SEQ ID NO: 309 and SEQ ID NO: 113; SEQ ID NO: 310 and SEQ ID NO: 113; SEQ ID NO: 311 and SEQ ID NO: 113; SEQ ID NO: 312 and SEQ ID NO: 113; SEQ ID NO: 313 and SEQ ID NO: 113; SEQ ID NO: The amino acid sequences of SEQ ID NO: 314 and SEQ ID NO: 113; the amino acid sequences of SEQ ID NO: 315 and SEQ ID NO: 113; the amino acid sequences of SEQ ID NO: 316 and SEQ ID NO: 113;The amino acid sequences of SEQ ID NO: 317 and SEQ ID NO: 113; the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 115; the amino acid sequences of SEQ ID NO: 2 and SEQ ID NO: 115; the amino acid sequences of SEQ ID NO: 3 and SEQ ID NO: 115; the amino acid sequences of SEQ ID NO: 4 and SEQ ID NO: 115; the amino acid sequences of SEQ ID NO: 5 and SEQ ID NO: 115; the amino acid sequences of SEQ ID NO: 6 and SEQ ID NO: 115; the amino acid sequences of SEQ ID NO: 7 and SEQ ID NO: 115; the amino acid sequences of SEQ ID NO: 8 and SEQ ID NO: 115; the amino acid sequences of SEQ ID NO: 307 and SEQ ID NO: 115; the amino acid sequences of SEQ ID NO: 308 and SEQ ID NO: 115; and the amino acid sequences of SEQ ID NO: 115 and SEQ ID NO:

115. The amino acid sequences of SEQ ID NO: 115; SEQ ID NO: 309 and SEQ ID NO: 115; SEQ ID NO: 310 and SEQ ID NO: 115; SEQ ID NO: 311 and SEQ ID NO: 115; SEQ ID NO: 312 and SEQ ID NO: 115; SEQ ID NO: 313 and SEQ ID NO: 115; SEQ ID NO: 314 and SEQ ID NO: 115; SEQ ID NO: 315 and SEQ ID NO: 115; SEQ ID NO: 316 and SEQ ID NO: 115; SEQ ID NO: 317 and SEQ ID NO: 115; SEQ ID NO: 1 and SEQ ID NO: 117; SEQ ID NO: 1 The amino acid sequences of SEQ ID NO: 2 and SEQ ID NO: 117; the amino acid sequences of SEQ ID NO: 3 and SEQ ID NO: 117; the amino acid sequences of SEQ ID NO: 4 and SEQ ID NO: 117;The amino acid sequences of SEQ ID NO: 5 and SEQ ID NO: 117; the amino acid sequences of SEQ ID NO: 6 and SEQ ID NO: 117; the amino acid sequences of SEQ ID NO: 7 and SEQ ID NO: 117; the amino acid sequences of SEQ ID NO: 8 and SEQ ID NO: 117; the amino acid sequences of SEQ ID NO: 307 and SEQ ID NO: 117; the amino acid sequences of SEQ ID NO: 308 and SEQ ID NO: 117; the amino acid sequences of SEQ ID NO: 309 and SEQ ID NO: 117; the amino acid sequences of SEQ ID NO: 310 and SEQ ID NO: 117; the amino acid sequences of SEQ ID NO: 311 and SEQ ID NO: 117; the amino acid sequences of SEQ ID NO: 312 and SEQ ID NO: 117; the amino acid sequences of SEQ ID NO: 313 and SEQ ID NO: 117; and the amino acid sequences of SEQ ID NO: 117 and SEQ ID NO:

117. The amino acid sequences of SEQ ID NO: 117; SEQ ID NO: 314 and SEQ ID NO: 117; SEQ ID NO: 315 and SEQ ID NO: 117; SEQ ID NO: 316 and SEQ ID NO: 117; SEQ ID NO: 317 and SEQ ID NO: 117; SEQ ID NO: 1 and SEQ ID NO: 119; SEQ ID NO: 2 and SEQ ID NO: 119; SEQ ID NO: 3 and SEQ ID NO: 119; SEQ ID NO: 4 and SEQ ID NO: 119; SEQ ID NO: 5 and SEQ ID NO: 119; SEQ ID NO: 6 and SEQ ID NO: 119; SEQ ID NO: The amino acid sequences of SEQ ID NO: 7 and SEQ ID NO: 119; the amino acid sequences of SEQ ID NO: 8 and SEQ ID NO: 119; the amino acid sequences of SEQ ID NO: 307 and SEQ ID NO: 119;The amino acid sequences of SEQ ID NO: 308 and SEQ ID NO: 119; the amino acid sequences of SEQ ID NO: 309 and SEQ ID NO: 119; the amino acid sequences of SEQ ID NO: 310 and SEQ ID NO: 119; the amino acid sequences of SEQ ID NO: 311 and SEQ ID NO: 119; the amino acid sequences of SEQ ID NO: 312 and SEQ ID NO: 119; the amino acid sequences of SEQ ID NO: 313 and SEQ ID NO: 119; the amino acid sequences of SEQ ID NO: 314 and SEQ ID NO: 119; the amino acid sequences of SEQ ID NO: 315 and SEQ ID NO: 119; the amino acid sequences of SEQ ID NO: 316 and SEQ ID NO: 119; the amino acid sequences of SEQ ID NO: 317 and SEQ ID NO: 119; SEQ ID NO: The amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 121; the amino acid sequences of SEQ ID NO: 2 and SEQ ID NO: 121; the amino acid sequences of SEQ ID NO: 3 and SEQ ID NO: 121; the amino acid sequences of SEQ ID NO: 4 and SEQ ID NO: 121; the amino acid sequences of SEQ ID NO: 5 and SEQ ID NO: 121; the amino acid sequences of SEQ ID NO: 6 and SEQ ID NO: 121; the amino acid sequences of SEQ ID NO: 7 and SEQ ID NO: 121; the amino acid sequences of SEQ ID NO: 8 and SEQ ID NO: 121; the amino acid sequences of SEQ ID NO: 307 and SEQ ID NO: 121; the amino acid sequences of SEQ ID NO: 308 and SEQ ID NO: 121; the amino acid sequences of SEQ ID NO: 309 and SEQ ID NO: 121; SEQ ID The amino acid sequences of SEQ ID NO: 310 and SEQ ID NO: 121; the amino acid sequences of SEQ ID NO: 311 and SEQ ID NO: 121; the amino acid sequences of SEQ ID NO: 312 and SEQ ID NO: 121;The amino acid sequences of SEQ ID NO: 313 and SEQ ID NO: 121; the amino acid sequences of SEQ ID NO: 314 and SEQ ID NO: 121; the amino acid sequences of SEQ ID NO: 315 and SEQ ID NO: 121; the amino acid sequences of SEQ ID NO: 316 and SEQ ID NO: 121; the amino acid sequences of SEQ ID NO: 317 and SEQ ID NO: 121; the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 123; the amino acid sequences of SEQ ID NO: 2 and SEQ ID NO: 123; the amino acid sequences of SEQ ID NO: 3 and SEQ ID NO: 123; the amino acid sequences of SEQ ID NO: 4 and SEQ ID NO: 123; the amino acid sequences of SEQ ID NO: 5 and SEQ ID NO: 123; the amino acid sequences of SEQ ID NO: 6 and SEQ ID NO: 123; the amino acid sequences of SEQ ID NO: 314 and SEQ ID NO: 121; the amino acid sequences of SEQ ID NO: 315 and SEQ ID NO: 121; the amino acid sequences of SEQ ID NO: 316 and SEQ ID NO: 121; the amino acid sequences of SEQ ID NO: 317 and SEQ ID NO: 121; the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 123; the amino acid sequences of SEQ ID NO: 314 and SEQ ID NO: 121; the amino acid sequences of SEQ ID NO: 315 and SEQ ID NO: 121; the amino acid sequences of SEQ ID NO: 316 and SEQ ID NO: 123; the amino acid sequences of SEQ ID NO: 317 and SEQ ID NO: 121; the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 123; the amino The amino acid sequences of SEQ ID NO: 123; SEQ ID NO: 7 and SEQ ID NO: 123; SEQ ID NO: 8 and SEQ ID NO: 123; SEQ ID NO: 307 and SEQ ID NO: 123; SEQ ID NO: 308 and SEQ ID NO: 123; SEQ ID NO: 309 and SEQ ID NO: 123; SEQ ID NO: 310 and SEQ ID NO: 123; SEQ ID NO: 311 and SEQ ID NO: 123; SEQ ID NO: 312 and SEQ ID NO: 123; SEQ ID NO: 313 and SEQ ID NO: 123; SEQ ID NO: 314 and SEQ ID NO: 123; SEQ ID NO: The amino acid sequences of SEQ ID NO: 315 and SEQ ID NO: 123; the amino acid sequences of SEQ ID NO: 316 and SEQ ID NO: 123; the amino acid sequences of SEQ ID NO: 317 and SEQ ID NO: 123;The amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 125; the amino acid sequences of SEQ ID NO: 2 and SEQ ID NO: 125; the amino acid sequences of SEQ ID NO: 3 and SEQ ID NO: 125; the amino acid sequences of SEQ ID NO: 4 and SEQ ID NO: 125; the amino acid sequences of SEQ ID NO: 5 and SEQ ID NO: 125; the amino acid sequences of SEQ ID NO: 6 and SEQ ID NO: 125; the amino acid sequences of SEQ ID NO: 7 and SEQ ID NO: 125; the amino acid sequences of SEQ ID NO: 8 and SEQ ID NO: 125; the amino acid sequences of SEQ ID NO: 307 and SEQ ID NO: 125; the amino acid sequences of SEQ ID NO: 308 and SEQ ID NO: 125; the amino acid sequences of SEQ ID NO: 309 and SEQ ID NO: 125; the amino acid sequences of SEQ ID NO: 308 and SEQ ID NO: 125; the amino acid sequences of SEQ ID NO: 309 and SEQ ID NO: 125; the amino acid sequences of SEQ ID NO: 309 and SEQ ID NO: 125; the amino acid sequences of SEQ ID NO: 307 and SEQ ID NO: 125; the amino acid sequences of SEQ ID NO: 308 and SEQ ID NO: 125; the amino acid sequences of SEQ ID NO: 309 ... The amino acid sequences of SEQ ID NO: 125; SEQ ID NO: 310 and SEQ ID NO: 125; SEQ ID NO: 311 and SEQ ID NO: 125; SEQ ID NO: 312 and SEQ ID NO: 125; SEQ ID NO: 313 and SEQ ID NO: 125; SEQ ID NO: 314 and SEQ ID NO: 125; SEQ ID NO: 315 and SEQ ID NO: 125; SEQ ID NO: 316 and SEQ ID NO: 125; SEQ ID NO: 317 and SEQ ID NO: 125; SEQ ID NO: 1 and SEQ ID NO: 127; SEQ ID NO: 2 and SEQ ID NO: 127; SEQ ID NO: The amino acid sequences of SEQ ID NO: 3 and SEQ ID NO: 127; the amino acid sequences of SEQ ID NO: 4 and SEQ ID NO: 127; the amino acid sequences of SEQ ID NO: 5 and SEQ ID NO: 127;The amino acid sequences of SEQ ID NO: 6 and SEQ ID NO: 127; the amino acid sequences of SEQ ID NO: 7 and SEQ ID NO: 127; the amino acid sequences of SEQ ID NO: 8 and SEQ ID NO: 127; the amino acid sequences of SEQ ID NO: 307 and SEQ ID NO: 127; the amino acid sequences of SEQ ID NO: 308 and SEQ ID NO: 127; the amino acid sequences of SEQ ID NO: 309 and SEQ ID NO: 127; the amino acid sequences of SEQ ID NO: 310 and SEQ ID NO: 127; the amino acid sequences of SEQ ID NO: 311 and SEQ ID NO: 127; the amino acid sequences of SEQ ID NO: 312 and SEQ ID NO: 127; the amino acid sequences of SEQ ID NO: 313 and SEQ ID NO: 127; SEQ ID NO: The amino acid sequences of SEQ ID NO: 314 and SEQ ID NO: 127; the amino acid sequences of SEQ ID NO: 315 and SEQ ID NO: 127; the amino acid sequences of SEQ ID NO: 316 and SEQ ID NO: 127; the amino acid sequences of SEQ ID NO: 317 and SEQ ID NO: 127; the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 129; the amino acid sequences of SEQ ID NO: 2 and SEQ ID NO: 129; the amino acid sequences of SEQ ID NO: 3 and SEQ ID NO: 129; the amino acid sequences of SEQ ID NO: 4 and SEQ ID NO: 129; the amino acid sequences of SEQ ID NO: 5 and SEQ ID NO: 129; the amino acid sequences of SEQ ID NO: 6 and SEQ ID NO: 129; the amino acid sequences of SEQ ID NO: 7 and SEQ ID NO: 129; SEQ The amino acid sequences of SEQ ID NO: 8 and SEQ ID NO: 129; the amino acid sequences of SEQ ID NO: 307 and SEQ ID NO: 129; the amino acid sequences of SEQ ID NO: 308 and SEQ ID NO: 129;The amino acid sequences of SEQ ID NO: 309 and SEQ ID NO: 129; the amino acid sequences of SEQ ID NO: 310 and SEQ ID NO: 129; the amino acid sequences of SEQ ID NO: 311 and SEQ ID NO: 129; the amino acid sequences of SEQ ID NO: 312 and SEQ ID NO: 129; the amino acid sequences of SEQ ID NO: 313 and SEQ ID NO: 129; the amino acid sequences of SEQ ID NO: 314 and SEQ ID NO: 129; the amino acid sequences of SEQ ID NO: 315 and SEQ ID NO: 129; the amino acid sequences of SEQ ID NO: 316 and SEQ ID NO: 129; the amino acid sequences of SEQ ID NO: 317 and SEQ ID NO: 129; the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 131; SEQ ID NO: The amino acid sequences of SEQ ID NO: 2 and SEQ ID NO: 131; the amino acid sequences of SEQ ID NO: 3 and SEQ ID NO: 131; the amino acid sequences of SEQ ID NO: 4 and SEQ ID NO: 131; the amino acid sequences of SEQ ID NO: 5 and SEQ ID NO: 131; the amino acid sequences of SEQ ID NO: 6 and SEQ ID NO: 131; the amino acid sequences of SEQ ID NO: 7 and SEQ ID NO: 131; the amino acid sequences of SEQ ID NO: 8 and SEQ ID NO: 131; the amino acid sequences of SEQ ID NO: 307 and SEQ ID NO: 131; the amino acid sequences of SEQ ID NO: 308 and SEQ ID NO: 131; the amino acid sequences of SEQ ID NO: 309 and SEQ ID NO: 131; the amino acid sequences of SEQ ID NO: 310 and SEQ ID NO: 131; SEQ The amino acid sequences of SEQ ID NO: 311 and SEQ ID NO: 131; the amino acid sequences of SEQ ID NO: 312 and SEQ ID NO: 131; the amino acid sequences of SEQ ID NO: 313 and SEQ ID NO: 131;The amino acid sequences of SEQ ID NO: 314 and SEQ ID NO: 131; the amino acid sequences of SEQ ID NO: 315 and SEQ ID NO: 131; the amino acid sequences of SEQ ID NO: 316 and SEQ ID NO: 131; the amino acid sequences of SEQ ID NO: 317 and SEQ ID NO: 131; the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 133; the amino acid sequences of SEQ ID NO: 2 and SEQ ID NO: 133; the amino acid sequences of SEQ ID NO: 3 and SEQ ID NO: 133; the amino acid sequences of SEQ ID NO: 4 and SEQ ID NO: 133; the amino acid sequences of SEQ ID NO: 5 and SEQ ID NO: 133; the amino acid sequences of SEQ ID NO: 6 and SEQ ID NO: 133; the amino acid sequences of SEQ ID NO: 7 and SEQ ID NO: 133; the amino acid sequences of SEQ ID NO: 13 ... Amino acid sequence of SEQ ID NO: 133; amino acid sequences of SEQ ID NO: 8 and SEQ ID NO: 133; amino acid sequences of SEQ ID NO: 307 and SEQ ID NO: 133; amino acid sequences of SEQ ID NO: 308 and SEQ ID NO: 133; amino acid sequences of SEQ ID NO: 309 and SEQ ID NO: 133; amino acid sequences of SEQ ID NO: 310 and SEQ ID NO: 133; amino acid sequences of SEQ ID NO: 311 and SEQ ID NO: 133; amino acid sequences of SEQ ID NO: 312 and SEQ ID NO: 133; amino acid sequences of SEQ ID NO: 313 and SEQ ID NO: 133; amino acid sequences of SEQ ID NO: 314 and SEQ ID NO: 133; amino acid sequences of SEQ ID NO: 315 and SEQ ID NO: 133; SEQ The amino acid sequences of SEQ ID NO: 316 and SEQ ID NO: 133; the amino acid sequences of SEQ ID NO: 317 and SEQ ID NO: 133; the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 135;The amino acid sequences of SEQ ID NO: 2 and SEQ ID NO: 135; the amino acid sequences of SEQ ID NO: 3 and SEQ ID NO: 135; the amino acid sequences of SEQ ID NO: 4 and SEQ ID NO: 135; the amino acid sequences of SEQ ID NO: 5 and SEQ ID NO: 135; the amino acid sequences of SEQ ID NO: 6 and SEQ ID NO: 135; the amino acid sequences of SEQ ID NO: 7 and SEQ ID NO: 135; the amino acid sequences of SEQ ID NO: 8 and SEQ ID NO: 135; the amino acid sequences of SEQ ID NO: 307 and SEQ ID NO: 135; the amino acid sequences of SEQ ID NO: 308 and SEQ ID NO: 135; the amino acid sequences of SEQ ID NO: 309 and SEQ ID NO: 135; the amino acid sequences of SEQ ID NO: 310 and SEQ ID NO: 135; the amino acid sequences of ... The amino acid sequences of SEQ ID NO: 135; SEQ ID NO: 311 and SEQ ID NO: 135; SEQ ID NO: 312 and SEQ ID NO: 135; SEQ ID NO: 313 and SEQ ID NO: 135; SEQ ID NO: 314 and SEQ ID NO: 135; SEQ ID NO: 315 and SEQ ID NO: 135; SEQ ID NO: 316 and SEQ ID NO: 135; SEQ ID NO: 317 and SEQ ID NO: 135; SEQ ID NO: 1 and SEQ ID NO: 137; SEQ ID NO: 2 and SEQ ID NO: 137; SEQ ID NO: 3 and SEQ ID NO: 137; SEQ ID NO: The amino acid sequences of SEQ ID NO: 4 and SEQ ID NO: 137; the amino acid sequences of SEQ ID NO: 5 and SEQ ID NO: 137; the amino acid sequences of SEQ ID NO: 6 and SEQ ID NO: 137;The amino acid sequences of SEQ ID NO: 7 and SEQ ID NO: 137; the amino acid sequences of SEQ ID NO: 8 and SEQ ID NO: 137; the amino acid sequences of SEQ ID NO: 307 and SEQ ID NO: 137; the amino acid sequences of SEQ ID NO: 308 and SEQ ID NO: 137; the amino acid sequences of SEQ ID NO: 309 and SEQ ID NO: 137; the amino acid sequences of SEQ ID NO: 310 and SEQ ID NO: 137; the amino acid sequences of SEQ ID NO: 311 and SEQ ID NO: 137; the amino acid sequences of SEQ ID NO: 312 and SEQ ID NO: 137; the amino acid sequences of SEQ ID NO: 313 and SEQ ID NO: 137; the amino acid sequences of SEQ ID NO: 314 and SEQ ID NO: 137; SEQ ID NO: The amino acid sequences of SEQ ID NO: 315 and SEQ ID NO: 137; the amino acid sequences of SEQ ID NO: 316 and SEQ ID NO: 137; the amino acid sequences of SEQ ID NO: 317 and SEQ ID NO: 137; the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 376; the amino acid sequences of SEQ ID NO: 2 and SEQ ID NO: 376; the amino acid sequences of SEQ ID NO: 3 and SEQ ID NO: 376; the amino acid sequences of SEQ ID NO: 4 and SEQ ID NO: 376; the amino acid sequences of SEQ ID NO: 5 and SEQ ID NO: 376; the amino acid sequences of SEQ ID NO: 6 and SEQ ID NO: 376; the amino acid sequences of SEQ ID NO: 7 and SEQ ID NO: 376; the amino acid sequences of SEQ ID NO: 8 and SEQ ID NO: 376; SEQ ID NO: 1 and SEQ ID NO: 376; SEQ ID NO: 315 and SEQ ID NO: 137; SEQ ID NO: 316 and SEQ ID NO: 137; SEQ ID NO: 317 and SEQ ID NO: 137; SEQ ID NO: 1 and SEQ ID NO: 376; SEQ ID NO: 2 and SEQ ID NO: 376; the amino acid sequences of SEQ ID NO: 3 and SEQ ID NO: 376; SEQ ID NO: 315 and SEQ ID NO: 137; SEQ ID NO: 316 and SEQ ID NO: 137; SEQ ID NO: 317 ... The amino acid sequences of SEQ ID NO: 307 and SEQ ID NO: 376; the amino acid sequences of SEQ ID NO: 308 and SEQ ID NO: 376; the amino acid sequences of SEQ ID NO: 309 and SEQ ID NO: 376;The amino acid sequences of SEQ ID NO: 310 and SEQ ID NO: 376; the amino acid sequences of SEQ ID NO: 311 and SEQ ID NO: 376; the amino acid sequences of SEQ ID NO: 312 and SEQ ID NO: 376; the amino acid sequences of SEQ ID NO: 313 and SEQ ID NO: 376; the amino acid sequences of SEQ ID NO: 314 and SEQ ID NO: 376; the amino acid sequences of SEQ ID NO: 315 and SEQ ID NO: 376; the amino acid sequences of SEQ ID NO: 316 and SEQ ID NO: 376; the amino acid sequences of SEQ ID NO: 317 and SEQ ID NO: 376; the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 378; the amino acid sequences of SEQ ID NO: 2 and SEQ ID NO: 378; SEQ ID NO: The amino acid sequences of SEQ ID NO: 3 and SEQ ID NO: 378; SEQ ID NO: 4 and SEQ ID NO: 378; SEQ ID NO: 5 and SEQ ID NO: 378; SEQ ID NO: 6 and SEQ ID NO: 378; SEQ ID NO: 7 and SEQ ID NO: 378; SEQ ID NO: 8 and SEQ ID NO: 378; SEQ ID NO: 307 and SEQ ID NO: 378; SEQ ID NO: 308 and SEQ ID NO: 378; SEQ ID NO: 309 and SEQ ID NO: 378; SEQ ID NO: 310 and SEQ ID NO: 378; SEQ ID NO: 311 and SEQ ID NO: The amino acid sequences of SEQ ID NO: 378; SEQ ID NO: 312 and SEQ ID NO: 378; SEQ ID NO: 313 and SEQ ID NO: 378; SEQ ID NO: 314 and SEQ ID NO: 378;The amino acid sequences of SEQ ID NO: 315 and SEQ ID NO: 378; the amino acid sequences of SEQ ID NO: 316 and SEQ ID NO: 378; or the amino acid sequences of SEQ ID NO: 317 and SEQ ID NO:

378.

81. The molecule of any one of claims 1-80, wherein the second polypeptide comprises: (i) An amino acid sequence that is at least 90% identical to SEQ ID NO: 104; (ii) An amino acid sequence that is at least 90% identical to SEQ ID NO: 106; (iii) An amino acid sequence that is at least 90% identical to SEQ ID NO: 108; (iv) An amino acid sequence that is at least 90% identical to SEQ ID NO: 110; (v) an amino acid sequence that is at least 90% identical to SEQ ID NO: 209, an amino acid sequence that is at least 90% identical to SEQ ID NO: 210, and an amino acid sequence that is at least 90% identical to SEQ ID NO: 106; (vi) An amino acid sequence that is at least 90% identical to SEQ ID NO: 114; (vii) An amino acid sequence that is at least 90% identical to SEQ ID NO: 116; (viii) An amino acid sequence that is at least 90% identical to SEQ ID NO: 118; (ix) An amino acid sequence that is at least 90% identical to SEQ ID NO: 120; (x) An amino acid sequence that is at least 90% identical to SEQ ID NO: 122; (xi) is an amino acid sequence that is at least 90% identical to SEQ ID NO: 124; (xii) An amino acid sequence that is at least 90% identical to SEQ ID NO: 126; (xiii) An amino acid sequence that is at least 90% identical to SEQ ID NO: 128; (xiv) is at least 90% identical to the amino acid sequence of SEQ ID NO: 130; (xv) is at least 90% identical to the amino acid sequence of SEQ ID NO: 132; (xvi) An amino acid sequence that is at least 90% identical to SEQ ID NO: 134; (xvii) is at least 90% identical to the amino acid sequence of SEQ ID NO: 136; (xviii) An amino acid sequence that is at least 90% identical to SEQ ID NO: 138; (xix) An amino acid sequence that is at least 90% identical to SEQ ID NO: 377; or (xx) is at least 90% identical to the amino acid sequence of SEQ ID NO:

379.

82. The molecule of claim 81, wherein the second polypeptide comprises: (i) The amino acid sequence of SEQ ID NO: 104; (ii) The amino acid sequence of SEQ ID NO: 106; (iii) The amino acid sequence of SEQ ID NO: 108; (iv) The amino acid sequence of SEQ ID NO: 110; (v) The amino acid sequences of SEQ ID NO: 209, SEQ ID NO: 210, and SEQ ID NO: 106; (vi) The amino acid sequence of SEQ ID NO: 114; (vii) The amino acid sequence of SEQ ID NO: 116; (viii) The amino acid sequence of SEQ ID NO: 118; (ix) The amino acid sequence of SEQ ID NO: 120; (x) The amino acid sequence of SEQ ID NO: 122; (xi) The amino acid sequence of SEQ ID NO: 124; (xii) The amino acid sequence of SEQ ID NO: 126; (xiii) The amino acid sequence of SEQ ID NO: 128; (xiv) Amino acid sequence of SEQ ID NO: 130; (xv) The amino acid sequence of SEQ ID NO: 132; (xvi) The amino acid sequence of SEQ ID NO: 134; (xvii) The amino acid sequence of SEQ ID NO: 136; (xviii) The amino acid sequence of SEQ ID NO: 138; (xix) The amino acid sequence of SEQ ID NO: 377; or (xx) amino acid sequence of SEQ ID NO:

379.

83. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 1 and the amino acid sequence of SEQ ID NO: 107, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 108; or (ii) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 1 and the amino acid sequence of SEQ ID NO: 108, and the second polypeptide comprises the amino acid sequence of SEQ ID NO:

107.

84. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 2 and the amino acid sequence of SEQ ID NO: 107, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 108; or (ii) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 2 and the amino acid sequence of SEQ ID NO: 108, and the second polypeptide comprises the amino acid sequence of SEQ ID NO:

107.

85. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 3 and the amino acid sequence of SEQ ID NO: 107, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 108; or (ii) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 3 and the amino acid sequence of SEQ ID NO: 108, and the second polypeptide comprises the amino acid sequence of SEQ ID NO:

107.

86. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 4 and the amino acid sequence of SEQ ID NO: 107, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 108; or (ii) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 4 and the amino acid sequence of SEQ ID NO: 108, and the second polypeptide comprises the amino acid sequence of SEQ ID NO:

107.

87. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 5 and the amino acid sequence of SEQ ID NO: 107, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 108; or (ii) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 5 and the amino acid sequence of SEQ ID NO: 108, and the second polypeptide comprises the amino acid sequence of SEQ ID NO:

107.

88. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 6 and the amino acid sequence of SEQ ID NO: 107, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 108; or (ii) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 6 and the amino acid sequence of SEQ ID NO: 108, and the second polypeptide comprises the amino acid sequence of SEQ ID NO:

107.

89. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 7 and the amino acid sequence of SEQ ID NO: 107, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 108; or (ii) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 7 and the amino acid sequence of SEQ ID NO: 108, and the second polypeptide comprises the amino acid sequence of SEQ ID NO:

107.

90. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 8 and the amino acid sequence of SEQ ID NO: 107, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 108; or (ii) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 8 and the amino acid sequence of SEQ ID NO: 108, and the second polypeptide comprises the amino acid sequence of SEQ ID NO:

107.

91. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence containing SEQ ID NO: 1 and SEQ ID NO: 109, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 110; or (ii) The first polypeptide comprises an amino acid sequence containing SEQ ID NO: 1 and SEQ ID NO: 110, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO:

109.

92. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence containing SEQ ID NO: 2 and SEQ ID NO: 109, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 110; or (ii) The first polypeptide comprises an amino acid sequence containing SEQ ID NO: 3 and SEQ ID NO: 110, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO:

109.

93. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence containing SEQ ID NO: 4 and SEQ ID NO: 109, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 110; or (ii) The first polypeptide comprises an amino acid sequence containing SEQ ID NO: 4 and SEQ ID NO: 110, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO:

109.

94. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence containing SEQ ID NO: 5 and SEQ ID NO: 109, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 110; or (ii) The first polypeptide comprises an amino acid sequence containing SEQ ID NO: 5 and SEQ ID NO: 110, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO:

109.

95. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence containing SEQ ID NO: 6 and SEQ ID NO: 109, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 110; or (ii) The first polypeptide comprises an amino acid sequence containing SEQ ID NO: 6 and SEQ ID NO: 110, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO:

109.

96. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence containing SEQ ID NO: 7 and SEQ ID NO: 109, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 110; or (ii) The first polypeptide comprises an amino acid sequence containing SEQ ID NO: 7 and SEQ ID NO: 110, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO:

109.

97. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence containing SEQ ID NO: 8 and SEQ ID NO: 109, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 110; or (ii) The first polypeptide comprises an amino acid sequence containing SEQ ID NO: 8 and SEQ ID NO: 110, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO:

109.

98. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence containing SEQ ID NO: 1 and SEQ ID NO: 113, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 114; or (ii) The first polypeptide comprises an amino acid sequence containing SEQ ID NO: 1 and SEQ ID NO: 114, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO:

113.

99. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence containing SEQ ID NO: 2 and SEQ ID NO: 113, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 114; or (ii) The first polypeptide comprises an amino acid sequence containing SEQ ID NO: 2 and SEQ ID NO: 114, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO:

113.

100. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence containing SEQ ID NO: 3 and SEQ ID NO: 113, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 114; or (ii) The first polypeptide comprises an amino acid sequence containing SEQ ID NO: 3 and SEQ ID NO: 114, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO:

113.

101. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence containing SEQ ID NO: 4 and SEQ ID NO: 113, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 114; or (ii) The first polypeptide comprises an amino acid sequence containing SEQ ID NO: 4 and SEQ ID NO: 114, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO:

113.

102. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence containing SEQ ID NO: 5 and SEQ ID NO: 113, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 114; or (ii) The first polypeptide comprises an amino acid sequence containing SEQ ID NO: 5 and SEQ ID NO: 114, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO:

113.

103. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence containing SEQ ID NO: 6 and SEQ ID NO: 113, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 114; or (ii) The first polypeptide comprises an amino acid sequence containing SEQ ID NO: 6 and SEQ ID NO: 114, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO:

113.

104. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence containing SEQ ID NO: 7 and SEQ ID NO: 113, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 114; or (ii) The first polypeptide comprises an amino acid sequence containing SEQ ID NO: 7 and SEQ ID NO: 114, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO:

113.

105. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence containing SEQ ID NO: 8 and SEQ ID NO: 113, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 114; or (ii) The first polypeptide comprises an amino acid sequence containing SEQ ID NO: 8 and SEQ ID NO: 114, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO:

113.

106. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence containing SEQ ID NO: 1 and SEQ ID NO: 115, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 116; or (ii) The first polypeptide comprises an amino acid sequence containing SEQ ID NO: 1 and SEQ ID NO: 116, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO:

115.

107. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence containing SEQ ID NO: 2 and SEQ ID NO: 115, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 116; or (ii) The first polypeptide comprises an amino acid sequence containing SEQ ID NO: 2 and SEQ ID NO: 116, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO:

115.

108. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence containing SEQ ID NO: 3 and SEQ ID NO: 115, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 116; or (ii) The first polypeptide comprises an amino acid sequence containing SEQ ID NO: 3 and SEQ ID NO: 116, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO:

115.

109. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence containing SEQ ID NO: 4 and SEQ ID NO: 115, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 116; or (ii) The first polypeptide comprises an amino acid sequence containing SEQ ID NO: 4 and SEQ ID NO: 116, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO:

115.

110. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence containing SEQ ID NO: 5 and SEQ ID NO: 115, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 116; or (ii) The first polypeptide comprises an amino acid sequence containing SEQ ID NO: 5 and SEQ ID NO: 116, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO:

115.

111. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence containing SEQ ID NO: 6 and SEQ ID NO: 115, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 116; or (ii) The first polypeptide comprises an amino acid sequence containing SEQ ID NO: 6 and SEQ ID NO: 116, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO:

115.

112. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence containing SEQ ID NO: 7 and SEQ ID NO: 115, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 116; or (ii) The first polypeptide comprises an amino acid sequence containing SEQ ID NO: 7 and SEQ ID NO: 116, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO:

115.

113. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence containing SEQ ID NO: 8 and SEQ ID NO: 115, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 116; or (ii) The first polypeptide comprises an amino acid sequence containing SEQ ID NO: 8 and SEQ ID NO: 116, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO:

115.

114. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence containing SEQ ID NO: 1 and SEQ ID NO: 119, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 120; or (ii) The first polypeptide comprises an amino acid sequence containing SEQ ID NO: 1 and SEQ ID NO: 120, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO:

119.

115. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence containing SEQ ID NO: 2 and SEQ ID NO: 119, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 120; or (ii) The first polypeptide comprises an amino acid sequence containing SEQ ID NO: 2 and SEQ ID NO: 120, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO:

119.

116. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence containing SEQ ID NO: 3 and SEQ ID NO: 119, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 120; or (ii) The first polypeptide comprises an amino acid sequence containing SEQ ID NO: 3 and SEQ ID NO: 120, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO:

119.

117. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence containing SEQ ID NO: 4 and SEQ ID NO: 119, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 120; or (ii) The first polypeptide comprises the amino acid sequence containing SEQ ID NO: 4 and SEQ ID NO: 120, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO:

119.

118. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence containing SEQ ID NO: 5 and SEQ ID NO: 119, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 120; or (ii) The first polypeptide comprises an amino acid sequence containing SEQ ID NO: 5 and SEQ ID NO: 120, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO:

119.

119. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence containing SEQ ID NO: 6 and SEQ ID NO: 119, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 120; or (ii) The first polypeptide comprises an amino acid sequence containing SEQ ID NO: 6 and SEQ ID NO: 120, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO:

119.

120. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence containing SEQ ID NO: 7 and SEQ ID NO: 119, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 120; or (ii) The first polypeptide comprises an amino acid sequence containing SEQ ID NO: 7 and SEQ ID NO: 120, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO:

119.

121. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence containing SEQ ID NO: 8 and SEQ ID NO: 119, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 120; or (ii) The first polypeptide comprises the amino acid sequence containing SEQ ID NO: 8 and SEQ ID NO: 120, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO:

119.

122. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence containing SEQ ID NO: 1 and SEQ ID NO: 131, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 132; or (ii) The first polypeptide comprises an amino acid sequence containing SEQ ID NO: 1 and SEQ ID NO: 132, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO:

131.

123. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence containing SEQ ID NO: 2 and SEQ ID NO: 131, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 132; or (ii) The first polypeptide comprises an amino acid sequence containing SEQ ID NO: 3 and SEQ ID NO: 132, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO:

131.

124. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence containing SEQ ID NO: 3 and SEQ ID NO: 131, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 132; or (ii) The first polypeptide comprises an amino acid sequence containing SEQ ID NO: 3 and SEQ ID NO: 132, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO:

131.

125. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence containing SEQ ID NO: 4 and SEQ ID NO: 131, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 132; or (ii) The first polypeptide comprises an amino acid sequence containing SEQ ID NO: 4 and SEQ ID NO: 132, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO:

131.

126. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence containing SEQ ID NO: 5 and SEQ ID NO: 131, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 132; or (ii) The first polypeptide comprises an amino acid sequence containing SEQ ID NO: 5 and SEQ ID NO: 132, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO:

131.

127. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence containing SEQ ID NO: 6 and SEQ ID NO: 131, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 132; or (ii) The first polypeptide comprises an amino acid sequence containing SEQ ID NO: 6 and SEQ ID NO: 132, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO:

131.

128. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence containing SEQ ID NO: 7 and SEQ ID NO: 131, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 132; or (ii) The first polypeptide comprises an amino acid sequence containing SEQ ID NO: 7 and SEQ ID NO: 132, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO:

131.

129. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence containing SEQ ID NO: 8 and SEQ ID NO: 131, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 132; or (ii) The first polypeptide comprises an amino acid sequence containing SEQ ID NO: 8 and SEQ ID NO: 132, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO:

131.

130. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence containing SEQ ID NO: 1 and SEQ ID NO: 378, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 379; or (ii) The first polypeptide comprises an amino acid sequence containing SEQ ID NO: 1 and SEQ ID NO: 379, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO:

378.

131. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence containing SEQ ID NO: 2 and SEQ ID NO: 378, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 379; or (ii) The first polypeptide comprises an amino acid sequence containing SEQ ID NO: 2 and SEQ ID NO: 379, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO:

378.

132. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence containing SEQ ID NO: 3 and SEQ ID NO: 378, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 379; or (ii) The first polypeptide comprises an amino acid sequence containing SEQ ID NO: 3 and SEQ ID NO: 379, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO:

378.

133. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence containing SEQ ID NO: 4 and SEQ ID NO: 378, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 379; or (ii) The first polypeptide comprises an amino acid sequence containing SEQ ID NO: 4 and SEQ ID NO: 379, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO:

378.

134. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence containing SEQ ID NO: 5 and SEQ ID NO: 378, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 379; or (ii) The first polypeptide comprises an amino acid sequence containing SEQ ID NO: 5 and SEQ ID NO: 379, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO:

378.

135. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence containing SEQ ID NO: 6 and SEQ ID NO: 378, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 379; or (ii) The first polypeptide comprises an amino acid sequence containing SEQ ID NO: 6 and SEQ ID NO: 379, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO:

378.

136. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence containing SEQ ID NO: 7 and SEQ ID NO: 378, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 379; or (ii) The first polypeptide comprises an amino acid sequence containing SEQ ID NO: 7 and SEQ ID NO: 379, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO:

378.

137. The molecule according to any one of claims 1-82, wherein (i) The first polypeptide comprises the amino acid sequence containing SEQ ID NO: 8 and SEQ ID NO: 378, and the second polypeptide comprises the amino acid sequence containing SEQ ID NO: 379; or (ii) The first polypeptide comprises an amino acid sequence containing SEQ ID NO: 8 and SEQ ID NO: 379, and the second polypeptide comprises an amino acid sequence containing SEQ ID NO:

378.

138. The molecule of any one of claims 1-82, wherein the first polypeptide comprises the amino acid sequence of any one of SEQ ID NO: 211-217, 225-227, 231-237, 245-247, 318-331 or 346-359, and the second polypeptide comprises the amino acid sequence of any one of SEQ ID NO: 218-224, 228-230, 238-244, 248-250, 332-345 or 360-373.

139. The molecule according to any one of claims 1-82, wherein: (i) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 211, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 218; (ii) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 212, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 219; (iii) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 213, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 220; (iv) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 214, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 221; (v) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 215, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 222; (vi) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 216, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 223; (vii) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 217, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 224; (viii) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 225, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 228; (ix) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 226, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 229; (x) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 227, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 230; (xi) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 231, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 238; (xii) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 232, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 239; (xiii) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 233, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 240; (xiv) The first polypeptide contains the amino acid sequence of SEQ ID NO: 234, and the second polypeptide contains the amino acid sequence of SEQ ID NO: 241; (xv) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 235, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 242; (xvi) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 236, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 243; (xvii) The first polypeptide contains the amino acid sequence of SEQ ID NO: 237, and the second polypeptide contains the amino acid sequence of SEQ ID NO: 244; (xviii) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 245, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 248; (xix) The first polypeptide contains the amino acid sequence of SEQ ID NO: 246, and the second polypeptide contains the amino acid sequence of SEQ ID NO: 249; (xx) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 247, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 250; (xxi) The first polypeptide contains the amino acid sequence of SEQ ID NO: 318, and the second polypeptide contains the amino acid sequence of SEQ ID NO: 332; (xxi) The first polypeptide contains the amino acid sequence of SEQ ID NO: 319, and the second polypeptide contains the amino acid sequence of SEQ ID NO:

333. (xxii) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 320, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 334; (xxiii) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 321, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 335; (xxiv) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 322, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 336; (xxv) The first polypeptide contains the amino acid sequence of SEQ ID NO: 323, and the second polypeptide contains the amino acid sequence of SEQ ID NO: 337; (xxvi) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 324, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 338; (xxvii) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 325, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 339; (xxviii) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 326, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 340; (xxix) The first polypeptide contains the amino acid sequence of SEQ ID NO: 327, and the second polypeptide contains the amino acid sequence of SEQ ID NO: 341; (xxx) The first polypeptide contains the amino acid sequence of SEQ ID NO: 329, and the second polypeptide contains the amino acid sequence of SEQ ID NO: 343; (xxxi) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 330, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 344; (xxxii) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 331, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 345; (xxxiii) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 346, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 360; (xxxiv) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 347, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 361; (xxxv) The first polypeptide contains the amino acid sequence of SEQ ID NO: 348, and the second polypeptide contains the amino acid sequence of SEQ ID NO: 362; (xxxvi) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 349, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 363; (xxxvii) The first polypeptide contains the amino acid sequence of SEQ ID NO: 350, and the second polypeptide contains the amino acid sequence of SEQ ID NO: 364; (xxxviii) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 351, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 365; (xxxix) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 352, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 366; (xl) The first polypeptide contains the amino acid sequence of SEQ ID NO: 353, and the second polypeptide contains the amino acid sequence of SEQ ID NO: 367; (xli) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 350, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 368; (xlii) The first polypeptide contains the amino acid sequence of SEQ ID NO: 355, and the second polypeptide contains the amino acid sequence of SEQ ID NO: 369; (xliii) The first polypeptide contains the amino acid sequence of SEQ ID NO: 356, and the second polypeptide contains the amino acid sequence of SEQ ID NO: 370; (xliv) The first polypeptide contains the amino acid sequence of SEQ ID NO: 357, and the second polypeptide contains the amino acid sequence of SEQ ID NO: 371; (xlv) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 358, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 372; or (xlvi) The first polypeptide contains the amino acid sequence of SEQ ID NO: 359, and the second polypeptide contains the amino acid sequence of SEQ ID NO:

373.

140. The molecule of any one of claims 1-139, wherein the molecule further comprises an antigen-binding domain.

141. The molecule of claim 140, wherein the antigen-binding domain is covalently linked to the second Fc domain.

142. The molecule of claim 141, wherein the C-terminus of the antigen-binding domain is covalently linked to the N-terminus of the second Fc domain.

143. The molecule of claim 141, wherein the N-terminus of the antigen-binding domain is covalently linked to the C-terminus of the second Fc domain.

144. The molecule of claim 141, wherein the antigen-binding domain is covalently linked to the first Fc domain.

145. The molecule of claim 144, wherein the C-terminus of the antigen-binding domain is covalently linked to the N-terminus of the first Fc domain.

146. The molecule of claim 144, wherein the N-terminus of the antigen-binding domain is covalently linked to the C-terminus of the first Fc domain.

147. The molecule of any one of claims 140-146, wherein the antigen-binding domain is selected from the group consisting of: Fab, Fab', Fab'2, Fab2, Fab3, F(ab')2, Fd, Fv, sdAb, scFv, SMIP, biantibody, triantibody, tetraantibody, microantibody, nanoantibody, large antibody, tandab, DVD, BiTe, TandAb or any combination thereof.

148. The molecule of any one of claims 140-147, wherein the antigen-binding domain binds to an internalized receptor expressed on the cell surface.

149. The molecule of claim 148, wherein the internalizing receptor is selected from the group consisting of: FcγRIIB, FcRn, ASGPR, CD38, SLAMF7, GPCR5D and BCMA.

150. The molecule of claim 149, wherein the internalization receptor is ASGPR.

151. The molecule of any one of claims 140-150, wherein the antigen-binding domain comprises Fab.

152. The molecule of claim 151, wherein the Fab comprises an antibody heavy chain sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 209 and an antibody light chain sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:

210.

153. The molecule of claim 151 or 152, wherein the Fab comprises the antibody heavy chain sequence of SEQ ID NO: 209 and the antibody light chain sequence of SEQ ID NO:

210.

154. The molecule of any one of claims 1-153, wherein the second Fc domain further comprises a second autoantibody binding domain.

155. The molecule of claim 154, wherein the N-terminus of the second Fc domain is covalently linked to the C-terminus of the second autoantibody binding domain.

156. The molecule of claim 155, wherein the C-terminus of the second Fc domain is covalently linked to the C-terminus of the second autoantibody-binding domain.

157. The molecule of any one of claims 154-156, wherein the second autoantibody-binding domain binds to the anti-TSHR autoantibody.

158. The molecule of any one of claims 1-157, wherein when administered to a subject, the molecule is capable of selectively depleting the anti-TSHR autoantibody bound to the autoantibody-binding domain.

159. The molecule of claim 158, wherein the anti-TSHR autoantibody bound to the autoantibody-binding domain is selectively depleted by uptake into the cell and shuttle transport of the autoantibody to the lysosome for degradation.

160. The molecule of any one of claims 1-159, wherein the second polypeptide does not contain an autoantibody-binding domain that binds to the anti-TSHR autoantibody.

161. A nucleic acid comprising a nucleotide sequence encoding a molecule according to any one of claims 1-160.

162. A host cell containing the nucleic acid of claim 161.

163. A vector comprising the nucleic acid of claim 161.

164. The vector of claim 163, wherein the vector comprises a viral vector.

165. The vector of claim 164, wherein the viral vector comprises a retroviral vector, a lentiviral vector, an adeno-associated virus (AAV) vector, or an adenovirus vector.

166. A pharmaceutical composition comprising a molecule of any one of claims 1-160 or a nucleic acid encoding a molecule of any one of claims 1-160 and a pharmaceutically acceptable carrier.

167. A method for preparing a molecule, the method comprising expressing the nucleic acid of claim 161 in a host cell and recovering the molecule.

168. A method of treating a subject who has or is susceptible to an autoimmune disease, the method comprising: The subject is given a pharmaceutical composition comprising a molecule according to any one of claims 1-160 or a nucleic acid encoding a molecule according to any one of claims 1-160.

169. A method of treating a subject who has or is susceptible to an autoimmune disease, the method comprising: The subject is administered a first pharmaceutical composition comprising a molecule according to any one of claims 1-160 or a nucleic acid encoding a molecule according to any one of claims 1-160; as well as The subject is administered a second pharmaceutical composition that selectively depletes plasma cells that generate autoantibodies targeted by an autoantibody-binding domain.

170. The method of claim 168 or 169, wherein the autoimmune disease is Graves' disease (GD), thyroid ophthalmopathy, or another autoimmune disease involving anti-TSHR autoantibodies.

171. The method of claim 169, wherein the first pharmaceutical composition is administered prior to the second pharmaceutical composition.

172. The method of claim 169, wherein the first pharmaceutical composition is administered after the second pharmaceutical composition.

173. The method of claim 169, wherein the first pharmaceutical composition and the second pharmaceutical composition are administered together.

174. The method of any one of claims 168-173, wherein the level of anti-TSHR autoantibodies in the subject or in a biological sample from the subject is reduced after administration relative to the level before administration.

175. The method of claim 174, wherein the level of anti-TSHR autoantibody is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% relative to the level before administration.

176. The method of claim 174 or 175, wherein the reduced level of the anti-TSHR autoantibody persists over time.

177. The method of claim 176, wherein the duration of the duration includes at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 10 weeks, 12 weeks or longer.

178. The method of any one of claims 168-177, wherein the pharmaceutical composition is administered intravenously, intramuscularly, or subcutaneously to the subject.

179. The method of any one of claims 168-178, wherein the subject is a human.

180. A method for selectively depleting anti-TSHR autoantibodies in a subject, the method comprising administering a pharmaceutical composition to the subject, the pharmaceutical composition comprising a molecule of any one of claims 1-160 or a nucleic acid encoding a molecule of any one of claims 1-160.

181. A method of treating a human subject who has or is susceptible to Graves' disease (GD), thyroid eye disease, or another autoimmune disease involving anti-TSHR autoantibodies, the method comprising administering to the subject a molecule comprising any one of claims 1-160 or a nucleic acid encoding any one of claims 1-160.

182. A pharmaceutical composition comprising: The molecule of any one of claims 1-160 or the nucleic acid encoding the molecule of any one of claims 1-160; Selectively deplete plasma cell molecules or nucleic acids encoding said molecules that generate autoantibodies targeted by autoantibody-binding domains; and Pharmaceutically acceptable carrier.

183. A composition for reducing the titer of anti-TSHR autoantibodies in the serum of a subject in need, said composition comprising: Multiple molecules, each molecule comprising (a) a first polypeptide comprising a first Fc domain and an autoantibody-binding domain that binds to an anti-TSHR autoantibody; and (b) a second polypeptide comprising a second Fc domain, wherein the first Fc domain and the second Fc domain form a homodimer or heterodimer of the first polypeptide and the second polypeptide. The first Fc domain and / or the second Fc domain contain one or more mutant amino acid residues and have increased binding affinity for FcγRIIB relative to the corresponding wild-type Fc domain. in, Following administration of the plurality of molecules, the molecules bind to an anti-TSHR autoantibody to form an immune complex comprising two molecules that bind to the anti-TSHR autoantibody, wherein the immune complex binds to and is internalized with FcγRIIB expressed on the surface of liver sinusoidal endothelial cells (LSEC) with a higher affinity, thereby reducing the titer of anti-TSHR autoantibody in the subject's serum, wherein the higher affinity is relative to an immune complex comprising two corresponding molecules having a wild-type Fc domain.

184. The composition of claim 183, wherein the molecule is the molecule of any one of claims 1-160.

185. An immune complex comprising: (i) Anti-TSHR autoantibodies; and (ii) Two molecules, each containing: A first polypeptide, the first polypeptide comprising a first Fc domain and an autoantibody-binding domain that binds to the anti-TSHR autoantibody; and A second polypeptide, wherein the second polypeptide contains a second Fc domain; The first Fc domain and the second Fc domain form a homodimer or heterodimer of the first polypeptide and the second polypeptide; wherein the first Fc domain and / or the second Fc domain contains one or more mutant amino acid residues and has increased binding affinity for FcγRIIB relative to the corresponding wild-type Fc domain; and The immune complex described therein has enhanced binding kinetics with FcγRIIB relative to the immune complex comprising the anti-TSHR autoantibody which binds to two corresponding molecules having wild-type Fc domains.

186. The immune complex of claim 185, wherein the immune complex has enhanced binding kinetics with FcγRIIB relative to an immune complex comprising the anti-TSHR autoantibody and only a single molecule.

187. The immune complex of claim 185, wherein the immune complex has enhanced binding kinetics with FcγRIIB relative to the anti-TSHR autoantibody alone.

188. The immune complex of any one of claims 185-187, wherein the binding domain of each of the two molecules binds to the anti-TSHR autoantibody.

189. The immune complex of any one of claims 185-188, wherein the enhanced binding kinetics comprises an increase in association rate, a decrease in dissociation rate, and / or a change in equilibrium dissociation constant.

190. The immune complex of any one of claims 185-189, wherein the enhanced binding kinetics result in an increase in the affinity, stability, strength, frequency, and / or duration of the binding between the immune complex and FcγRIIB.

191. The immune complex of any one of claims 185-190, wherein the first Fc domain and / or the second Fc domain comprising one or more mutant amino acid residues does not have increased binding affinity for FcγRI, FcγRIIA167H, FcγRIIA167R, FcγRIIIA176F, FcγRIIIA176V, FcγRIIIB and / or FcRn relative to the corresponding wild-type Fc domain.

192. The immune complex of any one of claims 185-191, wherein the first Fc domain and / or the second Fc domain comprising one or more mutant amino acid residues has a reduced binding affinity for FcγRI, FcγRIIA167H, FcγRIIA167R, FcγRIIIA176F, FcγRIIIA176V, FcγRIIIB and / or FcRn relative to the corresponding wild-type Fc domain.

193. The immune complex of any one of claims 185-192, wherein the first Fc domain and / or the second Fc domain comprising one or more mutant amino acid residues have negligible or no binding affinity for FcγRI, FcγRIIA167H, FcγRIIA167R, FcγRIIIA176F, FcγRIIIA176V, FcγRIIIB and / or FcRn relative to the corresponding wild-type Fc domain.

194. The immune complex of any one of claims 185-193, wherein the enhanced binding kinetics comprises an immune complex having a binding affinity for FcγRIIB that is at least 10% higher.

195. The immune complex of claim 194, wherein the binding affinity of at least 10% comprises at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% or higher.

196. The immune complex of claim 194 or 195, wherein the binding affinity comprises the binding affinity to a cell line overexpressing FcγRIIB (e.g., CHO cell line) as measured by flow cytometry.

197. The immune complex of any one of claims 185-196, wherein the immune complex preferentially binds to immune cells expressing FcγRIIB relative to immune cells expressing FcγRIIA.

198. The immune complex of any one of claims 185-197, wherein the immune complex crosslinks FcγRIIB with B cell receptors on B cells.

199. The immune complex of any one of claims 185-198, wherein the molecule is the molecule of any one of claims 1-160.

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