Molecules for controlling autoimmune responses

Abstract

This disclosure provides, in particular, a molecule comprising an autoantibody-binding domain and at least one modified Fc domain. This disclosure also provides methods and compositions that enable the selective depletion and / or neutralization of pathogenic autoantibodies. The molecule described herein comprises a first polypeptide and a second polypeptide, the first polypeptide comprising an autoantibody-binding domain and a first Fc domain, and the second polypeptide comprising a second Fc domain. As described herein, such a molecule neutralizes and depletes specific pathogenic autoantibodies.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefits of U.S. Provisional Application No. 63 / 517,101, filed on 1 August 2023. The entirety of the aforementioned application is incorporated herein by reference. [Background technology]

[0002] Autoimmune diseases develop when the body's immune system attacks its own healthy cells. Autoimmune diseases include various types such as Graves' disease, type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, eclampsia, multiple sclerosis, and vasculitis. Autoantibodies are antibodies that target self-antigens and healthy cells, and are produced by pathogenic plasma cells. Autoantibodies are considered markers of immune diseases, and methods to target and deplete autoantibodies in patients with autoimmune diseases have been investigated. However, therapeutic approaches to autoimmune diseases often fail to selectively deplete pathogenic autoantibodies, instead leading to the depletion of antibodies that provide an appropriate immune response against invading pathogens. [Overview of the project]

[0003] In particular, in some embodiments, the present disclosure provides molecules that selectively target, neutralize, and / or deplete pathogenic autoantibodies in a subject.

[0004] The molecules described herein comprise a first polypeptide and a second polypeptide, the first polypeptide comprising an autoantibody-binding domain and a first Fc domain, and the second polypeptide comprising 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 by a mechanism that targets immune complexes containing autoantibodies to cellular lysosomes 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 involving autoantibodies targeting the thyroid-stimulating hormone receptor (TSHR). In some embodiments, the molecules include an autoantigen domain that is a TSHR autoantigen domain, or a fragment or variant thereof.

[0006] In addition to containing an autoantibody-binding domain that targets autoantibodies, the molecules described herein may also include modifications to target specific internally distributed receptors. In some embodiments, the molecules described herein include an Fc domain that binds to a receptor on a cell, causing internal distribution of the bound molecule. Such molecules can bind to anti-TSHR autoantibodies via the autoantigen domain and be targeted to lysosomes for degradation via binding to internally distributed receptors. In some embodiments, the molecule may include modifications to its first and / or second Fc domains to increase binding affinity to Fc-gamma-RIIB (FcγRIIB). In some embodiments, the first and / or second Fc domains of the molecule may include modifications to increase binding affinity to human neonatal Fc receptor (FcRn).

[0007] In some embodiments, the molecules described herein include an antigen-binding domain that binds to a receptor on a cell that internalizes the bound molecule (see, for example, Figure 3). In some embodiments, the antigen-binding domain binds to an internalized receptor, e.g., FcγRIIB, ASPGR, and / or FcRn. Molecules targeting an internalized receptor, e.g., FcγRIIB, can inhibit / deplete autoantigen-specific B cells on the cell surface that express autoantibodies (as described, e.g., in Chu et al., Mol Immunol 45:3926-3933 (2008), which is incorporated herein in its entirety by reference).

[0008] All such strategies aim to deplete specific autoantibodies involved in autoimmune diseases. In some embodiments, the autoantibody is an anti-TSHR autoantibody, and the disease is Graves' disease, Graves' ophthalmopathy (thyroid eye disease), or another autoimmune disease caused by an anti-TSHR autoantibody. The molecule may include a TSHR autoantigen domain that targets the anti-TSHR autoantibody, as well as an Fc domain and / or antigen-binding domain that target the complex (molecule and autoantibody) to cellular lysosomes for selective degradation.

[0009] In one embodiment, the disclosure provides a molecule comprising a first polypeptide comprising a first Fc domain and an autoantibody-binding domain that binds to an 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 an anti-TSHR autoantibody, and the molecule is a homodimer. In some embodiments, the second polypeptide further comprises an autoantibody-binding domain that binds to an anti-TSHR autoantibody, and the molecule is a heterodimer. In some embodiments, the second polypeptide does not contain an autoantibody-binding domain that binds to an anti-TSHR autoantibody, and the molecule is a heterodimer.

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

[0011] In some embodiments, the first and the second Fc domains form a heterodimer as a result of knobs-in-holes (KIH) mutations. In some embodiments, the KIH mutations include Y349T and T394F according to the EU numbering scheme. In some embodiments, the first Fc domain includes the Y349T mutation and the second Fc domain includes the T394F mutation. In some embodiments, the KIH mutations include T366W, S354C, T366S, L368A, Y407V, and Y349C according to the EU numbering scheme. In some embodiments, the first Fc domain includes the T366W and the S354C mutations according to the EU numbering scheme, and the second Fc domain includes the T366S, the L368A, the Y407V, and the Y349C mutations.

[0012] In some embodiments, the first and / or the second Fc domain includes an IgG1 isotype. In some embodiments, the first and / or the second Fc domain includes a human IgG1 isotype.

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

[0014] In some embodiments, the first and / or the second Fc domain comprises one or more mutant amino acid residues that modify its binding to an internalization receptor on the cell, and the internalization receptor can transport its cargo to the lysosome of the cell for degradation. In some embodiments, the modification of the binding to the internalization receptor includes an increase in the binding to the internalization receptor. In some embodiments, the molecule that binds to the autoantibody via the autoantibody-binding domain binds to the internalization receptor on the cell, the internalization receptor internalizes the molecule, and the autoantibody is transported to the lysosome of the cell for degradation. In some embodiments, the internalization receptor comprises one of FcγRIIB, FcRn, ASGPR, CD38, or BCMA.

[0015] In some embodiments, the first and / or the second Fc domain comprises one or more mutant amino acid residues that increase its binding to FcγRIIB as compared to the corresponding wild-type Fc domain.

[0016] In some embodiments, the first and / or the second Fc domain comprising one or more mutant amino acid residues does not have an increased binding affinity for FcγRI, FcγRIIA167H, FcγRIIA167R, FcγRIIIA176F, FcγRIIIA176V, FcγRIIIB, and / or FcRn as compared to the corresponding wild-type Fc domain. In some embodiments, the first and / or the second Fc domain comprising one or more mutant amino acid residues has a decreased binding affinity for FcγRI, FcγRIIA167H, FcγRIIA167R, FcγRIIIA176F, FcγRIIIA176V, FcγRIIIB, and / or FcRn as compared to the corresponding wild-type Fc domain. In some embodiments, the first and / or the second Fc domain comprising one or more mutant amino acid residues has substantially no binding affinity for FcγRI, FcγRIIA167H, FcγRIIA167R, FcγRIIIA176F, FcγRIIIA176V, FcγRIIIB, and / or FcRn as compared to the corresponding wild-type Fc domain.

[0017] In some embodiments, when two molecules bind to an anti-TSHR autoantibody, an immune complex is formed that exhibits improved binding kinetics with FcγRIIB compared to an immune complex containing the anti-TSHR autoantibody and two corresponding molecules having wild-type Fc domains. In some embodiments, when two molecules bind to an anti-TSHR autoantibody, an immune complex is formed that exhibits improved binding kinetics with FcγRIIB compared to an immune complex containing the anti-TSHR autoantibody bound to only one molecule. In some embodiments, when two molecules bind to an anti-TSHR autoantibody, an immune complex is formed that exhibits improved binding kinetics with FcγRIIB compared to the anti-TSHR autoantibody alone. In some embodiments, the improved binding kinetics include an increased association rate, a decreased dissociation rate, and / or a change in the equilibrium dissociation constant. In some embodiments, the improved binding kinetics result in increased avidity, stability, strength, frequency, and / or duration of binding between the immune complex and FcγRIIB.

[0018] In some embodiments, the improved binding kinetics include at least 10% higher binding affinity of the immune complex to FcγRIIB. In some embodiments, the at least 10% higher binding affinity includes 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 more binding affinity. In some embodiments, the molecule binds to FcγRIIB with affinity in the range of about 1 μM to 0.001 μM. In some embodiments, the molecule binds to FcγRIIB with affinity in the range of about 1 μM to 0.001 μM. In some embodiments, the molecule binds to FcγRIIB with affinity in the range of about 0.1 μM to 0.01 μM. In some embodiments, the binding affinity includes binding affinity to a cell line overexpressing FcγRIIB (e.g., CHO cell line) as measured by flow cytometry.

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

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

[0021] In some embodiments, the molecule does not activate immune cells (for example, it does not activate immune cells to secrete inflammatory cytokines, such as IL-6).

[0022] In some embodiments, the molecule inhibits B cells by crosslinking FcγRIIB with the B cell receptor. In some embodiments, the molecule crosslinks FcγRIIB with the B cell receptor. In some embodiments, an immune complex of one or two molecules with an anti-TSHR autoantibody crosslinks FcγRIIB with the B cell receptor.

[0023] In some embodiments, the one or more mutant amino acid residues that increase binding to FcγRIIB are, according to the EU numbering scheme, the following amino acid mutations: E233V, L234D, L235F, G236R, G237D, S239L, S267D, H268P, S298G, T299A, A327L, L328A, A330H, E333I, R2 Includes one or more of the following: 92Q, 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 embodiments, the one or more mutant amino acid residues that increase binding to FcγRIIB are, according to the EU numbering scheme, 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, L2 (iii) E233V, L 234D, L235F, G236R, G237D, S239L, H268P, R292Q, S298G, T299A, A327L, L328A, A330H, and E333I; (iv) E233P, G2 37D, 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 D2 70E; (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, comprising one or more of the above. In some embodiments, the one or more mutant amino acid residues include the mutant amino acid residue P238D according to the EU numbering scheme. In some embodiments, the one or more mutant amino acid residues do not include the following mutant amino acid residues: S267E and L328F according to the EU numbering scheme.

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

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

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

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

[0029] In some embodiments, the first and second Fc domains contain a human IgG1 isotype and remain bound to FcRn even when entering an environment with an acidic pH and / or a low calcium concentration (e.g., cellular endosomes). In some embodiments, the first and / or second Fc domains contain at least one of the following mutant amino acid residues according to the EU numbering scheme: M252Y, S254T, T256E, H433K, and N434F. In some embodiments, the first and / or second Fc domains contain a combination of the following mutant amino acid residues according to the EU numbering scheme: M252Y, S254T, T256E, H433K, and N434F.

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

[0031] In some embodiments, the first Fc domain includes a sequence selected from sequence numbers 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 (for example, a sequence selected from sequence numbers 107, 109, 113, 115, 119, 131, 139, 140, 142, 148, 374, or 378). In some embodiments, the second Fc domain includes a sequence selected from sequence numbers 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 (for example, a sequence selected from sequence numbers 108, 110, 114, 116, 120, 132, 139, 140, 142, 148, 374, or 379).

[0032] In some embodiments, the autoantibody-binding domain is covalently bound to the first Fc domain via a linker. In some embodiments, the linker includes 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 (GGGGSGGGGSGGGGSGGGGS), SEQ ID NO: 155 (GGGGSGGGGSGGGGSGGGGSSGGGGS), 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 includes an autoantigen, or a fragment or variant thereof. In some embodiments, the autoantigen includes a TSHR autoantigen domain, or a fragment or variant thereof. In some embodiments, the TSHR autoantigen domain includes 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 includes the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 5. In some embodiments, the autoantibody-binding domain includes a TSHR autoantigen domain variant that includes one or more of the following mutations, or any combination thereof, to the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 5: R112P, D143P, V169R, I253R, H63S. In some embodiments, the autoantibody-binding domain includes a TSHR autoantigen domain variant that includes the following mutations, R112P and D143P, to the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 5. In some embodiments, the autoantibody-binding domain includes a TSHR autoantigen domain variant containing the following mutations to the amino acid sequence of SEQ ID NO: 1, D143P, V169R, and I253R. In some embodiments, the autoantibody-binding domain includes a TSHR autoantigen domain variant containing the following mutations to the amino acid sequence of SEQ ID NO: 1, D143P, and H63S. In some embodiments, the autoantibody-binding domain includes a TSHR autoantigen domain variant containing any one of the sequences of SEQ ID NOs: 1 to 8. In some embodiments, the autoantibody-binding domain includes a TSHR autoantigen domain variant containing any one of the sequences of SEQ ID NOs: 307 to 317.

[0034] In some embodiments, the first polypeptide has an amino acid sequence that is at least 90% identical to SEQ ID NO: 1 and 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 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 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 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 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 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 at least 90% identical to SEQ ID NO: 103; an amino acid sequence that is at least 90% identical to SEQ ID NO: 8 and at least 90% identical to SEQ ID NO: 103; an amino acid sequence that is at least 90% identical to SEQ ID NO: 307 Amino acid sequences that are at least 90% identical to the acid sequence and SEQ ID NO: 103; Amino acid sequences that are at least 90% identical to SEQ ID NO: 308 and SEQ ID NO: 103; Amino acid sequences that are at least 90% identical to SEQ ID NO: 309 and SEQ ID NO: 103; Amino acid sequences that are at least 90% identical to SEQ ID NO: 310 and SEQ ID NO: 103; Amino acid sequences that are at least 90% identical to SEQ ID NO: 311 and SEQ ID NO: 103; Amino acid sequences that are at least 90% identical to SEQ ID NO: 312 and SEQ ID NO: 103; Amino acid sequences that are at least 90% identical to SEQ ID NO: 313 and SEQ ID NO: 103; Amino acid sequences that are at least 90% identical to SEQ ID NO: 314 and SEQ ID NO: 103; Amino acid sequences that are at least 90% identical to SEQ ID NO: 315 and SEQ ID NO: 103;Amino acid sequences that are at least 90% identical to SEQ ID NO: 316 and SEQ ID NO: 103; Amino acid sequences that are at least 90% identical to SEQ ID NO: 317 and SEQ ID NO: 103; Amino acid sequences that are at least 90% identical to SEQ ID NO: 1 and SEQ ID NO: 105; Amino acid sequences that are at least 90% identical to SEQ ID NO: 2 and SEQ ID NO: 105; Amino acid sequences that are at least 90% identical to SEQ ID NO: 3 and SEQ ID NO: 105; Amino acid sequences that are at least 90% identical to SEQ ID NO: 4 and SEQ ID NO: 105; Amino acid sequences that are at least 90% identical to SEQ ID NO: 5 and SEQ ID NO: 105; Amino acid sequences that are at least 90% identical to SEQ ID NO: 6 and SEQ ID NO: 105; Amino acid sequences that are at least 90% identical to SEQ ID NO: 7 and SEQ ID NO: 1 Amino acid sequences that are at least 90% identical to 05; amino acid sequences that are at least 90% identical to SEQ ID NO: 8 and at least 90% identical to SEQ ID NO: 105; amino acid sequences that are at least 90% identical to SEQ ID NO: 307 and at least 90% identical to SEQ ID NO: 105; amino acid sequences that are at least 90% identical to SEQ ID NO: 308 and at least 90% identical to SEQ ID NO: 105; amino acid sequences that are at least 90% identical to SEQ ID NO: 309 and at least 90% identical to SEQ ID NO: 105; amino acid sequences that are at least 90% identical to SEQ ID NO: 310 and at least 90% identical to SEQ ID NO: 105; amino acid sequences that are at least 90% identical to SEQ ID NO: 311 and at least 90% identical to SEQ ID NO: 105; amino acid sequences that are at least 90% identical to SEQ ID NO: 312 and at least 90% identical to SEQ ID NO: 105; amino acid sequences that are 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: 107; Amino acid sequences that are at least 90% identical to SEQ ID NO: 2 and at least 90% identical to SEQ ID NO: 107; Amino acid sequences that are at least 90% identical to SEQ ID NO: 3 amino acid sequences that are at least 90% identical to sequence number 107; amino acid sequences that are at least 90% identical to sequence number 4 and at least 90% identical to sequence number 107; amino acid sequences that are at least 90% identical to sequence number 5 and at least 90% identical to sequence number 107; amino acid sequences that are at least 90% identical to sequence number 6 and at least 90% identical to sequence number 107; amino acid sequences that are at least 90% identical to sequence number 7 and at least 90% identical to sequence number 107; amino acid sequences that are at least 90% identical to sequence number 8 and at least 90% identical to sequence number 107; amino acid sequences that are at least 90% identical to sequence number 307 and at least 90% identical to sequence number 107; amino acid sequences that are at least 90% identical to sequence number 308 and at least 90% identical to sequence number 107; amino acid sequences that are at least 90% identical to sequence number 309 and at least 90% identical to sequence number 107;Amino acid sequences that are at least 90% identical to SEQ ID NO: 310 and at least 90% identical to SEQ ID NO: 107; Amino acid sequences that are at least 90% identical to SEQ ID NO: 311 and at least 90% identical to SEQ ID NO: 107; Amino acid sequences that are at least 90% identical to SEQ ID NO: 312 and at least 90% identical to SEQ ID NO: 107; Amino acid sequences that are at least 90% identical to SEQ ID NO: 313 and at least 90% identical to SEQ ID NO: 107; Amino acid sequences that are at least 90% identical to SEQ ID NO: 314 and at least 90% identical to SEQ ID NO: 107; Amino acid sequences that are at least 90% identical to SEQ ID NO: 315 and at least 90% identical to SEQ ID NO: 107; Amino acid sequences that are at least 90% identical to SEQ ID NO: 316 and at least 90% identical to SEQ ID NO: 107; Amino acid sequences that are at least 90% identical to SEQ ID NO: 317 and at least 90% identical to SEQ ID NO: 107; Amino acid sequences that are at least 90% identical to SEQ ID NO: 1 Amino acid sequences and 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: 2 and 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: 3 and 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: 4 and amino acid sequences that are at least 90% identical to SEQ ID NO: 5 and 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: 6 and 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: 7 and 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 and 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 and 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: 308 and at least 90% identical to SEQ ID NO: 109; Amino acid sequences that are at least 90% identical to SEQ ID NO: 309 and at least 90% identical to SEQ ID NO: 109; Amino acid sequences that are at least 90% identical to SEQ ID NO: 310 and at least 90% identical to SEQ ID NO: 109; Amino acid sequences that are at least 90% identical to SEQ ID NO: 311 and at least 90% identical to SEQ ID NO: 109; Amino acid sequences that are at least 90% identical to SEQ ID NO: 312 and at least 90% identical to SEQ ID NO: 109; Amino acid sequences that are at least 90% identical to SEQ ID NO: 313 and at least 90% identical to SEQ ID NO: 109; Amino acid sequences that are at least 90% identical to SEQ ID NO: 314 and at least 90% identical to SEQ ID NO: 109; Amino acid sequences that are at least 90% identical to SEQ ID NO: 315 and at least 90% identical to SEQ ID NO: 109; Amino acid sequences that are at least 90% identical to SEQ ID NO: 316 Amino acid sequences that are at least 90% identical to the amino acid sequence and sequence number 109; amino acid sequences that are at least 90% identical to sequence number 317 and sequence number 109; amino acid sequences that are at least 90% identical to sequence number 1 and sequence number 113; amino acid sequences that are at least 90% identical to sequence number 2 and sequence number 113; amino acid sequences that are at least 90% identical to sequence number 3 and sequence number 113; amino acid sequences that are at least 90% identical to sequence number 4 and sequence number 113; amino acid sequences that are at least 90% identical to sequence number 5 and sequence number 113; amino acid sequences that are at least 90% identical to sequence number 6 and sequence number 113; amino acid sequences that are at least 90% identical to sequence number 7 and sequence number 113;Amino acid sequences that are at least 90% identical to SEQ ID NO: 8 and at least 90% identical to SEQ ID NO: 113; Amino acid sequences that are at least 90% identical to SEQ ID NO: 307 and at least 90% identical to SEQ ID NO: 113; Amino acid sequences that are at least 90% identical to SEQ ID NO: 308 and at least 90% identical to SEQ ID NO: 113; Amino acid sequences that are at least 90% identical to SEQ ID NO: 309 and at least 90% identical to SEQ ID NO: 113; Amino acid sequences that are at least 90% identical to SEQ ID NO: 310 and at least 90% identical to SEQ ID NO: 113; Amino acid sequences that are at least 90% identical to SEQ ID NO: 311 and at least 90% identical to SEQ ID NO: 113; Identical amino acid sequences; amino acid sequences that are at least 90% identical to SEQ ID NO: 312 and at least 90% identical to SEQ ID NO: 113; amino acid sequences that are at least 90% identical to SEQ ID NO: 313 and at least 90% identical to SEQ ID NO: 113; amino acid sequences that are at least 90% identical to SEQ ID NO: 314 and at least 90% identical to SEQ ID NO: 113; amino acid sequences that are at least 90% identical to SEQ ID NO: 315 and at least 90% identical to SEQ ID NO: 113; amino acid sequences that are at least 90% identical to SEQ ID NO: 316 and at least 90% identical to SEQ ID NO: 113; amino acid sequences that are at least 90% identical to SEQ ID NO: 317 and at least 90% identical to SEQ ID NO: 113; amino acid sequences that are at least 90% identical to SEQ ID NO: 1 and at least 90% identical to SEQ ID NO: 115; amino acid sequences that are at least 90% identical to SEQ ID NO: 2 and at least 90% identical to SEQ ID NO: 115; amino acid sequences that are at least 90% identical to SEQ ID NO: 3 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: 4; Amino acid sequences that are at least 90% identical to SEQ ID NO: 5; 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: 6; 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: 7; 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: 115; 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: 115; 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: 115; 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: 115;Amino acid sequences that are at least 90% identical to SEQ ID NO: 310 and at least 90% identical to SEQ ID NO: 115; Amino acid sequences that are at least 90% identical to SEQ ID NO: 311 and at least 90% identical to SEQ ID NO: 115; Amino acid sequences that are at least 90% identical to SEQ ID NO: 312 and at least 90% identical to SEQ ID NO: 115; Amino acid sequences that are at least 90% identical to SEQ ID NO: 313 and at least 90% identical to SEQ ID NO: 115; Amino acid sequences that are at least 90% identical to SEQ ID NO: 314 and at least 90% identical to SEQ ID NO: 115; Amino acid sequences that are at least 90% identical to SEQ ID NO: 315 and at least 90% identical to SEQ ID NO: 115; Amino acid sequences that are at least 90% identical to SEQ ID NO: 316 and at least 90% identical to SEQ ID NO: 115; Amino acid sequences that are at least 90% identical to SEQ ID NO: 317 and at least 90% identical to SEQ ID NO: 115; Amino acid sequences that are at least 90% identical to SEQ ID NO: 1 Amino acid sequences 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 amino acid sequences that are at least 90% identical to SEQ ID NO: 5 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: 6 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: 7 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: 8 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: 307 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: 308 and at least 90% identical to SEQ ID NO: 117; Amino acid sequences that are at least 90% identical to SEQ ID NO: 309 and at least 90% identical to SEQ ID NO: 117; Amino acid sequences that are at least 90% identical to SEQ ID NO: 310 and at least 90% identical to SEQ ID NO: 117; Amino acid sequences that are at least 90% identical to SEQ ID NO: 311 and at least 90% identical to SEQ ID NO: 117; Amino acid sequences that are at least 90% identical to SEQ ID NO: 312 and at least 90% identical to SEQ ID NO: 117; Amino acid sequences that are at least 90% identical to SEQ ID NO: 313 and at least 90% identical to SEQ ID NO: 117; Amino acid sequences that are at least 90% identical to SEQ ID NO: 314 and at least 90% identical to SEQ ID NO: 117; Amino acid sequences that are at least 90% identical to SEQ ID NO: 315 and at least 90% identical to SEQ ID NO: 117; Amino acid sequences that are at least 90% identical to SEQ ID NO: 316 Amino acid sequences that are at least 90% identical to the amino acid sequence and sequence number 117; amino acid sequences that are at least 90% identical to sequence number 317 and sequence number 117; amino acid sequences that are at least 90% identical to sequence number 1 and sequence number 119; amino acid sequences that are at least 90% identical to sequence number 2 and sequence number 119; amino acid sequences that are at least 90% identical to sequence number 3 and sequence number 119; amino acid sequences that are at least 90% identical to sequence number 4 and sequence number 119; amino acid sequences that are at least 90% identical to sequence number 5 and sequence number 119; amino acid sequences that are at least 90% identical to sequence number 6 and sequence number 119; amino acid sequences that are at least 90% identical to sequence number 7 and sequence number 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 at least 90% identical to SEQ ID NO: 307 and at least 90% identical to SEQ ID NO: 119; Amino acid sequences that are at least 90% identical to SEQ ID NO: 308 and at least 90% identical to SEQ ID NO: 119; Amino acid sequences that are at least 90% identical to SEQ ID NO: 309 and at least 90% identical to SEQ ID NO: 119; Amino acid sequences that are at least 90% identical to SEQ ID NO: 310 and at least 90% identical to SEQ ID NO: 119; Amino acid sequences that are at least 90% identical to SEQ ID NO: 311 and at least 90% identical to SEQ ID NO: 119; Amino acid sequences that are at least 90% identical to SEQ ID NO: 312 and at least 90% identical to SEQ ID NO: 119; Amino acid sequences that are at least 90% identical to SEQ ID NO: 313 and at least 90% identical to SEQ ID NO: 119; Amino acid sequences that are at least 90% identical to SEQ ID NO: 314 Amino acid sequences that are at least 90% identical to the acid sequence and SEQ ID NO: 119; Amino acid sequences that are at least 90% identical to SEQ ID NO: 315 and SEQ ID NO: 119; Amino acid sequences that are at least 90% identical to SEQ ID NO: 316 and SEQ ID NO: 119; Amino acid sequences that are at least 90% identical to SEQ ID NO: 317 and SEQ ID NO: 119; Amino acid sequences that are at least 90% identical to SEQ ID NO: 1 and SEQ ID NO: 121; Amino acid sequences that are at least 90% identical to SEQ ID NO: 2 and SEQ ID NO: 121; Amino acid sequences that are at least 90% identical to SEQ ID NO: 3 and SEQ ID NO: 121; Amino acid sequences that are at least 90% identical to SEQ ID NO: 4 and SEQ ID NO: 121; Amino acid sequences that are at least 90% identical to SEQ ID NO: 5 and 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: 7 and 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: 312 and 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: 313 and at least 90% identical to SEQ ID NO: 121; Amino acid sequences that are at least 90% identical to SEQ ID NO: 314 and at least 90% identical to SEQ ID NO: 121; Amino acid sequences that are at least 90% identical to SEQ ID NO: 315 and at least 90% identical to SEQ ID NO: 121; Amino acid sequences that are at least 90% identical to SEQ ID NO: 316 and at least 90% identical to SEQ ID NO: 121; Amino acid sequences that are at least 90% identical to SEQ ID NO: 317 and at least 90% identical to SEQ ID NO: 121; Amino acid sequences that are at least 90% identical to SEQ ID NO: 1 and at least 90% identical to SEQ ID NO: 123; 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: 3 and at least 90% identical to SEQ ID NO: 123;Amino acid sequences that are at least 90% identical to SEQ ID NO: 4 and 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; Sequence; Amino acid sequences that are at least 90% identical to sequence number 308 and at least 90% identical to sequence number 123; Amino acid sequences that are at least 90% identical to sequence number 309 and at least 90% identical to sequence number 123; Amino acid sequences that are at least 90% identical to sequence number 310 and at least 90% identical to sequence number 123; Amino acid sequences that are at least 90% identical to sequence number 311 and at least 90% identical to sequence number 123; Amino acid sequences that are at least 90% identical to sequence number 312 and at least 90% identical to sequence number 123; Amino acid sequences that are at least 90% identical to sequence number 313 and at least 90% identical to sequence number 123; Amino acid sequences that are at least 90% identical to sequence number 314 and at least 90% identical to sequence number 123; Amino acid sequences that are at least 90% identical to sequence number 315 and at least 90% identical to sequence number 123; Amino acid sequences that are at least 90% identical to sequence number 316 Amino acid sequences and 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: 317 and 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: 1 and 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: 2 and 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: 3 and 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: 5 and 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: 6 and 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: 7 and 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: 8 and at least 90% identical to SEQ ID NO: 125; Amino acid sequences that are at least 90% identical to SEQ ID NO: 307 and at least 90% identical to SEQ ID NO: 125; Amino acid sequences that are at least 90% identical to SEQ ID NO: 308 and at least 90% identical to SEQ ID NO: 125; Amino acid sequences that are at least 90% identical to SEQ ID NO: 309 and at least 90% identical to SEQ ID NO: 125; Amino acid sequences that are at least 90% identical to SEQ ID NO: 310 and at least 90% identical to SEQ ID NO: 125; Amino acid sequences that are at least 90% identical to SEQ ID NO: 311 and at least 90% identical to SEQ ID NO: 125; Amino acid sequences that are at least 90% identical to SEQ ID NO: 312 and at least 90% identical to SEQ ID NO: 125; Amino acid sequences that are at least 90% identical to SEQ ID NO: 313 and at least 90% identical to SEQ ID NO: 125; Amino acid sequences that are at least 90% identical to SEQ ID NO: 314 Amino acid sequences that are at least 90% identical to the acid sequence and SEQ ID NO: 125; Amino acid sequences that are at least 90% identical to SEQ ID NO: 315 and SEQ ID NO: 125; Amino acid sequences that are at least 90% identical to SEQ ID NO: 316 and SEQ ID NO: 125; Amino acid sequences that are at least 90% identical to SEQ ID NO: 317 and SEQ ID NO: 125; Amino acid sequences that are at least 90% identical to SEQ ID NO: 1 and SEQ ID NO: 127; Amino acid sequences that are at least 90% identical to SEQ ID NO: 2 and SEQ ID NO: 127; Amino acid sequences that are at least 90% identical to SEQ ID NO: 3 and SEQ ID NO: 127; Amino acid sequences that are at least 90% identical to SEQ ID NO: 4 and SEQ ID NO: 127; Amino acid sequences that are at least 90% identical to SEQ ID NO: 5 and SEQ ID NO: 127;Amino acid sequences that are at least 90% identical to SEQ ID NO: 6 and at least 90% identical to SEQ ID NO: 127; Amino acid sequences that are 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: 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; Amino acid sequences that are at least 90% identical to SEQ ID NO: 309 and at least 90% identical to SEQ ID NO: 127; Amino acid sequences that are at least 90% identical to SEQ ID NO: 310 and at least 90% identical to SEQ ID NO: 127; Amino acid sequences that are at least 90% identical to SEQ ID NO: 311 and at least 90% identical to SEQ ID NO: 127; Amino acid sequences that are at least 90% identical to SEQ ID NO: 312 and 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: 313 and at least 90% identical to SEQ ID NO: 127; Amino acid sequences that are at least 90% identical to SEQ ID NO: 314 and at least 90% identical to SEQ ID NO: 127; Amino acid sequences that are at least 90% identical to SEQ ID NO: 315 and at least 90% identical to SEQ ID NO: 127; Amino acid sequences that are at least 90% identical to SEQ ID NO: 316 and at least 90% identical to SEQ ID NO: 127; Amino acid sequences that are at least 90% identical to SEQ ID NO: 317 and at least 90% identical to SEQ ID NO: 127; Amino acid sequences that are at least 90% identical to SEQ ID NO: 1 and at least 90% identical to SEQ ID NO: 129; Amino acid sequences that are at least 90% identical to SEQ ID NO: 2 and at least 90% identical to SEQ ID NO: 129; Amino acid sequences that are at least 90% identical to SEQ ID NO: 3 and at least 90% identical to SEQ ID NO: 129;Amino acid sequences that are at least 90% identical to SEQ ID NO: 4 and at least 90% identical to SEQ ID NO: 129; Amino acid sequences that are at least 90% identical to SEQ ID NO: 5 and at least 90% identical to SEQ ID NO: 129; Amino acid sequences that are at least 90% identical to SEQ ID NO: 6 and at least 90% identical to SEQ ID NO: 129; Amino acid sequences that are at least 90% identical to SEQ ID NO: 7 and at least 90% identical to SEQ ID NO: 129; Amino acid sequences that are at least 90% identical to SEQ ID NO: 8 and at least 90% identical to SEQ ID NO: 129; Amino acid sequences that are at least 90% identical to SEQ ID NO: 307 and at least 90% identical to SEQ ID NO: 129; Amino acid sequences that are at least 90% identical to SEQ ID NO: 308 and at least 90% identical to SEQ ID NO: 129; Amino acid sequences that are at least 90% identical to SEQ ID NO: 309 and at least 90% identical to SEQ ID NO: 129; Amino acid sequences that are at least 90% identical to SEQ ID NO: 310 and sequence number Amino acid sequences that are at least 90% identical to sequence number 129; amino acid sequences that are at least 90% identical to sequence number 311 and at least 90% identical to sequence number 129; amino acid sequences that are at least 90% identical to sequence number 312 and at least 90% identical to sequence number 129; amino acid sequences that are at least 90% identical to sequence number 313 and at least 90% identical to sequence number 129; amino acid sequences that are at least 90% identical to sequence number 314 and at least 90% identical to sequence number 129; amino acid sequences that are at least 90% identical to sequence number 315 and at least 90% identical to sequence number 129; amino acid sequences that are at least 90% identical to sequence number 316 and at least 90% identical to sequence number 129; amino acid sequences that are at least 90% identical to sequence number 317 and at least 90% identical to sequence number 129; amino acid sequences that are at least 90% identical to sequence number 1 and at least 90% identical to sequence number 131;Amino acid sequences that are at least 90% identical to SEQ ID NO: 2 and SEQ ID NO: 131; Amino acid sequences that are at least 90% identical to SEQ ID NO: 3 and SEQ ID NO: 131; Amino acid sequences that are at least 90% identical to SEQ ID NO: 4 and SEQ ID NO: 131; Amino acid sequences that are at least 90% identical to SEQ ID NO: 5 and SEQ ID NO: 131; Amino acid sequences that are at least 90% identical to SEQ ID NO: 6 and SEQ ID NO: 131; Amino acid sequences that are at least 90% identical to SEQ ID NO: 7 and SEQ ID NO: 131; Amino acid sequences that are at least 90% identical to SEQ ID NO: 8 and SEQ ID NO: 131; Amino acid sequences that are at least 90% identical to SEQ ID NO: 307 and SEQ ID NO: 131; Amino acid sequences that are at least 90% identical to SEQ ID NO: 308 and SEQ ID NO: 13 Amino acid sequences that are at least 90% identical to 1; 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 at least 90% identical to SEQ ID NO: 312 and at least 90% identical to SEQ ID NO: 131; amino acid sequences that are at least 90% identical to SEQ ID NO: 313 and at least 90% identical to SEQ ID NO: 131; amino acid sequences that are at least 90% identical to SEQ ID NO: 314 and at least 90% identical to SEQ ID NO: 131; amino acid sequences that are at least 90% identical to SEQ ID NO: 315 and at least 90% identical to SEQ ID NO: 131; amino acid sequences that are at least 90% identical to SEQ ID NO: 316 and at least 90% identical to SEQ ID NO: 131;Amino acid sequences that are at least 90% identical to SEQ ID NO: 317 and at least 90% identical to SEQ ID NO: 131; Amino acid sequences that are at least 90% identical to SEQ ID NO: 1 and at least 90% identical to SEQ ID NO: 133; Amino acid sequences that are at least 90% identical to SEQ ID NO: 2 and at least 90% identical to SEQ ID NO: 133; Amino acid sequences that are at least 90% identical to SEQ ID NO: 3 and at least 90% identical to SEQ ID NO: 133; Amino acid sequences that are at least 90% identical to SEQ ID NO: 4 and at least 90% identical to SEQ ID NO: 133; Amino acid sequences that are at least 90% identical to SEQ ID NO: 5 and at least 90% identical to SEQ ID NO: 133; Amino acid sequences that are at least 90% identical to SEQ ID NO: 6; The amino acid sequence is 90% identical to the amino acid sequence of SEQ ID NO: 133; the amino acid sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 7; the amino acid sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 8; the amino acid sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 133; the amino acid sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 307; the amino acid sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 133; the amino acid sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 308; the amino acid sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 133; the amino acid sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 309; the amino acid sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 133; the amino acid sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 310; the amino acid sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 133; the amino acid sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 311; the amino acid sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 133; the amino acid sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 312; the amino acid sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 312. Amino acid sequences that are at least 90% identical to 133; amino acid sequences that are at least 90% identical to SEQ ID NO: 313 and at least 90% identical to SEQ ID NO: 133; amino acid sequences that are at least 90% identical to SEQ ID NO: 314 and at least 90% identical to SEQ ID NO: 133; amino acid sequences that are at least 90% identical to SEQ ID NO: 315 and at least 90% identical to SEQ ID NO: 133; amino acid sequences that are at least 90% identical to SEQ ID NO: 316 and at least 90% identical to SEQ ID NO: 133; amino acid sequences that are at least 90% identical to SEQ ID NO: 317 and at least 90% identical to SEQ ID NO: 133; amino acid sequences that are at least 90% identical to SEQ ID NO: 1 and at least 90% identical to SEQ ID NO: 135; amino acid sequences that are at least 90% identical to SEQ ID NO: 2 and at least 90% identical to 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: 308 and at least 90% identical to SEQ ID NO: 135; Amino acid sequences that are at least 90% identical to SEQ ID NO: 309 and at least 90% identical to SEQ ID NO: 135; Amino acid sequences that are at least 90% identical to SEQ ID NO: 310 and sequence number Amino acid sequences that are at least 90% identical to sequence number 135; amino acid sequences that are at least 90% identical to sequence number 311 and at least 90% identical to sequence number 135; amino acid sequences that are at least 90% identical to sequence number 312 and at least 90% identical to sequence number 135; amino acid sequences that are at least 90% identical to sequence number 313 and at least 90% identical to sequence number 135; amino acid sequences that are at least 90% identical to sequence number 314 and at least 90% identical to sequence number 135; amino acid sequences that are at least 90% identical to sequence number 315 and at least 90% identical to sequence number 135; amino acid sequences that are at least 90% identical to sequence number 316 and at least 90% identical to sequence number 135; amino acid sequences that are at least 90% identical to sequence number 317 and at least 90% identical to sequence number 135; amino acid sequences that are at least 90% identical to sequence number 1 and at least 90% identical to sequence number 137; amino acid sequences that are at least 90% identical to sequence number 1 and at least 90% identical to sequence number 137;Amino acid sequences that are at least 90% identical to SEQ ID NO: 2 and SEQ ID NO: 137; Amino acid sequences that are at least 90% identical to SEQ ID NO: 3 and SEQ ID NO: 137; Amino acid sequences that are at least 90% identical to SEQ ID NO: 4 and SEQ ID NO: 137; Amino acid sequences that are at least 90% identical to SEQ ID NO: 5 and SEQ ID NO: 137; Amino acid sequences that are at least 90% identical to SEQ ID NO: 6 and SEQ ID NO: 137; Amino acid sequences that are at least 90% identical to SEQ ID NO: 7 and SEQ ID NO: 137; Amino acid sequences that are at least 90% identical to SEQ ID NO: 8 and SEQ ID NO: 137; Amino acid sequences that are at least 90% identical to SEQ ID NO: 307 and SEQ ID NO: 137; Amino acid sequences that are at least 90% identical to SEQ ID NO: 308 and SEQ ID NO: 13 Amino acid sequences that are at least 90% identical to 7; amino acid sequences that are at least 90% identical to SEQ ID NO: 309 and at least 90% identical to SEQ ID NO: 137; amino acid sequences that are at least 90% identical to SEQ ID NO: 310 and at least 90% identical to SEQ ID NO: 137; amino acid sequences that are at least 90% identical to SEQ ID NO: 311 and at least 90% identical to SEQ ID NO: 137; amino acid sequences that are at least 90% identical to SEQ ID NO: 312 and at least 90% identical to SEQ ID NO: 137; amino acid sequences that are at least 90% identical to SEQ ID NO: 313 and at least 90% identical to SEQ ID NO: 137; amino acid sequences that are at least 90% identical to SEQ ID NO: 314 and at least 90% identical to SEQ ID NO: 137; amino acid sequences that are at least 90% identical to SEQ ID NO: 315 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 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 and at least 90% identical to SEQ ID NO: 376; Amino acid sequences that are at least 90% identical to SEQ ID NO: 6 and at least 90% identical to SEQ ID NO: 376; Amino acid sequences that are at least 90% identical to SEQ ID NO: 7 and at least 90% identical to SEQ ID NO: 376; Amino acid sequences that are at least 90% identical to SEQ ID NO: 8 and at least 90% identical to SEQ ID NO: 376 Amino acid sequences that are at least 90% identical to: 307; 308; 376; 309; 312; 313; 314; 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: 3 and at least 90% identical to SEQ ID NO: 3; Amino acid sequences that are at least 90% identical to SEQ ID NO: 4 and at least 90% identical to SEQ ID NO: 378; Amino acid sequences that are at least 90% identical to SEQ ID NO: 5 and at least 90% identical to SEQ ID NO: 378; Amino acid sequences that are at least 90% identical to SEQ ID NO: 6 and sequence number Amino acid sequences that are at least 90% identical to sequence number 378; amino acid sequences that are at least 90% identical to sequence number 7 and at least 90% identical to sequence number 378; amino acid sequences that are at least 90% identical to sequence number 8 and at least 90% identical to sequence number 378; amino acid sequences that are at least 90% identical to sequence number 307 and at least 90% identical to sequence number 378; amino acid sequences that are at least 90% identical to sequence number 308 and at least 90% identical to sequence number 378; amino acid sequences that are at least 90% identical to sequence number 309 and at least 90% identical to sequence number 378; amino acid sequences that are at least 90% identical to sequence number 310 and at least 90% identical to sequence number 378; amino acid sequences that are at least 90% identical to sequence number 311 and at least 90% identical to sequence number 378; amino acid sequences that are at least 90% identical to sequence number 312 and at least 90% identical to sequence number 378;It includes an amino acid sequence that is at least 90% identical to SEQ ID NO: 313 and 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: 314 and 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: 315 and 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: 316 and 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: 317 and an amino acid sequence that is at least 90% identical to SEQ ID NO: 378.

[0035] In the embodiments described above, the first polypeptide is the amino acid sequence of SEQ ID NO: 1 and SEQ ID NO: 103; the amino acid sequence of SEQ ID NO: 2 and SEQ ID NO: 103; the amino acid sequence of SEQ ID NO: 3 and SEQ ID NO: 103; the amino acid sequence of SEQ ID NO: 4 and SEQ ID NO: 103; the amino acid sequence of SEQ ID NO: 5 and SEQ ID NO: 103; the amino acid sequence of SEQ ID NO: 6 and SEQ ID NO: 103; the amino acid sequence of SEQ ID NO: 7 and SEQ ID NO: 103; the amino acid sequence of SEQ ID NO: 8 and SEQ ID NO: 103; the amino acid sequence of SEQ ID NO: 307 and SEQ ID NO: 103; the amino acid sequence of SEQ ID NO: 308 and SEQ ID NO: 103; the amino acid sequence of SEQ ID NO: 309 and SEQ ID NO: 103; the amino acid sequence of SEQ ID NO: 310 and SEQ ID NO: 103; the amino acid sequence of SEQ ID NO: 311 and SEQ ID NO: 103; the amino acid sequence of SEQ ID NO: 312 and SEQ ID NO: 103; the amino acid sequence of SEQ ID NO: 313 and SEQ ID NO: 103; the amino acid sequence of SEQ ID NO: 314 and sequence number The amino acid sequence of sequence 103; the amino acid sequence of sequence number 315 and the amino acid sequence of sequence number 103; the amino acid sequence of sequence number 316 and the amino acid sequence of sequence number 103; the amino acid sequence of sequence number 317 and the amino acid sequence of sequence number 103; the amino acid sequence of sequence number 1 and the amino acid sequence of sequence number 105; the amino acid sequence of sequence number 2 and the amino acid sequence of sequence number 105; the amino acid sequence of sequence number 3 and the amino acid sequence of sequence number 105; the amino acid sequence of sequence number 4 and the amino acid sequence of sequence number 105; the amino acid sequence of sequence number 5 and the amino acid sequence of sequence number 105 Amino acid sequence; amino acid sequence of SEQ ID NO: 6 and SEQ ID NO: 105; amino acid sequence of SEQ ID NO: 7 and SEQ ID NO: 105; amino acid sequence of SEQ ID NO: 8 and SEQ ID NO: 105; amino acid sequence of SEQ ID NO: 307 and SEQ ID NO: 105; amino acid sequence of SEQ ID NO: 308 and SEQ ID NO: 105; amino acid sequence of SEQ ID NO: 309 and SEQ ID NO: 105; amino acid sequence of SEQ ID NO: 310 and SEQ ID NO: 105; amino acid sequence of SEQ ID NO: 311 and SEQ ID NO: 105;The amino acid sequences of SEQ ID NO: 312 and 105; the amino acid sequences of SEQ ID NO: 313 and 105; the amino acid sequences of SEQ ID NO: 314 and 105; the amino acid sequences of SEQ ID NO: 315 and 105; the amino acid sequences of SEQ ID NO: 316 and 105; the amino acid sequences of SEQ ID NO: 317 and 105; the amino acid sequences of SEQ ID NO: 4, 209, 210, and 105; sequences The amino acid sequence of number 1 and the amino acid sequence of SEQ ID NO: 107; the amino acid sequence of SEQ ID NO: 2 and the amino acid sequence of SEQ ID NO: 107; the amino acid sequence of SEQ ID NO: 3 and the amino acid sequence of SEQ ID NO: 107; the amino acid sequence of SEQ ID NO: 4 and the amino acid sequence of SEQ ID NO: 5 and the amino acid sequence of SEQ ID NO: 107; the amino acid sequence of SEQ ID NO: 6 and the amino acid sequence of SEQ ID NO: 107; the amino acid sequence of SEQ ID NO: 7 and the amino acid sequence of SEQ ID NO: 107; the amino acid sequence of SEQ ID NO: 8 and the amino acid sequence of SEQ ID NO: 107; the amino acid sequence of SEQ ID NO: 307 and sequence The amino acid sequence of sequence number 107; the amino acid sequence of sequence number 308 and the amino acid sequence of sequence number 107; the amino acid sequence of sequence number 309 and the amino acid sequence of sequence number 107; the amino acid sequence of sequence number 310 and the amino acid sequence of sequence number 107; the amino acid sequence of sequence number 311 and the amino acid sequence of sequence number 107; the amino acid sequence of sequence number 312 and the amino acid sequence of sequence number 107; the amino acid sequence of sequence number 313 and the amino acid sequence of sequence number 107; the amino acid sequence of sequence number 314 and the amino acid sequence of sequence number 107; the amino acid sequence of sequence number 315 and sequence The amino acid sequence for sequence number 107; the amino acid sequence for sequence number 316 and sequence number 107; the amino acid sequence for sequence number 317 and sequence number 107; the amino acid sequence for sequence number 1 and sequence number 109; the amino acid sequence for sequence number 2 and sequence number 109; the amino acid sequence for sequence number 3 and sequence number 109; the amino acid sequence for sequence number 4 and sequence number 109; the amino acid sequence for sequence number 5 and sequence number 109; the amino acid sequence for sequence number 6 and sequence number 109;The amino acid sequences of SEQ ID NO: 7 and 109; the amino acid sequences of SEQ ID NO: 8 and 109; the amino acid sequences of SEQ ID NO: 307 and 109; the amino acid sequences of SEQ ID NO: 308 and 109; the amino acid sequences of SEQ ID NO: 309 and 109; the amino acid sequences of SEQ ID NO: 310 and 109; the amino acid sequences of SEQ ID NO: 311 and 109; the amino acid sequences of SEQ ID NO: 312 and 109; SEQ ID NO: 31 The amino acid sequence of 3 and the amino acid sequence of SEQ ID NO: 109; the amino acid sequence of SEQ ID NO: 314 and the amino acid sequence of SEQ ID NO: 109; the amino acid sequence of SEQ ID NO: 315 and the amino acid sequence of SEQ ID NO: 109; the amino acid sequence of SEQ ID NO: 316 and the amino acid sequence of SEQ ID NO: 109; the amino acid sequence of SEQ ID NO: 317 and the amino acid sequence of SEQ ID NO: 109; the amino acid sequence of SEQ ID NO: 1 and the amino acid sequence of SEQ ID NO: 113; the amino acid sequence of SEQ ID NO: 2 and the amino acid sequence of SEQ ID NO: 113; the amino acid sequence of SEQ ID NO: 3 and the amino acid sequence of SEQ ID NO: 113; the amino acid sequence of SEQ ID NO: 4 and The amino acid sequence of SEQ ID NO: 113; the amino acid sequence of SEQ ID NO: 5 and the amino acid sequence of SEQ ID NO: 113; the amino acid sequence of SEQ ID NO: 6 and the amino acid sequence of SEQ ID NO: 113; the amino acid sequence of SEQ ID NO: 7 and the amino acid sequence of SEQ ID NO: 113; the amino acid sequence of SEQ ID NO: 8 and the amino acid sequence of SEQ ID NO: 113; the amino acid sequence of SEQ ID NO: 307 and the amino acid sequence of SEQ ID NO: 113; the amino acid sequence of SEQ ID NO: 308 and the amino acid sequence of SEQ ID NO: 113; the amino acid sequence of SEQ ID NO: 309 and the amino acid sequence of SEQ ID NO: 113; the amino acid sequence of SEQ ID NO: 310 and the amino acid sequence of SEQ ID NO: 113 No acid sequence; amino acid sequence of SEQ ID NO 311 and amino acid sequence of SEQ ID NO 113; amino acid sequence of SEQ ID NO 312 and amino acid sequence of SEQ ID NO 113; amino acid sequence of SEQ ID NO 313 and amino acid sequence of SEQ ID NO 113; amino acid sequence of SEQ ID NO 314 and amino acid sequence of SEQ ID NO 113; amino acid sequence of SEQ ID NO 315 and amino acid sequence of SEQ ID NO 113; amino acid sequence of SEQ ID NO 316 and amino acid sequence of SEQ ID NO 113; amino acid sequence of SEQ ID NO 317 and amino acid sequence of SEQ ID NO 113; amino acid sequence of SEQ ID NO 1 and amino acid sequence of SEQ ID NO 115;The amino acid sequences of SEQ ID NO: 2 and 115; the amino acid sequences of SEQ ID NO: 3 and 115; the amino acid sequences of SEQ ID NO: 4 and 115; the amino acid sequences of SEQ ID NO: 5 and 115; the amino acid sequences of SEQ ID NO: 6 and 115; the amino acid sequences of SEQ ID NO: 7 and 115; the amino acid sequences of SEQ ID NO: 8 and 115; the amino acid sequences of SEQ ID NO: 307 and 115; the amino acid sequences of SEQ ID NO: 308 and the amino acid sequence of SEQ ID NO: 115; the amino acid sequence of SEQ ID NO: 309 and the amino acid sequence of SEQ ID NO: 115; the amino acid sequence of SEQ ID NO: 310 and the amino acid sequence of SEQ ID NO: 115; the amino acid sequence of SEQ ID NO: 311 and the amino acid sequence of SEQ ID NO: 115; the amino acid sequence of SEQ ID NO: 312 and the amino acid sequence of SEQ ID NO: 115; the amino acid sequence of SEQ ID NO: 313 and the amino acid sequence of SEQ ID NO: 115; the amino acid sequence of SEQ ID NO: 314 and the amino acid sequence of SEQ ID NO: 115; the amino acid sequence of SEQ ID NO: 315 and the amino acid sequence of SEQ ID NO: 115; the amino acid sequence of SEQ ID NO: 316 and the amino acid sequence of SEQ ID NO: 115; the amino acid sequence of SEQ ID NO: 317 and the amino acid sequence of SEQ ID NO: 115; the amino acid sequence of SEQ ID NO: 1 and the amino acid sequence of SEQ ID NO: 117; the amino acid sequence of SEQ ID NO: 2 and the amino acid sequence of SEQ ID NO: 117; the amino acid sequence of SEQ ID NO: 3 and the amino acid sequence of SEQ ID NO: 117; the amino acid sequence of SEQ ID NO: 4 and the amino acid sequence of SEQ ID NO: 117; the amino acid sequence of SEQ ID NO: 5 and the amino acid sequence of SEQ ID NO: 117; the amino acid sequence of SEQ ID NO: 6 and the amino acid sequence of SEQ ID NO: 117; the amino acid sequence of SEQ ID NO: 7 and the amino acid sequence of SEQ ID NO: 117 Sequence; Amino acid sequence of SEQ ID NO: 8 and SEQ ID NO: 117; Amino acid sequence of SEQ ID NO: 307 and SEQ ID NO: 117; Amino acid sequence of SEQ ID NO: 308 and SEQ ID NO: 117; Amino acid sequence of SEQ ID NO: 309 and SEQ ID NO: 117; Amino acid sequence of SEQ ID NO: 310 and SEQ ID NO: 117; Amino acid sequence of SEQ ID NO: 311 and SEQ ID NO: 117; Amino acid sequence of SEQ ID NO: 312 and SEQ ID NO: 117; Amino acid sequence of SEQ ID NO: 313 and SEQ ID NO: 117;The amino acid sequences of SEQ ID NO: 314 and 117; the amino acid sequences of SEQ ID NO: 315 and 117; the amino acid sequences of SEQ ID NO: 316 and 117; the amino acid sequences of SEQ ID NO: 317 and 117; the amino acid sequences of SEQ ID NO: 1 and 119; the amino acid sequences of SEQ ID NO: 2 and 119; the amino acid sequences of SEQ ID NO: 3 and 119; the amino acid sequences of SEQ ID NO: 4 and 119; the amino acid sequences of SEQ ID NO: 5 The amino acid sequence of SEQ ID NO: 119; the amino acid sequence of SEQ ID NO: 6 and the amino acid sequence of SEQ ID NO: 119; the amino acid sequence of SEQ ID NO: 7 and the amino acid sequence of SEQ ID NO: 119; the amino acid sequence of SEQ ID NO: 8 and the amino acid sequence of SEQ ID NO: 119; the amino acid sequence of SEQ ID NO: 307 and the amino acid sequence of SEQ ID NO: 119; the amino acid sequence of SEQ ID NO: 308 and the amino acid sequence of SEQ ID NO: 119; the amino acid sequence of SEQ ID NO: 309 and the amino acid sequence of SEQ ID NO: 119; the amino acid sequence of SEQ ID NO: 310 and the amino acid sequence of SEQ ID NO: 119; the amino acid sequence of SEQ ID NO: 311 and The amino acid sequence of SEQ ID NO: 119; the amino acid sequence of SEQ ID NO: 312 and SEQ ID NO: 119; the amino acid sequence of SEQ ID NO: 313 and SEQ ID NO: 119; the amino acid sequence of SEQ ID NO: 314 and SEQ ID NO: 119; the amino acid sequence of SEQ ID NO: 315 and SEQ ID NO: 119; the amino acid sequence of SEQ ID NO: 316 and SEQ ID NO: 119; the amino acid sequence of SEQ ID NO: 317 and SEQ ID NO: 119; the amino acid sequence of SEQ ID NO: 1 and SEQ ID NO: 121; the amino acid sequence of SEQ ID NO: 2 and sequence number The amino acid sequence of sequence number 121; the amino acid sequence of sequence number 3 and sequence number 121; the amino acid sequence of sequence number 4 and sequence number 121; the amino acid sequence of sequence number 5 and sequence number 121; the amino acid sequence of sequence number 6 and sequence number 121; the amino acid sequence of sequence number 7 and sequence number 121; the amino acid sequence of sequence number 8 and sequence number 121; the amino acid sequence of sequence number 307 and sequence number 121; the amino acid sequence of sequence number 308 and sequence number 121;The amino acid sequence of SEQ ID NO: 309 and SEQ ID NO: 121; the amino acid sequence of SEQ ID NO: 310 and SEQ ID NO: 121; the amino acid sequence of SEQ ID NO: 311 and SEQ ID NO: 121; the amino acid sequence of SEQ ID NO: 312 and SEQ ID NO: 121; the amino acid sequence of SEQ ID NO: 313 and SEQ ID NO: 121; sequence number; The amino acid sequence of sequence number 314 and the amino acid sequence of sequence number 121; the amino acid sequence of sequence number 315 and the amino acid sequence of sequence number 121; the amino acid sequence of sequence number 316 and the amino acid sequence of sequence number 121; the amino acid sequence of sequence number 317 and the amino acid sequence of sequence number 121; the amino acid sequence of sequence number 1 and the amino acid sequence of sequence number 123; the amino acid sequence of sequence number 2 and the amino acid sequence of sequence number 123; the amino acid sequence of sequence number 3 and the amino acid sequence of sequence number 123; the amino acid sequence of sequence number 4 and the amino acid sequence of sequence number 123; the amino acid sequence of sequence number 5 The amino acid sequences of sequence numbers 123 and 307; the amino acid sequences of sequence number 6 and 123; the amino acid sequences of sequence number 7 and 123; the amino acid sequences of sequence number 8 and 123; the amino acid sequences of sequence number 307 and 123; the amino acid sequences of sequence number 308 and 123; the amino acid sequences of sequence number 309 and 123; the amino acid sequences of sequence number 310 and 123; the amino acid sequences of sequence number 311 and 307 The amino acid sequence of sequence number 123; the amino acid sequence of sequence number 312 and the amino acid sequence of sequence number 123; the amino acid sequence of sequence number 313 and the amino acid sequence of sequence number 123; the amino acid sequence of sequence number 314 and the amino acid sequence of sequence number 123; the amino acid sequence of sequence number 315 and the amino acid sequence of sequence number 123; the amino acid sequence of sequence number 316 and the amino acid sequence of sequence number 123; the amino acid sequence of sequence number 317 and the amino acid sequence of sequence number 123; the amino acid sequence of sequence number 1 and the amino acid sequence of sequence number 125; the amino acid sequence of sequence number 2 and sequence number The amino acid sequence of 125; the amino acid sequence of SEQ ID NO: 3 and SEQ ID NO: 125; the amino acid sequence of SEQ ID NO: 4 and SEQ ID NO: 125; the amino acid sequence of SEQ ID NO: 5 and SEQ ID NO: 125; the amino acid sequence of SEQ ID NO: 6 and SEQ ID NO: 125; the amino acid sequence of SEQ ID NO: 7 and SEQ ID NO: 125; the amino acid sequence of SEQ ID NO: 8 and SEQ ID NO: 125; the amino acid sequence of SEQ ID NO: 307 and SEQ ID NO: 125; the amino acid sequence of SEQ ID NO: 308 and SEQ ID NO: 125;The amino acid sequence of SEQ ID NO: 309 and SEQ ID NO: 125; the amino acid sequence of SEQ ID NO: 310 and SEQ ID NO: 125; the amino acid sequence of SEQ ID NO: 311 and SEQ ID NO: 125; the amino acid sequence of SEQ ID NO: 312 and SEQ ID NO: 125; the amino acid sequence of SEQ ID NO: 313 and SEQ ID NO: 125; the amino acid sequence of SEQ ID NO: 314 and SEQ ID NO: 125; the amino acid sequence of SEQ ID NO: 315 and SEQ ID NO: 125; the amino acid sequence of SEQ ID NO: 316 and SEQ ID NO: 125; The amino acid sequence of sequence number 317 and the amino acid sequence of sequence number 125; the amino acid sequence of sequence number 1 and the amino acid sequence of sequence number 127; the amino acid sequence of sequence number 2 and the amino acid sequence of sequence number 127; the amino acid sequence of sequence number 3 and the amino acid sequence of sequence number 127; the amino acid sequence of sequence number 4 and the amino acid sequence of sequence number 127; the amino acid sequence of sequence number 5 and the amino acid sequence of sequence number 127; the amino acid sequence of sequence number 6 and the amino acid sequence of sequence number 127; the amino acid sequence of sequence number 7 and the amino acid sequence of sequence number 127; the amino acid sequence of sequence number 8 and sequence Amino acid sequence of sequence number 127; Amino acid sequence of sequence number 307 and amino acid sequence of sequence number 127; Amino acid sequence of sequence number 308 and amino acid sequence of sequence number 127; Amino acid sequence of sequence number 309 and amino acid sequence of sequence number 127; Amino acid sequence of sequence number 310 and amino acid sequence of sequence number 127; Amino acid sequence of sequence number 311 and amino acid sequence of sequence number 127; Amino acid sequence of sequence number 312 and amino acid sequence of sequence number 127; Amino acid sequence of sequence number 313 and amino acid sequence of sequence number 127; Amino acid sequence of sequence number 314 and sequence number The amino acid sequence of sequence number 127; the amino acid sequence of sequence number 315 and sequence number 127; the amino acid sequence of sequence number 316 and sequence number 127; the amino acid sequence of sequence number 317 and sequence number 127; the amino acid sequence of sequence number 1 and sequence number 129; the amino acid sequence of sequence number 2 and sequence number 129; the amino acid sequence of sequence number 3 and sequence number 129; the amino acid sequence of sequence number 4 and sequence number 129; the amino acid sequence of sequence number 5 and sequence number 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; 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; SEQ ID NO. 312 Amino acid sequence and amino acid sequence of SEQ ID NO: 129; Amino acid sequence of SEQ ID NO: 313 and amino acid sequence of SEQ ID NO: 129; Amino acid sequence of SEQ ID NO: 314 and amino acid sequence of SEQ ID NO: 129; Amino acid sequence of SEQ ID NO: 315 and amino acid sequence of SEQ ID NO: 129; Amino acid sequence of SEQ ID NO: 316 and amino acid sequence of SEQ ID NO: 129; Amino acid sequence of SEQ ID NO: 317 and amino acid sequence of SEQ ID NO: 129; Amino acid sequence of SEQ ID NO: 1 and amino acid sequence of SEQ ID NO: 131; Amino acid sequence of SEQ ID NO: 2 and amino acid sequence of SEQ ID NO: 131; Amino acid sequence of SEQ ID NO: 3 and The amino acid sequence of SEQ ID NO: 131; the amino acid sequence of SEQ ID NO: 4 and the amino acid sequence of SEQ ID NO: 131; the amino acid sequence of SEQ ID NO: 5 and the amino acid sequence of SEQ ID NO: 131; the amino acid sequence of SEQ ID NO: 6 and the amino acid sequence of SEQ ID NO: 131; the amino acid sequence of SEQ ID NO: 7 and the amino acid sequence of SEQ ID NO: 131; the amino acid sequence of SEQ ID NO: 8 and the amino acid sequence of SEQ ID NO: 131; the amino acid sequence of SEQ ID NO: 307 and the amino acid sequence of SEQ ID NO: 131; the amino acid sequence of SEQ ID NO: 308 and the amino acid sequence of SEQ ID NO: 131; the amino acid sequence of SEQ ID NO: 309 and the amino acid sequence of SEQ ID NO: 131 Sequence; Amino acid sequence of SEQ ID NO: 310 and SEQ ID NO: 131; Amino acid sequence of SEQ ID NO: 311 and SEQ ID NO: 131; Amino acid sequence of SEQ ID NO: 312 and SEQ ID NO: 131; Amino acid sequence of SEQ ID NO: 313 and SEQ ID NO: 131; Amino acid sequence of SEQ ID NO: 314 and SEQ ID NO: 131; Amino acid sequence of SEQ ID NO: 315 and SEQ ID NO: 131; Amino acid sequence of SEQ ID NO: 316 and SEQ ID NO: 131; Amino acid sequence 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: 8 and SEQ ID NO: 133; the amino acid sequences of SEQ ID NO: 307 and The amino acid sequence of SEQ ID NO: 133; the amino acid sequence of SEQ ID NO: 308 and the amino acid sequence of SEQ ID NO: 133; the amino acid sequence of SEQ ID NO: 309 and the amino acid sequence of SEQ ID NO: 133; the amino acid sequence of SEQ ID NO: 310 and the amino acid sequence of SEQ ID NO: 133; the amino acid sequence of SEQ ID NO: 311 and the amino acid sequence of SEQ ID NO: 133; the amino acid sequence of SEQ ID NO: 312 and the amino acid sequence of SEQ ID NO: 133; the amino acid sequence of SEQ ID NO: 313 and the amino acid sequence of SEQ ID NO: 133; the amino acid sequence of SEQ ID NO: 314 and the amino acid sequence of SEQ ID NO: 133; the amino acid sequence of SEQ ID NO: 315 and The amino acid sequence of SEQ ID NO: 133; the amino acid sequence of SEQ ID NO: 316 and SEQ ID NO: 133; the amino acid sequence of SEQ ID NO: 317 and SEQ ID NO: 133; the amino acid sequence of SEQ ID NO: 1 and SEQ ID NO: 135; the amino acid sequence of SEQ ID NO: 2 and SEQ ID NO: 135; the amino acid sequence of SEQ ID NO: 3 and SEQ ID NO: 135; the amino acid sequence of SEQ ID NO: 4 and SEQ ID NO: 135; the amino acid sequence of SEQ ID NO: 5 and SEQ ID NO: 135; the amino acid sequence of SEQ ID NO: 6 and SEQ ID NO: 135 Amino acid sequence; amino acid sequence of SEQ ID NO: 7 and SEQ ID NO: 135; amino acid sequence of SEQ ID NO: 8 and SEQ ID NO: 135; amino acid sequence of SEQ ID NO: 307 and SEQ ID NO: 135; amino acid sequence of SEQ ID NO: 308 and SEQ ID NO: 135; amino acid sequence of SEQ ID NO: 309 and SEQ ID NO: 135; amino acid sequence of SEQ ID NO: 310 and SEQ ID NO: 135; amino acid sequence of SEQ ID NO: 311 and SEQ ID NO: 135; amino acid sequence of SEQ ID NO: 312 and SEQ ID NO: 135;The amino acid sequences of SEQ ID NO: 313 and 135; the amino acid sequences of SEQ ID NO: 314 and 135; the amino acid sequences of SEQ ID NO: 315 and 135; the amino acid sequences of SEQ ID NO: 316 and 135; the amino acid sequences of SEQ ID NO: 317 and 135; the amino acid sequences of SEQ ID NO: 1 and 137; the amino acid sequences of SEQ ID NO: 2 and 137; the amino acid sequences of SEQ ID NO: 3 and 137; SEQ ID NO: 4 The amino acid sequence of and the amino acid sequence of SEQ ID NO: 137; the amino acid sequence of SEQ ID NO: 5 and the amino acid sequence of SEQ ID NO: 137; the amino acid sequence of SEQ ID NO: 6 and the amino acid sequence of SEQ ID NO: 137; the amino acid sequence of SEQ ID NO: 7 and the amino acid sequence of SEQ ID NO: 137; the amino acid sequence of SEQ ID NO: 8 and the amino acid sequence of SEQ ID NO: 137; the amino acid sequence of SEQ ID NO: 307 and the amino acid sequence of SEQ ID NO: 137; the amino acid sequence of SEQ ID NO: 308 and the amino acid sequence of SEQ ID NO: 137; the amino acid sequence of SEQ ID NO: 309 and the amino acid sequence of SEQ ID NO: 137; the amino acid sequence of SEQ ID NO: 310 and The amino acid sequence of SEQ ID NO: 137; the amino acid sequence of SEQ ID NO: 311 and the amino acid sequence of SEQ ID NO: 137; the amino acid sequence of SEQ ID NO: 312 and the amino acid sequence of SEQ ID NO: 137; the amino acid sequence of SEQ ID NO: 313 and the amino acid sequence of SEQ ID NO: 137; the amino acid sequence of SEQ ID NO: 314 and the amino acid sequence of SEQ ID NO: 137; the amino acid sequence of SEQ ID NO: 315 and the amino acid sequence of SEQ ID NO: 137; the amino acid sequence of SEQ ID NO: 316 and the amino acid sequence of SEQ ID NO: 137; the amino acid sequence of SEQ ID NO: 317 and the amino acid sequence of SEQ ID NO: 137; the amino acid sequence of SEQ ID NO: 1 and The amino acid sequence of sequence number 376; the amino acid sequence of sequence number 2 and sequence number 376; the amino acid sequence of sequence number 3 and sequence number 376; the amino acid sequence of sequence number 4 and sequence number 376; the amino acid sequence of sequence number 5 and sequence number 376; the amino acid sequence of sequence number 6 and sequence number 376; the amino acid sequence of sequence number 7 and sequence number 376; the amino acid sequence of sequence number 8 and sequence number 376; the amino acid sequence of sequence number 307 and sequence number 376;The amino acid sequences of SEQ ID NO: 308 and 376; the amino acid sequences of SEQ ID NO: 309 and 376; the amino acid sequences of SEQ ID NO: 310 and 376; the amino acid sequences of SEQ ID NO: 311 and 376; the amino acid sequences of SEQ ID NO: 312 and 376; Sequence; Amino acid sequence of SEQ ID NO: 313 and SEQ ID NO: 376; Amino acid sequence of SEQ ID NO: 314 and SEQ ID NO: 376; Amino acid sequence of SEQ ID NO: 315 and SEQ ID NO: 376; Amino acid sequence of SEQ ID NO: 316 and SEQ ID NO: 376; Amino acid sequence of SEQ ID NO: 317 and SEQ ID NO: 376; Amino acid sequence of SEQ ID NO: 1 and SEQ ID NO: 378; Amino acid sequence of SEQ ID NO: 2 and SEQ ID NO: 378; Amino acid sequence of SEQ ID NO: 3 and SEQ ID NO: 378; Amino acid sequence of SEQ ID NO: 4 and SEQ ID NO: 378; Amino acid sequence of SEQ ID NO: 5 and SEQ ID NO: 378; Amino acid sequence of SEQ ID NO: 6 and SEQ ID NO: 378; Amino acid sequence of SEQ ID NO: 7 and SEQ ID NO: 378; Amino acid sequence of SEQ ID NO: 8 This includes the amino acid sequence and the amino acid sequence of SEQ ID NO: 378; the amino acid sequence of SEQ ID NO: 307 and the amino acid sequence of SEQ ID NO: 378; the amino acid sequence of SEQ ID NO: 308 and the amino acid sequence of SEQ ID NO: 378; the amino acid sequence of SEQ ID NO: 309 and the amino acid sequence of SEQ ID NO: 378; the amino acid sequence of SEQ ID NO: 310 and the amino acid sequence of SEQ ID NO: 378; the amino acid sequence of SEQ ID NO: 311 and the amino acid sequence of SEQ ID NO: 378; the amino acid sequence of SEQ ID NO: 312 and the amino acid sequence of SEQ ID NO: 378; the amino acid sequence of SEQ ID NO: 313 and the amino acid sequence of SEQ ID NO: 378; the amino acid sequence of SEQ ID NO: 314 and the amino acid sequence of SEQ ID NO: 378; the amino acid sequence of SEQ ID NO: 315 and the amino acid sequence of SEQ ID NO: 378; the amino acid sequence of SEQ ID NO: 316 and the amino acid sequence of SEQ ID NO: 378; and the amino acid sequence of SEQ ID NO: 317 and the amino acid sequence of SEQ ID NO: 378.

[0036] In some embodiments, the second polypeptide is (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 A column containing: (x) an amino acid sequence that is at least 90% identical to sequence number 122; (xi) an amino acid sequence that is at least 90% identical to sequence number 124; (xii) an amino acid sequence that is at least 90% identical to sequence number 126; (xiii) an amino acid sequence that is at least 90% identical to sequence number 128; (xiv) an amino acid sequence that is at least 90% identical to sequence number 130; (xv) an amino acid sequence that is at least 90% identical to sequence number 132; (xvi) an amino acid sequence that is at least 90% identical to sequence number 134; (xvii) an amino acid sequence that is at least 90% identical to sequence number 136; (xviii) an amino acid sequence that is at least 90% identical to sequence number 138; (xix) an amino acid sequence that is at least 90% identical to sequence number 377; or (xx) an amino acid sequence that is at least 90% identical to sequence number 379.

[0037] In some embodiments, the second polypeptide is (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 sequence 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 The sequence includes (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) the 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) the 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 (v) The peptide comprises the amino acid sequence of SEQ ID NO: 221; (vi) 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 (ix) The first polypeptide contains an amino acid sequence, and the second polypeptide contains the amino acid sequence of SEQ ID NO 228; (x) 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; (xi) 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 (xiii) 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; (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 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 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 comprises the amino acid sequence of SEQ ID NO: 237, and the second polypeptide comprises 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 comprises the amino acid sequence of SEQ ID NO: 246, and the second polypeptide comprises the sequence (xx) The first polypeptide contains the amino acid sequence of sequence number 249; (xx) The first polypeptide contains the amino acid sequence of sequence number 247, and the second polypeptide contains the amino acid sequence of sequence number 250; (xxi) The first polypeptide contains the amino acid sequence of sequence number 318, and the second polypeptide contains the amino acid sequence of sequence number 332; (xxi) The first polypeptide contains the amino acid sequence of sequence number 319, and the second polypeptide contains the amino acid sequence of sequence number 333; (xxii) The first polypeptide contains the amino acid sequence of sequence number 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 comprises the amino acid sequence of SEQ ID NO: 323, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 337; (xxvi) the first polypeptide comprises the sequence (xxvii) The first polypeptide contains the amino acid sequence of sequence number 324, and the second polypeptide contains the amino acid sequence of sequence number 338; (xxviii) The first polypeptide contains the amino acid sequence of sequence number 325, and the second polypeptide contains the amino acid sequence of sequence number 339; (xxix) The first polypeptide contains the amino acid sequence of sequence number 326, and the second polypeptide contains the amino acid sequence of sequence number 340; (xxix) The first polypeptide contains the amino acid sequence of sequence number 327, and the second polypeptide contains the amino acid sequence of sequence number 341;(xxx) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 329, and the second polypeptide comprises 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 (xxxiv) The first polypeptide contains the amino acid sequence of sequence number 347, and the second polypeptide contains the amino acid sequence of sequence number 361; (xxxv) The first polypeptide contains the amino acid sequence of sequence number 348, and the second polypeptide contains the amino acid sequence of sequence number 362; (xxxvi) The first polypeptide contains the amino acid sequence of sequence number 349, and the second polypeptide contains the amino acid sequence of sequence number 363; (xxxvii) The first polypeptide contains the amino acid sequence of sequence number 350 The first polypeptide includes the amino acid sequence of SEQ ID NO: 364; (xxxviii) The first polypeptide includes the amino acid sequence of SEQ ID NO: 351, and the second polypeptide includes the amino acid sequence of SEQ ID NO: 365; (xxxix) The first polypeptide includes the amino acid sequence of SEQ ID NO: 352, and the second polypeptide includes the amino acid sequence of SEQ ID NO: 366; (xl) The first polypeptide includes the amino acid sequence of SEQ ID NO: 353, and the second polypeptide includes the amino acid sequence of SEQ ID NO: 367; (xli) The first polypeptide includes the amino acid sequence of SEQ ID NO: 353 (xlii) 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; (xliii) 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 comprises the amino acid sequence of SEQ ID NO: 359, and the second polypeptide comprises 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 bonded to the second Fc domain. In some embodiments, the C-terminus of the antigen-binding domain is covalently bonded to the N-terminus of the second Fc domain. In some embodiments, the N-terminus of the antigen-binding domain is covalently bonded to the C-terminus of the second Fc domain. In some embodiments, the antigen-binding domain is covalently bonded to the first Fc domain. In some embodiments, the C-terminus of the antigen-binding domain is covalently bonded to the N-terminus of the first Fc domain. In some embodiments, the N-terminus of the antigen-binding domain is covalently bonded 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, diabody, triabody, tetrabody, minibody, nanobody, maxibody, tandab, DVD, BiTe, TandAb, or any combination thereof. In some embodiments, the antigen-binding domain binds to an internally distributed receptor expressed on the surface of the cell. In some embodiments, the internally distributed receptor is selected from the group consisting of FcγRIIB, FcRn, ASGPR, CD38, SLAMF7, GPCR5D, and BCMA. In some embodiments, the internally distributed receptor is ASGPR. In some embodiments, the antigen-binding domain includes Fab. In some embodiments, the Fab includes 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, the Fab includes 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 comprises a second autoantibody-binding domain. In some embodiments, the N-terminus of the second Fc domain is covalently bonded to the C-terminus of the second autoantibody-binding domain. In some embodiments, the C-terminus of the second Fc domain is covalently bonded 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, the molecule can selectively deplete anti-TSHR autoantibodies that bind to the autoantibody-binding domain when administered to a target. In some embodiments, the anti-TSHR autoantibodies that bind to the autoantibody-binding domain are selectively depleted by being taken up by cells and transported to lysosomes for degradation.

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

[0043] In another aspect, the Disclosure provides nucleic acids comprising a nucleotide sequence encoding a molecule of the Disclosure.

[0044] In another aspect, the Disclosure provides a host cell comprising a nucleic acid containing a nucleotide sequence encoding a molecule of the Disclosure.

[0045] In another embodiment, the Disclosure provides a vector comprising a nucleic acid containing a nucleotide sequence encoding a molecule of the Disclosure. In some embodiments, the vector includes 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 embodiment, the Disclosure provides a pharmaceutical composition comprising a molecule or nucleic acid encoding a molecule and a pharmaceutically acceptable carrier.

[0047] In another aspect, the Disclosure provides a method for generating the molecule of the Disclosure, comprising expressing a nucleic acid containing a nucleotide sequence encoding the molecule in a host cell, and recovering the molecule.

[0048] In another embodiment, the 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 the molecule of the Disclosure or a nucleic acid encoding the molecule. In some embodiments, the autoimmune disease is Graves' disease (GD), thyroid eye disease, or another autoimmune disease involving anti-TSHR autoantibodies.

[0049] In another embodiment, the Disclosure provides a method for treating a subject suffering from or susceptible to an autoimmune disease, comprising administering to the subject a first pharmaceutical composition comprising a molecule of the Disclosure or a nucleic acid encoding the molecule, and administering to the subject a second pharmaceutical composition that selectively depletes plasma cells producing autoantibodies targeted by the autoantibody-binding domain. In some embodiments, the autoimmune disease is Graves' disease (GD), thyroid eye disease, 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 and second pharmaceutical compositions are co-administered.

[0050] In some embodiments, the level of anti-TSHR autoantibodies in or from the subject after administration is reduced compared to the level before 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% compared to the level before administration. In some embodiments, the reduction in the level of anti-TSHR autoantibodies persists for a long period of time. In some embodiments, 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. 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 embodiment, the Disclosure provides a method for selectively depleting an anti-TSHR autoantibody in a subject, the method comprising administering to the subject a pharmaceutical composition comprising the molecule of the Disclosure or a nucleic acid encoding the molecule.

[0052] In another embodiment, the 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 the molecule of the Disclosure or a nucleic acid encoding the molecule.

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

[0054] In another aspect, the present disclosure relates to a composition for reducing the titer of anti-TSHR autoantibodies in serum in subjects requiring a reduction in the titer of anti-TSHR autoantibodies in serum, 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, and the first and / or the second Fc domain The present invention provides a composition comprising one or more mutant amino acid residues having increased binding affinity to FcγRIIB compared to the corresponding wild-type Fc domain, wherein upon administration of the plurality of molecules, the molecules bind to an anti-TSHR autoantibody to form an immune complex comprising two molecules bound to the anti-TSHR autoantibody, and the immune complex binds to FcγRIIB expressed on the surface of hepatic sinusoidal endothelial cells (LSECs) with higher avidity compared to an immune complex comprising two corresponding molecules having wild-type Fc domains, undergoes endocytosis, thereby reducing the titer of the anti-TSHR autoantibody in the target's serum.

[0055] In another embodiment, the Disclosure provides an immune complex comprising an anti-TSHR autoantibody and two molecules of the Disclosure, the immune complex having improved binding kinetics with FcγRIIB compared to an immune complex comprising the anti-TSHR autoantibody bound to two corresponding molecules having wild-type Fc domains.

[0056] In another embodiment, the present disclosure provides an immune complex comprising (i) an anti-TSHR autoantibody; and (ii) two molecules, each 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 and second Fc domains form a homodimer or heterodimer of the first and second polypeptides, and the first and / or second Fc domains comprise one or more mutant amino acid residues that increase the binding affinity to FcγRIIB compared to the corresponding wild-type Fc domains, and the immune complex has improved binding kinetics with FcγRIIB compared to an immune complex comprising the anti-TSHR autoantibody bound to two corresponding molecules having wild-type Fc domains. In some embodiments, the immune complex has improved binding kinetics with FcγRIIB compared to an immune complex comprising the anti-TSHR autoantibody and only one molecule. In some embodiments, the immune complex exhibits improved binding kinetics with FcγRIIB compared to the anti-TSHR autoantibody alone. In some embodiments, the autoantibody-binding domain of each of the two molecules is bound to the anti-TSHR autoantibody.

[0057] In some embodiments, the improved coupling dynamics include an increase in the association rate, a decrease in the dissociation rate, and / or a change in the equilibrium dissociation constant.

[0058] In some embodiments, the improved binding kinetics result in increased avidity, stability, strength, frequency, and / or duration of 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 show increased binding affinity to FcγRI, FcγRIIA167H, FcγRIIA167R, FcγRIIIA176F, FcγRIIIA176V, FcγRIIIB, and / or FcRn compared to the corresponding wild-type Fc domain. In some embodiments, the first and / or second Fc domains containing one or more mutant amino acid residues show decreased binding affinity to FcγRI, FcγRIIA167H, FcγRIIA167R, FcγRIIIA176F, FcγRIIIA176V, FcγRIIIB, and / or FcRn compared to the corresponding wild-type Fc domain. In some embodiments, the first and / or second Fc domains, which include one or more mutant amino acid residues, have negligible or no binding affinity to FcγRI, FcγRIIA167H, FcγRIIA167R, FcγRIIIA176F, FcγRIIIA176V, FcγRIIIB, and / or FcRn compared to the corresponding wild-type Fc domains.

[0060] In some embodiments, the improved binding kinetics include at least 10% higher binding affinity of the immune complex to FcγRIIB. In some embodiments, the at least 10% higher binding affinity includes 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 more binding affinity.

[0061] In some embodiments, the binding affinity includes the binding affinity to cell lines (e.g., CHO cell lines) that overexpress FcγRIIB as measured by flow cytometry. In some embodiments, the immune complex preferentially binds to immune cells expressing FcγRIIB rather than immune cells expressing FcγRIIA. In some embodiments, the immune complex crosslinks FcγRIIB with B cell receptors on B cells. [Brief explanation of the drawing]

[0062] [Figure 1] A schematic diagram of an exemplary molecule described herein for the selective depletion of autoantibodies targeted by an autoantibody-binding domain is shown.

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

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

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

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

[0067] [Figure 6] The results of binding assays using anti-TSHR autoantibodies M22 and K1-70 as Fab fragments are shown. A shows that M22 binds to TSHR260 variants 2P, 2P2R, and 2P1S at pH 7.4 using single-cycle kinetics. A shows that K1-70 binds to TSHR260 variants 2P, 2P2R, and 2P1S at pH 7.4 using single-cycle kinetics.

[0068] [Figure 7-1] The results of binding assays using full-length IgG anti-TSHR autoantibodies M22, K1-70, CS-17, and K1-18 are shown. This indicates that M22, K1-70, CS-17, and K1-18 bind to TSHR260 variant 2P2R (variant D3 and variant E3) fused to various Fc domains at pH 7.4 using multicycle kinetics. [Figure 7-2]The results of binding assays using full-length IgG anti-TSHR autoantibodies M22, K1-70, CS-17, and K1-18 are shown. This indicates that M22, K1-70, CS-17, and K1-18 bind to TSHR260 variant 2P2R (variant D3 and variant E3) fused to various Fc domains at pH 7.4 using multicycle kinetics.

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

[0070] [Figure 8B] The results of the cAMP assay after the addition of gradually increasing concentrations of agonists (M22, K1-18, and TSH) are shown.

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

[0072] [Figure 10] The results of cAMP assays are shown for the exemplary molecule (variant D3) alone or after administration with an anti-TSHR autoantibody (M22 or K1-18).

[0073] [Figure 11] The results of cAMP assays using serum samples from healthy donors or patients containing anti-TSHR autoantibodies with and without the exemplary molecule (variant D3) are shown.

[0074] [Figure 12] The results of the cAMP assay are shown, in which an exemplary molecule (variant D3) reduced TSHR activity (measured by downstream cAMP activity) in individual patient serum samples (A) and pooled patient serum samples (B).

[0075] [Figure 13] Some exemplary mechanisms of action of the molecules described herein, which include mutations in the Fc domain that increase affinity for FcγRIIB, are shown below, including (A) neutralization of autoantibodies, (B) elimination of autoantibodies by targeting FcγRIIB isoform 2 on hepatic sinusoidal endothelial cells, (C) targeting pathogenic B cells that produce targeted autoantibodies (e.g., anti-TSHR autoantibodies) by targeting FcγRIIB isoform 1 to the B cell receptor (BCR), resulting in apoptosis and inhibition of B cells, and (D) prevention of binding to FcγRIIB on T cells and T cell activation.

[0076] [Figure 14] The results of binding assays are shown, in which exemplary molecules are captured on an SPR sensor chip and the binding activity of trastuzumab control (A), variant B3 (B), variant D3 (C), and variant E3 (D) to the activating receptor FcγRIIA167H is measured using FcγR as the analyte.

[0077] [Figure 15] The results of binding assays are shown, in which exemplary molecules are captured on an SPR sensor chip and the binding activity of trastuzumab control (A), variant B3 (B), variant D3 (C), and variant E3 (D) to the activating receptor FcγRIIA167R is measured using FcγR as the analyte.

[0078] [Figure 16] The results of binding assays are shown, in which exemplary molecules are captured on an SPR sensor chip and the binding activity of trastuzumab control (A), variant B3 (B), variant D3 (C), and variant E3 (D) to the inhibitory receptor FcγRIIB is measured using FcγR as the analyte.

[0079] [Figure 17]The results of a binding assay are shown, in which His-tagged FcγR is captured on an SPR sensor chip, and the binding activity of trastuzumab control (A), variant B3 (B), variant D3 (C), and variant E3 (D) to the activating receptor FcγRIIA167H is measured using exemplary molecules as analytes.

[0080] [Figure 18] The results of a binding assay are shown, in which His-tagged FcγR is captured on an SPR sensor chip, and the binding activity of trastuzumab control (A), variant B3 (B), variant D3 (C), and variant E3 (D) to the activating receptor FcγRIIA167R is measured using exemplary molecules as analytes.

[0081] [Figure 19] The results of a binding assay are shown, in which His-tagged FcγR is captured on an SPR sensor chip, and the binding activity of trastuzumab control (A), variant B3 (B), variant D3 (C), and variant E3 (D) to the inhibitory receptor FcγRIIB is measured using exemplary molecules as analytes.

[0082] [Figure 20] The following are ELISA results showing the binding of exemplary molecules to C1q.

[0083] [Figure 21] This document presents the results of a binding assay measuring the binding of TSHR autoantibodies (M22) to FcγRIIB-expressing CHO cells when M22 is pre-complexed with exemplary molecules so that most M22 binds to two molecules (added in a 4:1 molar ratio of molecules:M22), compared to when M22 primarily binds to one molecule (added in a 1:1 molar ratio of molecules:M22). Results are also shown when the anti-FcγRIIB blocking antibody 2B6 is included in the 4:1 experiment.

[0084] [Figure 22]This concerns FcγRIIB protein expression among various immune cell types. Figure A is a modified version based on Kerntke, et al., (2020) Frontiers in immunology. 11:489401, incorporated herein by reference, and shows that B cells highly express FcγRIIB. Figure B shows that the immune complex of M22 and exemplary molecules bound most strongly to B cells and unclassified cells. Unclassified cells represent cells that could not be classified as monocytes, B cells, NK cells, or T cells because they are negative for CD16, CD19, CD56, and CD3. Such cells may be non-classical monocytes or basophils.

[0085] [Figure 23A] This shows that M22, pre-complexed with an exemplary molecule, binds to FcγRIIB-expressing cells: B cells. Results are also shown when the anti-FcγRIIB blocking antibody 2B6 is included in the experiment. [Figure 23B] This shows that M22, pre-complexed with exemplary molecules, binds to FcγRIIB-expressing cells: monocytes. Results are also shown when the anti-FcγRIIB blocking antibody 2B6 was included in the experiment.

[0086] [Figure 24A] This shows that M22, pre-complexed with exemplary molecules, binds to NK cells. Results are also shown when the anti-FcγRIIB blocking antibody 2B6 was included in the experiment. [Figure 24B] This shows that M22, pre-complexed with exemplary molecules, binds to unclassified cells. Results are also shown when the anti-FcγRIIB blocking antibody 2B6 is included in the experiment.

[0087] [Figure 25]This shows that variant D3 does not strongly bind to CHO-FcγRIIB+ cells. In contrast, variant B3 binds to CHO-FcγRIIB+ cells at a low concentration of 1 nM. Binding of variant D3 to CHO-FcγRIIB+ cells was evident only at 1 μM. Binding of variants B3 and D3 is completely blocked by the anti-FcγRIIB blocking antibody 2B6.

[0088] [Figure 26] This shows an example of how molecules bind to B cells.

[0089] [Figure 27] The diagram shows exemplary molecular binding to both classical cells (CD14+) (A) and unclassified cells (B). Unclassified cells represent cells that could not be classified as monocytes, B cells, NK cells, or T cells because they are negative for CD16, CD19, CD56, and CD3. Such cells may be non-classical monocytes or basophils.

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

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

[0092] [Figure 30]The results of a pK experiment (A) measuring the concentration (ng / mL) of a molecule ("ASP") in serum over time, with each point representing the median value for 5 mice (wild-type BALB / c mice) and the bar indicating the mean half-life of the molecule represented by SEM (B).

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

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

[0095] [Figure 33] The results of a pK experiment (A) measuring the concentration (ng / mL) of a molecule ("ASP") in serum over time, with each point representing the median value for 5 mice (B-hFcRn) and the bar indicating the mean half-life of the molecule represented by SEM (B).

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

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

[0098] [Figure 36] The results of a pK experiment (A) measuring the concentration (ng / mL) of a molecule ("ASP") in serum over time, with each point representing the median value for five mice (huFcγR-huFcRn mice) and the bar indicating the mean half-life of the molecule represented by SEM (B).

[0099] [Figure 37] This section presents exemplary results from experiments testing the formation of an immune complex between an exemplary molecule (variant D3) and the M22 antibody. The M22 antibody and the exemplary molecule were mixed in various ratios, and complex formation was evaluated by HPLC-SEC.

[0100] [Figure 38] The following are exemplary results from an experiment testing the formation of immune complexes between exemplary molecules and the M22 antibody. Patient serum samples were incubated with a fluorescently labeled molecule, and it was shown that the molecule formed complexes as 2:1 and 1:1 (molecule:autoantibody) complexes (represented by characteristic peaks).

[0101] [Figure 39] The results of an ELISA assay measuring inflammatory cytokines to evaluate the immune response to a representative molecule are shown. A shows the level of IL-6 secreted into the supernatant of human PBMCs cultured with the representative molecule and M22 antibody. B shows the level of MCP-1 secreted into the supernatant of human PBMCs cultured with the representative molecule and M22 antibody.

[0102] [Figure 40] The results of experiments measuring the activation of monocytes (A) and NK cells (B) after culturing with exemplary molecules and the M22 antibody are shown.

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

[0104] [Figure 42] The results of experiments using AC-SINS (affinity-captured self-interacting nanoparticle spectroscopy) to identify the self-association tendencies of exemplary molecules are shown.

[0105] [Figure 43] The results of experiments using DSC to measure the thermal stability of exemplary molecular variants D3(A) and E3(B) are shown.

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

[0107] [Figure 45] The results of binding assays are shown, in which molecules are captured on an SPR sensor chip and the binding activity of trastuzumab control, variant G1, variant G2, variant G3, variant G6, variant G7, and variant G8 to the activating receptor FcγRIIA167R is measured using FcγR as the analyte.

[0108] [Figure 46]The results of binding assays are shown, in which molecules are captured on an SPR sensor chip and the binding activity of variants G9, G10, G11, G12, G13, G14, and G4 to the activating receptor FcγRIIA167R is measured using FcγR as the analyte.

[0109] [Figure 47] The results of binding assays are shown, in which molecules are captured on an SPR sensor chip and the binding activity of trastuzumab control, variant G1, variant G2, variant G3, variant G6, variant G7, and variant G8 to the activating receptor FcγRIIA167H is measured using FcγR as the analyte.

[0110] [Figure 48] The results of binding assays are shown, in which molecules are captured on an SPR sensor chip and the binding activity of variants G9, G10, G11, G12, G13, G14, and G4 to the activating receptor FcγRIIA167H is measured using FcγR as the analyte.

[0111] [Figure 49] The results of binding assays are shown, in which molecules are captured on an SPR sensor chip and the binding activity of trastuzumab control, variant G1, variant G2, variant G3, variant G6, variant G7, and variant G8 to the inhibitory receptor FcγRIIB is measured using FcγR as the analyte.

[0112] [Figure 50] The results of binding assays measuring the binding activity of variants G9, G10, G11, G12, G13, G14, and G4 to the inhibitory receptor FcγRIIB, using FcγR as the analyte, are shown.

[0113] [Figure 51] This bar graph shows the mean fluorescence intensity (MFI) of an Alexa Fluor647-labeled M22 autoantibody detected by flow cytometry at increasing concentrations of free molecules bound to ectopically expressed FcγRIIB in genetically modified CHO-K1 cell lines (CHO-FcγRIIB). FcγRIIB-dependent binding of exemplary molecules was evaluated using pretreatment of CHO-FcγRIIB cells with 10 μg / mL anti-FcγRIIB blocking antibody clone 2B6. MFI values ​​were calculated from single living cells. Each condition was evaluated individually.

[0114] [Figure 52-1] This image shows a flow cytometry half-offset histogram of the fluorescence signal of Alexa Fluor647-labeled M22 autoantibody, indicating the detection of binding of free molecules to ectopically expressed FcγRIIB in genetically modified CHO-K1 cell lines (CHO-FcγRIIB) at increasing concentrations. FcγRIIB-dependent binding of exemplary molecules was evaluated using pretreatment of CHO-FcγRIIB cells with 10 μg / mL anti-FcγRIIB blocking antibody clone 2B6. Signals were calculated from single living cells. Each condition was evaluated individually. [Figure 52-2] This image shows a flow cytometry half-offset histogram of the fluorescence signal of Alexa Fluor647-labeled M22 autoantibody, indicating the detection of binding of free molecules to ectopically expressed FcγRIIB in genetically modified CHO-K1 cell lines (CHO-FcγRIIB) at increasing concentrations. FcγRIIB-dependent binding of exemplary molecules was evaluated using pretreatment of CHO-FcγRIIB cells with 10 μg / mL anti-FcγRIIB blocking antibody clone 2B6. Signals were calculated from single living cells. Each condition was evaluated individually.

[0115] [Figure 53]This bar graph shows the mean fluorescence intensity (MFI) of an Alexa Fluor647-labeled M22 autoantibody detected by flow cytometry at increasing concentrations of free molecules bound to ectopically expressed FcγRIIA167R in a genetically modified CHO-K1 cell line (CHO-FcγRIIA167R). FcγRIIA-dependent binding of the molecule was evaluated using pretreatment of CHO-FcγRIIA167R cells with 10 μg / mL anti-FcγRIIA blocking antibody clone IV.3. MFI values ​​were calculated from single living cells. Each condition was evaluated individually. Data represent biological replication and mean ± sd for n=2.

[0116] [Figure 54-1] This image shows a flow cytometry half-offset histogram of the fluorescence signal of Alexa Fluor647-labeled M22 autoantibody, indicating the detection of binding of the free molecule to ectopically expressed FcγRIIA167R in the genetically modified CHO-K1 cell line (CHO-FcγRIIA167R) at increasing concentrations. FcγRIIA-dependent binding of the molecule was evaluated using pretreatment of CHO-FcγRIIA167R cells with 10 μg / mL anti-FcγRIIA blocking antibody clone IV.3. Signals were calculated from single living cells. Representative data from one of two independent experiments. [Figure 54-2] This image shows a flow cytometry half-offset histogram of the fluorescence signal of Alexa Fluor647-labeled M22 autoantibody, indicating the detection of binding of the free molecule to ectopically expressed FcγRIIA167R in the genetically modified CHO-K1 cell line (CHO-FcγRIIA167R) at increasing concentrations. FcγRIIA-dependent binding of the molecule was evaluated using pretreatment of CHO-FcγRIIA167R cells with 10 μg / mL anti-FcγRIIA blocking antibody clone IV.3. Signals were calculated from single living cells. Representative data from one of two independent experiments. [Modes for carrying out the invention]

[0117] definition To make this disclosure easier to understand, certain terms are first defined below. Further definitions of the terms below, and any additional terms, are provided throughout this specification. Publications and other reference materials referenced herein to provide background and additional details relating to their implementation are incorporated herein by reference.

[0118] In this specification, the articles "a" and "an" are used to refer to one or more (i.e., at least one) grammatical objects of the article. For example, "an element" means one or more elements.

[0119] Administration: As used herein, generally refers to the administration of a composition to a subject or system. Those skilled in the art will recognize various routes that may be used for administration to a subject, e.g., a human, in appropriate circumstances. For example, in some embodiments, administration may be intraocular, oral, parenteral, topical, etc. In some specific embodiments, administration may be bronchial (e.g., by bronchial infusion), buccal, percutaneous (e.g., one or more of the following, or including, topical, intradermal, interdermal, transdermal, etc.), enteral, intra-arterial, intradermal, gastric, intramedullary, intramuscular, intranasal, intraperitoneal, subarachnoid, intravenous, intraventricular, intraspecific organ (e.g., intrahepatic), mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (e.g., by intratracheal infusion), transvaginal, intravitreal, etc. In some specific embodiments, administration may be parenteral (e.g., by intravenous injection). In some embodiments, administration may include intermittent administration (e.g., multiple doses spaced apart) and / or cyclical administration (e.g., individual doses spaced apart by a common period). In some embodiments, administration may include continuous administration over at least a selected period (e.g., perfusion).

[0120] Affinity: As is known in the art, "affinity" is a measure of the firmness with which two or more binding partners (e.g., an antibody and a target antigen) associate with each other. Those skilled in the art will be familiar with the various assays available for assessing affinity, and also with appropriate controls for such assays. In some embodiments, affinity is assessed by quantitative assays. In some embodiments, affinity is assessed over multiple concentrations (e.g., one binding partner at a time). In some embodiments, affinity is assessed in the presence of one or more potential competitors (e.g., relevant, e.g., those that may be present in a physiological context). In some embodiments, affinity is assessed in comparison to a reference (e.g., a "positive control" reference with a known affinity above a certain threshold, or a "negative control" reference with a known affinity below a certain threshold). In some embodiments, affinity may be assessed in comparison to a contemporaneous reference. In some embodiments, affinity may be assessed in comparison to a past reference. Typically, when affinity is assessed in comparison to a reference, it is assessed under equivalent conditions.

[0121] Approximately or about: When used herein and applied to one or more values ​​of interest, means a value similar to the given reference value. In some embodiments, the terms “approximately” or “about” mean a range of values ​​that are within 20% (more than or less than) of the given reference value in either direction, unless otherwise specified or evident from the context (except where such a number exceeds 100% of the possible reference value).

[0122] Antibody: As used herein, refers to a polypeptide containing a canonical immunoglobulin sequence element sufficient to result in specific binding to a particular target antigen. As known in the art, an intact antibody, such as one produced naturally, is a tetrameric drug composed of 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-shaped" structure. Each heavy chain contains at least four domains: an amino-terminal variable (VH) domain (located at the tip of the Y structure), followed by three constant domains: CH1, CH2, and carboxy-terminal CH3 (located at the base of the trunk portion of the Y). A short region known as the "switch" connects the heavy-chain variable and constant domains. The "hinge" connects the CH2 and CH3 domains to the rest of the antibody. Two disulfide bonds in this hinge region conjugate the two heavy-chain polypeptides together in the intact antibody. Each light chain consists of two domains. In other words, an amino-terminal variable (VL) domain is followed by a carboxy-terminal constant (CL) domain, which are separated from each other by another "switch." Intact antibody tetramers consist of two heavy-light chain dimers, in which the heavy and light chains are linked to each other by one disulfide bond, and two other disulfide bonds connect the heavy chain hinge regions to each other, thereby linking the dimers together to form a tetramer. Naturally produced antibodies are also typically glycosylated at the CH2 domain. Each domain in natural antibodies has a structure characterized by an "immunoglobulin fold" formed by two beta sheets (e.g., 3, 4, or 5-strand sheets) bundled together in a compressed antiparallel beta barrel. Each variable domain contains three hypervariable loops or "CDRs" (CDR1, CDR2, and CDR3) and four somewhat invariant "framework" regions (FR1, FR2, FR3, and FR4) known as "complementarity-determining regions." When the natural antibody folds, the FR region forms a β-sheet that confers a structural framework to the domain, and the CDR loop regions of both the heavy and light chains come together in three-dimensional space to form a single hypervariable antigen-binding site located at the tip of a Y-shaped structure.The Fc region of naturally occurring antibodies is located at the base of the Y structure and binds to complement system elements, including, for example, effector cells that mediate cytotoxicity, and also to receptors on effector cells. The affinity and / or other binding properties of the Fc region to Fc receptors can be regulated through glycosylation or other modifications. In some embodiments, antibodies produced and / or utilized according to this disclosure include a glycosylated Fc domain, which includes an Fc domain that has been modified or manipulated in terms of glycosylation. In some embodiments, any polypeptide, or a polypeptide complex containing a sufficient immunoglobulin domain sequence as found in naturally occurring antibodies, may be referred to and / or used as an “antibody,” regardless of whether such polypeptides are produced naturally (e.g., by organisms that react to antigens) or by recombinant operations, chemosynthesis, or other artificial systems or methodologies. In some embodiments, the antibody is polyclonal. In some embodiments, the antibody is monoclonal. In some embodiments, the antibody has a constant region sequence characteristic of mouse antibodies, rabbit antibodies, primate antibodies, or human antibodies. In some embodiments, the antibody sequence elements are human, humanized, primated, chimeric, and the like, as are known in the art. Furthermore, as used herein, the term “antibody” may refer to any construct or format known or developed in the art for utilizing the structural and functional features of an antibody in an alternative presentation, in a suitable embodiment (unless otherwise stated or evident from the context). For example, in some embodiments, the antibodies utilized in accordance with this disclosure may be intact IgA, IgG, IgE, or IgM antibodies; bispecific or multispecific antibodies; or forms used herein in a broad sense, selected from, but not limited to, antibody fragments (preferably those fragments exhibiting desired antigen-binding activity) that encompass a variety of antibody structures.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 immunological binding moieties known in the art, including, for example, Fab, Fab', Fab'2, Fab2, Fab3, F(ab')2, Fd, Fv, sdAb, scFv, SMIP, diabody, triabody, tetrabody, minibody, nanobody, maxibody, tandab, DVD, BiTe, TandAb, or any combination thereof. The subunit structures and three-dimensional configurations of different classes of antibodies are known in the art. In some embodiments, antibodies may lack covalent modifications (e.g., glycan binding) that they would have if naturally produced. In some embodiments, antibodies may include covalent modifications, e.g., glycan binding, cargo moieties (e.g., detectable moieties, therapeutic moieties, catalytic moieties, etc.), or other pendant groups (e.g., polyethylene glycol, etc.).

[0123] Antigen-binding domain: The “antigen-binding domain” refers to the portion of an antibody that binds to the antigen to which an intact antibody binds. Antigen-binding domains of antibodies include any naturally occurring, enzymatically available, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds to the 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, diabody, triabody, tetrabody, minibody, nanobody, maxibody, tandab, DVD, BiTe, TandAb, or 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 only the VHH domain. As with complete antibody molecules, the antigen-binding domain may be monospecific or multispecific (e.g., bispecific). The multispecific antigen-binding domain of an antibody may include at least two different variable domains, each of which can specifically bind to a different antigen or to a different epitope of the same antigen.

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

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

[0126] Synthetic antibody: As used herein, this refers to an antibody produced using recombinant DNA technology. This term should also be interpreted to mean an antibody produced by the synthesis of an antibody-encoding DNA molecule, and an antibody on which the DNA molecule expresses an antibody protein, or an amino acid sequence that identifies an antibody, where the DNA or amino acid sequence is obtained using synthetic DNA or amino acid sequence techniques that are available and well known in the art.

[0127] Antigen: As used herein, the term “antigen” refers to a molecule (e.g., a 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 both full-length polypeptides and parts or immunogenic fragments of polypeptides, as well as peptide epitopes within polypeptides (e.g., peptide epitopes conjugated by 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 and is identified, for example, from cells or tissues that are targets of an autoimmune response, or from healthy cells or tissues.

[0128] Autoantigen: As used herein, “autoantigen” refers to an antigen that triggers an autoimmune response. An autoantigen is an endogenous (self) antigen that is recognized by the immune system as non-self, i.e., an exogenous pathogen. An autoantigen may be a protein, an immunogenic fragment of a protein, or a complex of proteins that is recognized by the immune system of a person suffering from or susceptible to an autoimmune disease.

[0129] Autoimmune disease: As used herein, “autoimmune disease” refers to an immune response to an autoantigen (or self-antigen).

[0130] Related: Two events or entities are “related” to each other if, as the term is used herein, the existence, level, degree, type and / or form of one correlates with that of the other. For example, a particular entity (e.g., polypeptide, genetic signature, metabolite, microorganism, etc.) is considered related to a particular disease, disorder, or condition if its existence, level and / or form correlates (e.g., across a relevant population) with the onset, susceptibility, severity, stage, etc., of a disease, disorder, or condition.

[0131] Binding domain: As used herein, refers to a portion or element that specifically binds to a target portion or element. Typically, the interaction between the binding domain and its target is non-covalent. In some embodiments, the binding domain may be, or include, a portion or element of any chemical classification, including, for example, carbohydrates, lipids, nucleic acids, metals, polypeptides, and small molecules. In some embodiments, the binding domain may be, or include, a polypeptide (or a complex thereof). In some embodiments, the binding domain may be, or include, a target-binding portion of an antibody drug, a cytokine, a ligand (e.g., a receptor ligand), a receptor, a toxin, etc. In some embodiments, the binding domain may be, or include, an aptamer. In some embodiments, the binding domain may be, or include, a peptide nucleic acid (PNA). In some embodiments, the binding domain may be an antigen (e.g., an autoantigen). In some embodiments, the binding domain binds to an antibody (i.e., a “target antibody”).

[0132] Effective dose: As used herein in relation to drug dosage, this refers to a dose sufficient to prevent or treat a target disease or disorder in a subject. The effective dose for therapeutic or prophylactic use will depend, for example, on the stage and severity of the disease or disorder being treated, the subject's age, weight, and overall health status, as well as the prescribing physician's judgment. The amount of the dose will also depend on the drug selected, the method of administration, the timing and frequency of administration, the presence, nature, and extent of any adverse side effects that may be associated with the administration of a particular drug, and the desired physiological effect. It will be understood by those skilled in the art that various diseases or disorders may require long-term treatment involving multiple doses, each or in a variety of processes, using the molecules of the present invention.

[0133] To code: As used herein, “to code” refers to the inherent properties and resulting biological properties of a particular nucleotide sequence in a polynucleotide, such as a gene, cDNA, or mRNA, which has either a defined nucleotide (i.e., rRNA, tRNA, and mRNA) sequence or a defined amino acid sequence, and which acts as a template for the synthesis of other polymers and macromolecules in biological processes. Thus, a gene codes for a protein if the transcription and translation of the mRNA corresponding to that gene produces a protein in a cell or other biological system. Both the coding strand, which is identical to the mRNA sequence and is usually a nucleotide sequence listed in a sequence listing, and the non-coding strand, which is used as a template for the transcription of a gene or cDNA, can be said to code for a protein, or other products of that gene or cDNA.

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

[0135] Expression: As used herein, the term “expression” of a nucleic acid sequence refers to the generation of any gene product from a 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 includes one or more of the following: (1) generation of 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) translation of the RNA into a polypeptide or protein, and (4) post-translational modification of the polypeptide or protein.

[0136] Fragment: As used herein, the terms “fragment” or “part” refer to a structure that includes a distinct part of the whole but lacks one or more parts found in the whole structure. In some embodiments, a fragment consists of such a distinct part. In some embodiments, a fragment consists of or includes characteristic structural elements or parts found in the whole. In some embodiments, the nucleotide fragment contains or consists 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 throughout the nucleotide. In some embodiments, the nucleotide fragment contains or consists 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 monomeric units (e.g., nucleic acids) found throughout the nucleotide. In some embodiments, the polypeptide or protein fragment contains or comprises 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 throughout the polypeptide or protein.In some embodiments, a polypeptide or protein fragment contains or consists 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 monomeric units (e.g., amino acids) found in the polypeptide or protein as a whole. In some embodiments, the whole substance or entity may be referred to as the “parent” of the fragment.

[0137] Identity: As used herein, the term “identity” refers to the overall relationship between macromolecules, e.g., between nucleic acid molecules (e.g., between DNA molecules and / or RNA molecules) and / or between polypeptide molecules. In some embodiments, macromolecules are considered “substantially identical” to one another if their sequences are identical by at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%. For example, the calculation of the identity percentage of two nucleic acid or polypeptide sequences can be performed by aligning the two sequences for the purpose of best comparison (for example, gaps can be introduced in one or both of the first and second sequences for best alignment, and non-identical sequences can be ignored for the purpose of comparison). In some embodiments, the length of the sequences aligned 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. The nucleotides at the corresponding positions are then compared. If a position in the first sequence is occupied by the same residue (e.g., a nucleotide or amino acid) as the corresponding position in the second sequence, then the molecules are identical at that position. The percentage of identity between two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps that need to be introduced to optimally align the two sequences and the length of each gap. The comparison of sequences and the determination of the percentage of identity between two sequences can be achieved using mathematical algorithms. For example, the percentage of identity between two nucleotide sequences can be determined using the Meyers and Miller algorithm (CABIOS, 1989, 4:11-17), which is incorporated into the ALIGN program (version 2.0). In some exemplary embodiments, the comparison of nucleic acid sequences by the ALIGN program uses a PAM120 weighted residue table, a gap length penalty 12, and a gap penalty 4.Alternatively, the percentage of identity between two nucleotide sequences can also be determined using the GAP program in the GCG software package and the NWSgapdna.CMP matrix.

[0138] Human antibodies: As used herein, these are intended to include antibodies having variable and constant regions generated (or assembled) from human immunoglobulin sequences. In some embodiments, an antibody (or antibody component) may be considered "human" even if, for example, one or more CDRs and a particular CDR3 contain residues or elements whose amino acid sequences are not encoded by human germline immunoglobulin sequences (e.g., including sequence diversity, which may have been introduced (inherently), for example, by random or site-directed mutagenesis in vitro or by somatic mutation in vivo).

[0139] Immune cells: As used herein, this refers to cells involved in an immune response, e.g., promoting 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. Sources of immune cells (e.g., T lymphocytes) can be obtained from the subject.

[0140] Immune mediators: As used herein, the term “immune mediator” refers to any molecule that influences cells and processes involved in the immune response. Examples of immune mediators include cytokines, chemokines, soluble proteins, enzymes, and cell surface markers.

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

[0142] Immunoglobulin or Ig: As used herein, this refers to a class of proteins that function as antibodies. Antibodies expressed by B cells are sometimes referred to as BCRs (B cell receptors) or antigen receptors. The five members of this class of proteins are IgA, IgG, IgM, IgD, and IgE. IgA is a primary antibody found in body secretions such as saliva, tears, breast milk, gastrointestinal secretions, and mucus secretions of the respiratory and urogenital tracts. IgG is the most common circulating antibody. IgM is the major immunoglobulin produced in the primary immune response to most targets. It is the most efficient immunoglobulin in agglutination, complement binding, and other antibody responses and is important for protection against bacteria and viruses. IgD is an immunoglobulin whose antibody function is unknown, but it may function as an antigen receptor. IgE is an immunoglobulin that mediates immediate-type hypersensitivity by triggering the release of mediators from mast cells and basophils upon exposure to allergens.

[0143] Improved, Increased, or Reduced: As used herein, the terms “improved,” “increased,” or “reduced,” or grammatically equivalent terms, indicate a value compared to an equivalent reference measure. For example, in some embodiments, an evaluation value achieved by the drug of interest may be “improved” compared to one obtained by an equivalent reference drug. Alternatively or additionally, in some embodiments, an evaluation value achieved in the subject or system of interest may be “improved” compared to a value obtained in the same subject or system under different conditions (e.g., before or after an event such as administration of the drug of interest) or in a different equivalent subject (e.g., in the presence of one or more indicators of the particular disease, disorder, or condition of interest, or in an equivalent subject or system different from the subject or system of interest that has been previously exposed to the condition or drug, etc.). In some embodiments, the comparative term refers to a statistically significant difference (e.g., a rate and / or magnitude large enough to achieve a statistical significance). A person skilled in the art will know, or can easily determine, the degree and / or rate of difference necessary or sufficient to achieve such a statistically significant difference in a given context.

[0144] Isolated: As used herein, this refers to something that has been modified or removed from its natural state. For example, a nucleic acid or polypeptide that is naturally present in a living animal is not “isolated,” but the same nucleic acid or peptide that has been partially or completely separated from its naturally occurring coexisting substances is “isolated.” Isolated nucleic acids or polypeptides may exist in a substantially purified form or in a non-natural environment, such as a host cell.

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

[0146] K off:As used herein, this refers to the dissociation rate constant of the dissociation of a binder (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 binds).

[0147] K on :As used herein, this refers to the binding rate constant of the association of a binder (e.g., an antibody or its binding component) from a complex with its partner (e.g., an antibody or its binding component to which it binds).

[0148] To modulate: As used herein, the term “modulate” means to mediate a detectable increase or decrease in the level of response and / or a change in the nature of the response in an object compared to the level and / or nature of the response in the object in the absence of treatment and / or compared to the level and / or nature of the response in an otherwise identical but untreated object. The term encompasses, in an object, preferably a human, disrupting and / or influencing a natural signal or response, thereby mediating a beneficial therapeutic response.

[0149] Nucleic acid: As used herein, refers to a polymer of at least three nucleotides. In some embodiments, nucleic acid comprises DNA. In some embodiments, nucleic acid comprises RNA. In some embodiments, nucleic acid is single-stranded. In some embodiments, nucleic acid is double-stranded. In some embodiments, nucleic acid comprises both single-stranded and double-stranded portions. In some embodiments, nucleic acid comprises a backbone comprising one or more phosphodiester bonds. In some embodiments, nucleic acid comprises a backbone comprising both phosphodiester and non-phosphodiester bonds. For example, in some embodiments, nucleic acid may comprise a backbone comprising one or more phosphorothioate or 5'-N-phosphoramidite links and / or one or more peptide bonds, such as in "peptide nucleic acid". In some embodiments, nucleic acid comprises one or more, or all, native residues (e.g., adenine, cytosine, deoxyadenosine, deoxycytidine, deoxyguanosine, deoxythymidine, guanine, thymine, uracil). In some embodiments, nucleic acid comprises one or more, or all, non-native residues. In some embodiments, the non-natural residues include nucleoside analogs (e.g., 2-aminoadenosine, 2-thiothymidine, inosine, pyrrolo-pyrimidine, 3-methyladenosine, 5-methylcytidine, C-5 propynylcytidine, C-5 propynyluridine, 2-aminoadenosine, C5-bromouridine, C5-fluorouridine, C5-iodouridine, C5-propynyluridine, C5-propynylcytidine, C5-methylcytidine, 2-aminoadenosine, 7-deazaadenosine, 7-deazaguanosine, 8-oxoadenosine, 8-oxoguanosine, 0(6)-methylguanine, 2-thiocytidine, methylated bases, intercalated bases, and combinations thereof). In some embodiments, the non-natural residues include one or more modified sugars (e.g., 2'-fluororibose, ribose, 2'-deoxyribose, arabinose, and hexose) compared to those of the natural residues. In some embodiments, the nucleic acid has a nucleotide sequence encoding a functional gene product such as RNA or polypeptide. In some embodiments, the nucleic acid has a nucleotide sequence containing one or more introns.In some embodiments, nucleic acids can be prepared by isolation from natural sources, enzymatic synthesis (e.g., polymerization based on a complementary template, such as in vivo or in vitro replication in recombinant cells or systems, or by chemical synthesis). In some embodiments, the nucleic acid has a residue length of 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, or 5000.

[0150] Operatively linked: As used herein, this means a functional link between, for example, a regulatory sequence and a heterologous nucleic acid sequence, resulting in the expression of the latter. For example, if a first nucleic acid sequence is functionally related to a second nucleic acid sequence, the first nucleic acid sequence is operably linked to the second nucleic acid sequence. For example, a promoter is operably linked to a coding sequence if the promoter affects the transcription or expression of the coding sequence. Generally, operably linked DNA sequences are adjacent to each other in the same reading frame and, if necessary, are used to link two protein-coding regions.

[0151] Pharmaceutical composition: As used herein, refers to an active agent formulated with one or more pharmaceutically acceptable carriers. In some embodiments, the active agent of interest exists in a unit dose suitable for administration in a therapeutic regimen that exhibits a statistically significant probability of achieving a predetermined therapeutic effect when administered to an appropriate population. In some embodiments, the pharmaceutical composition may be specifically formulated for administration in solid or liquid form, such as: oral administration, e.g., liquid drugs (aqueous solutions or non-aqueous solutions or suspensions), tablets, e.g., those targeting oral absorption, sublingual absorption, and systemic absorption, pills, powders, granules, pastes for application to the tongue; parenteral administration, e.g., parenteral administration by subcutaneous, intramuscular, intravenous, or epidural injection, e.g., sterile solutions or suspensions or sustained-release formulations; topical application, e.g., creams, ointments, or sustained-release patches, or sprays applied to the skin, lungs, or mouth; vaginal or rectal use, e.g., pessaries, creams, or foams; sublingual use; ocular use; transdermal use; or transnasal, transpulmonary, and other mucosal surface use.

[0152] Polynucleotide: As used herein, refers to a chain of nucleotides. Furthermore, nucleic acids are polymers of nucleotides. Thus, as used herein, nucleic acids and polynucleotides are interchangeable. Those skilled in the art have general knowledge that nucleic acids are polynucleotides and can be hydrolyzed to monomeric "nucleotides." Monomeric nucleotides can be hydrolyzed to nucleosides. Polynucleotides as used herein include, but are not limited to, all nucleic acid sequences obtained by any means available in the art, including recombinant means, i.e., cloning of nucleic acid sequences from recombinant libraries or cell genomes, using conventional cloning techniques and PCR, and synthetic means.

[0153] Protein: as used herein, refers to polypeptides (i.e., a series of at least two amino acids linked together by peptide bonds). Therefore, proteins and polypeptides as used herein are interchangeable. Proteins may contain non-amino acid portions (e.g., glycoproteins, proteoglycans, etc.) and / or may be processed or modified. Those skilled in the art will understand that “protein” may be a complete polypeptide (with or without a signal sequence) produced by a cell, or a characteristic portion thereof. Those skilled in the art will understand that a protein may contain two or more polypeptides linked, for example, by one or more disulfide bonds, or associated by other covalent or noncovalent means. Polypeptides may contain L-amino acids, D-amino acids, or both, and may contain any of the various amino acid modifications or analogs known in the art. Useful modifications include, for example, terminal acetylation, amidation, and methylation. In some embodiments, proteins 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 having a length of less than approximately 100 amino acids, less than approximately 50 amino acids, less than 20 amino acids, or less than 10 amino acids. In some embodiments, proteins are antibodies, antibody fragments, their biologically active portions, and / or characteristic portions thereof.

[0154] Specific Binding: As used herein, the term “specifically binding” in relation to an antigen-binding domain, for example, an antigen-binding domain found in an antibody, refers to an antigen-binding domain that recognizes a specific antigen but substantially does not recognize or bind to other molecules in the sample. For example, an antigen-binding domain that specifically binds to an antigen of one species may also bind to one or more antigens of other species. However, such cross-reactivity itself does not change the classification of the antigen-binding domain as specific. In another example, an antigen-binding domain that specifically binds to an antigen may also bind to different alleles of the antigen. However, such cross-reactivity itself does not change the classification of the antigen-binding domain as specific. In some cases, the terms “specific binding” or “specifically binding” may be used in relation to the interaction between an antigen-binding domain and a second chemical species, meaning that the interaction depends on the presence of a specific structure on the chemical species (e.g., an antigenic determinant or epitope). For example, an antigen-binding domain recognizes and binds to a specific protein structure rather than the protein in general. If the antigen-binding domain is specific to epitope "A", then in reactions involving labeled "A" and the antigen-binding domain, the presence of a molecule containing epitope A (or free unlabeled A) reduces the amount of labeled A bound to the antigen-binding domain.

[0155] Subject: As used herein, subject means an organism, e.g., a mammal (e.g., human, non-human mammal, non-human primate, primate, laboratory animal, mouse, rat, hamster, gerbil, cat, or dog). In some embodiments, a human subject is an adult, adolescent, or child subject. In some embodiments, a subject suffers from a disease, disorder, or condition, e.g., a disease, disorder, or condition that can be treated as provided herein, e.g., an autoimmune disease. In some embodiments, a subject is susceptible to a disease, disorder, or condition, and in some embodiments, a susceptible subject is predisposed to developing a disease, disorder, or condition and / or exhibits increased risk (compared to the mean risk observed in a reference subject or reference population). In some embodiments, a subject exhibits one or more symptoms of a disease, disorder, or condition. In some embodiments, a subject does not exhibit any particular symptoms (e.g., clinical symptoms of a disease) or features of a disease, disorder, or condition. In some embodiments, a subject does not exhibit any symptoms or features of a disease, disorder, or condition. In some embodiments, a subject is a patient. In some embodiments, the subject is an individual to be diagnosed and / or treated.

[0156] Target: When used herein, this refers to cells, tissues, organs, or sites in the body that are the target of the methods, systems, and / or compositions provided, for example, cells, tissues, organs, or sites in the body that require treatment or are preferentially bound by the molecules described herein.

[0157] To treat: As used herein, the terms “to treat,” “to treat,” or “to treat” mean partial or complete reduction, improvement, delay, inhibition, prevention, mitigation, and / or reduction of incidence and / or severity of one or more symptoms or characteristics of a disease, disorder, and / or condition. In some embodiments, treatment may be administered to a subject that does not exhibit any signs or characteristics of a disease, disorder, and / or condition (e.g., it may be prophylactic). In some embodiments, treatment may be administered to a subject that exhibits only early or mild signs or characteristics of a disease, disorder, and / or condition, for example, to reduce the risk of developing a condition associated with the disease, disorder, and / or condition. In some embodiments, treatment may be administered to a subject exhibiting established, severe, and / or late signs of a disease, disorder, or condition. As used herein, “therapeutic agent” is any agent used to treat a subject.

[0158] Vector: As used herein, the term “vector” refers to a composition of substances comprising isolated nucleic acids that can be used to deliver isolated nucleic acids into the interior of cells. Numerous vectors are known in the art, including but not limited to linear polynucleotides, polynucleotides associated with ionic or amphiphilic compounds, plasmids, and viruses. Thus, the term “vector” includes plasmids or viruses that autonomously replicate. The term should also be interpreted to include non-plasmid and non-viral components that facilitate the delivery of nucleic acids into cells, such as polylysine compounds and liposomes. Examples of viral vectors include, but are not limited to, adenovirus vectors, adeno-associated virus vectors, retroviral vectors, and lentiviral vectors.

[0159] Throughout this disclosure, various aspects may be presented in range form. It should be understood that descriptions in range form are merely for convenience and conciseness and should not be interpreted as immutable limitations on ranges. Therefore, a range description should be considered to specifically disclose not only the individual numbers within that range, but also all possible subranges. For example, a range description such as 1 to 6 should be considered to have not only the individual numbers within that range, such as 1, 2, 2.7, 3, 4, 5, 5.3, and 6, but also specifically disclosed subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, and 3 to 6. This applies regardless of the width of the range.

[0160] Detailed explanation Certain autoimmune diseases are caused by autoantibodies that initiate an immune response against self-antigens (i.e., autoantigens). Despite the identification of specific autoantibody-antigen pairs and their association in autoimmune diseases (e.g., TSHR and Graves' disease), many are not adequately controlled with current treatments. Current standard treatments involve suppressing the autoimmune response by inhibiting or depleting complete immune components or cell populations, including those essential 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 result in pan-IgG depletion and, often, incomplete depletion of autoantibodies.

[0161] This disclosure encompasses molecules for selectively depleting autoantibodies (i.e., anti-TSHR autoantibodies) to treat autoimmune diseases (e.g., Graves' disease and thyroid eye disease). The molecules described herein include, in some embodiments, a first polypeptide comprising a first Fc domain and an autoantibody-binding domain that binds to autoantibodies (i.e., anti-TSHR autoantibodies); and a second polypeptide comprising a second Fc domain, wherein the first and second Fc domains form a homodimer or heterodimer of the first and second polypeptides. In some embodiments, the second polypeptide further comprises an autoantibody-binding domain that binds to autoantibodies (i.e., anti-TSHR autoantibodies). In some embodiments, the autoantibody-binding domains in the first and second polypeptides are identical, and the molecule is a homodimer. In some embodiments, the autoantibody-binding domains in the first and second polypeptides are different, and the molecule is a heterodimer. In some embodiments, the second polypeptide further lacks an autoantibody-binding domain that binds to an autoantibody (i.e., an anti-TSHR autoantibody), and the molecule is a heterodimer.

[0162] This disclosure provides, in particular, molecules that selectively target and deplete autoantibodies by targeting autoantibodies to internally distributed receptors that bind to the complex and cause the complex to move into the cell for lysosomal degradation. In some embodiments, the autoantibody-binding domain includes an autoantigen. For example, if the specific autoantibody to be targeted is an anti-TSHR autoantibody (e.g., for the treatment of Graves' disease and thyroid eye disease), the autoantigen domain may include a TSHR autoantigen domain. In addition to including an autoantibody-binding domain, the molecule may also include modifications to its first and / or second Fc domains to increase binding to internally distributed receptors or endocytosis receptors on the cell surface (e.g., those that cause their ligands to move internally and target them to lysosomes). In some embodiments, the molecule may include an antigen-binding domain that binds to internally distributed receptors or endocytosis receptors on the cell surface (e.g., those that cause their ligands to move internally and target them to lysosomes).

[0163] Graves' disease, thyroid eye disease, and TSHR In some embodiments, the molecules described herein can be used to treat Graves' disease, thyroid eye disease, and other autoimmune diseases involving autoantibodies targeting the thyroid-stimulating hormone receptor (TSHR) by comprising an autoantibody-binding domain containing 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) localized in thyroid follicular cells or thyroid cells. These antibodies can bind to TSH receptors in retroorbital tissue, potentially causing Graves' ophthalmopathy or thyroid eye disease (see Burch and Cooper, JAMA 314(23):2544(2015)). Therefore, stimulating thyrotropin receptor antibodies are a major cause of Graves' disease and GO, and are an important indicator in diagnosis and prediction of clinical severity.

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

[0166] The thyrotropin receptor, or thyroid-stimulating hormone receptor (TSHR), is the primary autoantigen causing Graves' hyperthyroidism and related eye diseases (Graves' ophthalmopathy or thyroid eye disease). TSHR peptides are recognized by the immune system upon ingestion and presented on antigen-presenting cells (APCs) via MHC class II. Helper T cells recognize the TSHR autoantigen domain by binding to its fragment on APCs. Upon activation of helper T cells, they bind to B cells, causing the inflammatory cytokines interleukin II and gamma interferon to mature the B cells into TSHR antibody-secreting plasma cells. The synthesized TSHR antibody binds to TSH-R expressed by thyroid cells and orbital target cells (fibroblasts, preadipocytes). This activates pathways such as the Gαs adenylyl cyclase (AC) pathway, stimulating protein kinase A and inducing gene activation by the cAMP response element-binding (CREB) protein. Additional pathways, including the Gαq protein kinase C (PKC) pathway, are also activated, leading to the activation of protein kinase B (Akt) and the induction of mammalian target of rapamycin (mTOR). This induction of gene expression can lead to differentiation into preadipocytes and the synthesis of glycosaminoglycans in the orbital space, potentially causing edema and subsequent fibrosis, which are the clinical phenotypes of thyroid eye disease (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, high levels of thyroxine (T4) and triiodothyronine (T3), and undetectable levels of TSH. Levels of TSHR antibodies are also an important indicator (see Burch and Cooper, JAMA 314(23):2544 (2015)). Standard treatment for hyperthyroidism due to Graves' disease includes antithyroid drugs to normalize thyroid hormone production, thyroid atrophy using RAIs, or surgical removal of the thyroid (see Burch and Cooper, JAMA 314(23):2544 (2015)). However, these therapies do not target the stimulant TSHR antibodies associated with the disease.

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

[0169] Other treatments recently developed 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 plasma exchange. However, such strategies target all B cells or plasma cells, not just the cells that produce pathogenic autoantibodies. In the case of CD38, targeting such cells also depletes other CD38+ cells, including monocytes, T cells, and NK cells. FcRn inhibitors result in pan-IgG depletion and, in many cases, incomplete depletion of autoantibodies.

[0170] This disclosure recognizes that essential immunity can be preserved and further selectively introduced to enhance the potency of antibodies targeting exogenous pathogens, such as viral antigens. The molecules described herein include further selectivity to target autoantibodies associated with autoimmune diseases. In some embodiments, this strategy involves utilizing the TSHR autoantigen domain, or a fragment or variant thereof, for targeted degradation of anti-TSHR autoantibodies, thereby eliminating autoimmune responses associated with Graves' disease and thyroid eye disease.

[0171] Exemplary molecules This disclosure provides molecules for selectively depleting and / or neutralizing autoantibodies (i.e., anti-TSHR autoantibodies) to treat autoimmune diseases (e.g., Graves' disease). The molecules described herein, in some embodiments, comprise a first polypeptide comprising a first Fc domain and an autoantibody-binding domain that binds to an autoantibody (i.e., anti-TSHR autoantibody); and a second polypeptide comprising a second Fc domain, wherein the first and second Fc domains form a homodimer or heterodimer of the first and second polypeptides. In some embodiments, the second polypeptide further comprises an autoantibody-binding domain that binds to an anti-TSHR autoantibody, and the molecule is a homodimer. In some embodiments, the second polypeptide further comprises an autoantibody-binding domain that binds to an 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 an anti-TSHR autoantibody, and the molecule is a heterodimer.

[0172] In some embodiments, the first and / or second polypeptide further comprises 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, resulting in increased binding affinity to internalized receptors (e.g., FcγRIIB) compared to the corresponding wild-type Fc domains.

[0175] In some embodiments, when one or two molecules bind to an autoantibody (i.e., an anti-TSHR autoantibody), an immune complex is formed. In some embodiments, the immune complex formed by one molecule and an autoantibody (i.e., an anti-TSHR autoantibody) as described herein has improved binding kinetics with FcγRIIB compared to an immune complex containing an autoantibody (i.e., an anti-TSHR autoantibody) bound to one corresponding molecule having a wild-type Fc domain. In some embodiments, the immune complex formed by two molecules and autoantibodies (i.e., anti-TSHR autoantibodies) as described herein has improved binding kinetics with FcγRIIB compared to an immune complex containing an autoantibody (i.e., an anti-TSHR autoantibody) bound to two corresponding molecules having wild-type Fc domains. Such improved 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 include any domain that binds to an autoantibody that causes 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, an scFv domain, a VHH, an Fc domain, a peptide sequence, a mimotope, and / or any portion of the autoantigen domain targeted by the autoantibody.

[0177] In some embodiments, the autoantibody-binding domain described herein prevents the autoantibody from binding to its allogeneic autoantigen (e.g., the autoantibody to the TSHR autoantigen).

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

[0179] TSHR belongs to a family of leucine-rich repeat-containing class A G protein-coupled receptors, including follicle-stimulating hormone. The first 21 amino acids (shown in SEQ ID NO: 9) form a signal peptide, which is ultimately cleaved. The remaining amino acid sequence consists of 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 involved in Graves' disease and hyperthyroidism bind to the LRD (see Miller-Gallacher et al., Journal of Molecular Endocrinology 62(3):117(2019), which is incorporated in its entirety herein by reference).

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

[0181] In some embodiments, the TSHR autoantigen domain contains one or more mutations that increase stability while retaining binding to irritating anti-TSHR autoantibodies (e.g., M22) or TSH-blocking anti-TSHR autoantibodies (e.g., K1-70). Specific mutations introduced into TSHR260 have been shown to produce TSHR260 variants that are approximately 900 times more heat-stable 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 autoantigen domain comprises a human TSHR autoantigen domain variant containing one or more of the following mutations to the amino acid sequence of SEQ ID NO: R112P, D143P, V169R, I253R, H63S, or any combination thereof. In some embodiments, the autoantigen domain comprises a human TSHR autoantigen domain variant containing the following mutations to the amino acid sequence of SEQ ID NO: R112P and D143P (see, for example, SEQ ID NOs: 2 and 6). In some embodiments, the autoantigen domain comprises a human TSHR autoantigen domain variant containing the following mutations to the amino acid sequence of SEQ ID NO: R112P, D143P, V169R, and I253R (see, for example, SEQ ID NOs: 3 and 7). In some embodiments, the autoantigen domain comprises a human TSHR autoantigen domain variant containing the following mutations to the amino acid sequence of SEQ ID NO: R112P, D143P, and H63S (see, for example, SEQ ID NOs: 4 and 8).

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

[0184] In some embodiments, the autoantigen domain comprises a human TSHR autoantigen domain variant containing a sequence that is at least 90% identical to one of sequence numbers 1-8 and 307-317 (shown in Table 1 below). [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0185] antigen-binding domain In some embodiments, the molecules provided herein include one or more antigen-binding domains (for example, shown in Figure 3). In some embodiments, the antigen-binding domains bind to internally distributed receptors (e.g., FcγRIIB, FcRn, ASGPR, BCMA, CD38, SLAMF7, GPCR5D, and / or CD138).

[0186] Examples of antigen-binding domains include, but are not limited to, monoclonal antibodies, synthetic antibodies, human antibodies, humanized antibodies, non-human antibodies, and any fragments thereof. Therefore, in one embodiment, the antigen-binding domain portion includes a mammalian antibody or a fragment thereof. In some embodiments, the antigen-binding domain contained in the molecule may be any binding polypeptide, for example, protein scaffolds with antibody-like properties (e.g., antibody-variable domains), as well as any other immunological binding moieties known in the art, such as Fab, Fab', Fab'2, Fab2, Fab3, F(ab')2, Fd, Fv, sdAb, scFv, SMIP, diabody, triabody, tetrabody, minibody, nanobody, maxibody, tandab, DVD, BiTe, TandAb, VHH, peptide sequences, or mimotopes, 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 internally distributed receptor (e.g., FcγRIIB, FcRn, ASGPR, BCMA, CD38, SLAMF7, GPCR5D, and / or CD138).

[0188] In some embodiments, the molecules described herein include an antigen-binding domain that targets two or more targets. In some embodiments, the antigen-binding domain is a bispecific antigen-binding domain. In some embodiments, the antigen-binding domain includes a triplicate antigen-binding domain. In some embodiments, the antigen-binding domain targets two non-overlapping epitopes on the same target (for example, in the case of an antigen-binding domain targeting two non-overlapping epitopes of an internally distributed receptor or autoantibody, two non-overlapping epitopes on FcγRIIB, FcRn, ASGPR, BCMA, CD38, SLAMF7, GPCR5D, and / or CD138).

[0189] In some embodiments, the molecule may include a first antigen-binding domain and a second antigen-binding domain so that each antigen-binding domain can bind 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 internally distributed receptor (e.g., FcγRIIB, FcRn, ASGPR, BCMA, CD38, SLAMF7, GPCR5D, and / or CD138).

[0190] In some embodiments, the antigen-binding domain comprises a Fab containing heavy chain and light chain antibody components. In some embodiments, the antigen-binding domain comprises a Fab containing one of the following specific heavy chain 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 SEQ ID NO: 209 and / or an antibody light chain sequence that is at least 90% identical to SEQ ID NO: 210. In some embodiments, the antigen-binding domain is a Fab comprising the antibody heavy chain sequence SEQ ID NO: 209 and / or the antibody light chain sequence SEQ ID NO: 210. [Table 2]

[0192] FC Domain In some embodiments, the molecule described herein comprises a first polypeptide comprising an autoantigen domain containing a TSHR autoantigen domain or a fragment or variant thereof linked to a first Fc domain, and a second polypeptide comprising a second Fc domain. The TSHR autoantigen domain or a fragment or variant thereof targets an anti-TSHR autoantibody, and upon binding, the complex is targeted to an internally distributed receptor and transported to a lysosome for degradation of the anti-TSHR autoantibody.

[0193] In some embodiments, the Fc domains described herein include one or more mutations that alter the binding affinity to specific 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 the same (e.g., in a homodimer molecule). In some embodiments, the first Fc domain and the second Fc domain are different (e.g., in a heterodimer molecule).

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

[0196] In some embodiments, the first and / or second Fc domains of the molecule include modifications (e.g., one or more mutations) that enhance binding to internally localized receptors. In some embodiments, the first and / or second Fc domains of the molecule include modifications (e.g., one or more mutations) that reduce binding to specific Fc receptors. In some embodiments, the first and / or second Fc domains of the molecule include modifications (e.g., one or more mutations) that enhance other features of the molecules described herein (e.g., extension of half-life, heterodimerization, etc.).

[0197] The Fc domain contained in the molecule may contain one of the five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM. In some embodiments, the conventional antibody contains an IgG antibody. In some embodiments, the Fc domain described herein contains a specific isotype selected from the group of IgG isotypes: IgG1, IgG2, IgG3, and IgG4. In some embodiments, the molecule contains a first and / or second Fc domain which is the IgG1 isotype. In some embodiments, the molecule contains a first and / or second Fc domain which is the human IgG1 isotype. Furthermore, in some embodiments, the Fc domain may contain any specific heavy chain constant domains corresponding to different classes of immunoglobulins, including α, δ, ε, γ, and μ, respectively. In some embodiments, the conventional antibody is an intact IgG1 antibody or other antibody class or isotype 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); WO1993 / 01161; and U.S. Patents No. 5,571,894, No. 5,869,046, No. 6,248,516, and No. 5,587,458, respectively, which are incorporated herein by reference).

[0198] The Fc domain of antibodies contained in the molecules described herein binds to complement system elements, including, for example, effector cells that mediate cytotoxicity, and also to receptors on effector cells. As is known in the art, the affinity and / or other binding attributes of the Fc domain to Fc receptors can be modulated through glycosylation or other modifications. In some embodiments, the molecules described herein include glycosylated Fc domains, which include modified or manipulated glycosylation Fc domains. In some embodiments, the molecules are naturally produced (e.g., generated by organisms that react to antigens) or generated by genetic engineering, chemosynthesis, or other artificial systems or methodologies.

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

[0200] In some embodiments, improved binding kinetics include an immune complex binding affinity to one or more Fc receptors (e.g., FcγRIIB) that is at least 10% higher. In some embodiments, improved 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 more.

[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 includes one or more modifications such that the molecule described herein does not activate immune cells (for example, does not activate immune cells to secrete inflammatory cytokines, such as IL-6).

[0203] Table 3 below shows exemplary Fc domain sequences for use in accordance with this disclosure. It will 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 will also be understood that any exemplary Fc domain sequence having a knob mutation (identified by the reference "knob") can be used together with an exemplary Fc domain sequence having a hole mutation (identified by the reference "hole") when preparing heterodimer molecules. In some embodiments, the Fc domain sequences shown in Table 3 can be used in pairs based on the reference numbers found in Table 3 when preparing heterodimer molecules, for example, but not limited to the following (e.g., the human IgG1 Fc 1.1 knob can be used with the human IgG1 Fc 1.1 hole, and the human IgG1 Fc 1.2 knob can be used with the human IgG1 Fc 1.2 hole). The references in Table 3 to Fc domain sequences useful for "antigen depletion antigen arms" (i.e., in polypeptides including an autoantibody binding domain) or "antigen depletion free arms" (i.e., in polypeptides not including an autoantibody binding domain) are intended to be illustrative and non-limiting, meaning that Fc domain sequences identified in Table 3 as useful for "antigen depletion antigen arms" may be used for "antigen depletion free arms" in some embodiments, and vice versa. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10] [Table 3-11]

[0204] In some embodiments, the first Fc domain includes sequences selected from SEQ ID NOs: 103, 105, 107, 109, 113, 115, 117, 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 376, and 378, and the second Fc domain includes sequences selected from SEQ ID NOs: 104, 106, 108, 110, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 377, and 379.

[0205] In some embodiments, the first Fc domain includes sequences selected from SEQ ID NOs: 103, 105, 113, 115, 117, 121, 123, 125, 376, and 378, and the second Fc domain includes sequences selected from SEQ ID NOs: 104, 106, 114, 116, 118, 122, 124, 126, 377, and 379.

[0206] In some embodiments, the first Fc domain includes sequences selected from SEQ ID NOs: 107, 109, 119, 127, 129, 131, 133, 135, and 137, and the second Fc domain includes sequences selected from SEQ ID NOs: 108, 110, 120, 128, 130, 132, 134, 136, and 138.

[0207] In some embodiments, the first Fc domain includes the sequence of sequence number 103, and the second Fc domain includes the sequence of sequence number 104. In some embodiments, the first Fc domain includes the sequence of sequence number 105, and the second Fc domain includes the sequence of sequence number 106. In some embodiments, the first Fc domain includes the sequence of sequence number 107, and the second Fc domain includes the sequence of sequence number 108. In some embodiments, the first Fc domain includes the sequence of sequence number 109, and the second Fc domain includes the sequence of sequence number 110. In some embodiments, the first Fc domain includes the sequence of sequence number 113, and the second Fc domain includes the sequence of sequence number 114. In some embodiments, the first Fc domain includes the sequence of sequence number 115, and the second Fc domain includes the sequence of sequence number 116. In some embodiments, the first Fc domain includes the sequence of sequence number 117, and the second Fc domain includes the sequence of sequence number 118. In some embodiments, the first Fc domain includes the sequence of sequence number 119, and the second Fc domain includes the sequence of sequence number 120. In some embodiments, the first Fc domain includes the sequence of sequence number 121, and the second Fc domain includes the sequence of sequence number 122. In some embodiments, the first Fc domain includes the sequence of sequence number 123, and the second Fc domain includes the sequence of sequence number 124. In some embodiments, the first Fc domain includes the sequence of sequence number 125, and the second Fc domain includes the sequence of sequence number 126. In some embodiments, the first Fc domain includes the sequence of sequence number 127, and the second Fc domain includes the sequence of sequence number 128. In some embodiments, the first Fc domain includes the sequence of sequence number 129, and the second Fc domain includes the sequence of sequence number 130. In some embodiments, the first Fc domain includes the sequence of sequence number 131, and the second Fc domain includes the sequence of sequence number 132. In some embodiments, the first Fc domain includes the sequence of sequence number 133, and the second Fc domain includes the sequence of sequence number 134. In some embodiments, the first Fc domain includes the sequence of sequence number 135, and the second Fc domain includes the sequence of sequence number 136.In some embodiments, the first Fc domain includes the sequence of sequence number 137, and the second Fc domain includes the sequence of sequence number 138. In some embodiments, the first Fc domain includes the sequence of sequence number 376, and the second Fc domain includes the sequence of sequence number 377. In some embodiments, the first Fc domain includes the sequence of sequence number 378, and the second Fc domain includes the sequence of sequence number 379. In some embodiments, the first Fc domain includes the sequence of sequence number 111, and the second Fc domain includes the sequence of sequence number 111. In some embodiments, the first Fc domain includes the sequence of sequence number 139, and the second Fc domain includes the sequence of sequence number 139. In some embodiments, the first Fc domain includes the sequence of sequence number 140, and the second Fc domain includes the sequence of sequence number 140. In some embodiments, the first Fc domain includes the sequence of sequence number 141, and the second Fc domain includes the sequence of sequence number 141. In some embodiments, the first Fc domain includes the sequence of sequence number 142, and the second Fc domain includes the sequence of sequence number 142. In some embodiments, the first Fc domain includes the sequence of sequence number 143, and the second Fc domain includes the sequence of sequence number 143. In some embodiments, the first Fc domain includes the sequence of sequence number 144, and the second Fc domain includes the sequence of sequence number 144. In some embodiments, the first Fc domain includes the sequence of sequence number 145, and the second Fc domain includes the sequence of sequence number 145. In some embodiments, the first Fc domain includes the sequence of sequence number 146, and the second Fc domain includes the sequence of sequence number 146. In some embodiments, the first Fc domain includes the sequence of sequence number 147, and the second Fc domain includes the sequence of sequence number 147. In some embodiments, the first Fc domain includes the sequence of sequence number 148, and the second Fc domain includes the sequence of sequence number 148. In some embodiments, the first Fc domain includes the sequence of sequence number 149, and the second Fc domain includes the sequence of sequence number 149. In some embodiments, the first Fc domain includes the sequence of sequence number 163, and the second Fc domain includes the sequence of sequence number 163.In some embodiments, the first Fc domain includes the sequence of sequence number 164, and the second Fc domain includes the sequence of sequence number 164. In some embodiments, the first Fc domain includes the sequence of sequence number 374, and the second Fc domain includes the sequence of sequence number 374. In some embodiments, the first Fc domain includes the sequence of sequence number 375, and the second Fc domain includes the sequence of sequence number 375.

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

[0209] In this regard, it should be understood that any of the exemplary Fc domain sequences shown in Table 3 may be modified by replacing the hinge sequence of SEQ ID NO: 299 (DKTHTCPPCP) or SEQ ID NO: 300 (EPKSSDKTHTCPPCP) with the hinge sequences 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 SEQ ID NOs: 299-304 hinge sequences containing one, two, three, four, five or more mutations.

[0210] Mutations to increase binding to the internal localization receptor In some embodiments, additional mutations are introduced into the Fc domain of the molecules described herein to target cell surface receptors (i.e., endocytosis receptors) that bind to ligands, cause them to move internally, and target them to lysosomes. By modifying the Fc domain to increase binding to endocytosis receptors, the molecules described herein and autoantibodies bound to them are targeted for internal movement and lysosomal degradation.

[0211] In some embodiments, the molecule comprises a first and / or second Fc domain containing one or more mutant amino acid residues that modify binding to an internal localization receptor on a cell, allowing the internal localization receptor to deliver its cargo to the cell's lysosomes for degradation. In some embodiments, the modification of binding to the internal localization receptor includes increased binding to the internal localization receptor. While we do not wish to be bound by any theory, when a molecule bound to an autoantibody binds to an internal localization receptor on a cell, the internal localization receptor allows the molecule to move internally, and the autoantibody is delivered to the cell's lysosomes for degradation.

[0212] Examples of internally distributed 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 domain comprises one or more mutant amino acid residues that increase binding to human FcγR, particularly FcγRIIB. In some embodiments, such mutations comprise at least one of the following mutant amino acid residues: S267E and L328F, according to the EU numbering scheme. In some embodiments, the first and / or second Fc domain comprises a combination of the following mutant amino acid residues: S267E and L328F, according to the EU numbering scheme. In some embodiments, the first and / or second Fc domain comprises the mutant amino acid residue P238D, according to the EU numbering scheme. In some embodiments, the first and / or second Fc domain comprises at least one of the following mutant amino acid residues: L234A, L235A, and P238D, according to the EU numbering scheme. In some embodiments, the first and / or second Fc domain comprises the following mutant amino acid residues: L234A, L235A, and P238D, according to the EU numbering scheme. In some embodiments, the first and / or second Fc domain comprises at least one of the following mutant amino acid residues: L234A, L235A, P238D, and P329G, according to the EU numbering scheme. In some embodiments, the first and / or second Fc domain comprises the following mutant amino acid residues: L234A, L235A, P238D, and P329G, according to the EU numbering scheme. In some embodiments, the first and / or second Fc domain comprises at least one of the following mutant amino acid residues: L234A, L235A, and P238D, according to the EU numbering scheme. In some embodiments, the first and / or second Fc domain comprises the following mutant amino acid residues: L234A, L235A, and P238D, according to the EU numbering scheme. In some embodiments, the first and / or second Fc domain comprises at least one of the following mutant amino acid residues: N297A and P238D, according to the EU numbering scheme. In some embodiments, the first and / or second Fc domain comprises the following mutant amino acid residues: N297A and P238D, according to the EU numbering scheme.

[0214] In some embodiments, one or more Fc mutations are introduced to increase binding to the neonatal receptor (FcRn). In some embodiments, the Fc domain is an IgG1 Fc domain. Human IgG1 binds naturally to FcRn at acidic pH, which allows it to bind to FcRn, translocate into the cell, recycle back to the cell surface, and not be degraded in the lysosome. 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 receptor-mediated internalization into cells and trafficking of autoantibodies (bound to the molecule) to the lysosome by increasing the binding of the Fc domain to FcRn on the cell surface in a neutral pH environment.

[0215] In some embodiments, the first and / or second Fc domain comprises one or more mutant amino acid residues that increase binding to FcRn at a neutral or near-neutral pH (e.g., a pH between about 6.8 and 7.5). In some embodiments, the first and / or second Fc domain comprises the human IgG1 isotype and remains bound to FcRn even when entering an environment having an acidic pH and / or an environment having a low calcium concentration (e.g., the endosome of a cell). In some embodiments, the first and / or second Fc domain comprises at least one of the following mutant amino acid residues according to the EU numbering scheme: M252Y, S254T, T256E, H433K, and N434F. In some embodiments, such mutations include combinations (i.e., "MST-HN") that include the following mutations according to the EU numbering scheme: M252Y, S254T, T256E, H433K, N434F. In some embodiments, the first and / or second Fc domain comprises a combination (i.e., "MST-HN") of the following mutant amino acid residues according to the EU numbering scheme: M252Y, S254T, T256E, H433K, and N434F.

[0216] In some embodiments, the first and / or second Fc domains include at least one mutant amino acid sequence that reduces binding to one or more Fc-gamma receptors (FcγRs). Such modifications may also interfere with immune crosslinking (i.e., between the molecule, autoantibodies, and FcγRs) that leads to an inflammatory response. Such mutations may focus on the molecule's primary mechanism of action, namely, targeted internal translocation and subsequent degradation of autoantibodies. In some embodiments, the first and / or second Fc domains include at least one of the following mutant amino acid residues: G236R and L328R, according to the EU numbering scheme.

[0217] In some embodiments, the molecules described herein may include any combination of the above Fc mutations that modify binding to an internal localization receptor or an Fc receptor. In some embodiments, the molecules described herein include an Fc domain comprising the "MST-HN" modification described herein in combination with the "RR" mutation described herein. In some embodiments, the molecules described herein include an Fc domain comprising the "MST-HN" modification described herein in combination with the "P238D" mutation described herein. In some embodiments, the molecules described herein include an Fc domain comprising the "MST-HN" modification described herein in combination with the "RR" mutation and the "P238D" mutation 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 utilized in molecules described herein that include one or more mutations that improve the binding kinetics of an immune complex containing one or more molecules bound to a target antibody to FcγRIIB. In some embodiments, the improved 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 more. In some embodiments, the improved binding kinetics include an increase in the avidity, stability, strength, frequency, and / or duration of binding between the immune complex and FcγRIIB. In some embodiments, the improved 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 include one or more mutations in the first and / or second Fc domains to increase binding to FcγRIIB, and when the two molecules bind to a target antibody, an immune complex is formed with improved binding kinetics to FcγRIIB compared to an immune complex containing a target antibody bound to two corresponding molecules having wild-type Fc domains. While we do not wish to be bound by any theory, the molecules described herein may have one or more mutations that increase binding affinity to FcγRIIB, although the binding affinity of the molecules alone to FcγRIIB is moderate. In some embodiments, the molecules bind to FcγRIIB with affinity in the range of about 1 μM to 0.001 μM. In some embodiments, the molecules bind to FcγRIIB with affinity in the range of about 1 μM to 0.01 μM. In some embodiments, the molecules bind to FcγRIIB with affinity in the range of about 0.1 μM to 0.01 μM. In some embodiments, when such mutations are introduced into the Fc domain of the molecules described herein, they confer an avidity-mediated binding effect to FcγRIIB when two or more molecules are present in the immune complex with the target antibody. In some embodiments, the molecules described herein exhibit increased binding to FcγRIIB when the immune complex contains two molecules bound to the target antibody compared to an immune complex with only one molecule bound to the target antibody. While we do not wish to be bound by any theory, such avidity-mediated effects allow for selective binding and depletion of the immune complex, as well as weaker binding (and therefore depletion) of the molecule if it is not part of the immune complex. These features allow the molecules described herein to circulate longer in the target bloodstream before being eliminated by internal translocation and degradation via FcγRIIB.

[0221] Furthermore, this disclosure provides Fc domain mutations that achieve binding affinity to FcγRIIB, conferring avidity-mediated effects that utilize the advantages and additional selectivity described herein. Exemplary Fc domain mutations that may be used to achieve these binding dynamics with FcγRIIB include, for example, in some embodiments, the following mutations according to the EU numbering scheme: E233V, L234D, L235F, G236R, G237D, S239L, S267D, H268P, S298G, T299A, A327L, L328A, A330H, E3 Includes one or more of the following: 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, the Fc domain includes the following set of mutations according to the EU numbering scheme: E233V, L234D, L235F, G236R, G237D, S239L, S267D, H268P, S298G, T299A, A327L, L328A, A330H, and E333I (see, for example, SEQ ID NOs: 113, 114, and 139).

[0223] In some embodiments, the Fc domain mutation includes one or more of the following mutations according to the EU numbering scheme: E233V, L234D, L235F, G236R, G237D, S239L, S267D, R292Q, H268P, S298G, T299A, A327L, L328A, A330H, or E333I. In some embodiments, the Fc domain includes the following set of mutations according to the EU numbering scheme: E233V, L234D, L235F, G236R, G237D, S239L, S267D, R292Q, H268P, S298G, T299A, A327L, L328A, A330H, and E333I (see, for example, SEQ ID NOs: 115, 116, and 140).

[0224] In some embodiments, the Fc domain mutation includes one or more of the following mutations according to the EU numbering scheme: E233V, L234D, L235F, G236R, G237D, S239L, H268P, R292Q, S298G, T299A, A327L, L328A, A330H, or E333I. In some embodiments, the Fc domain includes the following set of mutations according to the EU numbering scheme: E233V, L234D, L235F, G236R, G237D, S239L, H268P, R292Q, S298G, T299A, A327L, L328A, A330H, and E333I (see, for example, SEQ ID NOs: 117, 118, and 141).

[0225] In some embodiments, the Fc domain mutation includes one or more of the following mutations according to the EU numbering scheme: L234Y, P238D, T250V, V264I, T307P, Q311R, A330K, P343R, M428L, N434A, Y436T, Q438R, or S440E. In some embodiments, the Fc domain includes the following set of mutations according to the EU numbering scheme: L234Y, P238D, T250V, V264I, T307P, Q311R, A330K, P343R, M428L, N434A, Y436T, Q438R, and S440E (see, for example, SEQ ID NOs. 119, 120, and 142).

[0226] In some embodiments, the Fc domain mutation includes one or more of the following mutations according to the EU numbering scheme: L234D, G236N, or S267E. In some embodiments, the Fc domain includes the following set of mutations according to the EU numbering scheme: L234D, G236N, and S267E (see, for example, SEQ ID NOs. 121, 122, and 143).

[0227] In some embodiments, the Fc domain mutation includes L235R according to the EU numbering scheme (see, for example, SEQ ID NOs: 123, 124, and 144).

[0228] In some embodiments, the Fc domain mutation includes one or both of the following mutations G236N and S267E, according to the EU numbering scheme. In some embodiments, the Fc domain includes the following set of mutations: G236N and S267E, according to the EU numbering scheme (see, for example, SEQ ID NOs. 125, 126, and 145).

[0229] In some embodiments, the Fc domain mutation includes one or both of the following mutations P238D and D270E, according to the EU numbering scheme. In some embodiments, the Fc domain includes the following set of mutations: P238D and D270E, according to the EU numbering scheme (see, for example, SEQ ID NOs. 127, 128, and 146).

[0230] In some embodiments, the Fc domain mutation includes one or both of the following mutations P238D and P271G, according to the EU numbering scheme. In some embodiments, the Fc domain includes the following set of mutations: P238D and P271G, according to the EU numbering scheme (see, for example, Sequence IDs 129, 130, and 147).

[0231] In some embodiments, the Fc domain mutation includes one or more of the following mutations according to the EU numbering scheme: P238D, D270E, or P271G. In some embodiments, the Fc domain includes the following set of mutations according to the EU numbering scheme: P238D, D270E, and P271G (see, for example, Sequence IDs 131, 132, and 148).

[0232] In some embodiments, the Fc domain mutation includes one or more of the following mutations according to the EU numbering scheme: G237D, P238D, P271G, or A330R. In some embodiments, the Fc domain includes the following set of mutations according to the EU numbering scheme: G237D, P238D, P271G, and A330R (see, for example, Sequence IDs 133, 134, and 149).

[0233] In some embodiments, the Fc domain mutation includes one or more of the following mutations according to the EU numbering scheme: G237D, P238D, D270E, P271G, or A330R. In some embodiments, the Fc domain includes the following set of mutations according to the EU numbering scheme: G237D, P238D, D270E, P271G, and A330R (see, for example, Sequence IDs 135, 136, and 163).

[0234] In some embodiments, the Fc domain mutation includes one or more of the following mutations according to the EU numbering scheme: E233D, G237D, P238D, H268D, P271G, or A330R. In some embodiments, the Fc domain includes the following set of mutations according to the EU numbering scheme: E233D, G237D, P238D, H268D, P271G, and A330R (see, for example, Sequence IDs 137, 138, and 164).

[0235] In some embodiments, the Fc domain mutation includes P238D according to the EU numbering scheme (see, for example, SEQ ID NOs. 107 and 108).

[0236] In some embodiments, the Fc domain having a mutation that increases the binding affinity for FcγRIIB also has a reduced or undetectable binding to certain activating Fc receptors. In some embodiments, the activating Fc receptors include one or more of FcγRI, FcγRIIA167H, FcγRIIA167R, FcγRIIIA176F, FcγRIIIA176V, FcγRIIIB, and / or FcRn. Such binding characteristics lead to additional beneficial properties of the molecules described herein, including, for example, a low risk of toxicity because there is a low risk of activating the innate immune response (via activating Fc receptors) depending on the molecule introduced.

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

[0238] Mutations for heterodimerization In some embodiments, Fc mutations are introduced to promote heterodimerization of two polypeptides, each polypeptide includes an Fc domain, and the first and second Fc domains heterodimerize to produce a complete molecule.

[0239] In particular, generating heterodimerized Fc domains of two different polypeptides from a single composition presents challenges because random pairing of different polypeptides can result in undesirable species. The presence of erroneous pairing byproducts significantly reduces the yield, requiring advanced purification procedures to isolate the desired antibody drug in such situations. Generally, the same problem of erroneous pairing byproducts persists even when recombinant expression techniques are used. One approach to address the erroneous pairing byproduct problem is known as the "knob-into-hole technique" (KIH), which aims to force pairing of two different polypeptides containing Fc domains by introducing mutations into the CH3 region of the Fc domain to alter the contact interface. In one CH3 region, a large amino acid is replaced with an amino acid having a short side chain to create a "hole," while an amino acid with a large side chain is introduced into the other CH3 region to create a "knob." For example, it has been observed that co-expression of two heavy chains of an antibody having such modifications with two light chains leads to a higher yield of heterodimer formation compared to homodimer formation (see Ridgway et al., Protein Eng. 9:617 (1996) and WO1996 / 027011, incorporated herein by reference). In some embodiments, the molecules described herein utilize the KIH technology described, for example, in WO1998 / 050431, which is incorporated entirely herein by reference.

[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 a CH2 region variant and / or a CH3 region variant, each of which independently comprises at least one different amino acid substitution such that heterodimerization of the first and second Fc domains of the molecule of the present invention is promoted more than homodimerization, and such variants independently generate a heterodimer domain pair.

[0241] As described herein, the first and / or second Fc domains of the molecules described herein may include certain mutations utilizing the KIH technique, including but not limited to CH3 modifications. In some embodiments, the molecule includes first and second Fc domains that form a heterodimer using a knob-in-hole (KIH) modification. In some embodiments, the KIH mutations include Y349T and T394F according to the EU numbering scheme. In some embodiments, the first Fc domain includes the Y349T mutation and the second Fc domain includes the T394F mutation. In some embodiments, the first Fc domain includes the T394F mutation and the second Fc domain includes the Y349T mutation. In some embodiments, the KIH mutations include T366W, S354C, T366S, L368A, Y407V, and Y349C according to the EU numbering scheme. In some embodiments, the first Fc domain includes the T366W and S354C mutations, and the second Fc domain includes the T366S, L368A, Y407V, and Y349C mutations. In some embodiments, the first Fc domain includes the T366S, L368A, Y407V, and Y349C mutations, and the second Fc domain includes the T366W and S354C 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 that charge-to-charge swap designs (e.g., the "DD-KK" mutation pair) and isotype-strand swap designs (e.g., "SEED Fc") (see Ha et al., Frontiers in Immunology 7:394 (2016), which is incorporated herein by reference) may be used in the molecules described herein.

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

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

[0245] Linker 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 expected to be used in the molecules described herein. The linkers may be between the autoantibody-binding domain and the Fc domain, but they may also be between other domains of the molecule, for example, linking one or more autoantigen domains within the autoantibody-binding domain.

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

[0247] An example of a flexible linker is glycine polymer (G). n , glycine-serine polymer (e.g., (GS) n (GSGGS: Sequence ID 156) n , and (GGGS: Sequence ID 151) n Examples include glycine-alanine polymers, alanine-serine polymers, and other flexible linkers known in the art (wherein n is an integer of at least 1), glycine-alanine polymers, alanine-serine polymers, and other flexible linkers known in the art. Because glycine and glycine-serine polymers are relatively unstructured, they may be able to act as neutral chains between their constituents. Glycine has even greater access to the phi-psy space than alanine and is less restricted than residues with longer side chains (see Scheraga, Rev. Computational Chem. 11:173-142 (1992)). In some embodiments, the linker includes 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] Further exemplary flexible linkers include, but are not limited to, SEQ ID NOs: 157 (GGSG), 158 (GGSGG), 159 (GSGSG), 160 (GSGGG), 161 (GGGSG), and 162 (GSSSG). Further exemplary linkers also include: GGGGSGGGGSGGGGSGGGGS (SEQ ID NOs: 154) and GGGGSGGGGSGGGGSGGGGSGGGS (SEQ ID NOs: 155).

[0249] Those skilled in the art will recognize that the molecular designs described herein may include a linker that is entirely or partially flexible, so that the linker may include not only a flexible linker but also one or more parts that impart a less flexible structure to provide the desired molecular structure.

[0250] Suitable linkers can be easily selected and may have various lengths, such as 1 amino acid (e.g., Gly) to 20 or more amino acids, 2 amino acids to 15 amino acids, or 3 amino acids to 12 amino acids, including 4 to 10 amino acids, 5 to 9 amino acids, 6 to 8 amino acids, or 7 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 an amino acid-free synthetic linker, e.g., a polyethylene (PEG) linker, or a chemical conjugation, e.g., other known synthetic linkers commonly used in antibody-drug conjugates, or may include such a linker. In this context, it should also be understood that the molecules described herein also encompass molecules in which components of a first or second polypeptide (i.e., an autoantigen domain, an antigen-binding domain, or an Fc domain) are linked by a chemical conjugation, e.g., "click" chemistry or other chemistry, using optionally intervening amino acids or synthetic linkers.

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

[0253] Exemplary configuration Various configurations of the molecules described herein are anticipated. 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. Such 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 shown in Table 4 below. In some embodiments, any one of the combinations in Table 4 may be included in the molecular configuration shown, for example, in Figure 2. In such a configuration, the C-terminus of the self-antigen domain (A) is linked to the N-terminus of a first Fc domain (Fc1) via an optional linker (L) (first polypeptide), forming a heterodimer with a second Fc domain (Fc2) of the second polypeptide.

[0255] In some embodiments, any one of the combinations in Table 4 may be included in the molecular configuration shown, for example, in Figure 3. In such configurations, the C-terminus of the self-antigen domain (A) is linked to the N-terminus of the first Fc domain (Fc1) via an optional linker (L) (first polypeptide), and this molecule also includes an antigen-binding domain (second polypeptide) in which the C-terminus of the antigen-binding domain (HC / LC Fab) is linked to the N-terminus of the second Fc domain (Fc2). In some embodiments (not shown), the N-terminus of the antigen-binding domain (HC / LC Fab) is linked to the C-terminus of the second Fc domain (Fc2) instead (second polypeptide). In some embodiments (not shown), the C-terminus of the first Fc domain (Fc1) is linked to the N-terminus of the first self-antigen domain (A) via an optional linker (L) instead (first polypeptide). In some embodiments (not shown), the C-terminus of the first Fc domain (Fc1) is instead linked to the N-terminus of the first autoantigen domain (A) via an optional linker (L) (first polypeptide), and the N-terminus of the antigen-binding domain (HC / LC Fab) is instead linked to the C-terminus of the second Fc domain (Fc2) (second polypeptide).

[0256] In some embodiments, any one of the combinations in Table 4 may be represented, for example, by the molecular configuration shown in Figure 4. In such a configuration, the C-terminus of the first Fc domain (Fc1) is linked to the N-terminus of the autoantigen domain (A) via an optional linker (L) (first polypeptide), which forms a heterodimer with the second Fc domain (Fc2) of the second polypeptide.

[0257] In some embodiments, any one of the combinations in Table 4 may be represented, for example, in the molecular configuration shown in Figure 5A. In such a configuration, the molecule comprises two autoantigen domains, where the C-terminus of a first Fc domain (Fc1) is linked to the N-terminus of a first autoantigen domain (A') via an optional linker (L') (first polypeptide), and the C-terminus of a second Fc domain (Fc2) is linked to the N-terminus of a second autoantigen domain (A') via an optional linker (L') (second polypeptide). In some embodiments, the two autoantigen domains are the same (e.g., in the homodimer molecule of this disclosure). In some embodiments, the two autoantigen domains are different (e.g., in the heterodimer molecule of this disclosure).

[0258] In some embodiments, any one of the combinations in Table 4 may be represented, for example, in the molecular configuration shown in Figure 5B. In such a configuration, the molecule comprises two autoantigen domains, where the C-terminus of a first autoantigen domain (A) is linked to the N-terminus of a first Fc domain (Fc1) via an optional linker (L) (first polypeptide), and the C-terminus of a second autoantigen domain (A) is linked to the N-terminus of a second Fc domain (Fc2) via an optional linker (L) (second polypeptide). In some embodiments, the two autoantigen domains are the same (e.g., in the homodimer molecule of this disclosure). In some embodiments, the two autoantigen domains are different (e.g., in the heterodimer molecule of this disclosure).

[0259] Here, Figures 2–5 label the antigen (e.g., any antigen described herein) as "A" or "A'", and this disclosure also includes any domain in the molecules described herein that targets autoantibodies against this component.

[0260] Furthermore, or alternatively, in some embodiments, the molecule may include a first antigen-binding domain and a second antigen-binding domain so that each antigen-binding domain can bind to the same or different target antigens. In some embodiments, the first and / or second polypeptide of the molecule includes an antigen-binding domain. In some embodiments, the first polypeptide of the molecule includes an antigen-binding domain. In some embodiments, the second polypeptide of the molecule includes an antigen-binding domain. In some embodiments, both the first and second polypeptides of the molecule include antigen-binding domains. In some embodiments, the first antigen-binding domain targets an anti-TSHR autoantibody, and the second antigen-binding domain targets an internally distributed receptor (e.g., ASPGR). [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5]

[0261] In some embodiments, the molecule comprises an amino acid sequence containing one of the sequence combinations shown in Table 4. In some embodiments, the molecule comprises an amino acid sequence containing one of the sequence combinations shown in Table 4, and includes a linker (L) between the autoantigen domain and the Fc domain (for example, as shown in one of the configurations in Figures 2-5).

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

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

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

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

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

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

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

[0269] In some embodiments, the molecule comprises a first and a second polypeptide, (i) the first polypeptide comprises an amino acid sequence including SEQ ID NO: 1 and SEQ ID NO: 115, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 116; or (ii) the first polypeptide comprises an amino acid sequence including SEQ ID NO: 1 and SEQ ID NO: 116, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 115. In some embodiments, the molecule comprises a first and a second polypeptide, (i) the first polypeptide comprises an amino acid sequence including SEQ ID NO: 2 and SEQ ID NO: 115, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 116; or (ii) the first polypeptide comprises an amino acid sequence including SEQ ID NO: 2 and SEQ ID NO: 116, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 115. In some embodiments, the molecule comprises a first and a second polypeptide, (i) the first polypeptide comprises an amino acid sequence including SEQ ID NO: 3 and SEQ ID NO: 115, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 116; or (ii) the first polypeptide comprises an amino acid sequence including SEQ ID NO: 3 and SEQ ID NO: 116, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 115. In some embodiments, the molecule comprises a first and a second polypeptide, (i) the first polypeptide comprises an amino acid sequence including SEQ ID NO: 4 and SEQ ID NO: 115, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 116; or (ii) the first polypeptide comprises an amino acid sequence including SEQ ID NO: 4 and SEQ ID NO: 116, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 115. In some embodiments, the molecule comprises a first and a second polypeptide, (i) the first polypeptide comprising the amino acid sequence comprising SEQ ID NO: 5 and SEQ ID NO: 115, and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 116; or (ii) the first polypeptide comprising the amino acid sequence comprising SEQ ID NO: 5 and SEQ ID NO: 116, and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 115.In some embodiments, the molecule comprises a first and a second polypeptide, (i) the first polypeptide comprises an amino acid sequence including SEQ ID NO: 6 and SEQ ID NO: 115, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 116; or (ii) the first polypeptide comprises an amino acid sequence including SEQ ID NO: 6 and SEQ ID NO: 116, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 115. In some embodiments, the molecule comprises a first and a second polypeptide, (i) the first polypeptide comprises an amino acid sequence including SEQ ID NO: 7 and SEQ ID NO: 115, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 116; or (ii) the first polypeptide comprises an amino acid sequence including SEQ ID NO: 7 and SEQ ID NO: 116, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 115. In some embodiments, the molecule comprises a first and a second polypeptide, (i) the first polypeptide comprises an amino acid sequence including SEQ ID NO: 8 and SEQ ID NO: 115, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 116; or (ii) the first polypeptide comprises an amino acid sequence including SEQ ID NO: 8 and SEQ ID NO: 116, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 115. In some embodiments, the molecule comprises a first and a second polypeptide, (i) the first polypeptide comprises an amino acid sequence including SEQ ID NO: 307 and SEQ ID NO: 115, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 116; or (ii) the first polypeptide comprises an amino acid sequence including SEQ ID NO: 307 and SEQ ID NO: 116, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 115. In some embodiments, the molecule comprises a first and a second polypeptide, (i) the first polypeptide comprising the amino acid sequence comprising SEQ ID NO: 308 and SEQ ID NO: 115, and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 116; or (ii) the first polypeptide comprising the amino acid sequence comprising SEQ ID NO: 308 and SEQ ID NO: 116, and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 115.In some embodiments, the molecule comprises a first and a second polypeptide, (i) the first polypeptide comprises an amino acid sequence including SEQ ID NO: 309 and SEQ ID NO: 115, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 116; or (ii) the first polypeptide comprises an amino acid sequence including SEQ ID NO: 309 and SEQ ID NO: 116, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 115. In some embodiments, the molecule comprises a first and a second polypeptide, (i) the first polypeptide comprises an amino acid sequence including SEQ ID NO: 310 and SEQ ID NO: 115, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 116; or (ii) the first polypeptide comprises an amino acid sequence including SEQ ID NO: 310 and SEQ ID NO: 116, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 115. In some embodiments, the molecule comprises a first and a second polypeptide, (i) the first polypeptide comprises an amino acid sequence including SEQ ID NO: 311 and SEQ ID NO: 115, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 116; or (ii) the first polypeptide comprises an amino acid sequence including SEQ ID NO: 311 and SEQ ID NO: 116, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 115. In some embodiments, the molecule comprises a first and a second polypeptide, (i) the first polypeptide comprises an amino acid sequence including SEQ ID NO: 312 and SEQ ID NO: 115, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 116; or (ii) the first polypeptide comprises an amino acid sequence including SEQ ID NO: 312 and SEQ ID NO: 116, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 115. In some embodiments, the molecule comprises a first and a second polypeptide, (i) the first polypeptide comprising the amino acid sequence comprising SEQ ID NO: 313 and SEQ ID NO: 115, and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 116; or (ii) the first polypeptide comprising the amino acid sequence comprising SEQ ID NO: 313 and SEQ ID NO: 116, and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 115.In some embodiments, the molecule comprises a first and a second polypeptide, (i) the first polypeptide comprises an amino acid sequence comprising SEQ ID NOs. 314 and SEQ ID NOs. 115, and the second polypeptide comprises the amino acid sequence of SEQ ID NOs. 116; or (ii) the first polypeptide comprises an amino acid sequence comprising SEQ ID NOs. 314 and SEQ ID NOs. 116, and the second polypeptide comprises the amino acid sequence of SEQ ID NOs. 115. In some embodiments, the molecule comprises a first and a second polypeptide, (i) the first polypeptide comprises an amino acid sequence including SEQ ID NO: 316 and SEQ ID NO: 115, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 116; or (ii) the first polypeptide comprises an amino acid sequence including SEQ ID NO: 316 and SEQ ID NO: 116, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 115. In some embodiments, the molecule comprises a first and a second polypeptide, (i) the first polypeptide comprises an amino acid sequence including SEQ ID NO: 317 and SEQ ID NO: 115, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 116; or (ii) the first polypeptide comprises an amino acid sequence including SEQ ID NO: 317 and SEQ ID NO: 116, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 115.

[0270] In some embodiments, the molecule comprises a first and a second polypeptide, (i) the first polypeptide comprises an amino acid sequence including SEQ ID NO: 1 and SEQ ID NO: 117, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 118; or (ii) the first polypeptide comprises an amino acid sequence including SEQ ID NO: 1 and SEQ ID NO: 118, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 117. In some embodiments, the molecule comprises a first and a second polypeptide, (i) the first polypeptide comprises an amino acid sequence including SEQ ID NO: 2 and SEQ ID NO: 117, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 118; or (ii) the first polypeptide comprises an amino acid sequence including SEQ ID NO: 2 and SEQ ID NO: 118, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 117. In some embodiments, the molecule comprises a first and a second polypeptide, (i) the first polypeptide comprises an amino acid sequence including SEQ ID NO: 3 and SEQ ID NO: 117, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 118; or (ii) the first polypeptide comprises an amino acid sequence including SEQ ID NO: 3 and SEQ ID NO: 118, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 117. In some embodiments, the molecule comprises a first and a second polypeptide, (i) the first polypeptide comprises an amino acid sequence including SEQ ID NO: 4 and SEQ ID NO: 117, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 118; or (ii) the first polypeptide comprises an amino acid sequence including SEQ ID NO: 4 and SEQ ID NO: 118, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 117. In some embodiments, the molecule comprises a first and a second polypeptide, (i) the first polypeptide comprising the amino acid sequence comprising SEQ ID NO: 5 and SEQ ID NO: 117, and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 118; or (ii) the first polypeptide comprising the amino acid sequence comprising SEQ ID NO: 5 and SEQ ID NO: 118, and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 117.In some embodiments, the molecule comprises a first and a second polypeptide, (i) the first polypeptide comprises an amino acid sequence including SEQ ID NO: 6 and SEQ ID NO: 117, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 118; or (ii) the first polypeptide comprises an amino acid sequence including SEQ ID NO: 6 and SEQ ID NO: 118, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 117. In some embodiments, the molecule comprises a first and a second polypeptide, (i) the first polypeptide comprises an amino acid sequence including SEQ ID NO: 7 and SEQ ID NO: 117, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 118; or (ii) the first polypeptide comprises an amino acid sequence including SEQ ID NO: 7 and SEQ ID NO: 118, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 117. In some embodiments, the molecule comprises a first and a second polypeptide, (i) the first polypeptide comprises an amino acid sequence includin...

Claims

1. A first polypeptide comprising a first Fc domain and an autoantibody-binding domain that binds to an anti-TSHR autoantibody; and Second polypeptide containing a second Fc domain A molecule containing, The molecule wherein 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 according to claim 1, wherein the second polypeptide further comprises an autoantibody-binding domain that binds to an anti-TSHR autoantibody, and the molecule is a homodimer.

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

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

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

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

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

8. The molecule according to any one of claims 1 to 7, wherein the first and second Fc domains form a heterodimer as a result of a knob-in-hole (KIH) mutation.

9. The molecule according to claim 8, wherein the KIH mutations include Y349T and T394F according to the EU numbering scheme.

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

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

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

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

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

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

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

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

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

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

20. The molecule according to any one of claims 1 to 19, wherein the first and / or second Fc domain comprises one or more mutant amino acid residues that modify binding to an internally localized receptor on a cell, and the internally localized receptor can deliver its cargo to the lysosome of the cell and allow it to be degraded.

21. The molecule according to claim 20, wherein the modification of binding to the internally localized receptor includes an increase in binding to the internally localized receptor.

22. The molecule according to claim 20 or 21, wherein the molecule, bound to an autoantibody via the autoantibody-binding domain, binds to the internal localization receptor on the cell, the internal localization receptor causes the molecule to move internally, and the autoantibody is transported to the cell's lysosome for degradation.

23. The molecule according to any one of claims 20 to 22, wherein the internally distributed receptor comprises one of FcγRIIB, FcRn, ASGPR, CD38, or BCMA.

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

25. The molecule according to claim 24, wherein the first and / or second Fc domains containing one or more mutant amino acid residues do not have increased binding affinity to FcγRI, FcγRIIA167H, FcγRIIA167R, FcγRIIA176F, FcγRIIA176V, FcγRIIB, and / or FcRn compared to the corresponding wild-type Fc domain.

26. The molecule according to claim 24 or 25, wherein the first and / or second Fc domains containing one or more mutant amino acid residues have reduced binding affinity to FcγRI, FcγRIIA167H, FcγRIIA167R, FcγRIIA176F, FcγRIIA176V, FcγRIIB, and / or FcRn compared to the corresponding wild-type Fc domain.

27. The molecule according to any one of claims 24 to 26, wherein the first and / or second Fc domains comprising one or more mutant amino acid residues have substantially no binding affinity to FcγRI, FcγRIIA167H, FcγRIIA167R, FcγRIIIIIA176F, FcγRIIIIIA176V, FcγRIIIIB, and / or FcRn compared to the corresponding wild-type Fc domain.

28. The molecule according to any one of claims 24 to 27, wherein when the two molecules bind to an anti-TSHR autoantibody, an immune complex is formed that has improved binding dynamics with FcγRIIB compared to an immune complex comprising the anti-TSHR autoantibody and two corresponding molecules having wild-type Fc domains.

29. The molecule according to any one of claims 24 to 28, wherein when two molecules bind to an anti-TSHR autoantibody, an immune complex is formed that has improved binding dynamics with FcγRIIB compared to an immune complex containing the anti-TSHR autoantibody bound to only one molecule.

30. The molecule according to any one of claims 24 to 29, wherein when the two molecules bind to an anti-TSHR autoantibody, an immune complex is formed that has improved binding dynamics with FcγRIIB compared to the anti-TSHR autoantibody alone.

31. The molecule according to any one of claims 28 to 30, wherein the improved binding dynamics include an increase in the association rate, a decrease in the dissociation rate, and / or a change in the equilibrium dissociation constant.

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

33. The molecule according to any one of claims 28 to 32, wherein the improved binding kinetics include at least a 10% higher binding affinity of the immune complex to FcγRIIB.

34. The molecule according to claim 33, wherein the binding affinity that is at least 10% higher includes 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 more.

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

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

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

41. The molecule according to claim 40, wherein the molecule has substantially no binding affinity to cells that do not express FcγRIIB.

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

43. The molecule according to 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 according to any one of claims 24 to 43, wherein the molecule does not activate immune cells (for example, does not activate immune cells for secreting inflammatory cytokines, such as IL-6).

45. The molecule is the molecule according to any one of claims 24 to 44, which inhibits B cells by crosslinking FcγRIIB with the B cell receptor.

46. The molecule according to claim 45, wherein the molecule crosslinks FcγRIIB with the B cell receptor.

47. The molecule according to claim 45, wherein one or two molecules of an immune complex with an anti-TSHR autoantibody crosslinks FcγRIIB with the B cell receptor.

48. The one or more mutant amino acid residues that increase binding to FcγRIIB are, according to the EU numbering scheme, the following amino acid mutations: E233V, L234D, L235F, G236R, G237D, S239L, S267D, H268P, S298G, T299A, A327L, L328A, A330H, E333I, R292Q, E233P, P238D, A molecule according to any one of claims 24 to 47, comprising one or more of H268D, P271G, A330R, L234Y, T250V, V264I, T307P, Q311R, A330K, P343R, M428L, N434A, Y436T, Q438R, S440E, G236N, S267E, L235R, D270E, E233D, and G237D.

49. The one or more mutant amino acid residues that increase binding to FcγRIIB are, according to the EU numbering scheme, the following set 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; (viiii) G236N and S267E; (ix) P238D and D270E; (x) P238D and P271G; (xi) P238D, D270E, and P271G; (xi) G237D, P238D, P271G, and A330R; (xiiii) G237D, P238D, D270E, P271G, and A330R (xiv) E233D, G237D, P238D, H268D, P271G, and A330R; and (xv) P238D The molecule according to claim 48, comprising one or more of the following.

50. The molecule according to any one of claims 24 to 49, comprising one or more mutant amino acid residues, in accordance with the EU numbering scheme, the mutant amino acid residue P238D.

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

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

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

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

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

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

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

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

59. The molecule according to claim 57 or 58, wherein the first and second Fc domains contain a human IgG1 isotype and remain bound to FcRn even when entering an environment having an acidic pH and / or a low calcium concentration (e.g., cellular endosomes).

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

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

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

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

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

65. The molecule according to any one of claims 1 to 64, wherein the first Fc domain comprises a sequence selected from SEQ ID NOs: 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 (for example, a sequence selected from SEQ ID NOs: 107, 109, 113, 115, 119, 131, 139, 140, 142, 148, 374, or 378).

66. The molecule according to any one of claims 1 to 65, wherein the second Fc domain comprises a sequence selected from SEQ ID NOs: 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 (for example, a sequence selected from SEQ ID NOs: 108, 110, 114, 116, 120, 132, 139, 140, 142, 148, 374, or 379).

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

68. The molecule according to claim 67, wherein the linker comprises the amino acid sequence of SEQ ID NO: 150 (GGGGGS), SEQ ID NO: 151 (GGGGGSGGGGGS), SEQ ID NO: 152 (GGGGGSGGGGGGGGGGGS), SEQ ID NO: 153 (VDGGGGGSGGGGGGGGGGGGGS), SEQ ID NO: 154 (GGGGGSGGGGGGGGGGGSGGGGGS), SEQ ID NO: 155 (GGGGGSGGGGGGGGGGGGGGGGGSGGGGGS), SEQ ID NO: 156 (GSGGGS), SEQ ID NO: 157 (GGSG), SEQ ID NO: 158 (GGSG), SEQ ID NO: 159 (GSSGSG), SEQ ID NO: 160 (GSGGGG), SEQ ID NO: 161 (GGGGSG), or SEQ ID NO: 162 (GSSSSG).

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

70. The molecule according to claim 69, wherein the autoantigen comprises a TSHR autoantigen domain, or a fragment or variant thereof.

71. The molecule according to claim 70, wherein 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.

72. The molecule according to claim 71, wherein the TSHR autoantigen domain comprises the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO:

5.

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

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

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

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

77. The molecule according to any one of claims 1 to 71, wherein the autoantibody-binding domain comprises a TSHR autoantigen domain variant containing any one sequence of SEQ ID NOs: 1 to 8.

78. The molecule according to any one of claims 1 to 71, wherein the autoantibody-binding domain comprises a TSHR autoantigen domain variant containing any one sequence of sequence numbers 307 to 317.

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

80. The first polypeptide is, 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 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; the amino acid sequence of SEQ ID NO: 309 and the amino acid sequence of SEQ ID NO: 103; the amino acid sequence of SEQ ID NO: 310 and the amino acid sequence of SEQ ID NO: 103; the amino acid sequence of SEQ ID NO: 311 and the amino acid sequence of SEQ ID NO: 103; the amino acid sequence of SEQ ID NO: 312 and the amino acid sequence of SEQ ID NO: 103; the amino acid sequence of SEQ ID NO: 313 and the amino acid sequence of SEQ ID NO: 103; the amino acid sequence of SEQ ID NO: 314 and the amino acid sequence of SEQ ID NO: 103; the amino acid sequence of SEQ ID NO: 315 and The amino acid sequence of SEQ ID NO: 103; the amino acid sequence of SEQ ID NO: 316 and the amino acid sequence of SEQ ID NO: 103; the amino acid sequence of SEQ ID NO: 317 and the amino acid sequence of SEQ ID NO: 103; the amino acid sequence of SEQ ID NO: 1 and the amino acid sequence of SEQ ID NO: 105; the amino acid sequence of SEQ ID NO: 2 and the amino acid sequence of SEQ ID NO: 105; the amino acid sequence of SEQ ID NO: 3 and the amino acid sequence of SEQ ID NO: 105; the amino acid sequence of SEQ ID NO: 4 and the amino acid sequence of SEQ ID NO: 105; the amino acid sequence of SEQ ID NO: 5 and the amino acid sequence of SEQ ID NO: 105; the amino acid sequence of SEQ ID NO: 6 and the amino acid sequence of SEQ ID NO: 105 Amino acid sequence; amino acid sequence of SEQ ID NO: 7 and amino acid sequence of SEQ ID NO: 105; amino acid sequence of SEQ ID NO: 8 and amino acid sequence of SEQ ID NO: 105; amino acid sequence of SEQ ID NO: 307 and amino acid sequence of SEQ ID NO: 105; amino acid sequence of SEQ ID NO: 308 and amino acid sequence of SEQ ID NO: 105; amino acid sequence of SEQ ID NO: 309 and amino acid sequence of SEQ ID NO: 105; amino acid sequence of SEQ ID NO: 310 and amino acid sequence of SEQ ID NO: 105; amino acid sequence of SEQ ID NO: 311 and amino acid sequence of SEQ ID NO: 105; amino acid sequence of SEQ ID NO: 312 and amino acid sequence of SEQ ID NO: 105;The amino acid sequence of SEQ ID NO: 313 and SEQ ID NO: 105; the amino acid sequence of SEQ ID NO: 314 and SEQ ID NO: 105; the amino acid sequence of SEQ ID NO: 315 and SEQ ID NO: 105; the amino acid sequence of SEQ ID NO: 316 and SEQ ID NO: 105; the amino acid sequence of SEQ ID NO: 317 and SEQ ID NO: 105; the amino acid sequence of SEQ ID NO: 4, SEQ ID NO: 209, SEQ ID NO: 210, and SEQ ID NO: 105; the amino acid sequence of SEQ ID NO: 1 and SEQ ID NO: 107; sequence number The amino acid sequence of No. 2 and the amino acid sequence of SEQ ID NO. 107; the amino acid sequence of SEQ ID NO. 3 and the amino acid sequence of SEQ ID NO. 107; the amino acid sequence of SEQ ID NO. 4 and the amino acid sequence of SEQ ID NO. 107; the amino acid sequence of SEQ ID NO. 5 and the amino acid sequence of SEQ ID NO. 107; the amino acid sequence of SEQ ID NO. 6 and the amino acid sequence of SEQ ID NO. 107; the amino acid sequence of SEQ ID NO. 7 and the amino acid sequence of SEQ ID NO. 107; the amino acid sequence of SEQ ID NO. 8 and the amino acid sequence of SEQ ID NO. 107; the amino acid sequence of SEQ ID NO. 307 and the amino acid sequence of SEQ ID NO. 107; the amino acid sequence of SEQ ID NO. 308 and The amino acid sequence of sequence number 107; the amino acid sequence of sequence number 309 and the amino acid sequence of sequence number 107; the amino acid sequence of sequence number 310 and the amino acid sequence of sequence number 107; the amino acid sequence of sequence number 311 and the amino acid sequence of sequence number 107; the amino acid sequence of sequence number 312 and the amino acid sequence of sequence number 107; the amino acid sequence of sequence number 313 and the amino acid sequence of sequence number 107; the amino acid sequence of sequence number 314 and the amino acid sequence of sequence number 107; the amino acid sequence of sequence number 315 and the amino acid sequence of sequence number 107; the amino acid sequence of sequence number 316 and The amino acid sequence of sequence number 107; the amino acid sequence of sequence number 317 and the amino acid sequence of sequence number 107; the amino acid sequence of sequence number 1 and the amino acid sequence of sequence number 109; the amino acid sequence of sequence number 2 and the amino acid sequence of sequence number 109; the amino acid sequence of sequence number 3 and the amino acid sequence of sequence number 109; the amino acid sequence of sequence number 4 and the amino acid sequence of sequence number 109; the amino acid sequence of sequence number 5 and the amino acid sequence of sequence number 109; the amino acid sequence of sequence number 6 and the amino acid sequence of sequence number 109; the amino acid sequence of sequence number 7 and the amino acid sequence of sequence number 109;The amino acid sequence of SEQ ID NO: 8 and SEQ ID NO: 109; the amino acid sequence of SEQ ID NO: 307 and SEQ ID NO: 109; the amino acid sequence of SEQ ID NO: 308 and SEQ ID NO: 109; the amino acid sequence of SEQ ID NO: 309 and SEQ ID NO: 109; the amino acid sequence of SEQ ID NO: 310 and SEQ ID NO: 109; the amino acid sequence of SEQ ID NO: 311 and SEQ ID NO: 109; the amino acid sequence of SEQ ID NO: 312 and SEQ ID NO: 109; the amino acid sequence of SEQ ID NO: 313 and SEQ ID NO: 109; SEQ ID NO: The amino acid sequence of 314 and the amino acid sequence of SEQ ID NO: 109; the amino acid sequence of SEQ ID NO: 315 and the amino acid sequence of SEQ ID NO: 109; the amino acid sequence of SEQ ID NO: 316 and the amino acid sequence of SEQ ID NO: 109; the amino acid sequence of SEQ ID NO: 317 and the amino acid sequence of SEQ ID NO: 109; the amino acid sequence of SEQ ID NO: 1 and the amino acid sequence of SEQ ID NO: 113; the amino acid sequence of SEQ ID NO: 2 and the amino acid sequence of SEQ ID NO: 113; the amino acid sequence of SEQ ID NO: 3 and the amino acid sequence of SEQ ID NO: 113; the amino acid sequence of SEQ ID NO: 4 and the amino acid sequence of SEQ ID NO: 5 and The amino acid sequence of SEQ ID NO: 113; the amino acid sequence of SEQ ID NO: 6 and the amino acid sequence of SEQ ID NO: 113; the amino acid sequence of SEQ ID NO: 7 and the amino acid sequence of SEQ ID NO: 113; the amino acid sequence of SEQ ID NO: 8 and the amino acid sequence of SEQ ID NO: 113; the amino acid sequence of SEQ ID NO: 307 and the amino acid sequence of SEQ ID NO: 113; the amino acid sequence of SEQ ID NO: 308 and the amino acid sequence of SEQ ID NO: 113; the amino acid sequence of SEQ ID NO: 309 and the amino acid sequence of SEQ ID NO: 113; the amino acid sequence of SEQ ID NO: 310 and the amino acid sequence of SEQ ID NO: 113; the amino acid sequence of SEQ ID NO: 311 and the amino acid sequence of SEQ ID NO: 113 Amino acid sequences; Amino acid sequences of SEQ ID NO: 312 and 113; Amino acid sequences of SEQ ID NO: 313 and 113; Amino acid sequences of SEQ ID NO: 314 and 113; Amino acid sequences of SEQ ID NO: 315 and 113; Amino acid sequences of SEQ ID NO: 316 and 113; Amino acid sequences of SEQ ID NO: 317 and 113; Amino acid sequences of SEQ ID NO: 1 and 115; Amino acid sequences of SEQ ID NO: 2 and 115;The amino acid sequences of SEQ ID NO: 3 and 115; the amino acid sequences of SEQ ID NO: 4 and 115; the amino acid sequences of SEQ ID NO: 5 and 115; the amino acid sequences of SEQ ID NO: 6 and 115; the amino acid sequences of SEQ ID NO: 7 and 115; the amino acid sequences of SEQ ID NO: 8 and 115; the amino acid sequences of SEQ ID NO: 307 and 115; the amino acid sequences of SEQ ID NO: 308 and 115; the amino acid sequences of SEQ ID NO: 309 The amino acid sequence of sequence number 115; the amino acid sequence of sequence number 310 and the amino acid sequence of sequence number 115; the amino acid sequence of sequence number 311 and the amino acid sequence of sequence number 115; the amino acid sequence of sequence number 312 and the amino acid sequence of sequence number 115; the amino acid sequence of sequence number 313 and the amino acid sequence of sequence number 115; the amino acid sequence of sequence number 314 and the amino acid sequence of sequence number 115; the amino acid sequence of sequence number 315 and the amino acid sequence of sequence number 115; the amino acid sequence of sequence number 316 and the amino acid sequence of sequence number 115; the amino acid sequence of sequence number 317 The amino acid sequences of sequence number 115; the amino acid sequences of sequence number 1 and sequence number 117; the amino acid sequences of sequence number 2 and sequence number 117; the amino acid sequences of sequence number 3 and sequence number 117; the amino acid sequences of sequence number 4 and sequence number 117; the amino acid sequences of sequence number 5 and sequence number 117; the amino acid sequences of sequence number 6 and sequence number 117; the amino acid sequences of sequence number 7 and sequence number 117; the amino acid sequences of sequence number 8 and sequence number 117 ; Amino acid sequence of SEQ ID NO: 307 and amino acid sequence of SEQ ID NO: 117; Amino acid sequence of SEQ ID NO: 308 and amino acid sequence of SEQ ID NO: 117; Amino acid sequence of SEQ ID NO: 309 and amino acid sequence of SEQ ID NO: 117; Amino acid sequence of SEQ ID NO: 310 and amino acid sequence of SEQ ID NO: 117; Amino acid sequence of SEQ ID NO: 311 and amino acid sequence of SEQ ID NO: 117; Amino acid sequence of SEQ ID NO: 312 and amino acid sequence of SEQ ID NO: 117; Amino acid sequence of SEQ ID NO: 313 and amino acid sequence of SEQ ID NO: 117; Amino acid sequence of SEQ ID NO: 314 and amino acid sequence of SEQ ID NO: 117;The amino acid sequences of SEQ ID NO: 315 and 117; the amino acid sequences of SEQ ID NO: 316 and 117; the amino acid sequences of SEQ ID NO: 317 and 117; the amino acid sequences of SEQ ID NO: 1 and 119; the amino acid sequences of SEQ ID NO: 2 and 119; the amino acid sequences of SEQ ID NO: 3 and 119; the amino acid sequences of SEQ ID NO: 4 and 119; the amino acid sequences of SEQ ID NO: 5 and 119; the amino acid sequences of SEQ ID NO: 6 The amino acid sequence and amino acid sequence of SEQ ID NO: 119; the amino acid sequence of SEQ ID NO: 7 and the amino acid sequence of SEQ ID NO: 119; the amino acid sequence of SEQ ID NO: 8 and the amino acid sequence of SEQ ID NO: 119; the amino acid sequence of SEQ ID NO: 307 and the amino acid sequence of SEQ ID NO: 119; the amino acid sequence of SEQ ID NO: 308 and the amino acid sequence of SEQ ID NO: 119; the amino acid sequence of SEQ ID NO: 309 and the amino acid sequence of SEQ ID NO: 119; the amino acid sequence of SEQ ID NO: 310 and the amino acid sequence of SEQ ID NO: 119; the amino acid sequence of SEQ ID NO: 311 and the amino acid sequence of SEQ ID NO: 119; the amino acid sequence of SEQ ID NO: 312 and The amino acid sequences of SEQ ID NO: 119; SEQ ID NO: 313 and SEQ ID NO: 119; SEQ ID NO: 314 and SEQ ID NO: 119; SEQ ID NO: 315 and SEQ ID NO: 119; SEQ ID NO: 316 and SEQ ID NO: 119; SEQ ID NO: 317 and SEQ ID NO: 119; SEQ ID NO: 1 and SEQ ID NO: 121; SEQ ID NO: 2 and SEQ ID NO: 121; SEQ ID NO: 3 and SEQ ID NO: 1 21 amino acid sequences; amino acid sequences of SEQ ID NO: 4 and 121; amino acid sequences of SEQ ID NO: 5 and 121; amino acid sequences of SEQ ID NO: 6 and 121; amino acid sequences of SEQ ID NO: 7 and 121; amino acid sequences of SEQ ID NO: 8 and 121; amino acid sequences of SEQ ID NO: 307 and 121; amino acid sequences of SEQ ID NO: 308 and 121; amino acid sequences of SEQ ID NO: 309 and 121;The amino acid sequence of SEQ ID NO: 310 and the amino acid sequence of SEQ ID NO: 121; the amino acid sequence of SEQ ID NO: 311 and the amino acid sequence of SEQ ID NO: 121; the amino acid sequence of SEQ ID NO: 312 and the amino acid sequence of SEQ ID NO: 121; the amino acid sequence of SEQ ID NO: 313 and the amino acid sequence of SEQ ID NO: 121; the amino acid sequence of SEQ ID NO: 314 and the amino acid sequence of SEQ ID NO: 121; Amino acid sequence; amino acid sequence of SEQ ID NO: 315 and amino acid sequence of SEQ ID NO: 121; amino acid sequence of SEQ ID NO: 316 and amino acid sequence of SEQ ID NO: 121; amino acid sequence of SEQ ID NO: 317 and amino acid sequence of SEQ ID NO: 121; amino acid sequence of SEQ ID NO: 1 and amino acid sequence of SEQ ID NO: 123; amino acid sequence of SEQ ID NO: 2 and amino acid sequence of SEQ ID NO: 123; amino acid sequence of SEQ ID NO: 3 and amino acid sequence of SEQ ID NO: 123; amino acid sequence of SEQ ID NO: 4 and amino acid sequence of SEQ ID NO: 123; amino acid sequence of SEQ ID NO: 5 and amino acid sequence of SEQ ID NO: 123; amino acid sequence of SEQ ID NO: 6 Amino acid sequence and amino acid sequence of SEQ ID NO: 123; Amino acid sequence of SEQ ID NO: 7 and amino acid sequence of SEQ ID NO: 123; Amino acid sequence of SEQ ID NO: 8 and amino acid sequence of SEQ ID NO: 123; Amino acid sequence of SEQ ID NO: 307 and amino acid sequence of SEQ ID NO: 123; Amino acid sequence of SEQ ID NO: 308 and amino acid sequence of SEQ ID NO: 123; Amino acid sequence of SEQ ID NO: 309 and amino acid sequence of SEQ ID NO: 123; Amino acid sequence of SEQ ID NO: 310 and amino acid sequence of SEQ ID NO: 123; Amino acid sequence of SEQ ID NO: 311 and amino acid sequence of SEQ ID NO: 123; Amino acid sequence of SEQ ID NO: 312 The amino acid sequences of sequence and sequence number 123; the amino acid sequence of sequence number 313 and sequence number 123; the amino acid sequence of sequence number 314 and sequence number 123; the amino acid sequence of sequence number 315 and sequence number 123; the amino acid sequence of sequence number 316 and sequence number 123; the amino acid sequence of sequence number 317 and sequence number 123; the amino acid sequence of sequence number 1 and sequence number 125; the amino acid sequence of sequence number 2 and sequence number 125; the amino acid sequence of sequence number 3 and sequence number The amino acid sequence of 125; the amino acid sequence of SEQ ID NO: 4 and SEQ ID NO: 125; the amino acid sequence of SEQ ID NO: 5 and SEQ ID NO: 125; the amino acid sequence of SEQ ID NO: 6 and SEQ ID NO: 125; the amino acid sequence of SEQ ID NO: 7 and SEQ ID NO: 125; the amino acid sequence of SEQ ID NO: 8 and SEQ ID NO: 125; the amino acid sequence of SEQ ID NO: 307 and SEQ ID NO: 125; the amino acid sequence of SEQ ID NO: 308 and SEQ ID NO: 125; the amino acid sequence of SEQ ID NO: 309 and SEQ ID NO: 125;The amino acid sequences of SEQ ID NO: 310 and 125; the amino acid sequences of SEQ ID NO: 311 and 125; the amino acid sequences of SEQ ID NO: 312 and 125; the amino acid sequences of SEQ ID NO: 313 and 125; the amino acid sequences of SEQ ID NO: 314 and 125; the amino acid sequences of SEQ ID NO: 315 and 125; the amino acid sequences of SEQ ID NO: 316 and 125; the amino acid sequences of SEQ ID NO: 317 and 125; The amino acid sequence of SEQ ID NO: 1 and SEQ ID NO: 127; the amino acid sequence of SEQ ID NO: 2 and SEQ ID NO: 127; the amino acid sequence of SEQ ID NO: 3 and SEQ ID NO: 127; the amino acid sequence of SEQ ID NO: 4 and SEQ ID NO: 127; the amino acid sequence of SEQ ID NO: 5 and SEQ ID NO: 127; the amino acid sequence of SEQ ID NO: 6 and SEQ ID NO: 127; the amino acid sequence of SEQ ID NO: 7 and SEQ ID NO: 127; the amino acid sequence of SEQ ID NO: 8 and SEQ ID NO: 127; the amino acid sequence of SEQ ID NO: 307 and The amino acid sequence of sequence number 127; the amino acid sequence of sequence number 308 and the amino acid sequence of sequence number 127; the amino acid sequence of sequence number 309 and the amino acid sequence of sequence number 127; the amino acid sequence of sequence number 310 and the amino acid sequence of sequence number 127; the amino acid sequence of sequence number 311 and the amino acid sequence of sequence number 127; the amino acid sequence of sequence number 312 and the amino acid sequence of sequence number 127; the amino acid sequence of sequence number 313 and the amino acid sequence of sequence number 127; the amino acid sequence of sequence number 314 and the amino acid sequence of sequence number 127; the amino acid sequence of sequence number 315 and sequence The amino acid sequence for sequence number 127; the amino acid sequence for sequence number 316 and sequence number 127; the amino acid sequence for sequence number 317 and sequence number 127; the amino acid sequence for sequence number 1 and sequence number 129; the amino acid sequence for sequence number 2 and sequence number 129; the amino acid sequence for sequence number 3 and sequence number 129; the amino acid sequence for sequence number 4 and sequence number 129; the amino acid sequence for sequence number 5 and sequence number 129; the amino acid sequence for sequence number 6 and sequence number 129;The amino acid sequences of SEQ ID NO: 7 and 129; the amino acid sequences of SEQ ID NO: 8 and 129; the amino acid sequences of SEQ ID NO: 307 and 129; the amino acid sequences of SEQ ID NO: 308 and 129; the amino acid sequences of SEQ ID NO: 309 and 129; the amino acid sequences of SEQ ID NO: 310 and 129; the amino acid sequences of SEQ ID NO: 311 and 129; the amino acid sequences of SEQ ID NO: 312 and 129; SEQ ID NO: 31 The amino acid sequence of 3 and the amino acid sequence of SEQ ID NO: 129; the amino acid sequence of SEQ ID NO: 314 and the amino acid sequence of SEQ ID NO: 129; the amino acid sequence of SEQ ID NO: 315 and the amino acid sequence of SEQ ID NO: 129; the amino acid sequence of SEQ ID NO: 316 and the amino acid sequence of SEQ ID NO: 129; the amino acid sequence of SEQ ID NO: 317 and the amino acid sequence of SEQ ID NO: 129; the amino acid sequence of SEQ ID NO: 1 and the amino acid sequence of SEQ ID NO: 131; the amino acid sequence of SEQ ID NO: 2 and the amino acid sequence of SEQ ID NO: 131; the amino acid sequence of SEQ ID NO: 3 and the amino acid sequence of SEQ ID NO: 131; the amino acid sequence of SEQ ID NO: 4 and The amino acid sequence of SEQ ID NO: 131; the amino acid sequence of SEQ ID NO: 5 and the amino acid sequence of SEQ ID NO: 131; the amino acid sequence of SEQ ID NO: 6 and the amino acid sequence of SEQ ID NO: 131; the amino acid sequence of SEQ ID NO: 7 and the amino acid sequence of SEQ ID NO: 131; the amino acid sequence of SEQ ID NO: 8 and the amino acid sequence of SEQ ID NO: 131; the amino acid sequence of SEQ ID NO: 307 and the amino acid sequence of SEQ ID NO: 131; the amino acid sequence of SEQ ID NO: 308 and the amino acid sequence of SEQ ID NO: 131; the amino acid sequence of SEQ ID NO: 309 and the amino acid sequence of SEQ ID NO: 131; the amino acid sequence of SEQ ID NO: 310 and the amino acid sequence of SEQ ID NO: 131 No amino acid sequence; amino acid sequence of SEQ ID NO 311 and amino acid sequence of SEQ ID NO 131; amino acid sequence of SEQ ID NO 312 and amino acid sequence of SEQ ID NO 131; amino acid sequence of SEQ ID NO 313 and amino acid sequence of SEQ ID NO 131; amino acid sequence of SEQ ID NO 314 and amino acid sequence of SEQ ID NO 131; amino acid sequence of SEQ ID NO 315 and amino acid sequence of SEQ ID NO 131; amino acid sequence of SEQ ID NO 316 and amino acid sequence of SEQ ID NO 131; amino acid sequence of SEQ ID NO 317 and amino acid sequence of SEQ ID NO 131; amino acid sequence of SEQ ID NO 1 and amino acid sequence of SEQ ID NO 133;The amino acid sequences of SEQ ID NO: 2 and 133; the amino acid sequences of SEQ ID NO: 3 and 133; the amino acid sequences of SEQ ID NO: 4 and 133; the amino acid sequences of SEQ ID NO: 5 and 133; the amino acid sequences of SEQ ID NO: 6 and 133; the amino acid sequences of SEQ ID NO: 7 and 133; the amino acid sequences of SEQ ID NO: 8 and 133; the amino acid sequences of SEQ ID NO: 307 and 133; the amino acid sequences of SEQ ID NO: 308 and the amino acid sequence of SEQ ID NO: 133; the amino acid sequence of SEQ ID NO: 309 and the amino acid sequence of SEQ ID NO: 133; the amino acid sequence of SEQ ID NO: 310 and the amino acid sequence of SEQ ID NO: 133; the amino acid sequence of SEQ ID NO: 311 and the amino acid sequence of SEQ ID NO: 133; the amino acid sequence of SEQ ID NO: 312 and the amino acid sequence of SEQ ID NO: 133; the amino acid sequence of SEQ ID NO: 313 and the amino acid sequence of SEQ ID NO: 133; the amino acid sequence of SEQ ID NO: 314 and the amino acid sequence of SEQ ID NO: 133; the amino acid sequence of SEQ ID NO: 315 and the amino acid sequence of SEQ ID NO: 133; the amino acid sequence of SEQ ID NO: 316 and the amino acid sequence of SEQ ID NO: 133; the amino acid sequence of SEQ ID NO: 317 and the amino acid sequence of SEQ ID NO: 133; the amino acid sequence of SEQ ID NO: 1 and the amino acid sequence of SEQ ID NO: 135; the amino acid sequence of SEQ ID NO: 2 and the amino acid sequence of SEQ ID NO: 135; the amino acid sequence of SEQ ID NO: 3 and the amino acid sequence of SEQ ID NO: 135; the amino acid sequence of SEQ ID NO: 4 and the amino acid sequence of SEQ ID NO: 135; the amino acid sequence of SEQ ID NO: 5 and the amino acid sequence of SEQ ID NO: 135; the amino acid sequence of SEQ ID NO: 6 and the amino acid sequence of SEQ ID NO: 135; the amino acid sequence of SEQ ID NO: 7 and the amino acid sequence of SEQ ID NO: 135 Sequence; amino acid sequence of SEQ ID NO: 8 and amino acid sequence of SEQ ID NO: 135; amino acid sequence of SEQ ID NO: 307 and amino acid sequence of SEQ ID NO: 135; amino acid sequence of SEQ ID NO: 308 and amino acid sequence of SEQ ID NO: 135; amino acid sequence of SEQ ID NO: 309 and amino acid sequence of SEQ ID NO: 135; amino acid sequence of SEQ ID NO: 310 and amino acid sequence of SEQ ID NO: 135; amino acid sequence of SEQ ID NO: 311 and amino acid sequence of SEQ ID NO: 135; amino acid sequence of SEQ ID NO: 312 and amino acid sequence of SEQ ID NO: 135; amino acid sequence of SEQ ID NO: 313 and amino acid sequence of SEQ ID NO: 135;The amino acid sequence of SEQ ID NO: 314 and SEQ ID NO: 135; the amino acid sequence of SEQ ID NO: 315 and SEQ ID NO: 135; the amino acid sequence of SEQ ID NO: 316 and SEQ ID NO: 135; the amino acid sequence of SEQ ID NO: 317 and SEQ ID NO: 135; the amino acid sequence of SEQ ID NO: 1 and SEQ ID NO: 137; the amino acid sequence of SEQ ID NO: 2 and SEQ ID NO: 137; the amino acid sequence of SEQ ID NO: 3 and SEQ ID NO: 137; the amino acid sequence of SEQ ID NO: 4 and SEQ ID NO: 137; the amino acid sequence of SEQ ID NO: 5 The amino acid sequence of SEQ ID NO: 137; the amino acid sequence of SEQ ID NO: 6 and the amino acid sequence of SEQ ID NO: 137; the amino acid sequence of SEQ ID NO: 7 and the amino acid sequence of SEQ ID NO: 137; the amino acid sequence of SEQ ID NO: 8 and the amino acid sequence of SEQ ID NO: 137; the amino acid sequence of SEQ ID NO: 307 and the amino acid sequence of SEQ ID NO: 137; the amino acid sequence of SEQ ID NO: 308 and the amino acid sequence of SEQ ID NO: 137; the amino acid sequence of SEQ ID NO: 309 and the amino acid sequence of SEQ ID NO: 137; the amino acid sequence of SEQ ID NO: 310 and the amino acid sequence of SEQ ID NO: 137; the amino acid sequence of SEQ ID NO: 311 and The amino acid sequence of SEQ ID NO: 137; the amino acid sequence of SEQ ID NO: 312 and the amino acid sequence of SEQ ID NO: 137; the amino acid sequence of SEQ ID NO: 313 and the amino acid sequence of SEQ ID NO: 137; the amino acid sequence of SEQ ID NO: 314 and the amino acid sequence of SEQ ID NO: 137; the amino acid sequence of SEQ ID NO: 315 and the amino acid sequence of SEQ ID NO: 137; the amino acid sequence of SEQ ID NO: 316 and the amino acid sequence of SEQ ID NO: 137; the amino acid sequence of SEQ ID NO: 1 and the amino acid sequence of SEQ ID NO: 376; the amino acid sequence of SEQ ID NO: 2 and sequence number The amino acid sequence of sequence number 376; the amino acid sequence of sequence number 3 and sequence number 376; the amino acid sequence of sequence number 4 and sequence number 376; the amino acid sequence of sequence number 5 and sequence number 376; the amino acid sequence of sequence number 6 and sequence number 376; the amino acid sequence of sequence number 7 and sequence number 376; the amino acid sequence of sequence number 8 and sequence number 376; the amino acid sequence of sequence number 307 and sequence number 376; the amino acid sequence of sequence number 308 and sequence number 376;The amino acid sequence of SEQ ID NO: 309 and SEQ ID NO: 376; the amino acid sequence of SEQ ID NO: 310 and SEQ ID NO: 376; the amino acid sequence of SEQ ID NO: 311 and SEQ ID NO: 376; the amino acid sequence of SEQ ID NO: 312 and SEQ ID NO: 376; the amino acid sequence of SEQ ID NO: 313 and SEQ ID NO: 37; The amino acid sequence of 6; the amino acid sequence of SEQ ID NO: 314 and SEQ ID NO: 376; the amino acid sequence of SEQ ID NO: 315 and SEQ ID NO: 376; the amino acid sequence of SEQ ID NO: 316 and SEQ ID NO: 376; the amino acid sequence of SEQ ID NO: 317 and SEQ ID NO: 376; the amino acid sequence of SEQ ID NO: 1 and SEQ ID NO: 378; the amino acid sequence of SEQ ID NO: 2 and SEQ ID NO: 378; the amino acid sequence of SEQ ID NO: 3 and SEQ ID NO: 378; the amino acid sequence of SEQ ID NO: 4 and SEQ ID NO: 378; the amino acid sequence of SEQ ID NO: 5 and SEQ ID NO: 378; the amino acid sequence of SEQ ID NO: 6 and SEQ ID NO: 378; the amino acid sequence of SEQ ID NO: 7 and SEQ ID NO: 378; the amino acid sequence of SEQ ID NO: 8 and SEQ ID NO: 378 The molecule according to claim 79, comprising: sequences; the amino acid sequence of SEQ ID NO: 307 and the amino acid sequence of SEQ ID NO: 378; the amino acid sequence of SEQ ID NO: 308 and the amino acid sequence of SEQ ID NO: 378; the amino acid sequence of SEQ ID NO: 309 and the amino acid sequence of SEQ ID NO: 378; the amino acid sequence of SEQ ID NO: 310 and the amino acid sequence of SEQ ID NO: 378; the amino acid sequence of SEQ ID NO: 311 and the amino acid sequence of SEQ ID NO: 378; the amino acid sequence of SEQ ID NO: 312 and the amino acid sequence of SEQ ID NO: 378; the amino acid sequence of SEQ ID NO: 313 and the amino acid sequence of SEQ ID NO: 378; the amino acid sequence of SEQ ID NO: 314 and the amino acid sequence of SEQ ID NO: 378; the amino acid sequence of SEQ ID NO: 315 and the amino acid sequence of SEQ ID NO: 378; the amino acid sequence of SEQ ID NO: 316 and the amino acid sequence of SEQ ID NO: 378; or the amino acid sequence of SEQ ID NO: 317 and the amino acid sequence of SEQ ID NO:

378.

81. The second polypeptide described above is (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 sequence number 106; (iii) An amino acid sequence that is at least 90% identical to sequence number 108; (iv) An amino acid sequence that is at least 90% identical to sequence number 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 sequence number 114; (vii) An amino acid sequence that is at least 90% identical to sequence number 116; (viiii) An amino acid sequence that is at least 90% identical to sequence number 118; (ix) An amino acid sequence that is at least 90% identical to sequence number 120; (x) an amino acid sequence that is at least 90% identical to sequence number 122; (xi) an amino acid sequence that is at least 90% identical to sequence number 124; (xi) An amino acid sequence that is at least 90% identical to sequence number 126; (xiiii) An amino acid sequence that is at least 90% identical to sequence number 128; (xiv) An amino acid sequence that is at least 90% identical to sequence number 130; (xv) An amino acid sequence that is at least 90% identical to sequence number 132; (xvi) An amino acid sequence that is at least 90% identical to sequence number 134; (xvii) An amino acid sequence that is at least 90% identical to sequence number 136; (xviiii) An amino acid sequence that is at least 90% identical to sequence number 138; (xix) an amino acid sequence that is at least 90% identical to sequence number 377; or (xx) Amino acid sequence that is at least 90% identical to sequence number 379 A molecule according to any one of claims 1 to 80, comprising:

82. The second polypeptide described above is (i) Amino acid sequence of SEQ ID NO: 104; (ii) Amino acid sequence of SEQ ID NO: 106; (iii) Amino acid sequence of sequence number 108; (iv) Amino acid sequence of SEQ ID NO: 110; (v) Amino acid sequence of SEQ ID NO: 209, amino acid sequence of SEQ ID NO: 210, and amino acid sequence of SEQ ID NO: 106; (vi) Amino acid sequence of SEQ ID NO: 114; (vii) Amino acid sequence of SEQ ID NO: 116; (viiii) Amino acid sequence of sequence number 118; (ix) Amino acid sequence of SEQ ID NO: 120; (x) Amino acid sequence of SEQ ID NO: 122; (xi) Amino acid sequence of sequence number 124; (xii) Amino acid sequence of SEQ ID NO: 126; (xiiii) Amino acid sequence of sequence number 128; (xiv) Amino acid sequence of sequence number 130; (xv) Amino acid sequence of sequence number 132; (xvi) Amino acid sequence of sequence number 134; (xvii) Amino acid sequence of sequence number 136; (xviiii) Amino acid sequence of sequence number 138; (xix) Amino acid sequence of SEQ ID NO: 377; or (xx) Amino acid sequence of SEQ ID NO: 379 The molecule according to claim 81, comprising:

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

109.

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

109.

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

109.

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

109.

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

109.

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

109.

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

109.

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

113.

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

113.

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

113.

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

113.

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

113.

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

113.

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

113.

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

113.

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

115.

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

115.

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

115.

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

115.

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

115.

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

115.

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

115.

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

115.

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

119.

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

119.

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

119.

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

119.

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

119.

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

119.

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

119.

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

119.

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

131.

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

131.

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

131.

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

131.

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

131.

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

131.

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

131.

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

131.

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

378.

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

378.

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

378.

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

378.

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

378.

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

378.

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

378.

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

378.

138. The molecule according to any one of claims 1 to 82, wherein the first polypeptide comprises any one amino acid sequence of SEQ ID NOs: 211-217, 225-227, 231-237, 245-247, 318-331, or 346-359, and the second polypeptide comprises any one amino acid sequence of SEQ ID NOs: 218-224, 228-230, 238-244, 248-250, 332-345, or 360-373.

139. (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; (viiii) 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; (xi) 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 comprises the amino acid sequence of SEQ ID NO: 234, and the second polypeptide comprises 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 comprises the amino acid sequence of SEQ ID NO: 237, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 244; (xviiii) 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 comprises the amino acid sequence of SEQ ID NO: 246, and the second polypeptide comprises 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 comprises the amino acid sequence of SEQ ID NO: 318, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 332; (xxi) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 319, and the second polypeptide comprises 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 comprises the amino acid sequence of SEQ ID NO: 323, and the second polypeptide comprises 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; (xxviiii) 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 comprises the amino acid sequence of SEQ ID NO: 327, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 341; (xxx) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 329, and the second polypeptide comprises 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 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; (xxxviiii) 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 comprises the amino acid sequence of SEQ ID NO: 353, and the second polypeptide comprises 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 comprises the amino acid sequence of SEQ ID NO: 355, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 369; (xliiii) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 356, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 370; (xliv) The first polypeptide comprises the amino acid sequence of SEQ ID NO: 357, and the second polypeptide comprises 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 comprises the amino acid sequence of SEQ ID NO: 359, and the second polypeptide comprises the amino acid sequence of SEQ ID NO:

373. A molecule according to any one of claims 1 to 82, comprising:

140. The molecule according to any one of claims 1 to 139, further comprising an antigen-binding domain.

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

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

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

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

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

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

147. The molecule according to any one of claims 140 to 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, diabody, triabody, tetrabody, minibody, nanobody, maxibody, tandab, DVD, BiTe, TandAb, or any combination thereof.

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

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

150. The molecule according to claim 149, wherein the internally distributed receptor is ASGPR.

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

152. The molecule according to claim 151, wherein 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 according to 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 according to any one of claims 1 to 153, wherein the second Fc domain further comprises a second autoantibody-binding domain.

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

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

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

158. The molecule according to any one of claims 1 to 157, which, when administered to a target, can selectively deplete the anti-TSHR autoantibody that binds to the autoantibody-binding domain.

159. The molecule according to claim 158, wherein the anti-TSHR autoantibody bound to the autoantibody-binding domain is taken up by a cell and selectively depleted by transporting the autoantibody to lysosomes for degradation.

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

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

162. A host cell comprising the nucleic acid described in claim 161.

163. A vector comprising the nucleic acid described in claim 161.

164. The vector according to claim 163, wherein the vector includes a viral vector.

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

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

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

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

169. A method of treating a person who has an autoimmune disease or is susceptible to it, Administering to the subject a first pharmaceutical composition containing a molecule according to any one of claims 1 to 160 or a nucleic acid encoding a molecule according to any one of claims 1 to 160, and The method comprising administering to the subject a second pharmaceutical composition that selectively depletes plasma cells that produce autoantibodies targeted by the autoantibody-binding domain.

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

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

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

173. The method according to claim 169, wherein the first pharmaceutical composition and the second pharmaceutical composition are co-administered.

174. The method according to any one of claims 168 to 173, wherein the level of anti-TSHR autoantibodies in or from the subject after administration is lower than the level before administration.

175. The method according to claim 174, wherein 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% compared to the level before administration.

176. The method according to claim 174 or 175, wherein the reduction in the level of anti-TSHR autoantibodies is sustained over a long period of time.

177. The method according to claim 176, wherein the duration includes at least one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, ten weeks, twelve weeks, or more.

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

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

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

181. 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 according to any one of claims 1 to 160 or a nucleic acid encoding a molecule according to any one of claims 1 to 160.

182. A molecule according to any one of claims 1 to 160 or a nucleic acid encoding a molecule according to any one of claims 1 to 160; a molecule that selectively depletes plasma cells that produce the autoantibody targeted by the autoantibody-binding domain, or a nucleic acid encoding the same; and Pharmacologically acceptable carriers A pharmaceutical composition containing the following:

183. A composition for reducing the titer of anti-TSHR autoantibodies in serum in subjects requiring a reduction in the titer of anti-TSHR autoantibodies in serum, wherein the composition is The present invention comprises 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 and / or second Fc domains contain one or more mutant amino acid residues and have increased binding affinity to FcγRIIB compared to the corresponding wild-type Fc domains. The composition, wherein, upon administration of the plurality of molecules, the molecules bind to an anti-TSHR autoantibody to form an immune complex containing two molecules bound to the anti-TSHR autoantibody, and the immune complex binds to FcγRIIB expressed on the surface of hepatic sinusoidal endothelial cells (LSEC) with higher avidity compared to an immune complex containing two corresponding molecules having wild-type Fc domains, undergoes endocytosis, thereby reducing the titer of the anti-TSHR autoantibody in the target serum.

184. The composition according to claim 183, wherein the molecule is the molecule described in any one of claims 1 to 160.

185. (i) anti-TSHR autoantibodies; and (ii) Two molecules An immune complex comprising, each molecule, A first polypeptide comprising a first Fc domain and an autoantibody-binding domain that binds to the anti-TSHR autoantibody; and Second polypeptide containing a second Fc domain Includes, The first Fc domain and the second Fc domain form homodimers or heterodimers of the first polypeptide and the second polypeptide, and the first and / or second Fc domains contain one or more mutant amino acid residues and have increased binding affinity to FcγRIIB compared to the corresponding wild-type Fc domain. The immune complex exhibits improved binding kinetics with FcγRIIB compared to the immune complex comprising the anti-TSHR autoantibody bound to two corresponding molecules having wild-type Fc domains.

186. The immune complex according to claim 185, wherein the immune complex has improved binding kinetics with FcγRIIB compared to an immune complex comprising only the anti-TSHR autoantibody and one molecule.

187. The immune complex according to claim 185, wherein the immune complex has improved binding dynamics with FcγRIIB compared to the anti-TSHR autoantibody alone.

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

189. The improved binding dynamics include an increase in the association rate, a decrease in the dissociation rate, and / or a change in the equilibrium dissociation constant, according to any one of claims 185 to 188.

190. The immune complex according to any one of claims 185 to 189, wherein the improved binding dynamics result in an increase in the avidity, stability, strength, frequency, and / or duration of binding between the immune complex and FcγRIIB.

191. The immunocomplex according to any one of claims 185 to 190, wherein the first and / or second Fc domains comprising one or more mutant amino acid residues do not show increased binding affinity to FcγRI, FcγRIIA167H, FcγRIIA167R, FcγRIIA176F, FcγRIIA176V, FcγRIIB, and / or FcRn compared to the corresponding wild-type Fc domain.

192. The immunocomplex according to any one of claims 185 to 191, wherein the first and / or second Fc domains, each containing one or more mutant amino acid residues, have reduced binding affinity to FcγRI, FcγRIIA167H, FcγRIIA167R, FcγRIIA176F, FcγRIIA176V, FcγRIIB, and / or FcRn compared to the corresponding wild-type Fc domain.

193. The immunocomplex according to any one of claims 185 to 192, wherein the first and / or second Fc domains comprising one or more mutant amino acid residues have negligible or no binding affinity to FcγRI, FcγRIIA167H, FcγRIIA167R, FcγRIIA176F, FcγRIIA176V, FcγRIIB, and / or FcRn compared to the corresponding wild-type Fc domain.

194. The immune complex according to any one of claims 185 to 193, wherein the improved binding dynamics include at least a 10% higher binding affinity of the immune complex to FcγRIIB.

195. The immunocomplex according to claim 194, wherein the binding affinity of at least 10% higher includes 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 more.

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

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

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

199. The immunocomplex according to any one of claims 185 to 198, wherein the molecule is the molecule according to any one of claims 1 to 160.

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