Molecules for controlling immune response

Abstract

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

Description

Attorney Docket No. 2017420-0064MOLECULES FOR CONTROLLING IMMUNE RESPONSE CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U. S. Provisional Application No.63 / 754,478, filed February 5, 2025, which is herein incorporated by reference in its entirety.BACKGROUND

[0002] Autoimmune disease develops when the body’s immune system attacks its own healthy cells. There are various types of autoimmune diseases, for instance, antiphospholipid syndrome (APS), Myasthenia Gravis (MG), Graves’ Disease, type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, pre-eclampsia, multiple sclerosis, neuromyelitis optica (NMO) spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein (MOG) antibody (ab) associated disorder (MOGAD), membranous nephropathy (MN), and vasculitis. A number of these diseases are driven by autoantibodies. Autoantibodies are antibodies that target self-antigens and are produced by pathogenic plasma cells.Autoantibodies are considered markers of antibody-driven autoimmune disease, and methods of targeting and depleting autoantibodies in patients with autoimmune disease have been explored. Certain autoantibodies (e.g., anti-B2GPl antibodies that are implicated in APS) are also implicated in other diseases, disorders or conditions that are not necessarily recognized as autoimmune - including stroke and a subset of normal pregnancy. However, therapeutic approaches for autoantibody-driven diseases, disorders or conditions oftentimes do not selectively deplete pathogenic autoantibodies and lead to depletion of all antibodies of a specific isotype, or depletion of complete cell populations (e.g., B cells or plasma cells), that provide appropriate immune response to invading pathogens.SUMMARY

[0003] Molecules described herein comprise a first polypeptide and a second polypeptide, wherein the first polypeptide comprises an autoantibody-binding domain and a first Fc domain and the second polypeptide comprises a second Fc domain. As described herein, such molecules neutralize and deplete specific pathogenic autoantibodies.Page 1 of 22413278080v 1Attorney Docket No. 2017420-0064

[0004] Molecules described herein may be used for treatment of autoimmune diseases such as antiphospholipid syndrome (APS) and / or other diseases, disorders or conditions implicated by autoantibodies that target Beta-2-Glycoprotein I (B2GP1). In some embodiments, a molecule comprises an autoantigen domain that is a B2GP1 autoantigen domain, or a fragment or variant thereof.

[0005] In addition to including an autoantibody -binding domain that targets autoantibodies, a molecule described herein may also include modifications to target specific internalizing receptors. In some embodiments, targeting and depletion of autoantibodies is through a mechanism of targeting immune complexes including the autoantibodies to the lysosome of a cell for degradation. In some embodiments, a molecule described herein includes an Fc domain that binds to a receptor on a cell that causes internalization of the bound molecule. Such molecules allow for binding of anti-B2GPl antibodies through the autoantigen domain and targeting to the lysosome for degradation through binding of an internalizing receptor. In some embodiments, a molecule may include in its first and / or second Fc domains, a modification that increases its binding affinity to Fc-gamma-RIIB (FcyRIIB). In some embodiments, a first and / or second Fc domain of a molecule may include a modification that increases its binding affinity to the human neonatal Fc receptor (FcRn).

[0006] In some embodiments, molecules described herein include an antigen-binding domain, wherein the antigen-binding domain binds to a receptor on a cell that internalizes the bound molecule (e.g., see FIG. 1). In some embodiments, an antigen-binding domain binds to an internalizing receptor such as FcyRIIB, ASPGR and / or FcRn. A molecule that targets an internalizing receptor such as FcyRIIB may inhibit / deplete autoantigen-specific B cells on which the autoantibody is expressed on the cell surface (e.g., as described in Chu et al., Mol Immunol 45:3926-3933 (2008), which is herein incorporated by reference in its entirety).

[0007] All of such strategies aim to deplete certain autoantibodies implicated in a particular disease, disorder or condition. In some embodiments, an autoantibody is an anti-B2GPl autoantibody and the disease is APS or other diseases, disorders or conditions caused by anti-B2GP1 autoantibodies. Molecules may include a B2GP1 autoantigen domain that targets anti-Page 2 of22413278080v 1Attorney Docket No. 2017420-0064B2GP1 antibodies and an Fc domain and / or an antigen-binding domain that targets the complex (molecule and antibody) to the lysosome of a cell for selective degradation.

[0008] In one aspect, the present disclosure provides, a molecule comprising: a first polypeptide comprising a first Fc domain and an autoantibody -binding domain that binds to anti-B2GP1 autoantibodies; 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 anti-B2GPl autoantibodies and the molecule is a homodimer. In some embodiments, the second polypeptide further comprises an autoantibody-binding domain that binds to anti-B2GPl autoantibodies and the molecule is a heterodimer. In some embodiments, the second polypeptide does not comprise an autoantibodybinding domain that binds to anti-B2GPl autoantibodies and the molecule is a heterodimer.

[0009] In some embodiments, the autoantibody-binding domain is covalently linked to the first Fc domain. In some embodiments, the C-terminus of the autoantibody-binding domain is covalently linked to the N-terminus of the first Fc domain. In some embodiments, the N-terminus of the autoantibody-binding domain is covalently linked to the C-terminus of the first Fc domain.

[0010] In some embodiments, the first and second Fc domains form a heterodimer as a result of knobs-in-holes (KIH) mutations. In some embodiments, the KIH mutations comprise Y349T and T394F, according to EU numbering scheme. In some embodiments, the first Fc domain comprises the Y349T mutation and the second Fc domain comprises the T394F mutation. In some embodiments, the KIH mutations comprise T366W, S354C, T366S, L368A, Y407V, and Y349C, according to the EU numbering scheme. In some embodiments, the first Fc domain comprises the T366W and S354C mutations and the second Fc domain comprises the T366S, L368A, Y407V, and Y349C mutations, according to the EU numbering scheme.

[0011] In some embodiments, the first and / or second Fc domains comprise an IgGl isotype. In some embodiments, the first and / or second Fc domains comprise a human IgGl isotype.Page 3 of 22413278080v 1Attorney Docket No. 2017420-0064

[0012] In some embodiments, the first and / or second Fc domain comprises one or more mutated amino acid residues that increase half-life. In some embodiments, the first and / or second Fc domain comprises one of the following mutated amino acid residues: M252Y, S254T, and T256E, according to the EU numbering scheme. In some embodiments, the first and / or second Fc domain comprises a combination of the following mutated amino acid residues:M252Y, S254T, and T256E, according to the EU numbering scheme. In some embodiments, the first and / or second Fc domain comprises one of the following mutated amino acid residues: M428L and N434S, according to the EU numbering scheme. In some embodiments, the first and / or second Fc domain comprises a combination of the following mutated amino acid residues: M428L and N434S, according to the EU numbering scheme.

[0013] In some embodiments, the first and / or second Fc domain comprises one or more mutated amino acid residues that alters its binding to an internalizing receptor on a cell, where the internalizing receptor is capable of shuttling its cargo to the lysosome of the cell leading to degradation. In some embodiments, the altered binding to the internalizing receptor comprises increased binding to an internalizing receptor. In some embodiments, the molecule that is bound to an autoantibody through the autoantibody-binding domain binds to the internalizing receptor on a cell, the internalizing receptor internalizes the molecule and the autoantibody is shuttled to the lysosome of the cell for degradation. In some embodiments, the internalizing receptor comprises one of the following: FcyRIIB, FcRn, ASGPR, BCMA, CD38, SLAMF7, GPCR5D, and / or CD 138.

[0014] In some embodiments, the first and / or second Fc domain comprises one or more mutated amino acid residues that increases binding to FcyRIIB relative to a corresponding wildtype Fc domain.

[0015] In some embodiments, the first and / or second Fc domain comprising one or more mutated amino acid residues has greater binding affinity to FcyRIIB than to activating Fc receptors including FcyRI, FcyRIIA167H, FcyRIIA167R, FcyRIIIA176F, FcyRIIIA176V, and / or FcyRIIIB.Page 4 of 22413278080v 1Attorney Docket No. 2017420-0064

[0016] In some embodiments, the first and / or second Fc domain comprising one or more mutated amino acid residues has no binding affinity, decreased binding affinity, or slight increased binding affinity (e.g., within a 2-fold increase) to FcyRI, FcyRIIA167H, FcyRIIA167R, FcyRIII A l 76F, FcyRIIIA176V, FcyRIIIB, and / or FcRn relative to the corresponding wild-type Fc domain. In some embodiments, the first and / or second Fc domain comprising one or more mutated amino acid residues has decreased binding affinity to FcyRI, FcyRIIA167H, FcyRIIA167R, FcyRIIIA176F, FcyRIIIA176V, FcyRIIIB, and / or FcRn relative to the corresponding wild-type Fc domain. In some embodiments, the first and / or second Fc domain comprising one or more mutated amino acid residues has substantially no binding affinity to FcyRI, FcyRIIA167H, FcyRIIA167R, FcyRIIIA176F, FcyRIIIA176V, FcyRIIIB, and / or FcRn relative to the corresponding wild-type Fc domain.

[0017] In some embodiments, a molecule described herein promotes clearance of target anti-B2GP1 autoantibodies in serum when administered to a subject by binding to and forming an immune complex with the target anti-B2GPl autoantibodies. In some embodiments, the immune complex promotes faster clearance of target anti-B2GPl autoantibodies compared to anti-B2GPl autoantibody clearance in a subject not administered the molecule. In some embodiments, upon binding of the molecule to an anti-B2GPl autoantibody, an immune complex is formed that has enhanced binding kinetics with FcyRIIB relative to an anti-B2GPl autoantibody not present in an immune complex with the molecule. In some embodiments, the ratio of molecule to anti-B2GP1 autoantibody in an immune complex is 1:1, 2:1, or 1:2.

[0018] In some embodiments, upon binding of a molecule described herein to an anti-B2GPl autoantibody, an immune complex is formed that has enhanced binding kinetics with FcyRIIB relative to an immune complex that comprises the anti-B2GP l autoantibody and a corresponding molecule with a wild-type Fc domain. In some embodiments, upon binding of a molecule described herein to an anti-B2GPl autoantibody, an immune complex is formed that has enhanced binding kinetics with FcyRIIB relative to the anti-B2GPl autoantibody alone. In some embodiments, the enhanced binding kinetics comprise an increase in the rate of association, a decrease in the rate of disassociation, and / or a change in the equilibrium dissociation constant. InPage 5 of 22413278080v 1Attorney Docket No. 2017420-0064some embodiments, the enhanced binding kinetics produce an increase in avidity, stability, strength, frequency, and / or duration of binding between the immune complex and FcyRIIB.

[0019] In some embodiments, upon binding of two molecules to an anti-B2GPl autoantibody, an immune complex is formed that has enhanced binding kinetics with FcyRIIB relative to an immune complex that comprises the anti-B2GPl autoantibody and two corresponding molecules with wild-type Fc domains. In some embodiments, upon binding of two molecules to an anti-B2GPl autoantibody, an immune complex is formed that has enhanced binding kinetics with FcyRIIB relative to an immune complex that comprises the anti-B2GPl autoantibody bound to only a single molecule. In some embodiments, upon binding of two molecules to an anti-B2GPl autoantibody, an immune complex is formed that has enhanced binding kinetics with FcyRIIB relative to the anti-B2GPl autoantibody alone. In some embodiments, the enhanced binding kinetics comprise an increase in the rate of association, a decrease in the rate of disassociation, and / or a change in the equilibrium dissociation constant. In some embodiments, the enhanced binding kinetics produce an increase in avidity, stability, strength, frequency, and / or duration of binding between the immune complex and FcyRIIB.

[0020] In some embodiments, the enhanced binding kinetics comprises at least 10% greater binding affinity of the immune complex to FcyRIIB. In some embodiments, the at least 10% greater binding affinity comprises at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% or greater binding affinity. In some embodiments, the molecule binds to FcyRIIB with an affinity within the range of about 1 pM to 0.001 pM. In some embodiments, the molecule binds to FcyRIIB with an affinity within the range of about 1 pM to 0.01 pM. In some embodiments, the molecule binds to FcyRIIB with an affinity within the range of about 0.1 pM to 0.01 pM. In some embodiments, the binding affinity comprises binding affinity to a cell line (e.g., a CHO cell line or HepG2 cell line) endogenously expressing or overexpressing FcyRIIB measured by flow cytometry.

[0021] In some embodiments, upon binding of a molecule described herein to an anti-B2GPl autoantibody, an immune complex is formed that has no binding affinity, or decreased binding affinity, or slight increased binding affinity (e.g., within a 2-fold increase) to FcyRI, FcyRIIA167H, FcyRIIA167R, FcyRIIIA176F, FcyRIIIA176V, FcyRIIIB, and / or FcRn relative to Page 6 of 22413278080v 1Attorney Docket No. 2017420-0064an immune complex that comprises the anti-B2GPl autoantibody and a corresponding molecule with wild-type Fc domains. In some embodiments, upon binding of a molecule described herein to an anti-B2GPl autoantibody, an immune complex is formed that has no binding affinity, or decreased binding affinity, or slight increased binding affinity (e.g., within a 2-fold increase) to FcyRI, FcyRIIA167H, FcyRIIA167R, FcγRIIIA176F, FcyRIIIA176V, FcyRIIIB, and / or FcRn relative to the anti-B2GPl autoantibody alone.

[0022] In some embodiments, upon binding of two molecules to an anti-B2GPl autoantibody, an immune complex is formed that has no binding affinity, or decreased binding affinity, or slight increased binding affinity (e.g., within a 2-fold increase) to FcyRI, FcyRIIA167H, FcyRIIA167R, FcγRIIIA176F, FcyRIIIA176V, FcyRIIIB, and / or FcRn relative to an immune complex that comprises the anti-B2GPl autoantibody and two corresponding molecules with wild-type Fc domains. In some embodiments, upon binding of two molecules to an anti-B2GPl autoantibody, an immune complex is formed that has no binding affinity, or decreased binding affinity, or slight increased binding affinity (e.g., within a 2-fold increase) to FcyRI, FcyRIIA167H, FcyRIIA167R, FcγRIIIA176F, FcyRIIIA176V, FcyRIIIB, and / or FcRn relative to an immune complex that comprises the anti-B2GPl autoantibody bound to only a single molecule. In some embodiments, upon binding of two molecules to an anti-B2GPl autoantibody, an immune complex is formed that has no binding affinity, or decreased binding affinity, or slight increased binding affinity (e.g., within a 2-fold increase) to FcyRI, FcyRIIA167H, FcyRIIA167R, FcyRIIIA176F, FcyRIIIA176V, FcyRIIIB, and / or FcRn relative to the anti-B2GPl autoantibody alone.

[0023] In some embodiments, the decreased binding affinity comprises at least 10% decrease in binding affinity of the immune complex to FcyRI, FcyRIIA167H, FcyRIIA167R, FcyRIIIA176F, FcyRIIIA176V, FcyRIIIB, and / or FcRn. In some embodiments, the at least 10% decrease binding affinity comprises at least 15% decrease, at least 20% decrease, at least 25% decrease, at least 30% decrease, at least 35% decrease, at least 40% decrease, at least 45% decrease, or at least 50% or greater decrease in binding affinity. In some embodiments, the binding affinity comprises binding affinity to a cell line (e.g., a CHO cell line or HepG2 cell line)Page 7 of 22413278080v 1Attorney Docket No. 2017420-0064endogenously expressing or overexpressing FcyRI, FcyRIIA167H, FcyRIIA167R, FcyRIIIA176F, FcyRIIIAl 76V, FcyRIIIB, and / or FcRn measured by flow cytometry.

[0024] In some embodiments, the molecule does not have increased binding affinity to complement (Clq) compared to a molecule with a wildtype Fc domain. In some embodiments, the molecule has decreased binding affinity to complement (Clq) compared to a molecule with a wildtype Fc domain. In some embodiments, the molecule does not bind to complement (Clq).

[0025] In some embodiments, the molecule preferentially binds to immune cells expressing FcyRIIB over immune cells expressing FcyRIIA. In some embodiments, the molecule comprises substantially no binding affinity for cells that do not express FcyRIIB. In some embodiments, the immune cells expressing FcyRIIB comprise B cells, monocytes and / or basophils. In some embodiments, the immune cells that do not express FcyRIIB comprise T cells, NK cells, neutrophils, and / or eosinophils.

[0026] In some embodiments, the molecule does not activate immune cells (e.g., does not activate immune cells to secrete pro-inflammatory cytokines, e.g., IL-6).

[0027] In some embodiments, the molecule inhibits B cells by cross-linking FcyRIIB with a B cell receptor. In some embodiments, the molecule cross-links FcyRIIB with a self antigenspecific B cell receptor. In some embodiments, an immune complex of one or two molecules with an anti-B2GPl autoantibody cross-links FcyRIIB with a self antigen-specific B cell receptor.

[0028] In some embodiments, the one or more mutated amino acid residues that increases binding to FcyRIIB comprises one or more of the following amino acid mutations, according to the EU numbering scheme: E233V, L234D, L235F, G236D, G236R, G237D, S239L, S267D, H268P, S298G, T299A, A327L, L328A, A330H, E333I, R292Q, E233P, P238D, H268D, P271G, A330R, L234Y, T250V, V264I, T307P, Q311R, A330K, P343R, M428L, N434A, Y436T, Q438R, S440E, G236N, S267E, L235R, D270E, E233D, and G237D.

[0029] In some embodiments, the one or more mutated amino acid residues that increases binding to FcyRIIB comprises one or more of the following sets of amino acid mutations,Page 8 of 22413278080v 1Attorney Docket No. 2017420-0064according to the EU numbering scheme: (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, A33OH, and E333I; (iii) E233V, L234D, L235F, G236R, G237D, S239L, H268P, R292Q, S298G, T299A, A327L, L328A, A330H, and E333I;(iv) E233P, G237D, P238D, H268D, P271G, and A330R; (v) L234Y, P238D, T250V, V264I, T307P, Q311R, A330K, P343R, M428L, N434A, Y436T, Q438R, and S440E; (vi) L234D, G236N, and S267E; (vii) L235R; (viii) G236N and S267E; (ix) P238D and D270E; (x) P238D and P271G; (xi) P238D, D270E, and P271G; (xii) G237D, P238D, P271G, and A330R;(xiii) G237D, P238D, D270E, P271G, and A330R; (xiv) E233D, G237D, P238D, H268D, P271G, and A330R; (xv) P238D; (xvi) S267E / L328F; and (xvii) S267E / L328F / G236D. In some embodiments, the one or more mutated amino acid residues comprises the mutated amino acid residue P238D, according to the EU numbering scheme. In some embodiments, the one or more mutated amino acid residues does not comprise the following mutated amino acid residues: S267E and L328F, according to the EU numbering scheme. In some embodiments, the one or more mutated amino acid residues comprises the mutated amino acid residues G237D, P238D, P271G, and A330R, according to the EU numbering scheme.

[0030] In some embodiments, the first and / or second Fc domain comprises the following mutated 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 mutated amino acid residues: L234A, L235A, P238D and P329G, according to the EU numbering scheme. In some embodiments, the one or more mutated amino acid residues comprises the mutated amino acid residues L234A, L235A, P329G, G237D, P238D, P271G, and A330R, according to the EU numbering scheme.

[0031] In some embodiments, the first and / or second Fc domain comprises the following mutated amino acid residues: M428L, N434S, and P238D, according to the EU numbering scheme. In some embodiments, the first and / or second Fc domain comprises the following mutated amino acid residues: M428L, N434S, P238D, and P271G, according to the EU numbering scheme. In some embodiments, the first and / or second Fc domain comprises thePage 9 of 22413278080v 1Attorney Docket No. 2017420-0064following mutated amino acid residues: M428L, N434S, G237D, P238D, P271G, A330R, according to the EU numbering scheme. In some embodiments, the first and / or second Fc domain comprises the following mutated amino acid residues: M428L, N434S, G237D, P238D, D270E, P271G, A330R, according to the EU numbering scheme.

[0032] In some embodiments, the first and / or second Fc domain comprises at least one mutated amino acid sequence that decreases binding to one or more Fc-gamma receptors (FcyRs). In some embodiments, the first and / or second Fc domain comprises at least one of the following mutated amino acid residues: G236R and L328R, according to the EU numbering scheme. In some embodiments, the first and / or second Fc domain comprises the following mutated amino acid residues: G236R and L328R, according to the EU numbering scheme.

[0033] In some embodiments, the first Fc domain and / or the second Fc domain comprises a sequence selected from SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 32, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 99, SEQ ID NO: 125, SEQ ID NO: 126, SEQ ID NO: 124, and SEQ ID NO: 131, or a fragment or variant thereof.

[0034] In some embodiments, a first Fc domain comprises a sequence selected from SEQ ID NO: 22, SEQ ID NO: 24, SEQ ID NO: 26, SEQ ID NO: 28, SEQ ID NO: 30, SEQ ID NO: 33, SEQ ID NO: 35, SEQ ID NO: 37, SEQ ID NO: 39, SEQ ID NO: 41, SEQ ID NO: 43, SEQ ID NO: 45, SEQ ID NO: 47, SEQ ID NO: 49, SEQ ID NO: 51, SEQ ID NO: 53, SEQ ID NO: 55, SEQ ID NO: 57, SEQ ID NO: 74, SEQ ID NO: 127, SEQ ID NO: 129, SEQ ID NO: 392, SEQ ID NO: 394, SEQ ID NO: 396, SEQ ID NO: 398, SEQ ID NO: 400, SEQ ID NO: 402, SEQ ID NO: 404, and SEQ ID NO: 406, or a fragment or variant thereof.

[0035] In some embodiments, a second Fc domain comprises a sequence selected from SEQ ID NO: 23, SEQ ID NO: 25, SEQ ID NO: 27, SEQ ID NO: 29, SEQ ID NO: 31, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 38, SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID NO: 50, SEQ ID NO: 52, SEQ ID NO: 54, SEQ ID NO:Page 10 of 22413278080v 1Attorney Docket No. 2017420-006456, SEQ ID NO: 58, SEQ ID NO: 75, SEQ ID NO: 128, SEQ ID NO: 130, SEQ ID NO: 393, SEQ ID NO: 395, SEQ ID NO: 397, SEQ ID NO: 399, SEQ ID NO: 401, SEQ ID NO: 403, SEQ ID NO: 405, and SEQ ID NO: 407, or a fragment or variant thereof.

[0036] In some embodiments, the autoantibody-binding domain is covalently linked to the first Fc domain through a linker. In some embodiments, the linker comprises the amino acid sequence of SEQ ID NO: 84 (GGGGS), SEQ ID NO: 85 (GGGGSGGGGS), SEQ ID NO: 86 (GGGGSGGGGSGGGGS), SEQ ID NO: 87 (VDGGGGSGGGGSGGGGSG), SEQ ID NO: 88 (GGSG), SEQ ID NO: 89 (GGSGG), SEQ ID NO: 90 (GSGSG), SEQ ID NO: 91 (GSGGG), SEQ ID NO: 92 (GGGSG), SEQ ID NO: 93 (GSSSG), SEQ ID NO: 94 (GGGGSGGGGSGGGGSGGGGS) or SEQ ID NO: 95 (GGGGSGGGGSGGGGSGGGGSSGGGGS).

[0037] In some embodiments, the autoantibody-binding domain comprises an autoantigen, or a fragment or variant thereof. In some embodiments, the autoantigen comprises a B2GP1 autoantigen domain, or a fragment or variant thereof. In some embodiments, the B2GP1 autoantigen domain comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to the amino acid sequence of any one of SEQ ID NOs: 1-6 In some embodiments, the B2GP1 autoantigen domain comprises the amino acid sequence of any one of SEQ ID NOs: 1-6. In some embodiments, the autoantibody-binding domain comprises a B2GP1 autoantigen domain variant that includes one or more mutations relative to the amino acid sequence of SEQ ID NO: 2. In some embodiments, an autoantibody-binding domain comprises a B2GP1 autoantigen domain variant that includes a D8S and a D9G mutation relative to the amino acid sequence of SEQ ID NO: 2. In some embodiments, the autoantibody-binding domain comprises a B2GP1 autoantigen domain variant that comprises the sequence of any one of SEQ ID NOs: 1-6.

[0038] In some embodiments, a molecule described herein contains a second polypeptide that further comprises a second autoantibody-binding domain.Page 11 of 22413278080v 1Attorney Docket No. 2017420-0064

[0039] In some embodiments, a molecule described herein includes a first polypeptide that comprises: an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 2 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 19; an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 3 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 19; an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 4 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 19; an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 2 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 28; an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 3 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 28; an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 4 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 28; an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 2 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, atPage 12 of 22413278080v 1Attorney Docket No. 2017420-0064least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 99; an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 3 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 99; an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 4 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 99; an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 2, an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 402; an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 3, an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 402; or an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 4 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 402; an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 2 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 124; an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 4 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) toPage 13 of 22413278080v 1Attorney Docket No. 2017420-0064SEQ ID NO: 124; an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 6 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 124; an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 6 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 131; an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 4, an amino acid sequence that is at least 90% identical to SEQ ID NO: 86, and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 124; an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 2 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 131; an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 4 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 131; or an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 4, an amino acid sequence that is at least 90% identical to SEQ ID NO: 86, and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 131.

[0040] In some embodiments, a molecule described herein includes a first polypeptide that comprises: an amino acid sequence comprising SEQ ID NO: 2 and an amino acid sequence Page 14 of 22413278080v 1Attorney Docket No. 2017420-0064comprising SEQ ID NO: 19; an amino acid sequence comprising SEQ ID NO: 3 and an amino acid sequence comprising SEQ ID NO: 19; an amino acid sequence comprising SEQ ID NO: 4 and an amino acid sequence comprising SEQ ID NO: 19; an amino acid sequence comprising SEQ ID NO: 2 and an amino acid sequence comprising SEQ ID NO: 28; an amino acid sequence comprising SEQ ID NO: 3 and an amino acid sequence comprising SEQ ID NO: 28; an amino acid sequence comprising SEQ ID NO: 4 and an amino acid sequence comprising SEQ ID NO: 28; an amino acid sequence comprising SEQ ID NO: 2 and an amino acid sequence comprising SEQ ID NO: 99; an amino acid sequence comprising SEQ ID NO: 3 and an amino acid sequence comprising SEQ ID NO: 99; an amino acid sequence comprising SEQ ID NO: 4 and an amino acid sequence comprising SEQ ID NO: 99; an amino acid sequence comprising SEQ ID NO: 2 and an amino acid sequence comprising SEQ ID NO: 402; an amino acid sequence comprising SEQ ID NO: 3 and an amino acid sequence comprising SEQ ID NO: 402; an amino acid sequence comprising SEQ ID NO: 4 and an amino acid sequence comprising SEQ ID NO: 402; an amino acid sequence comprising SEQ ID NO: 2 and an amino acid sequence comprising SEQ ID NO: 124; an amino acid sequence comprising SEQ ID NO: 4 and an amino acid sequence comprising SEQ ID NO: 124; an amino acid sequence comprising SEQ ID NO: 6 and an amino acid sequence comprising SEQ ID NO: 124; an amino acid sequence comprising SEQ ID NO: 6 and an amino acid sequence comprising SEQ ID NO: 131; an amino acid sequence comprising SEQ ID NO: 4, and amino acid sequence comprising SEQ ID NO: 86, and an amino acid sequence comprising SEQ ID NO: 124; an amino acid sequence comprising SEQ ID NO: 2 and an amino acid sequence comprising SEQ ID NO: 131; an amino acid sequence comprising SEQ ID NO: 4 and an amino acid sequence comprising SEQ ID NO: 131; or an amino acid sequence comprising SEQ ID NO: 4, an amino acid comprising SEQ ID NO: 86, and an amino acid sequence comprising SEQ ID NO: 131.

[0041] In some embodiments, a molecule described herein includes a second polypeptide that comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 2 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 19; an amino acid sequence that is at least 90% identical Page 15 of 22413278080v 1Attorney Docket No. 2017420-0064(e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 3 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 19; an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 4 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 19; an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 29; an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 2 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 99; an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 3 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 99, an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 4 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 99; an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 403; an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 2 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 124; an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%,Page 16 of 22413278080v 1Attorney Docket No. 2017420-0064at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 4 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 124; an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 6 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 124; an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 6 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 131; an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 4, an amino acid sequence that is at least 90% identical to SEQ ID NO: 86, and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 124; an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 2 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 131; an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 4 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 131; or an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 4, an amino acid sequence that is at least 90% identical to SEQ ID NO: 86, and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at leastPage 17 of 22413278080v 1Attorney Docket No. 2017420-006492%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 131.

[0042] In some embodiments, a molecule described herein includes a second polypeptide that comprises an amino acid sequence comprising SEQ ID NO: 2 and an amino acid sequence comprising SEQ ID NO: 19; an amino acid sequence comprising SEQ ID NO: 3 and an amino acid sequence comprising SEQ ID NO: 19; an amino acid sequence comprising SEQ ID NO: 4 and an amino acid sequence comprising SEQ ID NO: 19; an amino acid sequence comprising SEQ ID NO: 29; an amino acid sequence comprising SEQ ID NO: 2 and an amino acid sequence comprising SEQ ID NO: 99; an amino acid sequence comprising SEQ ID NO: 3 and an amino acid sequence comprising SEQ ID NO: 99, an amino acid sequence comprising SEQ ID NO: 4 and an amino acid sequence comprising SEQ ID NO: 99; an amino acid sequence comprising SEQ ID NO: 403; an amino acid sequence comprising SEQ ID NO: 2 and an amino acid sequence comprising SEQ ID NO: 124; an amino acid sequence comprising SEQ ID NO: 4 and an amino acid sequence comprising SEQ ID NO: 124; an amino acid sequence comprising SEQ ID NO: 6 and an amino acid sequence comprising SEQ ID NO: 124; an amino acid sequence comprising SEQ ID NO: 6 and an amino acid sequence comprising SEQ ID NO: 131; an amino acid sequence comprising SEQ ID NO: 4, and amino acid sequence comprising SEQ ID NO: 86, and an amino acid sequence comprising SEQ ID NO: 124; an amino acid sequence comprising SEQ ID NO: 2 and an amino acid sequence comprising SEQ ID NO: 131; an amino acid sequence comprising SEQ ID NO: 4 and an amino acid sequence comprising SEQ ID NO: 131; or an amino acid sequence comprising SEQ ID NO: 4, and amino acid comprising SEQ ID NO: 86, and an amino acid sequence comprising SEQ ID NO: 131.In some embodiments, a molecule described herein includes a first polypeptide and a second polypeptide where (i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 2 and the amino acid sequence of SEQ ID NO: 19, and (ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 2 and the amino acid sequence of SEQ ID NO: 19. In some embodiments, a molecule described herein includes a first polypeptide and a second polypeptide where (i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 3 and the amino acid sequence of SEQ ID NO: 19, and (ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 3 and the amino acid sequence of SEQ ID NO: 19. In Page 18 of 22413278080v 1Attorney Docket No. 2017420-0064some embodiments, a molecule described herein includes a first polypeptide and a second polypeptide where (i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 4 and the amino acid sequence of SEQ ID NO: 19, and (ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 4 and the amino acid sequence of SEQ ID NO: 19. In some embodiments, a molecule described herein includes a first polypeptide and a second polypeptide where (i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 2 and the amino acid sequence of SEQ ID NO: 28, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 29; or (ii) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 2 and the amino acid sequence of SEQ ID NO: 29, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 28. In some embodiments, a molecule described herein includes a first polypeptide and a second polypeptide where (i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 3 and the amino acid sequence of SEQ ID NO: 28, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 29; or (ii) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 3 and the amino acid sequence of SEQ ID NO: 29, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 28. In some embodiments, a molecule described herein includes a first polypeptide and a second polypeptide where (i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 4 and the amino acid sequence of SEQ ID NO: 28, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 29; or (ii) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 4 and the amino acid sequence of SEQ ID NO: 29, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 28. In some embodiments, a molecule described herein includes a first polypeptide and a second polypeptide where (i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 2 and the amino acid sequence of SEQ ID NO: 99, and (ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 2 and the amino acid sequence of SEQ ID NO: 99. In some embodiments, a molecule described herein includes a first polypeptide and a second polypeptide where (i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 3 and the amino acid sequence of SEQ ID NO: 99, and (ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 3 and the amino acid sequence of SEQ ID NO: 99. In some embodiments, a molecule described herein includes a first polypeptide and aPage 19 of 22413278080v 1Attorney Docket No. 2017420-0064second polypeptide where (i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 4 and the amino acid sequence of SEQ ID NO: 99, and (ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 4 and the amino acid sequence of SEQ ID NO: 99. In some embodiments, a molecule described herein includes a first polypeptide and a second polypeptide where (i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 2 and the amino acid sequence of SEQ ID NO: 402, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 403; or (ii) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 2 and the amino acid sequence of SEQ ID NO: 403, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 402. In some embodiments, a molecule described herein includes a first polypeptide and a second polypeptide where (i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 3 and the amino acid sequence of SEQ ID NO: 402, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 403; or (ii) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 3 and the amino acid sequence of SEQ ID NO: 403, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 402. In some embodiments, a molecule described herein includes a first polypeptide and a second polypeptide where (i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 4 and the amino acid sequence of SEQ ID NO: 402, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 403; or (ii) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 4 and the amino acid sequence of SEQ ID NO: 403, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 402. In some embodiments, a molecule described herein includes a first polypeptide and a second polypeptide where (i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 2 and the amino acid sequence of SEQ ID NO: 124, and (ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 2 and the amino acid sequence of SEQ ID NO: 124. In some embodiments, a molecule described herein includes a first polypeptide and a second polypeptide where (i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 4 and the amino acid sequence of SEQ ID NO: 124, and (ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 4 and the amino acid sequence of SEQ ID NO: 124. In some embodiments, a molecule described herein includes a first polypeptide and a second polypeptide where (i) the first polypeptide comprises the aminoPage 20 of 22413278080v 1Attorney Docket No. 2017420-0064acid sequence of SEQ ID NO: 6 and the amino acid sequence of SEQ ID NO: 124, and (ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 6 and the amino acid sequence of SEQ ID NO: 124. In some embodiments, a molecule described herein includes a first polypeptide and a second polypeptide where (i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 6 and the amino acid sequence of SEQ ID NO: 131, and (ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 6 and the amino acid sequence of SEQ ID NO: 131. In some embodiments, a molecule described herein includes a first polypeptide and a second polypeptide where (i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 4, the amino acid sequence of SEQ ID NO: 86, and the amino acid sequence of SEQ ID NO: 124, and (ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 4, the amino acid sequence of SEQ ID NO: 86, and the amino acid sequence of SEQ ID NO: 124. In some embodiments, a molecule described herein includes a first polypeptide and a second polypeptide where (i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 2 and the amino acid sequence of SEQ ID NO: 131, and (ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 2 and the amino acid sequence of SEQ ID NO: 131. In some embodiments, a molecule described herein includes a first polypeptide and a second polypeptide where (i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 4 and the amino acid sequence of SEQ ID NO: 131, and (ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 4 and the amino acid sequence of SEQ ID NO: 131. In some embodiments, a molecule described herein includes a first polypeptide and a second polypeptide where (i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 4, the amino acid sequence of SEQ ID NO: 86, and the amino acid sequence of SEQ ID NO: 131, and (ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 4, the amino acid sequence of SEQ ID NO: 86, and the amino acid sequence of SEQ ID NO: 131.

[0043] In some embodiments, a molecule described herein comprises a first polypeptide that comprises the amino acid sequence of any one of SEQ ID NOs: 100-106, 108, 110, 112-118, 120, 122, and 133-140, and a second polypeptide comprises the amino acid sequence of any one of SEQ ID NOs: 100-105, 107, 109, 111-117, 119, 121, 123, and 133-140.Page 21 of 22413278080v 1Attorney Docket No. 2017420-0064

[0044] In some embodiments, a molecule described herein comprises a first polypeptide and a second polypeptide, where the first polypeptide comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to any one of SEQ ID NOs: 100-106, 108, 110, 112-118, 120, 122, and 133-140, and the second polypeptide comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to any one of SEQ ID NOs: 100-105, 107, 109, 111-117, 119, 121, 123, and 133-140.

[0045] In some embodiments, a molecule described herein comprises a first polypeptide and a second polypeptide, where the first polypeptide comprises the amino acid sequence of any one of SEQ ID NOs: 100-106, 108, 110, 112-118, 120, 122, and 133-140, and the second polypeptide comprises the amino acid sequence of any one of SEQ ID NOs: 100-105, 107, 109, 111-117, 119, 121, 123, and 133-140.

[0046] In some embodiments, a molecule described herein comprises a first polypeptide and a second polypeptide, where (i) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 100, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 100; (ii) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 101 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 101; (iii) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 102 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 102; (iv) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 103 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 103; (v) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 104 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 104; (vi) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 105 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 105; (vii) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 106 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 107; (viii) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 108 and the second polypeptide comprises the amino acid sequence ofPage 22 of 22413278080v 1Attorney Docket No. 2017420-0064SEQ ID NO: 109; (ix) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 110 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 111; (x) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 112 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 112; (xi) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 113 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 113; (xii) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 114 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 114; (xiii) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 115 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 115; (xiv) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 116 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 116; (xv) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 117 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 117; (xvi) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 118 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 119; (xvii) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 120 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 121; (xviii) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 122 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 123; (xix) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 133, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 133; (xx) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 134, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 134; (xxi) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 135, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 135; (xxii) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 136, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 136; (xxiii) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 137, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 137; (xxiv) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 138, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 138;Page 23 of 22413278080v 1Attorney Docket No. 2017420-0064(xxv) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 139, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 139; or (xxvi) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 140, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 140.

[0047] In some embodiments, the second polypeptide further comprises a second autoantibody-binding domain. In some embodiments, the N-terminus of the second Fc domain is covalently linked to the C-terminus of the second autoantibody-binding domain. In some embodiments, the C-terminus of the second Fc domain is covalently linked to the C-terminus of the second autoantibody-binding domain. In some embodiments, the second autoantibodybinding domain binds to anti-B2GPl autoantibodies.

[0048] In some embodiments, the molecule is capable of selectively depleting anti-B2GPl autoantibodies that bind to the autoantibody -binding domain when administered to a subject. In some embodiments, the anti-B2GPl autoantibodies that bind to the autoantibody-binding domain are selectively depleted by uptake into cells and shuttling of the autoantibodies to the lysosome for degradation.

[0049] In some embodiments, the second polypeptide does not comprise an autoantibodybinding domain that binds to anti-B2GPl autoantibodies.

[0050] In another aspect, the present disclosure provides a nucleic acid comprising a nucleotide sequence encoding a molecule of the present disclosure.

[0051] In another aspect, the present disclosure provides a host cell containing a nucleic acid comprising a nucleotide sequence encoding a molecule of the present disclosure.

[0052] In another aspect, the present disclosure provides a vector comprising a nucleic acid comprising a nucleotide sequence encoding a molecule of the present disclosure. In some embodiments, the vector comprises a viral vector. In some embodiments, the viral vector comprises a retroviral vector, a lentiviral vector, an adeno-associated viral (AAV) vector, or an adenoviral vector.Page 24 of 22413278080v 1Attorney Docket No. 2017420-0064

[0053] In another aspect, the present disclosure provides a pharmaceutical composition comprising a molecule of the present disclosure or a nucleic acid encoding a molecule and a pharmaceutically acceptable carrier.

[0054] In another aspect, the present disclosure provides a method of making a molecule of the present disclosure, the method comprising expressing a nucleic acid comprising a nucleotide sequence encoding a molecule in a host cell, and recovering the molecule.

[0055] In another aspect, the present disclosure provides a method of treating a subject suffering from or susceptible to an autoimmune disease or other disease, disorder or condition involving anti-B2GPl autoantibodies, the method comprising: administering to the subject a pharmaceutical composition comprising a molecule of the present disclosure or a nucleic acid encoding the molecule. In some embodiments, the autoimmune disease is APS.

[0056] In another aspect, the present disclosure provides a method of treating a subject suffering from or susceptible to an autoimmune disease or other disease, disorder or condition involving anti-B2GPl autoantibodies, the method comprising: administering to the subject a first pharmaceutical composition comprising a molecule of the present disclosure or a nucleic acid encoding the molecule; and administering to the subject a second pharmaceutical composition that selectively depletes plasma cells producing autoantibodies that are targeted by the autoantibody-binding domain. In some embodiments, the autoimmune disease is APS. In some embodiments, the first pharmaceutical composition is administered before the second pharmaceutical composition. In some embodiments, the first pharmaceutical composition is administered after the second pharmaceutical composition. In some embodiments, the first pharmaceutical composition and the second pharmaceutical composition are co-administered.

[0057] In some embodiments, the level of anti-B2GPl autoantibodies in the subject or in a biological sample from the subject after administration is reduced relative to a level before administration. In some embodiments, the level of anti-B2GPl autoantibodies is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% relative to a level before the Page 25 of 22413278080v 1Attorney Docket No. 2017420-0064administration. In some embodiments, the reduced level of anti-B2GPl autoantibodies is sustained over time. In some embodiments, a sustained period of time comprises 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 intravenously, intramuscularly, or subcutaneously to the subject. In some embodiments, the subject is a human.

[0058] In another aspect, the present disclosure provides a method of selectively depleting anti-B2GPl autoantibodies in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a molecule of the present disclosure or a nucleic acid encoding the molecule.

[0059] In another aspect, the present disclosure provides a method of treating a human subject suffering from or susceptible to APS, or other disease, disorder or condition involving anti-B2GPl autoantibodies, the method comprising administering to the subject a pharmaceutical composition comprising a molecule of the present disclosure or a nucleic acid encoding the molecule.

[0060] In another aspect, the present disclosure provides a pharmaceutical composition comprising: a molecule of the present disclosure or a nucleic acid encoding the molecule; a molecule that selectively depletes plasma cells producing the autoantibodies that are targeted by the autoantibody -binding domain, or a nucleic acid encoding the same; and a pharmaceutically acceptable carrier.

[0061] In another aspect, the present disclosure provides a composition for decreasing the titer of anti-B2GPl autoantibodies in the blood serum of a subject in need thereof, 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 anti-B2GP1 autoantibodies; and (b) a second polypeptide comprising a second Fc domain, wherein the first Fc domain and the second Fc domain form a homodimer or heterodimer of the first polypeptide and the second polypeptide; wherein the first and / or second Fc domain comprises one or more mutated amino acid residues and has increased binding affinity to FcyRIIB relative Page 26 of 22413278080v 1Attorney Docket No. 2017420-0064to a corresponding wild-type Fc domain, and wherein, upon administration of the plurality of molecules, the molecules bind to anti-B2GPl autoantibodies to form immune complexes comprising two molecules bound to an anti-B2GPl autoantibody, and wherein the immune complex binds with higher avidity to FcyRIIB expressed on the surface of liver sinusoidal endothelial cells (LSECs) and are endocytosed thereby decreasing the titer of the anti-B2GPl autoantibodies in the subject’s blood serum, wherein the higher avidity is relative to an immune complex comprising two corresponding molecules with wild-type Fc domains.

[0062] In another aspect, the present disclosure provides an immune complex comprising an anti-B2GPl autoantibody and a molecule of the present disclosure, wherein the immune complex has enhanced binding kinetics with FcyRIIB relative to an immune complex that comprises the anti-B2GPl autoantibody bound to a corresponding molecule with wild-type Fc domains.

[0063] In another aspect, the present disclosure provides an immune complex comprising: (i) an anti-B2GPl autoantibody; and (ii) a molecule of the present disclosure, wherein the molecule comprises: a first polypeptide comprising a first Fc domain, and an autoantibody-binding domain that binds to the anti-B2GPl autoantibody; and a second polypeptide comprising a second Fc domain; wherein the first Fc domain and the second Fc domain form a homodimer or heterodimer of the first polypeptide and the second polypeptide; wherein the first and / or second Fc domain comprises one or more mutated amino acid residues and has increased binding affinity to FcyRIIB relative to a corresponding wild-type Fc domain; and wherein the immune complex has enhanced binding kinetics with FcyRIIB relative to an immune complex that comprises the anti-B2GPl autoantibody bound to a corresponding molecule with wild-type Fc domains. In some embodiments, the immune complex has enhanced binding kinetics with FcyRIIB relative to the anti-B2GP l autoantibody alone.

[0064] In another aspect, the present disclosure provides an immune complex comprising an anti-B2GPl autoantibody and two molecules of the present disclosure, wherein the immune complex has enhanced binding kinetics with FcyRIIB relative to an immune complex that comprises the anti-B2GPl autoantibody bound to two corresponding molecules with wild-type Fc domains.Page 27 of 22413278080v 1Attorney Docket No. 2017420-0064

[0065] In another aspect, the present disclosure provides an immune complex comprising: (i) an anti-B2GPl autoantibody; and (ii) two molecules, wherein each molecule comprises: a first polypeptide comprising a first Fc domain, and an autoantibody -binding domain that binds to the anti-B2GPl autoantibody; and a second polypeptide comprising a second Fc domain; wherein the first Fc domain and the second Fc domain form a homodimer or heterodimer of the first polypeptide and the second polypeptide; wherein the first and / or second Fc domain comprises one or more mutated amino acid residues and has increased binding affinity to FcyRIIB relative to a corresponding wild-type Fc domain; and wherein the immune complex has enhanced binding kinetics with FcyRIIB relative to an immune complex that comprises the anti-B2GPl autoantibody bound to two corresponding molecules with wild-type Fc domains. In some embodiments, the immune complex has enhanced binding kinetics with FcyRIIB relative to an immune complex that comprises the anti-B2GPl autoantibody and only a single molecule. In some embodiments, the immune complex has enhanced binding kinetics with FcyRIIB relative to the anti-B2GPl autoantibody alone. In some embodiments, the autoantibody -binding domain of each of the two molecules is bound to the anti-B2GPl autoantibody.

[0066] In some embodiments, the enhanced binding kinetics comprise an increase in the rate of association, a decrease in the rate of disassociation, and / or a change in the equilibrium dissociation constant.

[0067] In some embodiments, the enhanced binding kinetics produce an increase in avidity, stability, strength, frequency, and / or duration of the binding between the immune complex and FcyRIIB.

[0068] In some embodiments, the first and / or second Fc domain comprising one or more mutated amino acid residues has no binding affinity, or decreased binding affinity, or slightly increased binding affinity (e.g., within a 2-fold increase) to FcyRI, FcyRIIA167H, FcyRIIA167R, FcyRIIIA176F, FcyRIIIA176V, FcyRIIIB, and / or FcRn relative to the corresponding wild-type Fc domain. In some embodiments, the first and / or second Fc domain comprising one or more mutated amino acid residues has decreased binding affinity to FcyRI, FcyRIIA167H, FcyRIIA167R, FcyRIIIA176F, FcyRIIIA176V, FcyRIIIB, and / or FcRn relative to the corresponding wild-type Fc domain. In some embodiments, the first and / or second Fc domain Page 28 of 22413278080v 1Attorney Docket No. 2017420-0064comprising one or more mutated amino acid residues has negligible or no binding affinity to FcyRI, FcγRIIA167H, FcyRIIA167R, FcyRIIIA176F, FcyRIIIA176V, FcyRIIIB, and / or FcRn relative to the corresponding wild-type Fc domain.

[0069] In some embodiments, the enhanced binding kinetics comprise at least 10% greater binding affinity of the immune complex to FcyRIIB. In some embodiments, the at least 10% greater binding affinity comprises at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% or greater binding affinity.

[0070] In some embodiments, the binding affinity comprises binding affinity to a cell line (e.g, a CHO cell line or HepG2 cell line) overexpressing FcyRIIB measured by flow cytometry. In some embodiments, the immune complex preferentially binds to immune cells expressing FcyRIIB over immune cells expressing FcyRIIA. In some embodiments, the immune complex cross-links FcyRIIB with a B cell receptor on a B cell.BRIEF DESCRIPTION OF THE DRAWING

[0071] FIG. 1 shows a schematic of an exemplary molecule described herein for selective depletion of autoantibodies targeted by an autoantibody-binding domain.

[0072] FIG. 2 shows an exemplary molecule format described herein.

[0073] FIG. 3 shows an exemplary molecule format described herein.

[0074] FIG. 4 shows an exemplary molecule format described herein.

[0075] FIGs. 5A-5B show exemplary molecule formats described herein. FIG. 5A shows an exemplary bivalent molecule with A’ and L’ antigens and linker domains, respectively. FIG. 5B shows an exemplary bivalent molecule with A and L antigens and linker domains, respectively.

[0076] FIGs. 6A-6D show some exemplary mechanisms of action of molecules described herein that contain mutations in the Fc domain to increase affinity for FcyRIIB including neutralization of autoantibodies (FIG. 6A), clearing of autoantibodies by targeting FcyRIIB isoform 2 on liver sinusoidal endothelial cells (FIG. 6B), targeting pathogenic B cells producing Page 29 of 22413278080v 1Attorney Docket No. 2017420-0064target autoantibodies (e.g., anti-B2GPl autoantibodies), by targeting FcyRIIB isoform 1 to the B cell receptor (BCR), which leads to B cell apoptosis and inhibition (FIG. 6C), and binding FcyRIIB on T cells and preventing T-cell activation (FIG. 6D).

[0077] FIGs. 7A-7C show exemplary monovalent molecule formats described herein. FIG.7A shows an exemplary monovalent molecule (“Variant A7”) that includes a first polypeptide that includes a non-native IgH signal peptide, a B2GP1 G20-V83 antigen fragment, and an Fc domain and a second polypeptide that includes an Fc domain. FIG. 7B shows an exemplary monovalent molecule (“Variant A8”) that includes a first polypeptide that includes a non-native IgH signal peptide, a B2GP1 G20-V83 antigen fragment with D8S and D9G mutations, and an Fc domain and a second polypeptide that includes an Fc domain. FIG. 7C shows an exemplary monovalent molecule (“Variant A9”) that includes a first polypeptide that includes a non-native IgH signal peptide, a B2GP1 G20-A262 antigen fragment, and an Fc domain and a second polypeptide that includes an Fc domain.

[0078] FIGs. 8A-8B show images of gels after protein electrophoresis technique using sodium dodecyl sulfate (SDS) polyacrylamide gel electrophoresis (PAGE) (FIG. 8A) and results from size exclusion chromatography (SEC-HPLC) (FIG. 8B) of molecules expressed from a construct encoding Variant Al. Samples were heated to 95°C in a sample buffer with reducing agent like beta-mercaptoethanol or dithiothreitol (lanes denoted with “R” to indicate reduced) and in a sample buffer without a reducing agent like beta-mercaptoethanol or dithiothreitol (lanes denoted with “NR” to indicate non-reduced). The SDS-PAGE images show that the molecule was correctly expressed. The SEC results show that the molecule was 99% pure post protein A purification.

[0079] FIGs. 9A-9B show images of gels after protein electrophoresis technique using sodium dodecyl sulfate (SDS) polyacrylamide gel electrophoresis (PAGE) (FIG. 9A) and results from size exclusion chromatography (SEC-HPLC) (FIG. 9B) of molecules expressed from a construct encoding Variant A3. Samples were heated to 95°C in a sample buffer with reducing agent like beta-mercaptoethanol or dithiothreitol (lanes denoted with “R” to indicate reduced) and in a sample buffer without a reducing agent like beta-mercaptoethanol or dithiothreitol (lanes denoted with “NR” to indicate non-reduced). The SDS-PAGE images show that the molecule Page 30 of 22413278080v 1Attorney Docket No. 2017420-0064was correctly expressed. The SEC results show that the molecule was 99% pure post protein A purification.

[0080] FIG. 10 shows an ELISA set up that was used to confirm binding of exemplary molecules to anti-B2GPl antibodies.

[0081] FIG. 11 shows results from an ELISA measuring the binding of Variants A1-A9 to anti-B2GPl antibody (HCAL) when coated at 15 nM.

[0082] FIG. 12 shows results from an ELISA measuring the binding of Variants A1-A9 to anti-B2GPl antibody (HCAL) when coated at 1.5 nM.

[0083] FIG. 13 shows results from an ELISA measuring the binding of Variants A1-A9 to anti-B2GPl antibody (MBB2) when coated at 15 nM.

[0084] FIG. 14 shows results from an ELISA measuring the binding of Variants A1-A9 to anti-B2GPl antibody (MBB2) when coated at 1.5 nM.

[0085] FIGs. 15A-15D shows normalized results from an ELISA measuring the binding of Variants A1-A9 to anti-B2GPl antibody (HCAL / MBB2) when coated at 15 nM or 1.5 nM.

[0086] FIGs. 16A-16E show exemplary molecule formats described herein. FIG. 16A shows an exemplary bivalent molecule (e.g., Variant Al or Variant A19) that includes a first and second polypeptide that includes a B2GP1 Domain 1 antigen fragment (e.g., a G20-V83 antigen fragment), and an Fc domain. FIG. 16B shows an exemplary bivalent molecule (e.g, Variant A2 or Variant A20) that includes a first and second polypeptide that includes a B2GP1 domain 1 antigen fragment (e.g., a G20-V83 antigen fragment) with D8S and D9G mutations, and an Fc domain. FIG. 16C shows an exemplary monovalent molecule (e.g, Variant A8) that includes a first polypeptide that includes aB2GPl domain 1 antigen fragment (e.g, a G20-V83 antigen fragment) with D8S and D9G mutations, and an Fc domain, and a second polypeptide that includes an Fc domain. FIG. 16D shows an exemplary molecule (e.g., Variant A21 and Variant A22) that includes a first and second polypeptide that includes a B2GP1 G20-I141 antigen fragment with D8S and D9G mutations and an Fc domain. FIG. 16E shows an exemplaryPage 31 of 22413278080v 1Attorney Docket No. 2017420-0064molecule (e.g., Variant A23) that includes a first and second polypeptide that includes a B2GP1 domain 1 antigen fragment e.g., a G20-V83 antigen fragment) with D8S and D9G mutations, a linker (G4S)3 (SEQ ID NO: 86), and an Fc domain.

[0087] FIGs. 17A-17B show results from an ELISA measuring binding of Variant Al, Variant A2, and Variant A8, to anti-B2GPl antibody (HCAL), coated at 15 nM in PBS, as both raw OD values (OD 450nM) (FIG. 17A) and normalized OD values (FIG. 17B). Variant Al, Variant A2, and Variant A8 were tested for binding at concentrations 1000 nM, 100 nM, 10 nM, 1 nM, and 0.1 nM.

[0088] FIGs. 18A-18B show results from an ELISA measuring binding of Variant Al, Variant A2, and Variant A8 to anti-B2GPl antibody P1SW-54, coated at 15 nM in PBS, as both raw OD values (OD 450nM) (FIG. 18A) and normalized OD values (FIG. 18B). Variant Al, Variant A2, and Variant A8 were tested for binding at concentrations 1000 nM, 100 nM, 10 nM, 1 nM, and 0.1 nM.

[0089] FIG. 19 shows results from an FcyRIIB-binding assay, measuring binding of exemplary molecules Variant A2, Variant A8, Variant A21, and Variant A23 to CHO cells ectopically expressing FcyRIIB by anti-B2GPl antibody HCAL labelled with AF647 by flow cytometry. Free molecule binding by exemplary molecules was directly detected by staining with HCAL-AF647. For immune complexes, a 1:1 ratio of exemplary molecules and HCAL-AF647 were mixed and left to incubate for 20 minutes at ambient temperature prior to staining CHO cells. Binding to FcyRIIB was confirmed by selective blocking with a FcyRIIB binding antibody (2B6) that binds to FcyRIIB at the Fc binding epitope.

[0090] FIG. 20 shows results from an FcyRIIA-binding assay, measuring binding of exemplary molecules Variant Al, Variant Al 9, Variant A2, Variant A20, Variant A21, Variant A22, and Variant A23 to CHO cells ectopically expressing FcγRIIA by anti-B2GPl antibody HCAL labelled with AF647 by flow cytometry. Free molecule binding by exemplary molecules was directly detected by staining with HCAL-AF647. For immune complexes, a 1: 1 ratio of exemplary molecules and HCAL-AF647 were mixed and left to incubate for 20 minutes at ambient temperature prior to staining CHO cells.Page 32 of 22413278080v 1Attorney Docket No. 2017420-0064

[0091] FIGs. 21A-21B show results from a cellular internalization assay measuring lysosomal internalization and degradation of B2GP1 autoantibody (HCAL) labelled with LysoLight Deep Red (LLDR) when complexed with exemplary molecule. LLDR dye only fluoresces following proteolytic cleavage in the endosome by cathepsin B. 1:1 ratios of exemplary molecules and HCAL-LLDR were incubated 20 minutes at ambient temperature. Complexes were added to RAMOS cells that ectopically express FcyRIIB at 2 nM for three hours. FIG. 21A shows results expressed as % of LLDR+ cells, indicative of the % of cells containing lysosomal autoantibody HCAL. FIG.21B shows the LLDR MFI, which indicates lysosomal localization of autoantibody.

[0092] FIG. 22 shows results from a APhL neutralization assay measuring exemplary molecule neutralization of target autoantibody HCAL by preventing binding to native B2GP1 in the presence of a mixture of phospholipids. This assay was performed according to instructions by the manufacturer (Louisville APL) but was edited to include exemplary molecules added to wells prior to addition of the B2GP1 specific autoantibody (HCAL). Exemplary molecules were tested at concentrations of 1 μM, 100 nM, and 10 nM. HCAL was tested at 40 nM. Calibrators and positive negative controls were included from the manufacturer.

[0093] FIG. 23 shows results from a APhL neutralization assay measuring exemplary molecule neutralization of target polyclonal autoantibodies from pooled serum from patients with APS (aCL) by preventing binding to native B2GP1 in the presence of a mixture of phospholipids. This assay was performed according to instructions by the manufacturer (Louisville APL) but was edited to include exemplary molecules added to wells prior to addition of pooled serum from patients with APS. Exemplary molecules were tested at concentrations of 1 μM, 100 nM, and 10 nM. Pooled serum from patients with APS was tested at a 1:50 dilution as recommended by the manufacturer. Calibrators and positive negative controls were included from the manufacturer.

[0094] FIG. 24 shows in vivo activity of exemplary molecules when administered to genO-hFcgR / hFcRn mice previously administered target anti-B2GPl autoantibodies (HCAL). HCAL was administered to genO-hFcgR / hFcRn mice at a dose of 50 pg per animal, to target a serum concentration of approximately 250 nM. Exemplary molecules were dosed at approximately six- Page 33 of 22413278080v 1Attorney Docket No. 2017420-0064fold excess and serum samples were drawn at five minutes, one hour, six hours, 24 hours, 48 hours, 72 hours, and 7 days following exemplary molecule administration to determine remaining levels of HCAL autoantibody.

[0095] FIG. 25 shows pharmacokinetic profile and half-life of exemplary molecules when administered to genO-hFcgR / hFcRn mice. Exemplary molecules were dosed to genO-hFcgR / hFcRn mice to target serum concentrations of approximately 1.5 pM. Serum samples were drawn at five minutes, one hour, six hours, 24 hours, 48 hours, 72 hours, 7 days, 10 days, and 14 days following exemplary molecule administration.DEFINITIONS

[0096] In order for the present disclosure to be more readily understood, certain terms are first defined below. Additional definitions for the following terms and other terms are set forth throughout the specification. The publications and other reference materials referenced herein to describe the background and to provide additional detail regarding its practice are hereby incorporated by reference.

[0097] The articles “a” and “an” are used herein to refer to one or to more than one (z.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0098] Administration: As used herein, typically refers to the administration of a composition to a subject or system. Those of ordinary skill in the art will be aware of a variety of routes that may, in appropriate circumstances, be utilized for administration to a subject, for example a human. For example, in some embodiments, administration may be ocular, oral, parenteral, topical, etc. In some particular embodiments, administration may be bronchial (e.g, by bronchial instillation), buccal, dermal (which may be or comprise, for example, one or more of topical to the dermis, intradermal, interdermal, transdermal, etc.), enteral, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, within a specific organ (e.g., intrahepatic), mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (e.g, by intratracheal instillation), vaginal, vitreal, etc. In some particular embodiments, administration may be parenteral (e.g., by Page 34 of 22413278080v 1Attorney Docket No. 2017420-0064intravenous injection). In some embodiments, administration may involve dosing that is intermittent (e.g., a plurality of doses separated in time) and / or periodic (e.g., individual doses separated by a common period of time) dosing. In some embodiments, administration may involve continuous dosing (e.g., perfusion) for at least a selected period of time.

[0099] Affinity: As is known in the art, “affinity” is a measure of the tightness with which two or more binding partners associate with one another (e.g., an antibody and target antigen). Those skilled in the art are aware of a variety of assays that can be used to assess affinity, and will furthermore be aware of appropriate controls for such assays. In some embodiments, affinity is assessed in a quantitative assay. In some embodiments, affinity is assessed over a plurality of concentrations (e.g., of one binding partner at a time). In some embodiments, affinity is assessed in the presence of one or more potential competitor entities (e.g., that might be present in a relevant - e.g., physiological - setting). In some embodiments, affinity is assessed relative to a reference (e.g., that has a known affinity above a particular threshold - a “positive control” reference - or that has a known affinity below a particular threshold - a “negative control” reference”). In some embodiments, affinity may be assessed relative to a contemporaneous reference. In some embodiments, affinity may be assessed relative to a historical reference. Typically, when affinity is assessed relative to a reference, it is assessed under comparable conditions.

[0100] Approximately or about: As used herein and as applied to one or more values of interest, refers to a value that is similar to a stated reference value. In some embodiments, the term “approximately” or “about” refers to a range of values that fall within 20% in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible reference value).

[0101] Antibody: As used herein, refers to a polypeptide that includes canonical immunoglobulin sequence elements sufficient to confer specific binding to a particular target antigen. As is known in the art, intact antibodies as produced in nature are tetrameric agents comprising two identical heavy chain polypeptides and two identical light chain polypeptides that associate with each other into what is commonly referred to as a “Y-shaped” structure. Each Page 35 of 22413278080v 1Attorney Docket No. 2017420-0064heavy chain comprises at least four domains - an amino-terminal variable (VH) domain (located at the tips of the Y structure), followed by three constant domains: CHI, CH2, and the carboxyterminal CH3 (located at the base of the Y’s stem). A short region, known as the “switch”, connects the heavy chain variable and constant regions. The “hinge” connects CH2 and CH3 domains to the rest of the antibody. Two disulfide bonds in this hinge region connect the two heavy chain polypeptides to one another in an intact antibody. Each light chain comprises two domains - an amino-terminal variable (VL) domain, followed by a carboxy-terminal constant (CL) domain, separated from one another by another “switch”. Intact antibody tetramers comprise two heavy chain-light chain dimers in which the heavy and light chains are linked to one another by a single disulfide bond; two other disulfide bonds connect the heavy chain hinge regions to one another, so that the dimers are connected to one another and a tetramer is formed. Naturally produced antibodies are also glycosylated, typically on the CH2 domain. Each domain in a natural antibody has a structure characterized by an “immunoglobulin fold” formed from two beta sheets (e.g., 3-, 4-, or 5-stranded sheets) packed against each other in a compressed antiparallel beta barrel. Each variable domain contains three hypervariable loops known as “complementarity determining regions” or “CDRs” (CDR1, CDR2, and CDR3) and four somewhat invariant “framework” regions (FR1, FR2, FR3, and FR4). When natural antibodies fold, the FR regions form the beta sheets that provide the structural framework for the domains, and the CDR loop regions from both the heavy and light chains are brought together in three-dimensional space so that they create a single hypervariable antigen binding site located at the tip of the Y structure. The Fc region of naturally occurring antibodies is located at the bottom of the Y structure and binds to elements of the complement system, and also to receptors on effector cells, including, for example, effector cells that mediate cytotoxicity. Affinity and / or other binding attributes of Fc regions for Fc receptors can be modulated through glycosylation or other modification. In some embodiments, antibodies produced and / or utilized in accordance with the present disclosure include glycosylated Fc domains, including Fc domains with modified or engineered glycosylation. In some embodiments, any polypeptide or complex of polypeptides that includes sufficient immunoglobulin domain sequences as found in natural antibodies can be referred to and / or used as an “antibody”, whether such polypeptide is naturally produced e.g., generated by an organism reacting to an antigen), or produced by recombinant engineering,Page 36 of 22413278080v 1Attorney Docket No. 2017420-0064chemical synthesis, or other artificial system or methodology. In some embodiments, an antibody is polyclonal. In some embodiments, an antibody is monoclonal. In some embodiments, an antibody has constant region sequences that are characteristic of mouse, rabbit, primate, or human antibodies. In some embodiments, antibody sequence elements are humanized, primatized, chimeric, etc., as is known in the art. Moreover, the term “antibody”, as used herein, can refer in appropriate embodiments (unless otherwise stated or clear from context) to any of the art-known or developed constructs or formats for utilizing antibody structural and functional features in alternative presentation. For example, in some embodiments, an antibody utilized in accordance with the present disclosure is in a format selected from, but not limited to, intact IgA, IgG, IgE or IgM antibodies; bi- or multi- specific antibodies; antibody fragments such as is used herein in the broadest sense and encompasses various antibody structures (preferably those fragments that exhibit the desired antigen-binding activity). For example, an antibody described herein can be an immunoglobulin, heavy chain antibody, light chain antibody, LRR-based antibody, or other protein scaffold with antibody-like properties, as well as any other immunological binding moiety known in the art, including, e.g., a 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 the like, or any combination thereof. The subunit structures and three-dimensional configurations of different classes of antibodies are known in the art. In some embodiments, an antibody may lack a covalent modification (e.g., attachment of a glycan) that it would have if produced naturally. In some embodiments, an antibody may contain a covalent modification, e.g., attachment of a glycan, a cargo moiety (e.g., a detectable moiety, a therapeutic moiety, a catalytic moiety, etc.), or other pendant group (e.g., polyethylene glycol, etc.).

[0102] Antigen-binding domain: An “anti gen -binding domain” refers to a portion of an antibody that binds the antigen to which the intact antibody binds. An antigen-binding domain of an antibody includes any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds an antigen to form a complex. Exemplary antigen-binding domains include, but are not limited to, a 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 the like, or any combination thereof. In some embodiments, the antigen-binding domain of the antibodies described herein are scFvs. In some Page 37 of 22413278080v 1Attorney Docket No. 2017420-0064embodiments, the antigen-binding domains of the antibodies described herein are VHH domains only. As with full antibody molecules, antigen-binding domains may be mono-specific or multispecific (e.g., bispecific). A multispecific antigen-binding domain of an antibody may comprise at least two different variable domains, wherein each variable domain is capable of specifically binding to a separate antigen or to a different epitope of the same antigen.

[0103] Antibody heavy chain: As used herein, refers to the larger of the two types of polypeptide chains present in intact antibodies as produced in nature.

[0104] Antibody light chain: As used herein, refers to the smaller of the two types of polypeptide chains present in intact antibodies as produced in nature.

[0105] Synthetic antibody: As used herein, refers to an antibody that is generated using recombinant DNA technology. The term should also be construed to mean an antibody which has been generated by the synthesis of a DNA molecule encoding the antibody and which DNA molecule expresses an antibody protein, or an amino acid sequence specifying the antibody, wherein the DNA or amino acid sequence has been obtained using synthetic DNA or amino acid sequence technology which is available and well known in the art.

[0106] Antigen. The term “antigen”, as used herein, refers to a molecule (e.g., a peptide, a polypeptide or a polysaccharide) that elicits a specific immune response. Antigen-specific immunological 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, an antigen is a T cell antigen, and elicits a cellular immune response. In some embodiments, an antigen is a B cell antigen, and elicits a humoral (i.e., antibody) response. In some embodiments, an antigen is both a T cell antigen and a B cell antigen. As used herein, the term “antigen” encompasses both a full-length polypeptide as well as a portion or immunogenic fragment of the polypeptide, and a peptide epitope within the polypeptides (e.g., a peptide epitope bound by a Major Histocompatibility Complex (MHC) molecule e.g., MHC class I, or MHC class II)). In some embodiments, an antigen is an autoantigen. In some embodiments, an antigen is tissue-specific or non-specific, e.g., identified from a cell or tissue that is a target of an autoimmune response, or from a healthy cell or tissue.Page 38 of 22413278080v 1Attorney Docket No. 2017420-0064

[0107] Autoantigen. An “autoantigen” as used herein refers to antigen that elicits an autoimmune response. An autoantigen refers to an endogenous (self) antigen that is recognized by an immune system as non-self, i.e., a foreign pathogen. An autoantigen may be a protein or an immunogenic fragment of a protein, or complexes of proteins recognized by the immune system of a subject suffering from or susceptible to an autoimmune disease.

[0108] Autoimmune disease. An “autoimmune disease” as used herein refers to an immune response directed against an autoantigen or self-antigen.

[0109] Associated: Two events or entities are “associated” with one another, as that term is used herein, if the presence, level, degree, type and / or form of one is correlated with that of the other. For example, a particular entity (e.g., polypeptide, genetic signature, metabolite, microbe, etc.) is considered to be associated with a particular disease, disorder, or condition, if its presence, level and / or form correlates with incidence of, susceptibility to, severity of, stage of, etc. the disease, disorder, or condition (e.g., across a relevant population).

[0110] Binding domain. As used herein, refers to a moiety or entity that specifically binds to a target moiety or entity. Typically, the interaction between a binding domain and its target is non-covalent. In some embodiments, a binding domain may be or comprise a moiety or entity of any chemical class including, for example, a carbohydrate, a lipid, a nucleic acid, a metal, a polypeptide, a small molecule. In some embodiments, a binding domain may be or comprise a polypeptide (or complex thereof). In some embodiments, a binding domain may be or comprise a target-binding portion of an antibody agent, a cytokine, a ligand (e.g., a receptor ligand), a receptor, a toxin, etc. In some embodiments, a binding domain may be or comprise an aptamer. In some embodiments, a binding domain may be or comprise a peptide nucleic acid (PNA). In some embodiments, a binding domain may be an antigen (e.g., an autoantigen). In some embodiments, a binding domain binds an antibody (i.e., a “target antibody”).

[0111] Effective amount: As used herein with reference to a dose of an agent, refers to a dose that is adequate to prevent or treat a target disease or disorder in a subject. Amounts effective for a therapeutic or prophylactic use will depend on, for example, the stage and severity of the disease or disorder being treated, the age, weight, and general state of health of the subject,Page 39 of 22413278080v 1Attorney Docket No. 2017420-0064and the judgment of the prescribing physician. The size of the dose will also be determined by the agent selected, method of administration, timing and frequency of administration, the existence, nature, and extent of any adverse side effects that might accompany the administration of a particular agent, and the desired physiological effect. It will be appreciated by one of skill in the art that various diseases or disorders could require prolonged treatment involving multiple administrations, perhaps using the inventive molecules in each or various rounds of administration.

[0112] Encoding: As used herein, “encoding” refers to the inherent property of specific sequences of nucleotides in a polynucleotide, such as a gene, a cDNA, or an mRNA, to serve as templates for synthesis of other polymers and macromolecules in biological processes having either a defined sequence of nucleotides ( / .e., rRNA, tRNA and mRNA) or a defined sequence of amino acids and the biological properties resulting therefrom. Thus, a gene encodes a protein if transcription and translation of mRNA corresponding to that gene produces the protein in a cell or other biological system. Both the coding strand, the nucleotide sequence of which is identical to the mRNA sequence and is usually provided in sequence listings, and the non-coding strand, used as the template for transcription of a gene or cDNA, can be referred to as encoding the protein or other product of that gene or cDNA.

[0113] Epitope: as used herein, refers to a moiety that is specifically recognized by an immunoglobulin e.g., antibody) binding component. In some embodiments, an epitope is comprised of a plurality of chemical atoms or groups on an antigen. In some embodiments, such chemical atoms or groups are surface-exposed when the antigen adopts a relevant three-dimensional conformation. In some embodiments, such chemical atoms or groups are physically near to each other in space when the antigen adopts such a conformation. In some embodiments, at least some such chemical atoms are groups are physically separated from one another when the antigen adopts an alternative conformation (e.g., is linearized or denatured).

[0114] Expression: As used herein, the term “expression” of a nucleic acid sequence refers to generation of any gene product from a nucleic acid sequence. In some embodiments, a gene product can be a transcript. In some embodiments, a gene product can be a polypeptide. In some embodiments, expression of a nucleic acid sequence involves one or more of the following:Page 40 of 22413278080v 1Attorney Docket No. 2017420-0064(1) production of an RNA template from a DNA sequence (e.g., by transcription); (2) processing of an RNA transcript (e.g., by splicing, editing, 5’ cap formation, and / or 3’ end formation); (3) translation of an RNA into a polypeptide or protein; and (4) post -translational modification of a polypeptide or protein.

[0115] Fragment: As used herein, the terms “fragment” or “portion” refers to a structure that includes a discrete portion of the whole, but lacks one or more moieties found in the whole structure. In some embodiments, a fragment consists of such a discrete portion. In some embodiments, a fragment consists of or comprises a characteristic structural element or moiety found in the whole. In some embodiments, a nucleotide fragment comprises 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) as found in the whole nucleotide. In some embodiments, a nucleotide fragment comprises 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 of the monomeric units (e.g., nucleic acids) found in the whole nucleotide. In some embodiments, a polypeptide or protein fragment comprises 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., amino acids) as found in the whole polypeptide or protein. In some embodiments, a polypeptide or protein fragment comprises 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 of the monomeric units (e.g., amino acids) found in the whole polypeptide or protein. The whole material or entity may, in some embodiments, be referred to as the “parent” of the fragment.

[0116] Identity. As used herein, the term “identity” refers to the overall relatedness between polymeric molecules, e.g., between nucleic acid molecules (e.g., DNA molecules and / or RNA molecules) and / or between polypeptide molecules. In some embodiments, polymeric molecules are considered to be “substantially identical” to one another if their sequences are at least 25%,Page 41 of 22413278080v 1Attorney Docket No. 2017420-006430%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical. Calculation of the percent identity of two nucleic acid or polypeptide sequences, for example, can be performed by aligning the two sequences for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second sequences for optimal alignment and non-identical sequences can be disregarded for comparison purposes). In some embodiments, the length of a sequence 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 a reference sequence. The nucleotides at corresponding positions are then compared. When a position in the first sequence is occupied by the same residue (e.g., nucleotide or amino acid) as the corresponding position in the second sequence, then the molecules are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which needs to be introduced for optimal alignment of the two sequences. The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. For example, the percent identity between two nucleotide sequences can be determined using the algorithm of Meyers and Miller (CABIOS, 1989, 4: 11-17), which has been incorporated into the ALIGN program (version 2.0). In some exemplary embodiments, nucleic acid sequence comparisons made with the ALIGN program use a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. The percent identity between two nucleotide sequences can, alternatively, be determined using the GAP program in the GCG software package using an NWSgapdna.CMP matrix.

[0117] Human antibody: As used herein, is intended to include antibodies having variable and constant regions generated (or assembled) from human immunoglobulin sequences. In some embodiments, antibodies (or antibody components) may be considered to be “human” even though their amino acid sequences include residues or elements not encoded by human germline immunoglobulin sequences (e.g., include sequence variations, for example that may (originally) have been introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example in one or more CDRs and in particular CDR3.Page 42 of 22413278080v 1Attorney Docket No. 2017420-0064

[0118] Immune cell: As used herein, refers to a cell that is involved in an immune response, e.g., promotion of 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. A source of immune cells (e.g., T lymphocytes) can be obtained from a subject.

[0119] Immune mediator. As used herein, the term “immune mediator” refers to any molecule that affects the cells and processes involved in immune responses. Immune mediators include cytokines, chemokines, soluble proteins, enzymes, and cell surface markers.

[0120] Immune response: As used herein, refers to a cellular and / or systemic response to an antigen that occurs when an immune cell identifies an antigenic molecule as foreign and induces the formation of antibodies and / or activates itself or other immune cells to remove the antigen.

[0121] Immunoglobulin or Ig: As used herein, refers to a class of proteins that function as antibodies. Antibodies expressed by B cells are sometimes referred to as a BCR (B cell receptor) or antigen receptor. The five members included in this class of proteins are IgA, IgG, IgM, IgD, and IgE. IgA is the primary antibody that is present in body secretions, such as saliva, tears, breast milk, gastrointestinal secretions and mucus secretions of the respiratory and genitourinary tracts. IgG is the most common circulating antibody. IgM is the main immunoglobulin produced in the primary immune response in most subjects. It is the most efficient immunoglobulin in agglutination, complement fixation, and other antibody responses, and is important in defense against bacteria and viruses. IgD is an immunoglobulin that has no known antibody function, but may serve as an antigen receptor. IgE is an immunoglobulin that mediates immediate hypersensitivity by causing release of mediators from mast cells and basophils upon exposure to allergen.

[0122] Improved, increased or reduced: As used herein, the terms “improved”, “increased” or “reduced”, or grammatically comparable comparative terms, indicate values that are relative to a comparable reference measurement. For example, in some embodiments, an assessed value achieved with an agent of interest may be “improved” relative to that obtained with a comparable Page 43 of 22413278080v 1Attorney Docket No. 2017420-0064reference agent. Alternatively or additionally, in some embodiments, an assessed value achieved in a subject or system of interest may be “improved” relative to that obtained in the same subject or system under different conditions (e.g., prior to or after an event such as administration of an agent of interest), or in a different, comparable subject (e.g., in a comparable subject or system that differs from the subject or system of interest in presence of one or more indicators of a particular disease, disorder or condition of interest, or in prior exposure to a condition or agent, etc.. In some embodiments, comparative terms refer to statistically relevant differences (e.g., that are of a prevalence and / or magnitude sufficient to achieve statistical relevance). Those skilled in the art will be aware, or will readily be able to determine, in a given context, a degree and / or prevalence of difference that is required or sufficient to achieve such statistical significance.

[0123] Isolated: As used herein, refers to something altered or removed from the natural state. For example, a nucleic acid or a polypeptide naturally present in a living animal is not “isolated,” but the same nucleic acid or polypeptide partially or completely separated from the coexisting materials of its natural state is “isolated.” An isolated nucleic acid or polypeptide can exist in substantially purified form, or can exist in a non-native environment such as, for example, a host cell.

[0124] KD: As used herein, refers to the dissociation constant of a binding agent e.g., an antibody or binding component thereof) from a complex with its partner (e.g., the epitope to which the antibody or binding component thereof binds).

[0125] Koff: As used herein, refers to the off rate constant for dissociation of a binding agent (e.g., an antibody or binding component thereof) from a complex with its partner (e.g., the epitope to which the antibody or binding component thereof binds).

[0126] Kon: As used herein, refers to the on rate constant for association of a binding agent (e.g., an antibody or binding component thereof) with its partner (e.g., the epitope to which the antibody or binding component thereof binds).

[0127] Modulating: As used herein the term “modulating,” refers to mediating a detectable increase or decrease in the level of a response and / or a change in the nature of a response in a Page 44 of 22413278080v 1Attorney Docket No. 2017420-0064subject compared with the level and / or nature of a response in the subject in the absence of a treatment, and / or compared with the level and / or nature of a response in an otherwise identical but untreated subject. The term encompasses perturbing and / or affecting a native signal or response thereby mediating a beneficial therapeutic response in a subject, preferably, a human.

[0128] Nucleic acid. As used herein, refers to a polymer of at least three nucleotides. In some embodiments, a nucleic acid comprises DNA. In some embodiments, a nucleic acid comprises RNA. In some embodiments, a nucleic acid is single stranded. In some embodiments, a nucleic acid is double stranded. In some embodiments, a nucleic acid comprises both single and double stranded portions. In some embodiments, a nucleic acid comprises a backbone that comprises one or more phosphodiester linkages. In some embodiments, a nucleic acid comprises a backbone that comprises both phosphodiester and non-phosphodiester linkages. For example, in some embodiments, a nucleic acid may comprise a backbone that comprises one or more phosphorothioate or 5’-N-phosphoramidite linkages and / or one or more peptide bonds, e.g., as in a “peptide nucleic acid”. In some embodiments, a nucleic acid comprises one or more, or all, natural residues (e.g., adenine, cytosine, deoxy adenosine, deoxy cytidine, deoxyguanosine, deoxythymidine, guanine, thymine, uracil). In some embodiments, a nucleic acid comprises one or more, or all, non-natural residues. In some embodiments, a non-natural residue comprises a nucleoside analog (e.g, 2-aminoadenosine, 2-thiothymidine, inosine, pyrrolo-pyrimidine, 3 -methyl adenosine, 5 -methyl cytidine, C-5 propynyl-cytidine, C-5 propynyl -uridine, 2-aminoadenosine, C5-bromouridine, C5-fluorouridine, C5-iodouridine, C5-propynyl-uridine, C5 -propynyl-cytidine, C5-methylcytidine, 2-aminoadenosine, 7-deazaadenosine, 7-deazaguanosine, 8-oxoadenosine, 8-oxoguanosine, 0(6)-methylguanine, 2-thiocytidine, methylated bases, intercalated bases, and combinations thereof). In some embodiments, a non-natural residue comprises one or more modified sugars (e.g, 2 ’-fluororibose, ribose, 2’-deoxyribose, arabinose, and hexose) as compared to those in natural residues. In some embodiments, a nucleic acid has a nucleotide sequence that encodes a functional gene product such as an RNA or polypeptide. In some embodiments, a nucleic acid has a nucleotide sequence that comprises one or more introns. In some embodiments, a nucleic acid may be prepared by isolation from a natural source, enzymatic synthesis (e.g, by polymerization based on a complementary template, e.g., in vivo or in vitro reproduction in a recombinant cell or system, or chemical synthesis. In somePage 45 of 22413278080v 1Attorney Docket No. 2017420-0064embodiments, a nucleic acid is at least 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 20, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000 or more residues long.

[0129] Operably linked: As used herein, refers to functional linkage between, for example, a regulatory sequence and a heterologous nucleic acid sequence resulting in expression of the latter. For example, a first nucleic acid sequence is operably linked with a second nucleic acid sequence when the first nucleic acid sequence is placed in a functional relationship with the second nucleic acid sequence. For instance, 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 contiguous and, where necessary to join two protein coding regions, in the same reading frame.

[0130] Pharmaceutical composition: As used herein, refers to an active agent, formulated together with one or more pharmaceutically acceptable carriers. In some embodiments, an active agent of interest is present in unit dose amount appropriate for administration in a therapeutic regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream, or foam; sublingually; ocularly; transdermally; or nasally, pulmonary, and to other mucosal surfaces.

[0131] Polynucleotide: As used herein, refers to a chain of nucleotides. Furthermore, nucleic acids are polymers of nucleotides. Thus, nucleic acids and polynucleotides as used Page 46 of 22413278080v 1Attorney Docket No. 2017420-0064herein are interchangeable. One skilled in the art has the general knowledge that nucleic acids are polynucleotides, which can be hydrolyzed into the monomeric “nucleotides.” The monomeric nucleotides can be hydrolyzed into nucleosides. As used herein polynucleotides include, but are not limited to, all nucleic acid sequences which are obtained by any means available in the art, including, without limitation, recombinant means, i.e., the cloning of nucleic acid sequences from a recombinant library or a cell genome, using ordinary cloning technology and PCR, and the like, and by synthetic means.

[0132] Protein: As used herein, refers to a polypeptide i.e., a string of at least two amino acids linked to one another by peptide bonds). Thus, proteins and polypeptides as used herein are interchangeable. Proteins may include moieties other than amino acids (e.g., may be glycoproteins, proteoglycans, etc.) and / or may be otherwise processed or modified. Those of ordinary skill in the art will appreciate that a “protein” can be a complete polypeptide as produced by a cell (with or without a signal sequence), or can be a characteristic portion thereof. Those of ordinary skill will appreciate that a protein can sometimes include more than one polypeptide, for example linked by one or more disulfide bonds or associated by other covalent or non-covalent means. Polypeptides may contain L-amino acids, D-amino acids, or both and may contain any of a variety of amino acid modifications or analogs known in the art. Useful modifications include, e.g., terminal acetylation, amidation, methylation, etc. In some embodiments, proteins may comprise natural amino acids, non-natural amino acids, synthetic amino acids, and combinations thereof. The term “peptide” is generally used to refer to a polypeptide having a length of less than about 100 amino acids, less than about 50 amino acids, less than 20 amino acids, or less than 10 amino acids. In some embodiments, proteins are antibodies, antibody fragments, biologically active portions thereof, and / or characteristic portions thereof.

[0133] Specifically binds: As used herein, the term “specifically binds,” with respect to an antigen-binding domain, such as those found in an antibody, refers to an antigen-binding domain which recognizes a specific antigen, but does not substantially recognize or bind other molecules in a sample. For example, an antigen-binding domain that specifically binds to an antigen from one species may also bind to that antigen from one or more other species. But, such cross-Page 47 of 22413278080v 1Attorney Docket No. 2017420-0064species reactivity does not itself alter the classification of an antigen-binding domain as specific. In another example, an antigen-binding domain that specifically binds to an antigen may also bind to different allelic forms of the antigen. However, such cross reactivity does not itself alter the classification of an antigen-binding domain as specific. In some instances, the terms “specific binding” or “specifically binding,” can be used in reference to the interaction of an antigen binding domain with a second chemical species, to mean that the interaction is dependent upon the presence of a particular structure (e.g., an antigenic determinant or epitope) on the chemical species; for example, an antigen binding domain recognizes and binds to a specific protein structure rather than to proteins generally. If an antigen binding domain is specific for epitope “A”, the presence of a molecule containing epitope A (or free, unlabeled A), in a reaction containing labeled “A” and the antigen binding domain, will reduce the amount of labeled A bound to the antigen binding domain.

[0134] Subject: As used herein, refers to an organism, for example, a mammal (e.g., a human, a non-human mammal, a non-human primate, a primate, a laboratory animal, a mouse, a rat, a hamster, a gerbil, a cat, or a dog). In some embodiments a human subject is an adult, adolescent, or pediatric subject. In some embodiments, a subject is suffering 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; in some embodiments, a susceptible subject is predisposed to and / or shows an increased risk (as compared to the average risk observed in a reference subject or population) of developing the disease, disorder, or condition. In some embodiments, a subject displays one or more symptoms of a disease, disorder, or condition. In some embodiments, a subject does not display a particular symptom e.g., clinical manifestation of disease) or characteristic of a disease, disorder, or condition. In some embodiments, a subject does not display any symptom or characteristic of a disease, disorder, or condition. In some embodiments, a subject is a patient. In some embodiments, a subject is an individual to whom diagnosis and / or therapy is and / or has been administered.

[0135] Target: As used herein, refers to a cell, tissue, organ, or site within the body that is the subject of provided methods, systems, and / or compositions, for example, a cell, tissue, organPage 48 of 22413278080v 1Attorney Docket No. 2017420-0064or site within a body that is in need of treatment or is preferentially bound by, for example, a molecule described herein.

[0136] Treat: As used herein, the term “treat,” “treatment,” or “treating” refers to partial or complete alleviation, amelioration, delay of onset of, inhibition, prevention, relief, and / or reduction in incidence and / or severity of one or more symptoms or features of a disease, disorder, and / or condition. In some embodiments, treatment may be administered to a subject who does not exhibit signs or features of a disease, disorder, and / or condition (e.g, may be prophylactic). In some embodiments, treatment may be administered to a subject who exhibits only early or mild signs or features of the disease, disorder, and / or condition, for example for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and / or condition. In some embodiments, treatment may be administered to a subject who exhibits established, severe, and / or late-stage signs of the disease, disorder, or condition. As used herein, a “therapeutic” is any agent used to treat a subject.

[0137] Vector: As used herein, the term “vector” refers to a composition of matter that comprises an isolated nucleic acid and which can be used to deliver the isolated nucleic acid to the interior of a cell. 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 an autonomously replicating plasmid or a virus. The term should also be construed to include non-plasmid and non-viral components which facilitate transfer of nucleic acid into cells, such as, for example, polylysine compounds, liposomes, and the like. Examples of viral vectors include, but are not limited to, adenoviral vectors, adeno-associated virus vectors, retroviral vectors, lentiviral vectors, and the like.

[0138] Throughout this disclosure, various aspects can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on scope. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within Page 49 of 22413278080v 1Attorney Docket No. 2017420-0064that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.DETAILED DESCRIPTION

[0139] Certain autoimmune diseases are driven by autoantibodies that mount an immune response to self-antigens (z.e., autoantigens). Certain autoantibodies (e.g, anti-B2GPl antibodies that are implicated in APS) are also implicated in other diseases, disorders or conditions that are not necessarily recognized as autoimmune - including stroke and a subset of normal pregnancy. Despite the identification of certain autoantibody-antigen pairs and their implication in autoimmune diseases (e.g., antiphospholipid syndrome (APS)), many are poorly controlled with current treatments. Current standards of care involve tamping down 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 that target plasma cells, antibodies that target FcRn “FcRn inhibitors”, and plasmapheresis. FcRn inhibitors result in pan IgG depletion, and often an incomplete depletion of autoantibodies.

[0140] The present disclosure encompasses molecules for selectively depleting autoantibodies (i.e., anti-B2GPl autoantibodies), to treat autoimmune diseases (e.g., APS) or other diseases, disorders or conditions involving anti-B2GPl autoantibodies. Molecules described herein in some embodiments include a first polypeptide comprising a first Fc domain and an autoantibody -binding domain that binds to autoantibodies (z.e., anti-B2GPl autoantibodies); 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 autoantibodies (z.e., anti-B2GPl 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 does not further comprise an autoantibody-bindingPage 50 of 22413278080v 1Attorney Docket No. 2017420-0064domain that binds to autoantibodies (i.e., anti-B2GP1 autoantibodies) and the molecule is a heterodimer.

[0141] The disclosure provides, among other things, molecules that selectively target and deplete autoantibodies, for example, by targeting them to internalizing receptors which bind to and internalize the complex into a cell for lysosomal degradation. In some embodiments, the autoantibody-binding domain comprises an autoantigen. For example, if the particular autoantibodies to be targeted are anti-B2GPl autoantibodies (e.g., for treatment of APS), an autoantigen domain may comprise a B2GP1 autoantigen domain. In addition to including an autoantibody-binding domain, a molecule may also include in its first and / or second Fc domains, a modification that increases its binding to an internalizing receptor or endocytic receptor on a cell surface (e.g., that internalizes its ligands and targets them to the lysosome). In some embodiments, a molecule may include an antigen-binding domain that binds to an internalizing receptor or endocytic receptor on a cell surface (e.g., that internalizes its ligands and targets them to the lysosome).Antiphospholipid antibodies and APS

[0142] In some embodiments, molecules described herein may be used for the treatment of antiphospholipid syndrome (APS), and other diseases, disorders or conditions implicated by antiphospholipid antibodies, by including an autoantibody binding domain that comprises a B2GP1 autoantigen domain, or a fragment or variant thereof.

[0143] Antiphospholipid syndrome is defined by the presence of antiphospholipid antibodies (APLAs) in the setting of thrombosis or pregnancy loss / complications. See Grygiel-Gomiak and Mazurkiewicz, J. Thromb Thrombolysis 56(2):301-314 (2023) and Dabit et al., Curr Rheumatol Rep. 23(12):85 (2022). It is now generally accepted that these antiphospholipid antibodies are not directed against negatively charged phospholipids, but towards proteins bound to these phospholipids. The three known APLAs include anti-cardiolipin antibodies, anti-B2GPl antibodies and lupus anticoagulants. Anti-cardiolipin antibodies bind to a complex of B2GP1 and cardiolipin. Lupus anticoagulants have an unknown specificity but can cross react with B2GP1 and prothrombin.Page 51 of 22413278080v 1Attorney Docket No. 2017420-0064

[0144] Animal studies have shown that the most prominent antigen in APS is B2GP1, a protein with (relatively low) affinity for anionic phospholipids. B2GPl’s primary function is the regulation of complement and coagulation. See McDonnell et al., Blood reviews 39: 100610 (2020). B2GP1 is also known as apolipoprotein H (ApoH) and consists of 326 amino acids organized in five complement control protein (CCP) domains (Domains 1-5). See Lozier et al., PNAS 81:3640-3644 (1991). Member of the CCP superfamily are composed of repeating stretches of about 60 amino acids with two fully conserved disulfide bonds. The first four domains have the regular, conserved sequences, but the fifth domain is aberrant. Domain 5 mediates phospholipid association through a hydrophobic loop. Analysis of the specificity of antiphospholipid antibodies has identified an epitope on Domain 1 of B2GP1 to which the antibodies are directed. See Iverson et al., J Immunol 169:7097-7103 (2002), De Laat et al., Blood 105:1540-1545 (2005), and Ioannou et al., Arthritis Rheum 56:280-290 (2007). This discontinuous epitope includes R39 and R43. Domain 1 specificity has been shown to independently predict thrombotic risk in a prospective cohort study. See Zhou et al., Lupus Science & Medicine 10(2):e000924 (2023).

[0145] Anti-B2GP1 autoantibodies have diverse direct effects on a multitude of cells secondary to binding of B2GP1 which can nonspecifically interact with the cell membranes of these cells. B2GP1 association with cell membrane exposes immunogenic target. Subsequent binding by anti-B2GPl autoantibodies has a pathological effect on multiple cells. Each of these actions independently predispose to clot formation or damage of trophoblasts that support fetal development. The complex of APLA and B2GP1 can also induce complement ultimately leading to endothelial / trophoblast cell damage and thrombosis. See McDonnell et al., Blood reviews 39:100610 (2020).

[0146] APS can be primary when there is no evidence of autoimmune disease or secondary to autoimmune processes, such as systemic lupus erythematosus (SLE), in 40% of cases. See Levine et al., N Engl J Med. 346(10):752-63 (2002). A study found positive APLAs in 6% of all pregnant patients, 13.5% of stroke patients, and 9.5% of patients with deep venous thromboses (DVTs). See Grygiel-Gomiak and Mazurkiewicz, J. Thromb Thrombolysis 56(2):301-314 (2023). Genetic risk factors, such as coagulation factor mutations, increase the risk ofPage 52 of 22413278080v 1Attorney Docket No. 2017420-0064antiphospholipid antibody-associated thrombosis. HLA-DR7, DR4, DRw53, DQw7, and C4 null alleles have been reported to be associated with APS. Infections, particularly viral, are associated with elevated APLA levels compared to bacterial infections. Some of these include Borrelia burgdorferi, Coxiella burnetii, Treponema, hepatitis C, HIV, COVID-19, Epstein-Barr virus (EBV), and Leptospira have been implicated in APLA formation. In fact, a large meta-analysis found that almost 50% of patients diagnosed with COVID-19 had positive APS, most commonly lupus anticoagulant. However, this analysis found no increased thrombotic risk in APLA-positive COVID-19 patients. See Grygiel-Gorniak and Mazurkiewicz, J. Thromb Thrombolysis 56(2):301 -314 (2023) and Arvieux et al., Thromb Haemost. 87(4):599-605 (2002).

[0147] Several drugs, including chlorpromazine, procainamide, quinidine, and phenytoin, can induce APLA production. Low levels of APLAs may also be normally present and may be transient, leading to the requirement of positive antibodies at least 12 weeks apart for diagnosis. See Grygiel-Gorniak and Mazurkiewicz, J. Thromb Thrombolysis 56(2):301-314 (2023).

[0148] APS can be further classified based on clinical manifestations, such as obstetric, thrombotic, or both, and whether it involves life-threatening multi organ involvement.Thrombotic APS: Patients are diagnosed with APS based on arterial or venous thrombosis and persistent laboratory criteria for APLA. The most common presentation is a DVT. See Dabit et al., Curr Rheumatol Rep. 23 (12): 85 (2022). Obstetric APS: Patients are diagnosed based on APS-defining pregnancy morbidity, such as including premature birth due to severe preeclampsia, fetal death after 10 weeks of gestation, placental insufficiency, or multiple embryonic losses before 10 weeks of gestation, and persistent laboratory criteria for APLA. Patients with both thromboembolic complications and APS-defining pregnancy morbidity are recognized as having both thrombotic and obstetric APS. Catastrophic APS: This rare and lifethreatening form of APS is defined as thrombotic complications affecting multiple organs, both microvascular and macrovascular. See Garra et al., A case series and literature review. Medicine (Baltimore) 102(6):e32949 (2023).

[0149] The present disclosure recognizes that further selectivity in APS treatments based on depletion of autoantibodies can be introduced in order to preserve essential immunity and increase efficacy of, e.g., antibodies that target foreign pathogens such as viral antigens.Page 53 of 22413278080v 1Attorney Docket No. 2017420-0064Molecules described herein include a further selectivity to target autoantibodies (e.g., anti-B2GP1 autoantibodies). This strategy includes, in some embodiments, utilizing a B2GP1 autoantigen domain, or a fragment or variant thereof, for targeted destruction of anti-B2GPl autoantibodies, thus removing the autoimmune response that implicates APS.Exemplary Molecules

[0150] The present disclosure provides molecules for selectively depleting and / or neutralizing autoantibodies (i.e., anti-B2GPl autoantibodies), to treat autoimmune diseases (e.g., APS) or other diseases, disorders or conditions involving anti-B2GPl autoantibodies. Molecules described herein in some embodiments include a first polypeptide comprising a first Fc domain and an autoantibody -binding domain that binds to autoantibodies (i.e., anti- B2GP1 autoantibodies); 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 anti-B2GPl autoantibodies and the molecule is a homodimer. In some embodiments, the second polypeptide further comprises an autoantibodybinding domain that binds to anti-B2GPl autoantibodies and the molecule is a heterodimer. In some embodiments, the second polypeptide does not comprise an autoantibody-binding domain that binds to anti-B2GPl autoantibodies and the molecule is a heterodimer.

[0151] In some embodiments, the first and / or second polypeptide further comprises an antigen-binding domain (e.g., a Fab domain).

[0152] In some embodiments, a first and second polypeptide of a molecule described herein can be in the form of a fusion protein. In some embodiments, a first and second polypeptide of a molecule described herein can be in the form of a chemically conjugated molecule.

[0153] In some embodiments, the first and / or second Fc domain comprises one or more mutated amino acid residues and has increased binding affinity to an internalizing receptor (e.g., FcyRIIB) relative to a corresponding wild-type Fc domain.Page 54 of 22413278080v 1Attorney Docket No. 2017420-0064

[0154] In some embodiments, upon binding of one or two molecules to an autoantibody (i.e., anti-B2GP1 autoantibody), an immune complex is formed. In some embodiments, immune complexes formed with one molecule described herein and an autoantibody ( / .<?., anti-B2GPl autoantibody) have enhanced binding kinetics with FcyRIIB relative to an immune complex that comprises the autoantibody i.e., anti-B2GPl autoantibody) bound to one corresponding molecule with wild-type Fc domains. In some embodiments, immune complexes formed with two molecules described herein and an autoantibody (i.e., anti-B2GP1 autoantibody) have enhanced binding kinetics with FcγRIIB relative to an immune complex that comprises the autoantibody (i.e., anti-B2GP1 autoantibody) bound to two corresponding molecules with wildtype Fc domains. In some embodiments, such enhanced binding kinetics increases clearance of the immune complex.Autoantibody-binding domain

[0155] The present disclosure provides molecules that include an autoantibody-binding domain. An autoantibody-binding domain may include any domain that binds to autoantibodies that drive an autoimmune disease (e.g., anti-B2GPl autoantibodies) or other diseases, disorders or conditions involving anti-B2GPl autoantibodies. In some embodiments, the autoantibodybinding domain comprises an autoantigen, or a fragment or variant thereof (e.g., a B2GP1 autoantigen domain, or fragment or variant thereof). In some embodiments, the autoantibodybinding domain comprises a binding domain that targets any portion or region or epitope on an autoantibody. In some embodiments, the autoantibody-binding domain comprises a Fab domain, scFv domain, VHH, Fc domain, peptide sequence, mimotope, and / or any part of an autoantigen domain that the autoantibody targets.

[0156] In some embodiments, the autoantibody-binding domain described herein prevents binding of an autoantibody to its cognate autoantigen (e.g., autoantibodies to B2GP1 autoantigens).Autoantigens

[0157] In some embodiments a molecule comprises an autoantibody-binding domain that comprises an autoantigen, or a fragment or variant thereof. Such autoantigen domains target Page 55 of 22413278080v 1Attorney Docket No. 2017420-0064autoantibodies that are implicated in various autoimmune diseases. For example, a B2GPI autoantigen domain (or a fragment or variant thereof) may be used in a molecule in order to target anti-B2GPI autoantibodies that are known to cause autoimmune diseases such as APS.

[0158] Beta-2-Glycoprotein I (B2GP1) is a five domain protein comprising four similar complement control protein (CCP)-like domains (Domains 1-4) and one different domain (Domain 5) with a large lysine loop (1C1Z, Ensemble) See McDonnell et al., Blood Rev.Jan;39: 100610 (2020). Human wildtype B2GPI is 345 amino acids in length (SEQ ID NO: 1). The first 19 amino acids (MISPVLILFSSFLCHVAIA, SEQ ID NO: 12) is a signal peptide, which ultimately gets cleaved.

[0159] In some embodiments, an autoantigen domain includes a Beta-2 Glycoprotein 1 (B2GP1) autoantigen domain, or a fragment or variant thereof. In some embodiments, a B2GP1 autoantigen domain comprises a fragment or variant of SEQ ID NO: 1. In some embodiments, an autoantigen fragment is 5-345, 5-250, 5-100, 5-50, 10-500, 10-250, 10-100, 10-50, 20-500, 20-250, 20-200, 20-50, 25-500, 25-250, 25-100, 25-50, 50-500, 50-250, 50-100, 100-500, or 100-250 amino acids of SEQ ID NO: 1. In some embodiments, an autoantigen fragment comprises at least 5, 10 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100 amino acids of SEQ ID NO: 1. In some embodiments, an autoantigen fragment comprises at most 20, 30, 40, 50, 60, 70, 75, 80,90, 100, 110, 120, 125, 130, 140, 150, 160, 170, 175, 180, 190, 200, 210, 220, 225, 230, 240, 250, 260, 270, 275, 280, 290, 300, 310, 320, 325, 330, 340 amino acids of SEQ ID NO: 1.

[0160] In some embodiments, a B2GP1 autoantigen domain comprises B2GP1 Domain 1. In some embodiments, a B2GP1 autoantigen domain comprises amino acids 20-83 of SEQ ID NO: 1 or “G20-V83” as represented in SEQ ID NO: 2. In some embodiments, an autoantigen domain includes a B2GP1 Domain 1 and all or part of a B2GP1 Domain 2. In some embodiments, an autoantigen domain includes a B2GP1 Domain 1, a B2GP1 Domain 2, and all or part of a B2GP1 Domain 3. In some embodiments, an autoantigen domain includes a B2GP1 Domain 1, a B2GP1 Domain 2, B2GP1 Domain 3, and B2GP1 Domain 4. In some embodiments, a B2GP1 autoantigen domain comprises a fragment of B2GP1 that corresponds to amino acids 20-262 of SEQ ID NO: 1 or “G20-A262” as represented in SEQ ID NO: 3. In some Page 56 of 22413278080v 1Attorney Docket No. 2017420-0064embodiments, a B2GP1 autoantigen domain comprises a fragment of B2GP1 that corresponds to amino acids 20-141 of SEQ ID NO: 1 or “G20-I141” as represented in SEQ ID NOs: 5 and 6. In some embodiments, an autoantigen domain comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to the amino acid sequence of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, or a fragment thereof. In some embodiments, an autoantigen domain comprises the amino acid sequence of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, or a fragment thereof.

[0161] In some embodiments, a B2GP1 autoantigen domain comprises one or more mutations compared to the wildtype B2GP1 sequence (e.g., as shown in SEQ ID NO: 1). In some embodiments, an autoantigen domain comprises a human B2GP1 autoantigen domain variant that includes a D8S and a D9G mutation relative to the amino acid sequence of SEQ ID NO: 2. In some embodiments, B2GP1 autoantigen domain comprises SEQ ID NO: 4 or SEQ ID NO: 6.

[0162] In some embodiments, an autoantigen domain comprises a human B2GP1 autoantigen domain variant that comprises a sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to any one of SEQ ID NOs: 1-6 (shown below in Table 1). In some embodiments, an autoantigen domain comprises a human B2GP1 autoantigen domain variant that comprises a sequence selected from SEQ ID NOs: 1-6 (shown below in Table 1).Table 1: Exemplary B2GP1 Antigen SequencesSEQ IDAntigen SequencesNOhuman MISPVLILFSSFLCHVAIAGRTCPKPDDLPFSTVVPLKT 1 B2GP1 FYEPGEEITYSCKPGYVSRGGMRKFICPLTGLWPINTLK (UniProt CTPRVCPFAGILENGAVRYTTFEYPNTISFSCNTGFYLN GADSAKCTEEGKWSPELPVCAPIICPPPSIPTFATLRVYP02749)KPSAGNNSLYRDTAVFECLPQHAMFGNDTITCTTHGNWT(M1-C345) KLPECREVKCPFPSRPDNGFVNYPAKPTLYYKDKATFGC Signal HDGYSLDGPEEIECTKLGNWSAMPSCKASCKVPVKKATVsequencePage 57 of 22413278080v 1Attorney Docket No. 2017420-0064SEQ IDAntigen SequencesNO VYQGERVKIQEKFKNGMLHGDKVSFFCKNKEKKCSYTED AQCIDGTIEVPKCFKEHSSLAFWKTDASDVKPChuman GRTCPKPDDLPFSTVVPLKTFYEPGEEITYSCKPGYVSR 2 B2GP1 GGMRKFICPLTGLWPINTLKCTPRVDomain 1(G20-V83)fragmenthuman GRTCPKPDDLPFSTVVPLKTFYEPGEEITYSCKPGYVSR 3 B2GP1 GGMRKFICPLTGLWPINTLKCTPRVCPFAGILENGAVRY Domain 1-4 TTFEYPNTISFSCNTGFYLNGADSAKCTEEGKWSPELPV CAPIICPPPSIPTFATLRVYKPSAGNNSLYRDTAVFECL(G20-A262)PQHAMFGNDTITCTTHGNWTKLPECREVKCPFPSRPDNGfragment FVNYPAKPTLYYKDKATFGCHDGYSLDGPEEIECTKLGN WSAMPSCKAhuman D8S, D9G GRTCPKPSGLPFSTVVPLKTFYEPGEEITYSCKPGYVSR 4 B2GP1 mutations GGMRKFICPLTGLWPINTLKCTPRVDomain 1(G20-V83)fragmentHuman - GRTCPKPDDLPFSTVVPLKTFYEPGEEITYSCKPGYVSR 5 B2GP1 GGMRKFICPLTGLWPINTLKCTPRVCPFAGILENGAVRY Domain 1-2 TTFEYPNTISFSCNTGFYLNGADSAKCTEEGKWSPELPVCAP 11G20-I141Human D8S, D9G GRTCPKPSGLPFSTVVPLKTFYEPGEEITYSCKPGYVSR 6 B2GP1 mutations GGMRKFICPLTGLWPINTLKCTPRVCPFAGILENGAVRY Domain 1-2 TTFEYPNTISFSCNTGFYLNGADSAKCTEEGKWSPELPVCAP 11G20-I141Antigen-binding domains

[0163] In some embodiments, a molecule provided herein includes one or more antigenbinding domains (e.g., as shown in FIG.3). In some embodiments, an antigen-binding domain binds to an internalizing receptor (e.g., FcγRIIB, FcRn, ASGPR, BCMA, CD38, SLAMF7, GPCR5D, and / or CD138). In some embodiments, an antigen-binding domain binds to an autoantibody (e.g., an anti-B2GPl autoantibody).Page 58 of 22413278080v 1Attorney Docket No. 2017420-0064

[0164] An antigen-binding domain can include, but is not limited to, a monoclonal antibody, a synthetic antibody, a human antibody, a humanized antibody, a non-human antibody, and any fragment thereof. Thus, in one embodiment, the antigen-binding domain portion comprises a mammalian antibody or a fragment thereof. In some embodiments, an antigen-binding domain included in a molecule can be any binding polypeptide such as, but not limited protein scaffold with antibody -like properties (e.g., an antibody variable domain), as well as any other immunological binding moiety known in the art, including, e.g., a 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 sequence, or mimotope, or any combination thereof.

[0165] In some embodiments, a molecule described herein includes an antigen-binding domain that targets two or more targets. In some embodiments an antigen-binding domain is a bispecific antigen-binding domain. In some embodiments, an antigen-binding domain comprises a tri specific antigen-binding domain. In some embodiments, an antigen-binding domain targets two non-overlapping epitopes on the same target (e.g., two non-overlapping epitopes on FcyRIIB, FcRn, ASGPR, BCMA, CD38, SLAMF7, GPCR5D, and / or CD138 in the case of antigen-binding domain that targets an internalizing receptor or two-non-overlapping epitopes of an autoantibody).

[0166] In some embodiments, a molecule may include a first antigen-binding domain and a second antigen-binding domain such that each antigen-binding domain is capable of binding to the same or different target antigen. In some embodiments, a first antigen-binding domain targets an autoantibody (e.g., an anti-B2GPl autoantibody) and a second antigen-binding domain targets an internalizing receptor (e.g., FcyRIIB, FcRn, ASGPR, BCMA, CD38, SLAMF7, GPCR5D, and / or CD 138).

[0167] In some embodiments, an antigen-binding domain comprises a Fab comprising a heavy chain and light chain antibody component. In some embodiments, an antigen-binding domain comprises a Fab that comprises any of the following particular heavy chain and light chain antibody sequences shown in Table 2.Page 59 of 22413278080v 1Attorney Docket No. 2017420-0064

[0168] In some embodiments, an antigen-binding domain is a Fab that comprises an antibody heavy chain sequence that is at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) identical to SEQ ID NO: 14, and / or an antibody light chain sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 15. In some embodiments, an antigen-binding domain is a Fab that comprises an antibody heavy chain sequence SEQ ID NO: 14 and / or an antibody light chain sequence SEQ ID NO: 15.Table 2: Exemplary Additional Antigen-binding domain sequencesSEQ IDFab Targeting Arm SequencesNO4F3 Anti- HC EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWV 14 RQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDN ASGPR Fab (HeavySKNTLYLQMNSLRAEDTAVYYCAKDFSSRRWYLEYWGChain) QGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKS C LC SSELTQDPAVSVALGQTVRITCQGDSLRSYYASWYQQ 15 KPGQAPVLVIYGKNNRPSGIPDRFSGSSSGNTASLTI(LightTGAQAEDEADYYCNSLERIGYLSYVFGGGTKLTVLGQChain) PKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVT VAWKADGSPVKAGVETTKPSKQSNNKYAASSYLSLTP EQWKSHRSYSCQVTHEGSTVEKTVAPTECSFc domains

[0169] In some embodiments, a molecule described herein includes a first polypeptide comprising an autoantigen domain comprising a B2GP1 autoantigen domain or fragment or variant thereof linked to a first Fc domain and a second polypeptide comprising a second Fc domain. A B2GP1 autoantigen domain or fragment or variant thereof targets anti-B2GPl autoantibodies and upon binding, the complexes are targeted to an internalizing receptor and shuttled to the lysosome for degradation of the anti-B2GPl autoantibodies.Page 60 of 22413278080v 1Attorney Docket No. 2017420-0064

[0170] In some embodiments, an Fc domain described herein includes one or more mutations that alter its binding affinity to certain Fc receptors (e.g., FcyRIIB, FcyRI, FcyRIIA167H, FcyRIIA167R, FcyRIIIA176F, FcγRIIIA176V, FcyRIIIB, and / or FcRn).

[0171] In some embodiments, a first Fc domain and a second Fc domain are the same (e.g., in the case of a homodimeric molecule). In some embodiments, a first Fc domain and a second Fc domain are different (e.g., in the case of a heterodimeric molecule).

[0172] In some embodiments, an Fc domain includes one or more mutated amino acid residues and has greater binding affinity to FcyRIIB than to one or more activating Fc receptors FcyRI, FcγRIIA167H, FcγRIIA167R, FcyRIIIA176F, FcyRIIIA176V, and / or FcyRIIIB. In some embodiments, an Fc domain includes one or more mutated amino acid residues and has decreased binding affinity to FcyRI, FcyRIIA167H, FcyRIIA167R, FcyRIIIA176F, FcyRIIIA176V, FcyRIIIB, and / or FcRn relative to the corresponding wild-type Fc domain. In some embodiments, an Fc domain includes one or more mutated amino acid residues and has substantially no binding affinity to FcyRI, FcyRIIA167H, FcyRIIA167R, FcyRIIIA176F, FcγRIIIA176V, FcyRIIIB, and / or FcRn relative to the corresponding wild-type Fc domain.

[0173] In some embodiments, a first and / or second Fc domain of a molecule comprise a modification (e.g., one or more mutations) that enhances binding to an internalizing receptor. In some embodiments, a first and / or second Fc domain of a molecule comprise a modification (e.g., one or more mutations) that decrease binding to certain Fc-receptors. In some embodiments, a first and / or second Fc domain of a molecule comprise a modification (e.g., one or more mutations) that enhances other characteristics of a molecule described herein (e.g., increased half-life, heterodimerization, etc.).

[0174] An Fc domain included in a molecule may comprise any one of the five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM. In some embodiments, a conventional antibody comprises an IgG antibody. In some embodiments, an Fc domain described herein comprises a particular isotype selected from the group of IgG isotypes: IgGl, IgG2, IgG3, IgG4. In some embodiments, a molecule comprises a first and / or second Fc domains that are an IgGl isotype. In some embodiments, a molecule comprises a first and / or second Fc domains that are a human Page 61 of 22413278080v 1Attorney Docket No. 2017420-0064IgGl isotype. Additionally, in some embodiments, an Fc domain may include any particular heavy chain constant domains that correspond to the different classes of immunoglobulins which include a, 8, e, y, and p, respectively. In some embodiments, a conventional antibody is an intact IgGl antibody or other antibody class or isotype as described herein (see, e.g., Hudson et al., Nat. Med. 9:129 (2003); Pluckthun, The Pharmacology of Monoclonal Antibodies, 113:269 (1994); Hollinger et al., Proc. Natl. Acad. Sci. USA 90: 6444 (1993); WO 1993 / 01161; and U. S. Pat. Nos. 5,571,894, 5,869,046, 6,248,516, and 5,587,458, each of which are herein incorporated by reference).

[0175] The Fc region of an antibody and included in molecules described herein may bind to elements of the complement system, and also to receptors on effector cells, including for example effector cells that mediate cytotoxicity. As is known in the art, affinity and / or other binding attributes of Fc regions for Fc receptors can be modulated through glycosylation or other modification. In some embodiments, a molecule described herein includes glycosylated Fc domains, including Fc domains with modified or engineered glycosylation. In some embodiments, a molecule is naturally produced (e.g., generated by an organism reacting to an antigen), or produced by recombinant engineering, chemical synthesis, or other artificial system or methodology.

[0176] In some embodiments, one or more modifications made to an Fc domain increases clearance of an immune complex formed by one or more molecules described herein bound to an autoantibody (e.g., an anti-B2GPl autoantibody). In some embodiments, one or more modifications made to an Fc domain may 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, binding of one or more molecules to an autoantibody (e.g., an anti-B2GPl autoantibody) forms an immune complex that has enhanced binding kinetics with one or more Fc receptors (e.g., FcyRIIB) relative to binding kinetics of the autoantibody (e.g., an anti-B2GPl autoantibody) with the one or more Fc receptors (FcyRIIB). In some embodiments, binding of one or more molecules to an autoantibody (e.g., an anti-B2GPl autoantibody) forms an immune complex that has enhanced binding kinetics with one or more Fc receptors (e.g., FcyRIIB) relative to binding kinetics of the molecule with the one or more Fc receptorsPage 62 of 22413278080v 1Attorney Docket No. 2017420-0064(FcyRIIB) In some embodiments, wherein upon binding of one or more molecules to an autoantibody (e.g., an anti-B2GPl autoantibody), an immune complex is formed that has enhanced binding kinetics with one or more Fc receptors (e.g., FcyRIIB) relative to an immune complex that comprises the autoantibody (e.g., anti-B2GPl autoantibody) bound to one or more corresponding molecules with wild-type Fc domains. For example, in some embodiments, wherein upon binding of two molecules to an autoantibody (e.g., an anti-B2GPl autoantibody), an immune complex is formed that has enhanced binding kinetics with one or more Fc receptors (e.g., FcyRIIB) relative to an immune complex that comprises the autoantibody (e.g., anti-B2GP1 autoantibody) bound to two corresponding molecules with wild-type Fc domains.Binding kinetics may be characterized by, e.g., an increase rate of association, a decrease in the rate of disassociation, and / or a change in the equilibrium dissociation constant. In some embodiments, an Fc domain preferentially binds to immune cells expressing FcyRIIB over immune cells expressing FcyRIIA. In some embodiments, an Fc domain comprises substantially no binding affinity for cells that do not express FcyRIIB (e.g., T cells, NK cells, neutrophils, and / or eosinophils). In some embodiment, cells that express FcyRIIB are B cells, monocytes and / or basophils.

[0177] In some embodiments, enhanced binding kinetics comprises at least 10% greater binding affinity of the immune complex to one or more Fc receptors (e.g., FcyRIIB). In some embodiments, enhanced binding kinetics comprises at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% or greater binding affinity.

[0178] In some embodiments, the molecule binds to FcyRIIB with an affinity within the range of about 1 pM to 0.001 pM. In some embodiments, the molecule binds to FcyRIIB with an affinity within the range of about 1 pM to 0.01 pM. In some embodiments, the molecule binds to FcyRIIB with an affinity within the range of about 0.1 pM to 0.01 pM. In some embodiments, binding affinity is binding affinity to a cell line (e.g., a CHO or HEPG2 cell line) overexpressing FcyRIIB.

[0179] In some embodiments, an Fc domain described herein comprises one or more mutations that increase binding to an internalizing receptor (e.g., FcyRIIB) and one or morePage 63 of 22413278080v 1Attorney Docket No. 2017420-0064mutations that increase half-life (e.g., M428L and N434S according to EU numbering, also referred to herein as an “LS mutation”).

[0180] In some embodiments, an Fc domain described herein comprises one or more modifications such that a molecule described herein does not activate immune cells (e.g., does not activate immune cells to secrete pro-inflammatory cytokines, e.g., IL-6).

[0181] Exemplary Fc domain sequences for use in accordance with the present disclosure are shown below in Table 3. It will be understood that any of these Fc domain sequences can be used in a first or second polypeptide of a molecule of the present disclosure. It will also be understood that any of the exemplary Fc domain sequences with knob mutations (identified with a “Knob” reference) can be used with any of the exemplary Fc domain sequences with hole mutations (identified with a “Hole” reference) in preparing a heterodimeric molecule. In some embodiments, Fc domain sequences shown in Table 3 can be used in pairs in preparing a heterodimeric molecule, e.g., without limitation based on the numerical references found in Table 3 (e.g., Human IgGl Fc 1.1 Knob can be used with Human IgGl Fc 1.1 Hole, Human IgGl Fc 1.2 Knob can be used with Human IgGl Fc 1.2 Hole, etc.). It will also be understood that references in Table 3 to an Fc domain sequence being useful for an “Antigen Arm for Ag Depletion” (i.e., in a polypeptide that also includes an autoantibody-binding domain) or a “Free arm for Ag Depletion” (i.e., in a polypeptide that does not include an autoantibody-binding domain) is intended to be exemplary and non-limiting, i.e., an Fc domain sequence that is identified in Table 3 as being useful for an “Antigen Arm for Ag Depletion” can, in some embodiments, be used in a “Free arm for Ag Depletion” and an Fc domain sequence that is noted in Table 3 as being useful for a “Free arm for Ag Depletion” can, in some embodiments, be used in an “Antigen Arm for Ag Depletion”. It is also to be understood that the present disclosure encompasses the use of variants of any of these Fc domain sequences, including for example, Fc domain sequences with allotypic variations, including the variations found in Glml7, also known as Glm(z), with Lys (K) at position 214 in the CHI domain (EU numbering); Glm3, also known as Glm(f), with Arg (R) at position 214 in the CHI domain; Glml, also known as Glm(a), with Asp (D) and Leu (L) at positions 356 and 358 in the CH3 domain (EU numbering); nGlml, also known as nGlm(a), with Glu (E) and Met (M) at positions 356 and 358; Glm2,Page 64 of 22413278080v 1Attorney Docket No. 2017420-0064also known as Glm(x), with Gly (G) at position 431 in the CH3 domain (EU numbering); or nGlm2, also known as nGlm(x), with Ala (A) at position 431 in the CH3 domain.

[0182] It is also to be understood that the present disclosure encompasses the use of variants of any of these Fc domain sequences, including for example, Fc domain sequences with allotypic variations, including the variations found in Glml7, also known as Glm(z), with Lys (K) at position 214 in the CHI domain (EU numbering); Glm3, also known as Glm(f), with Arg (R) at position 214 in the CHI domain; Glml, also known as Glm(a), with Asp (D) and Leu (L) at positions 356 and 358 in the CH3 domain (EU numbering); nGlml, also known as nGlm(a), with Glu (E) and Met (M) at positions 356 and 358; Glm2, also known as Glm(x), with Gly (G) at position 431 in the CH3 domain (EU numbering); or nGlm2, also known as nGlm(x), with Ala (A) at position 431 in the CH3 domain.Table 3: Exemplary Fc Domain SequencesSEQ IDFc Sequences SequencesNOHuman IgGl Fc Bivalent EPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDT 16 (wild-type) Fc LMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKHinge sequence CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENN YKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC SVMHEALHNHYTQKSLSLSPGKHuman IgGl Fc Bivalent DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISR 17 (wild-type) Fc TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNHinge sequence KALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGKHuman IgGl Fc Bivalent APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD 18 (wild-type) Fc VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS LSLSPGKHuman IgGl Fc Bivalent EPKSSDKTHTCPPCPAPELLGGDSVFLFPPKPKDT 19Fc LMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHP238D NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKPage 65 of 22413278080v 1Attorney Docket No. 2017420-0064SEQ IDFc Sequences SequencesNOHinge sequence CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENN YKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC SVMHEALHNHYTQKSLSLSPGKHuman IgGl Fc Bivalent DKTHTCPPCPAPELLGGDSVFLFPPKPKDTLMISR 20 Fc TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK P238D PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN Hinge sequence KALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGKHuman IgGl Fc Bivalent APELLGGDSVFLFPPKPKDTLMISRTPEVTCVVVD 21 Fc VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY P238D RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS LSLSPGKHuman IgGl Fc Antigen DKTHTCPPCPAPELLRGPSVFLFPPKPKDTLYITR 22 1.1 Knob Arm for EPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNS354C / T366W, AgKARPAPIEKTISKAKGQPREPQVYTLPPCRDELTKDepletionNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPG236R / L328R,PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEM252Y / S254T / ALKFHYTQKSLSLSPGKT256E,H433K / N434F(MST-HN)Hinge sequenceHuman IgGl Fc Free Arm DKTHTCPPCPAPELLRGPSVFLFPPKPKDTLYITR 23 1.1 Hole for Ag EPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK Depletion PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN T366S / L368A / KARPAPIEKTISKAKGQPREPQVCTLPPSRDELTK Y407V / Y349C, NQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEG236R / L328R,ALKFHYTQKSLSLSPGKM252Y / S254T / T256E,H433K / N434F(MST-HN)Hinge sequencePage 66 of 22413278080v 1Attorney Docket No. 2017420-0064SEQ IDFc Sequences SequencesNOHuman IgGl Fc Antigen DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISR 24 1.2 Knob Arm for TPEVTCVVVDVEHEDPEVKFNWYVDGVEVHNAKTK PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNS354C / T366W, AgKAFPAPIEKTISKAKGQPREPQVYTLPPCREEMTKDepletionNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPS267E / L328FPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEHinge sequence ALHNHYTQKSLSLSPGKHuman IgGl Fc Free Arm DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISR 25 1.2 Hole for Ag TPEVTCVVVDVEHEDPEVKFNWYVDGVEVHNAKTK Depletion PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN T366S / L368A / KAFPAPIEKTISKAKGQPREPQVCTLPPSREEMTK Y407V / Y349C, NQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHES267E / L328FALHNHYTQKSLSLSPGKHinge sequenceHuman IgGl Fc Antigen DKTHTCPPCPAPELLGGDSVFLFPPKPKDTLMISR 26 1.3a Knob Arm for TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNS354C / T366W, AgKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKDepletionNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPP238DPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEHinge sequence ALHNHYTQKSLSLSPGKHuman IgGl Fc Free Arm DKTHTCPPCPAPELLGGDSVFLFPPKPKDTLMISR 27 1.3a Hole for Ag TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK Depletion PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN T366S / L368A / KALPAPIEKTISKAKGQPREPQVCTLPPSRDELTK Y407V / Y349C, NQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEP238DALHNHYTQKSLSLSPGKHinge sequenceHuman IgGl Fc Antigen EPKSSDKTHTCPPCPAPELLGGDSVFLFPPKPKDT 28 1.3b Knob Arm for LMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKS354C / T366W, AgCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDepletionDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNP238DYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCHinge sequence SVMHEALHNHYTQKSLSLSPGKHuman IgGl Fc Free Arm EPKSSDKTHTCPPCPAPELLGGDSVFLFPPKPKDT 29 1.3b Hole for Ag LMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH Depletion NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK T366S / L368A / CKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSR Y407V / Y349C, DELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENN YKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCP238DSVMHEALHNHYTQKSLSLSPGKPage 67 of 22413278080v 1Attorney Docket No. 2017420-0064SEQ IDFc Sequences SequencesNOHinge sequenceHuman IgGl Fc Antigen DKTHTCPPCPAPELLGGDSVFLFPPKPKDTLMISR 30 1.4 Knob Arm for TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNS354C / T366W, AgKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKDepletionNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPP238D / M428L / PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEN434SALHSHYTQKSLSLSPGKHinge sequenceHuman IgGl Fc Free Arm DKTHTCPPCPAPELLGGDSVFLFPPKPKDTLMISR 31 1.4 Hole for Ag TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK Depletion PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN T366S / L368A / KALPAPIEKTISKAKGQPREPQVCTLPPSRDELTK Y407V / Y349C, NQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEP238D / M428L / ALHSHYTQKSLSLSPGKN434SHinge sequenceHuman IgGl Fc Bivalent DKTHTCPPCPAPELLRGPSVFLFPPKPKDTLYITR 32 Fc EPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK G236R / L328R, PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN M252Y / S254T / KARPAPIEKTISKAKGQPREPQVYTLPPSRDELTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPT256E,PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEH433K / N434F ALKFHYTQKSLSLSPGKHinge sequenceHuman IgGl Fc Antigen DKTHTCPPCPAPVDFRDPLVFLFPPKPKDTLMISR 33 1.5 Knob Arm for TPEVTCVVVDVDPEDPEVKFNWYVDGVEVHNAKTK PREEQYNGAYRVVSVLTVLHQDWLNGKEYKCKVSNS354C / T366W, AgKLAPHPIIKTISKAKGQPREPQVYTLPPCRDELTKDepletionNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPE233V / L234D / PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEL235F / G236R / ALHNHYTQKSLSLSPGKG237D / S239L / S267D / H268P / S298G / T299A / A327L / L328A / A330H / E333IHinge sequencePage 68 of 22413278080v 1Attorney Docket No. 2017420-0064SEQ IDFc Sequences SequencesNOHuman IgGl Fc Free Arm DKTHTCPPCPAPVDFRDPLVFLFPPKPKDTLMISR 34 1.5 Hole for Ag TPEVTCVVVDVDPEDPEVKFNWYVDGVEVHNAKTK Depletion PREEQYNGAYRVVSVLTVLHQDWLNGKEYKCKVSN T366S / L368A / KLAPHPIIKTISKAKGQPREPQVCTLPPSRDELTK Y407V / Y349C, NQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEE233V / L234D / ALHNHYTQKSLSLSPGKL235F / G236R / G237D / S239L / S267D / H268P / S298G / T299A / A327L / L328A / A330H / E333IHinge sequenceHuman IgGl Fc Antigen DKTHTCPPCPAPVDFRDPLVFLFPPKPKDTLMISR 35 1.6 Knob Arm for TPEVTCVVVDVDPEDPEVKFNWYVDGVEVHNAKTK PQEEQYNGAYRVVSVLTVLHQDWLNGKEYKCKVSNS354C / T366W, AgKLAPHPIIKTISKAKGQPREPQVYTLPPCRDELTKDepletionNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPE233V / L234D / PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEL235F / G236R / ALHNHYTQKSLSLSPGKG237D / S239L / S267D / R292Q / H268P / S298G / T299A / A327L / L328A / A330H / E333IHinge sequenceHuman IgGl Fc Free Arm DKTHTCPPCPAPVDFRDPLVFLFPPKPKDTLMISR 36 1.6 Hole for Ag TPEVTCVVVDVDPEDPEVKFNWYVDGVEVHNAKTK Depletion PQEEQYNGAYRVVSVLTVLHQDWLNGKEYKCKVSN T366S / L368A / KLAPHPIIKTISKAKGQPREPQVCTLPPSRDELTK Y407V / Y349C, NQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEE233V / L234D / ALHNHYTQKSLSLSPGKL235F / G236R / G237D / S239L / S267D / R292Q / H268P / S298G / T299A / A327L / L328A / A330H / E333IHinge sequencePage 69 of 22413278080v 1Attorney Docket No. 2017420-0064SEQ IDFc Sequences SequencesNOHuman IgGl Fc Antigen DKTHTCPPCPAPVDFRDPLVFLFPPKPKDTLMISR 37 1.7 Knob Arm for TPEVTCVVVDVSPEDPEVKFNWYVDGVEVHNAKTK PQEEQYNGAYRVVSVLTVLHQDWLNGKEYKCKVSNS354C / T366W, AgKLAPHPIIKTISKAKGQPREPQVYTLPPCRDELTKDepletionNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPE233V / L234D / PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEL235F / G236R / ALHNHYTQKSLSLSPGKG237D / S239L / H268P / R292Q / S298G / T299A / A327L / L328A / A330H / E3331Hinge sequenceHuman IgGl Fc Free Arm DKTHTCPPCPAPVDFRDPLVFLFPPKPKDTLMISR 38 1.7 Hole for Ag TPEVTCVVVDVSPEDPEVKFNWYVDGVEVHNAKTK Depletion PQEEQYNGAYRVVSVLTVLHQDWLNGKEYKCKVSN T366S / L368A / KLAPHPIIKTISKAKGQPREPQVCTLPPSRDELTK Y407V / Y349C, NQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEE233V / L234D / ALHNHYTQKSLSLSPGKL235F / G236R / G237D / S239L / H268P / R292Q / S298G / T299A / A327L / L328A / A330H / E333IHinge sequenceHuman IgGl Fc Antigen DKTHTCPPCPAPEYLGGDSVFLFPPKPKDVLMISR 39 1.8 Knob Arm for TPEVTCVVIDVSHEDPEVKFNWYVDGVEVHNAKTK PREEQYNSTYRVVSVLPVLHRDWLNGKEYKCKVSNS354C / T366W, AgKALPKPIEKTISKAKGQRREPQVYTLPPCREEMTKDepletionNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPL234Y / P238D / PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHET250V / V264I / TALHAHTTRKELSLS PGK307P / Q311R / A330K / P343R / M428L / N434A / Y436T / Q438R / S440EHinge sequenceHuman IgGl Fc Free Arm DKTHTCPPCPAPEYLGGDSVFLFPPKPKDVLMISR 40 1.8 Hole for Ag TPEVTCVVIDVSHEDPEVKFNWYVDGVEVHNAKTK Depletion PREEQYNSTYRVVSVLPVLHRDWLNGKEYKCKVSNKALPKPIEKTISKAKGQRREPQVCTLPPSREEMTK Page 70 of 22413278080v 1Attorney Docket No. 2017420-0064SEQ IDFc Sequences SequencesNOT366S / L368A / NQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEY407V / Y349C,ALHAHTTRKELSLS PGKL234Y / P238D / T250V / V264I / T307P / Q311R / A330K / P343R / M428L / N434A / Y436T / Q438R / S440EHinge sequenceHuman IgGl Fc Antigen DKTHTCPPCPAPEDLNGPSVFLFPPKPKDTLMISR 411.9 Knob Arm for TPEVTCVVVDVEHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNS354C / T366W, AgKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKDepletionNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPL234D / G236N / PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHES267EALHNHYTQKSLSLSPGKHinge sequenceHuman IgGl Fc Free Arm DKTHTCPPCPAPEDLNGPSVFLFPPKPKDTLMISR 42 1.9 Hole for Ag TPEVTCVVVDVEHEDPEVKFNWYVDGVEVHNAKTK Depletion PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN T366S / L368A / KALPAPIEKTISKAKGQPREPQVCTLPPSRDELTK Y407V / Y349C, NQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEL234D / G236N / ALHNHYTQKSLSLSPGKS267EHinge sequenceHuman IgGl Fc Antigen DKTHTCPPCPAPELRGGPSVFLFPPKPKDTLMISR 43 1.10 Knob Arm for TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNS354C / T366W, AgKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKDepletionNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPL235RPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEHinge sequence ALHNHYTQKSLSLSPGKHuman IgGl Fc Free Arm DKTHTCPPCPAPELRGGPSVFLFPPKPKDTLMISR 44 1.10 Hole for Ag TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK Depletion PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN T366S / L368A / KALPAPIEKTISKAKGQPREPQVCTLPPSRDELTK Y407V / Y349C, NQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEL235RALHNHYTQKSLSLSPGKHinge sequencePage 71 of 22413278080v 1Attorney Docket No. 2017420-0064SEQ IDFc Sequences SequencesNOHuman IgGl Fc Antigen DKTHTCPPCPAPELLNGPSVFLFPPKPKDTLMISR 45 1.11 Knob Arm for TPEVTCVVVDVEHEDPEVKFNWYVDGVEVHNAKTK PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNS354C / T366W, AgKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKDepletionNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPG236N / S267EPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEHinge sequence ALHNHYTQKSLSLSPGKHuman IgGl Fc Free Arm DKTHTCPPCPAPELLNGPSVFLFPPKPKDTLMISR 46 1.11 Hole for Ag TPEVTCVVVDVEHEDPEVKFNWYVDGVEVHNAKTK Depletion PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN T366S / L368A / KALPAPIEKTISKAKGQPREPQVCTLPPSRDELTK Y407V / Y349C, NQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEG236N / S267EALHNHYTQKSLSLSPGKHinge sequenceHuman IgGl Fc Antigen DKTHTCPPCPAPELLGGDSVFLFPPKPKDTLMISR 47 1.12 Knob Arm for TPEVTCVVVDVSHEEPEVKFNWYVDGVEVHNAKTK PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNS354C / T366W, AgKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKDepletionNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPP238D / D270EPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEHinge sequence ALHNHYTQKSLSLSPGKHuman IgGl Fc Free Arm DKTHTCPPCPAPELLGGDSVFLFPPKPKDTLMISR 48 1.12 Hole for Ag TPEVTCVVVDVSHEEPEVKFNWYVDGVEVHNAKTK Depletion PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN T366S / L368A / KALPAPIEKTISKAKGQPREPQVCTLPPSRDELTK Y407V / Y349C, NQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEP238D / D270EALHNHYTQKSLSLSPGKHinge sequenceHuman IgGl Fc Antigen DKTHTCPPCPAPELLGGDSVFLFPPKPKDTLMISR 49 1.13 Knob Arm for TPEVTCVVVDVSHEDGEVKFNWYVDGVEVHNAKTK PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNS354C / T366W, AgKALPAPIEKTISKAKGQPREPQVYTLPPCREEMTKDepletionNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPP238D / P271GPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEHinge sequence ALHNHYTQKSLSLSPGKHuman IgGl Fc Free Arm DKTHTCPPCPAPELLGGDSVFLFPPKPKDTLMISR 50 1.13 Hole for Ag TPEVTCVVVDVSHEDGEVKFNWYVDGVEVHNAKTK Depletion PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN T366S / L368A / KALPAPIEKTISKAKGQPREPQVCTLPPSREEMTK Y407V / Y349C, NQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEP238D / P271G ALHNHYTQKSLSLSPGKPage 72 of 22413278080v 1Attorney Docket No. 2017420-0064SEQ IDFc Sequences SequencesNOHinge sequenceHuman IgGl Fc Antigen DKTHTCPPCPAPELLGGDSVFLFPPKPKDTLMISR 51 1.14 Knob Arm for TPEVTCVVVDVSHEEGEVKFNWYVDGVEVHNAKTK PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNS354C / T366W, AgKALPAPIEKTISKAKGQPREPQVYTLPPCREEMTKDepletionNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPP238D / D270E / PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEP271GALHNHYTQKSLSLSPGKHinge sequenceHuman IgGl Fc Free Arm DKTHTCPPCPAPELLGGDSVFLFPPKPKDTLMISR 52 1.14 Hole for Ag TPEVTCVVVDVSHEEGEVKFNWYVDGVEVHNAKTK Depletion PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN T366S / L368A / KALPAPIEKTISKAKGQPREPQVCTLPPSREEMTK Y407V / Y349C, NQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEP238D / D270E / ALHNHYTQKSLSLSPGKP271GHinge sequenceHuman IgGl Fc Antigen DKTHTCPPCPAPELLGDDSVFLFPPKPKDTLMISR 53 1.15 Knob Arm for TPEVTCVVVDVSHEDGEVKFNWYVDGVEVHNAKTK PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNS354C / T366W, AgKALPRPIEKTISKAKGQPREPQVYTLPPCREEMTKDepletionNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPG237D / P238D / PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEP271G / A330RALHNHYTQKSLSLSPGKHinge sequenceHuman IgGl Fc Free Arm DKTHTCPPCPAPELLGDDSVFLFPPKPKDTLMISR 54 1.15 Hole for Ag TPEVTCVVVDVSHEDGEVKFNWYVDGVEVHNAKTK Depletion PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN T366S / E368A / KALPRPIEKTISKAKGQPREPQVCTLPPSREEMTK Y407V / Y349C, NQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEG237D / P238D / ALHNHYTQKSLSLSPGKP271G / A330RHinge sequenceHuman IgGl Fc Antigen DKTHTCPPCPAPELLGDDSVFLFPPKPKDTLMISR 55 1.16 Knob Arm for TPEVTCVVVDVSHEEGEVKFNWYVDGVEVHNAKTK PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNS354C / T366W, AgKALPRPIEKTISKAKGQPREPQVYTLPPCREEMTKDepletionNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGKPage 73 of 22413278080v 1Attorney Docket No. 2017420-0064SEQ IDFc Sequences SequencesNOG237D / P238D / D270E / P271G / A330RHinge sequenceHuman IgGl Fc Free Arm DKTHTCPPCPAPELLGDDSVFLFPPKPKDTLMISR 56 1.16 Hole for Ag TPEVTCVVVDVSHEEGEVKFNWYVDGVEVHNAKTK Depletion PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN T366S / E368A / KALPRPIEKTISKAKGQPREPQVCTLPPSREEMTK Y407V / Y349C, NQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEG237D / P238D / ALHNHYTQKSLSLSPGKD270E / P271G / A330RHinge sequenceHuman IgGl Fc Antigen DKTHTCPPCPAPDLLGDDSVFLFPPKPKDTLMISR 57 1.17 Knob Arm for TPEVTCVVVDVSDEDGEVKFNWYVDGVEVHNAKTK PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNS354C / T366W, AgKALPRPIEKTISKAKGQPREPQVYTLPPCRDELTKDepletionNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPE233D / G237D / PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEP238D / H268D / ALHNHYTQKSLSLSPGKP271G / A330RHinge sequenceHuman IgGl Fc Free Arm DKTHTCPPCPAPDLLGDDSVFLFPPKPKDTLMISR 58 1.17 Hole for Ag TPEVTCVVVDVSDEDGEVKFNWYVDGVEVHNAKTK Depletion PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN T366S / L368A / KALPRPIEKTISKAKGQPREPQVCTLPPSRDELTK Y407V / Y349C, NQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEE233D / G237D / ALHNHYTQKSLSLSPGKP238D / H268D / P271G / A330RHinge sequenceHuman IgGl Fc Bivalent DKTHTCPPCPAPVDFRDPLVFLFPPKPKDTLMISR 59 Fc TPEVTCVVVDVDPEDPEVKFNWYVDGVEVHNAKTK E233V / L234D / PREEQYNGAYRVVSVLTVLHQDWLNGKEYKCKVSN L235F / G236R / KLAPHPIIKTISKAKGQPREPQVYTLPPSRDELTK G237D / S239L / NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP S267D / H268P / PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE S298G / T299A / ALHNHYTQKSLSLSPGKA327L / L328A / A330H / E333IPage 74 of 22413278080v 1Attorney Docket No. 2017420-0064SEQ IDFc Sequences SequencesNOHinge sequenceHuman IgGl Fc Bivalent DKTHTCPPCPAPVDFRDPLVFLFPPKPKDTLMISR 60 Fc TPEVTCVVVDVDPEDPEVKFNWYVDGVEVHNAKTK E233V / L234D / PQEEQYNGAYRVVSVLTVLHQDWLNGKEYKCKVSN L235F / G236R / KLAPHPIIKTISKAKGQPREPQVYTLPPSRDELTK G237D / S239L / NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP S267D / R292Q / PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE H268P / S298G / ALHNHYTQKSLSLSPGKT299A / A327L / L328A / A330H / E333IHinge sequenceHuman IgGl Fc Bivalent DKTHTCPPCPAPVDFRDPLVFLFPPKPKDTLMISR 61 Fc TPEVTCVVVDVSPEDPEVKFNWYVDGVEVHNAKTK E233V / L234D / PQEEQYNGAYRVVSVLTVLHQDWLNGKEYKCKVSN L235F / G236R / KLAPHPIIKTISKAKGQPREPQVYTLPPSRDELTK G237D / S239L / NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP H268P / R292Q / PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE S298G / T299A / ALHNHYTQKSLSLSPGKA327L / L328A / A330H / E333IHinge sequenceHuman IgGl Fc Bivalent DKTHTCPPCPAPEYLGGDSVFLFPPKPKDVLMISR 62 Fc TPEVTCVVIDVSHEDPEVKFNWYVDGVEVHNAKTK L234Y / P238D / PREEQYNSTYRVVSVLPVLHRDWLNGKEYKCKVSN T250V / V264I / T KAL PKP I E KT I S KAKGQRRE PQ VYT LP P S RE EMT K 307P / Q311R / A NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP 330K / P343R / M PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHE 428L / N434A / Y ALHAHTTRKELSLS PGK436T / Q438R / S440EHinge sequenceHuman IgGl Fc Bivalent DKTHTCPPCPAPEDLNGPSVFLFPPKPKDTLMISR 63 Fc TPEVTCVVVDVEHEDPEVKFNWYVDGVEVHNAKTK L234D / G236N / PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN S267E KALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPHinge sequencePVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGKPage 75 of 22413278080v 1Attorney Docket No. 2017420-0064SEQ IDFc Sequences SequencesNOHuman IgGl Fc Bivalent DKTHTCPPCPAPELRGGPSVFLFPPKPKDTLMISR 64 Fc TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK L235R PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN Hinge sequence KALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGKHuman IgGl Fc Bivalent DKTHTCPPCPAPELLNGPSVFLFPPKPKDTLMISR 65 Fc TPEVTCVVVDVEHEDPEVKFNWYVDGVEVHNAKTK G236N / S267E PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN Hinge sequence KALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGKHuman IgGl Fc Bivalent DKTHTCPPCPAPELLGGDSVFLFPPKPKDTLMISR 66 Fc TPEVTCVVVDVSHEEPEVKFNWYVDGVEVHNAKTK P238D / D270E PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN Hinge sequence KALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGKHuman IgGl Fc Bivalent DKTHTCPPCPAPELLGGDSVFLFPPKPKDTLMISR 67 Fc TPEVTCVVVDVSHEDGEVKFNWYVDGVEVHNAKTK P238D / P271G PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN Hinge sequence KALPAPIEKTISKAKGQPREPQVYTLPPSREEMTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGKHuman IgGl Fc Bivalent DKTHTCPPCPAPELLGGDSVFLFPPKPKDTLMISR 68 Fc TPEVTCVVVDVSHEEGEVKFNWYVDGVEVHNAKTK P238D / D270E / PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN P271G KALPAPIEKTISKAKGQPREPQVYTLPPSREEMTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPHinge sequencePVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGKHuman IgGl Fc Bivalent DKTHTCPPCPAPELLGDDSVFLFPPKPKDTLMISR 69 Fc TPEVTCVVVDVSHEDGEVKFNWYVDGVEVHNAKTK G237D / P238D / PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN P271G / A330R KALPRPIEKTISKAKGQPREPQVYTLPPSREEMTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPHinge sequencePVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGKPage 76 of 22413278080v 1Attorney Docket No. 2017420-0064SEQ IDFc Sequences SequencesNOHuman IgGl Fc Bivalent DKTHTCPPCPAPELLGDDSVFLFPPKPKDTLMISR 70 Fc TPEVTCVVVDVSHEEGEVKFNWYVDGVEVHNAKTK G237D / P238D / PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN D270E / P271G / KALPRPIEKTISKAKGQPREPQVYTLPPSREEMTK A330R NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEHinge sequenceALHNHYTQKSLSLSPGKHuman IgGl Fc Bivalent DKTHTCPPCPAPDLLGDDSVFLFPPKPKDTLMISR 71 Fc TPEVTCVVVDVSDEDGEVKFNWYVDGVEVHNAKTK E233D / G237D / PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN P238D / H268D / KALPRPIEKTISKAKGQPREPQVYTLPPSRDELTK P271G / A330R NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEHinge sequence ALHNHYTQKSLSLSPGKHuman IgGl Fc Bivalent DKTHTCPPCPAPELLGGDSVFLFPPKPKDTLMISR 72 Fc TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK P238D PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN Hinge sequence KALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGKHuman IgGl Fc Bivalent DKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISR 73 Fc TPEVTCVVVDVSDEDPEVKFNWYVDGVEVHNAKTK S239D / H268D / PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN L328W KAWPAPIEKTISKAKGQPREPQVYTLPPSRDELTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPHinge sequencePVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGKHuman IgGl Fc Antigen DKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISR 74 1.18 Knob Arm for TPEVTCVVVDVSDEDPEVKFNWYVDGVEVHNAKTK PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNS354C / T366W, AgKAWPAPIEKTISKAKGQPREPQVYTLPPCRDELTKDepletionS239D / H268D / NQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEL328W ALHNHYTQKSLSLSPGKHinge sequenceHuman IgGl Fc Free arm DKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISR 75 1.18 Hole for Ag TPEVTCVVVDVSDEDPEVKFNWYVDGVEVHNAKTK Depletion PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN T366S / L368A / KAWPAPIEKTISKAKGQPREPQVCTLPPSRDELTK Y407V / Y349C, NQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHES239D / H268D / ALHNHYTQKSLSLSPGKL328WPage 77 of 22413278080v 1Attorney Docket No. 2017420-0064SEQ IDFc Sequences SequencesNOHinge sequenceHuman IgGl Fc Antigen DKTHTCPPCPAPELLGGDSVFLFPPKPKDTLMISR 392 1.19a Knob Arm for TPEVTCVVVDVSHEDGEVKFNWYVDGVEVHNAKTK PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNS354C / T366W, AgKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKDepletionNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPP238D / P271GPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEHinge sequence ALHNHYTQKSLSLSPGKHuman IgGl Fc Free Arm DKTHTCPPCPAPELLGGDSVFLFPPKPKDTLMISR 393 1.19a Hole for Ag TPEVTCVVVDVSHEDGEVKFNWYVDGVEVHNAKTK Depletion PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN T366S / L368A / KALPAPIEKTISKAKGQPREPQVCTLPPSRDELTK Y407V / Y349C, NQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEP238D / P271GALHNHYTQKSLSLSPGKHinge sequenceHuman IgGl Fc Antigen EPKSSDKTHTCPPCPAPELLGGDSVFLFPPKPKDT 394 1.19b Knob Arm for LMISRTPEVTCVVVDVSHEDGEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKS354C / T366W, AgCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDepletionDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNP238D / P271GYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCHinge sequence SVMHEALHNHYTQKSLSLSPGKHuman IgGl Fc Free Arm EPKSSDKTHTCPPCPAPELLGGDSVFLFPPKPKDT 395 1.19b Hole for Ag LMISRTPEVTCVVVDVSHEDGEVKFNWYVDGVEVH Depletion NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK T366S / L368A / CKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSR Y407V / Y349C, DELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENN YKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCP238D / P271GSVMHEALHNHYTQKSLSLSPGKHinge sequenceHuman IgGl Fc Antigen DKTHTCPPCPAPELLGGDSVFLFPPKPKDTLYITR 396 1.20 Knob Arm for EPEVTCVVVDVSHEDGEVKFNWYVDGVEVHNAKTK PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNS354C / T366W, AgKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKDepletionNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPP238D / P271G,PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEM252Y / S254T / ALHNHYTQKSLSLSPGKT256E (YTE)Hinge sequenceHuman IgGl Fc Free Arm DKTHTCPPCPAPELLGGDSVFLFPPKPKDTLYITR 397 1.20 Hole for Ag EPEVTCVVVDVSHEDGEVKFNWYVDGVEVHNAKTK Depletion PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNPage 78 of 22413278080v 1Attorney Docket No. 2017420-0064SEQ IDFc Sequences SequencesNOT366S / L368A / KALPAPIEKTISKAKGQPREPQVCTLPPSRDELTK NQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPY407V / Y349C,PVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEP238D / P271G, ALHNHYTQKSLSLSPGKM252Y / S254T / T256E (YTE)Hinge sequenceHuman IgGl Fc Antigen DKTHTCPPCPAPELLGGDSVFLFPPKPKDTLMISR 398 1.21 Knob Arm for TPEVTCVVVDVSHEDGEVKFNWYVDGVEVHNAKTK PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNS354C / T366W, AgKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKDepletionNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPP238D / P271G,PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEM428L / N434S ALHSHYTQKSLSLSPGK(LS)Hinge sequenceHuman IgGl Fc Free Arm DKTHTCPPCPAPELLGGDSVFLFPPKPKDTLMISR 399 1.21 Hole for Ag TPEVTCVVVDVSHEDGEVKFNWYVDGVEVHNAKTK Depletion PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN T366S / L368A / KALPAPIEKTISKAKGQPREPQVCTLPPSRDELTK Y407V / Y349C, NQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEP238D / P271G, ALHSHYTQKSLSLSPGKM428L / N434S(LS)Hinge sequenceHuman IgGl Fc Bivalent EPKSSDKTHTCPPCPAPELLGDDSVFLFPPKPKDT 99 Fc LMISRTPEVTCVVVDVSHEDGEVKFNWYVDGVEVH G237D, P238D, NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK P271G, A330R CKVSNKALPRPIEKTISKAKGQPREPQVYTLPPSR DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNHinge sequenceYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC SVMHEALHNHYTQKSLSLSPGKHuman IgGl Fc Bivalent PPKSSPKTHTCPPCPAPELLGDDSVFLFPPKPKDT 124 Fc LMISRTPEVTCVVVDVSHEDGEVKFNWYVDGVEVH G237D, P238D, NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK P271G, A330R CKVSNKALPRPIEKTISKAKGQPREPQVYTLPPSR EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNHinge sequenceYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC(allotypic SVMHEALHNHYTQKSLSLSPGKvariant)Page 79 of 22413278080v 1Attorney Docket No. 2017420-0064SEQ IDFc Sequences SequencesNOHuman IgGl Fc Bivalent EPKSSDKTHTCPPCPAPELLGDDSVFLFPPKPKDT 125 Fc LYITREPEVTCVVVDVSHEDGEVKFNWYVDGVEVH G237D, P238D, NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK P271G, A330R CKVSNKALPRPIEKTISKAKGQPREPQVYTLPPSR DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENN YTE (M252Y,YKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS254T, T256E)SVMHEALHNHYTQKSLSLSPGKHinge sequenceHuman IgGl Bivalent EPKSSDKTHTCPPCPAPELLGDDSVFLFPPKPKDT 126 Fc LMISRTPEVTCVVVDVSHEDGEVKFNWYVDGVEVH G237D, P238D, NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK P271G, A330R CKVSNKALPRPIEKTISKAKGQPREPQVYTLPPSR DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENN LS (M428L,YKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCN434S)SVLHEALHSHYTQKSLSLSPGKHinge sequenceHuman IgGl Bivalent EPASSPAPHTCPPCPAPELLGDDSVFLFPPKPKDT 131 Fc LMISRTPEVTCVVVDVSHEDGEVKFNWYVDGVEVH G237D, P238D, NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK P271G, A330R CKVSNKALPRPIEKTISKAKGQPREPQVYTLPPSR EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENN LS (M428L,YKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCN434S)SVLHEALHSHYTQKSLSLSPGK(allotypicvariant)Hinge sequenceHuman IgGl Fc Antigen DKTHTCPPCPAPELLGDDSVFLFPPKPKDTLMISR 400 1.22a Knob Arm for TPEVTCVVVDVSHEDGEVKFNWYVDGVEVHNAKTK PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNS354C / T366W, AgKALPRPIEKTISKAKGQPREPQVYTLPPCRDELTKDepletionNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPG237D / P238D / PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEP271G / A330R ALHNHYTQKSLSLSPGKHinge sequenceHuman IgGl Fc Free Arm DKTHTCPPCPAPELLGDDSVFLFPPKPKDTLMISR 401 1.22a Hole for Ag TPEVTCVVVDVSHEDGEVKFNWYVDGVEVHNAKTK Depletion PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN T366S / L368A / KALPRPIEKTISKAKGQPREPQVCTLPPSRDELTK Y407V / Y349C, NQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEG237D / P238D / ALHNHYTQKSLSLSPGKP271G / A330RHinge sequencePage 80 of 22413278080v 1Attorney Docket No. 2017420-0064SEQ IDFc Sequences SequencesNOHuman IgGl Fc Antigen EPKSSDKTHTCPPCPAPELLGDDSVFLFPPKPKDT 402 1.22b Knob Arm for LMISRTPEVTCVVVDVSHEDGEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKS354C / T366W, AgCKVSNKALPRPIEKTISKAKGQPREPQVYTLPPCRDepletionDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNG237D / P238D / YKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCP271G / A330RSVMHEALHNHYTQKSLSLSPGKHinge sequenceHuman IgGl Fc Free Arm EPKSSDKTHTCPPCPAPELLGDDSVFLFPPKPKDT 403 1.22b Hole for Ag LMISRTPEVTCVVVDVSHEDGEVKFNWYVDGVEVH Depletion NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK T366S / L368A / CKVSNKALPRPIEKTISKAKGQPREPQVCTLPPSR Y407V / Y349C, DELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENN YKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCG237D / P238D / SVMHEALHNHYTQKSLSLSPGKP271G / A330RHinge sequenceHuman IgGl Fc Antigen EPKSSDKTHTCPPCPAPELLGDDSVFLFPPKPKDT 97 1.22c Knob Arm for LMISRTPEVTCVVVDVSHEDGEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKS354C / T366W AgCKVSNKALPRPIEKTISKAKGQPREPQVYTLPPCRDepletionDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNG237D, P238D,YKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCP271G, A330RSVMHEALHNHYTQKSLSLSPGKHinge sequenceHuman IgGl Fc Free Arm DKTHTCPPCPAPELLGDDSVFLFPPKPKDTLMISR 98 1.22c Hole for Ag TPEVTCVVVDVSHEDGEVKFNWYVDGVEVHNAKTK Depletion PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN Y349C / T366S / KALPRPIEKTISKAKGQPREPQVCTLPPSRDELTK L368A / Y407V NQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEG237D, P238D,ALHNHYTQKSLSLSPGKP271G, A330RHinge sequenceHuman IgGl Fc Antigen DKTHTCPPCPAPELLGDDSVFLFPPKPKDTLYITR 404 1.23 a Knob Arm for EPEVTCVVVDVSHEDGEVKFNWYVDGVEVHNAKTK PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNS354C / T366W, AgKALPRPIEKTISKAKGQPREPQVYTLPPCRDELTKDepletionNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPG237D / P238D / PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEP271G / A330R,ALHNHYTQKSLSLSPGKM252Y / S254T / T256E (YTE)Hinge sequencePage 81 of 22413278080v 1Attorney Docket No. 2017420-0064SEQ IDFc Sequences SequencesNOHuman IgGl Fc Free Arm DKTHTCPPCPAPELLGDDSVFLFPPKPKDTLYITR 405 1.23a Hole for Ag EPEVTCVVVDVSHEDGEVKFNWYVDGVEVHNAKTK Depletion PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN T366S / L368A / KALPRPIEKTISKAKGQPREPQVCTLPPSRDELTK Y407V / Y349C, NQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEG237D / P238D / ALHNHYTQKSLSLSPGKP271G / A330R,M252Y / S254T / T256E (YTE)Hinge sequenceHuman IgGl Fc Antigen EPKSSDKTHTCPPCPAPELLGDDSVFLFPPKPKDT 127 1.23b Knob Arm for LYITREPEVTCVVVDVSHEDGEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKS354C / T366W AgCKVSNKALPRPIEKTISKAKGQPREPQVYTLPPCRDepletionDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNG237D, P238D,YKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCP271G, A330R SVMHEALHNHYTQKSLSLSPGKYTE (M252Y,S254T, T256E)Hinge sequenceHuman IgGl Fc Free Arm DKTHTCPPCPAPELLGDDSVFLFPPKPKDTLYITR 128 1.23b Hole for Ag EPEVTCVVVDVSHEDGEVKFNWYVDGVEVHNAKTK Depletion PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN Y349C, T366S, KALPRPIEKTISKAKGQPREPQVCTLPPSRDELTK L368A, Y407V NQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEG237D, P238D,ALHNHYTQKSLSLSPGKP271G, A330RYTE (M252Y,S254T, T256E)Hinge sequenceHuman IgGl Fc Antigen DKTHTCPPCPAPELLGDDSVFLFPPKPKDTLMISR 406 1.24a Knob Arm for TPEVTCVVVDVSHEDGEVKFNWYVDGVEVHNAKTK PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNS354C / T366W, AgKALPRPIEKTISKAKGQPREPQVYTLPPCRDELTKDepletionNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPG237D / P238D / PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEP271G / A330R,ALHSHYTQKSLSLSPGKM428L / N434S(LS)Hinge sequencePage 82 of 22413278080v 1Attorney Docket No. 2017420-0064SEQ IDFc Sequences SequencesNOHuman IgGl Fc Free Arm DKTHTCPPCPAPELLGDDSVFLFPPKPKDTLMISR 407 1.24a Hole for Ag TPEVTCVVVDVSHEDGEVKFNWYVDGVEVHNAKTK Depletion PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN T366S / L368A / KALPRPIEKTISKAKGQPREPQVCTLPPSRDELTK Y407V / Y349C, NQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEG237D / P238D / ALHSHYTQKSLSLSPGKP271G / A330R,M428L / N434S(LS)Hinge sequenceHuman IgGl Fc Antigen EPKSSDKTHTCPPCPAPELLGDDSVFLFPPKPKDT 129 1.24b Knob Arm for LMISRTPEVTCVVVDVSHEDGEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKS354C / T366W AgCKVSNKALPRPIEKTISKAKGQPREPQVYTLPPCRDepletionDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNG237D, P238D,YKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCP271G, A330R SVLHEALHSHYTQKSLSLSPGKLS (M428L,N434S)Hinge sequenceHuman IgGl Fc Free Arm DKTHTCPPCPAPELLGDDSVFLFPPKPKDTLMISR 130 1.24b Hole for Ag TPEVTCVVVDVSHEDGEVKFNWYVDGVEVHNAKTK Depletion PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN Y349C, T366S, KALPRPIEKTISKAKGQPREPQVCTLPPSRDELTK L368A, Y407V NQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEG237D, P238D,ALHSHYTQKSLSLSPGKP271G, A330RLS (M428L,N434S)Hinge sequence

[0183] In some embodiments, a first Fc domain and / or a second Fc domain comprises a sequence selected from SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 32, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ IDPage 83 of 22413278080v 1Attorney Docket No. 2017420-0064NO: 72, SEQ ID NO: 73, SEQ ID NO: 99, SEQ ID NO: 124, SEQ ID NO: 125, SEQ ID NO: 126, and SEQ ID NO: 131, or a fragment or variant thereof.

[0184] In some embodiments, a first Fc domain comprises a sequence selected from SEQ ID NO: 22, SEQ ID NO: 24, SEQ ID NO: 26, SEQ ID NO: 28, SEQ ID NO: 30, SEQ ID NO: 33, SEQ ID NO: 35, SEQ ID NO: 37, SEQ ID NO: 39, SEQ ID NO: 41, SEQ ID NO: 43, SEQ ID NO: 45, SEQ ID NO: 47, SEQ ID NO: 49, SEQ ID NO: 51, SEQ ID NO: 53, SEQ ID NO: 55, SEQ ID NO: 57, SEQ ID NO: 74, SEQ ID NO: 124, SEQ ID NO: 127, and SEQ ID NO: 129, SEQ ID NO: 131, SEQ ID NO: 392, SEQ ID NO: 394, SEQ ID NO: 396, SEQ ID NO: 398, SEQ ID NO: 400, SEQ ID NO: 402, SEQ ID NO: 404, and SEQ ID NO: 406, and a second Fc domain comprises a sequence selected from SEQ ID NO: 23, SEQ ID NO: 25, SEQ ID NO: 27, SEQ ID NO: 29, SEQ ID NO: 31, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 38, SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID NO: 50, SEQ ID NO: 52, SEQ ID NO: 54, SEQ ID NO: 56, SEQ ID NO: 58, SEQ ID NO: 75, SEQ ID NO: 124, SEQ ID NO: 128, SEQ ID NO: 130, SEQ ID NO: 131, SEQ ID NO: 393, SEQ ID NO: 395, SEQ ID NO: 397, SEQ ID NO: 399, SEQ ID NO: 401, SEQ ID NO: 403, SEQ ID NO: 405, and SEQ ID NO: 407.

[0185] In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 16 and a second Fc domain comprises a sequence of SEQ ID NO: 16. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 17 and a second Fc domain comprises a sequence of SEQ ID NO: 17. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 18 and a second Fc domain comprises a sequence of SEQ ID NO: 18. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 19 and a second Fc domain comprises a sequence of SEQ ID NO: 19. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 20 and a second Fc domain comprises a sequence of SEQ ID NO: 20. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 21 and a second Fc domain comprises a sequence of SEQ ID NO: 21. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 22 and a second Fc domain comprises a sequence of SEQ ID NO: 23. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 24 and a second Fc domain comprises a sequence of SEQ ID NO: 25. In somePage 84 of 22413278080v 1Attorney Docket No. 2017420-0064embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 26 and a second Fc domain comprises a sequence of SEQ ID NO: 27. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 28 and a second Fc domain comprises a sequence of SEQ ID NO: 29. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 30 and a second Fc domain comprises a sequence of SEQ ID NO: 31. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 32 and a second Fc domain comprises a sequence of SEQ ID NO: 32. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 33 and a second Fc domain comprises a sequence of SEQ ID NO: 34. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 35 and a second Fc domain comprises a sequence of SEQ ID NO: 36. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 37 and a second Fc domain comprises a sequence of SEQ ID NO: 38. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 39 and a second Fc domain comprises a sequence of SEQ ID NO: 40. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 41 and a second Fc domain comprises a sequence of SEQ ID NO: 42. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 43 and a second Fc domain comprises a sequence of SEQ ID NO: 44. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 45 and a second Fc domain comprises a sequence of SEQ ID NO: 46. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 47 and a second Fc domain comprises a sequence of SEQ ID NO: 48. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 49 and a second Fc domain comprises a sequence of SEQ ID NO: 50. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 51 and a second Fc domain comprises a sequence of SEQ ID NO: 52. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 53 and a second Fc domain comprises a sequence of SEQ ID NO: 54. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 55 and a second Fc domain comprises a sequence of SEQ ID NO: 56. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 57 and a second Fc domain comprises a sequence of SEQ ID NO: 58. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 59 and a second Fc domain comprises a sequence of SEQ ID NO: 59. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 60 and a second Fc domain comprises aPage 85 of 22413278080v 1Attorney Docket No. 2017420-0064sequence of SEQ ID NO: 60. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 61 and a second Fc domain comprises a sequence of SEQ ID NO: 61. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 62 and a second Fc domain comprises a sequence of SEQ ID NO: 62. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 63 and a second Fc domain comprises a sequence of SEQ ID NO: 63. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 64 and a second Fc domain comprises a sequence of SEQ ID NO: 64. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 65 and a second Fc domain comprises a sequence of SEQ ID NO: 65. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 66 and a second Fc domain comprises a sequence of SEQ ID NO: 66. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 67 and a second Fc domain comprises a sequence of SEQ ID NO: 67. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 68 and a second Fc domain comprises a sequence of SEQ ID NO: 68. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 69 and a second Fc domain comprises a sequence of SEQ ID NO: 69. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 70 and a second Fc domain comprises a sequence of SEQ ID NO: 70. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 71 and a second Fc domain comprises a sequence of SEQ ID NO: 71. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 72 and a second Fc domain comprises a sequence of SEQ ID NO: 72. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 73 and a second Fc domain comprises a sequence of SEQ ID NO: 73. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 74 and a second Fc domain comprises a sequence of SEQ ID NO: 75. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 99 and a second Fc domain comprises a sequence of SEQ ID NO: 99. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 125 and a second Fc domain comprises a sequence of SEQ ID NO: 125. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 126 and a second Fc domain comprises a sequence of SEQ ID NO: 126. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 127 and a second Fc domain comprises a sequence of SEQ ID NO: 128. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 129Page 86 of 22413278080v 1Attorney Docket No. 2017420-0064and a second Fc domain comprises a sequence of SEQ ID NO: 130. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 392 and a second Fc domain comprises a sequence of SEQ ID NO: 393. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 394 and a second Fc domain comprises a sequence of SEQ ID NO: 395. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 396 and a second Fc domain comprises a sequence of SEQ ID NO: 397. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 398 and a second Fc domain comprises a sequence of SEQ ID NO: 399. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 400 and a second Fc domain comprises a sequence of SEQ ID NO: 401. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 402 and a second Fc domain comprises a sequence of SEQ ID NO: 403. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 404 and a second Fc domain comprises a sequence of SEQ ID NO: 405. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 406 and a second Fc domain comprises a sequence of SEQ ID NO: 407. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 124 and a second Fc domain comprises a sequence of SEQ ID NO: 124. In some embodiments, a first Fc domain comprises a sequence of SEQ ID NO: 131 and a second Fc domain comprises a sequence of SEQ ID NO: 131.Hinge sequences

[0186] In some embodiments, an Fc domain comprises a hinge sequence. In some embodiments, an Fc domain comprises the amino acid sequence of SEQ ID NO: 76 (DKTHTCPPCP). In some embodiments, an Fc domain comprises the amino acid sequence of SEQ ID NO: 77 (DKTHTCPPC). In some embodiments, an Fc domain comprises the amino acid sequence of SEQ ID NO: 78 (EPKSSDKTHTCPPCP). In some embodiments, an Fc domain comprises the amino acid sequence of SEQ ID NO: 79 (EPKSSDKTHTCPPC). In some embodiments, an Fc domain comprises the amino acid sequence of SEQ ID NO: 80 (ERKCCVECPPCP). In some embodiments, an Fc domain comprises the amino acid sequence of SEQ ID NO: 81 (ELKTRPLGDTTHTCPPCP). In some embodiments, an Fc domain comprises the amino acid sequence of SEQ ID NO: 82 (ELKTRPLGDTTHTCPRCP(EPKSCDTPPPCPRCP)3). In some embodiments, an Fc domain comprises the amino acid sequence of SEQ ID NO: 83 (ESKYGPPCPPCP).Page 87 of 22413278080v 1Attorney Docket No. 2017420-0064

[0187] In this context, it is to be understood that any of the exemplary Fc domain sequences provided in Table 3 can be modified by replacing the hinge sequence of SEQ ID NO: 76 (DKTHTCPPCP), SEQ ID NO: 77 (DKTHTCPPC) or SEQ ID NO: 78 (EPKSSDKTHTCPPCP) with the hinge sequence of SEQ ID NO: 80 (ERKCCVECPPCP), SEQ ID NO: 81 (ELKTRPLGDTTHTCPPCP), SEQ ID NO: 82 (ELKTRPLGDTTHTCPRCP(EPKSCDTPPPCPRCP)3), SEQ ID NO: 83 (ESKYGPPCPPCP) or any other suitable hinge sequence including variants of the hinge sequences of SEQ ID NOs: 76-83 that include 1, 2, 3, 4, 5 or more mutations.Mutations to increase binding to internalizing receptors

[0188] In some embodiments, additional mutations are introduced into Fc domains of molecules described herein in order to target cell surface receptors that bind and internalize ligands and target them to the lysosome (z.e., internalizing receptors or endocytic receptors). By modifying Fc domains to increase binding to internalizing receptors, molecules described herein and their bound autoantibodies are targeted for internalization and lysosomal degradation.

[0189] In some embodiments, a molecule comprises a first and / or second Fc domain that comprises one of more mutated amino acid residues that alters its binding to an internalizing receptor on a cell, where the internalizing receptor is capable of shuttling its cargo to the lysosome of the cell leading to degradation. In some embodiments, altered binding to the internalizing receptor comprises increased binding to an internalizing receptor. Without wishing to be bound to any theory, once a molecule bound to an autoantibody binds to an internalizing receptor on a cell, the internalizing receptor internalizes the molecule and the autoantibody is shuttled to the lysosome of the cell for degradation.

[0190] Exemplary internalizing receptors include but are not limited to FcyRIIB, FcRn, ASGPR, BCMA, CD38, SLAMF7, GPCR5D, or CD138.

[0191] In some embodiments, a first and / or second Fc domain comprises one or more mutated amino acid residues that increase binding to the human FcyR, specifically FcyRIIB. In some embodiments, such a mutation comprises at least one of the following mutated amino acid residues: S267E and L328F, according to the EU numbering scheme. In some embodiments, a Page 88 of 22413278080v 1Attorney Docket No. 2017420-0064first and / or second Fc domain comprise a combination of the following mutated amino acid residues: S267E and L328F, according to the EU numbering scheme. In some embodiments, such a mutation comprises at least one of the following mutated amino acid residues: G236D, S267E and L328F, according to the EU numbering scheme. In some embodiments, a first and / or second Fc domain comprise a combination of the following mutated amino acid residues:G236D, S267E and L328F, according to the EU numbering scheme. In some embodiments, a first and / or second Fc domain comprises the mutated amino acid residue P238D, according to the EU numbering scheme.

[0192] In some embodiments, a first and / or second Fc domain comprises a P238D mutation and at least one of the following mutated amino acid residues: L234A and L235A, according to the EU numbering scheme. In some embodiments, a first and / or second Fc domain comprises the following mutated amino acid residues: L234A, L235A, and P238D, according to the EU numbering scheme. In some embodiments, a first and / or second Fc domain comprises P238D and P329G mutations and at least one of the following mutated amino acid residues: L234A and L235A, according to the EU numbering scheme. In some embodiments, a first and / or second Fc domain comprises the following mutated amino acid residues: L234A, L235A, P238D and P329G, according to the EU numbering scheme.

[0193] In some embodiments, a first and / or second Fc domain comprises P238D and P271G mutations and at least one of the following mutated amino acid residues: L234A and L235A, according to the EU numbering scheme. In some embodiments, a first and / or second Fc domain comprises the following mutated amino acid residues: L234A, L235A, P238D, and P271G according to the EU numbering scheme. In some embodiments, a first and / or second Fc domain comprises P238D, P271G, and P329G mutations and at least one of the following mutated amino acid residues: L234A and L235A, according to the EU numbering scheme. In some embodiments, a first and / or second Fc domain comprises the following mutated amino acid residues: L234A, L235A, P238D, P271G, and P329G, according to the EU numbering scheme.

[0194] In some embodiments, a first and / or second Fc domain comprises G237D, P238D, P271G, and A330R mutations and at least one of the following mutated amino acid residues: L234A and L235A, according to the EU numbering scheme. In some embodiments, a first Page 89 of 22413278080v 1Attorney Docket No. 2017420-0064and / or second Fc domain comprises the following mutated amino acid residues: L234A, L235A, G237D, P238D, P271G, and A330R according to the EU numbering scheme. In some embodiments, a first and / or second Fc domain comprises G237D, P238D, P271G, A330R, and P329G mutations and at least one of the following mutated amino acid residues: L234A and L235A, according to the EU numbering scheme. In some embodiments, a first and / or second Fc domain comprises the following mutated amino acid residues: L234A, L235A, G237D, P238D, P271G, A330R, and P329G, according to the EU numbering scheme.

[0195] In some embodiments, a first and / or second Fc domain comprises the following mutated amino acid residues: N297A and P238D, according to the EU numbering scheme. In some embodiments, a first and / or second Fc domain comprises the following mutated amino acid residues: N297A, P238D, and P271G according to the EU numbering scheme. In some embodiments, a first and / or second Fc domain comprises the following mutated amino acid residues: N297A, G237D, P238D, P271G, and A330R, according to the EU numbering scheme.

[0196] In some embodiments, one or more Fc mutations are introduced in order to increase binding to the human neonatal receptor (FcRn). In some embodiments, an Fc domain is an IgGl Fc domain. Human IgGl naturally binds FcRn at an acidic pH, which allows it to, upon binding FcRn and internalization into a cell, be recycled back to the surface of the cell and not to be degraded in the lysosome. In some embodiments, Fc mutations comprise mutation that increase binding to FcRn in neutral pH environments (e.g., extracellular environment). Without wishing to be bound by any theory, such mutations are included in the molecules described herein in order to increase binding of the Fc domain to FcRn on the surface of a cell in a neutral pH environment, such that there will be increased receptor-mediated internalization into cells and shuttling of the autoantibodies (bound to the molecule) to the lysosome.

[0197] In some embodiments, a first and / or second Fc domain comprises one or more mutated amino acid residues that increase binding to FcRn at a neutral or near-neutral pH (e.g, pH between about 6.8 and 7.5). In some embodiments, a first and / or second Fc domain comprises a human IgGl isotype and remains bound to FcRn upon entry into an environment having an acidic pH and / or having low calcium concentration (e.g, into an endosome of a cell). In some embodiments, a first and / or second Fc domain comprises one or more mutated amino Page 90 of 22413278080v 1Attorney Docket No. 2017420-0064acid residues that increase binding to FcRn upon entry into an environment having an acidic pH and / or having low calcium concentration (e.g., into an endosome of a cell). In some embodiments, a first and / or second Fc domain comprises at least one of the following mutated amino acid residues: M252Y, S254T, T256E, H433K, and N434F, according to the EU numbering scheme. In some embodiments, such mutations include a combination that includes the following mutations: M252Y, S254T, T256E, H433K, N434F (z.e., “MST-HN”), according to the EU numbering scheme. In some embodiments, the first and / or second Fc domain comprises a combination of the following mutated amino acid residues: M252Y, S254T, T256E, H433K, and N434F (i.e., “MST-HN”), according to the EU numbering scheme.

[0198] In some embodiments, a first and / or second Fc domain comprises at least one mutated amino acid sequence that decreases binding to one or more Fc-gamma receptors (FcyRs). Such modifications may prevent immune crosslinking (i.e., of a molecule, autoantibody, FcyRs) that leads to inflammatory responses. Such mutations may focus the primary mechanism of action of the molecules, i.e., to the targeted internalization and subsequent degradation of autoantibodies. In some embodiments, a first and / or second Fc domain comprises at least one of the following mutated amino acid residues: G236R and L328R, according to the EU numbering scheme. In some embodiments, a first and / or second Fc domain comprises the following mutated amino acid residues: G236R and L328R, according to the EU numbering scheme.

[0199] In some embodiments, a molecule described herein may include any combination of the above-described Fc mutations that alter binding to an internalizing receptor or Fc receptor. In some embodiments, a molecule described herein includes an Fc domain that comprises an “MST-HN” modification described herein in combination with an “RR” mutation described herein. In some embodiments, a molecule described herein includes an Fc domain that comprises an “MST-HN” modification described herein in combination with the “P238D” mutation described herein. In some embodiments, a molecule described herein includes an Fc domain that comprises an “MST-HN” modification described herein in combination with an “RR” mutation and “P238D” mutation described herein. In some embodiments, a molecule described herein includes an Fc domain that comprises an “MST-HN” modification described herein in combination with G237D, P238D, P271G, and A330R mutations, according to the EU number scheme. In somePage 91 of 22413278080v 1Attorney Docket No. 2017420-0064embodiments, a molecule described herein includes an Fc domain that comprises an “MST-HN” modification described herein in combination with an “RR” mutation and G237D, P238D, P271G, and A330R mutations, according to the EU number scheme.i. Exemplary FcyRIIB Mutations

[0200] In some embodiments, an Fc domain comprises one or more amino acid mutations that increase affinity for FcyRIIB. In some embodiments FcyRIIB is human FcyRIIB. In some embodiments, FcyRIIB is murine FcyRIIB.

[0201] In some embodiments, an Fc domain is utilized in a molecule described herein that comprises one or more mutations that enhances binding kinetics of an immune complex comprising the one or more molecules bound to a target antibody to FcyRIIB. In some embodiments, enhanced binding kinetics comprises at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% or greater binding affinity. In some embodiments, an Fc domain includes one or more mutated amino acid residues and has greater binding affinity to FcyRIIB than to one or more activating Fc receptors FcyRI, FcyRIIA167H, FcyRIIA167R, FcyRIIIA176F, FcyRIIIA176V, and / or FcyRIIIB. In some embodiments, an Fc domain includes one or more mutated amino acid residues and has decreased binding affinity to FcyRI, FcyRIIA167H, FcyRIIA167R, FcyRIIIA176F, FcyRIIIA176V, FcyRIIIB, and / or FcRn relative to the corresponding wild-type Fc domain. In some embodiments, an Fc domain includes one or more mutated amino acid residues and has substantially no binding affinity to FcyRI, FcyRIIA167H, FcyRIIA167R, FcyRIIIA176F, FcyRIIIA176V, FcyRIIIB, and / or FcRn relative to the corresponding wild-type Fc domain. In some embodiments, enhanced binding kinetics comprises an increase in avidity, stability, strength, frequency, and / or duration of binding between the immune complex and FcyRIIB. In some embodiments, enhanced binding kinetics comprise an increase in the rate of association, a decrease in the rate of disassociation, and / or a change in the equilibrium dissociation constant.

[0202] In some embodiments, a molecule described herein having a first and second Fc domain comprise one or more mutations in the first and / or second Fc domain to increase binding to FcyRIIB, upon binding of one or more molecules to the target autoantibody forms an immune complex that has enhanced binding kinetics with FcyRIIB relative to an immune complex that Page 92 of 22413278080v 1Attorney Docket No. 2017420-0064comprises the target autoantibody bound to one or more corresponding molecules with wild-type Fc domains. In some embodiments, a molecule described herein comprising one or more mutations in the first and / or second Fc domain to increase binding to FcyRIIB, upon binding to an autoantibody (e.g., an anti-B2GP1 autoantibody) form an immune complex that has enhanced binding kinetics with FcyRIIB relative to binding kinetics of the autoantibody e.g., anti-B2GP1 autoantibody) with FcγRIIB.

[0203] In some embodiments, molecules described herein having a first and second Fc domain comprise one or more mutations in the first and / or second Fc domain to increase binding to FcyRIIB, wherein upon binding of two molecules to the target antibody, an immune complex is formed that has enhanced binding kinetics with FcyRIIB relative to an immune complex that comprises the target antibody bound to two corresponding molecules with wild-type Fc domains. Without wishing to be bound by any theory, a molecule described herein may have one or more mutations that increase binding affinity for FcyRIIB, but the binding affinity of the molecule alone to FcyRIIB is moderate.

[0204] In some embodiments, a molecule binds to FcyRIIB with an affinity within the range of about 1 pM to 0.001 pM. In some embodiments, a molecule binds to FcyRIIB with an affinity within the range of about 1 pM to 0.01 pM. In some embodiments, a molecule binds to FcyRIIB with an affinity within the range of about 0.1 pM to 0.01 pM. In some embodiments, such mutations when introduced into an Fc domain of a molecule described herein confer an avidity-mediated binding effect to FcyRIIB when two or more molecules are present in an immune complex with a target antibody. In some embodiments, a molecule described herein has increased binding to FcyRIIB when the immune complex comprises two molecules bound to a target antibody compared to an immune complex with only one molecule bound to the target antibody. Without wishing to be bound by any theory, such avidity-mediated effects allow for selective binding and depletion of immune complexes and weaker binding (and hence depletion) of molecules when they are not part of an immune complex. These characteristics allow for molecules described herein to remain circulating longer in the bloodstream of a subject before being cleared by FcyRIIB-mediated internalization and degradation.Page 93 of 22413278080v 1Attorney Docket No. 2017420-0064

[0205] Additionally, the present disclosure provides Fc domain mutations that achieve the binding affinity to FcγRIIB to confer avidity-mediated effects to take advantage of the benefits and additional selectively described herein. Exemplary Fc domain mutations that may be used to achieve these binding kinetics with FcyRIIB include, e.g., in some embodiments, one or more of the following mutations: E233V, L234D, L235F, G236D, G236R, G237D, S239L, S267D, H268P, S298G, T299A, A327L, L328A, A330H, E333I, R292Q, E233P, P238D, H268D, P271G, A330R, L234Y, T250V, V264I, T307P, Q311R, A330K, P343R, M428L, N434A, Y436T, Q438R, S440E, G236N, S267E, L235R, D270E, E233D, and G237D, according to the EU numbering scheme.

[0206] In some embodiments, an Fc domain mutation comprises 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, an Fc domain comprises the following set of mutations: E233V, L234D, L235F, G236R, G237D, S239L, S267D, H268P, S298G, T299A, A327L, L328A, A330H, and E333I, according to the EU numbering scheme (e.g., see SEQ ID NOs: 33, 34, and 59).

[0207] In some embodiments, an Fc domain mutation comprises one or more of the following mutations: E233V, L234D, L235F, G236R, G237D, S239L, S267D, R292Q, H268P, S298G, T299A, A327L, L328A, A330H, or E333I, according to the EU numbering scheme. In some embodiments, an Fc domain comprises the following set of mutations: E233V, L234D, L235F, G236R, G237D, S239L, S267D, R292Q, H268P, S298G, T299A, A327L, L328A, A330H, and E333I, according to the EU numbering scheme (e.g., see SEQ ID NOs: 35, 36, and 60).

[0208] In some embodiments, an Fc domain mutation comprises one or more of the following mutations: E233V, L234D, L235F, G236R, G237D, S239L, H268P, R292Q, S298G, T299A, A327L, L328A, A330H, or E333I, according to the EU numbering scheme. In some embodiments, an Fc domain comprises the following set of mutations: E233V, L234D, L235F, G236R, G237D, S239L, H268P, R292Q, S298G, T299A, A327L, L328A, A330H, and E333I, according to the EU numbering scheme (e.g, see SEQ ID NOs: 37, 38, and 61).Page 94 of 22413278080v 1Attorney Docket No. 2017420-0064

[0209] In some embodiments, an Fc domain mutation comprises one or more of the following mutations: L234Y, P238D, T250V, V264I, T307P, Q311R, A330K, P343R, M428L, N434A, Y436T, Q438R, or S440E, according to the EU numbering scheme. In some embodiments, an Fc domain comprises the following set of mutations: L234Y, P238D, T250V, V264I, T307P, Q311R, A330K, P343R, M428L, N434A, Y436T, Q438R, and S440E, according to the EU numbering scheme (e.g., see SEQ ID NOs: 39, 40, and 62).

[0210] In some embodiments, an Fc domain mutation comprises at least one of the following mutated amino acid residues: G236D, S267E and L328F, according to the EU numbering scheme. In some embodiments, a first and / or second Fc domain comprise a combination of the following mutated amino acid residues: G236D, S267E and L328F, according to the EU numbering scheme.

[0211] In some embodiments, an Fc domain mutation comprises one or more of the following mutations: L234D, G236N, or S267E, according to the EU numbering scheme. In some embodiments, an Fc domain comprises the following set of mutations: L234D, G236N, and S267E, according to the EU numbering scheme (e.g., see SEQ ID NOs: 41, 42, and 63).

[0212] In some embodiments, an Fc domain mutation comprises L235R, according to the EU numbering scheme e.g., see SEQ ID NOs: 43, 44, and 64).

[0213] In some embodiments, an Fc domain mutation comprises one or both of the following mutations G236N and S267E, according to the EU numbering scheme. In some embodiments, an Fc domain comprises the following set of mutations: G236N and S267E, according to the EU numbering scheme (e.g., see SEQ ID NOs: 45, 46, and 65).

[0214] In some embodiments, an Fc domain mutation comprises one or both of the following mutations P238D and D270E, according to the EU numbering scheme. In some embodiments, an Fc domain comprises the following set of mutations: P238D and D270E, according to the EU numbering scheme (e.g., see SEQ ID NOs: 47, 48, and 66).

[0215] In some embodiments, an Fc domain mutation comprises one or both of the following mutations P238D and P271G, according to the EU numbering scheme. In some embodiments, an Page 95 of 22413278080v 1Attorney Docket No. 2017420-0064Fc domain comprises the following set of mutations: P238D and P271G, according to the EU numbering scheme (e.g., see SEQ ID NOs: 49, 50, and 67).

[0216] In some embodiments, an Fc domain mutation comprises one or more of the following mutations: P238D, D270E, or P271G, according to the EU numbering scheme. In some embodiments, an Fc domain comprises the following set of mutations: P238D, D270E, and P271G, according to the EU numbering scheme (e.g., see SEQ ID NOs: 51, 52, and 68).

[0217] In some embodiments, an Fc domain mutation comprises one or more of the following mutations: G237D, P238D, P271G, or A330R, according to the EU numbering scheme. In some embodiments, an Fc domain comprises the following set of mutations: G237D, P238D, P271G, and A33OR, according to the EU numbering scheme (e.g., see SEQ ID NOs: 53, 54, and 69).

[0218] In some embodiments, an Fc domain mutation comprises one or more of the following mutations: G237D, P238D, D270E, P271G, or A330R, according to the EU numbering scheme. In some embodiments, an Fc domain comprises the following set of mutations: G237D, P238D, D270E, P271G, and A330R, according to the EU numbering scheme (e.g., see SEQ ID NOs: 55, 56, and 70).

[0219] In some embodiments, an Fc domain mutation comprises one or more of the following mutations: E233D, G237D, P238D, H268D, P271G, or A33OR, according to the EU numbering scheme. In some embodiments, an Fc domain comprises the following set of mutations: E233D, G237D, P238D, H268D, P271G, and A330R, according to the EU numbering scheme (e.g., see SEQ ID NOs: 57, 58, and 71).

[0220] In some embodiments, an Fc domain mutation comprises P238D, according to the EU numbering scheme (e.g., see SEQ ID NOs: 27 and 28).

[0221] In some embodiments, Fc domains with mutations that increase binding affinity for FcyRIIB also have decreased or undetectable binding to certain activating Fc receptors. In some embodiments, an activating Fc receptor includes one or more of FcyRI, FcγRIIA167H, FcyRIIA167R, FcyRIIIA176F, FcyRIIIA176V, FcyRIIIB, and / or FcRn. Such binding properties Page 96 of 22413278080v 1Attorney Docket No. 2017420-0064lead to additional beneficial properties of molecules described herein including, e.g., a low risk of toxicity as there is less risk of activating the innate immune response (through activating Fc receptors) in response to molecules being introduced.

[0222] In some embodiments, an Fc domain described herein comprises one or more modifications such that a molecule described herein does not activate immune cells (e.g., does not activate immune cells to secrete pro-inflammatory cytokines, e.g., IL-6).Mutations for heterodimerization

[0223] In some embodiments, Fc mutations are introduced to promote heterodimerization of the two polypeptides, where each polypeptide comprises an Fc domain, and the first and second Fc domains heterodimerize in order to generate the full molecule.

[0224] Challenges exist in producing heterodimerized Fc domains of two different polypeptides from a single composition, particularly because the random pairing of different polypeptides can yield undesired species. Due to the presence of mispaired byproducts, and significantly reduced production yields, sophisticated purification procedures are required to isolate the desired antibody agent in those situations. In general, the same problem of mispaired byproducts remains if recombinant expression techniques are used. One approach to solve the problem of mispaired byproducts is known as “knob-into-holes technology” (KIH), which aims to force the pairing of two different polypeptides containing Fc domains by introducing mutations into the CH3 regions of the Fc domains to modify the contact interface. On one CH3 region, bulky amino acids are replaced by amino acids with short side chains to create a “hole” and amino acids with large side chains are introduced into the other CH3 region, to create a “knob”. For example, co-expressing two heavy chains of an antibody with such a modification with two light chains, leads to high yields of heterodimer formation versus homodimer was observed (see Ridgway et al., Protein Eng. 9:617 (1996); and WO 1996 / 027011, which are herein incorporated by reference). In some embodiments, a molecule described herein utilizes KIH technology as described in, e.g., WO 1998 / 050431, which is herein incorporated by reference in its entirety.Page 97 of 22413278080v 1Attorney Docket No. 2017420-0064

[0225] As described herein, a molecule comprises a first Fc domain and a second Fc domain. In some embodiments a first Fc domain and / or a second Fc domain comprises a CH2 region variant and / or a CH3 region variant, wherein such variants each independently comprise at least one different amino acid substitution such that a heterodimeric domain pair is generated such that heterodimerization of the first and second Fc domains of the inventive molecule is favored over homodimerization.

[0226] As described herein, a first and / or second Fc domain in a molecule described herein may comprise certain mutations that utilize KIH technology that include, but are not limited to, a CH3 modification. In some embodiments, a molecule comprises first and second Fc domains that form a heterodimer using knobs-in-holes (KIH) modifications. In some embodiments, a KIH mutation comprises Y349T and T394F, according to the EU numbering scheme. In some embodiments, the first Fc domain comprises the Y349T mutation and the second Fc domain comprises the T394F mutation. In some embodiments, the first Fc domain comprises the T394F mutation and the second Fc domain comprises the Y349T mutation. In some embodiments, a KIH mutation comprises T366W, S354C, T366S, L368A, Y407V, and Y349C, according to the EU numbering scheme. In some embodiments, the first Fc domain comprises the T366W and S354C mutations and the second Fc domain comprises the T366S, L368A, Y407V, and Y349C mutations. In some embodiments, the first Fc domain comprises the T366S, L368A, Y407V, and Y349C mutations and the second Fc domain comprises the T366W and S354C mutations.

[0227] One of skill in the art will understand that other known KIH mutations or other Fc modifications are known in the art to promote heterodimerization and may be used in the molecules described herein, such as charge-to-charge swap design (e.g., “DD-KK” mutation pairs) and isotype strand swap design (e.g., “SEED Fc” ) (see Ha et al., Frontiers in Immunology 7: 394 (2016), which is herein incorporated by reference in its entirety).Mutations for half-life extension

[0228] In some embodiments, a first and / or second Fc domain in a molecule includes one or more mutated amino acid residues that increase half-life. In some embodiments, a first and / or second Fc domain comprises one of the following mutated amino acid residues: M252Y, S254T, and T256E (“MST” or “YTE”), according to the EU numbering scheme to increase half-life. In Page 98 of 22413278080v 1Attorney Docket No. 2017420-0064some embodiments, a first and / or second Fc domain comprises a combination of the following mutated amino acid residues: M252Y, S254T, and T256E, according to the EU numbering scheme to increase half-life. In some embodiments, a first and / or second Fc domain comprises one of the following mutated amino acid residues: M428L and N434S (“L / S”), according to the EU numbering scheme. In some embodiments, a first and / or second Fc domain comprises a combination of the following mutated amino acid residues: M428L and N434S, according to the EU numbering scheme.

[0229] In some embodiments, a first and / or second Fc domain comprises one of the following mutated amino acid residues: T250Q and M428L (“QL”), according to the EU numbering scheme to increase half-life. In some embodiments, a first and / or second Fc domain comprises one of the following mutated amino acid residues: H433K and N434F (“KF”), according to the EU numbering scheme to increase half-life. In some embodiments, a first and / or second Fc domain comprises one of the following mutated amino acid residues: T307A, E380A and N434A (“AAA”), according to the EU numbering scheme to increase half-life. In some embodiments, a first and / or second Fc domain comprises the following mutated amino acid residues: V308P, according to the EU numbering scheme to increase half-life. In some embodiments, a first and / or second Fc domain comprises one of the following mutated amino acid residues: M252Y, V308P, and N434Y (“YPY”), according to the EU numbering scheme to increase half-life. In some embodiments, a first and / or second Fc domain comprises one of the following mutated amino acid residues: H285D, T307Q, and A378V (“DQV”), according to the EU numbering scheme to increase half-life. In some embodiments, a first and / or second Fc domain comprises one of the following mutated amino acid residues: L309D, Q311H, N434S (“DHS”), according to the EU numbering scheme to increase half-life. Exemplary Fc mutations are described in e.g., Liu et al., Antibodies 9(4): 64 (2020), which is hereby incorporated by reference in its entirety.

[0230] In some embodiments, a first and / or second Fc domain in a molecule includes one or more mutated amino acid residues that increase half-life and one or more mutations that increases binding to one or more internalizing receptors (e.g., FcyRIIB). The present disclosure provides exemplary molecules that have one or more mutations in the first and / or second FcPage 99 of 22413278080v 1Attorney Docket No. 2017420-0064domain that may provide more than one beneficial properties such as increased half-life and / or increased binding to one or more internalizing receptors such as FcyRIIB compared to a corresponding molecule that does not contain the one or more mutations. Without wishing to be bound by any theory, the present disclosure recognizes that molecules described herein containing one or more mutations that increase half-life and binding to an internalizing receptor may be beneficial for depleting target autoantibodies (e.g., anti-B2GPl autoantibodies) implicated in an autoimmune disease (e.g., APS). Additionally, the present disclosure recognizes that such combination of mutations may also increase binding specificity of the molecule to the internalizing receptor FcyRIIB over other activating receptors such as FcyRI, FcyRIIA167H, FcyRIIA167R, FcγRIIIA176F, FcyRIIIA176V, and / or FcyRIIIB. In some embodiments, such properties are enhanced when molecules described herein are present in an immune complex with one or more target autoantibodies.

[0231] In some embodiments, a first and / or second Fc domain comprises a combination of the following mutated amino acid residues: M428L, N434S, P238D and D270E, according to the EU numbering scheme.

[0232] In some embodiments, a first and / or second Fc domain comprises the following set of mutations: M428L, N434S, P238D and P271G, according to the EU numbering scheme.

[0233] In some embodiments, a first and / or second Fc domain comprises the following set of mutations: M428L, N434S, P238D, D270E, and P271G, according to the EU numbering scheme.

[0234] In some embodiments, a first and / or second Fc domain comprises the following set of mutations: M428L, N434S, G237D, P238D, P271G, and A330R, according to the EU numbering scheme.

[0235] In some embodiments, a first and / or second Fc domain comprises the following set of mutations: M428L, N434S, G237D, P238D, D270E, P271G, and A330R, according to the EU numbering scheme.Page 100 of 22413278080v 1Attorney Docket No. 2017420-0064

[0236] In some embodiments, a first and / or second Fc domain comprises the following set of mutations: M428L, N434S, E233D, G237D, P238D, H268D, P271G, and A330R, according to the EU numbering scheme.

[0237] In some embodiments, a first and / or second Fc domain comprises M428L, N434S, and P238D, according to the EU numbering scheme.Mutations to ablate effector function

[0238] In some embodiments, additional Fc mutations are introduced in order to ablate effector function of molecules described herein. By ablating the Fc effector function of the molecule, molecules not bound to an anti-B2GPl autoantibody will not be targeted for destruction.

[0239] In some embodiments, a first and / or second Fc domain of a molecule includes a modification that silences effector function. In some embodiments, a modification that silences effector function comprises one or more of the following mutations: L234A, L235A, P329G, P329A, N297A, or N297D, according to the EU numbering scheme. In some embodiments, a modification that silences effector function comprises the following mutated amino acid residues: L234A and L235A (“LALA”), according to the EU numbering scheme. In some embodiments, mutations used to ablate effector function include the following: L234A, L235A, and P329G (“LALAPG”), according to EU numbering. In some embodiments, a modification that silences effector function comprises the following mutated amino acid residues: L234A, L235A, and P329A (“LALAPA”), according to the EU numbering scheme. In some embodiments, a modification that silences effector function further comprises N297A, or N297D. In some embodiments, a modification that silences effector function includes the following Fc mutations: L234A, L235A, P329G and N297A. In some embodiments, a modification that silences effector function includes the following Fc mutations: L234A, L235A, P329G, and N297D. In some embodiments, a modification that silences effector function includes the following Fc mutations: L234A, L235A, and N297A. In some embodiments, a modification that silences effector function includes the following Fc mutations: L234A, L235A, and N297D. In some embodiments, a modification that silences effector function includes the following Fc mutations: L234A, L235A, P329A, and N297A. In some embodiments, a Page 101 of 22413278080v 1Attorney Docket No. 2017420-0064modification that silences effector function includes the following Fc mutations: L234A, L235A, P329A, andN297D. In some embodiments, a modification that silences effector function includes the following Fc mutations: G236R and L328R (“GRLR”). In some embodiments, a modification that silences effector function includes the following Fc mutations: L234S, L235T, and G236R (“STR”). In some embodiments, a modification that silences effector function includes the following Fc mutations: L234A and L235E (“LALE”). In some embodiments, a modification that silences effector function includes the following Fc mutations: D265A and P329A (“DAPA”). In some embodiments, a modification that silences effector function includes the following Fc mutations: L234A, L235A, and K322A (“LALAKA”). In some embodiments, a modification that silences effector function includes the following Fc mutations: L234F, L235E, and P331 S (“FES”). In some embodiments, a modification that silences effector function includes the following Fc mutations: L234F, L235Q, and K322Q (“FQQ”). In some embodiments, a modification that silences effector function includes the following Fc mutations: L234A, L235A, G237A, P238S, H268A, A330S, and P331S (“Sigma”). In some embodiments, a modification that silences effector function includes the following Fc mutations: E233P, L234V, L235A, D236G, A327G, A330S, P331S (“PVA-GSS”). In some embodiments, a modification that silences effector function includes the following Fc mutations: L235G and G236R (“LGGR”). One of ordinary skill in the art will appreciate that other modifications known in the art could be used in order to ablate effector function.Linkers

[0240] Molecules described herein include an Fc domain linked to an autoantibody-binding domain. In some embodiments, the autoantibody -binding domain is connected directly to an Fc domain. In some embodiments, the autoantibody-binding domain is connected to an Fc domain through a linker. Various linkers are contemplated to be used in molecules described herein. While linkers may be between an autoantibody-binding domain and an Fc domain they may also be between other domains of the molecule, e.g., connecting one or more autoantigen domains within the autoantibody-binding domain.Page 102 of 22413278080v 1Attorney Docket No. 2017420-0064

[0241] In some embodiments, a linker includes a flexible linker so as to provide flexibility in a molecule (e.g., between an autoantigen domain and a Fc domain). In some embodiments, a flexible linker contains at least 1 flexible amino acid (e.g., Gly).

[0242] Exemplary flexible linkers include glycine polymers (G)n, glycine-serine polymers (including, for example, (GS)n, (GSGGS: SEQ ID NO: 116)nand (GGGS: SEQ ID NO: 132)n, where n is an integer of at least one), glycine-alanine polymers, alanine-serine polymers, and other flexible linkers known in the art. Glycine and glycine-serine polymers are relatively unstructured, and therefore may be able to serve as a neutral tether between components.Glycine accesses significantly more phi-psi space than even alanine, and is much less restricted than residues with longer side chains (see Scheraga, Rev. Computational Chem. 11:173-142 (1992)). In some embodiments, a linker comprises the amino acid sequence of SEQ ID NO: 84 (GGGGS), SEQ ID NO: 85 (GGGGSGGGGS), SEQ ID NO: 86 (GGGGSGGGGSGGGGS) or SEQ ID NO: 87 (VDGGGGSGGGGSGGGGSG).

[0243] Additional exemplary flexible linkers include, but are not limited to, SEQ ID NO: 88 (GGSG), SEQ ID NO: 89 (GGSGG), SEQ ID NO: 90 (GSGSG), SEQ ID NO: 91 (GSGGG), SEQ ID NO: 92 (GGGSG), SEQ ID NO: 93 (GSSSG), and the like. Additional exemplary linkers also include the following: GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 94) and GGGGSGGGGSGGGGSGGGGSSGGGGS (SEQ ID NO: 95).

[0244] The ordinarily skilled artisan will recognize that the design of a molecule described herein can include a linker that is all or partially flexible, such that the linker can include a flexible linker as well as one or more portions that confer less flexible structure to provide for a desired molecule structure.

[0245] Suitable linkers can be readily selected and can be of various lengths, such as from 1 amino acid (e.g., Gly) to 20 amino acids or more, from 2 amino acids to 15 amino acids, from 3 amino acids to 12 amino acids, including 4 amino acids to 10 amino acids, 5 amino acids to 9 amino acids, 6 amino acids to 8 amino acids, or 7 amino acids to 8 amino acids (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 amino acids).Page 103 of 22413278080v 1Attorney Docket No. 2017420-0064

[0246] In some embodiments a linker may be or comprise a synthetic linker that does not comprise amino acids, e.g., a polyethylene (PEG) linker or other known synthetic linkers that are commonly used for chemical conjugation, e.g., in antibody-drug conjugates. In this context, it is also to be understood that the molecules described herein encompass molecules where the components of the first or second polypeptides (i.e., autoantigen domain, antigen-binding domain, Fc domains) are linked via chemical conjugation, e.g., “click” or other chemistry, optionally with an intervening amino acid or synthetic linker.

[0247] In some embodiments, a molecule described herein is a fusion protein wherein the first and second polypeptides can be encoded by a single nucleic acid sequence. In some embodiments, a molecule described herein is a chemically conjugated molecule that includes components conjugated using synthetic chemistry.Exemplary Configurations

[0248] Various configurations of molecules as described herein are contemplated. Such configurations include various elements of molecules as 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 may be assembled in different configurations to generate a molecule as described herein.

[0249] Exemplary combinations of specific autoantigen domains, antigen-binding domains, Fc domains, and linkers are provided in Table 4 below. In some embodiments, any one of the combinations in Table 4 may be included in a molecule configuration as shown, e.g., in FIG. 2.In such a configuration, the C-terminus of an autoantigen domain (A) is linked to the N-terminus of a first Fc domain (Fcl) through an optional linker (L) (first polypeptide) and forms a heterodimer with a second Fc domain (Fc2) of the second polypeptide.

[0250] In some embodiments, any one of the combinations in Table 4 may be included in a molecule configuration as shown, e.g., in FIG. 3. In such a configuration, the C-terminus of an autoantigen domain (A) is linked to the N-terminus of a first Fc domain (Fcl) though an optional linker (L) (first polypeptide) and the molecule also includes an antigen-binding domain, where Page 104 of 22413278080v 1Attorney Docket No. 2017420-0064the C-terminus of the antigen-binding domain (HC / LC Fab) is linked to the N-terminus of a second Fc domain (Fc2) (second polypeptide). In some embodiments (not shown), the N-terminus of the antigen-binding domain (HC / LC Fab) is instead linked to the C-terminus of a second Fc domain (Fc2) (second polypeptide). In some embodiments (not shown), the C-terminus of a first Fc domain (Fcl) is instead linked to the N-terminus of a first autoantigen domain (A) through an optional linker (L) (first polypeptide). In some embodiments (not shown), the C-terminus of a first Fc domain (Fcl) is instead linked to the N-terminus of a first autoantigen domain (A) through 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 a second Fc domain (Fc2) (second polypeptide).

[0251] In some embodiments, any one of the combinations in Table 4 may be included in a molecule configuration as shown, e.g., in FIG. 4. In such a configuration, the C-terminus of a first Fc domain (Fcl) is linked to the N-terminus of an autoantigen domain (A) through an optional linker (L’) (first polypeptide) and forms a heterodimer with a second Fc domain (Fc2) of the second polypeptide.

[0252] In some embodiments, any one of the combinations in Table 4 may be included in a molecule configuration as shown, e.g., in FIG. 5A. In such a configuration, a molecule includes two autoantigen domains, where the C-terminus of a first Fc domain (Fcl) is linked to the N-terminus of a first autoantigen domain (A) through 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’) through an optional linker (L’) (second polypeptide). In some embodiments, the two autoantigen domains are the same (e.g., in a homodimeric molecule of the present disclosure). In some embodiments, the two autoantigen domains are different (e.g., in a heterodimeric molecule of the present disclosure).

[0253] In some embodiments, any one of the combinations in Table 4 may be included in a molecule configuration as shown, e.g., in FIG. 5B. In such a configuration, a molecule includes two autoantigen domains, where the C-terminus of a first autoantigen domain (A) is linked to the N-terminus of a first Fc domain (Fcl) through 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 Page 105 of 22413278080v 1Attorney Docket No. 2017420-0064domain (Fc2) through an optional linker (L) (second polypeptide). In some embodiments, the two autoantigen domains are the same (e.g., in a homodimeric molecule of the present disclosure). In some embodiments, the two autoantigen domains are different (e.g., in a heterodimeric molecule of the present disclosure).

[0254] Where FIGs. 2-5 label “A” or “A’ ” as an antigen (e.g., any antigen described herein), the present disclosure also encompasses any domain that targets an autoantibody for this component in the molecules described herein.

[0255] Additionally or alternatively, in some embodiments, a molecule may include a first antigen-binding domain and a second antigen-binding domain such that each antigen-binding domain is capable of binding to the same or different target antigen. In some embodiments, a first and / or second polypeptide of a molecule comprises an antigen binding domain. In some embodiments, a first polypeptide of a molecule comprises an antigen-binding domain. In some embodiments, a second polypeptide of a molecule comprises an antigen-binding domain. In some embodiments, both a first and second polypeptide of a molecule comprise an antigenbinding domain. In some embodiments, a first antigen-binding domain targets an anti-B2GPl autoantibody and a second antigen-binding domain targets an internalizing receptor (e.g., ASPGR).

[0256] In some embodiments, a B2GP1 autoantigen domain described herein may include a native or non-native signal peptide sequence. The native B2GP1 signal peptide sequence is shown in SEQ ID NO: 12. In some embodiments, a B2GP1 autoantigen domain may include a non-native signal peptide. In some embodiments, a non-native signal peptide may be IgH signal peptide (e.g., MGWSCIILFLVATATGVHS, SEQ ID NO: 96), or a fragment or variant thereof.

[0257] In some embodiments, a B2GP1 autoantigen domain described herein does not include a signal peptide sequence.

[0258] In some embodiments, an exemplary molecule described herein comprises the combination of amino acid sequences as shown in Table 4 below. Table 4 below includes the signal peptide sequence (SP), the autoantigen domain sequence (A), the linker sequence (L), the Fcl domain (Fc of the first polypeptide) and the Fc2 domain (Fc of the second polypeptide). In Page 106 of 22413278080v 1Attorney Docket No. 2017420-0064some embodiments, a molecule described herein (e.g., as described in Table 4) is bivalent (e.g., as shown in FIG. 5), where there are two autoantigen domains available to target an autoantibody. In some embodiments, a molecule described herein (e.g, as described in Table 4) is monovalent (e.g., as shown in FIG. 2, FIG. 4 and FIGs. 7A-7C).

[0259] FIGs. 16A-16E show exemplary bivalent and monovalent molecule formats described herein. FIG. 16A shows an exemplary bivalent molecule that includes a first and second polypeptide that includes a B2GP1 Domain 1 antigen fragment (e.g., G20-V83 antigen fragment), and an Fc domain. FIG. 16B shows an exemplary bivalent molecule that includes a first and second polypeptide having a B2GP1 Domain 1 antigen fragment (e.g., G20-V83 antigen fragment) with D8S and D9G mutations, and an Fc domain. FIG. 16C shows an exemplary monovalent molecule that includes a first polypeptide that includes a B2GP1 Domain 1 antigen fragment (e.g., G20-V83 antigen fragment) with D8S and D9G mutations, and an Fc domain, and a second polypeptide that includes an Fc domain. FIG. 16D shows an exemplary bivalent molecule that includes a first and second polypeptide that utilizes a larger fragment of human B2GP1 (including Domain 1 and Domain 2) (e.g., a G20-I141 antigen fragment) with D8S and D9G mutations and an Fc domain. FIG. 16E shows an exemplary bivalent molecule where the autoantigen fragment utilizes a linker to lengthen the antigen fragment of human B2GP1 Domain 1, where the first and second polypeptides include a B2GP1 Domain 1 (e.g., a G20-V83 antigen fragment) with D8S and D9G mutations, a linker (G4S)3 (SEQ ID NO: 86), and an Fc domain.Table 4: Exemplary B2GP1 Antibody Depletion CombinationsMolecule ID Name SP A or L or Fcl Fc2A’ L’Variant Al IgH SP B2GP1 G20-V83 96 2 - 19 19 hlgGl Fc with P238D mutation(bivalent)Variant A2 IgH SP B2GP1 G20-V83 with D8S, 96 4 - 19 19D9G mutationshlgGl Fc with P238D mutation(bivalent)Page 107 of 22413278080v 1Attorney Docket No. 2017420-0064Molecule ID Name SP A or L or Fcl Fcl A’ L’Variant A3 IgH SP B2GP1 G20-A262 96 3 - 19 19 hlgGl Fc with P238D mutation(bivalent)Variant A4 IgH SPB2GP1 G20-V83 C-terminal 96 2 84 19 19 with G4S linkerhlgGl Fc with P238D mutation(bivalent)Variant A5 IgH SP B2GP1 G20-V83 with D8S, 96 4 84 19 19D9G mutations C-terminal with G4SlinkerhlgGl Fc with P238D mutation(bivalent)Variant A6 IgH SPB2GPl G20-A262 C- 96 3 84 19 19 terminal with G4S linkerhlgGl Fc with P238D (bivalent)Variant A7 IgH SP B2GP1 G20-V83 96 2 - 28 29 hlgGl Fc with P238D mutation andKIH mutations (monovalent)Variant A8 IgH SP B2GP1 G20-V83 with D8S, 96 4 - 28 29D9G mutationshlgGl Fc with P238D mutation andKIH mutations (monovalent)Variant A9 IgH SP B2GP1 G20-A262 96 3 - 28 29 hlgGl Fc with P238D mutation andKIH mutations (monovalent)Variant Al 0 IgH SP B2GP1 G20-V83 96 2 - 99 99 hlgGl Fc with G237D, P238D,P271G, A330R mutations (bivalent)Variant All IgH SP B2GP1 G20-V83 with D8S, 96 4 - 99 99D9G mutationshlgGl Fc with G237D, P238D,P271G, A330R mutations (bivalent)Page 108 of 22413278080v 1Attorney Docket No. 2017420-0064Molecule ID Name SP A or L or Fcl Fcl A’ L’Variant Al 2 IgH SPB2GP1 G20-A262 96 3 - 99 99 hlgGl Fc with G237D, P238D,P271G, A330R mutations (bivalent)Variant Al 3 IgH SPB2GP1 G20-V83 C-terminal 96 2 84 99 99 with G4S linkerhlgGl Fc with G237D, P238D,P271G, A330R mutations (bivalent)Variant Al 4 IgH SP B2GP1 G20-V83 with D8S, 96 4 84 99 99D9G mutations C-terminal with G4SlinkerhlgGl Fc with G237D, P238D,P271G, A330R mutations (bivalent)Variant Al 5 IgH SP B2GP1 G20-A262 C-terminal 96 3 84 99 99 with G4S linkerhlgGl Fc with G237D, P238D,P271G, A330R mutations (bivalent)Variant Al 6 IgH SP B2GP1 G20-V83 96 2 - 402 403 hlgGl Fc with G237D, P238D,P271G, A330R mutations and KIHmutations (monovalent)Variant Al 7 IgH SP B2GP1 G20-V83 with D8S, 96 4 - 402 403D9G mutationshlgGl Fc with G237D, P238D,P271G, A330R mutations and KIHmutations (monovalent)Variant Al 8 IgH SPB2GP1 G20-A262 96 3 - 402 403 hlgGl Fc with G237D, P238D,P271G, A330R mutations and KIHmutations (monovalent)Variant Al 9 IgH SP B2GP1 G20-V83 96 2 - 124 124 huIgGl Fc with G237D, P238D,P271G, A330R (bivalent)Page 109 of 22413278080v 1Attorney Docket No. 2017420-0064Molecule ID Name SP A or L or Fcl Fcl A’ L’Variant A20 IgH SP B2GP1 G20-V83 with D8S, 96 4 - 124 124D9G mutationshlgGl Fc with G237D, P238D,P271G, A330R mutations (bivalent)Variant A21 IgH SP B2GP1 G20-I141 with D8S 96 6 - 124 124 and D9G mutationshlgGl Fc with G237D, P238D,P271G, A330R mutations (bivalent)Variant A22 IgH SP B2GP1 G20-I141 with D8S, 96 6 - 131 131D9G mutationshlgGl Fc with G237D, P238D,P271G, A330R and M428L andN434S mutations (bivalent)Variant A23 IgH SP B2GP1 G20-V83 with D8S 96 4 86 124 124 and D9G mutations(G4S) linker x 3hlgGl Fc with G237D, P238D,P271G, A330R mutations (bivalent)Variant A24 IgH SP B2GP1 G20-V83 96 2 - 131 131 huIgGl Fc with G237D, P238D,P271G, A330R and M428L andN434S mutations (bivalent)Variant A25 IgH SP B2GP1 G20-V83 with D8S, 96 4 - 131 131D9G mutationshlgGl Fc with G237D, P238D,P271G, A330R and M428L andN434S mutations (bivalent)Variant A26 IgH SP B2GP1 G20-V83 with D8S 96 4 86 131 131 and D9G mutations(G4S) linker x 3hlgGl Fc with G237D, P238D,P271G, A330R and M428L andN434S mutations (bivalent)Page 110 of 22413278080v 1Attorney Docket No. 2017420-0064

[0260] In some embodiments, a molecule comprises an amino acid sequence comprising any of the combinations of sequences shown in Table 4. In some embodiments, a molecule comprises an amino acid sequence comprising any of the combinations of sequences shown in Table 4 and includes a linker (L) between the autoantigen domain and Fc domain (e.g., as shown in any one of the configurations in FIGs. 2-5). In some embodiments, a molecule comprises an amino acid sequence comprising any of the combinations of sequences shown in Table 4, without a signal peptide. In some embodiments, a molecule comprises an amino acid sequence comprising any of the combinations of sequences shown in Table 4, with a different signal peptide. In some embodiments, a molecule comprises an amino acid sequence comprising any of the combinations of sequences shown in Table 4, with a native signal peptide. In some embodiments, a molecule comprises an amino acid sequence comprising any of the combinations of sequences shown in Table 4, with a non-native signal peptide.

[0261] In some embodiments, a molecule comprises a first polypeptide, wherein the first polypeptide comprises: (i) an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 2 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 19; (ii) an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 3 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 19; (iii) an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 4 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 19; (iv) an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 2 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at Page 111 of 22413278080v 1Attorney Docket No. 2017420-0064least 99%) to SEQ ID NO: 28; (v) an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 3 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 28; (vi) an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 4 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 28; (vii) an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 2 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 99; (viii) an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 4 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 99; (ix) an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 3 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 99; (x) an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 2 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 402; (xi) an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 3 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, atPage 112 of 22413278080v 1Attorney Docket No. 2017420-0064least 99%) to SEQ ID NO: 402; (xii) an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 4 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 402; (xiii) an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 2 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 124; (xiv) an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 4 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 124; (xv) an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 6 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 124; (xvi) an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 6 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 131; (xvii) an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 4, and amino acid that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 86, and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 124; (xviii) an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) toPage 113 of 22413278080v 1Attorney Docket No. 2017420-0064SEQ ID NO: 2 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 131; (xix) an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 4 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 131; or (xx) an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 4, and amino acid that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 86, and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 131.

[0262] In some embodiments, a molecule comprises a first polypeptide, wherein the first polypeptide comprises: (i) an amino acid sequence comprising SEQ ID NO: 2 and an amino acid sequence comprising SEQ ID NO: 19; (ii) an amino acid sequence comprising SEQ ID NO: 3 and an amino acid sequence comprising SEQ ID NO: 19; (iii) an amino acid sequence comprising SEQ ID NO: 4 and an amino acid sequence comprising SEQ ID NO: 19; (iv) an amino acid sequence comprising SEQ ID NO: 2 and an amino acid sequence comprising SEQ ID NO: 28; (v) an amino acid sequence comprising SEQ ID NO: 3 and an amino acid sequence comprising SEQ ID NO: 28; (vi) an amino acid sequence comprising SEQ ID NO: 4 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 28; (vii) an amino acid sequence comprising SEQ ID NO: 2 and an amino acid sequence comprising SEQ ID NO: 99; (viii) an amino acid sequence comprising SEQ ID NO: 3 and an amino acid sequence comprising SEQ ID NO: 99; (ix) an amino acid sequence comprising SEQ ID NO: 3 and an amino acid sequence comprising SEQ ID NO: 99; (x) an amino acid sequence comprising SEQ ID NO: 2 and an amino acid sequence comprising SEQ ID NO: 402; (xi) an amino acid sequence comprising SEQ ID NO: 3 and an amino acid sequence comprising SEQ ID NO: 402; (xii) an amino acid sequence comprising SEQ ID NO: 4 and an amino acid sequence Page 114 of 22413278080v 1Attorney Docket No. 2017420-0064comprising SEQ ID NO: 402; (xiii) an amino acid sequence comprising SEQ ID NO: 2 and an amino acid sequence comprising SEQ ID NO: 124; (xiv) an amino acid sequence comprising SEQ ID NO: 4 and an amino acid sequence comprising SEQ ID NO: 124; (xv) an amino acid sequence comprising SEQ ID NO: 6 and an amino acid sequence comprising SEQ ID NO: 124; (xvi) an amino acid sequence comprising SEQ ID NO: 6 and an amino acid sequence comprising SEQ ID NO: 131; (xvii) an amino acid sequence comprising SEQ ID NO: 4, an amino acid sequence comprising SEQ ID NO: 86, and an amino acid sequence comprising SEQ ID NO: 124; (xviii) an amino acid sequence comprising SEQ ID NO: 2 and an amino acid sequence comprising SEQ ID NO: 131; (xix) an amino acid sequence comprising SEQ ID NO: 4 and an amino acid sequence comprising SEQ ID NO: 131; or (xx) an amino acid sequence comprising SEQ ID NO: 4, an amino acid sequence comprising SEQ ID NO: 86, and an amino acid sequence comprising SEQ ID NO: 131.

[0263] In some embodiments, a molecule comprises a second polypeptide, wherein the second polypeptide comprises: (i) an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 2 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 19; (ii) an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 3 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 19; (iii) an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 4 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 19; (iv) an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 29; (v) an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at Page 115 of 22413278080v 1Attorney Docket No. 2017420-0064least 98%, at least 99%) to SEQ ID NO: 2 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 99; (vi) an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 3 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 99, (vii) an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 4 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 99; or (viii) an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 403; (ix) an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 2 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 124; (x) an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 4 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 124; (xi) an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 6 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 124; (xii) an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 6 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, atPage 116 of 22413278080v 1Attorney Docket No. 2017420-0064least 98%, at least 99%) to SEQ ID NO: 131; (xiii) an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 4, and amino acid that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 86, and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 124; (xiv) an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 2 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 131; (xv) an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 4 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 131; or (xvi) an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 4, and amino acid that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 86, and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 131.

[0264] In some embodiments, a molecule comprises a second polypeptide, wherein the second polypeptide comprises: (i) an amino acid sequence comprising SEQ ID NO: 2 and an amino acid sequence comprising SEQ ID NO: 19; (ii) an amino acid sequence comprising SEQ ID NO: 3 and an amino acid sequence comprising SEQ ID NO: 19; (iii) an amino acid sequence comprising SEQ ID NO: 4 and an amino acid sequence comprising SEQ ID NO: 19; (iv) an amino acid sequence comprising SEQ ID NO: 29; (v) an amino acid sequence comprising SEQ ID NO: 2 and an amino acid sequence comprising SEQ ID NO: 99; (vi) an amino acid sequence comprising SEQ ID NO: 3 and an amino acid sequence comprising SEQ ID NO: 99, (vii) an Page 117 of 22413278080v 1Attorney Docket No. 2017420-0064amino acid sequence comprising SEQ ID NO: 4 and an amino acid sequence comprising SEQ ID NO: 99; or (viii) an amino acid sequence comprising SEQ ID NO: 403; (ix) an amino acid sequence comprising SEQ ID NO: 2 and an amino acid sequence comprising SEQ ID NO: 124; (x) an amino acid sequence comprising SEQ ID NO: 4 and an amino acid sequence comprising SEQ ID NO: 124; (xi) an amino acid sequence comprising SEQ ID NO: 6 and an amino acid sequence comprising SEQ ID NO: 124; (xii) an amino acid sequence comprising SEQ ID NO: 6 and an amino acid sequence comprising SEQ ID NO: 131; (xiii) an amino acid sequence comprising SEQ ID NO: 4, an amino acid sequence comprising SEQ ID NO: 86, and an amino acid sequence comprising SEQ ID NO: 124; (xiv) an amino acid sequence comprising SEQ ID NO: 2 and an amino acid sequence comprising SEQ ID NO: 131; (xv) an amino acid sequence comprising SEQ ID NO: 4 and an amino acid sequence comprising SEQ ID NO: 131; or (xvi) an amino acid sequence comprising SEQ ID NO: 4, an amino acid sequence comprising SEQ ID NO: 86, and an amino acid sequence comprising SEQ ID NO: 131.

[0265] In some embodiments, a molecule comprises a first and second polypeptide wherein, (i) the first polypeptide comprises an amino acid sequence comprising SEQ ID NO: 2 and SEQ ID NO: 28, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 29; or (ii) the first polypeptide comprises an amino acid sequence comprising SEQ ID NO: 3 and SEQ ID NO: 28, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 29. In some embodiments, a molecule comprises a first and second polypeptide wherein, (i) the first polypeptide comprises an amino acid sequence comprising SEQ ID NO: 4 and SEQ ID NO: 28, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 29; or (ii) the first polypeptide comprises an amino acid sequence comprising SEQ ID NO: 2 and SEQ ID NO: 402, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 403. In some embodiments, a molecule comprises a first and second polypeptide wherein, (i) the first polypeptide comprises an amino acid sequence comprising SEQ ID NO: 3 and SEQ ID NO: 402, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 403; or (ii) the first polypeptide comprises an amino acid sequence comprising SEQ ID NO: 4 and SEQ ID NO: 402, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 403.Page 118 of 22413278080v 1Attorney Docket No. 2017420-0064

[0266] In some embodiments, a molecule comprises (a) a first polypeptide, wherein the first polypeptide comprises: (i) an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to any one of SEQ ID NOs: 1-6 and (ii) an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to any one of: SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 32, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 99, (e.g., a sequence selected from SEQ ID NOs: 19 or 99), SEQ ID NO: 124, SEQ ID NO: 125, SEQ ID NO: 126, and SEQ ID NO: 131 and (b) a second polypeptide, wherein the second polypeptide comprises: (i) an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to any one of SEQ ID NOs: 1-6 and (ii) an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to any one of SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 32, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 99 (e.g., a sequence selected from SEQ ID NOs: 19 or 99), SEQ ID NO: 124, SEQ ID NO: 125, SEQ ID NO: 126, and SEQ ID NO: 131.

[0267] In some embodiments, a molecule comprises (a) a first polypeptide, wherein the first polypeptide comprises: (i) an amino acid sequence comprising any one of SEQ ID NOs: 1-6 and (ii) an amino acid sequence comprising any one of: SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 32, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 99, (e.g., a sequence selected Page 119 of 22413278080v 1Attorney Docket No. 2017420-0064from SEQ ID NOs: 19 or 99), SEQ ID NO: 125, and SEQ ID NO: 126, and (b) a second polypeptide, wherein the second polypeptide comprises: (i) an amino acid sequence comprising any one of SEQ ID NOs: 1-4 and (ii) an amino acid sequence comprising any one of SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 32, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 99 (e.g., a sequence selected from SEQ ID NOs: 19 or 99), SEQ ID NO: 125, and SEQ ID NO: 126.

[0268] In some embodiments, a molecule comprises (a) a first polypeptide, wherein the first polypeptide comprises: (i) an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to any one of SEQ ID NOs: 1-6 and (ii) an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to any one of: SEQ ID NO: 22, SEQ ID NO: 24, SEQ ID NO: 26, SEQ ID NO: 28, SEQ ID NO: 30, SEQ ID NO: 33, SEQ ID NO: 35, SEQ ID NO: 37, SEQ ID NO: 39, SEQ ID NO: 41, SEQ ID NO: 43, SEQ ID NO: 45, SEQ ID NO: 47, SEQ ID NO: 49, SEQ ID NO: 51, SEQ ID NO: 53, SEQ ID NO: 55, SEQ ID NO: 57, SEQ ID NO: 74, SEQ ID NO: 127, SEQ ID NO: 129, SEQ ID NO: 392, SEQ ID NO: 394, SEQ ID NO: 396, SEQ ID NO: 398, SEQ ID NO: 400, SEQ ID NO: 402, SEQ ID NO: 404, and SEQ ID NO: 406, and (b) a second polypeptide, wherein the second polypeptide comprises: an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to any one of SEQ ID NO: 23, SEQ ID NO: 25, SEQ ID NO: 27, SEQ ID NO: 29, SEQ ID NO: 31, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 38, SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID NO: 50, SEQ ID NO: 52, SEQ ID NO: 54, SEQ ID NO: 56, SEQ ID NO: 58, SEQ ID NO: 75, SEQ ID NO: 128, SEQ ID NO: 130, SEQ ID NO: 393, SEQ ID NO: 395, SEQ ID NO: 397, SEQ ID NO: 399, SEQ ID NO: 401, SEQ ID NO: 403, SEQ ID NO: 405, and SEQ ID NO: 407.Page 120 of 22413278080v 1Attorney Docket No. 2017420-0064

[0269] In some embodiments, a molecule comprises (a) a first polypeptide, wherein the first polypeptide comprises: (i) an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to any one of SEQ ID NOs: 1-6 and (ii) an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to any one of: SEQ ID NO: 23, SEQ ID NO: 25, SEQ ID NO: 27, SEQ ID NO: 29, SEQ ID NO: 31, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 38, SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID NO: 50, SEQ ID NO: 52, SEQ ID NO: 54, SEQ ID NO: 56, SEQ ID NO: 58, SEQ ID NO: 75, SEQ ID NO: 128, SEQ ID NO: 130, SEQ ID NO: 393, SEQ ID NO: 395, SEQ ID NO: 397, SEQ ID NO: 399, SEQ ID NO: 401, SEQ ID NO: 403, SEQ ID NO: 405, and SEQ ID NO: 407, and (b) a second polypeptide, wherein the second polypeptide comprises: an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to any one of SEQ ID NO: 22, SEQ ID NO: 24, SEQ ID NO: 26, SEQ ID NO: 28, SEQ ID NO: 30, SEQ ID NO: 33, SEQ ID NO: 35, SEQ ID NO: 37, SEQ ID NO: 39, SEQ ID NO: 41, SEQ ID NO: 43, SEQ ID NO: 45, SEQ ID NO: 47, SEQ ID NO: 49, SEQ ID NO: 51, SEQ ID NO: 53, SEQ ID NO: 55, SEQ ID NO: 57, SEQ ID NO: 74, SEQ ID NO: 127, SEQ ID NO: 129, SEQ ID NO: 392, SEQ ID NO: 394, SEQ ID NO: 396, SEQ ID NO: 398, SEQ ID NO: 400, SEQ ID NO: 402, SEQ ID NO: 404, and SEQ ID NO: 406.

[0270] In some embodiments, a molecule comprises (a) a first polypeptide, wherein the first polypeptide comprises: (i) an amino acid sequence comprising any one of SEQ ID NOs: 1-6 and (ii) an amino acid sequence comprising any one of: SEQ ID NO: 22, SEQ ID NO: 24, SEQ ID NO: 26, SEQ ID NO: 28, SEQ ID NO: 30, SEQ ID NO: 33, SEQ ID NO: 35, SEQ ID NO: 37, SEQ ID NO: 39, SEQ ID NO: 41, SEQ ID NO: 43, SEQ ID NO: 45, SEQ ID NO: 47, SEQ ID NO: 49, SEQ ID NO: 51, SEQ ID NO: 53, SEQ ID NO: 55, SEQ ID NO: 57, SEQ ID NO: 74, SEQ ID NO: 127, SEQ ID NO: 129, SEQ ID NO: 392, SEQ ID NO: 394, SEQ ID NO: 396, SEQ ID NO: 398, SEQ ID NO: 400, SEQ ID NO: 402, SEQ ID NO: 404, and SEQ ID NO: 406, and (b) a second polypeptide, wherein the second polypeptide comprises: an amino acid sequence comprising any one of SEQ ID NO: 23, SEQ ID NO: 25, SEQ ID NO: 27, SEQ ID NO: 29, SEQ Page 121 of 22413278080v 1Attorney Docket No. 2017420-0064ID NO: 31, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 38, SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID NO: 50, SEQ ID NO: 52, SEQ ID NO: 54, SEQ ID NO: 56, SEQ ID NO: 58, SEQ ID NO: 75, SEQ ID NO: 128, SEQ ID NO: 130, SEQ ID NO: 393, SEQ ID NO: 395, SEQ ID NO: 397, SEQ ID NO: 399, SEQ ID NO: 401, SEQ ID NO: 403, SEQ ID NO: 405, and SEQ ID NO: 407.

[0271] In some embodiments, a molecule comprises (a) a first polypeptide, wherein the first polypeptide comprises: (i) an amino acid sequence comprising any one of SEQ ID NOs: 1-6 and (ii) an amino acid sequence comprising any one of: SEQ ID NO: 23, SEQ ID NO: 25, SEQ ID NO: 27, SEQ ID NO: 29, SEQ ID NO: 31, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 38, SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID NO: 50, SEQ ID NO: 52, SEQ ID NO: 54, SEQ ID NO: 56, SEQ ID NO: 58, SEQ ID NO: 75, SEQ ID NO: 128, SEQ ID NO: 130, SEQ ID NO: 393, SEQ ID NO: 395, SEQ ID NO: 397, SEQ ID NO: 399, SEQ ID NO: 401, SEQ ID NO: 403, SEQ ID NO: 405, and SEQ ID NO: 407, and (b) a second polypeptide, wherein the second polypeptide comprises: an amino acid sequence comprising any one of SEQ ID NO: 22, SEQ ID NO: 24, SEQ ID NO: 26, SEQ ID NO: 28, SEQ ID NO: 30, SEQ ID NO: 33, SEQ ID NO: 35, SEQ ID NO: 37, SEQ ID NO: 39, SEQ ID NO: 41, SEQ ID NO: 43, SEQ ID NO: 45, SEQ ID NO: 47, SEQ ID NO: 49, SEQ ID NO: 51, SEQ ID NO: 53, SEQ ID NO: 55, SEQ ID NO: 57, SEQ ID NO: 74, SEQ ID NO: 127, SEQ ID NO: 129, SEQ ID NO: 392, SEQ ID NO: 394, SEQ ID NO: 396, SEQ ID NO: 398, SEQ ID NO: 400, SEQ ID NO: 402, SEQ ID NO: 404, and SEQ ID NO: 406.

[0272] In some embodiments, molecules described herein include a first polypeptide comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to any one of the first polypeptide sequences shown in Table 5 below. In some embodiments, molecules described herein include a first polypeptide comprising an amino acid sequence of any one of the first polypeptide sequences shown in Table 5 below. In some embodiments, molecules described herein include a second polypeptide comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to any one of the second polypeptide sequencesPage 122 of 22413278080v 1Attorney Docket No. 2017420-0064shown in Table 5 below. In some embodiments, molecules described herein include a second polypeptide comprising amino acid sequence of any one of the second polypeptide sequences shown in Table 5 below. In some embodiments, molecules described herein include a first polypeptide and a second polypeptide combination according to any one of the combination of first and second polypeptide amino acid sequences shown in Table 5 below.Table 5: Exemplary B2GP1 molecule sequencesSEQ SEQMoleculeDescription First Polypeptide ID Second polypeptide ID ID NO: NO:Variant Human B2GP1 MGWSCIILFLVATATGVHSG 100 MGWSCIILFLVATATGVHSG 100 Al G20-V83 RTCPKPDDLPFSTVVPLKTF RTCPKPDDLPFSTVVPLKTF YEPGEEITYSCKPGYVSRGG YEPGEEITYSCKPGYVSRGGhlgGl Fc with MRKFICPLTGLWPINTLKCT MRKFICPLTGLWPINTLKCT P238D PRVEPKSSDKTHTCPPCPAP PRVEPKSSDKTHTCPPCPAP mutation ELLGGDSVFLFPPKPKDTLM ELLGGDSVFLFPPKPKDTLM (bivalent) ISRTPEVTCVVVDVSHEDPE ISRTPEVTCVVVDVSHEDPE VKFNWYVDGVEVHNAKTKPR VKFNWYVDGVEVHNAKTKPR EEQYNSTYRVVSVLTVLHQD EEQYNSTYRVVSVLTVLHQD WLNGKEYKCKVSNKALPAPI WLNGKEYKCKVSNKALPAPI EKTISKAKGQPREPQVYTLP EKTISKAKGQPREPQVYTLP PSRDELTKNQVSLTCLVKGF PSRDELTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYK YPSDIAVEWESNGQPENNYK TTPPVLDSDGSFFLYSKLTV TTPPVLDSDGSFFLYSKLTV DKSRWQQGNVFSCSVMHEAL DKSRWQQGNVFSCSVMHEAL HNHYTQKSLSLSPGK HNHYTQKSLSLSPGKVariant Human B2GP1 MGWSCIILFLVATATGVHSG 101 MGWSCIILFLVATATGVHSG 101 A2 G20-V83 with RTCPKPSGLPFSTVVPLKTF RTCPKPSGLPFSTVVPLKTF D8S, D9G YEPGEEITYSCKPGYVSRGG YEPGEEITYSCKPGYVSRGG MRKFICPLTGLWPINTLKCT MRKFICPLTGLWPINTLKCTmutationsPRVEPKSSDKTHTCPPCPAP PRVEPKSSDKTHTCPPCPAPhlgGl Fc with ELLGGDSVFLFPPKPKDTLM ELLGGDSVFLFPPKPKDTLM P238D ISRTPEVTCVVVDVSHEDPE ISRTPEVTCVVVDVSHEDPE mutation VKFNWYVDGVEVHNAKTKPR VKFNWYVDGVEVHNAKTKPR (bivalent) EEQYNSTYRVVSVLTVLHQD EEQYNSTYRVVSVLTVLHQD WLNGKEYKCKVSNKALPAPI WLNGKEYKCKVSNKALPAPI EKTISKAKGQPREPQVYTLP EKTISKAKGQPREPQVYTLP PSRDELTKNQVSLTCLVKGF PSRDELTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYK YPSDIAVEWESNGQPENNYK TTPPVLDSDGSFFLYSKLTV TTPPVLDSDGSFFLYSKLTV DKSRWQQGNVFSCSVMHEAL DKSRWQQGNVFSCSVMHEAL HNHYTQKSLSLSPGK HNHYTQKSLSLSPGKPage 123 of 22413278080v 1Attorney Docket No. 2017420-0064SEQ SEQMoleculeDescription First Polypeptide ID Second polypeptide ID ID NO: NO:Variant Human B2GP1 MGWSCIILFLVATATGVHSG 102 MGWSCIILFLVATATGVHSG 102 A3 G20-A262 RTCPKPDDLPFSTVVPLKTF RTCPKPDDLPFSTVVPLKTF YEPGEEITYSCKPGYVSRGG YEPGEEITYSCKPGYVSRGGhlgGl Fc with MRKFICPLTGLWPINTLKCT MRKFICPLTGLWPINTLKCT P238D PRVCPFAGILENGAVRYTTF PRVCPFAGILENGAVRYTTF mutation EYPNTISFSCNTGFYLNGAD EYPNTISFSCNTGFYLNGAD (bivalent) SAKCTEEGKWSPELPVCAPI SAKCTEEGKWSPELPVCAPI ICPPPSIPTFATLRVYKPSA ICPPPSIPTFATLRVYKPSA GNNSLYRDTAVFECLPQHAM GNNSLYRDTAVFECLPQHAM FGNDTITCTTHGNWTKLPEC FGNDTITCTTHGNWTKLPEC REVKCPFPSRPDNGFVNYPA REVKCPFPSRPDNGFVNYPA KPTLYYKDKATFGCHDGYSL KPTLYYKDKATFGCHDGYSL DGPEEIECTKLGNWSAMPSC DGPEEIECTKLGNWSAMPSC KAEPKSSDKTHTCPPCPAPE KAEPKSSDKTHTCPPCPAPE LLGGDSVFLFPPKPKDTLMI LLGGDSVFLFPPKPKDTLMI SRTPEVTCVVVDVSHEDPEV SRTPEVTCVVVDVSHEDPEV KFNWYVDGVEVHNAKTKPRE KFNWYVDGVEVHNAKTKPRE EQYNSTYRVVSVLTVLHQDW EQYNSTYRVVSVLTVLHQDW LNGKEYKCKVSNKALPAPIE LNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPP KTISKAKGQPREPQVYTLPP SRDELTKNQVSLTCLVKGFY SRDELTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKT PSDIAVEWESNGQPENNYKT TPPVLDSDGSFFLYSKLTVD TPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALH KSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPGK NHYTQKSLSLSPGKVariant human B2GP 1 MGWSCIILFLVATATGVHSE 103 MGWSCIILFLVATATGVHSE 103 A4 G20-V83 C- PKSSDKTHTCPPCPAPELLG PKSSDKTHTCPPCPAPELLG terminal with GDSVFLFPPKPKDTLMISRT GDSVFLFPPKPKDTLMISRT PEVTCVVVDVSHEDPEVKFN PEVTCVVVDVSHEDPEVKFNG4S linkerWYVDGVEVHNAKTKPREEQY WYVDGVEVHNAKTKPREEQYhlgGl Fc with NSTYRVVSVLTVLHQDWLNG NSTYRVVSVLTVLHQDWLNG P238D KEYKCKVSNKALPAPIEKTI KEYKCKVSNKALPAPIEKTI mutation SKAKGQPREPQVYTLPPSRD SKAKGQPREPQVYTLPPSRD ELTKNQVSLTCLVKGFYPSD ELTKNQVSLTCLVKGFYPSD(bivalent)IAVEWESNGQPENNYKTTPP IAVEWESNGQPENNYKTTPP VLDSDGSFFLYSKLTVDKSR VLDSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHY WQQGNVFSCSVMHEALHNHY TQKSLSLSPGKGGGGSGRTC TQKSLSLSPGKGGGGSGRTC PKPDDLPFSTVVPLKTFYEP PKPDDLPFSTVVPLKTFYEP GEEITYSCKPGYVSRGGMRK GEEITYSCKPGYVSRGGMRK FICPLTGLWPINTLKCTPRV FICPLTGLWPINTLKCTPRVVariant human B2GP 1 MGWSCIILFLVATATGVHSE 104 MGWSCIILFLVATATGVHSE 104 A5 G20-V83 with PKSSDKTHTCPPCPAPELLG PKSSDKTHTCPPCPAPELLG GDSVFLFPPKPKDTLMISRT GDSVFLFPPKPKDTLMISRTD8S, D9GPage 124 of 22413278080v 1Attorney Docket No. 2017420-0064SEQ SEQMoleculeDescription First Polypeptide ID Second polypeptide ID ID NO: NO: mutations C- PEVTCVVVDVSHEDPEVKFN PEVTCVVVDVSHEDPEVKFN terminal with WYVDGVEVHNAKTKPREEQY WYVDGVEVHNAKTKPREEQY G4S linker NSTYRVVSVLTVLHQDWLNG NSTYRVVSVLTVLHQDWLNG KEYKCKVSNKALPAPIEKTI KEYKCKVSNKALPAPIEKTIhlgGl Fc with SKAKGQPREPQVYTLPPSRD SKAKGQPREPQVYTLPPSRD P238D ELTKNQVSLTCLVKGFYPSD ELTKNQVSLTCLVKGFYPSD mutation IAVEWESNGQPENNYKTTPP IAVEWESNGQPENNYKTTPP (bivalent) VLDSDGSFFLYSKLTVDKSR VLDSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHY WQQGNVFSCSVMHEALHNHY TQKSLSLSPGKGGGGSGRTC TQKSLSLSPGKGGGGSGRTC PKPSGLPFSTVVPLKTFYEP PKPSGLPFSTVVPLKTFYEP GEEITYSCKPGYVSRGGMRK GEEITYSCKPGYVSRGGMRK FICPLTGLWPINTLKCTPRV FICPLTGLWPINTLKCTPRVVariant human B2GP 1 MGWSCIILFLVATATGVHSE 105 MGWSCIILFLVATATGVHSE 105 A6 G20-A262 C- PKSSDKTHTCPPCPAPELLG PKSSDKTHTCPPCPAPELLG terminal with GDSVFLFPPKPKDTLMISRT GDSVFLFPPKPKDTLMISRT PEVTCVVVDVSHEDPEVKFN PEVTCVVVDVSHEDPEVKFNG4S linkerWYVDGVEVHNAKTKPREEQY WYVDGVEVHNAKTKPREEQYhlgGl Fc with NSTYRVVSVLTVLHQDWLNG NSTYRVVSVLTVLHQDWLNG P238D KEYKCKVSNKALPAPIEKTI KEYKCKVSNKALPAPIEKTI (bivalent) SKAKGQPREPQVYTLPPSRD SKAKGQPREPQVYTLPPSRD ELTKNQVSLTCLVKGFYPSD ELTKNQVSLTCLVKGFYPSD IAVEWESNGQPENNYKTTPP IAVEWESNGQPENNYKTTPP VLDSDGSFFLYSKLTVDKSR VLDSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHY WQQGNVFSCSVMHEALHNHY TQKSLSLSPGKGGGGSGRTC TQKSLSLSPGKGGGGSGRTC PKPDDLPFSTVVPLKTFYEP PKPDDLPFSTVVPLKTFYEP GEEITYSCKPGYVSRGGMRK GEEITYSCKPGYVSRGGMRK FICPLTGLWPINTLKCTPRV FICPLTGLWPINTLKCTPRV CPFAGILENGAVRYTTFEYP CPFAGILENGAVRYTTFEYP NTISFSCNTGFYLNGADSAK NTISFSCNTGFYLNGADSAK CTEEGKWSPELPVCAPIICP CTEEGKWSPELPVCAPIICP PPSIPTFATLRVYKPSAGNN PPSIPTFATLRVYKPSAGNN SLYRDTAVFECLPQHAMFGN SLYRDTAVFECLPQHAMFGN DTITCTTHGNWTKLPECREV DTITCTTHGNWTKLPECREV KCPFPSRPDNGFVNYPAKPT KCPFPSRPDNGFVNYPAKPT LYYKDKATFGCHDGYSLDGP LYYKDKATFGCHDGYSLDGP EEIECTKLGNWSAMPSCKA EEIECTKLGNWSAMPSCKAVariant human B2GP1 MGWSCIILFLVATATGVHSG 106 MGWSCIILFLVATATGVHSE 107 A7 G20-V83 RTCPKPDDLPFSTVVPLKTF PKSSDKTHTCPPCPAPELLG YEPGEEITYSCKPGYVSRGG GDSVFLFPPKPKDTLMISRThlgGl Fc with MRKFICPLTGLWPINTLKCT PEVTCVVVDVSHEDPEVKFN P238D PRVEPKSSDKTHTCPPCPAP WYVDGVEVHNAKTKPREEQYELLGGDSVFLFPPKPKDTLM NSTYRVVSVLTVLHQDWLNG Page 125 of 22413278080v 1Attorney Docket No. 2017420-0064SEQ SEQMoleculeDescription First Polypeptide ID Second polypeptide ID ID NO: NO: mutation and ISRTPEVTCVVVDVSHEDPE KEYKCKVSNKALPAPIEKTI KIH mutations VKFNWYVDGVEVHNAKTKPR SKAKGQPREPQVCTLPPSRD EEQYNSTYRVVSVLTVLHQD ELTKNQVSLSCAVKGFYPSD(monovalent) WLNGKEYKCKVSNKALPAPI IAVEWESNGQPENNYKTTPP EKTISKAKGQPREPQVYTLP VLDSDGSFFLVSKLTVDKSR PCRDELTKNQVSLWCLVKGF WQQGNVFSCSVMHEALHNHY YPSDIAVEWESNGQPENNYK TQKSLSLSPGK TTPPVLDSDGSFFLYSKLTV DKSRWQQGNVFSCSVMHEAL HNHYTQKSLSLSPGKVariant human B2GP1 MGWSCIILFLVATATGVHSG 108 MGWSCIILFLVATATGVHSE 109 A8 G20-V83 with RTCPKPSGLPFSTVVPLKTF PKSSDKTHTCPPCPAPELLG D8S, D9G YEPGEEITYSCKPGYVSRGG GDSVFLFPPKPKDTLMISRT MRKFICPLTGLWPINTLKCT PEVTCVVVDVSHEDPEVKFNmutationsPRVEPKSSDKTHTCPPCPAP WYVDGVEVHNAKTKPREEQYhlgGl Fc with ELLGGDSVFLFPPKPKDTLM NSTYRVVSVLTVLHQDWLNG P238D ISRTPEVTCVVVDVSHEDPE KEYKCKVSNKALPAPIEKTI mutation and VKFNWYVDGVEVHNAKTKPR SKAKGQPREPQVCTLPPSRD KIH mutations EEQYNSTYRVVSVLTVLHQD ELTKNQVSLSCAVKGFYPSD WLNGKEYKCKVSNKALPAPI IAVEWESNGQPENNYKTTPP(monovalent) EKTISKAKGQPREPQVYTLP VLDSDGSFFLVSKLTVDKSR PCRDELTKNQVSLWCLVKGF WQQGNVFSCSVMHEALHNHY YPSDIAVEWESNGQPENNYK TQKSLSLSPGK TTPPVLDSDGSFFLYSKLTV DKSRWQQGNVFSCSVMHEAL HNHYTQKSLSLSPGKVariant human B2GP1 MGWSCIILFLVATATGVHSG 110 MGWSCIILFLVATATGVHSE 111 A9 G20-A262 RTCPKPDDLPFSTVVPLKTF PKSSDKTHTCPPCPAPELLG YEPGEEITYSCKPGYVSRGG GDSVFLFPPKPKDTLMISRT MRKFICPLTGLWPINTLKCT PEVTCVVVDVSHEDPEVKFNhlgGl Fc with PRVCPFAGILENGAVRYTTF WYVDGVEVHNAKTKPREEQY P238D EYPNTISFSCNTGFYLNGAD NSTYRVVSVLTVLHQDWLNG mutation and SAKCTEEGKWSPELPVCAPI KEYKCKVSNKALPAPIEKTI KIH mutations ICPPPSIPTFATLRVYKPSA SKAKGQPREPQVCTLPPSRD GNNSLYRDTAVFECLPQHAM ELTKNQVSLSCAVKGFYPSD(monovalent) FGNDTITCTTHGNWTKLPEC IAVEWESNGQPENNYKTTPP REVKCPFPSRPDNGFVNYPA VLDSDGSFFLVSKLTVDKSR KPTLYYKDKATFGCHDGYSL WQQGNVFSCSVMHEALHNHY DGPEEIECTKLGNWSAMPSC TQKSLSLSPGK KAEPKSSDKTHTCPPCPAPE LLGGDSVFLFPPKPKDTLMI SRTPEVTCVVVDVSHEDPEV KFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWPage 126 of 22413278080v 1Attorney Docket No. 2017420-0064SEQ SEQMoleculeDescription First Polypeptide ID Second polypeptide ID ID NO: NO:LNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPP CRDELTKNQVSLWCLVKGFY PSDIAVEWESNGQPENNYKT TPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPGKVariant human B2GP 1 MGWSCIILFLVATATGVHSG 112 MGWSCIILFLVATATGVHSG 112 A10 G20-V83 RTCPKPDDLPFSTVVPLKTF RTCPKPDDLPFSTVVPLKTF YEPGEEITYSCKPGYVSRGG YEPGEEITYSCKPGYVSRGG MRKFICPLTGLWPINTLKCT MRKFICPLTGLWPINTLKCThlgGl Fc with PRVEPKSSDKTHTCPPCPAP PRVEPKSSDKTHTCPPCPAP G237D, ELLGDDSVFLFPPKPKDTLM ELLGDDSVFLFPPKPKDTLM P238D, ISRTPEVTCVVVDVSHEDGE ISRTPEVTCVVVDVSHEDGE P271G, A330R VKFNWYVDGVEVHNAKTKPR VKFNWYVDGVEVHNAKTKPR EEQYNSTYRVVSVLTVLHQD EEQYNSTYRVVSVLTVLHQDmutationsWLNGKEYKCKVSNKALPRPI WLNGKEYKCKVSNKALPRPI(bivalent) EKTISKAKGQPREPQVYTLP EKTISKAKGQPREPQVYTLP PSRDELTKNQVSLTCLVKGF PSRDELTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYK YPSDIAVEWESNGQPENNYK TTPPVLDSDGSFFLYSKLTV TTPPVLDSDGSFFLYSKLTV DKSRWQQGNVFSCSVMHEAL DKSRWQQGNVFSCSVMHEAL HNHYTQKSLSLSPGK HNHYTQKSLSLSPGKVariant human B2GP 1 MGWSCIILFLVATATGVHSG 113 MGWSCIILFLVATATGVHSG 113 All G20-V83 with RTCPKPSGLPFSTVVPLKTF RTCPKPSGLPFSTVVPLKTF D8S, D9G YEPGEEITYSCKPGYVSRGG YEPGEEITYSCKPGYVSRGG MRKFICPLTGLWPINTLKCT MRKFICPLTGLWPINTLKCTmutationsPRVEPKSSDKTHTCPPCPAP PRVEPKSSDKTHTCPPCPAP ELLGDDSVFLFPPKPKDTLM ELLGDDSVFLFPPKPKDTLMhlgGl Fc with ISRTPEVTCVVVDVSHEDGE ISRTPEVTCVVVDVSHEDGE G237D, VKFNWYVDGVEVHNAKTKPR VKFNWYVDGVEVHNAKTKPR P238D, EEQYNSTYRVVSVLTVLHQD EEQYNSTYRVVSVLTVLHQD WLNGKEYKCKVSNKALPRPI WLNGKEYKCKVSNKALPRPIP271G, A330REKTISKAKGQPREPQVYTLP EKTISKAKGQPREPQVYTLPmutations PSRDELTKNQVSLTCLVKGF PSRDELTKNQVSLTCLVKGF (bivalent) YPSDIAVEWESNGQPENNYK YPSDIAVEWESNGQPENNYK TTPPVLDSDGSFFLYSKLTV TTPPVLDSDGSFFLYSKLTV DKSRWQQGNVFSCSVMHEAL DKSRWQQGNVFSCSVMHEAL HNHYTQKSLSLSPGK HNHYTQKSLSLSPGKVariant human B2GP1 MGWSCIILFLVATATGVHSG 114 MGWSCIILFLVATATGVHSG 114 A12 G20-A262 RTCPKPDDLPFSTVVPLKTF RTCPKPDDLPFSTVVPLKTF YEPGEEITYSCKPGYVSRGG YEPGEEITYSCKPGYVSRGG MRKFICPLTGLWPINTLKCT MRKFICPLTGLWPINTLKCTPRVCPFAGILENGAVRYTTF PRVCPFAGILENGAVRYTTF Page 127 of 22413278080v 1Attorney Docket No. 2017420-0064SEQ SEQMoleculeDescription First Polypeptide ID Second polypeptide ID ID NO: NO:EYPNTISFSCNTGFYLNGAD EYPNTISFSCNTGFYLNGADhlgGl Fc withSAKCTEEGKWSPELPVCAPI SAKCTEEGKWSPELPVCAPIG237D,ICPPPSIPTFATLRVYKPSA ICPPPSIPTFATLRVYKPSAP238D, GNNSLYRDTAVFECLPQHAM GNNSLYRDTAVFECLPQHAM P271G, A330R FGNDTITCTTHGNWTKLPEC FGNDTITCTTHGNWTKLPEC mutations REVKCPFPSRPDNGFVNYPA REVKCPFPSRPDNGFVNYPA KPTLYYKDKATFGCHDGYSL KPTLYYKDKATFGCHDGYSL(bivalent)DGPEEIECTKLGNWSAMPSC DGPEEIECTKLGNWSAMPSC KAEPKSSDKTHTCPPCPAPE KAEPKSSDKTHTCPPCPAPE LLGDDSVFLFPPKPKDTLMI LLGDDSVFLFPPKPKDTLMI SRTPEVTCVVVDVSHEDGEV SRTPEVTCVVVDVSHEDGEV KFNWYVDGVEVHNAKTKPRE KFNWYVDGVEVHNAKTKPRE EQYNSTYRVVSVLTVLHQDW EQYNSTYRVVSVLTVLHQDW LNGKEYKCKVSNKALPRPIE LNGKEYKCKVSNKALPRPIE KTISKAKGQPREPQVYTLPP KTISKAKGQPREPQVYTLPP SRDELTKNQVSLTCLVKGFY SRDELTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKT PSDIAVEWESNGQPENNYKT TPPVLDSDGSFFLYSKLTVD TPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALH KSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPGK NHYTQKSLSLSPGKVariant human B2GP 1 MGWSCIILFLVATATGVHSE 115 MGWSCIILFLVATATGVHSE 115 A13 G20-V83 C- PKSSDKTHTCPPCPAPELLG PKSSDKTHTCPPCPAPELLG DDSVFLFPPKPKDTLMISRTterminal with DDSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDGEVKFN PEVTCVVVDVSHEDGEVKFNG4S linkerWYVDGVEVHNAKTKPREEQY WYVDGVEVHNAKTKPREEQYhlgGl Fc with NSTYRVVSVLTVLHQDWLNG NSTYRVVSVLTVLHQDWLNG G237D, KEYKCKVSNKALPRPIEKTI KEYKCKVSNKALPRPIEKTI P238D, SKAKGQPREPQVYTLPPSRD SKAKGQPREPQVYTLPPSRD P271G, A330R ELTKNQVSLTCLVKGFYPSD ELTKNQVSLTCLVKGFYPSD IAVEWESNGQPENNYKTTPP IAVEWESNGQPENNYKTTPPmutationsVLDSDGSFFLYSKLTVDKSR VLDSDGSFFLYSKLTVDKSR(bivalent) WQQGNVFSCSVMHEALHNHY WQQGNVFSCSVMHEALHNHY TQKSLSLSPGKGGGGSGRTC TQKSLSLSPGKGGGGSGRTC PKPDDLPFSTVVPLKTFYEP PKPDDLPFSTVVPLKTFYEP GEEITYSCKPGYVSRGGMRK GEEITYSCKPGYVSRGGMRK FICPLTGLWPINTLKCTPRV FICPLTGLWPINTLKCTPRVVariant human B2GP1 MGWSCIILFLVATATGVHSE 116 MGWSCIILFLVATATGVHSE 116 A14 G20-V83 with PKSSDKTHTCPPCPAPELLG PKSSDKTHTCPPCPAPELLG D8S, D9G DDSVFLFPPKPKDTLMISRT DDSVFLFPPKPKDTLMISRT PEVTCVVVDVSHEDGEVKFN PEVTCVVVDVSHEDGEVKFNmutations C- WYVDGVEVHNAKTKPREEQY WYVDGVEVHNAKTKPREEQYterminal with NSTYRVVSVLTVLHQDWLNG NSTYRVVSVLTVLHQDWLNG G4S linker KEYKCKVSNKALPRPIEKTI KEYKCKVSNKALPRPIEKTISKAKGQPREPQVYTLPPSRD SKAKGQPREPQVYTLPPSRD Page 128 of 22413278080v 1Attorney Docket No. 2017420-0064SEQ SEQMoleculeDescription First Polypeptide ID Second polypeptide ID ID NO: NO:ELTKNQVSLTCLVKGFYPSD ELTKNQVSLTCLVKGFYPSDhlgGl Fc withIAVEWESNGQPENNYKTTPP IAVEWESNGQPENNYKTTPPG237D,VLDSDGSFFLYSKLTVDKSR VLDSDGSFFLYSKLTVDKSRP238D, WQQGNVFSCSVMHEALHNHY WQQGNVFSCSVMHEALHNHY P271G, A330R TQKSLSLSPGKGGGGSGRTC TQKSLSLSPGKGGGGSGRTC mutations PKPSGLPFSTVVPLKTFYEP PKPSGLPFSTVVPLKTFYEP GEEITYSCKPGYVSRGGMRK GEEITYSCKPGYVSRGGMRK(bivalent)FICPLTGLWPINTLKCTPRV FICPLTGLWPINTLKCTPRVVariant human B2GP1 MGWSCIILFLVATATGVHSE 117 MGWSCIILFLVATATGVHSE 117 A15 G20-A262 C- PKSSDKTHTCPPCPAPELLG PKSSDKTHTCPPCPAPELLG terminal with DDSVFLFPPKPKDTLMISRT DDSVFLFPPKPKDTLMISRT PEVTCVVVDVSHEDGEVKFN PEVTCVVVDVSHEDGEVKFNG4S linkerWYVDGVEVHNAKTKPREEQY WYVDGVEVHNAKTKPREEQYhlgGl Fc with NSTYRVVSVLTVLHQDWLNG NSTYRVVSVLTVLHQDWLNG G237D, KEYKCKVSNKALPRPIEKTI KEYKCKVSNKALPRPIEKTI P238D, SKAKGQPREPQVYTLPPSRD SKAKGQPREPQVYTLPPSRD P271G, A330R ELTKNQVSLTCLVKGFYPSD ELTKNQVSLTCLVKGFYPSD IAVEWESNGQPENNYKTTPP IAVEWESNGQPENNYKTTPPmutationsVLDSDGSFFLYSKLTVDKSR VLDSDGSFFLYSKLTVDKSR(bivalent) WQQGNVFSCSVMHEALHNHY WQQGNVFSCSVMHEALHNHY TQKSLSLSPGKGGGGSGRTC TQKSLSLSPGKGGGGSGRTC PKPDDLPFSTVVPLKTFYEP PKPDDLPFSTVVPLKTFYEP GEEITYSCKPGYVSRGGMRK GEEITYSCKPGYVSRGGMRK FICPLTGLWPINTLKCTPRV FICPLTGLWPINTLKCTPRV CPFAGILENGAVRYTTFEYP CPFAGILENGAVRYTTFEYP NTISFSCNTGFYLNGADSAK NTISFSCNTGFYLNGADSAK CTEEGKWSPELPVCAPIICP CTEEGKW...

Claims

Attorney Docket No. 2017420-0064CLAIMS1. A m ol ecul e compri si ng:a first polypeptide comprising a first Fc domain and an autoantibody-binding domain that binds to anti-B2GPl autoantibodies; anda 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.

2. The molecule of claim 1, wherein the second polypeptide further comprises an autoantibody-binding domain that binds to anti-B2GPl autoantibodies and the molecule is a homodimer.

3. The molecule of claim 1, wherein the second polypeptide further comprises an autoantibody-binding domain that binds to anti-B2GPl autoantibodies and the molecule is a heterodimer.

4. The molecule of claim 1, wherein the second polypeptide does not comprise an autoantibody -binding domain that binds to anti-B2GPl autoantibodies and the molecule is a heterodimer.

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

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

7. The molecule of claim 5, wherein the N-terminus of the autoantibody-binding domain is covalently linked to the C-terminus of the first Fc domain.Page 189 of 22413278080v 1Attorney Docket No. 2017420-00648. The molecule of any one of claims 1-7, wherein the first and second Fc domains form a heterodimer as a result of knobs-in-holes (KIH) mutations.

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

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

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

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

13. The molecule of any one of claims 1-12, wherein the first and / or second Fc domains comprise an IgGl isotype.

14. The molecule of claim 13, wherein the first and / or second Fc domains comprise a human IgGl isotype.

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

16. The molecule of claim 15, wherein the first and / or second Fc domain comprises one of the following mutated amino acid residues: M252Y, S254T, and T256E, according to the EU numbering scheme.Page 190 of 22413278080v 1Attorney Docket No. 2017420-006417. The molecule of claim 15 or 16, wherein the first and / or second Fc domain comprises a combination of the following mutated amino acid residues: M252Y, S254T, and T256E, according to the EU numbering scheme.

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

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

20. The molecule of any one of claims 1-19, wherein the first and / or second Fc domain comprises one or more mutated amino acid residues that alters its binding to an internalizing receptor on a cell.

21. The molecule of claim 20, wherein the altered binding to the internalizing receptor comprises increased binding to an internalizing receptor.

22. The molecule of claim 20 or 21, wherein when the molecule that is bound to an autoantibody through the autoantibody-binding domain binds to the internalizing receptor on a cell, the internalizing receptor internalizes the molecule and the autoantibody is shuttled to the lysosome of the cell for degradation.

23. The molecule of any one of claims 20-22, wherein the internalizing receptor comprises one of the following: FcyRIIB, FcRn, ASGPR, BCMA, CD38, SLAMF7, GPCR5D, and / or CD138.Page 191 of 22413278080v 1Attorney Docket No. 2017420-006424. The molecule of any one of claims 1-23, wherein the first and / or second Fc domain comprises one or more mutated amino acid residues that increases binding to FcyRIIB relative to a corresponding wildtype Fc domain.

25. The molecule of claim 24, wherein the first and / or second Fc domain comprising one or more mutated amino acid residues has greater binding affinity to FcyRIIB than to activating Fc receptors comprising FcyRI, FcγRIIA167H, FcyRIIA167R, FcyRIIIA176F, FcyRIIIA176V, and / or FcyRIIIB.

26. The molecule of claim 24, wherein the first and / or second Fc domain comprising one or more mutated amino acid residues does not have increased binding affinity to FcyRI, FcyRIIA167H, FcyRIIA167R, FcyRIIIA176F, FcyRIIIA176V, and / or FcyRIIIB relative to the corresponding wild-type Fc domain.

27. The molecule of any one of claims 1-24, wherein the first and / or second Fc domain comprising one or more mutated amino acid residues has decreased binding affinity to FcyRI, FcγRIIA167H, FcyRIIA167R, FcyRIIIA176F, FcyRIIIA176V, and / or FcyRIIIB relative to the corresponding wild-type Fc domain.

28. The molecule of any one of claims 24-27, wherein the first and / or second Fc domain comprising one or more mutated amino acid residues has substantially no binding affinity to FcyRI, FcyRIIA167H, FcyRIIA167R, FcyRIIIA176F, FcyRIIIA176V, and / or FcyRIIIB relative to the corresponding wild-type Fc domain.

29. The molecule of any one of claims 1-28, wherein the molecule promotes clearance of target anti-B2GPl autoantibodies in serum when administered to a subject by binding to and forming an immune complex with the target anti-B2GPl autoantibodies.Page 192 of 22413278080v 1Attorney Docket No. 2017420-006430. The molecule of claim 29, wherein the immune complex promotes faster clearance of target anti-B2GPl autoantibodies compared to anti-B2GPl autoantibody clearance in a subject not administered the molecule.

31. The molecule of any one of claims 1-30, wherein upon binding of the molecule to an anti-B2GPl autoantibody, and immune complex is formed that has enhanced binding kinetics with FcyRIIB relative to the anti-B2GPl autoantibody not present in an immune complex with the molecule.

32. The molecule of any one of claims 29-31, wherein the ratio of molecule to anti-B2GPl autoantibody in an immune complex is 1: 1, 2: 1, or 1:2.

33. The molecule of any one of claims 24-32, wherein upon binding of the molecule to an anti-B2GPl autoantibody, an immune complex is formed that has enhanced binding kinetics with FcyRIIB relative to an immune complex that comprises the anti-B2GPl autoantibody and a corresponding molecule with a wild-type Fc domains.

34. The molecule of any one of claims 24-33, wherein upon binding of the molecule to an anti-B2GPl autoantibody, an immune complex is formed that has enhanced binding kinetics with FcyRIIB relative to the anti-B2GPl autoantibody alone.

35. The molecule of any one of claims 24-34, wherein upon binding of two molecules to an anti-B2GPl autoantibody, an immune complex is formed that has enhanced binding kinetics with FcyRIIB relative to an immune complex that comprises the anti-B2GPl autoantibody and two corresponding molecules with wild-type Fc domains.

36. The molecule of any one of claims 24-35, wherein upon binding of two molecules to an anti-B2GPl autoantibody, an immune complex is formed that has enhanced binding kinetics with FcyRIIB relative to an immune complex that comprises the anti-B2GPl autoantibody bound to only a single molecule.Page 193 of 22413278080v 1Attorney Docket No. 2017420-006437. The molecule of any one of claims 24-36, wherein upon binding of two molecules to an anti-B2GPl autoantibody, an immune complex is formed that has enhanced binding kinetics with FcyRIIB relative to the anti-B2GPl autoantibody alone.

38. The molecule of any one of claims 33-37, wherein the enhanced binding kinetics comprise an increase in the rate of association, a decrease in the rate of disassociation, and / or a change in the equilibrium dissociation constant.

39. The molecule of any one of claims 33-38, wherein the enhanced binding kinetics produce an increase in avidity, stability, strength, frequency, and / or duration of binding between the immune complex and FcyRIIB.

40. The molecule of any one of claims 33-39, wherein the enhanced binding kinetics comprises at least 10% greater binding affinity of the immune complex to FcyRIIB.

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

42. The molecule of claim 41, wherein the molecule binds to FcyRIIB with an affinity within the range of about 1 pM to 0.001 pM.

43. The molecule of claim 42, wherein the molecule binds to FcyRIIB with an affinity within the range of about 1 pM to 0.01 pM.

44. The molecule of claim 43, wherein the molecule binds to FcyRIIB with an affinity within the range of about 0.1 pM to 0.01 pM.Page 194 of 22413278080v 1Attorney Docket No. 2017420-006445. The molecule of any one of claims 40-44, wherein the binding affinity comprises binding affinity to a cell line (e.g., a CHO cell line or HepG2) overexpressing FcyRIIB measured by flow cytometry.

46. The molecule of any one of claims 24-45, wherein the molecule does not bind to complement (Clq).

47. The molecule of any one of claims 24-46, wherein the molecule preferentially binds to immune cells expressing FcyRIIB over immune cells expressing FcyRIIA.

48. The molecule of claim 47, wherein the molecule comprises substantially no binding affinity for cells that do not express FcyRIIB.

49. The molecule of claim 47 or 48, wherein the immune cells expressing FcyRIIB comprise B cells, monocytes and / or basophils.

50. The molecule of claim 48 or 49, wherein the immune cells that do not express FcyRIIB comprise T cells, NK cells, neutrophils, and / or eosinophils.

51. The molecule of any one of claims 24-50, wherein the molecule does not activate immune cells (e.g., does not activate immune cells to secrete pro-inflammatory cytokines, e.g., IL-6).

52. The molecule of any one of claims 24-51, wherein the molecule inhibits B cells by crosslinking FcyRIIB with a B cell receptor.

53. The molecule of claim 52, wherein the molecule cross-links FcyRIIB with a B cell receptor.Page 195 of 22413278080v 1Attorney Docket No. 2017420-006454. The molecule of claim 52, wherein an immune complex of one or two molecules with an anti-B2GPl autoantibody cross-links FcyRIIB with a B cell receptor.

55. The molecule of any one of claims 24-54, wherein the one or more mutated amino acid residues that increases binding to FcyRIIB comprises one or more of the following amino acid mutations, according to the EU numbering scheme: E233V, L234D, L235F, G236D, G236R, G237D, S239L, S267D, H268P, S298G, T299A, A327L, L328A, A330H, E333I, R292Q, E233P, P238D, H268D, P271G, A330R, L234Y, T250V, V264I, T307P, Q311R, A330K, P343R, M428L, N434A, Y436T, Q438R, S440E, G236N, S267E, L235R, D270E, E233D, and G237D.

56. The molecule of claim 55, wherein the one or more mutated amino acid residues that increases binding to FcyRIIB comprises one or more of the following sets of amino acid mutations, according to the EU numbering scheme:(i) E233V, L234D, L235F, G236R, G237D, S239L, S267D, H268P, S298G, T299A, A327L, L328A, A33OH, and E333I;(ii) E233V, L234D, L235F, G236R, G237D, S239L, S267D, R292Q, H268P, S298G, T299A, A327L, L328A, A33 OH, and E3331;(iii) E233V, L234D, L235F, G236R, G237D, S239L, H268P, R292Q, S298G, T299A, A327L, L328A, A33OH, and E333I;(iv) E233P, G237D, P238D, H268D, P271G, and A330R;(v) L234Y, P238D, T250V, V264I, T307P, Q311R, A330K, P343R, M428L, N434A, Y436T, Q438R, and S440E;(vi) L234D, G236N, and S267E;(vii) L235R;(viii) G236N and S267E;(ix) P238D and D270E;(x) P238D and P271G;(xi) P238D, D270E, and P271G;(xii) G237D, P238D, P271G, and A330R;(xiii) G237D, P238D, D270E, P271G, and A330RPage 196 of 22413278080v 1Attorney Docket No. 2017420-0064(xiv) E233D, G237D, P238D, H268D, P271G, and A330R;(xv) P238D;(xvi) S267E / L328F; and(xvii) S267E / L328F / G236D.

57. The molecule of any one of claims 24-56, wherein the one or more mutated amino acid residues comprises the mutated amino acid residue P238D, according to the EU numbering scheme.

58. The molecule of any one of claims 24-57, wherein the one or more mutated amino acid residues comprises the mutated amino acid residues G237D, P238D, P271G, and A330R, according to the EU numbering scheme.

59. The molecule of any one of claims 24-58, wherein the one or more mutated amino acid residues does not comprise the following mutated amino acid residues: S267E and L328F, according to the EU numbering scheme.

60. The molecule of claim 24-59, wherein the first and / or second Fc domain comprises one or more of the following mutated amino acid residues: M428L, N434S, and P238D, according to the EU numbering scheme.

61. The molecule of claim 1-60, wherein the first and / or second Fc domain comprises the following mutated amino acid residues: M428L, N434S, and P238D, according to the EU numbering scheme.

62. The molecule of claim 1-61, wherein the first and / or second Fc domain comprises the following mutated amino acid residues: M428L, N434S, P238D, and P271G, according to the EU numbering scheme.Page 197 of 22413278080v 1Attorney Docket No. 2017420-006463. The molecule of claim 1 -62, wherein the first and / or second Fc domain comprises the following mutated amino acid residues: M428L, N434S, G237D, P238D, P271G, A330R, according to the EU numbering scheme.

64. The molecule of claim 1-63, wherein the first and / or second Fc domain comprises the following mutated amino acid residues: M428L, N434S, G237D, P238D, D270E, P271G, A330R, according to the EU numbering scheme.

65. The molecule of any one of claims 24-56, wherein the first and / or second Fc domain comprises at least one of the following mutated amino acid residues: S267E and L328F, according to the EU numbering scheme.

66. The molecule of any one of claims 1-65, wherein the first and / or second Fc domain comprises at least one mutated amino acid sequence that decreases binding to one or more Fc-gamma receptors (FcyRs).

67. The molecule of claim 66, wherein the first and / or second Fc domain comprises at least one of the following mutated amino acid residues: G236R and L328R, according to the EU numbering scheme.

68. The molecule of claim 67, wherein the first and / or second Fc domain comprises the following mutated amino acid residues: G236R and L328R, according to the EU numbering scheme.

69. The molecule of any one of claims 1-68, wherein the first Fc domain and / or the second Fc domain comprises a sequence selected from SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 32, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQPage 198 of 22413278080v 1Attorney Docket No. 2017420-0064ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 99, SEQ ID NO: 125, SEQ ID NO: 126, SEQ ID NO: 124, and SEQ ID NO: 131, or a fragment or variant thereof.

70. The molecule of any one of claims 1-69, wherein the first Fc domain comprises a sequence selected from SEQ ID NO: 22, SEQ ID NO: 24, SEQ ID NO: 26, SEQ ID NO: 28, SEQ ID NO: 30, SEQ ID NO: 33, SEQ ID NO: 35, SEQ ID NO: 37, SEQ ID NO: 39, SEQ ID NO: 41, SEQ ID NO: 43, SEQ ID NO: 45, SEQ ID NO: 47, SEQ ID NO: 49, SEQ ID NO: 51, SEQ ID NO: 53, SEQ ID NO: 55, SEQ ID NO: 57, SEQ ID NO: 74, SEQ ID NO: 127, SEQ ID NO: 129, SEQ ID NO: 392, SEQ ID NO: 394, SEQ ID NO: 396, SEQ ID NO: 398, SEQ ID NO: 400, SEQ ID NO: 402, SEQ ID NO: 404, SEQ ID NO: 406, or a fragment or variant thereof.

71. The molecule of any one of claims 1-70, wherein the second Fc domain comprises a sequence selected from SEQ ID NO: 23, SEQ ID NO: 25, SEQ ID NO: 27, SEQ ID NO: 29, SEQ ID NO: 31, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 38, SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID NO: 50, SEQ ID NO: 52, SEQ ID NO: 54, SEQ ID NO: 56, SEQ ID NO: 58, SEQ ID NO: 75, SEQ ID NO: 128, SEQ ID NO: 130, SEQ ID NO: 393, SEQ ID NO: 395, SEQ ID NO: 397, SEQ ID NO: 399, SEQ ID NO: 401, SEQ ID NO: 403, SEQ ID NO: 405, and SEQ ID NO: 407, or a fragment or variant thereof.

72. The molecule of any one of claims 1-71, wherein autoantibody-binding domain is covalently linked to the first Fc domain through a linker.

73. The molecule of claim 72, wherein the linker comprises the amino acid sequence of SEQ ID NO: 84 (GGGGS), SEQ ID NO: 85 (GGGGSGGGGS), SEQ ID NO: 86 (GGGGSGGGGSGGGGS), SEQ ID NO: 87 (VDGGGGSGGGGSGGGGSG), SEQ ID NO: 88 (GGSG), SEQ ID NO: 89 (GGSGG), SEQ ID NO: 90 (GSGSG), SEQ ID NO: 91 (GSGGG), SEQ ID NO: 92 (GGGSG), SEQ ID NO: 93 (GSSSG), SEQ ID NO: 94 (GGGGSGGGGSGGGGSGGGGS) or SEQ ID NO: 95 (GGGGSGGGGSGGGGSGGGGSSGGGGS).Page 199 of 22413278080v 1Attorney Docket No. 2017420-006474. The molecule of any one of claims 1-73, wherein the autoantibody -binding domain comprises an autoantigen, or a fragment or variant thereof.

75. The molecule of claim 74, wherein the autoantigen comprises a B2GP1 autoantigen domain, or a fragment or variant thereof.

76. The molecule of claim 75, wherein the B2GP1 autoantigen domain comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to the amino acid sequence of any one of SEQ ID NOs: 1-6.

77. The molecule of any one of claims 1-76, wherein the autoantibody -binding domain comprises a B2GP1 autoantigen domain variant that includes one or more mutations relative to the amino acid sequence of SEQ ID NO: 1.

78. The molecule of any one of claims 1-77, wherein the autoantibody-binding domain comprises a B2GP1 autoantigen domain variant that includes a D8S and a D9G mutation relative to the amino acid sequence of SEQ ID NO: 2.

79. The molecule of any one of claims 1-78, wherein the autoantibody -binding domain comprises a B2GP1 autoantigen domain variant that comprises the sequence of any one of SEQ ID NOs: 1-6.

80. The molecule of any one of claims 1-79, wherein the second polypeptide further comprises a second autoantibody-binding domain, e.g., an autoantigen domain.

81. The molecule of any one of claims 1-80, wherein the first polypeptide comprises:an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 2 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, atPage 200 of 22413278080v 1Attorney Docket No. 2017420-0064least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 19;an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 3 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 19;an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 4 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 19;an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 2 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 28;an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 3 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 28;an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 4 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 28;an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 2 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, atPage 201 of 22413278080v 1Attorney Docket No. 2017420-0064least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 99;an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 3 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 99;an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 4 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 99;an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 2, an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 402;an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 3, an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 402;an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 4 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 402;an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 2 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, atPage 202 of 22413278080v 1Attorney Docket No. 2017420-0064least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 124;an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 4 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 124;an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 6 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 124;an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 6 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 131;an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 4, an amino acid sequence that is at least 90% identical to SEQ ID NO: 86, and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 124;an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 2 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 131;an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) toPage 203 of 22413278080v 1Attorney Docket No. 2017420-0064SEQ ID NO: 4 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 131; oran amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 4, an amino acid sequence that is at least 90% identical to SEQ ID NO: 86, and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 131.

82. The molecule of claim 81, wherein the first polypeptide comprises:an amino acid sequence comprising SEQ ID NO: 2 and an amino acid sequence comprising SEQ ID NO: 19;an amino acid sequence comprising SEQ ID NO: 3 and an amino acid sequence comprising SEQ ID NO: 19;an amino acid sequence comprising SEQ ID NO: 4 and an amino acid sequence comprising SEQ ID NO: 19;an amino acid sequence comprising SEQ ID NO: 2 and an amino acid sequence comprising SEQ ID NO: 28;an amino acid sequence comprising SEQ ID NO: 3 and an amino acid sequence comprising SEQ ID NO: 28;an amino acid sequence comprising SEQ ID NO: 4 and an amino acid sequence comprising SEQ ID NO: 28;an amino acid sequence comprising SEQ ID NO: 2 and an amino acid sequence comprising SEQ ID NO: 99;an amino acid sequence comprising SEQ ID NO: 3 and an amino acid sequence comprising SEQ ID NO: 99;an amino acid sequence comprising SEQ ID NO: 4and an amino acid sequence comprising SEQ ID NO: 99;Page 204 of 22413278080v 1Attorney Docket No. 2017420-0064an amino acid sequence comprising SEQ ID NO: 2, an amino acid sequence comprising SEQ ID NO: 402;an amino acid sequence comprising SEQ ID NO: 3, an amino acid sequence comprising SEQ ID NO: 402;an amino acid sequence comprising SEQ ID NO: 4 and an amino acid sequence comprising SEQ ID NO: 402an amino acid sequence comprising SEQ ID NO: 2 and an amino acid sequence comprising SEQ ID NO: 124;an amino acid sequence comprising SEQ ID NO: 4 and an amino acid sequence comprising SEQ ID NO: 124;an amino acid sequence comprising SEQ ID NO: 6 and an amino acid sequence comprising SEQ ID NO: 124;an amino acid sequence comprising SEQ ID NO: 6 and an amino acid sequence comprising SEQ ID NO: 131;an amino acid sequence comprising SEQ ID NO: 4, and amino acid sequence comprising SEQ ID NO: 86, and an amino acid sequence comprising SEQ ID NO: 124;an amino acid sequence comprising SEQ ID NO: 2 and an amino acid sequence comprising SEQ ID NO: 131;an amino acid sequence comprising SEQ ID NO: 4 and an amino acid sequence comprising SEQ ID NO: 131; oran amino acid sequence comprising SEQ ID NO: 4, and amino acid comprising SEQ ID NO: 86, and an amino acid sequence comprising SEQ ID NO: 131.

83. The molecule of any one of claims 1-82, wherein the second polypeptide comprises:an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 2 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 19;Page 205 of 22413278080v 1Attorney Docket No. 2017420-0064an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 3 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 19;an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 4 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 19;an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 29;an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 2 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 99;an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 3 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 99,an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 4 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 99;Page 206 of 22413278080v 1Attorney Docket No. 2017420-0064an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 403;an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 2 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 124;an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 4 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 124;an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 6 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 124;an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 6 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 131;an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 4, an amino acid sequence that is at least 90% identical to SEQ ID NO: 86, and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 124;Page 207 of 22413278080v 1Attorney Docket No. 2017420-0064an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 2 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 131;an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 4 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 131; oran amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 4, an amino acid sequence that is at least 90% identical to SEQ ID NO: 86, and an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 131.

84. The molecule of claim 83, wherein the second polypeptide comprises:an amino acid sequence comprising SEQ ID NO: 2 and an amino acid sequence comprising SEQ ID NO: 19;an amino acid sequence comprising SEQ ID NO: 3 and an amino acid sequence comprising SEQ ID NO: 19;an amino acid sequence comprising SEQ ID NO: 4 and an amino acid sequence comprising SEQ ID NO: 19;an amino acid sequence comprising SEQ ID NO: 29;an amino acid sequence comprising SEQ ID NO: 2 and an amino acid sequence comprising SEQ ID NO: 99;an amino acid sequence comprising SEQ ID NO: 3 and an amino acid sequence comprising SEQ ID NO: 99,Page 208 of 22413278080v 1Attorney Docket No. 2017420-0064an amino acid sequence comprising SEQ ID NO: 4 and an amino acid sequence comprising SEQ ID NO: 99;an amino acid sequence comprising SEQ ID NO: 403;an amino acid sequence comprising SEQ ID NO: 2 and an amino acid sequence comprising SEQ ID NO: 124;an amino acid sequence comprising SEQ ID NO: 4 and an amino acid sequence comprising SEQ ID NO: 124;an amino acid sequence comprising SEQ ID NO: 6 and an amino acid sequence comprising SEQ ID NO: 124;an amino acid sequence comprising SEQ ID NO: 6 and an amino acid sequence comprising SEQ ID NO: 131;an amino acid sequence comprising SEQ ID NO: 4, and amino acid sequence comprising SEQ ID NO: 86, and an amino acid sequence comprising SEQ ID NO: 124;an amino acid sequence comprising SEQ ID NO: 2 and an amino acid sequence comprising SEQ ID NO: 131;an amino acid sequence comprising SEQ ID NO: 4 and an amino acid sequence comprising SEQ ID NO: 131; oran amino acid sequence comprising SEQ ID NO: 4, and amino acid comprising SEQ ID NO: 86, and an amino acid sequence comprising SEQ ID NO: 131.

85. The molecule of any one of claims 1-84, wherein(i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 2 and the amino acid sequence of SEQ ID NO: 19, and(ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 2 and the amino acid sequence of SEQ ID NO: 19.

86. The molecule of any one of claims 1-84, wherein(i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 3 and the amino acid sequence of SEQ ID NO: 19, andPage 209 of 22413278080v 1Attorney Docket No. 2017420-0064(ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 3 and the amino acid sequence of SEQ ID NO: 19.

87. The molecule of any one of claims 1-84, wherein(i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 4 and the amino acid sequence of SEQ ID NO: 19, and(ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 4 and the amino acid sequence of SEQ ID NO: 19.

88. The molecule of any one of claims 1-84, wherein(i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 2 and the amino acid sequence of SEQ ID NO: 28, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 29; or(ii) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 2 and the amino acid sequence of SEQ ID NO: 29, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 28.

89. The molecule of any one of claims 1-84, wherein(i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 3 and the amino acid sequence of SEQ ID NO: 28, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 29; or(ii) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 3 and the amino acid sequence of SEQ ID NO: 29, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 28.

90. The molecule of any one of claims 1-84, wherein(i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 4 and the amino acid sequence of SEQ ID NO: 28, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 29; orPage 210 of 22413278080v 1Attorney Docket No. 2017420-0064(ii) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 4 and the amino acid sequence of SEQ ID NO: 29, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 28.

91. The molecule of any one of claims 1-84, wherein(i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 2 and the amino acid sequence of SEQ ID NO: 99, and(ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 2 and the amino acid sequence of SEQ ID NO: 99.

92. The molecule of any one of claims 1-84, wherein(i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 3 and the amino acid sequence of SEQ ID NO: 99, and(ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 3 and the amino acid sequence of SEQ ID NO: 99.

93. The molecule of any one of claims 1-84, wherein(i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 4 and the amino acid sequence of SEQ ID NO: 99, and(ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 4 and the amino acid sequence of SEQ ID NO: 99.

94. The molecule of any one of claims 1-84, wherein(i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 2 and the amino acid sequence of SEQ ID NO: 402, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 403; or(ii) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 2 and the amino acid sequence of SEQ ID NO: 403, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 402.Page 211 of 22413278080v 1Attorney Docket No. 2017420-006495. The molecule of any one of claims 1-84, wherein(i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 3 and the amino acid sequence of SEQ ID NO: 402, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 403; or(ii) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 3 and the amino acid sequence of SEQ ID NO: 403, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 402.

96. The molecule of any one of claims 1-84, wherein(i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 4 and the amino acid sequence of SEQ ID NO: 402, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 403; or(ii) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 4 and the amino acid sequence of SEQ ID NO: 403, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 402.

97. The molecule of any one of claims 1-84, wherein(i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 2 and the amino acid sequence of SEQ ID NO: 124, and(ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 2 and the amino acid sequence of SEQ ID NO: 124.

98. The molecule of any one of claims 1-84, wherein(i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 4 and the amino acid sequence of SEQ ID NO: 124, and(ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 4 and the amino acid sequence of SEQ ID NO: 124.

99. The molecule of any one of claims 1-84, whereinPage 212 of 22413278080v 1Attorney Docket No. 2017420-0064(i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 6 and the amino acid sequence of SEQ ID NO: 124, and(ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 6 and the amino acid sequence of SEQ ID NO: 124.

100. The molecule of any one of claims 1-84, wherein(i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 6 and the amino acid sequence of SEQ ID NO: 131, and(ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 6 and the amino acid sequence of SEQ ID NO: 131.

101. The molecule of any one of claims 1-84, wherein(i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 4, the amino acid sequence of SEQ ID NO: 86, and the amino acid sequence of SEQ ID NO: 124, and (ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 4, the amino acid sequence of SEQ ID NO: 86, and the amino acid sequence of SEQ ID NO: 124.

102. The molecule of any one of claims 1-84, wherein(i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 2 and the amino acid sequence of SEQ ID NO: 131, and(ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 2 and the amino acid sequence of SEQ ID NO: 131.

103. The molecule of any one of claims 1-84, wherein(i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 4 and the amino acid sequence of SEQ ID NO: 131, and(ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 4 and the amino acid sequence of SEQ ID NO: 131.

104. The molecule of any one of claims 1-84, whereinPage 213 of 22413278080v 1Attorney Docket No. 2017420-0064(i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 4, the amino acid sequence of SEQ ID NO: 86, and the amino acid sequence of SEQ ID NO: 131, and (ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 4, the amino acid sequence of SEQ ID NO: 86, and the amino acid sequence of SEQ ID NO: 131.

105. The molecule of any one of claims 1-104, wherein the first polypeptide comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to any one of SEQ ID NOs: 100-106, 108, 110, 112-118, 120, 122, and 133-140.

106. The molecule of any one of claims 1-105, wherein the second polypeptide comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to any one of SEQ ID NOs: 100-105, 107, 109, 111-117, 119, 121, 123, and 133-140.

107. The molecule of any one of claims 1-106, wherein the first polypeptide comprises the amino acid sequence of any one of SEQ ID NOs: 100-106, 108, 110, 112-118, 120, 122, and 133-140, and the second polypeptide comprises the amino acid sequence of any one of SEQ ID NOs: 100-105, 107, 109, 111-117, 119, 121, 123, and 133-140.

108. The molecule of any one of claims 1-107, wherein:(i) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 100, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 100;(ii) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 101 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 101;(iii) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 102 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 102;(iv) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 103 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 103;Page 214 of 22413278080v 1Attorney Docket No. 2017420-0064(v) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 104 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 104;(vi) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 105 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 105;(vii) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 106 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 107;(viii) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 108 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 109;(ix) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 110 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 111;(x) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 112 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 112;(xi) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 113 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 113;(xii) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 114 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 114;(xiii) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 115 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 115;(xiv) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 116 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 116;(xv) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 117 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 117;(xvi) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 118 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 119;(xvii) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 120 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 121;(xviii) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 122 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 123;(xix) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 133, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 133;Page 215 of 22413278080v 1Attorney Docket No. 2017420-0064(xx) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 134, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 134;(xxi) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 135, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 135;(xxii) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 136, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 136;(xxiii) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 137, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 137;(xxiv) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 138, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 138;(xxv) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 139, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 139; or (xxvi) the first polypeptide comprises the amino acid sequence comprising SEQ ID NO: 140, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 140.

109. The molecule of claim 108, wherein the N-terminus of the second Fc domain is covalently linked to the C-terminus of the second autoantibody -binding domain.

110. The molecule of claim 109, wherein the C-terminus of the second Fc domain is covalently linked to the C-terminus of the second autoantibody-binding domain.

111. The molecule of any one of claims 108-110, wherein the second autoantibody -binding domain binds to anti-B2GPl autoantibodies.

112. The molecule of any one of claims 1-111, wherein the molecule is capable of selectively depleting anti-B2GPl autoantibodies that bind to the autoantibody-binding domain when administered to a subject.Page 216 of 22413278080v 1Attorney Docket No. 2017420-0064113. The molecule of claim 112, wherein the anti-B2GPl autoantibodies that bind to the autoantibody-binding domain are selectively depleted by uptake into cells and shuttling of the autoantibodies to the lysosome for degradation.

114. The molecule of any one of claims 1-79, 81-108, and 112-113, wherein the second polypeptide does not comprise an autoantibody -binding domain that binds to anti-B2GPl autoantibodies.

115. A nucleic acid comprising a nucleotide sequence encoding the molecule of any one of claims 1-114.

116. A host cell containing the nucleic acid of claim 115.

117. A vector comprising the nucleic acid of claim 115.

118. The vector of claim 117, wherein the vector comprises a viral vector.

119. The vector of claim 118, wherein the viral vector comprises a retroviral vector, a lentiviral vector, an adeno-associated viral (AAV) vector, or an adenoviral vector.

120. A pharmaceutical composition comprising the molecule of any one of claims 1-114 or a nucleic acid encoding the molecule of any one of claims 1-114 and a pharmaceutically acceptable carrier.

121. A method of making a molecule, the method comprising expressing the nucleic acid of claim 115 in a host cell, and recovering the molecule.

122. A method of treating a subject suffering from or susceptible to an autoimmune disease or another disease, disorder or condition involving anti-B2GPl autoantibodies, the method comprising:Page 217 of 22413278080v 1Attorney Docket No. 2017420-0064administering to the subject a pharmaceutical composition comprising the molecule of any one of claims 1-114 or a nucleic acid encoding the molecule of any one of claims 1-114.

123. A method of treating a subject suffering from or susceptible to an autoimmune disease or another disease, disorder or condition involving anti-B2GPl autoantibodies, the method comprising:administering to the subject a first pharmaceutical composition comprising the molecule of any one of claims 1-114 or a nucleic acid encoding the molecule of any one of claims 1-114; andadministering to the subject a second pharmaceutical composition that selectively depletes plasma cells producing autoantibodies that are targeted by the autoantibody-binding domain.

124. The method of claim 122 or 123, wherein the autoimmune disease is APS.

125. The method of claim 123, wherein the first pharmaceutical composition is administered before the second pharmaceutical composition.

126. The method of claim 123, wherein the first pharmaceutical composition is administered after the second pharmaceutical composition.

127. The method of claim 123, wherein the first pharmaceutical composition and the second pharmaceutical composition are co-administered.

128. The method of any one of claims 122-127, wherein the level of anti-B2GPl autoantibodies in the subject or in a biological sample from the subject after administration is reduced relative to a level before administration.

129. The method of claim 128, wherein the level of anti-B2GPl 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%, atPage 218 of 22413278080v 1Attorney Docket No. 2017420-0064least 80%, at least 85%, at least 90%, at least 95%, or at least 99% relative to a level before the administration.

130. The method of claim 128 or 129, wherein the reduced level of anti-B2GPl autoantibodies is sustained over time.

131. The method of claim 130, wherein a sustained period of time comprises 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.

132. The method of any one of claims 122-131, wherein the pharmaceutical composition is administered intravenously, intramuscularly, or subcutaneously to the subject.

133. The method of any one of claims 122-132, wherein the subject is a human.

134. A method of selectively depleting anti-B2GPl autoantibodies in a subject, the method comprising administering to the subject a pharmaceutical composition comprising the molecule of any one of claims 1-114 or a nucleic acid encoding the molecule of any one of claims 1-114.

135. A method of treating a human subject suffering from or susceptible to an autoimmune disease (e.g., APS) or another disease, disorder or condition involving anti-B2GPl autoantibodies, the method comprising administering to the subject a pharmaceutical composition comprising the molecule of any one of claims 1-114 or a nucleic acid encoding the molecule of any one of claims 1-114.

136. A pharmaceutical composition comprising:the molecule of any one of claims 1-114 or a nucleic acid encoding the molecule of any one of claims 1-114;a molecule that selectively depletes plasma cells producing the autoantibodies that are targeted by the autoantibody -binding domain, or a nucleic acid encoding the same; andPage 219 of 22413278080v 1Attorney Docket No. 2017420-0064a pharmaceutically acceptable carrier.

137. A composition for decreasing the titer of anti-B2GPl autoantibodies in the blood serum of a subject in need thereof, 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 anti-B2GPl autoantibodies; and (b) a second polypeptide comprising a second Fc domain, wherein the first Fc domain and the second Fc domain form a homodimer or heterodimer of the first polypeptide and the second polypeptide;wherein the first and / or second Fc domain comprises one or more mutated amino acid residues and has increased binding affinity to FcyRIIB relative to a corresponding wild-type Fc domain, andwherein, upon administration of the plurality of molecules, the molecules bind to anti-B2GP1 autoantibodies to form immune complexes comprising two molecules bound to an anti-B2GP1 autoantibody, and wherein the immune complex binds with higher avidity to FcyRIIB expressed on the surface of liver sinusoidal endothelial cells (LSECs) and are endocytosed thereby decreasing the titer of the anti-B2GPl autoantibodies in the subject’s blood serum, wherein the higher avidity is relative to an immune complex comprising two corresponding molecules with wild-type Fc domains.

138. The composition of claim 137, wherein the molecules are molecules of any one of claims 1-114.

139. An immune complex comprising:(i) an anti-B2GPl autoantibody; and(ii) a molecule comprising:a first polypeptide comprising a first Fc domain, and an autoantibody -binding domain that binds to the anti-B2GPl autoantibody; anda second polypeptide comprising a second Fc domain;Page 220 of 22413278080v 1Attorney Docket No. 2017420-0064wherein the first Fc domain and the second Fc domain form a homodimer or heterodimer of the first polypeptide and the second polypeptide; wherein the first and / or second Fc domain comprises one or more mutated amino acid residues and has increased binding affinity to FcyRIIB relative to a corresponding wild-type Fc domain; andwherein the immune complex has enhanced binding kinetics with FcyRIIB relative to an immune complex that comprises the anti-B2GPl autoantibody bound to a corresponding molecule with wild-type Fc domains.

140. The immune complex of claim 139, wherein the immune complex has enhanced binding kinetics with FcyRIIB relative to the anti-B2GPl autoantibody alone.

141. The immune complex of claim 139 or 140, wherein the immune complex comprises two molecules, where each molecule comprises:a first polypeptide comprising a first Fc domain, and an autoantibody-binding domain that binds to the anti-B2GPl autoantibody; and a second polypeptide comprising a second Fc domain; wherein the first Fc domain and the second Fc domain form a homodimer or heterodimer of the first polypeptide and the second polypeptide; wherein the first and / or second Fc domain comprises one or more mutated amino acid residues and has increased binding affinity to FcyRIIB relative to a corresponding wild-type Fc domain.

142. The immune complex of claim 141, wherein the immune complex has enhanced binding kinetics with FcyRIIB relative to an immune complex that comprises the anti-B2GPl autoantibody bound to two corresponding molecules with wild-type Fc domains.

143. The immune complex of claim 141 or 142, wherein the immune complex has enhanced binding kinetics with FcyRIIB relative to an immune complex that comprises the anti-B2GPl autoantibody and only a single molecule.

144. The immune complex of claim 141, wherein the immune complex has enhanced binding kinetics with FcyRIIB relative to the anti-B2GPl autoantibody alone.Page 221 of 22413278080v 1Attorney Docket No. 2017420-0064145. The immune complex of any one of claims 141-144, wherein the binding domain of each of the two molecules is bound to the anti-B2GPl autoantibody.

146. The immune complex of any one of claims 139-145, wherein the enhanced binding kinetics comprise an increase in the rate of association, a decrease in the rate of disassociation, and / or a change in the equilibrium dissociation constant.

147. The immune complex of any one of claims 139-146, wherein the enhanced binding kinetics produce an increase in avidity, stability, strength, frequency, and / or duration of the binding between the immune complex and FcyRIIB.

148. The immune complex of any one of claims 139-147, wherein the first and / or second Fc domain comprising one or more mutated amino acid residues has slightly increased binding affinity (e.g., within 2-fold) to FcyRI, FcyRIIA167H, FcyRIIA167R, FcyRIIIA176F, FcyR. HI A l 76V, and / or FcyRIIIB relative to the corresponding wild-type Fc domain.

149. The immune complex of any one of claims 139-147, wherein the first and / or second Fc domain comprising one or more mutated amino acid residues does not have increased binding affinity to FcyRI, FcyRIIA167H, FcyRIIA167R, FcyRIIIA176F, FcyRIIIA176V, and / or FcyRIIIB relative to the corresponding wild-type Fc domain.

150. The immune complex of any one of claims 139-149, wherein the first and / or second Fc domain comprising one or more mutated amino acid residues has decreased binding affinity to FcyRI, FcyRIIA167H, FcyRIIA167R, FcyRIIIA176F, FcyRIIIA176V, and / or FcyRIIIB relative to the corresponding wild-type Fc domain.

151. The immune complex of any one of claims 139-150, wherein the first and / or second Fc domain comprising one or more mutated amino acid residues has negligible or no bindingPage 222 of 22413278080v 1Attorney Docket No. 2017420-0064affinity to FcyRI, FcyRIIA167H, FcyRIIA167R, FcyRIIIA176F, FcyRIIIA176V, and / or FcyRIIIB relative to the corresponding wild-type Fc domain.

152. The immune complex of any one of claims 140-151, wherein the enhanced binding kinetics comprises at least 10% greater binding affinity of the immune complex to FcyRIIB.

153. The immune complex of claim 152, wherein the at least 10% greater binding affinity comprises at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% or greater binding affinity.

154. The immune complex of claim 152 or 153, wherein the binding affinity comprises binding affinity to a cell line endogenously expressing or overexpressing FcyRIIB measured by flow cytometry.

155. The immune complex of any one of claims 139-154, wherein the immune complex preferentially binds to immune cells expressing FcyRIIB over immune cells expressing FcyRIIA.

156. The immune complex of any one of claims 139-155, wherein the immune complex crosslinks FcyRIIB with a B cell receptor on a B cell.

157. The immune complex of any one of claims 139-156, wherein the molecules are molecules of any one of claims 1-99.Page 223 of 22413278080v 1

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