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. 2017420-0065MOLECULES FOR CONTROLLING IMMUNE RESPONSE CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to United States Provisional Application No. 63 / 754519, filed February 5, 2025, the entirety of which is incorporated herein by reference.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, 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. However, therapeutic approaches for antibody-driven autoimmune disease 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.

[0004] Molecules described herein may be used for treatment of autoimmune diseases such as myelin oligodendrocyte glycoprotein (MOG) autoantibody (ab) associated disorder (MOGAD) and / or other autoimmune diseases implicated by autoantibodies that target myelinPage 1 of 17813278299v 1Attorney Docket No. 2017420-0065oligodendrocyte glycoprotein (MOG). Tn some embodiments, a molecule comprises an autoantigen domain that is a MOG 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-MOG 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 autoimmune disease. In some embodiments, an autoantibody is an anti-MOG autoantibody and the disease is MOGAD or another autoimmune disease caused by anti-MOG autoantibodies. Molecules may include a MOG autoantigen domain that targets anti-MOG 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.Page 2 of 17813278299v 1Attorney Docket No. 2017420-0065

[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-MOG 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-MOG autoantibodies and the molecule is a homodimer. In some embodiments, the second polypeptide further comprises an autoantibody -binding domain that binds to anti-MOG autoantibodies and the molecule is a heterodimer. In some embodiments, the second polypeptide does not comprise an autoantibodybinding domain that binds to anti-MOG 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.

[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,Page 3 of 17813278299v 1Attorney Docket No. 2017420-0065and T256E, according to the EU numbering scheme. Tn 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: FcyRllB, 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, FcyR.II A l 67H, FcyRIIA167R, FcyRIIIA176F, FcyRIIIA176V, and / or FcyRIIIB.

[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, FcyRIIIA176F, FcyRIIIA176V, FcyRIIIB, and / or FcRn relative to the corresponding wild-type Page 4 of 17813278299v 1Attorney Docket No. 2017420-0065Fc domain. Tn 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-MOG autoantibodies in serum when administered to a subject by binding to and forming an immune complex with the target anti-MOG autoantibodies. In some embodiments, the immune complex promotes faster clearance of target anti-MOG autoantibodies compared to anti-MOG autoantibody clearance in a subject not administered the molecule. In some embodiments, upon binding of the molecule to an anti-MOG autoantibody, and immune complex is formed that has enhanced binding kinetics with FcyRIIB relative to an anti-MOG autoantibody not present in an immune complex with the molecule. In some embodiments, the ratio of molecule to anti-MOG 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-MOG autoantibody, an immune complex is formed that has enhanced binding kinetics with FcyRIIB relative to an immune complex that comprises the anti-MOG autoantibody and a corresponding molecule with a wild-type Fc domains. In some embodiments, upon binding of a molecule described herein to an anti-MOG autoantibody, an immune complex is formed that has enhanced binding kinetics with FcyRIIB relative to the anti-MOG 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.

[0019] In some embodiments, upon binding of two molecules to an anti-MOG autoantibody, an immune complex is formed that has enhanced binding kinetics with FcyRIIB relative to an immune complex that comprises the anti-MOG autoantibody and two corresponding molecules Page 5 of 17813278299v 1Attorney Docket No. 2017420-0065with wild-type Fc domains. In some embodiments, upon binding of two molecules to an anti-MOG autoantibody, an immune complex is formed that has enhanced binding kinetics with FcyRIIB relative to an immune complex that comprises the anti-MOG autoantibody bound to only a single molecule. In some embodiments, upon binding of two molecules to an anti-MOG autoantibody, an immune complex is formed that has enhanced binding kinetics with FcyRIIB relative to the anti-MOG 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) endogenously expressing or overexpressing FcyRIIB measured by flow cytometry.

[0021] In some embodiments, upon binding of a molecule described herein to an anti-MOG 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 an immune complex that comprises the anti-MOG autoantibody and a corresponding molecule with wild-type Fc domains. In some embodiments, upon binding of a molecule described herein to an anti-MOG 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) toPage 6 of 17813278299v 1Attorney Docket No. 2017420-0065FcyRI, FcyRIIA167H, FcyRIIA167R, FcyRIIIA176F, FcyRIIIA176V, FcyRIIIB, and / or FcRn relative to the anti-MOG autoantibody alone.

[0022] In some embodiments, upon binding of two molecules to an anti-MOG 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, FcyRIII Al 76F, FcyRIIIA176V, FcyRIIIB, and / or FcRn relative to an immune complex that comprises the anti-MOG autoantibody and two corresponding molecules with wild-type Fc domains. In some embodiments, upon binding of two molecules to an anti-MOG 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 an immune complex that comprises the anti-MOG autoantibody bound to only a single molecule. In some embodiments, upon binding of two molecules to an anti-MOG 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-MOG 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) endogenously expressing or overexpressing FcyRI, FcyRIIA167H, FcyRIIA167R, FcyRIIIA176F, FcyRIIIA176V, 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).Page 7 of 17813278299v 1Attorney Docket No. 2017420-0065

[0025] In some embodiments, the molecule preferentially binds to immune cells expressing FcyRJIB 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 FcyRJIB 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 (c.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 -MOG 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, according 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, 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,Page 8 of 17813278299v 1Attorney Docket No. 2017420-0065P238D, 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, and P238D, according to the ELTnumbering 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 the following 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 Page 9 of 17813278299v 1Attorney Docket No. 2017420-0065(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, and SEQ ID NO: 126, 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: 97, 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: 56, SEQ ID NO: 58, SEQ ID NO: 75, SEQ ID NO: 98, 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 Page 10 of 17813278299v 1Attorney Docket No. 2017420-0065(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 MOG autoantigen domain, or a fragment or variant thereof. In some embodiments, the MOG 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 MOG 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 MOG autoantigen domain variant that includes one or more mutations relative to the amino acid sequence of SEQ ID NO: 1. In some embodiments, an autoantibody -binding domain comprises a MOG autoantigen domain variant that includes a N60Q mutation relative to the amino acid sequence of SEQ ID NO: 1. In some embodiments, the autoantibody -binding domain comprises a MOG autoantigen domain variant that comprises the sequence of any one of SEQ ID NOs: 1-11.

[0038] In some embodiments, a molecule described herein contains a second polypeptide that further comprises a second autoantibody-binding domain.

[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: 9 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: 10 and an amino acid sequence that is at least 90% identical Page 11 of 17813278299v 1Attorney Docket No. 2017420-0065(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: 11 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: 11 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: 11 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: 97; 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: 9 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: 97; 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: 10 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: 97; 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: 9 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: 10 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%,Page 12 of 17813278299v 1Attorney Docket No. 2017420-0065at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 99; 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: 11 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.

[0040] In some embodiments, a molecule described herein includes a first polypeptide that comprises: the amino acid sequence of SEQ ID NO: 9 and the amino acid sequence of SEQ ID NO: 19; the amino acid sequence of SEQ ID NO: 10 and the amino acid sequence of SEQ ID NO: 19; the amino acid sequence of SEQ ID NO: 11 and the amino acid sequence of SEQ ID NO: 28; the amino acid sequence of SEQ ID NO: 11 and the amino acid sequence of SEQ ID NO: 19; the amino acid sequence of SEQ ID NO: 11 and the amino acid sequence of SEQ ID NO: 97; the amino acid sequence of SEQ ID NO: 9 and the amino acid sequence of SEQ ID NO: 97; the amino acid sequence of SEQ ID NO: 10 and the amino acid sequence of SEQ ID NO: 97; the amino acid sequence of SEQ ID NO: 9 and the amino acid sequence of SEQ ID NO: 99; the amino acid sequence of SEQ ID NO: 10 and the amino acid sequence of SEQ ID NO: 99; or the amino acid sequence of SEQ ID NO: 11 and the amino acid sequence of SEQ ID NO: 99.

[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: 9 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: 10 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: 27; an amino acid sequencePage 13 of 17813278299v 1Attorney Docket No. 2017420-0065that 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: 11 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: 98; 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: 9 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: 10 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: 11 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.

[0042] In some embodiments, a molecule described herein includes a second polypeptide that comprises (i) the amino acid sequence of SEQ ID NO: 9 and SEQ ID NO: 19; (ii) the amino acid sequence of SEQ ID NO: 10 and SEQ ID NO: 19; (iii) the amino acid sequence of SEQ ID NO: 27; (iv) the amino acid sequence of SEQ ID NO: 11 and SEQ ID NO: 19; (v) the amino acid sequence of SEQ ID NO: 98; (vi) the amino acid sequence of SEQ ID NO: 9 and SEQ ID NO: 99; (vii) the amino acid sequence of SEQ ID NO: 10 and SEQ ID NO: 99; or (viii) the amino acid sequence of SEQ ID NO: 11 and 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: 9 and the amino acid sequence of SEQ ID NO: 19, and (ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 9 and the amino acid sequence of SEQ ID NO: 19. In some embodiments, a molecule Page 14 of 17813278299v 1Attorney Docket No. 2017420-0065described herein includes a first polypeptide and a second polypeptide where (i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 10 and the amino acid sequence of SEQ ID NO: 19, and (ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 9 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: 11 and the amino acid sequence of SEQ ID NO: 28, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 27; or (ii) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 11 and the amino acid sequence of SEQ ID NO: 27, 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: 11 and the amino acid sequence of SEQ ID NO: 19, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 11 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: 11 and the amino acid sequence of SEQ ID NO: 97, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 98; or (ii) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 11 and the amino acid sequence of SEQ ID NO: 98, and the second polypeptide comprises 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: 9 and the amino acid sequence of SEQ ID NO: 97, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 98; or (ii) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 9 and the amino acid sequence of SEQ ID NO: 98, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 97.

[0043] 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 of SEQ ID NO: 10 and the amino acid sequence of SEQ ID NO: 97, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 98; or (ii) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 10 and the amino acid sequence of SEQ ID NO: 98, and the Page 15 of 17813278299v 1Attorney Docket No. 2017420-0065second polypeptide comprises the amino acid sequence of SEQ ID NO: 97. 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 of SEQ ID NO: 9 and the amino acid sequence of SEQ ID NO: 99, and (ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 99. 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 of SEQ ID NO: 10 and the amino acid sequence of SEQ ID NO: 99, and (ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 99. 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 of SEQ ID NO: 11 and the amino acid sequence of SEQ ID NO: 99, and (ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 99.

[0044] 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, 101, 102, 103, 104, 106, 107, 109, 111, 113, 114, and 115, and a second polypeptide comprises the amino acid sequence of any one of SEQ ID NOs: 100, 101, 102, 103, 105, 106, 108, 110, 112, 113, 114, and 115.

[0045] 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, 101, 102, 103, 104, 106, 107, 109, 111, 113, 114, and 115, 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, 101, 102, 103, 105, 106, 108, 110, 112, 113, 114, and 115.

[0046] 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, 101, 102, 103, 104, 106, 107, 109, 111, 113, 114, and 115, and the second polypeptide comprises the amino acid sequence of any one of SEQ ID NOs: 100, 101, 102, 103, 105, 106, 108, 110, 112, 113, 114, and 115.Page 16 of 17813278299v 1Attorney Docket No. 2017420-0065

[0047] 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 of 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 of 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 of 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 of 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 of SEQ ID NO: 104 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 105; (vi) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 106 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 106; (vii) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 107 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 108; (viii) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 109 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 110; (ix) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 111 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 112; (x) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 113 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 1; (xi) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 107 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 108; or (xii) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 107 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 108.

[0048] 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 -MOG autoantibodies.Page 17 of 17813278299v 1Attorney Docket No. 2017420-0065

[0049] In some embodiments, the molecule is capable of selectively depleting anti-MOG autoantibodies that bind to the autoantibody -binding domain when administered to a subject. In some embodiments, the anti-MOG 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.

[0050] In some embodiments, the second polypeptide does not comprise an autoantibodybinding domain that binds to anti-MOG autoantibodies.

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

[0052] 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.

[0053] 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.

[0054] 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.

[0055] 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.

[0056] In another aspect, the present disclosure provides a method of treating a subject suffering from or susceptible to an autoimmune disease, the method comprising: administering to the subject a pharmaceutical composition comprising a molecule of the present disclosure or aPage 18 of 17813278299v 1Attorney Docket No. 2017420-0065nucleic acid encoding the molecule. In some embodiments, the autoimmune disease is MOGAD or another autoimmune disease involving anti-MOG autoantibodies.

[0057] In another aspect, the present disclosure provides a method of treating a subject suffering from or susceptible to an autoimmune disease, the method comprising: administering to the subject a first pharmaceutical composition comprising a molecule of 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 MOGAD, or another autoimmune disease involving anti-MOG autoantibodies. In some embodiments, the first pharmaceutical composition is administered before the second pharmaceutical composition. In some embodiments, the first pharmaceutical composition is administered after the second pharmaceutical composition. In some embodiments, the first pharmaceutical composition and the second pharmaceutical composition are co-administered.

[0058] In some embodiments, the level of anti-MOG 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-MOG 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 administration. In some embodiments, the reduced level of anti-MOG 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.

[0059] In another aspect, the present disclosure provides a method of selectively depleting anti-MOG 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.Page 19 of 17813278299v 1Attorney Docket No. 2017420-0065

[0060] In another aspect, the present disclosure provides a method of treating a human subject suffering from or susceptible to MOGAD, or another autoimmune disease involving anti-MOG 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.

[0061] 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.

[0062] In another aspect, the present disclosure provides a composition for decreasing the titer of anti -MOG 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 -MOG 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, and wherein, upon administration of the plurality of molecules, the molecules bind to anti-MOG autoantibodies to form immune complexes comprising at least one molecule bound to an anti-MOG 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-MOG autoantibodies in the subject’s blood serum, wherein the higher avidity is relative to an immune complex comprising at least one corresponding molecule with wild-type Fc domains.

[0063] In another aspect, the present disclosure provides an immune complex comprising an anti-MOG autoantibody and a molecule of the present disclosure, wherein the immune complex has enhanced binding kinetics with FcyRlIB relative to an immune complex that comprises the anti-MOG autoantibody bound to a corresponding molecule with wild-type Fc domains.Page 20 of 17813278299v 1Attorney Docket No. 2017420-0065

[0064] In another aspect, the present disclosure provides an immune complex comprising: (i) an anti-MOG 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-MOG 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-MOG 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-MOG autoantibody alone.

[0065] In another aspect, the present disclosure provides an immune complex comprising an anti-MOG 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-MOG autoantibody bound to two corresponding molecules with wild-type Fc domains.

[0066] In another aspect, the present disclosure provides an immune complex comprising: (i) an anti-MOG autoantibody; and (ii) at least one two molecule, wherein the at least one molecule comprises: a first polypeptide comprising a first Fc domain, and an autoantibody-binding domain that binds to the anti-MOG 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-MOG autoantibody bound to the at least one 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-MOG autoantibodyPage 21 of 17813278299v 1Attorney Docket No. 2017420-0065and only a single molecule. In some embodiments, the immune complex has enhanced binding kinetics with FcyRIIB relative to the anti -MOG autoantibody alone. In some embodiments, the autoantibody-binding domain of each of the two molecules is bound to the anti-MOG autoantibody.

[0067] 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.

[0068] 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.

[0069] 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, FcyR.II A l 67H, FcyRIIA167R, FcyRIIIA176F, FcyRIIIA176V, FcyRIITB, 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 negligible or no binding affinity to FcyRI, FcyRIIA167H, FcyRIIA167R, FcyRIIIA176F, FcyRIIIA176V, FcyRIIIB, and / or FcRn relative to the corresponding wild-type Fc domain.

[0070] 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.

[0071] In some embodiments, the binding affinity comprises binding affinity to a cell line (e.g., a CHO cell line) overexpressing FcyRIIB measured by flow cytometry. In some embodiments, the immune complex preferentially binds to immune cells expressing FcyRIIB Page 22 of 17813278299v 1Attorney Docket No. 2017420-0065over immune cells expressing FcyRTIA. Tn some embodiments, the immune complex cross-links FcyRIIB with a B cell receptor on a B cell.BRIEF DESCRIPTION OF THE DRAWING

[0072] FIG. 1 shows a schematic of an exemplary molecule described herein for selective depletion of autoantibodies targeted by an autoantibody -binding domain.

[0073] FIG. 2 shows an exemplary molecule format described herein.

[0074] FIG. 3 shows an exemplary molecule format described herein.

[0075] FIG. 4 shows an exemplary molecule format described herein.

[0076] FIGs. 5A-5B shows 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.

[0077] 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 Fc / RIIB isoform 2 on liver sinusoidal endothelial cells (FIG. 6B), targeting pathogenic B cells producing target autoantibodies (e.g., anti -MOG 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).

[0078] FIGs. 7A-7D show exemplary molecule formats described herein. FIG. 7A shows an exemplary bivalent molecule (“Variant Al”) that includes a homodimer of a first and second polypeptide that each include a native signal peptide, a MOG G30-P147 antigen fragment, a G4S linker, and an Fc domain. FIG. 7B shows an exemplary bivalent molecule (“Variant A2”) that includes a homodimer of a first and second polypeptide that each include a native signal peptide, a MOG G30-G154 antigen fragment, and an Fc domain. FIG. 7C shows an exemplary bivalent molecule (“Variant A3”) that includes a homodimer of a first and second polypeptide that each Page 23 of 17813278299v 1Attorney Docket No. 2017420-0065include an IgH signal peptide, a MOG G30-P147 antigen fragment, a G4S linker, and an Fc domain. FIG. 7D shows an exemplary bivalent molecule (“Variant A4”) that includes a homodimer of a first and second polypeptide that each include an IgH signal peptide, a MOG G30-G154 antigen fragment, and an Fc domain.

[0079] FIGs. 8A-8B show exemplary molecule formats described herein. FIG. 8A shows an exemplary monovalent molecule (“Variant A5”) that includes first polypeptide that includes a native signal peptide, a MOG G30-V144 antigen fragment, and an Fc domain and a second polypeptide that includes an Fc domain. FIG. 8B shows an exemplary bivalent molecule (“Variant A6”) that includes a homodimer of a first and second polypeptide that each include a native signal peptide, a MOG G30-V144 antigen fragment and an Fc domain.

[0080] FIGs. 9A-9D show results from size exclusion chromatography (SEC) of molecules expressed from constructs encoding Variant Al (FIG. 9A), Variant A2 (FIG. 9B), Variant A3 (FIG. 9C), and Variant A4 (FIG. 9D). Results show that proteins expressed from all constructs and were > 99% pure post protein A purification.

[0081] FIGs. 10A-10B show results from size exclusion chromatography (SEC) of molecules expressed from constructs encoding Variant A5 (FIG. 10A) and Variant A6 (FIG. 10B) Results show that proteins expressed from all constructs and were > 99% pure post protein A purification.

[0082] FIGs. 11A-11F show images of gels after protein electrophoresis technique using sodium dodecyl sulfate (SDS) polyacrylamide gel electrophoresis (PAGE) where samples containing protein expressed from constructs comprising Variant Al (FIG. HA), Variant A2 (FIG. HB), Variant A3 (FIG. 11C), Variant A4 (FIG. HD), Variant A5 (FIG. HE), and Variant A6 (FIG. 11F). Samples were heated to 95°C in a sample buffer with reducing agent like betamercaptoethanol 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 images show that the molecules were correctly expressed.Page 24 of 17813278299v 1Attorney Docket No. 2017420-0065

[0083] FTG. 12 shows results from an ELISA measuring the binding of Variants A1-A6 to anti-MOG antibody (8-18C5). Results show that all constructs bind anti-MOG with comparable EC50s.

[0084] FIGs. 13A-13F show results from a surface plasmon resonance (SPR) binding assay measuring binding of Variants Al (FIG. 13A), Variant A2 (FIG. 13B), Variant A3 (FIG. 13C), Variant A4 (FIG. 13D), Variant A5 (FIG. 13E), Variant A6 (FIG. 13F) to 8-18C5, when 8-18C5 anti-MOG antibodies were captured on an SPR sensor chip and the exemplary molecules were used as the analyte.DEFINITIONS

[0085] 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.

[0086] 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.

[0087] 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 25 of 17813278299v 1Attorney Docket No. 2017420-0065intravenous 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.

[0088] 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.

[0089] 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).

[0090] 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 26 of 17813278299v 1Attorney Docket No. 2017420-0065heavy 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 27 of 17813278299v 1Attorney Docket No. 2017420-0065chemical synthesis, or other artificial system or methodology. Tn 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.).

[0091] 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. Tn some Page 28 of 17813278299v 1Attorney Docket No. 2017420-0065embodiments, 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 (c. ., 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.

[0092] 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.

[0093] 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.

[0094] 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.

[0095] 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 29 of 17813278299v 1Attorney Docket No. 2017420-0065

[0096] 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.

[0097] Autoimmune disease. An “autoimmune disease” as used herein refers to an immune response directed against an autoantigen or self-antigen.

[0098] 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. ., 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).

[0099] 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”).

[0100] 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 30 of 17813278299v 1Attorney Docket No. 2017420-0065and 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.

[0101] 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.

[0102] 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).

[0103] 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 31 of 17813278299v 1Attorney Docket No. 2017420-0065(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.

[0104] 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.

[0105] 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 atPage 32 of 17813278299v 1Attorney Docket No. 2017420-0065least 25%, 30%, 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.

[0106] 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 33 of 17813278299v 1Attorney Docket No. 2017420-0065

[0107] 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.

[0108] 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.

[0109] 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.

[0110] 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.

[0111] 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 34 of 17813278299v 1Attorney Docket No. 2017420-0065reference 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.

[0112] 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.

[0113] KDAs 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).

[0114] 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).

[0115] 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).

[0116] 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 35 of 17813278299v 1Attorney Docket No. 2017420-0065subject 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.

[0117] 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, pyrrol o-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 36 of 17813278299v 1Attorney Docket No. 2017420-0065embodiments, 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.

[0118] 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.

[0119] 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.

[0120] 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 37 of 17813278299v 1Attorney Docket No. 2017420-0065herein 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.

[0121] 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.

[0122] 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 38 of 17813278299v 1Attorney Docket No. 2017420-0065species 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.

[0123] 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.

[0124] 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 39 of 17813278299v 1Attorney Docket No. 2017420-0065or site within a body that is in need of treatment or is preferentially bound by, for example, a molecule described herein.

[0125] 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.

[0126] 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.

[0127] 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 40 of 17813278299v 1Attorney Docket No. 2017420-0065that 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

[0128] Certain autoimmune diseases are driven by autoantibodies that mount an immune response to self-antigens ( / .< .. autoantigens). Despite the identification of certain autoantibodyantigen pairs and their implication in autoimmune diseases (e.g., myelin oligodendrocyte glycoprotein (MOG) and MOG antibody (ab) associated disorder (MOGAD)), 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.

[0129] The present disclosure encompasses molecules for selectively depleting autoantibodies (i.e., anti -MOG autoantibodies), to treat autoimmune diseases (e.g., MOGAD). 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-MOG 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 (i.e., anti-MOG 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-binding domain that binds to autoantibodies (i.e., anti-MOG autoantibodies) and the molecule is a heterodimer.

[0130] The disclosure provides, among other things, molecules that selectively target and deplete autoantibodies, for example, by targeting them to internalizing receptors which bind to Page 41 of 17813278299v 1Attorney Docket No. 2017420-0065and internalize the complex into a cell for lysosomal degradation. Tn some embodiments, the autoantibody-binding domain comprises an autoantigen. For example, if the particular autoantibodies to be targeted are anti-MOG autoantibodies (e.g., for treatment ofMOGAD), an autoantigen domain may comprise a MOG 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).MOG Autoantigens and MOGAD

[0131] In some embodiments, molecules described herein may be used for the treatment of myelin oligodendrocyte glycoprotein (MOG) antibody (ab) associated disorder (MOGAD), and other autoimmune diseases implicated by autoantibodies that target MOG, by including an autoantibody binding domain that comprises a MOG autoantigen domain, or a fragment or variant thereof.

[0132] MOG is a glycoprotein, classified as a type I integral membrane protein. MOG includes a single extracellular Ig variable domain (“Ig-V”). MOG is expressed in the central nervous system (CNS), and particularly in the outermost lamellae of the myelin sheath, and the cell body and processes of oligodendrocytes. MOG functions as an adhesion protein within the CNS, and is involved in maintenance of myelin, intracellular signaling, and modulation of CNS autoimmunity. Additionally, MOG is known to bind Clq, suggesting additional function as an immune regulator. See Clements et al., PNAS. 5; 100(19): 11059-11064 (2003).

[0133] MOG antibodies are considered biomarkers of atypical demyelinating disorders or MOG antibody-associated disorders (MOGAD). Such disorders include Acute Disseminated Encephalomyelitis (ADEM), optic neuritis including chronic relapsing inflammatory optic neuropathy, transverse myelitis, and brain or brainstem syndrome compatible with demyelination. MOG antibodies are also implicated in Neuromyelitis optica (NMO) spectrum disorder, a disease that affects the spinal cord and optic nerve. See Montalvo et al., Neurobiology Page 42 of 17813278299v 1Attorney Docket No. 2017420-0065of Brain Disorders (2nd Ed.) Biological Basis of Neurological and Psychiatric Disorders, (Ch.31): 525-558 (2023).

[0134] MOGAD presents itself in many varying clinical phenotypes and encompasses a range of CNS inflammatory disorders (e.g., acute disseminated encephalomyelitis (ADEM), optic neuritis, transverse myelitis, cortical encephalitis, cerebral lesions, and brainstem or cerebellar syndromes). Diagnosis of MOGAD requires detection of antibodies that bind to exposed epitopes of MOG. These antibodies can cause autoimmune responses within the body including complement deposition, antibody-dependent cell-mediated cytotoxicity, and antibodydependent cellular phagocytosis.

[0135] There are several known antigenic determinants targeted by MOG-specific immune cells. One example is the N-terminal extracellular domain of MOG (residues 1-117 Ig-like domain). Residues 35-55 and 92-106 of MOG have been shown to be implicated in experimental autoimmune encephalomyelitis (EAE). Identified immunogenic regions of MOG are not limited to the extracellular region. For example, a pathogenic determinant of full-length MOG is found within the transmembrane domain of residues 119-132. Currently, there are no approved therapies for MOGAD. Moseley et al., Neurology: Neuroimmunology & Neuroinflammation, ll(5):e200275 (2024).

[0136] MOGAD causes inflammation of the spinal cord, brain, and the optic nerve.Symptoms of MOGAD include blurred vision or loss of vision, double vision, eye pain, color blindness, muscle stiffness, muscle weakness, paralysis of the arms and legs, trouble walking, loss of sensations, numbness and tingling in the arms, legs, neck, back, or abdomen, loss of bowel or bladder control, brain fog such as confusion, seizures, headache, behavioral changes, loss of balance and coordination, cognitive impairment, among others.

[0137] The present disclosure recognizes that further selectivity can be introduced in order to preserve essential immunity and increase efficacy of, e.g., antibodies that target foreign pathogens such as viral antigens. Molecules described herein include a further selectivity to target autoantibodies that implicate autoimmune disease. This strategy includes, in some embodiments, utilizing a MOG autoantigen domain, or a fragment or variant thereof, for targeted Page 43 of 17813278299v 1Attorney Docket No. 2017420-0065destruction of anti-MOG autoantibodies, thus removing the autoimmune response that implicates MOGAD.Exemplary Molecules

[0138] The present disclosure provides molecules for selectively depleting and / or neutralizing autoantibodies (i.e., anti-MOG autoantibodies), to treat autoimmune diseases (e.g., MOGAD). 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-MOG 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-MOG autoantibodies and the molecule is a homodimer. In some embodiments, the second polypeptide further comprises an autoantibody-binding domain that binds to anti-MOG autoantibodies and the molecule is a heterodimer. In some embodiments, the second polypeptide does not comprise an autoantibodybinding domain that binds to anti-MOG autoantibodies and the molecule is a heterodimer.

[0139] In some embodiments, the first and / or second polypeptide further comprises an antigen-binding domain (e.g., a Fab domain).

[0140] 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.

[0141] 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.

[0142] In some embodiments, upon binding of one or two molecules to an autoantibody (i.e., anti-MOG autoantibody), an immune complex is formed. In some embodiments, immune complexes formed with one molecule described herein and an autoantibody (i.e., anti-MOG autoantibody) have enhanced binding kinetics with FcyRIIB relative to an immune complex thatPage 44 of 17813278299v 1Attorney Docket No. 2017420-0065comprises the autoantibody (i.e., anti-MOG 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 (z.c., anti-MOG autoantibody) have enhanced binding kinetics with FcyRIIB relative to an immune complex that comprises the autoantibody (z.e., anti-MOG autoantibody) bound to two corresponding molecules with wild-type Fc domains. In some embodiments, such enhanced binding kinetics increases clearance of the immune complex.Autoantibody-binding domain

[0143] 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 (z?.g., anti-MOG autoantibodies). In some embodiments, the autoantibody-binding domain comprises an autoantigen, or a fragment or variant thereof (e.g., a MOG autoantigen domain, or fragment or variant thereof). In some embodiments, the autoantibody-binding 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.

[0144] In some embodiments, the autoantibody-binding domain described herein prevents binding of an autoantibody to its cognate autoantigen (c.g, autoantibodies to MOG autoantigens).Autoantigens

[0145] In some embodiments a molecule comprises an autoantibody-binding domain that comprises an autoantigen, or a fragment or variant thereof. Such autoantigen domains target autoantibodies that are implicated in various autoimmune diseases. For example, a MOG autoantigen domain (or a fragment or variant thereof) may be used in a molecule in order to target anti-MOG autoantibodies that are known to cause autoimmune diseases such as MOGAD.

[0146] MOG is a glycoprotein, classified as a type I integral membrane protein and includes an extracellular Ig variable domain (“Ig-V”). See Clements et al., PNAS. 5; 100(19): 11059-11064Page 45 of 17813278299v 1Attorney Docket No. 2017420-0065(2003). Human wildtype MOG is 252 amino acids in length (SEQ ID NO: 1). The first 29 amino acids (MASLSRPSLPSCLCSFLLLLLLQVSSSYA, SEQ ID NO: 12) is a signal peptide, which ultimately gets cleaved. The remaining amino acid sequence includes an Ig-like domain (amino acid residues 46-145 of the 252 amino acid sequence SEQ ID NO: 1, as shown in SEQ ID NO: 3).

[0147] In some embodiments, an autoantigen domain includes a myelin oligodendrocyte glycoprotein (MOG) autoantigen domain, or a fragment or variant thereof. In some embodiments, a MOG autoantigen domain comprises a fragment or variant of SEQ ID NO: 1. In some embodiments, a MOG autoantigen domain comprises amino acids 30-154 of SEQ ID NO: 1 or “G30-G154” as represented in SEQ ID NO: 5. Residues 101-108 (DHSYQEE, SEQ ID NO: 13) of MOG are known to interact with certain stimulating MOG antibodies, including a mouse-derived demyelinating antibody known as 8-18C5, which binds to three loops located at the membrane-distal side of MOG (see Breithaupt et al., Structural insights into the antigenicity of myelin oligodendrocyte glycoprotein, 100(16):9446-9451 (2003)). In some embodiments, a MOG autoantigen domain comprises a fragment of MOG that corresponds to amino acids 30-147 of SEQ ID NO: 1 or “G30-P147” as represented in SEQ ID NO: 4. In some embodiments, a MOG autoantigen domain comprises a fragment of MOG that corresponds to amino acids 30-144 of SEQ ID NO: 1 or “G30-V144” as represented in SEQ ID NO: 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. In some embodiments, an autoantigen domain contains the amino acid sequence of SEQ ID NO: 13.

[0148] In some embodiments, a MOG autoantigen domain comprises one or more mutations compared to the wildtype MOG sequence (e.g., as shown in SEQ ID NO: 1). In some embodiments, an autoantigen domain comprises a human MOG autoantigen domain variant thatPage 46 of 17813278299v 1Attorney Docket No. 2017420-0065includes an N60Q mutation relative to the amino acid sequence of SEQ ID NO: 1. In some embodiments, an autoantigen domain comprises an amino acid sequence of SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, or a fragment or variant thereof.

[0149] In some embodiments, an autoantigen domain comprises a human MOG 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: 1-11 (shown below in Table 1). In some embodiments, an autoantigen domain comprises a human MOG autoantigen domain variant that comprises a sequence selected from SEQ ID NOs: 1-11 (shown below in Table 1).Table 1: Exemplary MOG Antigen SequencesPage 47 of 17813278299v 1Attorney Docket No. 2017420-0065Antigen-binding domains

[0150] 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., FcvRIIB, FcRn, ASGPR, BCMA, CD38, SLAMF7,Page 48 of 17813278299v 1Attorney Docket No. 2017420-0065GPCR5D, and / or CD 138). In some embodiments, an antigen-binding domain binds to an autoantibody (e.g., an anti -MOG autoantibody).

[0151] 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.

[0152] 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).

[0153] 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 -MOG autoantibody) and a second antigen-binding domain targets an internalizing receptor (e.g., FcyRIIB, FcRn, ASGPR, BCMA, CD38, SLAMF7, GPCR5D, and / or CD 138).

[0154] In some embodiments, an antigen-binding domain comprises a Fab comprising a heavy chain and light chain antibody component. In some embodiments, an antigen-bindingPage 49 of 17813278299v 1Attorney Docket No. 2017420-0065domain comprises a Fab that comprises any of the following particular heavy chain and light chain antibody sequences shown in Table 2.

[0155] In some embodiments, an antigen-binding domain is a Fab that comprises an antibody heavy 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: 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 sequencesFc domains

[0156] In some embodiments, a molecule described herein includes a first polypeptide comprising an autoantigen domain comprising a MOG autoantigen domain or fragment or variant thereof linked to a first Fc domain and a second polypeptide comprising a second Fc domain. A MOG autoantigen domain or fragment or variant thereof targets anti -MOG autoantibodies and upon binding, the complexes are targeted to an internalizing receptor and shuttled to the lysosome for degradation of the anti-MOG autoantibodies.Page 50 of 17813278299v 1Attorney Docket No. 2017420-0065

[0157] 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, FcyRIIlAI76V, FcyRIIIB, and / or FcRn).

[0158] 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).

[0159] 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, FcyRlIAI67H, FcyRIIAl 67R, 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, FcyRlllA176V, FcyRIIIB, and / or FcRn relative to the corresponding wild-type Fc domain.

[0160] 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.).

[0161] 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 51 of 17813278299v 1Attorney Docket No. 2017420-0065IgGl 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).

[0162] 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.

[0163] 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-MOG 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-MOG 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-MOG 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-MOG 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 52 of 17813278299v 1Attorney Docket No. 2017420-0065(FcyRIIB) Tn some embodiments, wherein upon binding of one or more molecules to an autoantibody (e.g., an anti-MOG 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-MOG 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-MOG 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-MOG 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.

[0164] 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.

[0165] 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.

[0166] 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 53 of 17813278299v 1Attorney Docket No. 2017420-0065mutations that increase half-life (e.g., M428L and N434S according to EU numbering, also referred to herein as an “LS mutation”).

[0167] 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).

[0168] 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 54 of 17813278299v 1Attorney Docket No. 2017420-0065also 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.

[0169] 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 SequencesPage 55 of 17813278299v 1Attorney Docket No. 2017420-0065Page 56 of 17813278299v 1Attorney Docket No. 2017420-0065Page 57 of 17813278299v 1Attorney Docket No. 2017420-0065Page 58 of 17813278299v 1Attorney Docket No. 2017420-0065Page 59 of 17813278299v 1Attorney Docket No. 2017420-0065Page 60 of 17813278299v 1Attorney Docket No. 2017420-0065Page 61 of 17813278299v 1Attorney Docket No. 2017420-0065Page 62 of 17813278299v 1Attorney Docket No. 2017420-0065Page 63 of 17813278299v 1Attorney Docket No. 2017420-0065Page 64 of 17813278299v 1Attorney Docket No. 2017420-0065Page 65 of 17813278299v 1Attorney Docket No. 2017420-0065Page 66 of 17813278299v 1Attorney Docket No. 2017420-0065Page 67 of 17813278299v 1Attorney Docket No. 2017420-0065Page 68 of 17813278299v 1Attorney Docket No. 2017420-0065Page 69 of 17813278299v 1Attorney Docket No. 2017420-0065Page 70 of 17813278299v 1Attorney Docket No. 2017420-0065Page 71 of 17813278299v 1Attorney Docket No. 2017420-0065Page 72 of 17813278299v 1Attorney Docket No. 2017420-0065

[0170] 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 ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 99, SEQ ID NO: 125, and SEQ ID NO: 126, or a fragment or variant thereof.

[0171] 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: 97, SEQ ID NO: 127, and 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 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, Page 73 of 17813278299v 1Attorney Docket No. 2017420-0065SEQ 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: 98, 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.

[0172] 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 some embodiments, 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 Page 74 of 17813278299v 1Attorney Docket No. 2017420-0065and 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 a sequence 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 domainPage 75 of 17813278299v 1Attorney Docket No. 2017420-0065comprises a sequence of SEQ TD 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 SEQ ID NO: 97 and a second Fc domain comprises a sequence of SEQ ID NO: 98. 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: 129 and 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 firstPage 76 of 17813278299v 1Attorney Docket No. 2017420-0065Fc 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.Hinge sequences

[0173] 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).

[0174] 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

[0175] 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 (i.e., internalizing receptors or endocytic receptors). By Page 77 of 17813278299v 1Attorney Docket No. 2017420-0065modifying Fc domains to increase binding to internalizing receptors, molecules described herein and their bound autoantibodies are targeted for internalization and lysosomal degradation.

[0176] 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.

[0177] Exemplary internalizing receptors include but are not limited to FcyRIIB, FcRn, ASGPR, BCMA, CD38, SLAMF7, GPCR5D, or CD138.

[0178] 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 first 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.

[0179] 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 Page 78 of 17813278299v 1Attorney Docket No. 2017420-0065numbering 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.

[0180] 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.

[0181] 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 and / or second Fc domain comprises the following mutated amino acid residues: L234A, L23 A, 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, A33OR, 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.

[0182] 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 somePage 79 of 17813278299v 1Attorney Docket No. 2017420-0065embodiments, 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.

[0183] 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.

[0184] 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 has 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 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.

[0185] 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 (z.c., 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.Page 80 of 17813278299v 1Attorney Docket No. 2017420-0065In 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.

[0186] 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 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 G237D, P238D, P271G, and A330R mutations, according to the EU number scheme.i. Exemplary FcyRIIB Mutations

[0187] 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.

[0188] 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,Page 81 of 17813278299v 1Attorney Docket No. 2017420-0065FcyRIIA 167H, FcyRIIA 167R, FcyRIIIA 176F, FcyRIIIA 176V, and / or FcyRIIIB . Tn some embodiments, an Fc domain includes one or more mutated amino acid residues and has decreased binding affinity to FcyRI, FcyRIIA 167H, FcyRIIA 167R, FcyRIIIA 176F, 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.

[0189] 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 comprises 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 -MOG autoantibody) form an immune complex that has enhanced binding kinetics with FcyRIIB relative to binding kinetics of the autoantibody (e.g., anti-MOG autoantibody) with FcyRIIB.

[0190] 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.Page 82 of 17813278299v 1Attorney Docket No. 2017420-0065

[0191] In some embodiments, a molecule binds to FcyRIIB with an affinity within the range of about 1 pM to 0.001 gM. 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.

[0192] Additionally, the present disclosure provides Fc domain mutations that achieve the binding affinity to FcyRIIB 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.

[0193] 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).Page 83 of 17813278299v 1Attorney Docket No. 2017420-0065

[0194] 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).

[0195] 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).

[0196] In some embodiments, an Fc domain mutation comprises one or more of the following mutations: L234Y, P238D, T250V, V2641, 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 (c.g., see SEQ ID NOs: 39, 40, and 62).

[0197] 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.

[0198] 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).Page 84 of 17813278299v 1Attorney Docket No. 2017420-0065

[0199] 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).

[0200] 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).

[0201] 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).

[0202] 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 Fc 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).

[0203] In some embodiments, an Fc domain mutation comprises one or more of the following mutations: P238D, D270E, or P271 G, 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).

[0204] 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).

[0205] 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,Page 85 of 17813278299v 1Attorney Docket No. 2017420-0065P238D, D270E, P271G, and A330R, according to the EU numbering scheme (e.g., see SEQ ID NOs: 55, 56, and 70).

[0206] 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).

[0207] In some embodiments, an Fc domain mutation comprises P238D, according to the EU numbering scheme (e.g, see SEQ ID NOs: 27 and 28).

[0208] 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, FcyRIIA167H, FcyRIIA167R, FcyRIIIA176F, FcyRIIlA176V, FcyRIIIB, and / or FcRn. Such binding properties lead 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.

[0209] 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

[0210] 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.

[0211] 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 Page 86 of 17813278299v 1Attorney Docket No. 2017420-0065isolate the desired antibody agent in those situations. Tn 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.

[0212] 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 horn odi m eri zati on .

[0213] 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 andPage 87 of 17813278299v 1Attorney Docket No. 2017420-0065S354C 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.

[0214] 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

[0215] 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 some 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.

[0216] 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 Page 88 of 17813278299v 1Attorney Docket No. 2017420-0065embodiments, 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.

[0217] 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 Fc domain 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 -MOG autoantibodies) implicated in an autoimmune disease (e.g., MOGAD). 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, FcyRIIIAl 76F, FcyRIIIAl 76V, 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.

[0218] 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.Page 89 of 17813278299v 1Attorney Docket No. 2017420-0065

[0219] 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.

[0220] 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.

[0221] 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.

[0222] 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.

[0223] 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.

[0224] 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

[0225] 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-MOG autoantibody will not be targeted for destruction.

[0226] 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,Page 90 of 17813278299v 1Attorney Docket No. 2017420-0065and 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 modification 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, A33OS, P331S (“PVA-GSS”). In some embodiments, a modification that silences effector function includes the following Fc mutations: L235G andPage 91 of 17813278299v 1Attorney Docket No. 2017420-0065G236R (“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

[0227] 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.

[0228] 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).

[0229] 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: 117)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).

[0230] 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 exemplaryPage 92 of 17813278299v 1Attorney Docket No. 2017420-0065linkers also include the following: GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 94) and GGGGSGGGGSGGGGSGGGGSSGGGGS (SEQ ID NO: 95).

[0231] 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.

[0232] 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).

[0233] 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 (z.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.

[0234] 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

[0235] 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,Page 93 of 17813278299v 1Attorney Docket No. 2017420-0065antigen-binding domains, Fc domains, and linkers are described. Such components may be assembled in different configurations to generate a molecule as described herein.

[0236] 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.

[0237] 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 the 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).

[0238] 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.Page 94 of 17813278299v 1Attorney Docket No. 2017420-0065

[0239] 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 (U) (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).

[0240] 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 domain (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).

[0241] 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.

[0242] 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-MOG Page 95 of 17813278299v 1Attorney Docket No. 2017420-0065autoantibody and a second antigen-binding domain targets an internalizing receptor (e.g., ASPGR).

[0243] In some embodiments, a MOG autoantigen domain described herein may include a native or non-native signal peptide sequence. The native MOG signal peptide sequence is shown in SEQ ID NO: 12. In some embodiments, a MOG autoantigen domain may include a nonnative 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.

[0244] In some embodiments, a MOG autoantigen domain described herein does not include a signal peptide sequence.

[0245] 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 some embodiments, a molecule described herein (e.g., as described in Table 4) is bivalent (e.g., as shown in FIG. 5, FIG. 7, and FIG. 8B), 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 FIG. 8A).Table 4: Exemplary MOG Antibody Depletion CombinationsPage 96 of 17813278299v 1Attorney Docket No. 2017420-0065

[0246] 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 Page 97 of 17813278299v 1Attorney Docket No. 2017420-0065in any one of the configurations in FTGs. 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.

[0247] 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: 9 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: 10 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: 11 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; (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: 11 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; (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: 9 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 Page 98 of 17813278299v 1Attorney Docket No. 2017420-006596%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 97; (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: 10 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: 97; (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: 9 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: 10 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 (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: 11, 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.

[0248] In some embodiments, a molecule comprises a first polypeptide, wherein the first polypeptide comprises: (i) an amino acid sequence comprising SEQ ID NO: 9 and an amino acid comprising SEQ ID NO: 19; (ii) an amino acid sequence comprising SEQ ID NO: 10 and an amino acid sequence comprising SEQ ID NO: 19; (iii) an amino acid sequence comprising SEQ ID NO: 11 and an amino acid sequence comprising SEQ ID NO: 28; (iv) an amino acid sequence comprising SEQ ID NO: 11 and an amino acid sequence comprising SEQ ID NO: 19; (v) an amino acid sequence comprising SEQ ID NO: 9 and an amino acid sequence comprising SEQ ID NO: 97; (vi) an amino acid sequence comprising SEQ ID NO: 10 and an amino acid sequence comprising SEQ ID NO: 97; (vii) an amino acid sequence comprising SEQ ID NO: 9 and an amino acid comprising SEQ ID NO: 99; (viii) an amino acid sequence comprising SEQ ID NO: 10 and an amino acid sequence comprising SEQ ID NO: 99; or (ix) an amino acid sequence comprising SEQ ID NO: 11, an amino acid sequence comprising SEQ ID NO: 99.Page 99 of 17813278299v 1Attorney Docket No. 2017420-0065

[0249] 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: 9 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: 10 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: 27; (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: 11 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; (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: 98; or (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: 99.

[0250] In some embodiments, a molecule comprises a second polypeptide, wherein the second polypeptide comprises: (i) an amino acid sequence comprising SEQ ID NO: 9 and an amino acid sequence comprising SEQ ID NO: 19; (ii) an amino acid comprising SEQ ID NO: 10 and an amino acid sequence comprising SEQ ID NO: 19; (iii) an amino acid sequence comprising SEQ ID NO: 27; (iv) an amino acid sequence comprising SEQ ID NO: 11 and an amino acid sequence comprising SEQ ID NO: 19; (v) an amino acid sequence comprising SEQ ID NO: 98; or (vi) an amino acid sequence comprising SEQ ID NO: 99.Page 100 of 17813278299v 1Attorney Docket No. 2017420-0065

[0251] 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: 11 and SEQ ID NO: 28, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 27; or (ii) the first polypeptide comprises an amino acid sequence comprising SEQ ID NO: 11 and SEQ ID NO: 27, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 28. 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: 11 and SEQ ID NO: 97, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 98; or (ii) the first polypeptide comprises an amino acid sequence comprising SEQ ID NO: 11 and SEQ ID NO: 98, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 97. 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: 9 and SEQ ID NO: 97, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 98; or (ii) the first polypeptide comprises an amino acid sequence comprising SEQ ID NO: 9 and SEQ ID NO: 98, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 97. 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: 10 and SEQ ID NO: 97, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 98; or (ii) the first polypeptide comprises an amino acid sequence comprising SEQ ID NO: 9 and SEQ ID NO: 98, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 97.

[0252] 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: 1-11 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 Page 101 of 17813278299v 1Attorney Docket No. 2017420-0065sequence selected from 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 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: 1-11 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: 125, and SEQ ID NO: 126.

[0253] 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: 1-11 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, and (b) a second polypeptide, wherein the second polypeptide comprises: (i) an amino acid sequence comprising any one of SEQ ID NOs: 1-11 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.Page 102 of 17813278299v 1Attorney Docket No. 2017420-0065

[0254] 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: 1-11 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: 97 (e.g., SEQ ID NO: 28 or SEQ ID NO: 97), 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: 98 (e.g., SEQ ID NO: 27 or SEQ ID NO: 98) 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.

[0255] 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: 1-11 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 Page 103 of 17813278299v 1Attorney Docket No. 2017420-0065ID NO: 75, SEQ ID NO: 98 (e.g, SEQ ID NO: 27 or SEQ ID NO: 98) 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: 97 (e.g., SEQ ID NO: 28 or SEQ ID NO: 97) 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.

[0256] 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: 1-11 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: 97 (e.g., SEQ ID NO: 28 or SEQ ID NO: 97), 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 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: 98 (e.g, SEQ ID NO: 27 or SEQ ID NO: 98) 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 104 of 17813278299v 1Attorney Docket No. 2017420-0065

[0257] 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: 1-11 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: 98 (e.g., SEQ ID NO: 27 or SEQ ID NO: 98) 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: 97 (e.g, SEQ ID NO: 28 or SEQ ID NO: 97), 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.

[0258] 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 sequences shown 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.Page 105 of 17813278299v 1Attorney Docket No. 2017420-0065Table 5: Exemplary MOG molecule sequencesPage 106 of 17813278299v 1Attorney Docket No. 2017420-0065Page 107 of 17813278299v 1Attorney Docket No. 2017420-0065Page 108 of 17813278299v 1Attorney Docket No. 2017420-0065Page 109 of 17813278299v 1Attorney Docket No. 2017420-0065

[0259] 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, amolecule comprises a first and second polypeptide described in Table 7, without a signal peptide.In some embodiments, a molecule comprises a first and second polypeptide described in Table 7,Page 110 of 17813278299v 1Attorney Docket No. 2017420-0065with a different signal peptide. Tn some embodiments, a signal peptide is a non-native TgH signal peptide (e.g., SEQ ID NO: 96). In some embodiments, a signal peptide is a native signal peptide.

[0260] In some embodiments, a molecule comprises the first polypeptide and second polypeptide sequences of Variants Al-Variants A12 without the signal peptide sequence included (SEQ ID NO: 96 or SEQ ID NO: 12). In some embodiments, a molecule comprises the first polypeptide and second polypeptide sequences of Variants Al-Variants A12 with a different signal peptide sequence.

[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: 100; (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: 101 ; (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: 102; (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: 103 ; (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: 104; (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: 106; (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: 107; (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: 109; (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: 111; (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 Page 111 of 17813278299v 1Attorney Docket No. 2017420-0065least 96%, at least 97%, at least 98%, at least 99%) to SEQ ID NO: 113; (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: 114; or (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: 115.

[0262] In some embodiments, a molecule comprises a first polypeptide, wherein the first polypeptide comprises: (i) an amino acid sequence comprising SEQ ID NO: 100; (ii) an amino acid sequence comprising SEQ ID NO: 101; (iii) an amino acid sequence comprising SEQ ID NO: 102; (iv) an amino acid sequence comprising SEQ ID NO: 103; (v) an amino acid sequence comprising SEQ ID NO: 104; (vi) an amino acid sequence comprising SEQ ID NO: 106; (vii) an amino acid sequence comprising SEQ ID NO: 107; (viii) an amino acid sequence comprising SEQ ID NO: 109; (ix) an amino acid sequence comprising SEQ ID NO: 111; (x) an amino acid sequence comprising SEQ ID NO: 113; (xi) an amino acid sequence comprising SEQ ID NO: 114; or (xii) an amino acid sequence comprising SEQ ID NO: 115.

[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: 100; (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: 101 ; (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: 102; (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: 103 ; (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: 105; (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 Page 112 of 17813278299v 1Attorney Docket No. 2017420-0065SEQ ID NO: 106; (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: 108; (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: 110; (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: 112; (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: 113; (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: 114; or (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: 115.

[0264] In some embodiments, a molecule comprises a second polypeptide, wherein the first polypeptide comprises: (i) an amino acid sequence comprising SEQ ID NO: 100; (ii) an amino acid sequence comprising SEQ ID NO: 101; (iii) an amino acid sequence comprising SEQ ID NO: 102; (iv) an amino acid sequence comprising SEQ ID NO: 103; (v) an amino acid sequence comprising SEQ ID NO: 105; (vi) an amino acid sequence comprising SEQ ID NO: 106; (vii) an amino acid sequence comprising SEQ ID NO: 108; (viii) an amino acid sequence comprising SEQ ID NO: 110; (ix) an amino acid sequence comprising SEQ ID NO: 112; (x) an amino acid sequence comprising SEQ ID NO: 113; (xi) an amino acid sequence comprising SEQ ID NO: 114; or (xii) an amino acid sequence comprising SEQ ID NO: 115.

[0265] In some embodiments, a molecule comprises a first and second polypeptide 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: 100-115 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 Page 113 of 17813278299v 1Attorney Docket No. 2017420-0065least 99%) to any one of SEQ ID NOs: 100-115. Tn some embodiments, a molecule comprises a first and second polypeptide wherein, the first polypeptide comprises the amino acid sequence of any one of SEQ ID NOs: 100-115 and the second polypeptide comprises the amino acid sequence of any one of SEQ ID NOs: 100-115.

[0266] 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: 100, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 100; (ii) the first polypeptide comprises an 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 an 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 an 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 an amino acid sequence comprising SEQ ID NO: 104 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 105; (vi) the first polypeptide comprises an amino acid sequence comprising SEQ ID NO: 106 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 106; (vii) the first polypeptide comprises an amino acid sequence comprising SEQ ID NO: 107 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 108; (viii) the first polypeptide comprises an amino acid sequence comprising SEQ ID NO: 109 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 110; (ix) the first polypeptide comprises an amino acid sequence comprising SEQ ID NO: 111 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 112; (x) the first polypeptide comprises an amino acid sequence comprising SEQ ID NO: 113 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 113; (xi) the first polypeptide comprises an amino acid sequence comprising SEQ ID NO: 114 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 114; or (xii) the first polypeptide comprises an amino acid sequence comprising SEQ ID NO: 115 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 115.Page 114 of 17813278299v 1Attorney Docket No. 2017420-0065Characteristics of Exemplary Molecules

[0267] Molecules described herein may be identified, assessed, and / or characterized for one or more of their physical / chemical properties and / or biological activities. Those skilled in the art will be aware of a variety of approaches, including particular assays, that may be utilized for such identification, assessment, and / or characterization. Antigen-binding domains and autoantigen domains of molecules described herein may be selected according to various criteria including, but not limited to, binding affinity, or the potency of the response (e.g., neutralization / removal of autoantibodies).Binding Properties

[0268] Antigen-binding domains and autoantigens can be selected based on, among other things, their binding properties for their targets. The binding properties of an antigen-binding domain of molecules described herein can be measured by methods known in the art, e.g., one of the following methods: BIACORE analysis, Enzyme Linked Immunosorbent Assay (ELISA), x-ray crystallography, sequence analysis and scanning mutagenesis. The binding interaction of an antibody and target antigen can be analyzed using surface plasmon resonance (SPR). SPR or Biomolecular Interaction Analysis (BIA) detects bio-specific interactions in real time, without labeling any of the interactants. Changes in the mass at the binding surface (indicative of a binding event) of the BIA chip result in alterations of the refractive index of light near the surface. The changes in the refractivity generate a detectable signal, which are measured as an indication of real-time reactions between biological molecules. Methods for using SPR are described, for example, in U.S. Pat. No. 5,641,640; Raether (1988) Surface Plasmons Springer Verlag; Sjolander and Urbaniczky, Anal. Chem. 63:2338-2345 (1991); Szabo et al., Curr. Opin. Struct. Biol. 5:699-705 (1995) and on-line resources provided by BIAcore (Cytiva, USA).Additionally, a KinExA (Kinetic Exclusion Assay) assay, available from Sapidyne Instruments (Boise, Idaho), and / or an Octet BLI (Bio-Layer Interferometry) from Sartorius (Goettingen, Germany) can also be used.

[0269] Information from SPR or from similar BIA methods can be used to provide an accurate and quantitative measure of the equilibrium dissociation constant (KD), and kinetic parameters, including Konand Koff, for the binding of an antigen-binding domain to a target Page 115 of 17813278299v 1Attorney Docket No. 2017420-0065antigen. Such data can be used to compare different molecules. Information from SPR can also be used to develop structure-activity relationships (SAR). Variant amino acids at given positions can be identified that correlate with particular binding parameters, e.g., high affinity.

[0270] In some embodiments, an antigen-binding domain described herein exhibits high affinity for binding for an autoantibody or an internalizing receptor. In various embodiments, KD of an antigen-binding domain as described herein for a target antigen is less than about 10'4, 10'5, ICT6, 10'7, 10'8, 10’9, IO'10, 10'11, 10'12, 10‘13, 10’14, or 10‘15M or any range there between. In certain instances, KD of an antigen-binding domain as described herein for an immune cell target is between 0.001 and 1 nM, e.g., 0.001 nM, 0.005 nM, 0.01 nM, 0.05 nM, 0.1 nM, 0.5 nM, or 1 nM or any range there between.

[0271] In some embodiments, an autoantigen domain binds to an autoantibody with a high binding affinity. In various embodiments, KD of an autoantigen domain as described herein for an autoantibody is less than about 10‘4, 10'5, 10‘6, 10‘7, 10‘8, 10‘9, 10'10, 10’11, 10‘12, 10’13, 10‘14, or 10‘15M or any range there between. In some embodiments, an autoantigen domain binds to an autoantibody with a binding affinity that is comparable or higher than an affinity of a natural autoantigen domain to an autoantibody. In certain instances, KD of an autoantigen domain for an autoantibody is between 0.001 and 1 nM, e.g., 0.001 nM, 0.005 nM, 0.01 nM, 0.05 nM, 0.1 nM, 0.5 nM, or 1 nM or any range there between.

[0272] In some embodiments, a molecule is characterized in its ability to selectively reduce or deplete circulating autoantibodies in a sample or patient.

[0273] In some embodiments, levels of target autoantibodies (e.g., anti-MOG autoantibodies) in a subject or in a biological sample from the subject after administration is reduced relative to a level before administration. In some embodiments, a level of target autoantibodies (e.g., anti-MOG 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 administration of the molecule. In some embodiments, level of target autoantibodies (e.g., anti-MOG autoantibodies) is sustained over time. In somePage 116 of 17813278299v 1Attorney Docket No. 2017420-0065embodiments, 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.

[0274] In some embodiments, a molecule described herein has an increased affinity for FcyRIIB. In some embodiments FcyRIIB is human FcyRIIB. In some embodiments, FcyRIIB is murine FcyRIIB. In some embodiments, an increased affinity for FcyRIIB is provided by mutating one or both of the molecule’s Fc domains, as described herein.

[0275] In some embodiments, a molecule described herein comprises one or more mutations in one of both of the Fc domains that enhances binding kinetics of an immune complex comprising one or more molecules and 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, 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.

[0276] 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 an autoantibody (e. ., an anti -MOG autoantibody), an immune complex is formed that has enhanced binding kinetics with FcyRIIB relative to an immune complex that comprises the autoantibody (e.g., an anti -MOG autoantibody) bound to two corresponding molecules with wild-type Fc domains.

[0277] 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 a molecule to an autoantibody (e.g., an anti -MOG autoantibody), an immune complex is formed that has enhanced binding kinetics with FcyRIIB relative to an immune complex that comprises the autoantibody (e.g., an anti-MOG autoantibody) bound to a corresponding molecule with wild-type Fc domains.Page 117 of 17813278299v 1Attorney Docket No. 2017420-0065

[0278] In some embodiments, binding of one or more molecules described herein, having one or more mutations in the first and / or second Fc domain to increase binding to FcyRIIB, to a target autoantibody (e.g., an anti -MOG autoantibody) forms an immune complex that has enhanced binding kinetics with FcyRIIB relative to an immune complex that comprises the autoantibody (e.g., anti -MOG autoantibody) and one or more corresponding molecules with a wild-type Fc domain. In some embodiments, binding of one or more molecules described herein, having one or more mutations in the first and / or second Fc domain to increase binding to FcyRIIB, to an autoantibody (e.g., an anti-MOG autoantibody) forms an immune complex that has enhanced binding kinetics with FcyRIIB relative to binding kinetics of the autoantibody (e.g., anti-MOG autoantibody) alone with FcyRIIB.

[0279] 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 more mutations that increase half-life (e.g., M428L and N434S according to EU numbering, also referred to herein as an “LS mutation”).

[0280] 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 recognizes that molecules described herein containing one or more mutations that increase halflife and binding to an internalizing receptor may be beneficial for depleting target autoantibodies (e.g., anti-MOG autoantibodies) implicated in an autoimmune disease (e.g., MOGAD). In some embodiments, 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, FcyRIIIA176F, 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.

[0281] In some embodiments, molecules described herein promote clearance of target auto-antibodies (e.g., anti-MOG autoantibodies) in serum when administered to a subject by binding to and forming an immune complex with the target auto-antibodies. In some embodiments, an immune complex promotes faster clearance of target autoantibodies compared Page 118 of 17813278299v 1Attorney Docket No. 2017420-0065to clearance of target autoantibodies in a subject not administered the molecule. In some embodiments, an immune complex comprises one molecule bound to two target autoantibodies (e.g., anti-MOG autoantibodies). In some embodiments, an immune complex comprises one molecule bound to one target autoantibody (e.g., an anti-MOG autoantibody). In some embodiments, an immune complex comprises two molecules bound to one target autoantibody (e.g, an anti-MOG autoantibody).

[0282] In some embodiments, a molecule described herein, having a first and / or second Fc domain including one or more mutations that increase half life and one or more mutations that increase binding relative to FcyRIIB, upon binding to a target autoantibody, forms an immune complex that has enhanced binding kinetics with Fey RUB relative to the same molecule not in an immune complex with the autoantibody (an un-complexed molecule).

[0283] In some embodiments, a molecule described herein, having a first and / or second Fc domain including one or more mutations that increase half life and one or more mutations that increase binding relative to FcyRIIB, upon binding of the molecule to a target autoantibody forms an immune complex that has enhanced binding kinetics with FcyRIIB relative to an immune complex comprising the target auto-antibody and a molecule that does not comprise the one or more mutations that increase half-life.

[0284] In some embodiments, a molecule described herein, having a first and / or second Fc domain including one or more mutations that increase half life and one or more mutations that increase binding relative to FcyRIIB, not present in an immune complex with a target autoantibody (an un-complexed molecule), has decreased binding kinetics with FcyRIIB compared to a molecule that does not comprise the one or more mutations that increase half-life.

[0285] In some embodiments, one or more Fc mutations that increase half-life of a molecule comprise M428L and N434S, according to the EU numbering scheme (i.e., an “LS mutation”). In some embodiments, one or more Fc mutations that increase binding of a molecule to FcyRIIB comprise G237D, P238D, D270E, P271G, and / or A330R, according to the EU numbering scheme.Page 119 of 17813278299v 1Attorney Docket No. 2017420-0065

[0286] 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. In some embodiments, an Fc domain comprises a combination of the following mutations: M428L, N434S, P238D and P271G, according to the EU numbering scheme. In some embodiments, an Fc domain comprises a combination the following mutations: M428L, N434S, P238D, D270E, and P271G, according to the EU numbering scheme. In some embodiments, an Fc domain comprises a combination of the following mutations: M428L, N434S, G237D, P238D, P271G, and A330R, according to the EU numbering scheme. In some embodiments, an Fc domain comprises a combination of the following mutations: M428L, N434S, G237D, P238D, D270E, P271G, and A330R, according to the EU numbering scheme. In some embodiments, an Fc domain comprises a combination of the following mutations:M428L, N434S, E233D, G237D, P238D, H268D, P271G, and A330R, according to the EU numbering scheme. In some embodiments, an Fc domain comprises a combination of the following mutations: M428L, N434S, and P238D, according to the EU numbering scheme.

[0287] In some embodiments, a molecule described herein that is not present in an immune complex has a moderate binding affinity to FcyRIIB (e.g, where the Fc domains of the molecule have slightly increased binding affinity to FcyRIIB compared to a molecule comprising wildtype Fc domains). 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, a molecule described herein exhibits avidity-mediated binding to FcyRIIB when part of an immune complex comprising two molecules bound to an autoantibody (e.g., an anti -MOG autoantibody). In some embodiments, a molecule described herein has increased binding to FcyRIIB when the molecule is present in an immune complex with two molecules bound to an autoantibody (e.g., an anti-MOG autoantibody) compared to the same immune complex with only one molecule bound to the autoantibody (e.g, the anti-MOG autoantibody). In some embodiments, a molecule described herein has increased binding to FcyRIIB when the molecule is present in an immune complex with two molecules bound to an autoantibody (e.g, an anti-MOG autoantibody) compared to the autoantibody (e.g, an anti-MOG autoantibody) alone. Without wishing to be Page 120 of 17813278299v 1Attorney Docket No. 2017420-0065bound by any theory, such avidity-mediated effects allow for selective binding and depletion of immune complexes, z.e., two molecules described herein and one autoantibody (e.g., an anti-MOG autoantibody) and weaker binding to the 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.

[0288] In some embodiments, a molecule described herein having a first and second Fc domain comprises one or more mutations in the first and / or second Fc domain to increase binding to FcyRIIB, and upon binding of a molecule described herein to an anti -MOG 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, FcyRIIAl 67R, FCYRIIIA176F, FCYRIIIA176V, FCYRHIB, and / or FcRn relative to an immune complex that comprises the anti-MOG autoantibody and a corresponding molecule with wild-type Fc domains. In some embodiments, a molecule described herein forms an immune complex with one or more target autoantibodies (e.g., anti-MOG autoantibodies). In some embodiments, a ratio of molecule to target autoantibody present in an immune complex is 1:1. In some embodiments, a ratio of molecule to target autoantibody present in an immune complex is 2:1 (i.e., two target molecules bound to a target autoantibody). In some embodiments, a ratio of molecule to target autoantibody present in an immune complex is 1 :2 (i.e., two target autoantibodies bound to a molecule described herein). In some embodiments, a molecule described herein having a first and second Fc domain comprises one or more mutations in the first and / or second Fc domain to increase binding to FcyRIIB, and upon binding of the molecule to an anti-MOG 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, FcyRIHB, and / or FcRn relative to the anti-MOG autoantibody alone. In some embodiments, a molecule described herein has greater binding affinity to FcyRJIB than to one or more activating Fc receptors comprising Fey Rd, FCYRIIA167H, FCYRIIA167R, FCYRIIIA176F, FCYRIIIA176V, and / or FCYRIIIB.Page 121 of 17813278299v 1Attorney Docket No. 2017420-0065

[0289] In some embodiments, molecules described herein having a first Fc domain and a second Fc domain comprise one or more mutations in the first and / or second Fc domain to increase binding to FcyRIIB, and upon binding of at least one molecule (e.g., one or two molecules) to an anti-MOG 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 an immune complex that comprises the anti-MOG autoantibody and the corresponding one or more molecule with a wild-type Fc domain. In some embodiments, molecules described herein having a first Fc domain and a second Fc domain comprise one or more mutations in the first and / or second Fc domain to increase binding to FcyRIIB, and upon binding of two molecules to an anti-MOG 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 an immune complex that comprises the anti-MOG autoantibody bound to only a single molecule. In some embodiments, upon binding of two molecules to an anti-MOG 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-MOG autoantibody alone.

[0290] 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 a HepG2 cell line) endogenously expressing or overexpressing FcyRI, FcyRIIA167H, FcyRIIA167R, FcyRIIIA176F, FcyRIIIA176V, FcyRIIIB, and / or FcRn measured by flow cytometry.Page 122 of 17813278299v 1Attorney Docket No. 2017420-0065

[0291] Additionally, the present disclosure provides molecules comprising Fc domains that that have increased binding affinity for FcyRIIB and also have decreased or undetectable binding to certain activating Fc receptors. In some embodiments, an activating Fc receptor includes one or more of FcyRI, FcyRIIA167H, FcyRIIA167R, FcyRIIIAl 76F, FcyRIIIA176V, FcyRIIIB, and / or FcRn. In some embodiments, Fc domains of molecules described herein do not have increased binding affinity to FcyRI, FcyRIIA167H, FcyRIIA167R, FcyRIIIA176F, FcyRIIIA176V, FcyRIIIB relative to the corresponding wild-type Fc domain. In some embodiments, Fc domains of molecules described herein have greater binding affinity to FcyRIIB compared to one or more activating Fc receptors (e.g., FcyRI, FcyRIIA167H, FcyRIIA167R, FcyRIIIA176F, FcyRIIIA176V, FcyRIIIB) relative to the corresponding wild-type Fc domain. In some embodiments, Fc domains of molecules described herein preferentially bind to FcyRIIB over one or more activating Fc receptors e.g., FcyRI, FcyRIIA167H, FcyRIIA167R, FcyRIIIA176F, FcyRIIIA176V, and / or FcyRIIIB) relative to the corresponding wild-type Fc domain. In some embodiments, Fc domains of molecules described herein have decreased binding affinity to FcyRI, FcyRIIA167H, FcyRIIA167R, FcyRIIIA176F, FcyRIIIA176V, FcyRIIIB, and / or FcRn relative to the corresponding wild-type Fc domain. In some embodiments, Fc domains of molecules described herein have substantially no binding affinity to FcyRI, FcyRIIA167H, FcyRIIA167R, FcyRIIIA176F, FcyRIIIA176V, FcyRIIIB, and / or FcRn relative to the corresponding wild-type Fc domain. Such binding properties are beneficial in molecules described herein and may lessen risk of toxicity as there is less risk of activating the innate immune response (through activating Fc receptors) in response to the molecules being introduced into the body of a subject.

[0292] In some embodiments, a molecule described herein preferentially binds to immune cells expressing FcyRIIB over immune cells expressing FcyRIIA. In some embodiments, a molecule described herein has substantially no binding affinity for cells that do not express FcyRIIB (e.g., T cells, NK cells, neutrophils, and / or eosinophils). Immune cells known to express FcyRIIB include B cells, monocytes and / or basophils.

[0293] In some embodiments, a molecule described herein prevents binding of autoantibody (e.g, an anti -MOG autoantibody) to its cognate autoantigen (e.g., MOG autoantigen). In somePage 123 of 17813278299v 1Attorney Docket No. 2017420-0065embodiments, a molecule described herein neutralizes an autoantibody (e.g, an anti-MOG autoantibody). In some embodiments, one or more molecules described herein form an immune complex with an autoantibody (e.g, an anti-MOG autoantibody) and the immune complex is internalized and degraded by an immune cell expressing FcyRIIB. In some embodiments, an immune complex comprises one or more molecules (e.g., two or more molecules) bound to an autoantibody (e.g, an anti-MOG autoantibody) and is cleared from circulation, e.g., destroyed, by any one of the mechanisms contemplated in FIG. 6. FcyRIIB is an internalizing receptor that binds to its target, internalizes the complex and shuttles the target to the lysosome for degradation. Without wishing to be bound by any theory, molecules described herein that have increased FcyRIIB binding may deplete target autoantibodies and / or antigen-specific B cells producing autoantibodies through various mechanisms including those shown in FIGs. 6A-D. FIG. 6B shows a potential mechanism of action which includes clearing autoantibodies by targeting FcyRIIB isoform 2 on liver sinusoidal endothelial cells (LSECs). In this exemplary mechanism of action, the binding domain of the molecule (e.g, an antigen domain) binds to target autoantibodies and the Fc domain binds to FcyRIIB isoform 2 on liver sinusoidal endothelial cells. Target autoantibodies are internalized into the liver sinusoidal endothelial cells and targeted to the lysosome for degradation. In another exemplary mechanism as shown in FIG. 6C, molecules described herein may target pathogenic B cells producing target autoantibodies, by targeting FcyRIIB isoform 1 on a B cell that comprises antigen-specific B cell receptor (BCR) (e.g, a target autoantibody expressed on the surface of the B cell), which leads to B cell apoptosis and inhibition. In another exemplary mechanism shown in FIG. 6D, molecules described herein may target FcyRIIB on T cells and prevent T-cell activation.

[0294] In some embodiments, a molecule described herein binds to a target autoantibody (e.g., an anti-MOG autoantibody) expressed by a plasma cell or a B-cell. In some embodiments, a target autoantibody is membrane-bound. In some embodiments, a target autoantibody is expressed on the surface of a B-cell as a B-cell receptor (BCR). In some embodiments, binding of a molecule described herein to a target autoantibody BCR and FcyRIIB on the same B-cell prevents B-cell activation. In some embodiments, binding of a molecule to a target autoantibody BCR and FcyRIIB on the same B-cell promotes B-cell inhibition. Targeting B-cells expressing target autoantibodies provides a further mechanism by which molecules described herein can Page 124 of 17813278299v 1Attorney Docket No. 2017420-0065deplete target autoantibodies by promoting inhibition or preventing activation of B-cells producing the target autoantibodies.

[0295] 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).

[0296] In some embodiments, molecules described herein do not bind to certain components of the complement system (e.g., Clq). In some embodiments, molecules described herein do not bind to Clq. In some embodiments, molecules described herein do not activate the complement system.Methods of Generating Exemplary Molecules

[0297] The present disclosure features methods that include generating a molecule described herein.

[0298] Molecules as described herein may be produced using recombinant methods and compositions (see, e.g., U.S. Pat. No. 4,816,567). In some embodiments, an isolated nucleic acid encoding a molecule as described herein can be provided. Such nucleic acid may encode an amino acid sequence comprising the first and / or second polypeptide. In a further embodiment, one or more vectors comprising such nucleic acid can be provided. A vector can be a nucleic acid molecule capable of propagating another nucleic acid to which it is linked. The term can include the vector as a self-replicating nucleic acid structure as well as the vector incorporated into the genome of a host cell into which it has been introduced. Certain vectors can be capable of directing the expression of nucleic acids to which they are operatively linked.

[0299] In a further embodiment, a host cell comprising such nucleic acid can be provided. Host cells can be cells into which an exogenous nucleic acid has been introduced, including the progeny of such cells. Host cells can include “transformants” and “transformed cells,” which can include the primary transformed cell and progeny derived therefrom without regard to the number of passages. Progeny may not be completely identical in nucleic acid content to a parent cell, but may contain mutations. Mutant progeny that have the same function or biologicalPage 125 of 17813278299v 1Attorney Docket No. 2017420-0065activity as screened or selected for in the originally transformed cell are included herein. In one such embodiment, a host cell can comprise (e.g., has been transformed with) a vector comprising a nucleic acid that encodes an amino acid sequence comprising a first polypeptide and a second polypeptide of a molecule. In some embodiments, a first vector comprises a nucleic acid that encodes an amino acid sequence comprising a first polypeptide of a molecule and a second vector comprising a nucleic acid that encodes an amino acid sequence comprising the second polypeptide of a molecule. In some embodiments, the host cell can be eukaryotic, e.g., a Chinese Hamster Ovary (CHO) cell, a lymphoid cell (e.g., YO, NSO, Sp20 cell), or a Human Embryonic Kidney (HEK293) cell. In some embodiments, a method of making molecule and / or an antigenbinding domain described herein can be provided, wherein the method can comprise culturing a host cell comprising a nucleic acid encoding the molecule and / or an antigen-binding domain, as provided above, under conditions suitable for expression of the molecule and / or an antigenbinding domain, and optionally recovering the molecule from the host cell or host cell culture medium.

[0300] For recombinant production of a molecule and / or an antigen-binding domain, an isolated nucleic acid encoding a molecule and / or an antigen-binding domain, e.g., as described above, can be inserted into one or more vectors for further cloning and / or expression in a host cell. Such nucleic acid may be readily isolated and sequenced using conventional procedures.

[0301] Suitable host cells for cloning or expression of antibody-encoding vectors can include prokaryotic or eukaryotic cells described herein. For example, molecules and / or an antigenbinding domains may be produced in bacteria, e.g., when glycosylation and Fc effector function are not needed (see, e.g., U.S. Pat. Nos. 5,648,237, 5,789,199, and 5,840,523; Charlton, Methods in Molecular Biology 248:245-254 (2003)). After expression, the molecule and / or an antigenbinding domain may be isolated from the bacterial cell paste in a soluble fraction and can be further purified.

[0302] In addition to prokaryotes, eukaryotic microbes such as filamentous fungi or yeast can be suitable cloning or expression hosts for molecule and / or an antigen-binding domainencoding vectors (see, e.g., Gemgross Nat. Biotech. 22: 1409-1414 (2004) and Li et al. Nat. Biotech. 24:210-215(2006)). Suitable host cells for the expression of glycosylated antibody can Page 126 of 17813278299v 1Attorney Docket No. 2017420-0065also be derived from multicellular organisms, including invertebrates and vertebrates. Examples of invertebrates can include plant and insect cells (see, e.g., U.S. Pat. Nos. 5,959,177, 6,040,498, 6,420,548, 7,125,978, and 6,417,429). Examples of vertebrate cells can include mammalian cell lines, monkey kidney CV1 line transformed by SV40 (COS-7); human embryonic kidney line (293 or 293T cells as described, e.g., in Graham et al. J. Gen Virol. 36:59-74 (1977)); baby hamster kidney cells (BHK); mouse sertoli cells (TM4 cells); monkey kidney cells (CV1);African green monkey kidney cells (VERO-76); human cervical carcinoma cells (HELA); canine kidney cells (MDCK; buffalo rat liver cells (BRL 3 A); human lung cells (W138); human liver cells (Hep G2); mouse mammary tumor (MMT 060562); TRI cells; MRC 5 cells; FS4 cells; Chinese hamster ovary (CHO) cells, including DHFR- CHO cells; and myeloma cell lines such as Y0, NS0 and Sp2 / 0. (see, e.g., Yazaki and Wu, Methods in Molecular Biology 248:255-268 (2003)).

[0303] Molecules described herein may be purified by any technique. For example, not wishing to be bound by theory, molecules described herein can be recovered and purified from recombinant cell cultures by well-known methods including, but not limited to, protein A purification, protein G purification, ammonium sulfate or ethanol precipitation, acid extraction, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography and lectin chromatography. High performance liquid chromatography (“HPLC”) can also be employed for purification. See, e.g., Colligan, Current Protocols in Immunology, or Current Protocols in Protein Science, John Wiley & Sons, NY, N.Y, (1997-2001), e.g., chapters 1, 4, 6, 8, 9, and 10, each entirely incorporated herein by reference.

[0304] As discussed herein, some or all of the components of a molecule may also be linked using “click” or other chemistry, optionally via an amino acid or synthetic linker. For such molecules some or all of the components of the molecule may be prepared recombinantly and then chemically modified for conjugation. Suitable methods are well known in the art, e.g., as used in the preparation of antibody-drug conjugates.

[0305] Purified molecules and antigen-binding domains included in such can be characterized by, for example, ELISA, ELISPOT, flow cytometry, immunocytology, BIACORE Page 127 of 17813278299v 1Attorney Docket No. 2017420-0065analysis, Octet BLI analysis, KINEXA kinetic exclusion assay, SDS-PAGE and Western blot, or by HPLC analysis as well as by a number of other functional assays disclosed herein. The contents of all cited references (including literature references, issued patents, published patent applications, and co-pending patent applications) cited throughout this application are hereby expressly incorporated by reference.Applications

[0306] The present disclosure provides technologies for selective depletion of autoantibodies implicated in autoimmune disease such as MOGAD (e.g., ADEM, optic neuritis including chronic relapsing inflammatory optic neuropathy, transverse myelitis, and brain or brainstem syndrome compatible with demyelination).

[0307] In some embodiments, a molecule can be administered in a pharmaceutical composition can be used in combination with, by administering before, concurrently or after administration of a second therapy.

[0308] In some embodiments, molecules of the present disclosure are used to treat a subject suffering from an autoimmune disease (an autoimmune disease caused by anti-MOG autoantibodies) that would benefit from the selective neutralization and / or depletion of autoantibodies. Such molecules are generated such that they bind to an internalizing receptor and include an autoantibody-binding domain that binds to autoantibodies. Molecules may also include a modification to enhance binding to internalizing receptors (e.g., FcyRIIB).

[0309] For use in therapeutic methods, molecules of the present disclosure would be formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disease or disorder being treated, the particular subject being treated, the clinical condition of the individual subject, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.

[0310] In some embodiments, the present disclosure provides a method for treating a disease. In some embodiments, the method comprises administering to a subject having such disease aPage 128 of 17813278299v 1Attorney Docket No. 2017420-0065therapeutically effective amount of a molecule described herein. In some embodiments, a composition is administered to said subject, comprising a molecule described herein in a pharmaceutically acceptable form. In some embodiments, the disease to be treated is an autoimmune disease. In some embodiments, the autoimmune disease is caused by anti-MOG antibodies. In some embodiments, the autoimmune disease is MOGAD (e.g., ADEM, optic neuritis including chronic relapsing inflammatory optic neuropathy, transverse myelitis, and brain or brainstem syndrome compatible with demyelination). In some embodiments the method further comprises administering to the subject a therapeutically effective amount of at least one additional therapeutic agent. A “subject” may be a mammal, including a human.

[0311] Any of such methods can optionally comprise administering an effective amount of at least one composition or pharmaceutical composition comprising at least one molecule described herein to a subject in need of such modulation, treatment, diagnosis, and / or therapy (e.g., a subject suffering from an autoimmune disease such as MOGAD, e.g., ADEM, optic neuritis including chronic relapsing inflammatory optic neuropathy, transverse myelitis, and brain or brainstem syndrome compatible with demyelination).

[0312] In some embodiments, provided methods include therapeutic methods that comprise administering an effective amount of a composition that comprises and / or delivers a molecule described herein to a subject such that the molecule binds an autoantibody and an internalizing receptor, such that the complex is internalized and targeted to the lysosome. In some embodiments an autoantibody is an anti-MOG autoantibody and the internalizing receptor is Fey RUB

[0313] In some embodiments, provided methods include therapeutic methods that comprise administering an effective amount of a composition that comprises and / or delivers a molecule described herein to a subject such that the molecule binds a target autoantibody (e.g., anti-MOG autoantibody) and an internalizing receptor (e.g., FcyRIIB) on a cell, such that the complex is internalized and targeted to the lysosome. In some embodiments, a target autoantibody is expressed on the surface of a B-cell as a BCR and the molecule binds to the BCR and FcyRIIB on the B-cell. In some embodiments, an effective amount of a composition comprises an effective amount of molecules described herein, wherein upon binding of one or more molecules Page 129 of 17813278299v 1Attorney Docket No. 2017420-0065to the target autoantibody (e.g., anti -MOG autoantibody), an immune complex is formed that has enhanced binding kinetics with FcyRIIB relative to an immune complex that comprises the target antibody bound to the one or more corresponding molecules with wild-type Fc domains. Such activity mediates clearance of immune complexes comprising the target antibody when bound to the molecule. In some embodiments, a molecule described herein may also include an antigenbinding domain (see FIG.3). 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 B cells on which the auto-antibody is expressed (e.g., as described in Chu et al., Mol Immunol 45, 3926-3933 (2008), which is herein incorporated by reference in its entirety).

[0314] Therapeutic methods described herein can optionally further comprise coadministration or combination therapy for treating such diseases, wherein the administering a composition comprises a molecule described herein, further comprises administering, before concurrently, and / or after, at least one additional therapeutic agent.

[0315] The present disclosure also provides methods of treating a subject suffering from or susceptible to an autoimmune disease (e.g., MOGAD, e.g., ADEM, optic neuritis including chronic relapsing inflammatory optic neuropathy, transverse myelitis, and brain or brainstem syndrome compatible with demyelination, or another autoimmune disease involving anti-MOG antibodies), for example, by administering to the subject a pharmaceutical composition comprising a molecule described herein, a nucleic acid molecule encoding the molecule. In some embodiments, such a treatment decreases or ameliorates one or more signs or symptoms of an autoimmune disease. For example, in a subject with MOGAD, e.g., ADEM, optic neuritis including chronic relapsing inflammatory optic neuropathy, transverse myelitis, and brain or brainstem syndrome compatible with demyelination, treatment with a pharmaceutical composition comprising a molecule described herein may decrease or ameliorate one or more signs or symptoms of MOGAD such as blurred vision or loss of vision, double vision, eye pain, color blindness, muscle stiffness, muscle weakness, paralysis of the arms and legs, trouble walking, loss of sensations, numbness and tingling in the arms, legs, neck, back, or abdomen,Page 130 of 17813278299v 1Attorney Docket No. 2017420-0065low of bowel or bladder control, brain fog such as confusion, seizures, headache, behavioral changes, loss of balance and coordination, cognitive impairment, among others.

[0316] In some embodiments, treatment with a molecule described herein reduces the levels of target autoantibodies (e.g., anti -MOG autoantibodies) in a subject or in a biological sample relative to a level before administration. In some embodiments, a level of target autoantibodies (e.g., anti-MOG 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 administration. In some embodiments, treatment with a molecule described herein reduces target autoantibodies (e.g., anti-MOG autoantibodies) in a subject for a sustained period of time, e.g., 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.Pharmaceutical Compositions

[0317] In some embodiments, a molecule described herein may be formulated as a pharmaceutical composition and administered to a subject (e.g., to treat an autoimmune disease). In various embodiments, molecules described herein can be incorporated into pharmaceutical compositions. Such a pharmaceutical composition can be useful, e.g., for the prevention and / or treatment of diseases, e.g., autoimmune diseases. Pharmaceutical compositions can be formulated by methods known to those skilled in the art (such as described in Remington’s Pharmaceutical Sciences, 17th edition, ed. Alfonso R. Gennaro, Mack Publishing Company, Easton, Pa. (1985)).

[0318] In some embodiments, a pharmaceutical composition comprises a nucleic acid molecule comprising a nucleotide sequence encoding a molecule described herein and a pharmaceutically acceptable carrier. In some embodiments, a molecule is expressed in a host cell containing a nucleic acid molecule comprising a nucleotide sequence encoding a molecule described herein. In some embodiments, a molecule described herein is encoded by a vector (e.g., a viral vector such as a retroviral vector, a lentiviral vector, an adeno-associated viral (AAV) vector, or an adenoviral vector).Page 131 of 17813278299v 1Attorney Docket No. 2017420-0065

[0319] In some embodiments, a pharmaceutical composition comprises a first molecule described herein or a nucleic acid molecule encoding the molecule, and also comprises a therapeutic agent or a nucleic acid molecule encoding a second therapeutic agent that selectively depletes pathogenic plasma cells that produce the autoantibodies; and a pharmaceutically acceptable carrier.

[0320] In some embodiments, a pharmaceutical composition can be formulated to include a pharmaceutically acceptable carrier or excipient. Examples of pharmaceutically acceptable carriers include, without limitation, any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. Compositions of the present disclosure can include a pharmaceutically acceptable salt, e.g, an acid addition salt or a base addition salt.

[0321] In some embodiments, a composition including a molecule as described herein, c.g, a sterile formulation for injection, can be formulated in accordance with conventional pharmaceutical practices using distilled water for injection as a vehicle. For example, physiological saline or an isotonic solution containing glucose and other supplements such as D-sorbitol, D-mannose, D-mannitol, and sodium chloride may be used as an aqueous solution for injection, optionally in combination with a suitable solubilizing agent, such as, for example, an alcohol such as ethanol and / or a polyalcohol such as propylene glycol or polyethylene glycol, and / or a nonionic surfactant such as polysorbate 80 or HCO-50.

[0322] As disclosed herein, a pharmaceutical composition may be in any form known in the art. Such forms include, e.g., liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g, injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories.

[0323] Selection or use of any particular form may depend, in part, on the intended mode of administration and therapeutic application. For example, compositions containing a composition intended for systemic or local delivery can be in the form of injectable or infusible solutions. Accordingly, compositions can be formulated for administration by a parenteral mode (e.g, intravenous, subcutaneous, intraperitoneal, or intramuscular injection). As used herein,Page 132 of 17813278299v 1Attorney Docket No. 2017420-0065parenteral administration refers to modes of administration other than enteral and topical administration, usually by injection, and include, without limitation, intravenous, intranasal, intraocular, pulmonary, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intrapulmonary, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, intracerebral, intracranial, intracarotid and intrasternal injection and infusion.

[0324] Route of administration can be parenteral, for example, administration by injection, transnasal administration, transpulmonary administration, or transcutaneous administration. Administration can be systemic or local by intravenous injection, intramuscular injection, intraperitoneal injection, or subcutaneous injection.

[0325] In some embodiments, a pharmaceutical composition of the present disclosure can be formulated as a solution, microemulsion, dispersion, liposome, or other ordered structure suitable for stable storage at high concentration. Sterile injectable solutions can be prepared by incorporating a composition described herein in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filter sterilization. Generally, dispersions are prepared by incorporating a composition described herein into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods for preparation include vacuum drying and freeze-drying that yield a powder of a composition described herein plus any additional desired ingredient (see below) from a previously sterile-filtered solution thereof. The proper fluidity of a solution can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prolonged absorption of injectable compositions can be brought about by including in the composition a reagent that delays absorption, for example, monostearate salts, and gelatin.

[0326] In some embodiments, a composition described herein can be therapeutically delivered to a subject by way of local administration. As used herein, “local administration” or “local delivery,” can refer to delivery that does not rely upon transport of the composition or agent to its intended target tissue or site via the vascular system. For example, the composition Page 133 of 17813278299v 1Attorney Docket No. 2017420-0065may be delivered by injection or implantation of the composition or agent or by injection or implantation of a device containing the composition or agent. In some embodiments, following local administration in the vicinity of a target tissue or site, the composition or agent, or one or more components thereof, may diffuse to an intended target tissue or site that is not the site of administration.

[0327] In some embodiments, compositions can be formulated with a carrier that will protect the compound against rapid release, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for the preparation of such formulations are known in the art. See, e.g., J. R. Robinson (1978) “Sustained and Controlled Release Drug Delivery Systems,” Marcel Dekker, Inc., New York.

[0328] In some embodiments, administration of a molecule as described herein is achieved by administering to a subject a nucleic acid encoding the molecule. In some embodiments, a nucleic acid is an RNA (e.g, an mRNA). In some embodiments an RNA encoding a molecule described herein is associated with a delivery agent, i.e., a substance or entity that is non-covalently or covalently associated with a molecule or is co-administered with a molecule and serves one or more functions that increase the stability and / or efficacy of the biologically active agent beyond that which would result if the biologically active agent was delivered (e.g., administered to a subject) in the absence of the delivery agent. For example, a delivery agent may protect an RNA from degradation (e.g., in blood), may facilitate entry of an RNA into cells or into a cellular compartment of interest (e.g, the cytoplasm), and / or may enhance associations with particular cells containing the molecular target to be modulated. Those of ordinary skill in the art are aware of numerous delivery agents that may be used to deliver inhibitory RNA, e.g., mRNAs. See Kanasty, R., et al. Nat Mater. 12(11):967-77 (2013). In some embodiments, e.g., for administering an RNA systemically, the RNA may be associated with a delivery agent such as a nanoparticle, a dendrimer, a polymer, liposomes, or a cationic delivery system. Without wishing to be bound by any theory, positively charged cationic delivery systems are believed to facilitate binding of a negatively charged RNA and also enhance interactions at the negativelyPage 134 of 17813278299v 1Attorney Docket No. 2017420-0065charged cell membrane to permit efficient uptake of an RNA by the cell. Lipids (e.g, cationic lipids, or neutral lipids), dendrimers, or polymers may be bound to an inhibitory RNA or may form a vesicle or micelle that encapsulates an inhibitory RNA. Methods for making and administering complexes comprising a cationic agent and an RNA are known in the art. In some embodiments it is particularly contemplated to use any of the delivery agents described in US Pub. 2016 / 0298124. In some embodiments an RNA encoding a molecule described herein is administered in association with a lipid or lipid-containing particle. In some embodiments an RNA is administered in association with a cationic polymer (which may be a polypeptide or a non-polypeptide polymer), a lipid, a peptide, PEG, cyclodextrin, or combination thereof, which may be in the form of a nanoparticle or microparticle. The lipid or peptide may be cationic. A nanoparticle may have a targeting moiety and / or cell-penetrating moiety or membrane active moiety covalently or noncovalently attached thereto. Nanoparticles, such as lipid nanoparticles, are described in, e.g., Tatiparti et al., Nanomaterials 7:77 (2017).

[0329] Nucleic acids encoding a molecule described herein can be incorporated into a gene construct to be used as a part of a gene therapy protocol to deliver nucleic acids that can be used to express and produce a molecule within cells. Expression constructs of such components may be administered in any therapeutically effective carrier, e.g. any formulation or composition capable of effectively delivering the component gene to cells in vivo. Approaches include insertion of the subject gene in viral vectors including recombinant retroviruses, adenovirus, adeno-associated virus, lentivirus, and herpes simplex virus- 1 (HSV-1), or recombinant bacterial or eukaryotic plasmids. Viral vectors can transfect cells directly; plasmid DNA can be delivered with the help of, for example, cationic liposomes (lipofectin) or derivatized, polylysine conjugates, gramicidin S, artificial viral envelopes or other such intracellular carriers, as well as direct injection of the gene construct or CaPCL precipitation (see, e.g., WO 2004 / 060407).Examples of suitable retroviruses include pLJ, pZIP, pWE and pEM which are known to those skilled in the art (see, e.g., Eglitis et al., Science 230:1395-1398 (1985); Danos and Mulligan Proc. Natl. Acad. Sci. USA 85:6460-6464 (1988); Wilson et al., Proc. Natl. Acad. Sci. USA 85:3014-3018 (1988); Armentano et al., Proc. Natl. Acad. Sci. USA 87:6141-6145 (1990); Huber et al., Proc. Natl. Acad. Sci. USA 88:8039-8043 (1991); Ferry et al., Proc. Natl. Acad. Sci. USA 88:8377-8381 (1991); Chowdhury et al. Science 254:1802-1805 (1991); van Beusechem et al.,Page 135 of 17813278299v 1Attorney Docket No. 2017420-0065Proc. Natl. Acad. Sci. USA 89:7640-7644 (1992); Kay et al., Human Gene Therapy 3:641-647 (1992); Dai et al., Proc. Natl. Acad. Sci. USA 89:10892-10895 (1992); Hwu et al., J Immunol 150:4104-4115 (1993); U.S. Pat. Nos. 4,868,116 and 4,980,286; and PCT Publication Nos. WO 1989 / 07136, WO 1989 / 02468, WO 1989 / 05345, and WO 1992 / 07573). Another viral gene delivery system utilizes adenovirus-derived vectors (see, e.g., Berkner et al., BioTechniques 6:616 (1988); Rosenfeld et al., Science 252:431-434 (1991); and Rosenfeld et al., Ce / / 68:143-155 (1992)). Suitable adenoviral vectors derived from the adenovirus strain Ad type 5 dl324 or other strains of adenovirus (e.g., Ad2, Ad3, Ad7, etc.) are known to those skilled in the art. Yet another viral vector system useful for delivery of the subject gene is the adeno-associated virus (AAV). See, e.g., Flotte et al., Am J Respir Cell Mol Biol 7:349-356 (1992); Samulski et al., J Virol 63:3822-3828 (1989); and McLaughlin et al., J Virol 62:1963-1973 (1989).

[0330] A pharmaceutical solution can include a therapeutically effective amount of a composition described herein. Such effective amounts can be readily determined by one of ordinary skill in the art based, in part, on the effect of the administered composition, or the combinatorial effect of the composition and one or more additional agents, if more than one agent is used. A therapeutically effective amount of a composition described herein can also vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the composition (and one or more additional agents) to elicit a desired response in the individual, e.g., amelioration of at least one condition parameter, e.g., amelioration of at least one symptom of an autoimmune disease. For example, a therapeutically effective amount of a composition described herein can inhibit (lessen the severity of or eliminate the occurrence of) and / or prevent a particular disorder, and / or any one of the symptoms of the particular disorder known in the art or described herein. A therapeutically effective amount is also one in which any toxic or detrimental effects of the composition are outweighed by the therapeutically beneficial effects.

[0331] Suitable human doses of any of the compositions described herein can further be evaluated in, e.g., Phase I dose escalation studies. See, e.g., van Gurp et al., Am J Transplantation 8(8): 1711 - 1718 (2008); Hanouska et al., Clin Cancer Res 13(2, part l):523-531Page 136 of 17813278299v 1Attorney Docket No. 2017420-0065n),' and Hetherington et al., Antimicrobial Agents and Chemotherapy 50(10): 3499-3500 (2006).

[0332] Toxicity and therapeutic efficacy of compositions can be determined by known pharmaceutical procedures in cell cultures or experimental animals (e.g., animal models of any of the cancers described herein). These procedures can be used, e. , for determining the LD?o (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50 / ED50. A composition described herein that exhibits a high therapeutic index is preferred. While compositions that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue and to minimize potential damage to normal cells and, thereby, reduce side effects.

[0333] Those of skill in the art will appreciate that data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. Appropriate dosages of compositions described herein lie generally within a range of circulating concentrations of the compositions that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For a composition described herein, the therapeutically effective dose can be estimated initially from cell culture assays. A dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (z.e., the concentration of the antibody which achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma may be measured, for example, by high performance liquid chromatography. In some embodiments, e.g., where local administration (e.g., to the eye or a joint) is desired, cell culture or animal modeling can be used to determine a dose required to achieve a therapeutically effective concentration within the local site.

[0334] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. Unless otherwise defined, all technical and Page 137 of 17813278299v 1Attorney Docket No. 2017420-0065scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Although methods and materials similar or equivalent to those described herein can be used, suitable methods and materials are described herein.

[0335] The disclosure is further illustrated by the following examples. The examples are provided for illustrative purposes only. They are not to be construed as limiting the scope or content of the disclosure in any way.Additional Embodiments

[0336] In some embodiments, molecules described herein comprise: a first polypeptide comprising a first Fc domain and an autoantibody -binding domain (e.g., an autoantigen domain, or fragment or variant thereof) that binds to 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; and wherein the first and / or second Fc domain comprises one or more mutated amino acid residues that increases binding to FcyRIIB. Molecules described herein comprising increased binding to FcyRIIB target and bind to particular autoantibodies that implicate various autoimmune diseases through the autoantigenbinding domain (e.g., an autoantigen domain, or fragment or variant thereof), and are shuttled to the lysosome of a cell for degradation through FcyRIIB

[0337] Combining increased binding to the endocytic receptor FcyRIIB and also including a particular autoantigen (or fragment or variant thereof) allows for selective depletion of autoantibodies that target the autoantigen. One of skill in the art will appreciate that such molecules may be used to treat a variety of autoimmune diseases that are implicated by particular autoantibodies.

[0338] In some embodiments, a molecule described herein may be used to treat an autoimmune disease implicated by autoantibodies targeting MOG. Anti-MOG autoantibodies in a subject can lead to development of autoimmune diseases such as MOGAD, e.g., CNS inflammatory disorders, e.g., ADEM, optic neuritis, transverse myelitis, cortical encephalitis, cerebral lesions, and brainstem or cerebellar syndromes. In some embodiments, molecules described herein may be used in the treatment of MOGAD or other autoimmune diseases caused Page 138 of 17813278299v 1Attorney Docket No. 2017420-0065by anti-MOG autoantibodies. In some embodiments, a molecule described herein used to treat an autoimmune disease (e.g., MOGAD) comprises a MOG autoantigen domain (or a fragment or variant thereof) that targets anti-MOG autoantibodies and an Fc domain that comprises one or more modifications that increase its binding to FcyRIIB, as described herein.

[0339] Other autoantibodies that are involved in the development of particular autoimmune diseases are known in the art, and molecules described herein may include all or a portion of the particular autoantigen domains that are targeted by these autoantibodies in order to selectively target and deplete these autoantibodies.EXAMPLESExample 1: Generation and Testing of Exemplary Molecules

[0340] The present example demonstrates generation and testing of exemplary molecules described herein that target and selectively deplete circulating autoantibodies. In this Example, the targeted autoantibodies are anti-MOG autoantibodies, which implicate various diseases like MOGAD, e.g., CNS inflammatory disorders, e.g., acute disseminated encephalomyelitis (ADEM), optic neuritis, transverse myelitis, cortical encephalitis, cerebral lesions, and brainstem or cerebellar syndromes).Generation of Exemplary Molecules

[0341] Autoantibody Binding Domain: Exemplary molecules in this example were designed to include an autoantigen domain as the autoantibody-binding domain. Specifically, human MOG was selected as the autoantigen. Fragments and mutations in the human wild-type MOG sequence were tested for their ability to selectively target and bind to anti-MOG autoantibodies.

[0342] Several fragments of wildtype MOG (as shown in SEQ ID NO: 1) were used as a starting point. The MOG autoantigen fragments include fragments that corresponded to amino acid residues G30-P147, G40-G154, and G30-V144 of the full-length wildtype MOG sequence (SEQ ID NO: 1). Additionally, the MOG autoantigen fragments were modified to include the mutation N60Q. The exemplary MOG autoantigen fragments used in the present example are shown in Table 1, corresponding to SEQ ID NOs: 9-11.Page 139 of 17813278299v 1Attorney Docket No. 2017420-0065

[0343] Fc Domain: Exemplary molecules in this example were designed to include Fc domains comprising particular mutations and modifications.

[0344] Human IgGl Fc domains were chosen to be included in the molecules generated and tested in this example. 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.

[0345] In some molecules, Fc mutations were introduced to increase binding of the Fc domains to human FcyRIIB. Such mutations include G237D, P238D, P271G, and / or A330R according to EU numbering. Such mutations allow for binding to FcyRIlB at neutral pH.Without wishing to be bound by any theory, upon binding, the molecule / autoantibody complex may be internalized into the cell and targeted to the lysosome for degradation. Such a mechanism destroys autoantibodies, while preserving free molecules in circulation.

[0346] In this example, Fc mutations were also introduced in certain molecules 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. Such mutations are known as knobs-in-holes (KIH) modifications. The specific mutations used in this Example include: T366W and S354C mutation (first Fc domain) and T366S, L368A, Y407V, and Y349C (second Fc domain). One of skill in the art will understand that the present disclosure encompasses molecules where the T366W and S354C mutations are included on second Fc domain (instead of the first Fc domain) and the T366S, L368A, Y407V, and Y349C mutations are included on the first Fc domain (instead of the second Fc domain). One of skill in the art will also 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 in this Example and as described in the disclosure.

[0347] Exemplary Fc domain sequences used in the molecules made and tested in this Example are shown below in Table 6.Page 140 of 17813278299v 1Attorney Docket No. 2017420-0065Table 6: Exemplary Fc Domain SequencesPage 141 of 17813278299v 1Attorney Docket No. 2017420-0065

[0348] The first and second polypeptides with the modifications described above were used to generate exemplary molecules as described below in Table 7 based on the exemplary molecule formats shown in FIG. 2 (Variants A5, A7, A8, and A9) and FIG. 5B (Variants Al, A2, A3, A4, A6, A10, All, and A12). Various signal peptides were included in the exemplary molecules including a human MOG native signal peptide (SEQ ID NO: 12) or a non-native IgH signal peptide (SEQ ID NO: 96).

[0349] FIGs. 7A-7D and FIGs. 8A-8B show exemplary molecule formats generated in the present example. FIGs. 7A-7D show exemplary molecule formats described herein. FIG. 7A shows an exemplary bivalent molecule (“Variant Al”) that includes a homodimer of a first and second polypeptide that each include a native signal peptide, a MOG G30-P147 antigen fragment, a G4S linker, and an Fc domain. FIG. 7B shows an exemplary bivalent molecule (“Variant A2”) that includes a homodimer of a first and second polypeptide that each include a native signal peptide, a MOG G30-G154 antigen fragment, and an Fc domain. FIG. 7C shows an exemplary bivalent molecule (“Variant A3”) that includes a homodimer of a first and second polypeptide that each include an IgH signal peptide, a MOG G30-P147 antigen fragment, a G4S linker, and an Fc domain. FIG. 7D shows an exemplary bivalent molecule (“ Variant A4”) that includes a homodimer of a first and second polypeptide that each include an IgH signal peptide, a MOG G30-G154 antigen fragment, and an Fc domain.

[0350] FIGs. 8A-8B show exemplary molecule formats described herein. FIG. 8A shows an exemplary monovalent molecule (“Variant A5”) that includes first polypeptide that includes a native signal peptide, a MOG G30-V144 antigen fragment, and an Fc domain and a second polypeptide that includes an Fc domain. FIG. 8B shows an exemplary bivalent molecule (“Variant A6”) that includes a homodimer of a first and second polypeptide that each include a native signal peptide, a MOG G30-V144 antigen fragment and an Fc domain.Page 142 of 17813278299v 1Attorney Docket No. 2017420-0065

[0351] Exemplary molecule configurations of Variants Al -A6 produced in this example are shown below in Table 7.Table 7: Exemplary MOG Antibody Depletion Combinations

[0352] These sequences were encoded by expression plasmids e.g., pTT5, pcDNA) then transfected into a suitable host cell (e.g., CHO, HEK293) and expressed using standard transfection techniques. After expression for 5-14 days or if cell viability dropped, cells were harvested. Conditioned media was then purified using standard chromatography techniques such as protein A affinity, ion exchange chromatography, and size exclusion chromatography to generate molecules with greater than 95% purity (as assessed by HPLC). Molecules were then buffer exchanged to a suitable formulation buffer and stored at 4C or -80C prior to use.

[0353] Results including titer and yield after a single Protein A purification step are shown below in Table 8. These results showed that all constructs were expressed. Additionally, resultsPage 143 of 17813278299v 1Attorney Docket No. 2017420-0065from SEC are shown below in Table 8 and in FIGs. 9A-9D and FTGs. 10A-10B, for Variants Al-A4 and Variants A5-A6, respectively. SEC results showed 99% purity after the single Protein A purification step.Table 8: Purity and yield of exemplary MOG variants fused to Fc domain

[0354] Purified proteins from the above experiment were analyzed for correct size, expression and assembly. FIGs. 11A-11F show images of gels after protein electrophoresis technique using sodium dodecyl sulfate (SDS) polyacrylamide gel electrophoresis (PAGE) where samples containing protein expressed from constructs comprising Variant Al (FIG. HA), Variant A2 (FIG. HB), Variant A3 (FIG. 11C), Variant A4 (FIG. 11D), Variant A5 (FIG. HE), and Variant A6 (FIG. HF), were heated to 95°C in a sample buffer without a reducing agent like beta-mercaptoethanol or dithiothreitol. The images show that the molecules were correctly expressed.Example 2; Testing and Characterization of Exemplary Molecules.

[0355] The present example demonstrates that the molecules generated in Example 1 are able to bind anti-MOG autoantibodies in vitro.

[0356] The exemplary anti-MOG autoantibody used in the present example was “8-18C5” which is known binds to three loops located at the membrane-distal side of MOG (see BreithauptPage 144 of 17813278299v 1Attorney Docket No. 2017420-0065et al., Structural insights into the antigenicity of myelin oligodendrocyte glycoprotein, 100(16): 9446-9451 (2003)).ELISA

[0357] The present examples utilized an ELISA to measure binding affinity of each variant (Variant A1-A6) to a mouse-derived demyelinating anti-MOG antibody 8-18C5. Briefly, exemplary molecules were tested for binding to 8-18C5 by ELISA where Variant A1-A6 were coated on a plate at 12.05 nM overnight at 4 °C. After blocking and subsequent wash steps, serial dilutions of 8-18C5 (top concentration of 2 pg / mL, 8-point, 3 fold serial dilution) were added to the ELISA plate for 1 hour at room temperature. The plate was washed and an anti-human-kappa-HRP antibody at 1:5,000 dilution was added and incubated for an additional 1 hour. Development of the ELISA plate was carried out by addition of TMB. Color development was then stopped with addition of H2S04. Plate absorbance was read at 450 nm using a plate ready.

[0358] FIG. 12 and Table 9 below show results from an ELISA measuring the binding of Variants A1-A6 to anti-MOG antibody (8-18C5). Results show that all constructs bind the anti-MOG autoantibodies with comparable EC50s.Table 9: ELISA ResultsSPR

[0359] Binding assays using SPR were performed to determine the binding affinity of the exemplary molecules to anti-MOG antibody 8-18C5. Anti-Fab antibodies were immobilized on a CM5 SPR chip allowing the capture of 8-18C5. Increasing concentrations of molecules werePage 145 of 17813278299v 1Attorney Docket No. 2017420-0065subsequently injected over the captured 8-18C5 and a single dissociation performed using single cycle kinetics. The data was then analyzed using 1 : 1 binding analysis.

[0360] FIGs. 13A-13F and Table 10 below show results from SPR binding assay measuring binding of Variants Al (FIG. 13A), Variant A2 (FIG. 13B), Variant A3 (FIG. 13C), Variant A4(FIG. 13D), Variant A5 (FIG. 13E), Variant A6 (FIG. 13F) to 8-18C5, when 8-18C5 anti-MOG autoantibodies were captured by immobilized anti -Fab antibodies on an SPR sensor chip and the exemplary molecules were used as the analyte. Results indicate that the exemplary molecules all showed binding affinity to 8-18C5 antibodies. Each variant showed similar binding affinity to 8- 18C5 (KD), with the exception of Variant A5, which showed slightly lower affinity (see Table10).Table 10: His-Tagged 8-18C5 captured onto SPR sensor chip and molecule used as analytePage 146 of 17813278299v 1Attorney Docket No. 2017420-0065Autoantibody-Molecule Complex Recycling Assay

[0361] Anti -MOG monoclonal antibody (e.g., 8-18C5) is labelled with a fluorescent tag (i.e., PE). A complex is then formed by co-incubating the molecule comprising modifications that enhance FcyRIIB binding as described above with labelled anti -MOG monoclonal autoantibody for 15 minutes at room temperature at either a 1 : 1 or 4: 1 ratio (molecule:anti-MOG antibody). Cells expressing FcyRIIB are seeded in a 96-well plate and stained with Live / Dead Violet Fixable Dye. Next, the pre-complexed molecule and autoantibody are incubated with the cells at various concentrations at either 4C (to assess binding) or 37C (to assess uptake). After incubation, cells are washed with PBS (binding) or acidic media to remove surface-bound complexes (uptake). Cellular fluorescence is determined by flow cytometry.In vitro SEC-based Assessment of Immune Complexes

[0362] To assess the size of the immune complexes formed upon anti-MOG autoantibody binding to molecule, molecule is incubated with MOGAD patient serum containing anti-MOG autoantibodies, or with anti-MOG monoclonal autoantibodies as positive control. Analysis of the size of the immune complexes formed between molecule and autoantibodies present in patient serum is estimated using SEC-based method similar as described in Boysen et al., Journal of Immunology Research 2: 1-9 (2016), which is herein incorporated by reference.Example 3; Testing and Characterization of Exemplary MoleculesIdentification of Fc mutations that confer specific binding to FcyRIIB

[0363] Exemplary molecules described above are tested for their ability to selectively bind to FcyRIIB through their Fc domains. Additionally, in some instances, exemplary molecules were tested for their ability to have to have no binding affinity, or decreased binding affinity, or only slightly increased binding affinity (e.g., within a 2-fold increase) for other Fc receptors FcyRIIA167H and FcyRIIA167R.

[0364] FcyRIIB isoform 2 is an endocytic receptor that binds to its target, internalizes the complex and shuttles the target to the lysosome for degradation. Without wishing to be bound by any theory, molecules described herein that have increased FcyRIIB binding may deplete anti-anti-MOG autoantibodies and / or antigen-specific B cells producing anti-MOG autoantibodies Page 147 of 17813278299v 1Attorney Docket No. 2017420-0065through various mechanisms including those shown in FTGs. 6A-D. FIG. 6B shows a potential mechanism of action which includes clearing autoantibodies by targeting FcyRlIB isoform 2 on liver sinusoidal endothelial cells (LSECs). In this exemplary mechanism of action, the autoantigen domain (MOG or a fragment or variant thereof) binds to autoantibodies (anti -MOG autoantibodies) and the Fc domain binds to FcyRlIB isoform 2 on liver sinusoidal endothelial cells. Autoantibodies are internalized into the liver sinusoidal endothelial cells and targeted to the lysosome for degradation. In another exemplary mechanism as shown in FIG. 6C, molecules described herein may target pathogenic B cells producing target autoantibodies (c. ., anti-MOG autoantibodies), by targeting FcyRlIB isoform 1 to the B cell receptor (BCR), which leads to B cell apoptosis and inhibition. In another exemplary mechanism shown in FIG. 6D, molecule:autoantibody immune complexes described herein may target FcyRlIB on dendritic cells and reduce / inhibit antigen presentation to T cells.

[0365] Binding assays using SPR are performed to determine the binding affinity of the exemplary molecules described in Example 1. His-tagged FcyRIIA167H, FcyRIIA167R, or FcyRlIB are captured on a CM5 SPR chip previously coupled with an anti-His capture antibody by standard amine coupling. Increasing concentrations of molecules are subsequently injected over the captured FcyR and a single dissociation performed using single cycle kinetics. The data is then analyzed using steady state analysis which is suitable for low affinity interactions. In particular, a plot of response at equilibrium against the molecule concentration is generated. The KD value is equal to the concentration that gives 50% of the maximum response.Testing of Exemplary Molecules for Avidity -Mediated Effects

[0366] In this experiment, CHO cells expressing FcyRlIB (CHO-FcyRIIB+) are incubated with exemplary molecules described in Example 1 and an anti-MOG autoantibody (“Ab”) either at the same molar ratio or at a 4 molar excess (z.e., 1 : 1 molar ratio of molecule:Ab or 4: 1 molar ratio of molecule:Ab) with and without 2B6 antibody which is an anti-FcyRIIB antibody that blocks binding of FcyRlIB to antibody Fc domains.

[0367] Without wishing to be bound by any theory, present disclosure provides exemplary Fc mutations (e.g., P238D, among others) that can confer selective affinity for the inhibitory FcyRlIB of molecules described herein, with various autoantigens. Additionally, conferring a Page 148 of 17813278299v 1Attorney Docket No. 2017420-0065“medium” binding affinity through introducing the exemplary mutations creates an avidity-mediated effect in molecules described herein, thereby allowing for avidity-induced FcyRIIB-mediated intracellular uptake and degradation. Additionally, the present disclosure recognizes that such avidity-mediated effects can be utilized in molecules with different antigens, thereby targeting different autoantibodies, with a low risk of intracellular toxicity in part due to the relatively small size of the molecule and little to no affinity for activating Fey receptors.Example 4: In vivo Testing of Exemplary Molecules

[0368] The present Example examines in vivo activity of exemplary molecules described in Examples 1.Molecule and Autoantibody clearance in Wildtype Mice

[0369] In this experiment, wild-type BALBc mice are injected with anti-MOG autoantibodies and 24 hours later the mice are injected with molecule. Serum from the mice is collected and analyzed for concentration of molecule and autoantibody at timepoints: -10 minutes, 10 minutes, 30 minutes, 3 hours, 12 hours, 48 hours, and 7 days after molecule administration.Molecule and Autoantibody clearance in mice humanized for FcRn

[0370] In this experiment, mice humanized for FcRn are injected with anti-MOG autoantibodies and 24 hours later the mice are injected with molecule. Serum from the mice is collected and analyzed for concentration of molecule and anti-MOG antibodies at t...

Claims

Attorney Docket No. 2017420-0065CLAIMS1. 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-MOG 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-MOG 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-MOG 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-MOG 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 151 of 17813278299v 1Attorney Docket No. 2017420-00658. 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 152 of 17813278299v 1Attorney Docket No. 2017420-006517. 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 153 of 17813278299v 1Attorney Docket No. 2017420-006524. 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 any one of claims 1-24, 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, FcyRIIAl 67H, FcyRIIAl 67R, FcyRIIIAl 76F, FcyRIIIAl 76 V, and / or FcyRIIIB.

26. The molecule of any one of claims 1-25 wherein the first and / or second Fc domain comprising one or more mutated amino acid residues does not have increased binding affinity to FcyRI, FcyRIIAl 67H, FcyRIIAl 67R, FcyRIIIA176F, FcyRIIIA176V, FcyRIIIB, and / or FcRn relative to the corresponding wild-type Fc domain.

27. The molecule of any one of claims 1-26, wherein the first and / or second Fc domain comprising one or more mutated amino acid residues has decreased binding affinity to FcyRI, FcyRIIAl 67H, FcyRIIAl 67R, FcyRIIIA176F, FcyRIIIAl 76 V, FcyRIIIB, and / or FcRn relative to the corresponding wild-type Fc domain.

28. The molecule of any one of claims 1-27, 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, FcyRIIIAf 76F, FcyRIIIA176V, FcyRIIIB, and / or FcRn 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-MOG autoantibodies in serum when administered to a subject by binding to and forming an immune complex with the target anti-MOG autoantibodies.Page 154 of 17813278299v 1Attorney Docket No. 2017420-006530. The molecule of claim 29, wherein the immune complex promotes faster clearance of target anti -MOG autoantibodies compared to anti -MOG autoantibody clearance in a subject not administered the molecule.

31. The molecule of any of claims 1-30, wherein upon binding of the molecule to an anti-MOG autoantibody, and immune complex is formed that has enhanced binding kinetics with FcyRIIB relative to the anti-MOG 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-MOG 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-MOG autoantibody, an immune complex is formed that has enhanced binding kinetics with FcyRIIB relative to an immune complex that comprises the anti-MOG autoantibody and a corresponding molecule with a wild-type Fc domain.

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

35. The molecule of any one of claims 24-34, wherein upon binding of two molecules to an anti-MOG autoantibody, an immune complex is formed that has enhanced binding kinetics with FcyRIIB relative to an immune complex that comprises the anti-MOG 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-MOG autoantibody, an immune complex is formed that has enhanced binding kinetics with FcyRIIB relative to an immune complex that comprises the anti-MOG autoantibody bound to only a single molecule.Page 155 of 17813278299v 1Attorney Docket No. 2017420-006537. The molecule of any one of claims 24-36, wherein upon binding of two molecules to an anti -MOG autoantibody, an immune complex is formed that has enhanced binding kinetics with FcyRIIB relative to the anti-MOG autoantibody alone.

38. The molecule of any one of claims 24-37, 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 156 of 17813278299v 1Attorney Docket No. 2017420-006545. 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) endogenously expressing or 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 157 of 17813278299v 1Attorney Docket No. 2017420-006554. The molecule of claim 52, wherein an immune complex of one or two molecules with an anti -MOG 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 A33 OR;(v) L234Y, P238D, T250V, V264I, T307P, Q311R, A33OK, 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 A33 OR;(xiii) G237D, P238D, D270E, P271G, and A330R;Page 158 of 17813278299v 1Attorney Docket No. 2017420-0065(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 24-57, 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.

61. 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.

62. The molecule of any one of claims 1-56 and 61, wherein the first and / or second Fc domain comprises the following mutated amino acid residues: M428L, N434S, S267E and L328F, according to the EU numbering scheme.Page 159 of 17813278299v 1Attorney Docket No. 2017420-006563. The molecule of any one of claims 1-60, 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.

64. The molecule of any one of claims 1-60, 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.

65. The molecule of any one of claims 1-60, wherein the first and / or second Fc domain comprises the following mutated amino acid residues: M428L, N434S, G237D, P238D, D270E, P271G, A33 OR, 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 160 of 17813278299v 1Attorney Docket No. 2017420-0065ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 99, SEQ ID NO: 125, and SEQ ID NO: 126, 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: 97, 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.

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: 98, 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: 94Page 161 of 17813278299v 1Attorney Docket No. 2017420-0065(GGGGSGGGGSGGGGSGGGGS) or SEQ TD NO: 95 (GGGGSGGGGSGGGGSGGGGSSGGGGS).

74. 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 MOG autoantigen domain, or a fragment or variant thereof.

76. The molecule of claim 75, wherein the MOG 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 MOG 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 MOG autoantigen domain variant that includes a N60Q mutation relative to the amino acid sequence of SEQ ID NO: 1.

79. The molecule of any one of claims 1-78, wherein the autoantibody -binding domain comprises a MOG autoantigen domain variant that comprises the sequence of any one of SEQ ID NOs: 1-11.

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:Page 162 of 17813278299v 1Attorney Docket No. 2017420-0065an 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: 9 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: 10 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: 11 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: 11 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: 11 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: 97;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: 9 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: 97;Page 163 of 17813278299v 1Attorney Docket No. 2017420-0065an 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: 10 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: 97;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: 9 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: 10 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; 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: 11 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.

82. The molecule of claim 81, wherein the first polypeptide comprises:the amino acid sequence of SEQ ID NO: 9 and the amino acid sequence of SEQ ID NO: 19;the amino acid sequence of SEQ ID NO: 10 and the amino acid sequence of SEQ ID NO: 19;the amino acid sequence of SEQ ID NO: 11 and the amino acid sequence of SEQ ID NO: 28;the amino acid sequence of SEQ ID NO: 11 and the amino acid sequence of SEQ ID NO: 19;Page 164 of 17813278299v 1Attorney Docket No. 2017420-0065the amino acid sequence of SEQ ID NO: 11 and the amino acid sequence of SEQ ID NO: 97;the amino acid sequence of SEQ ID NO: 9 and the amino acid sequence of SEQ ID NO: 97;the amino acid sequence of SEQ ID NO: 10 and the amino acid sequence of SEQ ID NO: 97;the amino acid sequence of SEQ ID NO: 9 and the amino acid sequence of SEQ ID NO: 99;the amino acid sequence of SEQ ID NO: 10 and the amino acid sequence of SEQ ID NO: 99; orthe amino acid sequence of SEQ ID NO: 11 and the amino acid sequence of SEQ ID NO: 99.

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: 9 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: 10 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: 27;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: 11 and an amino acid sequence that is at least 90% identical (e.g., at least 91%, atPage 165 of 17813278299v 1Attorney Docket No. 2017420-0065least 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: 98;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: 9 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: 10 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; 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: 11 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.

84. The molecule of claim 83, wherein the second polypeptide comprises:(i) the amino acid sequence of SEQ ID NO: 9 and SEQ ID NO: 19;(ii) the amino acid sequence of SEQ ID NO: 10 and SEQ ID NO: 19;(iii) the amino acid sequence of SEQ ID NO: 27;(iv) the amino acid sequence of SEQ ID NO: 11 and SEQ ID NO: 19;(v) the amino acid sequence of SEQ ID NO: 98;(vi) the amino acid sequence of SEQ ID NO: 9 and SEQ ID NO: 99;(vii) the amino acid sequence of SEQ ID NO: 10 and SEQ ID NO: 99; or(viii) the amino acid sequence of SEQ ID NO: 11 and SEQ ID NO: 99.Page 166 of 17813278299v 1Attorney Docket No. 2017420-006585. The molecule of any one of claims 1-84, wherein:(i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 9 and the amino acid sequence of SEQ ID NO: 19; and(ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 9 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: 10 and the amino acid sequence of SEQ ID NO: 19; and(ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 9 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: 11 and the amino acid sequence of SEQ ID NO: 28, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 27; or(ii) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 11 and the amino acid sequence of SEQ ID NO: 27, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 28.

88. The molecule of any one of claims 1-84, wherein:the first polypeptide comprises the amino acid sequence of SEQ ID NO: 11 and the amino acid sequence of SEQ ID NO: 19, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 11 and the amino acid sequence of SEQ ID NO: 19.

89. The molecule of any one of claims 1-84, wherein:(i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 11 and the amino acid sequence of SEQ ID NO: 97, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 98; orPage 167 of 17813278299v 1Attorney Docket No. 2017420-0065(ii) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 11 and the amino acid sequence of SEQ ID NO: 98, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 99.

90. The molecule of any one of claims 1-84, wherein:(i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 9 and the amino acid sequence of SEQ ID NO: 97, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 98; or(ii) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 9 and the amino acid sequence of SEQ ID NO: 98, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 97.

91. The molecule of any one of claims 1-84, wherein:(i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 10 and the amino acid sequence of SEQ ID NO: 97, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 98; or(ii) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 10 and the amino acid sequence of SEQ ID NO: 98, and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 97.

92. The molecule of any one of claims 1-84, wherein:(i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 9 and the amino acid sequence of SEQ ID NO: 99; and(ii) the second polypeptide comprises 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: 10 and the amino acid sequence of SEQ ID NO: 99; and(ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 99.Page 168 of 17813278299v 1Attorney Docket No. 2017420-006594. The molecule of any one of claims 1-84, wherein:(i) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 11 and the amino acid sequence of SEQ ID NO: 99; and(ii) the second polypeptide comprises the amino acid sequence of SEQ ID NO: 99.

95. The molecule of any one of claims 1-94, 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, 101, 102, 103, 104, 106, 107, 109, 111, 113, 114, and 115.

96. The molecule of any one of claims 1-95, 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, 101, 102, 103, 105, 106, 108, 110, 112, 113, 114, and 115.

97. The molecule of any one of claims 1-96, wherein the first polypeptide comprises the amino acid sequence of any one of SEQ ID NOs: 100, 101, 102, 103, 104, 106, 107, 109, 111, 113, 114, and 115, and the second polypeptide comprises the amino acid sequence of any one of SEQ ID NOs: 100, 101, 102, 103, 105, 106, 108, 110, 112, 113, 114, and 115.

98. The molecule of any one of claims 1-97, wherein:(i) the first polypeptide comprises the amino acid sequence of 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 of 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 of 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 of SEQ ID NO: 103 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 103;Page 169 of 17813278299v 1Attorney Docket No. 2017420-0065(v) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 104 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 105;(vi) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 106 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 106;(vii) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 107 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 108;(viii) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 109 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 110;(ix) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 111 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 112;(x) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 113 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 113;(xi) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 107 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 108; or(xii) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 107 and the second polypeptide comprises the amino acid sequence of SEQ ID NO: 108.

99. The molecule of any one of claims 80-98, wherein the N-terminus of the second Fc domain is covalently linked to the C-terminus of the second autoantibody-binding domain.

100. The molecule of claim 99, wherein the C-terminus of the second Fc domain is covalently linked to the C-terminus of the second autoantibody -binding domain.

101. The molecule of any one of claims 80-100, wherein the second autoantibody -binding domain binds to anti-MOG autoantibodies.

102. The molecule of any one of claims 1-101, wherein the molecule is capable of selectively depleting anti-MOG autoantibodies that bind to the autoantibody -binding domain when administered to a subject.Page 170 of 17813278299v 1Attorney Docket No. 2017420-0065103. The molecule of claim 101 or 102, wherein the anti-MOG autoantibodies that bind to the autoantibody-binding domain are selectively depleted by uptake into cells.

104. The molecule of any one of claims 1-79 or 81-98, wherein the second polypeptide does not comprise an autoantibody-binding domain that binds to anti-MOG autoantibodies.

105. A nucleic acid comprising a nucleotide sequence encoding the molecule of any one of claims 1-104.

106. A host cell containing the nucleic acid of claim 105.

107. A vector comprising the nucleic acid of claim 105.

108. The vector of claim 107, wherein the vector comprises a viral vector.

109. The vector of claim 108, wherein the viral vector comprises a retroviral vector, a lentiviral vector, an adeno-associated viral (AAV) vector, or an adenoviral vector.

110. A pharmaceutical composition comprising the molecule of any one of claims 1-104 or a nucleic acid encoding the molecule of any one of claims 1-104 and a pharmaceutically acceptable carrier.

111. A method of making a molecule, the method comprising expressing the nucleic acid of claim 105 in a host cell, and recovering the molecule.

112. A method of treating a subject suffering from or susceptible to an autoimmune disease, the method comprising:administering to the subject a pharmaceutical composition comprising the molecule of any one of claims 1-104 or a nucleic acid encoding the molecule of any one of claims 1-104.Page 171 of 17813278299v 1Attorney Docket No. 2017420-0065113. A method of treating a subject suffering from or susceptible to an autoimmune disease, the method comprising:administering to the subject a first pharmaceutical composition comprising the molecule of any one of claims 1-104 or a nucleic acid encoding the molecule of any one of claims 1-104; andadministering to the subject a second pharmaceutical composition that selectively depletes plasma cells producing autoantibodies that are targeted by the autoantibody-binding domain.

114. The method of claim 112 or 113, wherein the autoimmune disease is MOGAD, or another autoimmune disease involving anti -MOG autoantibodies.

115. The method of claim 113, wherein the first pharmaceutical composition is administered before the second pharmaceutical composition.

116. The method of claim 113, wherein the first pharmaceutical composition is administered after the second pharmaceutical composition.

117. The method of claim 113, wherein the first pharmaceutical composition and the second pharmaceutical composition are co-administered.

118. The method of any one of claims 112-117, wherein the level of anti -MOG autoantibodies in the subject or in a biological sample from the subject after administration is reduced relative to a level before administration.

119. The method of claim 118, wherein the level of anti -MOG 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 administration.Page 172 of 17813278299v 1Attorney Docket No. 2017420-0065120. The method of claim 118 or 119, wherein the reduced level of anti-MOG autoantibodies is sustained overtime.

121. The method of claim 120, 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.

122. The method of any one of claims 112-121, wherein the pharmaceutical composition is administered intravenously, intramuscularly, or subcutaneously to the subject.

123. The method of any one of claims 112-122, wherein the subject is a human.

124. A method of selectively depleting anti-MOG autoantibodies in a subject, the method comprising administering to the subject a pharmaceutical composition comprising the molecule of any one of claims 1-104 or a nucleic acid encoding the molecule of any one of claims 1-104.

125. A method of treating a human subject suffering from or susceptible to MOGAD, or another autoimmune disease involving anti-MOG autoantibodies, the method comprising administering to the subject a pharmaceutical composition comprising the molecule of any one of claims 1-104 or a nucleic acid encoding the molecule of any one of claims 1-104.

126. A pharmaceutical composition comprising:the molecule of any one of claims 1-104 or a nucleic acid encoding the molecule of any one of claims 1-104;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; anda pharmaceutically acceptable carrier.Page 173 of 17813278299v 1Attorney Docket No. 2017420-0065127. A composition for decreasing the titer of anti-MOG 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-MOG 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-MOG autoantibodies to form immune complexes comprising at least one molecule bound to an anti-MOG 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-MOG autoantibodies in the subject’s blood serum, wherein the higher avidity is relative to an immune complex comprising the at least one corresponding molecule with a wild-type Fc domain.

128. The composition of claim 127, wherein the molecules are molecules of any one of claims 1-104.

129. An immune complex comprising:(i) an anti-MOG autoantibody; and(ii) a molecule comprising:a first polypeptide comprising a first Fc domain, and an autoantibody-binding domain that binds to the anti-MOG autoantibody; 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; wherein the first and / or second Fc domainPage 174 of 17813278299v 1Attorney Docket No. 2017420-0065comprises 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-MOG autoantibody bound to a corresponding molecule with wild-type Fc domains.

130. The immune complex of claim 129, wherein the immune complex has enhanced binding kinetics with FcyRIIB relative to the anti-MOG autoantibody alone.

131. The immune complex of claim 129 or 130, 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-MOG 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.

132. The immune complex of claim 131, wherein the immune complex has enhanced binding kinetics with FcyRIIB relative to an immune complex that comprises the anti-MOG autoantibody bound to two corresponding molecules with wild-type Fc domains.

133. The immune complex of claim 131 or 132, wherein the immune complex has enhanced binding kinetics with FcyRIIB relative to an immune complex that comprises the anti-MOG autoantibody and only a single molecule.

134. The immune complex of claim 131, wherein the immune complex has enhanced binding kinetics with FcyRIIB relative to the anti-MOG autoantibody alone.Page 175 of 17813278299v 1Attorney Docket No. 2017420-0065135. The immune complex of any one of claims 131-134, wherein the binding domain of each of the two molecules is bound to the anti-MOG autoantibody.

136. The immune complex of any one of claims 129-135, 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.

137. The immune complex of any one of claims 129-136, 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.

138. The immune complex of any one of claims 129-137, 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, FcyRIIIA176V, and / or FcyRIIIB relative to the corresponding wild-type Fc domain.

139. The immune complex of any one of claims 129-137, 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.

140. The immune complex of any one of claims 129-137, 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.

141. The immune complex of any one of claims 129-137, wherein the first and / or second Fc domain comprising one or more mutated amino acid residues has negligible or no binding affinity to FcyRI, FcyRIIA167H, FcyRIIA167R, FcyRIIIA176F, FcyRIIIA176V, and / or FcyRIIIB relative to the corresponding wild-type Fc domain.Page 176 of 17813278299v 1Attorney Docket No. 2017420-0065142. The immune complex of any one of claims 129-141, wherein the enhanced binding kinetics comprises at least 10% greater binding affinity of the immune complex to FcyRIIB.

143. The immune complex of claim 142, 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.

144. The immune complex of claim 142 or 143, wherein the binding affinity comprises binding affinity to a cell line endogenously expressing or overexpressing FcyRIIB measured by flow cytometry.

145. The immune complex of any one of claims 129-144, wherein the immune complex preferentially binds to immune cells expressing Fey RUB over immune cells expressing FcyRIIA.

146. The immune complex of any one of claims 129-145, wherein the immune complex crosslinks FcyRllB with a B cell receptor on a B cell.

147. The immune complex of any one of claims 129-146, wherein the molecules are molecules of any one of claims 1-104.Page 177 of 17813278299v 1

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