Modified FC polypeptides

Abstract

Polypeptides comprising modified Fc polypeptides, the modified Fc polypeptides comprising an aliphatic residue (e.g., alanine residue) at position (241) according to Kabat and at least one other modification at a position selected from the group consisting of (233, 236, 237, 239, 252, 254, 256, 267, 268, 271, 296, 328, 330, 428, 433, 434, 436), and combinations thereof according to Kabat.

Description

MODIFIED Fc POLYPEPTIDESCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 657,772, filed on June 7, 2024; and to U.S. Provisional Application No. 63 / 797,005, filed on April 29, 2025, the disclosures of each of which are hereby incorporated by reference in their entireties for all purposes.SEQUENCE LISTING

[0002] This application contains a Sequence Listing XML. which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. The XML copy of the Sequence Listing, created on June 1, 2025, is named NVG-007WO_SL.xml and is 71,078 bytes in size.BACKGROUND

[0003] The Fc region of an antibody interacts with a number of Fc receptors and ligands, imparting an array of important functional capabilities referred to as effector functions. For IgG, the Fc region comprises immunoglobulin (1g) domains Cy2 and Cy3 (also referred to as CH2 and CH 3 respectively) and the N-terminal hinge leading into Cy2. An important family of Fc receptors for the IgG class are the Fc gamma receptors (FcyRs). These receptors mediate communication between antibodies and the cellular arm of the immune system.

[0004] In humans, this protein family includes FcyRI (CD64), including isoforms Fey Ria, FcyRIb, and FcyRIc; FcyRII (CD32), including isoforms FcyRIIa (including allotypes H131 and R131), FcyRIIb (including FcyRIIb-1 and FcyRIIb-2), and FcyRIIc; and FcyRIII (CD16), including isoforms FcyRIIIa (including allotypes V158 and F158) and FcyRIIIb (including allotypes FcyRIIIb-NAl and FcyRIIIbNA2).

[0005] Inflammatory disorders, including autoimmune diseases, are disorders involving abnormal activation and subsequent migration of white blood cells to affected areas of the body. These conditions encompass a wide range of ailments that affect the lives of millions of people throughout the world. Although various treatments are presently available, many possess significant side effects or are insufficiently effective in alleviating symptoms.

[0006] Thus, there remains a need for improved agents for treating autoimmune diseases.SUMMARY

[0007] The present disclosure provides polypeptides and composition thereof comprising modified Fc polypeptides and method of producing and using the same.

[0008] In one aspect, provided herein is a modified Fc polypeptide having an amino acid sequence at least 75% identical to the sequence of SEQ ID NO: 1, and further comprising: (i) a sialic acid (SA) moiety attached to an N-glycan of the Fc polypeptide; (ii) an aliphatic amino acid residue at position 241 or position 243, and (iii) amino acid modifications selected from the group consisting of: (a) an aspartic acid residue at position 233 (E233D), an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 238 (P238D). an aspartic acid residue at position 268 (H268D), a glycine residue at position 271 (P271G), and an arginine residue at position 330 (A330R); (b) an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 238 (P238D), a glycine residue at position 271 (P271G), and an arginine residue at position 330 (A330R); (c) an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 238 (P238D), an aspartic acid residue at position 268 (H268D), a glycine residue at position 271 (P271G), and an arginine residue at position 330 (A330R); (d) an aspartic acid residue at position 233 (E233D), an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 238 (P238D), an aspartic acid residue at position 268 (H268D), a glycine residue at position 271 (P271G), an arginine residue at position 330 (A330R), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S); (e) an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 238 (P238D), a glycine residue at position 271 (P271G), and an arginine residue at position 330 (A330R). a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S); and (f) an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 238 (P238D), an aspartic acid residue at position 268 (H268D), a glycine residue at position 271 (P271G), and an arginine residue at position 330 (A330R), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S); wherein the position numbering is according to the EU index of Kabat.

[0009] In another aspect, provided herein is a modified Fc polypeptide having: an amino acid sequence at least 75% identical to the sequence of SEQ ID NO: 1, and further comprising: (i) an aliphatic amino acid residue at position 241 or position 243, (ii) an amino acid modification at position 238; (iii) a sialic acid (SA) moiety attached to an N-glycan of the Fc polypeptide; and (iv) at least one additional amino acid modification at a position selected fromthe group consisting of: 233, 236, 237, 239, 267, 268, 271, 296, 328, 330, and combinations thereof; wherein the position numbering is according to the EU index of Kabat.

[0010] In some embodiments, the at least one additional amino acid modification is selected from the group consisting of: (a) an aspartic acid residue at position 233 (E233D), (b) an aspartic acid residue at position 236 (G236D), (c) an aspartic acid residue at position 237 (G237D), (d) an aspartic acid residue at position 239 (S239D), (e) a glutamic acid residue at position 267 (S267E), (f) an aspartic acid residue at position 268 (H268D), (g) a glycine residue at position 271 (P271G), (h) an aspartic acid residue at position 296 (Y296D), (i) a phenylalanine at position 328 (L328F), (j) an arginine residue at position 330 (A330R), and combinations thereof; wherein the position numbering is according to the EU index of Kabat.

[0011] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 233 (E233D), wherein the position numbering is according to the EU index of Kabat.

[0012] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 236 (G236D), wherein the position numbering is according to the EU index of Kabat.

[0013] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 237 (G237D), wherein the position numbering is according to the EU index of Kabat.

[0014] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 239 (S239D), wherein the position numbering is according to the EU index of Kabat.

[0015] In some embodiments, the modified Fc polypeptide comprises a glutamic acid residue at position 267 (S267E), wherein the position numbering is according to the EU index of Kabat.

[0016] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 268 (H268D), wherein the position numbering is according to the EU index of Kabat.

[0017] In some embodiments, the modified Fc polypeptide comprises a glycine residue at position 271 (P271G), wherein the position numbering is according to the EU index of Kabat.

[0018] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 296 (Y296D), wherein the position numbering is according to the EU index of Kabat.

[0019] In some embodiments, the modified Fc polypeptide comprises a phenylalanine at position 328 (L328F), wherein the position numbering is according to the EU index of Kabat.

[0020] In some embodiments, the modified Fc polypeptide comprises an arginine residue at position 330 (A330R), wherein the position numbering is according to the EU index of Kabat.

[0021] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 233 (E233D) and an arginine at position 330 (A330R). wherein the position numbering is according to the EU index of Kabat.

[0022] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 233 (E233D), a glycine residue at position 271 (P271G), and an arginine residue at position 330 (A330R). wherein the position numbering is according to the EU index of Kabat.

[0023] In some embodiments, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 268 (H268D), and a glycine residue at position 271 (P271G), wherein the position numbering is according to the EU index of Kabat.

[0024] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 237 (G237D), a glycine residue at position 271 (P271G), and an arginine residue at position 330 (A330R). wherein the position numbering is according to the EU index of Kabat.

[0025] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 233 (E233D), an aspartic acid residue at position 268 (H268D), a glycine residue at position 271 (P271G), and an arginine residue at position 330 (A330R), wherein the position numbering is according to the EU index of Kabat.

[0026] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 268 (H268D), a glycine residue at position 271 (P271G), and an arginine residue at position 330 (A330R), wherein the position numbering is according to the EU index of Kabat.

[0027] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 233 (E233D), an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 268 (H268D), a glycine residue at position 271 (P271G), and an arginine residue at position 330 (A330R), wherein the position numbering is according to the EU index of Kabat.

[0028] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 233 (E233D) and an aspartic acid residue at position 269 (Y296D), wherein the position numbering is according to the EU index of Kabat.

[0029] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 237 (G237D) and an aspartic acid residue at position 269 (Y296D), wherein the position numbering is according to the EU index of Kabat.

[0030] In some embodiments, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 237 (G237D) and an aspartic acid residue at position 269 (Y296D), wherein the position numbering is according to the EU index of Kabat.

[0031] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 268 (H268D) and an aspartic acid residue at position 269 (Y296D), wherein the position numbering is according to the EU index of Kabat.

[0032] In some embodiments, the modified Fc polypeptide comprises a glycine residue at position 271 (P271G) and an aspartic acid residue at position 269 (Y296D), wherein the position numbering is according to the EU index of Kabat.

[0033] In some embodiments, the modified Fc polypeptide comprises an arginine residue at position 330 (A330R) and an aspartic acid residue at position 269 (Y296D), wherein the position numbering is according to the EU index of Kabat.

[0034] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 237 (G237D) and an aspartic acid residue at position 269 (Y296D), wherein the position numbering is according to the EU index of Kabat.

[0035] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 233 (E233D) and an aspartic acid residue at position 269 (Y296D) and an arginine at position 330 (A330R), wherein the position numbering is according to the EU index of Kabat.

[0036] In some embodiments, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 233 (E233D), a glycine residue at position 271 (P271G), an aspartic acid residue at position 269 (Y296D), and an arginine residue at position 330 (A330R), wherein the position numbering is according to the EU index of Kabat.

[0037] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 268 (H268D), an aspartic acid residue at position 269 (Y296D), and a glycine residue at position 271 (P271G), wherein the position numbering is according to the EU index of Kabat.

[0038] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 237 (G237D), a glycine residue at position 271 (P271G), an aspartic acid residue at position 269 (Y296D), and an arginine residue at position 330 (A330R), wherein the position numbering is according to the EU index of Kabat.

[0039] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 233 (E233D), an aspartic acid residue at position 268 (H268D), an aspartic acid residue at position 269 (Y296D). a glycine residue at position 271 (P271G), and an arginine residue at position 330 (A330R), wherein the position numbering is according to the EU index of Kabat.

[0040] In some embodiments, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 268 (H268D). an aspartic acid residue at position 269 (Y296D), a glycine residue at position 271 (P271G), and an arginine residue at position 330 (A330R), wherein the position numbering is according to the EU index of Kabat.

[0041] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 233 (E233D). an aspartic acid residue at position 237 (G237D). an aspartic acid residue at position 268 (H268D), an aspartic acid residue at position 269 (Y296D), a glycine residue at position 271 (P271G), and an arginine residue at position 330 (A330R), wherein the position numbering is according to the EU index of Kabat.

[0042] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 236 (G236D) and a glutamic acid residue at position 267 (S267E), wherein the position numbering is according to the EU index of Kabat.

[0043] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 239 (S239D) and a glutamic acid residue at position 267 (S267E), wherein the position numbering is according to the EU index of Kabat.

[0044] In some embodiments, the modified Fc polypeptide comprises a glutamic acid residue at position 267 (S267E) and a pheny lalanine residue at position 328 (L328F), wherein the position numbering is according to the EU index of Kabat.

[0045] In some embodiments, the modified Fc polypeptide further comprises an amino acid modification at a position selected from the group consisting of 252, 254, 256, 428, 433, 434, 436, and combinations thereof, wherein the position numbering is according to the EU index of Kabat.

[0046] In some embodiments, the amino acid modification is selected from the group consisting of: (a) a tyrosine residue at position 252 (M252Y), (b) a threonine residue at position254 (S254T), (c) a glutamic acid residue at position 256 (T256E), (d) a leucine residue at position 428 (M428L), (e) a lysine residue at position 433 (H433K), (f) a serine residue at position 434 (N434S) or a phenylalanine residue at position 434 (N434F), and (g) a histidine residue at position 436 (Y 436H), and combinations thereof; wherein the position numbering is according to the EU index of Kabat.

[0047] In some embodiments, the modified Fc polypeptide comprises a tyrosine residue at position 252 (M252Y). wherein the position numbering is according to the EU index of Kabat.

[0048] In some embodiments, the modified Fc polypeptide comprises a threonine residue at position 254 (S254T), wherein the position numbering is according to the EU index of Kabat.

[0049] In some embodiments, the modified Fc polypeptide comprises a glutamic acid residue at position 256 (T256E). wherein the position numbering is according to the EU index of Kabat.

[0050] In some embodiments, the modified Fc polypeptide comprises a leucine residue at position 428 (M428L), wherein the position numbering is according to the EU index of Kabat.

[0051] In some embodiments, the modified Fc polypeptide comprises a lysine residue at position 433 (H433K). wherein the position numbering is according to the EU index of Kabat.

[0052] In some embodiments, the modified Fc polypeptide comprises a serine residue at position 434 (N434S) or a phenylalanine residue at position 434 (N434F), wherein the position numbering is according to the EU index of Kabat.

[0053] In some embodiments, the modified Fc polypeptide comprises a histidine residue at position 436 (Y436H), wherein the position numbering is according to the EU index of Kabat.

[0054] In some embodiments, the modified Fc polypeptide comprises a tyrosine residue at position 252 (M252Y), a threonine residue at position 254 (S254T), and a glutamic acid residue at position 256 (T256E), wherein the position numbering is according to the EU index of Kabat.

[0055] In some embodiments, the modified Fc polypeptide comprises a leucine residue at position 428 (M428L) and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

[0056] In some embodiments, the modified Fc polypeptide comprises a lysine residue at position 433 (H433K). a phenylalanine residue at position 434 (N434F). and a histidine residue at position 436 (Y436H), wherein the position numbering is according to the EU index of Kabat.

[0057] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 233 (E233D). a leucine residue at position 428 (M428L) and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

[0058] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 236 (G236D). a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

[0059] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 237 (G237D). a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S). wherein the position numbering is according to the EU index of Kabat.

[0060] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 239 (S239D), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

[0061] In some embodiments, the modified Fc polypeptide comprises a glutamic acid residue at position 267 (S267E), a leucine residue at position 428 (M428E), and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

[0062] In some embodiments, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 268 (H268D) a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

[0063] In some embodiments, the modified Fc polypeptide comprises a glycine residue at position 271 (P271G), a leucine residue at position 428 (M428L). and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

[0064] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 296 (Y296D), a leucine residue at position 428 (M428E), and a serine residue at position 434 (N434S). wherein the position numbering is according to the EU index of Kabat.

[0065] In some embodiments, the modified Fc polypeptide comprises a phenylalanine at position 328 (L328F), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

[0066] In some embodiments, the modified Fc polypeptide comprises an arginine residue at position 330 (A330R), a leucine residue at position 428 (M428E), and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

[0067] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 233 (E233D), an arginine at position 330 (A330R). a leucine residue atposition 428 (M428L), and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

[0068] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 233 (E233D), a glycine residue at position 271 (P271G), an arginine residue at position 330 (A330R), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

[0069] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 268 (H268D), a glycine residue at position 271 (P271G), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

[0070] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 237 (G237D), a glycine residue at position 271 (P271G), an arginine residue at position 330 (A330R), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

[0071] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 233 (E233D), an aspartic acid residue at position 268 (H268D), a glycine residue at position 271 (P271G), an arginine residue at position 330 (A330R), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

[0072] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 268 (H268D), a glycine residue at position 271 (P271G), an arginine residue at position 330 (A330R), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

[0073] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 233 (E233D), an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 268 (H268D), a glycine residue at position 271 (P271G), an arginine residue at position 330 (A330R), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S). wherein the position numbering is according to the EU index of Kabat.

[0074] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 233 (E233D), an aspartic acid residue at position 269 (Y296D), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

[0075] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 269 (Y296D), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

[0076] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 269 (Y296D), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

[0077] In some embodiments, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 268 (H268D), an aspartic acid residue at position 269 (Y296D), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

[0078] In some embodiments, the modified Fc polypeptide comprises a glycine residue at position 271 (P271G), an aspartic acid residue at position 269 (Y296D), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

[0079] In some embodiments, the modified Fc polypeptide comprises an arginine residue at position 330 (A330R), an aspartic acid residue at position 269 (Y296D), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

[0080] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 269 (Y296D), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

[0081] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 233 (E233D), an aspartic acid residue at position 269 (Y296D) and an arginine at position 330 (A330R), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S). wherein the position numbering is according to the EU index of Kabat.

[0082] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 233 (E233D), a glycine residue at position 271 (P271G), an aspartic acid residue at position 269 (Y296D), an arginine residue at position 330 (A330R), aleucine residue at position 428 (M428L), and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

[0083] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 268 (H268D), an aspartic acid residue at position 269 (Y296D), a glycine residue at position 271 (P271G), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

[0084] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 237 (G237D), a glycine residue at position 271 (P271G), an aspartic acid residue at position 269 (Y296D), an arginine residue at position 330 (A330R), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

[0085] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 233 (E233D), an aspartic acid residue at position 268 (H268D), an aspartic acid residue at position 269 (Y296D), a glycine residue at position 271 (P271G), an arginine residue at position 330 (A330R), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S). wherein the position numbering is according to the EU index of Kabat.

[0086] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 268 (H268D), an aspartic acid residue at position 269 (Y296D). a glycine residue at position 271 (P271G), an arginine residue at position 330 (A330R). a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

[0087] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 233 (E233D), an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 268 (H268D), an aspartic acid residue at position 269 (Y296D), a glycine residue at position 271 (P271G), an arginine residue at position 330 (A330R), aleucine residue at position 428 (M428L), and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

[0088] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 236 (G236D), a glutamic acid residue at position 267 (S267E), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

[0089] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 239 (S239D), a glutamic acid residue at position 267 (S267E), a leucineresidue at position 428 (M428L), and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

[0090] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 237 (G237D), a glycine residue at position 271 (P271G), an arginine residue at position 330 (A330R), a lysine residue at position 433 (H433K), a phenylalanine residue at position 434 (N434F), and a histidine residue at position 436 (Y436H), wherein the position numbering is according to the EU index of Kabat.

[0091] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 233 (E233D), an aspartic acid residue at position 268 (H268D), a glycine residue at position 271 (P271G), an arginine residue at position 330 (A330R), a lysine residue at position 433 (H433K), a phenylalanine residue at position 434 (N434F), and a histidine residue at position 436 (Y436H), wherein the position numbering is according to the EU index of Kabat.

[0092] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 268 (H268D), a glycine residue at position 271 (P271G). an arginine residue at position 330 (A330R), a lysine residue at position 433 (H433K), a phenylalanine residue at position 434 (N434F), and a histidine residue at position 436 (Y436H), wherein the position numbering is according to the EU index of Kabat.

[0093] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 233 (E233D), an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 268 (H268D), a glycine residue at position 271 (P271G), an arginine residue at position 330 (A330R), a lysine residue at position 433 (H433K), a phenylalanine residue at position 434 (N434F). and a histidine residue at position 436 (Y436H), wherein the position numbering is according to the EU index of Kabat.

[0094] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 237 (G237D), a glycine residue at position 271 (P271G), an arginine residue at position 330 (A330R), a tyrosine residue at position 252 (M252Y). a threonine residue at position 254 (S254T). and a glutamic acid residue at position 256 (T256E). wherein the position numbering is according to the EU index of Kabat.

[0095] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 233 (E233D), an aspartic acid residue at position 268 (H268D), a glycine residue at position 271 (P271G), an arginine residue at position 330 (A330R), atyrosine residue at position 252 (M252Y), a threonine residue at position 254 (S254T), and a glutamic acidresidue at position 256 (T256E), wherein the position numbering is according to the EU index of Kabat.

[0096] In some embodiments, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 268 (H268D), a glycine residue at position 271 (P271G), an arginine residue at position 330 (A330R), a tyrosine residue at position 252 (M252Y), a threonine residue at position 254 (S254T), and a glutamic acid residue at position 256 (T256E), wherein the position numbering is according to the EU index of Kabat.

[0097] In some embodiments, the modified Fc polypeptide comprises an aspartic acid residue at position 233 (E233D), an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 268 (H268D). a glycine residue at position 271 (P271G), an arginine residue at position 330 (A330R), a tyrosine residue at position 252 (M252Y), a threonine residue at position 254 (S254T), and a glutamic acid residue at position 256 (T256E), wherein the position numbering is according to the EU index of Kabat.

[0098] In another aspect, provided herein is a modified Fc polypeptide having an amino acid sequence at least 75% identical to the sequence of SEQ ID NO: 1, and further comprising: (i) an aliphatic amino acid residue at position 241 or position 243, (ii) n amino acid modification at position 267 and 328, and (iii) a sialic acid (SA) moiety7attached to an N-glycan of the Fc polypeptide; wherein the position numbering is according to the EU index of Kabat.

[0099] In some embodiments, the modified Fc polypeptide comprises a glutamic acid residue at position 267 (S267E), wherein the position numbering is according to the EU index of Kabat.

[0100] In some embodiments, the modified Fc polypeptide comprises a phenylalanine residue at position 328 (L328F), wherein the position numbering is according to the EU index of Kabat.

[0101] In some embodiments, the modified Fc polypeptide comprises a glutamic acid residue at position 267 (S267E) and a pheny lalanine residue at position 328 (L328F), wherein the position numbering is according to the EU index of Kabat.

[0102] In some embodiments, the aliphatic amino acid residue at position 241 is an alanine residue (F241 A) or a leucine residue (F241L), or the aliphatic amino acid residue at position 243 is an alanine (F234A) or a leucine (F243L), wherein the position numbering is according to the EU index of Kabat.

[0103] In some embodiments, the aliphatic amino acid residue at position 241 is an alanine (F241A). In some embodiments, the aliphatic amino acid residue at position 241 is a leucine(F241L). In some embodiments, the aliphatic amino acid residue at position 234 is a leucine (F243L). In some embodiments, the aliphatic amino acid residue at position 234 is an alanine (F243A).

[0104] In some embodiments, the modified Fc polypeptide comprises a sialic acid (SA) moiety attached to an N-glycan of the Fc polypeptide via an a(2,6) linkage.

[0105] In some embodiments, the N-glycan is attached to an asparagine (Asn) at amino acid residue 297 (Asn297; numbered according to the EU index of Kabat: corresponding to amino acid residue 88 of SEQ ID NO: 1).

[0106] In some embodiments, the N-glycan of the modified Fc polypeptides is mono- sialylated or di-sialylated. In some embodiments, the N-glycan is di-sialylated. In some embodiments, two sialic acid moieties are attached to the N-glycan via a(2,6) linkages.

[0107] In some embodiments, the Fc polypeptide comprises a galactose moiety. In some embodiments, the galactose moiety is attached to an a(l,3) arm and / or a(l,6) arm of the N- glycan. In some embodiments, the galactose moiety is a branched galactose moiety.

[0108] In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 85% identical to the sequence of any one of SEQ ID NOs: 1. 2, 11, and 12. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% identical to the sequence of any one of SEQ ID NOs: 1, 2, 11, and 12. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 92.5% identical to the sequence of any one of SEQ ID NOs: 1, 2, 11, and 12. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% identical to the sequence of any one of SEQ ID NOs: 1, 2, 11, and 12. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 96% identical to the sequence of any one of SEQ ID NOs: 1, 2, 11, and 12. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 97% identical to the sequence of any one of SEQ ID NOs: 1, 2, 11, and 12. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 98% identical to the sequence of any one of SEQ ID NOs: 1, 2, 11, and 12. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 99% identical to the sequence of any one of SEQ ID NOs: I, 2, 11, and 12. In some embodiments, the modified Fc polypeptide comprises amino acid modifications in no more than 20 amino acid residues relative to the amino acid sequence of any one of SEQ ID NOs: 1, 2, 11, and 12. In some embodiments, the modified Fc polypeptide comprises 3-20 amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs: 1. 2, 11, and 12.

[0109] In some embodiments, the modified Fc polypeptide does not comprise a C-terminal lysine residue. In some embodiments, the modified Fc polypeptide comprises a C-terminal lysine residue.

[0110] In some embodiments, the modified Fc polypeptide is an IgG polypeptide. In some embodiments, the IgG polypeptide is an IgGl polypeptide.[OHl] In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% identical to the sequence of any one of sequences listed in Table 1 . In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% identical to the sequence of any one of sequences listed in Table 1.

[0112] Also provided herein is a pharmaceutical composition, comprising: (a) the modified Fc polypeptide disclosed herein and (b) a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutically acceptable carrier, diluent, or excipient is selected from the group consisting of: a stabilizer, buffer, surfactant, filler, solvent, tonicity or osmolarity adjusting agent, antioxidant, adjuvant, and antimicrobial agent.

[0113] In one aspect, provided herein are methods of treating an inflammatory disease or condition in a subject in need thereof, comprising a step of administering to the subject a therapeutically effective amount of the polypeptide disclosed herein or the pharmaceutical composition disclosed herein. In certain embodiments, the inflammatory' disease or condition is an autoimmune disease or condition.

[0114] In certain embodiments, the subject is a mammal. In certain embodiments, the mammal is a human. In certain embodiments, the step of administering comprises systemic administration. In certain embodiments, the systemic administration comprises intravenous administration. In certain embodiments, the systemic administration comprises subcutaneous administration.

[0115] In some embodiments, the subject is a mammal. In some embodiments, the mammal is a human.

[0116] In some embodiments, the autoimmune disease or condition affects the skin. In some embodiments, the autoimmune disease or condition is epidermal bullosa acquisita (EBA). In some embodiments, the autoimmune disease or condition affects the kidney. In some embodiments, the autoimmune disease or condition is immune-mediated glomerulonephritis. In some embodiments, the autoimmune disease or condition is an arthritic disease. In some embodiments, the autoimmune disease or condition is a neuroinflammatory disease. In some embodiments, the autoimmune disease or condition is multiple sclerosis.

[0117] In another aspect, provided herein are methods of improving Fc half-life and bioavailability comprising decreasing affinity for asialoglycoprotein receptor (ASGPR) in a subject in need thereof comprising a step of administering to the subject a therapeutically effective amount of the modified Fc polypeptide disclosed herein or the pharmaceutical composition disclosed herein.

[0118] In another aspect, provided herein are methods of exerting immune protection through anti-inflammatory type II Fey receptors SIGN-R1 and DC-SIGN in a subject in need thereof comprising a step of administering to the subject a therapeutically effective amount of the modified Fc polypeptide disclosed herein or the pharmaceutical composition disclosed herein.

[0119] In another aspect, provided herein are methods increasing the level of regulatory T (Treg) cells in a subject in need thereof comprising a step of administering to the subject a therapeutically effective amount of the modified Fc polypeptide disclosed herein or the pharmaceutical composition disclosed herein.

[0120] In another aspect, provided herein is a modified Fc polypeptide comprising a modified Fc polypeptide with means for binding to FcyRIIB. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 75% identical to the sequence of SEQ ID NO: 1, and further comprising: (i) a sialic acid (SA) moiety attached to an N-glycan of the Fc polypeptide; (ii) an aliphatic amino acid residue at position 241 or position 243, and (iii) amino acid modifications selected from the group consisting of: (a) an aspartic acid residue at position 233 (E233D), an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 238 (P238D), an aspartic acid residue at position 268 (H268D), a glycine residue at position 271 (P271G), and an arginine residue at position 330 (A330R); (b) an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 238 (P238D), a glycine residue at position 271 (P271G), and an arginine residue at position 330 (A330R); (c) an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 238 (P238D), an aspartic acid residue at position 268 (H268D), a glycine residue at position 271 (P271G). and an arginine residue at position 330 (A330R); (d) an aspartic acid residue at position 233 (E233D), an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 238 (P238D), an aspartic acid residue at position 268 (H268D), a glycine residue at position 271 (P271G), an arginine residue at position 330 (A330R), aleucine residue at position 428 (M428L), and a serine residue at position 434 (N434S); (e) an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 238 (P238D), a glycine residue at position 271 (P271G), and an arginine residue at position 330 (A330R), a leucineresidue at position 428 (M428L), and a serine residue at position 434 (N434S); and (f) an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 238 (P238D), an aspartic acid residue at position 268 (H268D), a glycine residue at position 271 (P271G), and an arginine residue at position 330 (A330R), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S); wherein the position numbering is according to the EU index of Kabat.

[0121] In some embodiments, the modified Fc polypeptide comprises an amino acid sequence at least 75% identical to the sequence of SEQ ID NO: 1, and further comprising: (i) an aliphatic amino acid residue at position 241 or position 243; (ii) an amino acid modification at position 238; (iii) a sialic acid (SA) moiety attached to an N-glycan of the Fc polypeptide; and (iv) at least one additional amino acid modification at a position selected from the group consisting of: 233, 236, 237, 239, 267, 268, 271, 296, 328, 330, and combinations thereof; wherein the position numbering is according to the EU index of Kabat.

[0122] In some embodiments, the at least one additional amino acid modification is selected from the group consisting of: (a) an aspartic acid residue at position 233 (E233D). (b) an aspartic acid residue at position 236 (G236D), (c) an aspartic acid residue at position 237 (G237D), (d) an aspartic acid residue at position 239 (S239D), (e) a glutamic acid residue at position 267 (S267E), (f) an aspartic acid residue at position 268 (H268D), (g) a glycine residue at position 271 (P271G), (h) an aspartic acid residue at position 296 (Y296D), (i) a phenylalanine at position 328 (L328F), (j) an arginine residue at position 330 (A330R), and combinations thereof; wherein the position numbering is according to the EU index of Kabat.

[0123] In some embodiments, the modified Fc polypeptide further comprises an amino acid modification at a position selected from the group consisting of: 252, 254, 256, 428, 433, 434, 436 and combinations thereof; wherein the position numbering is according to the EU index of Kabat.

[0124] In some embodiments, the amino acid modification is selected from the group consisting of: a ty rosine residue at position 252 (M252Y), a threonine residue at position 254 (S254T), a glutamic acid residue at position 256 (T256E). a leucine residue at position 428 (M428L), a lysine residue at position 433 (H433K), a serine residue at position 434 (N434S) or a phenylalanine residue at position 434 (N434F), a histidine residue at position 436 (Y 436H), and combinations thereof, wherein the position numbering is according to the EU index of Kabat.

[0125] In some embodiments, the aliphatic amino acid residue at position 241 is an alanine (F241 A) or the aliphatic amino acid residue at position 243 is an alanine (F243A).

[0126] In some embodiments, the aliphatic amino acid residue at position 241 is an alanine (F241A). In some embodiments, the aliphatic amino acid residue at position 243 is an alanine (F243A). In some embodiments, the aliphatic amino acid residue at position 241 is a leucine (F241L). In some embodiments, the aliphatic amino acid residue at position 243 is an alanine (F243L).

[0127] In some embodiments, the modified Fc polypeptide does not comprise a C-terminal lysine residue. In some embodiments, the modified Fc polypeptide does comprise a C-terminal lysine residueBRIEF DESCRIPTION OF THE DRAWINGS

[0128] FIG. 1 is a line graph showing binding of wild-type Fc (“WT-Fc”) and modified Fc polypeptides (modified Fc polypeptides comprising F241A amino acid modification (“F241A- Fc”), modified Fc polypeptides comprising E233D. G237D, P238D, H268D, P271G, and A330R amino acid modifications (“E233D / G237D / P238D / H268D / P271G / A330R-Fc”), modified Fc polypeptides comprising E233D and P238D amino acid modifications (“E233D / P238D-Fc”), or modified Fc polypeptides comprising G237D, P238D, H268D, P271G, and A330R amino acid modifications (“G237D / P238D / H268D / P271G / A330R-Fc”)) to FcyRIIB. The graph shows the FRET ratio (665 nm / 620 nm) from a FRET assay read at 2 hrs. The x-axis depicts log [antibody (Ab)] concentration (pM).

[0129] FIG. 2 is a line graph showing binding of WT-Fc and modified Fc polypeptides F241A-Fc, modified Fc polypeptides comprising F241A, E233D, G237D, P238D, H268D, P271G. and A330R amino acid modifications(“F241A / E233D / G237D / P238D / H268D / P271G / A330R-FC”), modified Fc polypeptides comprising F241A, E233D and P238D amino acid modifications (“F241A / E233D / P238D- Fc")- or modified Fc polypeptides comprising F241A, G237D, P238D, H268D, P271G, and A330R amino acid modifications (“F241A / G237D / P238D / H268D / P271G / A330R-Fc”)) to FcyRIIB. The graph shows the FRET ratio (665 nm / 620 nm) from a FRET assay. The x-axis depicts log [Ab] concentration (pM).

[0130] FIG. 3 is a line graph showing binding of WT-Fc and modified Fc polypeptides (F241A-Fc, modified Fc polypeptides comprising S267E and L328F amino acid modifications (“S267E / L328F-Fc”), or modified Fc polypeptides comprising F241A, S267E, and L328F amino acid modifications (“F241A / S267E / L328F-Fc”)) to FcyRIIB. The graph shows theFRET ratio (665 nm / 620 nm) from a FRET assay. The x-axis depicts log [Ab] concentration (pM).

[0131] FIG. 4 is a line graph showing binding of WT-Fc and modified Fc polypeptides (E233D / G237D / P238D / H268D / P271G / A330R-Fc, E233D / P238D-Fc. orG237D / P238D / H268D / P271G / A330R-Fc) to FcyRIITA (V158 polymorphic variant). The graph shows the FRET ratio (665 nm / 620 nm) from a FRET assay read at 2 hrs. The x-axis depicts log [Ab] concentration (pM).

[0132] FIG. 5 is a line graph showing binding of modified Fc polypeptides (F241A-Fc, F241A / E233D / G237D / P238D / H268D / P271G / A330R-Fc, F241A / E233D / P238D-Fc, orF241A / G237D / P238D / H268D / P271G / A330R-Fc to FcyRIIIA (V158 polymorphic variant). The graph shows the FRET ratio (665 nm / 620 nm) from a FRET assay read at 2 hrs. The x- axis depicts log [Ab] concentration (pM).DETAILED DESCRIPTION OF CERTAIN EMBODIMENTSDefinitions

[0133] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the claimed subject matter belongs. Generally, nomenclatures utilized in connection with and techniques of immunology, oncology, cell and tissue culture, molecular biology, and protein chemistry described herein are those well-known and commonly used in the art. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0134] As used herein, singular forms ‘"a,” "‘and / ’ and "‘the” include plural referents unless the context clearly indicates otherwise. Thus, e.g, reference to “a polypeptide” includes a plurality of polypeptides.

[0135] As used herein, all numerical values or numerical ranges include whole integers within or encompassing such ranges and fractions of the values or the integers within or encompassing ranges unless the context clearly indicates otherwise. Thus, e.g., reference to a range of 90-100%. includes 91%. 92%. 93%. 94%, 95%, 96%, 97%, etc., as well as 91.1%. 91.2%, 91.3%, 91.4%, 91.5%, etc., 92.1%, 92.2%, 92.3%, 92.4%, 92.5%, etc., and so forth. Inanother example, reference to a range of 1-5,000 fold includes 1. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 fold, etc., as well as 1.1, 1.2, 1.3, 1.4. 1.5 fold, etc., 2.1, 2.2, 2.3, 2.4, 2.5 fold, etc., and so forth.

[0136] The terms “about’ and “approximately.” when used herein in reference to a value, are used interchangeably and refer to a value that is similar to the referenced value. In general, those skilled in the art, familiar with the context, will appreciate the relevant degree of variation encompassed by “about” or “approximately” in that context. For example, in some embodiments, the terms “about” and “approximately” may encompass a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the referred value.

[0137] As used herein, the terms “alter,” “altered,” “decrease,” “decreased,” “increase,” “increased,” or “reduction,” “reduced,” (e.g., in reference to certain outcomes or effects) have meanings relative to a reference level. In some embodiments, in the context of discussing amino acid modifications in an Fc chain or Fc polypeptide, the reference level is a level known or as determined with an IgG that does not contain the referenced amino acid modification(s) in the Fc region.

[0138] The term “polypeptide,” as used herein, generally has its art-recognized meaning of a polymer of at least three amino acids, e g., linked to each other by peptide bonds. Those of ordinary skill in the art will appreciate that the term “polypeptide” is intended to be sufficiently general as to encompass not only polypeptides having a complete sequence recited herein, but also to encompass polypeptides that represent functional fragments (i.e., fragments retaining at least one activity) of such complete polypeptides. Moreover, those of ordinary skill in the art understand that protein sequences generally tolerate some substitution without destroying activity. Thus, any polypeptide that retains activity and shares at least about 30-40% overall sequence identity, often greater than about 50%, 60%, 70%, or 80%, and further usually including at least one region of much higher identity, often greater than 90% or even 95%, 96%, 97%. 98%, or 99% in one or more highly conserved regions, usually encompassing at least 3-4 and often up to 20 or more amino acids, with another polypeptide of the same class, is encompassed within the relevant term “polypeptide” as used herein. 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, glycosylation etc. In some embodiments, proteins maycomprise natural amino acids, non-natural amino acids, synthetic amino acids, and combinations thereof.

[0139] As used herein, “administration” refers to providing or giving a subject a therapeutic agent (e.g. , a modified Fc polypeptide of the disclosure or a composition containing the same) by any effective route. Exemplar}' routes of administration are described in the sections that follow.

[0140] The term “effective amount” as used herein, refers to that amount of Fc polypeptides or compositions of the disclosure that is sufficient to induce a disclosed effect, e.g., to effect treatment, prognosis, or diagnosis of a disease (e.g, autoimmune disorder), as described herein, when administered to a subject. Therapeutically effective amounts of the compositions provided herein, when used alone or in combination, will vary depending upon the relative activity of the disclosed compositions and combinations (e.g, in treating, reducing, or ameliorating a disease or disorder described herein) and depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration, and the like.

[0141] As used herein, the terms “Fc polypeptide,” “Fc peptide,” “Fc fragment,” “Fc region,” and “Fc domain” are interchangeably used to define a C-terminal region of an immunoglobulin heavy chain. The “Fc polypeptide” is a native sequence Fc region or a variant Fc region, in some embodiments. Although the boundaries of the Fc region of an immunoglobulin heavy chain might vary, the human IgG heavy chain Fc region is usually defined to stretch from an amino acid residue at position Cys226, or from Pro230, to the carboxyl-terminus thereof. In certain embodiments, the “Fc domain” comprises at least a portion of a hinge (e.g., upper, middle, and / or lower hinge region) domain, a CH2 domain, and a CH3 domain.

[0142] A “native” or “parental” Fc region comprises an ammo acid sequence identical to the amino acid sequence of an Fc region found in nature. A “variant” or “modified” Fc region includes an amino acid sequence which differs from that of a native sequence Fc region by virtue of at least one amino acid modification, such as an amino acid substitution (e.g. , F241A). In some embodiments, a modified Fc region has at least one amino acid substitution compared to a native sequence Fc region or to the Fc region of a parent polypeptide, e.g. , from about one to about ten amino acid substitutions. The modified Fc region described herein will, in some embodiments, possess at least 75% (e.g., at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%. 85%. 86%. 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,99%, or more) sequence identity with the native sequence Fc region and / or with an Fc region of a parent polypeptide.

[0143] “Percent (%) sequence identity’' with respect to a reference polynucleotide or polypeptide sequence is defined as the percentage of nucleic acids or amino acids in a candidate sequence that are identical to the nucleic acids or amino acids in the reference polynucleotide or polypeptide sequence, after aligning the sequences and introducing gaps, if necessary', to achieve the maximum percent sequence identity'. Alignment for purposes of determining percent nucleic acid or amino acid sequence identity can be achieved in various ways that are within the capabilities of one of skill in the art, for example, using publicly available computer software such as BLAST (e.g., BLASTp for protein sequence alignment), BLAST-2, or Megalign softw are. Appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared, are determined by any suitable means. For example, percent sequence identity values may be generated using the sequence comparison computer program BLAST. As an illustration, the percent sequence identity' of a given nucleic acid or amino acid sequence, A, to, with, or against a given nucleic acid or amino acid sequence, B, (which can alternatively be phrased as a given nucleic acid or amino acid sequence, A that has a certain percent sequence identity to, with, or against a given nucleic acid or amino acid sequence, B) is calculated as follows:100 multiplied by (the fraction X / Y) where X is the number of nucleotides or amino acids scored as identical matches by a sequence alignment program (e.g., BLAST) in that program’s alignment of A and B, and where Y is the total number of nucleic acids in B. It w ill be appreciated that where the length of nucleic acid or amino acid sequence A is not equal to the length of nucleic acid or amino acid sequence B, the percent sequence identity' of A to B will not equal the percent sequence identity of B to A.

[0144] As used herein, the term “specifically binds, “ specifically binding,” “binds specifically,” or similar terms, means that a binding moiety' (e.g., an antibody or an antigenbinding fragment thereof) forms a complex with an antigen that is relatively stable under physiologic conditions. Specific binding can be characterized by an equilibrium dissociation constant of lxl0‘6M or less , IxlO’7M or less, lxl0‘8M or less, or IxlO-9M or less (e.g., a smaller KD denotes a tighter binding). Methods for determining whether tw'O molecules specifically bind are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, enzyme-linked immunosorbent assay, or biolayer interferometry measurements, etc. In some embodiments, “specifically binds” and similar terms refers to acharacteristic of the binding moiety in that the binding moiety is capable of binding to a target antigen but does is not capable of binding to other antigens such as distantly related family members of the antigen.

[0145] As used herein, the terms “recipient,” “individual,” “subject,” “host,” and “patient” are used interchangeably herein and refer to an organism, ty pically a mammal (e.g., a human). In some embodiments, a subj ect is suffering from or susceptible to a relevant disease, disorder or condition, e.g., an autoimmune disease, disorder, or condition. In some embodiments, a subject displays one or more symptoms or characteristics of a disease, disorder or condition. In some embodiments, a subject is someone with one or more features characteristic of susceptibility' to or risk of a disease, disorder, or condition. In some embodiments, a subject is a patient. In some embodiments, a subject is a subject to whom diagnosis and / or therapy is and / or has been administered.

[0146] As used herein, the term “treatment” (also “treat” or “treating”) refers to any administration of a therapy that partially or completely alleviates, ameliorates, relieves, inhibits, delays onset of, reduces severity’ of, and / or reduces incidence of one or more symptoms, features, and / or causes of a particular disease, disorder, and / or condition. In some embodiments, such treatment may be of a subj ect who does not exhibit signs of the relevant disease, disorder and / or condition and / or of a subject who exhibits only early signs of the disease, disorder, and / or condition. Alternatively, or additionally, such treatment may be of a subject who exhibits one or more established signs of the relevant disease, disorder and / or condition. In some embodiments, treatment may be of a subject who has been diagnosed as suffering from the relevant disease, disorder, and / or condition. In some embodiments, treatment may be of a subject known to have one or more susceptibility factors that are statistically correlated with increased risk of development of the relevant disease, disorder, and / or condition.

[0147] The term “therapeutically effective amount” generally refers to an amount of a disclosed composition effective to “treat” a disease or disorder in a subject or mammal. In some embodiments, a composition described herein is administered to a subject in an amount that is effective for producing some desired therapeutic effect by inhibiting a disease or disorder as described herein at a reasonable benefit / risk ratio applicable to any medical treatment. A therapeutically effective amount is an amount that achieves at least partially a desired therapeutic or prophylactic effect in an organ or tissue. The amount of a therapeutic agent necessary to bring about prevention and / or therapeutic treatment of a disease or disorder is not fixed per se. In some embodiments, the amount of the therapeutic agent administered varieswith the type and extensiveness of the disease, and the size of the mammal suffering from the disease or disorder. When used in conjunction with therapeutic methods involving administration of a therapeutic agent after the subject presents symptoms of a disease or disorder, the term “therapeutically effective’’ means that, after treatment, one or more signs or symptoms of the disease or disorder is ameliorated or eliminated.Immunoglobulin and Fc Glycosylation

[0148] IgG is a glycoprotein composed of two identical heavy chains and two light chains which are composed of variable and constant domains. IgG contains a single. N-linked glycan at asparagine 297 (Asn297) in the CH2 domain on each of its two heavy chains. The covalently -linked, complex carbohydrate is composed of a core biantennary penta-saccharide containing N-acetylglucosamine (GlcNAc) and mannose (Man). Further modification of the core carbohydrate structure is observed in serum antibodies with the presence of fucose (Fuc), branching GlcNAc, galactose (Gal) and variably present terminal sialic acid (SA) moieties. Over 40 different glycoforms have thus been detected to be covalently attached to this single glycosylation site. Glycosylation of IgG has been shown to be essential for binding to all FcyRs by maintaining an open conformation of the two heavy chains. It is believed that this IgG glycosylation for FcyR binding accounts for the inability of de-glycosylated IgG antibodies to mediate in vivo triggered inflammatory responses, such as antibody-dependent cellular cytotoxicity (ADCC), phagocytosis, and release of inflammatory mediators. That individual IgG glycoforms may contribute to modulation of inflammatory' responses has been suggested by the altered affinities for individual FcyRs reported for IgG antibodies containing or lacking Fuc and its consequential effects on cytotoxicity. A link between autoimmune states and specific glycosylation patterns of IgG antibodies has been observed in patients with rheumatoid arthritis and autoimmune vasculitis in which decreased galactosylation and sialylation of IgG antibodies have been reported.Compositions

[0149] Disclosed herein, in some embodiments, are compositions (e.g., therapeutic compositions) comprising modified Fc polypeptides having sequences of variants of a wildty pe human IgG Fc polypeptide of SEQ ID NO: 2 or SEQ ID NO: 12 (or an allotype variant, e.g., an alloty pe variant comprising the amino acid sequence of SEQ ID NO: 4, 5, 8, and / or 9) and having high levels of sialylation, such as at least 50% a(2,6) sialylation (e.g., at least 50%, 51%. 52%. 53%. 54%. 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%,83%, 84%, 85%, 86%. 87%. 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%. or more) or about 40% a(2,3) sialylation (e.g, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%). In some embodiments, disclosed are compositions (e.g., therapeutic compositions) comprising modified Fc polypeptides having an amino acid sequence listed in Table 1 and having high levels of sialylation, such as at least 50% a(2,6) sialylation (e.g.. at least 50%, 51 %, 52%, 53%, 54%. 55%. 56%. 57%. 58%. 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%. 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) or about 40% a(2,3) sialylation (e.g, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%. 41%. 42%. 43%. 44%. 45%. 46%. 47%. 48%. 49%. 50%).

[0150] In some embodiments, the composition comprises a modified Fc polypeptide having an amino acid sequence at least 85% (e.g.. at least 86%, 87%, 88%, 89%, etc.) identical to SEQ ID NO: 13 and having high levels of sialylation, such as at least 50% a(2,6) sialylation (e.g, at least 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%. 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%. 82%. 83%. 84%. 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) or about 40% a(2,3) sialylation (e.g, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%).

[0151] In some embodiments, the composition comprises a modified Fc polypeptide having an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to SEQ ID NO: 15 and having high levels of sialylation, such as at least 50% a(2,6) sialylation (e.g, at least 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) or about 40% a(2,3) sialylation (e.g., 30%, 31%, 32%, 33%, 34%, 35%, 36%. 37%, 38%. 39%. 40%. 41%. 42%. 43%. 44%. 45%. 46%. 47%. 48%. 49%. 50%).

[0152] In some embodiments, the composition comprises a modified Fc polypeptide having an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to SEQ ID NO: 17 and having high levels of sialylation, such as at least 50% a(2,6) sialylation (e.g, at least 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%. 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%. 83%. 84%. 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%,97%, 98%, 99%, or more) or about 40% a(2,3) sialylation (e.g., 30%, 31%, 32%, 33%, 34%, 35%. 36%. 37%. 38%. 39%. 40%. 41%. 42%. 43%. 44%. 45%. 46%. 47%. 48%. 49%. 50%).

[0153] In some embodiments, the composition comprises a modified Fc polypeptide having an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to SEQ ID NO: 19 and having high levels of sialylation, such as at least 50% a(2,6) sialylation e.g., at least 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%. 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%. 82%. 83%. 84%. 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) or about 40% a(2,3) sialylation (e.g., 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%).

[0154] In some embodiments, the composition comprises a modified Fc polypeptide having an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to SEQ ID NO: 21 and having high levels of sialylation, such as at least 50% a(2,6) sialylation (e.g, at least 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) or about 40% a(2,3) sialylation (e.g., 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%. 42%. 43%. 44%. 45%. 46%. 47%. 48%. 49%. 50%).

[0155] In some embodiments, the composition comprises a modified Fc polypeptide having an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to SEQ ID NO: 23 and having high levels of sialylation, such as at least 50% a(2,6) sialylation (e.g, at least 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%. 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%. 84%. 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%. 98%. 99%. or more) or about 40% a(2,3) sialylation (e.g, 30%, 31%, 32%, 33%, 34%. 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%).

[0156] In some embodiments, the composition comprises a modified Fc polypeptide having an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to SEQ ID NO: 25 and having high levels of sialylation, such as at least 50% a(2,6) sialylation (e.g, at least 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%. 66%. 67%. 68%. 69%. 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%. 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%,97%, 98%, 99%, or more) or about 40% a(2,3) sialylation (e.g., 30%, 31%, 32%, 33%, 34%, 35%. 36%. 37%. 38%. 39%. 40%. 41%. 42%. 43%. 44%. 45%. 46%. 47%. 48%. 49%. 50%).

[0157] In some embodiments, the composition comprises a modified Fc polypeptide having an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to SEQ ID NO: 26 and having high levels of sialylation, such as at least 50% a(2,6) sialylation e.g., at least 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%. 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%. 82%. 83%. 84%. 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) or about 40% a(2,3) sialylation (e.g., 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%).

[0158] In some embodiments, the composition comprises a modified Fc polypeptide having an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to SEQ ID NO: 27 and having high levels of sialylation, such as at least 50% a(2,6) sialylation (e.g, at least 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) or about 40% a(2,3) sialylation (e.g., 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%. 42%. 43%. 44%. 45%. 46%. 47%. 48%. 49%. 50%).

[0159] In some embodiments, the composition comprises a modified Fc polypeptide having an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to SEQ ID NO: 28 and having high levels of sialylation, such as at least 50% a(2,6) sialylation (e.g, at least 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%. 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%. 84%. 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%. 98%. 99%. or more) or about 40% a(2,3) sialylation (e.g, 30%, 31%, 32%, 33%, 34%. 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%).

[0160] In some embodiments, the composition comprises a modified Fc polypeptide having an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to SEQ ID NO: 29 and having high levels of sialylation, such as at least 50% a(2,6) sialylation (e.g, at least 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%. 66%. 67%. 68%. 69%. 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%. 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%,97%, 98%, 99%, or more) or about 40% a(2,3) sialylation (e.g., 30%, 31%, 32%, 33%, 34%, 35%. 36%. 37%. 38%. 39%. 40%. 41%. 42%. 43%. 44%. 45%. 46%. 47%. 48%. 49%. 50%).

[0161] In some embodiments, the composition comprises a modified Fc polypeptide having an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to SEQ ID NO: 30 and having high levels of sialylation, such as at least 50% a(2,6) sialylation e.g., at least 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%. 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%. 82%. 83%. 84%. 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) or about 40% a(2,3) sialylation (e.g., 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%).

[0162] In some embodiments, the composition comprises a modified Fc polypeptide having an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to SEQ ID NO: 31 and having high levels of sialylation, such as at least 50% a(2,6) sialylation (e.g, at least 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) or about 40% a(2,3) sialylation (e.g., 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%. 42%. 43%. 44%. 45%. 46%. 47%. 48%. 49%. 50%).

[0163] In some embodiments, the composition comprises a modified Fc polypeptide having an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to SEQ ID NO: 32 and having high levels of sialylation, such as at least 50% a(2,6) sialylation (e.g, at least 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%. 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%. 84%. 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%. 98%. 99%. or more) or about 40% a(2,3) sialylation (e.g, 30%, 31%, 32%, 33%, 34%. 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%).

[0164] In some embodiments, the composition comprises a modified Fc polypeptide having an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to SEQ ID NO: 33 and having high levels of sialylation, such as at least 50% a(2,6) sialylation (e.g, at least 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%. 66%. 67%. 68%. 69%. 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%. 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%,97%, 98%, 99%, or more) or about 40% a(2,3) sialylation (e.g., 30%, 31%, 32%, 33%, 34%, 35%. 36%. 37%. 38%. 39%. 40%. 41%. 42%. 43%. 44%. 45%. 46%. 47%. 48%. 49%. 50%).

[0165] In some embodiments, the composition comprises a modified Fc polypeptide having an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to SEQ ID NO: 34 and having high levels of sialylation, such as at least 50% a(2,6) sialylation e.g., at least 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%. 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%. 82%. 83%. 84%. 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) or about 40% a(2,3) sialylation (e.g., 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%).

[0166] In some embodiments, the composition comprises a modified Fc polypeptide having an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to SEQ ID NO: 35 and having high levels of sialylation, such as at least 50% a(2,6) sialylation (e.g, at least 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) or about 40% a(2,3) sialylation (e.g., 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%. 42%. 43%. 44%. 45%. 46%. 47%. 48%. 49%. 50%).

[0167] In some embodiments, the composition comprises a modified Fc polypeptide having an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to SEQ ID NO: 36 and having high levels of sialylation, such as at least 50% a(2,6) sialylation (e.g, at least 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%. 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%. 84%. 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%. 98%. 99%. or more) or about 40% a(2,3) sialylation (e.g, 30%, 31%, 32%, 33%, 34%. 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%).

[0168] In some embodiments, the composition comprises a modified Fc polypeptide having an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to SEQ ID NO: 37 and having high levels of sialylation, such as at least 50% a(2,6) sialylation (e.g, at least 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%. 66%. 67%. 68%. 69%. 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%. 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%,97%, 98%, 99%, or more) or about 40% a(2,3) sialylation (e.g., 30%, 31%, 32%, 33%, 34%, 35%. 36%. 37%. 38%. 39%. 40%. 41%. 42%. 43%. 44%. 45%. 46%. 47%. 48%. 49%. 50%).

[0169] In some embodiments, the composition comprises a modified Fc polypeptide having an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to SEQ ID NO: 38 and having high levels of sialylation, such as at least 50% a(2,6) sialylation e.g., at least 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%. 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%. 82%. 83%. 84%. 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) or about 40% a(2,3) sialylation (e.g., 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%).

[0170] In some embodiments, the composition comprises a modified Fc polypeptide having an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to SEQ ID NO: 39 and having high levels of sialylation, such as at least 50% a(2,6) sialylation (e.g, at least 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) or about 40% a(2,3) sialylation (e.g., 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%. 42%. 43%. 44%. 45%. 46%. 47%. 48%. 49%. 50%).

[0171] In some embodiments, the composition comprises a modified Fc polypeptide having an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to SEQ ID NO: 40 and having high levels of sialylation, such as at least 50% a(2,6) sialylation (e.g, at least 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%. 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%. 84%. 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%. 98%. 99%. or more) or about 40% a(2,3) sialylation (e.g, 30%, 31%, 32%, 33%, 34%. 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%).

[0172] In some embodiments, the composition comprises a modified Fc polypeptide having an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to SEQ ID NO: 41 and having high levels of sialylation, such as at least 50% a(2,6) sialylation (e.g, at least 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%. 66%. 67%. 68%. 69%. 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%. 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%,97%, 98%, 99%, or more) or about 40% a(2,3) sialylation (e.g., 30%, 31%, 32%, 33%, 34%, 35%. 36%. 37%. 38%. 39%. 40%. 41%. 42%. 43%. 44%. 45%. 46%. 47%. 48%. 49%. 50%).

[0173] In some embodiments, the composition comprises a modified Fc polypeptide having an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to SEQ ID NO: 42 and having high levels of sialylation, such as at least 50% a(2,6) sialylation e.g., at least 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%. 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%. 82%. 83%. 84%. 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) or about 40% a(2,3) sialylation (e.g., 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%).

[0174] In some embodiments, the composition comprises a modified Fc polypeptide having an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to SEQ ID NO: 43 and having high levels of sialylation, such as at least 50% a(2,6) sialylation (e.g, at least 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) or about 40% a(2,3) sialylation (e.g., 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%. 42%. 43%. 44%. 45%. 46%. 47%. 48%. 49%. 50%).

[0175] In some embodiments, the composition comprises a modified Fc polypeptide having an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to SEQ ID NO: 44 and having high levels of sialylation, such as at least 50% a(2,6) sialylation (e.g, at least 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%. 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%. 84%. 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%. 98%. 99%. or more) or about 40% a(2,3) sialylation (e.g, 30%, 31%, 32%, 33%, 34%. 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%).

[0176] In some embodiments, the composition comprises a modified Fc polypeptide having an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to SEQ ID NO: 45 and having high levels of sialylation, such as at least 50% a(2,6) sialylation (e.g, at least 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%. 66%. 67%. 68%. 69%. 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%. 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%,97%, 98%, 99%, or more) or about 40% a(2,3) sialylation (e.g., 30%, 31%, 32%, 33%, 34%, 35%. 36%. 37%. 38%. 39%. 40%. 41%. 42%. 43%. 44%. 45%. 46%. 47%. 48%. 49%. 50%).

[0177] In some embodiments, the composition comprises a modified Fc polypeptide having an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to SEQ ID NO: 46 and having high levels of sialylation, such as at least 50% a(2,6) sialylation e.g., at least 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%. 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%. 82%. 83%. 84%. 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) or about 40% a(2,3) sialylation (e.g., 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%).

[0178] In some embodiments, the composition comprises a modified Fc polypeptide having an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to SEQ ID NO: 47 and having high levels of sialylation, such as at least 50% a(2,6) sialylation (e.g, at least 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) or about 40% a(2,3) sialylation (e.g., 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%. 42%. 43%. 44%. 45%. 46%. 47%. 48%. 49%. 50%).

[0179] In some embodiments, the composition comprises a modified Fc polypeptide having an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to SEQ ID NO: 48 and having high levels of sialylation, such as at least 50% a(2,6) sialylation (e.g, at least 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%. 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%. 84%. 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%. 98%. 99%. or more) or about 40% a(2,3) sialylation (e.g, 30%, 31%, 32%, 33%, 34%. 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%).

[0180] In some embodiments, the composition comprises a modified Fc polypeptide having an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to SEQ ID NO: 49 and having high levels of sialylation, such as at least 50% a(2,6) sialylation (e.g, at least 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%. 66%. 67%. 68%. 69%. 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%. 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%,97%, 98%, 99%, or more) or about 40% a(2,3) sialylation (e.g., 30%, 31%, 32%, 33%, 34%, 35%. 36%. 37%. 38%. 39%. 40%. 41%. 42%. 43%. 44%. 45%. 46%. 47%. 48%. 49%. 50%).

[0181] In some embodiments, the composition comprises a modified Fc polypeptide having an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to SEQ ID NO: 50 and having high levels of sialylation, such as at least 50% a(2,6) sialylation e.g., at least 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%. 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%. 82%. 83%. 84%. 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) or about 40% a(2,3) sialylation (e.g., 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%).

[0182] In some embodiments, the composition comprises a modified Fc polypeptide having an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to SEQ ID NO: 51 and having high levels of sialylation, such as at least 50% a(2,6) sialylation (e.g, at least 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) or about 40% a(2,3) sialylation (e.g., 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%. 42%. 43%. 44%. 45%. 46%. 47%. 48%. 49%. 50%).

[0183] In some embodiments, the composition comprises a modified Fc polypeptide having an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to SEQ ID NO: 52 and having high levels of sialylation, such as at least 50% a(2,6) sialylation (e.g, at least 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%. 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%. 84%. 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%. 98%. 99%. or more) or about 40% a(2,3) sialylation (e.g, 30%, 31%, 32%, 33%, 34%. 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%).

[0184] In some embodiments, the composition comprises a modified Fc polypeptide having an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to SEQ ID NO: 53 and having high levels of sialylation, such as at least 50% a(2,6) sialylation (e.g, at least 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%. 66%. 67%. 68%. 69%. 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%. 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%,97%, 98%, 99%, or more) or about 40% a(2,3) sialylation (e.g., 30%, 31%, 32%, 33%, 34%, 35%. 36%. 37%. 38%. 39%. 40%. 41%. 42%. 43%. 44%. 45%. 46%. 47%. 48%. 49%. 50%).

[0185] In some embodiments, the composition comprises a modified Fc polypeptide having an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to SEQ ID NO: 54 and having high levels of sialylation, such as at least 50% a(2,6) sialylation e.g., at least 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%,65%, 66%, 67%, 68%. 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%,81%. 82%. 83%. 84%. 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%,97%, 98%, 99%, or more) or about 40% a(2,3) sialylation (e.g., 30%, 31%, 32%, 33%, 34%,35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%).

[0186] In some embodiments, the composition comprises a modified Fc polypeptide having an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to SEQ ID NO: 55 and having high levels of sialylation, such as at least 50% a(2,6) sialylation (e.g, at least 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%,65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%,81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%,97%, 98%, 99%, or more) or about 40% a(2,3) sialylation (e.g., 30%, 31%, 32%, 33%, 34%,35%, 36%, 37%, 38%, 39%, 40%, 41%. 42%. 43%. 44%. 45%. 46%. 47%. 48%. 49%. 50%).

[0187] In some embodiments, the composition comprises a modified Fc polypeptide having an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to SEQ ID NO: 56 and having high levels of sialylation, such as at least 50% a(2,6) sialylation (e.g, at least 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%,65%, 66%, 67%, 68%, 69%. 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%,81%, 82%, 83%. 84%. 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%,97%. 98%. 99%. or more) or about 40% a(2,3) sialylation (e.g, 30%, 31%, 32%, 33%, 34%.35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%).

[0188] In some embodiments, the modified Fc polypeptides comprise a sialic acid (SA) moiety attached to an N-glycan of the modified Fc polypeptide via an a(2,6) linkage.Polypeptides

[0189] Polypeptides of the present disclosure may comprise or consist of Fc polypeptides as described herein. In other embodiments, provided polypeptides consist of Fc polypeptides as described herein. In some embodiments, provided polypeptides comprise one or more Fcpolypeptides and at least one another domain, e.g., an immunoglobulin variable domain which specifically binds an antigen of interest.Fc polypeptide Variants

[0190] In some embodiments, the Fc polypeptide comprises an IgG Fc chain. An IgG Fc chain (e.g., IgGl Fc chain) ty pical ly contains two constant heavy domains (CH2 and CH3) and a hinge region connected to the CH2 domain.

[0191] Fc polypeptides within polypeptides of the present disclosure generally have at least 75%, at least 80%, at least 85%, at least 90%, at least 92.5%, at least 95%. at least 96%, at least 97%. at least 98%, or at least 99% identity to SEQ ID NO: 1. provided that the amino acid residue at position 241 is an aliphatic residue, e.g., an alanine residue.

[0192] SEQ ID NO: 1 is shown below, with the amino acid residue at position 241 indicated by bold underlining. Throughout the disclosure, unless otherwise indicated, position numbering refers to that according to the EU index of Kabat.KVDKKVEPKSCDKTHTCPPCPAPELLGGPSVALFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPGK (SEQ ID NO: 1)

[0193] Position 297 corresponds to amino acid residue 88 of SEQ ID NO: 1.

[0194] Position 241 corresponds to amino acid residue 32 of SEQ ID NO: 1.

[0195] Disclosed herein, in some embodiments, are modified and highly sialylated Fc polypeptides having an amino acid substitution from phenylalanine (F) to an aliphatic amino acid residue (e.g. alanine, glycine, isoleucine, leucine, proline, valine, and methionine) at amino acid position 241 of the Fc heavy7chain (F241; numbered according to the EU index of Kabat). In some embodiments, provided herein are modified and highly sialylated Fc polypeptides having an amino acid substitution from phenylalanine (F) to an aliphatic amino acid residue (e.g, alanine, glycine, isoleucine, leucine, proline, valine, and methionine) at amino acid position 243 of the Fc heavy7chain (F243; numbered according to the EU index of Kabat).

[0196] The Fc polypeptide generally further generally comprise at least one other modification (e.g., relative to a wild type Fc polypeptide such as a wild type IgG (e.g., IgGl) Fc polypeptide). In some embodiments, the at least one other modification is associated withenhanced binding affinity to an Fey receptor, e.g, FcyRIIb. In some embodiments, the at least one other modification is associated with more than 10-fold, more than 50-fold, more than 75- fold, more than 100-fold, more than 125-fold, more than 150-fold, more than 175-fold, or more than 200-fold stronger binding affinity to FcyRIIb than a wild-ty pe Fc polypeptide (e.g., a wild type IgG (e.g., IgGl) Fc polypeptide) exhibits to FcyRIIb.

[0197] In some embodiments, the at least one other modification is associated with selectively enhanced binding to FcyRIIb over both FcyRIIbR131and FcyRIIb11131.

[0198] In some embodiments, the at least one other modification is at a position selected from the group consisting position 233, 237, 238, 268, 271, 296, 330, and combinations thereof. For example, Fc polypeptide may comprise a modification or combination of modifications selected from the group consisting of E233D, G237D, H268D. P271G, Y296D. A330R, E233D / A330R, E233D / P271G / A330R, G237D / H268D / P271G, G237D / P271G / A330R, E233D / H268D / P271G / A330R, G237D / H268D / P271G / A330R,E233D / G237D / H268D / P271G / A330R, E233D / Y296D, G237D / Y296D. H268D / Y296D, P271G / Y296D, Y296D / A330R, E233D / Y296D / A330R, E233D / P27IG / Y296D / A330R, G237D / H268D / P271 G / Y296D, G237D / P271 G / Y296D / A330R.E233D / H268D / P271G / Y296D / A330R, G237D / H268D / P271G / Y296D / A330R,E233D / G237D / H268D / P271G / Y296D / A330R, E233D / P238D / A330R,E233D / P238D / P271 G / A33 OR, G237D / P238D / H268D / P271 G,G237D / P238D / P271G / A330R, E233D / P238D / H268D / P271G / A330R,G237D / P238D / H268D / P271G / A330R, and E233D / P238D / G237D / H268D / P271 G / A330R.

[0199] In some embodiments, the at least one other modification is at a position selected from the group consisting position 236, 239, 267, 328, and combinations thereof. For example, Fc polypeptide may comprise a modification or combination of modifications selected from the group consisting of G236D, S239D, S267E, L328F, G236D / S267E, S239D / S267E, and S267E / L328F.

[0200] In some embodiments, the modified Fc polypeptide is a modified Fc poly peptide having an amino acid listed in Table 1.Table 1. Modified Fc Polypeptides (Amino acid modifications are underlined and bolded)Additional Fc Modifications

[0201] Various site-specific mutagenesis experiments have led to identification of certain critical amino acid residues involved in the interaction between IgG and FcRn. In certain embodiments, one or more amino acids in the Fc region can be modified to alter the half-hfe of the Fc polypeptide. In some embodiments, the half-life is altered (e.g., enhanced) due to altered binding to an Fc receptor such as the neonatal Fc receptor (FcRn). For example, in some embodiments, the modified Fc polypeptide of the disclosure further comprises one or more modifications to enhance the half-life of the Fc polypeptide.

[0202] In certain embodiments, the Fc polypeptides of the present disclosure are further modified (i.<?., in addition to an aliphatic amino acid substitution at amino acid residue 241 and / or 243 of the Fc domain).

[0203] The Fc polypeptides generally further comprise at least one other amino acid modification (e.g. , relative to a Fc polypeptide comprising an aliphatic amino acid substitution at amino acid residue 241 and / or 243 of the Fc domain). In some embodiments, the Fc polypeptides of the present disclosure are further modified to comprise one or more amino acid modifications at residues 252, 254, 256, 308, 309, 311, 385, 386, 387. 389, 428, 433, 434, 436, and / or combinations thereof e.g., YTE (M252Y, S254T, and T256E; numbered according to the EU index of Kabat), LS (M428L and N434S; numbered according to the EU index of Kabat), and KFH (H433K, N434F, and Y436H; numbered according to the EU index of Kabat). In some embodiments, the modified Fc polypeptide is a modified Fc polypeptide of Table 1. Furthermore, the present disclosure provides methods for treating an autoimmune disorder using a therapeutic agent or composition disclosed herein. A subject with the autoimmune disorder is treated in accord with the methods disclosed herein by administering the therapeutic agent or composition to the subject by any acceptable route.

[0204] In some embodiments, the at least one other amino acid modification is at a position selected from the group consisting of 252, 254. 256, 308, 309, 311, 385, 386, 387, 389. 428, 433, 434, 436, and combinations thereof (numbered according to the EU index of Kabat). In some embodiments, the at least one other amino acid modification may comprise an amino acid modification or combination of amino acid modifications selected from the group consisting of a tyrosine at residue 252, a tryptophan at residue 252, a phenylalanine at residue 252, a threonine at residue 254, a glutamic acid at residue 256. a glutamine at residue 256, an aspartic acid at residue 256, a threonine at residue 308, a proline at residue 309, a serine at residue 311, an aspartic acid at residue 385, an arginine at residue 385, a proline at residue 386, a threonine at residue 386, an arginine at residue 387, a serine at residue 389, a proline at residue 389, a leucine at residue 428. a lysine at residue 433. an arginine at residue 433, a serine at residue 434, a phenylalanine at residue 434, a tyrosine at residue 434, and a histidine at residue 436. In some embodiments, the at least one other amino acid modification may comprise an amino acid modification or combination of amino acid modifications selected from the group consisting of a methionine at position 252 substituted with a tyrosine (M252Y), a methionine at position 252 substituted with a tryptophan (M252W). a methionine at position 252 substituted with a phenylalanine (M252F), a serine at position 254 substituted with a threonine (S254T), threonine at position 256 substituted with a glutamic acid (T256E), a threonine at position 256 substituted with a glutamine (T256Q), a threonine at position 256 substituted with an aspartic acid (T256D). a valine at position 308 substituted with a threonine (V308T), a leucine at position 309 substituted with a proline (L309P), a glutamine at position 311 substituted with a serine (Q311S), a glycine at position 385 substituted with an aspartic acid (G385D), a glycine at position 385 substituted with an arginine (G385R), a glutamine at position 386 substituted with a proline (Q386P). a glutamine at position 386 substituted with a threonine (Q386T), a proline at position 387 substituted with an arginine (P387R), an asparagine at position 389 substituted with a proline (N389P), an asparagine at position 389 substituted with a serine (N389S), a methionine at position 428 substituted with a leucine (M428L), a histidine at position 433 substituted with a lysine (H433K), a histidine at position 433 substituted with an arginine (H433R), an asparagine at position 434 substituted with a phenylalanine (N434F), an asparagine at position 434 substituted with a tyrosine (N434Y), an asparagine at position 434 substituted with a serine (N434S) , and a tyrosine at position 436 substituted with a histidine (Y436H). In some embodiments, the combination of amino acid modifications is M252Y. S254T, and T256E. In some embodiments, the combination of amino acid modifications is M428L and N434S. In some embodiments, the combination of aminoacid modifications is H433K, N434F, and Y436H. In some embodiments, the combination of amino acid modifications is M252Y, S254T, T256E, M428L and N434S. In some embodiments, the combination of amino acid modifications is M252Y and T256Q. In some embodiments, the combination of amino acid modifications is M252F and T256D. In some embodiments, the combination of amino acid modifications is V308T, L309P, and Q311S. In some embodiments, the combination of amino acid modifications is G385D, Q386P, and N389S. In some embodiments, the combination of amino acid modifications is G385R, Q386T. P387R, and N389P. In some embodiments, the combination of amino acid modifications is N434 and Y436H. In some embodiments, the combination of amino acid modifications is H433R, N434Y, and Y436H. In some embodiments, the combination of amino acid modifications is M252Y, S254T, T256E, H433K. N434F. and Y436H. In some embodiments, the combination of amino acid modifications is M428L, H433K, N434F, and Y436H. In some embodiments, the combination of amino acid modifications is M252Y, S254T, T256E, G385R, Q386T, P387R, and N389P.

[0205] IgGl Fes containing Abdeg amino acid modifications exhibit enhanced affinity’ to FcRn, thereby allowing the mutated Fes to outcompete native IgGs for FcRn binding. As a result, FcAbdegpolypeptides accelerate the depletion of circulation total IgG by saturating FcRn. In some embodiments, the modified Fc polypeptide comprises phenylalanine (Phe; F) at position 241 of the Fc polypeptide (corresponding to amino acid position 20 of SEQ ID NO: 50; numbered according to the Kabat system).DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWY VDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENN YKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL HYTQKSLSLSPG (SEQ ID NO: 50)*Bolded and underlined amino acid residues correspond to Abdeg amino acid modifications (M252Y, S254T, T256E, H433K, and N434F).

[0206] In some embodiments, the modified Fc polypeptide comprises an amino acid sequence having at least 85% (e.g., at least 85%. 86%. 87%. 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity' to a sequence of Table 1. In some embodiments, the modified Fc polypeptide comprises an amino acid sequence having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more)sequence identity to a sequence of Table 1. In some embodiments, the modified Fc polypeptide comprises an amino acid sequence having at least 95% (e.g, at least 95%, 96%, 97%, 98%, 99%, or more) sequence identity to a sequence of Table 1. In some embodiments, the modified Fc polypeptide comprises an amino acid sequence having at least 98% (e.g. , at least 98%, 99%, or more) sequence identity to a sequence of Table 1.

[0207] In certain embodiments, the modified Fc polypeptide comprises 3-20 amino acid substitutions (e.g., 3. 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17. 18. 19. 20) relative to the amino acid sequence of SEQ ID NO: 2 or SEQ ID NO: 12.

[0208] In certain embodiments, the modified Fc polypeptide comprises amino acid modifications in no more than 20 amino acid residues (e.g. 1, 2, 3. 4, 5, 6. 7, 8, 9. 10. 11, 12, 13, 14, 15, 16, 17, 18, 19, 20) relative to the amino acid sequence of SEQ ID NO: 1, SEQ ID NO: 11, SEQ ID NO: 2, or SEQ ID NO: 12.Fc Allotypes

[0209] In some embodiments, the compositions described herein include a variant (i.e., modified) Fc polypeptide (e.g., IgGl Fc polypeptide) containing one or more (e.g., 1, 2. 3, 4, 5, 6, 7. 8, 9, 10, or more) amino acid substitutions relative to wild-type / parental amino acid sequences, for example the wild-type / parental amino acid sequence of SEQ ID NO: 2 (bolded and underlined phenylalanine residue (N) corresponds to Asn297, to which the Fc N-glycan is attached; numbered according to the Kabat system).KVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPGK(SEQ ID NO: 2)

[0210] A skilled person in the art would also appreciate that during protein production and / or storage, the C-terminal lysine (K) of a protein can be removed (e.g. spontaneously or catalyzed by an enzyme present during production and / or storage). Accordingly, in some embodiments where the C-terminal residue of an amino acid sequence of a polypeptide (e.g., a Fc domain sequence) is K, a corresponding amino acid sequence with the K removed is alsocontemplated herein. For example, SEQ ID NO: 12, as shown below, is a wild-type / parental amino acid sequence without C-terminal lysine (K).KVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPG(SEQ ID NO: 12)

[0211] In some embodiments, the modified Fc polypeptide includes the F241A substitution (as shown bolded and underlined A, below) and has an amino acid sequence of SEQ ID NO: 11 without C-terminal lysine (K), as shown below.KVDKKVEPKSCDKTHTCPPCPAPELLGGPSVALFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPG(SEQ ID NO: 11)

[0212] In some embodiments, the one or more amino acid substitutions is at a phenylalanine (Phe; F) at position 241 of the Fc polypeptide (corresponding to amino acid position 32 of SEQ ID NO: 2 or SEQ ID NO: 12; numbered according to the Kabat system). In some embodiments, the Phe at position 241 of the modified Fc polypeptide is substituted for an aliphatic amino acid residue (e.g., alanine, glycine, valine, leucine, isoleucine, and proline). In some embodiments, the Phe at position 241 of the modified Fc polypeptide is substituted for an alanine (Ala or A; F241A substitution). In some embodiments, the modified Fc polypeptide includes the F241A substitution and has the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 11 or is a variant thereof having at least 75% (e.g, at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 1 or SEQ ID NO: 11. In some embodiments, the modified Fc polypeptide includes the F241A substitution and has an amino acid sequence having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 1 or SEQ ID NO: 11. In some embodiments, the modified Fc polypeptide includes theF241A substitution and has an amino acid sequence having at least 85% (e.g, at least 85%, 86%. 87%. 88%, 89%, 90%, 91%, 92%, 93%, 94%. 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 1 or SEQ ID NO: 11. In some embodiments, the modified Fc polypeptide includes the F241A substitution and has an amino acid sequence having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 2 or SEQ ID NO: 12. In some embodiments, the modified Fc polypeptide includes the F241A substitution and has an amino acid sequence having at least 95% (e.g, at least 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 1 or SEQ ID NO: 11.

[0213] In some embodiments, the one or more amino acid substitutions is at a phenylalanine (Phe; F) at position 241 of the Fc polypeptide (corresponding to amino acid position 32 of SEQ ID NO: 2 or SEQ ID NO: 12; numbered according to the Kabat system). In some embodiments, the Phe at position 241 of the modified Fc polypeptide is substituted for an aliphatic amino acid residue (e.g., alanine, glycine, valine, leucine, isoleucine, and proline). In some embodiments, the Phe at position 241 of the modified Fc polypeptide is substituted for a leucine (Leu or L; F241L substitution). In some embodiments, the modified Fc polypeptide includes the F241L substitution having at least 75% (e.g.. at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 2 or SEQ ID NO: 12. In some embodiments, the modified Fc polypeptide includes the F241L substitution and has an amino acid sequence having at least 80% (e.g., at least 80%, 81%. 82%. 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%. 91%. 92%. 93%. 94%. 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 2 or SEQ ID NO: 12. In some embodiments, the modified Fc polypeptide includes the F241L substitution and has an amino acid sequence having at least 85% (e.g., at least 85%, 86%, 87%. 88%, 89%, 90%, 91%, 92%, 93%, 94%. 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 2 or SEQ ID NO: 12. In some embodiments, the modified Fc polypeptide includes the F241L substitution and has an amino acid sequence having at least 90% (e.g, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 2 or SEQ ID NO: 12. In some embodiments, the modified Fc polypeptide includes the F241L substitution and has an amino acid sequence having at least 95% (e.g, at least 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 2 or SEQ ID NO: 12. In some embodiments, the modified Fc polypeptide includes the F241Lsubstitution and has an amino acid sequence having at least 98% (e.g.. at least 98%, 99%, or more) sequence identity to SEQ ID NO: 2 or SEQ ID NO: 12.

[0214] In some embodiments, the one or more amino acid substitutions is at a phenylalanine (Phe; F) at position 243 of the Fc polypeptide (corresponding to amino acid position 34 of SEQ ID NO: 2 or SEQ ID NO: 12; numbered according to the Kabat system). In some embodiments, the Phe at position 243 of the modified Fc polypeptide is substituted for an aliphatic amino acid residue (e.g, alanine, glycine, valine, leucine, isoleucine, and proline). In some embodiments, the Phe at position 243 of the modified Fc polypeptide is substituted for an alanine (Ala or A; F243A substitution). In some embodiments, the modified Fc polypeptide includes the F243A substitution having at least 75% (e.g., at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 2 or SEQ ID NO: 12. In some embodiments, the modified Fc polypeptide includes the F243A substitution and has an amino acid sequence having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 2 or SEQ ID NO: 12. In some embodiments, the modified Fc polypeptide includes the F243A substitution and has an amino acid sequence having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 2 or SEQ ID NO: 12. In some embodiments, the modified Fc polypeptide includes the F243A substitution and has an amino acid sequence having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%. 98%. 99%. or more) sequence identity to SEQ ID NO: 2 or SEQ ID NO: 12. In some embodiments, the modified Fc polypeptide includes the F243A substitution and has an amino acid sequence having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 2 or SEQ ID NO: 12. In some embodiments, the modified Fc polypeptide includes the F243A substitution and has an amino acid sequence having at least 98% (e.g., at least 98%, 99%, or more) sequence identity to SEQ ID NO: 2 or SEQ ID NO: 12.

[0215] In some embodiments, the one or more amino acid substitutions is at a phenylalanine (Phe; F) at position 243 of the Fc polypeptide (corresponding to amino acid position 34 of SEQ ID NO: 2 or SEQ ID NO: 12; numbered according to the Kabat system). In some embodiments, the Phe at position 243 of the modified Fc polypeptide is substituted for an aliphatic amino acid residue (e.g.. alanine, glycine, valine, leucine, isoleucine, and proline). In some embodiments, the Phe at position 243 of the modified Fc polypeptide is substituted for a leucine (Leu or L;F243L substitution). In some embodiments, the modified Fc polypeptide includes the F243L substitution having at least 75% (e.g.. at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 2 or SEQ ID NO: 12. In some embodiments, the modified Fc polypeptide includes the F243L substitution and has an amino acid sequence having at least 80% (e.g., at least 80%, 81%, 82%. 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%. 91%. 92%. 93%. 94%. 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 2 or SEQ ID NO: 12. In some embodiments, the modified Fc polypeptide includes the F243L substitution and has an amino acid sequence having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 2 or SEQ ID NO: 12. In some embodiments, the modified Fc polypeptide includes the F243L substitution and has an amino acid sequence having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 2 or SEQ ID NO: 12. In some embodiments, the modified Fc polypeptide includes the F243L substitution and has an amino acid sequence having at least 95% (e.g, at least 95%, 96%. 97%. 98%. 99%. or more) sequence identity to SEQ ID NO: 2 or SEQ ID NO: 12. In some embodiments, the modified Fc polypeptide includes the F243L substitution and has an amino acid sequence having at least 98% (e.g., at least 98%, 99%, or more) sequence identity to SEQ ID NO: 2 or SEQ ID NO: 12.

[0216] In some embodiments, the compositions described herein include a variant (i.e., modified) Fc polypeptide (e.g., IgGl Fc polypeptide) containing one or more (e.g., 1, 2. 3, 4, 5, 6. 7, 8. 9, 10, or more) amino acid substitutions relative to an allotype variant of the wild-type / parental amino acid sequences, for example the allotype variant, K214R comprising the amino acid sequence of SEQ ID NO: 4 (bolded and underlined arginine residue (R) corresponds to K214R; numbered according to the Kabat system).KVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPGK (SEQ ID NO: 4)

[0217] In some embodiments, the one or more amino acid substitutions is at a phenylalanine (Phe; F) at position 241 of the Fc polypeptide (corresponding to amino acid position 32 of SEQ ID NO: 4 or SEQ ID NO: 58; numbered according to the Kabat system). In some embodiments, the Phe at position 241 of the modified Fc polypeptide is substituted for an aliphatic amino acid residue (e.g., alanine, glycine, valine, leucine, isoleucine, and proline). In some embodiments, the Phe at position 241 of the modified Fc polypeptide is substituted for an alanine (Ala or A; F241A substitution). In some embodiments, the Phe at position 241 of the modified Fc polypeptide is substituted for a leucine (Leu or L; F241L substitution).

[0218] In some embodiments, the modified Fc polypeptide includes the K214R and F241 A substitutions and has the amino acid sequence of SEQ ID NO: 3 or SEQ ID NO: 57, or is a variant thereof having at least 75% (e.g., at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%. 86%. 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%. or more) sequence identity to SEQ ID NO: 3 or SEQ ID NO: 57. In some embodiments, the modified Fc polypeptide includes the K214R and F241A substitutions and has an amino acid sequence having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%. 99%, or more) sequence identity to SEQ ID NO: 3 or SEQ ID NO: 57. In some embodiments, the modified Fc polypeptide includes the K214R and F241A substitutions and has an amino acid sequence having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 3 or SEQ ID NO: 57. In some embodiments, the modified Fc polypeptide includes the K214R and F241A substitutions and has an amino acid sequence having at least 90% (e.g., at least 90%, 91%. 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 3 or SEQ ID NO: 57. In some embodiments, the modified Fc polypeptide includes the K214R and F241A substitutions and has an amino acid sequence having at least 95% (e.g., at least 95%, 96%. 97%. 98%, 99%, or more) sequence identity to SEQ ID NO: 3 or SEQ ID NO: 57. In some embodiments, the modified Fc polypeptide includes the K214R and F241 A substitutions and has an amino acid sequence having at least 98% (e.g., at least 98%, 99%, or more) sequence identity to SEQ ID NO: 3 or SEQ ID NO: 57. In some embodiments, the modified Fc polypeptide includes the K214R and F241A substitutions (shown as a bolded and underlined R and A, below) and has an amino acid sequence of SEQ ID NO: 3, as shown below.KVDKRVEPKSCDKTHTCPPCPAPELLGGPSVALFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPGK(SEQ ID NO: 3)

[0219] In some embodiments, the modified Fc polypeptide includes the K214R and F241 A substitutions (shown as a bolded and underlined R and A, below) and has an amino acid sequence of SEQ ID NO: 57, as shown below.KVDKRVEPKSCDKTHTCPPCPAPELLGGPSVALFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALPAPIEKT1SKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPGSEQ ID NO: 57

[0220] In some embodiments, the one or more amino acid substitutions is at a phenylalanine (Phe; F) at position 243 of the Fc polypeptide (corresponding to amino acid position 34 of SEQ ID NO: 4; numbered according to the Kabat system). In some embodiments, the Phe at position 243 of the modified Fc polypeptide is substituted for an aliphatic amino acid residue (e.g., alanine, glycine, valine, leucine, isoleucine, and proline). In some embodiments, the Phe at position 243 of the modified Fc polypeptide is substituted for an alanine (Ala or A; F243A substitution). In some embodiments, the Phe at position 243 of the modified Fc polypeptide is substituted for a leucine (Leu or L; F243L substitution).

[0221] In some embodiments, the modified Fc polypeptide includes the K214R and F243A substitutions having at least 75% (e.g., at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 4 or SEQ ID NO: 58. In some embodiments, the modified Fc polypeptide includes the K214R and F243A substitutions and has an amino acid sequence having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 4 or SEQ ID NO: 58. In some embodiments, the modified Fc polypeptide includes the K214R and F243A substitutions and has an amino acid sequencehaving at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%. 96%. 97%. 98%. 99%. or more) sequence identity to SEQ ID NO: 4 or SEQ ID NO: 58. In some embodiments, the modified Fc polypeptide includes the K214R and F243A substitutions and has an amino acid sequence having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 4 or SEQ ID NO: 58. In some embodiments, the modified Fc polypeptide includes the K214R and F243A substitutions and has an amino acid sequence having at least 95% (e.g., at least 95%. 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 4 or SEQ ID NO: 58. In some embodiments, the modified Fc polypeptide includes the K214R and F243A substitutions and has an amino acid sequence having at least 98% (e.g., at least 98%, 99%, or more) sequence identity to SEQ ID NO: 4 or SEQ ID NO: 58.

[0222] In some embodiments, the modified Fc polypeptide includes the K214R and F241L substitutions having at least 75% (e.g., at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%. 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 4 or SEQ ID NO: 58. In some embodiments, the modified Fc polypeptide includes the K214R and F241L substitutions and has an amino acid sequence having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity7to SEQ ID NO: 4 or SEQ ID NO: 58. In some embodiments, the modified Fc polypeptide includes the K214R and F241L substitutions and has an amino acid sequence having at least 85% (e.g., at least 85%, 86%. 87%. 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%. 96%. 97%. 98%. 99%. or more) sequence identity to SEQ ID NO: 4 or SEQ ID NO: 58. In some embodiments, the modified Fc polypeptide includes the K214R and F241L substitutions and has an amino acid sequence having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 4 or SEQ ID NO: 58. In some embodiments, the modified Fc polypeptide includes the K214R and F241L substitutions and has an amino acid sequence having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 4 or SEQ ID NO: 58. In some embodiments, the modified Fc polypeptide includes the K214R and F241L substitutions and has an amino acid sequence having at least 98% (e.g., at least 98%, 99%, or more) sequence identity to SEQ ID NO: 4 or SEQ ID NO: 58.

[0223] In some embodiments, the modified Fc polypeptide includes the K214R and F243L substitutions having at least 75% (e.g., at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%,83%, 84%, 85%, 86%. 87%. 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%. or more) sequence identity to SEQ ID NO: 4 or SEQ ID NO: 58. In some embodiments, the modified Fc polypeptide includes the K214R and F243L substitutions and has an amino acid sequence having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 4 or SEQ ID NO: 58. In some embodiments, the modified Fc polypeptide includes the K214R and F243L substitutions and has an amino acid sequence having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 4 or SEQ ID NO: 58. In some embodiments, the modified Fc polypeptide includes the K214R and F243L substitutions and has an amino acid sequence having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 4 or SEQ ID NO: 58. In some embodiments, the modified Fc polypeptide includes the K214R and F243L substitutions and has an amino acid sequence having at least 95% (e.g., at least 95%, 96%, 97%. 98%, 99%, or more) sequence identity to SEQ ID NO: 4 or SEQ ID NO: 58. In some embodiments, the modified Fc polypeptide includes the K214R and F243L substitutions and has an amino acid sequence having at least 98% (e g., at least 98%, 99%, or more) sequence identity to SEQ ID NO: 4 or SEQ ID NO: 58.

[0224] In some embodiments, the compositions described herein include a variant (i.e., modified) Fc polypeptide (e.g., IgGl Fc polypeptide) containing one or more (e.g., 1, 2. 3, 4, 5, 6, 7, 8, 9, 10, or more) amino acid substitutions relative to an allotype variant of the wild-type / parental amino acid sequences, for example the alloty pe variant, D356E comprising the amino acid sequence of SEQ ID NO: 5 (bolded and underlined glutamic acid residue (E) corresponds to D356E; numbered according to the Kabat system).KVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREELTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPGK (SEQ ID NO: 5)

[0225] In some embodiments, the one or more amino acid substitutions is at a phenylalanine (Phe; F) at position 241 of the Fc polypeptide (corresponding to amino acid position 32 of SEQ ID NO: 5 or SEQ ID NO: 59; numbered according to the Kabat system). In some embodiments, the Phe at position 241 of the modified Fc polypeptide is substituted for an aliphatic amino acid residue (e.g., alanine, glycine, valine, leucine, isoleucine, and proline). In some embodiments, the Phe at position 241 of the modified Fc polypeptide is substituted for an alanine (Ala or A; F241A substitution). In some embodiments, the Phe at position 241 of the modified Fc polypeptide is substituted for a leucine (Leu or L; F241L substitution).

[0226] In some embodiments, the modified Fc polypeptide includes the D356E and F241 A substitutions and has the amino acid sequence of SEQ ID NO: 6 or SEQ ID NO: 60, or is a variant thereof having at least 75% (e.g., at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%. 86%. 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%. or more) sequence identity to SEQ ID NO: 6 or SEQ ID NO: 60. In some embodiments, the modified Fc polypeptide includes the D356E and F241A substitutions and has an amino acid sequence having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%. 99%, or more) sequence identity to SEQ ID NO: 6 or SEQ ID NO: 60. In some embodiments, the modified Fc polypeptide includes the D356E and F241A substitutions and has an amino acid sequence having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 6 or SEQ ID NO: 60. In some embodiments, the modified Fc polypeptide includes the D356E and F241A substitutions and has an amino acid sequence having at least 90% (e.g., at least 90%, 91%. 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 6 or SEQ ID NO: 60. In some embodiments, the modified Fc polypeptide includes the D356E and F241A substitutions and has an amino acid sequence having at least 95% (e.g., at least 95%, 96%. 97%. 98%, 99%, or more) sequence identity to SEQ ID NO: 6 or SEQ ID NO: 60. In some embodiments, the modified Fc polypeptide includes the D356E and F241 A substitutions and has an amino acid sequence having at least 98% (e.g., at least 98%, 99%, or more) sequence identity to SEQ ID NO: 6 or SEQ ID NO: 60. In some embodiments, the modified Fc polypeptide includes the D356E and F241 A substitutions (shown as a bolded and underlined E and A, below) and has an amino acid sequence of SEQ ID NO: 6, as shown below.KVDKKVEPKSCDKTHTCPPCPAPELLGGPSVALFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREELTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPGK (SEQ ID NO: 6)

[0227] In some embodiments, the modified Fc polypeptide includes the D356E and F241 A substitutions (shown as a bolded and underlined E and A, below) and has an amino acid sequence of SEQ ID NO: 60, as shown below.KVDKKVEPKSCDKTHTCPPCPAPELLGGPSVALFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREELTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPGSEQ ID NO: 60

[0228] In some embodiments, the one or more amino acid substitutions is at a phenylalanine (Phe; F) at position 243 of the Fc polypeptide (corresponding to amino acid position 34 of SEQ ID NO: 5 or SEQ ID NO: 59; numbered according to the Kabat system). In some embodiments, the Phe at position 243 of the modified Fc polypeptide is substituted for an aliphatic amino acid residue (e.g., alanine, glycine, valine, leucine, isoleucine, and proline). In some embodiments, the Phe at position 243 of the modified Fc polypeptide is substituted for an alanine (Ala or A; F243A substitution). In some embodiments, the Phe at position 243 of the modified Fc polypeptide is substituted for a leucine (Leu or L; F243L substitution).

[0229] In some embodiments, the modified Fc polypeptide includes the D356E and F243A substitutions having at least 75% (e.g., at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%. 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 5 or SEQ ID NO: 59. In some embodiments, the modified Fc polypeptide includes the D356E and F243A substitutions and has an amino acid sequence having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity7to SEQ ID NO: 5 or SEQ ID NO: 59. In some embodiments, the modified Fc polypeptide includes the D356E and F243A substitutions and has an amino acid sequence having at least 85% (e.g., at least 85%, 86%. 87%. 88%, 89%, 90%, 91%, 92%, 93%, 94%,95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 5 or SEQ ID NO: 59. In some embodiments, the modified Fc polypeptide includes the D356E and F243A substitutions and has an amino acid sequence having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 5 or SEQ ID NO: 59. In some embodiments, the modified Fc polypeptide includes the D356E and F243A substitutions and has an amino acid sequence having at least 95% (e.g., at least 95%, 96%. 97%. 98%. 99%, or more) sequence identity to SEQ ID NO: 5 or SEQ ID NO: 59. In some embodiments, the modified Fc polypeptide includes the D356E and F243A substitutions and has an amino acid sequence having at least 98% (e.g., at least 98%, 99%, or more) sequence identity to SEQ ID NO: 5 or SEQ ID NO: 59.

[0230] In some embodiments, the modified Fc polypeptide includes the D356E and F241L substitutions having at least 75% (e.g., at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%. 84%. 85%. 86%. 87%. 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%. 99%, or more) sequence identity to SEQ ID NO: 5 or SEQ ID NO: 59. In some embodiments, the modified Fc polypeptide includes the D356E and F241L substitutions and has an amino acid sequence having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%. 89%, 90%, 91%, 92%, 93%. 94%, 95%, 96%, 97%. 98%. 99%, or more) sequence identity to SEQ ID NO: 5 or SEQ ID NO: 59. In some embodiments, the modified Fc polypeptide includes the D356E and F241L substitutions and has an amino acid sequence having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%. 99%. or more) sequence identity to SEQ ID NO: 5 or SEQ ID NO: 59. In some embodiments, the modified Fc polypeptide includes the D356E and F241L substitutions and has an amino acid sequence having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 5 or SEQ ID NO: 59. In some embodiments, the modified Fc polypeptide includes the D356E and F241L substitutions and has an amino acid sequence having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 5 or SEQ ID NO: 59. In some embodiments, the modified Fc polypeptide includes the D356E and F241L substitutions and has an amino acid sequence having at least 98% (e.g., at least 98%, 99%, or more) sequence identity to SEQ ID NO: 5 or SEQ ID NO: 59.

[0231] In some embodiments, the modified Fc poly peptide includes the D356E and F243L substitutions having at least 75% (e.g., at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,99%, or more) sequence identity to SEQ ID NO: 5 or SEQ ID NO: 59. In some embodiments, the modified Fc polypeptide includes the D356E and F243L substitutions and has an amino acid sequence having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 5 or SEQ ID NO: 59. In some embodiments, the modified Fc polypeptide includes the D356E and F243L substitutions and has an amino acid sequence having at least 85% (e.g., at least 85%. 86%. 87%. 88%, 89%, 90%, 91%, 92%, 93%, 94%. 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 5 or SEQ ID NO: 59. In some embodiments, the modified Fc polypeptide includes the D356E and F243L substitutions and has an amino acid sequence having at least 90% (e.g., at least 90%, 91%, 92%. 93%. 94%. 95%. 96%. 97%. 98%. 99%. or more) sequence identity to SEQ ID NO: 5 or SEQ ID NO: 59. In some embodiments, the modified Fc polypeptide includes the D356E and F243L substitutions and has an amino acid sequence having at least 95% (e.g., at least 95%, 96%, 97%, 98%. 99%, or more) sequence identity to SEQ ID NO: 5 or SEQ ID NO: 59. In some embodiments, the modified Fc polypeptide includes the D356E and F243L substitutions and has an ammo acid sequence having at least 98% (e.g., at least 98%, 99%, or more) sequence identity to SEQ ID NO: 5 or SEQ ID NO: 59.

[0232] In some embodiments, the compositions described herein include a variant (z.e., modified) Fc polypeptide (e.g., IgGl Fc polypeptide) containing one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) amino acid substitutions relative to an allotype variant of the wild-type / parental amino acid sequences, for example the allotype variant, L358M comprising the amino acid sequence of SEQ ID NO: 7 (bolded and underlined methionine residue (M) corresponds to L358M; numbered according to the Kabat system).KVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEMTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPGK(SEQ ID NO: 7)

[0233] In some embodiments, the one or more amino acid substitutions is at a phenylalanine (Phe; F) at position 241 of the Fc polypeptide (corresponding to amino acid position 32 of SEQID NO: 7; numbered according to the Kabat system). In some embodiments, the Phe at position 241 of the modified Fc polypeptide is substituted for an aliphatic amino acid residue (e.g, alanine, glycine, valine, leucine, isoleucine, and proline). In some embodiments, the Phe at position 241 of the modified Fc polypeptide is substituted for an alanine (Ala or A; F241A substitution). In some embodiments, the Phe at position 241 of the modified Fc polypeptide is substituted for a leucine (Leu or L; F241L substitution).

[0234] In some embodiments, the modified Fc polypeptide includes the L358M and F241 A substitutions and has the amino acid sequence of SEQ ID NO: 8 or SEQ ID NO: 62, or is a variant thereof having at least 75% (e.g., at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 8 or SEQ ID NO: 62. In some embodiments, the modified Fc polypeptide includes the L358M and F241A substitutions and has an amino acid sequence having at least 80% (e.g.. at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%. 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 8 or SEQ ID NO: 62. In some embodiments, the modified Fc polypeptide includes the L358M and F241A substitutions and has an amino acid sequence having at least 85% (e.g., at least 85%. 86%. 87%. 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 8 or SEQ ID NO: 62. In some embodiments, the modified Fc polypeptide includes the L358M and F241A substitutions and has an amino acid sequence having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%. 97%. 98%. 99%. or more) sequence identity to SEQ ID NO: 8 or SEQ ID NO: 62. In some embodiments, the modified Fc polypeptide includes the L358M and F241A substitutions and has an amino acid sequence having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 8 or SEQ ID NO: 62. In some embodiments, the modified Fc polypeptide includes the L358M and F241A substitutions and has an amino acid sequence having at least 98% (e.g., at least 98%, 99%, or more) sequence identity' to SEQ ID NO: 8 or SEQ ID NO: 62. In some embodiments, the modified Fc polypeptide includes the L358M and F241 A substitutions (shown as a bolded and underlined M and A, below) and has an amino acid sequence of SEQ ID NO: 8, as shown below.KVDKKVEPKSCDKTHTCPPCPAPELLGGPSVALFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO: 8)

[0235] In some embodiments, the modified Fc polypeptide includes the L358M and F241A substitutions (shown as a bolded and underlined M and A, below) and has an amino acid sequence of SEQ ID NO: 62, as shown below.KVDKKVEPKSCDKTHTCPPCPAPELLGGPSVALFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEMTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPG (SEQ ID NO: 62)

[0236] In some embodiments, the one or more amino acid substitutions is at a phenylalanine (Phe; F) at position 243 of the Fc polypeptide (corresponding to amino acid position 34 of SEQ ID NO: 7; numbered according to the Kabat system). In some embodiments, the Phe at position 243 of the modified Fc polypeptide is substituted for an aliphatic amino acid residue (e.g, alanine, glycine, valine, leucine, isoleucine, and proline). In some embodiments, the Phe at position 243 of the modified Fc polypeptide is substituted for an alanine (Ala or A; F243A substitution).

[0237] In some embodiments, the modified Fc polypeptide includes the L358M and F243A substitutions having at least 75% (e.g., at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 7 or SEQ ID NO: 61. In some embodiments, the modified Fc polypeptide includes the L358M and F243A substitutions and has an amino acid sequence having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 7 or SEQ ID NO: 61. In some embodiments, the modified Fc polypeptide includes the L358M and F243A substitutions and has an amino acid sequence having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 7 or SEQ ID NO: 61. In some embodiments, the modified Fc polypeptide includes the L358M and F243A substitutions and has an amino acid sequence having at least 90% (e.g., at least 90%, 91%,92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 7 or SEQ ID NO: 61. In some embodiments, the modified Fc polypeptide includes the L358M and F243A substitutions and has an amino acid sequence having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 7 or SEQ ID NO: 61. In some embodiments, the modified Fc polypeptide includes the L358M and F243A substitutions and has an amino acid sequence having at least 98% (e g., at least 98%, 99%, or more) sequence identity to SEQ ID NO: 7 or SEQ ID NO: 61.

[0238] In some embodiments, the modified Fc polypeptide includes the L358M and F241L substitutions having at least 75% (e.g., at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 7 or SEQ ID NO: 61. In some embodiments, the modified Fc polypeptide includes the L358M and F241L substitutions and has an amino acid sequence having at least 80% (e.g.. at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%. 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 7 or SEQ ID NO: 61. In some embodiments, the modified Fc polypeptide includes the L358M and F241L substitutions and has an amino acid sequence having at least 85% (e.g., at least 85%. 86%. 87%. 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 7 or SEQ ID NO: 61. In some embodiments, the modified Fc polypeptide includes the L358M and F241L substitutions and has an amino acid sequence having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%. 97%. 98%. 99%. or more) sequence identity to SEQ ID NO: 7 or SEQ ID NO: 61. In some embodiments, the modified Fc polypeptide includes the L358M and F241L substitutions and has an amino acid sequence having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 7 or SEQ ID NO: 61. In some embodiments, the modified Fc polypeptide includes the L358M and F241L substitutions and has an amino acid sequence having at least 98% (e.g., at least 98%, 99%, or more) sequence identity’ to SEQ ID NO: 7 or SEQ ID NO: 61 .

[0239] In some embodiments, the modified Fc polypeptide includes the L358M and F243L substitutions having at least 75% (e.g., at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 7 or SEQ ID NO: 61. In some embodiments, the modified Fc polypeptide includes the L358M and F243L substitutions and has an amino acid sequence having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%,88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%. 99%, or more) sequence identity to SEQ ID NO: 7 or SEQ ID NO: 61. In some embodiments, the modified Fc polypeptide includes the L358M and F243L substitutions and has an amino acid sequence having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 7 or SEQ ID NO: 61. In some embodiments, the modified Fc polypeptide includes the L358M and F243L substitutions and has an amino acid sequence having at least 90% (e.g., at least 90%, 91%. 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 7 or SEQ ID NO: 61. In some embodiments, the modified Fc polypeptide includes the L358M and F243L substitutions and has an amino acid sequence having at least 95% (e.g., at least 95%, 96%. 97%. 98%, 99%, or more) sequence identity to SEQ ID NO: 7 or SEQ ID NO: 61. In some embodiments, the modified Fc polypeptide includes the L358M and F243L substitutions and has an amino acid sequence having at least 98% (e.g., at least 98%, 99%, or more) sequence identity to SEQ ID NO: 7 or SEQ ID NO: 61.

[0240] In some embodiments, the compositions described herein include a variant (z.e., modified) Fc polypeptide (e.g., IgGl Fc polypeptide) containing one or more (e.g., 1, 2. 3, 4, 5, 6, 7, 8, 9, 10, or more) amino acid substitutions relative to an allotype variant of the wild-type / parental amino acid sequences, for example the allot pe variant, A431G comprising the amino acid sequence of SEQ ID NO: 9 (bolded and underlined glycine residue (G) corresponds to A431G; numbered according to the Kabat system).KVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEGLHN HYTQKSLSLSPGK (SEQ ID NO: 9)

[0241] In some embodiments, the one or more amino acid substitutions is at a phenylalanine (Phe; F) at position 241 of the Fc polypeptide (corresponding to amino acid position 32 of SEQ ID NO: 9; numbered according to the Kabat system). In some embodiments, the Phe at position 241 of the modified Fc polypeptide is substituted for an aliphatic amino acid residue (e.g., alanine, glycine, valine, leucine, isoleucine, and proline). In some embodiments, the Phe atposition 241 of the modified Fc polypeptide is substituted for an alanine (Ala or A; F241A substitution).

[0242] In some embodiments, the modified Fc polypeptide includes the A431G and F241 A substitutions and has the amino acid sequence of SEQ ID NO: 10 or SEQ ID NO: 64, or is a variant thereof having at least 75% (e.g., at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 10 or SEQ ID NO: 64. In some embodiments, the modified Fc polypeptide includes the A431G and F241A substitutions and has an amino acid sequence having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 10 or SEQ ID NO: 64. In some embodiments, the modified Fc polypeptide includes the A431G and F241A substitutions and has an amino acid sequence having at least 85% (e.g., at least 85%. 86%. 87%. 88%, 89%, 90%, 91%, 92%, 93%, 94%. 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 10 or SEQ ID NO: 64. In some embodiments, the modified Fc polypeptide includes the A431G and F241A substitutions and has an amino acid sequence having at least 90% (e.g., at least 90%, 91%, 92%. 93%. 94%. 95%. 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 10 or SEQ ID NO: 64. In some embodiments, the modified Fc polypeptide includes the A431G and F241A substitutions and has an amino acid sequence having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 10 or SEQ ID NO: 64. In some embodiments, the modified Fc polypeptide includes the A431G and F241A substitutions and has an amino acid sequence having at least 98% (e.g., at least 98%, 99%, or more) sequence identity to SEQ ID NO: 10 or SEQ ID NO: 64. In some embodiments, the modified Fc polypeptide includes the A431G and F241 A substitutions (shown as a bolded and underlined G and A. below) and has an amino acid sequence of SEQ ID NO: 10, as shown below.KVDKKVEPKSCDKTHTCPPCPAPELLGGPSVALFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEGLHN HYTQKSLSLSPG(SEQ ID NO: 10)

[0243] In some embodiments, the modified Fc polypeptide includes the A431G and F241 A substitutions (shown as a bolded and underlined G and A, below) and has an amino acid sequence of SEQ ID NO: 64, as shown below.KVDKKVEPKSCDKTHTCPPCPAPELLGGPSVALFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEGLHN HYTQKSLSLSPG(SEQ ID NO: 64)

[0244] In some embodiments, the one or more amino acid substitutions is at a phenylalanine (Phe; F) at position 243 of the Fc polypeptide (corresponding to amino acid position 34 of SEQ ID NO: 9; numbered according to the Kabat system). In some embodiments, the Phe at position 243 of the modified Fc polypeptide is substituted for an aliphatic amino acid residue (e.g, alanine, glycine, valine, leucine, isoleucine, and proline). In some embodiments, the Phe at position 243 of the modified Fc polypeptide is substituted for an alanine (Ala or A; F243A substitution). In some embodiments, the Phe at position 243 of the modified Fc polypeptide is substituted for a leucine (Leu or L; F243L substitution).

[0245] In some embodiments, the modified Fc polypeptide includes the A431 G and F243 A substitutions having at least 75% (e.g., at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 9 or SEQ ID NO: 63. In some embodiments, the modified Fc polypeptide includes the A431G and F243A substitutions and has an amino acid sequence having at least 80% (e.g.. at least 80%, 81%. 82%. 83%. 84%. 85%. 86%. 87%. 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 9 or SEQ ID NO: 63. In some embodiments, the modified Fc polypeptide includes the A431G and F243A substitutions and has an amino acid sequence having at least 85% (e.g., at least 85%. 86%. 87%. 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity’ to SEQ ID NO: 9 or SEQ ID NO: 63. In some embodiments, the modified Fc polypeptide includes the A431G and F243A substitutions and has an amino acid sequence having at least 90% (e.g., at least 90%, 91%, 92%, 93%. 94%, 95%. 96%. 97%. 98%. 99%. or more) sequence identity to SEQ ID NO: 9 orSEQ ID NO: 63. In some embodiments, the modified Fc polypeptide includes the A431G and F243A substitutions and has an amino acid sequence having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 9 or SEQ ID NO: 63. In some embodiments, the modified Fc polypeptide includes the A431G and F243A substitutions and has an amino acid sequence having at least 98% (e.g., at least 98%, 99%, or more) sequence identity to SEQ ID NO: 9 or SEQ ID NO: 63.

[0246] In some embodiments, the modified Fc polypeptide includes the A431G and F243L substitutions having at least 75% (e.g., at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 9 or SEQ ID NO: 63. In some embodiments, the modified Fc polypeptide includes the A431G and F243L substitutions and has an amino acid sequence having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%. 89%. 90%, 91%, 92%. 93%. 94%, 95%, 96%, 97%. 98%. 99%, or more) sequence identity to SEQ ID NO: 9 or SEQ ID NO: 63. In some embodiments, the modified Fc polypeptide includes the A431G and F243L substitutions and has an amino acid sequence having at least 85% (e.g., at least 85%, 86%, 87%. 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%. 96%. 97%. 98%. 99%. or more) sequence identity to SEQ ID NO: 9 or SEQ ID NO: 63. In some embodiments, the modified Fc polypeptide includes the A431G and F243L substitutions and has an amino acid sequence having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 9 or SEQ ID NO: 63. In some embodiments, the modified Fc polypeptide includes the A431G and F243L substitutions and has an amino acid sequence having at least 95% (e.g., at least 95%. 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 9 or SEQ ID NO: 63. In some embodiments, the modified Fc polypeptide includes the A431G and F243L substitutions and has an amino acid sequence having at least 98% (e.g., at least 98%, 99%, or more) sequence identity to SEQ ID NO: 9 or SEQ ID NO: 63.

[0247] In some embodiments, the modified Fc polypeptide includes the A431G and F241L substitutions having at least 75% (e.g., at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity' to SEQ ID NO: 9 or SEQ ID NO: 63. In some embodiments, the modified Fc polypeptide includes the A431G and F241L substitutions and has an amino acid sequence having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequenceidentity to SEQ ID NO: 9 or SEQ ID NO: 63. In some embodiments, the modified Fc polypeptide includes the A431G and F241L substitutions and has an amino acid sequence having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 9 or SEQ ID NO: 63. In some embodiments, the modified Fc polypeptide includes the A431G and F241L substitutions and has an amino acid sequence having at least 90% (e.g., at least 90%, 91%, 92%. 93%. 94%. 95%. 96%. 97%. 98%. 99%. or more) sequence identity to SEQ ID NO: 9 or SEQ ID NO: 63. In some embodiments, the modified Fc polypeptide includes the A431G and F241L substitutions and has an amino acid sequence having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 9 or SEQ ID NO: 63. In some embodiments, the modified Fc polypeptide includes the A431G and F241L substitutions and has an amino acid sequence having at least 98% (e.g., at least 98%, 99%, or more) sequence identity to SEQ ID NO: 9 or SEQ ID NO: 63.

[0248] In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to the sequence of any one of SEQ ID NOs: 1, 2, 4, 5, 7, 9, 11, 12, 58, 59, 61, and 63. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to the sequence of SEQ ID NO: 1. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to the sequence of SEQ ID NO: 2. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 85% (e.g, at least 86%. 87%. 88%. 89%. etc.) identical to the sequence of SEQ ID NO: 4. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to the sequence of SEQ ID NO: 5. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 85% (e.g.. at least 86%. 87%. 88%. 89%. etc.) identical to the sequence of SEQ ID NO: 7. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to the sequence of SEQ ID NO: 9. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%. etc.) identical to the sequence of SEQ ID NO: 11. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 85% (e.g, at least 86%, 87%, 88%, 89%, etc.) identical to the sequence of SEQ ID NO: 12. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 85% (e.g. , at least 86%, 87%, 88%, 89%, etc.) identical to the sequence of SEQ ID NO: 58. In someembodiments, the modified Fc polypeptide has an amino acid sequence at least 85% (e.g., at least 86%, 87%. 88%, 89%, etc.) identical to the sequence of SEQ ID NO: 59. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 85% (e.g, at least 86%, 87%, 88%, 89%, etc.) identical to the sequence of SEQ ID NO: 61. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to the sequence of SEQ ID NO: 63.

[0249] In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% (e.g, at least 91%, 92%, 93%. 94%. etc.) identical to the sequence of any one of SEQ ID NOs: 1, 2, 4, 5, 7, 9, 11, 12, 58, 59, 61, and 63. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% (e.g, at least 91%, 92%, 93%, 94%, etc.) identical to the sequence of SEQ ID NO: 1. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, etc.) identical to the sequence of SEQ ID NO: 2. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% (e.g, at least 91%, 92%, 93%, 94%, etc.) identical to the sequence of SEQ ID NO: 4. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, etc.) identical to the sequence of SEQ ID NO: 5. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% (e.g, at least 91%, 92%, 93%, 94%, etc.) identical to the sequence of SEQ ID NO: 7. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% (e.g, at least 91%, 92%, 93%, 94%, etc.) identical to the sequence of SEQ ID NO: 9. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% (e.g, at least 91%, 92%, 93%. 94%. etc.) identical to the sequence of SEQ ID NO: 11. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, etc.) identical to the sequence of SEQ ID NO: 12. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% (e.g. , at least 91%, 92%, 93%, 94%, etc.) identical to the sequence of SEQ ID NO: 58. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% (e.g, at least 91%, 92%, 93%, 94%, etc.) identical to the sequence of SEQ ID NO: 59. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% (e.g., at least 91%, 92%. 93%, 94%, etc.) identical to the sequence of SEQ ID NO: 61. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% (e.g, at least 91%, 92%, 93%, 94%, etc.) identical to the sequence of SEQ ID NO: 63.

[0250] In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% (e.g, at least 96%, 97%, 98%. 99%. etc.) identical to the sequence of any one of SEQ ID NOs: 1, 2, 4, 5, 7, 9, 11, 12, 58, 59, 61, and 63. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% (e.g, at least 96%, 97%, 98%, 99%, etc.) identical to the sequence of SEQ ID NO: 1. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% (e.g., at least 96%, 97%, 98%, 99%, etc.) identical to the sequence of SEQ ID NO: 2. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% (e.g, at least 96%, 97%, 98%, 99%, etc.) identical to the sequence of SEQ ID NO: 4. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% (e.g., at least 96%, 97%, 98%, 99%, etc.) identical to the sequence of SEQ ID NO: 5. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% (e.g, at least 96%, 97%, 98%, 99%, etc.) identical to the sequence of SEQ ID NO: 7. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% (e.g, at least 96%, 97%, 98%, 99%, etc.) identical to the sequence of SEQ ID NO: 9. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% (e.g, at least 96%, 97%, 98%. 99%. etc. ) identical to the sequence of SEQ ID NO: 1 1. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% (e.g., at least 96%, 97%, 98%, 99%, etc.) identical to the sequence of SEQ ID NO: 12. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% (e.g. , at least 96%, 97%, 98%, 99%, etc.) identical to the sequence of SEQ ID NO: 58. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% (e.g, at least 96%, 97%, 98%, 99%, etc.) identical to the sequence of SEQ ID NO: 59. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% (e.g., at least 96%, 97%. 98%, 99%, etc.) identical to the sequence of SEQ ID NO: 61. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% (e.g, at least 96%, 97%, 98%, 99%, etc.) identical to the sequence of SEQ ID NO: 63.

[0251] In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 85% (e.g, at least 86%, 87%, 88%, 89%, etc.) identical to the sequence of any one of SEQ ID NOs: 13, 15, 17, 19, 21, 23, 25-28, 30-56. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 85% (e.g, at least 86%, 87%, 88%, 89%, etc.) identical to the sequence of SEQ ID NO: 13. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 85% (e.g, at least 86%, 87%, 88%, 89%, etc.) identical to the sequence of SEQ ID NO: 15. In some embodiments, the modified Fcpolypeptide has an amino acid sequence at least 85% (e.g, at least 86%, 87%, 88%, 89%, etc.) identical to the sequence of SEQ ID NO: 17. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 85% (e.g, at least 86%, 87%, 88%, 89%, etc.) identical to the sequence of SEQ ID NO: 19. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to the sequence of SEQ ID NO: 21. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to the sequence of SEQ ID NO: 23. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 85% (e.g, at least 86%, 87%, 88%, 89%, etc.) identical to the sequence of SEQ ID NO: 25. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to the sequence of SEQ ID NO: 26. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 85% (e.g, at least 86%, 87%, 88%, 89%, etc.) identical to the sequence of SEQ ID NO: 27. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 85% (e.g, at least 86%, 87%, 88%, 89%, etc.) identical to the sequence of SEQ ID NO: 28. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 85% (e.g, at least 86%, 87%, 88%, 89%, etc.) identical to the sequence of SEQ ID NO: 30. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to the sequence of SEQ ID NO: 31. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 85% (e.g, at least 86%, 87%, 88%, 89%, etc.) identical to the sequence of SEQ ID NO: 32. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to the sequence of SEQ ID NO: 33. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 85% (e.g, at least 86%, 87%, 88%, 89%, etc.) identical to the sequence of SEQ ID NO: 34. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to the sequence of SEQ ID NO: 35. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 85% (e.g, at least 86%, 87%, 88%, 89%, etc.) identical to the sequence of SEQ ID NO: 36. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 85% (e.g, at least 86%, 87%, 88%, 89%, etc.) identical to the sequence of SEQ ID NO: 37. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 85% (e.g, at least 86%, 87%, 88%, 89%, etc.) identical to the sequence of SEQ ID NO: 38. In some embodiments, the modified Fcpolypeptide has an amino acid sequence at least 85% (e.g, at least 86%, 87%, 88%, 89%, etc.) identical to the sequence of SEQ ID NO: 39. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 85% (e.g, at least 86%, 87%, 88%, 89%, etc.) identical to the sequence of SEQ ID NO: 40. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to the sequence of SEQ ID NO: 41. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to the sequence of SEQ ID NO: 42. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 85% (e.g, at least 86%, 87%, 88%, 89%, etc.) identical to the sequence of SEQ ID NO: 43. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to the sequence of SEQ ID NO: 44. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 85% (e.g, at least 86%, 87%, 88%, 89%, etc.) identical to the sequence of SEQ ID NO: 45. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 85% (e.g, at least 86%, 87%, 88%, 89%, etc.) identical to the sequence of SEQ ID NO: 46. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 85% (e.g, at least 86%, 87%, 88%, 89%, etc.) identical to the sequence of SEQ ID NO: 47. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to the sequence of SEQ ID NO: 48. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 85% (e.g, at least 86%, 87%, 88%, 89%, etc.) identical to the sequence of SEQ ID NO: 49. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to the sequence of SEQ ID NO: 50. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 85% (e.g, at least 86%, 87%, 88%, 89%, etc.) identical to the sequence of SEQ ID NO: 51. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 85% (e.g., at least 86%, 87%, 88%, 89%, etc.) identical to the sequence of SEQ ID NO: 52. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 85% (e.g, at least 86%, 87%, 88%, 89%, etc.) identical to the sequence of SEQ ID NO: 53. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 85% (e.g, at least 86%, 87%, 88%, 89%, etc.) identical to the sequence of SEQ ID NO: 54. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 85% (e.g, at least 86%, 87%, 88%, 89%, etc.) identical to the sequence of SEQ ID NO: 55. In some embodiments, the modified Fcpolypeptide has an amino acid sequence at least 85% (e.g, at least 86%, 87%, 88%, 89%, etc.) identical to the sequence of SEQ ID NO: 56.

[0252] In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% (e.g, at least 91%, 92%, 93%. 94%. etc. ) identical to the sequence of any one of SEQ ID NOs: 13, 15, 17, 19, 21, 23, 25-28, 30-56. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% (e.g, at least 91%, 92%, 93%, 94%, etc.) identical to the sequence of SEQ ID NO: 13. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% (e.g, at least 91%, 92%, 93%, 94%, etc.) identical to the sequence of SEQ ID NO: 15. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% (e.g, at least 91%, 92%, 93%, 94%, etc.) identical to the sequence of SEQ ID NO: 17. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, etc.) identical to the sequence of SEQ ID NO: 19. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% (e.g, at least 91%, 92%, 93%, 94%, etc.) identical to the sequence of SEQ ID NO: 21. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, etc.) identical to the sequence of SEQ ID NO: 23. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% (e.g, at least 91%, 92%, 93%, 94%, etc.) identical to the sequence of SEQ ID NO: 25. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, etc.) identical to the sequence of SEQ ID NO: 26. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% (e.g, at least 91%, 92%, 93%, 94%, etc.) identical to the sequence of SEQ ID NO: 27. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, etc.) identical to the sequence of SEQ ID NO: 28. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% (e.g, at least 91%, 92%, 93%, 94%, etc.) identical to the sequence of SEQ ID NO: 30. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% (e.g, at least 91%, 92%, 93%, 94%, etc.) identical to the sequence of SEQ ID NO: 31. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% (e.g, at least 91%, 92%, 93%, 94%, etc.) identical to the sequence of SEQ ID NO: 32. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% (e.g, at least 91%, 92%, 93%, 94%, etc.) identical to the sequence of SEQ ID NO: 33. In some embodiments, the modified Fcpolypeptide has an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, etc.) identical to the sequence of SEQ ID NO: 34. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% (e.g, at least 91%, 92%, 93%, 94%, etc.) identical to the sequence of SEQ ID NO: 35. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, etc.) identical to the sequence of SEQ ID NO: 36. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% (e.g, at least 91%, 92%, 93%, 94%, etc.) identical to the sequence of SEQ ID NO: 37. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% (e.g, at least 91%, 92%, 93%, 94%, etc. identical to the sequence of SEQ ID NO: 38. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% (e.g, at least 91%, 92%, 93%, 94%, etc.) identical to the sequence of SEQ ID NO: 39. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% (e.g, at least 91%, 92%, 93%, 94%, etc.) identical to the sequence of SEQ ID NO: 40. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% (e.g, at least 91%, 92%, 93%, 94%, etc.) identical to the sequence of SEQ ID NO: 41. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% (e.g, at least 91%, 92%, 93%, 94%, etc.) identical to the sequence of SEQ ID NO: 42. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, etc.) identical to the sequence of SEQ ID NO: 43. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% (e.g, at least 91 %, 92%, 93%, 94%, etc.) identical to the sequence of SEQ ID NO: 44. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, etc.) identical to the sequence of SEQ ID NO: 45. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% (e.g, at least 91%, 92%, 93%, 94%, etc.) identical to the sequence of SEQ ID NO: 46. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, etc.) identical to the sequence of SEQ ID NO: 47. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% (e.g, at least 91%, 92%, 93%, 94%, etc.) identical to the sequence of SEQ ID NO: 48. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% (e.g, at least 91%, 92%, 93%, 94%, etc.) identical to the sequence of SEQ ID NO: 49. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% (e.g, at least 91%, 92%, 93%, 94%, etc.) identical to the sequence of SEQ ID NO: 50. In some embodiments, the modified Fcpolypeptide has an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, etc.) identical to the sequence of SEQ ID NO: 51. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% (e.g, at least 91%, 92%, 93%, 94%, etc.) identical to the sequence of SEQ ID NO: 52. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, efc.) identical to the sequence of SEQ ID NO: 53. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% (e.g, at least 91%, 92%, 93%, 94%, etc.) identical to the sequence of SEQ ID NO: 54. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% (e.g, at least 91%, 92%, 93%, 94%, etc.) identical to the sequence of SEQ ID NO: 55. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 90% (e.g, at least 91%, 92%, 93%, 94%, etc.) identical to the sequence of SEQ ID NO: 56.

[0253] In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% (e.g, at least 96%, 97%, 98%, 99%, etc.) identical to the sequence of any one of SEQ ID NOs: 13, 15, 17, 19, 21, 23, 25-28, 30-56. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% (e.g., at least 96%, 97%, 98%, 99%, etc.) identical to the sequence of SEQ ID NO: 13. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% (e.g, at least 96%, 97%, 98%, 99%, etc.) identical to the sequence of SEQ ID NO: 15. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% (e.g., at least 96%, 97%, 98%, 99%, etc.) identical to the sequence of SEQ ID NO: 17. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% (e.g, at least 96%, 97%, 98%, 99%, etc.) identical to the sequence of SEQ ID NO: 19. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% (e.g., at least 96%, 97%, 98%, 99%, etc.) identical to the sequence of SEQ ID NO: 21. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% (e.g, at least 96%, 97%, 98%, 99%, etc.) identical to the sequence of SEQ ID NO: 23. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% (e.g, at least 96%, 97%, 98%, 99%, etc.) identical to the sequence of SEQ ID NO: 25. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% (e.g, at least 96%, 97%, 98%, 99%, etc.) identical to the sequence of SEQ ID NO: 26. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% (e.g, at least 96%, 97%, 98%, 99%, etc.) identical to the sequence of SEQ ID NO: 27. In some embodiments, the modified Fcpolypeptide has an amino acid sequence at least 95% (e.g, at least 96%, 97%, 98%, 99%, etc.) identical to the sequence of SEQ ID NO: 28. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% (e.g, at least 96%, 97%, 98%, 99%, etc.) identical to the sequence of SEQ ID NO: 30. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% (e.g., at least 96%, 97%, 98%, 99%, etc.) identical to the sequence of SEQ ID NO: 31. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% (e.g., at least 96%, 97%, 98%, 99%, etc.) identical to the sequence of SEQ ID NO: 32. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% (e.g, at least 96%, 97%, 98%, 99%, etc.) identical to the sequence of SEQ ID NO: 33. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% (e.g., at least 96%, 97%, 98%, 99%, etc.) identical to the sequence of SEQ ID NO: 34. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% (e.g, at least 96%, 97%, 98%, 99%, etc.) identical to the sequence of SEQ ID NO: 35. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% (e.g, at least 96%, 97%, 98%, 99%, etc.) identical to the sequence of SEQ ID NO: 36. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% (e.g, at least 96%, 97%, 98%, 99%, etc.) identical to the sequence of SEQ ID NO: 37. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% (e.g., at least 96%, 97%, 98%, 99%, etc.) identical to the sequence of SEQ ID NO: 38. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% (e.g, at least 96%, 97%, 98%, 99%, etc.) identical to the sequence of SEQ ID NO: 39. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% (e.g., at least 96%, 97%, 98%, 99%, etc.) identical to the sequence of SEQ ID NO: 40. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% (e.g, at least 96%, 97%, 98%, 99%, etc.) identical to the sequence of SEQ ID NO: 41. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% (e.g., at least 96%, 97%, 98%, 99%, etc.) identical to the sequence of SEQ ID NO: 42. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% (e.g, at least 96%, 97%, 98%, 99%, etc.) identical to the sequence of SEQ ID NO: 43. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% (e.g, at least 96%, 97%, 98%, 99%, etc.) identical to the sequence of SEQ ID NO: 44. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% (e.g, at least 96%, 97%, 98%, 99%, etc.) identical to the sequence of SEQ ID NO: 45. In some embodiments, the modified Fcpolypeptide has an amino acid sequence at least 95% (e.g, at least 96%, 97%, 98%, 99%, etc.) identical to the sequence of SEQ ID NO: 46. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% (e.g, at least 96%, 97%, 98%, 99%, etc.) identical to the sequence of SEQ ID NO: 47. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% (e.g., at least 96%, 97%, 98%, 99%, etc.) identical to the sequence of SEQ ID NO: 48. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% (e.g., at least 96%, 97%, 98%, 99%, etc.) identical to the sequence of SEQ ID NO: 49. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% (e.g, at least 96%, 97%, 98%, 99%, etc.) identical to the sequence of SEQ ID NO: 50. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% (e.g., at least 96%, 97%, 98%, 99%, etc.) identical to the sequence of SEQ ID NO: 51. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% (e.g, at least 96%, 97%, 98%, 99%, etc.) identical to the sequence of SEQ ID NO: 52. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% (e.g, at least 96%, 97%, 98%, 99%, etc.) identical to the sequence of SEQ ID NO: 53. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% (e.g, at least 96%, 97%, 98%, 99%, etc.) identical to the sequence of SEQ ID NO: 54. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% (e.g., at least 96%, 97%, 98%, 99%, etc.) identical to the sequence of SEQ ID NO: 55. In some embodiments, the modified Fc polypeptide has an amino acid sequence at least 95% (e.g, at least 96%, 97%, 98%, 99%, etc.) identical to the sequence of SEQ ID NO: 56.

[0254] In certain embodiments, the modified Fc polypeptide comprises 3-20 amino acid substitutions (e.g, 4, 5, 6, 7) relative to the amino acid sequence of any one of SEQ ID NOs: 1, 2, 4, 5, 7, 9, 11, and 12. In certain embodiments, the modified Fc polypeptide comprises 3- 20 amino acid substitutions (e.g., 4, 5, 6. 7) relative to the amino acid sequence of SEQ ID NO: 1. In certain embodiments, the modified Fc polypeptide comprises 3-20 amino acid substitutions (e.g, 4, 5, 6, 7) relative to the amino acid sequence of SEQ ID NO: 2. In certain embodiments, the modified Fc polypeptide comprises 3-20 amino acid substitutions (e.g., 4, 5, 6, 7) relative to the amino acid sequence of SEQ ID NO: 4. In certain embodiments, the modified Fc polypeptide comprises 3-20 amino acid substitutions (e.g, 4, 5, 6, 7) relative to the amino acid sequence of SEQ ID NO: 5. In certain embodiments, the modified Fc polypeptide comprises 3-20 amino acid substitutions (e.g, 4, 5, 6, 7) relative to the amino acidsequence of SEQ ID NO: 7. In certain embodiments, the modified Fc polypeptide comprises 3-20 amino acid substitutions (e.g, 4. 5, 6, 7) relative to the amino acid sequence of SEQ ID NO: 9. In certain embodiments, the modified Fc polypeptide comprises 3-20 amino acid substitutions (e.g, 4, 5, 6, 7) relative to the amino acid sequence of SEQ ID NO: 11. In certain embodiments, the modified Fc polypeptide comprises 3-20 amino acid substitutions (e.g, 4, 5,6, 7) relative to the amino acid sequence of SEQ ID NO: 12.

[0255] In certain embodiments, the modified Fc polypeptide comprises amino acid modifications in no more than 20 amino acid residues (e.g. 1, 2, 3. 4, 5, 6. 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20) relative to the amino acid sequence of any one of SEQ ID NOs: 1, 2, 4, 5, 7, 9, 11, and 12. In certain embodiments, the modified Fc polypeptide comprises amino acid modifications in no more than 20 amino acid residues (e.g, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20) relative to the amino acid sequence of SEQ ID NO: 1. In certain embodiments, the modified Fc polypeptide comprises amino acid modifications in no more than 20 amino acid residues (e g, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20) relative to the amino acid sequence of SEQ ID NO: 2. In certain embodiments, the modified Fc polypeptide comprises amino acid modifications in no more than 20 amino acid residues (e.g. 1, 2, 3, 4, 5, 6, 7. 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20) relative to the amino acid sequence of SEQ ID NO: 4. In certain embodiments, the modified Fc polypeptide comprises amino acid modifications in no more than 20 amino acid residues (e.g, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20) relative to the amino acid sequence of SEQ ID NO: 5. In certain embodiments, the modified Fc polypeptide comprises amino acid modifications in no more than 20 amino acid residues (e.g. 1, 2, 3. 4, 5, 6. 7, 8, 9. 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20) relative to the amino acid sequence of SEQ ID NO:7. In certain embodiments, the modified Fc polypeptide comprises amino acid modifications in no more than 20 amino acid residues (e.g, 1, 2. 3, 4, 5, 6, 7, 8, 9, 10, 11. 12, 13, 14, 15, 16, 17. 18, 19, 20) relative to the amino acid sequence of SEQ ID NO: 9. In certain embodiments, the modified Fc polypeptide comprises amino acid modifications in no more than 20 amino acid residues (e.g, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20) relative to the amino acid sequence of SEQ ID NO: 11. In certain embodiments, the modified Fc polypeptide comprises amino acid modifications in no more than 20 amino acid residues (e.g, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20) relative to the ammo acid sequence of SEQ ID NO: 12.

[0256] In certain embodiments, the modified Fc polypeptide comprises 3-20 amino acid substitutions (e.g, 4. 5, 6, 7) relative to the amino acid sequence of any one of SEQ ID NOs: 13, 15, 17, 19, 21, 23, 25-28, and 30-56. In certain embodiments, the modified Fc polypeptide comprises 3-20 amino acid substitutions (e.g, 4, 5, 6, 7) relative to the amino acid sequence of SEQ ID NO: 13. In certain embodiments, the modified Fc polypeptide comprises 3-20 amino acid substitutions (e.g., 4, 5. 6, 7) relative to the amino acid sequence of SEQ ID NO: 15. In certain embodiments, the modified Fc polypeptide comprises 3-20 amino acid substitutions (e.g , 4, 5, 6, 7) relative to the amino acid sequence of SEQ ID NO: 17. In certain embodiments, the modified Fc polypeptide comprises 3-20 amino acid substitutions (e.g, 4, 5, 6, 7) relative to the amino acid sequence of SEQ ID NO: 19. In certain embodiments, the modified Fc polypeptide comprises 3-20 amino acid substitutions (e.g, 4, 5, 6. 7) relative to the amino acid sequence of SEQ ID NO: 21. In certain embodiments, the modified Fc polypeptide comprises 3-20 amino acid substitutions (e.g, 4, 5, 6, 7) relative to the amino acid sequence of SEQ ID NO: 23. In certain embodiments, the modified Fc polypeptide comprises 3-20 amino acid substitutions (e.g., 4. 5, 6, 7) relative to the amino acid sequence of SEQ ID NO: 25. In certain embodiments, the modified Fc polypeptide comprises 3-20 ammo acid substitutions (e.g, 4, 5. 6, 7) relative to the amino acid sequence of SEQ ID NO: 28. In certain embodiments, the modified Fc polypeptide comprises 3-20 amino acid substitutions (e.g., 4, 5, 6, 7) relative to the amino acid sequence of SEQ ID NO: 30. In certain embodiments, the modified Fc polypeptide comprises 3-20 amino acid substitutions (e.g, 4, 5, 6. 7) relative to the amino acid sequence of SEQ ID NO: 31. In certain embodiments, the modified Fc polypeptide comprises 3-20 amino acid substitutions (e.g, 4, 5, 6, 7) relative to the amino acid sequence of SEQ ID NO: 32. In certain embodiments, the modified Fc polypeptide comprises 3-20 amino acid substitutions (e.g., 4. 5, 6, 7) relative to the amino acid sequence of SEQ ID NO: 33. In certain embodiments, the modified Fc polypeptide comprises 3-20 amino acid substitutions (e.g, 4, 5, 6, 7) relative to the amino acid sequence of SEQ ID NO: 34. In certain embodiments, the modified Fc polypeptide comprises 3-20 amino acid substitutions (e.g., 4, 5, 6, 7) relative to the amino acid sequence of SEQ ID NO: 35. In certain embodiments, the modified Fc polypeptide comprises 3-20 amino acid substitutions (e.g, 4, 5. 6. 7) relative to the amino acid sequence of SEQ ID NO: 36. In certain embodiments, the modified Fc polypeptide comprises 3-20 amino acid substitutions (e.g, 4, 5, 6, 7) relative to the amino acid sequence of SEQ ID NO: 37. In certain embodiments, the modified Fc polypeptide comprises 3-20 amino acid substitutions (e.g, 4. 5, 6, 7) relative to the amino acid sequence of SEQ ID NO: 38. In certain embodiments, the modified Fc polypeptide comprises 3-20 amino acid substitutions (e.g, 4, 5,6, 7) relative to the amino acid sequence of SEQ ID NO: 39. In certain embodiments, the modified Fc polypeptide comprises 3-20 amino acid substitutions (e.g, 4. 5, 6, 7) relative to the amino acid sequence of SEQ ID NO: 40. In certain embodiments, the modified Fc polypeptide comprises 3-20 amino acid substitutions (e.g, 4, 5, 6, 7) relative to the amino acid sequence of SEQ ID NO: 41. In certain embodiments, the modified Fc polypeptide comprises 3-20 amino acid substitutions (e.g, 4, 5, 6, 7) relative to the amino acid sequence of SEQ ID NO: 42. In certain embodiments, the modified Fc polypeptide comprises 3-20 amino acid substitutions (e.g., 4, 5, 6, 7) relative to the amino acid sequence of SEQ ID NO: 43. In certain embodiments, the modified Fc polypeptide comprises 3-20 amino acid substitutions (e.g, 4, 5, 6, 7) relative to the amino acid sequence of SEQ ID NO: 44. In certain embodiments, the modified Fc polypeptide comprises 3-20 amino acid substitutions (e.g, 4. 5, 6, 7) relative to the amino acid sequence of SEQ ID NO: 45. In certain embodiments, the modified Fc polypeptide comprises 3-20 amino acid substitutions (e.g., 4, 5, 6, 7) relative to the amino acid sequence of SEQ ID NO: 46. In certain embodiments, the modified Fc polypeptide comprises 3-20 amino acid substitutions (e.g, 4, 5, 6, 7) relative to the amino acid sequence of SEQ ID NO: 47. In certain embodiments, the modified Fc polypeptide comprises 3-20 amino acid substitutions (e.g, 4, 5, 6, 7) relative to the amino acid sequence of SEQ ID NO: 48. In certain embodiments, the modified Fc polypeptide comprises 3-20 amino acid substitutions (e.g, 4, 5, 6, 7) relative to the amino acid sequence of SEQ ID NO: 49. In certain embodiments, the modified Fc polypeptide comprises 3-20 amino acid substitutions (e.g, 4. 5, 6, 7) relative to the amino acid sequence of SEQ ID NO: 50. In certain embodiments, the modified Fc polypeptide comprises 3-20 amino acid substitutions (e.g., 4, 5, 6, 7) relative to the amino acid sequence of SEQ ID NO: 51. In certain embodiments, the modified Fc polypeptide comprises 3-20 amino acid substitutions (e.g, 4, 5, 6, 7) relative to the amino acid sequence of SEQ ID NO: 52. In certain embodiments, the modified Fc polypeptide comprises 3-20 amino acid substitutions (e.g, 4, 5, 6, 7) relative to the amino acid sequence of SEQ ID NO: 53. In certain embodiments, the modified Fc polypeptide comprises 3-20 amino acid substitutions (e.g, 4, 5, 6, 7) relative to the amino acid sequence of SEQ ID NO: 54. In certain embodiments, the modified Fc polypeptide comprises 3-20 amino acid substitutions (e.g, 4. 5, 6, 7) relative to the amino acid sequence of SEQ ID NO: 55. In certain embodiments, the modified Fc polypeptide comprises 3-20 amino acid substitutions (e.g, 4, 5, 6, 7) relative to the amino acid sequence of SEQ ID NO: 56.

[0257] In certain embodiments, the modified Fc polypeptide comprises amino acid modifications in no more than 20 amino acid residues (e.g. 1, 2, 3. 4, 5, 6. 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20) relative to the amino acid sequence of any one of SEQ ID NOs: 13, 15, 17, 19, 21, 23, 25-28, and 30-56. In certain embodiments, the modified Fc polypeptide comprises amino acid modifications in no more than 20 amino acid residues (e.g, 1, 2, 3, 4, 5, 6, 7, 8, 9. 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20) relative to the amino acid sequence of SEQ ID NO: 13. In certain embodiments, the modified Fc polypeptide comprises ammo acid modifications in no more than 20 amino acid residues (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20) relative to the amino acid sequence of SEQ ID NO: 15. In certain embodiments, the modified Fc polypeptide comprises amino acid modifications in no more than 20 amino acid residues (e.g, 1. 2, 3, 4, 5, 6, 7, 8. 9, 10, 11, 12, 13. 14. 15. 16. 17. 18, 19, 20) relative to the amino acid sequence of SEQ ID NO: 17. In certain embodiments, the modified Fc polypeptide comprises amino acid modifications in no more than 20 amino acid residues (e.g, 1, 2. 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20) relative to the amino acid sequence of SEQ ID NO: 19. In certain embodiments, the modified Fc polypeptide comprises ammo acid modifications in no more than 20 amino acid residues (e.g, 1. 2. 3, 4, 5. 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20) relative to the amino acid sequence of SEQ ID NO: 21. In certain embodiments, the modified Fc polypeptide comprises amino acid modifications in no more than 20 amino acid residues (e.g.. 1, 2, 3. 4, 5, 6, 7, 8, 9, 10, 11, 12, 13. 14, 15, 16, 17, 18, 19, 20) relative to the amino acid sequence of SEQ ID NO: 23. In certain embodiments, the modified Fc polypeptide comprises amino acid modifications in no more than 20 ammo acid residues (e.g, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20) relative to the amino acid sequence of SEQ ID NO: 25. In certain embodiments, the modified Fc polypeptide comprises amino acid modifications in no more than 20 amino acid residues (e.g, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20) relative to the amino acid sequence of SEQ ID NO: 26. In certain embodiments, the modified Fc polypeptide comprises amino acid modifications in no more than 20 amino acid residues (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9. 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20) relative to the amino acid sequence of SEQ ID NO: 28. In certain embodiments, the modified Fc polypeptide comprises ammo acid modifications in no more than 20 amino acid residues (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20) relative to the amino acid sequence of SEQ ID NO: 30. In certain embodiments, the modified Fc polypeptide comprises amino acid modifications in no more than 20 amino acid residues (e.g, 1. 2, 3, 4, 5. 6, 7, 8. 9, 10, 11, 12, 13. 14. 15. 16. 17. 18, 19, 20) relative to the amino acid sequence of SEQ ID NO: 31. In certain embodiments, themodified Fc polypeptide comprises amino acid modifications in no more than 20 amino acid residues (e.g, 1, 2. 3, 4, 5. 6, 7, 8. 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20) relative to the amino acid sequence of SEQ ID NO: 32. In certain embodiments, the modified Fc polypeptide comprises amino acid modifications in no more than 20 amino acid residues (e.g, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20) relative to the amino acid sequence of SEQ ID NO: 33. In certain embodiments, the modified Fc polypeptide comprises amino acid modifications in no more than 20 amino acid residues (e.g. 1, 2, 3. 4, 5, 6. 7, 8, 9. 10. 11. 12. 13, 14, 15, 16, 17, 18, 19, 20) relative to the amino acid sequence of SEQ ID NO: 34. In certain embodiments, the modified Fc polypeptide comprises amino acid modifications in no more than 20 ammo acid residues (e.g, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13. 14. 15, 16, 17, 18, 19, 20) relative to the amino acid sequence of SEQ ID NO: 35. In certain embodiments, the modified Fc polypeptide comprises amino acid modifications in no more than 20 amino acid residues (e.g, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20) relative to the amino acid sequence of SEQ ID NO: 36. In certain embodiments, the modified Fc poly peptide comprises amino acid modifications in no more than 20 amino acid residues (e.g, 1, 2, 3, 4, 5, 6, 7, 8. 9. 10. 11. 12. 13. 14, 15, 16, 17, 18, 19, 20) relative to the amino acid sequence of SEQ ID NO: 37. In certain embodiments, the modified Fc polypeptide comprises amino acid modifications in no more than 20 amino acid residues (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20) relative to the amino acid sequence of SEQ ID NO: 38. In certain embodiments, the modified Fc polypeptide comprises amino acid modifications in no more than 20 amino acid residues (e.g. , 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20) relative to the amino acid sequence of SEQ ID NO: 39. In certain embodiments, the modified Fc polypeptide comprises amino acid modifications in no more than 20 amino acid residues (e.g, 1, 2. 3, 4, 5. 6, 7, 8. 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20) relative to the amino acid sequence of SEQ ID NO: 40. In certain embodiments, the modified Fc polypeptide comprises amino acid modifications in no more than 20 amino acid residues (e.g, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20) relative to the amino acid sequence of SEQ ID NO: 41. In certain embodiments, the modified Fc polypeptide comprises amino acid modifications in no more than 20 amino acid residues (e.g. 1, 2, 3. 4, 5, 6. 7, 8, 9. 10. 11. 12. 13, 14, 15, 16, 17, 18, 19, 20) relative to the amino acid sequence of SEQ ID NO: 42. In certain embodiments, the modified Fc polypeptide comprises amino acid modifications in no more than 20 ammo acid residues (e.g, 1, 2, 3, 4, 5. 6, 7, 8, 9, 10, 11, 12, 13. 14, 15, 16, 17, 18, 19, 20) relative to the amino acid sequence of SEQ ID NO: 43. In certain embodiments, the modified Fc polypeptide comprises amino acid modifications in no more than 20 amino acidresidues (e.g., 1, 2. 3, 4, 5. 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20) relative to the amino acid sequence of SEQ ID NO: 44. In certain embodiments, the modified Fc polypeptide comprises amino acid modifications in no more than 20 amino acid residues (e.g, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20) relative to the amino acid sequence of SEQ ID NO: 45. In certain embodiments, the modified Fc polypeptide comprises amino acid modifications in no more than 20 amino acid residues (e.g.. 1, 2, 3. 4, 5, 6, 7, 8, 9, 10, 11, 12, 13. 14, 15, 16, 17, 18, 19, 20) relative to the amino acid sequence of SEQ ID NO: 46. In certain embodiments, the modified Fc polypeptide comprises amino acid modifications in no more than 20 amino acid residues (e.g, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20) relative to the amino acid sequence of SEQ ID NO: 47. In certain embodiments, the modified Fc polypeptide comprises amino acid modifications in no more than 20 amino acid residues (e.g, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20) relative to the amino acid sequence of SEQ ID NO: 48. In certain embodiments, the modified Fc polypeptide comprises amino acid modifications in no more than 20 amino acid residues (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9. 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20) relative to the amino acid sequence of SEQ ID NO: 49. In certain embodiments, the modified Fc polypeptide comprises ammo acid modifications in no more than 20 amino acid residues (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20) relative to the amino acid sequence of SEQ ID NO: 50. In certain embodiments, the modified Fc polypeptide comprises amino acid modifications in no more than 20 amino acid residues (e.g, 1. 2, 3, 4, 5. 6, 7, 8. 9, 10, 11, 12, 13. 14. 15. 16. 17. 18. 19, 20) relative to the amino acid sequence of SEQ ID NO: 51. In certain embodiments, the modified Fc polypeptide comprises amino acid modifications in no more than 20 amino acid residues (e.g., 1, 2. 3, 4, 5. 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20) relative to the amino acid sequence of SEQ ID NO: 52. In certain embodiments, the modified Fc polypeptide comprises ammo acid modifications in no more than 20 amino acid residues (e.g, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20) relative to the amino acid sequence of SEQ ID NO: 53. In certain embodiments, the modified Fc polypeptide comprises amino acid modifications in no more than 20 amino acid residues (e.g.. 1, 2, 3. 4, 5, 6, 7, 8, 9, 10, 11, 12, 13. 14, 15, 16, 17, 18, 19, 20) relative to the amino acid sequence of SEQ ID NO: 54. In certain embodiments, the modified Fc polypeptide comprises amino acid modifications in no more than 20 amino acid residues (e.g, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20) relative to the amino acid sequence of SEQ ID NO: 55. In certain embodiments, the modified Fc polypeptide comprises amino acid modifications in no more than 20 amino acidresidues (e.g., 1, 2. 3, 4, 5. 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20) relative to the amino acid sequence of SEQ ID NO: 56.Sialylation of Modified Fc Polypeptides

[0258] Glycosylation of immunoglobulins has been shown to have significant effects on their effector functions, structural stability, and rate of secretion from antibody-producing cells. The carbohydrate groups responsible for these properties are generally attached to the constant (C) regions of the antibodies. For example, glycosylation of IgG at Asn297 in the CH2 domain is required for the full capacity’ of IgG to activate the classical pathway of complement-dependent cytolysis.

[0259] Each antibody possesses a distinct array of N-linked glycan structures which variably affect protein assembly, secretion, and function. These N-linked glycans vary considerably, depending on the degree of processing, and include high-mannose, as well as complex biantennary oligosaccharides with or without bisecting N-acetylglucosamine (GlcNAc) and core fucose (Fuc) residues, in some embodiments. Typically, there is heterogeneous processing of the core oligosaccharide structures attached at a particular glycosylation site such that even monoclonal antibodies exist as multiple glycoforms. Likewise, it has been shown that major differences in antibody glycosylation occur between antibody-producing cell lines, and even minor differences are seen for a given cell line grown under different culture conditions.

[0260] The presence of sialic acid (SA) residues on the N-glycan of Fc polypeptides has recently been identified as an important factor in mediating anti-inflammatory effects of intravenous immunoglobulin (IVIG), which has been demonstrated in certain autoimmune diseases. It has been proposed that this anti-inflammatory effect is mediated by binding of sialylated Fc components of IVIG to inhibitory’ Fey RUB receptors and DC-SIGN receptors. Removal of the IVIg sialic acid results in loss of protection in animal models of multiple sclerosis, rheumatoid arthritis, Guillain-Barre syndrome, and idiopathic thrombocytopenic purpura (ITP), despite retaining normal circulating half-life and binding to FcRn. Conversely, hyper-sialylation of IVIg increases the potency of anti-inflammatory activity' 10-30-fold in several different animal models of autoimmune disease. The biological consequence of binding to and activating the type II Fc receptors is IL-33 release, inhibitory FcyRIIB upregulation, and T regulatory' cell expansion. In mice, knock-out of SIGN-R1 (the murine homologue of DC-SIGN) blocks the anti-inflammatory activity' of IVIg. Blocking the IL-33 receptor, knockout of FcyRIIB, or depletion of T regulatory cell, in different contexts, alsoblocks the anti-inflammatory properties of IVIg. However, only a minor portion of IgG in IVIG have glycans terminating in SA. thereby requiring administration of IVIG at high doses (1-2 g / kg) to elicit a therapeutic anti-inflammatory effect.

[0261] Disclosed herein, in some embodiments, are compositions (e.g., therapeutic compositions) comprising modified Fc polypeptides having sequences of variants of a wildtype human IgG Fc polypeptide of SEQ ID NO: 2 or SEQ ID NO: 12 (or an allotype variant, e.g., an allotype variant comprising the amino acid sequence of SEQ ID NO: 4, 5, 8, 9, 58, 59, 61 , and / or 63) and having high levels of sialylation, such as at least 50% a(2,6) sialylation (e.g. , at least 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%. or more) or about 40% a(2,3) sialylation (e.g., 30%, 31%, 32%, 33%, 34%, 35%. 36%. 37%. 38%. 39%. 40%. 41%. 42%. 43%. 44%, 45%, 46%, 47%, 48%, 49%, 50%). In some embodiments, the modified Fc polypeptides comprise a sialic acid (SA) moiety attached to an N-glycan of the modified Fc polypeptide via an a(2,6) linkage.

[0262] The present disclosure also provides methods for enhancing sialylation of IgG Fc polypeptides by providing modified Fc polypeptides (e.g., a modified Fc polypeptide listed in Table 1) in a recombinant expression system (e.g. one or more nucleic acid expression vectors introduced into a host cell, such as a mammalian host cell) alone or in combination with one or more (e.g., 1, 2, or more) recombinant glycosyltransferase enzymes (e.g., ST6GAL1 and B4GALT1) under conditions and for a time sufficient to yield desired levels of Fc sialylation. In some embodiments, the one or more recombinant glycosyltransferase enzymes is ST6GAL1. Activity of ST6GAL1 results in 6-sialylated oligosaccharides, including 6-sialylated galactose. The term “ST6GAL1” refers to a sialyltransferase enzyme capable of attaching SA to the sixth atom of the acceptor polysaccharide. In some embodiments, the one or more recombinant glycosyltransferase enzy mes is B4GALT1. The term “B4GALT1” refers to an enzyme belonging to a family of beta-l,4-galactosyltransferases that transfers galactose in a [3(1,4) linkage to acceptor sugars, such as GlcNAc, Glc, and Xyl. In some embodiments, the one or more recombinant glycosyltransferase enzymes are ST6GAL1 and B4GALT1.Pharmaceutical Compositions

[0263] Disclosed herein, in some embodiments, are pharmaceutical compositions comprising polypeptides disclosed herein and a pharmaceutically acceptable carrier, diluent, or excipient, for example, a stabilizer, buffer, surfactant, filler, solvent, tonicity or osmolarityadjusting agent, antioxidant, adjuvant, antimicrobial agent, or any combination of the foregoing.Methods of Treatment

[0264] Disclosed herein, in some embodiments, are methods of treatment comprising administering a polypeptide or pharmaceutical composition disclosed herein to a subject (e.g, a mammalian subject such as a human subject) in need thereof.Therapeutic effects

[0265] In some embodiments, a polypeptide or composition of the disclosure is administered in an amount and for a time effective to result in reduction in one or more (e.g, 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, or 10 or more) of: decrease immune cell (e.g., T cell, B cell, NK cell, ILC1. ILC2, ILC3, monocyte, macrophage (Ml and M2), dendritic cell, or antigen presenting cell) migration, decrease immune cell proliferation, decrease immune cell recruitment, increase immune cell lymph node homing, decrease immune cell lymph node egress, decrease immune cell differentiation, decrease immune cell activation, decrease immune cell polarization, decrease immune cell cytokine production, decrease immune cell degranulation, decrease immune cell maturation, decrease immune cell antibody-dependent cellular cytotoxicity (ADCC), decrease immune cell antibody-dependent cellular phagocytosis (ADCP), decrease immune cell antigen presentation, reduce immune cell serotonin receptor expression, treat the inflammatory disease or disorder, reduce symptoms of an inflammatory disease or disorder, reduce inflammation, reduce auto-antibody levels, increase organ function, and decrease rate or number of relapses or flare-ups. In some embodiments, a polypeptide or composition of the disclosure is administered in an amount and for a time effective to a subject suffering from a disease or condition regulated by FcyRIIB.

[0266] Reduction in the severity of the aforementioned symptoms is. in some embodiments, by any amount, so long as a therapeutic benefit is achieved in the patient. Treatment efficacy is measured across different timeframes, including e.g., in months to years, depending on prognostic factors including the number of relapses, stage of disease, and other factors.

[0267] In some embodiments, prolonged survival is a treatment benchmark that includes, without limitation, an increase in survival time by at least 1 month (mo), about at least 2 months (mos), about at least 3 mos, about at least 4 mos, about at least 6 mos, about at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50 years, or more. In some embodiments, overall survival ismeasured in months to years. In some embodiments, the subject's symptoms remain static or decrease.OTHER EMBODIMENTS

[0268] While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure that come within known or customary practice within the art to which the invention pertains and may be applied to the essential features set forth herein.EXAMPLES

[0269] The following examples are put forth to provide those of ordinary skill in the art with a description of how the compositions and methods described herein may be used, made, and evaluated, and are intended to be purely exemplary of the disclosure and are not intended to limit the scope of what the inventors regard as their invention.Example 1: FcyRIIB binding of F241A-Fc in combination with additional amino acid modifications

[0270] The binding of WT-Fc, F241A-Fc, E233D / G237D / P238D / H268D / P271G / A330R- Fc, E233D / P238D-Fc, or G237D / P238D / H268D / P271G / A330R-Fc to FcyRIIB was evaluated by Fluorescence Resonance Energy Transfer (FRET). Emission ratios were calculated (665 nm / 620 nm) and plotted against the log value of the Fc concentration (log[Ab] uM; FIG. 1) and EC so values were calculated. Calculated ECso values are provided in TABLE 2. Compared to WT-Fc, F241A-Fc decreased affinity7for FcyRIIB. The addition of amino acid modifications (E233D / G237D / P238D / H268D / P271G / A330R, E233D / P238D, andG237D / P238D / H268D / P271G / A330R) known to increase the affinity of WT-Fc to FcyRIIB increased show ed an expected increase in binding to FcyRIIB compared to WT-Fc (FIG. 1).Table 2. ECso values show binding of modified Fc polypeptides to FcyRIIB

[0271] In a second FRET experiment performed as described above, binding of WT-Fc, F241 A-Fc, F241 A / E233D / G237D / P238D / H268D / P271 G / A330R-Fc, F241 A / E233D / P238D- Fc, or F241A / G237D / P238D / H268D / P271G / A330R-Fc to FcyRIIB was evaluated by FRET (FIG. 2). Calculated ECso values are provided in TABLE 3. Compared to F241A-Fc, only the addition of the combination of six amino acid modifications (E233D / G237D / P238D / H268D / P271G / A330R) increased binding to FcyRIIB.Table 3. ECso values show binding of modified Fc polypeptides to FcyRIIB

[0272] The affect of the addition of SE / LF (S267E / L328F) amino acid modifications on F241A-Fc binding to FcyRIIB was also evaluated. WT-Fc, F241A-Fc, S267E / L328F-Fc, or F241A / S267E / L328F-Fc to FcyRIIB was evaluated by FRET as described above (FIG. 3). Calculated ECso values are provided in TABLE 4. Addition of the SE / LF amino acid modification to F241 A-Fc did not increase binding to FcyRIIB.Table 4. ECso values show binding of modified Fc polypeptides to FcyRIIB+Example 2: Fc RIIIA binding of F241A-Fc in combination with additional amino acid modifications

[0273] The binding of WT-Fc, E233D / G237D / P238D / H268D / P271G / A330R-Fc, E233D / P238D-Fc, or G237D / P238D / H268D / P271G / A330R-Fc to FcyRIIIA was evaluated by FRET as described in Example 1 (FIG. 4). Calculated ECso values are provided in TABLE 5. Compared to WT-Fc the addition of combinations of amino acid modifications (E233D / G237D / P238D / H268D / P271G / A330R, E233D / P238D, andG237D / P238D / H268D / P271G / A330R) abolished binding to FcyRIIIA (FIG. 4).Table 5. ECso values show binding of modified Fc polypeptides to FcyRIIIA

[0274] The binding of F241A-Fc, F241A / E233D / G237D / P238D / H268D / P271G / A330R- Fc, F241A / E233D / P238D-FC, or F241A / G237D / P238D / H268D / P271G / A330R-Fc to FcyRIIIA was also evaluated by FRET (FIG. 5). Calculated ECso values are provided in TABLE 6. Compared to F241A-Fc the addition of combinations of amino acid modifications (E233D / G237D / P238D / H268D / P271G / A330R, E233D / P238D, andG237D / P238D / H268D / P271G / A330R) abolished binding to FcyRIIIA.Table 6. ECso values show binding of modified Fc polypeptides to FcyRIIIAExample 3: Interaction analysis of FcyRIIB with WT-Fc, F241A-Fc and F241L-Fc in combination with additional amino acid modifications

[0275] Interaction of modified Fc polypeptides with FcyRIIB was evaluated using Surface plasmon resonance (SPR). Series S Sensor Chip CM5 was prepared in Running Buffer (HBS- ET+. pH7.4 (0.0 IM HEPES. 0. 15 M NaCl, 3 mM EDTA, 0.05% Tween-20)). For CM5 sensor chip activation, the activator was prepared by mixing 400 mM EDC and 100 mM NHS immediately prior to injection. The CM5 sensor chip was activated for 420 s with the mixture at a flow rate of 10 pL / min. 30 pg / mL of Human CD32b / c Protein (FcyRIIB) in 10 mM Sodium Acetate (pH 4.5) and was then injected to Fc2 sample channel at a flow rate of 10 pL / min to reach an immobilization level of about 1000 RU. The chip was deactivated by 1 M Ethanolamine-HCl (pH8.5) at a flow rate of 10 pL / min for 420 s. The reference surface Fcl channel was blocked by the same steps to Fc2 but without the step injecting ligand Human CD32b Protein (FcyRIIB).

[0276] The Analyte Proteins used in the SPR experiments are modified Fc polypeptides that are either WT (F241) or having the amino acid substitution F241 A, or F241L and (i) either LS (M428L / N434S), YTE (M252Y / S254T / T256E), or KFH (H433K / N434F / Y436H) amino acid modifications and (ii) additional amino acid modifications as indicated in Table 7. Analyte Proteins were diluted with the same Running Buffer to two concentrations (0 nM and 10 pM). Analyte Protein was injected to Fcl-Fc2 of channel at a flow rate of 30 pL / min for an association phase of 60 s, followed by 60 s dissociation. The association and dissociation process were all handled in the Running Buffer. Two cycles of running analyte were repeated according to analyte concentrations in ascending order. The other buffers used in SPR Assay process are the same as the injection buffer (10 mM Sodium Acetate (pH 4.5)), which is placed in the rack tray of sample compartment. FcyRIIB binding response was analyzed at 10 pM for each analyte protein and binding to FcyRIIB was ranked. + is binding response units less than or equal to F241 A-Fc binding; ++ is binding response units >1-2 fold higher than F241 A; +++ is binding response units >2-4.5 fold higher than F241A; ++++ is binding response units >4.5 fold higher. The results are shown in Table 7.

[0277] The addition of G237D / P238D / P271G / A330R,G237D / P238D / H268D / P271G / A330R, E233D / G237D / P238D / H268D / P271G / A330R amino acid modifications to F241A-Fc or F241L-Fc increased FcyRIIB Binding. F241A-Fc with the addition of YTE (M252Y / S254T / T256E) amino acid modifications had low binding to FcyRIIB which increased with the addition of either G237D / P238D / H268D / P271G / A330R or E233D / G237D / P238D / H268D / P271G / A330R amino acid modifications. F241A-Fc with theaddition of LS (M428L / N434S) amino acid modifications had low binding to FcyRIIB which increased with the addition of G237D / P238D / P271G / A330R, G237D / P238D / H268D / P271G / A330R, or E233D / G237D / P238D / H268D / P271G / A330R amino acid modifications. F241A-Fc with the addition of KFH (H433K / N434F / Y 436H) amino acid modifications had low binding to Fey RUB which increased with the addition of G237D / P238D / P271G / A330R, G237D / P238D / H268D / P271G / A330R, orE233D / G237D / P238D / H268D / P271G / A330R amino acid modifications. Similar results were observed with F241L-Fc in combination with YTE, LS, KFH and additional amino acid modifications (G237D / P238D / P271G / A330R, G237D / P238D / H268D / P271G / A330R, or E233D / G237D / P238D / H268D / P271 G / A330R).Table 7. SPR Binding DataLIST OF SEQUENCES

Claims

WHAT IS CLAIMED IS:

1. A modified Fc polypeptide having: an amino acid sequence at least 75% identical to the sequence of SEQ ID NO: 1, and further comprising:(i) a sialic acid (SA) moiety attached to an N-glycan of the Fc polypeptide:(ii) an aliphatic amino acid residue at position 241 or position 243, and(iii) amino acid modifications selected from the group consisting of:(a) an aspartic acid residue at position 233 (E233D), an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 238 (P238D), an aspartic acid residue at position 268 (H268D), a glycine residue at position 271 (P271 G), and an arginine residue at position 330 (A330R);(b) an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 238 (P238D), a glycine residue at position 271 (P271G), and an arginine residue at position 330 (A330R);(c) an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 238 (P238D), an aspartic acid residue at position 268 (H268D), a glycine residue at position 271 (P271G), and an arginine residue at position 330 (A330R);(d) an aspartic acid residue at position 233 (E233D). an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 238 (P238D), an aspartic acid residue at position 268 (H268D), a glycine residue at position 271 (P271G), an arginine residue at position 330 (A330R), a leucine residue at position 428 (M428L). and a serine residue at position 434 (N434S);(e) an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 238 (P238D), a glycine residue at position 271 (P271G), and an arginine residue at position 330 (A330R), a leucine residue at position 428 (M428L). and a serine residue at position 434 (N434S); and(1) an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 238 (P238D), an aspartic acid residue at position 268 (H268D), a glycine residue at position 271 (P271G), and an arginine residue atposition 330 (A330R), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S); wherein the position numbering is according to the EU index of Kabat.

2. A modified Fc polypeptide having: an amino acid sequence at least 75% identical to the sequence of SEQ ID NO: 1, and further comprising:(i) an aliphatic amino acid residue at position 241 or position 243,(ii) an amino acid modification at position 238;(iii) a sialic acid (SA) moiety attached to an N-glycan of the Fc polypeptide: and(iv) at least one additional amino acid modification at a position selected from the group consisting of: 233, 236, 237, 239, 267, 268, 271, 296, 328, 330, and combinations thereof; wherein the position numbering is according to the EU index of Kabat.

3. The modified Fc polypeptide of claim 2, wherein the at least one additional amino acid modification is selected from the group consisting of:(a) an aspartic acid residue at position 233 (E233D),(b) an aspartic acid residue at position 236 (G236D),(c) an aspartic acid residue at position 237 (G237D),(d) an aspartic acid residue at position 239 (S239D),(e) a glutamic acid residue at position 267 (S267E),(f) an aspartic acid residue at position 268 (H268D),(g) a glycine residue at position 271 (P271G),(h) an aspartic acid residue at position 296 (Y296D),(i) a phenylalanine at position 328 (L328F),(j) an arginine residue at position 330 (A330R), and combinations thereof; wherein the position numbering is according to the EU index of Kabat.

4. The modified Fc polypeptide of claim 3, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 233 (E233D), wherein the position numbering is according to the EU index of Kabat.

5. The modified Fc polypeptide of claim 3, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 236 (G236D), wherein the position numbering is according to the EU index of Kabat.

6. The modified Fc polypeptide of claim 3, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 237 (G237D), wherein the position numbering is according to the EU index of Kabat.

7. The modified Fc polypeptide of claim 3, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 239 (S239D), wherein the position numbering is according to the EU index of Kabat.

8. The modified Fc polypeptide of claim 3, wherein the modified Fc polypeptide comprises a glutamic acid residue at position 267 (S267E), wherein the position numbering is according to the EU index of Kabat.

9. The modified Fc polypeptide of claim 3, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 268 (H268D), wherein the position numbering is according to the EU index of Kabat.

10. The modified Fc polypeptide of claim 3. wherein the modified Fc polypeptide comprises a glycine residue at position 271 (P271G), wherein the position numbering is according to the EU index of Kabat.

11. The modified Fc polypeptide of claim 3, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 296 (Y296D), wherein the position numbering is according to the EU index of Kabat.

12. The modified Fc polypeptide of claim 3. wherein the modified Fc polypeptide comprises a phenylalanine at position 328 (L328F), wherein the position numbering is according to the EU index of Kabat.

13. The modified Fc polypeptide of claim 3, wherein the modified Fc polypeptide comprises an arginine residue at position 330 (A330R), wherein the position numbering is according to the EU index of Kabat.

14. The modified Fc polypeptide of claim 3, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 233 (E233D) and an arginine at position 330 (A330R), wherein the position numbering is according to the EU index of Kabat.

15. The modified Fc polypeptide of claim 3, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 233 (E233D), a glycine residue at position 271 (P271G), and an arginine residue at position 330 (A330R), wherein the position numbering is according to the EU index of Kabat.

16. The modified Fc polypeptide of claim 3. wherein the modified Fc polypeptide comprises an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 268 (H268D), and a glycine residue at position 271 (P271G), wherein the position numbering is according to the EU index of Kabat.

17. The modified Fc polypeptide of claim 3. wherein the modified Fc polypeptide comprises an aspartic acid residue at position 237 (G237D), a glycine residue at position 271 (P271G), and an arginine residue at position 330 (A330R), wherein the position numbering is according to the EU index of Kabat.

18. The modified Fc polypeptide of claim 3, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 233 (E233D), an aspartic acid residue at position 268 (H268D), a glycine residue at position 271 (P271G), and an arginine residue at position 330 (A330R), wherein the position numbering is according to the EU index of Kabat.

19. The modified Fc polypeptide of claim 3, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 268 (H268D), a glycine residue at position 271 (P271G), and an arginine residue at position 330 (A330R), wherein the position numbering is according to the EU index of Kabat.

20. The modified Fc polypeptide of claim 3. wherein the modified Fc polypeptide comprises an aspartic acid residue at position 233 (E233D), an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 268 (H268D), a glycine residue at position 271 (P271G), and an arginine residue at position 330 (A330R), wherein the position numbering is according to the EU index of Kabat.

21. The modified Fc polypeptide of claim 3. wherein the modified Fc polypeptide comprises an aspartic acid residue at position 233 (E233D) and an aspartic acid residue at position 269 (Y296D), wherein the position numbering is according to the EU index of Kabat.

22. The modified Fc polypeptide of claim 3, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 237 (G237D) and an aspartic acid residue at position 269 (Y296D), wherein the position numbering is according to the EU index of Kabat.

23. The modified Fc polypeptide of claim 3, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 237 (G237D) and an aspartic acid residue at position 269 (Y296D), wherein the position numbering is according to the EU index of Kabat.

24. The modified Fc polypeptide of claim 3. wherein the modified Fc polypeptide comprises an aspartic acid residue at position 268 (H268D) and an aspartic acid residue at position 269 (Y296D), wherein the position numbering is according to the EU index of Kabat.

25. The modified Fc polypeptide of claim 3, wherein the modified Fc polypeptide comprises a glycine residue at position 271 (P271G) and an aspartic acid residue at position 269 (Y296D), wherein the position numbering is according to the EU index of Kabat.

26. The modified Fc polypeptide of claim 3. wherein the modified Fc polypeptide comprises an arginine residue at position 330 (A330R) and an aspartic acid residue at position 269 (Y296D), wherein the position numbering is according to the EU index of Kabat.

27. The modified Fc polypeptide of claim 3, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 237 (G237D) and an aspartic acid residue at position 269 (Y296D), wherein the position numbering is according to the EU index of Kabat.

28. The modified Fc polypeptide of claim 3. wherein the modified Fc polypeptide comprises an aspartic acid residue at position 233 (E233D) and an aspartic acid residue at position 269 (Y296D) and an arginine at position 330 (A330R), wherein the position numbering is according to the EU index of Kabat.

29. The modified Fc polypeptide of claim 3. wherein the modified Fc polypeptide comprises an aspartic acid residue at position 233 (E233D), a glycine residue at position 271 (P271G), an aspartic acid residue at position 269 (Y296D), and an arginine residue at position 330 (A330R), wherein the position numbering is according to the EU index of Kabat.

30. The modified Fc polypeptide of claim 3, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 268 (H268D), an aspartic acid residue at position 269 (Y296D). and a glycine residue at position 271 (P271G), wherein the position numbering is according to the EU index of Kabat.

31. The modified Fc polypeptide of claim 3, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 237 (G237D), a glycine residue at position 271 (P271G), an aspartic acid residue at position 269 (Y296D), and an arginine residue at position 330 (A330R), wherein the position numbering is according to the EU index of Kabat.

32. The modified Fc polypeptide of claim 3, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 233 (E233D), an aspartic acid residue at position 268 (H268D), an aspartic acid residue at position 269 (Y296D), a glycine residue at position 271 (P271G), and an arginine residue at position 330 (A330R), wherein the position numbering is according to the EU index of Kabat.

33. The modified Fc polypeptide of claim 3, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 268 (H268D), an aspartic acid residue at position 269 (Y296D), a glycine residue at position 271 (P271G), and an arginine residue at position 330 (A330R), wherein the position numbering is according to the EU index of Kabat.

34. The modified Fc polypeptide of claim 3, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 233 (E233D), an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 268 (H268D), an aspartic acid residue at position 269 (Y296D), a glycine residue at position 271 (P271G), and an arginine residue at position 330 (A330R), wherein the position numbering is according to the EU index of Kabat.

35. The modified Fc polypeptide of claim 3, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 236 (G236D) and a glutamic acid residue at position 267 (S267E), wherein the position numbering is according to the EU index of Kabat.

36. The modified Fc polypeptide of claim 3, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 239 (S239D) and a glutamic acid residue at position 267 (S267E), wherein the position numbering is according to the EU index of Kabat.

37. The modified Fc polypeptide of claim 3. wherein the modified Fc polypeptide comprises a glutamic acid residue at position 267 (S267E) and a phenylalanine residue at position 328 (L328F), wherein the position numbering is according to the EU index of Kabat.

38. The modified Fc polypeptide of any one of claims 2-37, wherein the modified Fc polypeptide further comprises an amino acid modification at a position selected from thegroup consisting of 252, 254, 256, 428, 433. 434, 436, and combinations thereof, wherein the position numbering is according to the EU index of Kabat.

39. The modified Fc polypeptide of claim 38, wherein the amino acid modification is selected from the group consisting of:(a) a tyrosine residue at position 252 (M252Y),(b) a threonine residue at position 254 (S254T),(c) a glutamic acid residue at position 256 (T256E),(d) a leucine residue at position 428 (M428L),(e) a lysine residue at position 433 (H433K),(f) a serine residue at position 434 (N434S) or a phenylalanine residue at position 434 (N434F), and(g) a histidine residue at position 436 (Y436H), and combinations thereof: wherein the position numbering is according to the EU index of Kabat.

40. The modified Fc polypeptide of claim 39, wherein the modified Fc polypeptide comprises a ty rosine residue at position 252 (M252Y), wherein the position numbering is according to the EU index of Kabat.

41. The modified Fc polypeptide of claim 39, wherein the modified Fc polypeptide comprises a threonine residue at position 254 (S254T), wherein the position numbering is according to the EU index of Kabat.

42. The modified Fc polypeptide of claim 39, wherein the modified Fc polypeptide comprises a glutamic acid residue at position 256 (T256E), wherein the position numbering is according to the EU index of Kabat.

43. The modified Fc polypeptide of claim 39, wherein the modified Fc polypeptide comprises a leucine residue at position 428 (M428L), wherein the position numbering is according to the EU index of Kabat.

44. The modified Fc polypeptide of claim 39, wherein the modified Fc polypeptide comprises a lysine residue at position 433 (H433K), wherein the position numbering is according to the EU index of Kabat.

45. The modified Fc polypeptide of claim 39, wherein the modified Fc polypeptide comprises a serine residue at position 434 (N434S) or a phenylalanine residue at position 434 (N434F), wherein the position numbering is according to the EU index of Kabat.

46. The modified Fc polypeptide of claim 39, wherein the modified Fc polypeptide comprises a histidine residue at position 436 (Y436H). wherein the position numbering is according to the EU index of Kabat.

47. The modified Fc polypeptide of claim 39, wherein the modified Fc polypeptide comprises a ty rosine residue at position 252 (M252Y), a threonine residue at position 254 (S254T), and a glutamic acid residue at position 256 (T256E), wherein the position numbering is according to the EU index of Kabat.

48. The modified Fc polypeptide of claim 39, wherein the modified Fc polypeptide comprises a leucine residue at position 428 (M428L) and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

49. The modified Fc polypeptide of claim 39, wherein the modified Fc polypeptide comprises a lysine residue at position 433 (H433K), a phenylalanine residue at position 434 (N434F), and a histidine residue at position 436 (Y436H). wherein the position numbering is according to the EU index of Kabat.

50. The modified Fc polypeptide of claim 39, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 233 (E233D), a leucine residue at position 428 (M428L) and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

51. The modified Fc polypeptide of claim 39, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 236 (G236D), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

52. The modified Fc polypeptide of claim 39, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 237 (G237D), a leucine residue at position 428 (M428L),and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

53. The modified Fc polypeptide of claim 39, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 239 (S239D), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

54. The modified Fc polypeptide of claim 39, wherein the modified Fc polypeptide comprises a glutamic acid residue at position 267 (S267E), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

55. The modified Fc polypeptide of claim 39, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 268 (H268D) a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

56. The modified Fc polypeptide of claim 39, wherein the modified Fc polypeptide comprises a glycine residue at position 271 (P271G), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

57. The modified Fc polypeptide of claim 39, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 296 (Y296D), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

58. The modified Fc polypeptide of claim 39, wherein the modified Fc polypeptide comprises a phenylalanine at position 328 (L328F), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

59. The modified Fc polypeptide of claim 39, wherein the modified Fc polypeptide comprises an arginine residue at position 330 (A330R), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

60. The modified Fc polypeptide of claim 39, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 233 (E233D), an arginine at position 330 (A330R), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

61. The modified Fc polypeptide of claim 39, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 233 (E233D), a glycine residue at position 271 (P271G), an arginine residue at position 330 (A330R), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

62. The modified Fc polypeptide of claim 39, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 268 (H268D), a glycine residue at position 271 (P271G), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

63. The modified Fc polypeptide of claim 39, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 237 (G237D), a glycine residue at position 271 (P271G), an arginine residue at position 330 (A330R), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

64. The modified Fc polypeptide of claim 39, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 233 (E233D), an aspartic acid residue at position 268 (H268D), a glycine residue at position 271 (P271G), an arginine residue at position 330 (A330R), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

65. The modified Fc polypeptide of claim 39, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 268 (H268D), a glycine residue at position 271 (P271G), an arginine residue at position 330 (A330R), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

66. The modified Fc polypeptide of claim 39, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 233 (E233D), an aspartic acid residue at position 237(G237D), an aspartic acid residue at position 268 (H268D), a glycine residue at position 271 (P271G). an arginine residue at position 330 (A330R), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

67. The modified Fc polypeptide of claim 39, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 233 (E233D), an aspartic acid residue at position 269 (Y296D), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

68. The modified Fc polypeptide of claim 39, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 269 (Y296D), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S). wherein the position numbering is according to the EU index of Kabat.

69. The modified Fc polypeptide of claim 39, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 269 (Y296D), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

70. The modified Fc polypeptide of claim 39, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 268 (H268D), an aspartic acid residue at position 269 (Y296D), a leucine residue at position 428 (M428U), and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

71. The modified Fc polypeptide of claim 39, wherein the modified Fc polypeptide comprises a glycine residue at position 271 (P271G). an aspartic acid residue at position 269 (Y296D), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S). wherein the position numbering is according to the EU index of Kabat.

72. The modified Fc polypeptide of claim 39, wherein the modified Fc polypeptide comprises an arginine residue at position 330 (A330R), an aspartic acid residue at position 269 (Y296D), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S). wherein the position numbering is according to the EU index of Kabat.

73. The modified Fc polypeptide of claim 39. wherein the modified Fc polypeptide comprises an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 269(Y296D), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S). wherein the position numbering is according to the EU index of Kabat.

74. The modified Fc polypeptide of claim 39, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 233 (E233D), an aspartic acid residue at position 269 (Y296D) and an arginine at position 330 (A330R), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

75. The modified Fc polypeptide of claim 39, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 233 (E233D), a glycine residue at position 271 (P271G), an aspartic acid residue at position 269 (Y296D), an arginine residue at position 330 (A330R), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S). wherein the position numbering is according to the EU index of Kabat.

76. The modified Fc polypeptide of claim 39, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 268 (H268D), an aspartic acid residue at position 269 (Y296D), a glycine residue at position 271 (P271G), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S). wherein the position numbering is according to the EU index of Kabat.

77. The modified Fc polypeptide of claim 39, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 237 (G237D), a glycine residue at position 271 (P271G), an aspartic acid residue at position 269 (Y296D), an arginine residue at position 330 (A330R), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S). wherein the position numbering is according to the EU index of Kabat.

78. The modified Fc polypeptide of claim 39, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 233 (E233D), an aspartic acid residue at position 268 (H268D), an aspartic acid residue at position 269 (Y296D), a glycine residue at position 271 (P271G), an arginine residue at position 330 (A330R), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

79. The modified Fc polypeptide of claim 39, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 268 (H268D), an aspartic acid residue at position 269 (Y296D), a glycine residue at position 271(P271G), an arginine residue at position 330 (A330R), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S). wherein the position numbering is according to the EU index of Kabat.

80. The modified Fc polypeptide of claim 39, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 233 (E233D), an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 268 (H268D), an aspartic acid residue at position 269 (Y296D). a glycine residue at position 271 (P271G). an arginine residue at position 330 (A330R), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

81. The modified Fc polypeptide of claim 39, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 236 (G236D), a glutamic acid residue at position 267 (S267E), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S), wherein the position numbering is according to the EU index of Kabat.

82. The modified Fc polypeptide of claim 39, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 239 (S239D), a glutamic acid residue at position 267 (S267E), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S). wherein the position numbering is according to the EU index of Kabat.

83. The modified Fc polypeptide of claim 39, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 237 (G237D), a glycine residue at position 271 (P271G), an arginine residue at position 330 (A330R), a lysine residue at position 433 (H433K), a phenylalanine residue at position 434 (N434F), and a histidine residue at position 436(Y 436H), wherein the position numbering is according to the EU index of Kabat.

84. The modified Fc polypeptide of claim 39, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 233 (E233D), an aspartic acid residue at position 268 (H268D), a glycine residue at position 271 (P271G), an arginine residue at position 330 (A330R), a lysine residue at position 433 (H433K), a phenylalanine residue at position 434 (N434F). and a histidine residue at position 436 (Y 436H), wherein the position numbering is according to the EU index of Kabat.

85. The modified Fc polypeptide of claim 3, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 268 (H268D), a glycine residue at position 271 (P271G), an arginine residue at position 330(A330R), a lysine residue at position 433 (H433K), a phenylalanine residue at position 434 (N434F). and a histidine residue at position 436 (Y 436H), wherein the position numbering is according to the EU index of Kabat.

86. The modified Fc polypeptide of claim 39, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 233 (E233D), an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 268 (H268D), a glycine residue at position 271 (P271G). an arginine residue at position 330 (A330R), a lysine residue at position 433 (H433K), a phenylalanine residue at position 434 (N434F), and a histidine residue at position 436 (Y436H), wherein the position numbering is according to the EU index of Kabat.

87. The modified Fc polypeptide of claim 39, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 237 (G237D), a glycine residue at position 271 (P271G), an arginine residue at position 330 (A330R), a tyrosine residue at position 252 (M252Y), a threonine residue at position 254 (S254T), and a glutamic acid residue at position 256 (T256E), wherein the position numbering is according to the EU index of Kabat.

88. The modified Fc polypeptide of claim 39, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 233 (E233D), an aspartic acid residue at position 268 (H268D), a glycine residue at position 271 (P271G), an arginine residue at position 330 (A330R), a tyrosine residue at position 252 (M252Y), a threonine residue at position 254 (S254T), and a glutamic acid residue at position 256 (T256E), wherein the position numbering is according to the EU index of Kabat.

89. The modified Fc polypeptide of claim 39, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 268 (H268D), a glycine residue at position 271 (P271G), an arginine residue at position 330 (A330R), a tyrosine residue at position 252 (M252Y), a threonine residue at position 254 (S254T), and a glutamic acid residue at position 256 (T256E), wherein the position numbering is according to the EU index of Kabat.

90. The modified Fc polypeptide of claim 39, wherein the modified Fc polypeptide comprises an aspartic acid residue at position 233 (E233D), an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 268 (H268D), a glycine residue at position 271 (P271G), an arginine residue at position 330 (A330R), a tyrosine residue at position 252 (M252Y), a threonine residue at position 254 (S254T), and a glutamic acid residue at position 256 (T256E), wherein the position numbering is according to the EU index of Kabat.

91. A modified Fc polypeptide having: an amino acid sequence al least 75% identical to the sequence of SEQ ID NO: 1, and further comprising:(v) an aliphatic amino acid residue at position 241 or position 243,(vi) an amino acid modification at position 267 and 328, and(vii) a sialic acid (SA) moiety attached to an N-glycan of the Fc polypeptide; wherein the position numbering is according to the EU index of Kabat.

92. The modified Fc polypeptide of claim 92, wherein the modified Fc polypeptide comprises a glutamic acid residue at position 267 (S267E), wherein the position numbering is according to the EU index of Kabat.

93. The modified Fc polypeptide of claim 92, wherein the modified Fc polypeptide comprises a phenylalanine residue at position 328 (L328F), wherein the position numbering is according to the EU index of Kabat.

94. The modified Fc polypeptide of claim 92, wherein the modified Fc polypeptide comprises a glutamic acid residue at position 267 (S267E) and a phenylalanine residue at position 328 (L328F), wherein the position numbering is according to the EU index of Kabat.

95. The modified Fc polypeptide of any one of claims 1-94, wherein the aliphatic amino acid residue at position 241 is an alanine residue (F241A) or a leucine residue (F241L), or the aliphatic amino acid residue at position 243 is an alanine (F234A) or a leucine (F243L), wherein the position numbering is according to the EU index of Kabat.

96. The modified Fc polypeptide according to any one of claims 1-95, wherein the aliphatic amino acid residue at position 241 is an alanine (F241A).

97. The modified Fc polypeptide according to any one of claims 1-95, wherein the aliphatic amino acid residue at position 241 is a leucine (F241L).

98. The modified Fc polypeptide according to any one of claims 1-96, wherein the aliphatic amino acid residue at position 234 is a leucine (F243L).

99. The modified Fc polypeptide according to any one of claims 1-96, wherein the aliphatic amino acid residue at position 234 is an alanine (F243A).

100. The modified Fc polypeptide of any one of claims 1-99, wherein the modified Fc polypeptide comprises a sialic acid (SA) moiety attached to an N-glycan of the Fc polypeptide via an a(2,6) linkage.

101. The modified Fc polypeptide of claim 100, wherein the N-glycan is attached to an asparagine (Asn) at amino acid residue 297 (Asn297; numbered according to the EU index of Kabat; corresponding to amino acid residue 88 of SEQ ID NO: 1).

102. The modified Fc polypeptide according to claim 100 or 101, wherein the N-glycan of the modified Fc polypeptides is mono-sialylated or di-sialylated.

103. The modified Fc polypeptide according to claim 102, wherein the N-glycan is di- sialylated.

104. The modified Fc polypeptide according to claim 102, wherein two sialic acid moieties are attached to the N-glycan via a(2,6) linkages.

105. The modified Fc polypeptide according to any one of claims 1-104, wherein the Fc polypeptide comprises a galactose moiety.

106. The modified Fc polypeptide according to claim 105, wherein the galactose moiety is attached to an a(l,3) arm and / or a(l ,6) arm of the N-glycan.

107. The modified Fc polypeptide according to claim 105 or 106, wherein the galactose moiety7is a branched galactose moiety7.

108. The modified Fc polypeptide according to any one of claims 1-107, wherein the modified Fc polypeptide has an amino acid sequence at least 85% identical to the sequence of any one of SEQ ID NOs: 1, 2, 11, and 12.

109. The modified Fc polypeptide according to claim 108, wherein the modified Fc polypeptide has an amino acid sequence at least 90% identical to the sequence of any one of SEQ ID NOs: 1, 2, 11, and 12.

110. The modified Fc polypeptide according to claim 108, wherein the modified Fc polypeptide has an amino acid sequence at least 92.5% identical to the sequence of any one of SEQ ID NOs: 1, 2, 11, and 12.

111. The modified Fc polypeptide according to claim 108, wherein the modified Fc polypeptide has an amino acid sequence at least 95% identical to the sequence of any one of SEQ ID NOs: 1, 2, 11, and 12.

112. The modified Fc polypeptide according to claim 108, wherein the modified Fc polypeptide has an amino acid sequence at least 96% identical to the sequence of any one of SEQ ID NOs: 1, 2, 11, and 12.

113. The modified Fc polypeptide according to claim 108, wherein the modified Fc polypeptide has an amino acid sequence at least 97% identical to the sequence of any one of SEQ ID NOs: 1, 2, 11, and 12.

114. The modified Fc polypeptide according to claim 108, wherein the modified Fc polypeptide has an amino acid sequence at least 98% identical to the sequence of any one of SEQ ID NOs: 1, 2, 11, and 12.

115. The modified Fc polypeptide according to claim 108, wherein the modified Fc polypeptide has an amino acid sequence at least 99% identical to the sequence of any one of SEQ ID NOs: 1, 2, 11, and 12.

116. The modified Fc polypeptide of any one of claims 1-115, wherein the modified Fc polypeptide comprises amino acid modifications in no more than 20 amino acid residues relative to the amino acid sequence of any one of SEQ ID NOs: 1, 2, 11, and 12.

117. The modified Fc polypeptide of any one of claims 1-115, wherein the modified Fc polypeptide comprises 3-20 amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs: 1, 2, 11, and 12.

118. The modified Fc polypeptide of any one of claims 1-117, wherein the modified Fc polypeptide does not comprise a C-terminal lysine residue.

119. The modified Fc polypeptide of any one of claims 1-117, wherein the modified Fc polypeptide comprises a C-terminal lysine residue.

120. The modified Fc polypeptide of any one of claim 1-119, wherein the modified Fc polypeptide is an IgG polypeptide.

121. The modified Fc polypeptide of claim 120, wherein the IgG polypeptide is an IgGl polypeptide.

122. The modified Fc polypeptide of any one of claims 1-107, wherein the modified Fc polypeptide has an amino acid sequence at least 90% identical to the sequence of any one of sequences listed in Table 1 .

123. The modified Fc polypeptide of any one of claims 1-107, wherein the modified Fc polypeptide has an amino acid sequence at least 95% identical to the sequence of any one of sequences listed in Table 1.

124. A pharmaceutical composition, comprising: (a) the modified Fc polypeptide of any one of claims 1-123 and (b) a pharmaceutically acceptable carrier, diluent, or excipient.

125. The pharmaceutical composition of claim 124, wherein the pharmaceutically acceptable carrier, diluent, or excipient is selected from the group consisting of: a stabilizer, buffer, surfactant, filler, solvent, tonicity or osmolarity adjusting agent, antioxidant, adjuvant, and antimicrobial agent.

126. A method of treating an inflammatory disease or condition in a subject in need thereof, comprising a step of administering to the subject a therapeutically effective amount of the modified Fc polypeptide of any one of claims 1-123 or the pharmaceutical composition of claim 124 or 125.

127. The method of claim 126, wherein the inflammatory disease or condition is an autoimmune disease or condition.

128. The method of claim 126 or 127, wherein the subject is a mammal.

129. The method of claim 128, wherein the mammal is a human.

130. The method of any one of claims 126-129, wherein the step of administering comprises systemic administration.

131. The method of claim 130, wherein the systemic administration comprises intravenous administration.

132. The method of claim 130, wherein the systemic administration comprises subcutaneous administration.

133. The method of claim 127, wherein the autoimmune disease or condition affects the skin.

134. The method of claim 133, wherein the autoimmune disease or condition is epidermal bullosa acquisita (EBA).

135. The method of claim 127, wherein the autoimmune disease or condition affects the kidney.

136. The method of claim 135, wherein the autoimmune disease or condition is immune- mediated glomerulonephritis.

137. The method of claim 127, wherein the autoimmune disease or condition is an arthritic disease.

138. The method of claim 127, wherein the autoimmune disease or condition is a neuroinflammatory disease.

139. The method of claim 127, wherein the autoimmune disease or condition is multiple sclerosis.

140. A method of improving Fc half-life and bioavailability comprising decreasing affinity for asialoglycoprotein receptor (ASGPR) in a subject in need thereof comprising a step of administering to the subject a therapeutically effective amount of the modified Fc polypeptide of any one of claims 1-123 or the pharmaceutical composition of claim 124 or 125.

141. A method of exerting immune protection through anti-inflammatory type II Fey receptors SIGN-R1 and DC-SIGN in a subject in need thereof comprising a step of administering to the subject a therapeutically effective amount of the modified Fc polypeptide of any one of claims 1-123 or the pharmaceutical composition of claim 124 or 125.

142. A method increasing the level of regulator^' T (Treg) cells in a subject in need thereof comprising a step of administering to the subject a therapeutically effective amount of the modified Fc polypeptide of any one of claims 1-123 or the pharmaceutical composition of claim 124 or 125.

143. A modified Fc polypeptide comprising a modified Fc polypeptide with means for binding to FcyRIIB.

144. The modified Fc polypeptide of claim 143, wherein the modified Fc polypeptide has an amino acid sequence at least 75% identical to the sequence of SEQ ID NO: 1, and further comprising:(i) a sialic acid (SA) moiety attached to an N-glycan of the Fc polypeptide;(ii) an aliphatic amino acid residue at position 241 or position 243, and(iii) amino acid modifications selected from the group consisting of:(a) an aspartic acid residue at position 233 (E233D), an aspartic acid residue at position 237 (G237D). an aspartic acid residue at position 238 (P238D), an aspartic acid residue at position 268 (H268D), a glycine residue at position 271 (P271G), and an arginine residue at position 330 (A330R);(b) an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 238 (P238D), a glycine residue at position 271 (P271G). and an arginine residue at position 330 (A330R);(c) an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 238 (P238D), an aspartic acid residue at position 268 (H268D), a glycine residue at position 271 (P271G), and an arginine residue at position 330 (A330R);(d) an aspartic acid residue at position 233 (E233D), an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 238 (P238D), an aspartic acid residue at position 268 (H268D), a glycine residue at position 271 (P271G), an arginine residue at position 330 (A330R). a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S);(e) an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 238 (P238D), a glycine residue at position 271 (P271G), and anarginine residue at position 330 (A330R), a leucine residue at position 428 (M428L). and a serine residue at position 434 (N434S); and(f) an aspartic acid residue at position 237 (G237D), an aspartic acid residue at position 238 (P238D), an aspartic acid residue at position 268 (H268D), a glycine residue at position 271 (P271G), and an arginine residue at position 330 (A330R), a leucine residue at position 428 (M428L), and a serine residue at position 434 (N434S); wherein the position numbering is according to the EU index of Kabat.

145. The modified Fc polypeptide of claim 143, wherein the modified Fc polypeptide comprises: an amino acid sequence at least 75% identical to the sequence of SEQ ID NO: 1, and further comprising:(i) an aliphatic amino acid residue at position 241 or position 243;(ii) an amino acid modification at position 238;(iii) a sialic acid (SA) moiety7attached to an N-glycan of the Fc polypeptide; and(iv) at least one additional amino acid modification at a position selected from the group consisting of: 233, 236, 237, 239, 267, 268. 271, 296, 328, 330, and combinations thereof; wherein the position numbering is according to the EU index of Kabat.

146. The modified Fc polypeptide of claim 145, wherein the at least one additional amino acid modification is selected from the group consisting of:(a) an aspartic acid residue at position 233 (E233D),(b) an aspartic acid residue at position 236 (G236D),(c) an aspartic acid residue at position 237 (G237D).(d) an aspartic acid residue at position 239 (S239D).(e) a glutamic acid residue at position 267 (S267E),(f) an aspartic acid residue at position 268 (H268D).(g) a glycine residue at position 271 (P271G),(h) an aspartic acid residue at position 296 (Y296D),(i) a phenylalanine at position 328 (L328F),(j) an arginine residue at position 330 (A330R), and combinations thereof; wherein the position numbering is according to the EU index of Kabat.

147. The modified Fc polypeptide of any one of claims 145-146, wherein the modified Fc polypeptide further comprises an amino acid modification at a position selected from the group consisting of: 252, 254, 256, 428, 433, 434, 436 and combinations thereof wherein the position numbering is according to the EU index of Kabat.

148. The modified Fc polypeptide of claim 147. wherein the amino acid modification is selected from the group consisting of:(a) a tyrosine residue at position 252 (M252Y),(b) a threonine residue at position 254 (S254T),(c) a glutamic acid residue at position 256 (T256E),(d) a leucine residue at position 428 (M428L),(e) a lysine residue at position 433 (H433K),(f) a serine residue at position 434 (N434S) or a phenylalanine residue at position 434 (N434F),(g) a histidine residue at position 436 (Y436H), and combinations thereof, wherein the position numbering is according to the EU index of Kabat.

149. The modified Fc polypeptide of any one of claims 143-148, wherein the aliphatic amino acid residue at position 241 is an alanine (F241A) or the aliphatic amino acid residue at position 243 is an alanine (F243A).

150. The modified Fc polypeptide of any one of claims 143-148, wherein the aliphatic amino acid residue at position 241 is an alanine (F241A).

151. The modified Fc polypeptide of any one of claims 143-148, wherein the aliphatic amino acid residue at position 243 is an alanine (F243A).

152. The modified Fc polypeptide of any one of claims 143-148, wherein the aliphatic amino acid residue at position 241 is a leucine (F241L).

153. The modified Fc polypeptide of any one of claims 143-148, wherein the aliphatic amino acid residue at position 243 is an alanine (F243L).

154. The modified Fc polypeptide of any one of claims 1-153, wherein the modified Fc polypeptide does not comprise a C-terminal lysine residue.

155. The modified Fc polypeptide of any one of claims 1-153, wherein the modified Fc polypeptide does comprise a C-terminal lysine residue.

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