Methods of treating autoimmune disorders using modified FC polypeptides

Abstract

Methods of treating an autoimmune disorder affecting the myelin sheath or peripheral nerves, e.g., Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) in a human subject thereof, using a population of highly sialylated immunoglobulin Fc polypeptides having an amino acid substitution from phenylalanine to an aliphatic amino acid residue at amino acid residue 241 or 243 of the Fc heavy chain.

Description

Attorney Docket No. 00013.007.1801METHODS OF TREATING AUTOIMMUNE DISORDERS USING MODIFIED FC POLYPEPTIDESCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Application No. No. 63 / 763,723, filed on February 26, 2025; and to U.S. Provisional Patent Application No.63 / 825,462, filed on June 17, 2025, the disclosures of each of which are incorporated by reference herein in their entireties for all purposes.SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on February 6, 2026, is named 00013_007_1801_SL.xml and is 36,950 bytes in size.BACKGROUND

[0003] Inflammatory disorders, including autoimmune diseases, are disorders involving abnormal activation and subsequent migration of white blood cells to affected areas of the body.

[0004] Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a chronic progressive or relapsing and remitting disease that usually causes weakness and sensory loss. Patients experience progressive weakness and impaired sensory7function in the upper and lower limbs, with loss of deep tendon reflexes on examination. More than half of affected people cannot walk unaided when symptoms are at their worst.SUMMARY

[0005] The present disclosure provides methods of treating Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) in subjects, e.g., human subjects, in need thereof.

[0006] In one aspect, provided are methods of treating Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) in a human subject in need thereof, comprising: administering to the subject a therapeutically effective amount of a population of modified Fc polypeptides, or a pharmaceutical composition thereof, each modified Fc polypeptide having (i) an amino acid sequence at least 75% identical to the sequence of SEQ ID NO: 2 and (ii) an aliphatic amino acid residue at position 241 (numbered according to Kabat; corresponding to amino acid 1#607131Attorney Docket No. 00013.007.1801residue 32 of SEQ ID NO: 2) or an aliphatic amino acid residue at position 243 (numbered according to Kabat; corresponding to amino acid residue 34 of SEQ ID NO: 2). the population comprising at least about 50% of the modified Fc polypeptides having a sialic acid (SA) moiety attached to an N-glycan of the Fc polypeptide via an a(2,6) linkage. In another aspect, provided are methods of treating Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) in a human subject in need thereof, comprising: administering to the subject a therapeutically effective amount of a population of modified Fc polypeptides, or a pharmaceutical composition thereof, each modified Fc polypeptide having (i) an amino acid sequence at least 75% identical to the sequence of SEQ ID NO: 12 and (ii) an aliphatic amino acid residue at position 241 (numbered according to Kabat; corresponding to amino acid residue 32 of SEQ ID NO: 12) or an aliphatic amino acid residue at position 243 (numbered according to Kabat; corresponding to amino acid residue 34 of SEQ ID NO: 12), the population comprising at least about 50% of the modified Fc polypeptides having a sialic acid (SA) moiety attached to an N-glycan of the Fc polypeptide via an a(2,6) linkage.

[0007] In some embodiments, the aliphatic amino acid at position 241 is an alanine (Ala; F241A) or aleucine (Leu; F241L) or the aliphatic amino acid at position 243 is an alanine (Ala; F243A) or a leucine (Leu; F243L). In some embodiments, the N-glycan is attached to the asparagine (Asn) at amino acid residue 297 of the modified polypeptide (Asn297; numbered according to Kabat; corresponding to amino acid residue 88 of SEQ ID NO: 2 or SEQ ID NO: 12). In some embodiments, the modified Fc polypeptides are IgGl Fc polypeptides. In some embodiments, the modified Fc polypeptides are IgG3 Fc polypeptides. In some embodiments, no more than about 40% of the modified Fc polypeptides have a SA moiety' attached to the N-glycan of the modified Fc polypeptide via an a(2,3) linkage. In some embodiments, at least about 60%, at least about 70%, at least about 80%. or at least about 90% of the modified Fc polypeptides comprise the SA moiety attached to the N-glycan of the modified Fc polypeptides via the a(2,6) linkage. In some embodiments, at least about 10%, at least about 20%, at least about 30%, at least about 40%, or at least about 50% of the modified Fc polypeptides comprise mono-sialylated N-glycans comprising a SA moiety attached via the a(2,6) linkage. In some embodiments, at least about 30% of the modified Fc polypeptides comprise mono-sialylated N-glycans comprising a SA moiety attached via the a(2,6) linkage. In some embodiments, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least 85%, or at least about 90% of the modified Fc polypeptides comprise di-sialylated N-glycans comprising two SA moieties attached via the a(2,6) linkage. In some embodiments, about 80% of the modified Fc polypeptides comprise di-sialylated N-glycans 2#607131Attorney Docket No. 00013.007.1801comprising two SA moieties attached via the a(2,6) linkage. In some embodiments, about 85% of the modified Fc polypeptides comprise di-sialylated N-glycans comprising two SA moieties attached via the a(2,6) linkage. In some embodiments, about 90% of the modified Fc polypeptides comprise di-sialylated N-glycans comprising two SA moieties attached via the a(2,6) linkage. In some embodiments, at least about 60%, at least about 70%, at least about 80%, at least about 90%. or about 100% of the modified Fc polypeptides comprise 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. In some embodiments, provided methods further comprise administration of an additional therapeutic agent to the human subject. The additional therapeutic agent can be administered to the human subject prior to, concurrently with, or subsequent to administration of the population or the pharmaceutical composition. In some embodiments, the additional therapeutic agent is a second modified Fc polypeptide comprising one or more amino acid substitutions selected from the group consisting of M252Y, S254T, T256E, H433K, and N434F. In some embodiments, the second modified Fc polypeptide comprises amino acid substitutions M252Y, S254T, T256E, H433K, and N434F. In some embodiments, the second modified Fc polypeptide has an amino acid sequence set forth as SEQ ID NO: 5. In some embodiments, the additional therapeutic agent is selected from the group consisting of an antiinflammatory agent, an immuno-suppressive agent, physical therapy, and plasma exchange. In some embodiments, the anti-inflammatory agent is selected from the group consisting of nonsteroidal anti-inflammatory drug (NSAID), corticosteroid, anti-inflammatory antibody or an antigen-binding fragment thereof, anti-inflammatory cytokine, kinase inhibitor, and intravenous immunoglobulin (IVIG). In some embodiments, the corticosteroid is prednisone. In some embodiments, the corticosteroid is dexamethasone. In some embodiments, the immune-suppressive agent is cyclophosphamide.

[0008] In one aspect, provided are methods of treating Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) in a human in need thereof, comprising: administering to the human subject a therapeutically effective amount of a population of modified Fc polypeptides, or a pharmaceutical composition thereof, each modified Fc polypeptide having (i) an amino acid sequence at least 75% identical to the sequence of SEQ ID NO: 2 and (ii) an aliphatic amino acid residue at position 241 (numbered according to Kabat; corresponding to amino acid residue 32 of SEQ ID NO: 2) or an aliphatic amino acid residue at position 243 (numbered according to Kabat; corresponding to amino acid residue 34 of SEQ ID NO: 2). the population3#607131Attorney Docket No. 00013.007.1801comprising: no more than about 40% of the modified Fc polypeptides having a SA moiety attached to the N-glycan of the Fc polypeptide via an a(2.3) linkage.

[0009] In another aspect, provided are methods of treating Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) in a human in need thereof, comprising: administering to the human subject a therapeutically effective amount of a population of modified Fc polypeptides, or a pharmaceutical composition thereof, each modified Fc polypeptide having (i) an amino acid sequence at least 75% identical to the sequence of SEQ ID NO: 12 and (ii) an aliphatic amino acid residue at position 241 (numbered according to Kabat; corresponding to amino acid residue 32 of SEQ ID NO: 12) or an aliphatic amino acid residue at position 243 (numbered according to Kabat; corresponding to amino acid residue 34 of SEQ ID NO: 12), the population comprising: no more than about 40% of the modified Fc polypeptides having a SA moiety attached to the N-glycan of the Fc polypeptide via an a(2,3) linkage.

[0010] In some embodiments, the aliphatic amino acid at position 241 is an alanine (Ala; F241 A) or a leucine (Leu; F241L) or the aliphatic amino acid at position 243 is an alanine (Ala; F243A) or a leucine (Leu; F243L). In some embodiments, the N-glycan is attached to the asparagine (Asn) at ammo acid residue 297 of the modified polypeptide (Asn297; numbered according to Kabat; corresponding to amino acid residue 88 of SEQ ID NO: 2 or SEQ ID NO: 12). In some embodiments, the modified Fc polypeptides are IgGl Fc polypeptides. In some embodiments, the modified Fc polypeptides are IgG3 Fc polypeptides. In some embodiments, the population of modified Fc polypeptides comprises at least about 50% of the modified Fc polypeptides having a sialic acid (SA) moiety attached to an N-glycan of the modified Fc polypeptide via an a(2,6) linkage. In some embodiments, at least about 60%, at least about 70%, at least about 80%, or at least about 90% of the modified Fc polypeptides comprise the SA moiety attached to the N-glycan of the modified Fc polypeptides via the a(2,6) linkage. In some embodiments, at least about 10%, at least about 20%, at least about 30%, at least about 40%, or at least about 50% of the modified Fc polypeptides comprise mono-sialylated N-glycans comprising a SA moiety attached via the a(2,6) linkage. In some embodiments, at least about 30% of the modified Fc polypeptides comprise mono-sialylated N-glycans comprising a SA moiety attached via the a(2,6) linkage. In some embodiments, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% of the modified Fc polypeptides comprise di-sialylated N-glycans comprising two SA moieties attached via the a(2,6) linkage. In some embodiments, about 80% of the modified Fc polypeptides comprise di-sialylated N-glycans comprising two SA moieties attached via the a(2,6) linkage. In some embodiments, about 85% of the modified Fc 4#607131Attorney Docket No. 00013.007.1801polypeptides comprise di-sialylated N-glycans comprising two SA moieties attached via the a(2,6) linkage. In some embodiments, about 90% of the modified Fc polypeptides comprise di-sialylated N-glycans comprising two SA moieties attached via the a(2,6) linkage. In some embodiments, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100% of the modified Fc polypeptides comprise a galactose moiety. In some embodiments, the galactose moiety is attached to an a(l,3) arm and / or ot(1.6) arm of the N-glycan. In some embodiments, the galactose moiety is a branched galactose moiety. In some embodiments, provided methods further comprise administration of an additional therapeutic agent to the human subject. The additional therapeutic agent can be administered to the human subject prior to, concurrently with, or subsequent to administration of the population or the pharmaceutical composition. In some embodiments, the additional therapeutic agent is a second modified Fc polypeptide comprising one or more amino acid substitutions selected from the group consisting of M252Y, S254T, T256E, H433K, and N434F. In some embodiments, the second modified Fc polypeptide comprises amino acid substitutions M252Y, S254T, T256E. H433K, and N434F. In some embodiments, the second modified Fc polypeptide has an amino acid sequence set forth as SEQ ID NO: 5. In some embodiments, the additional therapeutic agent is selected from the group consisting of an anti-inflammatory agent, an immuno-suppressive agent, physical therapy, and plasma exchange. In some embodiments, the anti-inflammatory agent is selected from the group consisting of non-steroidal antiinflammatory drug (NSAID), corticosteroid, anti-inflammatory antibody or an antigen-binding fragment thereof, anti -infl ammatory cytokine, kinase inhibitor, and intravenous immunoglobulin (IVIG). In some embodiments, the corticosteroid is prednisone. In some embodiments, the corticosteroid is dexamethasone. In some embodiments, the immune-suppressive agent is cyclophosphamide.

[0011] In one aspect, provided are populations of modified Fc polypeptides, or pharmaceutical compositions thereof, each modified Fc polypeptide having (i) an amino acid sequence at least 75% identical to the sequence of SEQ ID NO: 2 and (ii) an aliphatic amino acid residue at position 241 (numbered according to Kabat; corresponding to amino acid residue 32 of SEQ ID NO: 2) or an aliphatic amino acid residue at position 243 (numbered according to Kabat; corresponding to amino acid residue 34 of SEQ ID NO: 2), the populations comprising: at least 50% of the modified Fc polypeptides having a sialic acid (SA) moiety attached to an N-glycan of the Fc polypeptide via an a(2,6) linkage, for use as a medicament for the treatment of Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) in a human subject in need thereof.5#607131Attorney Docket No. 00013.007.1801

[0012] In another aspect, provided are populations of modified Fc polypeptides, or pharmaceutical compositions thereof, each modified Fc polypeptide having (i) an amino acid sequence at least 75% identical to the sequence of SEQ ID NO: 12 and (ii) an aliphatic amino acid residue at position 241 (numbered according to Kabat; corresponding to amino acid residue 32 of SEQ ID NO: 12) or an aliphatic amino acid residue at position 243 (numbered according to Kabat; corresponding to amino acid residue 34 of SEQ ID NO: 12), the populations comprising: at least 50% of the modified Fc polypeptides having a sialic acid (SA) moiety attached to an N-glycan of the Fc polypeptide via an a(2,6) linkage, for use as a medicament for the treatment of Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) in a human subject in need thereof.

[0013] In one aspect, provided are populations of modified Fc polypeptides, or a pharmaceutical composition thereof, each modified Fc polypeptide having (i) an amino acid sequence at least 75% identical to the sequence of SEQ ID NO: 2 and (ii) an aliphatic amino acid residue at position 241 (numbered according to Kabat; corresponding to amino acid residue 32 of SEQ ID NO: 2) or an aliphatic amino acid residue at position 243 (numbered according to Kabat; corresponding to amino acid residue 34 of SEQ ID NO: 2), comprising: at least 50% of the modified Fc polypeptides having a sialic acid (SA) moiety attached to an N-glycan of the Fc polypeptide via an a(2,6) linkage, for use in the treatment of Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) in a human subject in need thereof.

[0014] In another aspect, provided are populations of modified Fc polypeptides, or a pharmaceutical composition thereof, each modified Fc polypeptide having (i) an amino acid sequence at least 75% identical to the sequence of SEQ ID NO: 12 and (ii) an aliphatic amino acid residue at position 241 (numbered according to Kabat; corresponding to amino acid residue 32 of SEQ ID NO: 12) or an aliphatic amino acid residue at position 243 (numbered according to Kabat; corresponding to amino acid residue 34 of SEQ ID NO: 12), comprising: at least 50% of the modified Fc polypeptides having a sialic acid (SA) moiety attached to an N-glycan of the Fc polypeptide via an a(2,6) linkage, for use in the treatment of Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) in a human subject in need thereof.BRIEF DESCRIPTION OF THE DRAWINGS

[0015] FIG. 1A-1C exemplify electrophysiological and behavioral assessments of antiganglioside antibody-mediated axonal nerve injury (AMANI) model mice following treatment with NVG-2089, intravenous immune globulin (IVIg), or phosphate-buffered saline (PBS).6#607131Attorney Docket No. 00013.007.1801FIG. 1A exemplifies a sciatic nerve conduction test. FIG. IB exemplifies a Pinprick Assessment. FIG. 1C exemplifies Body Weight measures.

[0016] FIG. 2 exemplifies a morphometric analysis of the tibial nerve in anti-ganglioside antibody-mediated axonal nerve injury (AMANI) model mice following treatment with NVG-2089, IVIg, or PBS.

[0017] FIG. 3 exemplifies the effects on endoneurial CD68-positive macrophages in anti-ganglioside antibody-mediated axonal nerve injury (AMANI) model mice following treatment with NVG-2089, IVIg, or PBS.

[0018] FIG.4 presents the study schema for the exemplary clinical trial described in Example 2. Briefly, cohort 1 (n=20; treatment-experienced individuals) will receive NVG-2089 at a dose of 150 mg / kg by IV infusion twice per week on Weeks 0. 2, 4, 6, 8, 10, and 12. Following safety monitoring committee (SMC) review of at least 10 patients of cohort 1 who have received 3 doses of NVG-2089, Cohort 2 will receive (n=20; treatment-experienced individuals) will receive NVG-2089 at a dose of 150 mg / kg by IV infusion twice per w eek on Weeks 0.2, 4, 6, 8, 10, and 12. Cohort 3 (n=20; treatment-naive individuals) will receive NVG-2089 at a dose of 150 mg / kg by IV infusion twice per week on Weeks 0, 2, 4, 6, 8, 10, and 12. Each cohort will receive treatment for 14 weeks following a screen of 6 weeks to confirm CIDP diagnosis. Each cohort will also receive 6 weeks of follow -up screening.DEFINITIONS

[0019] 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.

[0020] 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.

[0021] 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- 7#607131Attorney Docket No. 00013.007.1801100%, 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. In another 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.

[0022] “About” a number, as used herein, refers to range including the number and ranging from 10% below that number to 10% above that number. “About” a range refers to 10% below the lower limit of the range, spanning to 10% above the upper limit of the range.

[0023] 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. Exemplary routes of administration are described in the sections that follow.

[0024] 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 activity7of 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.

[0025] 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.

[0026] An “isolated” polypeptide or protein or a population thereof refers to a polypeptide or protein or a population thereof that has been separated from other proteins, lipids, and nucleic acids with which it is naturally associated. The polypeptide / protein or a population thereof constitutes at least 10% (i.e., any percentage between 10% and 100%, e.g., 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, and 99%) by dry' weight of the purified preparation, in some embodiments. Purity’ can be measured by any appropriate standard method, for example, by column chromatography, polyacrylamide gel electrophoresis, high 8#607131Attorney Docket No. 00013.007.1801performance- liquid chromatography (HPLC). size exclusion chromatography (SEC), or mass spectrometry (MS) analysis. An isolated polypeptide / protein or a population thereof described herein produced by recombinant DNA techniques or by chemical methods, in some embodiments. The isolated polypeptide includes SEQ ID NO: 2, in some embodiments.

[0027] A “native” or “parental” Fc region comprises an amino 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. , F241 A). 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.

[0028] “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, BLAST-2, or Megalign software. 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 9#607131Attorney Docket No. 00013.007.1801total number of nucleic acids in B. It will 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.

[0029] As used herein, the term “pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms, which are suitable for contact with the tissues of a subject, such as a mammal (e.g., a human) without excessive toxicity, irritation, allergic response, and other problem complications commensurate with a reasonable benefit / risk ratio.

[0030] The term “polypeptide” refers to a chain of amino acids. The polypeptides are not limited to a specific length of the product. Peptides, oligopeptides, and proteins are included within the definition of polypeptide, and such terms are used interchangeably herein unless specifically indicated otherwise. This term also encompasses chains of peptides with post-translation modifications, e.g., glycosylation, acetylation, phosphorylation, and the like, as well as other modifications known in the art, both naturally occurring and non-naturally occurring. In some embodiments, a polypeptide is an entire protein, or a fragment thereof.

[0031] The terms “recipient.” “individual,” “subject,” “host.” and “patient,” are used interchangeably herein and refer to any mammalian subject for whom diagnosis, treatment, or therapy is desired, particularly humans. “Mammal” for purposes of treatment refers to any animal classified as a mammal, including humans, domestic and farm animals, and laboratory, zoo, sports, or pet animals, such as dogs, horses, cats, cows, sheep, goats, pigs, mice, rats, rabbits, guinea pigs, monkeys, etc. In some embodiments, the mammal is a human. None of the terms require the supervision of a medical professional.

[0032] 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 varies with 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 or10#607131Attorney Docket No. 00013.007.1801disorder, the term “therapeutically effective” means that, after treatment, one or more signs or symptoms of the disease or disorder is ameliorated or eliminated.

[0033] An effective response of the present disclosure is achieved when the subject experiences partial or total alleviation or reduction of signs or symptoms of illness and, in the case of the treatment of a disease (e.g., an autoimmune disorder), specifically includes, without limitation, amelioration of symptoms, cure, remission, prolongation of survival, or other objective responses. In some embodiments, the expected progression-free survival times are measured in months to years, depending on prognostic factors including the number of relapses, stage of disease, and other factors. Prolonging survival includes without limitation times of at least 1 month (mo.), about at least 2 mos., about at least 3 mos.. about at least 4 mos., about at least 6 mos.. about at least 1 year, about at least 2 years, about at least 3 years, etc. Overall survival is also measured, e.g., in months to years. Alternatively, an effective response, in some embodiments, is that a subject’s symptoms remain static. Further indications of treatment of indications are described in more detail below.

[0034] In some embodiments, administration of a therapeutic agent in a prophylactic method occurs prior to the manifestation of symptoms of an undesired disease or disorder, such that the disease or disorder is prevented or, alternatively, delayed in its progression. Thus, when used in conjunction with prophylactic methods, the term “therapeutically effective” means that, after treatment, a smaller number of subjects (on average) develop the undesired disease or disorder or progress in severity of symptoms.

[0035] As used herein, the terms “treatment,” “treating,” and the like, in some cases, refer to administering an agent, or carry ing out a procedure, for the purposes of obtaining an effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and / or is therapeutic in terms of effecting a partial or complete cure for a disease and / or symptoms of the disease. “Treatment,” as used herein, includes treatment of a disease or disorder (e.g., an autoimmune disorder) in a mammal, particularly in a human, and includes: (a) preventing the disease or a symptom of a disease from occurring in a subj ect which is predisposed to the disease but has not yet been diagnosed as having it (e.g. , including diseases associated with or caused by a primary disease; (b) inhibiting the disease, i.e.. arresting its development; and (c) relieving the disease, i.e., causing regression of the disease. The term treating includes any indicia of success in the treatment, amelioration, or prevention of a disease or disorder, including any objective or subjective parameter such as abatement, remission, diminishing of symptoms or making the disease condition more tolerable to the patient, slowing in the rate of degeneration or decline, or making the final point of degeneration 11#607131Attorney Docket No. 00013.007.1801less debilitating. The treatment or amelioration of symptoms is based on one or more objective or subjective parameters, including the results of an examination by a physician. Accordingly, the term '‘treating’’ includes the administration of the agents or compositions of the present disclosure to prevent or delay, to alleviate, or to arrest or inhibit development of the symptoms or conditions associated with diseases. The term “therapeutic effect” refers to the reduction, elimination, or prevention of the disease, symptoms of the disease, or side effects of the disease in the subject. A subject is “treated” for a disease or disorder if, after receiving a therapeutic amount of a therapeutic agent or composition of the present disclosure, the patient shows observable and / or measurable change in a parameter or symptom of the disease or disorder.

[0036] As used herein, the term “vector” includes a nucleic acid vector, e.g., a DNA vector, such as a plasmid, an RNA vector, virus, or other suitable replicon (e. ., viral vector). A variety of vectors have been developed for the delivery of polynucleotides encoding exogenous proteins into a prokaryotic or eukaryotic cell. Expression vectors suitable for use with the compositions and methods described herein contain an expression cassette comprising a polynucleotide sequence as well as, e.g.. additional sequence elements used for the expression of proteins and, optionally, the integration of these polynucleotide sequences into the genome of a host cell. Certain vectors that can be used for the expression one or more (e.g., 1, 2, 3, or more) recombinant polypeptides, as described herein, include plasmids that contain regulator ' sequences, such as promoter and enhancer elements which direct gene transcription. Other useful vectors for expression of disclosed polypeptides contain polynucleotide sequences that enhance the rate of translation of these genes or improve the stability or nuclear export of the mRNA that results from gene transcription. These sequence elements may include, e.g., 5’ and 3’ untranslated regions (UTRs), an internal ribosomal entry site (IRES), and a polyadenylation signal site in order to direct efficient transcription of the transgene carried on the expression vector. The expression vectors suitable for use with the compositions and methods described herein may also contain a polynucleotide encoding a marker for selection of cells that contain such a vector. An example of a suitable selection marker is a glutamine synthetase (GS) gene. Additional examples of a suitable marker are genes that encode resistance to antibiotics, such as ampicillin, chloramphenicol, kanamycin, nourseothricin, zeocin, nourseothricin, carbenicillin, tetracycline, streptomycin, and spectinomycin.DETAILED DESCRIPTION

[0037] Inflammatory disorders, including autoimmune diseases, are disorders involving abnormal activation and subsequent migration of white blood cells to affected areas of the 12#607131Attorney Docket No. 00013.007.1801body. 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.

[0038] Immunoglobulin G (IgG) has long been appreciated to mediate both pro and anti-inflammatory activities through interactions mediated by its fragment crystallizable (Fc) region. While Fc:FcyR interactions are responsible for the proinflammalory properties of immune complexes and cytotoxic antibodies, intravenous gamma globulin (IVIG) and its constituent Fc fragments are anti-inflammatory and are widely used to suppress inflammation in disease states. It has been proposed that glycosylation of IgG is crucial for regulation of its cy totoxicity' and inflammatory' potential. For example, prior studies have demonstrated that anti-inflammatory activity of IVIG is a property of the Fc fragment and its linked N-glycan sialic acid (SA) moieties, indicating a combined requirement for a specific polypeptide backbone and glycosylation profile for its anti-inflammatory- effect.

[0039] Sialylation of recombinant therapeutic glycoproteins, such as Fc polypeptides, is generally performed in mammalian cell lines capable of reproducing mammalian or mammalian-like glycosylation profiles. Addition of terminal SA residues on the N-glycan of the Fc heavy chain, particularly at Asparagine 297 (Asn297), has been shown to impact various in vivo parameters of the Fc polypeptide, including absorption, blood half-life and clearance, as well as its immunogenic or immunosuppressive properties. Glycoengineering of Fc polypeptides with high levels of sialylation has faced significant obstacles, including limited and non-homogenous sialylation of pools of said polypeptides.

[0040] 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 heavy chain (e.g., F241A or F241L; numbered according to Kabat). Also 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 243 of the Fc heavy chain (e.g.. F243A or F243L; numbered according to Kabat). Additionally disclosed are methods of manufacturing the modified Fc polypeptides using arecombinant expression system that includes one or more (e.g., 1, 2, 3, or more) nucleic acid expression vectors and mammalian host cells. Furthermore, the present disclosure provides methods for treating an autoimmune disorder, such as Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), using a therapeutic agent or composition disclosed 13#607131Attorney Docket No. 00013.007.1801herein. 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.Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)

[0041] Disclosed herein, in some embodiments, are methods of treating Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) in an individual in need thereof. In some embodiments, the individual in need thereof is a mammalian subject (e.g., a human subject).

[0042] Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a chronic progressive or relapsing and remitting disease that usually causes weakness and sensory loss. Patients experience progressive weakness and impaired sensory function in the upper and lower limbs, with loss of deep tendon reflexes on examination. Specific symptoms included pain in the arms and / or legs, weakness in the arms and / or legs, paralysis in the arms and / or legs, tingling or numbness in fingers and toes, atrophy of muscles, and in some cases, difficulty swallowing. CIDP leads to fatigue, and clumsiness, significantly lowering the quality of life of individuals with CIDP. These symptoms will generally spread slowly for at least two months and are typically symmetric around the hips, shoulders, hands, and feet More than half of affected people cannot walk unaided when symptoms are at their worst. Without treatment, 1 in 3 people with CIDP will need a wheelchair. Symptoms of CIDP result from autoimmune inflammation of peripheral nerves. The annual incidence rate of CIDP ranges from 0.2 to 1.6 per 100,000 persons and prevalence was reported at 0.8 - 8.9 per 100,000 persons, depending on geography and diagnostic criteria.

[0043] CIDP usually responds to treatments that reduce inflammation, but current treatments are time consuming, expensive, have significant unwanted side effects, and the efficacy is variable across patients. The goal of CIDP treatments is to improve symptoms and delay or prevent progression of the disease. It is noted that patients with positive neurofascin or contractin- 1 are less likely to respond to IVIg treatment. If the response is inadequate or the required drug maintenance dose is poorly tolerated, then the addition of an immunosuppressing or immunomodulating treatment may be considered, but none are proven effective. There is currently an unmet need for additional treatment options for participants with CIDP.

[0044] The modified Fc polypeptides disclosed herein, and the populations thereof disclosed herein, has demonstrated efficacy in mouse models of autoantibody-mediated pemphigoid disease, RA, and nephrotoxic nephritis at doses that are 10- to 20-fold lower than immunoglobulin. Efficacy in these models is associated with increased cell surface FcyRIIB 14#607131Attorney Docket No. 00013.007.1801expression on peripheral blood B cells and neutrophils, as well as splenic B cells. Moreover, the modified Fc polypeptides disclosed herein, and the populations thereof disclosed herein, expand peripheral blood Tregs in mice, and demonstrate efficacy in the mouse experimental autoimmune EAE model of T cell-mediated neuroinflammation at a 20-30-fold lower dose relative to IVIg. These data demonstrate that the modified Fc polypeptides disclosed herein, and the populations thereof disclosed herein, activate the immunomodulatory type II Fc receptors and are efficacious in mouse models of autoantibody-mediated and T cell-mediated autoimmune disease.

[0045] The modified Fc polypeptides disclosed herein, and the populations thereof disclosed herein, have the potential to address the limitations of IVIg, in that the modified Fc polypeptide disclosed herein is a recombinant protein (not plasma derived), should not be supply constrained, and should require lower doses and shorter infusions times due to the increased potency. The molecule does not contain the variable regions of immune globulin and is therefore not intended to treat primary or secondary immunodeficiency. As the sequence of the modified Fc polypeptides disclosed herein is derived from the native human IgGl Fc sequence and contains the 2,6-sialylation pattern typically found in humans, it is likely to have a low risk for immunogenicity.

[0046] Compositions and methods described herein may be used to treat patients presenting with symptoms of Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), diagnosed with Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), and / or in remission from Chronic Inflammatory Demyelinating Polyneuropathy (CIDP).Compositions

[0047] Disclosed herein, in some embodiments, are methods of treating Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) in an individual in need thereof, comprising administering to the individual a composition (e.g., therapeutic composition) comprising modified Fc polypeptides having sequences of variants of a wild-type human IgG Fc polypeptide of SEQ ID NO: 1 or SEQ ID NO: 11 (or an allotype variant, e.g., an allotype variant comprising the amino acid sequence of SEQ ID NO: 6, 8, 9, and / or 10) and having high levels of sialylation, such as at least 50% a(2,6) sialylation (e.g., at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at 15#607131Attorney Docket No. 00013.007.1801least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) or about 40% a(2,3) sialylation (e.g. , at least 30%, at least 31 %, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, or at least 50%).Fc Polypeptide Variants

[0048] 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: 1 (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: 1)

[0049] 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 also contemplated herein. For example, SEQ ID NO: 11 is a wild-type / parental amino acid sequence without C-terminal lysine (K).KVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAV16#607131Attorney Docket No. 00013.007.1801EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPG(SEQ ID NO: 11)

[0050] 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: I or SEQ ID NO: 11; 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: 2 or SEQ ID NO: 12, or is a variant thereof having at least 75% (e.g. , at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 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 80% (e.g., at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%. at least 86%. at least 87%. at least 88%. at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 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 85% (e.g., at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 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 90% (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 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%, at least 96%, at least 97%, at least 98%. at least 99%. or more) sequence identity to SEQ ID NO: 2 or SEQ ID NO: 12. In some embodiments, the modified Fc polypeptide includes the F241 A substitution and has an amino 17#607131Attorney Docket No. 00013.007.1801acid sequence having at least 98% (e.g., at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 2 or SEQ ID NO: 12. In some embodiments, the modified Fc polypeptide includes the F241 A substitution (shown as a bolded and underlined A, below) and has an amino acid sequence of SEQ ID NO: 2, as shown below.KVDKKVEPKSCDKTHTCPPCPAPELLGGPSVALFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPGK(SEQ ID NO: 2)

[0051] In some embodiments, the modified Fc polypeptide includes the F241A substitution (shown as a bolded and underlined A, below) and has an amino acid sequence of SEQ ID NO: 12, as shown below.KVDKKVEPKSCDKTHTCPPCPAPELLGGPSVALFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPG(SEQ ID NO: 12)

[0052] 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: 1 or SEQ ID NO: 11; numbered according to the EU index of Kabat). 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%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%. at least 92%. at least 93%. at least 94%. at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 1 or SEQ ID NO: 11. In some 18#607131Attorney Docket No. 00013.007.1801embodiments, the modified Fc polypeptide includes the F241L substitution and has an amino acid sequence having at least 80% (e.g., at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 1 or SEQ ID NO: 11. 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%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 1 or SEQ ID NO: 11. 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%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 1 or SEQ ID NO: 11. 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%, at least 96%. at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 1 or SEQ ID NO: 11. In some embodiments, the modified Fc polypeptide includes the F241L substitution and has an amino acid sequence having at least 98% (e.g., at least 98%, at least 99%, or more) sequence identity7to SEQ ID NO: 1 or SEQ ID NO: 11.

[0053] 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: 1 or SEQ ID NO: 11 ; 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%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity7to SEQ ID NO: 1 or SEQ ID NO: 11. 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%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%,19#607131Attorney Docket No. 00013.007.1801at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity’ to SEQ ID NO: 1 or SEQ ID NO: 11. 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%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 1 or SEQ ID NO: 11. 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%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 1 or SEQ ID NO: 11. 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%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity' to SEQ ID NO: 1 or SEQ ID NO: 11. 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%, at least 99%, or more) sequence identity to SEQ ID NO: 1 or SEQ ID NO: 11.

[0054] In some embodiments, the modified Fc polypeptide includes the F243A substitution and has the amino acid sequence of SEQ ID NO: 16 or SEQ ID NO: 17, or is a variant thereof having at least 75% (e.g., at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%. at least 81%. at least 82%. at least 83%. at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity' to SEQ ID NO: 16 or SEQ ID NO: 17. 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%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 16 or SEQ ID NO: 17. 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%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 16 or SEQ ID NO: 17. 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%, at least 91%, at least 20#607131Attorney Docket No. 00013.007.180192%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%. or more) sequence identity to SEQ ID NO: 16 or SEQ ID NO: 17. 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%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 16 or SEQ ID NO: 17. 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%, at least 99%, or more) sequence identity to SEQ ID NO: 16 or SEQ ID NO: 17. In some embodiments, the modified Fc polypeptide includes the F243A substitution (shown as a bolded and underlined A, below) and has an amino acid sequence of SEQ ID NO: 16, as shown below.KVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLAPPKPKDTLMISRTPEVTCVVVDVSHEDPE VKFNWYVDGVEVHNAKTKP REEQ YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALP API EKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO: 16)

[0055] In some embodiments, the modified Fc polypeptide includes the F243A substitution (shown as a bolded and underlined A, below) and has an amino acid sequence of SEQ ID NO: 17, as shown below.KVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLAPPKPKDTLMISRTPEVTCVVVDVSHEDPE VKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPI EKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(SEQ ID NO: 17)

[0056] 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: 1 or SEQ ID NO: 11 ; 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%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 1 or SEQ ID NO: 11. 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%, at least 81%, at least 82%, at least 83%, at least 84%,21#607131Attorney Docket No. 00013.007.1801at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 1 or SEQ ID NO: 11. 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%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 1 or SEQ ID NO: 11. 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%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 1 or SEQ ID NO: 11. 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%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 1 or SEQ ID NO: 11. 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%, at least 99%, or more) sequence identity to SEQ ID NO: 1 or SEQ ID NO: 11.

[0057] In some embodiments, the modified Fc polypeptide includes the F243L substitution and has the amino acid sequence of SEQ ID NO: 18 or SEQ ID NO: 19, or is a variant thereof having at least 75% (e.g, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity’ to SEQ ID NO: 18 or SEQ ID NO: 19. 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%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 18 or SEQ ID NO: 19. 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%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 18 or SEQ ID NO: 19. In some embodiments, the modified Fc polypeptide includes the F243L substitution 22#607131Attorney Docket No. 00013.007.1801and has an amino acid sequence having at least 90% (e.g., at least 90%, at least 91%, at least 92%. at least 93%. at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 18 or SEQ ID NO: 19. 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%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 18 or SEQ ID NO: 19. 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%, at least 99%, or more) sequence identity to SEQ ID NO: 18 or SEQ ID NO: 19. In some embodiments, the modified Fc polypeptide includes the F243L substitution (shown as a bolded and underlined L, below) and has an amino acid sequence of SEQ ID NO: 18, as shown below.KVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLLPPKPKDTLMISRTPEVTCVVVDVSHEDPE VKFNWYVDGVE VEIN AKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALP API EKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO: 18)

[0058] In some embodiments, the modified Fc polypeptide includes the F243L substitution (shown as a bolded and underlined L, below) and has an amino acid sequence of SEQ ID NO: 19, as shown below.KVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLLPPKPKDTLMISRTPEVTCVVVDVSHEDPE VKFNWYVDGVE VEIN AKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALP API EKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(SEQ ID NO: 19)

[0059] 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: 6 (bolded and underlined arginine residue (R) corresponds to K214R; numbered according to the Kabat system).KVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPG(SEQ ID NO: 6)23#607131Attorney Docket No. 00013.007.1801

[0060] 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: 6; 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).

[0061] In some embodiments, the modified Fc polypeptide includes the K214R and F241A substitution and has the amino acid sequence of SEQ ID NO: 7 or is a variant thereof having at least 75% (e.g., at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%. at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 7. In some embodiments, the modified Fc polypeptide includes the K214R and F241A substitution and has an amino acid sequence having at least 80% (e.g., at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%. at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 7. In some embodiments, the modified Fc polypeptide includes the K214R and F241A substitution and has an amino acid sequence having at least 85% (e.g., at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 6. In some embodiments, the modified Fc polypeptide includes the K214R and F241A substitution and has an amino acid sequence having at least 90% (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 7. In some embodiments, the modified Fc polypeptide includes the K214R and F241 A substitution and has an amino acid sequence having at least 95% (e g., at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 7. In some embodiments, the modified Fc polypeptide includes the K214R and F241A substitution and has an amino acid sequence having at least 98% (e.g., at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 7. In some embodiments, the modified Fc 24#607131Attorney Docket No. 00013.007.1801polypeptide includes the K214R and F241A substitution (shown as a bolded and underlined R and A, below) and has an amino acid sequence of SEQ ID NO: 7. as shown below.KVDKRVEPKSCDKTHTCPPCPAPELLGGPSVALFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPG(SEQ ID NO: 7)

[0062] In some embodiments, the modified Fc polypeptide includes the K214R and F241L substitution having at least 75% (e.g., at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 7. In some embodiments, the modified Fc polypeptide includes the K214R and F241L substitution having at least 80% (e.g., at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 7. In some embodiments, the modified Fc polypeptide includes the K214R and F241L substitution having at least 85% (e.g., at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity' to SEQ ID NO: 6. In some embodiments, the modified Fc polypeptide includes the K214R and F241L substitution having at least 90% (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 7. In some embodiments, the modified Fc polypeptide includes the K214R and F241L substitution having at least 95% (e.g., at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 7. In some embodiments, the modified Fc polypeptide includes the K214R and F241L substitution having at least 98% (e.g., at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 7.

[0063] 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: 6; numbered according to the Kabat system). In some embodiments, the Phe at position 25#607131Attorney Docket No. 00013.007.1801243 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).

[0064] In some embodiments, the modified Fc polypeptide includes the K214R and F243A substitutions having at least 75% (e.g., at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 6. 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%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 6. In some embodiments, the modified Fc polypeptide includes the K214R and F243A substitutions and has an amino acid sequence having at least 85% (e.g., %, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%. at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 6. 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%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 6. 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%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 6. 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%, at least 99%, or more) sequence identity to SEQ ID NO: 6.

[0065] In some embodiments, the modified Fc polypeptide includes the K214R and F243A substitution and has the amino acid sequence of SEQ ID NO: 20 or is a variant thereof having at least 75% (e.g., at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 26#607131Attorney Docket No. 00013.007.180187%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%. at least 95%. at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 20. In some embodiments, the modified Fc polypeptide includes the K214R and F243A substitution and has an amino acid sequence having at least 80% (e.g., at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 20. In some embodiments, the modified Fc polypeptide includes the K214R and F243A substitution and has an amino acid sequence having at least 85% (e.g., at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 20. In some embodiments, the modified Fc polypeptide includes the K214R and F243A substitution and has an amino acid sequence having at least 90% (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 20. In some embodiments, the modified Fc polypeptide includes the K214R and F243A substitution and has an amino acid sequence having at least 95% (e g., at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity7to SEQ ID NO: 20. In some embodiments, the modified Fc polypeptide includes the K214R and F243A substitution and has an amino acid sequence having at least 98% (e.g., at least 98%, at least 99%, or more) sequence identity' to SEQ ID NO: 20. In some embodiments, the modified Fc polypeptide includes the K214R and F243A substitution (shown as a bolded and underlined R and A, below) and has an amino acid sequence of SEQ ID NO: 20, as shown below7.KVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLAPPKPKDTLMISRTPEVTCVVVDVSHEDPE VKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPI EKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(SEQ ID NO: 20)

[0066] In some embodiments, the modified Fc polypeptide includes the K214R and F243L substitutions having at least 75% (e.g., at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 6. In some embodiments, the modified Fc 27#607131Attorney Docket No. 00013.007.1801polypeptide includes the K214R and F243L substitutions and has an amino acid sequence having at least 80% (e.g., at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 6. 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%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 6. 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%. at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 6. 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%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 6. 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%, at least 99%, or more) sequence identity to SEQ ID NO: 6.

[0067] In some embodiments, the modified Fc polypeptide includes the K214R and F243L substitution and has the amino acid sequence of SEQ ID NO: 21 or is a variant thereof having at least 75% (e.g., at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity' to SEQ ID NO: 21. In some embodiments, the modified Fc polypeptide includes the K214R and F243L substitution and has an amino acid sequence having at least 80% (e.g., at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity' to SEQ ID NO: 21. In some embodiments, the modified Fc polypeptide includes the K214R and F243L substitution and has an amino acid sequence having at least 85% (e.g., at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at 28#607131Attorney Docket No. 00013.007.1801least 99%, or more) sequence identity to SEQ ID NO: 21. In some embodiments, the modified Fc polypeptide includes the K214R and F243L substitution and has an amino acid sequence having at least 90% (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 21. In some embodiments, the modified Fc polypeptide includes the K214R and F243L substitution and has an amino acid sequence having at least 95% (e.g., at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 21. In some embodiments, the modified Fc polypeptide includes the K214R and F243L substitution and has an amino acid sequence having at least 98% (e.g., at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 21. In some embodiments, the modified Fc polypeptide includes the K214R and F243L substitution (shown as a bolded and underlined R and L, below) and has an amino acid sequence of SEQ ID NO: 21 as shown below.KVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLLPPKPKDTLMISRTPEVTCVVVDVSHEDPE VKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPI EKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(SEQ ID NO: 21)

[0068] 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: 8 (bolded and underlined glutamic acid residue (E) corresponds to D356E; numbered according to the Kabat system).KVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREELTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPG(SEQ ID NO: 8)

[0069] 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 29#607131Attorney Docket No. 00013.007.1801ID NO: 8; 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).

[0070] In some embodiments, the modified Fc polypeptide includes the D356E and F241A substitutions and has the amino acid sequence of SEQ ID NO: 13 or is a variant thereof having at least 75% (e.g., at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%. at least 88%. at least 89%. at least 90%. at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 13. 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%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 13. 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%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 13. 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%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 13. 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%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 13. 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%, at least 99%, or more) sequence identity to SEQ ID NO: 13. 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: 13, as shown below.30#607131Attorney Docket No. 00013.007.1801KVDKKVEPKSCDKTHTCPPCPAPELLGGPSVALFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREELTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPG(SEQ ID NO: 13)

[0071] In some embodiments, the modified Fc polypeptide includes the D356E and F241L substitution having at least 75% (e.g., at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 8. In some embodiments, the modified Fc polypeptide includes the D356E and F241L substitution having at least 80% (e.g., at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 8. In some embodiments, the modified Fc polypeptide includes the D356E and F241L substitution having at least 85% (e.g., at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 8. In some embodiments, the modified Fc polypeptide includes the D356E and F241L substitution having at least 90% (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%. at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 8. In some embodiments, the modified Fc polypeptide includes the D356E and F241L substitution having at least 95% (e.g., at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 8. In some embodiments, the modified Fc polypeptide includes the D356E and F241L substitution having at least 98% (e.g., at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 8.

[0072] 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: 8; 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 31#607131Attorney Docket No. 00013.007.1801position 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).

[0073] In some embodiments, the modified Fc polypeptide includes the D356E and F243A substitutions having at least 75% (e.g., at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity' to SEQ ID NO: 8. 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%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 8. 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%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity7to SEQ ID NO: 8. 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%. at least 91%. at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity7to SEQ ID NO: 8. 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%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 8. 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%, at least 99%, or more) sequence identity to SEQ ID NO: 8.

[0074] In some embodiments, the modified Fc polypeptide includes the D356E and F243A substitutions and has the amino acid sequence of SEQ ID NO: 22 or is a variant thereof having at least 75% (e.g., at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%. at least 88%. at least 89%. at least 90%. at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence 32#607131Attorney Docket No. 00013.007.1801identity to SEQ ID NO: 22. 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%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 22. 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%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 22. 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%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 22. 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%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 22. 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%, at least 99%, or more) sequence identity to SEQ ID NO: 22. In some embodiments, the modified Fc polypeptide includes the D356E and F243A substitutions (shown as a bolded and underlined E and A, below) and has an amino acid sequence of SEQ ID NO: 22, as shown below.KVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLAPPKPKDTLMISRTPEVTCVVVDVSHEDPE VKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPI EKTISKAKGQPREPQVYTLPPSREELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(SEQ ID NO: 22)

[0075] In some embodiments, the modified Fc polypeptide includes the D356E and F243L substitutions having at least 75% (e.g., at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%. at least 87%. at least 88%. at least 89%. at least 90%. at least 91%. at least 92%. at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 8. 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%, at least 81%, at least 82%, at least 83%, at least 84%,33#607131Attorney Docket No. 00013.007.1801at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 8. 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%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 8. 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%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 8. 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%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 8. In some embodiments, the modified Fc polypeptide includes the D356E and F243L substitutions and has an amino acid sequence having at least 98% (e.g., at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 8.

[0076] In some embodiments, the modified Fc polypeptide includes the D356E and F243L substitutions and has the amino acid sequence of SEQ ID NO: 23 or is a variant thereof having at least 75% (e.g., at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 23. 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%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 23. 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%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 23. In some embodiments, the modified Fc polypeptide includes the D356E and F243L substitutions and has an amino acid sequence 34#607131Attorney Docket No. 00013.007.1801having at least 90% (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 23. 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%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 23. In some embodiments, the modified Fc polypeptide includes the D356E and F243L substitutions and has an amino acid sequence having at least 98% (e.g., at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 23. In some embodiments, the modified Fc polypeptide includes the D356E and F243L substitutions (shown as a bolded and underlined E and L, below) and has an amino acid sequence of SEQ ID NO: 23, as shown below;KVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLLPPKPKDTLMISRTPEVTCVVVDVSHEDPE VKFNWYVDGVE VEIN AKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALP API EKTISKAKGQPREPQVYTLPPSREELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(SEQ ID NO: 23)

[0077] 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, L358M comprising the amino acid sequence of SEQ ID NO: 9 (bolded and underlined methionine residue (M) corresponds to L358M; numbered according to the Kabat system).KVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEMTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPG(SEQ ID NO: 9)

[0078] 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 at 35#607131Attorney Docket No. 00013.007.1801position 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).

[0079] In some embodiments, the modified Fc polypeptide includes the L358M and F241A substitutions and has the amino acid sequence of SEQ ID NO: 14 or is a variant thereof having at least 75% (e.g., at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 14. In some embodiments, the modified Fc polypeptide includes the L358M and F241 A substitutions and has an amino acid sequence having at least 80% (e.g., at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 14. In some embodiments, the modified Fc polypeptide includes the L358M and F241 A substitutions and has an amino acid sequence having at least 85% (e.g., at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 14. 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%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 14. 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%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 14. In some embodiments, the modified Fc polypeptide includes the L358M and F241 A substitutions and has an amino acid sequence having at least 98% (e.g., at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 14. 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: 14, as shown below.KVDKKVEPKSCDKTHTCPPCPAPELLGGPSVALFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEMTKNQVSLTCLVKGFYPSDIAV36#607131Attorney Docket No. 00013.007.1801EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPG(SEQ ID NO: 14)

[0080] In some embodiments, the modified Fc polypeptide includes the L358M and F241L substitution having at least 75% (e.g., at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 9. In some embodiments, the modified Fc polypeptide includes the L358M and F241L substitution having at least 80% (e.g., at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 9. In some embodiments, the modified Fc polypeptide includes the L358M and F241L substitution having at least 85% (e.g., at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 9. In some embodiments, the modified Fc polypeptide includes the L358M and F241L substitution having at least 90% (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity7to SEQ ID NO: 9. In some embodiments, the modified Fc polypeptide includes the L358M and F241L substitution having at least 95% (e.g., at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 9. In some embodiments, the modified Fc polypeptide includes the L358M and F241L substitution having at least 98% (e.g., at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 9.

[0081] 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).37#607131Attorney Docket No. 00013.007.1801

[0082] In some embodiments, the modified Fc polypeptide includes the L358M and F243A substitutions having at least 75% (e.g., at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 24. 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%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 24. 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%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 24. 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%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 24. 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%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 24. 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%. at least 99%, or more) sequence identity to SEQ ID NO: 24. In some embodiments, the modified Fc polypeptide includes the L358M and F243A substitutions (shown as a bolded and underlined M and A, below) and has an amino acid sequence of SEQ ID NO: 24, as shown below.KVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLAPPKPKDTLMISRTPEVTCVVVDVSHEDPE VKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPI EKTISKAKGQPREPQVYTLPPSRDEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(SEQ ID NO: 24)

[0083] In some embodiments, the modified Fc polypeptide includes the L358M and F243L substitutions having at least 75% (e.g., at least 75%, at least 76%, at least 77%, at least 78%,38#607131Attorney Docket No. 00013.007.1801at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 25. 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%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 25. 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%. at least 86%. at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 25. 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%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 25. 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%, at least 96%. at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 25. 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%, at least 99%, or more) sequence identity to SEQ ID NO: 25. In some embodiments, the modified Fc polypeptide includes the L358M and F243L substitutions (shown as a bolded and underlined M and L, below) and has an amino acid sequence of SEQ ID NO: 25, as shown below.KVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLLPPKPKDTLMISRTPEVTCVVVDVSHEDPE VKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPI EKTISKAKGQPREPQVYTLPPSRDEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(SEQ ID NO: 25)

[0084] 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, A431G comprising 39#607131Attorney Docket No. 00013.007.1801the amino acid sequence of SEQ ID NO: 10 (bolded and underlined glycine residue (G) corresponds to A431G; numbered according to the Kabat system).KVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEGLHN HYTQKSLSLSPG(SEQ ID NO: 10)

[0085] 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: 10; 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).

[0086] In some embodiments, the modified Fc polypeptide includes the A431G and F241A substitutions and has the amino acid sequence of SEQ ID NO: 15 or is a variant thereof having at least 75% (e.g., at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%. at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 15. In some embodiments, the modified Fc polypeptide includes the A431G and F241 A substitutions and has an amino acid sequence having at least 80% (e.g., at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 15. 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%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 15. In some embodiments, the modified 40#607131Attorney Docket No. 00013.007.1801Fc polypeptide includes the A431G and F241A substitutions and has an amino acid sequence having at least 90% (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 15. 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%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 15. In some embodiments, the modified Fc poly peptide includes the A431 Gand F241A substitutions and has an amino acid sequence having at least 98% (e.g., at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 15. In some embodiments, the modified Fc polypeptide includes the A431G and F241A substitutions (shown as a bolded and underlined G and A. below) and has an amino acid sequence of SEQ ID NO: 15. as shown below.KVDKKVEPKSCDKTHTCPPCPAPELLGGPSVALFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEGLHN HYTQKSLSLSPG(SEQ ID NO: 15)

[0087] In some embodiments, the modified Fc polypeptide includes the A431G and F241L substitution having at least 75% (e.g., at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 10. In some embodiments, the modified Fc polypeptide includes the A431G and F241L substitution having at least 80% (e.g., at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 10. In some embodiments, the modified Fc polypeptide includes the A431G and F241L substitution having at least 85% (e.g., at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 10. In some embodiments, the modified Fc polypeptide includes the A431G and 41#607131Attorney Docket No. 00013.007.1801F241L substitution having at least 90% (e.g., at least 90%, at least 91%, at least 92%, at least 93%. at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%. or more) sequence identity to SEQ ID NO: 10. In some embodiments, the modified Fc polypeptide includes the A431G and F241L substitution having at least 95% (e.g., at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 10. In some embodiments, the modified Fc polypeptide includes the A431G and F241L substitution having at least 98% (e.g., at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 10.

[0088] 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: 10; 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).

[0089] In some embodiments, the modified Fc polypeptide includes the A431G and F243A substitutions having at least 75% (e.g., at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%. at least 87%. at least 88%. at least 89%. at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 26. 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%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 26. 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%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 26. 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%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 42#607131Attorney Docket No. 00013.007.180198%, at least 99%, or more) sequence identity to SEQ ID NO: 26. 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%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 26. 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%, at least 99%, or more) sequence identity to SEQ ID NO: 26. In some embodiments, the modified Fc polypeptide includes the A431G and F243A substitutions (shown as a bolded and underlined G and A, below) and has an amino acid sequence of SEQ ID NO: 26, as shown below.KVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLAPPKPKDTLMISRTPEVTCVVVDVSHEDPE VKFNWYVDGVEVHNAKTKP REEQ YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALP API EKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEGLHNHYTQKSLSLSPG(SEQ ID NO: 26)

[0090] In some embodiments, the modified Fc polypeptide includes the A431G and F243L substitutions having at least 75% (e.g., at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 27. 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%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 27. 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%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 27. 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%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 27. In some embodiments, the modified Fc polypeptide includes the A431G and F243L substitutions and has an amino acid 43#607131Attorney Docket No. 00013.007.1801sequence having at least 95% (e.g., at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to SEQ ID NO: 27. 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%, at least 99%, or more) sequence identity to SEQ ID NO: 27. In some embodiments, the modified Fc polypeptide includes the A431G and F243L substitutions (shown as a bolded and underlined G and L, below) and has an amino acid sequence of SEQ ID NO: 27, as shown below.KVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLLPPKPKDTLMISRTPEVTCVVVDVSHEDPE VKFNWYVDGVE VEIN AKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALP API EKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEGLHNHYTQKSLSLSPG(SEQ ID NO: 27)

[0091] The amino acid composition of a modified Fc polypeptide described herein vary without disrupting the ability of the polypeptide to bind to the respective receptor and trigger the respective cellular response, in some embodiments. For example, it contains one or more conservative amino acid substitutions, in some embodiments. A “conservative amino acid substitution" is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains are known. These families include amino acids with basic side chains (e.g, lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g. , glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g.. alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., ty rosine, phenylalanine, tryptophan, histidine). Thus, a predicted nonessential amino acid residue in, e.g., SEQ ID NO: 2, is preferably replaced with another amino acid residue from the same side chain family. Alternatively, mutations can be introduced randomly along all or part of the sequences, such as by saturation mutagenesis, and the resultant mutants can be screened for the ability to bind to the respective Fc receptor and trigger a corresponding cellular response to identity' mutants that retain the activity' as desired.

[0092] In some embodiments, the modified Fc polypeptide is IgGl isotype. In some embodiments, the modified Fc polypeptides is IgG3 isotype.Sialylation of Modified Fc Polypeptides

[0093] 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 44#607131Attorney Docket No. 00013.007.1801carbohydrate 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.

[0094] 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. 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 grow n under different culture conditions.

[0095] 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 FcyRIIB receptors and DC-SIGN receptors. Removal of the IVIg sialic acid results in loss of protection in animal models of multiple sclerosis, rheumatoid arthritis, and Guillain-Barre syndrome, 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 antiinflammatory activity of IVIg. Blocking the IL-33 receptor, knockout of FcyRIIB, or depletion of T regulatory cell, in different contexts, also blocks 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. Previous efforts to produce highly sialylated pools of IgG Fc focused on purifying sialylated fractions of Fc polypeptides from IVIG. However, there are no available methods for recombinantly producing pure, highly sialylated Fc peptides having predetermined levels of sialylation.45#607131Attorney Docket No. 00013.007.1801

[0096] The present disclosure provides methods for enhancing sialylation of IgG Fc polypeptides by providing modified Fc polypeptides (e.g, an FCF241Amutant of SEQ ID NO: 2 or a variant thereof) 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 enzymes 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.

[0097] In some embodiments, the polynucleotide encoding an ST6GAL1 enzyme encodes an ST6GAL1 enzyme having an amino acid sequence of SEQ ID NO: 3 or a variant thereof having at least 85% (e.g., at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%. at least 98%, at least 99%, or more) sequence identity to the amino acid sequence of SEQ ID NO: 3, as shown below.MIHTNLKKKFSCCVLVFLLFAVICVWKEKKKGSYYDSFKLQTKEFQVLKSLGKLAM GSDSQSVSSSSTQDPHRGRQTLGSLRGLAKAKPEASFQVWNKDSSSKNLIPRLQKIW KNYLSMNKYKVSYKGPGPGIKFSAEALRCHLRDHVNVSMVEVTDFPFNTSEWEGYL PKESIRTKAGPWGRCAVVSSAGSLKSSQLGREIDDHDAVLRFNGAPTANFQQDVGT KTTIRLMNSQLVTTEKRFLKDSLYNEGILIVWDPSVYHSDIPKWYQNPDYNFFNNYK TYRKLHPNQPFYILKPQMPWELWDILQEISPEEIQPNPPSSGMLGIIIMMTLCDQVDIY EFLPSKRKTDVCYYYQKFFDSACTMGAYHPLLYEKNLVKHLNQGTDEDIYLLGKAT LPGFRTIHC(SEQ ID NO: 3; UmProt ID No.: P15907-1)

[0098] In some embodiments, the polynucleotide encoding an B4GALT1 enzy me encodes an B4GALT1 enzyme having an amino acid sequence of SEQ ID NO: 4 or a variant thereof having at least 85% (e.g, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 46#607131Attorney Docket No. 00013.007.180197%, at least 98%, at least 99%, or more) sequence identity to the amino acid sequence of SEQ ID NO: 4, as shown below.MRLREPLLSGSAAMPGASLQRACRLLVAVCALHLGVTLVYYLAGRDLSRLPQLVGV STPLQGGSNSAAAIGQSSGELRTGGARPPPPLGASSQPRPGGDSSPVVDSGPGPASNL TSVPVPHTTALSLPACPEESPLLVGPMLIEFNMPVDLELVAKQNPNVKMGGRYAPRD CVSPHKVAIIIPFRNRQEHLKYWLYYLHPVLQRQQLDYGIYVINQAGDTIFNRAKLLN VGFQEALKDYDYTCFVFSDVDLIPMNDHNAYRCFSQPRHISVAMDKFGFSLPYVQY FGGVSALSKQQFLTINGFPNNYWGWGGEDDDIFNRLVFRGMSISRPNAVVGRCRMI RHSRDKKNEPNPQRFDRIAHTKETMLSDGLNSLTYQVLDVQRYPLYTQITVDIGTPS(SEQ ID NO: 4; UniProt ID No.: P15291-1)

[0099] The disclosed methods are used to achieve specified levels of Fc sialylation. In some embodiments, modified Fc polypeptides of the disclosure are expressed and / or cultured under conditions and for a time sufficient to produce a pool of Fc polypeptides having at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or about 100% sialylated Fc polypeptides within the pool. In some embodiments, the modified Fc polypeptides are expressed and / or cultured under conditions and for a time sufficient to produce a pool of Fc polypeptides having at least 40% sialylated Fc polypeptides within the pool. In some embodiments, the modified Fc polypeptides are expressed and / or cultured under conditions and for a time sufficient to produce a pool of Fc polypeptides having at least 45% sialylated Fc polypeptides within the pool. In some embodiments, the modified Fc polypeptides are expressed and / or cultured under conditions and for a time sufficient to produce a pool of Fc polypeptides having at least 50% sialylated Fc polypeptides within the pool. In some embodiments, the modified Fc polypeptides are expressed and / or cultured under conditions and for a time sufficient to produce a pool of Fc polypeptides having at least 55% sialylated Fc polypeptides within the pool. In some embodiments, the modified Fc polypeptides are expressed and / or cultured under conditions and for a time sufficient to produce a pool of Fc polypeptides having at least 60% sialylated Fc polypeptides within the pool. In some embodiments, the modified Fc polypeptides are expressed and / or cultured under conditions and for a time sufficient to produce a pool of Fc polypeptides having at least 65% sialylated Fc polypeptides within the pool. In some embodiments, the modified Fc polypeptides are expressed and / or cultured under conditions and for a time sufficient to produce a pool of Fc polypeptides having at least 70% sialylated Fc polypeptides within the pool. In some embodiments, the Fc polypeptides are expressed and / or 47#607131Attorney Docket No. 00013.007.1801cultured under conditions and for a time sufficient to produce a pool of Fc polypeptides having at least 75% sialylated Fc polypeptides within the pool. In some embodiments, the modified Fc polypeptides are expressed and / or cultured under conditions and for a time sufficient to produce a pool of Fc polypeptides having at least 80% sialylated Fc polypeptides within the pool. In some embodiments, the modified Fc polypeptides are expressed and / or cultured under conditions and for a time sufficient to produce a pool of Fc polypeptides having at least 85% sialylated Fc polypeptides within the pool. In some embodiments, the modified Fc polypeptides are expressed and / or cultured under conditions and for a time sufficient to produce a pool of Fc polypeptides having at least 90% sialylated Fc polypeptides within the pool. In some embodiments, the modified Fc polypeptides are expressed and / or cultured under conditions and for a time sufficient to produce a pool of Fc polypeptides having at least 95% sialylated Fc polypeptides within the pool. In some embodiments, the modified Fc polypeptides are expressed and / or cultured under conditions and for a time sufficient to produce a pool of Fc polypeptides having about 100% sialylated Fc polypeptides within the pool. In some embodiments, the modified Fc polypeptides are expressed and / or cultured under conditions and for a time sufficient to produce a pool of Fc polypeptides having between 40% and 100% sialylated Fc polypeptides within the pool, such as between 45% and 50%, between 50% and 55%, between 55% and 60%, between 60% and 65%, between 65% and 70%, between 70% and 75%, between 75% and 80%, between 80% and 85%. between 85% and 90%. between 90% and 95%, or between 95% and 100%.

[0100] In some embodiments, the modified Fc polypeptides are expressed and / or cultured under conditions and for a time sufficient to produce a pool of modified Fc polypeptides including at least 60% (e.g., at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) of the Fc polypeptides having an SA moiety attached to an N-glycan of the Fc polypeptide via an a(2,6) linkage. In some embodiments, at least 65% (e.g, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at 48#607131Attorney Docket No. 00013.007.1801least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) of the modified Fc polypeptides comprise the SA moiety attached to the N-glycan of the Fc polypeptides via the a(2,6) linkage. In some embodiments, at least 70% (e.g, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) of the modified Fc polypeptides comprise the SA moiety attached to the N-glycan of the Fc polypeptides via the a(2,6) linkage. In some embodiments, at least 75% (e.g., at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%. at least 82%. at least 83%. at least 84%. at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) of the modified Fc polypeptides comprise the SA moiety attached to the N-glycan of the Fc polypeptides via the a(2,6) linkage. In some embodiments, at least 80% (e.g., at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) of the modified Fc polypeptides comprise the SA moiety attached to the N-glycan of the Fc polypeptides via the a(2,6) linkage. In some embodiments, at least 85% (e.g, at least 85%, at least 86%. at least 87%. at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) of the modified Fc polypeptides comprise the SA moiety attached to the N-glycan of the Fc polypeptides via the a(2,6) linkage. In some embodiments, at least 90% (e.g., at least 90%, at least 91%. at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) of the modified Fc polypeptides comprise the SA moiety attached to the N-glycan of the Fc polypeptides via the a(2,6) linkage. In some embodiments, at least 95% (e.g., at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) of the modified Fc polypeptides comprise the SA moiety attached to the N-glycan of the Fc polypeptides via the a(2,6) linkage. In some embodiments, at least 98% (e.g, at least 98%, at least 99%, or more) of the modified Fc polypeptides comprise the SA moiety attached to the N-glycan of the Fc polypeptides via the a(2,6) linkage. In some embodiments, at least 99% of the modified Fc polypeptides comprise the SA moiety attached to the N-glycan of the Fc polypeptides via the a(2,6) linkage. In some embodiments, about 100% of the modified Fc polypeptides comprise the SA moiety 49#607131Attorney Docket No. 00013.007.1801attached to the N-glycan of the Fc polypeptides via the a(2,6) linkage. In some embodiments, the N-glycan of the modified Fc polypeptides is mono-sialylated or di-sialylated. In some embodiments, at least 30% of the modified Fc polypeptides comprise mono-sialylated N-glycans comprising a SA moiety attached via the a(2,6) linkage. In some embodiments, at least 30% of the modified Fc polypeptides comprise di-sialylated N-glycans comprising two SA moieties attached via the a(2,6) linkage. In some embodiments, about 90% of the modified Fc polypeptides comprise di-sialylated N-glycans comprising two SA moieties attached via the a(2,6) linkage.

[0101] In some embodiments, at least about 60% (e.g., at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%. at least 71%. at least 72%. at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) of the modified Fc polypeptides comprise a galactose moiety. In some embodiments, at least about 70% (e.g., at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%. at least 95%. at least 96%, at least 97%, at least 98%, at least 99%, or more) of the modified Fc polypeptides comprise a galactose moiety. In some embodiments, at least about 80% (e.g., at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) of the modified Fc polypeptides comprise a galactose moiety. In some embodiments, at least about 90% (e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) of the modified Fc polypeptides comprise a galactose moiety. In some embodiments, about 100% of the modified Fc polypeptides comprise 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.

[0102] In some embodiments, the modified Fc polypeptides are expressed and / or cultured under conditions and for a time sufficient to produce a pool of modified Fc polypeptides including about 40% (e.g., about 30%, about 31%, about 32%, about 33%, about 34%, about 50#607131Attorney Docket No. 00013.007.180135%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%. about 44%. about 45%, about 46%, about 47%, about 48%, about 49%, or about 50%) of the Fc polypeptides having an SA moiety attached to an N-glycan of the modified Fc polypeptide via an a(2,3) linkage.

[0103] In some embodiments, the N-glycan is attached to the asparagine (Asn) at amino acid residue 297 of the polypeptide (Asn297; numbered according to Kabat; corresponding to amino acid residue 88 of SEQ ID NO: 2).Therapeutic Effects

[0104] In some embodiments, methods of the present disclosure 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 autoimmune disorder, reduce symptoms of an autoimmune disorder, reduce inflammation, reduce auto-antibody levels, increase organ function, and decrease rate or number of relapses or flare-ups. In some embodiments, methods of the present disclosure result in reduction of alleviation of one or more symptoms of an autoimmune disease and / or reduction a clinical score associated with an autoimmune disease.

[0105] For example, in the context of an autoimmune disorder affecting the myelin sheath or peripheral nerves, e.g., Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), methods disclosed herein may result in reduction of symptoms associated with CIDP. For example, in the context of the myelin sheath or peripheral nerves, e.g., Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), methods disclosed herein may result in improvement in nerve function.

[0106] 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.51#607131Attorney Docket No. 00013.007.1801

[0107] Prolonging survival is another desired 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 is measured in months to years. In some embodiments, the subject's symptoms remain static or decrease.Pharmaceutical Compositions

[0108] Disclosed herein, in some embodiments, are methods of treating Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) in an individual in need thereof, comprising administering to the individual: (a) a population of modified Fc polypeptides, each modified Fc polypeptide having (i) an amino acid sequence at least 75% (e.g.. at least 75%. at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%. at least 99%, or more) identical to the sequence of SEQ ID NO: 2 and (ii) an aliphatic amino acid residue (e.g, Ala) at position 241 (numbered according to Kabat; corresponding to amino acid residue 32 of SEQ ID NO: 2) or an aliphatic amino acid residue (e.g, Ala) at position 243 (numbered according to Kabat; corresponding to amino acid residue 32 of SEQ ID NO: 2), comprising: at least 60% (e.g, at least 60%, at least 61%, at least 62%, at least 63%. at least 64%. at least 65%. at least 66%. at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) of the modified Fc polypeptide having a sialic acid (SA) moiety attached to an N-glycan of the Fc polypeptide via an a(2,6) linkage; and (b) a pharmaceutically acceptable carrier, diluent, or excipient. Such compositions are useful for in vitro or in vivo analysis or. in the case of pharmaceutical compositions, for administration to a subject in vivo or ex vivo for treating a subject having a disease or disorder (e.g, autoimmune disorder, such as an autoimmune disease or disorder) with the disclosed polypeptides.

[0109] Disclosed herein, in some embodiments, are methods of treating Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) in an individual in need thereof, comprising administering to the individual: (a) a population of modified Fc polypeptides, each modified Fc polypeptide having (i) an amino acid sequence at least 75% (e.g, at least 75%, at least 76%,52#607131Attorney Docket No. 00013.007.1801at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) identical to the sequence of SEQ ID NO: 12 and (ii) an aliphatic amino acid residue (c.g.. Ala) at position 241 (numbered according to Kabat; corresponding to amino acid residue 32 of SEQ ID NO: 12) or an aliphatic amino acid residue (e.g., Ala) at position 243 (numbered according to Kabat; corresponding to amino acid residue 32 of SEQ ID NO: 12), comprising: at least 60% (e g, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%. at least 78%. at least 79%. at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) of the modified Fc polypeptide having a sialic acid (SA) moiety attached to an N-glycan of the Fc polypeptide via an a(2.6) linkage; and (b) a pharmaceutically acceptable carrier, diluent, or excipient. Such compositions are useful for in vitro or in vivo analysis or, in the case of pharmaceutical compositions, for administration to a subject in vivo or ex vivo for treating a subject having a disease or disorder (e.g., autoimmune disorder, such as an autoimmune disease or disorder) with the disclosed polypeptides.

[0110] In some embodiments, the carrier, diluent, or excipient is a stabilizer, buffer, surfactant, filler, solvent, tonicity or osmolarity adjusting agent, antioxidant, adjuvant, and antimicrobial agent or other suitable materials. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient. The precise nature of the carrier or other material will depend on the route of administration.

[0111] Pharmaceutical formulations comprising an Fc polypeptide, identified by the methods described herein are prepared for storage by mixing the protein having the desired degree of purity with optional physiologically acceptable carrier, diluent, or excipient, in the form of lyophilized formulations or aqueous solutions, in some embodiments. Acceptable carriers, diluents, or excipients are those that are non-toxic to recipients at the dosages and concentrations employed, and include buffers such as acetate, phosphate, citrate, histidine, TRIS, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and 53#607131Attorney Docket No. 00013.007.1801m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as proline, glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g, Zn-protein complexes); and / or non-ionic surfactants such as TWEEN®, PLURONICS®, polyethylene glycol (PEG), polysorbate (e.g., polysorbate 20, 40, 60, and 80), and pol oxamer (e.g, P101, P105, P108, P122, P123, P124, Pl 81, P182, P183, P184, P185, P188, P212, P215, P217, P231, P234, P235, P237, P238, P282, P284, P288, P331, P333, P334, P335, P338, P401, P402, P403, and P407). In some embodiments, the pharmaceutical composition is stable as a liquid solution at 4°C. In some embodiments, the pharmaceutical composition is stable as a liquid solution at room temperature.

[0112] Acceptable carriers are physiologically acceptable to the administered subject and retain the therapeutic properties of the compounds with / in which it is administered. Acceptable carriers and their formulations are generally described in, e.g., Remington ’s Pharmaceutical Sciences, supra. One exemplar}' carrier is physiological saline. The phrase “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid fdler, diluent, excipient, solvent, or encapsulating material, involved in carrying or transporting the subject compounds from the administration site of one organ, or portion of the body, to another organ, or portion of the body, or in an in vitro assay system. Each carrier is acceptable in the sense of being compatible with the other ingredients of the formulation and not injurious to a subject to whom it is administered. Nor should an acceptable carrier alter the specific activity of the subject compounds.

[0113] In some embodiments, a pharmaceutical composition disclosed herein further comprises an acceptable additive to improve the stability of the compounds in composition and / or to control the release rate of the composition. Acceptable additives do not alter the specific activity’ of the subject compounds. Exemplary acceptable additives include, but are not limited to, a sugar such as mannitol, sorbitol, glucose, xylitol, trehalose, sorbose, sucrose, galactose, dextran, dextrose, fructose, lactose, and mixtures thereof. Acceptable additives are combined with acceptable carriers and / or excipients, such as dextrose, in some embodiments. Alternatively, exemplary acceptable additives include, but are not limited to a surfactant, such as polysorbate 20 or polysorbate 80, to increase stability of the polypeptide and decrease gelling54#607131Attorney Docket No. 00013.007.1801of the solution. Addition of such acceptable additives increases the stability and -half-life of the composition in storage.

[0114] In some embodiments, a pharmaceutical composition disclosed herein contains an isotonic buffer such as a phosphate, acetate, histidine, or TRIS buffer in combination with a tonicity agent such as a polyol, sorbitol, sucrose, or sodium chloride, which tonicifies and stabilizes.

[0115] In some embodiments, a pharmaceutical composition disclosed herein also contains more than one active compound as necessary for the indication being treated, such as those with complementary activities that do not adversely affect each other. Such molecules are suitably present in combination in amounts that are effective for the purpose intended.

[0116] In some embodiments, active ingredients are entrapped in microcapsule prepared, e.g., by coacervation techniques or by interfacial polymerization, e.g., hydroxy methylcellulose or -gelatin microcapsule and poly-(methylmethacrylate) microcapsule, respectively, in colloidal drug delivery systems (e g, liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or in macroemulsions.

[0117] Suspensions and crystal forms of polypeptides are also contemplated herein; any suitable methods may be used to make suspensions and crystal forms.

[0118] In some embodiments, a pharmaceutical composition disclosed herein is sterile. In some embodiments, a pharmaceutical composition disclosed herein is sterilized by conventional, or any suitable sterilization techniques. For example, sterilization is readily accomplished by filtration through sterile filtration membranes. In some embodiments, the resulting solution is packaged for use or filtered under aseptic conditions and lyophilized, the lyophilized preparation being combined with a sterile solution prior to administration.

[0119] Freeze-drying is employed to stabilize polypeptides for -long-term storage, such as when a polypeptide is relatively unstable in liquid compositions, in some embodiments.

[0120] In some embodiments, excipients such as, e.g., polyols (including mannitol, sorbitol, and glycerol), sugars (including glucose and sucrose), and amino acids (including alanine, glycine, and glutamic acid) act as stabilizers for -freeze-dried products. Polyols and sugars are also used to protect polypeptides from freezing and drying-induced damage and to enhance the stability during storage in the dried state, in some embodiments. Sugars are, in some embodiments, effective in both the -freeze-drying process and during storage. Other classes of molecules, including mono- and disaccharides and polymers, such as PVP, have also been reported as stabilizers of lyophilized products.55#607131Attorney Docket No. 00013.007.1801

[0121] For injection, in some embodiments, a pharmaceutical composition disclosed herein is a powder suitable for reconstitution with an appropriate solution as described above. Examples of these include, but are not limited to, freeze dried, rotary dried, or spray dried powders, amorphous powders, granules, precipitates, or particulates. For injection, the compositions optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers, and combinations of these.

[0122] Sustained-release preparations are prepared, in some embodiments. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the polypeptide, which matrices are in the form of shaped articles, e.g., films, or microcapsule. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)). polylactides, copolymers of L-glutamic acid and ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid: glycolic acid copolymers such as injectable microspheres composed of lactic acid: -gly colic acid copolymer and leuprolide acetate, and poly-D-)3-hydroxy butyric acid. While polymers such as ethylene-vinyl acetate and lactic acid:glycolic acid enable release of molecules for over 100 days, certain hydrogels release proteins for shorter time periods. While encapsulated polypeptides remain in the body for a long time, they denature or aggregate as a result of exposure to moisture at 37°C, resulting in a loss of biological activity and possible changes in immunogenicity. Rational strategies devised for stabilization are, in some cases, dependent on the mechanism involved. For example, if the aggregation mechanism is discovered to be intermol ecul ar S-bond formation through thio-disulfide interchange, stabilization is achieved, in some cases, by modifying sulfhydry l residues, lyophilizing from acidic solutions, controlling moisture content, using appropriate additives, and developing specific polymer matrix compositions.

[0123] In some embodiments, a pharmaceutical composition disclosed herein is designed to be short-acting, fast-releasing, long-acting, or sustained-releasing, as described herein. In some embodiments, a pharmaceutical composition disclosed herein is formulated for controlled release or for slow release.

[0124] The pharmaceutical composition is administered, e.g., by injection, including, but not limited to, subcutaneous, intravitreal, intradermal, intravenous, intra-arterial, intraperitoneal, intracerebrospinal, intraosseous, or intramuscular injection. Excipients and carriers for use in formulation of compositions for each type of injection are contemplated herein. The following descriptions are by example only and are not meant to limit the scope of the compositions. Compositions for injection include, but are not limited to, aqueous solutions (where water 56#607131Attorney Docket No. 00013.007.1801soluble) or dispersions, as well as sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, or phosphate buffered saline (PBS). In some embodiments, the carrier is a solvent or dispersion medium containing, e.g., water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. Fluidity is maintained, e.g., by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Antibacterial and antifungal agents include, e.g, parabens, chlorobutanol, phenol, ascorbic acid, and thimerosal. Isotonic agents, e.g., sugars, polyalcohols such as mannitol, sorbitol, and sodium chloride are included in the composition, in some embodiments. The resulting solutions are packaged for use as is, or lyophilized; the lyophilized preparation is later combined with a sterile solution prior to administration, in some embodiments. For intravenous injection or injection at the site of affliction, the active ingredient will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity, and stability. Any suitable solutions using, e.g, isotonic vehicles such as Sodium Chloride Injection, Ringer’s Injection, and Lactated Ringer’s Injection. Preservatives, stabilizers, buffers, antioxidants, and / or other additives are included as needed, in some embodiments. Sterile injectable solutions are prepared by incorporating an active ingredient in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization, in some embodiments. Generally, dispersions are prepared by incorporating the active ingredient into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0125] Compositions are administered intravenously, in some embodiments, such as by injection of a unit dose. For injection, in some embodiments, an active ingredient is in the form of a parenterally acceptable aqueous solution which is substantially pyrogen-free and has suitable pH, isotonicity, and stability. In some embodiments, one prepares suitable solutions using, e.g., isotonic vehicles such as Sodium Chloride Injection, Ringer’s Injection, Lactated Ringer's Injection. Preservatives, stabilizers, buffers, antioxidants, and / or other additives are included, as required, in some embodiments. Additionally, compositions are administered via aerosolization, in some embodiments.57#607131Attorney Docket No. 00013.007.1801

[0126] For parenteral administration, the polypeptides are formulated in a unit dosage injectable form (e.g. solution, suspension, or emulsion) in association with a pharmaceutically acceptable, parenteral vehicle. Examples of such vehicles are water, saline, Ringer’s solution, dextrose solution, and 5% human serum albumin. Nonaqueous vehicles such as fixed oils and ethyl oleate are also used. In some embodiments, liposomes are used as carriers. The vehicle contains minor amounts of additives such as substances that enhance isotonicity and chemical stability, e.g., buffers and preservatives. The polypeptides are typically formulated in such vehicles at concentrations of about 1 mg / mL to 10 mg / mL.

[0127] In some embodiments, a pharmaceutical composition disclosed herein is lyophilized, e.g., to increase shelf-life in storage. When the compositions are considered for use in medicaments or any of the methods provided herein, in some embodiments, it is contemplated that the composition are substantially free of pyrogens such that the composition will not cause an inflammatory reaction or an unsafe allergic reaction when administered to a human subject.

[0128] In some embodiments, acceptable carriers contain a compound that stabilizes, increases, or delays absorption or clearance. Such compounds include, e.g, carbohydrates, such as glucose, sucrose, or dextrans; low molecular weight proteins; compositions that reduce the clearance or hydrolysis of peptides; or excipients or other stabilizers and / or buffers. Agents that delay absorption include, e.g., aluminum monostearate and gelatin. In some embodiments, detergents also be used to stabilize or to increase or decrease the absorption of the pharmaceutical composition, including liposomal carriers. To protect from digestion, the compound is, in some embodiments, complexed with a composition to render it resistant to acidic and enzymatic hydrolysis, or the compound is complexed in an appropriately resistant carrier such as a liposome. Protecting compounds from digestion may be achieved using any suitable methods.Medicaments

[0129] The disclosure provides, in some embodiments, a use of the compositions described herein to make a medicament for treating Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) in an individual in need thereof. In some embodiments, medicaments are formulated based on the physical characteristics of the subject needing treatment and are formulated in single or multiple formulations based on the stage of the condition, disease, or disorder. Medicaments are packaged in a suitable package with appropriate labels for the distribution to hospitals and clinics in which the label is for the indication of treating a subject having a disease described herein, in some embodiments. Medicaments are packaged as a 58#607131Attorney Docket No. 00013.007.1801single or multiple units, in some embodiments. Instructions for the dosage and administration of the compositions are included with the packages as described below, in some embodiments. The disclosure is further directed to medicaments comprising a composition described herein and 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.Routes of Administration

[0130] The modified Fc polypeptides described herein or compositions containing the same are, in some embodiments, administered to a subject suffering from chronic inflammatory demyelinating polyneuropathy (CIDP) by a variety of routes, such as intravenously, intradermally, subcutaneously, percutaneously, transdermally, intramuscularly, transmucosally, or intraosseously. In some embodiments, the compositions described herein are administered to a subject systemically (e.g, intravenously). In some embodiments, the compositions described herein are administered to the subject locally (e.g., to the site of inflammation). The most suitable route for administration in any given case will depend on the particular composition administered, the patient, pharmaceutical formulation methods, administration methods (e.g., administration time and administration route), the patient's age, body weight, sex, severity of the disease being treated, the patient's diet, and the patient’s excretion rate. Multiple routes of administration may be used to treat a single subject. Multiple routes of administration may be used to treat a single subject at one time, or the subject may receive treatment via one route of administration first, and receive treatment via another route of administration during a second appointment, e.g. 1 week later. 2 weeks later, 1 month later, 6 months later, or 1 year later. Compositions of the disclosure may be administered to a subject once, or two or more times (e.g. , 2-10 times) per week, month, or year to a subject for treatment.Dosage

[0131] The amount of modified Fc polypeptides disclosed herein or compositions containing the same used with the methods of treatment disclosed herein will typically be a therapeutically effective amount. As a non-limiting example, an effective amount is an amount sufficient to reduce a symptom of chronic inflammatory demyelinating polyneuropathy (CIDP) in an59#607131Attorney Docket No. 00013.007.1801individual in need thereof, for example to reduce pain, weakness, numbness or tingling, or muscle atrophy.

[0132] The appropriate effective amount of a composition to be administered for a particular application of the disclosed methods can be determined by, e.g., using the guidance provided herein. For example, the effectiveness of a composition disclosed herein in treating a symptom of CIDP is determined by observing one or more clinical symptoms, and / or physiological indicators associated with the condition, in some embodiments. The response of an individual with CIDP to treatment may be monitored by determining the severity of their symptoms or by determining the frequency of autoreactive T cells in a sample from the individual. The severity of symptoms of CIDP may correlate with the number of autoreactive T cells. In addition, an increase in the number of autoreactive T cells in the sample may be used as an indication to apply treatments intended to minimize the severity of the symptoms and / or treat CIDP before the symptoms appear. As another example, the effectiveness of a composition disclosed herein in treating a symptom of CIDP can be determined by relying on the clinical experience with existing T cell infusion therapies. An improvement in CIDP also can be indicated by a reduced need for a concurrent therapy. Those of skill in the art will know the appropriate symptoms or indicators associated with CIDP and will know how to determine if an individual is a candidate for treatment as disclosed herein. The condition of the individual can be monitored throughout the course of therapy and that the effective amount of a compound or composition disclosed herein that is administered can be adjusted accordingly.

[0133] In some embodiments, a therapeutically effective amount of a composition disclosed herein reduces a symptom associated with CIDP by, e.g., at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 100%. In some embodiments, a therapeutically effective amount of a composition disclosed herein reduces a symptom associated with CIDP by, e.g., at most 10%, at most 20%, at most 30%, at most 40%, at most 50%, at most 60%, at most 70%, at most 80%, at most % or at most 100%. In some embodiments, a therapeutically effective amount of a composition disclosed herein reduces a symptom associated with CIDP by, e.g., about 10% to about 100%. about 10% to about 90%, about 10% to about 80%, about 10% to about %, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 20% to about 100%, about 20% to about 90%, about 20% to about 80%, about 20% to about 20%, about 20% to about %, about 20% to about 50%. about 20% to about 40%, about 30% to about 100%, about 30% to about %, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%. or about 30% to about 50%. In some embodiments, a therapeutically effective amount of a composition disclosed 60#607131Attorney Docket No. 00013.007.1801herein is a dosage sufficient to reduces a symptom associated with CIDP for. e.g, at least one week, at least one month, at least two months, at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, at least twelve months, or more. In some embodiments, a composition disclosed herein is administered to the subject at a dose of about 150 mg / kg. In some embodiments, a composition disclosed herein is administered to the subject weekly or bi-weekly.Combination Therapy

[0134] Disclosed herein, in some embodiments, are methods of treating Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) in an individual in need thereof. In some embodiments, the method comprises combing a composition disclosed herein in combination with one or more (e.g., 1, 2, 3, 4, 5 or more) additional therapeutic agents or modalities for treatment of a disease or disorder described herein (e.g., an autoimmune disorder, such as an autoimmune disease or disorder).

[0135] In some embodiments, the one or more additional therapeutic agents is a second modified Fc polypeptide. In some embodiments, the second modified Fc polypeptide is a human IgGl Fc polypeptide. In some embodiments, the second modified Fc polypeptide comprises one or more (e.g., 1, 2, 3, 4, or 5) mutations selected from the group consisting of M252Y, S254T, T256E. H433K, and N434F (numbered according to the EU index of Kabat; also known as “Abdeg’’ mutations; see also bolded and underlined residues of SEQ ID NO: 5, below). IgGl Fes containing Abdeg mutations 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 second modified Fc polypeptide comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 5.DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWY VDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENN YKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALKFHYTQKSLSLSPG(SEQ ID NO: 5)*Bolded and underlined amino acid residues correspond to Abdeg mutations (M252Y, S254T, T256E, H433K, and N434F).61#607131Attorney Docket No. 00013.007.1801

[0136] In some embodiments, the Fc polypeptide of the disclosure is co-administered to a subject (e.g, sequentially or simultaneously) with the second modified Fc polypeptide of SEQ ID NO: 5.

[0137] In some embodiments, the one or more additional therapeutic agents is selected from the group consisting of an anti-inflammatory agent, immuno-suppressive agent, physical therapy, plasma exchange, or any combination thereof. In some embodiments, the antiinflammatory agent is selected from the group consisting of a corticosteroid, a nonsteroidal anti-inflammatory medication (NS AID), anti-inflammatory antibody or an antigen-binding fragment thereof, anti-inflammatory cytokine, kinase inhibitor, IVIG, a FcRN inhibitor, a complement inhibitor, or any combination thereof. In some embodiments, the one or more additional therapeutic agents is prednisone, prednisolone, methylprednisolone, methotrexate, hydroxychloroquine, sulfasalazine, leflunomide, cyclophosphamide, azathioprine, or a biologic such as tofacitinib, adalimumab, abatacept, anakinra, kineret, certolizumab, etanercept, golimumab, infliximab, rituximab, efgartigimod, batoclimab, nipocalimab, riliprubart, empasiprubart, or tocilizumab.

[0138] Plasma exchange (plasmapheresis) involves the separation of plasma from blood, the removal of autoreactive antibodies in the plasma, and then the return of the treated plasma and blood to the body. Plasma exchange is typically only effective for a few weeks. You may need continued intermittent (on-and-off) treatments over the course of months or years.

[0139] In some embodiments, a composition of the disclosure is administered alone or in combination with the additional therapeutic agent either simultaneously or sequentially dependent upon the condition to be treated. When two or more compositions are administered, the compositions are, e.g. , administered in combination (either sequentially or simultaneously). In some embodiments, the one or more additional therapeutic agents are administered immediately before or after the composition, or 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 18 hours, 1 day, 2 days, 3 days, 4 days, one week, two weeks, 1 month, or more before or after administration of the composition. In some embodiments, a composition is administered in a single dose or multiple doses.OTHER EMBODIMENTS

[0140] Various modifications and variations of the described disclosure will be apparent to those skilled in the art without departing from the scope and spirit of the disclosure. Although the disclosure has been described in connection with specific embodiments, it should be understood that the disclosure as claimed should not be unduly limited to such specific 62#607131Attorney Docket No. 00013.007.1801embodiments. Indeed, various modifications of the described modes for carrying out the disclosure that are obvious to those skilled in the art are intended to be within the scope of the disclosure. Other embodiments are in the claims.EXAMPLES

[0141] 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: AMANI Mouse Model of GBS

[0142] This study evaluates NVG-2089 in the anti-ganglioside antibody-mediated axonal nerve injury (AMANI) model, comparing it to IVIg. The AMANI model is considered representative of Guillain-Barre syndrome (GBS), the acute form of CIDP, in humans and provides a well characterized system to study regeneration of axons after injury. Adult (8-12 week old) wild-type C57BL / 6 mice received NVG-2089, IVIg, or PBS placebo, followed by behavioral, electrophysiological, and morphometric analyses.

[0143] Submandibular blood collection from study mice was taken at day -3. On Day -1, Sciatic Conduction Nerve Tests and Pinprick Behavioral Assessments were conducted on the study mice. Model mice were generated by crushing the left sciatic nerve at the middle thigh (Day 0) followed by administration of a composition comprising an anti-ganglioside antibody on Day 3. On Day 4, PBS (control), IVIg (1 g / kg) or NVG-2089 (100 mg / kg) was administered to the study mice and blood was collected. On Day 5, a Pinprick Assessment was conducted on the study mice. On Day 6, Sciatic Conduction Nerve Tests were conducted on the study mice. On Day 7, submandibular blood was collected from the study mice. On Day 8, a Pinprick Behavioral Assessment was conducted on the study mice. On Day 9, PBS (control), IVIg or NVG-2089 was administered to the study mice. On Day 12, a Pinprick Behavioral Assessment was conducted on the study mice. On Day 13, PBS (control), IVIg or NVG-2089 was administered to the study mice and Sciatic Conduction Nerve Tests were conducted. On Day 14, PBS (control), IVIg or NVG-2089 was administered to the study mice and blood was collected. On Day 16, Sciatic Conduction Nerve Tests and Pinprick Behavioral Assessments were conducted on the study mice. On Day 18. Pinprick Behavioral Assessments were63#607131Attorney Docket No. 00013.007.1801conducted on the study mice. Finally, on Day 19 Sciatic Conduction Nerve Tests were conducted on the study mice.

[0144] Pinprick Behavioral Assessments were performed on the days indicated above to evaluate sensory functional recovery. The needle was gently applied to the lateral part of the plantar surface of the hind paw and the animal responses to the needle prick were recorded. The Pinprick Behavioral Assessments were performed blindly.

[0145] The Sciatic Conduction Nerve Tests were performed on the days indicated above to monitor motor function recovery. Mice were anesthetized and placed on a heating pad and their body temperature was monitored and maintained at 35-37 °C. Compound muscle action potential (CMAP) amplitude was recorded from the hind paw with needle electrodes inserted in the sole of the foot and sciatic and tibial nerves were stimulated proximally at the sciatic notch.

[0146] Following termination of the experiment on day 19, animals were perfused and sciatic and tibial nerves were harvested for morphometric analysis. The harvested sciatic and tibial nerves were post fixed in a mixture of 3% glutaraldehyde and 4% paraformaldehyde. The fixed nerves were embedded in Epon and stained with toluidine blue. All myelinated axons in a single, whole transverse section of the nerve were counted by using a motorized stage and stereotactic imaging software. Sciatic nene distal sections were stained and analyzed by microscopy to detect CD68 positive macrophage cells.

[0147] Both NVG-2089 and IVIg significantly improved nerve function. Nerve conduction studies (FIG. 1A) revealed higher compound muscle action potential (CMAP) amplitudes in treated animals compared to controls. Behavioral assessments showed restored pinprick responses by day 8 post-injury in both treatment groups (FIG. IB). Morphometric analysis demonstrated increased myelinated fiber counts in the tibial nerves of NVG-2089 and IVIg-treated animals (FIG.2) and a reduction of CD68 positive cells in NVG-2089 and IVIg-treated animals compared to PBS-treated animals (FIG.3). Notably, NVG-2089 achieved comparable efficacy to IVIg at one-tenth the dose.

[0148] NVG-2089 exhibits strong neuroprotective effects in the AMANI model, comparable to IVIg, but with a substantially lower dosage requirement. These findings position NVG-2089 as a promising alternative to IVIg for treating CIDP, potentially addressing current treatment limitations.Example 2: Prophetic Clinical Trial in Human Patients with CIDPProposed Indication64#607131Attorney Docket No. 00013.007.1801

[0149] The proposed initial indication for NVG-2089 is for the treatment of CIDP in adults. This is an open-label study in participants with CIDP who are being treated with IVIg / SCIg at the time of screening (Cohorts 1 and 2; treatment-experienced) or are treatment-naive (Cohort 3).Study Drug

[0150] NVG-2089 is a recombinant human immunoglobulin Gl(IgGl) Fc-domain homodimer that contains a single point mutation (F241A). The Fc-domain is further modified to contain high levels of 2,6-sialylation at Asn297. Details on administration of NVG-2089 are summarized in Table 1.Table 1. Study Drug AdministeredPrimary Ob Jedi ve / Endpoinls

[0151] To evaluate the safety and tolerability of NVG-2089 in participants with CIDP:• Incidence, nature, and severity of treatment-emergent adverse events (TEAEs), and serious adverse events (SAEs).• Clinically significant findings of laboratory, vital signs, electrocardiogram, and physical examinations.Key Secondary Objective / Endpoints

[0152] To evaluate the efficacy of NVG-2089 in participants with CIDP:• Treatment-naive Participants:

[0153] Percentage of participants with evidence of clinical improvement (ECI) at Week 14. ECI is defined as improvement of 1 point on the adjusted Inflammatory Neuropathy Cause and Treatment (adjusted INCAT) score, or 4 points on Inflammatory' Rasch-built Overall Disability7Scale (I-RODS) or 8 kilopascals (kPa) on mean grip strength (dominant hand).• Treatment-experienced Participants:

[0154] Percentage of participants who meet any of the following conditions:65#607131Attorney Docket No. 00013.007.1801

[0155] Achieving ECI at Week 14; No worsening in adjusted INCAT between Weeks 4 and 14; Worsening in adjusted INCAT between Day 1 and Week 4 (and have not received rescue medication) followed by an improvement to baseline by Week 4 and maintained through Week 14. Worsening is defined as an increase in the adjusted INCAT score of at least 1 point. A worsening by 1 point requires confirmation within 1 week; no confirmation is required for a worsening that is at least 2 points.

[0156] Percentage of participants who meet any of the following conditions: No worsening in adjusted INCAT between Weeks 4 and 14; Worsening in adjusted INCAT between Day 1 and Week 4 (and have not received rescue medication) followed by an improvement to baseline by Week 4 and maintained through Week 14.

[0157] Percentage of participants with ECI at Week 14.Secondary Objective' 'Endpoints• To further evaluate the efficacy of NVG-2089 in participants with CIDP:

[0158] Change from baseline overtime in: Adjusted INCAT score; Medical Research Council (MRC) sum score; I-RODS disability scores; mean grip strength.• To characterize the PK profile of NVG-2089 in participants with CIDP:

[0159] The PK parameters of NVG-2089 concentrations in plasma.• To evaluate the immunogenicity of NVG-2089 and the impact of the presence of antidrug antibodies (AD As) on plasma PK concentrations and clinical safety:

[0160] Incidence and characteristics of ADA after dosing.

[0161] PK concentrations and safety profile in participants with ADA.Study Design

[0162] Study schema is provided in FIG. 4.

[0163] After signing the informed consent form (ICF), participants will undergo screening procedures over a period of up to 6 weeks. Eligible participants must have history' and documentation of disease activity during the screening period.

[0164] There will be 3 cohorts, with 2 sequential cohorts (Cohorts 1 and 2, treatment-experienced with IVIg / SCIg) and a parallel cohort (Cohort 3, treatment-naive) which will enroll concurrently to both Cohorts 1 and 2. Within each dose cohort, on Day 1, eligible participants will enter a 14-week treatment period and initiate treatment with NVG-2089. Participants in Cohorts 1 and 3 will receive NVG-2089 every 2 weeks (Q2W) at Weeks 0, 2, 4, 6, 8. 10 and 12 for a total of 7 doses. All participants will be followed-up for 2 weeks post last treatment period visit (4 weeks post last dose of NVG-2089). In addition, participants will 66#607131Attorney Docket No. 00013.007.1801be contacted by phone at Week 20 for a safety follow-up (8 weeks after last dose of NVG-2089).Table 2. Cohorts

[0165] The Safety Monitoring Committee (“SMC”) will evaluate all available safety data (and PK data, if available) after approximately 10 participants in Cohort 1 have been followed for at least 7 days after receiving the third dose of NVG-2089 (Day 36). The SMC will assess safety, and any modification to monitoring or assessments is required to maintain participant safety as well as provide a recommendation for the next NVG-2089 dose. The Sponsor will determine NVG-2089 dosage for the next cohort based on SMC recommendation and review of available efficacy data from Cohort 1 and Cohort 3 (if available). The Sponsor will proceed to open Cohort 2 based on acceptable safety and efficacy profile from Cohort 1 that a dose exploration is warranted. Participants in Cohort 2 will initiate treatment after the last participant has been treated (with at least 1 dose with NVG-2089) in Cohort 1. The SMC will also be convened if a safety concern arises.

[0166] Participants who receive > 1 dose of NVG-2089 will be encouraged to complete all study visits. If participants do not complete all study visits, or terminate early from the study, they will be asked to return to the study site for an Early Termination (ET) visit within 7 days of their decision to w ithdraw their participation from the study.Inclusion Criteria

[0167] Males and females at least 18 years of age at the time of signing the ICF.

[0168] Diagnosed with CIDP or Possible CIDP according to criteria of the EAN / PNS 2021 (Van den Bergh, 2021). (Diagnosis is to be confirmed by an independent adjudication committee).

[0169] Must have an adjusted INCAT score as follows:• Treatment-naive participants: >2 at screening.• Treatment-experienced participants: 2-7 at screening.

[0170] Note: A score of 2 should be exclusively from leg disability component of adjusted INCAT. For participants with an adjusted INCAT score of >3 (and up to 7 for treatment-67#607131Attorney Docket No. 00013.007.1801experienced; no upper limit for treatment-naive) at study entry, there are no specific requirements for arm or leg scores.

[0171] Treatment-experienced participants: Participants who were treated with IVIg / SCIg at the time of screening must have documented evidence within 24 months of screening of:• Clinically meaningful deterioration on treatment interruption or dose reduction of standard of care (SOC) therapy, determined by clinical examination documented in the medical records. Clinically meaningful deterioration is defined as one of the following: >1 -point increase in adjusted INCAT score, decrease in I-RODS total score >4 points, decrease in MRC Sum score >3, grip strength worsening of >8 kPa (in either hand), or an equivalent deterioration based on information from medical records and at the investigator’s judgement.

[0172] OR• Improvement in CIDP symptoms with SOC therapy based on information in medical records and at the investigator's judgement.

[0173] Treatments:• Treatment-naive participants: No prior treatment with IVIg and / or SCIg and / or corticosteroids and / or investigational therapies for CIDP.

[0174] OR• Treatment-experienced participants: On stable dose of IVIg or SCIg with no disease exacerbations for 8 weeks prior to screening. Participants must be willing to discontinue IVIg or SCIg at least 3 weeks (±1 week) prior to dosing with the study drug. Participants on IVIg must be on maintenance dose of 0.4 to 1 g / kg every 2 to 6 weeks per EAN / PNS recommendation. Participants on SCIg should not exceed the dose of 0.4 g / kg per week.

[0175] Reproductive Considerations:

[0176] Female participants of childbearing potential must have a negative serum pregnancy test at Screening and a negative urine pregnancy test on Day 1.

[0177] Female participants who are sexually active with a male partner of reproductive potential must use double contraception (including a barrier contraceptive and another method) from at least 28 days prior to Screening and for 90 days after last dose of study drug; female participants must also refrain from oocyte donation for the purpose of reproduction during this period. Exceptions are made for surgically sterile participants, or post-menopausal females (defined as 12 months of spontaneous amenorrhea or 6 months of spontaneous amenorrhea with serum follicle stimulating hormone levels >40 mIU / mL or 6 weeks postsurgical bilateral 68#607131Attorney Docket No. 00013.007.1801oophorectomy with or without hysterectomy). Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the participant.

[0178] Male participants with female partners who are of reproductive potential must agree to the use of highly effective, barrier contraception for the duration of the study, and for 90 days after the last dose of study drug.

[0179] Informed Consent:

[0180] Participant is capable or has (a) legally authorized representative(s) (LAR[s]) capable of providing a signed informed consent which includes compliance with the requirements and restrictions listed in the ICF.Exclusion Criteria

[0181] Pure sensory or distal CIDP variants (EAN / PNS definition).

[0182] History of being non-responder or loss of response to IVIg or SCIg per Investigator’s determination. Note, participants who are on IVIg but relapsed on SCIg will be allowed to enter the study.

[0183] Polyneuropathy of other causes, including the following: multifocal motor neuropathy; polyneuropathy associated with anti-myelin associated glycoprotein (MAG) antibodies, polyneuropathy associated with IgM monoclonal gammopathy; hereditary demyelinating neuropathy; polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin change syndromes (POEMS); lumbosacral radiculoplexus neuropathy; polyneuropathy most likely due to diabetes mellitus; polyneuropathy most likely due to systemic illnesses; drug- or toxin-induced polyneuropathy.

[0184] Any other disease that could better explain the participant's signs and symptoms.

[0185] Any history of myelopathy or evidence of central demyelination.

[0186] Any other known autoimmune disease that, in the opinion of the investigator, would interfere with an accurate assessment of clinical symptoms of CIDP.

[0187] Severe psychiatric disorder (such as severe depression, psychosis, bipolar disorder), history of suicide attempt, or current suicidal ideation that in the opinion of the investigator could create undue risk to the patient or could affect adherence with the study protocol.

[0188] Active liver disease, with history of ascites or hepatic encephalopathy, total bilirubin > 2 mg / dL (except in the case of documented Gilbert’s disease), or transaminases > 2 X ULN at screening.

[0189] Hematology' abnormalities at screening including: hemoglobin < 10 g / dL in males and <9 g / dL in females, or neutrophils < 1.5 * 109 / L, or platelets <100 x 109 / L.

[0190] Glycated hemoglobin (HbAlc) >7.5%.69#607131Attorney Docket No. 00013.007.1801

[0191] Chronic kidney disease as defined by estimated glomerular filtration rate (eGFR) <50 mL / min / 1.73 m2 at screening.

[0192] History of malignancy except adequately treated basal cell or squamous cell skin cancer, Carcinoma in situ of the cervix, Carcinoma in situ of the breast, or Incidental histological finding of Prostate cancer (TNM [tumor, nodes, and metastases classification] stage Tla or Tib). The above malignancies must be deemed cured by adequate treatment with no evidence of recurrence for at least 3 years prior to screening.

[0193] Cardiac insufficiency (New York Heart Association III / IV), cardiomyopathy, or unstable or advanced ischemic heart disease, clinically significant cardiac dysrhythmia and / or clinically significant ECG findings at screening.

[0194] Clinically significant active or chronic uncontrolled bacterial, viral, or fungal infection at screening, including active viral infection at screening with: Active Hepatitis B Virus (HBV): Hepatitis surface antigen (HBsAg) positive; Active Hepatitis C Virus (HCV): serology positive for HCV-Ab; Human Immunodeficiency Virus (HIV) positive serology.

[0195] Clinical evidence of other significant serious disease, recent or planned major surgery, or any other reason which could confound the results of the study or put the participant at undue risk.

[0196] Prior Therapy - the following therapies are excluded:• Within 1 month before screening: Prednisone or systemic corticosteroids• Within 3 months (or 5 half-lives of the drug, whichever is longer) before screening:plasma exchange or immunoadsorption, any Fc-containing therapeutic agents or other biological, or any other investigational or approved product.• Within 6 months before screening: rituximab, alemtuzumab, any other monoclonal antibody, cyclophosphamide, interferon, tumor necrosis factor-alpha inhibitors, fingolimod, methotrexate, azathioprine, my cophenol ate, any other immunomodulating or immunosuppressive medications.

[0197] Participants who (intend to) use prohibited medications and therapies during the study.

[0198] Have received a live-attenuated vaccine within 28 days before screening. An inactivated, sub-unit, polysaccharide, or conjugate vaccine any time before screening is not exclusionary .

[0199] Previously participated in a study with NVG-2089 and have received at least one administration of study drug.

[0200] A known allergy to study drug and / or any of its components.70#607131Attorney Docket No. 00013.007.1801

[0201] Current or past history (within 12 months of screening) of alcohol, drug, or medication abuse. Positive urine drug screen at screening visit.

[0202] Pregnant and lactating women and those intending to become pregnant during the study or are unwilling to apply an effective birth control method (such as implants, injectables, combined oral contraceptives, intrauterine devices [IUDs], sexual abstinence, or vasectomized partner) up to 90 days after last study drug administration.Pharmacokinetics

[0203] Blood samples for determination of plasma concentrations of NVG-2089, will be collected at the timepoints described in Table 3. The actual 24-clock time and calendar date of each sample collection will be recorded.

[0204] Plasma concentrations of NVG-2089 will be measured by a specific and validated liquid chromatography-tandem mass spectroscopy (LC-MS / MS) method.Table 3. Blood Sample Collection TimepointsBiomarkers

[0205] Blood samples will be collected and analyzed for biomarkers including but not limited to neurofilament light chain, serum immunoglobulin levels autoantibodies (including neurofascin or contactin- 1), changes in serum cytokine concentrations and other serum protein markers of inflammation. Refer to the relevant SoA for the collection timepoints.

[0206] Immunoglobulin: Blood samples will be collected and analyzed for circulating IgG.

[0207] PBMC (substudy at selected sites): Blood samples will be collected for assessment of immune phenotype changes.

[0208] Flow cytometry analysis: Whole blood will be assessed by flow cytometry to evaluate treatment-induced changes in the number and functional activation status of regulatory T cells, as well as cell surface expression of activating and inhibitors' Type I and Type II Fc receptors.71#607131Attorney Docket No. 00013.007.1801These are exploratory endpoints designed to assess the potential effect of NVG-2089 on the activation potential of immune cell subpopulations.#607131

Claims

Attorney Docket No. 00013.007.1801CLAIMS1. A method of treating chronic inflammatory demyelinating polyneuropathy (CIDP) in a human subject in need thereof, comprising: administering to the subject a therapeutically effective amount of a population of modified Fc polypeptides, or a pharmaceutical composition thereof, each modified Fc polypeptide having (i) an amino acid sequence at least 75% identical to the sequence of SEQ ID NO: 2 and (ii) an aliphatic amino acid residue at position 241 (numbered according to Kabat; corresponding to amino acid residue 32 of SEQ ID NO: 2) or an aliphatic amino acid residue at position 243 (numbered according to Kabat; corresponding to amino acid residue 34 of SEQ ID NO: 2), the population comprising: at least 50% of the modified Fc polypeptides having a sialic acid (SA) moiety attached to an N-glycan of the Fc polypeptide via an a(2,6) linkage.

2. A method of treating chronic inflammatory demyelinating polyneuropathy (CIDP) in a human subject in need thereof, comprising: administering to the subject a therapeutically effective amount of a population of modified Fc polypeptides, or a pharmaceutical composition thereof, each modified Fc polypeptide having (i) an amino acid sequence at least 75% identical to the sequence of SEQ ID NO: 12 and (ii) an aliphatic amino acid residue at position 241 (numbered according to Kabat corresponding to amino acid residue 32 of SEQ ID NO: 12) or an aliphatic amino acid residue at position 243 (numbered according to Kabat; corresponding to amino acid residue 34 of SEQ ID NO: 12), the population comprising: at least 50% of the modified Fc polypeptides having a sialic acid (SA) moiety attached to an N-glycan of the Fc polypeptide via an a(2,6) linkage.

3. The method of claim 1 or 2, wherein: (a) the aliphatic amino acid residue at position 241 is an alanine (Ala; F241A) or a leucine (Leu; F241L); or (b) the aliphatic amino acid residue at position 243 is an alanine (Ala; F243A) or a leucine (Leu; F243L).

4. The method of any one of claims 1 -3, wherein the N-glycan is attached to the asparagine (Asn) at amino acid residue 297 of the polypeptide (Asn297; numbered according to Kabat; corresponding to amino acid residue 88 of SEQ ID NO: 2 or SEQ ID NO: 12).

5. The method of any one of claims 1-4, wherein at least 60% of the modified Fc polypeptides comprise the SA moiety attached to the N-glycan of the modified Fc polypeptides via the a(2.6) linkage.73#607131Attorney Docket No. 00013.007.18016. The method of any one of claims 1-5, wherein at least 70% of the modified Fc polypeptides comprise the SA moiety attached to the N-glycan of the modified Fc polypeptides via the a(2,6) linkage.

7. The method of any one of claims 1-6, wherein at least 80% of the modified Fc polypeptides comprise the SA moiety attached to the N-glycan of the modified Fc polypeptides via the a(2.6) linkage.

8. The method of any one of claims 1-7, wherein at least 90% of the modified Fc polypeptides comprise the SA moiety attached to the N-glycan of the modified Fc polypeptides via the a(2,6) linkage.

9. The method of any one of claims 1-8, wherein the N-glycan of the modified Fc polypeptides is mono-sialylated or di-sialylated.

10. The method of claim 9, wherein at least 30% of the modified Fc polypeptides comprise mono-sialylated N-glycans comprising a SA moiety7attached via the a(2,6) linkage.

11. The method of claim 9 or 10, wherein at least 40% of the modified Fc polypeptides comprise mono-sialylated N-glycans comprising a SA moiety7attached via the a(2,6) linkage.

12. The method of any one of claims 9-1 1, wherein at least 50% of the modified Fc polypeptides comprise mono-sialylated N-glycans comprising a SA moiety7attached via the a(2,6) linkage.

13. The method of any one of claims 9-11, wherein at least 60% of the modified Fc polypeptides comprise mono-sialylated N-glycans comprising a SA moiety attached via the a(2,6) linkage.

14. The method of any one of claims 9-13, wherein at least 70% of the modified Fc polypeptides comprise mono-sialylated N-glycans comprising a SA moiety attached via the a(2,6) linkage.

15. The method of any one of claims 9-14, wherein at least 80% of the modified Fc polypeptides comprise mono-sialylated N-glycans comprising a SA moiety attached via the a(2,6) linkage.74#607131Attorney Docket No. 00013.007.180116. The method of any one of claims 9-15, wherein at least 90% of the modified Fc polypeptides comprise mono-sialylated N-glycans comprising a SA moiety attached via the a(2,6) linkage.

17. The method of claim 9, wherein at least 30% of the modified Fc polypeptides comprise di-sialylated N-glycans comprising two SA moieties attached via the a(2,6) linkage.

18. The method of claim 9 or claim 17. wherein at least 40% of the modified Fc polypeptides comprise di-sialylated N-glycans comprising two SA moieties attached via the a(2,6) linkage.

19. The method of claim 9 or any one of claims 17-18, wherein at least 50% of the modified Fc polypeptides comprise di-sialylated N-glycans comprising two SA moieties attached via the a(2,6) linkage.

20. The method of claim 9 or any one of claims 17-19, wherein at least 60% of the modified Fc polypeptides comprise di-sialylated N-glycans comprising two SA moieties attached via the a(2,6) linkage.

21. The method of claim 9 or any one of claims 17-20, wherein at least 70% of the modified Fc polypeptides comprise di-sialylated N-glycans comprising two SA moieties attached viathe a(2,6) linkage.

22. The method of claim 9 or any one of claims 17-21, wherein at least 80% of the modified Fc polypeptides comprise di-sialylated N-glycans comprising two SA moieties attached viathe a(2,6) linkage.

23. The method of claim 9 or any one of claims 17-22, wherein about 90% of the modified Fc polypeptides comprise di-sialylated N-glycans comprising two SA moieties attached viathe a(2,6) linkage.

24. The method of any one of claims 1-23, wherein at least about 60% of the modified Fc polypeptides comprise a galactose moiety.75#607131Attorney Docket No. 00013.007.180125. The method of any one of claims 1-24, wherein at least about 70% of the modified Fc polypeptides comprise a galactose moiety.

26. The method of any one of claims 1-25, wherein at least about 80% of the modified Fc polypeptides comprise a galactose moiety.

27. The method of any one of claims 1-26, wherein at least about 90% of the modified Fc polypeptides comprise a galactose moiety.

28. The method of any one of claims 1-27, wherein about 100% of the modified Fc polypeptides comprise a galactose moiety.

29. The method of any one of claims 24-28, wherein the galactose moiety is attached to an a(l,3) arm and / or a(l,6) arm of the N-glycan.

30. The method of any one of claims 24-29, wherein the galactose moiety is a branched galactose moiety.

31. A method of treating chronic inflammatory demyelinating polyneuropathy (CIDP) in a human in need thereof, comprising: administering to the human subject a therapeutically effective amount of a population of modified Fc polypeptides, or a pharmaceutical composition thereof, each modified Fc polypeptide having (i) an amino acid sequence at least 75% identical to the sequence of SEQ ID NO: 2 and (ii) an aliphatic amino acid residue at position 241 (numbered according to Kabat; corresponding to amino acid residue 32 of SEQ ID NO: 2) or an aliphatic amino acid residue at position 243 (numbered according to Kabat; corresponding to amino acid residue 34 of SEQ ID NO: 2), the population comprising: no more than about 40% of the modified Fc polypeptides having a SA moiety attached to the N-glycan of the Fc polypeptide via an a(2,3) linkage.

32. A method of treating chronic inflammatory demyelinating polyneuropathy (CIDP) in a human in need thereof, comprising: administering to the human subject a therapeutically effective amount of a population of modified Fc polypeptides, or a pharmaceutical composition thereof, each modified Fc polypeptide having (i) an amino acid sequence at least 75% identical to the sequence of SEQ ID NO: 12 and (ii) an aliphatic amino acid residue at position 24176#607131Attorney Docket No. 00013.007.1801(numbered according to Kabat; corresponding to amino acid residue 32 of SEQ ID NO: 12) or an aliphatic amino acid residue at position 243 (numbered according to Kabat; corresponding to amino acid residue 34 of SEQ ID NO: 12), the population comprising: no more than about 40% of the modified Fc polypeptides having a SA moiety attached to the N-glycan of the Fc polypeptide via an a(2,3) linkage.

33. The method of claim 31 or 32, wherein: (a) the aliphatic amino acid residue at position 241 is an Ala (F241 A) or aLeu (F241L); or (b) the aliphatic amino acid residue at position 243 is an Ala (F243A) or a Leu (F243L).

34. The method of any one of claims 1-33. wherein the modified Fc polypeptides are IgGl Fc polypeptides.

35. The method of any one of claims 1-33, wherein the modified Fc polypeptides are IgG3 Fc polypeptides.

36. The method of any one of claims 1-35, further comprising administration of an additional therapeutic agent to the human subject.

37. The method of claim 36, wherein the additional therapeutic agent is administered to the human subject prior to, concurrently with, or subsequent to administration of the population or the pharmaceutical composition.

38. The method of any one of claims 36-37, wherein the additional therapeutic agent is selected from the group consisting of an anti-inflammatory agent, an immuno-suppressive agent, physical therapy, or plasma exchange.

39. The method of claim 38, wherein the anti-inflammatory agent is selected from the group consisting of non-steroidal anti-inflammatory drug (NS AID), corticosteroid, anti-inflammatory antibody or an antigen-binding fragment thereof, anti-inflammatory cytokine, kinase inhibitor, and intravenous immunoglobulin (IVIG).

40. A population of modified Fc polypeptides, or a pharmaceutical composition thereof, each modified Fc polypeptide having (i) an amino acid sequence at least 75% identical to the sequence of SEQ ID NO: 2 and (ii) an aliphatic amino acid residue at position 241 (numbered 77#607131Attorney Docket No. 00013.007.1801according to Kabat; corresponding to amino acid residue 32 of SEQ ID NO: 2) or an aliphatic amino acid residue at position 243 (numbered according to Kabat; corresponding to amino acid residue 34 of SEQ ID NO: 2), the population comprising: at least 50% of the modified Fc polypeptides having a sialic acid (SA) moiety attached to an N-glycan of the Fc polypeptide via an a(2,6) linkage, for use as a medicament for the treatment of CIDP in a human subject in need thereof.

41. A population of modified Fc polypeptides, or a pharmaceutical composition thereof, each modified Fc polypeptide having (i) an amino acid sequence at least 75% identical to the sequence of SEQ ID NO: 2 and (ii) an aliphatic amino acid residue at position 241 (numbered according to Kabat; corresponding to amino acid residue 32 of SEQ ID NO: 2) or an aliphatic amino acid residue at position 243 (numbered according to Kabat; corresponding to amino acid residue 34 of SEQ ID NO: 2), the population comprising: at least 50% of the modified Fc polypeptides having a sialic acid (SA) moiety attached to an N-glycan of the Fc polypeptide via an ot(2,6) linkage, for use in the treatment of CIDP in a human subject in need thereof.

42. A population of modified Fc polypeptides, or a pharmaceutical composition thereof, each modified Fc polypeptide having (i) an amino acid sequence at least 75% identical to the sequence of SEQ ID NO: 12 and (ii) an aliphatic amino acid residue at position 241 (numbered according to Kabat; corresponding to amino acid residue 32 of SEQ ID NO: 12) or an aliphatic amino acid residue at position 243 (numbered according to Kabat; corresponding to amino acid residue 34 of SEQ ID NO: 12). the population comprising: at least 50% of the modified Fc polypeptides having a sialic acid (SA) moiety attached to an N-glycan of the Fc polypeptide via an a(2,6) linkage, for use as a medicament for the treatment of CIDP in a human subject in need thereof.

43. A population of modified Fc polypeptides, or a pharmaceutical composition thereof, each modified Fc polypeptide having (i) an amino acid sequence at least 75% identical to the sequence of SEQ ID NO: 12 and (ii) an aliphatic amino acid residue at position 241 (numbered according to Kabat; corresponding to amino acid residue 32 of SEQ ID NO: 12) or an aliphatic amino acid residue at position 243 (numbered according to Kabat; corresponding to amino acid residue 34 of SEQ ID NO: 12), the population comprising: at least 50% of the modified Fc polypeptides having a sialic acid (SA) moiety attached to an N-glycan of the Fc polypeptide via an a(2,6) linkage, for use in the treatment of CIDP in a human subject in need thereof.78#607131

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