WO2024091999A1

WO2024091999A1 - Variant igg fc polypeptides and uses thereof

Info

Publication number: WO2024091999A1
Application number: PCT/US2023/077719
Authority: WO
Inventors: Nathan HIGGINSON-SCOTT; Daniela CIPOLLETTA; Yanfeng ZHOU; Timothy A. Springer; Kevin Lewis Otipoby
Original assignee: Seismic Therapeutic, Inc.
Priority date: 2022-10-25
Filing date: 2023-10-25
Publication date: 2024-05-02

Abstract

Embodiments provided herein, provide for variant IgG Fc polypeptides, dimeric molecules, pharmaceutical compositions, and methods that can be used to target at cells to modulate the activity of the same to treat disorders, such as autoimmune disorders or cancers.

Description

VARIANT IgG FC POLYPEPTIDES AND USES THEREOF

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No. 63/380,835, filed October 25, 2022, and U.S. Provisional Application No. 63/380,846, filed October 25, 2022, each of which is hereby incorporated by reference in its entirety.

REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY

The instant application contains a Sequence Listing which has been submitted electronically in XML file format and is hereby incorporated by reference in its entirety. Said XML copy, created on October 24, 2023, is named “SES-004WO_SEQ.XML” and is 38,555 bytes in size.

FIELD

The embodiments provided herein relate to compositions targeting cells to regulate an immune response.

BACKGROUND

FcyRIip is the only FcyR expressed on B cells (Smith, K. G. C., and Clatworthy, M. R., Nat Rev Immunol. 2010 May; 10(5): 328-343). Interaction of the antibody Fc region with FcyRIip has been reported to suppress the primary immune response of B cells (Smith, K. G. C., and Clatworthy, M. R., Nat Rev Immunol. 2010 May; 10(5): 328-343). Furthermore, it is reported that when FcyRIip on B cells and a B cell receptor (BCR) are cross-linked via an immune complex in blood, B cell activation is suppressed, and antibody production by B cells is suppressed IgGl, mainly used as a commercially available therapeutic antibody, is known to bind not only to FcyRIip, but also strongly to activating FcyR. It may be possible to develop therapeutic antibodies having greater immunosuppressive properties compared with those of IgGl, by utilizing an Fc region with enhanced FcyRIip binding, or improved FcyRIip-binding selectivity compared with activating FcyR. Accordingly, an antibody having an Fc with improved FcyRIip-binding activity is suggested to be promising as a therapeutic agent for inflammatory diseases such as autoimmune diseases. The embodiments provided for herein fulfill these needs as well as others. SUMMARY

In some embodiments, variant IgG Fc polypeptides that selectively bind to FcyRIip over FcyRIIa, wherein the variant IgG Fc polypeptide comprises a mutation selected from a mutation associated with any of VFC-1 to VFC-6, are provided.

In some embodiments, variant IgG Fc polypeptides comprising an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the variant IgG Fc polypeptide comprises: a deletion of amino acid Pro at position 238, as compared to SEQ ID NO: 7; a deletion of amino acid Gly at position 237, and a mutation of P238D, as compared to SEQ ID NO: 7; an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7; a mutation set of L234G, G236L, P238G, and an insertion of amino acid Asp between positions P238 and S239 as compared to SEQ ID NO: 7; a mutation set of L234G, G236L, and an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; or any combination thereof, are provided.

In some embodiments, variant IgG Fc polypeptides comprising a variant sequence of SEQ ID NO: 7, wherein the variant IgG Fc polypeptide comprises: a deletion of amino acid Pro at position 238, as compared to SEQ ID NO: 7; a deletion of amino acid Gly at position 237, and a mutation of P238D, as compared to SEQ ID NO: 7; an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7; a mutation set of L234G, G236L, P238G, and an insertion of amino acid Asp between positions P238 and S239 as compared to SEQ ID NO: 7; or a mutation set of L234G, G236L, and an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7, wherein the variant IgG Fc polypeptide further comprises at least, about, or exactly 1-10, 1-20, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19 or 20 mutations in addition to the mutation set as compared to SEQ ID NO: 7, are provided.

In some embodiments, polypeptides comprising: a variant IgG Fc polypeptide that selectively binds to FcyRIip over FcyRIIa, wherein the variant IgG Fc polypeptide comprises one or more sequence selected from Table 2 or Table 3; and an inhibitory receptor effector domain, are provided. In some embodiments, polypeptides comprising: a variant IgG Fc polypeptide that selectively binds to FcyRIip over FcyRIIa, wherein the variant IgG Fc polypeptide comprises one or more sequence selected from Table 2 or Table 3; an inhibitory receptor effector domain; and a FcyRII binding effector domain, are provided.

In some embodiments, pharmaceutical compositions comprising polypeptides provided herein, are provided.

In some embodiments, methods of treating an autoimmune disorder in a subject are provided. In some embodiments, methods of treating cancer in a subject are provided. In some embodiments, methods of modulating the interaction of cells of at least two distinct types are provided. In some embodiments, methods of inhibiting an activated immune cell that is in contact with a B cell, an antigen presenting cell (APC), or a myeloid cell, are provided. In some embodiments, method of activating or enhancing the behavior of an activated immune cell that is in contact with a B cell, an antigen presenting cell (APC), or a myeloid cell, are provided.

DETAILED DESCRIPTION

As used herein and in the appended claims, the singular forms “a”, “an” and “the” include plural reference unless the context clearly dictates otherwise.

As used herein, the term “about” means that the numerical value is approximate and small variations would not significantly affect the practice of the disclosed embodiments. Where a numerical limitation is used, unless indicated otherwise by the context, “about” means the numerical value can vary by ±5% and remain within the scope of the disclosed embodiments. Thus, about 100 means 95 to 105.

As used herein, the term “animal” includes, but is not limited to, humans and non-human vertebrates such as wild, domestic, and farm animals. As used herein, the term “mammal” means a rodent (i.e., a mouse, a rat, or a guinea pig), a monkey, a cat, a dog, a cow, a horse, a pig, or a human. In some embodiments, the mammal is a human.

As used herein, the term “contacting” means bringing together of two elements in an in vitro system or an in vivo system. For example, “contacting” a therapeutic compound with an individual or patient or cell includes the administration of the compound to an individual or patient, such as a human, as well as, for example, introducing a compound into a sample containing a cellular or purified preparation containing target.

As used herein, the terms “comprising” (and any form of comprising, such as “comprise”, “comprises”, and “comprised”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”), or “containing” (and any form of containing, such as “contains” and “contain”), are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. Any composition or method that recites the term “comprising” should also be understood to also describe such compositions as consisting, consisting of, or consisting essentially of the recited components or elements.

As used herein, the term “fused” or “linked” when used in reference to a protein or molecule having different domains or heterologous sequences means that the protein domains are part of the same peptide chain that are connected to one another with either peptide bonds or other covalent bonding. The domains or section can be linked or fused directly to one another or another domain or peptide sequence can be between the two domains or sequences and such sequences would still be considered to be fused or linked to one another.

As used herein, the term “individual,” “subject,” or “patient,” used interchangeably, means any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, such as humans.

As used herein, the term “inhibit” refers to a result, symptom, or activity being reduced as compared to the activity or result in the absence of the compound that is inhibiting the result, symptom, or activity. In some embodiments, the result, symptom, or activity, is inhibited by about, or, at least, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99%. An result, symptom, or activity can also be inhibited if it is completely elimination or extinguished.

As used herein, the phrase “in need thereof’ means that the subject has been identified as having a need for the particular method or treatment. In some embodiments, the identification can be by any means of diagnosis. In any of the methods and treatments described herein, the subject can be in need thereof. In some embodiments, the subject is in an environment or will be traveling to an environment in which a particular disease, disorder, or condition is prevalent.

As used herein, the phrase “integer from X to Y” means any integer that includes the endpoints. For example, the phrase “integer from 1 to 5” means 1, 2, 3, 4, or 5. As used herein, the phrase “ophthalmically acceptable” means having no persistent detrimental effect on the treated eye or the functioning thereof, or on the general health of the subject being treated. However, it will be recognized that transient effects such as minor irritation or a “stinging” sensation are common with topical ophthalmic administration of drugs and the existence of such transient effects is not inconsistent with the composition, formulation, or ingredient (e.g., excipient) in question being “ophthalmically acceptable” as herein defined. In some embodiments, the pharmaceutical compositions can be ophthalmically acceptable or suitable for ophthalmic administration.

In some embodiments, the term “therapeutic molecule” can be used interchangeably with “therapeutic compound,” “molecule,” or “therapeutic,” and refers to any polypeptide, or protein described herein.

"Specific binding" or "specifically binds to" or is "specific for" a particular antigen, target, or an epitope means binding that is measurably different from a non-specific interaction. Specific binding can be measured, for example, by determining binding of a molecule compared to binding of a control molecule, which generally is a molecule of similar structure that does not have binding activity. For example, specific binding can be determined by competition with a control molecule that is similar to the target.

Specific binding for a particular antigen, target, or an epitope can be exhibited, for example, by an antibody having a KD for an antigen or epitope of at least about 10'^4M, at least about 10'^3M, at least about 10'^{6 M}, at least about 10‘^7M, at least about 10’^8M, at least about 10'^9M, alternatively at least about 10'^{10 M}, at least about 10'^11M, at least about 10'^12M, or greater, where KD refers to a dissociation rate of a particular antibody -target interaction. Typically, an antibody that specifically binds an antigen or target will have a KD that is, or at least, 2-, 4-, 5-, 10-, 20-, 50-, 100-, 500-, 1000-, 5,000-, 10,000-, or more times greater for a control molecule relative to the antigen or epitope.

In some embodiments, specific binding for a particular antigen, target, or an epitope can be exhibited, for example, by an antibody having a KA or K_a for a target, antigen, or epitope of at least 2-, 4-, 5-, 20-, 50-, 100-, 500-, 1000-, 5,000-, 10,000- or more times greater for the target, antigen, or epitope relative to a control, where KA or K_a refers to an association rate of a particular antibody-antigen interaction. As provided herein, the compounds and compositions provided for herein can be used in methods of treatment as provided herein. As used herein, the terms “treat,” “treated,” or “treating” mean both therapeutic treatment and prophylactic measures wherein the object is to slow down (lessen) an undesired physiological condition, disorder or disease, or obtain beneficial or desired clinical results. For purposes of these embodiments, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of extent of condition, disorder or disease; stabilized (i.e., not worsening) state of condition, disorder or disease; delay in onset or slowing of condition, disorder or disease progression; amelioration of the condition, disorder or disease state or remission (whether partial or total), whether detectable or undetectable; an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient; or enhancement or improvement of condition, disorder or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival, as applicable for a specific disease, as compared to expected survival if not receiving treatment. Thus, “treatment of an autoimmune condition” or “treating autoimmunity” means an activity that alleviates or ameliorates any of the primary phenomena or secondary symptoms associated with the autoimmune condition other condition described herein when the terms “treat,” “treated,” or “treating” are used in conjunction with such condition.

As used herein, terms “variant,” “molecule,” “therapeutic,” “therapeutic compound,” “compound,” “polypeptide,” or “protein” can be used interchangeably and relate to the variants, molecules, therapeutics, therapeutic compounds, compounds, polypeptides, and proteins disclosed herein.

Variant Fc Molecules

As used herein, "isotype" refers to the immunoglobulin class (e.g., IgGl, IgG2, IgG3, IgG4, IgM, IgAl, IgA2, IgD, and IgE antibody) that is encoded by the heavy chain constant domain genes. The full-length amino acid sequence of each wild type human IgG constant region (including all domains, i.e., CHI domain, hinge, CH2 domain, and CH3 domain) is cataloged in the UniProt database available on-line, e.g., as P01857 (IgGl), P01859 (IgG2), P01860 (IgG3), and P01861 (IgG4), or different allotypes thereof (SEQ ID NOs: 1, 2, 3, and 4, respectively). As used herein, a domain of a heavy chain constant region, e.g., the hinge, is of an "IgGl isotype," "TgG2 isotype," "IgG3 isotype," or "IgG4 isotype," if the domain comprises the amino acid sequence of the corresponding domain of the respective isotype, or a variant thereof (that has a higher homology to the corresponding domain of the respective isotype than it does to that of the other isotypes).

“Allotype” refers to naturally occurring variants within a specific isotype group, which variants differ in a few amino acids (see, e.g., Jefferies et al. (2009) mAbs 1 :1). Molecules described herein may be of any allotype.

A “wild-type” protein or portion thereof is a version of the protein as it is found in nature. An amino acid sequence of a wild-type protein, e.g., a heavy chain constant region, is the amino acid sequence of the protein as it occurs in nature. Due to allotypic differences, there can be more than one amino acid sequence for a wild-type protein. For example, there are several allotypes of naturally occurring human IGgl heavy chain constant regions (e.g., Jeffries et al. (2009) mAbs 1: 1).

An immunoglobulin may be from any of the commonly known isotypes, including but not limited to IgA, secretory IgA, IgG and IgM. The IgG isotype is divided in subclasses in certain species: IgGl, IgG2, IgG3 and IgG4 in humans, and IgGl, IgG2a, IgG2b and IgG3 in mice. In certain embodiments, the antibodies described herein are of the human IgGl or IgG2 subtype. Immunoglobulins, e.g., human IgGl, exist in several allotypes, which differ from each other in at most a few amino acids.

In some embodiments, the IgG proteins (hinge region underlined) are as provided in Table 1.

An "Fc region" (fragment crystallizable region) or "Fc domain" or "Fc" refers to the C- terminal region of the heavy chain of an antibody that mediates the binding of the immunoglobulin to host tissues or factors, including binding to Fc receptors located on various cells of the immune system (e.g., effector cells) or to the first component (Clq) of the classical complement system. Thus, an Fc region of an antibody of isotype IgG comprises the heavy chain constant region of the antibody excluding the first constant region immunoglobulin domain (CHI). In IgG, IgA and IgD antibody isotypes, the Fc region comprises CH2 and CH3 constant domains in each of the antibody’s two heavy chains; IgM and IgE Fc regions comprise three heavy chain constant domains (CH domains 2-4) in each polypeptide chain. For IgG, the Fc region comprises immunoglobulin domains consisting of the hinge, CH2 and CH3. For purposes herein, the Fc region is defined as starting at amino acid 216 and ending at amino acid 447, wherein the numbering is according to the EU index as in Kabat. Kabat et al. (1991) Sequences of Proteins of Immunological Interest, National Institutes of Health, Bethesda, MD, and according to FIGs.3c-3f of U.S. Pat. App. Pub. No.2008/0248028. In some embodiments, the Fc region comprises the hinge region. The Fc may be a native (or naturally-occurring or wild-type) Fc, including any allotypic variant, or a variant Fc (e.g., a non- naturally occurring Fc), comprising, e.g., 1, 2, 3, 4, 5, 1-5, 1-10 or 5-10 or more amino acid mutations, e.g., substitutions, additions or deletions. For example, a variant Fc may comprise an amino acid sequence that is at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to a wild-type Fc. Modified or mutated Fes may have enhanced or reduced effector function and/or half-life. Fc may refer to this region in isolation or in the context of an Fc-comprising protein polypeptide such as a “binding protein comprising an Fc region,” also referred to as an “Fc fusion protein” (e.g., an antibody or immunoadhesin). In some embodiments, modified or variant Fc molecules have enhanced binding to FcyRIip.

A "hinge", "hinge domain" or "hinge region" or "antibody hinge region" refers to the domain of a heavy chain constant region that joins the CHI domain to the CH2 domain and includes the upper, middle, and lower portions of the hinge (Roux et al. J. Immunol.1998 161 :4083). The hinge provides varying levels of flexibility between the binding and effector regions of an antibody and also provides sites for intermolecular disulfide bonding between the two heavy chain constant regions. The term “hinge” includes wild-type hinges, as well as variants thereof (e.g., non-naturally-occurring hinges or modified hinges). For example, the term “IgGl hinge” includes wild-type IgGl hinge, as shown below, and variants having 1, 2, 3, 4, 5, 1-3, 1-5, 3-5 and/or at most 5, 4, 3, 2, or 1 mutations, e.g., substitutions, deletions or additions. In some embodiments, the hinge regions are as provided in Table 2.

The aligned sequences of wild-type IgGl, IgG2, IgG3 and IgG4 relevant hinge amino acid residues (amino acid residues 226 to 238 of wild-type IgGl, IgG2, IgG3, and IgG4) are shown below.

IgGl : CPPCPAPELLGGP ( SEQ ID NO : 15 )

IgG2: CPPCPAPPVAG-P ( SEQ ID NO : 16 )

IgG3: CPRCPAPELLGGP ( SEQ ID NO : 17 )

IgG4: CPSCPAPEFLGGP ( SEQ ID NO : 18 )

The term “CHI domain” refers to the heavy chain constant region linking the variable domain to the hinge in a heavy chain constant domain. As used herein, a CHI domain includes wild type CHI domains, as well as variants thereof (e.g., non-naturally-occurring CHI domains or modified CHI domains). As used herein, CHI domain includes amino acid residues 1-98 of IgGl; 1-98 of IgG2; 1-98 of IgG3; and 1-98 of IgG4. For example, the term “CHI domain” includes wild-type CHI domains and variants thereof having 1, 2, 3, 4, 5, 1-3, 1-5, 3-5 and/or at most 5, 4, 3, 2, or 1 mutations, e.g., substitutions, deletions or additions.

The term “CH2 domain” refers to the heavy chain constant region linking the hinge to the CH3 domain in a heavy chain constant domain. As used herein, a CH2 domain includes wildtype CH2 domains, as well as variants thereof (e.g., non-naturally-occurring CH2 domains or modified CH2 domains). As used herein, CH2 domain includes amino acid residues 111-223 of IgGl; 111-219 of IgG2; 161-270 of IgG3; and 111-220 of IgG4. For example, the term “CH2 domain” includes wild-type CH2 domains and variants thereof having 1, 2, 3, 4, 5, 1-3, 1-5, 3-5 and/or at most 5, 4, 3, 2, or 1 mutations, e.g., substitutions, deletions or additions.

The term “CH3 domain” refers to the heavy chain constant region that is C-terminal to the CH2 domain in a heavy chain constant domain. As used herein, a CH3 domain includes wildtype CH3 domains, as well as variants thereof (e.g., non-naturally- occurring CH3 domains or modified CH3 domains). As used herein, CH3 domain includes amino acid residues 224-330 of IgGl; 220-326 of IgG2; 271-376 of IgG3; and 226-322 of IgG4. For example, the term “CH3 domain” includes wild-type CH3 domains and variants thereof having 1, 2, 3, 4, 5, 1-3, 1-5, 3-5 and/or at most 5, 4, 3, 2, or 1 mutations, e.g., substitutions, deletions or additions.

In some embodiments, the hinge/CH2 domain has a sequence such as those provided in Table 3 below.

Without being bound to a particular theory, mutation, or isotype swapping, of the entire hinge region or CH2 region, or certain portions of a hinge region or CH2 region in an IgGl results in the modified IgGl having enhanced or altered properties relative to the IgGl with a wild-type TgGl constant region. For example, IgGl can have residues 11 1-223 replaced with residues 111-220 of IgG4. Other non-limiting examples include IgGl having at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% residues 111-223 replaced with at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% residues 111-220 of IgG4.

In some embodiments, a variant Fc polypeptide is a hybrid Fc polypeptide that comprises sequences from at least two IgG isotypes. For example, a variant Fc polypeptide may comprise the CH2 or CH3 region from one or more other isotypes. For example, a variant Fc can be an IgGl/IgG4 Fc polypeptide.

In some embodiments, a variant Fc comprises a CH2 region swapped from another IgG isotype. Non-limiting examples of CH2 regions include, but are not limited to:

SVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA ( IgGl CH2 , SEQ ID NO : 23 ) ; or SVFLFPPKPKDTLMISRTPEVTCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPR EEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKA ( IgG4 CH2 , SEQ ID NO : 24 ) .

Provided herein are variant Fc molecules comprising variant Fc domains, e.g., Fc domains that have a mutated hinge region and/or a non-wild-type CH2 domain, relative to wildtype Fc domain. Exemplary variant Fc polypeptides comprising variant Fc domains include an IgGl hinge, a CHI domain, a CH2 domain and a CH3 domain, wherein at least one of these constant domains is not of the IgGl isotype and may be, e.g., of an IgG2, IgG3 or IgG4. In some embodiments, a variant Fc polypeptide comprises an IgGl hinge and IgG4 CH2 domain. In some embodiments, a variant Fc polypeptide comprises a mutated IgGl hinge and IgG4 CH2 domain. Other non-limiting examples of variant Fc molecules include variant Fc domains comprising an IgGl hinge, a CHI domain, a CH2 domain and a CH3 domain, wherein at least one amino acid residue is mutated, wherein the mutation is a substitution, an insertion, or a deletion. In some embodiments, the insertion can be 1-5 residues. In some embodiments, a variant Fc molecule comprises an IgGl hinge and IgG4 CH2 domain. In some embodiments, a variant Fc molecule comprises a mutated IgGl hinge and IgG4 CH2 domain. A variant Fc molecule may have effector function similar to that of wild-type IgG, or may be engineered to have enhanced effector function relative to that of the wild-type IgG. In some embodiments, a variant Fc molecule may have FcyRIip binding affinity similar to that of wild-type IgG. Tn some embodiments, a variant Fc molecule may have FcyRIip binding affinity that is enhanced to that of wild-type IgG. A variant Fc molecule may comprise a wild-type CHI, hinge, CH2 and/or CH3 domain, or a variant thereof, e.g., a CHI, hinge, CH2 and/or CH3 domain having one or more amino acid substitutions, deletions or additions relative to the corresponding wild-type domain, and/or having an amino acid sequence that is at least 70%, at least 75&, at least 80%, at least 85%, 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%, or at least 99% identical, or more, to the corresponding wildtype sequence.

In some embodiments, a variant Fc molecule comprises a mutation that confers selective binding to FcyRIip over FcyRIIa. As used herein, in reference to FcyRIip, the term “selective binding” means that the Fc domain binds preferentially to FcyRIip over FcyRIIa, that is with a higher affinity to FcyRIip over FcyRIIa. Examples of such mutations are provided for in, for example, US 7662926, US 7655229, US 2009/0087428, US 10919952, US 2007/0253948, and US 2006/0073142, each of which is hereby incorporated by reference in its entirety, including the specific mutations that are descried that affect FcyRIip binding. In some embodiments, the mutation is as described in Shields et al., J. Biol. Chem. 2001, 276:6591-6604, which is hereby incorporated by reference in its entirety.

In some embodiments, a variant IgG Fc polypeptide comprises a mutation that confers selective binding to FcyRIip, wherein the mutation is in the hinge region of the Fc domain. In some embodiments, the mutation in the hinge region of the Fc domain is in the hinge region of IgGl, IgG2, IgG3, or IgG4. In some embodiments, the mutation in the hinge region of the Fc domain is in the hinge region of IgGl. In some embodiments, the mutation in the hinge region of the Fc domain is in the hinge region of IgG2. In some embodiments, the mutation in the hinge region of the Fc domain is in the hinge region of IgG3. In some embodiments, the mutation in the hinge region of the Fc domain is in the hinge region of IgG4.

In some embodiments, a variant IgG Fc polypeptide comprises a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 7, and the variant Fc selectively binds to FcyRIip over FcyRIIa. In some embodiments, a variant IgG Fc polypeptide comprises a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 7, and the variant Fc selectively binds to FcyRIip over FcyRIIa over FcyRIIa.

In some embodiments, a variant IgG Fc polypeptide comprises a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to of SEQ ID NO: 7, further comprises a mutation at position 228, 234, 235, or any combination thereof, as compared to SEQ ID NO: 7, and wherein the variant IgG Fc polypeptide selectively binds to FcyRIip over FcyRIIa.

In some embodiments, the variant IgG Fc polypeptide comprises a hinge region sequence having at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, 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%, or at least 99% identity to SEQ ID NO: 11-18. . In some embodiments, the variant IgG Fc polypeptide comprises a hinge region sequence having at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, 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%, or at least 99% identity to SEQ ID NO: 1 1. In some embodiments, the variant IgG Fc polypeptide comprises a hinge region sequence having at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, 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%, or at least 99% identity to SEQ ID NO: 12. In some embodiments, the variant IgG Fc polypeptide comprises a hinge region sequence having at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, 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%, or at least 99% identity to SEQ ID NO: 13. In some embodiments, the variant IgG Fc polypeptide comprises a hinge region sequence having at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, 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%, or at least 99% identity to SEQ ID NO: 14. In some embodiments, the variant IgG Fc polypeptide comprises a hinge region sequence having at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, 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%, or at least 99% identity to SEQ ID NO: 15. In some embodiments, the variant IgG Fc polypeptide comprises a hinge region sequence having at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, 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%, or at least 99% identity to SEQ ID NO: 16. In some embodiments, the variant IgG Fc polypeptide comprises a hinge region sequence having at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, 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%, or at least 99% identity to SEQ ID NO: 17. In some embodiments, the variant IgG Fc polypeptide comprises a hinge region sequence having at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, 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%, or at least 99% identity to SEQ ID NO: 18.

In some embodiments, the variant IgG Fc polypeptide comprises a hinge region sequence having at least 1, at least 2, at least 3, at least 4, at least 5, or at least 6 mutations as compared to the hinge region sequence of SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, or any combination thereof, according to SEQ ID NO: 7, wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 226 according to SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 227 according to SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 228 according to SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 229 according to SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 230 according to SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 231 according to SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 232 according to SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 233 according to SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 234 according to SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 235 according to SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 236 according to SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 237 according to SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 238 according to SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 228, 234, 235, or any combination thereof, according to SEQ ID NO: 7, and wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 228 and 234 according to SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 228 and 235 according to SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 234 and 235 according to SEQ ID NO: 7.

In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 268, 274, 276, 296, 300, 309, 327, 330, 331, 339, or any combination thereof, according to SEQ ID NO: 7, wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 228, 234, 235, 268, 274, 276, 296, 300, 309, 327, 330, 331, 339, or any combination thereof, according to SEQ ID NO: 7, wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 228, 234, 235, 268, 274, 296, 327, 330, 331, or any combination thereof, according to SEQ ID NO: 7, wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 228, 268, 274, 296, 327, 330, 331, or any combination thereof, according to SEQ ID NO: 7, wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 228, 234, 268, 274, 296, 327, 330, 331, or any combination thereof, according to SEQ ID NO: 7, wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 228, 235, 268, 274, 296, 327, 330, 331, or any combination thereof, according to SEQ ID NO: 7, wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 235, 268, 274, 296, 327, 330, 331, or any combination thereof, according to SEQ ID NO: 7, wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 234, 235, 268, 274, 296, 327, 330, 331, or any combination thereof, according to SEQ ID NO: 7, wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 234, 268, 274, 296, 327, 330, 331, or any combination thereof, according to SEQ ID NO: 7, wherein the mutation is an insertion, a deletion, or a substitution.

In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position C226, P227, P228, C229, P230, A231, P232, E233, L234, L235, G236, G237, P238, or any combination thereof, according to SEQ ID NO: 7, wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position C226 according to SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position P227 according to SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position P228 according to SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position C229 according to SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position P230 according to SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position A231 according to SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position P232 according to SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position E233 according to SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position L234 according to SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position L235 according to SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position G236 according to SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position G237 according to SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position P238 according to SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position P228, L234, L235, or any combination thereof, according to SEQ ID NO: 7, and wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position P228 and L234 according to SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position P228 and L235 according to SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position L234 and L235 according to SEQ ID NO: 7.

In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position C226, P227, P228, C229, P230, A231, P232, E233, L234, L235, G236, G237, P238, H268, K274, N276, Y296, Y300, L309, A327, A330, P331, A339, or any combination thereof, according to SEQ ID NO: 7, wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position P228, L234, L235, H268, K274, N276, Y296, Y300, L309, A327, A330, P331, A339, or any combination thereof, according to SEQ ID NO: 7, wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position P228, L234, L235, H268, K274, Y296, A327, A330, P331, or any combination thereof, according to SEQ ID NO: 7, wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position P228, H268, K274, Y296, A327, A330, P331, or any combination thereof, according to SEQ ID NO: 7, wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position P228, L234, H268, K274, Y296, A327, A330, P331, or any combination thereof, according to SEQ ID NO: 7, wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position P228, L235, H268, K274, Y296, A327, A330, P331, or any combination thereof, according to SEQ ID NO: 7, wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position L235, H268, K274, Y296, A327, A330, P331, or any combination thereof, according to SEQ ID NO: 7, wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position L234, L235, H268, K274, Y296, A327, A330, P331, or any combination thereof, according to SEQ ID NO: 7, wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position L234, H268, K274, Y296, A327, A330, P331, or any combination thereof, according to SEQ ID NO: 7, wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position P228, L234, L235, H268, K274, Y296, A330, P331, or any combination thereof, according to SEQ ID NO: 7, wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position P228, H268, K274, Y296, A330, P331, or any combination thereof, according to SEQ ID NO: 7, wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position P228, L234, H268, K274, Y296, A330, P331, or any combination thereof, according to SEQ ID NO: 7, wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position P228, L235, H268, K274, Y296, A330, P331, or any combination thereof, according to SEQ ID NO: 7, wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position L235, H268, K274, Y296, A330, P331, or any combination thereof, according to SEQ ID NO: 7, wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position L234, L235, H268, K274, Y296, A33O, P331, or any combination thereof, according to SEQ ID NO: 7, wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position L234, H268, K274, Y296, A330, P331, or any combination thereof, according to SEQ ID NO: 7, wherein the mutation is an insertion, a deletion, or a substitution.

In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation of S228P, L234F, L235E, H268Q, K274Q, N276K, Y296F, Y300F, L309V, A327G, A330S, P331S, A339T, or any combination thereof, according to SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation of S228P, L234F, L235E, H268Q, K274Q, Y296F, A327G, A330S, P331 S, or any combination thereof, according to SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position S228P according to SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position L234F according to SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position L235E according to SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position S228P and L234F according to SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position S228P and L235E according to SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position L234F and L235E according to SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation of S228P, H268Q, K274Q, Y296F, A327G, A330S, P331S, or any combination thereof, according to SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation of S228P, L234F, H268Q, K274Q, Y296F, A327G, A330S, P331S, or any combination thereof, according to SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation of S228P, L235E, H268Q, K274Q, Y296F, A327G, A330S, P331S, or any combination thereof, according to SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation of L235E, H268Q, K274Q, Y296F, A327G, A330S, P331S, or any combination thereof, according to SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation of L234F, L235E, H268Q, K274Q, Y296F, A327G, A330S, P331S, or any combination thereof, according to SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation of L234F, H268Q, K274Q, Y296F, A327G, A330S, P331S, or any combination thereof, according to SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation of S228P, L234F, L235E, H268Q, K274Q, Y296F, A330S, P331S, or any combination thereof, according to SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation of S228P, H268Q, K274Q, Y296F, A330S, P331 S, or any combination thereof, according to SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation of S228P, L234F, H268Q, K274Q, Y296F, A330S, P331S, or any combination thereof, according to SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation of S228P, L235E, H268Q, K274Q, Y296F, A330S, P331S, or any combination thereof, according to SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation of L235E, H268Q, K274Q, Y296F, A330S, P331S, or any combination thereof, according to SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation of L234F, L235E, H268Q, K274Q, Y296F, A330S, P331S, or any combination thereof, according to SEQ ID NO: 7. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation of L234F, H268Q, K274Q, Y296F, A33OS, P331S, or any combination thereof, according to SEQ ID NO: 7.

In some embodiments, a variant IgG2 Fc domain comprises a mutation that corresponds to a mutation at position 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, or any combination thereof, according to SEQ ID NO: 8, and wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant IgG2 Fc domain comprises a mutation that corresponds to a mutation at position 226 according to SEQ ID NO: 8. In some embodiments, a variant IgG2 Fc domain comprises a mutation that corresponds to a mutation at position 227 according to SEQ ID NO: 8. In some embodiments, a variant IgG2 Fc domain comprises a mutation that corresponds to a mutation at position 228 according to SEQ ID NO: 8. In some embodiments, a variant IgG2 Fc domain comprises a mutation that corresponds to a mutation at position 229 according to SEQ ID NO: 8. In some embodiments, a variant IgG2 Fc domain comprises a mutation that corresponds to a mutation at position 230 according to SEQ ID NO: 8. In some embodiments, a variant IgG2 Fc domain comprises a mutation that corresponds to a mutation at position 231 according to SEQ ID NO: 8. In some embodiments, a variant IgG2 Fc domain comprises a mutation that corresponds to a mutation at position 232 according to SEQ ID NO: 8. In some embodiments, a variant IgG2 Fc domain comprises a mutation that corresponds to a mutation at position 233 according to SEQ ID NO: 8. In some embodiments, a variant IgG2 Fc domain comprises a mutation that corresponds to a mutation at position 234 according to SEQ ID NO: 8. In some embodiments, a v IgG2 Fc domain comprises a mutation that corresponds to a mutation at position 235 according to SEQ ID NO: 8. In some embodiments, a variant IgG2 Fc domain comprises a mutation that corresponds to a mutation at position 236 according to SEQ ID NO: 8. In some embodiments, a variant IgG2 Fc domain comprises a mutation that corresponds to a mutation at position 237 according to SEQ ID NO: 8. In some embodiments, a variant IgG2 Fc domain comprises a mutation that corresponds to a mutation at position 238 according to SEQ ID NO: 8. In some embodiments, a variant IgG2 Fc domain comprises a mutation that corresponds to a mutation at position 228, 234, 235, or any combination thereof, according to SEQ ID NO: 8, and wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant IgG2 Fc domain comprises a mutation that corresponds to a mutation at position 228 and 234 according to SEQ ID NO: 8. In some embodiments, a variant IgG2 Fc domain comprises a mutation that corresponds to a mutation at position 228 and 235 according to SEQ ID NO: 8. In some embodiments, a variant IgG2 Fc domain comprises a mutation that corresponds to a mutation at position 234 and 235 according to SEQ ID NO: 8.

In some embodiments, a variant IgG3 Fc domain comprises a mutation that corresponds to a mutation at position 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 268, 274, 276, 296, 300, 309, 327, 330, 331, 339, or any combination thereof, according to SEQ ID NO: 9, and wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant IgG3 Fc domain comprises a mutation that corresponds to a mutation at position 226 according to SEQ ID NO: 9. In some embodiments, a variant IgG3 Fc domain comprises a mutation that corresponds to a mutation at position 227 according to SEQ ID NO: 9. In some embodiments, a variant IgG3 Fc domain comprises a mutation that corresponds to a mutation at position 228 according to SEQ ID NO: 9. In some embodiments, a variant IgG3 Fc domain comprises a mutation that corresponds to a mutation at position 229 according to SEQ ID NO: 9. In some embodiments, a variant IgG3 Fc domain comprises a mutation that corresponds to a mutation at position 230 according to SEQ ID NO: 9. In some embodiments, a variant IgG3 Fc domain comprises a mutation that corresponds to a mutation at position 231 according to SEQ ID NO: 9. In some embodiments, a variant IgG3 Fc domain comprises a mutation that corresponds to a mutation at position 232 according to SEQ ID NO: 9. In some embodiments, a variant IgG3 Fc domain comprises a mutation that corresponds to a mutation at position 233 according to SEQ ID NO: 9. In some embodiments, a variant IgG3 Fc domain comprises a mutation that corresponds to a mutation at position 234 according to SEQ ID NO: 9. In some embodiments, a variant IgG3 Fc domain comprises a mutation that corresponds to a mutation at position 235 according to SEQ ID NO: 9. In some embodiments, a variant IgG3 Fc domain comprises a mutation that corresponds to a mutation at position 236 according to SEQ ID NO: 9. In some embodiments, a variant IgG3 Fc domain comprises a mutation that corresponds to a mutation at position 237 according to SEQ ID NO: 9. In some embodiments, a variant IgG3 Fc domain comprises a mutation that corresponds to a mutation at position 238 according to SEQ ID NO: 9. In some embodiments, a variant IgG3 Fc domain comprises a mutation that corresponds to a mutation at position 228, 234, 235, or any combination thereof, according to SEQ ID NO: 9, and wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant IgG3 Fc domain comprises a mutation that corresponds to a mutation at position 228 and 234 according to SEQ ID NO: 9. In some embodiments, a variant IgG3 Fc domain comprises a mutation that corresponds to a mutation at position 228 and 235 according to SEQ ID NO: 9. In some embodiments, a variant IgG3 Fc domain comprises a mutation that corresponds to a mutation at position 234 and 235 according to SEQ ID NO: 9.

In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 268, 274, 276, 296, 300, 309, 327, 330, 331, 339, or any combination thereof, according to SEQ ID NO: 10, wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 226 according to SEQ ID NO: 10. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 227 according to SEQ ID NO: 10. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 228 according to SEQ ID NO: 10. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 229 according to SEQ ID NO: 10. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 230 according to SEQ ID NO: 10. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 231 according to SEQ ID NO: 10. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 232 according to SEQ ID NO: 10. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 233 according to SEQ ID NO: 10. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 234 according to SEQ ID NO: 10. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 235 according to SEQ ID NO: 10. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 236 according to SEQ ID NO: 10. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 237 according to SEQ ID NO: 10. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 238 according to SEQ ID NO: 10. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 228, 234, 235, or any combination thereof, according to SEQ ID NO: 10, and wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 228 and 234 according to SEQ ID NO: 10. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 228 and 235 according to SEQ ID NO: 10. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 234 and 235 according to SEQ ID NO: 10.

In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 268, 274, 276, 296, 300, 309, 327, 330, 331, 339, or any combination thereof, according to SEQ ID NO: 10, wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 228, 234, 235, 268, 274, 276, 296, 300, 309, 327, 330, 331, 339, or any combination thereof, according to SEQ ID NO: 10, wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 228, 234, 235, 268, 274, 296, 327, 330, 331, or any combination thereof, according to SEQ ID NO: 10, wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 228, 268, 274, 296, 327, 330, 331, or any combination thereof, according to SEQ ID NO: 10, wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 228, 234, 268, 274, 296, 327, 330, 331, or any combination thereof, according to SEQ ID NO: 10, wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 228, 235, 268, 274, 296, 327, 330, 331, or any combination thereof, according to SEQ ID NO: 10, wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 235, 268, 274, 296, 327, 330, 331, or any combination thereof, according to SEQ ID NO: 10, wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 234, 235, 268, 274, 296, 327, 330, 331, or any combination thereof, according to SEQ ID NO: 10, wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position 234, 268, 274, 296, 327, 330, 331, or any combination thereof, according to SEQ ID NO: 10, wherein the mutation is an insertion, a deletion, or a substitution.

In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position C226, P227, S228, C229, P230, A231, P232, E233, F234, L235, G236, G237, P238, or any combination thereof, according to SEQ ID NO: 10, wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position C226 according to SEQ ID NO: 10. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position P227 according to SEQ ID NO: 10. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position S228 according to SEQ ID NO: 10. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position C229 according to SEQ ID NO: 10. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position P230 according to SEQ ID NO: 10. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position A231 according to SEQ ID NO: 10. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position P232 according to SEQ ID NO: 10. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position E233 according to SEQ ID NO: 10. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position F234 according to SEQ ID NO: 10. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position L235 according to SEQ ID NO: 10. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position G236 according to SEQ ID NO: 10. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position G237 according to SEQ ID NO: 10. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position P238 according to SEQ ID NO: 10. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position S228, F234, L235, or any combination thereof, according to SEQ ID NO: 10, and wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position S228 and F234 according to SEQ ID NO: 10. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position S228 and L235 according to SEQ ID NO: 10. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position F234 and L235 according to SEQ ID NO: 10.

In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position C226, P227, S228, C229, P230, A231, P232, E233, F234, L235, G236, G237, P238, Q268, Q274, N276, F296, Y300, L309, G327, S330, S331, A339, or any combination thereof, according to SEQ ID NO: 10, wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position S228, F234, L235, Q268, Q274, N276, F296, Y300, L309, G327, S330, S331, A339, or any combination thereof, according to SEQ ID NO: 10, wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position S228, F234, L235, Q268, Q274, F296, G327, S330, S331, or any combination thereof, according to SEQ ID NO: 10, wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position S228, Q268, Q274, F296, G327,

5330, S331, or any combination thereof, according to SEQ ID NO: 10, wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position S228, F234, Q268, Q274, F296, G327, S330,

5331, or any combination thereof, according to SEQ ID NO: 10, wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position S228, L235, Q268, Q274, F296, G327, S330, S331, or any combination thereof, according to SEQ ID NO: 10, wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position L235, Q268, Q274, F296, G327, S330, S331, or any combination thereof, according to SEQ ID NO: 10, wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position F234, L235, Q268, Q274, F296, G327, S330, S331, or any combination thereof, according to SEQ ID NO: 10, wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position F234, Q268, Q274, F296, G327, S330, S331, or any combination thereof, according to SEQ ID NO: 10, wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position S228, F234, L235, Q268, Q274, F296, S330, S331, or any combination thereof, according to SEQ ID NO: 10, wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position S228, Q268, Q274, F296, S330, S331, or any combination thereof, according to SEQ ID NO: 10, wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position S228, F234, Q268, Q274, F296, S330, S331, or any combination thereof, according to SEQ ID NO: 10, wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position S228, L235, Q268, Q274, F296, S330, S331, or any combination thereof, according to SEQ ID NO: 10, wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position L235, Q268, Q274, F296, S330, S331, or any combination thereof, according to SEQ ID NO: 10, wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position F234, L235, Q268, Q274, F296, S330, S331, or any combination thereof, according to SEQ ID NO: 10, wherein the mutation is an insertion, a deletion, or a substitution. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position F234, Q268, Q274, F296, S330, S331, or any combination thereof, according to SEQ ID NO: 10, wherein the mutation is an insertion, a deletion, or a substitution.

In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation of S228P, F234L, L235E, Q268H, Q274K, N276K, F296Y, Y300F, L309V, G327A, S330A, S331P, A339T, or any combination thereof, according to SEQ ID NO: 10. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation of S228P, F234L, L235E, Q268H, Q274K, F296Y, G327A, S330 A, S33 IP, or any combination thereof, according to SEQ ID NO: 10. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position S228P according to SEQ ID NO: 10. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position F234L according to SEQ ID NO: 10. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position L235E according to SEQ ID NO: 10. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position S228P and F234L according to SEQ ID NO: 10. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position S228P and L235E according to SEQ ID NO: 10. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation at position F234L and L235E according to SEQ ID NO: 10. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation of S228P, Q268H, Q274K, F296Y, G327A, S330A, S331P, or any combination thereof, according to SEQ ID NO: 10. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation of S228P, F234L, Q268H, Q274K, F296Y, G327A, S330A, S331P, or any combination thereof, according to SEQ ID NO: 10. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation of S228P, L235E, Q268H, Q274K, F296Y, G327A, S330A, S331P, or any combination thereof, according to SEQ ID NO: 10. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation of L235E, Q268H, Q274K, F296Y, G327A, S330A, S331P, or any combination thereof, according to SEQ ID NO: 10. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation of F234L, L235E, Q268H, Q274K, F296Y, G327A, S330A, S331P, or any combination thereof, according to SEQ ID NO: 10. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation of F234L, Q268H, Q274K, F296Y, G327A, S330A, S331P, or any combination thereof, according to SEQ ID NO: 10. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation of S228P, F234L, L235E, Q268H, Q274K, F296Y, S330A, S331P, or any combination thereof, according to SEQ ID NO: 10. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation of S228P, Q268H, Q274K, F296Y, S330A, S33 IP, or any combination thereof, according to SEQ ID NO: 10. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation of S228P, F234L, Q268H, Q274K, F296Y, S330A, S331P, or any combination thereof, according to SEQ ID NO: 10. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation of S228P, L235E, Q268H, Q274K, F296Y, S330A, S331P, or any combination thereof, according to SEQ ID NO: 10. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation of L235E, Q268H, Q274K, F296Y, S33OA, S331P, or any combination thereof, according to SEQ ID NO: 10. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation of F234L, L235E, Q268H, Q274K, F296Y, S330A, S331P, or any combination thereof, according to SEQ ID NO: 10. In some embodiments, a variant Fc domain comprises a mutation that corresponds to a mutation of F234L, Q268H, Q274K, F296Y, S330A, S331P, or any combination thereof, according to SEQ ID NO: 10.

In some embodiments, a variant IgG Fc polypeptide is a chimeric IgG Fc polypeptide. In some embodiments, the chimeric IgG Fc polypeptide is a chimeric IgGl/IgG2 polypeptide, a chimeric IgGl/IgG3 polypeptide, a chimeric IgGl/IgG4 polypeptide, a chimeric IgG2/IgG3 polypeptide, a chimeric IgG2/IgG4 polypeptide, or a chimeric IgG3/IgG4 polypeptide.

In some embodiments, the variant IgG Fc polypeptide comprises a mutation in the CH2 region and/or hinge region. In some embodiments, the mutation is a substitution, an insertion, or a deletion. In some embodiments, the substation of the variant IgG Fc polypeptide replaces the CH2 region of the IgG isotype with a CH2 region of a different IgG isotype. In some embodiments, the variant IgG Fc polypeptide comprises a CH2 domain amino acid sequence having at least 50%, at least 85%, at least 90%, at least 94%, at least 95%, or at least 99% identity to SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, or SEQ ID NO: 24. In some embodiments, the variant IgG Fc polypeptide comprises a CH2 domain amino acid sequence having at least 50%, at least 85%, at least 90%, at least 94%, at least 95%, or at least 99% identity to SEQ ID NO: 19. In some embodiments, the variant IgG Fc polypeptide comprises a CH2 domain amino acid sequence having at least 50%, at least 85%, at least 90%, at least 94%, at least 95%, or at least 99% identity to SEQ ID NO: 20. In some embodiments, the variant IgG Fc polypeptide comprises a CH2 domain amino acid sequence having at least 50%, at least 85%, at least 90%, at least 94%, at least 95%, or at least 99% identity to SEQ ID NO: 21. In some embodiments, the variant IgG Fc polypeptide comprises a CH2 domain amino acid sequence having at least 50%, at least 85%, at least 90%, at least 94%, at least 95%, or at least 99% identity to SEQ ID NO: 22. In some embodiments, the variant IgG Fc polypeptide comprises a CH2 domain amino acid sequence having at least 50%, at least 85%, at least 90%, at least 94%, at least 95%, or at least 99% identity to SEQ ID NO: 23. In some embodiments, the variant IgG Fc polypeptide comprises a CH2 domain amino acid sequence having at least 50%, at least 85%, at least 90%, at least 94%, at least 95%, or at least 99% identity to SEQ ID NO: 24.

In some embodiments, a variant IgG Fc polypeptide comprises a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 7, provided that the variant IgG Fc polypeptide comprises a CH2 region comprising a sequence of SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, or SEQ ID NO: 24; and a mutation at position 228, 234, 235, or any combination thereof, as compared to SEQ ID NO: 7, and wherein the Fc polypeptide selectively binds to FcyRIip over FcyRIIa. In some embodiments, a variant IgG Fc polypeptide comprises a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 7, provided that the variant IgG Fc polypeptide comprises a CH2 region comprising a sequence of SEQ ID NO: 19; and a mutation at position 228, 234, 235, or any combination thereof, as compared to SEQ ID NO: 7, and wherein the Fc polypeptide selectively binds to FcyRIip over FcyRIIa. In some embodiments, a variant IgG Fc polypeptide comprises a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 7, provided that the variant IgG Fc polypeptide comprises a CH2 region comprising a sequence of SEQ ID NO: 20; and a mutation at position 228, 234, 235, or any combination thereof, as compared to SEQ ID NO: 7, and wherein the Fc polypeptide selectively binds to FcyRIip over FcyRIIa. In some embodiments, a variant IgG Fc polypeptide comprises a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 7, provided that the variant IgG Fc polypeptide comprises a CH2 region comprising a sequence of SEQ ID NO: 21; and a mutation at position 228, 234, 235, or any combination thereof, as compared to SEQ ID NO: 7, and wherein the Fc polypeptide selectively binds to FcyRIip over FcyRIIa. In some embodiments, a variant IgG Fc polypeptide comprises a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 7, provided that the variant IgG Fc polypeptide comprises a CH2 region comprising a sequence of SEQ ID NO: 22; and a mutation at position 228, 234, 235, or any combination thereof, as compared to SEQ ID NO: 7, and wherein the Fc polypeptide selectively binds to FcyRIip over FcyRIIa. In some embodiments, a variant IgG Fc polypeptide comprises a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 7, provided that the variant IgG Fc polypeptide comprises a CH2 region comprising a sequence of SEQ ID NO: 23; and a mutation at position 228, 234, 235, or any combination thereof, as compared to SEQ ID NO: 7, and wherein the Fc polypeptide selectively binds to FcyRIip over FcyRIIa. In some embodiments, a variant IgG Fc polypeptide comprises a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 7, provided that the variant IgG Fc polypeptide comprises a CH2 region comprising a sequence of SEQ ID NO: 24; and a mutation at position 228, 234, 235, or any combination thereof, as compared to SEQ ID NO: 7, and wherein the Fc polypeptide selectively binds to FcyRIip over FcyRIIa.

In some embodiments, a variant IgG Fc polypeptide comprises a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 7, provided that the variant IgG Fc polypeptide comprises a CH2 region comprising a sequence of SEQ ID NO: 19, SEQ ID NO; 14, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, or SEQ ID NO: 24; and a mutation at position 228, as compared to SEQ ID NO: 7, and wherein the Fc polypeptide selectively binds to FcyRIip over FcyRIIa. In some embodiments, a variant IgG Fc polypeptide comprises a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 7, provided that the variant IgG Fc polypeptide comprises a CH2 region comprising a sequence of SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, or SEQ ID NO: 24; and a mutation at position 234, as compared to SEQ ID NO: 7, and wherein the Fc polypeptide selectively binds to FcyRIip over FcyRIIa. In some embodiments, a variant IgG Fc polypeptide comprises a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 7, provided that the variant IgG Fc polypeptide comprises a CH2 region comprising a sequence of SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, or SEQ ID NO: 24; and a mutation at position 235, as compared to SEQ ID NO: 7, and wherein the Fc polypeptide selectively binds to FcyRIip over FcyRIIa. In some embodiments, a variant IgG Fc polypeptide comprises a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 7, provided that the variant IgG Fc polypeptide comprises a CH2 region comprising a sequence of SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, or SEQ ID NO: 24; and a mutation at position 228 and 234, as compared to SEQ ID NO: 7, and wherein the Fc polypeptide selectively binds to FcyRIip over FcyRIIa. In some embodiments, a variant IgG Fc polypeptide comprises a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 7, provided that the variant IgG Fc polypeptide comprises a CH2 region comprising a sequence of SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, OR SEQ ID NO: 24; and a mutation at position 228 and 235, as compared to SEQ ID NO: 7, and wherein the Fc polypeptide selectively binds to FcyRIip over FcyRIIa. In some embodiments, a variant IgG Fc polypeptide comprises a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 7, provided that the variant IgG Fc polypeptide comprises a CH2 region comprising a sequence of SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, OR SEQ ID NO: 24; and a mutation at position 234 and 235, as compared to SEQ ID NO: 7, and wherein the Fc polypeptide selectively binds to FcyRIip over FcyRIIa. In some embodiments, a variant IgG Fc polypeptide comprises a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 7, provided that the variant IgG Fc polypeptide comprises a CH2 region comprising a sequence of SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, OR SEQ ID NO: 24; and a mutation at position 228, 234, and 235, as compared to SEQ ID NO: 7, and wherein the Fc polypeptide selectively binds to FcyRIip over FcyRIIa. In some embodiments, a variant IgG Fc polypeptide comprises a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 7, provided that the variant IgG Fc polypeptide comprises a CH2 region comprising a sequence of SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, OR SEQ ID NO: 24; and a mutation of S228P, L234F, L235E, or any combination thereof, as compared to SEQ ID NO: 7, and wherein the Fc polypeptide selectively binds to FcyRIip over FcyRIIa. In some embodiments, a variant IgG Fc polypeptide comprises a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 7, provided that the variant IgG Fc polypeptide comprises a CH2 region comprising a sequence of SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, OR SEQ ID NO: 24; and a mutation of S228P, as compared to SEQ ID NO: 7, and wherein the Fc polypeptide selectively binds to FcyRIip over FcyRIIa. In some embodiments, a variant IgG Fc polypeptide comprises a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 7, provided that the variant IgG Fc polypeptide comprises a CH2 region comprising a sequence of SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, OR SEQ ID NO: 24; and a mutation of L234F, as compared to SEQ ID NO: 7, and wherein the Fc polypeptide selectively binds to FcyRIip over FcyRIIa. In some embodiments, a variant IgG Fc polypeptide comprises a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 7, provided that the variant IgG Fc polypeptide comprises a CH2 region comprising a sequence of SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, OR SEQ ID NO: 24; and a mutation of L235E, as compared to SEQ ID NO: 7, and wherein the Fc polypeptide selectively binds to FcyRIip over FcyRIIa. In some embodiments, a variant IgG Fc polypeptide comprises a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 7, provided that the variant IgG Fc polypeptide comprises a CH2 region comprising a sequence of SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, OR SEQ ID NO: 24; and a mutation of S228P and L234F, as compared to SEQ ID NO: 7, and wherein the Fc polypeptide selectively binds to FcyRIip over FcyRIIa. In some embodiments, a variant IgG Fc polypeptide comprises a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 7, provided that the variant IgG Fc polypeptide comprises a CH2 region comprising a sequence of SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, OR SEQ ID NO: 24; and a mutation of S228P and L235E, as compared to SEQ ID NO: 7, and wherein the Fc polypeptide selectively binds to FcyRIip over FcyRIIa. In some embodiments, a variant IgG Fc polypeptide comprises a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 7, provided that the variant IgG Fc polypeptide comprises a CH2 region comprising a sequence of SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, OR SEQ ID NO: 24; and a mutation of L234F and L235E, as compared to SEQ ID NO: 7, and wherein the Fc polypeptide selectively binds to FcyRIip over FcyRIIa. In some embodiments, a variant IgG Fc polypeptide comprises a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 7, provided that the variant IgG Fc polypeptide comprises a CH2 region comprising a sequence of SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, OR SEQ ID NO: 24; and a mutation of S228P, L234F, and L235E, as compared to SEQ ID NO: 7, and wherein the Fc polypeptide selectively binds to FcyRIip over FcyRIIa.

Non-limiting examples of variant IgG Fc polypeptide include those provided in Table 4 below.

Non-limiting examples of hinge mutations include those provided in Zhou et al. 2020. mAbs 12:1, 1814583, which is hereby incorporated by reference in its entirety.

The mutations and positions of the Fc region are according to EU numbering.

In some embodiments, a polypeptide comprises (1) a variant IgG Fc polypeptide comprising a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 7, provided that the variant IgG Fc polypeptide comprises a CH2 region comprising a sequence of SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, OR SEQ ID NO: 24; and a mutation at position 228, 234, 235, or any combination thereof, as compared to SEQ ID NO: 7, and wherein the variant IgG Fc polypeptide selectively binds to FcyRIip over FcyRIIa; (2) an inhibitory receptor effector domain; and (3) a FcyRII binding effector domain. In some embodiments, a polypeptide comprises (1) a variant IgG Fc polypeptide comprising a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 7, provided that the variant IgG Fc polypeptide comprises a CH2 region comprising a sequence of SEQ ID NO: 19; and a mutation at position 228, 234, 235, or any combination thereof, as compared to SEQ ID NO: 7, and wherein the variant IgG Fc polypeptide selectively binds to FcyRIip over FcyRIIa; (2) an inhibitory receptor effector domain; and (3) a FcyRII binding effector domain. In some embodiments, a polypeptide comprises (1) a variant IgG Fc polypeptide comprising a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 7, provided that the variant IgG Fc polypeptide comprises a CH2 region comprising a sequence of SEQ ID NO: 20; and a mutation at position 228, 234, 235, or any combination thereof, as compared to SEQ ID NO: 7, and wherein the variant IgG Fc polypeptide selectively binds to FcyRIip over FcyRIIa; (2) an inhibitory receptor effector domain; and (3) a FcyRII binding effector domain. In some embodiments, a polypeptide comprises (1) a variant IgG Fc polypeptide comprising a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 7, provided that the variant IgG Fc polypeptide comprises a CH2 region comprising a sequence of SEQ ID NO: 21; and a mutation at position 228, 234, 235, or any combination thereof, as compared to SEQ ID NO: 7, and wherein the variant IgG Fc polypeptide selectively binds to FcyRIip over FcyRIIa; (2) an inhibitory receptor effector domain; and (3) a FcyRII binding effector domain. In some embodiments, a polypeptide comprises (1) a variant IgG Fc polypeptide comprising a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 7, provided that the variant IgG Fc polypeptide comprises a CH2 region comprising a sequence of SEQ ID NO: 22; and a mutation at position 228, 234, 235, or any combination thereof, as compared to SEQ ID NO: 7, and wherein the variant IgG Fc polypeptide selectively binds to FcyRIip over FcyRIIa; (2) an inhibitory receptor effector domain; and (3) a FcyRII binding effector domain. In some embodiments, a polypeptide comprises (1) a variant IgG Fc polypeptide comprising a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 7, provided that the variant IgG Fc polypeptide comprises a CH2 region comprising a sequence of SEQ ID NO: 23; and a mutation at position 228, 234, 235, or any combination thereof, as compared to SEQ ID NO: 7, and wherein the variant IgG Fc polypeptide selectively binds to FcyRIip over FcyRIIa; (2) an inhibitory receptor effector domain; and (3) a Fey Rd I binding effector domain. In some embodiments, a polypeptide comprises (1) a variant IgG Fc polypeptide comprising a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 7, provided that the variant IgG Fc polypeptide comprises a CH2 region comprising a sequence of SEQ ID NO: 24; and a mutation at position 228, 234, 235, or any combination thereof, as compared to SEQ ID NO: 7, and wherein the variant IgG Fc polypeptide selectively binds to FcyRIip over FcyRIIa; (2) an inhibitory receptor effector domain; and (3) a FcyRII binding effector domain. zzzz

In some embodiments, a variant IgG Fc polypeptide comprises one or more mutations that confers selective binding to FcyRIip over FcyRIIa. In some embodiments, a variant IgG Fc polypeptide comprises one or more mutations that enhance selective binding to FcyRIip over FcyRIIa. In some embodiments, a variant IgG Fc polypeptide comprises one or more mutations selected from mutations associated with any one of VFC-1 to VFC-6, as provided in Table 2.

In some embodiments, a variant IgG Fc polypeptide comprises one or more mutations selected from mutations associated with any one of VFC-1, VFC-2, VFC-3, VFC-4, VFC-5, VFC-6, or any combination thereof. In some embodiments, a variant IgG Fc polypeptide comprises one or more mutations selected from mutations associated with VFC-1. In some embodiments, a variant IgG Fc polypeptide comprises one or more mutations selected from mutations associated with VFC-2. In some embodiments, a variant IgG Fc polypeptide comprises one or more mutations selected from mutations associated with VFC-3. In some embodiments, a variant IgG Fc polypeptide comprises one or more mutations selected from mutations associated with VFC-4. In some embodiments, a variant IgG Fc polypeptide comprises one or more mutations selected from mutations associated with VFC-5. In some embodiments, a variant IgG Fc polypeptide comprises one or more mutations selected from mutations associated with VFC- 6. In some embodiments, the mutation is a substitutions, an insertion, or a deletion. In some embodiments, the insertion can be 1-5 residues, or more.

In some embodiments, a variant IgG Fc polypeptide comprises a mutation selected from a mutation at one or more of the positions selected from 234, 236, 237, 238, 239, an insertion between positions 238 and 239, and any combination thereof, as compared to SEQ ID NO: 7.

In some embodiments, a variant IgG Fc polypeptide comprises a mutation at position 234, as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises a mutation at position 236, as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises a mutation at position 237, as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises a mutation at position 238, as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises a mutation at position 239, as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises an insertion between positions 238 and 239, as compared to SEQ ID NO: 7.

In some embodiments, a variant IgG Fc polypeptide comprises a mutation at position

236, as compared to SEQ ID NO: 7, wherein the mutation is a substitutions, an insertion, or a deletion. In some embodiments, a variant IgG Fc polypeptide comprises a mutation at position

237, as compared to SEQ ID NO: 7, wherein the mutation is a substitutions, an insertion, or a deletion. In some embodiments, a variant IgG Fc polypeptide comprises a mutation at position

238, as compared to SEQ ID NO: 7, wherein the mutation is a substitutions, an insertion, or a deletion. In some embodiments, a variant IgG Fc polypeptide comprises a mutation at position

239, as compared to SEQ ID NO: 7, wherein the mutation is a substitutions, an insertion, or a deletion.

In some embodiments, a variant IgG Fc polypeptide comprises a deletion at position 238, as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises a deletion at position 237, and a mutation at position 238, as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises an insertion between positions 238 and 239, as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises a set of mutations at positions 234, 236, 238, and an insertion between positions 238 and 239, as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises a set of mutations at positions 234, 236, and an insertion between positions 238 and 239, as compared to SEQ ID NO: 7.

In some embodiments, a variant IgG Fc polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7, provided that the variant IgG Fc polypeptide comprises one or more mutations selected from mutations associated with any one of VFC-1 to VFC-6. Non-limiting examples include variant IgG Fc polypeptides comprising an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7, provided that the variant TgG Fc polypeptide comprises one or more mutations selected from mutations associated with any one of VFC-1 to VFC-6, wherein variant IgG Fc polypeptides comprises one or more mutations selected from mutations associated with any one of VFC-1 to VFC-6 and one or more mutations in the amino acid sequence that is not the one or more mutations selected from mutations associated with any one of VFC-1 to VFC-6. For example, a variant IgG Fc polypeptide can comprise any one, or more, of mutations selected from 234, 236, 237, 238, 239, an insertion between positions 238 and 239, and any combination thereof, as compared to SEQ ID NO: 7; and at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity at positions that are positions 234, 236, 237, 238, 239, an insertion between positions 238 and 239, and any combination thereof, as compared to SEQ ID NO: 7.

In some embodiments, a variant IgG Fc polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the variant IgG Fc polypeptide comprises one or more mutations selected from mutations associated with any one of VFC-1, VFC-2, VFC-3, VFC-4, VFC-5, VFC-6, or any combination thereof. In some embodiments, a variant IgG Fc polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the variant IgG Fc polypeptide comprises one or more mutations selected from mutations associated with VFC-1. In some embodiments, a variant IgG Fc polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the variant IgG Fc polypeptide comprises one or more mutations selected from mutations associated with VFC-2. In some embodiments, a variant IgG Fc polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the variant IgG Fc polypeptide comprises one or more mutations selected from mutations associated with VFC-3. In some embodiments, a variant IgG Fc polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the variant IgG Fc polypeptide comprises one or more mutations selected from mutations associated with VFC-4. In some embodiments, a variant IgG Fc polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the variant IgG Fc polypeptide comprises one or more mutations selected from mutations associated with VFC-5. In some embodiments, a variant IgG Fc polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the variant IgG Fc polypeptide comprises one or more mutations selected from mutations associated with VFC-6.

In some embodiments, a variant IgG Fc polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the variant IgG Fc polypeptide comprises a mutation selected from a mutation at one or more of the positions selected from 234, 236, 237, 238, 239, an insertion between positions 238 and 239, and any combination thereof, as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the variant IgG Fc polypeptide comprises a mutation at position 234, as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the variant IgG Fc polypeptide comprises a mutation at position 236, as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the variant IgG Fc polypeptide comprises a mutation at position 237, as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the variant IgG Fc polypeptide comprises a mutation at position 238, as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the variant IgG Fc polypeptide comprises a mutation at position 239, as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the variant IgG Fc polypeptide comprises an insertion between positions 238 and 239, as compared to SEQ ID NO: 7.

In some embodiments, a variant IgG Fc polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the variant IgG Fc polypeptide comprises a deletion at position 238, as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the variant IgG Fc polypeptide comprises a deletion at position 237, and a mutation at position 238, as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the variant IgG Fc polypeptide comprises an insertion between positions 238 and 239, as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the variant IgG Fc polypeptide comprises a set of mutations at positions 234, 236, 238, and an insertion between positions 238 and 239, as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the variant IgG Fc polypeptide comprises a set of mutations at positions 234, 236, and an insertion between positions 238 and 239, as compared to SEQ ID NO: 7.

In some embodiments, a variant IgG Fc polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the variant IgG Fc polypeptide comprises a mutation selected from a mutation at one or more of the positions selected from L234, G236, G237, P238, S239, an insertion between positions 238 and 239, and any combination thereof, as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the variant IgG Fc polypeptide comprises a mutation at position L234, as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the variant IgG Fc polypeptide comprises a mutation at position G236, as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the variant IgG Fc polypeptide comprises a mutation at position G237, as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the variant IgG Fc polypeptide comprises a mutation at position P238, as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the variant IgG Fc polypeptide comprises a mutation at position S239, as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the variant IgG Fc polypeptide comprises an insertion between positions P238 and S239, as compared to SEQ ID NO: 7.

In some embodiments, a variant IgG Fc polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the variant IgG Fc polypeptide comprises a deletion at position P238, as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the variant IgG Fc polypeptide comprises a deletion at position G237, and a mutation at position 238, as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the variant IgG Fc polypeptide comprises an insertion between positions P238 and S239, as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the variant IgG Fc polypeptide comprises a set of mutations at positions 234, 236, 238, and an insertion between positions P238 and S239, as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the variant IgG Fc polypeptide comprises a set of mutations at positions L234, G236, and an insertion between positions P238 and S239, as compared to SEQ ID NO: 7.

In some embodiments, a variant IgG Fc polypeptide comprises one or more of the mutations selected from L234G, G236L, deletion of amino acid Gly at position 237, deletion of amino acid Pro at position 238, P238D, P238G, an insertion of amino acid Gly between positions P238 and S239, an insertion of amino acid Asp between positions P238 and S239, and any combination thereof, as compared to SEQ ID NO: 7.

In some embodiments, a variant IgG Fc polypeptide comprises a mutation set selected from: a deletion of amino acid Pro at position 238, as compared to SEQ ID NO: 7; a deletion of amino acid Gly at position 237, and a mutation of P238D, as compared to SEQ ID NO: 7; an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7; a mutation set of L234G, G236L, P238G, and an insertion of amino acid Asp between positions P238 and S239 as compared to SEQ ID NO: 7; or a mutation set of L234G, G236L, and an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7.

In some embodiments, a variant IgG Fc polypeptide comprises a deletion of amino acid Pro at position 238, as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises a deletion of amino acid Gly at position 237, and a mutation of P238D as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises a mutation set of L234G, G236L, P238G, and an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises a mutation set of L234G, G236L, and an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7.

In some embodiments, a variant IgG Fc polypeptide comprises a variant sequence of SEQ ID NO: 7, wherein the variant IgG Fc polypeptide comprises a deletion of amino acid Pro at position 238, as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises a variant sequence of SEQ ID NO: 7, wherein the variant IgG Fc polypeptide comprises a deletion of amino acid Gly at position 237, and a mutation of P238D as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises a variant sequence of SEQ ID NO: 7, wherein the variant IgG Fc polypeptide comprises an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises a variant sequence of SEQ ID NO: 7, wherein the variant IgG Fc polypeptide comprises an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises a variant sequence of SEQ ID NO: 7, wherein the variant IgG Fc polypeptide comprises a mutation set of L234G, G236L, P238G, and an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises a variant sequence of SEQ ID NO: 7, wherein the variant IgG Fc polypeptide comprises a mutation set of L234G, G236L, and an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7.

In some embodiments, a variant IgG Fc polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the variant IgG Fc polypeptide comprises one or more of the mutations selected from L234G, G236L, deletion of amino acid Gly at position 237, deletion of amino acid Pro at position 238, P238D, P238G, an insertion of amino acid Gly between positions P238 and S239, an insertion of amino acid Asp between positions P238 and S239, and any combination thereof, as compared to SEQ ID NO: 7.

In some embodiments, a variant IgG Fc polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the variant IgG Fc polypeptide comprises a mutation set selected from: a deletion of amino acid Pro at position 238, as compared to SEQ ID NO: 7; a deletion of amino acid Gly at position 237, and a mutation of P238D, as compared to SEQ ID NO: 7; an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7; a mutation set of L234G, G236L, P238G, and an insertion of amino acid Asp between positions P238 and S239 as compared to SEQ ID NO: 7; or a mutation set of L234G, G236L, and an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7.

In some embodiments, a variant IgG Fc polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the variant IgG Fc polypeptide comprises a deletion of amino acid Pro at position 238, as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the variant IgG Fc polypeptide comprises a deletion of amino acid Gly at position 237, and a mutation of P238D as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the variant IgG Fc polypeptide comprises an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the variant IgG Fc polypeptide comprises an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the variant IgG Fc polypeptide comprises a mutation set of L234G, G236L, P238G, and an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the variant IgG Fc polypeptide comprises a mutation set of L234G, G236L, and an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7.

In some embodiments, a variant IgG Fc polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the variant IgG Fc polypeptide comprises a variant sequence of SEQ ID NO: 7, wherein the variant IgG Fc polypeptide comprises a deletion of amino acid Pro at position 238, as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the variant IgG Fc polypeptide comprises a variant sequence of SEQ ID NO: 7, wherein the variant IgG Fc polypeptide comprises a deletion of amino acid Gly at position 237, and a mutation of P238D as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the variant IgG Fc polypeptide comprises a variant sequence of SEQ ID NO: 7, wherein the variant IgG Fc polypeptide comprises an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the variant IgG Fc polypeptide comprises a variant sequence of SEQ ID NO: 7, wherein the variant IgG Fc polypeptide comprises an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the variant IgG Fc polypeptide comprises a variant sequence of SEQ ID NO: 7, wherein the variant IgG Fc polypeptide comprises a mutation set of L234G, G236L, P238G, and an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the variant IgG Fc polypeptide comprises a variant sequence of SEQ ID NO: 7, wherein the variant IgG Fc polypeptide comprises a mutation set of L234G, G236L, and an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7.

In some embodiments, a variant IgG Fc polypeptide comprises one or more of the mutations selected from L234G, G236L, deletion of amino acid Gly at position 237, deletion of amino acid Pro at position 238, P238D, P238G, an insertion of amino acid Gly between positions P238 and S239, an insertion of amino acid Asp between positions P238 and S239, and any combination thereof, as compared to SEQ ID NO: 7, wherein the variant IgG Fc polypeptide further comprises at least, about, or exactly 1-10, 1-20, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19 or 20 mutations in addition to the mutation set as compared to SEQ ID NO: 7.

In some embodiments, a variant IgG Fc polypeptide comprises a mutation set selected from: a deletion of amino acid Pro at position 238, as compared to SEQ ID NO: 7; a deletion of amino acid Gly at position 237, and a mutation of P238D, as compared to SEQ ID NO: 7; an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7; a mutation set of L234G, G236L, P238G, and an insertion of amino acid Asp between positions P238 and S239 as compared to SEQ ID NO: 7; or a mutation set of L234G, G236L, and an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7, wherein the variant IgG Fc polypeptide further comprises at least, about, or exactly 1-10, 1-20, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19 or 20 mutations in addition to the mutation set as compared to SEQ ID NO: 7.

In some embodiments, a variant IgG Fc polypeptide comprises a deletion of amino acid Pro at position 238, as compared to SEQ ID NO: 7, wherein the variant IgG Fc polypeptide further comprises at least, about, or exactly 1-10, 1-20, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19 or 20 mutations in addition to the mutation set as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises a deletion of amino acid Gly at position 237, and a mutation of P238D as compared to SEQ ID NO: 7, wherein the variant IgG Fc polypeptide further comprises at least, about, or exactly 1-10, 1-20, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19 or 20 mutations in addition to the mutation set as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7, wherein the variant IgG Fc polypeptide further comprises at least, about, or exactly 1-10, 1-20, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19 or 20 mutations in addition to the mutation set as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7, wherein the variant IgG Fc polypeptide further comprises at least, about, or exactly 1-10, 1-20, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19 or 20 mutations in addition to the mutation set as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises a mutation set of L234G, G236L, P238G, and an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7, wherein the variant IgG Fc polypeptide further comprises at least, about, or exactly 1-10, 1-20, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19 or 20 mutations in addition to the mutation set as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises a mutation set of L234G, G236L, and an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7, wherein the variant IgG Fc polypeptide further comprises at least, about, or exactly 1-10, 1-20, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19 or 20 mutations in addition to the mutation set as compared to SEQ ID NO: 7.

In some embodiments, a variant IgG Fc polypeptide comprises a variant sequence of SEQ ID NO: 7, wherein the variant IgG Fc polypeptide comprises a deletion of amino acid Pro at position 238, as compared to SEQ ID NO: 7, wherein the variant IgG Fc polypeptide further comprises at least, about, or exactly 1-10, 1-20, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19 or 20 mutations in addition to the mutation set as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises a variant sequence of SEQ ID NO: 7, wherein the variant IgG Fc polypeptide comprises a deletion of amino acid Gly at position 237, and a mutation of P238D as compared to SEQ ID NO: 7, wherein the variant IgG Fc polypeptide further comprises at least, about, or exactly 1-10, 1-20, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19 or 20 mutations in addition to the mutation set as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises a variant sequence of SEQ ID NO: 7, wherein the variant IgG Fc polypeptide comprises an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7, wherein the variant IgG Fc polypeptide further comprises at least, about, or exactly 1-10, 1-20, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19 or 20 mutations in addition to the mutation set as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises a variant sequence of SEQ ID NO: 7, wherein the variant IgG Fc polypeptide comprises an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7, wherein the variant IgG Fc polypeptide further comprises at least, about, or exactly 1-10, 1-20, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19 or 20 mutations in addition to the mutation set as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises a variant sequence of SEQ ID NO: 7, wherein the variant IgG Fc polypeptide comprises a mutation set of L234G, G236L, P238G, and an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7, wherein the variant IgG Fc polypeptide further comprises at least, about, or exactly 1-10, 1-20, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19 or 20 mutations in addition to the mutation set as compared to SEQ ID NO: 7. In some embodiments, a variant IgG Fc polypeptide comprises a variant sequence of SEQ ID NO: 7, wherein the variant IgG Fc polypeptide comprises a mutation set of L234G, G236L, and an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7, wherein the variant IgG Fc polypeptide further comprises at least, about, or exactly 1-10, 1-20, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19 or 20 mutations in addition to the mutation set as compared to SEQ ID NO: 7.

In some embodiments, the variant IgG Fc polypeptide provided herein in Table 2 have mutations that enhance or confer selective binding to FcyRIip over FcyRIIa. In some embodiments, the mutations that enhance or confer selective binding to FcyRIip over FcyRIIa are such as any one of those associated with VFC-1, VFC-2, VFC-3, VFC-4, VFC-5, or VFC-6.

Dimeric Variant Fc Molecules

In some embodiments, two (or more) linkers associate, either covalently or non- covalently, e.g., to form a homo-dimeric therapeutic compound. In some embodiments, the linker can comprise an Fc region and two Fc regions associate with one another. In some embodiments of a therapeutic compound comprising two linker regions, the linker regions can self-associate, e g., as two identical Fc regions. In some embodiments of a therapeutic compound comprising two linker regions, the linker regions are not capable of, or not capable of substantial, selfassociation, e.g., the two Fc regions can be members of a knob and hole pair. In some embodiments, the polypeptide comprises a first polypeptide and a second polypeptide.

In some embodiments, a polypeptide can associate with another polypeptide. In some embodiments, the polypeptide associated with another polypeptide forms a dimer molecule. In some embodiments, the dimer is a homodimer molecule.

As used herein, the term “non-covalently conjugated” can mean that a polypeptide is tethered to another polypeptide through a linker. In some embodiments, the linker is a peptide linker. Non-limiting examples of peptide linkers that can be used are known in the art and are provide for herein. As discussed herein the different domains, molecules, or polypeptide can be linked together with a linker domain or region. Any linker region described herein can be used as a linker. Linkers can be for example, glycine/serine linkers. In some embodiments, the linker can comprise one or more repeats of GGGGS (SEQ ID NO: 27). In some embodiments, the linker comprises 1, 2, 3, 4, or 5 repeats. In some embodiments, the linker comprises GGGGSGGGGS (SEQ ID NO: 28). In some embodiments, the linker comprises GGGGS GGGGS GGGGS (SEQ ID NO: 29). In some embodiments, the linker comprises: GGGGS (SEQ ID NO: 27), (GGGGS)₃ (SEQ ID NO: 29), (GGGGS)n (n=l, 2, 3, 4) (SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30), (Gly)s (SEQ ID NO: 31), (Gly)₆ (SEQ ID NO: 32), (EAAAK)i (SEQ ID NO: 33), (EAAK)n (n=l-3) (SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36), A(EAAAK)₄ALEA(EAAAK)4A (SEQ ID NO: 37), or AEAAAKEAAAKA (SEQ ID NO: 38). These linkers can be used in any of the compounds or compositions provided herein.

In some embodiments, a dimer molecule comprises a first polypeptide and a second polypeptide. In some embodiments, a dimer molecule comprises a first polypeptide and a second polypeptide, wherein the first polypeptide and the second polypeptide comprise identical amino acid sequence. In some embodiments, a dimer molecule comprises a first polypeptide and a second polypeptide, wherein the first polypeptide and the second polypeptide comprise amino acid sequences that have 100% sequence identity to each other. In some embodiments, the dimer molecule is a variant IgG Fc polypeptide comprising a first polypeptide and a second polypeptide. In some embodiments, the first polypeptide is a first variant IgG Fc polypeptide. In some embodiments, the second polypeptide is a second variant IgG Fc polypeptide. In some embodiments, the first variant IgG Fc polypeptide and the second variant IgG Fc polypeptide are the same. In some embodiments, the first polypeptide is such a those provided herein, e.g., VFC- 1, VFC-2, VFC-3, VFC-4, VFC-5, or VFC-6. In some embodiments, the second polypeptide is such a those provided herein, e.g., VFC-1, VFC-2, VFC-3, VFC-4, VFC-5, or VFC-6. In some embodiments, the first polypeptide and the second polypeptide are as provided in Table 3.

In some embodiments, a first polypeptide comprises an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, 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%, or at least 99% sequence identity to any one sequence of VFC-1, VFC-2, VFC-3, VFC-4, VFC-5, or VFC-6. In some embodiments, a second polypeptide comprises an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, 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%, or at least 99% sequence identity to any one sequence of VFC-1, VFC-2, VFC-3, VFC-4, VFC-5, or VFC-6. In some embodiments, a dimer molecule comprises a first polypeptide comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, 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%, or at least 99% sequence identity to any one sequence of VFC-1, VFC-2, VFC-3, VFC-4, VFC-5, or VFC-6; and a second polypeptide comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, 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%, or at least 99% sequence identity to any one sequence of VFC-1, VFC-2, VFC-3, VFC-4, VFC-5, or VFC-6. In some embodiments, a dimer molecule comprises a first polypeptide comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, 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%, or at least 99% sequence identity to any one of SEQ ID NO: 1, 2, 3, 4, 5, or 6; and a second polypeptide comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, 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%, or at least 99% sequence identity to any one of SEQ ID NO: 1, 2, 3, 4, 5, or 6.

In some embodiments, a dimer molecule comprises a first polypeptide comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, 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%, or at least 99% sequence identity to SEQ ID NO: 1; and a second polypeptide comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, 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%, or at least 99% sequence identity to SEQ ID NO: 1. In some embodiments, a dimer molecule comprises a first polypeptide comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, 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%, or at least 99% sequence identity to SEQ ID NO: 2; and a second polypeptide comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, 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%, or at least 99% sequence identity to SEQ ID NO: 2. In some embodiments, a dimer molecule comprises a first polypeptide comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, 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%, or at least 99% sequence identity to SEQ ID NO: 3; and a second polypeptide comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, 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%, or at least 99% sequence identity to SEQ ID NO: 3. In some embodiments, a dimer molecule comprises a first polypeptide comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, 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%, or at least 99% sequence identity to SEQ ID NO: 4; and a second polypeptide comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, 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%, or at least 99% sequence identity to SEQ ID NO: 4. In some embodiments, a dimer molecule comprises a first polypeptide comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, 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%, or at least 99% sequence identity to SEQ ID NO: 5; and a second polypeptide comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, 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%, or at least 99% sequence identity to SEQ ID NO: 5. In some embodiments, a dimer molecule comprises a first polypeptide comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, 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%, or at least 99% sequence identity to SEQ ID NO: 6; and a second polypeptide comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, 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%, or at least 99% sequence identity to SEQ ID NO: 6.

In some embodiments, a variant IgG Fc polypeptide comprises a first polypeptide comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, 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%, or at least 99% sequence identity to any one of SEQ ID NO: 1, 2, 3, 4, 5, or 6; and a second polypeptide comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, 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%, or at least 99% sequence identity to any one of SEQ ID NO: 1, 2, 3, 4, 5, or 6. In some embodiments, a variant IgG Fc polypeptide comprises a first polypeptide comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, 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%, or at least 99% sequence identity to SEQ ID NO: 1; and a second polypeptide comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, 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%, or at least 99% sequence identity to SEQ ID NO: 1. In some embodiments, a variant IgG Fc polypeptide comprises a first polypeptide comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, 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%, or at least 99% sequence identity to

SEQ ID NO: 2; and a second polypeptide comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, 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%, or at least 99% sequence identity to SEQ ID NO: 2. In some embodiments, a variant IgG Fc polypeptide comprises a first polypeptide comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least

SEQ ID NO: 3; and a second polypeptide comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, 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%, or at least 99% sequence identity to SEQ ID NO: 3. In some embodiments, a variant IgG Fc polypeptide comprises a first polypeptide comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least

SEQ ID NO: 4; and a second polypeptide comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, 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%, or at least 99% sequence identity to SEQ ID NO: 4. In some embodiments, a variant IgG Fc polypeptide comprises a first polypeptide comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least

SEQ ID NO: 5; and a second polypeptide comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, 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%, or at least 99% sequence identity to SEQ ID NO: 5. In some embodiments, a variant IgG Fc polypeptide comprises a first polypeptide comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, 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%, or at least 99% sequence identity to SEQ ID NO: 6; and a second polypeptide comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, 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%, or at least 99% sequence identity to SEQ ID NO: 6.

In some embodiments, a dimer molecule comprises a first polypeptide comprising an amino acid sequence of any one sequence of VFC-1, VFC-2, VFC-3, VFC-4, VFC-5, or VFC-6; and a second polypeptide comprising an amino acid sequence of any one sequence of VFC-1, VFC-2, VFC-3, VFC-4, VFC-5, or VFC-6, respectively.

In some embodiments, a dimer molecule comprises a first polypeptide comprising an amino acid sequence of any one of SEQ ID NO: 1, 2, 3, 4, 5, or 6; and a second polypeptide comprising an amino acid sequence of any one of SEQ ID NO: 1, 2, 3, 4, 5, or 6, respectively. In some embodiments, a dimer molecule comprises a first polypeptide comprising an amino acid sequence of SEQ ID NO: 1; and a second polypeptide comprising an amino acid sequence of SEQ ID NO: 1. In some embodiments, a dimer molecule comprises a first polypeptide comprising an amino acid sequence of SEQ ID NO: 2; and a second polypeptide comprising an amino acid sequence of SEQ ID NO: 2. In some embodiments, a dimer molecule comprises a first polypeptide comprising an amino acid sequence of SEQ ID NO: 3; and a second polypeptide comprising an amino acid sequence of SEQ ID NO: 3. In some embodiments, a dimer molecule comprises a first polypeptide comprising an amino acid sequence of SEQ ID NO: 4; and a second polypeptide comprising an amino acid sequence of SEQ ID NO: 4. In some embodiments, a dimer molecule comprises a first polypeptide comprising an amino acid sequence of SEQ ID NO: 5; and a second polypeptide comprising an amino acid sequence of SEQ ID NO: 5. In some embodiments, a dimer molecule comprises a first polypeptide comprising an amino acid sequence of SEQ ID NO: 6; and a second polypeptide comprising an amino acid sequence of SEQ ID NO: 6.

In some embodiments, a variant IgG Fc polypeptide comprises a first polypeptide comprising an amino acid sequence of any one of SEQ ID NO: 1, 2, 3, 4, 5, or 6; and a second polypeptide comprising an amino acid sequence of any one of SEQ ID NO: 1, 2, 3, 4, 5, or 6, respectively. In some embodiments, a variant IgG Fc polypeptide comprises a first polypeptide comprising an amino acid sequence of SEQ ID NO: 1 ; and a second polypeptide comprising an amino acid sequence of SEQ ID NO: 1. In some embodiments, a variant IgG Fc polypeptide comprises a first polypeptide comprising an amino acid sequence of SEQ ID NO: 2; and a second polypeptide comprising an amino acid sequence of SEQ ID NO: 2. In some embodiments, a variant IgG Fc polypeptide comprises a first polypeptide comprising an amino acid sequence of SEQ ID NO: 3; and a second polypeptide comprising an amino acid sequence of SEQ ID NO: 3. In some embodiments, a variant IgG Fc polypeptide comprises a first polypeptide comprising an amino acid sequence of SEQ ID NO: 4; and a second polypeptide comprising an amino acid sequence of SEQ ID NO: 4. In some embodiments, a variant IgG Fc polypeptide comprises a first polypeptide comprising an amino acid sequence of SEQ ID NO: 5; and a second polypeptide comprising an amino acid sequence of SEQ ID NO: 5. In some embodiments, a variant IgG Fc polypeptide comprises a first polypeptide comprising an amino acid sequence of SEQ ID NO: 6; and a second polypeptide comprising an amino acid sequence of SEQ ID NO: 6.

In some embodiments, a dimer molecule comprises: a first polypeptide comprising an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the polypeptide comprises: a deletion of amino acid Pro at position 238, as compared to SEQ ID NO: 7; a deletion of amino acid Gly at position 237, and a mutation of P238D, as compared to SEQ ID NO: 7; an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7; a mutation set of L234G, G236L, P238G, and an insertion of amino acid Asp between positions P238 and S239 as compared to SEQ ID NO: 7; or a mutation set of L234G, G236L, and an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; or any combination thereof; and a second polypeptide comprising an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the polypeptide comprises: a deletion of amino acid Pro at position 238, as compared to SEQ ID NO: 7; a deletion of amino acid Gly at position 237, and a mutation of P238D, as compared to SEQ ID NO: 7; an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7; a mutation set of L234G, G236L, P238G, and an insertion of amino acid Asp between positions P238 and S239 as compared to SEQ ID NO: 7; or a mutation set of L234G, G236L, and an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; or any combination thereof.

In some embodiments, a dimer molecule comprises a first polypeptide comprising an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the polypeptide comprises a deletion of amino acid Pro at position 238, as compared to SEQ ID NO: 7; and a second polypeptide comprising an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the polypeptide comprises a deletion of amino acid Pro at position 238, as compared to SEQ ID NO: 7.

In some embodiments, a dimer molecule comprises a first polypeptide comprising an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the polypeptide comprises a deletion of amino acid Gly at position 237, and a mutation of P238D, as compared to SEQ ID NO: 7; and a second polypeptide comprising an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the polypeptide comprises a deletion of amino acid Gly at position 237, and a mutation of P238D, as compared to SEQ ID NO: 7.

In some embodiments, a dimer molecule comprises a first polypeptide comprising an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the polypeptide comprises an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; and a second polypeptide comprising an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the polypeptide comprises an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7.

In some embodiments, a dimer molecule comprises a first polypeptide comprising an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the polypeptide comprises an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7; and a second polypeptide comprising an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the polypeptide comprises an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7.

In some embodiments, a dimer molecule comprises a first polypeptide comprising an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the polypeptide comprises a mutation set of L234G, G236L, P238G, and an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7; and a second polypeptide comprising an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the polypeptide comprises a mutation set of L234G, G236L, P238G, and an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7. In some embodiments, a dimer molecule comprises a first polypeptide comprising an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the polypeptide comprises a mutation set of L234G, G236L, and an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; and a second polypeptide comprising an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the polypeptide comprises a mutation set of L234G, G236L, and an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7.

In some embodiments, a dimer molecule comprises: a first polypeptide comprises a variant sequence of SEQ ID NO: 7, wherein the first polypeptide comprises: a deletion of amino acid Pro at position 238, as compared to SEQ ID NO: 7; a deletion of amino acid Gly at position 237, and a mutation of P238D, as compared to SEQ ID NO: 7; an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7; a mutation set of L234G, G236L, P238G, and an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7; or a mutation set of L234G, G236L, and an insertion of amino acid Gly between positions

P238 and S239, as compared to SEQ ID NO: 7, wherein the first polypeptide further comprises at least, about, or exactly 1-10, 1-20, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19 or 20 mutations in addition to the mutation set as compared to SEQ ID NO: 7; and a second polypeptide comprises a variant sequence of SEQ ID NO: 7, wherein the second polypeptide comprises: a deletion of amino acid Pro at position 238, as compared to SEQ ID NO: 7; a deletion of amino acid Gly at position 237, and a mutation of P238D, as compared to SEQ ID NO: 7; an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID

NO: 7; an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7; a mutation set of L234G, G236L, P238G, and an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7; or a mutation set of L234G, G236L, and an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7, wherein the second polypeptide further comprises at least, about, or exactly 1-10, 1-20, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19 or 20 mutations in addition to the mutation set as compared to SEQ ID NO: 7.

In some embodiments, a dimer molecule comprises a first polypeptide comprising a variant sequence of SEQ ID NO: 7, provided that the polypeptide comprises a deletion of amino acid Pro at position 238, as compared to SEQ ID NO: 7, wherein the first polypeptide further comprises at least, about, or exactly 1-10, 1-20, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19 or 20 mutations in addition to the mutation set as compared to SEQ ID NO: 7; and a second polypeptide comprising a variant sequence of SEQ ID NO: 7, provided that the polypeptide comprises a deletion of amino acid Pro at position 238, as compared to SEQ ID NO: 7, wherein the second polypeptide further comprises at least, about, or exactly 1-10, 1-20, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19 or 20 mutations in addition to the mutation set as compared to SEQ ID NO: 7.

In some embodiments, a dimer molecule comprises a first polypeptide comprising a variant sequence of SEQ ID NO: 7, provided that the polypeptide comprises a deletion of amino acid Gly at position 237, and a mutation of P238D, as compared to SEQ ID NO: 7, wherein the first polypeptide further comprises at least, about, or exactly 1-10, 1-20, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19 or 20 mutations in addition to the mutation set as compared to SEQ ID NO: 7; and a second polypeptide comprising a variant sequence of SEQ ID NO: 7, provided that the polypeptide comprises a deletion of amino acid Gly at position 237, and a mutation of P238D, as compared to SEQ ID NO: 7, wherein the second polypeptide further comprises at least, about, or exactly 1-10, 1-20, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19 or 20 mutations in addition to the mutation set as compared to SEQ ID NO: 7. In some embodiments, a dimer molecule comprises a first polypeptide comprising a variant sequence of SEQ ID NO: 7, provided that the polypeptide comprises an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7, wherein the first polypeptide further comprises at least, about, or exactly 1-10, 1-20, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19 or 20 mutations in addition to the mutation set as compared to SEQ ID NO: 7; and a second polypeptide comprising a variant sequence of SEQ ID NO: 7, provided that the polypeptide comprises an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7, wherein the second polypeptide further comprises at least, about, or exactly 1-10, 1-20, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19 or 20 mutations in addition to the mutation set as compared to SEQ ID NO: 7.

In some embodiments, a dimer molecule comprises a first polypeptide comprising a variant sequence of SEQ ID NO: 7, provided that the polypeptide comprises an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7, wherein the first polypeptide further comprises at least, about, or exactly 1-10, 1-20, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19 or 20 mutations in addition to the mutation set as compared to SEQ ID NO: 7; and a second polypeptide comprising a variant sequence of SEQ ID NO: 7, provided that the polypeptide comprises an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7, wherein the second polypeptide further comprises at least, about, or exactly 1-10, 1-20, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19 or 20 mutations in addition to the mutation set as compared to SEQ ID NO: 7.

In some embodiments, a dimer molecule comprises a first polypeptide comprising a variant sequence of SEQ ID NO: 7, provided that the polypeptide comprises a mutation set of L234G, G236L, P238G, and an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7, wherein the first polypeptide further comprises at least, about, or exactly 1-10, 1-20, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19 or 20 mutations in addition to the mutation set as compared to SEQ ID NO: 7; and a second polypeptide comprising a variant sequence of SEQ ID NO: 7, provided that the polypeptide comprises a mutation set of L234G, G236L, P238G, and an insertion of amino acid Asp between positions P238 and S239, and an insertion of an amino acid sequence GEV between positions 233 and 234, as compared to SEQ ID NO: 7, wherein the second polypeptide further comprises at least, about, or exactly 1-10, 1-20, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15,16, 17, 18, 19 or 20 mutations in addition to the mutation set as compared to SEQ ID NO: 7.

In some embodiments, a dimer molecule comprises a first polypeptide comprising a variant sequence of SEQ ID NO: 7, provided that the polypeptide comprises a mutation set of L234G, G236L, and an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7, wherein the first polypeptide further comprises at least, about, or exactly 1-10, 1-20, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19 or 20 mutations in addition to the mutation set as compared to SEQ ID NO: 7; and a second polypeptide comprising a variant sequence of SEQ ID NO: 7, provided that the polypeptide comprises a mutation set of L234G, G236L, and an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7, wherein the second polypeptide further comprises at least, about, or exactly 1-10, 1-20, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19 or 20 mutations in addition to the mutation set as compared to SEQ ID NO: 7.

P238 and S239, as compared to SEQ ID NO: 7; and a second polypeptide comprises a variant sequence of SEQ ID NO: 7, wherein the second polypeptide comprises: a deletion of amino acid Pro at position 238, as compared to SEQ ID NO: 7; a deletion of amino acid Gly at position 237, and a mutation of P238D, as compared to SEQ ID NO: 7; an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7; a mutation set of L234G, G236L, P238G, and an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7; or a mutation set of L234G, G236L, and an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7.

In some embodiments, a dimer molecule comprises a first polypeptide comprising a variant sequence of SEQ ID NO: 7, provided that the polypeptide comprises a deletion of amino acid Pro at position 238, as compared to SEQ ID NO: 7; and a second polypeptide comprising a variant sequence of SEQ ID NO: 7, provided that the polypeptide comprises a deletion of amino acid Pro at position 238, as compared to SEQ ID NO: 7.

In some embodiments, a dimer molecule comprises a first polypeptide comprising a variant sequence of SEQ ID NO: 7, provided that the polypeptide comprises a deletion of amino acid Gly at position 237, as compared to SEQ ID NO: 7; and a second polypeptide comprising a variant sequence of SEQ ID NO: 7, provided that the polypeptide comprises a deletion of amino acid Gly at position 237, as compared to SEQ ID NO: 7.

In some embodiments, a dimer molecule comprises a first polypeptide comprising a variant sequence of SEQ ID NO: 7, provided that the polypeptide comprises an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; and a second polypeptide comprising a variant sequence of SEQ ID NO: 7, provided that the polypeptide comprises an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7.

In some embodiments, a dimer molecule comprises a first polypeptide comprising a variant sequence of SEQ ID NO: 7, provided that the polypeptide comprises an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7; and a second polypeptide comprising a variant sequence of SEQ ID NO: 7, provided that the polypeptide comprises an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7.

In some embodiments, a dimer molecule comprises a first polypeptide comprising a variant sequence of SEQ ID NO: 7, provided that the polypeptide comprises a mutation set of L234G, G236L, P238G, and an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7; and a second polypeptide comprising a variant sequence of SEQ ID NO: 7, provided that the polypeptide comprises a mutation set of L234G, G236L, P238G, and an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7.

In some embodiments, a dimer molecule comprises a first polypeptide comprising a variant sequence of SEQ ID NO: 7, provided that the polypeptide comprises a mutation set of L234G, G236L, and an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; and a second polypeptide comprising a variant sequence of SEQ ID NO: 7, provided that the polypeptide comprises a mutation set of L234G, G236L, and an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7.

In some embodiments, the variant IgG Fc polypeptide is conjugated to the inhibitory receptor effector domain. Non-limiting examples of Fc domains linked to inhibitory receptor effector domains can be found in U.S. Non-Provisional Application No. 18/048,747, or PCT Application No. PCT/US2022/078537, each of which is hereby incorporated by reference in its entirety. In some embodiments, the variant IgG Fc polypeptide is conjugated to a C-terminus of the inhibitory receptor effector domain. In some embodiments, when the inhibitory receptor effector domain is an antibody, the variant IgG Fc polypeptide is conjugated to the C-terminus of the heavy chain of the antibody that forms the inhibitor receptor effector domain. In some embodiments, the N-terminus of the variant IgG Fc polypeptide is conjugated to the C-terminus of the inhibitory receptor effector domain. In some embodiments, the variant IgG Fc polypeptide is directly conjugated, such as without a linker sequence, to the inhibitory receptor effector domain. In some embodiments, the variant IgG Fc polypeptide is conjugated to the inhibitory receptor effector domain through a linker, such as a peptide linker. In some embodiments, the linker is as provided for herein.

In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of inhibitory receptors encoded by the genes: LAG3, BTLA/CD272, CD200R1, CD200R1, CD22/Siglec2, CD300A, CD300LF/CD300F, CD33/Siglec3, CD5, CD72, CEACAM 1, CLEC12A, CLEC4A, CTLA4/CD152, FCGR2B/CD32B, KIRs, KLRB1/CD161, KLRC1, KLRG1, LAIR1, LILRB1, LILRB2, LILRB4, LILRB5, NCR2/NKp44, PDCD1, PECAM1/CD31, PILRA, PVR/CD155, SIGLEC11, SIGLEC5, SIGLEC7, SIGLEC8, SIGLEC9, SIRPA, TIGIT, VSTM1/SIRL1, MAFA, NKG2A, CMRF35H, CD66a, CD66d, CD33, SIGLEC6, ILT2, ILT3, ILT4, ILT5, LIR8, KIR2DL, KIR2DL1, KIR3DL, SIRPa, KIR2DL2/3, KIR2DL5, KIRDL1, KIRDL2, KIRDL3, TIM3, Tactile, IRp60, NKRP1, IAP, PIR-B, CD5, 2B4, GP49B, Ly49Q, MICL, CD160, FCRL4, KIR3DL1, KIR2DL2, LILRB3, DCIR, NKRP-1D, LY49, MAIR-I, CD79a, CD79b, CD19, CD21, CD40, TLR3, CD28, CCR5, or CCR1.

In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by BTLA/CD272. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by CD200R1. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by CD22/Siglec2. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by CD300A. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by CD3OOLF/CD3OOF. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by CD33/Siglec3. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by CD5. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by CD72. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by CEACAM 1. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by CLEC12A. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by CLEC4A. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by CTLA4/CD152. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by FCGR2B/CD32B. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by KIRs. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by KLRB1/CD161. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by KLRC1. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by KLRG1. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by LAIR1. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by LILRB 1. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by LILRB2. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by LILRB4. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by LILRB5. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by NCR2/NKp44. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by PDCD1. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by PECAM1/CD31. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by PILRA. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by PVR/CD155. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by SIGLEC11. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by SIGLEC5. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by SIGLEC7. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by SIGLEC8. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by SIGLEC9. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by SIRPA. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by TIGIT. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by VSTM1/SIRL1. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by MAFA. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by NKG2A. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by CMRF35H. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by CD66a. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by CD66d. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by CD33. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by SIGLEC6. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by ILT2. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by ILT3. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by ILT4. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by ILT5. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by LIR8. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by KIR2DL. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by KIR3DL. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by SIRPa. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by KIR2DL2/3. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by KIR2DL5. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by KIRDL1. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by KIRDL2. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by KIRDL3. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by TIM3. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by Tactile. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by IRp60. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by NKRP1. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by IAP. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by PIR-B. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by 2B4. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by GP49B. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by Ly49Q. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by MICL. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by LAG3. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by CD 160. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by FCRL4. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by KIR3DL1. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by KIR2DL2. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by LILRB3. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by DCIR. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by NKRP- 1D. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by LY49. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by MAIR-I. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by CD79a. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by CD79b. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by CD 19. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by CD21. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by CD40. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by TLR3. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by CD28. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by CCR5. In some embodiments, the inhibitory receptor effector domain binds and modulates the activity of the inhibitory receptor encoded by CCR1.

In some embodiments, the variant IgG Fc polypeptide is also linked to the FcyRII binding effector domain. Non-limiting examples of Fc domains linked to FcyRII binding effector domains can be found in U.S. Non-Provisional Application No. 18/048,747, or PCT Application No. PCT/US2022/078537, each of which is hereby incorporated by reference in its entirety. In some embodiments, the C-terminus of the variant IgG Fc polypeptide is linked to the N-terminus of the FcyRII binding effector domain. In some embodiments, the N-terminus of the variant IgG Fc polypeptide is linked to a C-terminus of the inhibitory receptor effector domain and the C- terminus of the variant IgG Fc polypeptide is linked to the N-terminus of the FcyRII binding effector domain. In some embodiments, the variant IgG Fc polypeptide is linked to the FcyRII binding effector domain directly, such as without a peptide linker. In some embodiments, the variant IgG Fc polypeptide is linked to the FcyRII binding effector domain through a peptide linker.

In some embodiments, the Fc domain is linked to an inhibitory receptor binding domain and an FcyRII binding effector domain, such as, but not limited to, those disclosed in U.S. NonProvisional Application No. 18/048,747, or PCT Application No. PCT/US2022/078537, each of which is hereby incorporated by reference in its entirety. In some embodiments, the C-terminus of the Fc domain is linked to the N-terminus of the FcyRII binding effector domain. In some embodiments, the N-terminus of the Fc domain is linked to a C-terminus of the inhibitory receptor effector domain and the C-terminus of the Fc domain is linked to the N-terminus of the FcyRII binding effector domain. In some embodiments, the Fc domain is linked to the FcyRII binding effector domain directly, such as without a peptide linker. In some embodiments, the Fc domain is linked to the FcyRII binding effector domain through a peptide linker.

Examples of peptide linkers that can be used are known in the art and non-limiting examples are provide for herein.

As used herein, the term “FcyRII binding effector domain” refers to a polypeptide, such as an antibody, that binds to FcyRII receptor. Examples of such receptors include the FcyRIIa or FcyRIIb receptor. In some embodiments, the FcyRII binding effector domain is an antibody. In some embodiments, the FcyRII binding effector domain is a scFv antibody. In some embodiments, the N-terminus of the FcyRII binding effector domain is bound to the C-terminus of the Fc domain.

In some embodiments, a method of modulating two types of cells is provided. In some embodiments, the method comprises contacting the two type of cells, with any one of the polypeptides provided herein. In some embodiments, the first cell is a T-cell, NK Cell, Dendritic cell, and the like; and the second cell is a B-Cell, an antigen presenting cell (APC), or a myeloid cell.

In some embodiments, a method of modulating the activity of two types of cells in a subject is provided. In some embodiments, the method comprises administering to the subject a polypeptide, such as those provided herein, or a pharmaceutical composition comprising the same. In some embodiments, the first cell is a T-cell, NK Cell, Dendritic cell, and the like; and the second cell is a B-Cell, an antigen presenting cell (APC), or a myeloid cell.

In some embodiments, a method of inhibiting an activated immune cell (e.g. T-cell) and the activity of a B-Cell, an antigen presenting cell (APC), or a myeloid cell, is provided. In some embodiments, the method comprises contacting the activated immune cell and the B Cell or antigen presenting cell with a polypeptide, such as those provided herein, or a pharmaceutical composition comprising the same.

In some embodiments, a method of activating or enhancing an activated immune cell (e.g. T-cell) and the activity of B-Cell, an antigen presenting cell (APC), or a myeloid cell, is provided. In some embodiments, the method comprises contacting the activated immune cell and the B Cell or antigen presenting cell with a polypeptide, such as those provided herein, or a pharmaceutical composition comprising the same.

In some embodiments, a method of bridging a first cell and a second cell with a heterologous molecule in a subject, is provided. In some embodiments, the method comprises administering to the subject a polypeptide, such as those provided herein, or a pharmaceutical composition comprising the same to the subject. In some embodiments, the polypeptide is bound to the first cell and the second cell at the same time. In some embodiments, the polypeptide is bound to the first cell and the second cell not at the same time. In some embodiments, the polypeptide is bound to the first cell and the second cell at nearly the same time. In some embodiments, the polypeptide is bound to the first cell and the second cell, wherein the polypeptide is bound to the first cell long enough to bridge it to the second cell. In some embodiments, the polypeptide is bound to the first cell and the second cell, wherein the polypeptide is bound to the second cell long enough to bridge it to the first cell.

In some embodiments, the variant IgG Fc polypeptides provided herein can be conjugated to effector domains and/or antibodies. Antibody molecule, as that term is used herein, refers to a polypeptide, e.g., an immunoglobulin chain or fragment thereof, comprising at least one functional immunoglobulin variable domain sequence. An antibody molecule encompasses antibodies (e.g., full-length antibodies) and antibody fragments. In some embodiments, an antibody molecule comprises an antigen binding or functional fragment of a full length antibody, or a full length immunoglobulin chain. For example, a full-length antibody is an immunoglobulin (Ig) molecule (e.g., an IgG antibody) that is naturally occurring or formed by normal immunoglobulin gene fragment recombinatorial processes). In embodiments, an antibody molecule refers to an immunologically active, antigen-binding portion of an immunoglobulin molecule, such as an antibody fragment. An antibody fragment, e.g., functional fragment, comprises a portion of an antibody, e.g., Fab, Fab', F(ab')2, F(ab)2, variable fragment (Fv), domain antibody (dAb), or single chain variable fragment (scFv). A functional antibody fragment binds to the same antigen as that recognized by the intact (e.g., full-length) antibody. The terms “antibody fragment” or “functional fragment” also include isolated fragments consisting of the variable regions, such as the “Fv” fragments consisting of the variable regions of the heavy and light chains or recombinant single chain polypeptide molecules in which light and heavy variable regions are connected by a peptide linker (“scFv proteins”). In some embodiments, an antibody fragment does not include portions of antibodies without antigen binding activity, such as Fc fragments or single amino acid residues. Exemplary antibody molecules include full length antibodies and antibody fragments, e.g., dAb (domain antibody), single chain, Fab, Fab’, and F(ab’)2 fragments, and single chain variable fragments (scFvs).

The term “antibody molecule” also encompasses whole or antigen binding fragments of domain, or single domain, antibodies, which can also be referred to as “sdAb” or “VHH.” Domain antibodies comprise either VH or VL that can act as stand-alone, antibody fragments. Additionally, domain antibodies include heavy-chain-only antibodies (HCAbs). Domain antibodies also include a CH2 domain of an IgG as the base scaffold into which CDR loops are grafted. It can also be generally defined as a polypeptide or protein comprising an amino acid sequence that is comprised of four framework regions interrupted by three complementarity determining regions. This is represented as FR1- CDR1 -FR2-CDR2-FR3-CDR3-FR4. sdAbs can be produced in camelids such as llamas, but can also be synthetically generated using techniques that are well known in the art. The numbering of the amino acid residues of a sdAb or polypeptide is according to the general numbering for VH domains given by Kabat et al. ("Sequence of proteins of immunological interest," US Public Health Services, NIH Bethesda, MD, Publication No. 91, which is hereby incorporated by reference). According to this numbering, FR1 of a sdAb comprises the amino acid residues at positions 1-30, CDR1 of a sdAb comprises the amino acid residues at positions 31-36, FR2 of a sdAb comprises the amino acids at positions 36-49, CDR2 of a sdAb comprises the amino acid residues at positions 50-65, FR3 of a sdAb comprises the amino acid residues at positions 66- 94, CDR3 of a sdAb comprises the amino acid residues at positions 95-102, and FR4 of a sdAb comprises the amino acid residues at positions 103-113. Domain antibodies are also described in W02004041862 and WO2016065323, each of which is hereby incorporated by reference. The domain antibodies can be a targeting moiety as described herein.

Antibody molecules can be monospecific (e.g., monovalent or bivalent), bispecific (e.g., bivalent, trivalent, tetravalent, pentavalent, or hexavalent), trispecific (e.g., trivalent, tetravalent, pentavalent, hexavalent), or with higher orders of specificity (e.g, tetraspecific) and/or higher orders of valency beyond hexavalency. An antibody molecule can comprise a functional fragment of a light chain variable region and a functional fragment of a heavy chain variable region, or heavy and light chains may be fused together into a single polypeptide. Effector, as that term is used herein, refers to an entity, e.g., a cell or molecule, e.g., a soluble or cell surface molecule, which mediates an immune response. In some embodiments, the effector is an antibody. In some embodiments, the effectors binding domains as provided for herein, refers to a polypeptide (e.g.) that has sufficient binding specificity that it can bind the effector with sufficient specificity that it can serve as an effector binding/modulating molecule. In some embodiments, it binds to effector with at least 10, 20, 30, 40, 50, 60, 70, 80, 90, or 95% of the affinity of the naturally occurring counter-ligand. In some embodiments, it has at least 60, 70, 80, 90, 95, 99, or 100% sequence identity ,or substantial sequence identity, with a naturally occurring counter-ligand for the effector.

Elevated risk, as used herein, refers to the risk of a disorder in a subject, wherein the subject has one or more of a medical history of the disorder or a symptom of the disorder, a biomarker associated with the disorder or a symptom of the disorder, or a family history of the disorder or a symptom of the disorder.

In some embodiments, the inhibitory effector binding domain can be referred to as an inhibitory immune checkpoint molecule. This can refer to a polypeptide that can bind to the checkpoint molecule and agonize its cognate inhibitory activity. For example, the antibody can be an anti-PD-1 antibody that binds to PD-1 and agonizes its activity. In some embodiments, the antibody inhibits the inhibitory checkpoint activity, such that it antagonizes the inhibitory activity. For example, the antibody can be an anti-PD-1 antibody that binds to PD-1 and antagonizes its activity. The same can be done if the target is any of the inhibitory receptors, such as those provided for herein. In some embodiments, the inhibitory checkpoint receptor is LAG-3.

The domains can have similarity to those as provided for herein or those that are incorporated by reference. Sequence identity, percentage identity, and related terms, as those terms are used herein, refer to the relatedness of two sequences, e.g., two nucleic acid sequences or two amino acid or polypeptide sequences. In the context of an amino acid sequence, the term "substantially identical" is used herein to refer to a first amino acid that contains a sufficient or minimum number of amino acid residues that are i) identical to, or ii) conservative substitutions of aligned amino acid residues in a second amino acid sequence such that the first and second amino acid sequences can have a common structural domain and/or common functional activity. For example, amino acid sequences that contain a common structural domain having at least about 85%, 90%. 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a reference sequence, e.g., an amino acid sequence provided herein.

In the context of nucleotide sequence, such as those encoding for the domains, the term "substantially identical" is used herein to refer to a first nucleic acid sequence that contains a sufficient or minimum number of nucleotides that are identical to aligned nucleotides in a second nucleic acid sequence such that the first and second nucleotide sequences encode a polypeptide having common functional activity, or encode a common structural polypeptide domain or a common functional polypeptide activity. For example, nucleotide sequences having at least about 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a reference sequence, e.g., an amino acid sequence provided herein.

The term “functional variant” refers to polypeptides that have a substantially identical amino acid sequence to the naturally-occurring sequence, or are encoded by a substantially identical nucleotide sequence, and are capable of having one or more activities of the naturally- occurring sequence. For example, a Fc variant can have the amino acid sequence of a Fc domain but comprise a mutation that affects its binding to the FcvRIIa or FcyRIIb receptor.

Calculations of homology or sequence identity between sequences (the terms are used interchangeably herein) can be performed as follows.

To determine the percent identity of two amino acid sequences, or of two nucleic acid sequences, the amino acid sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second amino acid or nucleic acid sequence for optimal alignment and non-homologous sequences can be disregarded for comparison purposes). In a preferred embodiment, the length of a reference sequence aligned for comparison purposes is at least 30%, preferably at least 40%, more preferably at least 50%, 60%, and even more preferably at least 70%, 80%, 90%, 100% of the length of the reference sequence. The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position (as used herein amino acid or nucleic acid "identity" is equivalent to amino acid or nucleic acid "homology"). The percent identity between the two sequences is a function of the number of identical positions shared by the amino acid sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences.

The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. In a preferred embodiment, the percent identity between two amino acid sequences is determined using the Needleman and Wunsch ((1970) J. Mol. Biol. 48:444-453 ) algorithm which has been incorporated into the GAP program in the GCG software package (available at http://www.gcg.com), using either a Blossum 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6. In yet another preferred embodiment, the percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package (available at http://www.gcg.com), using aNWSgapdna.CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6. A particularly preferred set of parameters (and the one that should be used unless otherwise specified) are a Blossum 62 scoring matrix with a gap penalty of 12, a gap extend penalty of 4, and a frameshift gap penalty of 5.

The percent identity between two amino acid or nucleotide sequences can be determined using the algorithm of E. Meyers and W. Miller ((1989) CABIOS, 4: 11-17) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4.

The nucleic acid and protein sequences described herein can be used as a "query sequence" to perform a search against public databases to, for example, identify other family members or related sequences. Such searches can be performed using the NBLAST and XBLAST programs (version 2.0) of Altschul, et al. (1990) J. Mol. Biol. 215:403-10. BLAST nucleotide searches can be performed with the NBLAST program, score = 100, wordlength = 12 to obtain nucleotide sequences homologous to for example any a nucleic acid sequence provided herein. BLAST protein searches can be performed with the XBLAST program, score = 50, wordlength = 3 to obtain amino acid sequences homologous to protein molecules provided herein. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al., (1997) Nucleic Acids Res. 25:3389-3402. When utilizing BLAST and Gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used. See http://www.ncbi.nlm.nih. ov. As used herein, the term “hybridizes under low stringency, medium stringency, high stringency, or very high stringency conditions” describes conditions for hybridization and washing. Guidance for performing hybridization reactions can be found in Current Protocols in Molecular Biology, John Wiley & Sons, N.Y. (1989), 6.3.1-6.3.6, which is incorporated by reference. Aqueous and nonaqueous methods are described in that reference and either can be used. Specific hybridization conditions referred to herein are as follows: 1) low stringency hybridization conditions in 6X sodium chloride/sodium citrate (SSC) at about 45°C, followed by two washes in 0.2X SSC, 0.1% SDS at least at 50°C (the temperature of the washes can be increased to 55°C for low stringency conditions); 2) medium stringency hybridization conditions in 6X SSC at about 45°C, followed by one or more washes in 0.2X SSC, 0.1% SDS at 60°C; 3) high stringency hybridization conditions in 6X SSC at about 45°C, followed by one or more washes in 0.2X SSC, 0.1% SDS at 65°C; and preferably 4) very high stringency hybridization conditions are 0.5M sodium phosphate, 7% SDS at 65°C, followed by one or more washes at 0.2X SSC, 1% SDS at 65°C. Very high stringency conditions (4) are the preferred conditions and the ones that should be used unless otherwise specified.

It is understood that the molecules of the present embodiments may have additional conservative or non-essential amino acid substitutions, which do not have a substantial effect on their functions.

The term "amino acid" is intended to embrace all molecules, whether natural or synthetic, which include both an amino functionality and an acid functionality and capable of being included in a polymer of naturally-occurring amino acids. Exemplary amino acids include naturally-occurring amino acids; analogs, derivatives and congeners thereof; amino acid analogs having variant side chains; and all stereoisomers of any of any of the foregoing. As used herein the term "amino acid" includes both the D- or L- optical isomers and peptidomimetics.

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 have been defined in the art. 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., tyrosine, phenylalanine, tryptophan, histidine).

The molecules and polypeptides provided for herein can be used to treat auto-immune diseases. Thus, in some embodiments, embodiments are provided for methods of treating an autoimmune disease or disorder in a subject. In some embodiments, the methods comprise administering to the subject a compound as provided for herein. In some embodiments, the subject has or is at risk of having an autoimmune disorder. In some embodiments, the autoimmune disorder is Type 1 Diabetes, Multiple Sclerosis, Cardiomyositis, vitiligo, alopecia, inflammatory bowel disease (IBD, e.g. Crohn’s disease or ulcerative colitis), Sjogren’s syndrome, focal segmented glomerular sclerosis (FSGS), scleroderma/systemic sclerosis (SSc) or rheumatoid arthritis. In some embodiments, the treatment minimizes rejection of, minimizes immune effector cell mediated damage to, prolongs the survival of subject tissue undergoing, or a risk for, autoimmune attack, such as from a transplant.

Other examples of autoimmune disorders and diseases that can be treated with the molecules and polypeptides described herein include, but are not limited to, myocarditis, postmyocardial infarction syndrome, postpericardiotomy syndrome, subacute bacterial endocarditis, anti-glomerular basement membrane nephritis, interstitial cystitis, lupus nephritis, membranous glomerulonephropathy, chronic kidney disease (CKD), autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, anti synthetase syndrome, alopecia areata, autoimmune angioedema, autoimmune progesterone dermatitis, overlap connective tissues disease syndromes, polymyalgia rheumatic, autoimmune urticaria, bullous pemphigoid, cicatricial pemphigoid, dermatitis herpetiformis, discoid lupus erythematosus, epidermolysis bullosa acquisita, erythema nodosum, anti -neutrophil cytoplasmic antibody associated vasculitis, Henoch-Schonlein purpura, Cogan’s syndrome, Buerger’s disease, Susan’s disease, immune complex vasculitis, primary angiitis of the CNS, gestational pemphigoid, hidradenitis suppurativa, lichen planus, lichen sclerosus, linear iga disease (lad), morphea, pemphigus vulgaris, pityriasis lichenoides et varioliformis acuta, mucha-habermann disease, psoriasis, systemic scleroderma, vitiligo, Addison's disease, autoimmune polyendocrine syndrome (APS) type 1, autoimmune polyendocrine syndrome (APS) type 2, juvenile idiopathic arthritis juvenile dermatomyositis, autoimmune brain disease, autoimmune polyendocrine syndrome (APS) type 3, autoimmune pancreatitis (AIP), diabetes mellitus type 1, autoimmune thyroiditis, Ord's thyroiditis, Graves' disease, autoimmune oophoritis, endometriosis, autoimmune orchitis, Sjogren's syndrome, autoimmune enteropathy, Coeliac disease, Crohn's disease, microscopic colitis, ulcerative colitis, thrombocytopenia, adiposis, dolorosa, adult-onset Still's disease, ankylosing spondylitis, CREST syndrome, drug-induced lupus, enthesitis-related arthritis, eosinophilic fasciitis, Felty syndrome, IgG4-related disease, juvenile arthritis, lyme disease (chronic), mixed connective tissue disease (MCTD), palindromic rheumatism, Parry Romberg syndrome, Parsonage-Tumer syndrome, psoriatic arthritis, IBD-associated arthritis, reactive arthritis, relapsing polychondritis, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, autoimmune complications of immune checkpoint inhibitors (IRAEs), sarcoidosis, neurosarcoidosis, Schnitzler syndrome, systemic lupus erythematosus (SLE), undifferentiated connective tissue disease (UCTD), dermatomyositis, IgG4 related disease, fibromyalgia, antiphospholipid syndrome, inclusion body myositis, myositis, myasthenia gravis, neuromyotonia, paraneoplastic cerebellar degeneration, polymyositis, acute disseminated encephalomyelitis (ADEM), adult onset Still's disease, acute motor axonal neuropathy, anti-N- Methyl-D-Aspartate (anti-NMDA) receptor encephalitis, warm antibody hemolytic anemia (wAIHA), immune thrombocytopenia, immune thrombotic thrombocytopenia, thrombotic thrombocytopenia, pernicious anemia, aplastic anemia, Evan's syndrome, autoimmune neutropenia, acquired von Willibrand syndrome, recurring fetal loss, Rh mismatch, Balo concentric sclerosis, Bickerstaff s encephalitis, chronic inflammatory demyelinating polyneuropathy, Guillain-Barre syndrome, Hashimoto’s encephalopathy, idiopathic inflammatory demyelinating diseases, Lambert-Eaton myasthenic syndrome, primary biliary sclerosis, glomerulonephritis, glomerular basement membrane disease, multiple sclerosis, Oshtoran syndrome, pediatric autoimmune neuropsychiatric disorder associated with Streptococcus (PANDAS), progressive inflammatory neuropathy, cutaneous lupus erythematosus, restless leg syndrome, pemphigus foliaceus including fogo selvage, transplantation, antibody -mediated rejection, alloantibody hypersensitization, xenoantibody mediated rejection, solid organ rejection, graft vs host disease acute and chronic, stiff person syndrome, Sydenham chorea, transverse myelitis, autoimmune retinopathy, autoimmune uveitis, uveitis, Cogan syndrome, Graves ophthalmopathy, amyotrophic lateral sclerosis (ALS), Parkinson's disease, autoimmune encephalitis, CNS vasculitis, chronic idiopathic demyelinating polyneuropathy (CIDP), keratitis, intermediate uveitis, ligneous conjunctivitis, Mooren’s ulcer, neuromyelitis optica, opsoclonus myoclonus syndrome, optic neuritis, scleritis, Susac’s syndrome, sympathetic ophthalmia, Tolosa-Hunt syndrome, rheumatic heart disease, chronic rhinosinusitis with nasal polyps, allergic bronchoplmonary mycosis, hypersensitivity pneumonitis, rheumatoid arthritis-associated interstitial lung disease (RA-ILD), nonspecific interstitial pneumonia, allergic asthma, infectious disease/vaccination, antibody dependent enhancement (as wit dengue virus infection), chronic meningitis, anti-myelin oligodendrocyte glycoprotein (MOG) disease, activated-DLBCL, anti-drug antibody, anti-gene therapy vector antibody (anti-AAV antibody), antibody to therapeutic biologic agents (cytokines, monoclonal antibodies, enzymes, coagulation factors), autoimmune inner ear disease (AIED), Meniere's disease, Behcet’s disease, eosinophilic granulomatosis with polyangiitis (EGPA), giant cell arteritis, polyglandular autoimmune endocrine syndromes, granulmatosis with polyangiitis (GPA), IgA vasculitis (IgAV), Kawasaki’s disease, leukocytoclastic vasculitis, lupus vasculitis, rheumatoid vasculitis, microscopic polyangiitis (MPA), polyarteritis nodosa (PAN), polymyalgia rheumaticia, vasculitis, primary immune deficiency, and the like.

Other examples of potential autoimmune disorders and diseases, as well as autoimmune comorbidities that can be treated with the molecules and polypeptides described herein include, but are not limited to, Chronic fatigue syndrome, Complex regional pain syndrome, Eosinophilic esophagitis, Gastritis, Interstitial lung disease, POEMS syndrome, Raynaud’s phenomenon, Primary immunodeficiency, Pyoderma gangrenosum, Agammaglobulinemia, Anyloidosis, Anyotrophic lateral sclerosis, Anti-tubular basement membrane nephritis, Atopic allergy, Atopic dermatitis, Autoimmune peripheral neuropathy, Blau syndrome, Castleman’s disease, Chagas disease, Chronic obstructive pulmonary disease, Chronic recurrent multifocal osteomyelitis, Complement component 2 deficiency, Contact dermatitis, Cushing’s syndrome, Cutaneous leukocytoclastic angiitis, Dego’ deiase, Eczema, Eosinophilic gastroenteritis, Eosinophilic pneumonia, Erythroblastosis fetalsis, Fibrodysplasia ossificans progressive, Gastrointestinal pemphigoid, Hypogammaglobulinemia, Idiopathic giant-cell myocarditis, Idiopathic pulmonary fibrosis, IgA nephropathy, Immunoregulatory lipoproteins, IPEX syndrome, Ligenous conjunctivitis, Majeed syndrome, Narcolepsy, Rasmussen’s encephalitis, Schizophrenia, Serum sickness, Spondyloathropathy, Sweet’s syndrome, Takayasu’s arteritis, and the like.

In some embodiments, the condition to be treated is a neoplastic disorder, such as a cancer. In contrast, to the molecule that is used to treat an autoimmune disorder the molecule is used to antagonize the inhibitor receptor to which the inhibitory receptor effector domain binds to. Additionally, the Fc domain comprises mutations that are not inhibitory. In some embodiments, the FcyRII binding effector domain binds preferentially to the FcyRII binding effector domain.

In some embodiments, the cancer is a solid or liquid tumor. In some embodiments, the liquid or solid tumor include, but are not limited to, hematopoietic cancer, lymphoid cancer, skin cancer, head and neck cancer, genitourinary cancer, blood cancer, lung cancer, breast cancer, brain cancer, esophageal cancer, colorectal cancer, pancreatic cancer, and any combination thereof.

As discussed elsewhere herein the different domains can be linked to together with a linker domain or region. Any linker region described herein can be used as a linker. Linkers can be for example, glycine/serine linkers. In some embodiments, the linker can comprise one or more repeats of GGGGS (SEQ ID NO: 27). In some embodiments, the linker comprises 1, 2, 3, 4, or 5 repeats. In some embodiments, the linker comprises GGGGSGGGGS (SEQ ID NO: 28). In some embodiments, the linker comprises GGGGSGGGGSGGGGS (SEQ ID NO: 29). In some embodiments, the linker comprises: GGGGS (SEQ ID NO: 27), (GGGGS)3 (SEQ ID NO:

29), (GGGGS)n (n=l, 2, 3, 4) (SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO:

30), (Gly)s (SEQ ID NO: 31), (Gly)₆ (SEQ ID NO: 32), (EAAAK)s (SEQ ID NO: 33), (EAAK)_n (n=l-3) (SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36), A(EAAAK)₄ALEA(EAAAK)4A (SEQ ID NO: 37), or AEAAAKEAAAKA (SEQ ID NO: 38). These linkers can be used in any of the compounds or compositions provided herein.

In some embodiments, the polypeptide that is the compound comprises at the N-terminus an antibody comprised of F(ab’)2 on an IgGl Fc backbone fused with scFvs on the C-terminus of the IgG Fc backbone. In some embodiments, the IgG Fc backbone is a IgGl Fc backbone. In some embodiments, the IgGl backbone is replaced with a IgG4 backbone, IgG2 backbone, or other similar IgG backbone. The IgG backbones described in this paragraph can be used throughout this application where a Fc region is referred to as part of the therapeutic compound. The Fc backbone can be the Fc region as provided for herein and have a mutation as provided for herein.

Thus, in some embodiments, the antibody comprised of F(ab’)2 on an IgGl Fc backbone can be an anti-PD-1 antibody, an anti-LAG-3, an anti-CTLA4 antibody (or any other antibody that binds to an inhibitory receptor) on an IgGl Fc. In some embodiments, the scFV segments fused to the C-terminus could be the FcyRII binding effector domain. In some embodiments, the polypeptide comprises two antibodies linked separately to two separate FcyRII binding effector domains. In some embodiments, the F(ab’)2 bind to PD-1 or LAG-3. In some embodiments, one antibody binds to PD-1 and the other binds to LAG-3.

In some embodiments, the FcyRII binding effector domain as provided for herein, for any of the polypeptides provided for herein are selective for FcyRIIb over the FcyRIIa-R131 isoform or the FcyRIIa-H131 isoform. Without being bound to any particular theory, these FcyRIIb binding effector domain can be used to help down regulate an immune response.

In some embodiments, when the inhibitory receptor effector domain is a checkpoint agonist, the Fc domain comprises mutations that are FcyRIIb selective mutations and the FcyRII binding effector domains is a FcyRIIb-specific scFv antibody.

Pharmaceutical Compositions and Kits

In some embodiments, the present embodiments provide compositions, e.g., pharmaceutically acceptable compositions, which include a therapeutic compound described herein, formulated together with a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, isotonic and absorption delaying agents, and the like that are physiologically compatible.

The carrier can be suitable for intravenous, intramuscular, subcutaneous, parenteral, rectal, local, ophthalmic, topical, spinal or epidermal administration (e.g. by injection or infusion). As used herein, the term “carrier” means a diluent, adjuvant, or excipient with which a compound is administered. In some embodiments, pharmaceutical carriers can also be liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical carriers can also be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, auxiliary, stabilizing, thickening, lubricating and coloring agents can be used. The carriers can be used in pharmaceutical compositions comprising the therapeutic compounds provided for herein.

The compositions and compounds of the embodiments provided for herein may be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, liposomes and suppositories. The preferred form depends on the intended mode of administration and therapeutic application. Typical compositions are in the form of injectable or infusible solutions. In some embodiments, the mode of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). In some embodiments, the therapeutic molecule is administered by intravenous infusion or injection. In another embodiment, the therapeutic molecule is administered by intramuscular or subcutaneous injection. In another embodiment, the therapeutic molecule is administered locally, e g., by injection, or topical application, to a target site.

The phrases "parenteral administration" and "administered parenterally" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion.

The compositions typically should be sterile and stable under the conditions of manufacture and storage. The composition can be formulated as a solution, microemulsion, dispersion, liposome, or other ordered structure suitable to high therapeutic molecule concentration. Sterile injectable solutions can be prepared by incorporating the active compound (i.e., therapeutic molecule) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile- filtered solution thereof. The proper fluidity of a solution can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prolonged absorption of injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin. As will be appreciated by the skilled artisan, the route and/or mode of administration will vary depending upon the desired results. In certain embodiments, the active compound may be prepared with a carrier that will protect the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for the preparation of such formulations are patented or generally known to those skilled in the art. See, e.g., Sustained and Controlled Release Drug Delivery Systems, J. R. Robinson, ed., Marcel Dekker, Inc., New York, 1978.

In certain embodiments, a therapeutic compound can be orally administered, for example, with an inert diluent or an assimilable edible carrier. The compound (and other ingredients, if desired) may also be enclosed in a hard or soft shell gelatin capsule, compressed into tablets, or incorporated directly into the subject's diet. For oral therapeutic administration, the compounds may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. To administer a compound by other than parenteral administration, it may be necessary to coat the compound with, or coadminister the compound with, a material to prevent its inactivation. Therapeutic compositions can also be administered with medical devices known in the art.

Dosage regimens are adjusted to provide the optimum desired response (e.g., a therapeutic response). For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms are dictated by and directly dependent on (a) the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals. An exemplary, non-limiting range for a therapeutically or prophylactically effective amount of a therapeutic compound is 0.1-30 mg/kg, more preferably 1-25 mg/kg. Dosages and therapeutic regimens of the therapeutic compound can be determined by a skilled artisan. In certain embodiments, the therapeutic compound is administered by injection (e.g., subcutaneously or intravenously) at a dose of about 1 to 40 mg/kg, e.g., 1 to 30 mg/kg, e.g., about 5 to 25 mg/kg, about 10 to 20 mg/kg, about 1 to 5 mg/kg, 1 to 10 mg/kg, 5 to 15 mg/kg, 10 to 20 mg/kg, 15 to 25 mg/kg, or about 3 mg/kg. The dosing schedule can vary from e.g., once a week to once every 2, 3, or 4 weeks. In one embodiment, the therapeutic compound is administered at a dose from about 10 to 20 mg/kg every other week. The therapeutic compound can be administered by intravenous infusion at a rate of more than 20 mg/min, e.g., 20-40 mg/min, and typically greater than or equal to 40 mg/min to reach a dose of about 35 to 440 mg/m2, typically about 70 to 310 mg/m2, and more typically, about 110 to 130 mg/m2. In embodiments, the infusion rate of about 110 to 130 mg/m2 achieves a level of about 3 mg/kg. In other embodiments, the therapeutic compound can be administered by intravenous infusion at a rate of less than 10 mg/min, e.g., less than or equal to 5 mg/min to reach a dose of about 1 to 100 mg/m2, e.g., about 5 to 50 mg/m2, about 7 to 25 mg/m2, or, about 10 mg/m2. In some embodiments, the therapeutic compound is infused over a period of about 30 min. It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.

The pharmaceutical compositions may include a "therapeutically effective amount" or a "prophylactically effective amount" of a therapeutic molecule. A "therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount of a therapeutic molecule may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the therapeutic compound to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of a therapeutic molecule t is outweighed by the therapeutically beneficial effects. A "therapeutically effective dosage" preferably inhibits a measurable parameter, e g., immune attack at least about 20%, more preferably by at least about 40%, even more preferably by at least about 60%, and still more preferably by at least about 80% relative to untreated subjects. The ability of a compound to inhibit a measurable parameter, e.g., immune attack, can be evaluated in an animal model system predictive of efficacy in transplant rejection or autoimmune disorders.

Alternatively, this property of a composition can be evaluated by examining the ability of the compound to inhibit, such inhibition in vitro by assays known to the skilled practitioner.

A "prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.

Also within the scope of the embodiments is a kit comprising a therapeutic compound described herein. The kit can include one or more other elements including: instructions for use; other reagents, e.g., a label, a therapeutic agent, or an agent useful for chelating, or otherwise coupling, a therapeutic molecule to a label or other therapeutic agent, or a radioprotective composition; devices or other materials for preparing the a therapeutic molecule for administration; pharmaceutically acceptable carriers; and devices or other materials for administration to a subject.

Enumerated Embodiments

1. A variant Fc polypeptide comprising a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 7, and wherein the variant Fc selectively binds to FcyRIip over FcyRIIa.

2. The variant Fc polypeptide of embodiment 1, wherein the variant Fc polypeptide is a variant IgGl polypeptide, a variant IgG2 polypeptide, a variant IgG3 polypeptide, a variant IgG4 polypeptide, a chimeric IgGl/IgG2 polypeptide, a chimeric IgGl/IgG3 polypeptide, a chimeric IgGl/IgG4 polypeptide, a chimeric IgG2/IgG3 polypeptide, a chimeric IgG2/IgG4 polypeptide, or a chimeric IgG3/IgG4 polypeptide.

3. The variant Fc polypeptide of any one of embodiments 1-2, wherein the variant Fc polypeptide comprises a mutation in the CH2 region and/or hinge region.

4. The variant Fc polypeptide of embodiment 3, wherein the mutation is a substitution, an insertion, or a deletion. 5. The variant Fc polypeptide of embodiment 4, wherein the substation of the variant polypeptide replaces the CH2 region of the IgG isotype with a CH2 region of a different IgG isotype.

6. The variant Fc polypeptide of any one of embodiments 1-5, wherein the variant Fc polypeptide comprises a CH2 domain polypeptide having at least 50%, at least 85%, at least 90%, at least 94%, at least 95%, or at least 99% identity to an amino acid sequence of SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, or SEQ ID NO: 24.

7. The variant Fc polypeptide of embodiment 6, wherein the CH2 domain polypeptide comprises an amino acid sequence of SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, or SEQ ID NO: 24.

8. The variant Fc polypeptide of any one of embodiments 1-7, wherein the variant Fc polypeptide comprises a hinge region sequence having at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, 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%, or at least 99% identity to SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, or SEQ ID NO: 18.

9. The variant Fc polypeptide of any one of embodiments 1-8, wherein the variant Fc polypeptide comprises a hinge region sequence having at least 1, at least 2, at least 3, at least 4, at least 5, or at least 6 mutations as compared to the hinge region of SEQ ID NO: 7.

10. The variant Fc polypeptide of any one of embodiment 8 or 9, wherein the variant Fc polypeptide comprises a mutation at position 228, 234, 235, 268, 274, 276, 296, 300, 309, 327, 330, 331, 339, or any combination thereof, as compared to SEQ ID NO: 7.

11. The variant Fc polypeptide of any one of embodiments 8-10, wherein the variant Fc polypeptide comprises a mutation at position 228, as compared to SEQ ID NO: 7.

12. The variant Fc polypeptide of any one of embodiments 8-10, wherein the variant Fc polypeptide comprises a mutation at position 234, as compared to SEQ ID NO: 7.

13. The variant Fc polypeptide of any one of embodiments 8-10, wherein the variant Fc polypeptide comprises a mutation at position 235, as compared to SEQ ID NO: 7.

14. The variant Fc polypeptide of any one of embodiments 8-10, wherein the variant Fc polypeptide comprises a mutation at position 228 and 235, as compared to SEQ ID NO: 7. 15. The variant Fc polypeptide of any one of embodiments 8-10, wherein the variant Fc polypeptide comprises a mutation at position 228 and 234, as compared to SEQ ID NO: 7.

16. The variant Fc polypeptide of any one of embodiments 8-10, wherein the variant Fc polypeptide comprises a mutation at position 234 and 235, as compared to SEQ ID NO: 7.

17. The variant Fc polypeptide of any one of embodiments 1-16, wherein the variant Fc polypeptide comprises a mutation of S228P, L234F, L235E, H268Q, K274Q, N276K, Y296F, Y300F, L309V, A327G, A330S, P331S, A339T, or any combination thereof, as compared to SEQ ID NO: 7.

18. The variant Fc polypeptide of embodiment 17, wherein the variant Fc polypeptide comprises a mutation of S228P, as compared to SEQ ID NO: 7.

19. The variant Fc polypeptide of embodiment 17, wherein the variant Fc polypeptide comprises a mutation of L234F, as compared to SEQ ID NO: 7.

20. The variant Fc polypeptide of embodiment 17, wherein the variant Fc polypeptide comprises a mutation of L235E, as compared to SEQ ID NO: 7.

21. The variant Fc polypeptide of embodiment 17, wherein the variant Fc polypeptide comprises a mutation of S228P and L234F as compared to SEQ ID NO: 7.

22. The variant Fc polypeptide of embodiment 17, wherein the variant Fc polypeptide comprises a mutation of S228P and L235E as compared to SEQ ID NO: 7.

23. The variant Fc polypeptide of embodiment 17, wherein the variant Fc polypeptide comprises a mutation of L234F and L235E as compared to SEQ ID NO: 7.

24. The variant Fc polypeptide of embodiment 17, wherein the variant Fc polypeptide comprises a mutation of S228P, L234F and L235E as compared to SEQ ID NO: 7.

25. The variant Fc polypeptide of embodiment 1, wherein the variant Fc polypeptide is selective for FcyRIip.

26. The variant Fc polypeptide of embodiment 1, wherein the variant Fc polypeptide comprises FcyRIip selective mutations, such as those provided for herein.

27. The variant Fc polypeptide of embodiment 26, wherein the FcyRIip selective mutations are in the CH2 domain and/or the hinge domain of the variant Fc polypeptide.

28. The variant Fc polypeptide of any one of embodiments 1-27, wherein the variant Fc polypeptide binds selectively to FcyRIip over FcyRIIa. 29. A variant Fc polypeptide comprising a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to of SEQ ID NO: 1, provided that the variant Fc polypeptide comprises a mutation at position 228, 234, 235, 268, 274, 276, 296, 300, 309, 327, 330, 331, 339, or any combination thereof, as compared to SEQ ID NO: 7, and wherein the variant Fc polypeptide selectively binds to FcyRIip over FcyRIIa.

30. The variant Fc polypeptide of embodiment C, wherein the variant Fc polypeptide is a variant IgGl polypeptide, a variant IgG2 polypeptide, a variant IgG3 polypeptide, a variant IgG4 polypeptide, a chimeric IgGl/IgG2 polypeptide, a chimeric IgGl/IgG3 polypeptide, a chimeric IgGl/IgG4 polypeptide, a chimeric IgG2/IgG3 polypeptide, a chimeric IgG2/IgG4 polypeptide, or a chimeric IgG3/IgG4 polypeptide.

31. The variant Fc polypeptide of embodiment 29, wherein the variant Fc polypeptide comprises a CH2 domain comprising a sequence of SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, or SEQ ID NO: 24.

32. The variant Fc polypeptide of any one of embodiments 29-31, wherein the variant Fc polypeptide comprises a hinge region sequence having at least 1, at least 2, at least 3, at least 4, at least 5, or at least 6 mutations as compared to the hinge region of SEQ ID NO: 7.

33. The variant Fc polypeptide of any one of embodiments 29-32, wherein the variant Fc polypeptide comprises a mutation at position 228, as compared to SEQ ID NO: 7.

34. The variant Fc polypeptide of any one of embodiments 29-32, wherein the variant Fc polypeptide comprises a mutation at position 234, as compared to SEQ ID NO: 7.

35. The variant Fc polypeptide of any one of embodiments 29-32, wherein the variant Fc polypeptide comprises a mutation at position 235, as compared to SEQ ID NO: 7.

36. The variant Fc polypeptide of any one of embodiments 29-32, wherein the variant Fc polypeptide comprises a mutation at position 228 and 235, as compared to SEQ ID NO: 7.

37. The variant Fc polypeptide of any one of embodiments 29-31, wherein the variant Fc polypeptide comprises a mutation at position 228 and 234, as compared to SEQ ID NO: 7.

38. The variant Fc polypeptide of any one of embodiments 29-32, wherein the variant Fc polypeptide comprises a mutation at position 234 and 235, as compared to SEQ ID NO: 7.

39. The variant Fc polypeptide of any one of embodiments 29-38, wherein the variant Fc polypeptide comprises a mutation of S228P, L234F, L235E, H268Q, K274Q, N276K, Y296F, Y300F, L309V, A327G, A330S, P331 S, A339T, or any combination thereof, as compared to SEQ ID NO: 7.

40. The variant Fc polypeptide of embodiment 39, wherein the variant Fc polypeptide comprises a mutation of S228P, as compared to SEQ ID NO: 7.

41. The variant Fc polypeptide of embodiment 39, wherein the variant Fc polypeptide comprises a mutation of L234F, as compared to SEQ ID NO: 7.

42. The variant Fc polypeptide of embodiment 39, wherein the variant Fc polypeptide comprises a mutation of L235E, as compared to SEQ ID NO: 7.

43. The variant Fc polypeptide of embodiment 39, wherein the variant Fc polypeptide comprises a mutation of S228P and L234F as compared to SEQ ID NO: 7.

44. The variant Fc polypeptide of embodiment 39, wherein the variant Fc polypeptide comprises a mutation of S228P and L235E as compared to SEQ ID NO: 7.

45. The variant Fc polypeptide of embodiment 39, wherein the variant Fc polypeptide comprises a mutation of L234F and L235E as compared to SEQ ID NO: 7.

46. The variant Fc polypeptide of embodiment 39, wherein the variant Fc polypeptide comprises a mutation of S228P, L234F and L235E as compared to SEQ ID NO: 7.

47. The variant Fc polypeptide of any one of embodiments 29-46, wherein the variant Fc polypeptide is selective for FcyRIip.

48. The variant Fc polypeptide of any one of embodiments 29-47, wherein the variant Fc polypeptide comprises FcyRIip selective mutations, such as those provided for herein.

49. The variant Fc polypeptide of embodiment 48, wherein the FcyRIip selective mutations are in the CH2 domain and/or the hinge domain of the Fc polypeptide.

50. The variant Fc polypeptide of any one of embodiments 29-49, wherein the variant Fc polypeptide binds to FcyRIip over FcyRIIa.

51. A variant Fc polypeptide comprising a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 1, provided that the variant Fc polypeptide comprises: a CH2 domain comprising a sequence of SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, or SEQ ID NO: 24; a mutation at position 228, 234, 235, 268, 274, 276, 296, 300, 309, 327, 330, 331, 339, or any combination thereof, as compared to SEQ ID NO: 7, and wherein the Fc polypeptide selectively binds to FcyRIip over FcyRIIa.

52. The variant Fc polypeptide of embodiment 51, wherein the variant Fc polypeptide is a chimeric IgGl/IgG4 polypeptide.

53. The variant Fc polypeptide of embodiment 51, wherein the variant Fc polypeptide comprises a hinge region sequence having at least 1, at least 2, at least 3, at least 4, at least 5, or at least 6 mutations as compared to the hinge region of SEQ ID NO: 7.

54. The variant Fc polypeptide of any one of embodiments 51-53, wherein the variant Fc polypeptide comprises a mutation at position 228, as compared to SEQ ID NO: 7.

55. The variant Fc polypeptide of any one of embodiments 51-53, wherein the variant Fc polypeptide comprises a mutation at position 234, as compared to SEQ ID NO: 7.

56. The variant Fc polypeptide of any one of embodiments 51-53, wherein the variant Fc polypeptide comprises a mutation at position 235, as compared to SEQ ID NO: 7.

57. The variant Fc polypeptide of any one of embodiments 51-53, wherein the variant Fc polypeptide comprises a mutation at position 228 and 235, as compared to SEQ ID NO: 7.

58. The variant Fc polypeptide of any one of embodiments 51-53, wherein the variant Fc polypeptide comprises a mutation at position 228 and 234, as compared to SEQ ID NO: 7.

59. The variant Fc polypeptide of any one of embodiments 51-53, wherein the variant Fc polypeptide comprises a mutation at position 234 and 235, as compared to SEQ ID NO: 7.

60. The variant Fc polypeptide of any one of embodiments 51-59, wherein the variant Fc polypeptide comprises a mutation of S228P, L234F, L235E, H268Q, K274Q, N276K, Y296F, Y300F, L309V, A327G, A330S, P331S, A339T, or any combination thereof, as compared to SEQ ID NO: 7.

61. The variant Fc polypeptide of embodiment 60, wherein the variant Fc polypeptide comprises a mutation of S228P, as compared to SEQ ID NO: 7.

62. The variant Fc polypeptide of embodiment 60, wherein the variant Fc polypeptide comprises a mutation of L234F, as compared to SEQ ID NO: 7.

63. The variant Fc polypeptide of embodiment 60, wherein the variant Fc polypeptide comprises a mutation of L235E, as compared to SEQ ID NO: 7.

64. The variant Fc polypeptide of embodiment 60, wherein the variant Fc polypeptide comprises a mutation of S228P and L234F as compared to SEQ ID NO: 7. 65. The variant Fc polypeptide of embodiment 60, wherein the variant Fc polypeptide comprises a mutation of S228P and L235E as compared to SEQ ID NO: 7.

66. The variant Fc polypeptide of embodiment 60, wherein the variant Fc polypeptide comprises a mutation of L234F and L235E as compared to SEQ ID NO: 7.

67. The variant Fc polypeptide of embodiment 60, wherein the variant Fc polypeptide comprises a mutation of S228P, L234F and L235E as compared to SEQ ID NO: 7.

68. The variant Fc polypeptide of any one of embodiments 51-67, wherein the variant Fc polypeptide comprises FcyRIip selective mutations, such as those provided for herein.

69. The variant Fc polypeptide of embodiment 68, wherein the FcyRIip selective mutations are in the CH2 domain and/or the hinge domain of the variant Fc polypeptide.

70. The variant Fc polypeptide of any one of embodiments 51-69, wherein the variant Fc polypeptide binds to FcyRIip over FcyRIIa.

71. A polypeptide comprising: a variant Fc polypeptide comprising a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 7, provided that the variant polypeptide comprises: a CH2 domain comprising a sequence of SEQ ID NO: 19, SEQ ID NO:

20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, or SEQ ID NO: 24; and a mutation at position 228, 234, 235, 268, 274, 276, 296, 300, 309, 327, 330, 331, 339, or any combination thereof, as compared to SEQ ID NO: 1, and wherein the variant Fc polypeptide selectively binds to FcyRIip over FcyRIIa; an inhibitory receptor effector domain; and a FcyRII binding effector domain.

72. The polypeptide of embodiment 71, wherein the polypeptide comprises 2 inhibitory receptor effector domains.

73. The polypeptide of embodiment 72, wherein the 2 inhibitory receptor effector domains bind to the same inhibitory receptor.

74. The polypeptide of embodiment 73, wherein the 2 inhibitory receptor effector domains bind to different inhibitory receptors.

75. The polypeptide of any one of embodiments 71-74, wherein the inhibitory receptor effector domain is an antibody. 76. The polypeptide of any one of embodiments 71 -75, wherein the inhibitory receptor effector domain is an antibody in the format of a scFv, Fab, Fab’, and F(ab’)2 antibody.

77. The polypeptide of any one of embodiments 71-76, wherein the inhibitor receptor effector domain binds to a receptor encoding by LAG3, BTLA/CD272, CD200R1, CD200R1, CD22/Siglec2, CD300A, CD3OOLF/CD3OOF, CD33/Siglec3, CD5, CD72, CEACAM 1, CLEC12A, CLEC4A, CTLA4/CD152, FCGR2B/CD32B, KIRs, KLRB 1/CD 161, KLRC1, KLRG1, LAIR1, LILRB1, LILRB2, LILRB4, LILRB5, NCR2/NKp44, PDCD1, PECAM1/CD31, PILRA, PVR/CD155, SIGLEC11, SIGLEC5, SIGLEC7, SIGLEC8, SIGLEC9, SIRPA, TIGIT, VSTM1/SIRL1, MAFA, NKG2A, CMRF35H, CD66a, CD66d, CD33, SIGLEC6, ILT2, ILT3, ILT4, ILT5, LIR8, KIR2DL, KIR2DL1, KIR3DL, SIRPa, KIR2DL2/3, KIR2DL5, KIRDL1, KIRDL2, KIRDL3, TIM3, Tactile, IRp60, NKRP1, IAP, PIR-B, CD5, 2B4, GP49B, Ly49Q, MICL, CD 160, FCRL4, KIR3DL1, KIR2DL2, LILRB3, DCIR, NKRP-1D, LY49, MAIR-I, CD79a, CD79b, CD19, CD21, CD40, TLR3, CD28, CCR5, or CCR1.

78. The polypeptide of embodiment 77, wherein the inhibitory receptor effector domain binds to PD-1, LAG-3, or CTLA4.

79. The polypeptide of any one of embodiments 71-78, wherein the inhibitory receptor effector domain is an agonist of the inhibitory receptor to which it binds.

80. The polypeptide of any one embodiments 71-79, wherein the inhibitory receptor effector domain is an antagonist of the inhibitory receptor to which it binds.

81. The polypeptide of embodiment 80, wherein the Fc region comprises FcyRIip selective mutations, such as those provided for herein.

82. The polypeptide of any one of embodiments 1-81, wherein the FcyRII binding effector domains binds to FcyRIip or FcyRIIa.

83. The polypeptide of embodiment 82, wherein the FcyRII binding effector domains is an antibody.

84. The polypeptide of embodiment 83, wherein the antibody is an scFv, Fab, Fab’, and F(ab’)2.

85. The variant IgG Fc polypeptide that selectively binds to FcyRIip over FcyRIIa, wherein the variant IgG Fc polypeptide comprises a mutation selected from a mutation associated with any of VFC-1 to VFC-6. 86. The variant IgG Fc polypeptide of embodiment 1 , wherein the variant IgG Fc polypeptide comprises a mutation that enhances selective binding to FcyRIip over FcyRIIa.

87. The variant IgG Fc polypeptide of embodiment 2, wherein the mutation is selected from a mutation at one or more of the positions selected from 234, 236, 237, 238, and 239, and any combination thereof, as compared to SEQ ID NO: 7.

88. The variant IgG Fc polypeptide of any one of embodiments 1-3, wherein the variant IgG Fc polypeptide comprises one or more of the mutations selected from L234G, G236L, P238D, P238G, a deletion of amino acid Gly at position 237, a deletion of amino acid Pro at position 238, an insertion of amino acid Gly between positions P238 and S239, an insertion of amino acid Asp between positions P238 and S239, and any combination thereof, as compared to SEQ ID NO: 7.

89. The variant IgG Fc polypeptide of embodiment 4, wherein the variant IgG Fc polypeptide comprises a mutation set selected from: a deletion of amino acid Pro at position 238, as compared to SEQ ID NO: 7; a deletion of amino acid Gly at position 237, and a mutation of P238D, as compared to SEQ ID NO: 7; an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7; a mutation set of L234G, G236L, P238G, and an insertion of amino acid Asp between positions P238 and S239 as compared to SEQ ID NO: 7; a mutation set of L234G, G236L, and an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; or any combination thereof.

90. A variant IgG Fc polypeptide comprising an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the variant IgG Fc polypeptide comprises: a deletion of amino acid Pro at position 238, as compared to SEQ ID NO: 7; a deletion of amino acid Gly at position 237, and a mutation of P238D, as compared to SEQ ID NO: 7; an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7; a mutation set of L234G, G236L, P238G, and an insertion of amino acid Asp between positions P238 and S239 as compared to SEQ ID NO: 7; a mutation set of L234G, G236L, and an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; or any combination thereof.

91. A variant IgG Fc polypeptide comprising a variant sequence of SEQ ID NO: 7, wherein the variant IgG Fc polypeptide comprises: a deletion of amino acid Pro at position 238, as compared to SEQ ID NO: 7; a deletion of amino acid Gly at position 237, and a mutation of P238D, as compared to SEQ ID NO: 7; an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7; a mutation set of L234G, G236L, P238G, and an insertion of amino acid Asp between positions P238 and S239 as compared to SEQ ID NO: 7; or a mutation set of L234G, G236L, and an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7, wherein the variant IgG Fc polypeptide further comprises at least, about, or exactly 1-10, 1-20, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19 or 20 mutations in addition to the mutation set as compared to SEQ ID NO: 7.

92. A variant IgG Fc polypeptide of any one of embodiments 85-91, wherein the polypeptide comprises one or more sequence as provided in Table 2 or Table 3.

93. The variant IgG Fc polypeptide of any one of embodiments 85-92, wherein the variant IgG Fc polypeptide comprises an amino acid sequence of SEQ ID NO: 1, 2, 3, 4, 5, or 6. 94. The variant IgG Fc polypeptide of any one of embodiments 85-93, wherein the variant IgG Fc polypeptide associates with another variant IgG Fc polypeptide to form a dimer molecule.

95. The variant IgG Fc polypeptide of embodiment 94, wherein the dimer molecule is a homodimer molecule.

96. The variant IgG Fc polypeptide of any one of embodiments 94 or 95, wherein the homodimer molecule comprises a first polypeptide and a second polypeptide, and wherein the first polypeptide and the second polypeptide comprise identical amino acid sequences.

97. The variant IgG Fc polypeptide of any one of embodiments 94-96, wherein the first polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the first polypeptide comprises: a deletion of amino acid Pro at position 238, as compared to SEQ ID NO: 7; a deletion of amino acid Gly at position 237, and a mutation of P238D, as compared to SEQ ID NO: 7; an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7; a mutation set of L234G, G236L, P238G, and an insertion of amino acid Asp between positions P238 and S239 as compared to SEQ ID NO: 7; a mutation set of L234G, G236L, and an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; or any combination thereof; and the second polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the polypeptide comprises: a deletion of amino acid Pro at position 238, as compared to SEQ ID NO: 7; a deletion of amino acid Gly at position 237, and a mutation of P238D, as compared to SEQ ID NO: 7; an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7; a mutation set of L234G, G236L, P238G, and an insertion of amino acid Asp between positions P238 and S239 as compared to SEQ ID NO: 7; a mutation set of L234G, G236L, and an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; or any combination thereof.

98. The variant IgG Fc polypeptide of any one of embodiments 94-97, wherein the first polypeptide comprises a variant sequence of SEQ ID NO: 7, wherein the first polypeptide comprises: a deletion of amino acid Pro at position 238, as compared to SEQ ID NO: 7; a deletion of amino acid Gly at position 237, and a mutation of P238D, as compared to SEQ ID NO: 7; an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7; a mutation set of L234G, G236L, P238G, and an insertion of amino acid Asp between positions P238 and S239 as compared to SEQ ID NO: 7; or a mutation set of L234G, G236L, and an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7, wherein the first polypeptide further comprises at least, about, or exactly 1-10, 1- 20, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19 or 20 mutations in addition to the mutation set as compared to SEQ ID NO: 7; and the second polypeptide comprises a variant sequence of SEQ ID NO: 7, wherein the second polypeptide comprises: a deletion of amino acid Pro at position 238, as compared to SEQ ID NO:

7; a deletion of amino acid Gly at position 237, and a mutation of P238D, as compared to SEQ ID NO: 7; an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7; a mutation set of L234G, G236L, P238G, and an insertion of amino acid Asp between positions P238 and S239 as compared to SEQ ID NO: 7; or a mutation set of L234G, G236L, and an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7, wherein the second polypeptide further comprises at least, about, or exactly 1-10, 1-20, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19 or 20 mutations in addition to the mutation set as compared to SEQ ID NO: 7.

99. The variant IgG Fc polypeptide of any of the preceding embodiments, wherein the first polypeptide comprises an amino acid sequence of SEQ ID NO: 1, 2, 3, 4, 5, or 6.

100. The variant IgG Fc polypeptide of any of the preceding embodiments, wherein the second polypeptide comprises an amino acid sequence of SEQ ID NO: 1, 2, 3, 4, 5, or 6.

101. The variant IgG Fc polypeptide of any of the preceding embodiments, wherein the first polypeptide comprises an amino acid sequence of SEQ ID NO: 1, 2, 3, 4, 5, or 6; and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 1, 2, 3, 4, 5, or 6, respectively.

102. The variant IgG Fc polypeptide of any of the preceding embodiments, wherein the first polypeptide comprises an amino acid sequence of SEQ ID NO: 1, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 1; the first polypeptide comprises an amino acid sequence of SEQ ID NO: 2, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 2; the first polypeptide comprises an amino acid sequence of SEQ ID NO: 3, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 3; the first polypeptide comprises an amino acid sequence of SEQ ID NO: 4, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 4; the first polypeptide comprises an amino acid sequence of SEQ ID NO: 5, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 5; or the first polypeptide comprises an amino acid sequence of SEQ ID NO: 6, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 6.

103. The variant IgG Fc polypeptide of any of the preceding embodiments, wherein the polypeptide has a selectivity, of 2 fold or greater, for FcyRIip relative to FcyRIIa.

104. A polypeptide comprising: a variant IgG Fc polypeptide that selectively binds to FcyRIip over FcyRIIa, wherein the variant IgG Fc polypeptide comprises one or more sequence selected from Table 2 or Table 3; and an inhibitory receptor effector domain.

105. The polypeptide of any of the preceding embodiments, wherein the variant IgG Fc polypeptide comprises an amino acid sequence of SEQ ID NO: 1, 2, 3, 4, 5, or 6.

106. The polypeptide of any of the preceding embodiments, wherein the variant IgG Fc polypeptide associates with another variant IgG Fc polypeptide to form a dimer molecule.

107. The polypeptide of any of the preceding embodiments, wherein the dimer molecule is a homodimer molecule.

108. The polypeptide of any of the preceding embodiments, wherein the homodimer molecule comprises a first polypeptide and a second polypeptide, and wherein the first polypeptide and the second polypeptide comprise identical amino acid sequences.

109. The polypeptide of any of the preceding embodiments, wherein the first polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the first polypeptide comprises: a deletion of amino acid Pro at position 238, as compared to SEQ ID NO: 7; a deletion of amino acid Gly at position 237, and a mutation of P238D, as compared to SEQ ID NO: 7; an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7; a mutation set of L234G, G236L, P238G, and an insertion of amino acid Asp between positions P238 and S239 as compared to SEQ ID NO: 7; a mutation set of L234G, G236L, and an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; or any combination thereof; and the second polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the second polypeptide comprises: a deletion of amino acid Pro at position 238, as compared to SEQ ID NO:

7; a deletion of amino acid Gly at position 237, and a mutation of P238D, as compared to SEQ ID NO: 7; an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7; a mutation set of L234G, G236L, P238G, and an insertion of amino acid Asp between positions P238 and S239 as compared to SEQ ID NO: 7; a mutation set of L234G, G236L, and an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; or any combination thereof.

110. The polypeptide of any of the preceding embodiments, wherein the first polypeptide comprises a variant sequence of SEQ ID NO: 7, wherein the first polypeptide comprises: a deletion of amino acid Pro at position 238, as compared to SEQ ID NO: 7; a deletion of amino acid Gly at position 237, and a mutation of P238D, as compared to SEQ ID NO: 7; an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7; a mutation set of L234G, G236L, P238G, and an insertion of amino acid Asp between positions P238 and S239 as compared to SEQ ID NO: 7; or a mutation set of L234G, G236L, and an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7, wherein the first polypeptide further comprises at least, about, or exactly 1-10, 1- 20, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19 or 20 mutations in addition to the mutation set as compared to SEQ ID NO: 7; and the second polypeptide comprises a variant sequence of SEQ ID NO: 7, wherein the second polypeptide comprises: a deletion of amino acid Pro at position 238, as compared to SEQ ID NO: 7; a deletion of amino acid Gly at position 237, and a mutation of P238D, as compared to SEQ ID NO: 7; an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7; a mutation set of L234G, G236L, P238G, and an insertion of amino acid

Asp between positions P238 and S239 as compared to SEQ ID NO: 7; or a mutation set of L234G, G236L, and an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7, wherein the second polypeptide further comprises at least, about, or exactly 1-10, 1-20, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19 or 20 mutations in addition to the mutation set as compared to SEQ ID NO: 7.

111. The polypeptide of any of the preceding embodiments, wherein the first polypeptide comprises an amino acid sequence of SEQ ID NO: 1, 2, 3, 4, 5, or 6. 112. The polypeptide of any of the preceding embodiments, wherein the second polypeptide comprises an amino acid sequence of SEQ ID NO: 1, 2, 3, 4, 5, or 6.

113. The polypeptide of any of the preceding embodiments, wherein the first polypeptide comprises an amino acid sequence of SEQ ID NO: 1, 2, 3, 4,

5, or 6; and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 1, 2, 3, 4, 5, 6, respectively.

114. The polypeptide of any of the preceding embodiments, wherein the first polypeptide comprises an amino acid sequence of SEQ ID NO: 1, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 1; the first polypeptide comprises an amino acid sequence of SEQ ID NO: 2, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 2; the first polypeptide comprises an amino acid sequence of SEQ ID NO: 3, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 3; the first polypeptide comprises an amino acid sequence of SEQ ID NO: 4, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 4; the first polypeptide comprises an amino acid sequence of SEQ ID NO: 5, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 5; or the first polypeptide comprises an amino acid sequence of SEQ ID NO: 6, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 6.

115. The polypeptide of any of the preceding embodiments, wherein the polypeptide comprises 2 inhibitory receptor effector domains.

116. The polypeptide of any of the preceding embodiments, wherein the 2 inhibitory receptor effector domains bind to the same inhibitory receptor.

117. The polypeptide of any of the preceding embodiments, wherein the 2 inhibitory receptor effector domains bind to different inhibitory receptors.

118. The polypeptide of any of the preceding embodiments, wherein the inhibitory receptor effector domain is an antibody.

119. The polypeptide of any of the preceding embodiments, wherein the inhibitory receptor effector domain is present in an antibody, in the format of an scFv, Fab, Fab’, or F(ab’)2. 120. The polypeptide of any of the preceding embodiments, wherein at least one inhibitory receptor effector domain binds to a receptor encoded by LAG3, RSV, BTLA/CD272, CD200R1, CD200R1, CD22/Siglec2, CD300A, CD300LF/CD300F, CD33/Siglec3, CD5, CD72, CEACAM 1, CLEC12A, CLEC4A, CTLA4/CD152, FCGR2B/CD32B, KIRs, KLRB1/CD161, KLRC1, KLRG1, LAIR1, LILRB1, LILRB2, LILRB4, LILRB5, NCR2/NKp44, PDCD1, PECAM1/CD31, PILRA, PVR/CD155, SIGLEC11, SIGLEC5, SIGLEC7, SIGLEC8, SIGLEC9, SIRPA, TIGIT, VSTM1/SIRL1, MAFA, NKG2A, CMRF35H, CD66a, CD66d, CD33, SIGLEC6, ILT2,3,4,5, LIR8, KIR2DL, KIR3DL, SIRPa, KIR2DL2/3, KIR2DL5, KIRDL1, KIRDL2, KIRDL3, TIM3, Tactile, IRp60, NKRP1, IAP, PIR-B, CD5, 2B4, GP49B, Ly49Q, or MICL.

121. The polypeptide of any of the preceding embodiments, wherein the inhibitory receptor effector domain binds to PD-1, LAG-3, RSV, or CTLA4.

122. The polypeptide of any of the preceding embodiments, wherein at least one inhibitory receptor effector domain is an agonist of the receptor to which it binds.

123. The polypeptide of any of the preceding embodiments, wherein at least one inhibitory receptor effector domain is an antagonist of the receptor to which it binds.

124. A polypeptide comprising: a variant IgG Fc polypeptide that selectively binds to FcyRIip over FcyRIIa, wherein the variant IgG Fc polypeptide comprises one or more sequence selected from Table 2 or Table 3; an inhibitory receptor effector domain; and a FcyRII binding effector domain.

125. The polypeptide of any of the preceding embodiments, wherein the variant IgG Fc polypeptide comprises an amino acid sequence of SEQ ID NO: 1, 2, 3, 4, 5, or 6.

126. The polypeptide of any of the preceding embodiments, wherein the variant IgG Fc polypeptide associates with another variant IgG Fc polypeptide to form a dimer molecule.

127. The polypeptide of any of the preceding embodiments, wherein the dimer molecule is a homodimer molecule.

128. The polypeptide of any of the preceding embodiments, wherein the homodimer molecule comprises a first polypeptide and a second polypeptide, and wherein the first polypeptide and the second polypeptide comprise identical amino acid sequences. The polypeptide of any of the preceding embodiments, wherein the first polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the first polypeptide comprises: a deletion of amino acid Pro at position 238, as compared to SEQ ID NO: 7; a deletion of amino acid Gly at position 237, and a mutation of P238D, as compared to SEQ ID NO: 7; an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7; a mutation set of L234G, G236L, P238G, and an insertion of amino acid Asp between positions P238 and S239 as compared to SEQ ID NO: 7; a mutation set of L234G, G236L, and an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; or any combination thereof; and the second polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the second polypeptide comprises: a deletion of amino acid Pro at position 238, as compared to SEQ ID NO: 7; a deletion of amino acid Gly at position 237, and a mutation of P238D, as compared to SEQ ID NO: 7; an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7; a mutation set of L234G, G236L, P238G, and an insertion of amino acid Asp between positions P238 and S239 as compared to SEQ ID NO: 7; a mutation set of L234G, G236L, and an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; or any combination thereof.

130. The polypeptide of any of the preceding embodiments, wherein the first polypeptide comprises a variant sequence of SEQ ID NO: 7, wherein the first polypeptide comprises: a deletion of amino acid Pro at position 238, as compared to SEQ ID NO: 7; a deletion of amino acid Gly at position 237, and a mutation of P238D, as compared to SEQ ID NO: 7; an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7; a mutation set of L234G, G236L, P238G, and an insertion of amino acid Asp between positions P238 and S239 as compared to SEQ ID NO: 7; or a mutation set of L234G, G236L, and an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7, wherein the first polypeptide further comprises at least, about, or exactly 1-10, 1- 20, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19 or 20 mutations in addition to the mutation set as compared to SEQ ID NO: 7; and the second polypeptide comprises a variant sequence of SEQ ID NO: 7, wherein the second polypeptide comprises: a deletion of amino acid Pro at position 238, as compared to SEQ ID NO: 7; a deletion of amino acid Gly at position 237, and a mutation of P238D, as compared to SEQ ID NO: 7; an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7; a mutation set of L234G, G236L, P238G, and an insertion of amino acid Asp between positions P238 and S239 as compared to SEQ ID NO: 7; or a mutation set of L234G, G236L, and an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7, wherein the second polypeptide further comprises at least, about, or exactly 1-10, 1-20, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19 or 20 mutations in addition to the mutation set as compared to SEQ ID NO: 7.

131. The polypeptide of any of the preceding embodiments, wherein the first polypeptide comprises an amino acid sequence of SEQ ID NO: 1, 2, 3, 4, 5, or 6.

132. The polypeptide of any of the preceding embodiments, wherein the second polypeptide comprises an amino acid sequence of SEQ ID NO: 1, 2, 3, 4, 5, or 6.

133. The polypeptide of any of the preceding embodiments, wherein the first polypeptide comprises an amino acid sequence of SEQ ID NO: 1, 2, 3, 4, 5, or 6; and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 1, 2, 3, 4, 5, or 6, respectively.

134. The polypeptide of any of the preceding embodiments, wherein the first polypeptide comprises an amino acid sequence of SEQ ID NO: 1, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 1; the first polypeptide comprises an amino acid sequence of SEQ ID NO: 2, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 2; the first polypeptide comprises an amino acid sequence of SEQ ID NO: 3, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 3; the first polypeptide comprises an amino acid sequence of SEQ ID NO: 4, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 4; the first polypeptide comprises an amino acid sequence of SEQ ID NO: 5, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 5; or the first polypeptide comprises an amino acid sequence of SEQ ID NO: 6, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 6.

135. The polypeptide of any of the preceding embodiments, wherein the polypeptide comprises 2 inhibitory receptor effector domains.

136. The polypeptide of any of the preceding embodiments, wherein the 2 inhibitory receptor effector domains bind to the same inhibitory receptor. 137. The polypeptide of any of the preceding embodiments, wherein the 2 inhibitory receptor effector domains bind to different inhibitory receptors.

138. The polypeptide of any of the preceding embodiments, wherein the inhibitory receptor effector domain is an antibody.

139. The polypeptide of any of the preceding embodiments, wherein the inhibitory receptor effector domain is present in an antibody, in the format of an scFv, Fab, Fab’, or F(ab’)2.

140. The polypeptide of any of the preceding embodiments, wherein at least one inhibitor receptor effector domain binds to a receptor encoded by LAG3, RSV, BTLA/CD272, CD200R1, CD200R1, CD22/Siglec2, CD300A, CD300LF/CD300F, CD33/Siglec3, CD5, CD72, CEACAM 1, CLEC12A, CLEC4A, CTLA4/CD152, FCGR2B/CD32B, KIRs, KLRB1/CD161, KLRC1, KLRG1, LAIR1, LILRB1, LILRB2, LILRB4, LILRB5, NCR2/NKp44, PDCD1, PECAM1/CD31, PILRA, PVR/CD155, SIGLEC11, SIGLEC5, SIGLEC7, SIGLEC8, SIGLEC9, SIRPA, TIGIT, VSTM1/SIRL1, MAFA, NKG2A, CMRF35H, CD66a, CD66d, CD33, SIGLEC6, ILT2,3,4,5, LIR8, KIR2DL, KIR3DL, SIRPa, KIR2DL2/3, KIR2DL5, KIRDL1, KIRDL2, KIRDL3, TIM3, Tactile, IRp60, NKRP1, IAP, PIR-B, CD5, 2B4, GP49B, Ly49Q, or MICL.

141. The polypeptide of any of the preceding embodiments, wherein the inhibitory receptor effector domain binds to PD-1, LAG-3, RSV, or CTLA4.

142. The polypeptide of any of the preceding embodiments, wherein at least one inhibitory receptor effector domain is an agonist of the receptor to which it binds.

143. The polypeptide of any of the preceding embodiments, wherein at least one inhibitory receptor effector domain is an antagonist of the receptor to which it binds.

144. The polypeptide of any of the preceding embodiments, wherein the FcyRII binding effector domain binds to FcyRIip or FcyRIIa.

145. The polypeptide of any of the preceding embodiments, wherein the FcyRII binding effector domains is an antibody.

146. The polypeptide of any of the preceding embodiments, wherein the antibody is in the form of an scFv, Fab, Fab’, and F(ab’)2.

147. A pharmaceutical composition comprising a variant IgG Fc polypeptide of any of the preceding embodiments, or a polypeptide of any of the preceding embodiments, and, for example, at least one pharmaceutically acceptable excipient. 148. A method of treating an autoimmune disorder in a subject, the method comprising administering a variant IgG Fc polypeptide of any of the preceding embodiments, or a polypeptide of any of the preceding embodiments, or a pharmaceutical composition comprising the same, to the subject.

149. The method of embodiment 148, wherein the autoimmune disorder is selected from myocarditis, postmyocardial infarction syndrome, postpericardiotomy syndrome, subacute bacterial endocarditis, anti -glomerular basement membrane nephritis, interstitial cystitis, lupus nephritis, membranous glomerulonephropathy, chronic kidney disease (CKD), autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, anti synthetase syndrome, alopecia areata, autoimmune angioedema, autoimmune progesterone dermatitis, overlap connective tissues disease syndromes, polymyalgia rheumatic, autoimmune urticaria, bullous pemphigoid, cicatricial pemphigoid, dermatitis herpetiformis, discoid lupus erythematosus, epidermolysis bullosa acquisita, erythema nodosum, anti-neutrophil cytoplasmic antibody associated vasculitis, Henoch-Schonlein purpura, Cogan’s syndrome, Buerger’s disease, Susan’s disease, immune complex vasculitis, primary angiitis of the CNS, gestational pemphigoid, hidradenitis suppurativa, lichen planus, lichen sclerosus, linear iga disease (lad), morphea, pemphigus vulgaris, pityriasis lichenoides et varioliformis acuta, mucha-habermann disease, psoriasis, systemic scleroderma, vitiligo, Addison's disease, autoimmune polyendocrine syndrome (APS) type 1, autoimmune polyendocrine syndrome (APS) type 2, juvenile idiopathic arthritis, juvenile dermatomyositis, autoimmune brain disease, autoimmune polyendocrine syndrome (APS) type 3, autoimmune pancreatitis (AIP), diabetes mellitus type 1, autoimmune thyroiditis, Ord's thyroiditis, Graves' disease, autoimmune oophoritis, endometriosis, autoimmune orchitis, Sjogren's syndrome, autoimmune enteropathy, Coeliac disease, Crohn's disease, microscopic colitis, ulcerative colitis, thrombocytopenia, adiposis, dolorosa, adult-onset Still's disease, ankylosing spondylitis, CREST syndrome, drug-induced lupus, enthesitis-related arthritis, eosinophilic fasciitis, Felty syndrome, IgG4-related diseasejuvenile arthritis, lyme disease (chronic), mixed connective tissue disease (MCTD), palindromic rheumatism, Parry Romberg syndrome, Parsonage-Turner syndrome, psoriatic arthritis, IBD-associated arthritis, reactive arthritis, relapsing polychondritis, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, autoimmune complications of immune checkpoint inhibitors (IRAEs), sarcoidosis, neurosarcoidosis, Schnitzler syndrome, systemic lupus erythematosus (SLE), undifferentiated connective tissue disease (UCTD), dermatomyositis, IgG4 related disease, fibromyalgia, antiphospholipid syndrome, inclusion body myositis, myositis, myasthenia gravis, neuromyotonia, paraneoplastic cerebellar degeneration, polymyositis, acute disseminated encephalomyelitis (ADEM), adult onset Still's disease, acute motor axonal neuropathy, anti-N- Methyl-D-Aspartate (anti-NMDA) receptor encephalitis, warm antibody hemolytic anemia (wAIHA), immune thrombocytopenia, immune thrombotic thrombocytopenia, thrombotic thrombocytopenia, pernicious anemia, aplastic anemia, Evan's syndrome, autoimmune neutropenia, acquired von Willibrand syndrome, recurring fetal loss, Rh mismatch, Balo concentric sclerosis, Bickerstaff s encephalitis, chronic inflammatory demyelinating polyneuropathy, Guillain-Barre syndrome, Hashimoto’s encephalopathy, idiopathic inflammatory demyelinating diseases, Lambert-Eaton myasthenic syndrome, primary biliary sclerosis, glomerulonephritis, glomerular basement membrane disease, multiple sclerosis, Oshtoran syndrome, pediatric autoimmune neuropsychiatric disorder associated with Streptococcus (PANDAS), progressive inflammatory neuropathy, cutaneous lupus erythematosus, restless leg syndrome, pemphigus foliaceus including fogo selvage, transplantation, antibody -mediated rejection, alloantibody hypersensitization, xenoantibody mediated rejection, solid organ rejection, graft vs host disease acute and chronic, stiff person syndrome, Sydenham chorea, transverse myelitis, autoimmune retinopathy, autoimmune uveitis, uveitis, Cogan syndrome, Graves ophthalmopathy, amyotrophic lateral sclerosis (ALS), Parkinson's disease, autoimmune encephalitis, CNS vasculitis, chronic idiopathic demyelinating polyneuropathy (CIDP), keratitis, intermediate uveitis, ligneous conjunctivitis, Mooren’s ulcer, neuromyelitis optica, opsoclonus myoclonus syndrome, optic neuritis, scleritis, Susac’s syndrome, sympathetic ophthalmia, Tolosa-Hunt syndrome, rheumatic heart disease, chronic rhinosinusitis with nasal polyps, allergic bronchoplmonary mycosis, hypersensitivity pneumonitis, rheumatoid arthritis-associated interstitial lung disease (RA-ILD), nonspecific interstitial pneumonia, allergic asthma, infectious disease/vaccination, antibody dependent enhancement (as wit dengue virus infection), chronic meningitis, anti-myelin oligodendrocyte glycoprotein (MOG) disease, activated-DLBCL, anti-drug antibody, anti-gene therapy vector antibody (anti-AAV antibody), antibody to therapeutic biologic agents (cytokines, monoclonal antibodies, enzymes, coagulation factors), autoimmune inner ear disease (AIED), Meniere's disease, Behcet’s disease, eosinophilic granulomatosis with polyangiitis (EGPA), giant cell arteritis, polyglandular autoimmune endocrine syndromes, granulmatosis with polyangiitis (GPA), IgA vasculitis (IgAV), Kawasaki’s disease, leukocytoclastic vasculitis, lupus vasculitis, rheumatoid vasculitis, microscopic polyangiitis (MPA), polyarteritis nodosa (PAN), polymyalgia rheumaticia, vasculitis, primary immune deficiency, pyoderma gangrenosum, agammaglobulinemia, anyloidosis, anyotrophic lateral sclerosis, anti-tubular basement membrane nephritis, atopic allergy, atopic dermatitis, autoimmune peripheral neuropathy, Blau syndrome, Castleman’s disease, Chagas disease, chronic obstructive pulmonary disease, chronic recurrent multifocal osteomyelitis, complement component 2 deficiency, contact dermatitis, Cushing’s syndrome, cutaneous leukocytoclastic angiitis, Dego’ deiase, eczema, eosinophilic gastroenteritis, eosinophilic pneumonia, erythroblastosis fetalsis, fibrodysplasia ossificans progressive, gastrointestinal pemphigoid, hypogammaglobulinemia, idiopathic giant-cell myocarditis, idiopathic pulmonary fibrosis, IgA nephropathy, immunoregulatory lipoproteins, IPEX syndrome, ligenous conjunctivitis, Majeed syndrome, narcolepsy, Rasmussen’s encephalitis, schizophrenia, serum sickness, spondyloathropathy, Sweet’s syndrome, Takayasu’s arteritis, or any combination thereof.

150. A method of treating cancer in a subject, the method comprising administering a variant IgG Fc polypeptide of any of the preceding embodiments, or a polypeptide of any of the preceding embodiments, or a pharmaceutical composition comprising the same, to the subject.

151. The method of embodiment 150, wherein the cancer is lung cancer, breast cancer, brain cancer, esophageal cancer, colorectal cancer, blood cancer, or pancreatic cancer.

152. A method of modulating the interaction of cells of at least two distinct types using a polypeptide, the method comprising introducing a variant IgG Fc polypeptide of any of the preceding embodiments, or a polypeptide of any of the preceding embodiments to the cells.

153. The method of embodiment 152, wherein at least one cell is a T-cell, NK Cell, or Dendritic cell, and at least one cell is a B-Cell, an antigen presenting cell (APC), or a myeloid cell.

154. The method of any one of embodiments 148-153, wherein the cells are present within the body of a subject.

155. A method of inhibiting an activated immune cell that is in contact with a B cell, an antigen presenting cell (APC), or a myeloid cell, the method comprising introducing a variant IgG Fc polypeptide of any of the preceding embodiments, or a polypeptide of any of the preceding embodiments, or a pharmaceutical composition comprising the same, to the cells. 155. A method of activating or enhancing the behavior of an activated immune cell that is in contact with a B cell, an antigen presenting cell (APC), or a myeloid cell, the method comprising introducing a variant IgG Fc polypeptide of any of the preceding embodiments, or a polypeptide of any of the preceding embodiments, or a pharmaceutical composition comprising the same, to the cells.

The following examples are illustrative, but not limiting, of the compounds, compositions and methods described herein. Other suitable modifications and adaptations known to those skilled in the art are within the scope of the following embodiments.

Examples

Example 1: Generating IgGl/IgG4 hybrid hinge-Fc to gain FcyRTip selectivity.

Mutations in the hinge and CH2 domains of IgGl Fc were designed so that IgGl Fc mimics the FcyRIip binding features as IgG4 Fc. It has been reported that IgG4 PE variant (S228P, L235E) has selective binding toward human FcyRIIp (Zhou et al. 2020. mAbs 12: 1, 1814583). Protein sequences of different IgG isotypes were aligned as shown herein. The critical residue differences between IgGl and IgG4 were identified. The critical mutations were identified as S228P, L234F, and/or L235E. Additionally, CH2 region of IgGl was replaced with the CH2 region of IgG4. The variant Fc polypeptides comprising IgGl/IgG4 hybrid domains show increased FcyRIip binding affinity.

Example 2: Variant IgG Fc Polypeptide Expression in Expi293F Cells and Purification Thereof.

The variant IgG Fc polypeptides described herein were transiently expressed in Expi293F cells. The variant IgG Fc polypeptides were purified by passing through PrismA resins. Target antibodies were eluted with buffer 0. IM Glycine, pH 2.7. The flow through and prismA eluted samples were loaded to CE-SDS to check purification result. All variants were purified with majority population as monomers on analytical SEC.

Example 3: High-throughput Screening of Antibodies Against Analytes PD-1 and FcyRII Receptors. Antibodies comprising variant IgG Fc polypeptides described herein were captured on aprotein A/G chip at 10 ug/mL, 1 ug/mL, and 0.1 ug/mL concentrations (in duplicates). Each analyte binder was injected at seven concentrations with 5-fold serial dilutions, and kinetics data was collected. Binding kinetics (KD affinity, Kon association rate, Koff dissociation rate) were collected. Affinity KD of each Fc variant against human FcyRIIa R l 67, FcyRIIa H l 67, FcyRIip, and cyno FcyRIIa and FcyRIip was described in Table 6 below. Due to the limitation of affinity measurement, KD values were categorized as ”no binding” when no response was observed, “>5uM” when KD is weaker than 5uM, and KD was measured if the KD was stronger than 5uM. For IgGl WT, KD of 5.1 uM is shown. This value was consistent with previous reports.

Table 4.

Ratio (iia/iib) = KD(iiA)/KD(iiB) (higher means stronger iib selectivity). Fold= KD(IgG_WT)/KD(variants) (higher number means stronger Fcg receptor affinity). Ratio (iib/iia) = KD(iiB)/KD(iiA) (lower means stronger iib selectivity). Compared to IgGl wild type, the FcyRIip selective clones may have stronger human FcyRIip binding, weaker human FcyRIIa binding, or both Ila & lip at the same time.

Example 4: Binding Profiles Of the Variant IgG F Polypeptides Provided Herein Are Comparable to the P238D Molecule.

CHOK1 lines overexpressing either FcyRIip or Ila (R131) were detached, resuspended in PBS 3% FBS and incubated for 30 minutes at +4C with 40 ug/mL of test articles. Cells were washed and incubated for additional 30 minutes at +4C with a detection antibody (BV421 conjugated) recognizing the human kappa chain of our test articles (Cat #316518). Cells were further washed, resuspend in fixation buffer (cat number) for 1 hour, then washed and resuspended in PBS before their acquisition at the flow cytometer. Binding curves (EC50) for each antibody against human FcyRIip and FcyRIIa (R131) were obtained, and are shown below in Table 5.

The data illustrated in Table 5 shows that the variant IgG Fc polypeptides have comparable EC50 values to the IgGl P238D molecule.

Example 5: Functional Assessment of the Variant IgG F Polypeptides Provided Herein Highlights Several Molecules With Stronger Agonism Than “PD-1 IgGl WT”.

Raji B cells were removed from cell culture, resuspended in cell plating reagent with 3% FBS and incubated for 1 hour at 37C with (lOOnM to 0.006nM) of test articles. Jurkat PD-1 (SHP2) reporter cells were removed from cell culture, resuspended in cell plating reagent with 3% FBS, and incubated with the Raji cells with test articles for an additional 2 hours at room temperature. Detection reagents were added to each well and luminescence was read using a plate reader. Agonism produced in reporter cell lines was enhanced by antibodies with greater affinities to FcyRIip over the wild-type antibody control.

The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated herein by reference in their entirety. While various embodiments have been disclosed with reference to specific aspects, it is apparent that other aspects and variations of these embodiments may be devised by others skilled in the art without departing from the true spirit and scope of the embodiments. The appended claims are intended to be construed to include all such aspects and equivalent variations.

Claims

What is claimed:

1. A variant Fc polypeptide comprising a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 7, provided that the variant Fc polypeptide comprises: a CH2 domain comprising a sequence of SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, or SEQ ID NO: 24; a mutation at position 228, 234, 235, 268, 274, 276, 296, 300, 309, 327, 330, 331, 339, or any combination thereof, as compared to SEQ ID NO: 7, and wherein the Fc polypeptide selectively binds to FcyRIip over FcyRIIa.

2. The variant Fc polypeptide of claim 1, wherein the variant Fc polypeptide comprises: a mutation at position 228, as compared to SEQ ID NO: 7; a mutation at position 234, as compared to SEQ ID NO: 7; a mutation at position 235, as compared to SEQ ID NO: 7; a mutation at position 228 and 235, as compared to SEQ ID NO: 7; a mutation at position 228 and 234, as compared to SEQ ID NO: 7; or a mutation at position 234 and 235, as compared to SEQ ID NO: 7.

3. The variant Fc polypeptide of claim 2, wherein the variant Fc polypeptide comprises: a mutation of S228P, as compared to SEQ ID NO: 7; a mutation of L234F, as compared to SEQ ID NO: 7; a mutation of L235E, as compared to SEQ ID NO: 7; a mutation of S228P and L234F as compared to SEQ ID NO: 7; a mutation of S228P and L235E as compared to SEQ ID NO: 7; a mutation of L234F and L235E as compared to SEQ ID NO: 7; or a mutation of S228P, L234F and L235E as compared to SEQ ID NO: 7.

4. The variant Fc polypeptide of any one of claims 1-3, wherein the variant Fc polypeptide comprises FcyRIip selective mutations, such as those provided for herein.

5. The variant Fc polypeptide of claim 4, wherein the FcyRIip selective mutations are in the CH2 domain and/or the hinge domain of the variant Fc polypeptide.

6. The variant Fc polypeptide of any one of claims 1-5, wherein the variant Fc polypeptide binds to FcyRIip over FcyRIIa.

7. A variant IgG Fc polypeptide comprising an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the variant IgG Fc polypeptide comprises: a deletion of amino acid Pro at position 238, as compared to SEQ ID NO: 7; a deletion of amino acid Gly at position 237, and a mutation of P238D, as compared to SEQ ID NO: 7; an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7; a mutation set of L234G, G236L, P238G, and an insertion of amino acid Asp between positions P238 and S239 as compared to SEQ ID NO: 7; a mutation set of L234G, G236L, and an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; or any combination thereof.

8. The variant IgG Fc polypeptide of claim 7, wherein the variant IgG Fc polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to any one of SEQ ID NO: 1, 2, 3, 4, 5, or 6.

9. The variant IgG Fc polypeptide of claim 7, wherein the variant IgG Fc polypeptide comprises an amino acid sequence of any one of SEQ ID NO: 1, 2, 3, 4, 5, or 6.

10. The variant IgG Fc polypeptide of any one of claims 7-9, wherein the variant IgG Fc polypeptide associates with another variant IgG Fc polypeptide to form a dimer molecule.

11. The variant IgG Fc polypeptide of claim 10, wherein the dimer molecule is a homodimer molecule.

12. The variant IgG Fc polypeptide of any one of claims 10-11, wherein the homodimer molecule comprises a first polypeptide and a second polypeptide, and wherein the first polypeptide and the second polypeptide comprise identical amino acid sequences.

13. The variant IgG Fc polypeptide of any one of claims 10-12, wherein the first polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the first polypeptide comprises: a deletion of amino acid Pro at position 238, as compared to SEQ ID NO: 7; a deletion of amino acid Gly at position 237, and a mutation of P238D, as compared to SEQ ID NO: 7; an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7; a mutation set of L234G, G236L, P238G, and an insertion of amino acid Asp between positions P238 and S239 as compared to SEQ ID NO: 7; a mutation set of L234G, G236L, and an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; or any combination thereof; and the second polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the polypeptide comprises: a deletion of amino acid Pro at position 238, as compared to SEQ ID NO: 7; a deletion of amino acid Gly at position 237, and a mutation of P238D, as compared to SEQ ID NO: 7; an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7; a mutation set of L234G, G236L, P238G, and an insertion of amino acid Asp between positions P238 and S239 as compared to SEQ ID NO: 7; a mutation set of L234G, G236L, and an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; or any combination thereof.

14. The variant IgG Fc polypeptide of any of claims 10-13, wherein the first polypeptide comprises an amino acid sequence of SEQ ID NO: 1, 2, 3, 4, 5, or 6; and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 1, 2, 3, 4, 5, or 6, respectively.

15. The variant IgG Fc polypeptide of any of claims 10-14, wherein the first polypeptide comprises an amino acid sequence of SEQ ID NO: 1, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 1; the first polypeptide comprises an amino acid sequence of SEQ ID NO: 2, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 2; the first polypeptide comprises an amino acid sequence of SEQ ID NO: 3, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 3; the first polypeptide comprises an amino acid sequence of SEQ ID NO: 4, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 4; the first polypeptide comprises an amino acid sequence of SEQ ID NO: 5, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 5; or the first polypeptide comprises an amino acid sequence of SEQ ID NO: 6, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 6.

16. The variant IgG Fc polypeptide of any one of claims 7-15, wherein the polypeptide has a selectivity for FcyRIip over FcyRIIa.

17. A polypeptide comprising: a variant IgG Fc polypeptide having an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to any one of SEQ ID NO: 1, 2, 3, 4, 5 or 6; and an inhibitory receptor effector domain.

18. The polypeptide of claim 17, wherein the variant IgG Fc polypeptide comprises: a deletion of amino acid Pro at position 238, as compared to SEQ ID NO: 7; a deletion of amino acid Gly at position 237, and a mutation of P238D, as compared to SEQ ID NO: 7; an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7; a mutation set of L234G, G236L, P238G, and an insertion of amino acid Asp between positions P238 and S239 as compared to SEQ ID NO: 7; or a mutation set of L234G, G236L, and an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7.

19. The polypeptide of any one of claims 17-18, wherein the variant IgG Fc polypeptide comprises an amino acid sequence of SEQ ID NO: 1, 2, 3, 4, 5, or 6.

20. The polypeptide of any one of claims 17-19, wherein the variant IgG Fc polypeptide associates with another variant IgG Fc polypeptide to form a dimer molecule, such as a homodimer molecule.

21 . The polypeptide of claim 20, wherein the homodimer molecule comprises a first polypeptide and a second polypeptide, and wherein the first polypeptide and the second polypeptide comprise identical amino acid sequences.

22. The polypeptide of any one of claims 20-21, wherein the first polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the first polypeptide comprises: a deletion of amino acid Pro at position 238, as compared to SEQ ID NO: 7; a deletion of amino acid Gly at position 237, and a mutation of P238D, as compared to SEQ ID NO: 7; an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7; a mutation set of L234G, G236L, P238G, and an insertion of amino acid Asp between positions P238 and S239 as compared to SEQ ID NO: 7; a mutation set of L234G, G236L, and an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; or any combination thereof; and the second polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the second polypeptide comprises: a deletion of amino acid Pro at position 238, as compared to SEQ ID NO: 7; a deletion of amino acid Gly at position 237, and a mutation of P238D, as compared to SEQ ID NO: 7; an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7; a mutation set of L234G, G236L, P238G, and an insertion of amino acid Asp between positions P238 and S239 as compared to SEQ ID NO: 7; a mutation set of L234G, G236L, and an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; or any combination thereof. The polypeptide of any of claims 20-22, wherein the first polypeptide comprises an amino acid sequence of SEQ ID NO: 1, 2, 3, 4,

5, or 6; and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 1, 2, 3, 4, 5, 6, respectively. The polypeptide of any of claims 20-23, wherein the first polypeptide comprises an amino acid sequence of SEQ ID NO: 1, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 1; the first polypeptide comprises an amino acid sequence of SEQ ID NO: 2, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 2; the first polypeptide comprises an amino acid sequence of SEQ ID NO: 3, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 3; the first polypeptide comprises an amino acid sequence of SEQ ID NO: 4, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 4; the first polypeptide comprises an amino acid sequence of SEQ ID NO: 5, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 5; or the first polypeptide comprises an amino acid sequence of SEQ ID NO: 6, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 6.

25. The polypeptide of claim 17, wherein the polypeptide comprises 2 inhibitory receptor effector domains that binds to the same, or different inhibitor receptor.

26. The polypeptide of any one of claims 17-25, wherein the inhibitory receptor effector domain is an antibody.

27. The polypeptide of any one of claims 17-26, wherein at least one inhibitory receptor effector domain binds to a receptor encoded by LAG3, RSV, BTLA/CD272, CD200R1, CD200R1, CD22/Siglec2, CD300A, CD300LF/CD300F, CD33/Siglec3, CD5, CD72, CEACAM 1, CLEC12A, CLEC4A, CTLA4/CD152, FCGR2B/CD32B, KIRs, KLRB1/CD161, KLRC1, KLRG1, LAIR1, LILRB1, LILRB2, LILRB4, LILRB5, NCR2/NKp44, PDCD1, PECAM1/CD31, PILRA, PVR/CD155, SIGLEC11, SIGLEC5, SIGLEC7, SIGLEC8, SIGLEC9, SIRPA, TIGIT, VSTM1/SIRL1, MAFA, NKG2A, CMRF35H, CD66a, CD66d, CD33, SIGLEC6, ILT2,3,4,5, LIR8, KIR2DL, KIR3DL, SIRPa, KIR2DL2/3, KIR2DL5, KIRDL1, KIRDL2, KIRDL3, TIM3, Tactile, IRp60, NKRP1, IAP, PIR-B, CD5, 2B4, GP49B, Ly49Q, or MICL.

28. The polypeptide of any one of claims 17-27, wherein the inhibitory receptor effector domain binds to PD-1, LAG-3, or CTLA4.

29. The polypeptide of any one of claims 17-28, wherein at least one inhibitory receptor effector domain is an agonist, or an antagonist of the receptor to which it binds.

30. A polypeptide comprising: a variant IgG Fc polypeptide having an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to any one of SEQ ID NO: 1, 2, 3, 4, 5 or 6; an inhibitory receptor effector domain; and a FcyRII binding effector domain.

31. The polypeptide of claim 30, wherein the variant IgG Fc polypeptide comprises: a deletion of amino acid Pro at position 238, as compared to SEQ ID NO: 7; a deletion of amino acid Gly at position 237, and a mutation of P238D, as compared to SEQ ID NO: 7; an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7; a mutation set of L234G, G236L, P238G, and an insertion of amino acid Asp between positions P238 and S239 as compared to SEQ ID NO: 7; or a mutation set of L234G, G236L, and an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7.

32. The polypeptide of any one of claims 30-31, wherein the variant IgG Fc polypeptide comprises an amino acid sequence of SEQ ID NO: 1, 2, 3, 4, 5, or 6.

33. The polypeptide of any one of claims 30-32, wherein the variant IgG Fc polypeptide associates with another variant IgG Fc polypeptide to form a dimer molecule, such as a homodimer molecule.

34. The polypeptide of claim 33, wherein the homodimer molecule comprises a first polypeptide and a second polypeptide, and wherein the first polypeptide and the second polypeptide comprise identical amino acid sequences.

35. The polypeptide of any one of claims 33-34, wherein the first polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the first polypeptide comprises: a deletion of amino acid Pro at position 238, as compared to SEQ ID NO:

7; a deletion of amino acid Gly at position 237, and a mutation of P238D, as compared to SEQ ID NO: 7; an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7; a mutation set of L234G, G236L, P238G, and an insertion of amino acid Asp between positions P238 and S239 as compared to SEQ ID NO: 7; a mutation set of L234G, G236L, and an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; or any combination thereof; and the second polypeptide comprises an amino acid sequence that is at least 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to a polypeptide comprising an amino acid sequence of SEQ ID NO: 7 provided that the second polypeptide comprises: a deletion of amino acid Pro at position 238, as compared to SEQ ID NO: 7; a deletion of amino acid Gly at position 237, and a mutation of P238D, as compared to SEQ ID NO: 7; an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; an insertion of amino acid Asp between positions P238 and S239, as compared to SEQ ID NO: 7; a mutation set of L234G, G236L, P238G, and an insertion of amino acid Asp between positions P238 and S239 as compared to SEQ ID NO: 7; a mutation set of L234G, G236L, and an insertion of amino acid Gly between positions P238 and S239, as compared to SEQ ID NO: 7; or any combination thereof.

36. The polypeptide of any of claims 33-35, wherein the first polypeptide comprises an amino acid sequence of SEQ ID NO: 1, 2, 3, 4, 5, or 6; and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 1, 2, 3, 4, 5, or 6, respectively.

37. The polypeptide of any of claims 33-36, wherein the first polypeptide comprises an amino acid sequence of SEQ ID NO: 1, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 1; the first polypeptide comprises an amino acid sequence of SEQ ID NO: 2, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 2; the first polypeptide comprises an amino acid sequence of SEQ ID NO: 3, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 3; the first polypeptide comprises an amino acid sequence of SEQ ID NO: 4, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 4; the first polypeptide comprises an amino acid sequence of SEQ ID NO: 5, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 5; or the first polypeptide comprises an amino acid sequence of SEQ ID NO: 6, and the second polypeptide comprises an amino acid sequence of SEQ ID NO: 6.

38. The polypeptide of claim 30, wherein the polypeptide comprises 2 inhibitory receptor effector domains that binds to the same, or different inhibitory receptors.

39. The polypeptide of any one of claims 30-38, wherein the inhibitory receptor effector domain is an antibody.

40. The polypeptide of any one of claims 30-39, wherein at least one inhibitor receptor effector domain binds to a receptor encoded by LAG3, RSV, BTLA/CD272, CD200R1, CD200R1, CD22/Siglec2, CD300A, CD300LF/CD300F, CD33/Siglec3, CD5, CD72, CEACAM 1, CLEC12A, CLEC4A, CTLA4/CD152, FCGR2B/CD32B, KIRs, KLRB1/CD161, KLRC1, KLRG1, LAIR1, LILRB1, LILRB2, LILRB4, LILRB5, NCR2/NKp44, PDCD1, PECAM1/CD31, PILRA, PVR/CD155, SIGLEC11, SIGLEC5, SIGLEC7, SIGLEC8, SIGLEC9, SIRPA, TIGIT, VSTM1/SIRL1, MAFA, NKG2A, CMRF35H, CD66a, CD66d, CD33, SIGLEC6, ILT2,3,4,5, LIR8, KIR2DL, KIR3DL, SIRPa, KIR2DL2/3, KIR2DL5, KIRDL1, KIRDL2, KIRDL3, TIM3, Tactile, IRp60, NKRP1, IAP, PIR-B, CD5, 2B4, GP49B, Ly49Q, or MICL.

41. The polypeptide of any one of claims 30-40, wherein the inhibitory receptor effector domain binds to PD-1, LAG-3, or CTLA4.

42. The polypeptide of any one of claims 30-41, wherein at least one inhibitory receptor effector domain is an agonist, or an antagonist of the receptor to which it binds.

43. The polypeptide of any one of claims 30-42, wherein the FcyRII binding effector domain binds to FcyRIip.

44. The polypeptide of claim 43, wherein the FcyRII binding effector domains is an antibody.

45. A pharmaceutical composition comprising a variant IgGFc polypeptide of any one of claims 1-16, or a polypeptide of any one of claims 17-44, and at least one pharmaceutically acceptable excipient.

46. A method of treating an autoimmune disorder in a subject, the method comprising administering a variant IgG Fc polypeptide of claims 1-16, or a polypeptide of any one of claims 17-44, or a pharmaceutical composition comprising the same, to the subject.

47. The method of claim 46, wherein the autoimmune disorder is selected from myocarditis, postmyocardial infarction syndrome, postpericardiotomy syndrome, subacute bacterial endocarditis, anti-glomerular basement membrane nephritis, interstitial cystitis, lupus nephritis, membranous glomerulonephropathy, chronic kidney disease (CKD), autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, anti synthetase syndrome, alopecia areata, autoimmune angioedema, autoimmune progesterone dermatitis, overlap connective tissues disease syndromes, polymyalgia rheumatic, autoimmune urticaria, bullous pemphigoid, cicatricial pemphigoid, dermatitis herpetiformis, discoid lupus erythematosus, epidermolysis bullosa acquisita, erythema nodosum, anti-neutrophil cytoplasmic antibody associated vasculitis, Henoch-Schonlein purpura, Cogan’s syndrome, Buerger’s disease, Susan’s disease, immune complex vasculitis, primary angiitis of the CNS, gestational pemphigoid, hidradenitis suppurativa, lichen planus, lichen sclerosus, linear iga disease (lad), morphea, pemphigus vulgaris, pityriasis lichenoides et varioliformis acuta, mucha-habermann disease, psoriasis, systemic scleroderma, vitiligo, Addison's disease, autoimmune polyendocrine syndrome (APS) type 1, autoimmune polyendocrine syndrome (APS) type 2, juvenile idiopathic arthritis juvenile dermatomyositis, autoimmune brain disease, autoimmune polyendocrine syndrome (APS) type 3, autoimmune pancreatitis (AIP), diabetes mellitus type 1, autoimmune thyroiditis, Ord's thyroiditis, Graves' disease, autoimmune oophoritis, endometriosis, autoimmune orchitis, Sjogren's syndrome, autoimmune enteropathy, Coeliac disease, Crohn's disease, microscopic colitis, ulcerative colitis, thrombocytopenia, adiposis, dolorosa, adult-onset Still's disease, ankylosing spondylitis, CREST syndrome, drug-induced lupus, enthesitis-related arthritis, eosinophilic fasciitis, Felty syndrome, IgG4-related disease uvenile arthritis, lyme disease (chronic), mixed connective tissue disease (MCTD), palindromic rheumatism, Parry Romberg syndrome, Parsonage-Turner syndrome, psoriatic arthritis, IBD-associated arthritis, reactive arthritis, relapsing polychondritis, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, autoimmune complications of immune checkpoint inhibitors (IRAEs), sarcoidosis, neurosarcoidosis, Schnitzler syndrome, systemic lupus erythematosus (SLE), undifferentiated connective tissue disease (UCTD), dermatomyositis, IgG4 related disease, fibromyalgia, antiphospholipid syndrome, inclusion body myositis, myositis, myasthenia gravis, neuromyotonia, paraneoplastic cerebellar degeneration, polymyositis, acute disseminated encephalomyelitis (ADEM), adult onset Still's disease, acute motor axonal neuropathy, anti-N- Methyl-D-Aspartate (anti-NMDA) receptor encephalitis, warm antibody hemolytic anemia (wAIHA), immune thrombocytopenia, immune thrombotic thrombocytopenia, thrombotic thrombocytopenia, pernicious anemia, aplastic anemia, Evan's syndrome, autoimmune neutropenia, acquired von Willibrand syndrome, recurring fetal loss, Rh mismatch, Balo concentric sclerosis, Bickerstaff s encephalitis, chronic inflammatory demyelinating polyneuropathy, Guillain-Barre syndrome, Hashimoto’s encephalopathy, idiopathic inflammatory demyelinating diseases, Lambert-Eaton myasthenic syndrome, primary biliary sclerosis, glomerulonephritis, glomerular basement membrane disease, multiple sclerosis, Oshtoran syndrome, pediatric autoimmune neuropsychiatric disorder associated with Streptococcus (PANDAS), progressive inflammatory neuropathy, cutaneous lupus erythematosus, restless leg syndrome, pemphigus foliaceus including fogo selvage, transplantation, antibody -mediated rejection, alloantibody hypersensitization, xenoantibody mediated rejection, solid organ rejection, graft vs host disease acute and chronic, stiff person syndrome, Sydenham chorea, transverse myelitis, autoimmune retinopathy, autoimmune uveitis, uveitis, Cogan syndrome, Graves ophthalmopathy, amyotrophic lateral sclerosis (ALS), Parkinson's disease, autoimmune encephalitis, CNS vasculitis, chronic idiopathic demyelinating polyneuropathy (CIDP), keratitis, intermediate uveitis, ligneous conjunctivitis, Mooren’s ulcer, neuromyelitis optica, opsoclonus myoclonus syndrome, optic neuritis, scleritis, Susac’s syndrome, sympathetic ophthalmia, Tolosa-Hunt syndrome, rheumatic heart disease, chronic rhinosinusitis with nasal polyps, allergic bronchoplmonary mycosis, hypersensitivity pneumonitis, rheumatoid arthritis-associated interstitial lung disease (RA-ILD), nonspecific interstitial pneumonia, allergic asthma, infectious disease/vaccination, antibody dependent enhancement (as wit dengue virus infection), chronic meningitis, anti-myelin oligodendrocyte glycoprotein (MOG) disease, activated-DLBCL, anti-drug antibody, anti-gene therapy vector antibody (anti-AAV antibody), antibody to therapeutic biologic agents (cytokines, monoclonal antibodies, enzymes, coagulation factors), autoimmune inner ear disease (AIED), Meniere's disease, Behcet’s disease, eosinophilic granulomatosis with polyangiitis (EGPA), giant cell arteritis, polyglandular autoimmune endocrine syndromes, granulmatosis with polyangiitis (GPA), IgA vasculitis (IgAV), Kawasaki’s disease, leukocytoclastic vasculitis, lupus vasculitis, rheumatoid vasculitis, microscopic polyangiitis (MPA), polyarteritis nodosa (PAN), polymyalgia rheumaticia, vasculitis, primary immune deficiency, pyoderma gangrenosum, agammaglobulinemia, anyloidosis, anyotrophic lateral sclerosis, anti-tubular basement membrane nephritis, atopic allergy, atopic dermatitis, autoimmune peripheral neuropathy, Blau syndrome, Castleman’s disease, Chagas disease, chronic obstructive pulmonary disease, chronic recurrent multifocal osteomyelitis, complement component 2 deficiency, contact dermatitis, Cushing’s syndrome, cutaneous leukocytoclastic angiitis, Dego’ deiase, eczema, eosinophilic gastroenteritis, eosinophilic pneumonia, erythroblastosis fetalsis, fibrodysplasia ossificans progressive, gastrointestinal pemphigoid, hypogammaglobulinemia, idiopathic giant-cell myocarditis, idiopathic pulmonary fibrosis, IgA nephropathy, immunoregulatory lipoproteins, IPEX syndrome, ligenous conjunctivitis, Majeed syndrome, narcolepsy, Rasmussen’s encephalitis, schizophrenia, serum sickness, spondyloathropathy, Sweet’s syndrome, Takayasu’s arteritis, or any combination thereof.

48. A method of treating cancer in a subject, the method comprising administering a variant IgG Fc polypeptide of any one of claims 1-16, or a polypeptide of any one of claims 17-44, or a pharmaceutical composition comprising the same, to the subject. 49. The method of claim 48, wherein the cancer is lung cancer, breast cancer, brain cancer, esophageal cancer, colorectal cancer, blood cancer, or pancreatic cancer.

50. A method of inhibiting an activated immune cell that is in contact with a B cell, an antigen presenting cell (APC), or a myeloid cell, the method comprising introducing a variant IgG Fc polypeptide of any one of claims 1-16, or a polypeptide of any one of claims 17-44, or a pharmaceutical composition comprising the same, to the cells.