FC fusion molecules and their uses

Abstract

Embodiments provided herein provide polypeptides and molecules, including polypeptides and variant Fc molecules, with protease activity, pharmaceutical compositions comprising same, and methods that can be used to treat disorders, such as IgG-mediated disorders.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 384,253, filed November 18, 2022, U.S. Provisional Application No. 63 / 483,127, filed February 3, 2023, and U.S. Provisional Application No. 63 / 493,385, filed March 31, 2023, each of which is incorporated by reference herein in its entirety.

[0002] Reference to an electronically submitted sequence listing This application contains a Sequence Listing that has been submitted electronically in XML file format, which is incorporated herein by reference in its entirety. The XML copy, created on November 16, 2023, is named "SES-006.XML" and is 63,289 bytes in size.

[0003] Embodiments provided herein relate to polypeptides having protease activity and polypeptides comprising an Fc portion, and compositions comprising the same. [Background technology]

[0004] S. pyogenes immunoglobulin G-degrading enzyme (IdeS) is an extracellular cysteine ​​protease produced by the human pathogen S. pyogenes. IdeS has an extremely high degree of substrate specificity, with immunoglobulin G (IgG) being its only identified substrate. IdeS catalyzes a single proteolytic cleavage in the lower hinge region of the heavy chains of all subclasses of human IgG. IdeS also catalyzes equivalent cleavage of the heavy chains of several subclasses of IgG in various animal species. IdeS efficiently cleaves IgG into Fc and F(ab')2 fragments. IdeS is a virulence factor of S. pyogenes, responsible for common infectious diseases such as tonsillitis and streptococcal pharyngitis. To date, no IdeS-Fc molecule resistant to autocleavage is available. Pathogenic IgG antibodies constitute a significant clinical problem, contributing to the pathogenesis of several autoimmune conditions and acute transplant rejection. Therefore, the ability to effectively reduce or eliminate such antibodies is a significant clinical challenge. The embodiments provided herein meet this and other needs. Summary of the Invention

[0005] In some embodiments, a variant Fc polypeptide comprises an amino acid sequence having 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, provided that the variant Fc polypeptide has at least one amino acid sequence identical to L234, compared to SEQ ID NO: 1. A, L235A, G237A, Y296Q, and P329K; L234A, L235A, G237A, Y296Q, S298K, and P329K; L234A, L235A, G237A, D265K, E269S, Y296Q, and P329K; or L234A, L235A, G237A, D265K, E269S, Y296Q, S298K, and P329K.

[0006] In some embodiments, a variant Fc polypeptide is provided that comprises the amino acid sequence of SEQ ID NO: 19, the amino acid sequence of SEQ ID NO: 21, the amino acid sequence of SEQ ID NO: 22, the amino acid sequence of SEQ ID NO: 23, the amino acid sequence of SEQ ID NO: 24, or the amino acid sequence of SEQ ID NO: 25.

[0007] In some embodiments, a polypeptide is provided comprising a polypeptide having protease activity and an Fc polypeptide, wherein the polypeptide having protease activity is covalently or non-covalently linked (e.g., conjugated via a peptide bond or through electrostatic interactions) to the Fc polypeptide.

[0008] In some embodiments, a polypeptide is provided having a formula from N-terminus to C-terminus selected from N1---P1---variant Fc, variant Fc---P1---N1, P1---variant Fc---N1, or N1---variant Fc---P1, wherein P1 comprises a polypeptide with protease activity, N1 comprises a nanobody, and the variant Fc is a variant Fc polypeptide.

[0009] In some embodiments, provided is a polypeptide having a formula from N-terminus to C-terminus selected from N1---P1---variant Fc, variant Fc---P1---N1, P1---variant Fc---N1, or N1---variant Fc---P1, wherein P1 comprises a polypeptide with protease activity, N1 comprises a Nanobody, the variant Fc is a variant Fc polypeptide, and optionally the protease is a glycosylation-resistant protease.

[0010] In some embodiments, a polypeptide is provided having a formula from N-terminus to C-terminus selected from N1---P1, or P1---N1, where P1 comprises a polypeptide having protease activity and N1 comprises a Nanobody, and optionally, the protease is a glycosylation-resistant protease.

[0011] In some embodiments, a polypeptide is provided having a formula from N-terminus to C-terminus selected from N1---IdeS---variant Fc, variant Fc---IdeS---N1, IdeS---variant Fc---N1, or N1---variant Fc---IdeS, wherein N1 comprises a nanobody and variant Fc is a variant Fc polypeptide.

[0012] In some embodiments, provided are methods of treating a disease or disorder in a subject, comprising administering any of the polypeptides provided herein to the subject to treat the disease or disorder.

[0013] In some embodiments, methods are provided for treating a transplant subject, comprising administering to the subject a therapeutically effective amount of any of the polypeptides provided herein, thereby treating the transplant (recipient) subject.

[0014] In some embodiments, provided are methods of improving gene therapy in a subject, comprising administering to the subject a therapeutically effective amount of any of the polypeptides provided herein, thereby improving gene therapy in the subject.

[0015] In some embodiments, provided are methods of treating a subject having, at risk of having, or at elevated risk of having an IgG-mediated disease or disorder, comprising administering a therapeutically effective amount of any of the polypeptides provided herein, thereby treating the subject.

[0016] In some embodiments, methods of making the polypeptides provided herein are provided. [Brief explanation of the drawings]

[0017] [Figure 1] 1 shows the performance of the IdeS-Fc polypeptide against IdeS. [Figure 2A] PK measurements are shown. [Figure 2B] PD measurements are shown. [Figure 3] PK and PD measurements are shown. [Figure 4A] The urine protein score is shown. [Figure 4B] Indicates blood urea nitrogen level. DETAILED DESCRIPTION OF THE INVENTION

[0018] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0019] As used herein, the term "about" means that a numerical value is approximate and that small variations do not significantly affect the practice of the disclosed embodiments. When a numerical limit is used, unless otherwise indicated by context, "about" means that the numerical value can vary by ±5% and remain within the range of the disclosed embodiments. Thus, about 100 means 95 to 105.

[0020] 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., mouse, rat, or guinea pig), monkey, cat, dog, cow, horse, pig, or human. In some embodiments, the mammal is a human.

[0021] As used herein, the term "contacting" refers to bringing two elements together in an in vitro system or in an in vivo system. For example, "contacting" a therapeutic compound with an individual or patient or cell includes administering the compound to an individual or patient, such as a human, and introducing the compound into a sample containing, for example, a cell or purified preparation containing the target.

[0022] As used herein, the terms "comprising" (and any form of comprising, e.g., "comprise," "comprises," and "comprised"), "having" (and any form of having, e.g., "have" and "has"), "including" (and any form of including, e.g., "includes" and "include"), or "containing" (and any form of containing, e.g., "contains" and "contain") are inclusive or open-ended and do not exclude additional, unrecited, elements or method steps. Any composition or method reciting the term "comprising" should be understood to also describe a composition that consists of, consists of, or consists essentially of the recited components or elements.

[0023] As used herein, the terms "fused" or "linked," when used in reference to proteins or molecules having different domains or heterologous sequences, mean that the protein domains are part of the same peptide chain, connected to each other either by peptide bonds or other covalent bonds. The domains or segments can be directly linked or fused to each other, or another domain or peptide sequence can be between the two domains or sequences, and such sequences would still be considered fused or linked to each other.

[0024] As used herein, the terms "individual," "subject," or "patient," used interchangeably, refer to any animal, including a mammal, e.g., a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse, or primate, such as a human.

[0025] As used herein, the term "inhibit" refers to a result, symptom, or activity that is reduced compared to the activity or result in the absence of the compound 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%. A result, symptom, or activity can also be inhibited if it is completely eliminated or abolished.

[0026] As used herein, the phrase "in need of" means that a subject has been identified as having a need for a particular method or treatment. In some embodiments, identification can be by any means of diagnosis. A subject may be in need of any of the methods and treatments described herein. In some embodiments, the subject is in or moves to an environment where a particular disease, disorder, or condition is prevalent.

[0027] As used herein, the phrase "an integer from X to Y" means any integer, inclusive. For example, the phrase "an integer from 1 to 5" means 1, 2, 3, 4, or 5.

[0028] As used herein, the phrase "ophthalmically acceptable" means having no lasting adverse effects on the treated eye or its function, or on the general health of the treated subject. However, it is recognized that transient effects, such as mild irritation or a "stinging" sensation, are common with topical ophthalmic administration of drugs, and the presence of such transient effects is not inconsistent with the composition, formulation, or ingredients (e.g., excipients) in question being "ophthalmically acceptable," as defined herein. In some embodiments, a pharmaceutical composition may be ophthalmically acceptable or suitable for ophthalmic administration.

[0029] In some embodiments, the term "therapeutic molecule" can be used interchangeably with "therapeutic compound," "molecule," or "therapeutic agent," and refers to any polypeptide or protein described herein.

[0030] As used herein, the term "position" is meant to refer to a location in the sequence of a polypeptide. Positions may be numbered sequentially or according to established formats, such as the EU numbering system based on Kabat amino acid positions. For example, position 298 is a position in human antibody IgG1.

[0031] "Specific binding" or "specifically binds to" or "specific for" a particular antigen, target, or epitope means binding that is measurably different from non-specific interactions. Specific binding can be measured, for example, by determining the binding of a molecule compared to the binding of a control molecule, which is generally 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.

[0032] Specific binding to a particular antigen, target, or epitope is, for example, at least about 10 -4M , at least about 10 -5M , at least about 10 -6M , at least about 10 -7M , at least about 10-8M , at least about 10 -9M , alternatively at least about 10 -10M , at least about 10 -11M , at least about 10 -12M , or K exceeding it D where K D refers to the off-rate of a particular antibody-target interaction. Typically, an antibody that specifically binds to an antigen or target has a K that is 2-fold, 4-fold, 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, 500-fold, 1000-fold, 5,000-fold, 10,000-fold, or more greater than a control molecule, or at least 2-fold, 4-fold, 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, 500-fold, 1000-fold, 5,000-fold, 10,000-fold, or more greater than a control molecule, compared to the antigen or epitope. D It has.

[0033] In some embodiments, specific binding to a particular antigen, target, or epitope is, for example, a K for the target, antigen, or epitope that is at least 2-fold, 4-fold, 5-fold, 20-fold, 50-fold, 100-fold, 500-fold, 1000-fold, 5,000-fold, 10,000-fold, or more, greater than a control. A or K a where K A or K a refers to the association rate of a particular antibody-antigen interaction.

[0034] As provided herein, the compounds and compositions provided herein can be used in the therapeutic methods provided herein. As used herein, the terms "treat," "treated," or "treating" refer to both therapeutic treatments and prophylactic measures, the purpose of which is to slow (alleviate) an undesirable physiological condition, disorder, or disease, or to obtain a beneficial or desired clinical result. For purposes of these embodiments, a beneficial or desired clinical result includes, but is not limited to, alleviation of symptoms; reduction in the severity of a condition, disorder, or disease; stabilization (i.e., not worsening) of the condition, disorder, or disease state; delay in onset or slowing of the condition, disorder, or disease progression; improvement or remission (whether partial or total) of the condition, disorder, or disease state, whether detectable or undetectable; improvement in at least one measurable physical parameter, not necessarily discernible by the patient; or enhancement or amelioration of the condition, disorder, or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment, where applicable to a particular disease, also includes prolonging survival compared to expected survival if not receiving treatment. Thus, "treatment of an autoimmune condition" or "treating autoimmunity" refers to the activity of alleviating or ameliorating any of the primary phenomena or secondary symptoms associated with the autoimmune conditions described herein, as well as other conditions, when the terms "treat," "treated," or "treating" are used in conjunction with such conditions.

[0035] As used herein, the terms "variant," "molecule," "therapeutic agent," "therapeutic compound," "compound," "polypeptide," or "protein" can be used interchangeably and refer to the variants, molecules, therapeutic agents, therapeutic compounds, compounds, polypeptides, and proteins disclosed herein.

[0036] Variant Fc molecules As used herein, "isotype" refers to the immunoglobulin class (e.g., IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE antibodies) encoded by heavy chain constant domain genes. The full-length amino acid sequence of each wild-type human IgG constant region (including all domains, i.e., CH1 domain, hinge, CH2 domain, and CH3 domain) is cataloged in the UniProt database available online, for example, as P01857 (IgG1), P01859 (IgG2), P01860 (IgG3), and P01861 (IgG4), or their different allotypes (SEQ ID NOs: 1, 2, 3, and 4, respectively). As used herein, a domain of a heavy chain constant region, e.g., a hinge, is of the "IgG1 isotype," "IgG2 isotype," "IgG3 isotype," or "IgG4 isotype" if the domain comprises the amino acid sequence of the corresponding domain of each isotype or a variant thereof (which has higher homology to the corresponding domain of each isotype than to that of other isotypes).

[0037] "Allotype" refers to naturally occurring variants within a particular isotype group, which variants differ in some amino acids (see, e.g., Jefferies et al. (2009) mAbs 1:1). The molecules described herein can be of any allotype.

[0038] A "wild-type" protein or portion thereof is a version of a protein found in nature. The amino acid sequence of a wild-type protein, e.g., a heavy chain constant region, is the amino acid sequence of a naturally occurring protein. Due to allotypic differences, there may be more than one amino acid sequence for a wild-type protein. For example, there are several allotypes of the naturally occurring human IGg1 heavy chain constant region (e.g., Jeffries et al. (2009) mAbs 1:1).

[0039] Immunoglobulins can be from any of the commonly known isotypes, including, but not limited to, IgA, secretory IgA, IgG, and IgM. The IgG isotype is divided into subclasses in certain species: IgG1, IgG2, IgG3, and IgG4 in humans, and IgG1, IgG2a, IgG2b, and IgG3 in mice. In certain embodiments, the antibodies described herein are of the human IgG1 or IgG2 subtype. Immunoglobulins, such as human IgG1, exist in several allotypes that differ from each other in at most a few amino acids.

[0040] In some embodiments, the IgG protein (hinge region underlined) is as provided in Table 1. [Table 1]

[0041] "Fc region" (Fragment crystallizable region) or "Fc polypeptide" or "Fc" refers to the C-terminal region of an antibody heavy chain that mediates binding of immunoglobulins 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 (C1q) of the classical complement system. Thus, the Fc region of an antibody of isotype IgG includes the heavy chain constant region of the antibody excluding the first constant region immunoglobulin domain (CH1). In IgG, IgA, and IgD antibody isotypes, the Fc region includes CH2 and CH3 constant domains in each of the antibody's two heavy chains, while IgM and IgE Fc regions include three heavy chain constant domains (CH domains 2-4) in each polypeptide chain. In the case of IgG, the Fc region includes immunoglobulin domains consisting of the hinge, CH2, and CH3. For purposes herein, the Fc region is defined as beginning at amino acid 216 and ending at amino acid 447, with numbering 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 Figures 3c-3f of U.S. Patent Application Publication No. 2008 / 0248028. In some embodiments, the Fc region includes the hinge region. The Fc can be a native (or naturally occurring or wild-type) Fc, including any allotypic variants, or a variant Fc (e.g., a non-naturally occurring Fc), including, for example, 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. A modified or mutated Fc may have enhanced or reduced effector function and / or half-life. Fc may refer to this region in isolation or in the context of a protein polypeptide that comprises the Fc, such as an "Fc region-containing binding protein" (e.g., an antibody or immunoadhesin), also referred to as an "Fc fusion protein."In some embodiments, the modified or variant Fc molecule has enhanced binding to FcγRIIb.

[0042] The terms "hinge," "hinge domain," or "hinge region," or "antibody hinge region" refer to the domain of the heavy chain constant region that connects the CH1 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 a site for intermolecular disulfide bonds between the two heavy chain constant regions. The term "hinge" includes wild-type hinges (such as those listed in Table 3) and variants thereof (e.g., non-naturally occurring hinges or modified hinges). For example, the term "IgG1 hinge" includes the wild-type IgG1 hinge shown below, as well as variants having 1, 2, 3, 4, 5, 1-3, 1-5, 3-5, and / or up to 5, 4, 3, 2, or 1 mutations, e.g., substitutions, deletions, or additions. In some embodiments, the hinge region is as provided in Table 2. [Table 2]

[0043] The term "CH1 domain" refers to a heavy chain constant region that connects a variable domain to a hinge within a heavy chain constant domain. As used herein, CH1 domains include wild-type CH1 domains and variants thereof (e.g., non-naturally occurring CH1 domains or modified CH1 domains). For example, the term "CH1 domain" includes wild-type CH1 domains and variants thereof having 1, 2, 3, 4, 5, 1-3, 1-5, 3-5, and / or up to 5, 4, 3, 2, or 1 mutations, e.g., substitutions, deletions, or additions.

[0044] The term "CH2 domain" refers to a heavy chain constant region that connects the hinge to the CH3 domain within the heavy chain constant domain. As used herein, CH2 domains include wild-type CH2 domains and variants thereof (e.g., non-naturally occurring CH2 domains or modified CH2 domains). 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 up to 5, 4, 3, 2, or 1 mutations, e.g., substitutions, deletions, or additions.

[0045] The term "CH3 domain" refers to a heavy chain constant region C-terminal to a CH2 domain within a heavy chain constant domain. As used herein, CH3 domains include wild-type CH3 domains and variants thereof (e.g., non-naturally occurring CH3 domains or modified CH3 domains). 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 up to 5, 4, 3, 2, or 1 mutations, e.g., substitutions, deletions, or additions.

[0046] Provided herein are variant Fc polypeptides, including, for example, Fc polypeptides having mutated sequence regions compared to a wild-type Fc polypeptide. Exemplary variant Fc molecules, including variant Fc polypeptides, include an IgG1 hinge, CH1 domain, CH2 domain, and CH3 domain, wherein at least one of these constant domains has a residue that is not the wild-type residue compared to SEQ ID NO: 1, 2, 3, or 4. The variant Fc polypeptides can have effector functions similar to those of wild-type IgG, or can be engineered to have enhanced effector functions compared to those of wild-type IgG. The variant Fc polypeptide may comprise a wild-type CH1, hinge, CH2, and / or CH3 domain, or a variant thereof, e.g., a CH1, hinge, CH2, and / or CH3 domain having one or more amino acid substitutions, deletions, or additions compared 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 wild-type sequence.

[0047] In some embodiments, the IgG protein is as provided in Table 6. [Table 3]

[0048] In some embodiments, the variant Fc polypeptide comprises one or more mutations that confer resistance to recognition by proteases. In some embodiments, the variant Fc polypeptide comprises one or more mutations that confer resistance to proteolytic cleavage. In some embodiments, the variant Fc polypeptide comprises one or more mutations that confer resistance to binding by proteases. In some embodiments, the variant Fc polypeptide comprises one or more mutations that confer resistance to recognition and proteolytic cleavage by proteases. In some embodiments, the variant Fc polypeptide is resistant to proteolytic cleavage. In some embodiments, the variant Fc polypeptide is resistant to binding by proteases. In some embodiments, the variant Fc polypeptide is resistant to proteolytic cleavage and / or binding by proteases.

[0049] In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:1, provided that the variant Fc polypeptide comprises an amino acid mutation at any one or more positions 234 to 329 compared to SEQ ID NO:1, wherein the mutation comprises an insertion, deletion, or substitution.

[0050] In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:1, provided that the variant Fc polypeptide comprises a mutation corresponding to the L234A mutation compared to SEQ ID NO:1.

[0051] In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:1, provided that the variant Fc polypeptide comprises a mutation corresponding to the L235A mutation compared to SEQ ID NO:1.

[0052] In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:1, provided that the variant Fc polypeptide comprises a mutation corresponding to the G237A mutation compared to SEQ ID NO:1.

[0053] In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:1, provided that the variant Fc polypeptide comprises a mutation corresponding to the Y296Q mutation compared to SEQ ID NO:1.

[0054] In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:1, provided that the variant Fc polypeptide comprises a mutation corresponding to the P329K mutation compared to SEQ ID NO:1.

[0055] In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:1, provided that the variant Fc polypeptide comprises a set of mutations corresponding to the L234A, L235A, and G237A mutations compared to SEQ ID NO:1.

[0056] In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:1, provided that the variant Fc polypeptide comprises a set of mutations corresponding to the Y296Q and P329K mutations compared to SEQ ID NO:1.

[0057] In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:1, provided that the variant Fc polypeptide comprises a set of mutations corresponding to the L234A, L235A, G237A, Y296Q, and P329K mutations compared to SEQ ID NO:1.

[0058] In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 56, provided that the variant Fc polypeptide comprises the set of mutations corresponding to the L234A, L235A, G237A, Y296Q, and P329K mutations compared to SEQ ID NO: 1.

[0059] In some embodiments, the variant Fc polypeptide comprises the set of mutations L234A, L235A, G237A, Y296Q, and P329K compared to SEQ ID NO:1, and the variant 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 set of mutations compared to SEQ ID NO:1. [Table 4]

[0060] In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to any of the sequences provided in Table 3. In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 19, 20, 21, 22, 23, 24, 25, 42, 43, 44, 45, 46, 47, 48, or 49. In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 19. In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:20.In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 21. In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 22. In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 23. In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 24. In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:25.In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 42. In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 43. In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 44. In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 45. In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:46.In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 47. In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 48. In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:49.

[0061] In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to any of the sequences provided in Table 3, provided that the variant Fc polypeptide comprises one or more mutations at positions 234, 235, 237, 265, 269, 296, 298, 329, or any combination thereof. In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 19, 20, 21, 22, 23, 24, or 25, provided that the variant Fc polypeptide comprises one or more mutations at positions 234, 235, 237, 265, 269, 296, 298, 329, or any combination thereof. In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 19, provided that the variant Fc polypeptide comprises one or more mutations at positions 234, 235, 237, 265, 269, 296, 298, 329, or any combination thereof.In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 20, provided that the variant Fc polypeptide comprises one or more mutations at positions 234, 235, 237, 265, 269, 296, 298, 329, or any combination thereof. In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 21, provided that the variant Fc polypeptide comprises one or more mutations at positions 234, 235, 237, 265, 269, 296, 298, 329, or any combination thereof. In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 22, provided that the variant Fc polypeptide comprises one or more mutations at positions 234, 235, 237, 265, 269, 296, 298, 329, or any combination thereof.In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 23, provided that the variant Fc polypeptide comprises one or more mutations at positions 234, 235, 237, 265, 269, 296, 298, 329, or any combination thereof. In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:24, provided that the variant Fc polypeptide comprises one or more mutations at positions 234, 235, 237, 265, 269, 296, 298, 329, or any combination thereof. In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 25, provided that the variant Fc polypeptide comprises one or more mutations at positions 234, 235, 237, 265, 269, 296, 298, 329, or any combination thereof.

[0062] In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to any of the sequences provided in Table 3, and further comprises one or more mutations: L234A, L235A, G237A, Y296Q, P329K, or any combination thereof. In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 19, 20, 21, 22, 23, 24, or 25, provided that the variant Fc polypeptide comprises one or more mutations of L234A, L235A, G237A, Y296Q, P329K, or any combination thereof. In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 19, provided that the variant Fc polypeptide comprises one or more mutations: L234A, L235A, G237A, Y296Q, P329K, or any combination thereof.In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 20, provided that the variant Fc polypeptide comprises one or more mutations: L234A, L235A, G237A, Y296Q, P329K, or any combination thereof. In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 21, provided that the variant Fc polypeptide comprises one or more mutations: L234A, L235A, G237A, Y296Q, P329K, or any combination thereof. In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 22, provided that the variant Fc polypeptide comprises one or more mutations: L234A, L235A, G237A, Y296Q, P329K, or any combination thereof. In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 23, provided that the variant Fc polypeptide comprises one or more mutations: L234A, L235A, G237A, Y296Q, P329K, or any combination thereof. In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 24, provided that the variant Fc polypeptide comprises one or more mutations: L234A, L235A, G237A, Y296Q, P329K, or any combination thereof. In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 25, provided that the variant Fc polypeptide comprises one or more mutations: L234A, L235A, G237A, Y296Q, P329K, or any combination thereof.In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 19, 20, 21, 22, 23, 24, or 25, provided that the variant Fc polypeptide comprises the set of mutations corresponding to the L234A, L235A, G237A, Y296Q, and P329K mutations. In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 19, provided that the variant Fc polypeptide comprises the set of mutations corresponding to the L234A, L235A, G237A, Y296Q, and P329K mutations. In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 20, provided that the variant Fc polypeptide comprises the set of mutations corresponding to the L234A, L235A, G237A, Y296Q, and P329K mutations.In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 21, provided that the variant Fc polypeptide comprises the set of mutations corresponding to the L234A, L235A, G237A, Y296Q, and P329K mutations. In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 22, provided that the variant Fc polypeptide comprises the set of mutations corresponding to the L234A, L235A, G237A, Y296Q, and P329K mutations. In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 23, provided that the variant Fc polypeptide comprises the set of mutations corresponding to the L234A, L235A, G237A, Y296Q, and P329K mutations. In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 24, provided that the variant Fc polypeptide comprises the set of mutations corresponding to the L234A, L235A, G237A, Y296Q, and P329K mutations. In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 25, provided that the variant Fc polypeptide comprises the set of mutations corresponding to the L234A, L235A, G237A, Y296Q, and P329K mutations.In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 19, 20, 21, 22, 23, 24, or 25, provided that the variant Fc polypeptide comprises the set of mutations corresponding to the L234A, L235A, G237A, D265K, E269S, Y296Q, and P329K mutations. In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 19, provided that the variant Fc polypeptide comprises the set of mutations corresponding to the L234A, L235A, G237A, D265K, E269S, Y296Q, and P329K mutations. In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 20, provided that the variant Fc polypeptide comprises the set of mutations corresponding to the L234A, L235A, G237A, D265K, E269S, Y296Q, and P329K mutations.In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 21, provided that the variant Fc polypeptide comprises a set of mutations corresponding to the L234A, L235A, G237A, D265K, E269S, Y296Q, and P329K mutations. In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 22, provided that the variant Fc polypeptide comprises the set of mutations corresponding to the L234A, L235A, G237A, D265K, E269S, Y296Q, and P329K mutations. In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 23, provided that the variant Fc polypeptide comprises the set of mutations corresponding to the L234A, L235A, G237A, D265K, E269S, Y296Q, and P329K mutations. In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 24, provided that the variant Fc polypeptide comprises the set of mutations corresponding to the L234A, L235A, G237A, D265K, E269S, Y296Q, and P329K mutations. In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 25, provided that the variant Fc polypeptide comprises the set of mutations corresponding to the L234A, L235A, G237A, D265K, E269S, Y296Q, and P329K mutations.

[0063] In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 19, 20, 21, 22, 23, 24, or 25, provided that the variant Fc polypeptide comprises the set of mutations corresponding to the L234A, L235A, G237A, D265K, E269S, Y296Q, S298K, and P329K mutations. In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 19, provided that the variant Fc polypeptide comprises a set of mutations corresponding to the L234A, L235A, G237A, D265K, E269S, Y296Q, S298K, and P329K mutations. In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 20, provided that the variant Fc polypeptide comprises a set of mutations corresponding to the L234A, L235A, G237A, D265K, E269S, Y296Q, S298K, and P329K mutations.In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 21, provided that the variant Fc polypeptide comprises a set of mutations corresponding to the L234A, L235A, G237A, D265K, E269S, Y296Q, S298K, and P329K mutations. In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 22, provided that the variant Fc polypeptide comprises the set of mutations corresponding to the L234A, L235A, G237A, D265K, E269S, Y296Q, S298K, and P329K mutations. In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 23, provided that the variant Fc polypeptide comprises the set of mutations corresponding to the L234A, L235A, G237A, D265K, E269S, Y296Q, S298K, and P329K mutations.In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 24, provided that the variant Fc polypeptide comprises the set of mutations corresponding to the L234A, L235A, G237A, D265K, E269S, Y296Q, S298K, and P329K mutations. In some embodiments, the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 25, provided that the variant Fc polypeptide comprises the set of mutations corresponding to the L234A, L235A, G237A, D265K, E269S, Y296Q, S298K, and P329K mutations.

[0064] In some embodiments, the variant Fc polypeptide comprises the set of mutations L234A, L235A, G237A, Y296Q, and P329K compared to SEQ ID NO: 19, 20, 21, 22, 23, 24, or 25, wherein the variant 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 set of mutations L234A, L235A, G237A, Y296Q, and P329K compared to SEQ ID NO: 19, 20, 21, 22, 23, 24, or 25. In some embodiments, the variant Fc polypeptide comprises the set of mutations L234A, L235A, G237A, Y296Q, and P329K compared to SEQ ID NO: 19, and the variant 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 set of mutations L234A, L235A, G237A, Y296Q, and P329K compared to SEQ ID NO: 19. In some embodiments, the variant Fc polypeptide comprises the set of mutations L234A, L235A, G237A, Y296Q, and P329K compared to SEQ ID NO:20, wherein the variant 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 set of mutations L234A, L235A, G237A, Y296Q, and P329K compared to SEQ ID NO:20.In some embodiments, the variant Fc polypeptide comprises the set of mutations L234A, L235A, G237A, Y296Q, and P329K compared to SEQ ID NO:21, wherein the variant 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 set of mutations L234A, L235A, G237A, Y296Q, and P329K compared to SEQ ID NO:21. In some embodiments, the variant Fc polypeptide comprises the set of mutations L234A, L235A, G237A, Y296Q, and P329K compared to SEQ ID NO: 22, wherein the variant 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 set of mutations L234A, L235A, G237A, Y296Q, and P329K compared to SEQ ID NO: 22. In some embodiments, the variant Fc polypeptide comprises the set of mutations L234A, L235A, G237A, Y296Q, and P329K compared to SEQ ID NO: 23, and the variant 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 set of mutations L234A, L235A, G237A, Y296Q, and P329K compared to SEQ ID NO: 23.In some embodiments, the variant Fc polypeptide comprises the set of mutations L234A, L235A, G237A, Y296Q, and P329K compared to SEQ ID NO:24, and the variant 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 set of mutations L234A, L235A, G237A, Y296Q, and P329K compared to SEQ ID NO:24. In some embodiments, the variant Fc polypeptide comprises the set of mutations L234A, L235A, G237A, Y296Q, and P329K compared to SEQ ID NO:25, wherein the variant 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 set of mutations L234A, L235A, G237A, Y296Q, and P329K compared to SEQ ID NO:25. In some embodiments, the variant Fc polypeptide comprises the following set of mutations compared to SEQ ID NO: 19, 20, 21, 22, 23, 24, or 25: L234A, L235A, G237A, D265K, E269S, Y296Q, and P329K; In addition to the set of L234A, L235A, G237A, D265K, E269S, Y296Q, and P329K mutations, the set further includes 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 some embodiments, the variant Fc polypeptide comprises the set of mutations L234A, L235A, G237A, D265K, E269S, Y296Q, and P329K compared to SEQ ID NO: 19, wherein the variant 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 set of mutations L234A, L235A, G237A, D265K, E269S, Y296Q, and P329K compared to SEQ ID NO: 19. In some embodiments, the variant Fc polypeptide comprises the set of mutations L234A, L235A, G237A, D265K, E269S, Y296Q, and P329K compared to SEQ ID NO:20, wherein the variant 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 set of mutations L234A, L235A, G237A, D265K, E269S, Y296Q, and P329K compared to SEQ ID NO:20. In some embodiments, the variant Fc polypeptide comprises the set of mutations L234A, L235A, G237A, D265K, E269S, Y296Q, and P329K compared to SEQ ID NO:21, wherein the variant 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 set of mutations L234A, L235A, G237A, D265K, E269S, Y296Q, and P329K compared to SEQ ID NO:21.In some embodiments, the variant Fc polypeptide comprises the set of mutations L234A, L235A, G237A, D265K, E269S, Y296Q, and P329K compared to SEQ ID NO:22, wherein the variant 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 set of mutations L234A, L235A, G237A, D265K, E269S, Y296Q, and P329K compared to SEQ ID NO:22. In some embodiments, the variant Fc polypeptide comprises the set of mutations L234A, L235A, G237A, D265K, E269S, Y296Q, and P329K compared to SEQ ID NO:23, wherein the variant 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 set of mutations L234A, L235A, G237A, D265K, E269S, Y296Q, and P329K compared to SEQ ID NO:23. In some embodiments, the variant Fc polypeptide comprises the set of mutations L234A, L235A, G237A, D265K, E269S, Y296Q, and P329K compared to SEQ ID NO:24, wherein the variant 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 set of mutations L234A, L235A, G237A, D265K, E269S, Y296Q, and P329K compared to SEQ ID NO:24.In some embodiments, the variant Fc polypeptide comprises the set of mutations L234A, L235A, G237A, D265K, E269S, Y296Q, and P329K compared to SEQ ID NO:25, wherein the variant 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 set of mutations L234A, L235A, G237A, D265K, E269S, Y296Q, and P329K compared to SEQ ID NO:25.

[0065] In some embodiments, the variant Fc polypeptide comprises the following set of mutations compared to SEQ ID NO: 19, 20, 21, 22, 23, 24, or 25: L234A, L235A, G237A, D265K, E269S, Y296Q, S298K, and P329K; In addition to the set of L234A, L235A, G237A, D265K, E269S, Y296Q, S298K, and P329K mutations, the set further includes 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 some embodiments, the variant Fc polypeptide comprises the set of mutations L234A, L235A, G237A, D265K, E269S, Y296Q, S298K, and P329K compared to SEQ ID NO: 19, wherein the variant 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 set of mutations L234A, L235A, G237A, D265K, E269S, Y296Q, S298K, and P329K compared to SEQ ID NO: 19. In some embodiments, the variant Fc polypeptide comprises the set of mutations L234A, L235A, G237A, D265K, E269S, Y296Q, S298K, and P329K compared to SEQ ID NO:20, wherein the variant 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 set of mutations L234A, L235A, G237A, D265K, E269S, Y296Q, S298K, and P329K compared to SEQ ID NO:20.In some embodiments, the variant Fc polypeptide comprises the set of mutations L234A, L235A, G237A, D265K, E269S, Y296Q, S298K, and P329K compared to SEQ ID NO:21, wherein the variant 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 set of mutations L234A, L235A, G237A, D265K, E269S, Y296Q, S298K, and P329K compared to SEQ ID NO:21. In some embodiments, the variant Fc polypeptide comprises the set of mutations L234A, L235A, G237A, D265K, E269S, Y296Q, S298K, and P329K compared to SEQ ID NO:22, wherein the variant 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 set of mutations L234A, L235A, G237A, D265K, E269S, Y296Q, S298K, and P329K compared to SEQ ID NO:22. In some embodiments, the variant Fc polypeptide comprises the set of mutations L234A, L235A, G237A, D265K, E269S, Y296Q, S298K, and P329K compared to SEQ ID NO:23, wherein the variant 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 set of mutations L234A, L235A, G237A, D265K, E269S, Y296Q, S298K, and P329K compared to SEQ ID NO:23.In some embodiments, the variant Fc polypeptide comprises the set of mutations L234A, L235A, G237A, D265K, E269S, Y296Q, S298K, and P329K compared to SEQ ID NO:24, wherein the variant 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 set of mutations L234A, L235A, G237A, D265K, E269S, Y296Q, S298K, and P329K compared to SEQ ID NO:24. In some embodiments, the variant Fc polypeptide comprises the set of mutations L234A, L235A, G237A, D265K, E269S, Y296Q, S298K, and P329K compared to SEQ ID NO:25, wherein the variant 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 set of mutations L234A, L235A, G237A, D265K, E269S, Y296Q, S298K, and P329K compared to SEQ ID NO:25.

[0066] In some embodiments, the variant Fc polypeptide comprises the amino acid sequence provided in Table 3. In some embodiments, the variant Fc polypeptide comprises the amino acid sequence of SEQ ID NO: 19, 20, 21, 22, 23, 24, 25, 42, 43, 44, 45, 46, 47, 48, or 49. In some embodiments, the variant Fc polypeptide comprises the amino acid sequence of SEQ ID NO: 19. In some embodiments, the variant Fc polypeptide comprises the amino acid sequence of SEQ ID NO: 20. In some embodiments, the variant Fc polypeptide comprises the amino acid sequence of SEQ ID NO: 21. In some embodiments, the variant Fc polypeptide comprises the amino acid sequence of SEQ ID NO: 22. In some embodiments, the variant Fc polypeptide comprises the amino acid sequence of SEQ ID NO: 23. In some embodiments, the variant Fc polypeptide comprises the amino acid sequence of SEQ ID NO: 24. In some embodiments, the variant Fc polypeptide comprises the amino acid sequence of SEQ ID NO: 25. In some embodiments, the variant Fc polypeptide comprises the amino acid sequence of SEQ ID NO: 42. In some embodiments, the variant Fc polypeptide comprises the amino acid sequence of SEQ ID NO: 43. In some embodiments, the variant Fc polypeptide comprises the amino acid sequence of SEQ ID NO: 44. In some embodiments, the variant Fc polypeptide comprises the amino acid sequence of SEQ ID NO: 45. In some embodiments, the variant Fc polypeptide comprises the amino acid sequence of SEQ ID NO: 46. In some embodiments, the variant Fc polypeptide comprises the amino acid sequence of SEQ ID NO: 47. In some embodiments, the variant Fc polypeptide comprises the amino acid sequence of SEQ ID NO: 48. In some embodiments, the variant Fc polypeptide comprises the amino acid sequence of SEQ ID NO: 49.

[0067] In some embodiments, the variant Fc polypeptide comprises an amino acid sequence that has a C-terminal lysine (K). In some embodiments, the variant Fc polypeptide comprises an amino acid sequence that does not have a C-terminal lysine (K).

[0068] In some embodiments, a variant Fc polypeptide such as those provided herein is conjugated to another polypeptide. In some embodiments, the other polypeptide is an antibody. In some embodiments, a variant Fc polypeptide such as those provided herein is conjugated to an effector binding / modulating polypeptide or a tissue-targeting polypeptide. In some embodiments, a variant Fc polypeptide such as those provided herein is conjugated to an antibody or antigen-binding fragment thereof. In some embodiments, a variant Fc polypeptide such as those is conjugated to another polypeptide via a linker or covalent bond. In some embodiments, the linker is a protein linker such as those provided herein.

[0069] Polypeptides with protease activity The present disclosure provides polypeptides, molecules, compounds, therapeutic agents, and compositions comprising a polypeptide with protease activity, which may be covalently or non-covalently linked to an Fc polypeptide domain, such as those provided herein. In some embodiments, the polypeptide with protease activity is IdeS, IdeSsuis, IdeZ, IdeE, IdeE2, IdeZ2, or IdeC.

[0070] Streptococcus pyogenes is an important bacterial pathogen that secretes two enzymes, EndoS and IdeS, that show remarkable specificity for IgG. EndoS, an endoglycosidase in Streptococcus pyogenes, specifically hydrolyzes functionally important N-linked glycans on IgG, and treatment with EndoS abolishes the pathogenic activity of IgG in mouse models of autoimmune disease. (Collin M, Olsen A. EndoS, a novel secreted protein from Streptococcus pyogenes with endoglycosidase activity on human IgG. Embo J. 2001;20:3046-3055; Nandakumar KS, Collin M, Olsen A, Nimmerjahn F, Blom AM, et al. Endoglycosidase treatment abrogates IgG arthritogenicity: importance of IgG glycosylation in arthritis. Eur J Immunol. 2007;37:2973-2982) IdeS (Immunoglobulin G-degrading enzyme from Streptococcus pyogenes) is a cysteine ​​proteinase that cleaves IgG in the hinge region with a unique degree of specificity. (Wenig K, Chatwell L, von Pawel-Rammingen U, Bjorck L, Huber R, et al. Structure of the streptococcal endopeptidase IdeS, a cysteine ​​proteinase with strict specificity for IgG. Proc Natl Acad Sci USA. 2004;101:17371-17376) IdeS is highly specific for IgG, hydrolyzing it at the hinge region after glycine residue 236 in both heavy chains, generating one F(ab')2 and two monomeric Fc fragments. IdeE is a homolog of the secreted IgG-specific protease IdeS / Mac from Streptococcus pyogenes.The activity of IdeE is comparable to that of the corresponding enzyme, IdeZ, from the closely related S. equi ssp. zooepidemicus.

[0071] The complete sequence of IdeS is publicly available under NCBI reference sequence number WP_010922160.1 and is provided herein as SEQ ID NO: 35: [ka]

[0072] This sequence contains an N-terminal methionine followed by a 28 amino acid secretory signal sequence. The N-terminal methionine and signal sequence (a total of 29 amino acids at the N-terminus) are typically removed to form the mature IdeS protein, the amino acid sequence of which is publicly available under UniProt identifier Q9F1R7_STRPY and is provided herein as SEQ ID NO: 36.

[0073] IdeZ is an IgG cysteine ​​protease produced by Streptococcus equi ssp. zooepidemicus, a bacterium found primarily in horses. Because IdeZ is not a human pathogen, human subjects typically do not have antibodies to this protein in their plasma. However, IdeZ has a level of IgG cysteine ​​protease activity against human IgG that is significantly lower than that of IdeS. The mature sequence of IdeZ is publicly available under the UniProt identifier A0A0D0YKS5_STRSZ and is provided herein as SEQ ID NO: 37.

[0074] In some embodiments, the polypeptide having protease activity is IdeS, IdeSsuis, IdeZ, IdeE, IdeE2, IdeZ2, or IdeC. In some embodiments, the IdeS, IdeZ, IdeE, IdeE2, IdeZ2, or IdeC protease has an amino acid sequence such as those provided herein. The mature sequence of IdeSsuis is publicly available under UniProt identifier C5W022 and is provided herein as SEQ ID NO: 55. The mature sequence of IdeE is publicly available under UniProt identifier C0M8U6_STRE4 and is provided herein as SEQ ID NO: 38. The mature sequence of IdeE2 is publicly available under UniProt identifier C7B615_9STRE and is provided herein as SEQ ID NO: 39. The mature sequence of IdeZ2 is publicly available under UniProt identifier B4U2F7_STREM and is provided herein as SEQ ID NO: 40. The mature sequence of IdeC is publicly available under the UniProt identifier A0A3P5YAY8_STRCB and is provided herein as SEQ ID NO: 41. In some embodiments, the protease is an IgG-degrading protease. In some embodiments, the protease is an IgM-degrading protease. [Table 5-1] [Table 5-2]

[0075] In some embodiments, the polypeptide having protease activity comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to any of the sequences provided in Table 4. In some embodiments, the polypeptide having protease activity is IdeS. In some embodiments, the polypeptide having protease activity is IdeS. In some embodiments, the polypeptide having protease activity is IdeE. In some embodiments, the polypeptide having protease activity is IdeZ. In some embodiments, the polypeptide having protease activity is IdeE2. In some embodiments, the polypeptide having protease activity is IdeZ2. In some embodiments, the polypeptide having protease activity is IdeC. In some embodiments, the polypeptide having protease activity comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 26, 28, 29, 31, 36, 37, 38, 39, 40, 41, 50, 51, 52, or 55. In some embodiments, the polypeptide having protease activity comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:26.In some embodiments, a polypeptide having protease activity comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 28. In some embodiments, a polypeptide having protease activity comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 29. In some embodiments, a polypeptide having protease activity comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 31. In some embodiments, a polypeptide having protease activity comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 36.In some embodiments, a polypeptide having protease activity comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 37. In some embodiments, a polypeptide having protease activity comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 38. In some embodiments, a polypeptide having protease activity comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 39. In some embodiments, a polypeptide having protease activity comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 40.In some embodiments, a polypeptide having protease activity comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 41. In some embodiments, a polypeptide having protease activity comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 50. In some embodiments, a polypeptide having protease activity comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 51. In some embodiments, a polypeptide having protease activity comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 52.In some embodiments, the polypeptide having protease activity comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:55.

[0076] In some embodiments, the polypeptide having protease activity comprises an amino acid sequence provided in Table 4. In some embodiments, the polypeptide having protease activity is IdeS. In some embodiments, the polypeptide having protease activity is IdeSsuis. In some embodiments, the polypeptide having protease activity is IdeE. In some embodiments, the polypeptide having protease activity is IdeZ. In some embodiments, the polypeptide having protease activity is IdeE2. In some embodiments, the polypeptide having protease activity is IdeZ2. In some embodiments, the polypeptide having protease activity is IdeC. In some embodiments, the polypeptide having protease activity comprises the amino acid sequence of SEQ ID NO: 26, 28, 29, 31, 36, 37, 38, 39, 40, 41, 50, 51, 52, or 55. In some embodiments, the polypeptide having protease activity comprises the amino acid sequence of SEQ ID NO: 26. In some embodiments, the polypeptide having protease activity comprises the amino acid sequence of SEQ ID NO: 28. In some embodiments, the polypeptide having protease activity comprises the amino acid sequence of SEQ ID NO: 29. In some embodiments, the polypeptide having protease activity comprises the amino acid sequence of SEQ ID NO: 31. In some embodiments, the polypeptide having protease activity comprises the amino acid sequence of SEQ ID NO: 36. In some embodiments, the polypeptide having protease activity comprises the amino acid sequence of SEQ ID NO: 37. In some embodiments, the polypeptide having protease activity comprises the amino acid sequence of SEQ ID NO: 38. In some embodiments, the polypeptide having protease activity comprises the amino acid sequence of SEQ ID NO: 39. In some embodiments, the polypeptide having protease activity comprises the amino acid sequence of SEQ ID NO: 40. In some embodiments, the polypeptide having protease activity comprises the amino acid sequence of SEQ ID NO: 41. In some embodiments, the polypeptide having protease activity comprises the amino acid sequence of SEQ ID NO: 50.In some embodiments, the polypeptide having protease activity comprises the amino acid sequence of SEQ ID NO: 51. In some embodiments, the polypeptide having protease activity comprises the amino acid sequence of SEQ ID NO: 52. In some embodiments, the polypeptide having protease activity comprises the amino acid sequence of SEQ ID NO: 55.

[0077] In some embodiments, the polypeptide with protease activity comprises one or more mutations at one or more N-glycosylation sites. In some embodiments, the polypeptide with protease activity comprises one or more mutations at one or more N-glycosylation sites that inhibit N-glycosylation. In some embodiments, the polypeptide with protease activity comprises one or more mutations at one or more N-glycosylation sites that prevent or inhibit N-glycosylation. In some embodiments, the polypeptide with protease activity comprises one or more mutations at one or more N-glycosylation sites that render the polypeptide with protease activity resistant to N-glycosylation. In some embodiments, the protease is IdeS. In some embodiments, the protease is IdeSsuis. In some embodiments, the protease is IdeE. In some embodiments, the protease is IdeZ. In some embodiments, the protease is IdeE2. In some embodiments, the protease is IdeZ2. In some embodiments, the protease is IdeC. In some embodiments, the IdeS protease comprises a mutation at one or more N-glycosylation sites. In some embodiments, the IdeS protease comprises a mutation at one or more of positions 42, 47, 61, 62, 63, 274, 288, 289, 290, 336, 337, 338, or any combination thereof.

[0078] In some embodiments, the IdeS protease comprises a mutation at one or more of positions 61, 62, 63, or any combination thereof. In some embodiments, the IdeS protease comprises a mutation at one or more of positions 288, 289, 290, or any combination thereof. In some embodiments, the IdeS protease comprises a mutation at one or more of positions 336, 337, 338, or any combination thereof. In some embodiments, the IdeS protease comprises a mutation at one or more of positions 61, 62, 63, 288, 289, 290, or any combination thereof. In some embodiments, the IdeS protease comprises a mutation at one or more of positions 61, 62, 63, 336, 337, 338, or any combination thereof. In some embodiments, the IdeS protease comprises a mutation at one or more of positions 336, 337, 338, or any combination thereof. In some embodiments, the IdeS protease comprises a mutation at one or more of positions 61, 288, 290, 336, or any combination thereof.

[0079] In some embodiments, the IdeS protease comprises a mutation at position 61. In some embodiments, the IdeS protease comprises a mutation at position 288. In some embodiments, the IdeS protease comprises a mutation at position 336. In some embodiments, the IdeS protease comprises a mutation at position 290. In some embodiments, the IdeS protease comprises a mutation at position N42. In some embodiments, the IdeS protease comprises a mutation at position N47. In some embodiments, the IdeS protease comprises a mutation at position N274. In some embodiments, the IdeS protease comprises mutations at positions N47 and N274. In some embodiments, the IdeS protease comprises a mutation at position N61. In some embodiments, the IdeS protease comprises a mutation at position N288. In some embodiments, the IdeS protease comprises a mutation at position S290. In some embodiments, the IdeS protease comprises a mutation at position N336. In some embodiments, the IdeS protease comprises mutations at positions N61 and S290. In some embodiments, the IdeS protease comprises mutations at positions N61 and N288. In some embodiments, the IdeS protease comprises mutations at positions N61 and N336. In some embodiments, the IdeS protease comprises mutations at positions N288 and N336. In some embodiments, the IdeS protease comprises mutations at positions S290 and N336.

[0080] In some embodiments, the protease comprises an amino acid sequence that includes a signal sequence. In some embodiments, the protease comprises an amino acid sequence that does not include a signal sequence. In some embodiments, the signal sequence can have the amino acid sequence of METDTLLLWVLLLWVPGSTG (SEQ ID NO: 53) or MNIQERFSLRKSAVGLVSVSLLCAIYTSTVAA (SEQ ID NO: 54).

[0081] In some embodiments, a polypeptide having IgG protease activity is as effective as, or more effective than, a wild-type protease at cleaving IgG and / or is less immunogenic or as immunogenic as, a wild-type protease. In some embodiments, a polypeptide having IgG protease activity is as effective as, or more effective than, a wild-type protease at cleaving IgG. In some embodiments, a polypeptide having IgG protease activity is more effective than, a wild-type protease at cleaving IgG. In some embodiments, a polypeptide having IgG protease activity is less immunogenic than, a wild-type protease. In some embodiments, a polypeptide having IgG protease activity is equally immunogenic as, a wild-type protease.

[0082] Fc fusion molecule Provided herein are therapeutic compounds, e.g., therapeutic protein molecules, e.g., fusion proteins, comprising an effector-binding / modulating moiety and a polypeptide having protease activity. Also provided are methods of using and making the therapeutic compounds. In some embodiments, the effector-binding / modulating moiety is a variant Fc polypeptide, such as, but not limited to, those provided herein.

[0083] The present disclosure provides, for example, a polypeptide comprising a polypeptide having protease activity and an Fc polypeptide domain, wherein the polypeptide having protease activity is covalently or non-covalently linked to the Fc polypeptide domain. In some embodiments, the Fc polypeptide domain is a variant Fc polypeptide such as those provided herein. Accordingly, in some embodiments, a polypeptide comprising a polypeptide having protease activity and an Fc polypeptide domain is provided, wherein the polypeptide having protease activity is covalently or non-covalently linked to the Fc polypeptide. The polypeptide having protease activity can be fused or linked (i.e., conjugated) to the Fc polypeptide. In some embodiments, the polypeptide having protease activity is non-covalently associated with the Fc polypeptide domain. In some embodiments, the protease is an IgG protease. In some embodiments, the protease is an IdeS, IdeSsuis, IdeE, IdeZ, IdeZ2, IdeE2, or IdeC protease, or a variant thereof. Such protease variants have at least one mutation, insertion, or deletion compared to the wild-type sequence. Examples of such proteases or variants thereof include those provided in U.S. Pat. No. 11,524,057, U.S. Pat. No. 10,696,959, U.S. Pat. No. 11,667,905, U.S. Pat. No. 11,214,784, U.S. Pat. No. 10,758,597, U.S. Patent Application Publication No. 2020 / 0345844, U.S. Patent Application Publication No. 2021 / 0260173, U.S. Patent Application Publication No. 2023 / 0357741, U.S. Patent Application Publication No. 2023 / 0302100, U.S. Patent Application Publication No. 2022 / 0133864, U.S. Pat. No. 8,133,483, PCT Publication No. 2023 / 175498, EP Patent No. 3256580, EP Patent No. 3256579, each of which is incorporated herein by reference in its entirety.

[0084] In some embodiments, the Fc polypeptide domain is an IgG Fc polypeptide, such as an Fc polypeptide that is or is derived from an IgG1, IgG2, IgG3, or IgG4 Fc polypeptide. In some embodiments, the Fc polypeptide domain is a variant Fc polypeptide domain, such as the variants provided herein. In some embodiments, the Fc polypeptide domain is protease resistant. The Fc polypeptide may be resistant to the protease to which it is attached, and therefore is resistant to protease cleavage and / or binding by a protease. In some embodiments, a variant Fc polypeptide, such as those provided herein, comprises a mutation that renders the IgG Fc polypeptide resistant to cleavage by a protease or a variant thereof. In some embodiments, a variant Fc polypeptide, such as those provided herein, comprises a mutation that renders the IgG Fc polypeptide resistant to binding by a protease or a variant thereof. In some embodiments, a variant Fc polypeptide, such as those provided herein, comprises a set of mutations that render the IgG Fc polypeptide resistant to cleavage by a protease or a variant thereof. In some embodiments, variant Fc polypeptides such as those provided herein comprise a set of mutations that render the IgG Fc polypeptide resistant to binding by a protease or variant thereof. In some embodiments, variant Fc polypeptides such as those provided herein comprise mutations that render the IgG Fc polypeptide resistant to cleavage by a protease or variant thereof and / or binding by a protease or variant thereof. In some embodiments, variant Fc polypeptides such as those provided herein comprise a set of mutations that render the IgG Fc polypeptide resistant to cleavage by a protease or variant thereof and / or binding by a protease or variant thereof. In some embodiments, variant Fc polypeptides such as those provided herein are resistant to cleavage by a protease or variant thereof.In some embodiments, variant Fc polypeptides such as those provided herein are resistant to binding by proteases or variants thereof. In some embodiments, variant Fc polypeptides such as those provided herein are resistant to cleavage by proteases or variants thereof and / or binding by proteases or variants thereof. They may also be resistant to other proteases to which the Fc polypeptide domain is not connected. Fc polypeptides can self-associate with each other to form dimers. Dimers can be homodimers, in which the Fc polypeptide is the same in each polypeptide molecule, or heterodimers, in which the Fc polypeptide is different in each polypeptide molecule that forms the dimer.

[0085] In some embodiments, the variant Fc polypeptide is covalently or non-covalently conjugated to a polypeptide having IgG protease activity, and the polypeptide having IgG protease activity may be conjugated to the N-terminus or C-terminus of the variant Fc polypeptide. In some embodiments, the variant Fc polypeptide is covalently or non-covalently conjugated to a polypeptide having IgG protease activity, and the polypeptide having IgG protease activity may be conjugated to the N-terminus of the variant Fc polypeptide. In some embodiments, the variant Fc polypeptide is covalently or non-covalently conjugated to a polypeptide having IgG protease activity, and the polypeptide having IgG protease activity may be conjugated to the C-terminus of the variant Fc polypeptide.

[0086] The Fc polypeptide and the polypeptide having protease activity can be physically tethered to each other, covalently or non-covalently, directly, or through a linker entity, e.g., as domains of the same linear primary amino acid sequence in a single polypeptide. The polypeptides can associate with each other through the Fc polypeptide, such that a dimer having a first and a second polypeptide is created. In some embodiments, a first polypeptide comprises a polypeptide having protease activity linked to an Fc polypeptide domain. In some embodiments, a second polypeptide comprises an Fc polypeptide domain, such as those provided herein. In some embodiments, the second polypeptide does not comprise a protease domain. In some embodiments, the second polypeptide comprises a protease domain.

[0087] This multidomain molecule may be referred to as a therapeutic protein molecule. In some embodiments, the protease and the IgG Fc molecule are provided in a therapeutic protein molecule, e.g., a fusion protein.

[0088] In some embodiments, the polypeptide comprising the polypeptide with protease activity, the Fc polypeptide domain, which may be a variant Fc polypeptide, or both, further comprises a single-domain antibody molecule, e.g., a nanobody, a camelid antibody VHH molecule, or a human soluble VH domain. Without wishing to be bound by any particular theory, a nanobody covalently or non-covalently conjugated to a polypeptide with protease activity and / or a polypeptide comprising an Fc polypeptide may extend the half-life of the polypeptide. In some embodiments, the single-domain antibody molecule, e.g., a nanobody, a camelid antibody VHH molecule, or a human soluble VH domain, is physically tethered, covalently or non-covalently, directly or through a linker entity, to the polypeptide with protease activity, the variant Fc polypeptide, or both. In some embodiments, the variant Fc polypeptide may also contain a single-chain fragment variable (scFv) or Fab domain. In some embodiments, a therapeutic protein molecule, or a nucleic acid, e.g., mRNA or DNA, encoding a therapeutic protein molecule, can be administered to a subject. In some embodiments, the polypeptide with protease activity and the variant Fc polypeptide are linked to a third entity, e.g., a carrier, e.g., a polymeric carrier, a dendrimer, or a particle, e.g., a nanoparticle. As used herein, the terms "nanobody" and "VHH" can be used interchangeably.

[0089] Non-limiting examples of nanobodies include those provided in McMahon et al., Nat Struct Mol Biol. 2018 March;25(3):289-296. doi:10.1038 / s41594-018-0028-6, which is incorporated by reference in its entirety. In some embodiments, the nanobody or VHH comprises an amino acid sequence as set forth in Table 5. [Table 6]

[0090] In some embodiments, a Nanobody comprises an amino acid sequence that has at least 50%, 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%, at least 99%, or 100% sequence identity to any of the sequences provided in Table 5. In some embodiments, a Nanobody comprises an amino acid sequence that has at least 50%, 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%, or 100% sequence identity to SEQ ID NOs: 30, 32, 33. In some embodiments, a Nanobody comprises an amino acid sequence that has at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 30. In some embodiments, a Nanobody comprises an amino acid sequence that has at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 32. In some embodiments, the Nanobody comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 33.

[0091] In some embodiments, a Nanobody comprises an amino acid sequence having the amino acid sequence of SEQ ID NO: 30, 32, or 33. In some embodiments, a Nanobody comprises an amino acid sequence having the amino acid sequence of SEQ ID NO: 30. In some embodiments, a Nanobody comprises an amino acid sequence having the amino acid sequence of SEQ ID NO: 32. In some embodiments, a Nanobody comprises an amino acid sequence having the amino acid sequence of SEQ ID NO: 33.

[0092] In some embodiments, a therapeutic compound or compounds comprises a polypeptide comprising a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide. In some embodiments, a therapeutic molecule comprises a fusion protein comprising a polypeptide with protease activity fused to a variant Fc polypeptide, e.g., directly or through a linking moiety comprising one or more amino acid residues. In some embodiments, a therapeutic compound or compounds comprises a polypeptide comprising a polypeptide with protease activity linked to a variant Fc polypeptide by a non-covalent or covalent bond, e.g., a covalent bond other than a peptide bond, e.g., a sulfhydryl bond.

[0093] In some embodiments, the protease is an IgG-cleaving protease. In some embodiments, the IgG-cleaving protease is selected from IdeS, IdeSsuis, IdeE, IdeZ, IdeE2, IdeZ2, and IdeC. In some embodiments, the IgG-cleaving protease is IdeS. In some embodiments, the IgG-cleaving protease is IdeSsuis. In some embodiments, the IgG-cleaving protease is IdeE. In some embodiments, the IgG-cleaving protease is IdeZ. In some embodiments, the IgG-cleaving protease is IdeE2. In some embodiments, the IgG-cleaving protease is IdeZ2. In some embodiments, the IgG-cleaving protease is IdeC. The IgG protease can be a variant protease of any of the foregoing. Examples of IgG proteases and variant proteases include WO2003 / 051914, WO2006 / 131347, WO2016 / 128558, WO2016 / 128559, WO2016 / 012285, WO2008 / 071418, WO2012 / 119983, WO2010 / 057626, WO2015 / 184325, WO2021 / 026264, WO2021 / 021989, WO2018 / 034346, WO2010 / 089126, WO2009 / 08027, WO2008 / 136735, WO20 No. 15 / 181356, WO2018 / 093868, WO2013 / 037824, WO2017 / 134274, WO2016 / 046220, WO2015 / 040125, WO2009 / 033670, WO2004 / 096157, WO2010 / 123885, WO2010 / 118337, WO2019 / 075360, WO2007 / 019376, and U.S. Pat. No. 10,836,815, each of which is incorporated herein by reference in its entirety.Non-limiting examples of proteases include, but are not limited to, proteases that comprise or are identical to an amino acid sequence having at least 50%, 60%, 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%, or 100% sequence identity to a sequence provided in Table 4.

[0094] In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to the N-terminus of the variant Fc polypeptide. In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to the C-terminus of the variant Fc polypeptide. In some embodiments, there may be a linker moiety, such as a peptide moiety or a non-peptide linkage, between the polypeptide with protease activity and the N-terminus or C-terminus of the Fc polypeptide.

[0095] In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a Nanobody and a variant Fc polypeptide, wherein the C-terminus of the polypeptide with protease activity is covalently or non-covalently conjugated to the N-terminus of the Nanobody and the N-terminus of the polypeptide with protease activity is covalently or non-covalently conjugated to the C-terminus of the variant Fc polypeptide. In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a Nanobody and a variant Fc polypeptide, wherein the N-terminus of the polypeptide with protease activity is covalently or non-covalently conjugated to the C-terminus of the Nanobody and the C-terminus of the polypeptide with protease activity is covalently or non-covalently conjugated to the N-terminus of the variant Fc polypeptide. In some embodiments, the polypeptide with protease activity is as provided herein. In some embodiments, the variant IgG Fc is as provided herein. In some embodiments, the Nanobody is as provided herein.

[0096] In some embodiments, a polypeptide comprising a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide further comprises a tag, such as a purification tag or a detection tag. The tag can be used to facilitate purification, isolation, or detection of the polypeptide. A non-limiting example of such a tag is a histidine tag, which is a plurality of histidines (e.g., six or more histidines). In some embodiments, a polypeptide comprising a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide further comprises a histidine tag, wherein the C-terminus of the polypeptide with protease activity is covalently or non-covalently conjugated to the N-terminus of the variant Fc polypeptide, and the C-terminus of the variant Fc polypeptide is covalently or non-covalently conjugated to the N-terminus of the tag. In some embodiments, a polypeptide comprising a Nanobody and a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide further comprises a tag. In some embodiments, the polypeptide comprising a Nanobody and a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide further comprises a tag, wherein the N-terminus of the polypeptide with protease activity is covalently or non-covalently conjugated to the C-terminus of the Nanobody, the C-terminus of the polypeptide with protease activity is covalently or non-covalently conjugated to the N-terminus of the variant Fc polypeptide, and the C-terminus of the variant Fc polypeptide is covalently or non-covalently conjugated to the N-terminus of the tag.In some embodiments, the polypeptide comprising a Nanobody and a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide further comprises a histidine tag, wherein the N-terminus of the polypeptide with protease activity is covalently or non-covalently conjugated to the C-terminus of the variant Fc polypeptide, the C-terminus of the polypeptide with protease activity is covalently or non-covalently conjugated to the N-terminus of the Nanobody, and the C-terminus of the Nanobody is covalently or non-covalently conjugated to the N-terminus of the tag.

[0097] In some embodiments, the variant Fc polypeptide comprises or is identical to an amino acid sequence having at least 50%, 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%, or 100% sequence identity to any of the sequences provided in Table 3. In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises or is identical to an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 19, 20, 21, 22, 23, 24, 25, 42, 43, 44, 45, 46, 47, 48, or 49. In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises or is identical to an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 19.In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises or is identical to an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:20. In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises or is identical to an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:21. In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises or is identical to an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:22.In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises or is identical to an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:23. In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises or is identical to an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:24. In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises or is identical to an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:25.In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises or is identical to an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:42. In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises or is identical to an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:43. In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises or is identical to an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:44.In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises or is identical to an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:45. In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises or is identical to an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:46. In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises or is identical to an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:47.In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises or is identical to an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:48. In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises or is identical to an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:49.

[0098] In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to a sequence provided in Table 3, and further comprises one or more mutations at positions 234, 235, 237, 296, 329, or any combination thereof.

[0099] In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to a sequence provided in Table 3, and further comprises one or more mutations at positions L234, L235, G237, Y296, P329, or any combination thereof.

[0100] As used herein, positions referenced in an Fc polypeptide for mutation refer to the EU numbering system. The Fc polypeptide can be aligned with the wild-type sequence to determine the positions to be mutated according to the numbering system.

[0101] As used herein with reference to a polypeptide having a % identity to a reference sequence and further comprising mutations at one or more positions, means a polypeptide having the recited % identity to the reference sequence and also having one or more of the mutations at the recited positions.

[0102] In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 19, 20, 21, 22, 23, 24, or 25, and further comprises one or more mutations at positions 234, 235, 237, 296, 329, or any combination thereof.

[0103] In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 19, and further comprises one or more mutations at positions 234, 235, 237, 296, 329, or any combination thereof.

[0104] In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 20, and further comprises one or more mutations at positions 234, 235, 237, 296, 329, or any combination thereof.

[0105] In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 21, and further comprises one or more mutations at positions 234, 235, 237, 296, 329, or any combination thereof.

[0106] In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 22, and further comprises one or more mutations at positions 234, 235, 237, 296, 329, or any combination thereof.

[0107] In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 23, and further comprises one or more mutations at positions 234, 235, 237, 296, 329, or any combination thereof.

[0108] In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:24, and further comprises one or more mutations at positions 234, 235, 237, 296, 329, or any combination thereof.

[0109] In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 25, and further comprises one or more mutations at positions 234, 235, 237, 296, 329, or any combination thereof.

[0110] In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 19, 20, 21, 22, 23, 24, or 25, and further comprises one or more mutations at positions L234, L235, G237, Y296, P329, or any combination thereof.

[0111] In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 19, and further comprises one or more mutations at positions L234, L235, G237, Y296, P329, or any combination thereof.

[0112] In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 20, and further comprises one or more mutations at positions L234, L235, G237, Y296, P329, or any combination thereof.

[0113] In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 21, and further comprises one or more mutations at positions L234, L235, G237, Y296, P329, or any combination thereof.

[0114] In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 22, and further comprises one or more mutations at positions L234, L235, G237, Y296, P329, or any combination thereof.

[0115] In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 23, and further comprises one or more mutations at positions L234, L235, G237, Y296, P329, or any combination thereof.

[0116] In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 24, and further comprises one or more mutations at positions L234, L235, G237, Y296, P329, or any combination thereof.

[0117] In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 25, and further comprises one or more mutations at positions L234, L235, G237, Y296, P329, or any combination thereof.

[0118] In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to any of the sequences provided in Table 3, and further comprises one or more mutations: L234A, L235A, G237A, Y296Q, P329K, or any combination thereof.

[0119] In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 19, 20, 21, 22, 23, 24, or 25, and further comprises one or more mutations of L234A, L235A, G237A, Y296Q, P329K, or any combination thereof.

[0120] In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 19, and further comprises one or more mutations: L234A, L235A, G237A, Y296Q, P329K, or any combination thereof.

[0121] In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 20, and further comprises one or more mutations: L234A, L235A, G237A, Y296Q, P329K, or any combination thereof.

[0122] In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 21, and further comprises one or more mutations of L234A, L235A, G237A, Y296Q, P329K, or any combination thereof.

[0123] In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 22, and further comprises one or more mutations of L234A, L235A, G237A, Y296Q, P329K, or any combination thereof.

[0124] In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 23, and further comprises one or more mutations: L234A, L235A, G237A, Y296Q, P329K, or any combination thereof.

[0125] In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 24, and further comprises one or more mutations: L234A, L235A, G237A, Y296Q, P329K, or any combination thereof.

[0126] In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 25, and further comprises one or more mutations: L234A, L235A, G237A, Y296Q, P329K, or any combination thereof.

[0127] In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence provided in Table 3.

[0128] In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises the amino acid sequence of SEQ ID NO: 19, 20, 21, 22, 23, 24, 25, 42, 43, 44, 45, 47, 48, or 49. In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises the amino acid sequence of SEQ ID NO: 19. In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises the amino acid sequence of SEQ ID NO: 20. In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises the amino acid sequence of SEQ ID NO: 21. In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises the amino acid sequence of SEQ ID NO: 22. In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises the amino acid sequence of SEQ ID NO: 23. In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises the amino acid sequence of SEQ ID NO: 24. In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises the amino acid sequence of SEQ ID NO: 25.In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises the amino acid sequence of SEQ ID NO: 42. In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises the amino acid sequence of SEQ ID NO: 43. In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises the amino acid sequence of SEQ ID NO: 44. In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises the amino acid sequence of SEQ ID NO: 45. In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises the amino acid sequence of SEQ ID NO: 46. In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises the amino acid sequence of SEQ ID NO: 47. In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises the amino acid sequence of SEQ ID NO: 48. In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises the amino acid sequence of SEQ ID NO: 49.

[0129] In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence with a C-terminal lysine (K). In some embodiments, the polypeptide comprises a polypeptide with protease activity covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence that does not have (or includes) a C-terminal lysine (K).

[0130] In some embodiments, the protease present in the polypeptides provided herein comprises or is identical to an amino acid sequence having at least 50%, at least 60%, 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%, or 100% sequence identity to a sequence provided in Table 4, The protease is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to any of the sequences provided in Table 3.

[0131] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 26, 28, 29, 31, 36, 37, 38, 39, 40, 41, 50, 51, 52, or 55; The variant Fc polypeptide is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO: 19, 20, 21, 22, 23, 24, 25, 42, 43, 44, 45, 47, 48, or 49.

[0132] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:26, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:19.

[0133] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:26, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:20. In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:26, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:21.

[0134] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:26, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:22.

[0135] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:26, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:23.

[0136] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:26, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:24.

[0137] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:26, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:25.

[0138] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:26, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:42.

[0139] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:26, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:43.

[0140] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:26, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:44.

[0141] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:26, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:45.

[0142] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:26, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:46.

[0143] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:26, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:47.

[0144] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:26, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:48.

[0145] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:26, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:49.

[0146] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:28, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:19.

[0147] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:28, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:20.

[0148] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:28, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:21.

[0149] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:28, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:22.

[0150] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:28, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:23.

[0151] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:28, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:24.

[0152] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:28, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:25.

[0153] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:28, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:42.

[0154] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:28, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:43.

[0155] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:28, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:44.

[0156] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:28, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:45.

[0157] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:28, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:46.

[0158] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:28, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:47.

[0159] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:28, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:48.

[0160] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:28, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:49.

[0161] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:29, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:19.

[0162] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:29, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:20.

[0163] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:29, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:21.

[0164] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:29, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:22.

[0165] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:29, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:23.

[0166] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:29, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:24.

[0167] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:29, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:25.

[0168] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:29, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:42.

[0169] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:29, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:43.

[0170] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:29, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:44.

[0171] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:29, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:45.

[0172] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:29, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:46.

[0173] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:29, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:47.

[0174] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:29, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:48.

[0175] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:29, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:49.

[0176] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:31, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:19.

[0177] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:31, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:20.

[0178] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:31, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:21.

[0179] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:31, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:22.

[0180] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:31, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:23.

[0181] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:31, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:24.

[0182] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:31, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:25.

[0183] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:31, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:42.

[0184] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:31, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:43.

[0185] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:31, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:44.

[0186] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:31, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:45.

[0187] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:31, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:46.

[0188] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:31, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:47.

[0189] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:31, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:48.

[0190] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:31, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:49.

[0191] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:36, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:19.

[0192] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:36, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:20.

[0193] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:36, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:21.

[0194] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:36, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:22.

[0195] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:36, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:23.

[0196] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:36, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:24.

[0197] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:36, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:25.

[0198] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:36, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:42.

[0199] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:36, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:43.

[0200] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:36, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:44.

[0201] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:36, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:45.

[0202] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:36, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:46.

[0203] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:36, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:47.

[0204] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:36, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:48.

[0205] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:36, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:49.

[0206] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:37, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:19.

[0207] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:37, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:20.

[0208] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:37, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:21.

[0209] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:37, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:22.

[0210] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:37, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:23.

[0211] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:37, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:24.

[0212] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:37, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:25.

[0213] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:37, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:42.

[0214] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:37, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:43.

[0215] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:37, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:44.

[0216] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:37, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:45.

[0217] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:37, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:46.

[0218] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:37, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:47.

[0219] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:37, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:48.

[0220] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:37, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:49.

[0221] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:38, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:19.

[0222] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:38, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:20.

[0223] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:38, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:21.

[0224] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:38, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:22.

[0225] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:38, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:23.

[0226] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:38, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:24.

[0227] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:38, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:25.

[0228] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:38, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:42.

[0229] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:38, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:43.

[0230] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:38, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:44.

[0231] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:38, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:45.

[0232] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:38, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:46.

[0233] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:38, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:47.

[0234] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:38, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:48.

[0235] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:38, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:49.

[0236] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:39, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:19.

[0237] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:39, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:20.

[0238] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:39, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:21.

[0239] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:39, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:22.

[0240] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:39, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:23.

[0241] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:39, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:24.

[0242] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:39, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:25.

[0243] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:39, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:42.

[0244] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:39, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:43.

[0245] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:39, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:44.

[0246] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:39, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:45.

[0247] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:39, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:46.

[0248] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:39, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:47.

[0249] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:39, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:48.

[0250] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:39, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:49.

[0251] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:40, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:19.

[0252] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:40, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:20.

[0253] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:40, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:21.

[0254] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:40, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:22.

[0255] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:40, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:23.

[0256] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:40, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:24.

[0257] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:40, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:25.

[0258] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:40, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:42.

[0259] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:40, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:43.

[0260] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:40, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:44.

[0261] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:40, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:45.

[0262] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:40, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:46.

[0263] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:40, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:47.

[0264] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:40, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:48.

[0265] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:40, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:49.

[0266] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:41, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:19.

[0267] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:41, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:20.

[0268] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:41, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:21.

[0269] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:41, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:22.

[0270] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:41, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:23.

[0271] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:41, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:24.

[0272] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:41, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:25.

[0273] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:41, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:42.

[0274] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:41, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:43.

[0275] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:41, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:44.

[0276] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:41, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:45.

[0277] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:41, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:46.

[0278] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:41, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:47.

[0279] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:41, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:48.

[0280] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:41, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:49.

[0281] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:50, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:19.

[0282] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:50, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:20.

[0283] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:50, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:21.

[0284] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:50, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:22.

[0285] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:50, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:23.

[0286] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:50, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:24.

[0287] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:50, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:25.

[0288] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:50, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:42.

[0289] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:50, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:43.

[0290] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:50, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:44.

[0291] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:50, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:45.

[0292] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:50, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:46.

[0293] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:50, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:47.

[0294] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:50, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:48.

[0295] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:50, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:49.

[0296] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:51, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:19.

[0297] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:51, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:20.

[0298] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:51, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:21.

[0299] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:51, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:22.

[0300] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:51, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:23.

[0301] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:51, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:24.

[0302] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:51, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:25.

[0303] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:51, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:42.

[0304] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:51, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:43.

[0305] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:51, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:44.

[0306] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:51, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:45.

[0307] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:51, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:46.

[0308] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:51, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:47.

[0309] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:51, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:48.

[0310] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:51, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:49.

[0311] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:52, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:19.

[0312] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:52, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:20.

[0313] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:52, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:21.

[0314] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:52, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:22.

[0315] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:52, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:23.

[0316] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:52, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:24.

[0317] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:52, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:25.

[0318] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:52, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:42.

[0319] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:52, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:43.

[0320] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:52, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:44.

[0321] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:52, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:45.

[0322] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:52, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:46.

[0323] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:52, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:47.

[0324] In some embodiments, the polypeptide comprises a polypeptide with protease activity comprising an amino acid sequence having at least 50%, 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%, or 100% sequence identity to SEQ ID NO:52, wherein the polypeptide with protease activity is covalently or non-covalently conjugated to a variant Fc polypeptide, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 50%, 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%, or at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:48.

[0325] In ...

Claims

1. 1. A variant Fc polypeptide comprising an amino acid sequence having 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: 56, provided that said variant Fc polypeptide has, compared to SEQ ID NO: 1: L234A, L235A, G237A, Y296Q, and P329K, L234A, L235A, G237A, Y296Q, S298K, and P329K, L234A, L235A, G237A, D265K, E269S, Y296Q, and P329K, or provided that the set of mutations selected from: L234A, L235A, G237A, D265K, E269S, Y296Q, S298K, and P329K; Variant Fc polypeptides.

2. 2. The variant Fc polypeptide of claim 1, wherein the variant Fc polypeptide comprises the set of L234A, L235A, G237A, Y296Q, and P329K mutations compared to SEQ ID NO:

1.

3. 2. The variant Fc polypeptide of claim 1, wherein the variant Fc polypeptide comprises the set of L234A, L235A, G237A, Y296Q, S298K, and P329K mutations compared to SEQ ID NO:

1.

4. 2. The variant Fc polypeptide of claim 1, wherein the variant Fc polypeptide comprises the set of L234A, L235A, G237A, D265K, E269S, Y296Q, and P329K mutations compared to SEQ ID NO:

1.

5. 2. The variant Fc polypeptide of claim 1, wherein the variant Fc polypeptide comprises the set of L234A, L235A, G237A, D265K, E269S, Y296Q, S298K, and P329K mutations compared to SEQ ID NO:

1.

6. 2. The variant Fc polypeptide of claim 1, wherein said variant Fc polypeptide comprises an amino acid sequence having at least 95% identity to an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 56, with the proviso that said polypeptide comprises an alanine (A) residue at position 234, an alanine (A) residue at position 235, an alanine (A) residue at position 237, a glutamine (Q) residue at position 296, and a lysine (K) residue at position 329, said positions being according to EU numbering.

7. 7. The variant Fc polypeptide of claim 6, wherein said variant Fc polypeptide has at least 95% identity to an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 1, with the proviso that said polypeptide comprises an alanine (A) residue at position 234, an alanine (A) residue at position 235, an alanine (A) residue at position 237, a glutamine (Q) residue at position 296, and a lysine (K) residue at position 329, said positions being according to EU numbering.

8. The variant Fc polypeptide of any one of claims 1 to 7, wherein said variant Fc polypeptide is resistant to proteolytic cleavage and / or binding by proteases.

9. 9. The variant Fc polypeptide of any one of claims 1 to 8, wherein said variant Fc polypeptide comprises an amino acid sequence having 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 any one of SEQ ID NOs: 23, 19, 20, 21, 22, 23, 24, 25, 42, 43, 44, 45, 46, 47, 48, or 49.

10. 10. The variant Fc polypeptide of claim 9, wherein the variant Fc polypeptide comprises the amino acid sequence of any one of SEQ ID NOs: 23, 19, 20, 21, 22, 23, 24, 25, 42, 43, 44, 45, 46, 47, 48, or 49.

11. The variant Fc polypeptide of any one of claims 1 to 10, wherein the variant Fc polypeptide forms a dimer, such as a homodimer or a heterodimer.

12. The variant Fc polypeptide of any one of claims 1 to 11, wherein said variant Fc polypeptide is linked or fused to a protease.

13. 13. The variant Fc polypeptide of claim 12, wherein the variant Fc polypeptide is linked to the protease via a peptide linker.

14. 14. The variant Fc polypeptide of claim 13, wherein the protease is selected from IdeS, IdeSsuis, IdeE, IdeZ, IdeE2, IdeZ2, or IdeC proteases, or variants thereof.

15. 23, 19, 20, 21, 22, 23, 24, 25, 42, 43, 44, 45, 46, 47, 48, or 49. A variant Fc polypeptide comprising an amino acid sequence having 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 any one of SEQ ID NOs: 23, 19, 20, 21, 22, 23, 24, 25, 42, 43, 44, 45, 46, 47, 48, or 49.

16. the variant Fc polypeptide has, compared to SEQ ID NO: 1: L234A, L235A, G237A, Y296Q, and P329K, L234A, L235A, G237A, Y296Q, S298K, and P329K, L234A, L235A, G237A, D265K, E269S, Y296Q, and P329K, or comprising a set of mutations selected from L234A, L235A, G237A, D265K, E269S, Y296Q, S298K, and P329K; 16. The variant Fc polypeptide of claim 15.

17. 17. The variant Fc polypeptide of claim 16, wherein said variant Fc polypeptide comprises an amino acid sequence having at least 95% identity to an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 56, with the proviso that said polypeptide comprises an alanine (A) residue at position 234, an alanine (A) residue at position 235, an alanine (A) residue at position 237, a glutamine (Q) residue at position 296, and a lysine (K) residue at position 329, said positions being according to EU numbering.

18. 18. The variant Fc polypeptide of claim 17, wherein said variant Fc polypeptide has at least 95% identity to an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 1, with the proviso that said polypeptide comprises an alanine (A) residue at position 234, an alanine (A) residue at position 235, an alanine (A) residue at position 237, a glutamine (Q) residue at position 296, and a lysine (K) residue at position 329, said positions being according to EU numbering.

19. The variant Fc polypeptide of any one of claims 15 to 18, wherein said variant Fc polypeptide is resistant to proteolytic cleavage and / or binding by proteases.

20. 20. The variant Fc polypeptide of claim 19, wherein the variant Fc polypeptide comprises the amino acid sequence of any one of SEQ ID NOs: 23, 19, 20, 21, 22, 23, 24, 25, 42, 43, 44, 45, 46, 47, 48, or 49.

21. 21. The variant Fc polypeptide of any one of claims 15 to 20, wherein the variant Fc polypeptide forms a dimer, such as a homodimer or a heterodimer.

22. The variant Fc polypeptide of any one of claims 15 to 21, wherein the variant Fc polypeptide is linked or fused to a protease.

23. 23. The variant Fc polypeptide of claim 22, wherein the variant Fc polypeptide is linked to the protease via a peptide linker.

24. 24. The variant Fc polypeptide of claim 23, wherein the protease is selected from IdeS, IdeSsuis, IdeE, IdeZ, IdeE2, IdeZ2, or IdeC proteases, or variants thereof.

25. A molecule, 1. A variant Fc polypeptide comprising an amino acid sequence having 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: 56, provided that said variant Fc polypeptide has, compared to SEQ ID NO: 1: L234A, L235A, G237A, Y296Q, and P329K, L234A, L235A, G237A, Y296Q, S298K, and P329K, L234A, L235A, G237A, D265K, E269S, Y296Q, and P329K, or provided that the set of mutations selected from: L234A, L235A, G237A, D265K, E269S, Y296Q, S298K, and P329K; a variant Fc polypeptide; and A molecule comprising a protease.

26. 26. The molecule of claim 25, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 95% identity to an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 56, with the proviso that the polypeptide comprises an alanine (A) residue at position 234, an alanine (A) residue at position 235, an alanine (A) residue at position 237, a glutamine (Q) residue at position 296, and a lysine (K) residue at position 329, wherein said positions are according to EU numbering.

27. 27. The molecule of claim 26, wherein the variant Fc polypeptide has at least 95% identity to an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 1, with the proviso that the polypeptide comprises an alanine (A) residue at position 234, an alanine (A) residue at position 235, an alanine (A) residue at position 237, a glutamine (Q) residue at position 296, and a lysine (K) residue at position 329, wherein said positions are according to EU numbering.

28. 28. The molecule of any one of claims 25 to 27, wherein the variant Fc polypeptide is resistant to proteolytic cleavage and / or binding by proteases.

29. 29. The molecule of any one of claims 25-28, wherein the variant Fc polypeptide comprises an amino acid sequence having 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 any one of SEQ ID NOs: 23, 19, 20, 21, 22, 23, 24, 25, 42, 43, 44, 45, 46, 47, 48, or 49.

30. 30. The molecule of claim 29, wherein the variant Fc polypeptide comprises the amino acid sequence of any one of SEQ ID NOs: 23, 19, 20, 21, 22, 23, 24, 25, 42, 43, 44, 45, 46, 47, 48, or 49.

31. 31. The molecule of any one of claims 25 to 30, wherein the variant Fc polypeptide forms a dimer, such as a homodimer or a heterodimer.

32. 32. The molecule of claim 31 , wherein the variant Fc polypeptide is linked or fused to the protease via a peptide linker.

33. 33. The molecule of any one of claims 25 to 32, wherein the protease is selected from IdeS, IdeSsuis, IdeE, IdeZ, IdeE2, IdeZ2, or IdeC proteases, or variants thereof.

34. A molecule, a variant Fc polypeptide comprising an amino acid sequence having 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 any one of SEQ ID NOs: 23, 19, 20, 21, 22, 23, 24, 25, 42, 43, 44, 45, 46, 47, 48, or 49; A molecule comprising a protease.

35. the variant Fc polypeptide has, compared to SEQ ID NO: 1: L234A, L235A, G237A, Y296Q, and P329K, L234A, L235A, G237A, Y296Q, S298K, and P329K, L234A, L235A, G237A, D265K, E269S, Y296Q, and P329K, or comprising a set of mutations selected from L234A, L235A, G237A, D265K, E269S, Y296Q, S298K, and P329K; 35. The molecule of claim 34.

36. 36. The molecule of claim 35, wherein the variant Fc polypeptide comprises an amino acid sequence having at least 95% identity to an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 56, with the proviso that the polypeptide comprises an alanine (A) residue at position 234, an alanine (A) residue at position 235, an alanine (A) residue at position 237, a glutamine (Q) residue at position 296, and a lysine (K) residue at position 329, wherein said positions are according to EU numbering.

37. 37. The molecule of claim 36, wherein the variant Fc polypeptide has at least 95% identity to an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 1, with the proviso that the polypeptide comprises an alanine (A) residue at position 234, an alanine (A) residue at position 235, an alanine (A) residue at position 237, a glutamine (Q) residue at position 296, and a lysine (K) residue at position 329, wherein said positions are according to EU numbering.

38. 38. The molecule of any one of claims 34 to 37, wherein the variant Fc polypeptide is resistant to proteolytic cleavage and / or binding by proteases.

39. 35. The molecule of claim 34, wherein the variant Fc polypeptide comprises the amino acid sequence of any one of SEQ ID NOs: 23, 19, 20, 21, 22, 23, 24, 25, 42, 43, 44, 45, 46, 47, 48, or 49.

40. 40. The molecule of any one of claims 34 to 39, wherein the variant Fc polypeptide forms a dimer, such as a homodimer or a heterodimer.

41. 41. The molecule of any one of claims 34 to 40, wherein the variant Fc polypeptide is linked to the protease via a peptide linker.

42. 42. The molecule of any one of claims 34 to 41, wherein the protease is selected from IdeS, IdeSsuis, IdeE, IdeZ, IdeE2, IdeZ2, or IdeC proteases, or variants thereof.

43. A pharmaceutical composition comprising a variant Fc polypeptide according to any one of claims 1 to 24 or a molecule according to any one of claims 25 to 42.

44. 42. A method of treating a disease or disorder in a subject, comprising administering to said subject a variant Fc polypeptide of any one of claims 1 to 24, or a molecule of any one of claims 25 to 42, thereby treating said disease or disorder.

45. The disease or disorder may be an IgG-mediated disease or disorder, Addison's disease, anti-GBM glomerulonephritis, antineutrophil cytoplasmic antibody-associated vasculitis, ANCA-associated vasculitis, granulomatous polyangiitis (Wegener's granulomatosis), eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome), microscopic polyangiitis, anti-NMDAR encephalitis, antiphospholipid syndrome (APS) and fulminant APS, autoimmune bullous skin diseases, pemphigus, pemphigus foliaceus (PF), pemphigus braziliensis (FS), pemphigus vulgaris (PV), autoimmune hemolytic anemia (AIHA), autoimmune hepatitis (AIH), autoimmune inflammatory bowel disease (AIBA), autoimmune leukemia (ALDE ... Neutropenia (AIN), Bullous Pemphigoid (BP), Celiac Disease, Chronic Urticaria, Complete Congenital Heart Block (CCHB), Type 1A Diabetes Mellitus (T1DM), Epidermolysis Bullosa Acquisita (EBA), Essential Mixed Cryoglobulinemia, Goodpasture's Syndrome, Anti-Glomerular Basement Membrane Disease, Graves' Disease, Goiter, Hyperthyroidism, Invasive Exophthalmos, Infiltrative Dermatopathy, Guillain-Barré Syndrome (GBS), Acute Inflammatory Demyelinating Polyneuropathy (AIDP), Acute Motor Axonal Neuropathy (AMAN), Hemophilia, Acquired FVII Deficiency, Idiopathic Thrombocytopenic Purpura (ITP), Lumbar Lambert-Eaton myasthenic syndrome (LEMS), mixed connective tissue disease (MCTD), multiple myeloma, myasthenia gravis, myasthenia gravis crisis, myocarditis, dilated cardiomyopathy (DCM), congestive cardiomyopathy, neuromyelitis optica (NMO), primary biliary cirrhosis (PBC), primary progressive multiple sclerosis (PPMS), relapsing rheumatic multiple sclerosis, acute exacerbation of multiple sclerosis, rheumatic heart disease (RHD), rheumatoid arthritis (RA), serum sickness, immune complex hypersensitivity (type III), Sjogren's syndrome (SS), lupus nephritis, systemic lupus erythematosus (SLE), cutaneous lupus (CL) E), transplant rejection, thrombotic thrombocytopenic purpura (TTP), idiopathic inflammatory myopathy, polymyositis, dermatomyositis, inclusion body myositis, uveitis, scleritis, ankylosing spondylitis, axial spondyloarthritis, reactive arthritis, psoriatic arthritis, IBD-associated arthritis, antiphospholipid syndrome, systemic sclerosis, giant cell arteritis, polymyalgia rheumatica, Takayasu's arteritis, antineutrophil cytoplasmic antibody-associated vasculitis, Henoch-Schonlein purpura, polyarteritis nodosa, Cogan's syndrome, Burger's disease, Susan's disease, immune complex vasculitis, primary vasculitis of the central nervous system (CNS), Behçet's disease, relapsing polychondritis,Juvenile idiopathic arthritis, juvenile dermatomyositis, autoimmune encephalopathy, sarcoidosis, neurosarcoidosis, IgG4-related disease, autoimmune complications of immune checkpoint inhibitors (IRAE), adult-onset Still's disease, warm antibody hemolytic anemia (wAIHA), immune thrombocytopenia, immune thrombocytopenia, thrombic thrombocytopenia, pernicious anemia, aplastic anemia, Evan's syndrome, autoimmune neutropenia, acquired von Willebrand syndrome Willebrand syndrome, recurrent abortion, Rh incompatibility, ulcerative colitis, autoimmune hepatitis, autoimmune pancreatitis, eosinophilic esophagitis / gastritis, primary sclerosing cholangitis, primary biliary sclerosis, glomerulonephritis, glomerular basement membrane disease, scleritis / episcleritis, uveitis, conjunctivitis, keratitis, type 1 diabetes mellitus, Hashimoto's thyroiditis, polyglandular autoimmune endocrine syndrome, atopic dermatitis, dermatitis herpetiformis, pemphigus foliaceus, pemphigus brazilianus, cutaneous lupus erythematosus, linear IgA Disease, lichen planus, transplantation, antibody-mediated rejection, alloantibody hypersensitivity, xenoantibody-mediated rejection, solid organ rejection, graft-versus-host disease (GVHD), multiple sclerosis, neuromyelitis optica, amyotrophic lateral sclerosis, Parkinson's disease, autoimmune encephalitis, CNS vasculitis, chronic idiopathic demyelinating polyneuropathy, transverse myelitis, optic neuritis, anti-myelin oligodendrocyte glycoprotein (MOG) disease, chronic meningitis, rheumatic heart disease 45. The method of claim 44, wherein the disease is selected from a disease, an infectious disease, a vaccination, antibody-dependent enhancement, an antibody against a therapeutic biological agent (cytokine, monoclonal antibody, enzyme, coagulation factor), allergic asthma, eosinophilic pneumonia, nonspecific interstitial pneumonia, rheumatoid arthritis-associated interstitial lung disease (RA-ILD), sarcoidosis, hypersensitivity pneumonitis, allergic bronchopulmonary mycosis, chronic rhinosinusitis with nasal polyps, or any combination thereof.

46. 42. A method of treating a transplant subject, comprising administering to said subject a therapeutically effective amount of a variant Fc polypeptide of any one of claims 1 to 24, or a molecule of any one of claims 25 to 42, thereby treating said transplant (recipient) subject.

47. 42. A method of improving gene therapy in a subject, comprising administering to said subject a therapeutically effective amount of a variant Fc polypeptide of any one of claims 1 to 24, or a molecule of any one of claims 25 to 42, thereby improving said gene therapy in said subject.

48. A nucleic acid encoding a variant Fc polypeptide according to any one of claims 1 to 24 or a molecule according to any one of claims 25 to 42.

49. A vector comprising the nucleic acid of claim 48.

50. 50. A cell comprising the nucleic acid of claim 48 or the vector of claim 49.

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