Il-17 antibody compositions and methods of use

Abstract

Variant IL-17 antibodies comprising modified Fc regions and methods of use

Description

Attorney Docket No. PRG-007WO IL-17 ANTIBODY COMPOSITIONS AND METHODS OF USE CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 509,694, filed on June 22, 2023, the entire contents of which is incorporated herein by reference. BACKGROUND

[0002] IL-17 cytokine family members (e.g., IL-17A and IL-17F) have diverse biological functions, promoting protective immunity against many pathogens but also driving inflammatory pathology during infection and autoimmunity. However, IL-17A and IL-17F are also associated with the pathogenesis of inflammatory diseases including rheumatoid arthritis, psoriasis, and inflammatory bowel diseases (IBD) such as Crohn’s disease and ulcerative colitis. Despite the association, current IL-17A and IL-17F inhibitors that are effective for other inflammatory diseases have not elicited positive effects on IBD patients. Taken together, this indicates the need for improved therapies targeting IL-17A and IL-17F. SUMMARY OF THE DISCLOSURE

[0003] The present disclosure addresses this need with IL-17 binding proteins having modified Fc regions which extend the half-life of the IL-17 binding proteins.

[0004] In one aspect, provided are IL-17A and IL-17F binding proteins comprising: a) a heavy chain variable region (VH) comprising (i) a CDR-H1 having an amino acid sequence according to SEQ ID NO: 1, (ii) a CDR-H2 having an amino acid sequence according to SEQ ID NO: 4, and (iii) a CDR-H3 having an amino acid sequence according to SEQ ID NO: 7; b) a light chain variable region (VL) comprising (i) a CDR-L1 having an amino acid sequence according to SEQ ID NO: 10, (ii) a CDR-L2 having an amino acid sequence according to SEQ ID NO: 13, and (iii) a CDR-L3 having an amino acid sequence according to SEQ ID NO: 16; and c) an Fc region comprising amino acid modifications M252Y, S254T, and T256E (YTE) and / or M428L and N434S (LS).

[0005] In some embodiments, the VH comprises a sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 55 and the VL comprises a sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 58.

[0006] In one aspect, provided are IL-17A and IL-17F binding proteins comprising: a) a heavy chain variable region (VH) comprising (i) a CDR-H1 having an amino acid sequence according to SEQ ID NO: 1, (ii) a CDR-H2 having an amino acid sequence according to SEQ ID 1 IPTS / 128625283.1Attorney Docket No. PRG-007WO NO: 4, and (iii) a CDR-H3 having an amino acid sequence according to SEQ ID NO: 7; b) a light chain variable region (VL) comprising (i) a CDR-L1 having an amino acid sequence according to SEQ ID NO: 10, (ii) a CDR-L2 having an amino acid sequence according to SEQ ID NO: 13, and (iii) a CDR-L3 having an amino acid sequence according to SEQ ID NO: 16; and c) a modified Fc region that extends half-life of the IL-17A and IL-17F binding protein as compared to an IL-17A and IL-17F binding protein that does not comprise the modified Fc region.

[0007] In one aspect, provided are IL-17A and IL-17F binding proteins which specifically bind to an epitope of IL-17A and IL-17F and comprises an Fc region comprising amino acid modifications M252Y, S254T, and T256E (YTE) and / or M428L and N434S (LS).

[0008] In some embodiments, the Fc region is an IgG1, IgG2 or IgG4 immunoglobulin Fc region. In some embodiments, the Fc region is an IgG1 immunoglobulin Fc region. In some embodiments, the Fc region is an IgG2 immunoglobulin Fc region. In some embodiments, the Fc region is an IgG4 immunoglobulin Fc region.

[0009] In one aspect, provided are IL-17A binding proteins comprising: a) a heavy chain variable region (VH) comprising complementarity-determining regions CDR-H1, CDR-H2, and CDR-H3; b) a light chain variable region (VL) comprising complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3; and c) an Fc region comprising amino acid modifications M252Y, S254T, and T256E (YTE) and / or M428L and N434S (LS), wherein the CDR-H1, CDR- H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprise the amino acid sequences of (i) SEQ ID NOs 2, 5, 8, 11, 14, and 17, respectively; or (ii) SEQ ID NOs 3, 6, 9, 12, 15, and 18, respectively.

[0010] In some embodiments, the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprise the amino acid sequences of SEQ ID NOs 2, 5, 8, 11, 14, and 17, respectively. In some embodiments, the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprise the amino acid sequences of SEQ ID NOs 3, 6, 9, 12, 15, and 18.

[0011] In some embodiments, the VH and VL comprises sequences having at least 80% sequence identity to the amino acid sequences of (i) SEQ ID NOs: 56 and 59, respectively; or (ii) SEQ ID NOs 57 and 60, respectively.

[0012] In some embodiments, the VH comprises a sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 56 and the VL comprises a sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 59. 2 IPTS / 128625283.1Attorney Docket No. PRG-007WO

[0013] In some embodiments, the VH comprises a sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 57 and the VL comprises a sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 60.

[0014] In some embodiments, the Fc region is an IgG1, IgG2 or IgG4 immunoglobulin Fc region. In some embodiments, the Fc region is an IgG1 immunoglobulin Fc region. In some embodiments, the Fc region is an IgG2 immunoglobulin Fc region. In some embodiments, the Fc region is an IgG4 immunoglobulin Fc region.

[0015] In one aspect, provided are IL-17A binding proteins comprising: a) a heavy chain variable region (VH) comprising complementarity-determining regions CDR-H1, CDR-H2, and CDR-H3; b) a light chain variable region (VL) comprising complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3; and c) a modified Fc region that extends half-life of the IL- 17A binding protein as compared to an IL-17A binding protein that does not comprise the modified Fc region, wherein the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprise the amino acid sequences of (i) SEQ ID NOs 2, 5, 8, 11, 14, and 17, respectively; or (ii) SEQ ID NOs 3, 6, 9, 12, 15, and 18, respectively.

[0016] In one aspect, provided are IL-17A binding proteins which specifically binds to an epitope of IL-17A and comprises an Fc region comprising amino acid modifications M252Y, S254T, and T256E (YTE) and / or M428L and N434S (LS).

[0017] In one aspect, provided are pharmaceutical compositions comprising (1) an effective amount of an IL-17A and IL-17F binding protein as disclosed herein or of an IL-17A binding protein of as disclosed herein; and (2) a pharmaceutically acceptable excipient.

[0018] In one aspect, provided are methods of treating an inflammatory bowel disease in an patient in need thereof, the method comprising a step of subcutaneously or intravenously administering to the patient an effective amount of an IL-17A and IL-17F binding protein as disclosed herein, an IL-17A binding protein as disclosed herein, or a pharmaceutical composition as disclosed herein.

[0019] In some embodiments, the inflammatory bowel disease is Crohn’s disease or ulcerative colitis. In some embodiments, the inflammatory bowel disease is ulcerative colitis. In some embodiments, the inflammatory bowel disease is Crohn’s disease.

[0020] In some embodiments, the step of administering comprises subcutaneous administration. In some embodiments, the step of administering comprises intravenous administration.

[0021] In one aspect, provided are methods of treating an inflammatory disease in an patient in need thereof, the method comprising a step of subcutaneously or intravenously administering 3 IPTS / 128625283.1Attorney Docket No. PRG-007WO to the patient an effective amount of an IL-17A and IL-17F binding protein as disclosed herein, an effective amount of an IL-17A binding protein as disclosed herein, or the pharmaceutical composition as disclosed herein.

[0022] In some embodiments, the inflammatory disease is psoriasis. In some embodiments, the inflammatory disease is psoriatic arthritis. In some embodiments, the inflammatory disease is hidradenitis suppurativa.

[0023] In some embodiments, the step of administering comprises subcutaneous administration. In some embodiments, the step of administering comprises intravenous administration. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 is a graph of serum concentration in ng / mL (y-axis) plotted against days post-injection (x-axis) in cynomolgus monkeys intravenously administered a single bolus dose (25 mg / kg) of an IL-17A / F binding protein without Fc mutations (“reference antibody”), with Fc YTE mutations (“+YTE”), or with Fc LS mutations (“+LS”). See Example 3.

[0025] Figure 2 is a graph of serum concentration in ng / mL (y-axis) plotted against days post-injection (x-axis) in cynomolgus monkeys subcutaneously administered a single bolus dose (25 mg / kg) of an IL-17A / F binding protein without Fc mutations (“reference antibody”), with Fc YTE mutations (“+YTE”), or with Fc LS mutations (“+LS”). See Example 3. DETAILED DESCRIPTION Definitions

[0026] To facilitate an understanding of the present disclosure, a number of terms and phrases are defined below.

[0027] As used herein, all numerical values or numerical ranges include whole integers within or encompassing such ranges and fractions of the values or the integers within or encompassing ranges unless the context clearly indicates otherwise. Thus, for example, reference to a range of 90-100%, includes 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, etc., as well as 91.1%, 91.2%, 91.3%, 91.4%, 91.5%, etc., 92.1%, 92.2%, 92.3%, 92.4%, 92.5%, etc., and so forth. In another example, reference to a range of 1-5,000-fold includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, fold, etc., as well as 1.1, 1.2, 1.3, 1.4, 1.5, fold, etc., 2.1, 2.2, 2.3, 2.4, 2.5, fold, etc., and so forth.

[0028] The terms “a” and “an” as used herein mean “one or more” and include the plural unless the context is inappropriate. 4 IPTS / 128625283.1Attorney Docket No. PRG-007WO

[0029] As used herein, the terms “about,” “approximately,” and “comparable to,” when used herein in reference to a value, refer to a value that is similar to the referenced value in the context of that referenced value. In general, those skilled in the art, familiar with the context, will appreciate the relevant degree of variance encompassed by “about,” “approximately,” and “comparable to” in that context. For example, in some embodiments, the terms "about," “approximately,” and “comparable to” may encompass a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the referred value.

[0030] As used herein, unless otherwise indicated, the term “antibody” is understood to mean an intact antibody (e.g., an intact monoclonal antibody), or a fragment thereof, such as an Fc fragment of an antibody (e.g., an Fc fragment of a monoclonal antibody), or an antigen- binding fragment of an antibody (e.g., an antigen-binding fragment of a monoclonal antibody), including an intact antibody, antigen-binding fragment, or Fc fragment that has been modified, engineered, or chemically conjugated. In general, antibodies are multimeric proteins that contain four polypeptide chains. Two of the polypeptide chains are called immunoglobulin heavy chains (H chains), and two of the polypeptide chains are called immunoglobulin light chains (L chains). The immunoglobulin heavy and light chains are connected by an interchain disulfide bond. The immunoglobulin heavy chains are connected by interchain disulfide bonds. A light chain consists of one variable region (VL) and one constant region (CL). The heavy chain consists of one variable region (VH) and at least three constant regions (CH1, CH2 and CH3). The variable regions determine the binding specificity of the antibody. Each variable region contains three hypervariable regions known as complementarity determining regions (CDRs) flanked by four relatively conserved regions known as framework regions (FRs). The extent of the FRs and CDRs has been defined (Kabat, E.A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No.91- 3242; and Chothia, C. et al. (1987) J. Mol. Biol.196:901-917). The three CDRs in each variable region (e.g., light chain variable region or heavy chain variable region, with six CDRs total in a typical antibody format), referred to as CDR1, CDR2, and CDR3, collectively contribute to antibody binding specificity. Naturally occurring antibodies have been used as starting material for engineered antibodies, such as chimeric antibodies and humanized antibodies. Examples of antibody-based antigen-binding fragments include Fab, Fab’, (Fab’)2, Fv, single chain antibodies (e.g., scFv), minibodies, and diabodies. Examples of antibodies that have been modified or engineered include chimeric antibodies, humanized antibodies, and multispecific 5 IPTS / 128625283.1Attorney Docket No. PRG-007WO antibodies (e.g., bispecific antibodies). An example of a chemically conjugated antibody is an antibody conjugated to a toxin moiety.

[0031] “Antibody-dependent cell-mediated cytotoxicity” or “ADCC” refers to a form of cytotoxicity in which secreted Ig bound onto Fc receptors (FcRs) present on certain cytotoxic cells (e.g. Natural Killer (NK) cells, neutrophils, and macrophages) enable these cytotoxic effector cells to bind specifically to an antigen-bearing target cell and subsequently kill the target cell with cytotoxins. The antibodies “arm” the cytotoxic cells and are absolutely required for such killing. The primary cells for mediating ADCC, NK cells, express FcγRIII only, whereas monocytes express FcγRI, FcγRII and FcγRIII. FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991). To assess ADCC activity of a molecule of interest, an in vitro ADCC assay, such as that described in U.S. Pat. No.5,500,362 or 5,821,337 may be performed. Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and Natural Killer (NK) cells. Alternatively, or additionally, ADCC activity of the molecule of interest may be assessed in vivo, e.g., in an animal model such as that disclosed in Clynes et al. PNAS (USA) 95:652-656 (1998).

[0032] An “antigen-binding fragment” of an antibody, or “antibody fragment" comprises a portion of an intact antibody, which portion is still capable of antigen binding. In some embodiments, the antibody has a function in addition to that of antigen-binding, and an antigen- binding fragment retains that function. Typically, an antigen-binding fragment comprises the variable region of the antibody. Papain digestion of antibodies produce two identical antigen- binding fragments, called “Fab” fragments, and a residual “Fc” fragment, a designation reflecting the ability to crystallize readily. The Fab fragment consists of an entire light chain along with the variable region domain of the heavy chain (VH), and the first constant domain of one heavy chain (CH1). Each Fab fragment is monovalent with respect to antigen binding, i.e., it has a single antigen-binding site. Pepsin treatment of an antibody yields a single large F(ab')2fragment which roughly corresponds to two disulfide linked Fab fragments having different antigen-binding activity and that is still capable of cross-linking antigen. Fab' fragments differ from Fab fragments by having a few additional residues at the carboxy terminus of the CH1 domain, including one or more cysteines from the antibody hinge region. Fab '-SH designates an Fab' in which the cysteine residue(s) of the constant domains bear a free thiol group. F(ab')2 antibody fragments originally were produced as pairs of Fab' fragments having hinge cysteines between them. Other chemical couplings of antibody fragments are also known. 6 IPTS / 128625283.1Attorney Docket No. PRG-007WO

[0033] As used herein, the term “chimeric antibody” refers to an antibody that has a portion of its heavy and / or light chain identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass.

[0034] A “complementarity determining region” (abbreviated “CDR”) is a region of hypervariability interspersed within regions that are more conserved, termed “framework regions” (abbreviated “FR”). In some embodiments, the sequences of the framework regions are identical to the framework regions in human germline sequences. In some embodiments, the sequences of the framework regions are modified with respect to the human germline sequence.

[0035] As used herein, the phrase “complement dependent cytotoxicity” or “CDC” refers to the lysis of a target cell in the presence of complement. Activation of the classical complement pathway is initiated by the binding of the first component of the complement system (C1q) to antibodies (of the appropriate subclass) which are bound to their cognate antigen. To assess complement activation, a CDC assay, e.g., as described in Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996), may be performed.

[0036] As used herein, antibody “effector functions” refer to those biological activities attributable to the Fc region (a native sequence Fc region or amino acid sequence variant Fc region) of an antibody (or binding protein), and which typically vary with the antibody isotype. Examples of antibody effector functions include, but are not limited to, C1q binding and complement dependent cytotoxicity, Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis, down regulation of cell surface receptors (e.g. B cell receptor), and B cell activation.

[0037] As used herein, the phrases “effective amount” and “therapeutically effective amount” of an agent (e.g., an IL-17 binding protein as described herein) are used interchangeably and refer to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result. An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route. As used herein, the term “treating” includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof. An effective amount may vary according to factors such as the type of disease (e.g., disease state, age, sex, 7 IPTS / 128625283.1Attorney Docket No. PRG-007WO and / or weight of the individual, and the ability of a binding protein (or pharmaceutical composition thereof) to elicit a desired response in the individual. An effective amount may also be an amount for which any toxic or detrimental effects of the antibody (or binding protein) or pharmaceutical composition thereof are outweighed by therapeutically beneficial effects.

[0038] As used herein, the term “epitope” is an antigenic determinant that interacts with a specific antigen binding site in the variable region of an antibody molecule (or binding protein), known as the paratope, and which is comprised of the six complementary-determining regions of the antibody (or binding protein). A single antigen may have more than one epitope. Epitopes may be conformational or linear. A conformational epitope is comprised of spatially juxtaposed amino acids from different segments of a linear polypeptide chain. A linear epitope is comprised of adjacent amino acid residues in a polypeptide chain.

[0039] An “Fc chain” of a dimeric Fc as used herein refers to one of the two polypeptides forming the dimeric Fc region, i.e. a polypeptide comprising C-terminal constant regions of an immunoglobulin heavy chain, capable of stable association with another similar polypeptide. For example, an Fc chain of a dimeric IgG Fc comprises an IgG CH2 and an IgG CH3 constant domain sequence. An Fc chain or a dimeric Fc (“Fc region”) can be of any of a variety of Ig classes, e.g., IgA, IgD, IgE, IgG, or IgM. These classes are also designated α, δ, ε, γ, and μ, respectively. Several of these may be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2.

[0040] The terms “Fc receptor” and “FcR” are used to describe a receptor that binds to the Fc region of an antibody (or binding protein). For example, an FcR can be a native sequence human FcR. Generally, an FcR is one which binds an IgG antibody (a gamma receptor) and includes receptors of the FcγRI, FcγRII, and FcγRIII subclasses, including allelic variants and alternatively spliced forms of these receptors. FcγRII receptors include FcγRIIA (an “activating receptor”) and FcγRIIB (an “inhibiting receptor”), which have similar amino acid sequences that differ primarily in the cytoplasmic domains thereof. Immunoglobulins of other isotypes can also be bound by certain FcRs (see, e.g., Janeway et al., Immuno Biology: the immune system in health and disease, (Elsevier Science Ltd., NY) (4th ed., 1999)). Activating receptor FcγRIIA contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain. Inhibiting receptor FcγRIIB contains an immunoreceptor tyrosine-based inhibition motif (ITIM) in its cytoplasmic domain (reviewed in Daëron, Annu. Rev. Immunol.15:203-234 (1997)). FcRs are reviewed in Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991); Capel et al., Immunomethods 4:25-34 (1994); and de Haas et al., J. Lab. Clin. Med.126:330-41 (1995). Other FcRs, including those to be identified in the future, are encompassed by the term “FcR” herein. 8 IPTS / 128625283.1Attorney Docket No. PRG-007WO The term also includes the neonatal receptor, FcRn, which is responsible for the transfer of maternal IgGs to the fetus (Guyer et al., J. Immunol.117:587 (1976); and Kim et al., J. Immunol. 24:249 (1994)).

[0041] As used herein, the term “humanized,” when used in reference to an antibody (or binding protein), refers to a form of a non-human (e.g., murine) antibody that is chimeric. A “humanized antibody” contains minimal sequences derived from non-human immunoglobulin. Typically, humanized antibodies are human immunoglobulins (recipient or acceptor antibody) in which hypervariable region residues of the recipient are replaced by hypervariable region residues from a non-human species (donor antibody) such as mouse, rat, rabbit or nonhuman primate having a desired specificity, affinity, and capacity. In some instances, Fv framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies may comprise residues which are not found in the recipient antibody or in the donor antibody. These modifications are made to further refine antibody performance such as binding affinity. Generally, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the framework regions are those of a human immunoglobulin sequence although the framework regions may include one or more amino acid substitutions that improve binding affinity. In some embodiments, no more than six amino acid substitutions in the heavy chain and no more than three amino acid substitutions are used in the light chain in the framework region. The humanized antibody optionally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin.

[0042] “Percent (%) identity” refers to the extent to which two sequences (nucleotide or amino acid) have the same residue at the same positions in an alignment. For example, “an amino acid sequence is X% identical to SEQ ID NO: Y” refers to % identity of the amino acid sequence to SEQ ID NO: Y and is elaborated as X% of residues in the amino acid sequence are identical to the residues of sequence disclosed in SEQ ID NO: Y. Generally, computer programs are employed for such calculations. Exemplary programs that compare and align pairs of sequences include ALIGN (Myers and Miller, 1988), FASTA (Pearson and Lipman, 1988; Pearson, 1990) and gapped BLAST (Altschul et al., 1997), BLASTP, BLASTN, or GCG (Devereux et al., 1984).

[0043] As used herein, the term “pharmaceutical composition” refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo. 9 IPTS / 128625283.1Attorney Docket No. PRG-007WO

[0044] As used herein, the term “pharmaceutically acceptable carrier” refers to any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions (e.g., such as an oil / water or water / oil emulsions), and various types of wetting agents. The compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers and adjuvants, see e.g., Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA (1975).

[0045] As used herein, “polypeptide,” which may be used interchangeably with “protein,” refers to a string of at least two amino acids attached to one another by a peptide bond. In some embodiments, a polypeptide may include at least 3-5 amino acids, each of which is attached to others by way of at least one peptide bond. Those of ordinary skill in the art will appreciate that polypeptides can include one or more “non-natural” amino acids or other entities that nonetheless are capable of integrating into a polypeptide chain. In some embodiments, a polypeptide may be glycosylated, e.g., a polypeptide may contain one or more covalently linked sugar moieties. In some embodiments, a single “polypeptide” (e.g., an antibody polypeptide) may comprise two or more individual polypeptide chains, which may in some cases be linked to one another, for example by one or more disulfide bonds or other means.

[0046] As used herein, the phrase “reference level” generally refers to a level considered “normal” for comparison purposes, e.g., a level of an appropriate control. For example, in the context of half-life (e.g. serum half-life) of a protein (e.g., a binding protein) a reference level may refer to the half-life of a “reference binding protein” which may be, e.g., an immunoglobulin of the same class (e.g., IgG1, IgG2, or IgG4) having a wild-type Fc region or an Fc region lacking a half-life extending mutation. In some embodiments, the reference binding protein comprises the same complementarity-determining regions as those of the binding protein of interest (e.g., an IL-17 binding protein as described herein). In some embodiments, the reference binding protein comprises the same variable regions (e.g., heavy chain and / or light chain variable region) as those of the binding protein of interest (e.g., an IL-17 binding protein as described herein.)

[0047] As used herein, the phrase “specifically binds” or “selectively binds” to a target (e.g., IL-17 or a subunit or form thereof, such as IL-17A and / or IL-17F), when referring to a binding protein as described herein, refers to a binding reaction by which the binding protein binds to the target with higher affinity, higher avidity and / or or longer duration than it binds to a structurally different target. In typical embodiments, the binding protein has an affinity of at least 5-fold, 6- fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 25-fold, 50-fold, 100-fold, 1,000-fold, 10,000-fold, or greater by a specific target compared to an unrelated target when tested under the same 10 IPTS / 128625283.1Attorney Docket No. PRG-007WO affinity assay conditions. The term “specific binding,” “binds specifically to,” or “is specific to” a particular target, as used herein, may be presented, for example, by a molecule that has an equilibrium dissociation constant Kd for the target to which it binds, e.g., on the order of 10-5M, 10-6M, 10-7M, 10-8M, 10-9M, 10-10M, 10-11M, or 10-12M, or less. In some embodiments, a binding protein can specifically bind to an epitope on a target that is conserved between species (e.g., structurally conserved between species), e.g., conserved between human and non-human primate species (e.g., structurally conserved between human and non-human primate species). In some embodiments, a binding protein may bind exclusively to a given target, e.g., exclusively to IL-17 but not to other interleukins.

[0048] The terms “subject,” “recipient”, “individual”, “host”, and “patient”, are used interchangeably herein and in some embodiments, refer to any mammalian subject for whom diagnosis, treatment, or therapy is desired, particularly humans. “Mammal” for purposes of treatment refers to any animal classified as a mammal, including humans, domestic and farm animals, and laboratory, zoo, sports, or pet animals, such as dogs, horses, cats, cows, sheep, goats, pigs, mice, rats, rabbits, guinea pigs, monkeys etc. In some embodiments, the mammal is human. None of these terms require the supervision of medical personnel.

[0049] As used herein, to “treat” a condition or “treatment” of the condition (e.g., the conditions described herein) is an approach for obtaining beneficial or desired results, such as clinical results. Beneficial or desired results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions; diminishment of extent of disease, disorder, or condition; stabilized (i.e., not worsening) state of disease, disorder, or condition; preventing spread of disease, disorder, or condition; delay or slowing the progress of the disease, disorder, or condition; amelioration or palliation of the disease, disorder, or condition; and remission (whether partial or total), whether detectable or undetectable. “Palliating” a disease, disorder, or condition means that the extent and / or undesirable clinical manifestations of the disease, disorder, or condition are lessened and / or time course of the progression is slowed or lengthened, as compared to the extent or time course in the absence of treatment.

[0050] The terms “variable domain” and “variable region” are used interchangeably and refer to the portions of the antibody (or binding protein) or immunoglobulin domains that exhibit variability in their sequence and that are involved in determining the specificity and binding affinity of a particular antibody. Variability is not evenly distributed throughout the variable domains of antibodies; it is concentrated in sub-domains of each of the heavy and light chain variable regions. These sub-domains are called “hypervariable regions” or “complementarity determining regions” (CDRs). The more conserved (i.e., non-hypervariable) portions of the 11 IPTS / 128625283.1Attorney Docket No. PRG-007WO variable domains are called the “framework” regions (FRM or FR) and provide a scaffold for the six CDRs in three-dimensional space to form an antigen-binding surface.

[0051] Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present disclosure that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present disclosure that consist essentially of, or consist of, the recited processing steps.

[0052] As a general matter, compositions specifying a percentage are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, then the previous definition of the variable controls IL-17 BINDING PROTEINS

[0053] In one aspect, provided are proteins capable of binding to IL-17 and which comprise a modified Fc region. In some embodiments, the proteins are capable of binding, e.g., specifically binding, to IL-17A (“IL-17A binding proteins”) or to both IL-17A and IL-17F ("IL- 17A / F binding proteins"). In some embodiments, IL-17A / F binding proteins are capable of binding, e.g., specifically binding, to an epitope of human IL-17A and an epitope of human IL- 17F. In some embodiments, IL-17A binding proteins are capable of binding an epitope that is specific to IL-17A. In some embodiments, IL-17A / F binding proteins are capable of binding an epitope that is specific to IL-17A and to IL-17F.

[0054] In some embodiments, the IL-17 binding proteins are antibodies or fragments thereof. In some embodiments, the antibodies or fragments thereof are monoclonal antibodies or fragments thereof. In some embodiments, the antibodies or fragments thereof are chimeric antibodies or fragments thereof. In some embodiments, the antibodies or fragments thereof are humanized antibodies or fragments thereof. In some embodiments, the antibodies or antigen- binding fragments are human antibodies.

[0055] In certain embodiments, IL-17 binding proteins comprise a) a heavy chain variable region (VH) comprising a CDR-H1, CDR-H2, and CDR-H3 of any of Antibodies 1-3 (see Table 1); and b) a light chain variable region (VL) comprising a CDR-L1, CDR-L2, and CDR-L3 of the same antibody of Antibodies 1-3; and c) an Fc region comprising amino acid modifications M252Y, S254T, and T256E (YTE) and / or M428L and N434S (LS).

[0056] In certain embodiments, IL-17 binding proteins comprise: a) a heavy chain variable region (VH) comprising a CDR-H1, CDR-H2, and CDR-H3 of any of Antibodies 1-3 (see Table 12 IPTS / 128625283.1Attorney Docket No. PRG-007WO 1); and b) a light chain variable region (VL) comprising a CDR-L1, CDR-L2, and CDR-L3 of the same antibody of Antibodies 1-3; and c) a modified Fc that extends half-life of the IL-17 binding protein as compared to an IL-17 binding protein that does not comprise the modified Fc.

[0057] In certain embodiments, IL-17 binding proteins specifically bind to an epitope of IL- 17A and / or IL-17A / F and comprises an Fc region comprising amino acid modifications M252Y, S254T, and T256E (YTE) and / or M428L and N434S (LS).

[0058] Amino acid sequences of exemplary CDRs of IL-17 binding proteins of the present disclosure are provided in Table 1. Antibody 1 is capable of binding to both IL-17A and IL-17F. Antibodies 2 and 3 are capable of binding to IL-17A. 13 IPTS / 128625283.1Attorney Docket No. PRG-007WO PCFCF 3DPLSS-WSPPPLW CFDSSG HPDPP WSPLG H R DTYTQTQS SSS L TYTSC Q W QTQS TWTG H YTSQTQ Q W QTQS T- RQV YGG Y RYY YPDGEDMEDMDTCITYTGNKIYGNA K KIVTTKFYTQ Y QPNPNTININI TQ ESDIO N4 5 62232420414241Y Y A N D NDY Y sH- M MHIS STD NDF S STR R N W HFTF S F FFSD D Y Y Y CFTFYTFTFYH f C D N D G G G Y G N G W G Y osecnQ eESDIO N9 0 1 7 8 9u1 2 3 1 2 2 3 3 3qeS.y1dyodydy y y y y y yel bi otbodit bod d d d d dit boit boit bo o o oit bit bit bit bibanAnA1 nA2 nA3 nA1 nA2 nAn ntnT 3A1A2A314 IPTS / 128625283.1Attorney Docket No. PRG-007WO

[0059] Amino acid sequences of exemplary heavy chain variable regions (VH) and light chain variable regions (VL) of IL-17 (e.g., IL-17 or IL-17A and IL-17F) binding proteins are provided in Table 2. Table 2. Sequences of heavy chain variable regions (VH) and light chain variable regions (VL) of IL-17 (e.g., IL-17A, IL-17F, or IL-17A and IL-17F) binding proteins Antibody SEQ ID VH AA Sequence SEQ VL AA Sequence NO ID NO D S D T LI S D F R S D R

[0060] In some embodiments, the IL-17 binding protein comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 92.5%, at least 95%, at least 97.5%, or at least 99% sequence identity with the VH of any of Antibodies 1-3 (see Table 2); and b) a light chain variable region (VL) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 92.5%, at least 95%, at least 97.5%, or at least 99% sequence identity with the VL of the same antibody of Antibodies 1- 3. 15 IPTS / 128625283.1Attorney Docket No. PRG-007WO Fc Modifications

[0061] IL-17 binding proteins of the present disclosure typically comprise a modified Fc region (as further explained herein). Fc regions typically comprises one or more Fc chains. An IgG Fc chain typically contains two constant heavy domains (CH2 and CH3) and a hinge region connected to the CH2 domain. Fc regions may typically comprise two Fc chains which dimerize with one another; however, an Fc region may have a single chain or more than two Fc chains, e.g., as may be present in some antibody formats.

[0062] In some embodiments, IL-17 binding proteins comprise an IgG1 Fc region (e.g., human IgG1 Fc region), that is, except for having particular residue(s) at certain positions as noted herein, the Fc region has an amino acid sequence that is substantially similar to that of the Fc region within a wild type IgG1 Fc. In some embodiments, the wild type IgG1 Fc is a human IgG1 Fc, in which each Fc chain has an amino acid sequence of SEQ ID NO: 61. In some embodiments, IL-17 binding proteins comprise an Fc region, each Fc chain of which has an amino acid sequence that is at least 85%, at least 87.5%, at least 90%, at least 91%, at 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 to that of an Fc chain within a wild-type IgG1 Fc.

[0063] In some embodiments, IL-17 binding proteins comprise an IgG2 Fc region (e.g., human IgG2 Fc region), that is, except for having particular residue(s) at certain positions as noted herein, the Fc region has an amino acid sequence that is substantially similar to that of the Fc region within a wild type IgG2 Fc. In some embodiments, the wild type IgG2 Fc is a human IgG2 Fc, in which each Fc chain has an amino acid sequence of SEQ ID NO: 63. In some embodiments, IL-17 binding proteins comprise an Fc region, each Fc chain of which has an amino acid sequence that is at least 85%, at least 87.5%, at least 90%, at least 91%, at 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 to that of an Fc chain within a wild-type IgG2 Fc.

[0064] In some embodiments, IL-17 binding proteins comprise an IgG4 Fc region (e.g., human IgG4 Fc region), that is, except for having particular residue(s) at certain positions as noted herein, the Fc region has an amino acid sequence that is substantially similar to that of the Fc region within a wild type IgG4 Fc. In some embodiments, the wild type IgG4 Fc is a human IgG4 Fc, in which each Fc chain has an amino acid sequence of SEQ ID NO: 62. In some embodiments, IL-17 binding proteins comprise an Fc region, each Fc chain of which has an amino acid sequence that is at least 85%, at least 87.5%, at least 90%, at least 91%, at 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 to that of an Fc chain within a wild-type IgG4 Fc. 16 IPTS / 128625283.1Attorney Docket No. PRG-007WO

[0065] In certain embodiments, Fc regions are modified (e.g., substituted) at one more amino acid residues. In certain embodiments, such modifications alter the half-life of a molecule (e.g., binding protein) which comprises the Fc region by altering (e.g., enhancing) binding to an Fc receptor such as the neonatal Fc receptor (FcRn.)

[0066] Unless otherwise specified herein, numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also called the EU index, as described in Kabat et al, Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

[0067] Amino acid sequences of exemplary Fc sequences are provided in Table 3. Table 3. Exemplary Fc Sequences Name SEQ Fc chain sequence ID S H K A P W T D E D E I Q T D EIPTS / 128625283.1Attorney Docket No. PRG-007WO IgG4-SPLE 65 ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVD (S228P / HKPSNTKVDKRVESKYGPPCPPCPAPEELGGPSVFLFPPKPKDT D E S H K A P W S H K A P W S H Y R S H Y R S H Y R S HIPTS / 128625283.1Attorney Docket No. PRG-007WO (L234A / KDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK L235A / TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALG P329G) APIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFY R S H K A P W S H K A P W S H K A P W S H Y R S H Y R S H YIPTS / 128625283.1Attorney Docket No. PRG-007WO PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPG hI G1 78 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS H G Y R S H K A P W S H K A P W S H K A P W S H Y R S H Y R20 IPTS / 128625283.1Attorney Docket No. PRG-007WO hIgG1- 84 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS LALAGA / L GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH S KPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKP Y R S H G Y R S H K A P W S H K A P W S H K A P W S H P Y R S HIPTS / 128625283.1Attorney Docket No. PRG-007WO KDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK TKPREEQYNSTYRVVSVLTVDHHDWLNGKEYKCKVSNKALP APIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFY R S H P Y R S H G Y R T R E T R E T R E T DIPTS / 128625283.1Attorney Docket No. PRG-007WO IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE GNVFSCSVLHEALHSYTQKSLSLSLGK hI G4 SP / LS 97 ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNS T D E T D E T E D E T E D E T E D E D R K A G23 IPTS / 128625283.1Attorney Docket No. PRG-007WO hIgG2-LS 103 ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVD HKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDT E I Q D E I Q T D E S H K A P W S H K A P W S H K A P W S HIPTS / 128625283.1Attorney Docket No. PRG-007WO KDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALP APIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFY R S H Y R S H Y R S H G Y R S H K A P W S H K A P W S H K A PIPTS / 128625283.1Attorney Docket No. PRG-007WO SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW QQGNVFSCSVMHEALHAHYTQKSLSLSPG hI G1 116 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS H Y R S H Y R S H Y R S H G Y R S H K A P W S H K A P W26 IPTS / 128625283.1Attorney Docket No. PRG-007WO hIgG1- 122 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS D265A / GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH N434W KPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPK A P W S H Y R S H Y R S H Y R S H G Y R S H K A P W27 IPTS / 128625283.1Attorney Docket No. PRG-007WO hIgG1- 128 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS N297A / DQ GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH KPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPK A P W S H K A P W S H K P Y R S H K P Y R S H K P Y R S H K G Y R S H KIPTS / 128625283.1Attorney Docket No. PRG-007WO (T256D / DTLMISRDPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT KPREEQYNSTYRVVSVLWVLHQDWLNGKEYKCKVSNKALPA T307W) PIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYP W S H K A P W S H K A P W S H K P Y R S H K P Y R S H K P Y R S H K GIPTS / 128625283.1Attorney Docket No. PRG-007WO APIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPG S H K A P W S H K A P W S H K A P W S H Y R S H Y R S H Y30 IPTS / 128625283.1Attorney Docket No. PRG-007WO PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPG hI G1 147 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS H G Y R S H K A P W S H K A P W S H K A P W S H P Y R S H P Y RIPTS / 128625283.1Attorney Docket No. PRG-007WO hIgG1- 153 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS LALAGA / Q GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH VV KPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKP P Y R S H G Y R S H K A P W S H K A P W S H K A P W S H K P Y R32 IPTS / 128625283.1Attorney Docket No. PRG-007WO hIgG1- 159 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS LAGA / DDR GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH VV KPSNTKVDKKVEPKSCDKTHTCPPCPAPELAGAPSVFLFPPKP K P Y R S H K P Y R S H K G Y R S H K P W T D E T D E33 IPTS / 128625283.1Attorney Docket No. PRG-007WO IgG4- 165 ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNS SPLE / Q311 GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVD R / M428L HKPSNTKVDKRVESKYGPPCPPCPAPEELGGPSVFLFPPKPKDT D E D I Q S H K P W S H K P W S H Y R S H Y R34 IPTS / 128625283.1Attorney Docket No. PRG-007WO hIgG1- 171 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS LALAGA / Q GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH 311R / M428L KPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKP Y R S H G Y R, . ., , , binding protein comprises an Fc region comprising one or more modifications in SEQ ID NO: 61. In some embodiments, the IL-17 binding protein comprises an Fc region comprising one or more modifications in SEQ ID NO: 62. In some embodiments, the IL-17 binding protein comprises an Fc region comprising one or more modifications in SEQ ID NO: 63. In some embodiments, the Fc region comprises an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to any one of SEQ ID NOs: 61-63. In some embodiments, the Fc region comprises an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to any one of SEQ ID NOs: 61-63. In some embodiments, the Fc region comprises an amino acid sequence having at least 90% sequence identity with the amino acid sequence according to any one of SEQ ID NOs: 61-63. In some embodiments, the Fc region comprises an amino acid sequence having at least 95% sequence identity with the amino acid sequence according to any one of SEQ ID NOs: 61-63. In some embodiments, the Fc region comprises an amino acid sequence having at least 96% sequence identity with the amino acid sequence according to any one of SEQ ID NOs: 61-63. In some embodiments, the Fc region comprises an amino acid sequence having at least 97% sequence identity with the amino acid sequence according to any one of SEQ ID NOs: 61-63. In some embodiments, the Fc region comprises an amino acid sequence having at least 98% sequence identity with the amino acid sequence according to any one of SEQ ID NOs: 61-63. In some embodiments, the Fc region comprises an amino acid sequence having at least 99% sequence identity with the amino acid sequence according to any one of SEQ ID NOs: 61-63. In some embodiments, the Fc region comprises the amino acid sequence according to any one of SEQ ID NOs: 61-63. 35 IPTS / 128625283.1Attorney Docket No. PRG-007WO

[0069] In some embodiments, one or more modifications in the modified Fc region is selected from the group consisting of: S298A, E333A, K334A, K326A, F243L, R292P, Y300L, V305I, P396L, F243L, R292P, Y300L, L235V, P396L, F243L, S239D, I332E, A330L, S267E, L328F, D265S, S239E, K326A, A327H, G237F, K326E, G236A, D270L, H268D, S324T, L234F, N325L, V266L, and S267D. In some embodiments, one or more modifications in the modified Fc region is selected from the group consisting of S228P, M252Y, S254T, T256E, T256D, T250Q, H285D, T307A, T307Q, T307R, T307W, L309D, Q411H, Q311V, A378V, E380A, M428L, N434A, N434S, N297A, D265A, L234A, L235A, and N434W.

[0070] In some embodiments, the modified Fc region comprises a specific combination of amino acid substitutions selected from the group consisting of: L234A / L235A; V234A / G237A; L235A / G237A / E318A; S228P / L236E; H268Q / V309L / A330S / A331S; C220S / C226S / C229S / P238S; C226S / C229S / E3233P / L235V / L235A; L234F / L235E / P331S; C226S / P230S; L234A / G237A; L234A / L235A / G237A; Q311R / M428L; and L234A / L235A / P329G.

[0071] In some embodiments, the modified Fc region comprises a specific combination of amino acid substitutions selected from the group consisting of M428L / N434S (LS); M252Y / S254T / T256E (YTE); T250Q / M428L; T307A / E380A / N434A; T256D / T307Q (DQ); T256D / T307W (DW); M252Y / T256D (YD); T307Q / Q311V / A378V (QVV); T256D / H285D / T307R / Q311V / A378V (DDRVV); L309D / Q311H / N434S (DHS); S228P / L235E (SPLE); L234A / L235A (LALA); M428L / N434A (LA); L234A / G237A (LAGA); L234A / L235A / G237A (LALAGA); L234A / L235A / P329G (LALAPG); N297A / YTE; D265A / YTE; LALA / YTE; LAGA / YTE; LALAGA / YTE; LALAPG / YTE; N297A / LS; D265A / LS; LALA / LS; LAGA / LS; LALAGA / LS; LALAPG / LS; N297A / DHS; D265A / DHS; LALA / DHS; LAGA / DHS; LALAGA / DHS; LALAPG / DHS; SP / YTE; SPLE / YTE; SP / LS; SPLE / LS; SP / DHS; SPLE / DHS; N297A / LA; D265A / LA; LALA / LA; LAGA / LA; LALAGA / LA; LALAPG / LA; N297A / N434A; D265A / N434A; LALA / N434A; LAGA / N434A; LALAGA / N434A; LALAPG / N434A; N297A / N434W; D265A / N434W; LALA / N434W; LAGA / N434W; LALAGA / N434W; LALAPG / N434W; N297A / DQ; D265A / DQ; LALA / DQ; LAGA / DQ; LALAGA / DQ; LALAPG / DQ; N297A / DW; D265A / DW; LALA / DW; LAGA / DW; LALAGA / DW; LALAPG / DW; N297A / YD; D265A / YD; LALA / YD; LAGA / YD; LALAGA / YD; LALAPG / YD; N297A / QVV; D265A / QVV; LALA / QVV; LAGA / QVV, LALAGA / QVV; LALAPG / QVV; N297A / DDRVV; D265A / DDRVV; LALA / DDRVV; LAGA / DDRVV; LALAGA / DDRVV; LALAPG / DDRVV; SP / Q311R / M428L; SPLE / Q311R / M428L; N297A / Q311R / M428L; D265A / Q311R / M428L; LALA / Q311R / M428L; 36 IPTS / 128625283.1Attorney Docket No. PRG-007WO LAGA / Q311R / M428L; LALAGA / Q311R / M428L; and LALAPG / Q311R / M428L. In some embodiments, the modified Fc region comprises a specific combination of amino acid substitutions selected from the group consisting of M428L / N434S (LS) and M252Y / S254T / T256E (YTE). In some embodiments, the modified Fc region comprises M428L / N434S (LS) (e.g., SEQ ID NO: 79, SEQ ID NO: 96, SEQ ID NO: 103) modifications. In some embodiments, the modified Fc region comprises M252Y / S254T / T256E (YTE) (e.g., SEQ ID NO: 72, SEQ ID NO: 93, SEQ ID NO: 102) modifications.

[0072] In some embodiments, the IL-17 (e.g., IL-17A, IL-17F, and IL-17A and IL-17F) binding proteins include modifications to improve its ability to mediate effector function. Such modifications are known in the art and include afucosylation, or engineering of the affinity of the Fc towards an activating receptor, mainly FCGR3a for antibody-dependent cellular cytotoxicity (ADCC), and towards C1q for complement-dependent cytotoxicity (CDC).

[0073] In some aspects, the IL-17 binding protein comprises an Fc region (e.g., an IgG1 Fc region) with reduced fucose content at position Asn 297 (EU numbering) compared to a naturally occurring Fc region. Such Fc regions are known to have improved ADCC. In some aspects, such antibodies do not comprise any fucose at position Asn 297.

[0074] In some embodiments, the IL-17 (e.g., IL-17A, IL-17F, and IL-17A and IL-17F) binding proteins comprise an Fc region with one or more amino acid substitutions which improve ADCC, such as a substitution at one or more of positions 298, 333, and 334 of the Fc region. In some embodiments, the IL-17 binding protein comprises an Fc region with one or more amino acid substitutions at positions 239, 332, and 330.

[0075] In some embodiments, the Fc region comprises an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to any one of SEQ ID NOs: 64-172. In some embodiments, the Fc region comprises an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to any one of SEQ ID NOs: 64- 172. In some embodiments, the Fc region comprises an amino acid sequence having at least 90% sequence identity with the amino acid sequence according to any one of SEQ ID NOs: 64-172. In some embodiments, the Fc region comprises an amino acid sequence having at least 95% sequence identity with the amino acid sequence according to any one of SEQ ID NOs: 64-172. In some embodiments, the Fc region comprises an amino acid sequence having at least 96% sequence identity with the amino acid sequence according to any one of SEQ ID NOs: 64-172. In some embodiments, the Fc region comprises an amino acid sequence having at least 97% sequence identity with the amino acid sequence according to any one of SEQ ID NOs: 64-172. In some embodiments, the Fc region comprises an amino acid sequence having at least 98% 37 IPTS / 128625283.1Attorney Docket No. PRG-007WO sequence identity with the amino acid sequence according to any one of SEQ ID NOs: 64-172. In some embodiments, the Fc region comprises an amino acid sequence having at least 99% sequence identity with the amino acid sequence according to any one of SEQ ID NOs: 64-172. In some embodiments, the Fc region comprises the amino acid sequence according to any one of SEQ ID NOs: 64-172.

[0076] In some embodiments, the IL-17 (e.g., IL-17A, IL-17F, and IL-17A and IL-17F) binding proteins comprise an Fc region with at least one galactose residue in the oligosaccharide attached to the Fc region. Such antibody variants may have improved CDC function.

[0077] In some embodiments, the IL-17 (e.g., IL-17A, IL-17F, and IL-17A and IL-17F) binding proteins comprise one or more alterations that improve or diminish C1q binding and / or CDC.

[0078] In certain embodiments, the Fc region comprises one or more amino acid substitutions, wherein the one or more substitutions result in an increase in one or more of antibody half-life, ADCC activity, ADCP activity, or CDC activity compared with the Fc without the one or more substitutions. In certain embodiments, the one or more amino acid substitutions results in increased antibody half-life at pH 6.0 compared to a binding protein comprising a wild-type Fc region. In certain embodiments, the antibody (or binding protein) has an increased half-life that is about 10,000-fold, 1,000-fold, 500-fold, 100-fold, 50-fold, 20-fold, 10-fold, 9-fold, 8-fold, 7-fold, 6-fold, 5-fold, 4.5-fold, 4-fold, 3.5-fold, 3-fold, 2.5-fold, 2-fold, 1.95-fold, 1.9-fold, 1.85-fold, 1.8-fold, 1.75-fold, 1.7-fold, 1.65-fold, 1.6-fold, 1.55-fold, 1.50- fold, 1.45-fold, 1.4-fold, 1.35-fold, 1.3-fold, 1.25-fold, 1.2-fold, 1.15-fold, 1.1-fold, or 1.05-fold longer compared to a binding protein comprising a wild-type Fc region.

[0079] In certain embodiments, the Fc region comprises one or more amino acid substitutions, wherein the one or more substitutions result in a decrease in one or more of ADCC activity, ADCP activity, or CDC activity compared with the Fc without the one or more substitutions.

[0080] In certain embodiments, the Fc region binds an Fcγ Receptor selected from the group consisting of: FcγRI, FcγRIIa, FcγRIIb, FcγRIIc, FcγRIIIa, and FcγRIIIb. In certain embodiments, the Fc region binds an Fcγ Receptor with higher affinity at pH 6.0 compared to a binding protein comprising a wild-type Fc region.

[0081] In some embodiments, the IL-17 (e.g., IL-17A, IL-17F, and IL-17A and IL-17F) binding proteins comprise an extended half-life (i.e., serum half-life), e.g., in human serum or in humans. In some embodiments, the IL-17 binding proteins comprise a half-life of at least about 14, 28, 42, 56, 70, 84, 96, or more than 96 weeks. In some embodiments, the IL-17 binding 38 IPTS / 128625283.1Attorney Docket No. PRG-007WO proteins comprise a half-life in a range of about 14 days to about 96 days, about 14 days to about 84 days, about 14 days to about 70 days, about 14 days to about 56 days, about 14 days to about 42 days, about 14 days to about 28 days, of about 28 days to about 96 days, about 28 days to about 84 days, about 28 days to about 70 days, about 28 days to about 56 days, about 28 days to about 42 days, of about 42 days to about 96 days, about 42 days to about 84 days, about 42 days to about 70 days, or about 42 days to about 56 days. In some embodiments, the IL-17 binding proteins comprise a half-life in a range of about 42 days to about 56 days. In some embodiments, the IL-17 binding proteins comprise a half-life in a range of about 62 days to about 71 days. In some embodiments, the IL-17 binding proteins comprise a half-life of at least about 50 days, at least about 55 days, at least about 60 days, at least about 65 days, at least about 70 days, or at least about 71 days. In some embodiments, the IL-17 binding proteins comprise a half-life of about 50 days, about 55 days, about 60 days, about 62 days, about 65 days, about 70 days, or about 71 days. Methods of measuring half-life are known in the art. In some embodiments, the half-life is measured in a non-human primate. In some embodiments, the half-life is measured in a human. In some embodiments, the half-life is measured following intravenous administration. In some embodiments, the half-life is measured following subcutaneous administration.

[0082] In some embodiments, the IL-17 (e.g., IL-17A, IL-17F, and IL-17A and IL-17F) binding proteins have a half-life that is at least 20% longer than a comparator antibody. In some embodiments, the comparator antibody comprises the same complementarity determining regions and variable regions but different Fc regions. In some embodiments, the half-life of the IL-17 binding proteins is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% longer than the half-life of the comparator antibody. In some embodiments, the half-life of the IL-17 binding proteins is longer than the half-life of the comparator antibody by at least 2 fold, at least 3 fold, at least 4 fold, at least 5 fold, at least 6 fold, at least 7 fold, at least 8 fold, at least 9 fold, or at least 10 fold. PHARMACEUTICAL COMPOSITIONS

[0083] The present disclosure also includes methods using pharmaceutical compositions that contain therapeutically effective amounts of the IL-17 (e.g., IL-17A, IL-17F, and IL-17A and IL- 17F) binding proteins. Compositions can be formulated for use in a variety of drug delivery systems. One or more physiologically acceptable excipients or carriers can also be included in the composition for proper formulation. Suitable formulations for use in the present disclosure are found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, Pa., 17th ed., 1985. For a brief review of methods for drug delivery, see, e.g., Langer (Science 249:1527-1533, 1990). 39 IPTS / 128625283.1Attorney Docket No. PRG-007WO

[0084] In some embodiments, a pharmaceutical composition may contain formulation materials for modifying, maintaining or preserving, for example, the pH, osmolarity, viscosity, clarity, color, isotonicity, odor, sterility, stability, rate of dissolution or release, adsorption or penetration of the composition. In such embodiments, suitable formulation materials include, but are not limited to, amino acids (such as glycine, glutamine, asparagine, arginine or lysine); antimicrobials; antioxidants (such as ascorbic acid, sodium sulfite or sodium hydrogen-sulfite); buffers (such as borate, bicarbonate, Tris-HCl, citrates, phosphates or other organic acids); bulking agents (such as mannitol or glycine); chelating agents (such as ethylenediamine tetraacetic acid (EDTA)); complexing agents (such as caffeine, polyvinylpyrrolidone, beta- cyclodextrin or hydroxypropyl-beta-cyclodextrin); fillers; monosaccharides; disaccharides; and other carbohydrates (such as glucose, mannose or dextrins); proteins (such as serum albumin, gelatin or immunoglobulins); coloring, flavoring and diluting agents; emulsifying agents; hydrophilic polymers (such as polyvinylpyrrolidone); low molecular weight polypeptides; salt- forming counterions (such as sodium); preservatives (such as benzalkonium chloride, benzoic acid, salicylic acid, thimerosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid or hydrogen peroxide); solvents (such as glycerin, propylene glycol or polyethylene glycol); sugar alcohols (such as mannitol or sorbitol); suspending agents; surfactants or wetting agents (such as pluronics, PEG, sorbitan esters, polysorbates such as polysorbate 20, polysorbate, triton, tromethamine, lecithin, cholesterol, tyloxapal); stability enhancing agents (such as sucrose or sorbitol); tonicity enhancing agents (such as alkali metal halides, preferably sodium or potassium chloride, mannitol sorbitol); delivery vehicles; diluents; excipients and / or pharmaceutical adjuvants (see, Remington’s Pharmaceutical Sciences, 18th ed. (Mack Publishing Company, 1990)).

[0085] In some embodiments, a pharmaceutical composition is citrate-free.

[0086] In some embodiments, a pharmaceutical composition may contain nanoparticles, e.g., polymeric nanoparticles, liposomes, or micelles.

[0087] In some embodiments, a pharmaceutical composition may contain a sustained- or controlled-delivery formulation. Techniques for formulating sustained- or controlled-delivery means, such as liposome carriers, bio-erodible microparticles or porous beads and depot injections, are also known to those skilled in the art. Sustained-release preparations may include, e.g., porous polymeric microparticles or semipermeable polymer matrices in the form of shaped articles, e.g., films, or microcapsules. Sustained release matrices may include polyesters, hydrogels, polylactides, copolymers of L-glutamic acid and gamma ethyl-L-glutamate, poly (2- hydroxyethyl-methacrylate), ethylene vinyl acetate, or poly-D(−)-3-hydroxybutyric acid. 40 IPTS / 128625283.1Attorney Docket No. PRG-007WO Sustained release compositions may also include liposomes that can be prepared by any of several methods known in the art.

[0088] Pharmaceutical compositions containing an IL-17 (e.g., IL-17A, IL-17F, and IL-17A and IL-17F) binding protein disclosed herein can be presented in a dosage unit form and can be prepared by any suitable method. A pharmaceutical composition should be formulated to be compatible with its intended route of administration. Examples of routes of administration are intravenous (IV), intradermal, inhalation, transdermal, topical, transmucosal, intrathecal and rectal administration. In some embodiments, the IL-17 binding protein disclosed herein is administered intravenously or subcutaneously. In some embodiments, the IL-17 binding protein disclosed herein is administered intravenously. In some embodiments, the IL-17 binding protein disclosed herein is administered subcutaneously.

[0089] Useful formulations can be prepared by methods known in the pharmaceutical art. For example, see Remington’s Pharmaceutical Sciences, 18th ed. (Mack Publishing Company, 1990). Formulation components suitable for parenteral administration include a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as EDTA; buffers such as acetates, citrates or phosphates; and agents for the adjustment of tonicity such as sodium chloride or dextrose. In some embodiments, the formulation for parenteral administration is citrate-free.

[0090] For intravenous or subcutaneous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). The carrier should be stable under the conditions of manufacture and storage, and should be preserved against microorganisms. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol), and suitable mixtures thereof.

[0091] An intravenous or subcutaneous drug delivery formulation may be contained in a syringe, pen, or bag. In some embodiments, the bag is connected to a channel comprising a tube and / or a needle. In some embodiments, the formulation is a lyophilized formulation or a liquid formulation.

[0092] These compositions may be sterilized by conventional sterilization techniques, or may be sterile filtered. The resulting aqueous solutions may be packaged for use as-is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. 41 IPTS / 128625283.1Attorney Docket No. PRG-007WO

[0093] A polyol, which acts as a tonicifier and may stabilize the IL-17 (e.g., IL-17A, IL-17F, and IL-17A and IL-17F) binding protein, may also be included in the formulation. The polyol is added to the formulation in an amount which may vary with respect to the desired isotonicity of the formulation. In some embodiments, the aqueous formulation is isotonic. The amount of polyol added may also be altered with respect to the molecular weight of the polyol. For example, a lower amount of a monosaccharide (e.g., mannitol) is added, compared to a disaccharide (such as trehalose). In some embodiments, the polyol which is used in the formulation as a tonicity agent is mannitol.

[0094] A detergent or surfactant may also be added to the formulation. Exemplary detergents include nonionic detergents such as polysorbates (e.g., polysorbates 20, 80 etc.) or poloxamers (e.g., poloxamer 188). The amount of detergent added is such that it reduces aggregation of the formulated antibody and / or minimizes the formation of particulates in the formulation and / or reduces adsorption. In some embodiments, the formulation may include a surfactant which is a polysorbate. In some embodiments, the formulation may contain the detergent polysorbate 80 or Tween 80. Tween 80 is a term used to describe polyoxyethylene (20) sorbitanmonooleate (see Fiedler, Lexikon der Hifsstoffe, Editio Cantor Verlag Aulendorf, 4th edi., 1996).

[0095] In embodiments, the protein product of the present disclosure is formulated as a liquid formulation. In some embodiments, the liquid formulation is prepared in combination with a sugar at stabilizing levels. In some embodiments, the liquid formulation is prepared in an aqueous carrier. In some embodiments, a stabilizer is added in an amount no greater than that which may result in a viscosity undesirable or unsuitable for intravenous administration. In some embodiments, the sugar is disaccharides, e.g., sucrose. In some embodiments, the liquid formulation may also include one or more of a buffering agent, a surfactant, and a preservative.

[0096] In some embodiments, the pH of the liquid formulation is set by addition of a pharmaceutically acceptable acid and / or base. In some embodiments, the pharmaceutically acceptable acid is hydrochloric acid. In some embodiments, the base is sodium hydroxide.

[0097] The aqueous carrier of interest herein is one which is pharmaceutically acceptable (safe and non-toxic for administration to a human) and is useful for the preparation of a liquid formulation. Illustrative carriers include sterile water for injection (SWFI), bacteriostatic water for injection (BWFI), a pH buffered solution (e.g., phosphate-buffered saline), sterile saline solution, Ringer's solution or dextrose solution.

[0098] A preservative may be optionally added to the formulations herein to reduce bacterial action. The addition of a preservative may, for example, facilitate the production of a multi-use (multiple-dose) formulation. 42 IPTS / 128625283.1Attorney Docket No. PRG-007WO

[0099] The IL-17 (e.g., IL-17A, IL-17F, and IL-17A and IL-17F) binding protein may be lyophilized to produce a lyophilized formulation including the proteins and a lyoprotectant. The lyoprotectant may be sugar, e.g., disaccharides. In some embodiments, the lyoprotectant is sucrose or maltose. The lyophilized formulation may also include one or more of a buffering agent, a surfactant, a bulking agent, and / or a preservative.

[0100] The amount of sucrose or maltose useful for stabilization of the lyophilized drug product may be in a weight ratio of at least 1:2 protein to sucrose or maltose. In some embodiments, the protein to sucrose or maltose weight ratio is of from 1:2 to 1:5. In some embodiments, the pH of the formulation, prior to lyophilization, is set by addition of a pharmaceutically acceptable acid and / or base. In some embodiments, the pharmaceutically acceptable acid is hydrochloric acid. In some embodiments, the pharmaceutically acceptable base is sodium hydroxide. METHODS OF TREATMENT

[0101] In certain embodiments, provided are methods of treating an inflammatory bowel disease in a patient in need thereof, the method comprising a step of subcutaneously or intravenously administering to the patient an effective amount of an IL-17 (e.g., IL-17A, IL-17F, or IL-17A and IL-17F) binding protein as disclosed herein.

[0102] In some embodiments, the inflammatory bowel disease is Crohn’s disease or ulcerative colitis. In some embodiments, the inflammatory bowel disease is ulcerative colitis. In some embodiments, the inflammatory bowel disease is Crohn’s disease.

[0103] In certain embodiments, provided are methods of treating an inflammatory disease in a patient in need thereof, the method comprising a step of subcutaneously or intravenously administering to the patient an effective amount of an IL-17 (e.g., IL-17A, IL-17F, or IL-17A and IL-17F) binding protein as disclosed herein.

[0104] In some embodiments, the inflammatory disease is psoriasis. In some embodiments, the inflammatory disease is psoriatic arthritis. In some embodiments, the inflammatory disease is hidradenitis suppurativa.

[0105] In some embodiments, the IL-17 (e.g., IL-17A, IL-17F, or IL-17A and IL-17F) binding protein is administered at a dose of about 75 mg to about 150 mg. In some embodiments, the IL-17 binding protein is administered at a dose of about 250 mg to about 750 mg. In some embodiments, the IL-17 binding protein is administered at a dose of about 300 mg to about 700 mg. In some embodiments, the IL-17 binding protein is administered at a dose of about 300 mg to about 600 mg. In some embodiments, the IL-17 binding protein is administered at a dose of 43 IPTS / 128625283.1Attorney Docket No. PRG-007WO about 300 mg to about 500 mg. In some embodiments, the IL-17 binding protein is administered at a dose of about 300 mg to about 400 mg. In some embodiments, the IL-17 binding protein is administered at a dose of about 400 mg to about 700 mg. In some embodiments, the IL-17 binding protein is administered at a dose of about 400 mg to about 600 mg. In some embodiments, the IL-17 binding protein is administered at a dose of about 300 mg to about 500 mg. In some embodiments, the IL-17 binding protein is administered at a dose of about 500 mg to about 700 mg. In some embodiments, the IL-17 binding protein is administered at a dose of about 500 mg to about 600 mg. In some embodiments, the IL-17 binding protein is administered at a dose of about 600 mg to about 700 mg. In some embodiments, the IL-17 binding protein is administered at a dose of about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg.

[0106] Administration of the IL-17 (e.g., IL-17A, IL-17F, and IL-17A and IL-17F) binding protein can occur at various intervals. In some embodiments, the IL-17 binding protein is administered to the patient at least once at an interval more than 8 weeks. In some embodiments, the interval is about 12 to about 26 weeks. In some embodiments, the IL-17 binding protein, the interval is about 12 to about 22 weeks. In some embodiments, the interval is about 12 to about 18 weeks. In some embodiments, the interval is about 12 to about 14 weeks. In some embodiments, the interval is about 16 to about 26 weeks. In some embodiments, the interval is about 16 to about 22 weeks. In some embodiments, the interval is about 16 to about 18 weeks. In some embodiments, the interval is about 20 to about 26 weeks. In some embodiments, the interval is about 20 to about 22 weeks. In some embodiments, the interval is about 12 weeks. In some embodiments, the interval is about 16 weeks. In some embodiments, the interval is about 26 weeks. Subjects

[0107] In certain embodiments, the subject to whom the IL-17 binding proteins are administered in accordance with the present disclosure is a mammal, such as a primate. In some embodiments, the subject is human.

[0108] Generally, the subject is suffering from, exhibits at least one symptom of, is diagnosed with, or is identified as at risk of having an inflammatory bowel disease (e.g., Crohn’s disease or ulcerative colitis) or an inflammatory disease (e.g., psoriasis, psoriatic arthritis, or hidradenitis suppurativa). 44 IPTS / 128625283.1Attorney Docket No. PRG-007WO

[0109] Psoriasis is a skin disease that causes a rash with itchy, scaly patches, most commonly on the knees, elbows, trunk and scalp. Plaque psoriasis, the most common type of psoriasis, causes dry, itchy, raised skin patches (plaques) covered with scales. Plaques usually appear on the elbows, knees, lower back and scalp.

[0110] Psoriatic arthritis (PsA) refers to chronic inflammatory arthritis associated with psoriasis. About 1 in 20 individuals with psoriasis will develop arthritis along with psoriasis, and in about 75% of cases, psoriasis precedes the arthritis. PsA exhibits itself in a variety of ways, ranging from mild to severe arthritis, wherein the arthritis usually affects the fingers and the spine.

[0111] Hidradenitis suppurativa is a painful, chronic skin condition which causes skin abscesses and scarring on the skin. Pea- to marble-sized lumps form under the skin. These lumps can be painful and usually occur where skin rubs together, such as in the armpits, groin, and buttocks. Routes of administration

[0112] In certain embodiments, the step of administering comprises systemic administration. In certain embodiments, systemic administration comprises parenteral administration, e.g., intravenous administration, intraarterial administration, intraperitoneal administration, subcutaneous administration, intramuscular administration, or intradermal administration. In some embodiments, systemic administration comprises enteric administration, e.g., trans- gastroenteric administration or oral administration.

[0113] In some embodiments, the step of administering comprises intravenous administration. In some embodiments, the step of administering comprises subcutaneous administration.

[0114] In some embodiments, the step of administering comprises intralesional, intraintestinal, intracolonic, intrarectal, or intrapouch administration. Outcomes

[0115] In many embodiments, methods disclosed herein result in a measurable improvement in the subject, e.g., in amelioration or resolution of symptoms. For example, such improvement may include an improvement in a clinical score or a score from a survey or questionnaire associated with, or suitable for assessing, a disease or condition as mentioned herein, e.g., inflammatory bowel disease (e.g., Crohn’s disease or ulcerative colitis) or an inflammatory disease (e.g., psoriasis, psoriatic arthritis, or hidradenitis suppurativa). 45 IPTS / 128625283.1Attorney Docket No. PRG-007WO

[0116] For example, in some embodiments, a reduction in the psoriasis area and severity index (PASI), e.g., a 50% reduction or a 75% reduction in the PASI score, is achieved.

[0117] Alternatively or additionally, an improvement of the score(s) or quality of life, as determined by any or any combination of the following instruments, may be achieved by the presently disclosed methods: Dermatology Life Quality Index (DLQI), Investigator Global Assessment (IGA), Nail Psoriasis Severity Index (NAPSI), Physician Global Assessment (PGA), or Medical Outcomes Study Short Form (36) Health Survey (SF-36), or Treatment Satisfaction Questionnaire for Medication (TSQM).

[0118] In some embodiments, an improvement in the clinical score or quality of life as measured by any or any combination of the following instruments is achieved: Composite Psoriatic Disease Activity Index (CPDAI), PsA Disease Activity Score (PASDAS), Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) Composite Exercise (GRACE) index, Psoriatic Arthritis Impact of Disease (PsAID) questionnaire, or Work Productivity and Activity Impairment (WPAI) questionnaire.

[0119] Alternatively or additionally, an improvement of the score(s) or quality of life, as determined by any or any combination of the following instruments, may be achieved by the presently disclosed methods: International Hidradenitis Suppurativa Severity Score System (HIS4), Hurley, Hurley Staging refined, Sartorius score (e.g., 2003, 2007, and / or 2009 versions), Hidradenitis Suppurativa Physician Global Assessment (HS-PGA), Severity Assessment of Hidradenitis Suppurativa (SAHS), Hidradenitis Suppurativa Severity Index (HSSI), Acne Inversa Severity Index (AISI),the Static Metascore, Hidradenitis Suppurativa Clinical Response (HiSCR), iHS4-55, and the Dynamic Metascore. METHODS OF PREPARATION

[0120] The IL-17 (e.g., IL-17A, IL-17F, and IL-17A and IL-17F) binding proteins described above can be made using recombinant DNA technology well known to a skilled person in the art. For example, one or more isolated polynucleotides encoding the IL-17 binding protein can be ligated to other appropriate nucleotide sequences, including, for example, constant region coding sequences, and expression control sequences, to produce conventional gene expression constructs (i.e., expression vectors) encoding the desired IL-17 binding proteins. Production of defined gene constructs is within routine skill in the art.

[0121] Nucleic acids encoding desired IL-17 (e.g., IL-17A, IL-17F, and IL-17A and IL-17F) binding proteins can be incorporated (ligated) into expression vectors, which can be introduced into host cells through conventional transfection or transformation techniques. Exemplary host 46 IPTS / 128625283.1Attorney Docket No. PRG-007WO cells are E. coli cells, Chinese hamster ovary (CHO) cells, human embryonic kidney 293 (HEK 293) cells, HeLa cells, baby hamster kidney (BHK) cells, monkey kidney cells (COS), human hepatocellular carcinoma cells (e.g., Hep G2), and myeloma cells that do not otherwise produce IgG protein. Transformed host cells can be grown under conditions that permit the host cells to express the genes that encode IL-17 binding proteins.

[0122] Specific expression and purification conditions will vary depending upon the expression system employed. For example, if a gene is to be expressed in E. coli, it is first cloned into an expression vector by positioning the engineered gene downstream from a suitable bacterial promoter, e.g., Trp or Tac, and a prokaryotic signal sequence. The expressed protein may be secreted. The expressed protein may accumulate in refractile or inclusion bodies, which can be harvested after disruption of the cells by French press or sonication. The refractile bodies then are solubilized, and the protein may be refolded and / or cleaved by methods known in the art.

[0123] If the engineered gene is to be expressed in eukaryotic host cells, e.g., CHO cells, it is first inserted into an expression vector containing a suitable eukaryotic promoter, a secretion signal, a poly A sequence, and a stop codon. Optionally, the vector or gene construct may contain enhancers and introns. In embodiments involving fusion proteins comprising an IL-17 (e.g., IL-17A, IL-17F, and IL-17A and IL-17F) binding protein or portion thereof, the expression vector optionally contains sequences encoding all or part of a constant region, enabling an entire, or a part of, a heavy or light chain to be expressed. The gene construct can be introduced into eukaryotic host cells using conventional techniques.

[0124] In some embodiments, in order to express an IL-17 (e.g., IL-17A, IL-17F, and IL- 17A and IL-17F) binding protein, an N-terminal signal sequence is included in the protein construct. Exemplary N-terminal signal sequences include signal sequences from interleukin-2, CD-5, IgG kappa light chain, trypsinogen, serum albumin, and prolactin.

[0125] After transfection, single clones can be isolated for cell bank generation using methods known in the art, such as limited dilution, ELISA, FACS, microscopy, or Clonepix. Clones can be cultured under conditions suitable for bio-reactor scale-up and maintained expression of the IL-17 (e.g., IL-17A, IL-17F, and IL-17A and IL-17F) binding proteins.

[0126] The IL-17 (e.g., IL-17A, IL-17F, and IL-17A and IL-17F) binding proteins can be isolated and purified using methods known in the art including centrifugation, depth filtration, cell lysis, homogenization, freeze-thawing, affinity purification, gel filtration, ion exchange chromatography, hydrophobic interaction exchange chromatography, and mixed-mode chromatography. 47 IPTS / 128625283.1Attorney Docket No. PRG-007WO EXAMPLES Example 1. Determination of Antibody Affinity to IL-17A and IL-17F

[0127] Binding affinity (KD) of antibodies (Antibody 1 with or without M252Y, S254T, and T256E (YTE) mutations) to human IL-17A and IL-17F was determined through surface plasmon resonance (SPR) using a BIACORE™ 8K SPR system (Cytiva). Series S Sensor Chip CM5 (Cytiva) sensor chips were prepared by immobilizing goat anti-human IgG (Jackson ImmunoResearch) and ultimately used to determine the binding kinetic rate and affinity constants at 25 °C in a running buffer of 10 mM HEPES pH 7.4, 300 mM NaCl, 0.003M EDTA, and 0.05% v / v Surfactant P20. Anti-IL17A / F mAb constructs (diluted to 2 μg / mL) were captured onto flow cell 2 (active) for 60 sec at a flow rate of 10 µL / min. Recombinant human IL- 17A or IL-17F was prepared at concentrations of 0, 0.62, 1.85, 5.56, 16.67, 50 nM and injected over flow cell 1 (reference) and flow cell 2 (active) for 180 sec at a flow rate of 50 μL / min. Samples were injected in a multi-cycle manner over freshly captured mAb, by regenerating the capture surfaces with injection of 10 mM glycine, pH 1.5 for 30 sec at a flow rate of 30 μL / min. A 1:1 kinetic binding model was utilized to determine the apparent association (ka) and dissociation rate constants (kd). Their ratio provides the apparent equilibrium dissociation constant or affinity constant (KD= kd / ka). Results are shown in Table 4 for human IL-17A and Table 5 for human IL-17F.

[0128] Under the conditions tested, the kd (and thus KD) of Antibody 1 and Antibody 1 YTE were not able to be determined as the limit of detection of BIACORE™ 8K SPR is 1 x 10-61 / s (both antibodies tested had dissociation rates below this limit). Table 4 hIL-17A kd Antibody hIL-17A ka (1 / Ms) (1 / s) hIL-17A KD (nM) Antibody 1 3.31 x 106< 1 x 10-6ND Antibody 1 YTE 3.57 x 106< 1 x 10-6ND ND, not determined Table 5 hIL-17F kd Antibody hIL-17F ka (1 / Ms) (1 / s) hIL-17F KD (nM) Antibody 1 8.14 x 105< 1 x 10-6ND Antibody 1 YTE 8.32 x 105< 1 x 10-6ND   ND, not determined 48 IPTS / 128625283.1Attorney Docket No. PRG-007WO Example 2. Inhibition of IL-17A or IL-17F-Induced Activation of NF-κB in HEK 293 IL- 17RA+ / IL-17RC+ NF-κB-Linked Luciferase Reporter Cells

[0129] Inhibition of NF- ^B activation in HEK 293 cells expressing IL-17RA, IL-17RC, and an NF- ^B-linked luciferase reporter (Acro Biosystems) was used to evaluate the functional activity of antibodies (Antibody 1 with or without M252Y, S254T, and T256E (YTE) mutations) to block IL-17A / F-induced biological activity. Briefly, reporter cells were seeded into a 96-well plate and allowed to recover overnight. A mixture of hIL-17A or hIL-17F and purified IL-17A / F antibodies (Antibody 1 with or without M252Y, S254T, and T256E (YTE) mutations) were added to cells, resulting in a final concentration of 5 ng / mL of hIL-17A and 0-10 nM of antibody or 1000 ng / mL hIL-17F and 0-200 nM of antibody. Cells were incubated at 37 °C for 16 hours and subsequently lysed with One-Glo luciferase assay buffer (Promega) at room temperature for 2 min under dark conditions. Luminescence was quantified by a Varioskan LUX plate reader (Thermo) and subsequent data were analyzed using GraphPad Prism. IC50values were determined as the concentration of antibody required to inhibit 50% of the maximum luminescent signal detected with incubation of 5 ng / mL of hIL-17A or 1000 ng / mL of hIL-17F alone.

[0130] As shown in Table 6, Antibody 1 and Antibody 1 YTE demonstrate comparable inhibition of IL-17A or IL-17F-induced activation of NF- ^B. Table 6 Antibody Relative IC50 (hIL-17A) Relative IC50 (hIL-17F) Antibody 1 1.000 1.000 Antibody 1 YTE 1.073 1.228 Values relative to Antibody 1, which is normalized to 1.000. Example 3. Pharmacokinetic Analysis of IL-17A / F Binding Proteins in Cynomolgus Monkey

[0131] In order to evaluate the impact of half-life extension mutations on IL-17A / F binding protein pharmacokinetics, male cynomolgus monkeys (Macaca fascicularis), ranging from 2.65 to 4.48 kg in weight, were administered a single bolus dose (25 mg / kg) of IL-17A / F binding protein (Antibody 1; see sequences in Tables 1 and 2) with Fc YTE mutations (see SEQ ID NO:72), Fc LS mutations (see SEQ ID NO:79), or neither (IgG1 Fc; see SEQ ID NO:61) by either intravenous (IV) and / or subcutaneous (SC) injection on Day 0. Serum samples were taken 49 IPTS / 128625283.1Attorney Docket No. PRG-007WO regularly through the study. Antibody 1 with the IgG1 Fc lacking mutations is referred to herein as the “reference antibody.”

[0132] Half-life was determined from cynomolgus serum samples for each dose-cohort up to day 56, with average PK curves shown in Figure 1 for IV administration and Figure 2 for SC administration. The β-elimination half-life of IL-17A / F binding protein with Fc YTE mutations was observed to be 23 days and 20 days for IV and SC dosing, respectively. Similarly, the observed half-life of IL-17A / F binding protein with Fc LS mutations was observed to be 20 and 19 days for IV and SC dosing, respectively. In contrast, the observed half-life of the reference antibody was 11 days and 9 days for IV and SC dosing, respectively. Scaling of the observed half-life in cynomolgus monkey of IL-17A / F binding protein with YTE modifications led to a human half-life projection of 62-71 days.

[0133] Therefore, the present example demonstrates enhanced half-life of an IL-17A / F binding protein having a half-life extending mutations in the Fc region. EQUIVALENTS

[0134] The disclosure may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting the disclosure described herein. Scope of the disclosure is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein. 50 IPTS / 128625283.1

Claims

Attorney Docket No. PRG-007WO CLAIMS 1. An IL-17A and IL-17F binding protein comprising: a) a heavy chain variable region (VH) comprising (i) a CDR-H1 having an amino acid sequence according to SEQ ID NO: 1, (ii) a CDR-H2 having an amino acid sequence according to SEQ ID NO: 4, and (iii) a CDR-H3 having an amino acid sequence according to SEQ ID NO: 7; b) a light chain variable region (VL) comprising (i) a CDR-L1 having an amino acid sequence according to SEQ ID NO: 10, (ii) a CDR-L2 having an amino acid sequence according to SEQ ID NO: 13, and (iii) a CDR-L3 having an amino acid sequence according to SEQ ID NO: 16; and c) an Fc region comprising amino acid modifications M252Y, S254T, and T256E (YTE) and / or M428L and N434S (LS).

2. The IL-17A and IL-17F binding protein of claim 1, wherein the VH comprises a sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 55 and the VL comprises a sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:

58.

3. An IL-17A and IL-17F binding protein comprising: a) a heavy chain variable region (VH) comprising (i) a CDR-H1 having an amino acid sequence according to SEQ ID NO: 1, (ii) a CDR-H2 having an amino acid sequence according to SEQ ID NO: 4, and (iii) a CDR-H3 having an amino acid sequence according to SEQ ID NO: 7; b) a light chain variable region (VL) comprising (i) a CDR-L1 having an amino acid sequence according to SEQ ID NO: 10, (ii) a CDR-L2 having an amino acid sequence according to SEQ ID NO: 13, and (iii) a CDR-L3 having an amino acid sequence according to SEQ ID NO: 16; and c) a modified Fc region that extends half-life of the IL-17A and IL-17F binding protein as compared to an IL-17A and IL-17F binding protein that does not comprise the modified Fc region.

4. An IL-17A and IL-17F binding protein, wherein the IL-17A and IL-17F binding protein specifically binds to an epitope of IL-17A and IL-17F and comprises an Fc region comprising amino acid modifications M252Y, S254T, and T256E (YTE) and / or M428L and N434S (LS). 51 IPTS / 128625283.1Attorney Docket No. PRG-007WO 5. The IL-17A and IL-17F binding protein of any one of claims 1-4, wherein the Fc region is an IgG1, IgG2 or IgG4 immunoglobulin Fc region.

6. The IL-17A and IL-17F binding protein of claim 5, wherein the Fc region is an IgG1 immunoglobulin Fc region.

7. The IL-17A and IL-17F binding protein of claim 5, wherein the Fc region is an IgG2 immunoglobulin Fc region.

8. The IL-17A and IL-17F binding protein of claim 5, wherein the Fc region is an IgG4 immunoglobulin Fc region.

9. An IL-17A binding protein comprising: a) a heavy chain variable region (VH) comprising complementarity-determining regions CDR-H1, CDR-H2, and CDR-H3; b) a light chain variable region (VL) comprising complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3; and c) an Fc region comprising amino acid modifications M252Y, S254T, and T256E (YTE) and / or M428L and N434S (LS), wherein the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprise the amino acid sequences of (i) SEQ ID NOs 2, 5, 8, 11, 14, and 17, respectively; or (ii) SEQ ID NOs 3, 6, 9, 12, 15, and 18, respectively.

10. The IL-17A binding protein of claim 9, wherein the CDR-H1, CDR-H2, CDR-H3, CDR- L1, CDR-L2, and CDR-L3 comprise the amino acid sequences of SEQ ID NOs 2, 5, 8, 11, 14, and 17, respectively.

11. The IL-17A binding protein of claim 9, wherein the CDR-H1, CDR-H2, CDR-H3, CDR- L1, CDR-L2, and CDR-L3 comprise the amino acid sequences of SEQ ID NOs 3, 6, 9, 12, 15, and 18.

12. The IL-17A binding protein of claim 9, wherein the VH and VL comprises sequences having at least 80% sequence identity to the amino acid sequences of (i) SEQ ID NOs: 56 and 59, respectively; or (ii) SEQ ID NOs 57 and 60, respectively.

13. The IL-17A binding protein of claim 12, wherein the VH comprises a sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 56 and the VL comprises a sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:

59. 52 IPTS / 128625283.1Attorney Docket No. PRG-007WO 14. The IL-17A binding protein of claim 12, wherein the VH comprises a sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 57 and the VL comprises a sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:

60.

15. The IL-17A binding protein of any one of claims 9-14, wherein the Fc region is an IgG1, IgG2 or IgG4 immunoglobulin Fc region.

16. The IL-17A binding protein of claim 15, wherein the Fc region is an IgG1 immunoglobulin Fc region.

17. The IL-17A binding protein of claim 15, wherein the Fc region is an IgG2 immunoglobulin Fc region.

18. The IL-17A binding protein of claim 15, wherein the Fc region is an IgG4 immunoglobulin Fc region.

19. An IL-17A binding protein comprising: a) a heavy chain variable region (VH) comprising complementarity-determining regions CDR-H1, CDR-H2, and CDR-H3; b) a light chain variable region (VL) comprising complementarity-determining regions CDR-L1, CDR-L2, and CDR-L3; and c) a modified Fc region that extends half-life of the IL-17A binding protein as compared to an IL-17A binding protein that does not comprise the modified Fc region, wherein the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprise the amino acid sequences of (i) SEQ ID NOs 2, 5, 8, 11, 14, and 17, respectively; or (ii) SEQ ID NOs 3, 6, 9, 12, 15, and 18, respectively.

20. An IL-17A binding protein which specifically binds to an epitope of IL-17A and comprises an Fc region comprising amino acid modifications M252Y, S254T, and T256E (YTE) and / or M428L and N434S (LS).

21. A pharmaceutical composition comprising (1) an effective amount of an IL-17A and IL- 17F binding protein of any one of claims 1-8 or of an IL-17A binding protein of any one of claims 9-20; and (2) a pharmaceutically acceptable excipient.

22. A method of treating an inflammatory bowel disease in an patient in need thereof, the method comprising a step of subcutaneously or intravenously administering to the patient an effective amount of an IL-17A and IL-17F binding protein of any one of claims 1-8, an effective amount of an IL-17A binding protein of any one of claims 9-20, or the pharmaceutical composition of claim 21. 53 IPTS / 128625283.1Attorney Docket No. PRG-007WO 23. The method of claim 22, wherein the inflammatory bowel disease is Crohn’s disease or ulcerative colitis.

24. The method of claim 23, wherein the inflammatory bowel disease is ulcerative colitis.

25. The method of claim 23, wherein the inflammatory bowel disease is Crohn’s disease.

26. The method of any one of claims 22-25, wherein the step of administering comprises subcutaneous administration.

27. The method of any one of claims 22-26, wherein the step of administering comprises intravenous administration.

28. A method of treating an inflammatory disease in an patient in need thereof, the method comprising a step of subcutaneously or intravenously administering to the patient an effective amount of an IL-17A and IL-17F binding protein of any one of claims 1-8, an effective amount of an IL-17A binding protein of any one of claims 9-20, or the pharmaceutical composition of claim 21.

29. The method of claim 28, wherein the inflammatory disease is psoriasis.

30. The method of claim 28, wherein the inflammatory disease is psoriatic arthritis.

31. The method of claim 28, wherein the inflammatory disease is hidradenitis suppurativa.

32. The method of any one of claim 28-31, wherein the step of administering comprises subcutaneous administration.

33. The method of any one of claims 28-31, wherein the step of administering comprises intravenous administration. 54 IPTS / 128625283.1

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