Human il-17 binding polypeptides

Abstract

Provided are de novo designed human IL-17 (hIL-17) binding polypeptides, compositions thereof, and methods for their use in treating subjects. The provided compositions can modulate the interaction of hIL-17 with the hIL-17 receptor, and can be used in the management of inflammatory disorders including psoriasis, psoriatic arthritis, ankylosing spondylitis, active non-radiographic axial spondyloarthritis, multiple sclerosis, asthma, and rheumatoid arthritis.

Description

[0001] HUMAN IL-17 BINDING POLYPEPTIDES

[0002] RELATED APPLICATIONS

[0003] Benefit of priority is claimed to U.S. provisional application Serial No. 63 / 638,118, entitled “Human IL- 17 Binding Polypeptides,” filed on April 24, 2024, to inventors Franziska SEEGER, Stephanie BERGER, David BAKER, Lauren Miller ARGUINCHONA, Lance Joseph STEWART, Alyssa BLACKSTONE, and Catherine SNIEZEK, and applicants Mopac Biologies, Inc. and University of Washington. Where permitted, the subject matter of this application is incorporated by reference in its entirety.

[0004] INCORPORATION BY REFERENCE OF SEQUENCE LISTING PROVIDED ELECTRONICALLY

[0005] An electronic version of the Sequence Listing is filed herewith, the contents of which are incorporated by reference in their entirety. The electronic file was created on April 24, 2025, is 76,718 bytes in size, and is titled 605SEQPCl.xml. BACKGROUND

[0006] The hIL-17 family pro-inflammatory cytokines play a critical role in autoinflammatory diseases. They are expressed by T helper type 17 (Thl7) cells, which interact with the hIL-17R family of cell surface receptors. The hIL-17 cytokines include hIL-17A-F, and the hIL-17R cell surface receptors include hlL- 17RA-RE. hIL-17R is a transmembrane receptor complex usually consisting of one hIL-17RA and one other hIL-17R subunit. hIL-17A and homolog hIL-17F can each form homodimers, and can form a hIL-17A / hIL-17F heterodimer. These dimers interact with the heterodimeric hIL-17 receptor complex composed of hIL-17RA and hIL-17RC, to stimulate production of pro-inflammatory cytokines including TNF- alpha, IL-6 and GM-CSF. These pro-inflammatory cytokines are involved in autoimmune conditions including psoriasis, psoriatic arthritis, ankylosing spondylitis, active non-radiographic axial spondyloarthritis, multiple sclerosis, asthma, and rheumatoid arthritis. Monoclonal antibodies targeting the hIL-17 cytokine-receptor interaction have been developed. There is a need for effective antagonists of the hlL- 17 ligand-receptor interaction that can be easily produced and administered. SUMMARY

[0007] Provided are small, easily manufactured, high-affinity and high-avidity de novo designed human IL- 17 (hIL-17) binding polypeptides, compositions thereof, and methods for their use. The hIL-17 binding polypeptide compositions provided herein can comprise a single hIL-17 binding polypeptide designed as described herein, or they can be high-avidity multimeric compositions comprising a fusion of two or more such hIL-17 binding polypeptides. Such a multimeric hIL-17 binding polypeptide composition can bind hIL-17 with high avidity relative to a non-multimeric hIL-17 binding polypeptide composition that comprises a single hIL-17 binding polypeptide. The provided hIL-17 binding polypeptide compositions can be used to treat subjects in need thereof, e.g., to modulate activities resulting from the interaction of hIL-17 with the hIL-17 receptor. A subject can have an hIL-17-r elated inflammatory disorder, e.g., psoriasis, psoriatic arthritis, ankylosing spondylitis, active nonradiographic axial spondyloarthritis, multiple sclerosis, asthma, and rheumatoid arthritis.

[0008] The present invention relates to a human IL- 17 (hIL-17) binding polypeptide composition, having a general formula from N-terminus to C-terminus, A-(linker-B)n, wherein: n=0 to 10; A is a polypeptide of the formula (X1-X2-X3-X4-X5-X6-X7-X8- X9-X10-X11); in A, XI, X2, X3, X4, X5, X6, X7, X8, X10, and XI 1, are optional; X9 comprises a polypeptide domain of 12-20 amino acids in length; X9 comprises an amino acid sequence of residues 42-51 of the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 1, 3, 4, 5, 6, 7, 34, 35, 36, 38, 64, 66, 71, 73, 74, and 77, wherein X9 can comprise at least one conservative amino acid substitution in residues 42-51 relative to the selected amino acid sequence, and wherein X9 can have 50% to 100% identity to residues 42-51 of the selected amino acid sequence; and B is a polypeptide of the formula (Xr-X2’-X3’-X4’-X5’-X6’-X7’-X8’-X9’-X10’- X1 L).

[0009] In some embodiments, when n=l-10: X9’ is present in B and comprises a polypeptide domain of 12-20 amino acids in length; X9’ comprises a polypeptide domain of 12-20 amino acids in length; X9’ comprises an amino acid sequence of residues 42-51 of the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 1, 3, 4, 5, 6, 7, 34, 35, 36, 38, 64, 66, 71, 73, 74, and 77, wherein X9’ can comprise at least one conservative amino acid substitution in residues 42-51 relative to the selected amino acid sequence, and X9’ can have 50% to 100% identity to residues 42-51 of the selected amino acid sequence.

[0010] In some embodiments, in A, X9 and any combination of XI, X2, X3, X4, X5, X6, X7, X8, X10, XI 1, are present. In some embodiments, n=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1-5, or 1-10. In some embodiments, in B, X9 is present, and further wherein XI’, X2’, X3’, X4’, X5’, X6’, X7’, X8’, X10’, XI 1,’ or any combination thereof, is present. In some embodiments, A and B have the same amino acid sequence. In some embodiments, A and B have different amino acid sequences.

[0011] In some embodiments: XI, when present, comprises a polypeptide domain of 1-7 amino acids in length; XI’, when present, comprises a polypeptide domain of 1-7 amino acids in length; X2, when present, comprises a polypeptide domain of 1-2 amino acids in length; X2’ , when present, comprises a polypeptide domain of 1-2 amino acids in length; X3, when present, comprises a polypeptide domain of 1-11 amino acids in length; X3’, when present, comprises a polypeptide domain of 1-11 amino acids in length; X4, when present, comprises a polypeptide domain of 1-2 amino acids in length; X4’, when present, comprises a polypeptide domain of 1-2 amino acids in length; X5, when present, comprises a polypeptide domain of 1-4 amino acids in length; X5’, when present, comprises a polypeptide domain of 1-4 amino acids in length; X6, when present, comprises a polypeptide domain of 1-4 amino acids in length; X6’, when present, comprises a polypeptide domain of 1-4 amino acids in length; X7, when present, comprises a polypeptide domain of 1-6 amino acids in length; X7’, when present, comprises a polypeptide domain of 1-6 amino acids in length; X8, when present, comprises a polypeptide domain of 1-2 amino acids in length; X8’, when present, comprises a polypeptide domain of 1-2 amino acids in length; X9’, when present, comprises a polypeptide domain of 12-20 amino acids in length; X10, when present, comprises a polypeptide domain of 1-2 amino acids in length; X10’, when present, comprises a polypeptide domain of 1-2 amino acids in length; XI 1, when present, comprises a polypeptide domain 1-7 amino acids in length; and XI 1’, when present, comprises a polypeptide domain 1-7 amino acids in length. In some embodiments: XI, when present, comprises an amino acid sequence of residues 1-7 of the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 1, 3, 4, 5, 6, 7, 34, 35, 36, 38, 64, 66, 71, 73, 74, and 77, wherein XI can comprise at least one conservative amino acid substitution in residues 1-7 relative to the selected amino acid sequence, and wherein XI can have 50% to 100% identity to residues 1-7 of the selected amino acid sequence; XI’, when present, comprises an amino acid sequence of residues 1-7 of the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 1, 3, 4, 5, 6, 7, 34, 35, 36, 38, 64, 66, 71, 73, 74, and 77, wherein XI’ can comprise at least one conservative amino acid substitution in residues 1-7 relative to the selected amino acid sequence, and wherein XI’ can have 50% to 100% identity to residues 1-7 of the selected amino acid sequence; X2, when present, comprises an amino acid sequence of residues 8-9 of the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 1, 3, 4, 5, 6, 7, 34, 35, 36, 38, 64, 66, 71, 73, 74, and 77, wherein X2 can comprise at least one conservative amino acid substitution in residues 8-9 relative to the selected amino acid sequence, and wherein X2 can have 50% to 100% identity to residues 8-9 of the selected amino acid sequence; X2’, when present, comprises an amino acid sequence of residues 8-9 of the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 1, 3, 4, 5, 6, 7, 34, 35, 36, 38, 64, 66, 71, 73, 74, and 77, wherein X2’ can comprise at least one conservative amino acid substitution in residues 8-9 relative to the selected amino acid sequence, and wherein X2’ can have 50% to 100% identity to residues 8-9 of the selected amino acid sequence; X3, when present, comprises an amino acid sequence of residues 10-20 of the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 1, 3, 4, 5, 6, 7, 34, 35, 36, 38, 64, 66, 71, 73, 74, and 77, wherein X3 can comprise at least one conservative amino acid substitution in residues 10-20 relative to the selected amino acid sequence, and wherein X3 can have 50% to 100% identity to residues 10-20 of the selected amino acid sequence; X3’, when present, comprises an amino acid sequence of residues 10-20 of the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 1, 3, 4, 5, 6, 7, 34, 35, 36, 38, 64, 66, 71, 73, 74, and 77, wherein X3’ can comprise at least one conservative amino acid substitution in residues 10-20 relative to the selected amino acid sequence, and wherein X3’ can have 50% to 100% identity to residues 10-20 of the selected amino acid sequence; X4, when present, comprises an amino acid sequence of residues 21-22 of the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 1, 3, 4, 5, 6, 7, 34, 35, 36, 38, 64, 66, 71, 73, 74, and 77, wherein X4 can comprise at least one conservative amino acid substitution in residues 21-22 relative to the selected amino acid sequence, and wherein X4 can have 50% to 100% identity to residues 21-22 of the selected amino acid sequence; X4’, when present, comprises an amino acid sequence of residues 21-22 of the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 1, 3, 4, 5, 6, 7, 34, 35, 36, 38, 64, 66, 71, 73, 74, and 77, wherein X4' can comprise at least one conservative amino acid substitution in residues 21-22 relative to the selected amino acid sequence, and wherein X4’ can have 50% to 100% identity to residues 21-22 of the selected amino acid sequence; X5, when present, comprises an amino acid sequence of residues 23-26 of the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 1, 3, 4, 5, 6, 7, 34, 35, 36, 38, 64, 66, 71, 73, 74, and 77, wherein X5 can comprise at least one conservative amino acid substitution in residues 23-26 relative to the selected amino acid sequence, and wherein X5 can have 50% to 100% identity to residues 23-26 of the selected amino acid sequence; X5’, when present, comprises an amino acid sequence of residues 23-26 of the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 1, 3, 4, 5, 6, 7, 34, 35, 36, 38, 64, 66, 71, 73, 74, and 77, wherein X5’ can comprise at least one conservative amino acid substitution in residues 23-26 relative to the selected amino acid sequence, and wherein X5’ can have 50% to 100% identity to residues 23-26 of the selected amino acid sequence; X6, when present, comprises an amino acid sequence of residues 27- 30 of the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 1, 3, 4, 5, 6, 7, 34, 35, 36, 38, 64, 66, 71, 73, 74, and 77, wherein X6 can comprise at least one conservative amino acid substitution in residues 27-30 relative to the selected amino acid sequence, and wherein X6 can have 50% to 100% identity to residues 27-30 of the selected amino acid sequence; X6’, when present, comprises an amino acid sequence of residues 27-30 of the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 1, 3, 4, 5, 6, 7, 34, 35, 36, 38, 64, 66, 71, 73, 74, and 77, wherein X6’ can comprise at least one conservative amino acid substitution in residues 27-30 relative to the selected amino acid sequence, and wherein X6’ can have 50% to 100% identity to residues 27-30 of the selected amino acid sequence; X7, when present, comprises an amino acid sequence of residues 31- 36 of the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 1, 3, 4, 5, 6, 7, 34, 35, 36, 38, 64, 66, 71, 73, 74, and 77, wherein X7 can comprise at least one conservative amino acid substitution in residues 31-36 relative to the selected amino acid sequence, and wherein X7 can have 50% to 100% identity to residues 31-36 of the selected amino acid sequence; X7’, when present, comprises an amino acid sequence of residues 31-36 of the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 1, 3, 4, 5, 6, 7, 34, 35, 36, 38, 64, 66, 71, 73, 74, and 77, wherein X7’ can comprise at least one conservative amino acid substitution in residues 31-36 relative to the selected amino acid sequence, and wherein X7’ can have 50% to 100% identity to residues 31-36 of the selected amino acid sequence; X8, when present, comprises an amino acid sequence of residues 37- 38 of the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 1, 3, 4, 5, 6, 7, 34, 35, 36, 38, 64, 66, 71, 73, 74, and 77, wherein X8 can comprise at least one conservative amino acid substitution in residues 37-38 relative to the selected amino acid sequence, and wherein X8 can have 50% to 100% identity to residues 37-38 of the selected amino acid sequence; X8’, when present, comprises an amino acid sequence of residues 37-38 of the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 1, 3, 4, 5, 6, 7, 34, 35, 36, 38, 64, 66, 71, 73, 74, and 77, wherein X8’ can comprise at least one conservative amino acid substitution in residues 37-38 relative to the selected amino acid sequence, and wherein X8’ can have 50% to 100% identity to residues 37-38 of the selected amino acid sequence; X9’, when present, comprises an amino acid sequence of residues 42- 51 of the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 1, 3, 4, 5, 6, 7, 34, 35, 36, 38, 64, 66, 71, 73, 74, and 77, wherein X9’ can comprise at least one conservative amino acid substitution in residues 42-51 relative to the selected amino acid sequence, and wherein X9’ can have 50% to 100% identity to residues 42-51 of the selected amino acid sequence; X10, when present, comprises an amino acid sequence of residues 53-54 of the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 1, 3, 4, 5, 6, 7, 34, 35, 36, 38, 64, 66, 71, 73, 74, and 77, wherein XI 0 can comprise at least one conservative amino acid substitution in residues 53-54 relative to the selected amino acid sequence, and wherein X10 can have 50% to 100% identity to residues 53-54 of the selected amino acid sequence; X10’, when present; comprises an amino acid sequence of residues 53- 54 of the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 1, 3, 4, 5, 6, 7, 34, 35, 36, 38, 64, 66, 71, 73, 74, and 77, wherein X10’ can comprise at least one conservative amino acid substitution in residues 53-54 relative to the selected amino acid sequence, and wherein XI 0’ can have 50% to 100% identity to residues 53-54 of the selected amino acid sequence; XI 1, when present, comprises an amino acid sequence of residues 55-61 of the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 1, 3, 4, 5, 6, 7, 34, 35, 36, 38, 64, 66, 71, 73, 74, and 77, wherein XI 1 can comprise at least one conservative amino acid substitution in residues 55-61 relative to the selected amino acid sequence, and wherein XI 1 can have 50% to 100% identity to residues 55-61 of the selected amino acid sequence; and XI 1 ’, when present, comprises an amino acid sequence of residues 55-61 of the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 1, 3, 4, 5, 6, 7, 34, 35, 36, 38, 64, 66, 71, 73, 74, and 77, wherein XU ’ can comprise at least one conservative amino acid substitution in residues 55-61 relative to the selected amino acid sequence, and wherein XI E can have 50% to 100% identity to residues 55-61 of the selected amino acid sequence.

[0012] In some embodiments: A comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in a sequence selected from SEQ ID NO: 71, SEQ ID NO: 73, SEQ ID NO: 74, and SEQ ID NO: 77; B, when present, B comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in a sequence selected from SEQ ID NO: 71, SEQ ID NO: 73, SEQ ID NO: 74, and SEQ ID NO: 77; and optionally wherein 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more of the N-terminal amino acids are deleted from the reference polypeptide and the deleted amino acids are not considered in the percent identity.

[0013] In some embodiments: A comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in a sequence selected from SEQ ID NOs: 8-38 and 63-66; B, when present, B comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in a sequence selected from ID NOs: 8-38 and 63-66; and optionally wherein 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more of the N-terminal amino acids are deleted from the reference polypeptide and the deleted amino acids are not considered in the percent identity.

[0014] In some embodiments, X9 comprises an alpha helix. In some embodiments: XI, when present, comprises a beta strand; XI ’, when present, comprises a beta strand; X2, when present, comprises a loop; X2’ , when present, comprises a loop; X3, when present, comprises an alpha helix; X3’, when present, comprises an alpha helix; X4, when present, comprises a loop; X4’, when present, comprises a loop; X5, when present, comprises a beta strand; X5’, when present, comprises a beta strand; X6, when present, comprises a loop; X6’, when present, comprises a loop; X7, when present, comprises a beta strand; X7’, when present, comprises a beta strand; X8, when present, comprises a loop; X8’, when present, comprises a loop; X9 comprises an alpha helix; X9’, when present, comprises an alpha helix; XI 0, when present, comprises a loop; XI O’, when present, comprises a loop; XI 1, when present, comprises a beta strand; and XI 1’, when present, comprises a beta strand. In some embodiments, X9 comprises an alpha helix, wherein X3 is present and comprises an alpha helix, and wherein when X9’ is present, X9’ comprises an alpha helix and X3’ is present and comprises an alpha helix. In some embodiments, X9 comprises an alpha helix, XI, X5, X7, and XI 1 are present and each comprises a beta strand, and when X9’ is present, X9’ comprises an alpha helix and XI’, X5’, X7’, and XI 1’ are present and each comprises a beta strand.

[0015] In some embodiments, each of XI, X2, X3, X4, X5, X6, X7, X8, X9, X10, and XI 1 are present, wherein: XI comprises an amino acid sequence at least 50%, 70%, 85%, or 100% identical to the amino acid sequence of an XI domain present in any of SEQ ID NOs: 8-38 and 63-66; X2 comprises an amino acid sequence at least 50%, 75%, or 100% identical to the amino acid sequence of an X2 domain present in any of SEQ ID NOs: 8-38 and 63-66; X3 comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of an X3 domain present in any of SEQ ID NOs: 8-38 and 63-66; X4 comprises an amino acid sequence at least 50%, 75%, or 100% identical to the amino acid sequence of an X4 domain present in any of SEQ ID NOs: 8-38 and 63-66; X5 comprises an amino acid sequence at least 50%, 75%, or 100% identical to the amino acid sequence of an X5 domain present in any of SEQ ID NOs: 8-38 and 63-66; X6 comprises an amino acid sequence at least 50%, 75%, or 100% identical to the amino acid sequence of an X6 domain present in any of SEQ ID NOs: 8-38 and 63-66; X7 comprises an amino acid sequence at least 50%, 70%, 85%, or 100% identical to the amino acid sequence of an X7 domain present in any of SEQ ID NOs: 8-38 and 63-66; X8 comprises an amino acid sequence at least 50%, 75%, or 100% identical to the amino acid sequence of an X8 domain present in any of SEQ ID NOs: 8-38 and 63-66; X9 comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of an X9 domain present in any of SEQ ID NOs: 8-38 and 63-66; X10 comprises an amino acid sequence at least 50%, 75%, or 100% identical to the amino acid sequence of an X10 domain present in any of SEQ ID NOs: 8-38 and 63-66; and XI 1 comprises an amino acid sequence at least 50%, 70%, 85%, or 100% identical to the amino acid sequence of an XI 1 domain present in any of SEQ ID NOs: 8-38 and 63-66.

[0016] In some embodiments, each of XI’, X2’, X3’, X4’, X5’, X6’, X7’, X8’, X9’, X10’, and XI E are present, wherein: XI’ comprises an amino acid sequence at least 50%, 70%, 85%, or 100% identical to the amino acid sequence of an XI domain present in any of SEQ ID NOs: 8-38 and 63-66; X2’ comprises an amino acid sequence at least 50%, 75%, or 100% identical to the amino acid sequence of an X2 domain present in any of SEQ ID NOs: 8-38 and 63-66; X3’ comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of an X3 domain present in any of SEQ ID NOs: 8-38 and 63-66; X4’ comprises an amino acid sequence at least 50%, 75%, or 100% identical to the amino acid sequence of an X4 domain present in any of SEQ ID NOs: 8-38 and 63-66; X5’ comprises an amino acid sequence at least 50%, 75%, or 100% identical to the amino acid sequence of an X5 domain present in any of SEQ ID NOs: 8-38 and 63-66; X6’ comprises an amino acid sequence at least 50%, 75%, or 100% identical to the amino acid sequence of an X6 domain present in any of SEQ ID NOs: 8-38 and 63-66; X7’ comprises an amino acid sequence at least 50%, 70%, 85%, or 100% identical to the amino acid sequence of an X7 domain present in any of SEQ ID NOs: 8-38 and 63-66; X8’ comprises an amino acid sequence at least 50%, 75%, or 100% identical to the amino acid sequence of an X8 domain present in any of SEQ ID NOs: 8-38 and 63-66; X9’ comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of an X9 domain present in any of SEQ ID NOs: 8-38 and 63-66; X10’ comprises an amino acid sequence at least 50%, 75%, or 100% identical to the amino acid sequence of an X10 domain present in any of SEQ ID NOs: 8-38 and 63-66; and XI E comprises an amino acid sequence at least 55%, 70%, 85%, or 100% identical to the amino acid sequence of an XI 1 domain present in any of SEQ ID NOs: 8-38 and 63-66.

[0017] In some embodiments: (i) in A, XI, X5, X7, and XI 1 are present and each comprises a beta strand, and X3 and X9 are present and each comprises an alpha helix; or (ii) n=l-10, wherein in A, XI, X5, X7 and XI 1 are present and each comprises a beta strand, and X3 and X9 are present and each comprises an alpha helix, and wherein in B, XI’, X5’, X7’ and XI 1’ are present and each comprises a beta strand, and X3’ and X9’ are present and each comprises an alpha helix. In some embodiments, in A, XI, X2, X3, X4, X5, X6, X7, X8, X10, and XI 1, or any combination thereof, are present in addition to X9. In some embodiments, in B, XI’, X2’, X3’, X4’, X5’, X6’, X7’, X8’, X9’, X10’, XI F, or any combination thereof, are present.

[0018] In some embodiments, one or more additional functional domains added at the N-terminus of the polypeptide, the C-terminus of the polypeptide, or both.

[0019] In some embodiments, in A, X9 comprises the amino acid sequence of residues 42-51 in the amino acid sequence selected from the group consisting of SEQ ID NOs: 21 and 30, and in B, when present, X9’ comprises the amino acid sequence of residues 42-51 in the amino acid sequence selected from the group consisting of SEQ ID NOs: 21 and 30. In some embodiments, the hIL-17 binding polypeptide composition comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in a sequence selected from SEQ ID NO: 21 and 30, optionally wherein 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more of the N-terminal amino acids are deleted from the selected polypeptide amino acid sequence and the deleted amino acids are not considered in the percent identity.

[0020] In some embodiments, n=l-10, wherein: A comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in a sequence selected from SEQ ID NOs: 21 and 30; B comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in a sequence selected from SEQ ID NOs: 21 and 30; optionally wherein 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more of the N-terminal amino acids are deleted from the selected amino acid sequence comprised by A, B, or from both A and B, wherein the deleted amino acids are not considered in the percent identity of A, B, or both, respectively, to the selected amino acid sequence; and the amino acid sequence of A can be 90% to 100% identical to the amino acid sequence of B.

[0021] In some embodiments, the hIL-17 binding polypeptide composition comprises at least one disulfide bond between two cysteine residues in the polypeptide, wherein: when A is present and B is not present, the at least one disulfide bond occurs within A; and when both A and B are present, the binding polypeptide composition comprises at least two disulfide bonds, wherein at least one of the at least two disulfide bonds is within A, and at least one of the at least two disulfide bonds is within B.

[0022] In some embodiments, the hIL-17 binding polypeptide composition has the amino acid sequence set forth in a sequence selected from SEQ ID NOs: 26-33, wherein: the amino acid sequence of the binding polypeptide composition can have at least 1-20 conservative substitutions relative to the amino acid sequence of the selected amino acid sequence, wherein cysteine residues are preserved in the substituted amino acid sequence; and the amino acid sequence of the binding polypeptide composition can have 50% to 100% identity to the selected amino acid sequence, wherein cysteine residues are preserved in the amino acid sequence of the binding polypeptide composition having 50% to 100% identity to the selected amino acid sequence, optionally wherein 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more of the N- terminal amino acids are deleted from the selected amino acid sequence, wherein the deleted amino acids are not considered in the percent identity to the selected amino acid sequence.

[0023] In some embodiments, the hIL-17 binding polypeptide composition has an amino acid sequence set forth as any one of: SEQ ID NO: 26, disulfide bonded between C6 and C56; SEQ ID NO: 27, disulfide bonded between C13 and C32; SEQ ID NO: 28, disulfide bonded between C3 and C35; SEQ ID NO: 29, disulfide bonded between C3 and C35, and between C13 and C32; SEQ ID NO: 30, disulfide bonded between C3 and C35; SEQ ID NO: 31, disulfide bonded between C6 and C56; SEQ ID NO: 32, disulfide bonded between C13 and C24; SEQ ID NO: 33, disulfide bonded between C6 and C56, and between C13 and C24; SEQ ID NO: 56, disulfide bonded between C6 and C33; SEQ ID NO: 57, disulfide bonded between C7 and C40; SEQ ID NO: 58, disulfide bonded between C6 and C33; SEQ ID NO: 59, disulfide bonded between C6 and C33, and between C70 and C97; SEQ ID NO: 60, disulfide bonded between C6 and C33, and between C74 and C101; SEQ ID NO: 61, disulfide bonded between C6 and C33, and between C86 and Cl 13; and SEQ ID NO: 62, disulfide bonded between C6 and C33, and between Cl 10 and C137.

[0024] In some embodiments, the linker is an amino acid linker, optionally wherein the linker is about 1 to about 100 amino acids in length. In some embodiments, the linker is selected from a linker having the formula (G4S)n, L(G4S)n, (GS)n, L(GS)n, (Gly)n, L(Gly)n, (EAAAK)n, L(EAAAK)n, (PAS)n, or L(PAS)n, wherein n=l-100. In some embodiments, the linker has the amino acid sequence set forth in any of SEQ ID NOs: 67-70 and 79-82.

[0025] In some embodiments, the hIL-17 binding polypeptide composition binds a target with high specificity, high avidity, and / or high affinity. The target can be hlL- 17. The target can be hIL-17A or hIL-17F. In some embodiments, the polypeptide is an hIL-17 antagonist or an hIL-17 agonist. In some embodiments, the polypeptide is an hIL-17 antagonist. In some embodiments, an assay is used to evaluate an activity of the hIL-17 binding polypeptide. In some embodiments, the activity is a binding parameter, e.g., specificity, avidity, or affinity, or the activity is potency. In some embodiments, the activity assay is a binding specificity assay that measures the ability of the binding polypeptide composition to inhibit binding of an hIL-17 to an hIL-17 receptor. In some embodiments, the activity assay is a cell signaling assay. In some embodiments, the activity is compared to a control. In some embodiments, the control is selected from: any hIL-17 binding composition known in the art or described herein, e.g., an original or parent hIL-17 binding polypeptide, an antibody, peptide, small molecule, or other compound selected by a skilled artisan for comparison with the hIL-17 binding polypeptide composition. In some embodiments, the binding polypeptide comprises A and not B, or A and B, wherein the binding polypeptide composition reduces stimulation of an hIL-17 receptor by hIL-17 by about 75 percent to about 100 percent at an IC50 of about 1.5 nM to about 0.1 pM. The IC50 can be determined by any methods known to those of skill in the art, including by an assay in which an IL-17 concentration was previously determined for use as a baseline. In some embodiments, the binding polypeptide composition comprises A and B, and blocks hIL-17-mediated cell signaling with a greater potency than a binding polypeptide composition comprising A and not B. In some embodiments, the binding polypeptide composition comprises A and B, and blocks hIL-17-mediated cell signaling with a potency of 10-fold to 10,000-fold greater than a binding polypeptide composition comprising A and not B. In some embodiments, the binding polypeptide comprises A and B, and wherein the binding polypeptide composition blocks hIL-17- mediated cell signaling with a potency of 2-fold to 250-fold greater than that of a clinical hIL-17 binding monoclonal antibody. In some embodiments, the binding polypeptide comprises A and B, and wherein the binding polypeptide composition reduces stimulation of an hIL-17 receptor by hIL-17 by about 75 percent to about 100 percent at an IC50 of about 150 pM to about 0.1 pM. In some embodiments, the binding polypeptide composition reduces stimulation of an hIL-17 receptor by hIL-17 by about 75 percent to about 100 percent at an IC50 of less than about 0.6 pM, less than about 1 pM, less than about 1.5 pM, less than about 2 pM, less than about 2.5 pM, less than about 3 pM, less than about 5 pM, less than about 10 pM, less than about 25 pM, less than about 50 pM, less than about 75 pM, or less than about 100 pM, less than about 150 pM, less than about 350 pM, less than about 500 pM, less than about 1 nM, or less than about 1.5 nM.

[0026] In some embodiments, the clinical hIL-17 binding monoclonal antibody is selected from: secukinumab, ixekizumab, brodalumab, and bimekizumab. In some embodiments, the hIL-17 is hIL-17A or hIL-17F. In some embodiments, the hIL-17 is hIL-17A, and wherein X9, X9’, or both, comprises the amino acid sequence of residues 42-51 set forth in a sequence selected from SEQ ID NOs: 71, 73, 74, and 77, wherein: X9, X9’, or both, of the binding polypeptide composition can have at least one conservative substitution relative to residues 42-51 of the selected amino acid sequence; and X9, X9’, or both, the binding polypeptide composition can have 50% to 100% identity to residues 42-51 of the selected amino acid sequence.

[0027] In some embodiments, the hIL-17 is hIL-17A and X9, X9’, or both, comprises an amino acid sequence of residues 42-51 of the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 8-33 and 63, wherein: X9, X9’, or both, of the binding polypeptide composition can have at least one conservative substitution relative to residues 42-51 of the selected amino acid sequence; and X9, X9’, or both, of the binding polypeptide composition can have 50% to 100% identity to residues 42-51 of the selected amino acid sequence. In some embodiments, the hIL-17 is hlL- 17A and the binding polypeptide composition comprises the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 8-33 and 63, wherein: the binding polypeptide composition can have at least 1-20 conservative substitutions relative to the amino acid sequence of the selected amino acid sequence; and the binding polypeptide composition can have 50% to 100% identity to the selected amino acid sequence, optionally wherein 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more of the N-terminal amino acids are deleted from the selected amino acid sequence, wherein the deleted amino acids are not considered in the percent identity to the selected amino acid sequence.

[0028] In some embodiments, the hIL-17 is hIL-17F and X9 comprises the amino acid sequence of residues 42-51 in the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 4, 5, 6, 7, 34-38, and 64-66, wherein: the binding polypeptide composition can have at least one conservative substitution relative to residues 42-51 of the selected amino acid sequence; and the binding polypeptide composition can have 50% to 100% identity to residues 42-51 of the selected amino acid sequence. In some embodiments, the hIL-17 is hIL-17F and the binding polypeptide composition comprises the amino acid sequence set forth in any one of: SEQ ID NOs: 4, 5, 6, 7, 34-38, and 64-66, wherein: the binding polypeptide composition can have at least 1-20 conservative substitutions relative to the amino acid sequence of the selected amino acid sequence; and the binding polypeptide composition can have 50% to 100% identity to the selected amino acid sequence, optionally wherein 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more of the N-terminal amino acids are deleted from the selected amino acid sequence, wherein the deleted amino acids are not considered in the percent identity to the selected amino acid sequence. In some embodiments, the hIL-17 is hIL-17F and the hIL-17F binding polypeptide composition X9 comprises the amino acid sequence of residues 42-51 set forth in a sequence selected from: SEQ ID NOs: 5, 6, and 7, wherein: the binding polypeptide composition can have at least one conservative substitution relative to residues 42-51 of the selected amino acid sequence; and the binding polypeptide composition can have 50% to 100% identity to residues 42-51 of the selected amino acid sequence. In some embodiments, the hIL-17 is hIL-17F and the hIL-17F binding polypeptide composition comprises the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 5, 6, and 7, wherein: the binding polypeptide composition can have at least 1-20 conservative substitutions relative to the amino acid sequence of the selected amino acid sequence; and the binding polypeptide composition can have 50% to 100% identity to the selected amino acid sequence, optionally wherein 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more of the N-terminal amino acids are deleted from the selected amino acid sequence, wherein the deleted amino acids are not considered in the percent identity to the selected amino acid sequence. In some embodiments, the hlL- 17 is hIL-17F and the hIL-17F binding polypeptide composition X9 comprises the amino acid sequence of residues 42-51 set forth in a sequence selected from: SEQ ID NOs: 34-38 and 64-66, wherein: the binding polypeptide composition can have at least one conservative substitution relative to residues 42-51 of the selected amino acid sequence; and the binding polypeptide composition can have 50% to 100% identity to residues 42-51 of the selected amino acid sequence. In some embodiments, the receptor is an hIL-17 receptor. In some embodiments, the receptor is hIL-17RA and / or hIL-17RC. In some embodiments, the hIL-17 binding polypeptide composition further comprises one or more additional functional domains added at the N-terminus and / or the C-terminus. In some embodiments, the binding polypeptide composition binds hIL-17 at a KD of about 0.1 pM to about 1.5 nM. In some embodiments, when n=l-10, each of A and B binds hIL-17 at a KD of about 0.1 pM to about 1.5 nM. In some embodiments, n=l or more, and B comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a selected amino acid sequence, wherein the selected amino acid sequence is A, optionally wherein 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more of the N-terminal amino acids are deleted from the selected amino acid sequence and the deleted amino acids are not considered in the percent identity. In some embodiments, amino acid changes from the selected amino acid sequence are conservative substitutions.

[0029] In addition, the present invention relates to a human IL-17 (hIL-17) binding polypeptide composition, comprising a polypeptide of the general formula from N- terminus to C terminus, A-(linker-B)n, wherein: n=0-10; A is a polypeptide of the formula (X1-X2-X3-X4-X5); in A, XI, X2, X4, and X5 are optional; X3 comprises a polypeptide domain of 9-15 amino acids in length; X3 comprises the amino acid sequence of residues 19-27 of the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 2, 72, 75, 76, and 78; wherein X3 can comprise at least one conservative amino acid substitution in residues 19-27 relative to the selected amino acid sequence, and wherein X3 can have 50% to 100% identity to residues 19- 27 of the selected amino acid sequence; and B is a polypeptide of the formula (XL- X2’-X3’-X4’-X5’).

[0030] In some embodiments, when n=l-10: X3’ is present and comprises a polypeptide domain of 9-15 amino acids in length; X3’ comprises the amino acid sequence of residues 19-27 a sequence selected from SEQ ID NOs: 2, 72, 75, 76, and 78, wherein X3 can comprise at least one conservative amino acid substitution in residues 19-27 relative to the selected amino acid sequence, and wherein X3 can have 50% to 100% identity to residues 19-27 of the selected amino acid sequence. In some embodiments, X3 and any combination of XI, X2, X4, and X5, are present. In some embodiments, n=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1-5, or 1-10. In some embodiments, in B, XI’, X2’, X3’, X4’, X5,’ or any combination thereof, are present. In some embodiments, A and B have the same amino acid sequence. In some embodiments, A and B have different amino acid sequences.

[0031] In some embodiments: XI, when present, comprises a polypeptide domain of 1-13 amino acids in length; XI’, when present, comprises a polypeptide domain of 1- 13 amino acids in length; X2, when present, comprises a polypeptide domain of 1-4 amino acids in length; X2’ , when present, comprises a polypeptide domain of 1-4 amino acids in length; X3’, when present, comprises a polypeptide domain of 9-15 amino acids in length; X4, when present, comprises a polypeptide domain of 1-3 amino acids in length; X4’, when present, comprises a polypeptide domain of 1-3 amino acids in length; X5, when present, comprises a polypeptide domain of 1-13 amino acids in length; and X5’ , when present, comprises a polypeptide domain of 1- 13 amino acids in length.

[0032] In some embodiments: XI, when present, comprises a polypeptide having the amino acid sequence of residues 1-13 in the amino acid sequence set forth in a sequence selected from SEQ ID NOs: 2, 72, 75, 76, and 78, wherein XI can comprise at least one conservative amino acid substitution in residues 1-13 relative to the selected amino acid sequence, and wherein XI can have 50% to 100% identity to residues 1-13 of the selected amino acid sequence; XI’, when present, comprises a polypeptide having the amino acid sequence of residues 1-13 in the amino acid sequence set forth in a sequence selected from SEQ ID NOs: 2, 72, 75, 76, and 78, wherein XI ’ can comprise at least one conservative amino acid substitution in residues 1-13 relative to the selected amino acid sequence, and wherein XI’ can have 50% to 100% identity to residues 1-13 of the selected amino acid sequence; X2, when present, comprises a polypeptide having the amino acid sequence of residues 14-17 in the amino acid sequence set forth in a sequence selected from SEQ ID NOs: 2, 72, 75, 76, and 78, wherein X2 can comprise at least one conservative amino acid substitution in residues 14-17 relative to the selected amino acid sequence, and wherein X2 can have 50% to 100% identity to residues 14-17 of the selected amino acid sequence; X2’, when present, comprises a polypeptide having the amino acid sequence of residues 14-17 in the amino acid sequence set forth in a sequence selected from SEQ ID NOs: 2, 72, 75, 76, and 78, wherein X2’ can comprise at least one conservative amino acid substitution in residues 14-17 relative to the selected amino acid sequence, and wherein X2’ can have 50% to 100% identity to residues 14-17 of the selected amino acid sequence; X3’, when present, comprises a polypeptide having the amino acid sequence of residues 19-27 in the amino acid sequence set forth in a sequence selected from SEQ ID NOs: 2, 72, 75, 76, and 78, wherein X3’ can comprise at least one conservative amino acid substitution in residues 19-27 relative to the selected amino acid sequence, and wherein X3’ can have 50% to 100% identity to residues 19- 27 of the selected amino acid sequence; X4, when present, comprises a polypeptide having the amino acid sequence of residues 28-30 in the amino acid sequence set forth in a sequence selected from SEQ ID NOs: 2, 72, 75, 76, and 78, wherein X4 can comprise at least one conservative amino acid substitution in residues 28-30 relative to the selected amino acid sequence, and wherein X4 can have 50% to 100% identity to residues 28-30 of the selected amino acid sequence; X4’, when present, comprises a polypeptide having the amino acid sequence of residues 28-30 in the amino acid sequence set forth in a sequence selected from SEQ ID NOs: 2, 72, 75, 76, and 78, wherein X4’ can comprise at least one conservative amino acid substitution in residues 28-30 relative to the selected amino acid sequence, and wherein X4’ can have 50% to 100% identity to residues 28-30 of the selected amino acid sequence; X5, when present, comprises a polypeptide having the amino acid sequence of residues 31-43 in the amino acid sequence set forth in a sequence selected from SEQ ID NOs: 2, 72, 75, 76, and 78, wherein X5 can comprise at least one conservative amino acid substitution in residues 31-43 relative to the selected amino acid sequence, and wherein X5 can have 50% to 100% identity to residues 31-43 of the selected amino acid sequence; and X5’, when present, comprises a polypeptide having the amino acid sequence of residues 31-43 in the amino acid sequence set forth in a sequence selected from SEQ ID NOs: 2, 72, 75, 76, and 78, wherein X5’ can comprise at least one conservative amino acid substitution in residues 31-43 relative to the selected amino acid sequence, and wherein X5’ can have 50% to 100% identity to residues 31-43 of the selected amino acid sequence.

[0033] In some embodiments: A comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in a sequence selected from SEQ ID NO: 72, SEQ ID NO: 75, SEQ ID NO: 76, and SEQ ID NO: 78; B, when present, B comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in a sequence selected from SEQ ID NO: 72, SEQ ID NO: 75, SEQ ID NO: 76, and SEQ ID NO: 78; and optionally wherein 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more of the N-terminal amino acids are deleted from the reference polypeptide and the deleted amino acids are not considered in the percent identity.

[0034] In some embodiments: A comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in a sequence selected from SEQ ID NOs: 40-62; B, when present, comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in a sequence selected from SEQ ID NOs: 40-62; and optionally, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more of the N-terminal amino acids are deleted from the reference polypeptide and the deleted amino acids are not considered in the percent identity.

[0035] In some embodiments, X3 comprises an alpha helix. In some embodiments: XI, when present, comprises an alpha helix; XI’, when present, comprises an alpha helix; X2, when present, comprises a loop; X2’ , when present, comprises a loop; X3 comprises an alpha helix; X3’, when present, comprises an alpha helix; X4, when present, comprises a loop; X4’, when present, comprises a loop; X5, when present, comprises an alpha helix; and X5’, when present, comprises an alpha helix. In some embodiments, each of XI, X2, X3, X4, and X5 are present, wherein: XI comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of an XI domain present in any of SEQ ID NOs: 40-62; X2 comprises an amino acid sequence at least 50%, 75%, or 100% identical to the amino acid sequence of an X2 domain present in any of SEQ ID NOs: 40-62; X3 comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of an X3 domain present in any of SEQ ID NOs: 40-62; X4 comprises an amino acid sequence at least 50%, 75%, or 100% identical to the amino acid sequence of an X4 domain present in any of SEQ ID NOs: 40-62; and X5 comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of an X5 domain present in any of SEQ ID NOs: 40-62.

[0036] In some embodiments, each of XT, X2’, X3’, X4’, and X5’ are present, wherein: XI’ comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of an XI’ domain present in any of SEQ ID NOs: 40-62; X2’ comprises an amino acid sequence at least 50%, 75%, or 100% identical to the amino acid sequence of an X2’ domain present in any of SEQ ID NOs: 40-62; X3’ comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of an X3’ domain present in any of SEQ ID NOs: 40-62; X4’ comprises an amino acid sequence at least 50%, 75%, or 100% identical to the amino acid sequence of an X4’ domain present in any of SEQ ID NOs: 40-62; and X5’ comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of an X5’ domain present in any of SEQ ID NOs: 40-62.

[0037] In some embodiments: (i) in A, XI, X3 and X5 are present and each comprises an alpha helix; or (ii) n=l-10, wherein in A, XI, X3 and X5 are present and each comprises an alpha helix, and wherein in B, XI’, X3’, X5’ are present and each comprises an alpha helix. In some embodiments, in A, XI, X2, X3, X4, X5, or any combination thereof, are present in addition to X3. In some embodiments, in B, each of XI’, X2’, X3’, X4’, X5’, or any combination thereof, are present. In some embodiments, the hIL-17 binding polypeptide composition further comprises one or more additional functional domains added at the N-terminus of the polypeptide, the C -terminus of the polypeptide, or both. In some embodiments, in A, X3 comprises the amino acid sequence of residues 19-27 in the amino acid sequence selected from the group consisting of SEQ ID NOs: 54 and 58, and wherein in B, when present, X3 comprises the amino acid sequence of residues 19-27 in the amino acid sequence selected from the group consisting of SEQ ID NOs: 54 and 58.

[0038] In some embodiments, the hIL-17 binding polypeptide composition comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a reference polypeptide amino acid sequence selected from SEQ ID NOs: 54 and 58, optionally wherein 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more of the N-terminal amino acids are deleted from the selected polypeptide amino acid sequence and the deleted amino acids are not considered in the percent identity.

[0039] In some embodiments, n=l-10, wherein: A comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in a sequence selected from SEQ ID NOs: 54 and 58; B comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in a sequence selected from SEQ ID NOs: 54 and 58; optionally wherein 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more of the N-terminal amino acids are deleted from the selected amino acid sequence comprised by A, B, or from both A and B, wherein the deleted amino acids are not considered in the percent identity of A, B, or both, respectively, to the selected amino acid sequence; and the amino acid sequence of A can be 90% to 100% identical to the amino acid sequence of B.

[0040] In some embodiments, the hIL-17 binding polypeptide composition comprises at least one disulfide bond between two cysteine residues in the polypeptide, wherein: when A is present and B is not present, the at least one disulfide bond occurs within A; and when both A and B are present, the binding polypeptide composition comprises at least two disulfide bonds, wherein at least one of the at least two disulfide bonds is within A, and at least one of the at least two disulfide bonds is within B.

[0041] In some embodiments, the binding polypeptide composition has an amino acid sequence set forth as any of SEQ ID NOs: 56-62. In some embodiments, the linker is an amino acid linker, optionally wherein the linker is about 1 to about 100 amino acids in length. In some embodiments, the linker is selected from a linker having the formula (G4S)n, L(G4S)n, (GS)n, L(GS)n, (Gly)n, L(Gly)n, (EAAAK)n, L(EAAAK)n, (PAS)n, or L(PAS)n, wherein n=l-100. In some embodiments, the linker has the amino acid sequence set forth in any of SEQ ID NOs: 67-70 and 79-82.

[0042] In some embodiments, the binding polypeptide composition binds the target molecule with high specificity, high avidity, and / or high affinity. The target can be hIL-17. The target can be hIL-17A or hIL-17F. In some embodiments, the polypeptide is an hIL-17 antagonist or an hIL-17 agonist. In some embodiments, the polypeptide is an hIL-17 antagonist. In some embodiments, an assay is used to evaluate an activity of the hIL-17 binding polypeptide. In some embodiments, the activity is a binding parameter, e.g., specificity, avidity, or affinity, or the activity is potency. In some embodiments, the activity assay is a binding specificity assay that measures the ability of the binding polypeptide composition to inhibit binding of an hIL-17 to an hIL-17 receptor. In some embodiments, the activity assay is a cell signaling assay. In some embodiments, the activity is compared to a control. In some embodiments, the control is selected from: any hIL-17 binding composition known in the art or described herein, e.g., an original or parent hIL-17 binding polypeptide, an antibody, peptide, small molecule, or other compound selected by a skilled artisan for comparison with the hIL-17 binding polypeptide composition. In some embodiments, the binding polypeptide comprises A and not B, or A and B, wherein the binding polypeptide composition reduces stimulation of an hIL-17 receptor by hIL-17 by about 75 percent to about 100 percent at an IC50 of about 1.5 nM to about 0.1 pM. The IC50 can be determined by any methods known to those of skill in the art, including by an assay in which an IL-17 concentration was previously determined for use as a baseline. In some embodiments, the binding polypeptide composition comprises A and B, and the binding polypeptide composition blocks hIL-17-mediated cell signaling with a greater potency than a binding polypeptide composition comprising A and not B. In some embodiments, the binding polypeptide composition comprises A and B, and blocks hIL-17-mediated cell signaling with a potency of 10- fold to 10,000-fold greater than a binding polypeptide composition comprising A and not B. In some embodiments, the binding polypeptide composition comprises A and B, and wherein the binding polypeptide composition blocks hIL-17-mediated cell signaling with a potency of 2-fold to 250-fold greater than that of a clinical hIL-17 binding monoclonal antibody. In some embodiments, the binding polypeptide composition comprises A and B, and wherein the binding polypeptide composition reduces the stimulation of an hIL-17 receptor by hIL-17 by about 75 percent to about 100 percent at an IC50 of about 150 pM to about 0.1 pM. In some embodiments, the binding polypeptide composition reduces the stimulation of an hIL-17 receptor by hIL-17 by about 75 percent to about 100 percent at an IC50 of less than about 0.6 pM, less than about 1 pM, less than about 1.5 pM, less than about 2 pM, less than about 2.5 pM, less than about 3 pM, less than about 5 pM, less than about 10 pM, less than about 25 pM, less than about 50 pM, less than about 75 pM, or less than about 100 pM, less than about 150 pM, less than about 350 pM, less than about 500 pM, less than about 1 nM, or less than about 1.5 nM.

[0043] In some embodiments, the clinical hIL-17 binding monoclonal antibody is selected from: secukinumab, ixekizumab, brodalumab and bimekizumab. In some embodiments, the hIL-17 is hIL-17A or hIL-17F. In some embodiments, the hIL-17 is hIL-17A and X3, X3’, or both, of the binding polypeptide composition comprises the amino acid sequence of residues 19-27 set forth in a sequence selected from SEQ ID NOs: 72, 75, 76 or 78, wherein: X3, X3’, or both, of the binding polypeptide composition can have at least one conservative substitution relative to residues 19-27 of the selected amino acid sequence; and X3, X3’, or both, of the binding polypeptide composition can have 50% to 100% identity to residues 42-51 of the selected amino acid sequence. In some embodiments, the hIL-17 is hIL-17A and X3, X3’, or both, of the binding polypeptide composition comprises the amino acid sequence of residues 19-27 set forth in a sequence selected from SEQ ID NOs: 40-62, wherein: X3, X3’, or both, of the binding polypeptide composition can have at least one conservative substitution relative to residues 19-27 of the selected amino acid sequence; and X3, X3’, or both, of the binding polypeptide composition can have 50% to 100% identity to residues 19-27 of the selected amino acid sequence.

[0044] In some embodiments, the receptor is an hIL-17 receptor. In some embodiments, the receptor is hIL-17RA and / or hIL-17RC. In some embodiments, the hIL-17 binding polypeptide composition, further comprises one or more additional functional domains added at the N-terminus and / or the C-terminus of the polypeptide, preferably at the C-terminus. In some embodiments, the binding polypeptide composition binds hIL-17 at a KD of about 0.1 pM to about 1.5 nM. In some embodiments, when both A and B are present, each of A and B binds hIL-17 at a KD of 0.1 pM to about 1.5 nM.

[0045] In some embodiments, n=l or more, and B comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a selected amino acid sequence, wherein the selected amino acid sequence is A, optionally wherein 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more of the N-terminal amino acids are deleted from the selected amino acid sequence and the deleted amino acids are not considered in the percent identity. In some embodiments, the amino acid changes from the selected amino acid sequence are conservative substitutions.

[0046] In some embodiments, the hIL-17 binding polypeptide composition is a multimer of the formula A-linker-B-(linker-B)l-10.

[0047] The present invention also relates to a pharmaceutical composition comprising an hIL-17 binding polypeptide composition provided herein, comprising at least one excipient. The pharmaceutical composition can be formulated for oral, topical, subcutaneous, intradermal, intramuscular, intravenous, or intraarticular administration. In some embodiments, the pharmaceutical composition is formulated for topical administration and the excipient is selected from: water, a buffer, an absorption enhancer, a stability enhancer, di aminobutyroyl benzylamide, diacetate, glycerin, a gum, a hydrophilic colloid or derivative, a cellulosic derivative, an emulsifier, a fatty alcohol, an acrylic derivative, a mineral, a surfactant, a fat, an oil, a preservative, a monosaccharide, a disaccharide, a polysaccharide, a glycosaminoglycan, and a chelating agent.

[0048] Also provided herein are pharmaceutical composition comprising an hIL-17 binding polypeptide composition provided herein for use in treatment of a patient having a condition selected from: plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, active non-radiographic axial spondyloarthritis, hidradenitis suppurativa, atopic dermatitis, multiple sclerosis, asthma, and rheumatoid arthritis.

[0049] Methods of manufacturing the pharmaceutical compositions also are provided as are uses of the compositions for the formulating a medicament comprising the compositions. These method and uses comprise an hIL-17 binding polypeptide composition provided herein which are for treatment of a patient having a condition selected from: psoriasis, psoriatic arthritis, ankylosing spondylitis, active nonradiographic axial spondyloarthritis, hidradenitis suppurativa, atopic dermatitis, multiple sclerosis, asthma, and rheumatoid arthritis.

[0050] Also provided are methods for treating a condition selected from psoriasis, psoriatic arthritis, ankylosing spondylitis, active non-radiographic axial spondyloarthritis, hidradenitis suppurativa, atopic dermatitis, multiple sclerosis, asthma, and rheumatoid arthritis, in a patient, comprising administering to the patient the pharmaceutical composition comprising an hIL-17 binding polypeptide composition provided herein.

[0051] Also provided are methods and use of the pharmaceutical compositions comprising an hIL-17 binding polypeptide composition provided herein to treat a patient having a condition selected from: plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, active non-radiographic axial spondyloarthritis, hidradenitis suppurativa, atopic dermatitis, multiple sclerosis, asthma, and rheumatoid arthritis.

[0052] Also provided are hIL-17 binding polypeptide compositions, where the polypeptides comprise an amino acid sequence 50% to 100%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of a polypeptide disclosed herein, e.g., as set forth in any of the sequences listed herein including SEQ ID NOs: 1-66 and 71-78. Nucleic acids encoding the polypeptides, e.g., as set forth in any of the sequences listed herein including SEQ ID NOs: 1-66 and 71-78 or the variants noted above. Also provided are expression constructs and vectors and plasmids comprising the nucleic acid. Method for producing an hIL-17 binding polypeptide compositions e.g., comprising a sequence as set forth in any of the sequences listed herein including SEQ ID NOs: 1-66 and 71-78, comprising expressing the polypeptide from an expression construct in a host cell, and optionally purifying the polypeptide to remove unwanted contaminants. In some embodiments, the host cell is a microbial host cell. In some embodiments, the host cell is a eukaryotic or prokaryotic host cell.

[0053] Also provided are monomeric and multimeric hIL-17 binding polypeptides and composition of any of the binding polypeptides described ore claimed herein, wherein: (a) the composition has an activity selected from: an hIL-17 target binding affinity; binding avidity; binding specificity; binding stability; and / or potency; that is increased by about 2-fold to about 70,000-fold relative to a control composition;

[0054] (b) the composition has an activity selected from: an hIL-17 target binding affinity; binding avidity; binding specificity; binding stability; and / or potency; that is decreased by about 2-fold to about 10,000-fold relative to a control composition, wherein the control is an agent that targets a different hIL-17 / hIL-17R interaction; (c) the composition has an activity selected from: an hIL-17 target binding affinity; binding avidity; binding specificity; binding stability; and / or potency; that is increased by about 2-fold to about 10,000-fold relative to a control composition, wherein the control is an agent that targets a similar or the same hIL-17 / hIL-17R interaction; (d) the composition is an hIL-17 binding polypeptide dimeric composition that has an activity relative to a corresponding monomeric control composition that is increased by about 2-fold to about 10,000-fold; (e) when the composition is administered to a test sample or subject, an hIL-17 activity is reduced or increased by about 10 to about 100 percent, about 0.2-fold to about 10-fold, or both, relative to an untreated control;

[0055] (f) the composition is modified, and the melting temperature (Tm) is greater than that of a control composition Tm by about 1 deg C to about 100 deg C; and / or (g) the composition is modified, and the concentration of Gdn at which at least 50% of the concentration is folded is about 0.1 M greater to about 6 M greater than the concentration of Gdn at which at least 50% of a control concentration is folded.

[0056] INCORPORATION BY REFERENCE

[0057] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0058] BRIEF DESCRIPTION OF THE DRAWINGS

[0059] The novel features of the polypeptides, compositions, methods, and uses are set forth with particularity in the appended claims. A better understanding of the features and advantages are obtained by reference to the following detailed description that sets forth illustrative embodiments and the accompanying drawings:

[0060] FIGS. 1A-1C. Deep mutational scanning analysis of designed hIL-17 antagonist 17-01. 1A. Computationally designed antagonist 17-01 (ribbon) is modeled in complex with hIL-17A (gray surface representation). Positional conservation scores were calculated using the enrichment ratios per mutation at each 17-01 position and the model shaded by positional conservation score, scaled to the minimum conservation (lightest shading) and maximum conservation (darkest shading) observed. IB. View of the model shown in 1A rotated by 90 degrees. 1C. The relative affinity for hIL-17A of each single position mutation of 17-01 was determined. The enrichment ratio of each mutation was calculated, and Log2 (enrichment ratio) relative to that of the original 17-01 sequence was plotted in a heatmap, with highly enriched mutations having darkest shading and highly depleted mutations having lightest shading. The 17-01 residues predicted to mediate binding to hIL-17A (“binding interface”) are identified with gray bars above the heatmap. The second row of gray bars indicate the predicted secondary structure (from left to right si, hl, s2, s3, h2, and s4, where s=beta strand domain and h=alpha helix domain). The third horizontal bar from the top of the figure indicates the conservation score at each position. De novo hotspots generated and used to seed computational design of the binder 17-01 are indicated by asterisks (peptide numbering: L47, F50, and 151). The 17-01 amino acid sequence is indicated from N-terminus to C-terminus, from left to right, directly above the heatmap. The mutation at each position is shown vertically at left.

[0061] FIGS. 2A-2C. Deep mutational scanning analysis of designed hIL-17 antagonist 17-02. 2A. Computationally designed antagonist 17-02 (ribbon), shaded by positional conservation score, is modeled in complex with hIL-17A (gray surface representation). 2B. View of the model shown in 2A rotated by 90 degrees. 2C. The relative affinity for hIL-17A of each single position mutation of 17-02 was determined, and enrichment ratios per position relative to that of the original 17-02 sequence were plotted in a heatmap as described in FIGS. 1 A-1C. Descriptors per amino acid position (e.g., predicted binding interface and secondary structure, conservation, hotspots, and original design sequence) are set forth as described above for FIGS. 1A-1C

[0062] FIGS. 3A-3C. Deep mutational scanning analysis of designed hIL-17 antagonist 17-03. 3A. Computationally designed antagonist 17-03 (ribbon), shaded by positional conservation score, is modeled in complex with hIL-17A (gray surface representation). 3B. View of the model shown in 3A rotated by 90 degrees. 3C. The relative affinity for hIL-17A of each single position mutation of 17-03 was determined, and enrichment ratios per position relative to that of the original 17-03 sequence were plotted in a heatmap as described in FIGS. 1A-1C. Descriptors per amino acid position (e.g., predicted binding interface and secondary structure, conservation, hotspots, and original design sequence) are set forth as described above for FIGS. 1A-1C

[0063] FIGS. 4A-4D. Cellular potency of 17-02 and derivative polypeptide hlL- 17 binders. 17-02 and derivative polypeptides bind and inhibit hIL-17A-mediated cell signaling in vitro. Engineered hIL-17 reporter cells (InvivoGen) expressing hlL- 17RA and hIL-17RC were incubated with the EC80 of recombinant hIL-17A (4A), hIL-17A / F (4B), or hIL-17F (4C), determined in a prior assay, with or without a titration of each inhibitor or PBS control. Titration experiments were carried out two or more times per inhibitor. Cytokine and inhibitor were pre-incubated for 30 minutes before they were applied to cells. The chromogenic signaling output was measured after 24 hours and plotted relative to maximum stimulation observed (cytokine with no inhibitor). 4D. Key to graphs in 4A-4C, with IC50 values reported as mean ± SD of at least two independent experiments. Dark gray circles: 17-02 (SEQ ID NO: 39); gray squares: 17-020 (SEQ ID NO: 54); light gray upright triangles: 17- 020dslf01 A7V (SEQ ID NO: 58); light gray inverted triangles: A7V-PAS8 (SEQ ID NO: 60); light gray diamonds: 17F-01 A4 (SEQ ID NO: 37); black circles with dashed line: Secukinumab; black squares with dashed line: Bimekizumab.

[0064] FIGS. 5A-5B. Cellular potency of 17-01 and derivative hIL-17 polypeptide binders. 5A. 17-01 and derivative polypeptides 17-01M and 17- OlMdslfOl bind and inhibit hIL-17A-mediated cell signaling in vitro. An engineered hIL-17 reporter cell line (InvivoGen) expressing hIL-17RA and hIL-17RC was treated with the EC80 concentration of hIL-17A and a titration of each inhibitor or PBS control (n>2). Cytokine and inhibitor were pre-incubated for 30 minutes before they were applied to cells. The chromogenic signaling output was measured after 24 hours and plotted relative to maximum stimulation observed (cytokine with no inhibitor). 5B. Key to graph in 5A, with IC50 values reported as mean ± SD of at least two independent experiments. Dark gray circles: 17-01 (SEQ ID NO: 8); dark gray squares: 17-01M (SEQ ID NO: 21); light gray triangles: 17-01Mdslf01 (SEQ ID NO: 30); black circles with dashed line: Secukinumab; black squares with dashed line: Bimekizumab.

[0065] FIGS. 6A-6F. Determination of the binding affinities of hIL-17A binding polypeptides using BLI. Biotinylated hIL-17A was immobilized on streptavidin coated sensor tips, then dipped in binding polypeptide solution at the concentrations indicated to the right of each graph (association), then in buffer (dissociation). Responses are shown in 6A-6F. 6A. 17-01; KD 51nM. 6B. 17-02; KD 200nM. 6C. 17- 03 (SEQ ID NO: 63); KD47nM. 6D. 17-020; KD3.3nM. 6E. 17-020dslf01A7V; KD5.7nM. 6F. A7V-PAS8; KDlOpM. For A7V-PAS8, sample data were fit to a 1 : 1 binding equation using ForteBio analysis software (dashed lines). The instrument (ForteBio Octet RED96) is not sensitive enough to accurately determine picomolar KD; nonetheless, the data indicate the very high affinity and slow dissociation rate of A7V-PAS8. For 6A-6E, data were fit to a 2: 1 binding equation (dashed lines), reflecting that two binding polypeptide molecules in solution can bind to each of two binding sites on immobilized hIL-17A each known to have a unique affinity that can be influenced by the first binding event. For each of 6A-6F, data plotted are representative of at least two independent experiments. In each graph, the binding polypeptide concentration corresponding to the experiment represented by each solid line, from top to bottom, is shown to the right of the graph, also from top to bottom.

[0066] FIGS. 7A-7B. Thermal and chemical stability of 17-02 and derivatives. Binding polypeptides were denatured with heat or chemical denaturant guanidinium hydrochloride (Gdn). Helicity (signal at 222 nm) was monitored using circular dichroism. Loss of signal was used to calculate the fraction folded relative to 0M Gdn at 25 degrees C. 7A. Thermal stability of 17-02 (black circles), and derivatives 17- 020 (dark gray squares), 17-020dslf 1A7V (light gray triangles), and 17- 020dslf01 A7V+TCEP (open triangles). 17-020dslf01 A7V was tested in the presence and absence of TCEP to test the effect of reducing the disulfide bond. TCEP treatment resulted in lower binding polypeptide stability. 7B. Chemical stability of the 17-02 and derivative binding polypeptides.

[0067] FIGS. 8A-8B. Thermal and chemical stability of 17-01 and derivatives. Binding polypeptides were denatured and stability measured as described for 17-02 binding polypeptide experiments of FIGS. 7A-7B. 8A. Thermal stability of 17-01 (black circles), and derivatives 17-0 IM (dark gray squares) and OlMdslfOl (light gray triangles) (also referred to as 17-01Mdslf01; SEQ ID NO: 30). 8B. Chemical stability of the 17-01 and derivative binding polypeptides.

[0068] FIGS. 9A-9B. Cellular potency of dimeric binding polypeptide. Two 17- 020dslf02A7V peptides were linearly fused in amino-carboxyl terminus orientation with a peptide linker to form a dimeric binding polypeptide. Inhibition of hIL-17A- mediated cell signaling by hIL-17A was determined in vitro as described for singlecopy binding polypeptides (see description of FIGS. 4A-4D). 9A. Chromogenic signaling output for each antagonist was measured and plotted relative to maximum stimulation observed (cytokine with no inhibitor). 9B. IC50 values in nM, and linker composition and length for each dimeric binding polypeptide. Upright gray triangles: A7V-GS10 (linker L(GS)io) (SEQ ID NO: 59)„ IC50=0.03±0.03; inverted gray triangles: A7V-PAS8 (linker L(PAS)8) (SEQ ID NO: 60), IC50=0.0005±0.0005; light gray diamonds: A7V-PAS12 (linker L(P AS) 12) (SEQ ID NO: 61), IC50=0.0007±0.0005; dark gray circles: A7V-PAS20 (linker L(PAS)2o) (SEQ ID NO: 62), IC50=0.0008±0.0010; black circles with dashed line: Secukinumab; black squares with dashed line: Bimekizumab.

[0069] DETAILED DESCRIPTION

[0070] While exemplary embodiments of the present invention(s) have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art. It should be understood that various alternatives to the embodiments provided and described herein can be employed in practicing the invention. It is intended that the following claims define the scope of the inventions provided herein and that methods and structures within the scope of these claims and their equivalents be covered thereby.

[0071] All references cited are herein incorporated by reference in their entirety. Within this application, unless otherwise stated, the techniques utilized can be found in any of several well-known references such as: Molecular Cloning: A Laboratory Manual (Sambrook, et cd.. 1989, Cold Spring Harbor Laboratory Press), Gene Expression Technology (Methods in Enzymology, Vol. 185, edited by D. Goeddel, 1991. Academic Press, San Diego, CA), “Guide to Protein Purification” in Methods in Enzymology (M.P. Deutshcer, ed., (1990) Academic Press, Inc.); PCR Protocols: A Guide to Methods and Applications (Innis, et al. 1990. Academic Press, San Diego, CA), Culture of Animal Cells: A Manual of Basic Technique, 2nd Ed. (R.I. Freshney. 1987. Liss, Inc. New York, NY), Gene Transfer and Expression Protocols, pp. 109- 128, ed. E.J. Murray, The Humana Press Inc., Clifton, N.J.), and the Ambion 1998 Catalog (Ambion, Austin, TX).

[0072] As used herein, the singular forms “a,” “an” and, “the” can include plural referents unless the context clearly dictates otherwise.

[0073] As used herein, the amino acid residues are abbreviated as follows: alanine (Ala; A), asparagine (Asn; N), aspartic acid (Asp; D), arginine (Arg; R), cysteine (Cys; C), glutamic acid (Glu; E), glutamine (Gin; Q), glycine (Gly; G), histidine (His; H), isoleucine (He; I), leucine (Leu; L), lysine (Lys; K), methionine (Met; M), phenylalanine (Phe; F), proline (Pro; P), serine (Ser; S), threonine (Thr; T), tryptophan (Trp; W), tyrosine (Tyr; Y), and valine (Vai; V).

[0074] In all embodiments of polypeptides disclosed herein, any N-terminal methionine residues are optional (i.e.: the N-terminal methionine residue can be present or can be absent).

[0075] All embodiments of any aspect of the disclosure can be used in any combination, unless the context clearly dictates otherwise.

[0076] All embodiments of any aspect of the disclosure can be used in any combination, unless the context clearly dictates otherwise.

[0077] All embodiments of any aspect of the disclosure can be used in any combination, unless the context clearly dictates otherwise.

[0078] Unless the context clearly requires otherwise, throughout the description and the claims, the words “comprise,” “comprising,” and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of “including, but not limited to.” Words using the singular or plural number also include the plural and singular number, respectively. Additionally, the words “herein,” “above,” and “below” and words of similar import, when used in this application, shall refer to this application as a whole and not to any particular portions of the application. Overview

[0079] IL 17 signaling has roles in diseases, such as, but are not limited to, psoriasis, asthma, psoriatic arthritis, and rheumatoid arthritis. Inhibiting the signaling can ameliorate diseases, disorders, and conditions in which IL- 17 signaling plays a role in the etiology or symptoms.

[0080] Minibinder peptides are provided herein that bind IL-17A at the surface mediating its interaction with IL-17RA or IL-17RC to thereby block the interaction of the cytokine and the cytokine receptor. Exemplary of minibinders are the polypeptides 17-01 (SEQ ID NO:8), 17-02 (SEQ ID NO:39), and 17-03 (SEQ ID NO:63), derivatives and variants thereof, and multimers thereof. The following is a brief summary of the various minibinder polypeptides provided herein. More detail, description, and examples are provided throughout the disclosure herein.

[0081] 1. 17-01*, 17-02*, and 17-03* genera of minibinder designs (* refers to the genus)

[0082] Three designs, 17-01 (ferredoxin fold design), 17-02 (three-helix bundle design) and 17-03 (ferredoxin fold design), set forth as SEQ ID NOs: 8, 39 and 63, respectively, bind hIL-17A with low nanomolar affinity. They have been sequence optimized via in vitro directed evolution to further improve affinity. The resulting peptides are designated 17-01, 17-02, and 17-03. The peptides were modeled in complex with hIL-17A (FIGS. 1A-1B, 2A-2B, and 3A-3B). All three designs incorporate de novo generated hotspots at the hIL-17A surface that mimic binding of hIL-17RA: a leucine hotspot mimicking hIL-17RA L27, an isoleucine mimicking hIL-17RA 132, and a phenylalanine mimicking hIL-17RA W31, indicated by asterisks in, e.g., FIG. 1C. As detailed herein, peptides that are derivatives, variants, multimers, other modifications thereof, and combinations thereof are provided.

[0083] 2. Nomenclature

[0084] Using the 17-02 genus as an example, the variants members of the 17-02 genus are designated with capital letters where, 17-02 is the parent sequence, and the variants are designated 17-02A, 17-02B, 17-02C . . .17-02N, 17-020, and 17-02P. Disulfide variants in which a C is added for disulfide bonding are referred to by reference to “dslf’ and the variant number 01, 02, etc. refers to variants that include a cysteine (C) or cysteines that is / are added for disulfide bonding at varying loci. For example, the polypeptide designated 17-020dslf01 is an intramolecular disulfide- containing binding polypeptide, variant 1, that is a variant of 17-020, and 17- 020dslf02 is an intramolecular disulfide-containing binding polypeptide variant 2. See table below, in which the cysteines are bolded and underlined.

[0085] 3. 17-01* family

[0086] Mutational scanning analysis (Figures 1A-1C) show that amino acids L47, F50, and 151 in the mini-binder 17-01 are hotspots for hIL-17A binding. Amino acids L47, F50, and 151 in the mini-binder mimic binding of hIL-17A to the hIL-17RA at positions L27, W31, and 132, respectively, of the receptor. Exemplary minibinders based on the 17-01 design include those designated 17-01, 17-01 A, 17-01B, 17-OIC, 17-01D, 17-01E, 17-01F, 17-01G, 17-01H, 17-011, 17-01 J, 17-01K, 17-01L, 17-01M, 17-0 IN, 17-010, 17-0 IP, and 17-0 IQ. Exemplary amino acid sequences of mini binders of the 17-01 design, including 17-01 to 17-0 IQ, are each set forth in SEQ ID NOs: 8-33. Additional variants that have IL-17 binding activity and / or IL-17 antagonist activity and have at least 80%, 85%, 90%, 95%, or more sequence identity to any of these minibinder polypeptides are contemplated.

[0087] 4. 17-02* family

[0088] 17-02 (Figures 2A-2C), mini -binder amino acids L23 and F26 mimic the binding of hIL-17RA receptor positions L27 and W31, respectively. Exemplary minibinders based on the 17-01 design include: 17-02, 17-02A, 17-02B, 17-02C, 17- 02D, 17-02E, 17-02F, 17-02G, 17-02H, 17-021, 17-02 J, 17-02K, 17-02L, 17-02M, 17- 02N, 17-020, and 17-02P. Disulfide variants include: 17-02 OdslfOl, 17-02 Odslfi)2, and 17-02 Odslf01A7V. Exemplary amino acid sequences of exemplary minibinders of the 17-02 are set forth in SEQ ID NOs: 39-58. Exemplary variants (17-01M, SEQ ID NO: 21) and (17-020, SEQ ID NO: 54) scaffolds were observed to block hIL-17- mediated cell signaling with 400- and 30-fold greater potency, respectively, than the initial designs 17-01 and 17-02. Additional variants of each of these that have greater than 80%, or at least 85%, 90%, 95%, or more sequence identity to any of the above and retain at least 90%, 95%, or greater of the binding activity or IL- 17 antagonist of the corresponding unmodified polypeptide.

[0089] 5. 17-03* family

[0090] 17-03 (Figures 3A-3C) polypeptide numbering: L47, F50, and 151 mimic the binding of hIL-17RA L27, W31, and 132 respectively. The amino acid of design 17- 03 is set forth in SEQ ID NO: 63.

[0091] 6. F01 and F03

[0092] In addition to binding poly peptides of IL-17A, binders enriched for IL-17F also are provided herein. IL-17A and IL-17F monomers pair to form homodimeric (A / A, F / F) and heterodimeric (A / F) cytokines that signal via a ternary complex with receptors IL-17RA and IL-17RC.

[0093] Minibinders enriched for IL-17F binding include IL-17F enriched binders based on 17-01 [e.g., F01 Al, F01 A2, F01 A3, F01 A4, F01 SI] and based on the 17- 03 design [F03 Al, F03 SI, F03 S2] are provided. Exemplary amino acid sequences of IL-17F enriched binders based on 17-01 are set forth in SEQ ID NOs: 34-38. Exemplary amino acid sequences of IL-17F enriched binders based on 17-03 are set forth in SEQ ID NOs: 64-66 show similarity to the minibinders set forth in the 17-03 design. Also provide are variants of the polypeptides of SEQ ID NOs: 34-38 and 64- 66 that or more sequence identity to any of the above and retain at least 90%, 95%, or greater of the binding activity of the corresponding unmodified polypeptide of SEQ ID NOs: 34-38 and 64-66.

[0094] 7. Disulfide linked variants (dslf)

[0095] Also provided herein are minibinders with improved stability containing one or more intramolecular disulfide(s) that ere computationally designed in affinity- optimized combinatorial variants. As shown herein minibinders including one or more intramolecular disulfide(s) retain high affinity when subjected to heat or chemical denaturation (e.g., FIG 7A-7B). Table 9 sets forth disulfide-containing combinatorial variants and dimer fusions, respective SEQ ID NOs, and Cysteine pairings. Exemplary of minibinders based on the 17-01 design containing one or more disulfide bond(s) and their respective amino acid sequences are set forth in SEQ ID NOs: 26- 33. Minibinders based on the 17-02 design and containing one or more disulfide bond(s) and their amino acid sequences are set forth in SEQ ID NOs: 56-58.

[0096] Variants having disulfide linkages (17-01Mdslf01, SEQ ID NO: 30, derived from 17-01; and 17-020dsfl01A7V, SEQ ID NO: 58, derived from 17-02) were significantly more stable than the related variants without the linkage (Fig. 7A-7B and 8A-8B), while potency was not significantly impacted (Fig. 4A-4D and 5A-5B).

[0097] Exemplary sequences and nomenclature are as follows

[0098] 8. Multimerized mini binders

[0099] Human IL-17A binding polypeptide compositions containing multiple hlL- 17A minibinders joined linearly by a flexible peptide linker are provided. Exemplary multimers are set forth in SEQ ID NOs: 59-62.

[0100] SEQ ID NO: 59 sets forth an amino acid sequence of the disulfide containing minibinder 17-02 OdslfOl A7V dimer which is linked by a 21 amino acids (GS10) linker.

[0101] SEQ ID NO: 60 sets forth an amino acid sequence of the disulfide containing minibinder 17-02 OdslfOl A7V dimer which is linked by a 25 amino acid (PAS8) linker.

[0102] SEQ ID NO: 61 sets forth an amino acid sequence of the disulfide containing minibinder 17-02 OdslfOl A7V dimer which is linked by a 37 amino acid (PAS12) linker. SEQ ID NO: 62 sets forth an amino acid sequence of the disulfide containing minibinder 17-02 OdslfOl A7V dimer which is linked by a 61 amino acid (PAS20) linker.

[0103] A7V designs are provided. They are variants of the polypeptide designated 17-02 OdslfOl (SEQ ID NO: 56) where the A at position 7 is substituted for V. The resulting polypeptide is designated 17-02 Odslf l A7V or A7V. Dimers of 17-02 Odslf l A7V also are provided, where one or more 17-02 OdslfOl A7V polypeptide is linked by a flexible linker. The disulfides are introduced to improve stability. Exemplary A7V dimer

[0104] A7V-PAS8:

[0105] A7V - PAS8 - A7V

[0106] SEQ ID NO: 58 - SEQ ID NO: 68 - SEQ ID NO: 58

[0107] A7V-PAS12:

[0108] A7V - PAS12 - A7V

[0109] SEQ ID NO: 58 - SEQ ID NO: 69 - SEQ ID NO: 58

[0110] A7V-PAS20:

[0111] A7V - PAS20 - A7V

[0112] SEQ ID NO: 58 - SEQ ID NO: 70 - SEQ ID NO: 58

[0113] Of these A7V-PAS8 (SEQ ID NO: 60) was the most potent dimer fusion (IC50 1 pM), at 100 times more potent than secukinumab (approved anti-IL-17A mAb) and 3 times more potent than bimekizumab (investigational mAb ) (FIGS. 9A- 9B). A7V-PAS8 showed a 2,800-fold increase in potency compared to the minibinder monomer and a 60,000-fold increase compared to the parent computational design, 17-02 (FIGS. 4A and 4D).

[0114] Uses of Human IL-17 Binding Polypeptide Composition

[0115] The hIL-17 binding polypeptide compositions provided herein (also referred to as “minibinders”) can be used for treating or preventing (or reducing the risk of) a condition, e.g., a disease or disorder, in a subject in need thereof. The condition can involve hIL-17 signaling. hIL-17 signaling can be dysregulated in the condition. The hIL-17 signaling cannot be dysregulated in the condition. hIL-17 signaling can occur upstream of an event that is dysregulated in the condition. The condition can be one for which there currently exist approved or experimental treatments comprising a compound that targets hIL-17. The condition can be one for which there currently do not exist approved or experimental treatments comprising a compound that targets hIL-17. The condition can be any identified as appropriate for treatment with a composition of the present invention by one of skill in the art. The condition can be an inflammatory disease. The inflammatory disease can be a T-cell mediated disease. The inflammatory disease can be selected from psoriasis, psoriatic arthritis, ankylosing spondylitis, active non-radiographic axial spondyloarthritis, multiple sclerosis, asthma, and rheumatoid arthritis.

[0116] Human IL-17 Binding Polypeptide Composition Structure

[0117] An hIL-17 binding polypeptide composition can comprise or consist of a polypeptide of the general formula, from amino (N) to carboxy (C) terminus, A- (linker-B)n, wherein A is a single occurrence of a designed high-affinity hIL-17 binding polypeptide as described herein, and when present B can be a second occurrence of A (i.e., A and B can be the same hIL-17 binding polypeptide) or an occurrence of a different designed high-affinity hIL-17 binding polypeptide as described herein. The hIL-17 binding polypeptide A-(linker-B)n can be a linear polypeptide wherein the amino acids of A, the linker, and B each are linked by peptide bonds.

[0118] In a first aspect, provided are hIL-17 binding polypeptide compositions comprising or consisting of a polypeptide of the general formula, from amino (N) to carboxy (C) terminus, A-(linker-B)n, wherein n=0 to 10, wherein A is a polypeptide of the formula (X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11), wherein in A, XI, X2, X3, X4, X5, X6, X7, X8, X10, and XI 1, are optional, wherein X9 comprises a polypeptide domain of 12-20 amino acids in length, wherein X9 comprises the amino acid sequence of residues 39-52, or 42-51, as set forth in SEQ ID NO: 1, 3, 4, 5, 6, 7, 34, 35, 36, 38, 64, or 66, and wherein B is a polypeptide of the formula (XI ’-X2’- X3’-X4’-X5’-X6’-X7’-X8’-X9’-X10’-Xl l’). X9 can comprise the amino acid sequence of residues 42-51, as set forth in SEQ ID NO: 1, 3, 4, 5, 6, 7, 34, 35, 36, 38, 64, or 66. In this aspect, the length of A or B, individually, can be from about 12 amino acids to about 61 amino acids in length. The length of A or B can be from about 12 amino acids to about 15 amino acids, about 12 amino acids to about 20 amino acids, about 12 amino acids to about 25 amino acids, about 12 amino acids to about 30 amino acids, about 12 amino acids to about 35 amino acids, about 12 amino acids to about 40 amino acids, about 12 amino acids to about 45 amino acids, about 12 amino acids to about 50 amino acids, about 12 amino acids to about 55 amino acids, about 12 amino acids to about 60 amino acids, about 12 amino acids to about 61 amino acids, about 15 amino acids to about 20 amino acids, about 15 amino acids to about 25 amino acids, about 15 amino acids to about 30 amino acids, about 15 amino acids to about 35 amino acids, about 15 amino acids to about 40 amino acids, about 15 amino acids to about 45 amino acids, about 15 amino acids to about 50 amino acids, about 15 amino acids to about 55 amino acids, about 15 amino acids to about 60 amino acids, about 15 amino acids to about 61 amino acids, about 20 amino acids to about 25 amino acids, about 20 amino acids to about 30 amino acids, about 20 amino acids to about 35 amino acids, about 20 amino acids to about 40 amino acids, about 20 amino acids to about 45 amino acids, about 20 amino acids to about 50 amino acids, about 20 amino acids to about 55 amino acids, about 20 amino acids to about 60 amino acids, about 20 amino acids to about 61 amino acids, about 25 amino acids to about 30 amino acids, about 25 amino acids to about 35 amino acids, about 25 amino acids to about 40 amino acids, about 25 amino acids to about 45 amino acids, about 25 amino acids to about 50 amino acids, about 25 amino acids to about 55 amino acids, about 25 amino acids to about 60 amino acids, about 25 amino acids to about 61 amino acids, about 30 amino acids to about 35 amino acids, about 30 amino acids to about 40 amino acids, about 30 amino acids to about 45 amino acids, about 30 amino acids to about 50 amino acids, about 30 amino acids to about 55 amino acids, about 30 amino acids to about 60 amino acids, about 30 amino acids to about 61 amino acids, about 35 amino acids to about 40 amino acids, about 35 amino acids to about 45 amino acids, about 35 amino acids to about 50 amino acids, about 35 amino acids to about 55 amino acids, about 35 amino acids to about 60 amino acids, about 35 amino acids to about 61 amino acids, about 40 amino acids to about 45 amino acids, about 40 amino acids to about 50 amino acids, about 40 amino acids to about 55 amino acids, about 40 amino acids to about 60 amino acids, about 40 amino acids to about 61 amino acids, about 45 amino acids to about 50 amino acids, about 45 amino acids to about 55 amino acids, about 45 amino acids to about 60 amino acids, about 45 amino acids to about 61 amino acids, about 50 amino acids to about 55 amino acids, about 50 amino acids to about 60 amino acids, about 50 amino acids to about 61 amino acids, about 55 amino acids to about 60 amino acids, about 55 amino acids to about 61 amino acids, or about 60 amino acids to about 61 amino acids. The length of A or B can be from about 12 amino acids, about 15 amino acids, about 20 amino acids, about 25 amino acids, about 30 amino acids, about 35 amino acids, about 40 amino acids, about 45 amino acids, about 50 amino acids, about 55 amino acids, about 60 amino acids, or about 61 amino acids. The length of A or B can be from at least about 12 amino acids, about 15 amino acids, about 20 amino acids, about 25 amino acids, about 30 amino acids, about 35 amino acids, about 40 amino acids, about 45 amino acids, about 50 amino acids, about 55 amino acids, or about 60 amino acids. The length of A or B can be from at most about 15 amino acids, about 20 amino acids, about 25 amino acids, about 30 amino acids, about 35 amino acids, about 40 amino acids, about 45 amino acids, about 50 amino acids, about 55 amino acids, about 60 amino acids, or about 61 amino acids.

[0119] In a second aspect, provided are hIL-17 binding polypeptide compositions comprising or consisting of a polypeptide of the general formula A-(linker-B)n, wherein n=0-10, wherein A is a polypeptide of the formula (X1-X2-X3-X4-X5), wherein in A, XI, X2, X4, and X5 are optional, wherein X3 comprises a polypeptide domain of 9-15 amino acids in length, wherein X3 comprises the amino acid sequence of residues 19-27 in SEQ ID NO: 2, and wherein B is a polypeptide of the formula (Xr-X2’-X3’-X4’-X5’). In this aspect, the length of A or B, individually can be from about 9 amino acids to about 43 amino acids. The length of A or B can be from about 9 amino acids to about 10 amino acids, about 9 amino acids to about 12 amino acids, about 9 amino acids to about 15 amino acids, about 9 amino acids to about 16 amino acids, about 9 amino acids to about 18 amino acids, about 9 amino acids to about 20 amino acids, about 9 amino acids to about 25 amino acids, about 9 amino acids to about 30 amino acids, about 9 amino acids to about 35 amino acids, about 9 amino acids to about 40 amino acids, about 9 amino acids to about 43 amino acids, about 10 amino acids to about 12 amino acids, about 10 amino acids to about 15 amino acids, about 10 amino acids to about 16 amino acids, about 10 amino acids to about 18 amino acids, about 10 amino acids to about 20 amino acids, about 10 amino acids to about 25 amino acids, about 10 amino acids to about 30 amino acids, about 10 amino acids to about 35 amino acids, about 10 amino acids to about 40 amino acids, about 10 amino acids to about 43 amino acids, about 12 amino acids to about 15 amino acids, about 12 amino acids to about 16 amino acids, about 12 amino acids to about 18 amino acids, about 12 amino acids to about 20 amino acids, about 12 amino acids to about 25 amino acids, about 12 amino acids to about 30 amino acids, about 12 amino acids to about 35 amino acids, about 12 amino acids to about 40 amino acids, about 12 amino acids to about 43 amino acids, about 15 amino acids to about 16 amino acids, about 15 amino acids to about 18 amino acids, about 15 amino acids to about 20 amino acids, about 15 amino acids to about 25 amino acids, about 15 amino acids to about 30 amino acids, about 15 amino acids to about 35 amino acids, about 15 amino acids to about 40 amino acids, about 15 amino acids to about 43 amino acids, about 16 amino acids to about 18 amino acids, about 16 amino acids to about 20 amino acids, about 16 amino acids to about 25 amino acids, about 16 amino acids to about 30 amino acids, about 16 amino acids to about 35 amino acids, about 16 amino acids to about 40 amino acids, about 16 amino acids to about 43 amino acids, about 18 amino acids to about 20 amino acids, about 18 amino acids to about 25 amino acids, about 18 amino acids to about 30 amino acids, about 18 amino acids to about 35 amino acids, about 18 amino acids to about 40 amino acids, about 18 amino acids to about 43 amino acids, about 20 amino acids to about 25 amino acids, about 20 amino acids to about 30 amino acids, about 20 amino acids to about 35 amino acids, about 20 amino acids to about 40 amino acids, about 20 amino acids to about 43 amino acids, about 25 amino acids to about 30 amino acids, about 25 amino acids to about 35 amino acids, about 25 amino acids to about 40 amino acids, about 25 amino acids to about 43 amino acids, about 30 amino acids to about 35 amino acids, about 30 amino acids to about 40 amino acids, about 30 amino acids to about 43 amino acids, about 35 amino acids to about 40 amino acids, about 35 amino acids to about 43 amino acids, or about 40 amino acids to about 43 amino acids. The length of A or B can be from about 9 amino acids, about 10 amino acids, about 12 amino acids, about 15 amino acids, about 16 amino acids, about 18 amino acids, about 20 amino acids, about 25 amino acids, about 30 amino acids, about 35 amino acids, about 40 amino acids, or about 43 amino acids. The length of A or B can be from at least about 9 amino acids, about 10 amino acids, about 12 amino acids, about 15 amino acids, about 16 amino acids, about 18 amino acids, about 20 amino acids, about 25 amino acids, about 30 amino acids, about 35 amino acids, or about 40 amino acids. The length of A or B can be from at most about 10 amino acids, about 12 amino acids, about 15 amino acids, about 16 amino acids, about 18 amino acids, about 20 amino acids, about 25 amino acids, about 30 amino acids, about 35 amino acids, about 40 amino acids, or about 43 amino acids.

[0120] Structural Genera

[0121] SEQ ID NOs: 1, 2, and 3 describe hIL-17 binding polypeptide sequence genera (genuses) provided herein. Table 1 shows the allowable residues per position of hIL-17 binding polypeptides of SEQ ID NOs: 1, 2, and 3 as indicated, based on the fitness of single mutants for binding hIL-17A determined during directed evolution. Allowable mutations include those showing enrichment greater than or equal to that of the respective wild-type (also referred to herein as “original,” or “starting”) sequence (17-01, 17-02, and 17-03, set forth as SEQ ID NOs: 8, 39, and 63, respectively) in the first selection. An asterisk indicates the genus sequence including the allowable residues identified based on directed evolution of the wild-type sequence.

[0122] Table 1. hIL-17 Binding Polypeptide Genera: Allowable Residues in Most Enriched Design Sequences Determined by SSM

[0123] Reference to positions in Table 1 A are with respect to positions in 17-01 set forth in SEQ ID NO: 8. Reference to positions in Table IB are with respect to positions in 17-02 set forth in SEQ ID NO: 39. Reference to positions in Table IB are with respect to positions in 17-03 set forth in SEQ ID NO: 63.

[0124] Table 2 shows the allowable residues per position of construct F01-A4 (SEQ

[0125] ID NO: 37), based on the fitness of single mutants for binding hIL-17F. The library of all possible single mutants of F01-A4 was sorted for (1) binding to labeled hIL-17F alone to select for enhanced target affinity alone (allowable residues shown under SEQ ID NO: 4), or (2) to labeled hIL-17F in the presence of unlabeled hIL-17A competitor to select for affinity and specificity to hIL-17F (allowable residues shown under SEQ ID NO: 5). All mutants showing enrichment greater than or equal to that of the wild-type sequence in the first selection were deemed allowable.

[0126] Table 2. hIL-17F Binding Polypeptide Genera: Allowable Residues Based on F01-A4 Reference to positions in Table 2 are with respect to positions in F01-A4 set forth in SEQ ID NO: 37.

[0127] Table 3 shows the allowable residues per position of construct F03-S1 (SEQ

[0128] ID NO: 65), based on the fitness of single mutants for binding hIL-17F as described herein in the Examples. The library of all possible single mutants of F03-S1 was sorted for (1) binding to labeled hIL-17F alone to select for enhanced target affinity alone (allowable residues shown under SEQ ID NO: 6), or (2) to labeled hIL-17F in the presence of unlabeled hIL-17A competitor to select for affinity and specificity to hIL-17F (allowable residues shown under SEQ ID NO: 7). All mutants showing enrichment greater than or equal to that of the wild-type sequence in the first selection were deemed allowable. Table 3. hIL-17F Binding Polypeptide Genera: Allowable Residues Based on F03-S1

[0129] Reference to positions in Table 3 are with respect to positions in F03-S1 set forth in SEQ ID NO: 65.

[0130] The sequence genera presented in Table 4 are based on the sequences of those combinatorial variants found to be highly enriched in the final sorts of the combinatorial libraries and therefore to have superior binding to hIL-17A over a multitude of other combinatorial variants. Table 4. 17-01 and 17-02 hIL-17 Binding Polypeptide Sub-Genera Based on Enriched Polypeptides. A. 17-01 sub-genus, SEQ ID NO: 71 (17-01 A-Q; SEQ ID NOs: 9-25). B. 17-02 sub-genus, SEQ ID NO: 72 (17-02 A-P; SEQ ID NOs: 40- 55). Reference to positions in Table 4A are with respect to positions in 17-01 set forth in SEQ ID NO: 8. Reference to positions in Table 4B are with respect to positions in 17-02 set forth in SEQ ID NO: 39.

[0131]

[0132] The sequence genuses presented in Table 5 are based on the sequences of the

[0133] BLI-tested 17-01 -based combinatorial variants found to have the best hIL-17A binding behavior (top 25% and top 50% estimated KD).

[0134] Table 5. 17-01 hIL-17A Binding Polypeptide Top Binding Sub-Genuses. A. Top 25% 17-01 sub-genus, SEQ ID NO: 73 (17-01B, 17-01M, 17-01N, 17-01P; SEQ ID NOs: 10, 21, 22, 24). B. Top 50% 17-01 sub-genus, SEQ ID NO: 74 (17- 01B, 17-01E, 17-01G, 17-01H, 17-01M, 17-01N, 17-01P; SEQ ID NOs: 10, 13, 15, 16, 21, 22, 24). Reference to positions in Table 5 are with respect to positions in 17-

[0135] 01 set forth in SEQ ID NO: 8. The sequence genuses presented in Table 6 are based on the sequences of the BLI-tested 17-02-based combinatorial variants found to have the best hIL-17A binding behavior (top 25% and top 50% estimated KD).

[0136] Table 6. 17-02 hIL-17A Binding Polypeptide Top Binding Sub-Genuses. A. Top 25% 17-02 sub-genus, SEQ ID NO: 75 (17-02C, 17-02E, 17-020, 17-02P; SEQ ID NOs: 42, 44, 54, 55). B. Top 50% 17-02 sub-genus, SEQ ID NO: 76 (17- 02C, 17-02E, 17-02G, 17-02H, 17-021, 17-02L, 17-020, 17-02P; SEQ ID NOs: 42, 44, 46, 47, 48, 51 54, 55). Reference to positions in Table 6 are with respect to positions in 17-02 set forth in SEQ ID NO: 39.

[0137] The sequence genuses presented in Table 7 are based on the sequences of the disulfide-stabilized 17-01 and 17-02 variants.

[0138] Table 7. 17-01 and 17-02 Disulfide-Stabilized hIL-17A Binding

[0139] Polypeptide Sub-Genuses. A. 17-01 disulfide-stabilized sub-genus, SEQ ID NO: 77 (17-01Bdslf01, 17-01Idslf01, 17-01Idslf02, 17-01Idslf03, 17-01Mdslf01, 17-

[0140] OlQdslfOl, 17-01Qdslf02, 17-01Qdslf03; SEQ ID NOs: 26-33). B. 17-02 disulfide- stabilized sub-genus, SEQ ID NO: 78 (17-020dslf01, 17-02Odslfi)2, 17- 020dslf01 A7V; SEQ ID NOs: 56-58). Reference to positions in Table 7A are with respect to positions in 17-01 set forth in SEQ ID NO: 8. Reference to positions in Table 7B are with respect to positions in 17-02 set forth in SEQ ID NO: 39.

[0141]

[0142] An hIL-17 binding polypeptide composition comprising one occurrence of an hIL-17 binding polypeptide can be designated as monomeric or referred to as a monomer. In a monomer, the n is equal to 0 in the formula A-(linker-B)n. A monomeric hIL-17 binding polypeptide composition can comprise the hIL-17 binding polypeptide in addition to other elements, e.g., N- and C-terminal modifications or molecules as described herein. In this context, the terms monomer and monomeric refer to the number of hIL-17 binding polypeptides (one) in the hIL-17 binding polypeptide composition. An additional element comprised by a monomeric or multimeric hIL-17 binding polypeptide composition can be selected from any known to those of skill in the art, including but not limited to: a peptide tag, for use in affinity chromatography purification (e.g., poly-HIS), for use in adjusting the overall biophysical properties such as net charge and / or isoelectric point, or to aid in detection in vitro or in vivo (e.g. Flag, HA); a cell penetrating peptide (e.g., for oral bioavailability / penetration of membranes); a solubility tag or domain (e.g., GFP, MBP, GST, DsbC); a degradation targeting domain, e.g., a lysosomal-targeting receptor binding domain, for targeted degradation of IL-17 (e.g., via the lysosomal pathway, such as LYTAC, AbTAC, GlueTAC), and other such technologies known in the art, e.g., as described by Zhao, etal., 2022, “Targeted protein degradation: mechanisms, strategies and application via the lysosomal pathway,” Signal Transduction and Targeted Therapy 7: 113, incorporated herein by reference); a domain that masks the activity of the IL- 17 binder, until the linker is cleaved by an environment-specific factor. The additional element can be any domain that binds a target as desired by one of skill in the art and appropriate for the intended purpose (for example, including but not limited to: a domain that binds a factor such as albumin or FcRn to extend serum half-life; a domain that binds a receptor that mediates active transport across a membrane, such as TfR, and; a domain that binds a complementary drug target in disease, such as TNF or TL1 A).

[0143] A monomeric hIL-17 binding polypeptide composition can comprise no elements other than a single hIL-17 binding polypeptide, or it can comprise additional elements. An hIL-17 binding polypeptide composition comprising multiple hIL-17 binding polypeptides can be designated as multimeric or referred to as a multimer, where the hIL-17 binding polypeptide composition comprises A and at least one instance of B. When the hIL-17 binding polypeptide is a multimer, in the formula A- (linker-B)n, n is equal to 1 or more. In some embodiments, n is equal to 1 to 10. In some embodiments, n is equal to 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, 1 to 7, 1 to 8, 1 to

[0144] 9, 1 to 10, 2 to 3, 2 to 4, 2 to 5, 2 to 6, 2 to 7, 2 to 8, 2 to 9, 2 to 10, 3 to 4, 3 to 5, 3 to

[0145] 6, 3 to 7, 3 to 8, 3 to 9, 3 to 10, 4 to 5, 4 to 6, 4 to 7, 4 to 8, 4 to 9, 4 to 10, 5 to 6, 5 to

[0146] 7, 5 to 8, 5 to 9, 5 to 10, 6 to 7, 6 to 8, 6 to 9, 6 to 10, 7 to 8, 7 to 9, 7 to 10, 8 to 9, 8 to

[0147] 10, or 9 to 10. In some embodiments, n is equal to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, n is equal to at least 1, 2, 3, 4, 5, 6, 7, 8, or 9. In some embodiments, n is equal to at most 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, the multimer is a dimer (n=2). In some embodiments, the multimer is a trimer (n=3). A multimeric hIL-17 binding polypeptide composition can comprise multiple hIL-17 binding polypeptides and linker(s) in addition to additional elements, e.g., N- and C- terminal modifications or molecules as described herein. A multimeric hIL-17 binding polypeptide composition can comprise no elements other than the hIL-17 binding polypeptides and linker(s).

[0148] As provided by the formula A-(linker-B)n, a linker or spacer can be present between occurrences of A and B, or B and B. For example, a dimer can comprise A- linker-B. A trimer can comprise A-linker-B-linker-B. A and B can have the same amino acid sequence or different amino acid sequences.

[0149] Amino Acid Substitutions

[0150] Provided are monomeric or multimeric hIL-17 binding polypeptides described herein wherein one or more amino acid has been substituted relative to the disclosed sequence. An amino acid substitution can be a conservative substitution, a nonconservative substitution, or an alternative substitution. A substitution can be selected by one of skill in the art, to preserve the activity of the corresponding unsubstituted hIL-17 binding polypeptide. A binding polypeptide activity as used herein can be any measurable characteristic understood by or desired to be measured by one of skill in the art, e.g., affinity, specificity, avidity, stability, or potency. For example, when a substitution is present, one or more amino acid important for hIL-17 binding can be preserved relative to the unsubstituted hIL-17 binding polypeptide. All amino acids in an hIL-17 binding region can be preserved in a substituted hIL-17 binding polypeptide. Substitutions including conservative, nonconservative, and alternative substitutions, include, but are not limited to, any known to those of skill in the art, e.g., those described herein. An hIL-17 binding polypeptide comprising such an amino acid substitution can retain substantially the same level of activity, potency, or stability as the unsubstituted hIL-17 binding polypeptide. In some embodiments, a substituted hIL-17 binding polypeptide comprises one or more amino acid substitutions relative to an hIL-17 binding polypeptide described herein (e.g., any one of SEQ ID NOs: 8 to 78), wherein the substituted hIL-17 binding polypeptide or hlL- 17 binding polypeptide composition retains 85-100% of one or more activity or stability of the unsubstituted hIL-17 binding polypeptide. The activity of the unsubstituted hIL-17 binding polypeptide that is retained by the substituted hIL-17 binding polypeptide can be about 85% to about 100%. The activity of the unsubstituted hIL-17 binding polypeptide that is retained by the substituted hIL-17 binding polypeptide can be about 85% to about 90%, about 85% to about 91%, about 85% to about 92%, about 85% to about 93%, about 85% to about 94%, about 85% to about 95%, about 85% to about 96%, about 85% to about 97%, about 85% to about 98%, about 85% to about 99%, about 85% to about 100%, about 90% to about 91%, about 90% to about 92%, about 90% to about 93%, about 90% to about 94%, about 90% to about 95%, about 90% to about 96%, about 90% to about 97%, about 90% to about 98%, about 90% to about 99%, about 90% to about 100%, about 91% to about 92%, about 91% to about 93%, about 91% to about 94%, about 91% to about 95%, about 91% to about 96%, about 91% to about 97%, about 91% to about 98%, about 91% to about 99%, about 91% to about 100%, about 92% to about 93%, about 92% to about 94%, about 92% to about 95%, about 92% to about 96%, about 92% to about 97%, about 92% to about 98%, about 92% to about 99%, about 92% to about 100%, about 93% to about 94%, about 93% to about 95%, about 93% to about 96%, about 93% to about 97%, about 93% to about 98%, about 93% to about 99%, about 93% to about 100%, about 94% to about 95%, about 94% to about 96%, about 94% to about 97%, about 94% to about 98%, about 94% to about 99%, about 94% to about 100%, about 95% to about 96%, about 95% to about 97%, about 95% to about 98%, about 95% to about 99%, about 95% to about 100%, about 96% to about 97%, about 96% to about 98%, about 96% to about 99%, about 96% to about 100%, about 97% to about 98%, about 97% to about 99%, about 97% to about 100%, about 98% to about 99%, about 98% to about 100%, or about 99% to about 100%. The activity of the unsubstituted hIL-17 binding polypeptide that is retained by the substituted hIL-17 binding polypeptide can be about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%. The activity of the unsubstituted hIL-17 binding polypeptide that is retained by the substituted hIL-17 binding polypeptide can be at least about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%. The activity of the unsubstituted hIL-17 binding polypeptide that is retained by the substituted hIL-17 binding polypeptide can be at most about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%.

[0151] A substituted hIL-17 binding polypeptide can comprise at least one amino acid substitution. A substituted hIL-17 binding polypeptide can comprise 1 amino acid substitution to 10 amino acid substitutions. A substituted hIL-17 binding polypeptide can comprise 1 amino acid substitution to 2 amino acid substitutions, 1 amino acid substitution to 3 amino acid substitutions, 1 amino acid substitution to 4 amino acid substitutions, 1 amino acid substitution to 5 amino acid substitutions, 1 amino acid substitution to 6 amino acid substitutions, 1 amino acid substitution to 7 amino acid substitutions, 1 amino acid substitution to 8 amino acid substitutions, 1 amino acid substitution to 9 amino acid substitutions, 1 amino acid substitution to 10 amino acid substitutions, 2 amino acid substitutions to 3 amino acid substitutions, 2 amino acid substitutions to 4 amino acid substitutions, 2 amino acid substitutions to 5 amino acid substitutions, 2 amino acid substitutions to 6 amino acid substitutions, 2 amino acid substitutions to 7 amino acid substitutions, 2 amino acid substitutions to 8 amino acid substitutions, 2 amino acid substitutions to 9 amino acid substitutions, 2 amino acid substitutions to 10 amino acid substitutions, 3 amino acid substitutions to 4 amino acid substitutions, 3 amino acid substitutions to 5 amino acid substitutions, 3 amino acid substitutions to 6 amino acid substitutions, 3 amino acid substitutions to 7 amino acid substitutions, 3 amino acid substitutions to 8 amino acid substitutions, 3 amino acid substitutions to 9 amino acid substitutions, 3 amino acid substitutions to 10 amino acid substitutions, 4 amino acid substitutions to 5 amino acid substitutions, 4 amino acid substitutions to 6 amino acid substitutions, 4 amino acid substitutions to 7 amino acid substitutions, 4 amino acid substitutions to 8 amino acid substitutions, 4 amino acid substitutions to 9 amino acid substitutions, 4 amino acid substitutions to 10 amino acid substitutions, 5 amino acid substitutions to 6 amino acid substitutions, 5 amino acid substitutions to 7 amino acid substitutions, 5 amino acid substitutions to 8 amino acid substitutions, 5 amino acid substitutions to 9 amino acid substitutions, 5 amino acid substitutions to 10 amino acid substitutions, 6 amino acid substitutions to 7 amino acid substitutions, 6 amino acid substitutions to 8 amino acid substitutions, 6 amino acid substitutions to 9 amino acid substitutions, 6 amino acid substitutions to 10 amino acid substitutions, 7 amino acid substitutions to 8 amino acid substitutions,

[0152] 7 amino acid substitutions to 9 amino acid substitutions, 7 amino acid substitutions to 10 amino acid substitutions, 8 amino acid substitutions to 9 amino acid substitutions,

[0153] 8 amino acid substitutions to 10 amino acid substitutions, or 9 amino acid substitutions to 10 amino acid substitutions. A substituted hIL-17 binding polypeptide can comprise 1 amino acid substitution, 2 amino acid substitutions, 3 amino acid substitutions, 4 amino acid substitutions, 5 amino acid substitutions, 6 amino acid substitutions, 7 amino acid substitutions, 8 amino acid substitutions, 9 amino acid substitutions, or 10 amino acid substitutions. A substituted hIL-17 binding polypeptide can comprise at least 1 amino acid substitution, 2 amino acid substitutions, 3 amino acid substitutions, 4 amino acid substitutions, 5 amino acid substitutions, 6 amino acid substitutions, 7 amino acid substitutions, 8 amino acid substitutions, or 9 amino acid substitutions. A substituted hIL-17 binding polypeptide can comprise at most 2 amino acid substitutions, 3 amino acid substitutions, 4 amino acid substitutions, 5 amino acid substitutions, 6 amino acid substitutions, 7 amino acid substitutions, 8 amino acid substitutions, 9 amino acid substitutions, or 10 amino acid substitutions.

[0154] A substituted hIL-17 binding polypeptide can comprise 1% to 5% substituted amino acids. A substituted hIL-17 binding polypeptide can comprise about 1% substituted amino acid to about 10% substituted amino acids. A substituted hIL-17 binding polypeptide can comprise about 1% substituted amino acid to about 2% substituted amino acids, about 1% substituted amino acid to about 3% substituted amino acids, about 1% substituted amino acid to about 4% substituted amino acids, about 1% substituted amino acid to about 5% substituted amino acids, about 1% substituted amino acid to about 6% substituted amino acids, about 1% substituted amino acid to about 7% substituted amino acids, about 1% substituted amino acid to about 8% substituted amino acids, about 1% substituted amino acid to about 9% substituted amino acids, about 1% substituted amino acid to about 10% substituted amino acids, about 2% substituted amino acids to about 3% substituted amino acids, about 2% substituted amino acids to about 4% substituted amino acids, about 2% substituted amino acids to about 5% substituted amino acids, about 2% substituted amino acids to about 6% substituted amino acids, about 2% substituted amino acids to about 7% substituted amino acids, about 2% substituted amino acids to about 8% substituted amino acids, about 2% substituted amino acids to about 9% substituted amino acids, about 2% substituted amino acids to about 10% substituted amino acids, about 3% substituted amino acids to about 4% substituted amino acids, about 3% substituted amino acids to about 5% substituted amino acids, about 3% substituted amino acids to about 6% substituted amino acids, about 3% substituted amino acids to about 7% substituted amino acids, about 3% substituted amino acids to about 8% substituted amino acids, about 3% substituted amino acids to about 9% substituted amino acids, about 3% substituted amino acids to about 10% substituted amino acids, about 4% substituted amino acids to about 5% substituted amino acids, about 4% substituted amino acids to about 6% substituted amino acids, about 4% substituted amino acids to about 7% substituted amino acids, about 4% substituted amino acids to about 8% substituted amino acids, about 4% substituted amino acids to about 9% substituted amino acids, about 4% substituted amino acids to about 10% substituted amino acids, about 5% substituted amino acids to about 6% substituted amino acids, about 5% substituted amino acids to about 7% substituted amino acids, about 5% substituted amino acids to about 8% substituted amino acids, about 5% substituted amino acids to about 9% substituted amino acids, about 5% substituted amino acids to about 10% substituted amino acids, about 6% substituted amino acids to about 7% substituted amino acids, about 6% substituted amino acids to about 8% substituted amino acids, about 6% substituted amino acids to about 9% substituted amino acids, about 6% substituted amino acids to about 10% substituted amino acids, about 7% substituted amino acids to about 8% substituted amino acids, about 7% substituted amino acids to about 9% substituted amino acids, about 7% substituted amino acids to about 10% substituted amino acids, about 8% substituted amino acids to about 9% substituted amino acids, about 8% substituted amino acids to about 10% substituted amino acids, or about 9% substituted amino acids to about 10% substituted amino acids. A substituted hIL-17 binding polypeptide can comprise about 1% substituted amino acid, about 2% substituted amino acids, about 3% substituted amino acids, about 4% substituted amino acids, about 5% substituted amino acids, about 6% substituted amino acids, about 7% substituted amino acids, about 8% substituted amino acids, about 9% substituted amino acids, or about 10% substituted amino acids. A substituted hIL-17 binding polypeptide can comprise at least about 1% substituted amino acid, about 2% substituted amino acids, about 3% substituted amino acids, about 4% substituted amino acids, about 5% substituted amino acids, about 6% substituted amino acids, about 7% substituted amino acids, about 8% substituted amino acids, or about 9% substituted amino acids. A substituted hIL-17 binding polypeptide can comprise at most about 2% substituted amino acids, about 3% substituted amino acids, about 4% substituted amino acids, about 5% substituted amino acids, about 6% substituted amino acids, about 7% substituted amino acids, about 8% substituted amino acids, about 9% substituted amino acids, or about 10% substituted amino acids. An hIL-17 binding polypeptide can block hIL-17A or hlL- 17F-mediated cell signaling in a dose-dependent manner.

[0155] Amino acids can be classified based on chemical and structural properties of their sidechains, for example, naturally-occurring amino acids can be classified as hydrophobic (Met, Ala, Vai, Leu, and He), neutral hydrophilic (Cys, Ser, Thr, Asn, and Gin), acidic (Asp and Glu), basic (His, Lys, and Arg), chain orienting (Gly and Pro), and aromatic (Trp, Tyr, and Phe).

[0156] In some embodiments, a conservative amino acid substitution is made by substituting an amino acid of one of the above classes with a different member of that class. In some embodiments, conservative substitutions encompass non-naturally occurring amino acid residues, including peptidomimetics and other reversed or inverted forms of amino acid moi eties. In some embodiments, a non-conservative substitution is made by substituting an amino acid of one of the above classes with a member of a different class.

[0157] In some embodiments, substitution takes into account the hydropathic index of an amino acid (see, e.g., Kyte et al.. 1982, J. Mol. Biol. 157: 105-131, incorporated herein by reference). The hydropathic profile of a peptide can be calculated by giving each amino acid a numerical value, or hydropathy index, and repetitively averaging these values along the peptide chain. In such embodiments, each amino acid is assigned a hydropathic index based on hydrophobicity and charge characteristics. In some embodiments, the hydropathic indices used are: isoleucine (+4.5); valine (+4.2); leucine (+3.8); phenylalanine (+2.8); cysteine / cystine (+2.5); methionine (+1.9); alanine (+1.8); glycine (-0.4); threonine (-0.7); serine (-0.8); tryptophan (-0.9); tyrosine (-1.3); proline (-1.6); histidine (-3.2); glutamate (-3.5); glutamine (-3.5); aspartate (-3.5); asparagine (-3.5); lysine (-3.9); and arginine (-4.5). In some embodiments, an amino acid is substituted with a different amino acid having a hydropathic index within 0.1 to 0.5 of the original amino acid. In some embodiments, the hydropathic index is within 0.1, 0.2, 0.3, 0.4, or 0.5 of the original amino acid.

[0158] In some embodiments, amino acid substitutions are be made based on hydrophilicity. In some embodiments, the hydrophilicity values used are: arginine (+3.0); lysine (+3.0); aspartate (+3.0.+-.1); glutamate (+3.0.+-.1); serine (+0.3); asparagine (+0.2); glutamine (+0.2); glycine (0); threonine (-0.4); proline (-0.5.+-.1); alanine (-0.5); histidine (-0.5); cysteine (-1.0); methionine (-1.3); valine (-1.5); leucine (-1.8); isoleucine (-1.8); tyrosine (-2.3); phenylalanine (-2.5) and tryptophan (-3.4).

[0159] In some embodiments, an amino acid is substituted with a different amino acid having a hydrophilicity value within 0.1 to 0.5 of the original amino acid. In some embodiments, the hydrophilicity value is within 0.1, 0.2, 0.3, 0.4, or 0.5 of the original amino acid.

[0160] In some embodiments, an amino acid is substituted as shown in the table below. In some embodiments, an amino acid is replaced with a conservative substitution as set forth in Table 8(1), or a derivative (also referred to as an analog herein) of a conservative substitution. In some embodiments, an amino acid is replaced with an alternative substitution as set forth in Table 8(11), showing each full list of alternatives for each amino acid, or a derivative of an alternative substitution. Table 8. Amino Acid Substitutions

[0161] Human IL-17 Binding Polypeptide Composition Activity

[0162] An hIL-17 binding polypeptide composition of the present invention can have a desired activity including, but not limited to a high hIL-17 binding affinity, binding avidity, binding specificity, stability, potency (e.g., a biological effect resulting from binding), or a combination thereof. An hIL-17 binding polypeptide multimer composition can bind to hIL-17 with high avidity. A binding polypeptide multimer composition can comprise a single-chain linked dimer. An hIL-17 binding polypeptide composition of the present invention, e.g., a monomeric or dimeric composition, can bind to the hIL-17 target with higher affinity, avidity, specificity, stability, or have a higher potency relative to a control composition (also referred to herein as “control”). The control can be any hIL-17 binding composition known in the art or described herein, e.g., an original or parent hIL-17 binding polypeptide, an antibody, peptide, small molecule, or other compound selected by a skilled artisan for comparison with the hIL-17 binding polypeptide composition. The hIL-17 binding antibody can be any known in the art, e.g., secukinumab or bimekizumab. In some embodiments, the hIL-17 binding polypeptide multimer composition is dimeric, wherein one monomer or binding region of the hIL-17 binding polypeptide dimer binds to the first of two hIL-17R binding surfaces of a single hIL-17 cytokine dimer, and the other monomer / binding region of the hIL-17 binding polypeptide dimer binds to the second of the two binding surfaces of the same single hIL-17 cytokine dimer. That is, the hIL-17 binding polypeptide multimer composition is dimeric, wherein each of the two monomers or binding regions binds to and / or otherwise interacts with a different surface of a single hIL-17A homodimer. In some embodiments, each of the two monomers or binding regions of the dimeric hIL-17 binding polypeptide binds to and / or interacts with a different surface of a single hIL-17F homodimer. In some embodiments, each of the two monomers or binding regions binds to and / or interacts with a different surface of a single hIL-17A / hIL-17F heterodimer. In some embodiments, one of the two monomers or binding regions binds to or otherwise interacts with one hIL-17A, hIL17F, or hIL-17A / hIL-17F cytokine dimer, and the second of the two monomers or binding regions binds to or interacts with a different hIL-17A, hIL17F, or hIL-17A / hIL-17F cytokine dimer. In some embodiments, the hIL-17 binding polypeptide multimer composition is monomeric, wherein the monomer or binding region binds to or otherwise interacts with one surface of one hIL-17A, hIL17F, or hIL-17A / hIL-17F cytokine dimer.

[0163] The presence of multiple hIL-17 binding polypeptides in a multimeric hIL-17 binding polypeptide composition of the present invention can result in an increase in the activity of the composition, e.g., hIL-17 target binding affinity, binding avidity, stability, binding specificity, and / or potency (which can be driven by a binding quality). A multimeric composition can comprise a linear fusion of multiple hIL-17 binding polypeptides, e.g., an hIL-17 binding polypeptide dimer wherein the two hlL- 17 binding polypeptides are fused through a linker as described herein and as provided by the formula, from N to C terminus, A-(linker-B)n. An hIL-17 binding polypeptide composition comprising more than one hIL-17 binding polypeptide, e.g., 1-10 hIL-17 binding polypeptides, can result in an increase in an activity, e.g., avidity, relative to a control, e.g., a monomeric composition (comprising a single hIL-17 binding polypeptide). The increased activity and / or potency of an hIL-17 binding polypeptide composition provided herein (including a multimeric composition), on its hIL-17 target can in turn result in a change in an hIL-17 activity. The change can be an increase or a decrease. The resulting change in an hIL-17 activity can be a decrease in an hIL-17-associated inflammatory activity relative to a control. The resulting change in an hIL-17 activity can be an increase in an hIL-17-associated antiinflammatory activity relative to a control. The hIL-17 activity can be any understood by one of skill in the art.

[0164] An hIL-17 binding polypeptide monomeric or multimeric composition can have an activity (e.g., hIL-17 target binding affinity, binding avidity, binding specificity, binding stability, and / or potency) relative a control that is increased by about 2-fold to about 70,000-fold. When compared to a control composition, an hlL- 17 binding polypeptide composition can be referred to as a test composition, and the control can be referred to as a control composition. The control can be any desired to be tested by one of skill in the art. As examples, the control can be selected from a composition comprising: a parent binding polypeptide, e.g., the original (wild-type) binding polypeptide, an intervening predecessor binding polypeptide (i.e., a predecessor binding polypeptide derived ultimately from the same original / parent binding polypeptide), a corresponding non-modified binding polypeptide (when the test binding polypeptide is modified by, e.g., one or more disulfide-bonds); a different number of linked binding polypeptide monomers (e.g., when the test binding polypeptide is multimeric, a control can be the corresponding monomer or can be a multimer comprising a different number of monomers, for example, a test trimer compared to a control dimer); a binding polypeptide composition comprising other differences (e.g., N- or C- terminal modifications, different linker sequence(s), etc.); any agent (including a polypeptide, an antibody, an antibody derivative, or a small molecule) that targets the same hIL-17 subunit(s); and any agent that targets a different hIL-17 subunit(s) than the test binding polypeptide.

[0165] An hIL-17 binding polypeptide composition (monomeric or multimeric, that binds to, e.g., hIL-17A or hIL-17F) can have an activity (e.g., hIL-17 target binding affinity, avidity, specificity, stability, and / or potency) relative a control that is increased by about 2-fold to about 70,000-fold. An hIL-17 binding polypeptide monomeric or multimeric composition can have an activity (e.g., hIL-17 target binding affinity, avidity, specificity, stability, and / or potency) that is increased relative to the same activity in a control by about 2-fold to about 70,000-fold. An hlL- 17 binding polypeptide monomeric or multimeric composition can have an activity (e.g., hIL-17 target binding affinity, avidity, specificity, stability, and / or potency) that is increased relative to the same activity in a control by about 2-fold to about 5-fold, about 2-fold to about 10-fold, about 2-fold to about 100-fold, about 2-fold to about 200-fold, about 2-fold to about 300-fold, about 2-fold to about 2,500-fold, about 2- fold to about 2,800-fold, about 2-fold to about 10,000-fold, about 2-fold to about 25,000-fold, about 2-fold to about 60,000-fold, about 2-fold to about 70,000-fold, about 5-fold to about 10-fold, about 5-fold to about 100-fold, about 5-fold to about 200-fold, about 5-fold to about 300-fold, about 5-fold to about 2,500-fold, about 5- fold to about 2,800-fold, about 5-fold to about 10,000-fold, about 5-fold to about 25,000-fold, about 5-fold to about 60,000-fold, about 5-fold to about 70,000-fold, about 10-fold to about 100-fold, about 10-fold to about 200-fold, about 10-fold to about 300-fold, about 10-fold to about 2,500-fold, about 10-fold to about 2,800-fold, about 10-fold to about 10,000-fold, about 10-fold to about 25,000-fold, about 10-fold to about 60,000-fold, about 10-fold to about 70,000-fold, about 100-fold to about 200- fold, about 100-fold to about 300-fold, about 100-fold to about 2,500-fold, about 100- fold to about 2,800-fold, about 100-fold to about 10,000-fold, about 100-fold to about 25,000-fold, about 100-fold to about 60,000-fold, about 100-fold to about 70,000- fold, about 200-fold to about 300-fold, about 200-fold to about 2,500-fold, about 200- fold to about 2,800-fold, about 200-fold to about 10,000-fold, about 200-fold to about 25,000-fold, about 200-fold to about 60,000-fold, about 200-fold to about 70,000- fold, about 300-fold to about 2,500-fold, about 300-fold to about 2,800-fold, about 300-fold to about 10,000-fold, about 300-fold to about 25,000-fold, about 300-fold to about 60,000-fold, about 300-fold to about 70,000-fold, about 2,500-fold to about

[0166] 2.800-fold, about 2,500-fold to about 10,000-fold, about 2,500-fold to about 25,000- fold, about 2,500-fold to about 60,000-fold, about 2,500-fold to about 70,000-fold, about 2,800-fold to about 10,000-fold, about 2,800-fold to about 25,000-fold, about

[0167] 2.800-fold to about 60,000-fold, about 2,800-fold to about 70,000-fold, about 10,000- fold to about 25,000-fold, about 10,000-fold to about 60,000-fold, about 10,000-fold to about 70,000-fold, about 25,000-fold to about 60,000-fold, about 25,000-fold to about 70,000-fold, or about 60,000-fold to about 70,000-fold. An hIL-17 binding polypeptide monomeric or multimeric composition can have an activity (e.g., hIL-17 target binding affinity, avidity, specificity, stability, and / or potency) that is increased relative to the same activity in a control by about 2-fold, about 5-fold, about 10-fold, about 100-fold, about 200-fold, about 300-fold, about 2,500-fold, about 2,800-fold, about 10,000-fold, about 25,000-fold, about 60,000-fold, or about 70,000-fold. An hIL-17 binding polypeptide monomeric or multimeric composition can have an activity (e.g., hIL-17 target binding affinity, avidity, specificity, stability, and / or potency) that is increased relative to the same activity in a control by at least about 2- fold, about 5-fold, about 10-fold, about 100-fold, about 200-fold, about 300-fold, about 2,500-fold, about 2,800-fold, about 10,000-fold, about 25,000-fold, or about 60,000-fold. An hIL-17 binding polypeptide monomeric or multimeric composition can have an activity (e.g., hIL-17 target binding affinity, avidity, specificity, stability, and / or potency) that is increased relative to the same activity in a control by at most about 5-fold, about 10-fold, about 100-fold, about 200-fold, about 300-fold, about 2,500-fold, about 2,800-fold, about 10,000-fold, about 25,000-fold, about 60,000-fold, or about 70,000-fold. The test binding polypeptide composition can be a dimeric hlL- 17A binding polypeptide composition. The test binding polypeptide composition can be a dimeric hIL-17A binding polypeptide composition and the control can be a corresponding monomeric hIL-17A binding polypeptide composition. The test binding polypeptide composition can be a dimeric hIL-17A binding polypeptide composition and the control composition can be an agent that targets the hlL- 17A / hIL-17R interaction. The test binding polypeptide composition can be a dimeric hIL-17A binding polypeptide composition and the control composition can be an agent that targets the hIL-17F / hIL-17R interaction. The test binding polypeptide composition can be a dimeric hIL-17F binding polypeptide composition. The test binding polypeptide composition can be a dimeric hIL-17F binding polypeptide composition and the control composition can be a corresponding monomeric hIL-17F binding polypeptide composition. The test binding polypeptide composition can be a dimeric hIL-17F binding polypeptide composition and the control composition can be an agent that targets the hIL-17F / hIL-17R interaction. The test binding polypeptide composition can be a dimeric hIL-17F binding polypeptide composition and the control composition can be an agent that targets the hIL-17A / hIL-17R interaction.

[0168] An hIL-17 monomeric or multimeric (e.g., dimeric or trimeric) binding polypeptide composition can have an activity (e.g., hIL-17 target binding affinity, binding avidity, binding specificity, binding stability, and / or potency) relative a control that is decreased by about 2-fold to about 10,000-fold, wherein the control is an agent that targets a different hIL-17 / hIL-17R interaction. As an example, an hlL- 17F-binding polypeptide composition can have an hIL-17A activity (e.g., hIL-17A target binding affinity, avidity, specificity, stability, and / or potency) relative to an agent that targets an hIL-17A / hIL-17R interaction that is decreased by about 2-fold to about 10,000-fold. Similarly, an hIL-17A-binding polypeptide composition can have an hIL-17F activity relative to an agent that targets an hIL-17F / hIL-17R interaction that is decreased by about 2-fold to about 10,000-fold. An hIL-17 monomeric or multimeric binding polypeptide composition can have an activity relative a control composition, wherein the control is an agent known to target a different hIL-17 / hIL- 17R interaction, that is decreased by about 2-fold to about 50-fold, about 2-fold to about 100-fold, about 2-fold to about 250-fold, about 2-fold to about 300-fold, about 2-fold to about 500-fold, about 2-fold to about 750-fold, about 2-fold to about 1,000- fold, about 2-fold to about 2,500-fold, about 2-fold to about 5,000-fold, about 2-fold to about 7,500-fold, about 2-fold to about 10,000-fold, about 50-fold to about 100- fold, about 50-fold to about 250-fold, about 50-fold to about 300-fold, about 50-fold to about 500-fold, about 50-fold to about 750-fold, about 50-fold to about 1,000-fold, about 50-fold to about 2,500-fold, about 50-fold to about 5,000-fold, about 50-fold to about 7,500-fold, about 50-fold to about 10,000-fold, about 100-fold to about 250- fold, about 100-fold to about 300-fold, about 100-fold to about 500-fold, about 100- fold to about 750-fold, about 100-fold to about 1,000-fold, about 100-fold to about 2,500-fold, about 100-fold to about 5,000-fold, about 100-fold to about 7,500-fold, about 100-fold to about 10,000-fold, about 250-fold to about 300-fold, about 250-fold to about 500-fold, about 250-fold to about 750-fold, about 250-fold to about 1,000- fold, about 250-fold to about 2,500-fold, about 250-fold to about 5,000-fold, about 250-fold to about 7,500-fold, about 250-fold to about 10,000-fold, about 300-fold to about 500-fold, about 300-fold to about 750-fold, about 300-fold to about 1,000-fold, about 300-fold to about 2,500-fold, about 300-fold to about 5,000-fold, about 300- fold to about 7,500-fold, about 300-fold to about 10,000-fold, about 500-fold to about 750-fold, about 500-fold to about 1,000-fold, about 500-fold to about 2,500-fold, about 500-fold to about 5,000-fold, about 500-fold to about 7,500-fold, about 500- fold to about 10,000-fold, about 750-fold to about 1,000-fold, about 750-fold to about

[0169] 2.500-fold, about 750-fold to about 5,000-fold, about 750-fold to about 7,500-fold, about 750-fold to about 10,000-fold, about 1,000-fold to about 2,500-fold, about 1,000-fold to about 5,000-fold, about 1,000-fold to about 7,500-fold, about 1,000-fold to about 10,000-fold, about 2,500-fold to about 5,000-fold, about 2,500-fold to about

[0170] 7.500-fold, about 2,500-fold to about 10,000-fold, about 5,000-fold to about 7,500- fold, about 5,000-fold to about 10,000-fold, or about 7,500-fold to about 10,000-fold. An hIL-17 monomeric or multimeric binding polypeptide composition can have an activity relative a control, wherein the control is an agent known to target a different hIL-17 / hIL-17R interaction, that is decreased by about 2-fold, about 50-fold, about 100-fold, about 250-fold, about 300-fold, about 500-fold, about 750-fold, about 1,000-fold, about 2,500-fold, about 5,000-fold, about 7,500-fold, or about 10,000- fold. An hIL-17 monomeric or multimeric binding polypeptide composition can have an activity relative a control composition, wherein the control is an agent known to target a different hIL-17 / hIL-17R interaction, that is decreased by at least about 2- fold, about 50-fold, about 100-fold, about 250-fold, about 300-fold, about 500-fold, about 750-fold, about 1,000-fold, about 2,500-fold, about 5,000-fold, or about 7,500- fold. An hIL-17 monomeric or multimeric binding polypeptide composition can have an activity relative a control composition, wherein the control is an agent known to target a different hIL-17 / hIL-17R interaction, that is decreased by at most about 50- fold, about 100-fold, about 250-fold, about 300-fold, about 500-fold, about 750-fold, about 1,000-fold, about 2,500-fold, about 5,000-fold, about 7,500-fold, or about 10,000-fold. The test binding polypeptide composition can be a dimeric hIL-17A binding polypeptide composition. The test binding polypeptide composition can be a dimeric hIL-17F binding polypeptide composition.

[0171] A monomeric or multimeric (e.g., dimeric or trimeric) hIL-17 binding polypeptide composition can have an activity (e.g., hIL-17 target binding affinity, binding avidity, binding specificity, binding stability, and / or potency) relative a control that is increased by about 2-fold to about 10,000-fold, wherein the control is an agent that targets a similar or the same hIL-17 / hIL-17R interaction. As an example, a monomeric or multimeric hIL-17A-binding polypeptide composition can have an hIL-17A activity (e.g., hIL-17A target binding affinity, avidity, specificity, stability, and / or potency) relative to a control agent that targets an hIL-17A / hIL-17R interaction (e.g., by binding to either hIL-17A or hIL-17R) that is increased by about 2-fold to about 10,000-fold. In some embodiments, an hIL-17 binding polypeptide dimeric composition can have an hIL-17 activity that is increased by about 2-fold to about 10,000-fold relative to the control agent. In some embodiments, an hIL-17A binding polypeptide dimeric composition can have an hIL-17A activity that is increased by about 2-fold to about 10,000-fold relative to a control, wherein the control is an antibody. The control can be bimekizumab or secukinumab. The monomeric or multimeric (e.g., dimeric) hIL-17 (e.g., hIL-17A or hIL-17F) binding polypeptide composition can have an activity (e.g., hIL-17A or hIL-17F, respectively, target binding affinity, avidity, specificity, stability, and / or potency) relative to a control composition, wherein the control is an agent that targets a similar or the same hIL-17 / hIL-17R interaction as the test binding polypeptide, that is increased by about 2-fold to about 10,000-fold. The monomeric or multimeric (e.g., dimeric) hIL-17 (e.g., hIL-17A or hIL-17F) binding polypeptide composition can have an activity (e.g., hIL-17A or hIL-17F, respectively, target binding affinity, avidity, specificity, stability, and / or potency) relative to a control composition, wherein the control is an agent that targets a similar or the same hIL-17 / hIL-17R interaction as the test binding polypeptide, that is increased by about 2-fold to about 10,000-fold. The monomeric or multimeric (e.g., dimeric) hIL-17 (e.g., hIL-17A or hIL-17F) binding polypeptide composition can have an activity (e.g., hIL-17A or hIL-17F, respectively, target binding affinity, avidity, specificity, stability, and / or potency) relative to a control composition, wherein the control is an agent that targets a similar or the same hlL- 17 / hIL-17R interaction as the test binding polypeptide, that is increased by about 2- fold to about 50-fold, about 2-fold to about 100-fold, about 2-fold to about 200-fold, about 2-fold to about 250-fold, about 2-fold to about 500-fold, about 2-fold to about 750-fold, about 2-fold to about 1,000-fold, about 2-fold to about 2,500-fold, about 2- fold to about 5,000-fold, about 2-fold to about 7,500-fold, about 2-fold to about 10,000-fold, about 50-fold to about 100-fold, about 50-fold to about 200-fold, about 50-fold to about 250-fold, about 50-fold to about 500-fold, about 50-fold to about 750-fold, about 50-fold to about 1,000-fold, about 50-fold to about 2,500-fold, about 50-fold to about 5,000-fold, about 50-fold to about 7,500-fold, about 50-fold to about 10,000-fold, about 100-fold to about 200-fold, about 100-fold to about 250-fold, about 100-fold to about 500-fold, about 100-fold to about 750-fold, about 100-fold to about 1,000-fold, about 100-fold to about 2,500-fold, about 100-fold to about 5,000- fold, about 100-fold to about 7,500-fold, about 100-fold to about 10,000-fold, about 200-fold to about 250-fold, about 200-fold to about 500-fold, about 200-fold to about 750-fold, about 200-fold to about 1,000-fold, about 200-fold to about 2,500-fold, about 200-fold to about 5,000-fold, about 200-fold to about 7,500-fold, about 200- fold to about 10,000-fold, about 250-fold to about 500-fold, about 250-fold to about 750-fold, about 250-fold to about 1,000-fold, about 250-fold to about 2,500-fold, about 250-fold to about 5,000-fold, about 250-fold to about 7,500-fold, about 250- fold to about 10,000-fold, about 500-fold to about 750-fold, about 500-fold to about 1,000-fold, about 500-fold to about 2,500-fold, about 500-fold to about 5,000-fold, about 500-fold to about 7,500-fold, about 500-fold to about 10,000-fold, about 750- fold to about 1,000-fold, about 750-fold to about 2,500-fold, about 750-fold to about 5,000-fold, about 750-fold to about 7,500-fold, about 750-fold to about 10,000-fold, about 1,000-fold to about 2,500-fold, about 1,000-fold to about 5,000-fold, about 1,000-fold to about 7,500-fold, about 1,000-fold to about 10,000-fold, about 2,500- fold to about 5,000-fold, about 2,500-fold to about 7,500-fold, about 2,500-fold to about 10,000-fold, about 5,000-fold to about 7,500-fold, about 5,000-fold to about 10,000-fold, or about 7,500-fold to about 10,000-fold. The monomeric or multimeric hIL-17 binding polypeptide composition can have an activity relative to a control composition, wherein the control is an agent that targets a similar or the same hlL- 17 / hIL-17R interaction as the test binding polypeptide, that is increased by about 2- fold, about 50-fold, about 100-fold, about 200-fold, about 250-fold, about 500-fold, about 750-fold, about 1,000-fold, about 2,500-fold, about 5,000-fold, about 7,500- fold, or about 10,000-fold. The monomeric or multimeric hIL-17 binding polypeptide composition can have an activity relative to a control composition, wherein the control is an agent that targets a similar or the same hIL-17 / hIL-17R interaction as the test binding polypeptide, that is increased by at least about 2-fold, about 50-fold, about 100-fold, about 200-fold, about 250-fold, about 500-fold, about 750-fold, about 1,000-fold, about 2,500-fold, about 5,000-fold, or about 7,500-fold. The monomeric or multimeric hIL-17 binding polypeptide composition can have an activity relative to a control composition, wherein the control is an agent that targets a similar or the same hIL-17 / hIL-17R interaction as the test binding polypeptide, that is increased by at most about 50-fold, about 100-fold, about 200-fold, about 250-fold, about 500-fold, about 750-fold, about 1,000-fold, about 2,500-fold, about 5,000-fold, about 7,500- fold, or about 10,000-fold.

[0172] As described above, an hIL-17 binding polypeptide dimeric composition can have an activity relative to the original or a predecessor monomer, or to the corresponding monomeric composition, that is increased by about 2-fold to about 70,000-fold.

[0173] In some embodiments, an hIL-17 binding polypeptide dimeric composition has an activity relative to a control corresponding monomeric composition (e.g., comprising the same monomer that is linked in the test dimer) that is increased by about 2-fold to about 10,000-fold. An hIL-17 binding polypeptide dimeric composition can have an activity relative to a control corresponding monomeric composition that is increased by about 2-fold to about 50-fold, about 2-fold to about 100-fold, about 2-fold to about 250-fold, about 2-fold to about 500-fold, about 2-fold to about 1,000-fold, about 2-fold to about 2,000-fold, about 2-fold to about 2,500- fold, about 2-fold to about 2,800-fold, about 2-fold to about 5,000-fold, about 2-fold to about 7,500-fold, about 2-fold to about 10,000-fold, about 50-fold to about 100- fold, about 50-fold to about 250-fold, about 50-fold to about 500-fold, about 50-fold to about 1,000-fold, about 50-fold to about 2,000-fold, about 50-fold to about 2,500- fold, about 50-fold to about 2,800-fold, about 50-fold to about 5,000-fold, about 50- fold to about 7,500-fold, about 50-fold to about 10,000-fold, about 100-fold to about 250-fold, about 100-fold to about 500-fold, about 100-fold to about 1,000-fold, about 100-fold to about 2,000-fold, about 100-fold to about 2,500-fold, about 100-fold to about 2,800-fold, about 100-fold to about 5,000-fold, about 100-fold to about 7,500- fold, about 100-fold to about 10,000-fold, about 250-fold to about 500-fold, about 250-fold to about 1,000-fold, about 250-fold to about 2,000-fold, about 250-fold to about 2,500-fold, about 250-fold to about 2,800-fold, about 250-fold to about 5,000- fold, about 250-fold to about 7,500-fold, about 250-fold to about 10,000-fold, about 500-fold to about 1,000-fold, about 500-fold to about 2,000-fold, about 500-fold to about 2,500-fold, about 500-fold to about 2,800-fold, about 500-fold to about 5,000- fold, about 500-fold to about 7,500-fold, about 500-fold to about 10,000-fold, about 1,000-fold to about 2,000-fold, about 1,000-fold to about 2,500-fold, about 1,000-fold to about 2,800-fold, about 1,000-fold to about 5,000-fold, about 1,000-fold to about 7,500-fold, about 1,000-fold to about 10,000-fold, about 2,000-fold to about 2,500- fold, about 2,000-fold to about 2,800-fold, about 2,000-fold to about 5,000-fold, about 2,000-fold to about 7,500-fold, about 2,000-fold to about 10,000-fold, about 2,500- fold to about 2,800-fold, about 2,500-fold to about 5,000-fold, about 2,500-fold to about 7,500-fold, about 2,500-fold to about 10,000-fold, about 2,800-fold to about 5,000-fold, about 2,800-fold to about 7,500-fold, about 2,800-fold to about 10,000- fold, about 5,000-fold to about 7,500-fold, about 5,000-fold to about 10,000-fold, or about 7,500-fold to about 10,000-fold. An hIL-17 binding polypeptide dimeric composition can have an activity relative to a control corresponding monomeric composition that is increased by about 2-fold, about 50-fold, about 100-fold, about 250-fold, about 500-fold, about 1,000-fold, about 2,000-fold, about 2,500-fold, about 2,800-fold, about 5,000-fold, about 7,500-fold, or about 10,000-fold. An hIL-17 binding polypeptide dimeric composition can have an activity relative to a control corresponding monomeric composition that is increased by at least about 2-fold, about 50-fold, about 100-fold, about 250-fold, about 500-fold, about 1,000-fold, about 2,000-fold, about 2,500-fold, about 2,800-fold, about 5,000-fold, or about 7,500-fold. An hIL-17 binding polypeptide dimeric composition can have an activity relative to a control corresponding monomeric composition that is increased by at most about 50- fold, about 100-fold, about 250-fold, about 500-fold, about 1,000-fold, about 2,000- fold, about 2,500-fold, about 2,800-fold, about 5,000-fold, about 7,500-fold, or about 10,000-fold.

[0174] The binding and / or other interaction between the one or more monomer or binding region of the hIL-17 binding polypeptide composition and the hIL-17 subunit targeted can modulate an hIL-17 activity. The activity can be the binding of hIL-17 to hIL-17R. The modulation can be upregulation of binding to hIL-17R or downregulation of binding to hIL-17R. The activity can be one that occurs upon or following binding of hIL-17 to hIL-17R, e.g., a downstream event. The activity can be one that occurs normally or in a subject having an abnormal, e.g., diseased, state. An abnormal state can be the presence of an inflammatory disorder, including those described herein. The modulation of hIL-17 to hIL-17R binding can be evaluated in vitro or in vivo by any known method, over any amount of time, including by measurement of any activity known to be affected by a compound that affects, e.g., inhibits or stimulates, hIL-17 binding to hIL-17R. The hIL-17 activity can be an effect on inflammation, e.g., an increase in inflammation in a subject. The inflammation can be Tnl7-mediated inflammation. The evaluation of the modulation of the activity by the hIL-17 binding polypeptide composition can comprise comparison to a control. A control can comprise the absence of the hIL-17 binding polypeptide composition, or the presence of another composition, e.g., peptide or other compound, selected by a skilled artisan for comparison with the hIL-17 binding polypeptide composition, including, but not limited to, any hIL-17-binding molecule known in the art or described herein. A control can comprise comparison with a composition that does not bind to hIL-17. The control can comprise comparison of the hIL-17 binding polypeptide composition in a diseased subject or sample with a healthy subject or sample, e.g., a comparison of the effect of the hIL-17 binding polypeptide composition on an hIL-17 activity in a subject having an inflammatory disorder with a healthy subject. The upregulated or downregulated hIL-17 activity can affect a disease biomarker in a subject, e.g., can reduce a disease symptom or improve an assessment score. A disease biomarker can be any tool or combination of tools known in the art for assessing the severity of the condition, including a disease activity score, inflammatory biomarker data, clinical examination data, transcriptomic data, and patient-reported data on symptom severity. For example, a disease biomarker in a subject having multiple sclerosis can be selected from brain lesion characteristics, CSF markers for inflammation (e.g., CSF neurofilament light chain (cNfL), immunoglobulin (Ig)G-index), a transcriptomic score, or any other marker known in the art, e.g., a biomarker as described in Yang, “Current and Future Biomarkers in Multiple Sclerosis,” Int. Journal of Molecular Sciences 23:5877, incorporated herein by reference, and any combination thereof. A disease biomarker in a subject having psoriasis can be selected from any known biomarker, e.g., skin clarity, itching, a blood marker for inflammation (e.g., C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR)), Psoriasis Area and Severity Index (PASI) score, Dermatology Life Quality Index (DLQI) score, Physician’s Global Assessment (PGA) score, a transcriptomic score, e.g., as described in WO 2023 / 278601, “METHODS AND SYSTEMS FOR MACHINE LEARNING ANALYSIS OF INFLAMMATORY SKIN DISEASES,” published Jan. 5, 2023 and incorporated herein by reference in its entirety, and any combination thereof. A disease biomarker in a subject having ankylosing spondylitis can be selected from any known biomarker, e.g., a transcriptomic score, disease scoring index, or a biomarker as described in J. D. Reveille, 2015, “Biomarkers for diagnosis, monitoring of progression, and treatment responses in ankylosing spondylitis and axial spondyloarthritis,” Clinical Rheumatology 34(6): 1009-1018, incorporated herein by reference, and any combination thereof. A disease biomarker in a subject having rheumatoid arthritis can be any known in the art, e.g.,: a blood marker for inflammation (e.g., C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR)), joint pain, joint swelling, joint erosion or other deformity measured by any known method (e.g., clinical examination, X-ray, or MRI), Clinical Disease Activity Index (CD Al), Disease Activity Scale-28 (DAS28-ESR / CRP), Patient Activity Scale II (PAS-II), Routine Assessment of Patient Index Data 3 (RAPID3), Simple Disease Activity Index (SDAI), Disease Activity Score (DAS), Patient Derived DAS28, Hospital Universitario La Princesa Index (HUP I), Multi-Biomarker Disease Activity Score (MBDA), Rheumatoid Arthritis Disease Activity Index (RAD Al), Rheumatoid Arthritis Disease Activity Index 5 (RADAI-5), Routine Assessment of Patient Index Data 5 (RAPID5), and any combination thereof.

[0175] An hIL-17 binding polypeptide composition can reduce or increase an hIL-17 activity in vitro or in vivo. An hIL-17 activity can be reduced or increased in a test sample in comparison to a control sample. The test sample can be from a test subject having a disorder, and a control sample can be from an untreated subject not having the disorder. The test sample can be from a test subject having a disorder treated with an hIL-17 binding polypeptide composition and the control sample from a subject having the disorder treated with a control composition (e.g., any as described herein). The test sample can be from a test subject having a disorder treated with a multimeric hIL-17 binding polypeptide composition and the control sample from a subject having the disorder treated with a monomeric hIL-17 binding polypeptide composition, respectively. The sample can be any understood to be useful in the art, e.g., any tissue -n- or body fluid, e.g., blood, or derived therefrom. In the test sample or subject, the hlL- 17 activity can be reduced or increased by about 10 to about 100 percent, e.g., in a treated test sample or subject compared with an untreated control. The hIL-17 activity can be reduced or increased by about 10% to about 20%, about 10% to about 25%, about 10% to about 35%, about 10% to about 50%, about 10% to about 60%, about 10% to about 70%, about 10% to about 80%, about 10% to about 85%, about 10% to about 90%, about 10% to about 95%, about 10% to about 100%, about 20% to about 25%, about 20% to about 35%, about 20% to about 50%, about 20% to about 60%, about 20% to about 70%, about 20% to about 80%, about 20% to about 85%, about 20% to about 90%, about 20% to about 95%, about 20% to about 100%, about 25% to about 35%, about 25% to about 50%, about 25% to about 60%, about 25% to about 70%, about 25% to about 80%, about 25% to about 85%, about 25% to about 90%, about 25% to about 95%, about 25% to about 100%, about 35% to about 50%, about 35% to about 60%, about 35% to about 70%, about 35% to about 80%, about 35% to about 85%, about 35% to about 90%, about 35% to about 95%, about 35% to about 100%, about 50% to about 60%, about 50% to about 70%, about 50% to about 80%, about 50% to about 85%, about 50% to about 90%, about 50% to about 95%, about 50% to about 100%, about 60% to about 70%, about 60% to about 80%, about 60% to about 85%, about 60% to about 90%, about 60% to about 95%, about 60% to about 100%, about 70% to about 80%, about 70% to about 85%, about 70% to about 90%, about 70% to about 95%, about 70% to about 100%, about 80% to about 85%, about 80% to about 90%, about 80% to about 95%, about 80% to about 100%, about 85% to about 90%, about 85% to about 95%, about 85% to about 100%, about 90% to about 95%, about 90% to about 100%, or about 95% to about 100%. The hIL-17 activity can be reduced or increased by about 10%, about 20%, about 25%, about 35%, about 50%, about 60%, about 70%, about 80%, about 85%, about 90%, about 95%, or about 100%. The hIL-17 activity can be reduced by at least about 10%, about 20%, about 25%, about 35%, about 50%, about 60%, about 70%, about 80%, about 85%, about 90%, or about 95%. The hIL-17 activity can be reduced or increased by at most about 20%, about 25%, about 35%, about 50%, about 60%, about 70%, about 80%, about 85%, about 90%, about 95%, or about 100%. For example, in a comparison between a treated disease subject or sample and an untreated healthy control subject or sample, a 100% reduction in an hIL-17 activity can indicate a reduction of the activity in the treated subject or sample to the level of the healthy control.

[0176] An hIL-17 binding polypeptide composition of the present invention can reduce or increase an hIL-17 activity by about 0.2-fold to about 10-fold in the test sample or subject compared to the control sample or subject. An hIL-17 binding polypeptide composition of the present invention can reduce or increase an hIL-17 activity by about 0.2-fold to about 10-fold. An hIL-17 binding polypeptide composition of the present invention can reduce or increase an hIL-17 activity by about 0.2-fold to about 0.5-fold, about 0.2-fold to about 1-fold, about 0.2-fold to about 2-fold, about 0.2-fold to about 3-fold, about 0.2-fold to about 4-fold, about 0.2- fold to about 5-fold, about 0.2-fold to about 6-fold, about 0.2-fold to about 7-fold, about 0.2-fold to about 8-fold, about 0.2-fold to about 9-fold, about 0.2-fold to about 10-fold, about 0.5-fold to about 1-fold, about 0.5-fold to about 2-fold, about 0.5-fold to about 3-fold, about 0.5-fold to about 4-fold, about 0.5-fold to about 5-fold, about 0.5-fold to about 6-fold, about 0.5-fold to about 7-fold, about 0.5-fold to about 8-fold, about 0.5-fold to about 9-fold, about 0.5-fold to about 10-fold, about 1-fold to about 2-fold, about 1-fold to about 3-fold, about 1-fold to about 4-fold, about 1-fold to about 5-fold, about 1-fold to about 6-fold, about 1-fold to about 7-fold, about 1-fold to about 8-fold, about 1-fold to about 9-fold, about 1-fold to about 10-fold, about 2-fold to about 3-fold, about 2-fold to about 4-fold, about 2-fold to about 5-fold, about 2-fold to about 6-fold, about 2-fold to about 7-fold, about 2-fold to about 8-fold, about 2-fold to about 9-fold, about 2-fold to about 10-fold, about 3-fold to about 4-fold, about 3-fold to about 5-fold, about 3-fold to about 6-fold, about 3-fold to about 7-fold, about 3-fold to about 8-fold, about 3 -fold to about 9-fold, about 3 -fold to about 10-fold, about 4- fold to about 5-fold, about 4-fold to about 6-fold, about 4-fold to about 7-fold, about 4-fold to about 8-fold, about 4-fold to about 9-fold, about 4-fold to about 10-fold, about 5-fold to about 6-fold, about 5-fold to about 7-fold, about 5-fold to about 8-fold, about 5-fold to about 9-fold, about 5-fold to about 10-fold, about 6-fold to about 7- fold, about 6-fold to about 8-fold, about 6-fold to about 9-fold, about 6-fold to about 10-fold, about 7-fold to about 8-fold, about 7-fold to about 9-fold, about 7-fold to about 10-fold, about 8-fold to about 9-fold, about 8-fold to about 10-fold, or about 9- fold to about 10-fold. An hIL-17 binding polypeptide composition of the present invention can reduce or increase an hIL-17 activity by about 0.2-fold, about 0.5-fold, about 1-fold, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, or about 10-fold. An hIL-17 binding polypeptide composition of the present invention can reduce or increase an hIL-17 activity by at least about 0.2-fold, about 0.5-fold, about 1-fold, about 2-fold, about 3- fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, or about 9- fold. An hIL-17 binding polypeptide composition of the present invention can reduce or increase an hIL-17 activity by at most about 0.5-fold, about 1-fold, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, or about 10-fold. For example, in a comparison between a test subject having an inflammatory disorder treated with a multimeric hIL-17 binding polypeptide composition with a control disease subject having the inflammatory disorder treated with a monomeric hIL-17 binding polypeptide composition, the hlL- 17 activity can be relatively reduced or increased by about 0.2-fold to about 10-fold.

[0177] The hIL-17 binding polypeptide or hIL-17 binding polypeptide composition can bind with high specificity, high avidity, and / or high affinity to the targeted hIL-17 subunit, e.g., a region of the subunit known involved in binding of the hIL-17 subunit to the hIL-17 receptor. The targeted hIL-17 subunit can be hIL-17A. The targeted hIL-17 subunit can be hIL-17F. The hIL-17 binding polypeptide or hIL-17 binding polypeptide composition can bind with higher specificity to hIL-17A than hIL-17F. The hIL-17 binding polypeptide or hIL-17 binding polypeptide composition can bind with higher specificity to hIL-17F than hIL-17A. An hIL-17 binding polypeptide can bind to both hIL-17A and hIL-17F with detectable affinities, e.g., as described in relation to peptides set forth in Table 2 and Table 3 herein, including peptides 17F- 01A4 (also referred to as F01A4; SEQ ID NO: 37) and derivatives, and 17F03S1 (also referred to as F03S1; SEQ ID NO: 65) and derivatives. This is further illustrated in Example 1 and FIGS. 4A-4D.

[0178] Activities including specificity, avidity, and affinity can be evaluated by any known method. The term “avidity” can be understood to refer to the resistance of a complex of two or more agents to dissociation after dilution. Apparent affinities can be determined by methods such as surface plasmon resonance (SPR), biolayer interferometry (BLI), a cell binding assay, an enzyme-linked immunosorbent assay (ELISA) or any other suitable technique. Avidities can be determined by methods such as a Scatchard analysis or any other suitable technique.

[0179] The term “affinity” can refer to the equilibrium constant for the reversible binding of two agents and is expressed as KD. The binding affinity (KD) of an IL- 17 binding polypeptide or composition described herein to IL- 17 can be less than 500 nM, 475 nM, 450 nM, 425 nM, 400 nM, 375 nM, 350 nM, 325 nM, 300 nM, 275 nM, 250 nM, 225 nM, 200 nM, 175 nM, 150 nM, 125 nM, 100 nM, 90 nM, 80 nM, 70 nM, 50 nM, 50 nM, 49 nM, 48 nM, 47 nM, 46 nM, 45 nM, 44 nM, 43 nM, 42 nM, 41 nM, 40 nM, 39 nM, 38 nM, 37 nM, 36 nM, 35 nM, 34 nM, 33 nM, 32 nM, 31 nM, 30 nM, 29 nM, 28 nM, 27 nM, 26 nM, 25 nM, 24 nM, 23 nM, 22 nM, 21 nM, 20 nM, 19 nM, 18 nM, 17 nM, 16 nM, 15 nM, 14 nM, 13 nM, 12 nM, 11 nM, 10 nM, 9 nM, 8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1.9 nM, 1.8 nM, 1.7 nM, 1.6 nM, 1.5 nM,

[0180] 1.4 nM, 1.3 nM, 1.2 nM, 1.1 nM, 1 nM, 990 pM, 980 pM, 970 pM, 960 pM, 950 pM, 940 pM, 930 pM, 920 pM, 910 pM, 900 pM, 890 pM, 880 pM, 870 pM, 860 pM, 850 pM, 840 pM, 830 pM, 820 pM, 810 pM, 800 pM, 790 pM, 780 pM, 770 pM, 760 pM, 750 pM, 740 pM, 730 pM, 720 pM, 710 pM, 700 pM, 690 pM, 680 pM, 670 pM, 660 pM, 650 pM, 640 pM, 630 pM, 620 pM, 610 pM, 600 pM, 590 pM, 580 pM, 570 pM, 560 pM, 550 pM, 540 pM, 530 pM, 520 pM, 510 pM, 500 pM, 490 pM, 480 pM, 470 pM, 460 pM, 450 pM, 440 pM, 430 pM, 420 pM, 410 pM, 400 pM, 390 pM, 380 pM, 370 pM, 360 pM, 350 pM, 340 pM, 330 pM, 320 pM, 310 pM, 300 pM, 290 pM, 280 pM, 270 pM, 260 pM, 250 pM, 240 pM, 230 pM, 220 pM, 210 pM, 200 pM, 190 pM, 180 pM, 170 pM, 160 pM, 150 pM, 140 pM, 130 pM, 120 pM, 110 pM, 100 pM, 90 pM, 80 pM, 70 pM, 60 pM, 50 pM, 40 pM, 30 pM, 20 pM, 10 pM, 0 pM, 8 pM, 7 pM, 6 pM, 5 pM, 4 pM, 3 pM, 2 pM, 1 pM, 0.9 pM, 0.8 pM, 0.7 pM, 0.6 pM, 0.5 pM, 0.4pM, 0.3 pM, 0.2 pM, 0.1 pM, 0.05 pM, any integer therebetween, or any range between any two of the preceding binding affinities. A monomeric or multimeric hlL- 17 binding polypeptide composition can bind hIL-17 at a KD of about 0.1 pM to about

[0181] 1.5 nM any integer therebetween, or any range therebetween.

[0182] An hIL-17 binding polypeptide composition can bind to any region of an hlL- 17 cytokine subunit as desired, based on its intended use. The region can be site 1 of the IL-17:IL-17R binding interface as described by Ely, 2009, Nature Immunol. https: / / www.ncbi.nlm.nih.gov / pmc / articles / PMC2783927 / (see Fig 2 therein). The hIL-17 binding polypeptide composition can directly bind to an active site or hIL-17 receptor binding surface to hinder hIL-17 to hIL-17R, or it can have an allosteric effect on hIL-17 that results in altered binding to the receptor.

[0183] Linkers

[0184] An hIL-17 binding polypeptide dimeric composition can comprise two hlL- 17A binding polypeptides, two hIL-17F binding polypeptides, or one hIL-17A binding polypeptide and one hIL-17A binding polypeptide.

[0185] Any appropriate linker can be used to fuse any two hIL-17 binding polypeptides described herein to form an hIL-17 multimeric binding polypeptide composition. Where multiple linkers are present in a single hIL-17 binding polypeptide composition (as in a multimer larger than a dimer), these linkers can be the same or different. The linker can be an amino acid linker. The amino acid linker can be from about 1 to about 100 amino acids in length. An hIL-17 binding polypeptide composition can comprise a peptide linker comprising or consisting of the amino acid sequences set forth in any of SEQ ID NOs: 67-70 and 79-82. An hlL- 17 binding polypeptide composition can comprise a peptide linker comprising or consisting of (GGGGS)n, (also referred to as (G4S)n), L(G4S)n, (Gly-Ser)n (also referred to as (GS)n), L(GS)n, (Gly)n, L(Gly)n, (EAAAK)n, L(EAAAK)n, (PAS)n, L(PAS)n, or any combination thereof. The hIL-17 binding polypeptide composition can comprise a peptide linker comprising or consisting of a PAS linker having the formula (PAS)n or L(PAS)n. The hIL-17 binding polypeptide composition can comprise a peptide linker comprising or consisting of a Gly-Ser linker having the formula (GS)n or L(GS)n. The value n in (G4S)n, L(G4S)n, (GS)n, L(GS)n, (Gly)n, L(Gly)n, (EAAAK)n, L(EAAAK)n, (PAS)n, or L(PAS)n, can be 1-100. The value n can be about 1 to about 100. The value n can be about 2 to about 8. The value n can be about 1 to about 100. The value n can be about 1 to about 2, about 1 to about 3, about 1 to about 4, about 1 to about 5, about 1 to about 6, about 1 to about 7, about 1 to about 8, about 1 to about 10, about 1 to about 20, about 1 to about 50, about 1 to about 100, about 2 to about 3, about 2 to about 4, about 2 to about 5, about 2 to about 6, about 2 to about 7, about 2 to about 8, about 2 to about 10, about 2 to about 20, about 2 to about 50, about 2 to about 100, about 3 to about 4, about 3 to about 5, about 3 to about 6, about 3 to about 7, about 3 to about 8, about 3 to about 10, about 3 to about 20, about 3 to about 50, about 3 to about 100, about 4 to about 5, about 4 to about 6, about 4 to about 7, about 4 to about 8, about 4 to about 10, about 4 to about 20, about 4 to about 50, about 4 to about 100, about 5 to about 6, about 5 to about 7, about 5 to about 8, about 5 to about 10, about 5 to about 20, about 5 to about 50, about 5 to about 100, about 6 to about 7, about 6 to about 8, about 6 to about 10, about 6 to about 20, about 6 to about 50, about 6 to about 100, about 7 to about 8, about 7 to about 10, about 7 to about 20, about 7 to about 50, about 7 to about 100, about 8 to about 10, about 8 to about 20, about 8 to about 50, about 8 to about 100, about 10 to about 20, about 10 to about 50, about 10 to about 100, about 20 to about 50, about 20 to about 100, or about 50 to about 100. The value n can be about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 10, about 20, about 50, or about 100. The value n can be about at least about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 10, about 20, or about 50. The value n can be about at most about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 10, about 20, about 50, or about 100. The value n can be about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 25, about 50, about 75, or about 100. The value n can be at least about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 25, about 50, or about 75. The value n can be at most about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 25, about 50, about 75, or about 100. The linker can improve affinity of the hIL-17 binding polypeptide for hIL-17. Linkers useful in the context of the present invention are described in the literature, e.g., by Chen, et al., Fusion Protein Linkers: Property, Design and Functionality,” 2013 October 15, Adv Drug Deliv Rev, 65(10): 1357-1369. A linker can be a flexible linker (e.g., a GS linker) or a rigid linker (e.g., a helical linker). The linker can comprise or consist of an amino acid sequence set forth in any of SEQ ID NOs: 67, 68, 69, and 70. The hIL-17 composition can be any set forth in the disclosure, comprising a linker comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 67, 68, 69, or 70.

[0186] Characterization Assays

[0187] An hIL-17 binding polypeptide composition can be evaluated using any appropriate in vitro or in vivo assay known in the art. The assay can measure binding of the hIL-17 binding polypeptide composition to hIL-17. The assay can measure binding of hIL-17 to hIL-17R in the presence of the hIL-17 binding polypeptide composition. The measure of activity can be any understood in the art, including but not limited to any of affinity, stability, specificity, and avidity. The assay can measure stability. The assay can be any known assay for measuring an hIL-17 activity, e.g., a known or suspected effect of hIL-17 binding to hIL-17R such as an effect on native or engineered biomarkers downstream of hIL-17R, macroscopic or histological inflammation, clinical symptoms, patient reported outcomes, and / or transcriptomic data, as described herein.

[0188] The effect of treatment with an hIL-17 binding polypeptide composition on a subject in need thereof can be evaluated by any method known in the art, e.g., a method for assessing the severity or progression of the disease or disorder intended to be treated in the subject by administration of the hIL-17 binding polypeptide composition. As discussed herein, the effect can be that observed relative to an appropriate control.

[0189] An in vitro binding assay can comprise, e.g., the detection of binding association and dissociation over time and subsequent determination of kinetic and / or equilibrium binding constants of an hIL-17 binding polypeptide composition to hlL- 17. An in vitro activity assay can comprise a potency assay measuring hIL-17 cell- mediated signaling in the presence or absence of a titration of an hIL-17 binding polypeptide composition.

[0190] Binding Targets

[0191] An hIL-17 binding polypeptide composition can target one or more hIL-17 surfaces. For example, as noted herein, an hIL-17 binding polypeptide dimeric composition can comprise two hIL-17A binding polypeptides, two hIL-17F binding polypeptides, or one hIL-17A binding polypeptide and one hIL-17F binding polypeptide. Such a dimeric polypeptide dimeric composition can respectively target an hIL-17A homodimer, an hIL-17F homodimer, or an hIL-17A-hIL-17F heterodimer. A monomeric or multimeric hIL-17 binding polypeptide composition can inhibit recognition of either receptor hIL-17RA or hIL-17RC by hIL-17A and / or hIL-17F. In some embodiments, an hIL-17A binding polypeptide composition can inhibit recognition of hIL-17RA. In related embodiments, an hIL-17A binding polypeptide composition that inhibits recognition of hIL-17RA is useful for treating a subject having psoriasis, psoriatic arthritis, or ankylosing spondylitis.

[0192] Polypeptide Stability

[0193] An hIL-17 binding polypeptide composition of the present invention can have increased stability. Stability can be increased by a modification, e.g., intramolecular disulfide bonding. The stability of the modified or unmodified hIL-17 binding polypeptide composition can be increased relative to a control. Where the hIL-17 binding polypeptide composition is not modified, a control can be a different hIL-17 binding polypeptide composition, or any control as desired to be tested by one of skill in the art. Where the hIL-17 binding polypeptide composition is modified, a control can be the corresponding unmodified hIL-17 binding polypeptide composition, the corresponding hIL-17 binding polypeptide composition having a different modification, a different modified or unmodified hIL-17 binding polypeptide composition, or any control as desired to be tested by one of skill in the art. A stability control can be any existing hIL-17 binding composition, e.g., small molecule, polypeptide, aptamer, etc., known to those of skill in the art, e.g., as described herein. As described in the Examples herein, a number of modified hIL-17 binding polypeptides were constructed and compared with controls including the corresponding unmodified hIL-17 binding polypeptide composition and existing hlL- 17 binding compositions.

[0194] Stability can be indicated by any measure known in the art, e.g., thermal stability or chemical stability, and evaluated accordingly. In some embodiments, an hIL-17 binding polypeptide composition has a Tm of about 65 deg C to about 100 deg C. In some embodiments, an hIL-17 binding polypeptide composition has a Tm of about 65 deg C to about 70 deg C, about 65 deg C to about 75 deg C, about 65 deg C to about 80 deg C, about 65 deg C to about 85 deg C, about 65 deg C to about 90 deg C, about 65 deg C to about 95 deg C, about 65 deg C to about 100 deg C, about 70 deg C to about 75 deg C, about 70 deg C to about 80 deg C, about 70 deg C to about 85 deg C, about 70 deg C to about 90 deg C, about 70 deg C to about 95 deg C, about 70 deg C to about 100 deg C, about 75 deg C to about 80 deg C, about 75 deg C to about 85 deg C, about 75 deg C to about 90 deg C, about 75 deg C to about 95 deg C, about 75 deg C to about 100 deg C, about 80 deg C to about 85 deg C, about 80 deg C to about 90 deg C, about 80 deg C to about 95 deg C, about 80 deg C to about 100 deg C, about 85 deg C to about 90 deg C, about 85 deg C to about 95 deg C, about 85 deg C to about 100 deg C, about 90 deg C to about 95 deg C, about 90 deg C to about 100 deg C, or about 95 deg C to about 100 deg C. In some embodiments, an hIL-17 binding polypeptide composition has a Tm of about 65 deg C, about 70 deg C, about 75 deg C, about 80 deg C, about 85 deg C, about 90 deg C, about 95 deg C, or about 100 deg C. In some embodiments, an hIL-17 binding polypeptide composition has a Tm of at least about 65 deg C, about 70 deg C, about 75 deg C, about 80 deg C, about 85 deg C, about 90 deg C, or about 95 deg C. In some embodiments, an hIL-17 binding polypeptide composition has a Tm of at most about 70 deg C, about 75 deg C, about 80 deg C, about 85 deg C, about 90 deg C, about 95 deg C, or about 100 deg C.

[0195] In some embodiments, a hIL-17 binding polypeptide composition has a guanidinium hydrochloride midpoint concentration, Gdn Cm (e.g., the concentration of Gdn at which half of the protein molecules are unfolded) of about 3M or greater. In some embodiments, a hIL-17 binding polypeptide composition has a guanidinium hydrochloride midpoint concentration, Gdn Cm, of about 3 M to about 8 M. In some embodiments, a hIL-17 binding polypeptide composition has a guanidinium hydrochloride midpoint concentration, Gdn Cm, of about 3 M to about 3.25 M, about 3 M to about 3.5 M, about 3 M to about 3.75 M, about 3 M to about 4 M, about 3 M to about 4.25 M, about 3 M to about 4.5 M, about 3 M to about 4.75 M, about 3 M to about 5 M, about 3 M to about 6 M, about 3 M to about 7 M, about 3 M to about 8 M, about 3.25 M to about 3.5 M, about 3.25 M to about 3.75 M, about 3.25 M to about 4 M, about 3.25 M to about 4.25 M, about 3.25 M to about 4.5 M, about 3.25 M to about 4.75 M, about 3.25 M to about 5 M, about 3.25 M to about 6 M, about 3.25 M to about 7 M, about 3.25 M to about 8 M, about 3.5 M to about 3.75 M, about 3.5 M to about 4 M, about 3.5 M to about 4.25 M, about 3.5 M to about 4.5 M, about 3.5 M to about 4.75 M, about 3.5 M to about 5 M, about 3.5 M to about 6 M, about 3.5 M to about 7 M, about 3.5 M to about 8 M, about 3.75 M to about 4 M, about 3.75 M to about 4.25 M, about 3.75 M to about 4.5 M, about 3.75 M to about 4.75 M, about 3.75 M to about 5 M, about 3.75 M to about 6 M, about 3.75 M to about 7 M, about 3.75 M to about 8 M, about 4 M to about 4.25 M, about 4 M to about 4.5 M, about 4 M to about 4.75 M, about 4 M to about 5 M, about 4 M to about 6 M, about 4 M to about 7 M, about 4 M to about 8 M, about 4.25 M to about 4.5 M, about 4.25 M to about 4.75 M, about 4.25 M to about 5 M, about 4.25 M to about 6 M, about 4.25 M to about 7 M, about 4.25 M to about 8 M, about 4.5 M to about 4.75 M, about 4.5 M to about 5 M, about 4.5 M to about 6 M, about 4.5 M to about 7 M, about 4.5 M to about 8 M, about 4.75 M to about 5 M, about 4.75 M to about 6 M, about 4.75 M to about 7 M, about 4.75 M to about 8 M, about 5 M to about 6 M, about 5 M to about 7 M, about 5 M to about 8 M, about 6 M to about 7 M, about 6 M to about 8 M, or about 7 M to about 8 M. In some embodiments, a hIL-17 binding polypeptide composition has a guanidinium hydrochloride midpoint concentration, Gdn Cm, of about 3 M, about 3.25 M, about 3.5 M, about 3.75 M, about 4 M, about 4.25 M, about 4.5 M, about 4.75 M, about 5 M, about 6 M, about 7 M, or about 8 M. In some embodiments, a hIL-17 binding polypeptide composition has a guanidinium hydrochloride midpoint concentration, Gdn Cm, of at least about 3 M, about 3.25 M, about 3.5 M, about 3.75 M, about 4 M, about 4.25 M, about 4.5 M, about 4.75 M, about 5 M, about 6 M, or about 7 M. In some embodiments, a hIL-17 binding polypeptide composition has a guanidinium hydrochloride midpoint concentration, Gdn Cm, of at most about 3.25 M, about 3.5 M, about 3.75 M, about 4 M, about 4.25 M, about 4.5 M, about 4.75 M, about 5 M, about 6 M, about 7 M, or about 8 M.

[0196] In some embodiments, a test hIL-17 binding polypeptide composition has a thermal stability or chemical stability that is increased relative to a control composition. Thermal stability can be evaluated by comparing the melt temperature (Tm) of the test composition to that of the control composition. The test composition Tm can be greater than that of the control composition Tm by about 1 deg C to about 100 deg C. The test composition Tm can be greater than that of the control composition Tm by about 1 deg C to about 5 deg C, about 1 deg C to about 10 deg C, about 1 deg C to about 20 deg C, about 1 deg C to about 30 deg C, about 1 deg C to about 40 deg C, about 1 deg C to about 50 deg C, about 1 deg C to about 60 deg C, about 1 deg C to about 70 deg C, about 1 deg C to about 80 deg C, about 1 deg C to about 90 deg C, about 1 deg C to about 100 deg C, about 5 deg C to about 10 deg C, about 5 deg C to about 20 deg C, about 5 deg C to about 30 deg C, about 5 deg C to about 40 deg C, about 5 deg C to about 50 deg C, about 5 deg C to about 60 deg C, about 5 deg C to about 70 deg C, about 5 deg C to about 80 deg C, about 5 deg C to about 90 deg C, about 5 deg C to about 100 deg C, about 10 deg C to about 20 deg C, about 10 deg C to about 30 deg C, about 10 deg C to about 40 deg C, about 10 deg C to about 50 deg C, about 10 deg C to about 60 deg C, about 10 deg C to about 70 deg C, about 10 deg C to about 80 deg C, about 10 deg C to about 90 deg C, about 10 deg C to about 100 deg C, about 20 deg C to about 30 deg C, about 20 deg C to about 40 deg C, about 20 deg C to about 50 deg C, about 20 deg C to about 60 deg C, about 20 deg C to about 70 deg C, about 20 deg C to about 80 deg C, about 20 deg C to about 90 deg C, about 20 deg C to about 100 deg C, about 30 deg C to about 40 deg C, about 30 deg C to about 50 deg C, about 30 deg C to about 60 deg C, about 30 deg C to about 70 deg C, about 30 deg C to about 80 deg C, about 30 deg C to about 90 deg C, about 30 deg C to about 100 deg C, about 40 deg C to about 50 deg C, about 40 deg C to about 60 deg C, about 40 deg C to about 70 deg C, about 40 deg C to about 80 deg C, about 40 deg C to about 90 deg C, about 40 deg C to about 100 deg C, about 50 deg C to about 60 deg C, about 50 deg C to about 70 deg C, about 50 deg C to about 80 deg C, about 50 deg C to about 90 deg C, about 50 deg C to about 100 deg C, about 60 deg C to about 70 deg C, about 60 deg C to about 80 deg C, about 60 deg C to about 90 deg C, about 60 deg C to about 100 deg C, about 70 deg C to about 80 deg C, about 70 deg C to about 90 deg C, about 70 deg C to about 100 deg C, about 80 deg C to about 90 deg C, about 80 deg C to about 100 deg C, or about 90 deg C to about 100 deg C. The test composition Tm can be greater than that of the control composition Tm by about 1 deg C, about 5 deg C, about 10 deg C, about 20 deg C, about 30 deg C, about 40 deg C, about 50 deg C, about 60 deg C, about 70 deg C, about 80 deg C, about 90 deg C, or about 100 deg C. The test composition Tm can be greater than that of the control composition Tm by at least about 1 deg C, about 5 deg C, about 10 deg C, about 20 deg C, about 30 deg C, about 40 deg C, about 50 deg C, about 60 deg C, about 70 deg C, about 80 deg C, or about 90 deg C. The test composition Tm can be greater than that of the control composition Tm by at most about 5 deg C, about 10 deg C, about 20 deg C, about 30 deg C, about 40 deg C, about 50 deg C, about 60 deg C, about 70 deg C, about 80 deg C, about 90 deg C, or about 100 deg C. The test composition can be a modified hIL-17 binding polypeptide, e.g., comprising at least one disulfide bond, and the control composition can be a less modified or unmodified hIL-17 binding polypeptide. Chemical stability can be evaluated by, comparing the resistance to chemical denaturant of the test composition to that of the control composition, e.g., by determining the presence of >50% folded in the presence of a given concentration of denaturant, e.g., Gdn. In some embodiments, the concentration of Gdn at which at least 50% of the test concentration is folded relative to the concentration of Gdn at which at least 50% of the control concentration is folded is about 0.1 M to about 6 M greater. In some embodiments, the concentration of Gdn at which at least 50% of the test concentration is folded relative to the concentration of Gdn at which at least 50% of the control concentration is folded is about 0.1 M greater to about 6 M greater. In some embodiments, the concentration of Gdn at which at least 50% of the test concentration is folded relative to the concentration of Gdn at which at least 50% of the control concentration is folded is about 0.1 M greater to about 0.25 M greater, about 0.1 M greater to about 0.5 M greater, about 0.1 M greater to about 1 M greater, about 0.1 M greater to about 1.5 M greater, about 0.1 M greater to about 2 M greater, about 0.1 M greater to about 2.5 M greater, about 0.1 M greater to about 3 M greater, about 0.1 M greater to about 3.5 M greater, about 0.1 M greater to about 4 M greater, about 0.1 M greater to about 5 M greater, about 0.1 M greater to about 6 M greater, about 0.25 M greater to about 0.5 M greater, about 0.25 M greater to about 1 M greater, about 0.25 M greater to about 1.5 M greater, about 0.25 M greater to about 2 M greater, about 0.25 M greater to about 2.5 M greater, about 0.25 M greater to about 3 M greater, about 0.25 M greater to about 3.5 M greater, about 0.25 M greater to about 4 M greater, about 0.25 M greater to about 5 M greater, about 0.25 M greater to about 6 M greater, about 0.5 M greater to about 1 M greater, about 0.5 M greater to about 1.5 M greater, about 0.5 M greater to about 2 M greater, about 0.5 M greater to about 2.5 M greater, about 0.5 M greater to about 3 M greater, about 0.5 M greater to about 3.5 M greater, about 0.5 M greater to about 4 M greater, about 0.5 M greater to about 5 M greater, about 0.5 M greater to about 6 M greater, about 1 M greater to about 1.5 M greater, about 1 M greater to about 2 M greater, about 1 M greater to about 2.5 M greater, about 1 M greater to about 3 M greater, about 1 M greater to about 3.5 M greater, about 1 M greater to about 4 M greater, about 1 M greater to about 5 M greater, about 1 M greater to about 6 M greater, about 1.5 M greater to about 2 M greater, about 1.5 M greater to about 2.5 M greater, about 1.5 M greater to about 3 M greater, about 1.5 M greater to about 3.5 M greater, about 1.5 M greater to about 4 M greater, about 1.5 M greater to about 5 M greater, about 1.5 M greater to about 6 M greater, about 2 M greater to about 2.5 M greater, about 2 M greater to about 3 M greater, about 2 M greater to about 3.5 M greater, about 2 M greater to about 4 M greater, about 2 M greater to about 5 M greater, about 2 M greater to about

[0197] 6 M greater, about 2.5 M greater to about 3 M greater, about 2.5 M greater to about 3.5 M greater, about 2.5 M greater to about 4 M greater, about 2.5 M greater to about 5 M greater, about 2.5 M greater to about 6 M greater, about 3 M greater to about 3.5 M greater, about 3 M greater to about 4 M greater, about 3 M greater to about 5 M greater, about 3 M greater to about 6 M greater, about 3.5 M greater to about 4 M greater, about 3.5 M greater to about 5 M greater, about 3.5 M greater to about 6 M greater, about 4 M greater to about 5 M greater, about 4 M greater to about 6 M greater, or about 5 M greater to about 6 M greater. In some embodiments, the concentration of Gdn at which at least 50% of the test concentration is folded relative to the concentration of Gdn at which at least 50% of the control concentration is folded is about 0.1 M greater, about 0.25 M greater, about 0.5 M greater, about 1 M greater, about 1.5 M greater, about 2 M greater, about 2.5 M greater, about 3 M greater, about 3.5 M greater, about 4 M greater, about 5 M greater, or about 6 M greater. In some embodiments, the concentration of Gdn at which at least 50% of the test concentration is folded relative to the concentration of Gdn at which at least 50% of the control concentration is folded is at least about 0.1 M greater, about 0.25 M greater, about 0.5 M greater, about 1 M greater, about 1.5 M greater, about 2 M greater, about 2.5 M greater, about 3 M greater, about 3.5 M greater, about 4 M greater, or about 5 M greater. In some embodiments, the concentration of Gdn at which at least 50% of the test concentration is folded relative to the concentration of Gdn at which at least 50% of the control concentration is folded is at most about 0.25 M greater, about 0.5 M greater, about 1 M greater, about 1.5 M greater, about 2 M greater, about 2.5 M greater, about 3 M greater, about 3.5 M greater, about 4 M greater, about 5 M greater, or about 6 M greater. The test composition can be a modified hIL-17 binding polypeptide, e.g., comprising at least one disulfide bond, and the control composition can be a less modified or unmodified hIL-17 binding polypeptide. Stability, e.g., thermal or chemical stability, can be determined using any assay known to those of skill in the art. For example, a stability assay can measure thermal stability by observing denaturation, e.g., by any known means including circular dichroism, when the hIL-17 binding polypeptide composition is exposed to increasing temperature. A stability assay can measure chemical stability by observing denaturation, e.g., by any known means including circular dichroism, when the hlL- 17 binding polypeptide composition is exposed to a chemical denaturant. The denaturant can be, e.g., guanidinium hydrochloride (Gdn).

[0198] An intramolecularly disulfide-bonded hIL-17 binding polypeptide can comprise at least one disulfide bond. An intramolecularly disulfide-bonded hIL-17 binding polypeptide can comprise 1-10 disulfide bonds. An intramolecularly disulfide-bonded hIL-17 binding polypeptide can comprise about 1 disulfide bond to about 10 disulfide bonds. An intramolecularly disulfide-bonded hIL-17 binding polypeptide can comprise about 1 disulfide bond to about 2 disulfide bonds, about 1 disulfide bond to about 3 disulfide bonds, about 1 disulfide bond to about 4 disulfide bonds, about 1 disulfide bond to about 5 disulfide bonds, about 1 disulfide bond to about 6 disulfide bonds, about 1 disulfide bond to about 7 disulfide bonds, about 1 disulfide bond to about 8 disulfide bonds, about 1 disulfide bond to about 9 disulfide bonds, about 1 disulfide bond to about 10 disulfide bonds, about 2 disulfide bonds to about 3 disulfide bonds, about 2 disulfide bonds to about 4 disulfide bonds, about 2 disulfide bonds to about 5 disulfide bonds, about 2 disulfide bonds to about 6 disulfide bonds, about 2 disulfide bonds to about 7 disulfide bonds, about 2 disulfide bonds to about 8 disulfide bonds, about 2 disulfide bonds to about 9 disulfide bonds, about 2 disulfide bonds to about 10 disulfide bonds, about 3 disulfide bonds to about 4 disulfide bonds, about 3 disulfide bonds to about 5 disulfide bonds, about 3 disulfide bonds to about 6 disulfide bonds, about 3 disulfide bonds to about 7 disulfide bonds, about 3 disulfide bonds to about 8 disulfide bonds, about 3 disulfide bonds to about 9 disulfide bonds, about 3 disulfide bonds to about 10 disulfide bonds, about 4 disulfide bonds to about 5 disulfide bonds, about 4 disulfide bonds to about 6 disulfide bonds, about 4 disulfide bonds to about 7 disulfide bonds, about 4 disulfide bonds to about 8 disulfide bonds, about 4 disulfide bonds to about 9 disulfide bonds, about 4 disulfide bonds to about 10 disulfide bonds, about 5 disulfide bonds to about 6 disulfide bonds, about 5 disulfide bonds to about 7 disulfide bonds, about 5 disulfide bonds to about 8 disulfide bonds, about 5 disulfide bonds to about 9 disulfide bonds, about 5 disulfide bonds to about 10 disulfide bonds, about 6 disulfide bonds to about 7 disulfide bonds, about 6 disulfide bonds to about 8 disulfide bonds, about 6 disulfide bonds to about 9 disulfide bonds, about 6 disulfide bonds to about 10 disulfide bonds, about 7 disulfide bonds to about 8 disulfide bonds, about 7 disulfide bonds to about 9 disulfide bonds, about 7 disulfide bonds to about 10 disulfide bonds, about 8 disulfide bonds to about 9 disulfide bonds, about 8 disulfide bonds to about 10 disulfide bonds, or about 9 disulfide bonds to about 10 disulfide bonds. An intramolecularly disulfide-bonded hIL-17 binding polypeptide can comprise about 1 disulfide bond, about 2 disulfide bonds, about 3 disulfide bonds, about 4 disulfide bonds, about 5 disulfide bonds, about 6 disulfide bonds, about 7 disulfide bonds, about 8 disulfide bonds, about 9 disulfide bonds, or about 10 disulfide bonds. An intramolecularly disulfide-bonded hIL-17 binding polypeptide can comprise at least about 1 disulfide bond, about 2 disulfide bonds, about 3 disulfide bonds, about 4 disulfide bonds, about 5 disulfide bonds, about 6 disulfide bonds, about 7 disulfide bonds, about 8 disulfide bonds, or about 9 disulfide bonds. An intramolecularly disulfide-bonded hIL-17 binding polypeptide can comprise at most about 2 disulfide bonds, about 3 disulfide bonds, about 4 disulfide bonds, about 5 disulfide bonds, about 6 disulfide bonds, about 7 disulfide bonds, about 8 disulfide bonds, about 9 disulfide bonds, or about 10 disulfide bonds. An intramolecularly disulfide-bonded hIL-17 binding polypeptide of the present invention can have an increased stability in comparison to the corresponding non-disulfide-bonded hIL-17 binding polypeptide of about 1.5 to about 25-fold. An intramolecularly disulfide- bonded hIL-17 binding polypeptide of the present invention can have an increased stability in comparison to the corresponding non-disulfide-bonded hIL-17 binding polypeptide of about 1.5 -fold to about 25 -fold. An intramolecularly disulfide-bonded hIL-17 binding polypeptide of the present invention can have an increased stability in comparison to the corresponding non-disulfide-bonded hIL-17 binding polypeptide of about 1.5 -fold to about 2 -fold, about 1.5 -fold to about 2.5 -fold, about 1.5 -fold to about 5 -fold, about 1.5 -fold to about 7.5 -fold, about 1.5 -fold to about 10 -fold, about 1.5 -fold to about 12.5 -fold, about 1.5 -fold to about 15 -fold, about 1.5 -fold to about 17.5 -fold, about 1.5 -fold to about 20 -fold, about 1.5 -fold to about 25 -fold, about 1.5 -fold to about 20 -fold, about 2 -fold to about 2.5 -fold, about 2 -fold to about 5 -fold, about 2 -fold to about 7.5 -fold, about 2 -fold to about 10 -fold, about 2 -fold to about 12.5 -fold, about 2 -fold to about 15 -fold, about 2 -fold to about 17.5 - fold, about 2 -fold to about 20 -fold, about 2 -fold to about 25 -fold, about 2 -fold to about 20 -fold, about 2.5 -fold to about 5 -fold, about 2.5 -fold to about 7.5 -fold, about 2.5 -fold to about 10 -fold, about 2.5 -fold to about 12.5 -fold, about 2.5 -fold to about 15 -fold, about 2.5 -fold to about 17.5 -fold, about 2.5 -fold to about 20 -fold, about 2.5 -fold to about 25 -fold, about 2.5 -fold to about 20 -fold, about 5 -fold to about 7.5 -fold, about 5 -fold to about 10 -fold, about 5 -fold to about 12.5 -fold, about 5 -fold to about 15 -fold, about 5 -fold to about 17.5 -fold, about 5 -fold to about 20 - fold, about 5 -fold to about 25 -fold, about 5 -fold to about 20 -fold, about 7.5 -fold to about 10 -fold, about 7.5 -fold to about 12.5 -fold, about 7.5 -fold to about 15 -fold, about 7.5 -fold to about 17.5 -fold, about 7.5 -fold to about 20 -fold, about 7.5 -fold to about 25 -fold, about 7.5 -fold to about 20 -fold, about 10 -fold to about 12.5 -fold, about 10 -fold to about 15 -fold, about 10 -fold to about 17.5 -fold, about 10 -fold to about 20 -fold, about 10 -fold to about 25 -fold, about 10 -fold to about 20 -fold, about

[0199] 12.5 -fold to about 15 -fold, about 12.5 -fold to about 17.5 -fold, about 12.5 -fold to about 20 -fold, about 12.5 -fold to about 25 -fold, about 12.5 -fold to about 20 -fold, about 15 -fold to about 17.5 -fold, about 15 -fold to about 20 -fold, about 15 -fold to about 25 -fold, about 15 -fold to about 20 -fold, about 17.5 -fold to about 20 -fold, about 17.5 -fold to about 25 -fold, about 17.5 -fold to about 20 -fold, about 20 -fold to about 25 -fold, about 20 -fold to about 20 -fold, or about 25 -fold to about 20 -fold. An intramolecularly disulfide-bonded hIL-17 binding polypeptide of the present invention can have an increased stability in comparison to the corresponding non- disulfide-bonded hIL-17 binding polypeptide of about 1.5 -fold, about 2 -fold, about

[0200] 2.5 -fold, about 5 -fold, about 7.5 -fold, about 10 -fold, about 12.5 -fold, about 15 - fold, about 17.5 -fold, about 20 -fold, about 25 -fold, or about 20 -fold. An intramolecularly disulfide-bonded hIL-17 binding polypeptide of the present invention can have an increased stability in comparison to the corresponding non- disulfide-bonded hIL-17 binding polypeptide of at least about 1.5 -fold, about 2 -fold, about 2.5 -fold, about 5 -fold, about 7.5 -fold, about 10 -fold, about 12.5 -fold, about 15 -fold, about 17.5 -fold, about 20 -fold, or about 25 -fold. An intramolecularly disulfide-bonded hIL-17 binding polypeptide of the present invention can have an increased stability in comparison to the corresponding non-disulfide-bonded hIL-17 binding polypeptide of at most about 2 -fold, about 2.5 -fold, about 5 -fold, about 7.5 - fold, about 10 -fold, about 12.5 -fold, about 15 -fold, about 17.5 -fold, about 20 -fold, about 25 -fold, or about 20 -fold. The stability can increase as the number of intramolecular disulfide bonds increases.

[0201] REDUCED SIDE EFFECTS

[0202] An hIL-17 binding polypeptide composition of the present invention can be safer and more effective in comparison to existing compositions for inhibiting the hIL-17-hIL-17R interaction. At least due to their relatively small size when compared with larger proteins, e.g., antibody-derived therapeutics, the compositions of the present invention can be administered at lower levels of total protein to achieve a similar or higher activity.

[0203] Production

[0204] An hIL-17 binding polypeptide comprised by an hIL-17 binding polypeptide composition of the present invention can be produced using any known method. The hIL-17 binding polypeptide can be produced by expression of a nucleic acid encoding the hIL-17 binding polypeptide in any appropriate expression system and purified accordingly using known methods. In embodiments, the protein expression system is any known in the art to be useful for producing heterologous proteins. In embodiments, the protein expression system is a bacteria, yeast, plant, insect, algal, cell free, or mammalian expression system. In embodiments, the protein expression system is a microbial expression system. In embodiments, the protein expression system is a prokaryotic or eukaryotic expression system. In embodiments, the protein expression system is a Gram-positive bacterial expression system. In embodiments, the bacterial expression system is E. coli, Bacillus, Lactobacillus, Streptomyces, or Pseudomonad expression system. In embodiments, the Pseudomonad expression system is a Pseudomonas expression system. In embodiments, the Pseudomonad expression system is a P. fluorescens expression system. In embodiments, the protein is expressed in Chinese hamster ovary (CHO) cells. The hIL-17 binding polypeptide can be produced by chemical synthesis. Modifications

[0205] A terminal modification of any hIL-17 binding polypeptide as described herein can be present at either the N- or the C- terminus, or both. The N-terminal amino group can be modified, e.g., by addition of an amino acid or derivative. The N- terminal amino group can be unmodified. The unmodified N terminus can comprise - H. The N-terminal amino group can be modified by C1-C6 acyl, C1-C8 alkyl, C6-C12 aralkyl, C5-C10 aryl, C4-C8 heteroaryl, formyl, Ac, or a lipid. The C-terminal acid group of an hIL-17 binding polypeptide as described can be modified, e.g., by addition of an amino acid or derivative. The C-terminal amino group can be unmodified. The unmodified C terminus can comprise -OH. A C-terminal modification can comprise an amino group, which is optionally substituted. A C- terminal modification can comprise an amino group that is not substituted (-NH2). A C-terminal modification can comprise -NH2, -amino-acyl, -amino-Cl-C8 alkyl, - amino-C6-C12-aralkyl, -amino-C5-C10 aryl, or -amino-C4-C8 heteroaryl, -amino- C4-C8 heteroaryl, or -O-(C1-C8 alkyl). An hIL-17 binding polypeptide as described herein can have N and C-termini independently selected from: Ac (acetylation, CH3CO), NH2 (amidation), and H. In some embodiments, the N-terminal amino group is modified by an acetyl group, e.g., attached to the free a-amino group at the N- terminal end of a binding polypeptide. In some embodiments, the C-terminal carboxy group is modified by amidation.

[0206] In some embodiments, an hIL-17 binding polypeptide can comprise a lipid moiety. The lipid moiety can be covalently attached to an amino acid in the peptide. The lipid moiety can be attached to the N-terminus, e.g., at a cysteine, serine, lysine, threonine or tyrosine residue of the hIL-17 binding polypeptide. The lipid can be attached to a modified or non-canonical amino acid that has been substituted into the hIL-17 binding polypeptide. A lipid can comprise a hydrophobic group or a fatty acid group. The lipid can facilitate topical absorption of the hIL-17 binding polypeptide.

[0207] Pharmaceutical Compositions

[0208] The present invention includes pharmaceutical compositions comprising an hIL-17 binding polypeptide or hIL-17 binding polypeptide composition as described herein, and methods for administration thereof. The pharmaceutical composition can be formulated for systemic, local, or topical administration. A pharmaceutical compositions provided herein can be formulated using any excipient, carrier, or additive as appropriate for the route of administration as described in, e.g., the most recent edition of e.g., Remington: The Science and Practice of Pharmacy, L. Allen, ed., 22nd edition.

[0209] A formulation or pharmaceutical composition comprising an hIL-17 binding polypeptide composition provided herein can be administered by any suitable method known in the art for delivery of a composition, e.g., orally, parenterally, or topically. Systemic administration can comprise injection (e.g., subcutaneous, intravenous, intrathecal, intraperitoneal), infusion, and implantation.

[0210] A topical formulation or pharmaceutical composition comprising an hIL-17 binding polypeptide composition can comprise one or more appropriate excipients or carriers. The use of any suitable excipient or carrier or combination thereof as known to those of skill in the art and described in the literature is contemplated. A topical formulation can comprise an inert excipient or carrier, a buffer, an absorption enhancer (penetrating agent), and / or a stability enhancer. For use of the topical formulation for a given condition, an excipient or carrier used in any approved or experimental treatment for the condition can be used. A topical formulation can be, e.g., a liquid, ointment, cream, or patch. The topical formulation or pharmaceutical composition can comprise a liposome delivery system, e.g., as selected to achieve the penetration characteristics.

[0211] A pharmaceutical composition can be formulated in combination with one or more other active agent, e.g., any other known therapeutic agent used to treat the intended condition. A pharmaceutical composition provided herein can comprise any hIL-17 binding polypeptide / composition described herein. The pharmaceutical composition can comprise an hIL-17 binding polypeptide / composition comprising an amino acid sequence set forth as SEQ ID NOs: 8 to 78. The pharmaceutical composition can consist of an hIL-17 binding polypeptide / composition comprising an amino acid sequence set forth as SEQ ID NOs: 8 to 78.

[0212] A therapeutically effective amount of the hIL-17 binding polypeptide pharmaceutical composition or formulation as used herein refers to an amount of the enzyme or formulation that is effective for treating a disease or condition. Dosage regimens can be adjusted to provide the optimum desired response, as determined by those of skill in the art. A suitable dosage range can be 0.1 ug / kg-100 mg / kg body weight; alternatively, it can be 0.5 ug / kg to 50 mg / kg; 1 ug / kg to 25 mg / kg, or 5 ug / kg to 10 mg / kg body weight. The hIL-17 binding polypeptide pharmaceutical composition or formulation can be delivered as a single dose, or can be administered multiple times, e.g., 2 to ten or more times and at desired intervals as desired or needed.

[0213] Methods of Use

[0214] The present invention includes methods for use of the hIL-17 binding polypeptide composition to treat a subject in need thereof. The use of methods according to published protocols and / or product labeling for known approved or experimental treatments for the intended condition, e.g., anti-hIL-17 antibody treatments, are contemplated for use or adaptation for use by one of skill in the art with the compositions of the present invention. Anti-hIL-17 or anti-hIL-17-receptor antibodies approved for use include, e.g., Secukinumab (anti-hIL-17A, prescribing information 5 / 2021, incorporated herein by reference), Ixekizumab (anti-hIL-17A, prescribing information 7 / 2022, incorporated herein by reference), Brodalumab (anti- IL-17RA, prescribing information 2 / 2017, incorporated herein by reference), Bimekizumab (anti-IL-17A and F, prescribing information 10 / 2023, incorporated herein by reference).

[0215] EXAMPLES

[0216] The following examples are given for the purpose of illustrating various embodiments of the disclosure and are not meant to limit the present disclosure in any fashion. The present examples, along with the methods described herein are presently representative embodiments, are exemplary, and are not intended as limitations on the scope. Changes therein and other uses which are encompassed within the spirit of the disclosure as defined by the scope of the claims will occur to those skilled in the art.

[0217] Materials and Methods

[0218] Computational Design of Inhibitors Targeting hIL-17 A

[0219] Using the crystal structure of human IL-17A in complex with hIL-17RA (PDB 4HSA) as a starting point for design, rotamer interaction field (RIF) of de novo hotspots were generated around selected hIL-17A residues at the hIL-17RA binding surface, including: IL-17A chain 1 : N40, R44, V46, QI 17, El 18, 1119, L120, R134, L135, K137, 1138, L139

[0220] IL-17A chain 2: L49, N50, 151, H52, N53, N55, T56, T58, R78, E80, P82, E83, R84, Y85, P86, S87, V88, 189, W90, QI 17, 1119, L120, L122, R123, R124, E125, P126, P127, P130, N131, S132, F133, R134, L135, V140.

[0221] The RIF residues (disembodied amino acid side chains) were generated so that side chain atoms formed favorable polar and apolar interactions with the given hlL- 17A surface residues. In parallel, about 12,345 scaffold proteins (inert de novo designed proteins with experimentally validated stability) were roughly placed at the desired hIL-17A interaction surface using PatchDock (ref. 8). After RIF generation and initial scaffold placement, scaffolds were docked with higher resolution at the IL- 23R interaction surface such that the backbone atoms of the de novo hotspots were matched with appropriate backbone atoms of each scaffold protein, replacing the amino acid previously at that scaffold position. All other scaffold residues, previously computationally optimized for the lowest monomer free energy, were retained. This step generated 409,045 docked configurations.

[0222] Each docked configuration was input into a Rosetta design protocol to optimize additional scaffold residues at the hIL-17A interface for high-affinity binding. Only scaffold side chains within 8 A of the hIL-17A surface were allowed to mutate. Scaffold sidechains at surface positions further than 8 A were not allowed to mutate, but were allowed to optimize rotamer conformation. hIL-17A residues within 8 A of the scaffold were allowed to optimize rotamer conformation. All hIL-17A and scaffold backbone atoms, all scaffold monomer core side chains, and hIL-17A side chains further than 8 A from the scaffold were not allowed to move. Designed hlL- 17A:inhibitor complexes were filtered on metrics thought to predict high-affinity binding, including but not limited to, inhibitor monomer free energy, binding energy, shape complementary of the inhibitor to the hIL-17A surface, buried apolar surface area at the interface, and buried unsatisfied polar atoms. 24,376 designs with the best metrics were selected for experimental testing.

[0223] Yeast Library Preparation, Selection and Analysis

[0224] DNA preparation For the initial design library, DNA encoding each design was commercially synthesized (Agilent). For site saturation mutagenesis (SSM) libraries, in some instances full-length genes were commercially synthesized (Agilent), and in other instances libraries were prepared using overlap PCR with custom primers (Integrated DNA Technologies) as described previously (ref. 9). Combinatorial libraries were prepared by gene assembly from custom oligos; oligos were designed such that all included mutations were represented either individually or as degenerate codons encoding two or more desired mutations. Oligo overlap regions had a length of 12-15 bp and a melt temperature of 40 ± 2 °C, enabling efficient gene assembly. All yeast libraries, including the initial design library, SSM libraries, and combinatorial libraries, were prepared with overhangs >20 bp to enable homologous recombination with the plasmid backbone (pETCON) for yeast expression and surface display via fusion to Aga2p (ref. 10).

[0225] Fluorescence-activated Cell Sorting (FACS)

[0226] Yeast strain EBY100 was transformed with each library and vector by electroporation and grow in minimal media selective for the yeast strain (-ura) and the transforming plasmid (-trp) (ref. 11). Expression was induced with 2% galactose. Surface expression was detected with anti-Myc-FITC (Immunology Consultants Laboratory) conjugate, and binding to biotinylated hIL-17A or hIL-17F was detected with streptavidin-PE (Invitrogen). In some experiments, unlabeled cytokine was added to increase selective pressure and bias selection toward variants with higher affinity and / or higher specificity. The initial design library, SSM and combinatorial libraries were prepared for selection as follows: after 16-24 hours induction, yeast were spun down, washed with PBS with 1% FBS (PBSF), and incubated for 30-60 minutes with biotinylated target with or without unlabeled competitor. Yeast were then washed with PBSF and incubated for 2-5 minutes with stain solution (1 : 100 each anti-Myc-FITC and streptavidin-PE), washed, and resuspended for analysis and selection by FACS. FACS consecutive gates were set as follows: (1) cell granularity and size, selecting for yeast cells (BSC vs. FSC); (2) cell morphology, selecting singlets (FSC-height vs. FSC-width); (3) expression, selecting expressors by proxy of the Myc-tag (FITC fluorescence histogram); and (4) binding signal, selecting the top 1-5% relative to total population (PE vs. FITC). Generally, design and combinatorial libraries were sorted to convergence in 4-7 consecutive rounds, and SSM libraries were sorted in two consecutive rounds and deep sequenced. The concentration of labeled target protein was decreased as sorting rounds progressed in order to efficiently separate the highest-affinity variants.

[0227] Deep Mutational Scanning

[0228] From SSM naive and sorted pools, DNA was prepared and sequenced as follows: Yeast were lysed with 125 U / ml Zymolase at 37 °C for 5 hr, and DNA was harvested (Zymoprep kit from Zymo Research). Genomic DNA was digested with 2 U / pl Exonuclease I and 0.25 U / pl Lambda exonuclease (New England Biolabs) for 90 min at 30°C, and plasmid DNA purified with a QIAquick kit (Qiagen). DNA was deep sequenced with MiSeq or NextSeq sequencers (Illumina): genes were PCR amplified using primers that annealed to external regions within the plasmid, followed by a second round of PCR to add flanking sequences for annealing to the Illumina flow cell oligonucleotides and a 6 bp sample identification sequence, or barcode. PCR rounds were 12 cycles each with high-fidelity Phusion® polymerase. Barcodes were read on a MiSeq or NextSeq sequencer per kit instructions (Illumina), and sequences were analyzed with adapted scripts from Enrich (ref. 12).

[0229] Recombinant Protein

[0230] All designed proteins were cloned into the pET29b plasmid for expression from the T7 promoter, between Ndel and Xhol cut sites, incorporating a C-terminal 6- histidine tag for downstream affinity chromatography. E. coli were transformed with the resulting plasmids: strain BL21*(DE3) (Invitrogen) for initial computational designs and affinity-matured combinatorial variants or strain Shuffle T7 Express (New England Biolabs) for all constructs containing disulfide linkages. E. coli were grown to OD600 of 0.6-0.8 in Terrific Broth II media (MP Biomedicals) at 37°C (BL21) or 30°C (Shuffle T7), then expression induced with IPTG added to 0.5-1.0 mM overnight at growth temperature of 18°C. Cells were harvested, lysed by sonication, and lysate cleared by centrifugation. Cleared lysate was incubated with NiNTA resin for 30 minutes rocking to allow binding of recombinant protein via the 6-histidine tag, then applied to a gravity column (Biorad), washed and eluted, concentrated and further purified by gel filtration chromatography (AKTA Pure, Cytiva; Superdex 75 increase and Superdex S200 increase columns, GE Life Sciences).

[0231] Biotinylated hIL-17A (BT7955), and non-biotinylated hIL-17A (7955-IL) were purchased from R&D Biotechne. Custom hIL-17F, mIL-17A, and mIL-17F constructs with C-terminal avi and 6-histidine tags (for enzymatic biotinylation and affinity chromatography, respectively) were commercially produced (WuXi) by expression from a stable insect cell line followed by IMAC and SEC purification. hIL-17F was enzymatically biotinylated via the avi -tag using recombinant BirA enzyme (Avidity).

[0232] Circular Dichroism

[0233] CD spectra were recorded with a J- 1500 Circular Dichroism Spectrometer (JASCO). Proteins were assayed at 40 pM in PBS with guanidinium hydrochloride from 0 to 6 M, and data were collected at 25 °C. For temperature melts, proteins at 40 pM in PBS were heated from 25°C to 95°C over approximately 1.5 hours.

[0234] Biolayer Interferometry

[0235] Qualitative and quantitative assessment of binding affinity was performed using biolayer interferometry (ForteBio Octet RED96 and associated software for analysis). Enzymatically biotinylated target protein (30 nM) was immobilized on streptavidin-coated sensor tips (SA, ForteBio), then sequentially dipped in wells with: buffer only (baseline), antagonist in solution (association), and buffer only (dissociation). Kinetic constants were determined from the mathematical fit of a 1 : 1 binding model. In some experiments the format was swapped, with antagonist immobilized on amine reactive sensor tips (AR2G, ForteBio) according to manufacturer’s protocol and cytokine in solution.

[0236] IL- 17 -Mediated Cell Signaling Assay

[0237] Commercial hIL-17 reporter cells (HEK-Blue IL- 17, Invivogen) engineered to express secreted embryonic alkaline phosphatase (SEAP) downstream of the hIL-17 receptor were used to assess antagonism of hIL-17-mediated cell signaling. Cells were cultured per manufacturer’s protocol. Prior to inhibition experiments, the EC80 value for each appropriate cytokine (hIL-17A, hIL-17F) was determined by treating cells with a titration of recombinant cytokine or control (media). For subsequent inhibition experiments, cells were treated with the EC80 of cytokine and a titration of each inhibitor or control (media); cytokine and inhibitor were pre-incubated at 37°C for 30 minutes at lOx assay concentration, after which 20 uL of each condition was added to 180 uL cell suspension in media (300,000 cells / mL) in a 96-well tissue culture treated microplate. After overnight incubation at 37°C (5% CO2), 180 uL of supernatant from each well was transferred to a clear 96-well microplate with 20 uL of chromogenic SEAP substrate (QUANTI-Blue, Invivogen) and incubated at 37°C for 2 hours. SEAP activity, as a proxy for hIL-17 signaling, was determined by measuring absorbance at 620 nM. Inhibitor response was plotted as percent maximum hIL-17 stimulation (without inhibitor) vs. inhibitor concentration, and IC50 values determined using a four-parameter nonlinear curve fit analysis in Prism.

[0238] Example 1: Computational Design and Characterization of hIL-17A Binding Polypeptides hIL-17A and hIL-17F monomers pair to form symmetric homodimeric and heterodimeric cytokines, and signal via a ternary complex with receptors hIL-17RA and hIL-17RC which each bind at one of the two binding surfaces of the cytokine dimer. Experiments were conducted using methods described under Materials and Methods unless otherwise specified.

[0239] Computational Design

[0240] De novo interface design methods (see, e.g., ref. 6) were used to generate proteins that bind hIL-17A at the hIL-17RA / hIL-17RC interaction surface, using a crystal structure of hIL-17A in complex with hIL-17RA (PDBID 4HSA) as a starting point (ref. 7). A rotamer interaction field (RIF), i.e., disembodied residues predicted to favorably interact with the hIL-17A target surface, was computationally generated. Next, thousands of de novo designed miniproteins with diverse topologies and experimentally validated stability were docked at the hIL-17A surface such that the de novo hotspots were incorporated. Then, with each docked configuration as input, the Rosetta molecular modeling suite was used to mutate scaffold residues at the hIL-17A interface to side chains favoring high-affinity binding. De novo hotspots, scaffold residues in the scaffold hydrophobic core, and scaffold residues far from the hIL-17A interface were not allowed to mutate. The resulting designed antagonist candidates were filtered on computational metrics thought to predict high binding affinity and antagonist monomer stability, and genes encoding the predicted best 15,000 were commercially synthesized and transformed into yeast for surface display. Yeast were selected for binding to labeled recombinant human IL-17A (hIL-17A) by multiple successive rounds of fluorescence-activated cell sorting (FACS). Naive and sorted pools were analyzed by next-generation sequencing (NGS) and designs were ranked by their relative enrichment or depletion.

[0241] Three designs, 17-01 (ferredoxin fold design), 17-02 (three-helix bundle design) and 17-03 (ferredoxin fold design), set forth as SEQ ID NOs: 8, 39 and 63, respectively, were observed to bind hIL-17A with low nanomolar affinity, and were chosen for sequence optimization via in vitro directed evolution to further improve affinity. All three designs incorporate de novo generated hotspots at the hIL-17A surface that mimic hIL-17RA: a leucine hotspot mimicking hIL-17RA L27, an isoleucine mimicking hIL-17RA 132, and a phenylalanine mimicking hIL-17RA W31, indicated by asterisks in FIGS. 1C (17-01 peptide numbering: L47, F50, and 151, mimicking hIL-17RA L27, hIL-17RA W31, and hIL-17RA 132, respectively), 2C (17-02 peptide numbering: L23 and F26, mimicking hIL-17RA L27 and hIL-17RA W31, respectively), and 3C (17-03 peptide numbering: L47, F50, and 151, mimicking hIL-17RA L27, hIL-17RA W31, and hIL-17RA 132, respectively).

[0242] Saturation Mutagenesis of Designed Antagonists

[0243] Computationally designed antagonists 17-01, 17-02, and 17-03 were modeled in complex with hIL-17A (FIGS. 1A-1B, 2A-2B, and 3A-3B). Deep mutational scanning was carried out to probe the binding fitness landscapes of each designed antagonist. DNA libraries encoding each possible single-position mutant of 17-01, 17- 02, or 17-03 were synthesized and transformed into yeast for surface display and were subjected to two rounds of selection for binding to labeled hIL-17A via FACS. Naive and sorted pools were sequenced, and the enrichment or depletion of each mutant in the sorted pools were calculated and served as a proxy for binding fitness. A sequence conservation score was calculated per position. Amino acid positions that contribute to the hydrophobic core or the binding interface in the design model are conserved, while surface positions distal to the interface are not conserved. The observed conservation scores and binding fitness for 17-01, 17-02, and 17-03 are depicted in FIGS. 1C, 2C, and 3C The deep mutational scanning analysis of the designed hIL-17 antagonists corroborated predicted design structure and binding mode, and showed which mutations improve or worsen affinity. These data indicate that the designed inhibitors are folded in the conformation predicted by the modeling, and bind their target via the predicted binder surface.

[0244] In vitro Evolution of Enriched Mutations

[0245] Table 1 shows the allowable residues per position of hIL-17 binding polypeptides 17-01, 17-02, or 17-03, in the respective indicated columns, based on the fitness of single mutants for binding hIL-17A determined during directed evolution. Allowable mutations were those showing enrichment greater than or equal to that of the wild-type sequence (17-01, 17-02, or 17-03) in the first selection. Mutations enriched for high affinity binding were included in a combinatorial library subjected to six rounds of selection for binding to hIL-17A (or hIL-17F, as described in Example 2 herein).

[0246] Variants present in the final hIL-17A sort (17-01 A to 17-01Q, SEQ ID NOs: 9-33, and 17-02A to 17-02P, SEQ ID NOs: 39-58) were expressed in E. coli, purified and characterized in a cell-based hIL-17A binding assay.

[0247] To enhance stability of the designed proteins, intramolecular disulfide bonds were introduced. All combinatorial variants sequenced from the final pool were modeled with up to two disulfides, and variants filtered based on disulfide geometry and monomer free energy. The best scoring sequences, listed in Table 9, also were expressed in E. coli and characterized in the cell-based hIL-17A binding assay.

[0248] The highest affinity hIL-17A evolved designed minibinder variants showed approximately 100-fold improvement in affinity and cellular potency relative to the parent designs.

[0249] Cellular Potency of Combinatorial Variants

[0250] Engineered IL- 17 reporter cells expressing hIL-17RA and hIL-17RC (HEKBlue, Invivogen) were incubated with the EC80 of recombinant human IL-17A (0.5 ng / mL, determined in a prior assay), hIL-17A / F (6.9 ng / mL, determined in a prior assay), or hIL-17F (1.5 ng / mL, determined in a prior assay), with or without a titration of each inhibitor. Titration experiments were carried out two or more times per inhibitor. Cytokine and inhibitor were pre-incubated for 30 minutes before they were applied to cells. The chromogenic signaling output was measured after 24 hours and plotted relative to maximum stimulation observed (cytokine with no inhibitor). Average IC50 (pM) ± standard deviation are shown in Table 10. The representative curves were plotted. Combinatorial variants from both the ferredoxin (17-01M, SEQ ID NO: 21) and helix bundle (17-020, SEQ ID NO: 54) scaffolds were observed to block hIL-17-mediated cell signaling with 400- and 30-fold greater potency, respectively, than the initial designs 17-01 and 17-02. (FIGS. 4A-4D and 5A-5B).

[0251] Binding Affinity Determination Using BLI

[0252] BLI was carried out to evaluate the binding affinities of the of hIL-17A binding polypeptides using ForteBio Octet RED96, and associated analysis software. Biotinylated target protein (hIL-17A, 30 nM) was immobilized on streptavidin coated sensor tips, then dipped in binding polypeptide solution at the concentrations indicated to the right of each graph (association), then in buffer (dissociation). Reference sensor data was averaged and subtracted from sample data. Responses for original designs 17-01, 17-02, 17-03, 17-02 combinatorial variant 17-020, and the 17- 020 intramolecular disulfide-containing binding polypeptide 17-020dslf01A7V, are shown in FIGS. 6A-6E. Data were fit to a 2: 1 binding equation (dashed lines), reflecting that two binding polypeptide molecules in solution can bind to each of two binding sites on immobilized hIL-17A each known to have a unique affinity that can be influenced by the first binding event. Reported KD are an average of the KD determined for the two unique interactions. Response for single-chain linked dimer A7V-PAS8 is shown in FIG. 6F. Data were fit to a 1 : 1 binding equation using ForteBio analysis software (dashed lines). The instrument (ForteBio Octet RED96) is not sensitive enough to accurately determine picomolar KD; nonetheless, the data indicate the very high affinity (low picomolar) and slow dissociation rate of dimer A7V-PAS8 in comparison to the respective monomer, 17-020dslf01 A7V (SEQ ID NO: 58), which has a low nanomolar affinity. Plots are representative of at least two independent experiments per binding polypeptide.

[0253] Stability of Combinatorial Variants

[0254] The stabilities of combinatorial variants with and without at least one disulfide linkage introduced were compared. Variants having disulfide linkages (17-01Mdslf01, SEQ ID NO: 30, derived from 17-01; and 17-020dsfl01A7V, SEQ ID NO: 58, derived from 17-02) were significantly more stable than the related variants without the linkage (FIGS. 7A-7B and 8A-8B), while potency was not significantly impacted (FIGS. 4A-4D and 5A-5B). The variants with disulfide linkages showing their cysteine pairings are listed in Table 9.

[0255] Thermal stability: the 17-01 and 17-02 derivatives were denatured with heat up to 95 °C. Circular dichroism was used to monitor helical signature (signal at 222 nM), and loss of signal relative to 25 °C was used to calculate the fraction folded as temperature increased. The stability of disulfide-linked 17-02-derived binding polypeptide 17-020dslf01A7V was tested in the presence and absence of TCEP to evaluate the effect of reducing the disulfide bond. TCEP treatment resulted in lower binding polypeptide stability. Thermal stabilization results are shown in FIGS. 7A (17-02 and derivatives), and 8A (17-01 and derivatives). Adding one disulfide to hlL- 17A combinatorial variant 17-020 (yielding 17-020dslf01A7V) significantly improved stability, increasing the Tm from 68°C to 95°C and similarly increasing resistance to chemical denaturant. This data shows that a binding polypeptide of the present invention with at least one added disulfide bond has increased stability.

[0256] Chemical stability: the 17-01 and 17-02 derivatives were denatured with guanidinium hydrochloride (Gdn) up to 6M. Circular dichroism was used to monitor helical signature (signal at 222 nM), and loss of signal relative to 0 M Gdn used to calculate the fraction folded as Gdn concentration increased. The results are shown in FIGS. 8B (17-01 and derivatives), and 7B (17-02 and derivatives).

[0257] Both thermal and chemical denaturation experiments generally showed cooperative unfolding, suggesting a well-packed core. hIL-17A binding polypeptide 17-0 IM exhibited unexpected behavior in two independent experiments. Perturbation of the 17-0 IM structure with heat or Gdn can allow sampling of an alternative conformation not sampled during in vivo folding that has a lower free energy of folding.

[0258] Evaluation of Multimerized hIL-17A Binding Polypeptide

[0259] Human IL-17A binding polypeptide compositions comprising multiple copies of an hIL-17A binding polypeptide joined linearly by a flexible peptide linker were constructed and characterized. Dimer A7V-PAS8 (SEQ ID NO: 60) was constructed to include two copies of monomer 17-020dslf01 A7V (SEQ ID NO: 58) containing two disulfide-linked hIL-17 binding domains, joined by a linker comprising (PAS)s (see SEQ ID NOs: 68 and 80). The goal of this approach was to enhance affinity through avid binding to both hIL-17R binding sites of the hIL-17A homodimer. To minimize the size of the resulting dimer fusions, we selected 17-020dslf01 A7V, which is less potent (IC50 1,420 pM) than OlMdslfOl (IC50 300 pM), but substantially smaller. Several constructs with variable linker length and composition were expressed, purified, and characterized (SEQ ID NOs: 59-62).

[0260] Potency

[0261] The dimerized hIL-17A binding combinatorial variants blocked hIL-17- mediated cell signaling 3- to 100-fold better than clinical anti-IL-17 antibodies. The monomeric combinatorial variants showed substantial improvement in potency compared to the initial (parent) designs, but were found to have lower potency than the approved anti-IL-17A mAb secukinumab (Cosentyx; Novartis) and the investigational mAb bimekizumab (UCB). Average IC50 values for 17-01 and 17-02, derived combinatorial variants, disulfide-linked combinatorial variants, dimers thereof, and clinical mAbs are set forth in Table 10. All dimer fusions improved potency, from 20- to 4,000-fold, compared to binder monomer. Representative IC50 plots including dimer A7V-PAS8 are shown in FIGS. 9A-9B. A7V-PAS8 was observed to be the most potent dimer fusion (IC50 1 pM), at 100 times more potent than secukinumab and 3 times more potent than bimekizumab (FIGS. 9A-9B). A7V- PAS8 showed a 2,800-fold increase in potency compared to the minibinder monomer and a 60,000-fold increase compared to the parent computational design, 17-02 (FIGS. 4A and 4D)

[0262] Linkers

[0263] The linked construct having the shortest linker, (GS)10, showed weaker potency than those having longer linkers (PAS)8, (PAS) 12, and (PAS)20, suggesting an effect of length, e.g., a minimum linker length, for sterically unhindered engagement of both hIL-17A homodimer binding sites (FIGS. 9A-9B).

[0264] Specificity

[0265] Dimer A7V-PAS8 was found to be highly specific for homodimeric hIL-17A, showing negligible inhibition of hIL-17F- or hIL-17 A / F -mediated cell signaling (FIGS. 4A-4D). The monomer (17-020dslf01A7V) and dimer fusion (A7V-PAS8) binding polypeptide compositions block the hIL-17A / F heterodimeric cytokine with similar relatively weak potency, indicating that the 17-020dslf01 A7V binding domain binds only weakly to one of the two receptor binding sites of hIL-17A / F. Neither 17- O20dslfi)l A7V nor A7V-PAS8 bind to homodimeric hIL-17F. Table 9. Disulfide-Containing Combinatorial Variants and Dimer Fusions

[0266] Table 10. Binding Comparison

[0267] Example 2: Identification and Characterization of hIL-17F Binding Polypeptides

[0268] As the hIL-17F homolog is also a clinically relevant target, the hIL-17A minibinder combinatorial libraries were screened for cross-reactivity with hIL-17F, and hits further optimized for affinity and specificity to hIL-17F by in vitro evolution. As described in Example 1 with regard to hIL-17A, mutations enriched for high affinity binding were included in a combinatorial library subjected to six rounds of selection for binding to hIL-17F as well as hIL-17A. Variants present in the final hlL- 17F sort included F01-A1 to F01-A4, and F01-S1, SEQ ID NOs: 34-38, respectively (derived from 17-01), and F03-A1, F03-S1, F03-S2, SEQ ID NOs: 64-66, respectively (derived from 17-03).

[0269] Table 2 shows the allowable residues per position of construct F01-A4 (SEQ ID NO: 37), based on the fitness of single mutants for binding hIL-17F. The library of all possible single mutants of F01-A4 was sorted for (1) binding to labeled hIL-17F alone to select for enhanced target affinity alone (allowable residues shown in the left column under SEQ ID NO: 4), or (2) to labeled hIL-17F in the presence of unlabeled hIL-17A competitor to select for affinity and specificity to hIL-17F (allowable residues shown in the right column under SEQ ID NO: 5). All mutants showing enrichment greater than or equal to that of the wild-type sequence in the first selection were deemed allowable.

[0270] Table 3 shows the allowable residues per position of construct F03-S1 (SEQ ID NO: 65), based on the fitness of single mutants for binding hIL-17F as described herein in the Examples. The library of all possible single mutants of F03-S1 was sorted for (1) binding to labeled hIL-17F alone to select for enhanced target affinity alone (allowable residues shown under SEQ ID NO: 6), or (2) to labeled hIL-17F in the presence of unlabeled hIL-17A competitor to select for affinity and specificity to hIL-17F (allowable residues shown under SEQ ID NO: 7). All mutants showing enrichment greater than or equal to that of the wild-type sequence in the first selection were deemed allowable. Characterization hIL-17F variants were expressed in E. coh. purified and characterized. To evaluate inhibition of hIL-17F-mediated cell signaling by the hIL-17F binding polypeptide combinatorial variants, engineered IL- 17 reporter cells (HEKBlue, Invivogen) were incubated with the EC80 of recombinant human IL-17F (1.5 ng / mL, determined in a prior assay) with or without a titration of each inhibitor. Titration experiments were carried out two or more times per inhibitor. Average IC50 (pM) ± standard deviation are determined and the representative curves were plotted. The most potent hIL-17F inhibitor, F01-A4, blocks hIL-17F -mediated signaling with potency 300-fold greater than hIL-17A-specific minibinder 17-020dslf 1 A7V, 3-fold greater than clinical anti-hIL-17 antibodies secukinumab and 1,000-fold lower than bimekizumab (FIGS. 4C and 4D).

[0271] Example 3: Identification and Characterization of Multimeric hIL-17F Binding Polypeptides

[0272] Multimerized hIL-17F designed antagonists hIL-17F variants, e.g., SEQ ID NOs: 67-70, with and without introduced disulfide bonds, are multimerized using one or more linkers. As described for the hlL- 17A binding polypeptide variants, the multimerized hIL-17F polypeptide binders are characterized, for binding to hIL-17F, potency, stability, and other features of interest. They are compared with monomers, wild-type (e.g., non-optimized and / or unevolved) sequences, and / or clinical mAbs that target hIL-17F.

[0273] Example 4: Testing of hIL-17A and hIL-17F Designed Antagonists in vivo

[0274] IL-17A or IL-17F targeting minibinder monomers or multimers are administered as oral or topical formulations in vivo to study their effect on disease, e.g. skin inflammation. The impact of minibinder(s) vs. controls (no treatment, or control therapy e.g. an anti-IL-17 mAb) are assessed using relevant disease metrics, e.g. skin thickness and histological inflammation, and biomarker response both locally (skin) and systemically (blood).

[0275] References

[0276] 1. Onishi, R. M. & Gaffen, S. L. Interleukin- 17 and its target genes: mechanisms of interleukin- 17 function in disease. Immunology 129, 311-321 (2010).

[0277] 2. Linsky, T. et al. Sampling of Structure and Sequence Space of Small Protein Folds. bioRxiv (2021) doi: 10.1101 / 2021.03.10.434454.

[0278] 3. Bhardwaj, G. et al. Accurate de novo design of hyperstable constrained peptides. Nature 538, 329-335 (2016).

[0279] 4. Rocklin, G. J. et al. Global analysis of protein folding using massively 5 parallel design, synthesis, and testing. Science 357, 168-175 (2017).

[0280] 5. Cao, L. et al. De novo design of picomolar SARS-CoV-2 miniprotein inhibitors. Science 370, 426-431 (2020).

[0281] 6. Cao, L. et al. Design of protein-binding proteins from the target structure alone. Nature 605, 551-560 (2022). 0 7. Liu, S. et al. Crystal structures of interleukin 17A and its complex with

[0282] IL-17 receptor A. Nat. Commun. 4, 1888 (2013).

[0283] 8. Schneidman-Duhovny, D., Inbar, Y., Nussinov, R. & Wolfson, H. J. PatchDock and SymmDock: servers for rigid and symmetric docking. Nucleic Acids Res. 33, W363-7 (2005). 5 9. Procko, E. et al. Computational design of a protein-based enzyme inhibitor. J. Mol. Biol. 425, 3563-3575 (2013).

[0284] 10. Chao, G. et al. Isolating and engineering human antibodies using yeast surface display. Nat. Protoc. 1, 755-768 (2006).

[0285] 11. Benatuil, L., Perez, J. M., Belk, J. & Hsieh, C.-M. An improved yeast 0 transformation method for the generation of very large human antibody libraries.

[0286] Protein Eng. Des. Sei. 23, 155-159 (2010).

[0287] 12. Fowler, D.M. et al. Enrich: software for analysis of protein function by enrichment and depletion of variants. Bioinformatics 27(24): 3430-3431 (2011). 5 Table 11. Sequences.

[0288] Since modifications will be apparent to those of skill in the art, it is intended that invention(s) herein only is / are limited by the scope of the appended claims.

Claims

WHAT IS CLAIMED:

1. A human IL-17 (hIL-17) binding polypeptide composition, having a general formula from N-terminus to C-terminus, A-(linker-B)n, wherein: n=0 to 10;A is a polypeptide of the formula (X1-X2-X3-X4-X5-X6-X7-X8-X9-X10- XI 1); in A, XI, X2, X3, X4, X5, X6, X7, X8, X10, and XI 1, are optional;X9 comprises a polypeptide domain of 12-20 amino acids in length;X9 comprises an amino acid sequence of residues 42-51 of the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 1, 3, 4, 5, 6, 7, 34, 35, 36, 38, 64, 66, 71, 73, 74, and 77, and X9 comprised at least one conservative amino acid substitution in residues 42-51 relative to the selected amino acid sequence, and X9 has 50% to 100% identity to residues 42-51 of the selected amino acid sequence;B is a polypeptide of the formula (Xl’-X2’-X3’-X4’-X5’-X6’-X7’-X8’-X9’- X10’-Xl l’);XI, when present, comprises a polypeptide domain of 1-7 amino acids in length;XI’, when present, comprises a polypeptide domain of 1-7 amino acids in length;X2, when present, comprises a polypeptide domain of 1-2 amino acids in length;X2’ , when present, comprises a polypeptide domain of 1-2 amino acids in length;X3, when present, comprises a polypeptide domain of 1-11 amino acids in length;X3’, when present, comprises a polypeptide domain of 1-11 amino acids in length;X4, when present, comprises a polypeptide domain of 1-2 amino acids in length;X4’, when present, comprises a polypeptide domain of 1-2 amino acids in length;X5, when present, comprises a polypeptide domain of 1-4 amino acids in length;X5’, when present, comprises a polypeptide domain of 1-4 amino acids in length;X6, when present, comprises a polypeptide domain of 1-4 amino acids in length;X6’, when present, comprises a polypeptide domain of 1-4 amino acids in length;X7, when present, comprises a polypeptide domain of 1-6 amino acids in length;X7’, when present, comprises a polypeptide domain of 1-6 amino acids in length;X8, when present, comprises a polypeptide domain of 1-2 amino acids in length;X8’, when present, comprises a polypeptide domain of 1-2 amino acids in length;X9’, when present, comprises a polypeptide domain of 12-20 amino acids in length;XI 0, when present, comprises a polypeptide domain of 1-2 amino acids in length;XI O’, when present, comprises a polypeptide domain of 1-2 amino acids in length;XI 1, when present, comprises a polypeptide domain 1-7 amino acids in length; andXI 1’, when present, comprises a polypeptide domain 1-7 amino acids in length.

2. The hIL-17 binding polypeptide composition of claim 1, wherein when n=l-10:X9’ is present in B and comprises a polypeptide domain of 12-20 amino acids in length;X9’ comprises a polypeptide domain of 12-20 amino acids in length;X9’ comprises an amino acid sequence of residues 42-51 of the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 1, 3, 4, 5, 6, 7, 34, 35, 36, 38, 64, 66, 71, 73, 74, and 77, wherein X9’ can comprise at least one conservative amino acid substitution in residues 42-51 relative to the selected amino acid sequence, and X9’ can have 50% to 100% identity to residues 42-51 of the selected amino acid sequence.

3. The hIL-17 binding polypeptide composition of claim 1 or 2, wherein in A, X9 and any combination of XI, X2, X3, X4, X5, X6, X7, X8, X10, XI 1, are present.

4. The hIL-17 binding polypeptide composition of any one of claims 1-3, wherein n=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1-5, or 1-10.

5. The hIL-17 binding polypeptide composition of any one of claims 1-4, wherein in B, X9 is present, and further wherein XI’, X2’, X3’, X4’, X5’ , X6’, X7’, X8’, X10’, XI 1,’ or any combination thereof, is present.

6. The hIL-17 binding polypeptide composition of any one of claims 1-5, wherein A and B have the same amino acid sequence.

7. The hIL-17 binding polypeptide composition of any one of claims 1-5, wherein A and B have different amino acid sequences.

8. The hIL-17 binding polypeptide composition of any one of claims 1-7, wherein the hIL-17 binding protein is a linear polypeptide.

9. The hIL-17 binding polypeptide composition of any one of claims 1-8, wherein:XI, when present, comprises an amino acid sequence of residues 1-7 of the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 1, 3, 4, 5, 6, 7, 34, 35, 36, 38, 64, 66, 71, 73, 74, and 77, wherein XI can comprise at least one conservative amino acid substitution in residues 1-7 relative to the selected amino acid sequence, and wherein XI can have 50% to 100% identity to residues 1-7 of the selected amino acid sequence;XI’, when present, comprises an amino acid sequence of residues 1-7 of the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 1, 3, 4, 5, 6, 7, 34, 35, 36, 38, 64, 66, 71, 73, 74, and 77, wherein XT can comprise at least one conservative amino acid substitution in residues 1-7 relative to the selected aminoacid sequence, and wherein XI’ can have 50% to 100% identity to residues 1-7 of the selected amino acid sequence;X2, when present, comprises an amino acid sequence of residues 8-9 of the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 1, 3, 4, 5, 6, 7, 34, 35, 36, 38, 64, 66, 71, 73, 74, and 77, wherein X2 can comprise at least one conservative amino acid substitution in residues 8-9 relative to the selected amino acid sequence, and wherein X2 can have 50% to 100% identity to residues 8-9 of the selected amino acid sequence;X2’ , when present, comprises an amino acid sequence of residues 8-9 of the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 1, 3, 4, 5, 6, 7, 34, 35, 36, 38, 64, 66, 71, 73, 74, and 77, wherein X2’ can comprise at least one conservative amino acid substitution in residues 8-9 relative to the selected amino acid sequence, and wherein X2’ can have 50% to 100% identity to residues 8-9 of the selected amino acid sequence;X3, when present, comprises an amino acid sequence of residues 10-20 of the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 1, 3, 4, 5, 6, 7, 34, 35, 36, 38, 64, 66, 71, 73, 74, and 77, wherein X3 can comprise at least one conservative amino acid substitution in residues 10-20 relative to the selected amino acid sequence, and wherein X3 can have 50% to 100% identity to residues 10-20 of the selected amino acid sequence;X3’, when present, comprises an amino acid sequence of residues 10-20 of the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 1, 3, 4, 5, 6, 7, 34, 35, 36, 38, 64, 66, 71, 73, 74, and 77, wherein X3’ can comprise at least one conservative amino acid substitution in residues 10-20 relative to the selected amino acid sequence, and wherein X3’ can have 50% to 100% identity to residues 10-20 of the selected amino acid sequence;X4, when present, comprises an amino acid sequence of residues 21-22 of the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 1, 3, 4, 5, 6, 7, 34, 35, 36, 38, 64, 66, 71, 73, 74, and 77, wherein X4 can comprise at least one conservative amino acid substitution in residues 21-22 relative to the selected amino acid sequence, and wherein X4 can have 50% to 100% identity to residues 21-22 of the selected amino acid sequence;X4’, when present, comprises an amino acid sequence of residues 21-22 of the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 1, 3, 4, 5, 6, 7, 34, 35, 36, 38, 64, 66, 71, 73, 74, and 77, wherein X4' can comprise at least one conservative amino acid substitution in residues 21-22 relative to the selected amino acid sequence, and wherein X4’ can have 50% to 100% identity to residues 21-22 of the selected amino acid sequence;X5, when present, comprises an amino acid sequence of residues 23-26 of the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 1, 3, 4, 5, 6, 7, 34, 35, 36, 38, 64, 66, 71, 73, 74, and 77, wherein X5 can comprise at least one conservative amino acid substitution in residues 23-26 relative to the selected amino acid sequence, and wherein X5 can have 50% to 100% identity to residues 23-26 of the selected amino acid sequence;X5’, when present, comprises an amino acid sequence of residues 23-26 of the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 1, 3, 4, 5, 6, 7, 34, 35, 36, 38, 64, 66, 71, 73, 74, and 77, wherein X5’ can comprise at least one conservative amino acid substitution in residues 23-26 relative to the selected amino acid sequence, and wherein X5’ can have 50% to 100% identity to residues 23-26 of the selected amino acid sequence;X6, when present, comprises an amino acid sequence of residues 27-30 of the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 1, 3, 4, 5, 6, 7, 34, 35, 36, 38, 64, 66, 71, 73, 74, and 77, wherein X6 can comprise at least one conservative amino acid substitution in residues 27-30 relative to the selected amino acid sequence, and wherein X6 can have 50% to 100% identity to residues 27-30 of the selected amino acid sequence;X6’, when present, comprises an amino acid sequence of residues 27-30 of the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 1, 3, 4, 5, 6, 7, 34, 35, 36, 38, 64, 66, 71, 73, 74, and 77, wherein X6’ can comprise at least one conservative amino acid substitution in residues 27-30 relative to the selected amino acid sequence, and wherein X6’ can have 50% to 100% identity to residues 27-30 of the selected amino acid sequence;X7, when present, comprises an amino acid sequence of residues 31-36 of the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 1, 3, 4, 5, 6,7, 34, 35, 36, 38, 64, 66, 71, 73, 74, and 77, wherein X7 can comprise at least one conservative amino acid substitution in residues 31-36 relative to the selected amino acid sequence, and wherein X7 can have 50% to 100% identity to residues 31-36 of the selected amino acid sequence;X7’, when present, comprises an amino acid sequence of residues 31-36 of the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 1, 3, 4, 5, 6, 7, 34, 35, 36, 38, 64, 66, 71, 73, 74, and 77, wherein X7’ can comprise at least one conservative amino acid substitution in residues 31-36 relative to the selected amino acid sequence, and wherein X7’ can have 50% to 100% identity to residues 31-36 of the selected amino acid sequence;X8, when present, comprises an amino acid sequence of residues 37-38 of the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 1, 3, 4, 5, 6, 7, 34, 35, 36, 38, 64, 66, 71, 73, 74, and 77, wherein X8 can comprise at least one conservative amino acid substitution in residues 37-38 relative to the selected amino acid sequence, and wherein X8 can have 50% to 100% identity to residues 37-38 of the selected amino acid sequence;X8’, when present, comprises an amino acid sequence of residues 37-38 of the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 1, 3, 4, 5, 6, 7, 34, 35, 36, 38, 64, 66, 71, 73, 74, and 77, wherein X8’ can comprise at least one conservative amino acid substitution in residues 37-38 relative to the selected amino acid sequence, and wherein X8’ can have 50% to 100% identity to residues 37-38 of the selected amino acid sequence;X9’, when present, comprises an amino acid sequence of residues 42-51 of the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 1, 3, 4, 5, 6, 7, 34, 35, 36, 38, 64, 66, 71, 73, 74, and 77, wherein X9’ can comprise at least one conservative amino acid substitution in residues 42-51 relative to the selected amino acid sequence, and wherein X9’ can have 50% to 100% identity to residues 42-51 of the selected amino acid sequence;X10, when present, comprises an amino acid sequence of residues 53-54 of the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 1, 3, 4, 5, 6, 7, 34, 35, 36, 38, 64, 66, 71, 73, 74, and 77, wherein X10 can comprise at least one conservative amino acid substitution in residues 53-54 relative to the selected aminoacid sequence, and wherein X10 can have 50% to 100% identity to residues 53-54 of the selected amino acid sequence;X10’, when present; comprises an amino acid sequence of residues 53-54 of the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 1, 3, 4, 5, 6, 7, 34, 35, 36, 38, 64, 66, 71, 73, 74, and 77, wherein X10’ can comprise at least one conservative amino acid substitution in residues 53-54 relative to the selected amino acid sequence, and wherein XI 0’ can have 50% to 100% identity to residues 53-54 of the selected amino acid sequence;XI 1, when present, comprises an amino acid sequence of residues 55-61 of the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 1, 3, 4, 5, 6, 7, 34, 35, 36, 38, 64, 66, 71, 73, 74, and 77, wherein XI 1 can comprise at least one conservative amino acid substitution in residues 55-61 relative to the selected amino acid sequence, and wherein XI 1 can have 50% to 100% identity to residues 55-61 of the selected amino acid sequence; andXI 1’, when present, comprises an amino acid sequence of residues 55-61 of the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 1, 3, 4, 5, 6, 7, 34, 35, 36, 38, 64, 66, 71, 73, 74, and 77, wherein XU ’ can comprise at least one conservative amino acid substitution in residues 55-61 relative to the selected amino acid sequence, and wherein XI E can have 50% to 100% identity to residues 55-61 of the selected amino acid sequence.

10. The hIL-17 binding polypeptide composition of any one of claims 1-9, wherein:A comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in a sequence selected from SEQ ID NO: 71, SEQ ID NO: 73, SEQ ID NO: 74, and SEQ ID NO: 77;B, when present, B comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in a sequence selected from SEQ ID NO: 71, SEQ ID NO: 73, SEQ ID NO: 74, and SEQ ID NO: 77; andoptionally wherein 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more of the N-terminal amino acids are deleted from the reference polypeptide and the deleted amino acids are not considered in the percent identity.

11. The hIL-17 binding polypeptide composition of any one of claims 1-10, wherein:A comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in a sequence selected from SEQ ID NOs: 8-38 and 63-66;B, when present, B comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in a sequence selected from ID NOS: 8-38 and 63-66; and optionally wherein 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more of the N-terminal amino acids are deleted from the reference polypeptide and the deleted amino acids are not considered in the percent identity.

12. The hIL-17 binding polypeptide composition of any one of claims 1-11, wherein X9 comprises an alpha helix.

13. The hIL-17 binding polypeptide composition of any one of claims 1-12, wherein:XI, when present, comprises a beta strand;XI’, when present, comprises a beta strand;X2, when present, comprises a loop;X2’ , when present, comprises a loop;X3, when present, comprises an alpha helix;X3’, when present, comprises an alpha helix;X4, when present, comprises a loop;X4’, when present, comprises a loop;X5, when present, comprises a beta strand;X5’, when present, comprises a beta strand;X6, when present, comprises a loop;X6’, when present, comprises a loop;X7, when present, comprises a beta strand;X7’, when present, comprises a beta strand;X8, when present, comprises a loop;X8’, when present, comprises a loop;X9 comprises an alpha helix;X9’, when present, comprises an alpha helix;XI 0, when present, comprises a loop;XI O’, when present, comprises a loop;XI 1, when present, comprises a beta strand; andXI 1’, when present, comprises a beta strand.

14. The hIL-17 binding polypeptide composition of any one of claims 1-13, wherein X9 comprises an alpha helix, wherein X3 is present and comprises an alpha helix, and wherein when X9’ is present, X9’ comprises an alpha helix and X3’ is present and comprises an alpha helix.

15. The hIL-17 binding polypeptide composition of any one of claims 1-14, wherein X9 comprises an alpha helix, and wherein XI, X5, X7, and XI 1 are present and each comprises a beta strand, and wherein when X9’ is present, X9’ comprises an alpha helix and XI’, X5’, X7’, and XI 1’ are present and each comprises a beta strand.

16. The hIL-17 binding polypeptide composition of any one of claims 1-15, wherein each of XI, X2, X3, X4, X5, X6, X7, X8, X9, X10, and XI 1 are present, wherein:XI comprises an amino acid sequence at least 50%, 70%, 85%, or 100% identical to the amino acid sequence of an XI domain present in any of SEQ ID NOs: 8-38 and 63-66;X2 comprises an amino acid sequence at least 50%, 75%, or 100% identical to the amino acid sequence of an X2 domain present in any of SEQ ID NOs: 8-38 and 63-66;X3 comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of an X3 domain present in any of SEQ ID NOs: 8-38 and 63-66;X4 comprises an amino acid sequence at least 50%, 75%, or 100% identical to the amino acid sequence of an X4 domain present in any of SEQ ID NOs: 8-38 and 63-66;X5 comprises an amino acid sequence at least 50%, 75%, or 100% identical to the amino acid sequence of an X5 domain present in any of SEQ ID NOs: 8-38 and 63-66;X6 comprises an amino acid sequence at least 50%, 75%, or 100% identical to the amino acid sequence of an X6 domain present in any of SEQ ID NOs: 8-38 and 63-66;X7 comprises an amino acid sequence at least 50%, 70%, 85%, or 100% identical to the amino acid sequence of an X7 domain present in any of SEQ ID NOs: 8-38 and 63-66;X8 comprises an amino acid sequence at least 50%, 75%, or 100% identical to the amino acid sequence of an X8 domain present in any of SEQ ID NOs: 8-38 and 63-66;X9 comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of an X9 domain present in any of SEQ ID NOs: 8-38 and 63-66;X10 comprises an amino acid sequence at least 50%, 75%, or 100% identical to the amino acid sequence of an X10 domain present in any of SEQ ID NOs: 8-38 and 63-66; andXI 1 comprises an amino acid sequence at least 50%, 70%, 85%, or 100% identical to the amino acid sequence of an XI 1 domain present in any of SEQ ID NOs: 8-38 and 63-66.

17. The hIL-17 binding polypeptide composition of any one of claims 1- 16, wherein each of XI’, X2’, X3’, X4’, X5’, X6’, X7’, X8’, X9’, X10’, and XI E are present, and wherein:XI’ comprises an amino acid sequence at least 50%, 70%, 85%, or 100% identical to the amino acid sequence of an XI domain present in any of SEQ ID NOs: 8-38 and 63-66;X2’ comprises an amino acid sequence at least 50%, 75%, or 100% identical to the amino acid sequence of an X2 domain present in any of SEQ ID NOs: 8-38 and 63-66;X3’ comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of an X3 domain present in any of SEQ ID NOs: 8-38 and 63-66;X4’ comprises an amino acid sequence at least 50%, 75%, or 100% identical to the amino acid sequence of an X4 domain present in any of SEQ ID NOs: 8-38 and 63-66;X5’ comprises an amino acid sequence at least 50%, 75%, or 100% identical to the amino acid sequence of an X5 domain present in any of SEQ ID NOs: 8-38 and 63-66;X6’ comprises an amino acid sequence at least 50%, 75%, or 100% identical to the amino acid sequence of an X6 domain present in any of SEQ ID NOs: 8-38 and 63-66;X7’ comprises an amino acid sequence at least 50%, 70%, 85%, or 100% identical to the amino acid sequence of an X7 domain present in any of SEQ ID NOs: 8-38 and 63-66;X8’ comprises an amino acid sequence at least 50%, 75%, or 100% identical to the amino acid sequence of an X8 domain present in any of SEQ ID NOs: 8-38 and 63-66;X9’ comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of an X9 domain present in any of SEQ ID NOs: 8-38 and 63-66;X10’ comprises an amino acid sequence at least 50%, 75%, or 100% identical to the amino acid sequence of an X10 domain present in any of SEQ ID NOs: 8-38 and 63-66; andXI 1’ comprises an amino acid sequence at least 55%, 70%, 85%, or 100% identical tothe amino acid sequence of an XI 1 domain present in any of SEQ ID NOs: 8- 38 and 63-66.

18. The hIL-17 binding polypeptide composition of any one of claims 1-17, wherein:(i) in A, XI, X5, X7, and XI 1 are present and each comprises a beta strand, and X3 and X9 are present and each comprises an alpha helix; or(ii) n=l-10, wherein in A, XI, X5, X7 and XI 1 are present and each comprises a beta strand, and X3 and X9 are present and each comprises an alpha helix, and wherein in B, XI’, X5’, X7’ and XI 1’ are present and each comprises a beta strand, and X3’ and X9’ are present and each comprises an alpha helix.

19. The hIL-17 binding polypeptide composition of any one of claims 1-18, wherein in A, XI, X2, X3, X4, X5, X6, X7, X8, X10, and XI 1, or any combination thereof, are present in addition to X9.

20. The hIL-17 binding polypeptide composition of any one of claims 1-19, wherein in B, XI’, X2’, X3’, X4’, X5’, X6’, X7’, X8’, X9’, X10’, XI F, or any combination thereof, are present.

21. The hIL-17 binding polypeptide composition of any one of claims 1-20, further comprising one or more additional functional domains added at the N- terminus of the polypeptide, the C-terminus of the polypeptide, or both.

22. The hIL-17 binding polypeptide composition of any one of claims 1-21, wherein in A, X9 comprises the amino acid sequence of residues 42-51 in the amino acid sequence selected from the group consisting of SEQ ID NOs: 21 and 30, and wherein in B, when present, X9’ comprises the amino acid sequence of residues 42-51 in the amino acid sequence selected from the group consisting of SEQ ID NOs: 21 and 30.

23. The hIL-17 binding polypeptide composition of any one of claims 1-22, comprising an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in a sequence selected from SEQ ID NO: 21 and 30, optionally wherein 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more of the N- terminal amino acids are deleted from the selected polypeptide amino acid sequence and the deleted amino acids are not considered in the percent identity.

24. The hIL-17 binding polypeptide composition of any one of claims 1-23, wherein n=l-10, wherein:A comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in a sequence selected from SEQ ID NOs: 21 and 30;B comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in a sequence selected from SEQ ID NOs: 21 and 30; optionally wherein 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more of the N-terminal amino acids are deleted from the selected amino acid sequence comprised by A, B, or from both A and B, wherein the deleted amino acids are not considered in the percent identity of A, B, or both, respectively, to the selected amino acid sequence; and the amino acid sequence of A can be 90% to 100% identical to the amino acid sequence of B.

25. The hIL-17 binding polypeptide composition of any one of claims 1-24, comprising at least one disulfide bond between two cysteine residues in the polypeptide, wherein: when A is present and B is not present, the at least one disulfide bond occurs within A; and when both A and B are present, the binding polypeptide composition comprises at least two disulfide bonds, wherein at least one of the at least two disulfide bonds is within A, and at least one of the at least two disulfide bonds is within B.

26. The hIL-17 binding polypeptide composition of any one of claims 1-25, having the amino acid sequence set forth in a sequence selected from SEQ ID NOs: 26-33, wherein: the amino acid sequence of the binding polypeptide composition can have at least 1-20 conservative substitutions relative to the amino acid sequence of the selected amino acid sequence, wherein cysteine residues are preserved in the substituted amino acid sequence; andthe amino acid sequence of the binding polypeptide composition can have 50% to 100% identity to the selected amino acid sequence, wherein cysteine residues are preserved in the amino acid sequence of the binding polypeptide composition having 50% to 100% identity to the selected amino acid sequence, optionally wherein 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more of the N-terminal amino acids are deleted from the selected amino acid sequence, wherein the deleted amino acids are not considered in the percent identity to the selected amino acid sequence.

27. The hIL-17 binding polypeptide composition of any one of claims 1-26, having an amino acid sequence set forth as any one of: SEQ ID NO: 26, disulfide bonded between C6 and C56; SEQ ID NO: 27, disulfide bonded between C13 and C32; SEQ ID NO: 28, disulfide bonded between C3 and C35; SEQ ID NO: 29, disulfide bonded between C3 and C35, and between C13 and C32; SEQ ID NO: 30, disulfide bonded between C3 and C35; SEQ ID NO: 31, disulfide bonded between C6 and C56; SEQ ID NO: 32, disulfide bonded between C13 and C24; SEQ ID NO: 33, disulfide bonded between C6 and C56, and between C13 and C24; SEQ ID NO: 56, disulfide bonded between C6 and C33; SEQ ID NO: 57, disulfide bonded between C7 and C40; SEQ ID NO: 58, disulfide bonded between C6 and C33; SEQ ID NO: 59, disulfide bonded between C6 and C33, and between C70 and C97; SEQ ID NO: 60, disulfide bonded between C6 and C33, and between C74 and C101; SEQ ID NO: 61, disulfide bonded between C6 and C33, and between C86 and Cl 13; and SEQ ID NO: 62, disulfide bonded between C6 and C33, and between Cl 10 and C137.

28. The hIL-17 binding polypeptide composition of any one of claims 1-27, wherein the linker is an amino acid linker, optionally wherein the linker is about 1 to about 100 amino acids in length.

29. The hIL-17 binding polypeptide composition of any one of claims 1-28, wherein the linker is selected from a linker having the formula (PAS)n, and linker having the formula (Gly-Ser)n, optionally wherein n=l-100.

30. The hIL-17 binding polypeptide composition of any one of claims 1-29, wherein the linker has the amino acid sequence set forth in any of SEQ ID NOs: 67-70.

31. The hIL-17 binding polypeptide composition of any one of claims 1-30 wherein the binding polypeptide composition binds a target with high specificity, high affinity, or both.

32. The hIL-17 binding polypeptide composition of claim 31, wherein the target is hIL-17.

33. The hIL-17 binding polypeptide composition of any one of claims 1-32, wherein the polypeptide is an hIL-17 antagonist or an hIL-17 agonist.

34. The hIL-17 binding polypeptide composition of any one of claims 1-33, wherein the polypeptide is an hIL-17 antagonist.

35. The hIL-17 binding polypeptide composition of any one of claims 31-34, wherein a binding assay is used to evaluate the binding of the polypeptide to the target.

36. The hIL-17 binding polypeptide composition of claim 35, wherein the binding assay is a binding specificity assay that measures the ability of the binding polypeptide composition to inhibit binding of hIL-17 to an hIL-17 receptor.

37. The hIL-17 binding polypeptide composition of any one of claims 35 and 36, wherein the binding specificity assay is a cell signaling assay.

38. The hIL-17 binding polypeptide composition of any one of claims 1-37, comprising A and not B, or A and B, wherein the binding polypeptide composition reduces stimulation of an hIL-17 receptor by hIL-17 by about 75 percent to about 100 percent at an IC50 of about 1.5 nM to about 0.1 pM.

39. The hIL-17 binding polypeptide composition of any one of claims 1-38, wherein the binding polypeptide composition comprises A and B, and blocks hlL- 17-mediated cell signaling with a greater potency than a binding polypeptide composition comprising A and not B.

40. The hIL-17 binding polypeptide composition of any one of claims 1-39, wherein the binding polypeptide composition comprises A and B, and blocks hlL- 17-mediated cell signaling with a potency of 10-fold to 10,000-fold greater than a binding polypeptide composition comprising A and not B.

41. The hIL-17 binding polypeptide of any one of claims 1-40, wherein the binding polypeptide comprises A and B, and wherein the binding polypeptidecomposition blocks hIL-17-mediated cell signaling with a potency of 2-fold to 250- fold greater than that of a clinical hIL-17 binding monoclonal antibody.

42. The hIL-17 binding polypeptide of any one of claims 1-41, wherein the binding polypeptide comprises A and B, and wherein the binding polypeptide composition reduces stimulation of an hIL-17 receptor by hIL-17 by about 75 percent to about 100 percent at an IC50 of about 150 pM to about 0.1 pM.

43. The hIL-17 binding polypeptide composition of any one of claims 1-42, wherein the binding polypeptide composition reduces stimulation of an hIL-17 receptor by hIL-17 by about 75 percent to about 100 percent at an IC50 of less than about 0.6 pM, less than about 1 pM, less than about 1.5 pM, less than about 2 pM, less than about 2.5 pM, less than about 3 pM, less than about 5 pM, less than about 10 pM, less than about 25 pM, less than about 50 pM, less than about 75 pM, or less than about 100 pM, less than about 150 pM, less than about 350 pM, less than about 500 pM, less than about 1 nM, or less than about 1.5 nM.

44. The hIL-17 binding polypeptide composition of any one of claims 41-43, wherein the clinical hIL-17 binding monoclonal antibody is selected from: secukinumab, ixekizumab, brodalumab, and bimekizumab.

45. The hIL-17 binding polypeptide composition of any one of claims 1-44, wherein the hIL-17 is hIL-17A or hIL-17F.

46. The hIL-17 binding polypeptide composition of any one of claims 1-45, wherein the hIL-17 is hIL-17A, and wherein X9, X9’, or both, comprises the amino acid sequence of residues 42-51 set forth in a sequence selected from SEQ ID NOs: 71, 73, 74, and 77, wherein:X9, X9’, or both, of the binding polypeptide composition can have at least one conservative substitution relative to residues 42-51 of the selected amino acid sequence; andX9, X9’, or both, the binding polypeptide composition can have 50% to 100% identity to residues 42-51 of the selected amino acid sequence.

47. The hIL-17 binding polypeptide composition of any one of claims 1-46, wherein the hIL-17 is hIL-17A and X9, X9’, or both, comprises an amino acid sequence of residues 42-51 of the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 8-33 and 63, wherein:X9, X9’, or both, of the binding polypeptide composition can have at least one conservative substitution relative to residues 42-51 of the selected amino acid sequence; andX9, X9’, or both, of the binding polypeptide composition can have 50% to 100% identity to residues 42-51 of the selected amino acid sequence.

48. The hIL-17 binding polypeptide composition of any one of claims 1- 47, wherein the hIL-17 is hIL-17A and the binding polypeptide composition comprises the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 8-33 and 63, wherein: the binding polypeptide composition can have at least 1-20 conservative substitutions relative to the amino acid sequence of the selected amino acid sequence; and the binding polypeptide composition can have 50% to 100% identity to the selected amino acid sequence, optionally wherein 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more of the N-terminal amino acids are deleted from the selected amino acid sequence, wherein the deleted amino acids are not considered in the percent identity to the selected amino acid sequence.

49. The hIL-17 binding polypeptide composition of any one of claims 1- 45, wherein the hIL-17 is hIL-17F and X9 comprises the amino acid sequence of residues 42-51 in the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 4, 5, 6, 7, 34-38, and 64-66, wherein: the binding polypeptide composition can have at least one conservative substitution relative to residues 42-51 of the selected amino acid sequence; and the binding polypeptide composition can have 50% to 100% identity to residues 42-51 of the selected amino acid sequence.

50. The hIL-17 binding polypeptide composition of any one of claims 1-45 and 49, wherein the hIL-17 is hIL-17F and the binding polypeptide composition comprises the amino acid sequence set forth in any one of: SEQ ID NOs: 4, 5, 6, 7, 34-38, and 64-66, wherein: the binding polypeptide composition can have at least 1-20 conservative substitutions relative to the amino acid sequence of the selected amino acid sequence; andthe binding polypeptide composition can have 50% to 100% identity to the selected amino acid sequence, optionally wherein 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more of the N-terminal amino acids are deleted from the selected amino acid sequence, wherein the deleted amino acids are not considered in the percent identity to the selected amino acid sequence.

51. The hIL-17 binding polypeptide composition of any one of claims 1- 45, 49, and 50, wherein the hIL-17 is hIL-17F and the hIL-17F binding polypeptide composition X9 comprises the amino acid sequence of residues 42-51 set forth in a sequence selected from: SEQ ID NOs: 5, 6, and 7, wherein: the binding polypeptide composition can have at least one conservative substitution relative to residues 42-51 of the selected amino acid sequence; and the binding polypeptide composition can have 50% to 100% identity to residues 42-51 of the selected amino acid sequence.

52. The hIL-17 binding polypeptide composition of any one of claims 1-45 and 49-51, wherein the hIL-17 is hIL-17F and the hIL-17F binding polypeptide composition comprises the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 5, 6, and 7, wherein: the binding polypeptide composition can have at least 1-20 conservative substitutions relative to the amino acid sequence of the selected amino acid sequence; and the binding polypeptide composition can have 50% to 100% identity to the selected amino acid sequence, optionally wherein 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more of the N-terminal amino acids are deleted from the selected amino acid sequence, wherein the deleted amino acids are not considered in the percent identity to the selected amino acid sequence.

53. The hIL-17 binding polypeptide composition of any one of claims 1-45 and 49-52, wherein the hIL-17 is hIL-17F and the hIL-17F binding polypeptide composition X9 comprises the amino acid sequence of residues 42-51 set forth in a sequence selected from: SEQ ID NOs: 34-38 and 64-66, wherein: the binding polypeptide composition can have at least one conservative substitution relative to residues 42-51 of the selected amino acid sequence; andthe binding polypeptide composition can have 50% to 100% identity to residues 42-51 of the selected amino acid sequence.

54. The hIL-17 binding polypeptide composition of any one of claims 36-53, wherein the receptor is an hIL-17 receptor.

55. The hIL-17 binding polypeptide composition of any one of claims 36-54, wherein the receptor is hIL-17RA and / or hIL-17RC.

56. The hIL-17 binding polypeptide composition of any one of claims 1-55, further comprising one or more additional functional domains added at the N- terminus and / or the C-terminus of the polypeptide.

57. The hIL-17 binding polypeptide composition of any one of claims 1-56, wherein the binding polypeptide composition binds hIL-17 at a KD of about 0.1 pM to about 1.5 nM.

58. The hIL-17 binding polypeptide composition of any one of claims 1-57, wherein when n=l-10, each of A and B binds hIL-17 at a KD of about 0.1 pM to about 1.5 nM.

59. The hIL-17 binding polypeptide composition of any one of claims 1-58, wherein n=l or more, wherein B comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a selected amino acid sequence, wherein the selected amino acid sequence is A, optionally wherein 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more of the N-terminal amino acids are deleted from the selected amino acid sequence and the deleted amino acids are not considered in the percent identity.

60. The hIL-17 binding polypeptide composition of any one of claims 1-59, wherein amino acid changes from the selected amino acid sequence are conservative substitutions.

61. A human IL-17 (hIL-17) binding polypeptide composition, comprising a polypeptide of the general formula from N-terminus to C terminus, A-(linker-B)n, wherein: n=0-10;A is a polypeptide of the formula (X1-X2-X3-X4-X5); in A, XI, X2, X4, and X5 are optional;X3 comprises a polypeptide domain of 9-15 amino acids in length;X3 comprises the amino acid sequence of residues 19-27 of the amino acid sequence set forth in a sequence selected from: SEQ ID NOs: 2, 72, 75, 76, and 78; wherein X3 can comprise at least one conservative amino acid substitution in residues 19-27 relative to the selected amino acid sequence, and wherein X3 can have 50% to 100% identity to residues 19-27 of the selected amino acid sequence;B is a polypeptide of the formula (Xr-X2’-X3’-X4’-X5’);XI, when present, comprises a polypeptide domain of 1-13 amino acids in length;XI’, when present, comprises a polypeptide domain of 1-13 amino acids in length;X2, when present, comprises a polypeptide domain of 1-4 amino acids in length;X2’ , when present, comprises a polypeptide domain of 1-4 amino acids in length;X3’, when present, comprises a polypeptide domain of 9-15 amino acids in length;X4, when present, comprises a polypeptide domain of 1-3 amino acids in length;X4’, when present, comprises a polypeptide domain of 1-3 amino acids in length;X5, when present, comprises a polypeptide domain of 1-13 amino acids in length; andX5’, when present, comprises a polypeptide domain of 1-13 amino acids in length.

62. The hIL-17 binding polypeptide composition of claim 61, wherein when n=l-10:X3’ is present and comprises a polypeptide domain of 9-15 amino acids in length;X3’ comprises the amino acid sequence of residues 19-27 a sequence selected from SEQ ID NOs: 2, 72, 75, 76, and 78, wherein X3 can comprise at least one conservative amino acid substitution in residues 19-27 relative to the selected aminoacid sequence, and wherein X3 can have 50% to 100% identity to residues 19-27 of the selected amino acid sequence.

63. The hIL-17 binding polypeptide composition of claim 61 or 62, wherein X3 and any combination of XI, X2, X4, and X5, are present.

64. The hIL-17 binding polypeptide composition of any one of claims 61-63, wherein n=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1-5, or 1-10.

65. The hIL-17 binding polypeptide composition of any one of claims 61-64, wherein in B, XI’, X2’, X3’, X4’, X5,’ or any combination thereof, are present.

66. The hIL-17 binding polypeptide composition of any one of claims 61-65, wherein A and B have the same amino acid sequence.

67. The hIL-17 binding polypeptide composition of any one of claims 61-66, wherein A and B have different amino acid sequences.

68. The hIL-17 binding polypeptide composition of any one of claims 61-67, wherein the hIL-17 binding protein is a linear polypeptide.

69. The hIL-17 binding polypeptide composition of any one of claims 61-68, wherein:XI, when present, comprises a polypeptide having the amino acid sequence of residues 1-13 in the amino acid sequence set forth in a sequence selected from SEQ ID NOs: 2, 72, 75, 76, and 78, wherein XI can comprise at least one conservative amino acid substitution in residues 1-13 relative to the selected amino acid sequence, and wherein XI can have 50% to 100% identity to residues 1-13 of the selected amino acid sequence;XI’, when present, comprises a polypeptide having the amino acid sequence of residues 1-13 in the amino acid sequence set forth in a sequence selected from SEQ ID NOs: 2, 72, 75, 76, and 78, wherein XI ’ can comprise at least one conservative amino acid substitution in residues 1-13 relative to the selected amino acid sequence, and wherein XI’ can have 50% to 100% identity to residues 1-13 of the selected amino acid sequence;X2, when present, comprises a polypeptide having the amino acid sequence of residues 14-17 in the amino acid sequence set forth in a sequence selected from SEQ ID NOs: 2, 72, 75, 76, and 78, wherein X2 can comprise at least one conservative amino acid substitution in residues 14-17 relative to the selected amino acid sequence,and wherein X2 can have 50% to 100% identity to residues 14-17 of the selected amino acid sequence;X2’ , when present, comprises a polypeptide having the amino acid sequence of residues 14-17 in the amino acid sequence set forth in a sequence selected from SEQ ID NOs: 2, 72, 75, 76, and 78, wherein X2’ can comprise at least one conservative amino acid substitution in residues 14-17 relative to the selected amino acid sequence, and wherein X2’ can have 50% to 100% identity to residues 14-17 of the selected amino acid sequence;X3’, when present, comprises a polypeptide having the amino acid sequence of residues 19-27 in the amino acid sequence set forth in a sequence selected from SEQ ID NOs: 2, 72, 75, 76, and 78, wherein X3’ can comprise at least one conservative amino acid substitution in residues 19-27 relative to the selected amino acid sequence, and wherein X3’ can have 50% to 100% identity to residues 19-27 of the selected amino acid sequence;X4, when present, comprises a polypeptide having the amino acid sequence of residues 28-30 in the amino acid sequence set forth in a sequence selected from SEQ ID NOs: 2, 72, 75, 76, and 78, wherein X4 can comprise at least one conservative amino acid substitution in residues 28-30 relative to the selected amino acid sequence, and wherein X4 can have 50% to 100% identity to residues 28-30 of the selected amino acid sequence;X4’, when present, comprises a polypeptide having the amino acid sequence of residues 28-30 in the amino acid sequence set forth in a sequence selected from SEQ ID NOs: 2, 72, 75, 76, and 78, wherein X4’ can comprise at least one conservative amino acid substitution in residues 28-30 relative to the selected amino acid sequence, and wherein X4’ can have 50% to 100% identity to residues 28-30 of the selected amino acid sequence;X5, when present, comprises a polypeptide having the amino acid sequence of residues 31-43 in the amino acid sequence set forth in a sequence selected from SEQ ID NOs: 2, 72, 75, 76, and 78, wherein X5 can comprise at least one conservative amino acid substitution in residues 31-43 relative to the selected amino acid sequence, and wherein X5 can have 50% to 100% identity to residues 31-43 of the selected amino acid sequence; andX5’, when present, comprises a polypeptide having the amino acid sequence of residues 31-43 in the amino acid sequence set forth in a sequence selected from SEQ ID NOs: 2, 72, 75, 76, and 78, wherein X5’ can comprise at least one conservative amino acid substitution in residues 31-43 relative to the selected amino acid sequence, and wherein X5’ can have 50% to 100% identity to residues 31-43 of the selected amino acid sequence.

70. The hIL-17 binding polypeptide composition of any one of claims 61-69, wherein:A comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in a sequence selected from SEQ ID NO: 72, SEQ ID NO: 75, SEQ ID NO: 76, and SEQ ID NO: 78;B, when present, B comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in a sequence selected from SEQ ID NO: 72, SEQ ID NO: 75, SEQ ID NO: 76, and SEQ ID NO: 78; and optionally wherein 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more of the N-terminal amino acids are deleted from the reference polypeptide and the deleted amino acids are not considered in the percent identity.

71. The hIL-17 binding polypeptide composition of any one of claims 61-70, wherein:A comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in a sequence selected from SEQ ID NOs: 40-62;B, when present, comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in a sequence selected from SEQ ID NOs: 40-62; andoptionally wherein 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more of the N-terminal amino acids are deleted from the reference polypeptide and the deleted amino acids are not considered in the percent identity.

72. The hIL-17 binding polypeptide composition of any one of claims 61-71, wherein X3 comprises an alpha helix.

73. The hIL-17 binding polypeptide composition of any one of claims 61-72, wherein:XI, when present, comprises an alpha helix;XI’, when present, comprises an alpha helix;X2, when present, comprises a loop;X2’ , when present, comprises a loop;X3 comprises an alpha helix;X3’, when present, comprises an alpha helix;X4, when present, comprises a loop;X4’, when present, comprises a loop;X5, when present, comprises an alpha helix; andX5’, when present, comprises an alpha helix.

74. The hIL-17 binding polypeptide composition of any one of claims 61-73, wherein each of XI, X2, X3, X4, and X5 are present, wherein:XI comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of an XI domain present in any of SEQ ID NOs: 40-62;X2 comprises an amino acid sequence at least 50%, 75%, or 100% identical to the amino acid sequence of an X2 domain present in any of SEQ ID NOs: 40-62;X3 comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of an X3 domain present in any of SEQ ID NOs: 40-62;X4 comprises an amino acid sequence at least 50%, 75%, or 100% identical to the amino acid sequence of an X4 domain present in any of SEQ ID NOs: 40-62; andX5 comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of an X5 domain present in any of SEQ ID NOs: 40-62.

75. The hIL-17 binding polypeptide composition of any one of claims 61-74, wherein each of XT, X2’, X3’, X4’, and X5’ are present, and wherein:XI’ comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of an XI’ domain present in any of SEQ ID NOs: 40-62;X2’ comprises an amino acid sequence at least 50%, 75%, or 100% identical to the amino acid sequence of an X2’ domain present in any of SEQ ID NOs: 40-62;X3’ comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of an X3’ domain present in any of SEQ ID NOs: 40-62;X4’ comprises an amino acid sequence at least 50%, 75%, or 100% identical to the amino acid sequence of an X4’ domain present in any of SEQ ID NOs: 40-62; andX5’ comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of an X5’ domain present in any of SEQ ID NOs: 40-62.

76. The hIL-17 binding polypeptide composition of any one of claims 61-75, wherein:(i) in A, XI, X3 and X5 are present and each comprises an alpha helix; or(ii) n=l-10, wherein in A, XI, X3 and X5 are present and each comprises an alpha helix, and wherein in B, XI’, X3’, X5’ are present and each comprises an alpha helix.

77. The hIL-17 binding polypeptide composition of any one of claims 61-76, wherein in A, XI, X2, X3, X4, X5, or any combination thereof, are present in addition to X3.

78. The hIL-17 binding polypeptide composition of any one of claims 61-77, wherein in B, each of XT, X2’, X3’, X4’, X5’, or any combination thereof, are present.

79. The hIL-17 binding polypeptide composition of any one of claims 61-78, further comprising one or more additional functional domains added at the N- terminus of the polypeptide, the C-terminus of the polypeptide, or both.

80. The hIL-17 binding polypeptide composition of any one of claims 61-79, wherein in A, X3 comprises the amino acid sequence of residues 19-27 in the amino acid sequence selected from the group consisting of SEQ ID NOs: 54 and 58, and wherein in B, when present, X3 comprises the amino acid sequence of residues 19-27 in the amino acid sequence selected from the group consisting of SEQ ID NOs: 54 and 58.

81. The hIL-17 binding polypeptide composition of any one of claims 61-80, comprising an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a reference polypeptide amino acid sequence selected from SEQ ID NOs: 54 and 58, optionally wherein 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more of the N-terminal amino acids are deleted from the selected polypeptide amino acid sequence and the deleted amino acids are not considered in the percent identity.

82. The hIL-17 binding polypeptide composition of any one of claims 61-81, wherein n=l-10, wherein:A comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in a sequence selected from SEQ ID NOs: 54 and 58;B comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in a sequence selected from SEQ ID NOs: 54 and 58; optionally wherein 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more of the N-terminal amino acids are deleted from the selected amino acid sequence comprised by A, B, or fromboth A and B, wherein the deleted amino acids are not considered in the percent identity of A, B, or both, respectively, to the selected amino acid sequence; and the amino acid sequence of A can be 90% to 100% identical to the amino acid sequence of B.

83. The hIL-17 binding polypeptide composition of any one of claims 61-82, comprising at least one disulfide bond between two cysteine residues in the polypeptide, wherein: when A is present and B is not present, the at least one disulfide bond occurs within A; and when both A and B are present, the binding polypeptide composition comprises at least two disulfide bonds, wherein at least one of the at least two disulfide bonds is within A, and at least one of the at least two disulfide bonds is within B.

84. The hIL-17 binding polypeptide composition of claim 83, wherein the binding polypeptide composition has an amino acid sequence set forth as any of SEQ ID NOs: 56-62.

85. The hIL-17 binding polypeptide composition of any one of claims 61-83, wherein the linker is an amino acid linker, optionally wherein the linker is about 1 to about 100 amino acids in length.

86. The hIL-17 binding polypeptide composition of any one of claims 61- 83, wherein the linker is selected from a linker having the formula (PAS)n, and linker having the formula (Gly-Ser)n, optionally wherein n=l-100.

87. The hIL-17 binding polypeptide composition of any one of claims 61-86, wherein the linker has the amino acid sequence set forth in any of SEQ ID NOs: 67-70.

88. The hIL-17 binding polypeptide composition of any one of claims 61-87, wherein the binding polypeptide composition binds the target molecule with high specificity, high affinity, or both.

89. The hIL-17 binding polypeptide composition of any one of claims 61-88, wherein the polypeptide is an hIL-17 antagonist or an hIL-17 agonist.

90. The hIL-17 binding polypeptide composition of any one of claims 61-89, wherein the polypeptide is an hIL-17 antagonist.

91. The hIL-17 binding polypeptide composition of any one of claims 61-90, wherein a binding assay is used to evaluate the binding of the polypeptide to the target.

92. The hIL-17 binding polypeptide composition of claim 91, wherein the binding specificity assay measures the ability of the binding polypeptide composition to inhibit binding of hIL-17 to an hIL-17 receptor.

93. The hIL-17 binding polypeptide composition of any one of claims 91 and 92, wherein the binding specificity assay is a cell signaling assay.

94. The hIL-17 binding polypeptide composition of any one of claims 61-93, wherein the binding polypeptide composition comprises A and not B, or A and B, and wherein the binding polypeptide composition reduces stimulation of an hIL-17 receptor by hIL-17 by about 75 percent to about 100 percent at an IC50 of about 1.5 nM to about 0.1 pM.

95. The hIL-17 binding polypeptide composition of any one of claims 61-94, wherein the binding polypeptide composition comprises A and B, and wherein the binding polypeptide composition blocks hIL-17-mediated cell signaling with a greater potency than a binding polypeptide composition comprising A and not B.

96. The hIL-17 binding polypeptide composition of any one of claims 61-95, wherein the binding polypeptide composition comprises A and B, and blocks hlL- 17-mediated cell signaling with a potency of 10-fold to 10,000-fold greater than a binding polypeptide composition comprising A and not B.

97. The hIL-17 binding polypeptide composition of any one of claims 61-96, wherein the binding polypeptide composition comprises A and B, and wherein the binding polypeptide composition blocks hIL-17-mediated cell signaling with a potency of 2-fold to 250-fold greater than that of a clinical hIL-17 binding monoclonal antibody.

98. The hIL-17 binding polypeptide composition of any one of claims 61-97, wherein the binding polypeptide composition comprises A and B, and wherein the binding polypeptide composition reduces the stimulation of an hIL-17 receptor by hIL-17 by about 75 percent to about 100 percent at an IC50 of about 150 pM to about 0.1 pM.

99. The hIL-17 binding polypeptide composition of any one of claims 61-98, wherein the binding polypeptide composition reduces the stimulation of an hIL-17 receptor by hIL-17 by about 75 percent to about 100 percent at an IC50 of less than about 0.6 pM, less than about 1 pM, less than about 1.5 pM, less than about 2 pM, less than about 2.5 pM, less than about 3 pM, less than about 5 pM, less than about 10 pM, less than about 25 pM, less than about 50 pM, less than about 75 pM, or less than about 100 pM, less than about 150 pM, less than about 350 pM, less than about 500 pM, less than about 1 nM, or less than about 1.5 nM.

100. The hIL-17 binding polypeptide composition of any one of claims 61-99, wherein the clinical hIL-17 binding monoclonal antibody is selected from: secukinumab, ixekizumab, brodalumab and bimekizumab.

101. The hIL-17 binding polypeptide composition of any one of claims 61-100, wherein the hIL-17 is hIL-17A or hIL-17F.

102. The hIL-17 binding polypeptide composition of claim 101, wherein the hIL-17 is hIL-17A and X3, X3’, or both, of the binding polypeptide composition comprises the amino acid sequence of residues 19-27 set forth in a sequence selected from SEQ ID NOs: 72, 75, 76 or 78, wherein:X3, X3’, or both, of the binding polypeptide composition can have at least one conservative substitution relative to residues 19-27 of the selected amino acid sequence; andX3, X3’, or both, of the binding polypeptide composition can have 50% to 100% identity to residues 42-51 of the selected amino acid sequence.

103. The hIL-17 binding polypeptide composition of claim 101, wherein the hIL-17 is hIL-17A and X3, X3’, or both, of the binding polypeptide composition comprises the amino acid sequence of residues 19-27 set forth in a sequence selected from SEQ ID NOs: 40-62, wherein:X3, X3’, or both, of the binding polypeptide composition can have at least one conservative substitution relative to residues 19-27 of the selected amino acid sequence; andX3, X3’, or both, of the binding polypeptide composition can have 50% to 100% identity to residues 19-27 of the selected amino acid sequence.

104. The hIL-17 binding polypeptide composition of any one of claims 61-103, wherein the receptor is an hIL-17 receptor.

105. The hIL-17 binding polypeptide composition of any one of claims 61-104, wherein the receptor is hIL-17RA and / or hIL-17RC.

106. The hIL-17 binding polypeptide composition of any one of claims 61-105, further comprising one or more additional functional domains added at the N- terminus and / or the C-terminus of the polypeptide, preferably at the C-terminus.

107. The hIL-17 binding polypeptide composition of any one of claims 61-106, wherein the binding polypeptide composition binds hIL-17 at a KD of about 0.1 pM to about 1.5 nM.

108. The hIL-17 binding polypeptide composition of any one of claims 61-107, wherein when both A and B are present, each of A and B binds hIL-17 at a KD of 0.1 pM to about 1.5 nM.

109. The hIL-17 binding polypeptide composition of any one of claims 61-108, wherein n=l or more, wherein B comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a selected amino acid sequence, wherein the selected amino acid sequence is A, optionally wherein 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more of the N-terminal amino acids are deleted from the selected amino acid sequence and the deleted amino acids are not considered in the percent identity.

110. The hIL-17 binding polypeptide composition of any one of claims 61-109, wherein amino acid changes from the selected amino acid sequence are conservative substitutions.

111. The hIL-17 binding polypeptide composition of any one of claims 1-60, wherein: each of A and B comprises the sequence of amino acids set forth in any one of SEQ ID NOs: 8-38 and 63-66; andA and B are the same or different.

112. The hIL-17 binding polypeptide composition of any one of claims 1-60, wherein: each of A and B consists of the sequence of amino acids set forth in any one of SEQ ID NOs: 8-38 and 63-66; andA and B are the same or different.

113. The hIL-17 binding polypeptide composition of any one of claims 61-110, wherein: each of A and B comprises the sequence of amino acids set forth in any one of SEQ ID NOs: 39-62; andA and B are the same or different.

114. The hIL-17 binding polypeptide composition of any one of claims bil l 0, wherein: each of A and B consist of the sequence of amino acids set forth in any one of SEQ ID NOs: 39-62; andA and B are the same or different.

115. The hIL-17 binding polypeptide composition of any one of claims 111-114, wherein the linker comprises one or more of SEQ ID NOs: 67-70 and 79-82.

116. The hIL-17 binding polypeptide composition of any one of claims 1-115, wherein the binding polypeptide composition is a multimer of the formula A- linker-B-(linker-B)i-io.

117. A hIL-17 binding polypeptide, comprising a sequence of amino acids set forth in any one of SEQ ID NOs: 8-33 or a hIL-17 binding polypeptide having at least 80%, 85%, 90% or 95% sequence identity with the corresponding polypeptide of SEQ ID NOs: 8-33, wherein: the hIL-17 is human IL-17A; and the hIL-17 binding polypeptide has ± 10%, the same, or greater antagonist activity or binding affinity for hIL-17A as 17-01 of SEQ ID NO:8118. A hIL-17 binding polypeptide, comprising a sequence of amino acids set forth in any one of SEQ ID NOs: 34-38 or a hIL-17 binding polypeptide having at least 80%, 85%, 90% or 95% sequence identity with the corresponding polypeptide of any of SEQ ID NOs: 34-38, wherein: the hIL-17 is human IL-17A or IL-17F; hIL-17 binding polypeptide has antagonist activity for IL-17A and for IL-17F; and the hIL-17 binding polypeptide has ± 10%, the same, or greater antagonist activity or binding affinity for IL-17F as 17F-01 A4 of SEQ ID NO:37.

119. A hIL-17 binding polypeptide, comprising a sequence of amino acids set forth in any one of SEQ ID NOs: 39-55 or a hIL-17 binding polypeptide having at least 80%, 85%, 90% or 95% sequence identity with the corresponding polypeptide of any of SEQ ID NOs: 39-55, wherein: the hIL-17 is human IL-17A; the hIL-17 binding polypeptide has the ± 10%, the same, or greater antagonist activity or binding affinity for hIL-17A as the polypeptide designated 17-02 of SEQ ID NO:39.

120. A hIL-17 binding polypeptide, comprising a sequence of amino acids set forth in SEQ ID NO: 63 or a hIL-17 binding polypeptide having at least 80%, 85%, 90% or 95% sequence identity with the polypeptide of any of SEQ ID NOs: 63, wherein: the hIL-17 is human IL-17A; the hIL-17 binding polypeptide has ± 10%, the same, or greater antagonist or binding affinity for hIL-17A as 17-03 of SEQ ID NO:37.

121. A hIL-17 binding polypeptide, comprising a sequence of amino acids set forth in any one of SEQ ID NOs: 64-66 or a hIL-17 binding polypeptide having at least 80%, 85%, 90% or 95% sequence identity with the corresponding polypeptide of any of SEQ ID NOs: 64-66, wherein: the hIL-17 is human IL-17F; the hIL-17 binding polypeptide has the ± 10%, the same, or greater antagonist same or greater binding affinity for IL-17F as 17F-01 A4.

122. The hIL-17 binding polypeptide of any of claims 1-121, wherein the polypeptide comprises at least one disulfide bond.

123. The hIL-17 binding polypeptide of any of claims 117-122, wherein the polypeptide comprises contains or is modified to comprise two cysteines to form least one disulfide bond.

124. A multimer, comprising the hIL-17 binding polypeptide of any of claims 117-123, wherein: the binding polypeptide is a multimer of the formula A-linker-B-(linker-B)i-io; whereinA and B have antagonist activity against human IL-17A or human IL17F, and A and B are the same or different polypeptide; and the linker is an amino acid linker.

125. The multimer of claim 124, wherein the linkers, which are the same or different, are selected from among polypeptide linkers having the amino acid sequence set forth in any of SEQ ID NOs: 67-70 and 79-82.

126. The multimer comprising the hIL-17 binding polypeptide of any of claims 117-125, wherein the multimer is a dimer having the formula A-linker-B.

127. A pharmaceutical composition, comprising an hIL-17 binding polypeptide composition or multimer any one of claims 1-126; and at least one excipient.

128. The pharmaceutical composition or multimer of claim 127 formulated for oral, topical, subcutaneous, intradermal, intramuscular, intravenous, or intraarticular administration.

129. The pharmaceutical composition or multimer of any one of claims 127 or 128, wherein the composition is formulated for topical administration and the excipient is selected from among water, a buffer, an absorption enhancer, a stability enhancer, diaminobutyroyl benzylamide, diacetate, glycerin, a gum, a hydrophilic colloid or derivative, a cellulosic derivative, an emulsifier, a fatty alcohol, an acrylic derivative, a mineral, a surfactant, a fat, an oil, a preservative, a monosaccharide, a disaccharide, a polysaccharide, a glycosaminoglycan, and a chelating agent.

130. The pharmaceutical composition or multimer of any one of claims 127-129, for use in treatment of a patient having a condition selected from among plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, active non-radiographic axial spondyloarthritis, hidradenitis suppurativa, atopic dermatitis, multiple sclerosis, asthma, and rheumatoid arthritis.

131. The pharmaceutical composition or multimer of any one of claims 127-130, for use in treatment of a patient having a condition selected from among psoriasis, psoriatic arthritis, ankylosing spondylitis, active non-radiographic axial spondyloarthritis, hidradenitis suppurativa, atopic dermatitis, multiple sclerosis, asthma, and rheumatoid arthritis.

132. A method for treating a condition selected from among psoriasis, psoriatic arthritis, ankylosing spondylitis, active non-radiographic axial spondyloarthritis, hidradenitis suppurativa, atopic dermatitis, multiple sclerosis, asthma, and rheumatoid arthritis, in a patient, comprising administering to the patient the pharmaceutical composition of any one of claims 127-130.

133. Use of the pharmaceutical composition of any one of claims 127-130 to treat a patient having a condition selected from among plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, active non-radiographic axial spondyloarthritis, hidradenitis suppurativa, atopic dermatitis, multiple sclerosis, asthma, and rheumatoid arthritis.

134. An hIL-17 binding polypeptide composition, comprising an amino acid sequence 50% to 100%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of a polypeptide disclosed herein.

135. A nucleic acid encoding a polypeptide of any one of claims 1-126 and 134 or as otherwise disclosed herein.

136. An expression construct comprising the nucleic acid of claim 135.

137. A vector comprising an expression construct of claim 136.

138. A method for producing a polypeptide of any one of claims 1-126 and 134 or as otherwise disclosed herein, comprising expressing the polypeptide from an expression construct in a host cell, and optionally purifying the polypeptide to remove unwanted contaminants.

139. The method of claim 138, wherein the host cell is a microbial host cell.

140. The method of claim 138, wherein the host cell is a eukaryotic or prokaryotic host cell.

141. A composition of any one of claims 1-131, comprising a monomeric or multimeric hIL-17 binding composition, wherein:(a) the composition has an activity selected from: an hIL-17 target binding affinity; binding avidity; binding specificity; binding stability; and / or potency; that is increased by about 2-fold to about 70,000-fold relative to a control composition;(b) the composition has an activity selected from: an hIL-17 target binding affinity; binding avidity; binding specificity; binding stability; and / or potency; that is decreased by about 2-fold to about 10,000-fold relative to a control composition, wherein the control is an agent that targets a different hIL-17 / hIL-17R interaction;(c) the composition has an activity selected from: an hIL-17 target binding affinity; binding avidity; binding specificity; binding stability; and / or potency; that is increased by about 2-fold to about 10,000-fold relative to a control composition, wherein the control is an agent that targets a similar or the same hlL- 17 / hIL-17R interaction;(d) the composition is an hIL-17 binding polypeptide dimeric composition that has an activity relative to a corresponding monomeric control composition that is increased by about 2-fold to about 10,000-fold;(e) when the composition is administered to a test sample or subject, an hIL-17 activity is reduced or increased by about 10 to about 100 percent, about 0.2- fold to about 10-fold, or both, relative to an untreated control;(f) the composition is modified, and the melting temperature (Tm) is greater than that of a control composition Tm by about 1 deg C to about 100 deg C; and / or(g) the composition is modified, and the concentration of Gdn at which at least 50% of the concentration is folded is about 0.1 M greater to about 6 M greater than the concentration of Gdn at which at least 50% of a control concentration is folded.

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