Osteopontin antibodies and uses thereof

Abstract

The present disclosure relates to therapeutic antibodies that target full-length or cleaved osteopontin and methods of use thereof.

Description

STDU244218.601(S23-351) OSTEOPONTIN ANTIBODIES AND USES THEREOFTECHNICAL FIELD

[0001] Embodiments of the present disclosure relate to therapeutic antibodies that target full-length or cleaved osteopontin and methods of use thereof.CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U. S. Provisional Application No. 63 / 743,125, filed January 8, 2025, the content of which is herein incorporated by reference in its entirety.SEQUENCE LISTING STATEMENT

[0003] The content of the electronic sequence listing titled STDU2_44218_601_SequenceListing.xml (Size: 182,782 bytes: and Date of Creation: January 6, 2026) is herein incorporated by reference in its entirety.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0004] This invention was made with government support under contract TR003142 awarded by the National Institutes of Health. The government has certain rights in the invention.BACKGROUND

[0005] Osteopontin (OPN) is a matricellular multifunctional protein with a highly conserved RGD domain that binds to a wide range of integrins. Thrombin cleavage at Argl68 in humans generates OPN-Arg (OPN-R) and OPN-C-terminal fragment (OPN-CTF). OPN-R binds to a subset of integrins (a4 1 and a9pi) that full-length OPN does not. The physiological role of the OPN-R fragment is thought to include a role as an immune modulator promoting cell adhesion, migration, and survival. OPN-R can be cleaved further by carboxypeptidase B by the removal of the C-terminal arginine, generating OPN-L that has reduced immune modulating functions compared to OPN-R. However, the function of OPN-L is largely unknown. Osteopontin and fragments thereof have also been implicated in dendritic cells chemotaxis, inflammatorySTDU244218.601(S23-351) disorders and possibly cancer. Thus, there remains a need for new therapeutic compositions and approaches for osteopontin related diseases and disorders.SUMMARY

[0006] Embodiments of the present disclosure include antibodies, and fragments thereof, directed against osteopontin and compositions and methods pertaining to antibodies directed against osteopontin.

[0007] Provided herein is an antibody, or antigen binding fragment thereof, which specifically binds osteopontin or a cleavage fragment thereof, wherein the osteopontin or a cleavage fragment thereof is a polypeptide comprising the amino acid sequence YGLRSKS (SEQ ID NO: 179), AYGLR (SEQ ID NO: 180), or VYGLR (SEQ ID NO: 181). In some embodiments, the antibody, or antigen binding fragment thereof exhibits any one or more the following functional characteristics: inhibits thrombin cleavage of osteopontin; inhibits integrin binding to the thrombin cleavage fragment of osteopontin; inhibits chemotactic enhancement of cellular migration of osteopontin; binds to thrombin cleaved osteopontin (OPN-R) but not full-length osteopontin (OPN-FL) or carboxypeptidase B cleaved fragment of osteopontin (OPN-L); binds to OPN-L but not OPN-FL or OPN-R; binds to OPN-FL; and binds to human and / or mouse osteopontin or a fragment thereof.

[0008] In some embodiments, the antibody, or antigen binding fragment thereof is monoclonal, optionally recombinant. In some embodiments, the antibody, or antigen binding fragment thereof is human, humanized, or chimeric.

[0009] In some embodiments, the antibody, or antigen binding fragment thereof is a full length antibody, a single chain antibody, a single chain variable fragment (scFv), a variable fragment (Fv), a fragment antigen-binding region (Fab), a Fab-C, a Fab’-SH, a (Fab’)2, a singledomain antibody (sdAb), a VHH antibody, a nanobody, a camelid-derived single-domain antibody, a shark IgNAR-derived single-domain antibody fragment (VNAR), a diabody, a triabody, an anticalin or an aptamer, optionally wherein the antibody is a full length antibody comprising an Fc region such as a human IgGl, IgG2, IgG3 or IgG4 region.

[0010] In some embodiments, the antibody, or antigen binding fragment thereof is conjugated to at least one additional moiety, optionally selected from: a therapeutic or cytotoxic moiety; a detection moiety; a purification moiety; and a half-life extension moiety.STDU244218.601(S23-351)

[0011] In some embodiments, the antibody, or antigen binding fragment thereof is a polypeptide comprising: one, two or all three HCDRs of any one of the exemplary antibodies the sequences of which are provided in Table 1. and optionally also one, two or all three of the corresponding LCDRs of the exemplary antibody; and / or a VH sequence having at least 90% identity to the VH sequence of any one of the exemplary antibodies the sequences of which are provided in Table 1. and optionally also a VL sequence having at least 90% identity to the corresponding VL sequence of the exemplary antibody; and / or all six CDRs of any one of the exemplary antibodies the sequences of which are provided in Table 1; and / or the VH and VL sequences of any one of the exemplary antibodies the sequences of which are provided in Table 1.

[0012] Also provided herein are polynucleotides encoding an antibody, or antigen binding fragment thereof, as disclosed herein. In some embodiments, the antibody, or antigen binding fragment thereof, is encoded by a nucleic acid sequence having at least 70, 80, 90 or 100% identity to a nucleic acid sequence of any one of the exemplary antibodies the sequences of which are provided in Table 1.

[0013] In some embodiments, the antibody, or antigen binding fragment thereof comprises a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3, and a light chain variable region (VL) comprising complementarity determining regions (CDRs) LCDR1, LCDR2, and LCDR3 of any one of the exemplary antibodies the sequences of which are provided in Table 1.

[0014] In some embodiments, the HCDR1 comprises an amino acid sequence of any of SEQ ID NOs: 62, 123, 124, 52, 72, and 89; the HCDR2 comprises an amino acid sequence of any of SEQ ID NOs: 18, 25, 33, 40, 44, 53, 63, 73, 82, and 90; and the HCDR3 comprises an amino acid sequence of any of SEQ ID NOs: 126, 130. 134, 54, 64, 74, and 91. In some embodiments, the LCDR1 comprises an amino acid sequence of any of SEQ ID NOs: 21, 28. 36. 46. 55. 65. 75.83, and 92; the LCDR2 comprises an amino acid sequence of any of SEQ ID NOs: 22, 29, 37, 56, 66, 76, and 93; and the LCDR3 comprises an amino acid sequence of any of SEQ ID NOs: 23, 30, 38, 47, 57, 67, 77, 84, or 94.

[0015] In some embodiments, the HCDR1 comprises an amino acid sequence of any of SEQ ID NOs: 2, 6, and 9; the HCDR2 comprises an amino acid sequence of any of SEQ ID NOs: 3, 7. and 10; and the HCDR3 comprises an amino acid sequence of any of SEQ ID NOs: 4 and 11. InSTDU244218.601(S23-351) some embodiments, the LCDR1 comprises an amino acid sequence of SEQ ID NO: 13; the LCDR2 comprises an amino acid sequence of SEQ ID NO: 14; and the LCDR3 comprises an amino acid sequence of SEQ ID NO: 15.

[0016] In some embodiments, the HCDR1 comprises an amino acid sequence of any of SEQ ID NOs: 99, 108 and 118; the HCDR2 comprises an amino acid sequence of any of SEQ ID NOs: 100, 109 and 119; and the HCDR3 comprises an amino acid sequence of any of SEQ ID NOs: 101, 110, and 120. In some embodiments, the LCDR1 comprises an amino acid sequence of any of SEQ ID NOs: 102, 111 and 121; the LCDR2 comprises an amino acid sequence of any of SEQ ID NO: 22, 29, 112; and the LCDR3 comprises an amino acid sequence of any of SEQ ID NOs: 103, 113, and 122.

[0017] In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 62; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 18; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 126. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 62; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 40; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 126. In some embodiments, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 21; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 22; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 23.

[0018] In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 62; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 25; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 130. In some embodiments, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 28: the LCDR2 comprises the amino acid sequence of SEQ ID NO: 29; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 30.

[0019] In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 123; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 33; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 134. In some embodiments, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 36; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 37; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 38.STDU244218.601(S23-351)

[0020] In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 124; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 44; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 134. In some embodiments, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 46; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 37; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 47.

[0021] In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 52; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 53; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 54. In some embodiments, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 55; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 56; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 57.

[0022] In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 62; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 63; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 64. In some embodiments, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 65; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 66; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 67.

[0023] In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 72; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 73; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 74. In some embodiments, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 75: the LCDR2 comprises the amino acid sequence of SEQ ID NO: 76; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 77.

[0024] In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 62; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 82; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 74. In some embodiments, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 83; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 29; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 84.STDU244218.601(S23-351)

[0025] In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 89; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 90; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 91. In some embodiments, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 92; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 93; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 94.

[0026] In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 2 or 6; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 3 or 7; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 4. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 9; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 10; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 11. In some embodiments, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 13; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 14; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 15.

[0027] In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 99; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 100; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 101. In some embodiments, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 102; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 22; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 103.

[0028] In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 108; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 109: and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 110. In some embodiments, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 111; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 112; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 113.

[0029] In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 118; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 119; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 120. In some embodiments, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 121; the LCDR2 comprises the amino acidSTDU244218.601(S23-351) sequence of SEQ ID NO: 29; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 122.

[0030] In some embodiments, the antibody, or antigen binding fragment thereof comprises a VH sequence having at least 90% identity to the VH sequence of any one of the exemplary antibodies the sequences of which are provided in Table 1. In some embodiments, the antibody, or antigen binding fragment thereof comprises a VL sequence having at least 90% identity to the corresponding VL sequence of any one of the exemplary antibodies the sequences of which are provided in Table 1.

[0031] In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to any of SEQ ID NOs: 16, 24, 31, 39, 42, 49, 59, 69, 79, or 86. In some embodiments, the VL comprises an amino acid sequence that is at least 90% identical to any of SEQ ID NOs: 20, 27, 35, 41, 45, 51, 61, 71, 81, 88.

[0032] In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 16 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 20. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 24 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 27. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 31 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 35. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 39 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 41. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 42 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 45. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 49 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 51. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 59 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 61. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 69 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 71. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 79 and theSTDU244218.601(S23-351) VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 81. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 86 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 88.

[0033] In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to any of SEQ ID NOs: 1. 5 and 8. In some embodiments, the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 12.

[0034] In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 1, 5, or 8 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 12.

[0035] In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to any of SEQ ID NOs: 96, 105 and 115. In some embodiments, the VL comprises an amino acid sequence that is at least 90% identical to any of SEQ ID NOs: 98, 107, and 117.

[0036] In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 96 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 98. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 105 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 107. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 115 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 117.

[0037] In some embodiments, the antibody, or antigen binding fragment thereof inhibits thrombin cleavage of osteopontin. In some embodiments, the antibody, or antigen binding fragment thereof inhibits integrin binding to the thrombin cleavage fragment of osteopontin.

[0038] In some embodiments, the antibody, or antigen binding fragment thereof, binds to thrombin cleaved osteopontin (OPN-R) but not full-length osteopontin (OPN-FL) or carboxypeptidase B cleaved fragment of osteopontin (OPN-L). In some embodiments, the antibody, or antigen binding fragment thereof, binds to OPN-L but not OPN-FL or OPN-R. In some embodiments, the antibody, or antigen binding fragment thereof, binds to OPN-FL.

[0039] In some embodiments, the antibody, or antigen binding fragment thereof, binds to human and / or mouse osteopontin or a fragment thereof.STDU244218.601(S23-351)

[0040] In some embodiments, the antibody is a monoclonal antibody, a human antibody, a humanized antibody, and / or a chimeric antibody.

[0041] In some embodiments, the antibody is a fragment selected from the group consisting of Fab, Fab-C, Fab'-SH, Fv, scFv, and (Fab')2 fragments.

[0042] In some embodiments, the antibody is a monospecific antibody.

[0043] In some embodiments, the antibody comprises a detection moiety, a purification moiety, a half-life extension moiety, or a combination thereof.

[0044] Also provided herein are pharmaceutical compositions comprising a disclosed antibody or an antigen binding fragment thereof.

[0045] Further provided are methods of treating a disease or disorder comprising administering an antibody, or an antigen binding fragment thereof, or a pharmaceutical composition, as disclosed herein, to a subject in need thereof. In some embodiments, the disease or disorder is a cancer associated with overexpression of osteopontin. In some embodiments, the disease or disorder is melanoma, glioblastoma, ovarian cancer, breast cancer, or lung cancer. In some embodiments, the disease or disorder is an inflammatory disease or disorder. In some embodiments, the disease or disorder is cardiac hypertrophy and / or myocardial fibrosis.

[0046] Other aspects and embodiments of the disclosure will be apparent in light of the following detailed description and accompanying figures.BRIEF DESCRIPTION OF THE DRAWING(S)

[0047] FIG. 1 is graphs of the binding of humanized A6 antibody variants to full-length mouse and human OPN (OPN-FL). hA6v3 binds to both human and mouse OPN (generated against peptide sequence YGLRSKS (SEQ ID NO: 179)).

[0048] FIG. 2 is a graph showing dose-dependent binding of hA6v3 to human OPN-FL.

[0049] FIG. 3 shows hA6v3 inhibits thrombin cleavage of mouse and human OPN-FL. hA6v3 binds to both mouse and human OPN-FL. hA6v3 inhibits thrombin cleavage of both mouse and human OPN-FL. hA6v3 has ~2.5-fold higher ICso than m / rA6.

[0050] FIG. 4 is a table of candidate monoclonal antibody sequences generated against AYGLR (SEQ ID NO: 180); C6R, A6R. E5R, D2R, and B4R. as indicated.

[0051] FIG. 5 is graph showing rabbit monoclonal abs against OPN-R, from FIG. 4, bind to both human and mouse OPN-R. For human OPN (hOPN) binding the ELISA assay used aSTDU244218.601(S23-351) coating of Mab 14331 (monoclonal mouse anti-hOPN) with the rabbit anti-OPN-R Mabs (0.5 ug / mL) as the detecting antibody, followed by HRP-goat anti-rabbit IgG. For mouse OPN (mOPN) binding the ELISA assay used a coating of AF808 (polyclonal goat anti-mOPN) with the rabbit anti-OPN-R Mabs (0.5 ug / mL) as the detecting antibody, followed by HRP-goat antirabbit IgG.

[0052] FIG. 6 shows m / rC6R chimera binds specifically to OPN-R but not OPN-FL or OPN-L in both human and mouse.

[0053] FIG. 7 shows a table of candidate monoclonal antibody sequences against human OPN-R (generated against peptide sequence VYGLR (SEQ ID NO: 181)) which are not reactive to OPN-FL or OPN-L. D2 and C5 have the same sequences.

[0054] FIGS. 8A-8C show the screening data against human OPNs (FIG. 8 A) and mouse OPN (FIG. 8B). FIG. 8C is a summary of select candidates from the screen.

[0055] FIG. 9 shows a table of candidate monoclonal antibody sequences against human OPN-L which are not reactive to OPN-FL or OPN-R.

[0056] FIG. 10 is a table showing the EC50 for the indicated antibodies binding to OPNs by direct Eliza. Osteopontins (OPN) were either human or murine full length (OPN) or the N-terminal fragment of OPN represented by thrombin cleavage (OPN-R).DETAILED DESCRIPTION

[0057] Embodiments of the present disclosure relate to therapeutic antibodies and antigen binding fragments thereof, that target osteopontin and cleavage fragments of osteopontin.

[0058] Section headings as used in this section and the entire disclosure herein are merely for organizational purposes and are not intended to be limiting.Definitions

[0059] The terms “comprise(s),” “include(s),” “having,” “has,” “can,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures. The singular forms “a,” “an” and “the” include plural references unless the context clearly dictates otherwise. As used herein, comprising a certain sequence or a certain SEQ ID NO usually implies that at least one copy of said sequence is present in recited peptide or polynucleotide. However, two or moreSTDU244218.601(S23-351) copies are also contemplated. The present disclosure also contemplates other embodiments “comprising,” “consisting of,” and “consisting essentially of,” the embodiments or elements presented herein, whether explicitly set forth or not. The use of the term “at least one” followed by a list of one or more items (for example, “at least one of A and B”) is to be construed to mean one item selected from the listed items (A or B) or any combination of two or more of the listed items (A and B), unless otherwise indicated herein or clearly contradicted by context.

[0060] The transitional phrase “consisting essentially of’ limits the scope of a claim to the specified materials or steps “and those that do not materially affect the basic and novel characteristic(s)” of the claimed invention, as discussed in In re Herz, 537 F.2d 549, 551-52, 190 USPQ 461, 463 (CCPA 1976). For example, a composition “consisting essentially of’ recited elements may contain an unrecited contaminant at a level such that, though present, the contaminant does not alter the function of the recited composition as compared to a pure composition, e.g., a composition “consisting of’ the recited components.

[0061] For the recitation of numeric ranges herein, each intervening number there between with the same degree of precision is explicitly contemplated. For example, for the range of 6-9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the number 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated.

[0062] As used herein, the modifier “about” used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (for example, it includes at least the degree of error associated with the measurement of the particular quantity). The modifier “about” should also be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the expression “from about 2 to about 4” also discloses the range “from 2 to 4.” The term “about” may refer to ±10% of the indicated number. For example, “about 10%” may indicate a range of 9% to 11%, and “about 1” may mean from 0.9 - 1.1. Other meanings of “about” may be apparent from the context, such as rounding off; for example, “about 1” may also mean from 0.5 to 1.4.

[0063] Unless otherwise defined herein, scientific, and technical terms used in connection with the present disclosure shall have the meanings that are commonly understood by those of ordinary skill in the art. The meaning and scope of the terms should be clear; in the event, however of any latent ambiguity, definitions provided herein take precedent over anySTDU244218.601(S23-351) dictionary or extrinsic definition. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

[0064] The term “amino acid” or “any amino acid” as used here refers to any and all amino acids, including naturally occurring amino acids (e.g., a-amino acids), unnatural amino acids, modified amino acids, and non-natural amino acids. It includes both D- and L-amino acids. Natural amino acids include those found in nature, such as, e.g.. the 23 amino acids that combine into peptide chains to form the building-blocks of a vast array of proteins. These are primarily L stereoisomers, although a few D-amino acids occur in bacterial envelopes and some antibiotics. The “non-standard,” natural amino acids include, for example, pyrolysine (found in methanogenic organisms and other eukaryotes), selenocysteine (present in many non-eukaryotes as well as most eukaryotes), and N-formylmethionine (encoded by the start codon AUG in bacteria, mitochondria, and chloroplasts). “Unnatural” or “non-natural” amino acids are non-proteinogenic amino acids (e.g., those not naturally encoded or found in the genetic code) that either occur naturally or are chemically synthesized. Over 140 unnatural amino acids are known and thousands of more combinations are possible. Examples of “unnatural” amino acids include β-amino acids (β3and β2), homo-amino acids, proline and pyruvic acid derivatives, 3-substituted alanine derivatives, glycine derivatives, ring-substituted phenylalanine and tyrosine derivatives, linear core amino acids, diamino acids, D-amino acids, alpha-methyl amino acids, and N-methyl amino acids. Unnatural or non-natural amino acids also include modified amino acids.“Modified” amino acids include amino acids (e.g., natural amino acids) that have been chemically modified to include a group, groups, or chemical moiety not naturally present on the amino acid. According to certain embodiments, a peptide inhibitor comprises an intramolecular bond between two amino acid residues present in the peptide inhibitor. It is understood that the amino acid residues that form the bond will be altered somewhat when bonded to each other as compared to when not bonded to each other. Reference to a particular amino acid is meant to encompass that amino acid in both its unbonded and bonded state.

[0065] For the most part, the names of naturally occurring and non-naturally occurring aminoacyl residues used herein follow the naming conventions suggested by the IUPAC Commission on the Nomenclature of Organic Chemistry and the IUPAC-IUB Commission on Biochemical Nomenclature as set out in “Nomenclature of a-Amino Acids (Recommendations, 1974)” Biochemistry, 14(2), (1975). To the extent that the names and abbreviations of aminoSTDU244218.601(S23-351) acids and aminoacyl residues employed in this specification and appended claims differ from those suggestions, they will be made clear to the reader.

[0066] Throughout the present specification, unless naturally occurring amino acids are referred to by their full name (e.g., alanine, arginine, etc.), they are designated by their conventional three-letter or single-letter abbreviations (e.g., Ala or A for alanine. Arg or R for arginine, etc.). The term “L-amino acid,” as used herein, refers to the “L” isomeric form of a peptide, and conversely the term “D-amino acid” refers to the “D” isomeric form of a peptide (e.g., Dphe, (D)Phe, D-Phe, orDF for the D isomeric form of Phenylalanine). Amino acid residues in the D isomeric form can be substituted for any L-amino acid residue, as long as the desired function is.

[0067] In the case of less common or non-naturally occurring amino acids, unless they are referred to by their full name (e.g. sarcosine, ornithine, etc.), frequently employed three- or four-character codes are employed for residues thereof, including, Sar or Sarc (sarcosine, i.e. N-methylglycine), Aib (a-aminoisobutyric acid). Dab (2,4-diaminobutanoic acid), Dapa (2,3-diaminopropanoic acid), y-Glu (y-glutamic acid), Gaba (y-aminobutanoic acid), 0-Pro (pyrrolidine-3-carboxylic acid), and 8Ado (8-amino-3,6-dioxaoctanoic acid), Abu (2-amino butyric acid), phPro (P-homoproline), hPhe (P-homophenylalanine) and Bip (P,p diphenylalanine), and Ida (Iminodiacetic acid).

[0068] “Antibody” and “antibodies” as used herein refer to monoclonal antibodies, polyclonal antibodies, monospecific antibodies (e.g., which can either be monoclonal, or may also be produced by other means than producing them from a common germ cell), multi- specific antibodies, human antibodies, humanized antibodies (fully or partially humanized), animal antibodies such as, but not limited to, a bird (for example, a duck or a goose), a shark, a whale, and a mammal, including a non-primate (for example, a cow, a pig, a camel, a llama, a horse, a goat, a rabbit, a sheep, a hamster, a guinea pig, a cat, a dog, a rat, a mouse, etc.) or a non-human primate (for example, a monkey, a chimpanzee, etc.), recombinant antibodies, chimeric antibodies, single-chain Fvs (“scFv”), single chain antibodies, single domain antibodies, Fab fragments, F(ab’) fragments, F(ab’)2 fragments, disulfide-linked Fvs (“sdFv”), and anti-idiotypic (“anti-Id”) antibodies, dual-domain antibodies, dual variable domain (DVD) or triple variable domain (TVD) antibodies (dual- variable domain immunoglobulins and methods for making them are described in Wu, C., et al., Nature Biotechnology, 25(11): 1290-1297 (2007) and PCTSTDU244218.601(S23-351) International Application WO 2001 / 058956, the contents of each of which are herein incorporated by reference), or domain antibodies (dAbs) (e.g., such as described in Holt et al., Trends in Biotechnology 21:484-490 (2014)), and including single domain antibodies sdAbs that are naturally occurring, e.g., as in cartilaginous fishes and camelids, or which are synthetic, e.g., nanobodies, VHH, or other domain structure), and functionally active epitope-binding fragments of any of the above. In particular, antibodies include immunoglobulin molecules and immunologically active fragments of immunoglobulin molecules, namely, molecules that contain an analyte-binding site. Immunoglobulin molecules can be of any type (for example, IgG, IgE, IgM, IgD, IgA, and IgY), class (for example, IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2), or subclass.

[0069] Typically, an immunoglobulin or antibody is a protein that comprises at least one complementarity determining region (CDR). The CDRs form the “hypervariable region” of an antibody, which is responsible for antigen binding. “CDR” is used herein to refer to the “complementarity determining region” within an antibody variable sequence.

[0070] There are three CDRs in each of the variable regions of the heavy chain (HCDR) and the light chain (LCDR). Proceeding from the N-terminus of a heavy or light chain, these regions are denoted “CDR1,” “CDR2,” and “CDR3,” for each of the variable regions. The term “CDR set” as used herein refers to a group of three CDRs that occur in a single variable region that binds the antigen. An antigen binding site, therefore, may include six CDRs, comprising the CDR set from each of a heavy and a light chain variable region. A polypeptide comprising a single CDR, (e.g., a CDR1, CDR2, or CDR3) may be referred to as a “molecular recognition unit.” Crystallographic analyses of antigen-antibody complexes have demonstrated that the amino acid residues of CDRs form extensive contact with bound antigen, wherein the most extensive antigen contact is with the heavy chain CDR3. Thus, the molecular recognition units may be primarily responsible for the specificity of an antigen binding site. In general, the CDR residues are directly and most substantially involved in influencing antigen binding.

[0071] A whole antibody typically consists of four polypeptides: two identical copies of a heavy (H) chain polypeptide and two identical copies of a light (L) chain polypeptide. Each of the heavy chains contains one N-terminal variable (VH or VH) region and three C-terminal constant (CHI, CH2, and CH3) regions, and each light chain contains one N-terminal variable (VL or VL) region and one C-terminal constant (CL) region. The light chains of antibodies can beSTDU244218.601(S23-351) assigned to one of two distinct types, either kappa (K) or lambda (X), based upon the amino acid sequences of their constant domains. In a typical antibody, each light chain is linked to a heavy chain by disulfide bonds, and the two heavy chains are linked to each other by disulfide bonds. The light chain variable region is aligned with the variable region of the heavy chain, and the light chain constant region is aligned with the first constant region of the heavy chain. The remaining constant regions of the heavy chains are aligned with each other.

[0072] The variable regions of each pair of light and heavy chains form the antigen binding site of an antibody. The VH and VL regions have the same general structure, with each region comprising four framework (FW or FR) regions. The term “framework region,” as used herein, refers to the relatively conserved amino acid sequences within the variable region which are located between the CDRs. There are four framework regions in each variable domain, which are designated FR1, FR2, FR3, and FR4. The framework regions form the 0 sheets that provide the structural framework of the variable region (see, e.g., C. A. Janeway et al. (eds.), Immunobiology, 5th Ed., Garland Publishing, New York, N. Y. (2001)).

[0073] “Humanized” forms of non-human (e.g., rodent) antibodies are chimeric antibodies that contain minimal sequence derived from the non-human antibody. For the most part, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a hypervariable region of the recipient are replaced by residues from a hypervariable region of a non-human species (donor antibody) such as mouse, rat, rabbit, or non-human primate having the desired antibody specificity, affinity, and capability. In some instances, framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies can comprise residues that are not found in the recipient antibody or in the donor antibody. These modifications are made to further refine antibody performance. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a nonhuman immunoglobulin and all or substantially all of the FRs are those of a human immunoglobulin sequence. The humanized antibody optionally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details, see Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992).STDU244218.601(S23-351)

[0074] As used herein, when an antibody or other entity (e.g., antigen binding domain) “specifically recognizes” or “specifically binds” an antigen or epitope, it preferentially recognizes the antigen in a complex mixture of proteins and / or macromolecules, and binds the antigen or epitope with affinity which is substantially higher than to other entities not displaying the antigen or epitope. In this regard, “affinity which is substantially higher” means affinity that is high enough to enable detection of an antigen or epitope which is distinguished from entities using a desired assay or measurement apparatus. Typically, it means binding affinity having a binding constant (Ka) of at least 107M’1(e.g., >107M’1, >108M’1, >109M’1, >1010M’1, >10nM’ \ >1012M-1, >1013M’1, etc.). In certain such embodiments, an antibody is capable of binding different antigens so long as the different antigens comprise that particular epitope. In certain instances, for example, homologous proteins from different species may comprise the same epitope.

[0075] The terms “fragment of an antibody,” “antibody fragment,” and “antigen binding fragment” of an antibody and the like are used interchangeably herein to refer to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (see, generally, Holliger et al., Nat. Biotech., 25(9): 1126-1129 (2005)). Any antigen binding fragment of the antibody described herein is within the scope of the present disclosure. The antibody fragment desirably comprises, for example, one or more CDRs, the variable region (or portions thereof), the constant region (or portions thereof), or combinations thereof. Examples of antibody fragments include, but are not limited to, (i) a Fab fragment, which is a monovalent fragment consisting of the VL, VH, CL, and CHI domains, (ii) a F(ab’)2 fragment, which is a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region, (iii) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (iv) a Fab’ fragment, which results from breaking the disulfide bridge of an F(ab’)2 fragment using mild reducing conditions, (v) a disulfide-stabilized Fv fragment (dsFv), and (vi) a domain antibody (dAb), which is an antibody single variable region domain (Vn or VL) polypeptide that specifically binds antigen.

[0076] The term “monoclonal antibody,” as used herein, refers to an antibody produced by a single clone of B lymphocytes that is directed against a single epitope on an antigen. Monoclonal antibodies typically are produced using hybridoma technology, as first described in Kohler and Milstein, Eur. J. Immunol., 5: 511-519 (1976). Monoclonal antibodies may also be producedSTDU244218.601(S23-351) using recombinant DNA methods, isolated from phage display antibody libraries, or produced from transgenic mice carrying a fully human immunoglobulin system. In contrast, “polyclonal” antibodies are antibodies that are secreted by different B cell lineages within an animal.Polyclonal antibodies are a collection of immunoglobulin molecules that recognize multiple epitopes on the same antigen.

[0077] The term “monospecific” antibody as used herein denotes a polyclonal antibody that is a mixture of antibodies each of which bind to the same epitope of the same antigen.

[0078] The terms “immunogen” and “antigen” are used interchangeably herein and refer to any molecule, compound, or substance that induces an immune response in an animal (e.g., a mammal). An “immune response” can entail, for example, antibody production and / or the activation of immune effector cells. An antigen in the context of the disclosure can comprise any subunit, fragment, or epitope of any proteinaceous or non-proteinaceous (e.g., carbohydrate or lipid) molecule that provokes an immune response in a mammal. The term “epitope” refers to a sequence of an antigen that is recognized by an antibody or an antigen receptor. Epitopes also are referred to in the art as “antigenic determinants.” In certain embodiments, an epitope is a region of an antigen that is specifically bound by an antibody. In certain embodiments, an epitope may include chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl, or sulfonyl groups. In certain embodiments, an epitope may have specific three-dimensional structural characteristics (e.g., a “conformational” epitope) and / or specific charge characteristics. The antigen can be a protein or peptide of viral, bacterial, parasitic, fungal, protozoan, prion, cellular, or extracellular origin, which provokes an immune response in a mammal, preferably leading to protective immunity.

[0079] As used herein, a “nucleic acid” or a “nucleic acid sequence” refers to a polymer or oligomer of pyrimidine and / or purine bases, preferably cytosine, thymine, and uracil, and adenine and guanine, respectively (See Albert L. Lehninger, Principles of Biochemistry, at 793-800 (Worth Pub. 1982)). The present technology contemplates any deoxyribonucleotide, ribonucleotide, or peptide nucleic acid component, and any chemical variants thereof, such as methylated, hydroxymethylated, or glycosylated forms of these bases, and the like. The polymers or oligomers may be heterogenous or homogenous in composition and may be isolated from naturally occurring sources or may be artificially or synthetically produced. In addition, the nucleic acids may be DNA or RNA, or a mixture thereof, and may exist permanently orSTDU244218.601(S23-351) transitionally in single-stranded or double-stranded form, including homoduplex, heteroduplex, and hybrid states. The term “nucleic acid” or “nucleic acid sequence” may also encompass a chain comprising non-natural nucleotides, modified nucleotides, and / or non- nucleotide building blocks that can exhibit the same function as natural nucleotides (e.g., “nucleotide analogs”); further, the term “nucleic acid sequence” as used herein refers to an oligonucleotide, nucleotide or polynucleotide, and fragments or portions thereof, and to DNA or RNA of genomic or synthetic origin, which may be single or double- stranded, and represent the sense or antisense strand. The terms “nucleic acid,” “polynucleotide,” “nucleotide sequence,” and “oligonucleotide” are used interchangeably. They refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof.

[0080] As used herein, the term “percent sequence identity” refers to the percentage of nucleotides or nucleotide analogs in a nucleic acid sequence, or amino acids in an amino acid sequence, that is identical with the corresponding nucleotides or amino acids in a reference sequence of the present disclosure after aligning the two sequences and introducing gaps, if necessary, to achieve the maximum percent identity. A number of mathematical algorithms for obtaining the optimal alignment and calculating identity between two or more sequences are known and incorporated into a number of available software programs. Examples of such programs include CLUSTAL-W, T-Coffee, and ALIGN (for alignment of nucleic acid and amino acid sequences), BLAST programs (e.g., BLAST 2.1, BL2SEQ, and later versions thereof) and FASTA programs (e.g., FASTA3x, FAS™, and S SEARCH) (for sequence alignment and sequence similarity searches). Sequence alignment algorithms also are disclosed in, for example, Altschul et al., J. Molecular Biol., 215(3): 403-410 (1990). Beigert et al., Proc. Natl. Acad. Sci. USA, 106(10): 3770-3775 (2009), Durbin et al., eds., Biological Sequence Analysis: Probabilistic Models of Proteins and Nucleic Acids, Cambridge University Press, Cambridge, UK (2009). Soding, Bioinformatics, 21(7): 951-960 (2005), Altschul et al., Nucleic Acids Res., 25(17): 3389-3402 (1997), and Gusfield, Algorithms on Strings, Trees and Sequences, Cambridge University Press, Cambridge UK (1997)).

[0081] A “peptide” or “polypeptide” is a linked sequence of two or more amino acids linked by peptide bonds. The peptide or polypeptide can be natural, synthetic, or a modification or combination of natural and synthetic. Polypeptides include proteins such as binding proteins,STDU244218.601(S23-351) receptors, and antibodies. The polypeptides may be modified by the addition of phosphates, sugars, lipids, or other moieties not included in the amino acid chain.

[0082] An “effective amount” refers to an amount sufficient to elicit a desired biological response (e.g., treating a condition). As will be appreciated by those skilled in the art, the effective amount may vary depending on such factors as the desired biological endpoint, the pharmacokinetics, the condition being treated, the mode of administration, and the age and health of the subject. An effective amount encompasses therapeutic and prophylactic treatment. For example, a “therapeutically effective amount” is an amount sufficient to provide a therapeutic benefit in the treatment of a condition, or to delay or minimize one or more symptoms associated with the condition. In some embodiments, a therapeutically effective amount is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to minimize one or more symptoms associated with the condition. A therapeutically effective amount means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces, or avoids symptoms or causes of the condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0083] A “pharmaceutically acceptable carrier” as used herein generally refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, which is nontoxic to a subject. A pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative.

[0084] The term “pharmaceutical formulation” as used herein generally refers to a preparation which is in such form as to permit the biological activity of an active ingredient (e.g., an anti-OPN antibody) contained therein to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered.

[0085] A “subject” or “patient” may be human or non-human and may include, for example, animal strains or species used as “model systems” for research purposes, such a mouse model as described herein. Likewise, subject may include either adults or juveniles (e.g., children).Moreover, subject may mean any living organism, preferably a mammal (e.g., humans and nonhumans) that may benefit from the administration of compositions contemplated herein.Examples of mammals include, but are not limited to, any member of the Mammalian class:STDU244218.601(S23-351) humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.Examples of non-mammals include, but are not limited to, birds, fish, and the like. In one embodiment, the mammal is a human.

[0086] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or condition, or one or more signs or symptoms thereof. In some embodiments, “treatment.” “treat,” and “treating” require that signs or symptoms of the disease disorder or condition have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease or condition. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.

[0087] The term “half-life” as used herein generally refers to the time required for the concentration of a substance (e.g., an anti-osteopontin antibody) to decrease by one-half, in vivo or in vitro.

[0088] As used herein, the terms “providing,” “administering,” and “introducing,” are used interchangeably herein and refer to the placement into a cell, organism, or subject by a method or route which results in at least partial localization to a desired site. The administration can be by any appropriate route which results in delivery to a desired location in the cell, organism, or subject.

[0089] Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in practice or testing of the present disclosure. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting.Anti-Osteopontin Antibodies

[0090] As described further herein, embodiments of the present disclosure relate to therapeutic antibodies that specifically bind to one or more epitopes of osteopontin. In some embodiments, the anti-osteopontin antibodies, or antigen binding fragments thereof, specificallySTDU244218.601(S23-351) bind to full length osteopontin (OPN-FL) and, optionally, inhibit thrombin cleavage of osteopontin, specifically bind to a thrombin cleavage fragment of osteopontin (e.g., OPN-R fragment) and reduce biological activity of the thrombin cleavage fragment, and / or specifically bind to a carboxypeptidase thrombin cleavage fragment of osteopontin (e.g., OPN-L fragment) and reduce biological activity of the carboxypeptidase thrombin cleavage fragment.

[0091] In some embodiments, the anti-osteopontin antibodies, or antigen binding fragments thereof, comprise one, two or all three HCDRs, and optionally, also one, two or all three of the corresponding LCDRs of any one of the exemplary antibodies the sequences of which are provided in Table 1 and FIGS. 4, 7, and 9. In some embodiments, the anti-osteopontin antibodies, or antigen binding fragments thereof, comprise all six CDRs of any one of the exemplary antibodies the sequences of which are provided in Table 1 and FIGS. 4, 7, and 9.

[0092] In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises an HCDR1 of any of SEQ ID NOs: 62, 123, 124, 52, 72, and 89; an HCDR2 of any of SEQ ID NOs: 18, 25, 33, 40. 44. 53. 63. 73, 82, and 90; and an HCDR3 of any of SEQ ID NOs: 126, 130, 134, 54, 64, 74, and 91.

[0093] In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the HCDR1 of SEQ ID NO: 62; the HCDR2 of SEQ ID NO: 18; and the HCDR3 of SEQ ID NO: 126. In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the HCDR1 of SEQ ID NO: 17; the HCDR2 of SEQ ID NO: 125; and the HCDR3 of SEQ ID NO: 19. In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the HCDR1 of SEQ ID NO: 62; the HCDR2 of SEQ ID NO: 40; and the HCDR3 of SEQ ID NO: 126. In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the HCDR1 of SEQ ID NO: 17; the HCDR2 of SEQ ID NO: 40; and the HCDR3 of SEQ ID NO: 19. In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the HCDR1 of SEQ ID NO: 62; the HCDR2 of SEQ ID NO: 25; and the HCDR3 of SEQ ID NO: 130. In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the HCDR1 of SEQ ID NO: 17; the HCDR2 of SEQ ID NO: 129; and the HCDR3 of SEQ ID NO: 26. In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the HCDR1 of SEQ ID NO: 123; the HCDR2 of SEQ ID NO: 33; and the HCDR3 of SEQ ID NO: 134. In some embodiments, an anti-osteopontin antibody, orSTDU244218.601(S23-351) antigen binding fragment thereof, comprises the HCDR1 of SEQ ID NO: 32; the HCDR2 of SEQ ID NO: 33; and the HCDR3 of SEQ ID NO: 34. In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the HCDR1 of SEQ ID NO: 124; the HCDR2 of SEQ ID NO: 44; and the HCDR3 of SEQ ID NO: 134. In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the HCDR1 of SEQ ID NO: 43; the HCDR2 of SEQ ID NO: 44; and the HCDR3 of SEQ ID NO: 34. In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the HCDR1 of SEQ ID NO: 52; the HCDR2 of SEQ ID NO: 53; and the HCDR3 of SEQ ID NO: 54. In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the HCDR1 of SEQ ID NO: 62; the HCDR2 of SEQ ID NO: 63; and the HCDR3 of SEQ ID NO: 64. In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the HCDR1 of SEQ ID NO: 72; the HCDR2 of SEQ ID NO: 73; and the HCDR3 of SEQ ID NO: 74. In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the HCDR1 of SEQ ID NO: 62; the HCDR2 of SEQ ID NO: 82; and the HCDR3 of SEQ ID NO: 74. In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the HCDR1 of SEQ ID NO: 89; the HCDR2 of SEQ ID NO: 90; and the HCDR3 of SEQ ID NO: 91.

[0094] In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises a LCDR1 of any of SEQ ID NOs: 21, 28, 36, 46. 55. 65, 75, 83, and 92; a LCDR2 of any of SEQ ID NOs: 22, 29, 37, 56, 66, 76, and 93; and a LCDR3 of any of SEQ ID NOs: 23, 30, 38, 47, 57, 67, 77, 84, and 94.

[0095] In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the LCDR1 of SEQ ID NO: 21; the LCDR2 of SEQ ID NO: 22; and the LCDR3 of SEQ ID NO: 23. In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the LCDR1 of SEQ ID NO: 28; the LCDR2 of SEQ ID NO: 29; and the LCDR3 of SEQ ID NO: 30. In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the LCDR1 of SEQ ID NO: 36; the LCDR2 of SEQ ID NO: 37; and the LCDR3 of SEQ ID NO: 38. In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the LCDR1 of SEQ ID NO: 46; the LCDR2 of SEQ ID NO: 37: and the LCDR3 of SEQ ID NO: 47. In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the LCDR1 of SEQ IDSTDU244218.601(S23-351) NO: 55; the LCDR2 of SEQ ID NO: 56; and the LCDR3 of SEQ ID NO: 57. In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the LCDR1 of SEQ ID NO: 65: the LCDR2 of SEQ ID NO: 66; and the LCDR3 of SEQ ID NO: 67. In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the LCDR1 of SEQ ID NO: 75; the LCDR2 of SEQ ID NO: 76; and the LCDR3 of SEQ ID NO: 77. In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the LCDR1 of SEQ ID NO: 83; the LCDR2 of SEQ ID NO: 29; and the LCDR3 of SEQ ID NO: 84. In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the LCDR1 of SEQ ID NO: 92; the LCDR2 of SEQ ID NO: 93; and the LCDR3 of SEQ ID NO: 94.

[0096] In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the HCDR1 of SEQ ID NO: 62; the HCDR2 of SEQ ID NO: 18; the HCDR3 of SEQ ID NO: 126; the LCDR1 of SEQ ID NO: 21; the LCDR2 of SEQ ID NO: 22; and the LCDR3 of SEQ ID NO: 23.

[0097] In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the HCDR1 of SEQ ID NO: 17; the HCDR2 of SEQ ID NO: 18; the HCDR3 of SEQ ID NO: 19; the LCDR1 of SEQ ID NO: 21; the LCDR2 of SEQ ID NO: 22; and the LCDR3 of SEQ ID NO: 23.

[0098] In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the HCDR1 of SEQ ID NO: 62; the HCDR2 of SEQ ID NO: 40; the HCDR3 of SEQ ID NO: 126; the LCDR1 of SEQ ID NO: 21; the LCDR2 of SEQ ID NO: 22; and the LCDR3 of SEQ ID NO: 23.

[0099] In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the HCDR1 of SEQ ID NO: 17; the HCDR2 of SEQ ID NO: 40; the HCDR3 of SEQ ID NO: 19; the LCDR1 of SEQ ID NO: 21; the LCDR2 of SEQ ID NO: 22; and the LCDR3 of SEQ ID NO: 23.

[0100] In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the HCDR1 of SEQ ID NO: 62; the HCDR2 of SEQ ID NO: 25; the HCDR3 of SEQ ID NO: 130; the LCDR1 of SEQ ID NO: 28; the LCDR2 of SEQ ID NO: 29; and the LCDR3 of SEQ ID NO: 30.STDU244218.601(S23-351)

[0101] In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the HCDR1 of SEQ ID NO: 17; the HCDR2 of SEQ ID NO: 25; the HCDR3 of SEQ ID NO: 26; the LCDR1 of SEQ ID NO: 28: the LCDR2 of SEQ ID NO: 29; and the LCDR3 of SEQ ID NO: 30.

[0102] In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the HCDR1 of SEQ ID NO: 123; the HCDR2 of SEQ ID NO: 33; the HCDR3 of SEQ ID NO: 134; the LCDR1 of SEQ ID NO: 36; the LCDR2 of SEQ ID NO: 37; and the LCDR3 of SEQ ID NO: 38.

[0103] In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the HCDR1 of SEQ ID NO: 32; the HCDR2 of SEQ ID NO: 33; the HCDR3 of SEQ ID NO: 34; the LCDR1 of SEQ ID NO: 36: the LCDR2 of SEQ ID NO: 37; and the LCDR3 of SEQ ID NO: 38.

[0104] In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the HCDR1 of SEQ ID NO: 124; the HCDR2 of SEQ ID NO: 44; the HCDR3 of SEQ ID NO: 134; the LCDR1 of SEQ ID NO: 46; the LCDR2 of SEQ ID NO: 37; and the LCDR3 of SEQ ID NO: 47.

[0105] In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the HCDR1 of SEQ ID NO: 43; the HCDR2 of SEQ ID NO: 44; the HCDR3 of SEQ ID NO: 34; the LCDR1 of SEQ ID NO: 46; the LCDR2 of SEQ ID NO: 37; and the LCDR3 of SEQ ID NO: 47.

[0106] In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the HCDR1 of SEQ ID NO: 52; the HCDR2 of SEQ ID NO: 53; the HCDR3 of SEQ ID NO: 54; the LCDR1 of SEQ ID NO: 55; the LCDR2 of SEQ ID NO: 56; and the LCDR3 of SEQ ID NO: 57.

[0107] In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the HCDR1 of SEQ ID NO: 62; the HCDR2 of SEQ ID NO: 63; the HCDR3 of SEQ ID NO: 64; the LCDR1 of SEQ ID NO: 65; the LCDR2 of SEQ ID NO: 66; and the LCDR3 of SEQ ID NO: 67.

[0108] In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the HCDR1 of SEQ ID NO: 72; the HCDR2 of SEQ ID NO: 73; the HCDR3STDU244218.601(S23-351) of SEQ ID NO: 74; the LCDR1 of SEQ ID NO: 75; the LCDR2 of SEQ ID NO: 76; and the LCDR3 of SEQ ID NO: 77.

[0109] In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the HCDR1 of SEQ ID NO: 62; the HCDR2 of SEQ ID NO: 82; the HCDR3 of SEQ ID NO: 74; the LCDR1 of SEQ ID NO: 83; the LCDR2 of SEQ ID NO: 29; and the LCDR3 of SEQ ID NO: 84.

[0110] In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the HCDR1 of SEQ ID NO: 89; the HCDR2 of SEQ ID NO: 90; the HCDR3 of SEQ ID NO: 91; the LCDR1 of SEQ ID NO: 92; the LCDR2 of SEQ ID NO: 93; and the LCDR3 of SEQ ID NO: 94.

[0111] In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises an HCDR1 of any of SEQ ID NOs: 2, 6, and 9; an HCDR2 of any of SEQ ID NOs: 3, 7, and 10; and an HCDR3 of any of SEQ ID NOs: 4 and 11. In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the HCDR1 of SEQ ID NO: 2 or 6; the HCDR2 of SEQ ID NO: 3 or 7; and the HCDR3 of SEQ ID NO: 4. In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the HCDR1 of SEQ ID NO: 9; the HCDR2 of SEQ ID NO: 10; and the HCDR3 of SEQ ID NO: 11.

[0112] In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the LCDR1 of SEQ ID NO: 13; the LCDR2 of SEQ ID NO: 14; and the LCDR3 of SEQ ID NO: 15.

[0113] In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the HCDR1 of SEQ ID NO: 2 or 6; the HCDR2 of SEQ ID NO: 3 or 7; the HCDR3 of SEQ ID NO: 4; the LCDR1 of SEQ ID NO: 13; the LCDR2 of SEQ ID NO: 14; and the LCDR3 of SEQ ID NO: 15.

[0114] In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the HCDR1 of SEQ ID NO: 9; the HCDR2 of SEQ ID NO: 10; the HCDR3 of SEQ ID NO: 11; the LCDR1 of SEQ ID NO: 13; the LCDR2 of SEQ ID NO: 14; and the LCDR3 of SEQ ID NO: 15.

[0115] In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises an HCDR1 of any of SEQ ID NOs: 99, 108 and 118; an HCDR2 of any of SEQ ID NOs: 100, 109 and 119; and an HCDR3 of any of SEQ ID NOs: 101, 110, and 120.STDU244218.601(S23-351)

[0116] In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the HCDR1 of SEQ ID NO: 99; the HCDR2 of SEQ ID NO: 100; and the HCDR3 of SEQ ID NO: 101. In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the HCDR1 of SEQ ID NO: 108; the HCDR2 of SEQ ID NO: 109; and the HCDR3 of SEQ ID NO: 110. In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the HCDR1 of SEQ ID NO: 118; the HCDR2 of SEQ ID NO: 119; and the HCDR3 of SEQ ID NO: 120.

[0117] In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises a LCDR1 of any of SEQ ID NOs: 102, 111 and 121; a LCDR2 of any of SEQ ID NO: 22, 29, 112; and a LCDR3 of any of SEQ ID NOs: 103, 113, and 122.

[0118] In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the LCDR1 of SEQ ID NO: 102; the LCDR2 of SEQ ID NO: 22; and the LCDR3 of SEQ ID NO: 103. In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the LCDR1 of SEQ ID NO: 111: the LCDR2 of SEQ ID NO: 112; and the LCDR3 of SEQ ID NO: 113. In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the LCDR1 of SEQ ID NO: 121; the LCDR2 of SEQ ID NO: 29; and the LCDR3 of SEQ ID NO: 122.

[0119] In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the HCDR1 of SEQ ID NO: 99; the HCDR2 of SEQ ID NO: 100; the HCDR3 of SEQ ID NO: 101; the LCDR1 of SEQ ID NO: 102; the LCDR2 of SEQ ID NO: 22; and the LCDR3 of SEQ ID NO: 103.

[0120] In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the HCDR1 of SEQ ID NO: 108; the HCDR2 of SEQ ID NO: 109; the HCDR3 of SEQ ID NO: 110; the LCDR1 of SEQ ID NO: 111; the LCDR2 of SEQ ID NO: 112; and the LCDR3 of SEQ ID NO: 113.

[0121] In some embodiments, an anti-osteopontin antibody, or antigen binding fragment thereof, comprises the HCDR1 of SEQ ID NO: 118; the HCDR2 of SEQ ID NO: 119; the HCDR3 of SEQ ID NO: 120; the LCDR1 of SEQ ID NO: 121; the LCDR2 of SEQ ID NO: 29; and the LCDR3 of SEQ ID NO: 122.

[0122] In certain cases it may be desirable to alter individual CDR amino acid residues, for example to remove a deamidation sensitive (asparagine deamidation) sites (NG, NS, NH, etc.),STDU244218.601(S23-351) aspartic acid isomerization (DG, DP) sensitive sites, N-glycosylation (N-{P}SIT) sensitive sites, oxidation sensitive sites, etc., or an undesired cysteine residue, to any residue that does not affect selectivity, affinity, avidity, and developability. N-linked glycosylation occurs by attachment of an oligosaccharide chain to an asparagine residue in the tripeptide sequence Asn-X-Ser or Asn-X-Thr, where X may be any amino acid except Pro. Removal of an N-glycosylation site may be achieved by mutating either the Asn or the Ser / Thr residue to a different residue, for instance by way of conservative substitution. Deamidation of asparagine and glutamine residues can occur depending on factors such as pH and surface exposure. Asparagine residues are particularly susceptible to deamidation, primarily when present in the sequence Asn-Gly, and to a lesser extent in other dipeptide sequences such as Asn- Ala. When such a site is present in a CDR sequence, it may therefore be desirable to remove the site, typically by conservative substitution to remove one of the implicated residues. Accordingly, substitution in a CDR sequence to remove one of the implicated residues is also encompassed by the present disclosure.

[0123] In some embodiments, the present disclosure provides anti-osteopontin antibodies, or antigen binding fragments thereof, that include a VH comprising complementarity determining regions HCDR1, HCDR2, and HCDR3, and a VL comprising complementarity determining regions LCDR1, LCDR2, and LCDR3. In some embodiments, the anti-osteopontin antibodies comprise a VH sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to a VH sequence of any one of the exemplary antibodies, the sequences of which are provided in Table 1. In some embodiments, the anti-osteopontin antibodies comprise a VH sequence having at least 90% identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to a VH sequence of any one of the exemplary antibodies, the sequences of which are provided in Table 1.

[0124] In some embodiments, the anti-osteopontin antibodies comprise a VL sequence having at least 70% identity (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity) to a VL sequence of any one of the exemplary antibodies, the sequences of which are provided in Table 1. In some embodiments, the anti-osteopontin antibodies comprise a VL sequence having at least 90% identity (e.g., at least 91%,STDU244218.601(S23-351) at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) to a VL sequence of any one of the exemplary antibodies, the sequences of which are provided in Table 1.

[0125] In some embodiments, the anti-osteopontin antibodies, or antigen binding fragments thereof, comprise a VH sequence having at least 70% identity and VL sequence having at least 70% identity to any one of the exemplary antibodies the sequences of which are provided in Table 1. In some embodiments, the anti-osteopontin antibodies comprise a VH sequence having at least 90% identity and VL sequence having at least 90% identity to any one of the exemplary antibodies the sequences of which are provided in Table 1. In some embodiments, the anti-osteopontin antibodies comprise a VH sequence and VL sequence of any one of the exemplary antibodies the sequences of which are provided in Table 1.

[0126] In some embodiments, the anti-osteopontin antibodies, or antigen binding fragments thereof, comprise a VH sequence having at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%. 99%, or completely) identity to any of SEQ ID NOs: 16, 24, 31, 39, 42, 49, 59, 69, 79, and 86. In some embodiments, the anti-osteopontin antibodies, or antigen binding fragments thereof, comprise a VH sequence of SEQ ID NO: 16, 24, 31, 39, 42, 49, 59, 69, 79, or 86.

[0127] In some embodiments, the anti-osteopontin antibodies, or antigen binding fragments thereof, comprise a VL sequence having at least 90% (e.g.. 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or completely) identity to any of SEQ ID NOs: 20, 27, 35, 41, 45, 51, 61, 71, 81, and 88. In some embodiments, the anti-osteopontin antibodies, or antigen binding fragments thereof, comprise a VL sequence of: SEQ ID NO: 20. 27. 35. 41, 45, 51, 61, 71, 81, or 88.

[0128] In some embodiments, the anti-osteopontin antibodies, or antigen binding fragments thereof, comprise a VH sequence at least 90% identical to SEQ ID NO: 16 and a VL sequence at least 90% identical to SEQ ID NO: 20. In some embodiments, the anti-osteopontin antibodies, or antigen binding fragments thereof, comprise a VH sequence at least 90% identical to SEQ ID NO: 24 and a VL sequence at least 90% identical to SEQ ID NO: 27. In some embodiments, the anti-osteopontin antibodies, or antigen binding fragments thereof, comprise a VH sequence at least 90% identical to SEQ ID NO: 31 and a VL sequence at least 90% identical to SEQ ID NO: 35. In some embodiments, the anti-osteopontin antibodies, or antigen binding fragments thereof,STDU244218.601(S23-351) comprise a VH sequence at least 90% identical to SEQ ID NO: 39 and to a VL sequence at least 90% identical to SEQ ID NO: 41. In some embodiments, the anti-osteopontin antibodies, or antigen binding fragments thereof, comprise a VH sequence at least 90% identical to SEQ ID NO: 42 and a VL sequence at least 90% identical to SEQ ID NO: 45. In some embodiments, the anti-osteopontin antibodies, or antigen binding fragments thereof, comprise a VH sequence at least 90% identical to SEQ ID NO: 49 and a VL sequence at least 90% identical to SEQ ID NO: 51. In some embodiments the anti-osteopontin antibodies, or antigen binding fragments thereof, comprise a VH sequence at least 90% identical to SEQ ID NO: 59 and a VL sequence at least 90% identical to SEQ ID NO: 61. In some embodiments, the anti-osteopontin antibodies, or antigen binding fragments thereof, comprise a VH sequence at least 90% identical to SEQ ID NO: 69 and a VL sequence at least 90% identical to SEQ ID NO: 71. In some embodiments, the anti-osteopontin antibodies, or antigen binding fragments thereof, comprise a VH sequence at least 90% identical to SEQ ID NO: 79 and a VL sequence at least 90% identical to SEQ ID NO: 81. In some embodiments, the anti-osteopontin antibodies, or antigen binding fragments thereof, comprise a VH sequence at least 90% identical to SEQ ID NO: 86 and a VL sequence at least 90% identical to SEQ ID NO: 88.

[0129] In some embodiments, the anti-osteopontin antibodies, or antigen binding fragments thereof, comprise a VH sequence having at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or completely) identity to any of SEQ ID NOs: 1, 5. and 8. In some embodiments, the anti-osteopontin antibodies, or antigen binding fragments thereof, comprise a VH sequence of SEQ ID NO: 1, 5 or 8. In some embodiments, the anti-osteopontin antibodies, or antigen binding fragments thereof, comprise a VL sequence having at least 90% (e.g., 90%. 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or completely) identity to SEQ ID NO: 12. In some embodiments, the anti-osteopontin antibodies, or antigen binding fragments thereof, comprise a VL sequence of SEQ ID NO: 12.

[0130] In some embodiments, the anti-osteopontin antibodies, or antigen binding fragments thereof, comprise a VH sequence at least 90% identical to SEQ ID NO: 1, 5, or 8 and a VL sequence at least 90% identical to SEQ ID NO: 12.

[0131] In some embodiments, the anti-osteopontin antibodies, or antigen binding fragments thereof, comprise a VH sequence having at least 90% (e.g., 90%, 91%, 92%, 93%. 94%, 95%, 96%, 97%, 98%, 99%, or completely) identity to any of SEQ ID NOs: 96, 105 and 115. In someSTDU244218.601(S23-351) embodiments, the anti-osteopontin antibodies, or antigen binding fragments thereof, comprise a VH sequence of SEQ ID NO: 96, 105, or 115. In some embodiments, the anti-osteopontin antibodies, or antigen binding fragments thereof, comprise a VL sequence having at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or completely) identity to any of SEQ ID NOs: 98, 107, and 117. In some embodiments, the anti-osteopontin antibodies, or antigen binding fragments thereof, comprise a VL sequence of SEQ ID NO: 98, 107, or 117.

[0132] In some embodiments, the anti-osteopontin antibodies, or antigen binding fragments thereof, comprise a VH sequence at least 90% identical to SEQ ID NO: 96 and a VL sequence at least 90% identical to SEQ ID NO: 98. In some embodiments, the anti-osteopontin antibodies, or antigen binding fragments thereof, comprise a VH sequence at least 90% identical to SEQ ID NO: 105 and a VL sequence at least 90% identical to SEQ ID NO: 107. In some embodiments, the anti-osteopontin antibodies, or antigen binding fragments thereof, comprise a VH sequence at least 90% identical to SEQ ID NO: 115 and a VL sequence at least 90% identical to SEQ ID NO: 117.

[0133] As would be recognized by one of ordinary skill in the art based on the present disclosure, one or more amino acids of the aforementioned anti-osteopontin antibodies, or antigen binding fragments thereof, can be replaced or substituted with a different amino acid. An amino acid “replacement” or “substitution” refers to the replacement of one amino acid at a given position or residue by another amino acid at the same position or residue within a polypeptide sequence. Amino acids are broadly grouped as “aromatic” or “aliphatic.” An aromatic amino acid includes an aromatic ring. Examples of “aromatic” amino acids include histidine (H or His), phenylalanine (F or Phe). tyrosine (Y or Tyr), and tryptophan (W or Trp). Non-aromatic amino acids are broadly grouped as “aliphatic.” Examples of “aliphatic” amino acids include glycine (G or Gly), alanine (A or Ala), valine (V or Vai), leucine (L or Leu), isoleucine (I or He), methionine (M or Met), serine (S or Ser), threonine (T or Thr), cysteine (C or Cys), proline (P or Pro), glutamic acid (E or Glu), aspartic acid (D or Asp), asparagine (N or Asn), glutamine (Q or Gin), lysine (K or Lys), and arginine (R or Arg). Aliphatic amino acids may be sub-divided into four sub-groups. The “large aliphatic non-polar sub-group” consists of valine, leucine, and isoleucine. The “aliphatic slightly-polar sub-group” consists of methionine, serine, threonine, and cysteine. The “aliphatic polar / charged sub-group” consists of glutamic acid, aspartic acid, asparagine, glutamine, lysine, and arginine. The “small-residue sub-group”STDU244218.601(S23-351) consists of glycine and alanine. The group of charged / polar amino acids may be sub-divided into three sub-groups: the “positively-charged sub-group” consisting of lysine and arginine, the “negatively-charged sub-group” consisting of glutamic acid and aspartic acid, and the “polar sub-group” consisting of asparagine and glutamine. Aromatic amino acids may be sub-divided into two sub-groups: the “nitrogen ring sub-group” consisting of histidine and tryptophan and the “phenyl sub-group” consisting of phenylalanine and tyrosine.

[0134] The amino acid replacement or substitution can be conservative, semi-conservative, or non-conservative. The phrase “conservative amino acid substitution” or “conservative mutation” refers to the replacement of one amino acid by another amino acid with a common property. A functional way to define common properties between individual amino acids is to analyze the normalized frequencies of amino acid changes between corresponding proteins of homologous organisms (Schulz and Schirmer, Principles of Protein Structure, Springer-Verlag, New York (1979)). According to such analyses, groups of amino acids may be defined where amino acids within a group exchange preferentially with each other and therefore resemble each other most in their impact on the overall protein structure. Examples of conservative amino acid substitutions include substitutions of amino acids within the sub-groups described above, for example, lysine for arginine and vice versa such that a positive charge may be maintained, glutamic acid for aspartic acid and vice versa such that a negative charge may be maintained, serine for threonine such that a free -OH can be maintained, and glutamine for asparagine such that a free -NH2 can be maintained. “Semi-conservative mutations” include amino acid substitutions of amino acids within the same groups listed above, but not within the same subgroup. For example, the substitution of aspartic acid for asparagine, or asparagine for lysine, involves amino acids within the same group, but different sub-groups. “Non-conservative mutations” involve amino acid substitutions between different groups, for example, lysine for tryptophan, or phenylalanine for serine, etc.

[0135] In addition, one or more amino acids can be inserted into the anti-osteopontin antibodies, or antigen binding fragments thereof (e.g., insertion into the heavy and / or light chain variable region amino acid sequence). Any number of suitable amino acids can be inserted into the amino acid sequence of the antibody or antigen binding fragment thereof. In this respect, at least one amino acid (e.g., 2 or more, 5 or more, or 10 or more amino acids), but not more than 20 amino acids (e.g., 18 or less, 15 or less, or 12 or less amino acids), can be inserted into theSTDU244218.601(S23-351) amino acid sequence of the antibody or antigen binding fragment thereof. For example, 1-10 amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids) may be inserted into the amino acid sequence of the monoclonal antibody or antigen binding fragment thereof. In this respect, the amino acid(s) can be inserted into an antibody, or antigen binding fragment thereof, in any suitable location. Preferably, the amino acid(s) are inserted into a CDR (e.g., CDR1, CDR2, or CDR3) of the antibody or antigen binding fragment thereof.

[0136] In addition, one or more amino acids can be deleted from the anti-osteopontin antibodies, or antigen binding fragments thereof (e.g., insertion into the heavy and / or light chain variable region amino acid sequence). Any number of suitable amino acids can be deleted from the amino acid sequence of the antibody or antigen binding fragment thereof. In this respect, at least one amino acid (e.g., 2 or more, 5 or more, or 10 or more amino acids), but not more than 20 amino acids (e.g., 18 or less, 15 or less, or 12 or less amino acids), can be deleted from the amino acid sequence of the antibody or antigen binding fragment thereof. For example, 1-10 amino acids (e.g., 1, 2, 3, 4, 5, 6, 7. 8, 9, or 10 amino acids) may be deleted from the amino acid sequence of the monoclonal antibody or antigen binding fragment thereof.

[0137] An anti-osteopontin antibody of the present disclosure may be a whole antibody, or an antigen binding fragment of a whole antibody. As defined herein, antigen binding antibody fragments encompassed by the present disclosure include, but are not limited to, F(ab’)2, Fab’, Fab, Fv, scFv, dsFv, dAb, and single chain binding polypeptides. Antibody fragments and their therapeutic utility are further described in, e.g., Nelson, A. L., MAbs. 2010 Jan-Feb; 2(1): 77-83; Joosten et al., Microbial Cell Factories volume 2, Article number: 1 (2003); and Bates A, Power CA„ Antibodies (Basel). 2019;8(2):28; doi:10.3390 / antib8020028). In some embodiments, the anti-osteopontin antigen binding fragment is a single-chain variable fragment (scFv), which is an engineered antibody generated by the fusion of the heavy (VH) and light chains (VL) of immunoglobulins through a short polypeptide linker. Single chain variable domain (Fv) fragments (scFv) are used in the art in a variety of clinical and therapeutic applications, primarily due to their improved pharmacokinetic properties as compared to the parent monoclonal antibodies and the relative ease of producing them in large quantities at low cost (Monnier et al., Antibodies 2013, 2(2), 193-208; doi.org / 10.3390 / antib2020193; Safdari et al., Mol Med. 2016; 22: 258-270; and Lu, R„ Hwang, Y., Liu, I. et al. Development of therapeutic antibodies for the treatment of diseases. J Biomed Sci 27, 1 (2020). https: / / doi.org / 10.1186 / sl2929-019-0592-z).STDU244218.601(S23-351)

[0138] An anti-osteopontin antibody of the present disclosure may be a diabody. Diabodies are antibody fragments with two antigen binding sites that may be bivalent or bispecific. See, for example, EP 404,097; WO 1993 / 01161; Hudson et al., Nat. Med. 9:129-134 (2003); and Hollinger et al., Proc. Natl. Acad. Sci. USA 90: 6444-6448 (1993). Triabodies and tetrabodies are also described in Hudson et al., Nat. Med. 9:129-134 (2003). An anti-osteopontin antibody of the present disclosure may be a single-domain antibody (also referred to as a nanobody). Singledomain antibodies are antibody fragments comprising all or a portion of the heavy chain variable domain or all or a portion of the light chain variable domain of an antibody. In certain embodiments, a single-domain antibody is a human single-domain antibody (Domantis, Inc., Waltham, Mass.; see, e.g., U. S. Pat. No. 6,248,516 Bl). Antibody fragments can be made by various techniques, including but not limited to proteolytic digestion of an intact antibody as well as production by recombinant host cells (e.g., E. coli or phage), as described herein.

[0139] In other embodiments, the anti-osteopontin antibody of the present disclosure is a whole antibody. As defined herein, a whole antibody comprises two identical copies of a heavy (H) chain polypeptide and two identical copies of a light (L) chain polypeptide. Each of the heavy chains contains one N-terminal variable (VH) region and three C-terminal constant (CHI, CH2, and CH3) regions, and each light chain contains one N-terminal variable (Vi.) region and one C-terminal constant (CL). The heavy chain C-terminal constant region contains the fragment crystallizable (Fc) domain, which determines antibody class and is responsible for humoral and cellular effector functions. Antibodies are divided into five major classes (or “isotypes”), IgG, IgM, IgA, IgD and IgE, which differ in their function in the immune system. IgGs are the most abundant immunoglobulins in the blood, representing 60% of total serum antibodies in humans. IgG antibodies may be subclassified as IgGl, IgG2, IgG3, and IgG4, named in order of their abundance in serum (IgGl being the most abundant) (Vidarsson et al., Frontiers in Immunology.5: 520 (2014)). A whole anti-osteopontin monoclonal antibody described herein may be of any suitable class and / or subclass. In some embodiments, the monoclonal antibody is of class IgG (e.g., IgGl, IgG2, IgG3, or IgG4). For example, the monoclonal antibody may be an IgGl antibody.

[0140] As discussed above, the Fc domain mediates several effector functions of antibodies, such as binding to receptors on target cells and complement fixation (triggering effector functions that eliminate the antigen). In some embodiments, the Fc domain may be modified orSTDU244218.601(S23-351) engineered to alter its effector functions. For example, Fc domains may be modified to improve antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), and to control serum half-life. In some embodiments, the Fc domain of the anti-osteopontin antibody may be engineered to modulate affinity for an Fc receptor, such as Fey receptors (FcyRs) and the neonatal Fc receptor (FcRn). Indeed, optimization of the interactions between antibodies and FcyRs has emerged as a promising approach for enhancing the activity of therapeutic antibodies for the treatment of various diseases (Mimoto et al., Curr. Pharm.Biotechnol. 17, 1298-1314 (2016); Lazar et al., Proc. Natl Acad. Sci. USA 103, 4005-4010 (2006); Richards et al„ Mol. Cancer Ther. 7, 2517-2527 (2008); Nordstrom et al„ Breast Cancer Res. 13, R123 (2011); and Kang, T. H., Jung, S. T., Exp Mol Med 51, 1-9 (2019)). The Fc domain also may be modified to improve serum half-life, e.g., by engineering IgG Fc for higher FcRn binding (Zalevsky et al., Nat. Biotechnol. 28, 157-159 (2010); and Dall’Acqua et al., J. Immunol.169, 5171-5180 (2002)). In other embodiments, the Fc domain may be modified to create monovalency or antibody bispecificity for improving therapeutic potency. For example, an Fc domain may be generated that does not form a homodimer but remains as a soluble monomer, mFc, that exhibits high affinity for FcyRI but no detectable binding to FcyRIIIa. In other embodiments, a heterodimeric Fc domain may be generated to obtain bispecific properties for antigen binding to circumvent homodimer formation. Engineered Fc domains may be generated by inducing point mutations or by modifying glycosylation of the Fc domain (Saunders. K. O., Front Immunol. 2019; 10: 1296; Kelley, R. F., Meng, Y. G., Liu et al., J Biol Chem.2014;289:3571-90; Monnet et al., MAbs. 2014;6:422-36; Li et al., Proc Natl Acad Sci U S A. 2017;114:3485-90; and Lin et al., Proc Natl Acad Sci U S A. 2015;112:10611-6; Kang and Jung, supra).

[0141] As described above, the anti-osteopontin antibodies of the present disclosure can be a monoclonal antibody, a human antibody, a humanized antibody, and / or a chimeric antibody. In some embodiments, the antibody is a fragment selected from the group consisting of Fab, Fab-C, Fab'-SH, Fv, scFv. and (Fab ' i fragments. In some embodiments, the anti-osteopontin antibody is a monospecific antibody. In some embodiments, the anti-osteopontin antibody is a bispecific antibody. In some embodiments, the anti-osteopontin antibody comprises two or more singledomain antibodies that form a bivalent antibody, a trivalent antibody, or a tetravalent antibody that recognizes different epitopes on the same or different antigens.STDU244218.601(S23-351)

[0142] In some embodiments, an anti-osteopontin antibody provided herein is a chimeric antibody. Certain chimeric antibodies are described, for example, in U. S. Pat. No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sei. USA. 81:6851-6855 (1984). In one example, a chimeric antibody comprises a non-human variable region (e.g., a variable domain derived from a mouse, rat, hamster, rabbit, or non-human primate, such as a monkey) and a human constant domain. In a further example, a chimeric antibody is a “class switched” antibody in which the class or subclass has been changed from that of the parent antibody. Chimeric antibodies include antigen binding fragments thereof.

[0143] In certain embodiments, a chimeric antibody is a humanized antibody. Typically, a non-human antibody is humanized to reduce immunogenicity to humans, while retaining the specificity and affinity of the parental non-human antibody. Generally, a humanized antibody comprises one or more variable domains in which HVRs, for example, CDRs, (or portions thereof) are derived from a non-human antibody, and FRs (or portions thereof) are derived from human antibody sequences. A humanized antibody optionally will also comprise at least a portion of a human constant region. In some embodiments, some FR residues in a humanized antibody are substituted with corresponding residues from a non-human antibody (e.g., the antibody from which the HVR residues are derived), e.g., to restore or improve antibody specificity or affinity.

[0144] Humanized antibodies and methods of making them are reviewed, for example, in Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008), and are further described, for example, in Riechmann et al., Nature 332:323-329 (1988); Queen et al., Proc. Nat'lAcad. Sci. USA 86:10029-10033 (1989); U. S. Pat. Nos. 5,821.337, 7,527,791, 6.982,321, and 7,087,409; Kashmiri et al., Methods 36:25-34 (2005) (describing specificity determining region (SDR) grafting); Padlan, Mol. Immunol. 28:489-498 (1991) (describing “resurfacing”); Dall'Acqua et al„ Methods 36:43-60 (2005) (describing “FR shuffling”); and Osbourn et al„ Methods 36:61-68 (2005) and Klimka et al., Br. J. Cancer, 83:252-260 (2000) (describing the “guided selection” approach to FR shuffling).

[0145] In accordance with the above embodiments, the anti-osteopontin antibodies of the present disclosure can be made into bivalent, trivalent, or tetravalent formats. For example, an anti-osteopontin antibody of the present disclosure can be a bivalent, bispecific antibody with heteromeric heavy chains (e.g., Triomab, knobs-into-holes (KIH), Duobody, etc). An anti-STDU244218.601(S23-351) osteopontin antibody of the present disclosure can be a tetravalent multispecific antibody comprised of IgGs with other binding domains fused to either the N- or C-termini of either the heavy or light chains (e.g., dual variable domain [DVD], IgG-scFv fusion, Mabtyrin (IgG with non-antibody binding scaffold “centyrin” fused to C-terminal end of heavy chains). An anti-osteopontin antibody of the present disclosure can be comprised of IgGs to which additional antigen combining sites have been added within the structure (e.g., two-in-one antibodies, MAT “Modular Antibody Technology” platform from F-Star). An anti-osteopontin antibody of the present disclosure can be an engineered antibody fragment linked by short peptide linkers which can be made into bivalent, trivalent, or tetravalent formats addressing two to three targets (e.g., bispecific T-cell engager (BiTE), Nanobody platform, dual- affinity re-targeting (DART) antibodies, “tandem antibody” structures (TandAbs)). An anti-osteopontin antibody of the present disclosure can be comprised of chemically coupled IgGs.

[0146] In some embodiments, an anti-osteopontin antibody of the present disclosure is a multispecific antibody, such as a bispecific antibody, which have binding specificities for at least two different antigens. In some embodiments, the anti-osteopontin antibodies of the present disclosure, or antigen binding fragments thereof, can be used to form one arm (e.g., antigen binding portion) of a bispecific antibody, whereas the other arm of the bispecific antibody can be specific for a different antigen.

[0147] Anti-osteopontin antibodies also find use in therapeutic and diagnostic (e.g., in vivo imaging, etc.) applications. For example, such an antibody may be conjugated to a payload, such as a therapeutic agent (e.g., a cytotoxic payload) or labeling agent (e.g., an in vivo imaging agent), where upon binding of the antibody to osteopontin or a thrombin cleavage fragment thereof, the therapeutic or labeling agent is delivered selectively to a target cell having elevated levels of osteopontin or thrombin cleavage fragments thereof (e.g., cancerous cell overexpressing osteopontin). The selective targeting of the therapeutic or imaging agent to cells overexpressing osteopontin reduces unwanted exposure of non-target cells to the therapeutic agent, and can reduce toxicity upon administration. Moreover, in imaging applications (e.g.. in vivo imaging for diagnostic, prognostic, and / or any other purpose), selective binding of the antibody to cells overexpressing osteopontin concentrates the imaging agent in such cells, thereby increasing the signal-to-noise ratio and diagnostic / prognostic value of the resulting images.STDU244218.601(S23-351)

[0148] Accordingly, any anti-osteopontin antibody described herein may be in unconjugated form, or may be conjugated directly to an agent, such as a therapeutic and / or imaging (e.g., diagnostic) agent, or may be conjugated indirectly to carrier polymers comprising such other therapeutic or imaging agents.

[0149] In some embodiments, the antibody is conjugated to a cytotoxic agent such as a chemotherapeutic agent, a drug, a growth inhibitory agent, a toxin (e.g., an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or fragments thereof), or a radioactive isotope (e.g., a radioconjugate). Suitable chemotherapeutic agents include: daunomycin, doxorubicin, methotrexate, and vindesine. Suitable toxins include: bacterial toxins such as diphtheria toxin; plant toxins such as ricin; and small molecule toxins such as geldanamycin, maytansinoids, auristatins and calicheamicin.

[0150] Antibodies can be detectably labeled through the use of radioisotopes, affinity labels (such as biotin, avidin, etc.), enzymatic labels (such as horseradish peroxidase, alkaline phosphatase, etc.) fluorescent or luminescent or bioluminescent labels (such as FITC or rhodamine, etc.), paramagnetic atoms, and the like. Procedures for accomplishing such labeling are known.

[0151] In certain aspects, the imaging agent of an anti-osteopontin antibody conjugate of the present disclosure is an imaging agent that finds use in in vivo imaging, such as near-infrared (NIR) optical imaging, single-photon emission computed tomography (SPECT) / CT imaging, or the like. Labeling agents that find use in such applications include, but are not limited to, fluorescent labels and radioisotopes, or the like. In certain aspects, the labeling agent is a multimodal in vivo imaging agent that permits in vivo imaging using two or more imaging approaches.

[0152] Conjugated antibodies can be prepared by directly conjugating an antibody component with a therapeutic agent or labeling agent. The general procedure is analogous to the indirect method of conjugation except that a therapeutic or labeling agent is directly attached to an oxidized antibody component. For example, a carbohydrate moiety of an antibody can be attached to polyethylene glycol to extend half-life.

[0153] A therapeutic or labeling agent can be attached at the hinge region of a reduced antibody component via disulfide bond formation, or using a heterobifunctional cross-linker, such as N-succinyl 3-(2-pyridyldithio)propionate (SPDP). General techniques for suchSTDU244218.601(S23-351) conjugation are well-known in the art. A variety of bifunctional protein coupling agents are known in the art, such as N-succinimidyl-3- (2-pyridyldithiol) propionate (SPDP), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCL), active esters (such as disuccinimidyl suberate), aldehydes (such as glutaraldehyde), bis-azido compounds (such as bis (p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as toluene 2,6-diisocyanate), and bisactive fluorine compounds (such as l,5-difluoro-2, 4-dinitrobenzene).Polypeptides and Expression Vectors

[0154] Embodiments of the present disclosure also include a polynucleotide encoding any of the anti-osteopontin antibodies of the present disclosure.

[0155] In accordance with these embodiments, the present disclosure includes an expression vector comprising any of the polynucleotides encoding an anti-osteopontin antibody, or antigen binding fragment thereof, of the present disclosure. In some embodiments, the expression vector is suitable for manufacturing an anti-osteopontin antibody, or antigen binding fragment thereof, of the present disclosure for delivery of the antibody to a subject. In certain embodiments, the nucleic acid sequence is in the form of a vector. The vector can be, for example, a plasmid, episome, cosmid, viral vector (e.g., retroviral or adenoviral), or phage. Suitable vectors and methods of vector preparation are well known in the art (see, e.g., Sambrook et al.. Molecular Cloning, a Laboratory’ Manual, 4th edition, Cold Spring Harbor Press, Cold Spring Harbor, N. Y. (2012), and Ausubel et al., Current Protocols in Molecular Biology, Greene Publishing Associates and John Wiley & Sons, New York, N. Y. (1994)).

[0156] In addition to the nucleic acid encoding an anti-osteopontin antibody, or antigen binding fragment thereof, the vector desirably comprises expression control sequences, such as promoters, enhancers, polyadenylation signals, transcription terminators, internal ribosome entry sites (IRES), and the like, that provide for the expression of the antibody-encoding nucleic sequence in a host cell. Exemplary expression control sequences are known in the art and described in, for example, Goeddel, Gene Expression Technology: Methods in Enzymology, Vol.185, Academic Press, San Diego, Calif. (1990).

[0157] A vector comprising a nucleic acid sequence encoding an anti-osteopontin antibody, or antigen binding fragment thereof, may be introduced into a host cell that is capable of expressing the polypeptides encoded thereby, including any suitable prokaryotic or eukaryoticSTDU244218.601(S23-351) cell. Examples of suitable prokaryotic cells include, but are not limited to, cells from the genera Bacillus (such as Bacillus subtilis and Bacillus brevis), Escherichia (such as E. coli), Pseudomonas, Streptomyces, Salmonella, and Erwinia. Particularly useful prokaryotic cells include the various strains of Escherichia coli (e.g., K12, HB101 (ATCC No. 33694), DH5a, DH10, MC1061 (ATCC No. 53338), and CC102). Suitable eukaryotic cells are known in the art and include, for example, yeast cells, insect cells, and mammalian cells. Examples of suitable yeast cells include those from the genera Hansenula, Kluyveromyces, Pichia, Rhinosporidium, Saccharomyces, and Schizosaccharomyces. Suitable insect cells include Sf-9 and HIS cells (Invitrogen, Carlsbad, Calif.) and are described in, for example, Kitts et al., Biotechniques, 14'.810-817 (1993); Lucklow, Curr. Opin. Biotechnol., 4: 564-572 (1993); and Lucklow et al., J. Virol., 67 4566-4579 (1993). Examples of suitable mammalian cells include, but are not limited to, Chinese hamster ovary cells (CHO) (ATCC No. CCL61), CHO DHFR-cells (Urlaub et al., Proc. Natl. Acad. Sci. USA, 97 4216-4220 (1980)), human embryonic kidney (HEK) 293 or 293T cells (ATCC No. CRL1573). and 3T3 cells (ATCC No. CCL92). Other suitable mammalian cell lines are the monkey COS-1 (ATCC No. CRL1650) and COS-7 cell lines (ATCC No. CRL1651), as well as the CV-1 cell line (ATCC No. CCL70). Further exemplary mammalian host cells include primate cell lines and rodent cell lines, including transformed cell lines. Normal diploid cells, cell strains derived from in vitro culture of primary tissue, as well as primary explants also are suitable. Other suitable mammalian cell lines include, but are not limited to, mouse neuroblastoma N2A cells, HeLa, mouse L-929 cells, and BHK or HaK hamster cell lines, all of which are available from the ATCC. Methods for selecting suitable mammalian host cells and methods for transformation, culture, amplification, screening, and purification of such cells are well known in the art (see, e.g., Ausubel et al., eds., Short Protocols in Molecular Biology, 5th ed., John Wiley & Sons, Inc., Hoboken, N. J. (2002)). In some embodiments, the mammalian cell is a human cell.

[0158] In some embodiments, the vector can include means for attaching a detection moiety to an anti-osteopontin antibody, or antigen binding fragment thereof, of the present disclosure. In some embodiments, the vector can include means for attaching a purification moiety to an anti-osteopontin antibody of the present disclosure. Exemplary detection and / or purification moieties / tags that can be coupled to an anti-osteopontin antibody of the present disclosure includes, but is not limited to, hemagglutinin (HA), c-Myc, V5, DYKDDDDK (SEQ ID NO:STDU244218.601(S23-351) 182), His tag (e.g., 6x-His), Glutathione S-Transferase (GST), Maltose Binding Protein (MBP), a fluorophore (e.g., Green Fluorescent Protein (GFP), Red Fluorescent Protein (RFP), mCherry, a chromophore, and / or a luminescent peptide (e.g., luciferase).

[0159] In some embodiments, the expression vector is suitable for use in gene therapy (e.g., an expression vector for delivering a polynucleotide encoding an anti-osteopontin antibody of the present disclosure to a subject). In some embodiments, the expression vector is a herpes simplex virus (HSV) vector, or a retrovirus vector. In some embodiments, the expression vector is an adeno-associated virus (AAV) vector or comprises an AAV backbone. For example.AAV vectors have been designed, produced, and used to mediate gene delivery in human subjects, including for therapeutic purposes. Typically, AAV vectors for use in gene transfer comprise a replication defective AAV genome lacking functional Rep and Cap coding viral sequences. In some embodiments, such replication defective AAV vectors lack most or all of the Rep and Cap coding sequences and essentially retain one or two AAV ITR sequences and a packaging sequence. The defective genome is packaged in a viral particle, to form a defective, recombined AAV virus, also termed “AAV vector.” Methods of producing suchAAV vectors have been disclosed in the literature, including using packaging cells, auxiliary viruses, or plasmids, and / or baculovirus. Methods of producing pseudotyped AAV vectors have also been reported (e.g., WO00 / 28004), as well as various modifications or formulations of AAV vectors, to reduce their immunogenicity upon in vivo administration (see e.g., W001 / 23001; WOOO / 73316; WO04 / 112727; W005 / 005610; WO99 / 06562). AAV vectors may be prepared or derived from various serotypes of AAVs, which may be even mixed together or with other types of viruses to produce chimeric (e.g., pseudotyped) AAV viruses. Examples of tAAVs are human AAV4 vectors, human AAV7 vectors, human AAV9 vectors, human AAV 10 vectors, or bovine AAV vectors. The AAV vector may be derived from a single AAV serotype or comprise sequences or components originating from at least two distinct AAV serotypes (pseudotyped AAV vector), e.g., an AAV vector comprising an AAV genome derived from one AAV serotype (for example AAV9), and a capsid derived at least in part from a distinct AAV serotype. An AAV vector, as used herein, is a vector which comprises at least one component part derivable from an adeno-associated virus. Preferably, that component part is involved in the biological mechanisms by which the vector infects or transduces target cells and expresses an anti-osteopontin antibody of the present disclosure.STDU244218.601(S23-351)

[0160] In other embodiments, the expression vector is a lentiviral vector (LV) or comprises an LV backbone. Lentiviruses are part of a larger group of retroviruses. A detailed list of lentiviruses may be found in Coffin et al (1997) “Retroviruses” Cold Spring Harbour Laboratory Press Eds: JM Coffin, SM Hughes, HE Varmus pp 758-763). For example, lentiviruses can be divided into primate and non-primate groups. Examples of primate lentiviruses include but are not limited to: the human immunodeficiency virus (HIV), the causative agent of human auto immunodeficiency syndrome (AIDS), and the simian immunodeficiency virus (SIV). The non-primate lentiviral group includes the prototype “slow virus” visna / maedi virus (VMV), as well as the related caprine arthritis-encephalitis virus (CAEV), equine infectious anaemia virus (EIAV), feline immunodeficiency virus (FIV), Maedi visna virus (MW) and bovine immunodeficiency virus (BIV). In one embodiment, the lentiviral vector is derived from HIV- 1, HIV-2, SIV, FIV, BIV, EIAV, CAEV or Visna lentivirus. The lentivirus family differs from retroviruses in that lentiviruses have the capability to infect both dividing and non-dividing cells. In contrast, other retroviruses, such as MLV, are unable to infect non-dividing or slowly dividing cells such as those that make up, for example, muscle, brain, lung, and liver tissue. A lentiviral vector, as used herein, is a vector which comprises at least one component part derivable from a lentivirus. Preferably, that component part is involved in the biological mechanisms by which the vector infects or transduces target cells and expresses an anti-osteopontin antibody of the present disclosure.Compositions and Methods of Treatment

[0161] The anti-osteopontin antibodies, or antigen binding fragments thereof, of the present disclosure can be administered as part of a pharmaceutical composition in a therapeutically effective amount to treat osteopontin related diseases and disorders. In accordance with these embodiments, the methods include administering a pharmaceutical composition comprising a therapeutically effective amount of an anti-osteopontin antibody, or antigen binding fragment thereof, of the present disclosure.

[0162] The osteopontin related diseases and disorder include, but are not limited to, inflammation, cardiac hypertrophy, myocardial fibrosis, and cancers over expressing osteopontin, such as melanoma, glioblastoma, ovarian cancer, breast cancer, and lung cancer. In certain embodiments, the osteopontin-associated disorder is a cancer that overexpresses osteopontin. For example, cancers overexpressing osteopontin include, without limitation,STDU244218.601(S23-351) melanoma, glioblastoma, ovarian cancer, breast cancer, and lung cancer. In certain embodiments, the osteopontin-associated disorder is melanoma.

[0163] Therapeutic or prophylactic efficacy can be monitored by periodic assessment of treated patients. For repeated administrations over several days or longer, depending on the condition, the treatment is repeated until a desired suppression of disease symptoms occurs. However, other dosage regimens may be useful and are within the scope of the present disclosure. The desired dosage can be delivered by a single bolus administration of the composition, by multiple bolus administrations of the composition, or by continuous infusion administration of the composition. The composition comprising an anti-osteopontin antibody, or antigen binding fragment thereof, can be administered to a mammal using standard administration techniques, including ocular, oral, intravenous, intraperitoneal, subcutaneous, pulmonary, transdermal, intramuscular, intranasal, buccal, sublingual, or suppository administration.

[0164] In accordance with the compositions and methods of treatment described herein, embodiments of the present disclosure include anti-osteopontin antibodies that have enhanced half-life (e.g., after administration), such that the anti-osteopontin antibody can be administered less often to a subject. In some embodiments, the antibody comprises a half-life extension moiety. In some embodiments, the half-life extension moiety comprises a polypeptide that can be coupled to an anti-osteopontin antibody of the present disclosure by any means known in the art.

[0165] The present disclosure also provides a composition comprising any of the anti-osteopontin antibodies or antigen binding fragments thereof described herein. The composition desirably is a pharmaceutically acceptable (e.g.. physiologically acceptable) composition, which comprises a carrier, preferably a pharmaceutically acceptable (e.g., physiologically acceptable) carrier, and the anti-osteopontin antibody or antigen binding fragment thereof. Any suitable carrier can be used within the context of the present disclosure, and such carriers are well known in the art. For example, the composition may contain preservatives, such as, for example, methylparaben, propylparaben, sodium benzoate, and benzalkonium chloride. A mixture of two or more preservatives optionally may be used. In addition, buffering agents may be included in the composition. Suitable buffering agents include, for example, citric acid, sodium citrate, phosphoric acid, potassium phosphate, and various other acids and salts. A mixture of two or more buffering agents optionally may be used. Methods for preparing compositions forSTDU244218.601(S23-351) pharmaceutical use are known to those skilled in the art and are described in, for example, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins; 21st ed. (May 1, 2005).

[0166] Once administered to a mammal (e.g., a human), the biological activity of the anti-osteopontin antibody, or antigen binding fragment thereof, can be measured by any suitable method known in the art. For example, the biological activity can be assessed by determining the stability of the anti-osteopontin antibody. Antibody stability (e.g., aggregation, susceptibility to proteases, etc.) can be measured using any art-recognized assay. The biological activity of the anti-osteopontin antibody also can be assessed by determining its binding affinity to osteopontin fragments and / or by assessing its binding affinity to peptides with which it may cross-react. The term “affinity” refers to the equilibrium constant for the reversible binding of two agents and is expressed as the dissociation constant (KD). Affinity of a binding agent to a ligand, such as affinity of an antibody for an epitope, can be, for example, from about 1 femtomolar (fM) to about 1 millimolar (mM) (e.g., from about 1 picomolar (pM) to about 1 nanomolar (nM), or from about 1 nM to about 1 micromolar (pM)). Antibody affinity for an antigen or epitope of interest can be measured using any art-recognized assay. Such methods include, for example, fluorescence activated cell sorting (FACS), separable beads (e.g., magnetic beads), antigen panning, and / or ELISA (see, e.g., Janeway et al. (eds.), Immunobiology, 5th ed., Garland Publishing, New York, N. Y., 2001).

[0167] In some embodiments, an anti-osteopontin antibody, or composition comprising an anti-osteopontin antibody, may be administered alone or in combination with other drugs. For example, the anti-osteopontin antibody can be administered in combination with other agents for the treatment or prevention of associated with overexpression of osteopontin, as disclosed herein. For example, anti-osteopontin antibodies of the present disclosure, or antibody conjugates, fusion proteins, or polymeric formulations thereof, can be used either alone or in combination with other agents in a therapy. For instance, an anti-osteopontin antibody may be co-administered with at least one additional therapeutic agent. In certain embodiments, an additional therapeutic agent is another antibody, a chemotherapeutic agent, a cytotoxic agent, an anti-angiogenic agent, an immunosuppressive agent, a prodrug, a cytokine, a cytokine antagonist, cytotoxic radiotherapy, a corticosteroid, an anti-emetic, a cancer vaccine, an analgesic, a growth-inhibitory agent, or combinations thereof.STDU244218.601(S23-351)

[0168] In certain embodiments, the additional therapeutic agent comprises an anti-cancer therapeutic agent including, but not limited to, a chemotherapeutic agent, an immunotherapeutic agent, a biologic therapeutic agent, a pro-apoptotic agent, an angiogenesis inhibitor, a photoactive agent, a radiosensitizing agent, and a radioisotope, or a combination thereof.

[0169] In certain embodiments, the additional therapeutic agent further comprises a B-Raf inhibitor, a MEK inhibitor, or a combination thereof. Exemplary B-Raf inhibitors include, without limitation, dabrafenib, vemurafenib, sorafenib, LGX818, GDC-0879, and PLX-4720. Exemplary MEK inhibitors include, without limitation, trametinib, cobimetinib, binimetinib, selumetinib, and PD- 325901.

[0170] For example, in certain embodiments, any of the preceding methods further comprises administering one or more additional compounds. In certain embodiments, the anti-osteopontin antibody, antibody conjugate, fusion protein, or polymeric formulation is administered simultaneously with the additional compound(s). In certain embodiments, the anti-osteopontin antibody, antibody conjugate, fusion protein, or polymeric formulation is administered before or after the additional compound(s). In some embodiments, the additional compound is an antibody or antigen binding fragment thereof.

[0171] In addition to therapeutic uses, an anti-osteopontin antibody or antigen binding fragment, described herein can be used in diagnostic or research applications. Research applications include, for example, methods that utilize the anti-osteopontin antibody and a label to detect osteopontin, or cleavage fragments thereof, in a sample, e.g., in a human body fluid or in a cell or tissue extract. The anti-osteopontin antibody, or antigen binding fragment thereof, may be employed in any suitable assay for measuring osteopontin, or cleavage fragments thereof, in a sample for diagnostic and / or research purposes. Such assays include, but are not limited to, sandwich immunoassays, enzyme immunoassays (EIA), enzyme-linked immunosorbent assays (ELISA), lateral flow assays, competitive inhibition immunoassays (e.g., forward and reverse), competitive binding assays, Forster resonance energy transfer (FRET), one-step antibody detection assays, single molecule detection assays, radioimmunoassays (RIA), and FACS. Such methods are disclosed in, for example, U. S. Patents 6,143,576; 6,113,855; 6,019,944; 5,985,579; 5,947,124; 5,939,272; 5,922,615; 5,885,527; 5,851,776; 5,824,799;5,679,526; 5.525,524; and 5,480,792; and Adamczyk et al., Anal. Chim. Acta, 579(1): 61-67 (2006).STDU244218.601(S23-351)

[0172] The anti-osteopontin antibody, or antigen binding fragment thereof, can be provided in a kit, e.g., a packaged combination of reagents in predetermined amounts with instructions for performing an assay using the antibody (e.g., an assay that detects osteopontin, or cleavage fragments thereof). As such, the disclosure provides a kit comprising the antibody or antigen binding fragment described herein and instructions for use thereof. The instructions can be in paper form or computer-readable form, such as a disk, CD, DVD, etc. Alternatively or additionally, the kit can comprise a calibrator or control, and / or at least one container (e.g., tube, microtiter plates, or strips) for conducting an assay, and / or a buffer, such as an assay buffer or a wash buffer. Ideally, the kit comprises all components, e.g., reagents, standards, buffers, diluents, etc., which are necessary to perform the assay. Other additives may be included in the kit, such as stabilizers, buffers (e.g., a blocking buffer or lysis buffer), and the like. The relative amounts of the various reagents can be varied to provide for concentrations in solution of the reagents which substantially optimize the sensitivity of the assay. The reagents may be provided as dry powders (typically lyophilized), including excipients which on dissolution will provide a reagent solution having the appropriate concentration.

[0173] The following examples further illustrate the various embodiments of the present disclosure but should not be construed as in any way limiting its scope.Examples

[0174] It will be readily apparent to those skilled in the art that other suitable modifications and adaptations of the methods of the present disclosure described herein are readily applicable and appreciable, and may be made using suitable equivalents without departing from the scope of the present disclosure or the aspects and embodiments disclosed herein. Having now described the present disclosure in detail, the same will be more clearly understood by reference to the following examples, which are merely intended only to illustrate some aspects and embodiments of the disclosure, and should not be viewed as limiting to the scope of the disclosure. The disclosures of all journal references, U. S. patents, and publications referred to herein are hereby incorporated by reference in their entireties.

[0175] The present disclosure has multiple aspects, illustrated by the following non-limiting examples.STDU244218.601(S23-351) EXAMPLE 1

[0176] This example describes binding characterization of the anti-osteopontin antibodies. KD values for binding affinity of the antibody clones to full length osteopontin (OPN) and the N-terminal osteopontin fragment (OPN-R) can be determined by either the Surface Plasma Resonance (SPR using the Biacore) or Biolayer Interferometry (BLI using the ForteBio). For direct ELISA, OPNs were coated onto 96 well plate, blocked then followed by serial dilutions of clone mAB. After washing, bound antibodies were quantitated using an HRP-linked antibody using standard methods. ECsos were determined by using a 4-parameter logistic (4PL) curve fit.Table 1. Antibody SequencesAntibody OPN SEQ Descriptor SequenceName Binding ID NO Humanized anti- VH (CDRs EVOLVESGGGLVOPGGSLRLSCAASGFTFSSYDMGWVR 1 A6 OPN-FL underlined) OAPGKGLEWVSAIGSDGSEYYADSVKGRFTISRDNSKN TLYLQMNSLRAEDTAVYYCAKDSHYSYGYDYDIWGOG TLVTVSS HCDR1 SSYDMG 2 HCDR2 AIGSDGSEYY 3 HCDR3 DSHYSYGYDYDI 4 Humanized anti- VH (CDRs EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYDMGWVR 5 A6 OPN-FL underlined) QAPGKGLEWVSAIGSDGSEYYVSWARGRFTISRDNSKN TLYLOMNSLRAEDTAVYYCAKDSHYSYGYDYDIWGOG TLVTVSS HCDR1 SYDMG 6 HCDR2 AIGSDGSEYYVSWARG 7 HCDR3 DSHYSYGYDYDI 4 Humanized anti- VH (CDRs EVQLVESGGGLVQPGGSLRLSCAASGFTVSSYDMGWVR 8 A6 OPN-FL underlined) OAPGKGLESIGAIGSDGSEYYVSWARGRFTISRDNSKNT LYLQMNSLRAEDTAVYYCARDSHYSYGYDYDIWGQGT LVTVSS HCDR1 FTVSSYDMG 9 HCDR2 SIGAIGSDGSEYYVSWARG 10 HCDR3 RDSHYSYGYDYDI 11 Humanized anti- VL (CDRs DIOMTOSPSSLSASVGDRVTITCOSSOSIYSNYLSWYOO 12 A6 OPN-FL underlined) KPGKVPKLLIYYASTLAS G VPSRFS GS GS GTDFTLTIS SL QPEDVATYYCQGTYYVTGWYDAFGGGTKVEIKG LCDR1 QSSQSIYSNYLS 13 LCDR2 LLIYYASTLA 14 LCDR3 QGTYYVTGWYDA 15 C6R anti- VH (CDRs QSVKESEGGLFKPTDTLTLTCTVSGFSLSSYDMSWVROA 16 OPN-R underlined) PGKGLEWIGFINIYGTAYYASWAKSRSTITRNTNLNTVT LKMTSLTAADTATYFCVRSVPGYSTDTGNIWGPGTLVT VSSSTDU244218.601(S23-351) HCDR1 GFSLSSYDMS 17 SYDMS 62 HCDR2 FINIYGTAYYASWAKS 18 WIGFINIYGTAYYASWAKS 125 HCDR3 VRSVPGYSTDTGNI 19 SVPGYSTDTGNI 126 C6R anti- VL (CDRs IVMTQTPSSKSVPVGDTVTINCQASESVYNNNYLAWFQ 20 OPN-R underlined) QKPGQPPKLLIYEASKLASGVPSRFKGSGSGTQFTLTISG VQCDDAATYYCAGYKGSGSDVTAFGGGTEVVVKGDP LCDR1 QASESVYNNNYLA 21 QASESVYNNNYLAWF 127 LCDR2 EASKLAS 22 LLIYEASKLAS 128 LCDR3 AGYKGSGSDVTA 23 A6R anti- VH (CDRs OSVEESRGGLIKPTDTLTLTCTVSGFSLSSYDMSWVRQA 24 OPN-R underlined) PGKELEWIGFINIYGGTYYASWAKSRSTITRNTNLNTVT LKMTSLTAADTATYFCVRGVPGYTTVSGIWGPGTLVTV SS HCDR1 GFSLSSYDMS 17 SYDMS 62 HCDR2 FINIYGGTYYASWAKS 25 WIGFINIYGGTYYASWAKS 129 HCDR3 VRGVPGYTTVSGI 26 GVPGYTTVSGI 130 A6R anti- VL (CDRs IVMTOTPSSKSVPVGDTVTINCOASESVADNNNLAWYO 27 OPN-R underlined) QKPGQPPKILI YLASTLAS G VPS RFKGS GS GTQFTLTISD V VCDDAATYYCAGYKSSSVDATAFGGGTEVVVEGDP LCDR1 QASESVADNNNLA 28 QASESVADNNNLAWY 131 LCDR2 LASTLAS 29 ILIYLASTLAS 132 LCDR3 AGYKSSSVDATA 30 D2R anti- VH (CDRs QSVKESEGGLFKPTATLTLTCTVSGFSLSTYDMSWVRQ 31 OPN-R underlined) APGNGLEWIGLINIYGNPYYASWAKSRSTITRNTNLNTV TLKMTSLTAADTATYFCVRGVPGYSTVSGIWGPGTLVT VSS HCDR1 GFSLSTYDMS 32 TYDMS 123 HCDR2 LINIYGNPYYASWAKS 33 WIGLINIYGNPYYASWAKS 133 HCDR3 VRGVPGYSTVSGI 34 GVPGYSTVSGI 134 D2R anti- VL (CDRs IVMTQTPSSKSVPVGDTVTINCQASESVTSNNYLAWYQ 35 OPN-R underlined) QKPGOPPKLLMYSASTLASGVPSRFKGSGSGTOFTLTIS DVVCDDAATYYCAGYKKTTTDATSFGGGTEVVVKGDP LCDR1 QASESVTSNNYLA 36 QASESVTSNNYLAW 135 LCDR2 SASTLAS 37 MYSASTLAS 136 LCDR3 AGYKKTTTDATS 38 E5R anti- VH (CDRs QSVKESEGGLFKPTDTLRLSCKVSGFSLSSYDMSWVRQ 39OPN-R underlined) APGKGLEWIGFINIFGDTYYASWAKSRSTISRNTNLSTVTSTDU244218.601(S23-351) LKMTSLTAADTATYFCVRSVPGYSTDTGNIWGPGTLVTvssHCDR1 GFSLSSYDMS 17 SYDMS 62 HCDR2 FINIFGDTYYASWAKS 40 WIGFINIFGDTYYASWAKS 137 HCDR3 VRSVPGYSTDTGNI 19 SVPGYSTDTGNI 126 E5R anti- VL (CDRs IVMTQTPSSKSVPVGDTVTINCQASESVYNNNYLAWFQ 41 OPN-R underlined) QKPGQPPNLLIYEASKLASGVPSRFKGSGSGTQFTLTISG VQCDDAATYYCAGYKGSGSDVTAFGGGTEVVVKGDP LCDR1 QASESVYNNNYLA 21 QASESVYNNNYLAWF 127 LCDR2 EASKLAS 22 LLIYEASKLAS 128 LCDR3 AGYKGSGSDVTA 23 B4R anti- VH (CDRs QSVKESEGGLFKPTATLTLTCTVSGFSLSIYDMSWVRQA 42 OPN-R underlined) PGNGLEWIGFINIYGNPYYASWAKSRSTITRNTNLNTVT LKMTSLTAADTATYFCVRGVPGYSTVSGIWGPGTLVTV SS HCDR1 GFSLSIYDMS 43 IYDMS 124 HCDR2 FINIYGNPYYASWAKS 44 WIGFINIYGNPYYASWAKS 138 HCDR3 VRGVPGYSTVSGI 34 GVPGYSTVSGI 134 B4R anti- VL (CDRs IVMTQTPSSKSVPVGDTVTINCQSSESVYNNNYLAWHQ 45 OPN-R underlined) QKPGQPPKLLIYSASTLASGVPSRFKGSGSGTQFTLTISG VQCEDAATYYCAGYKDSTTDATSFGGGTEVVVKGDP LCDR1 QSSESVYNNNYLA 46 QSSESVYNNNYLAWH 139 LCDR2 SASTLAS 37 LLIYSASTLAS 140 LCDR3 AGYKDSTTDATS 47 A2 anti- VH (DNA) ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTG 48 OPN-R TGCTCAAAGGTGTCCAGTGTCAGTCGGTGAAGGAGTC CGAGGGAGGTCTCTTCAAGCCAACGGATACCCTGACA CTCACCTGCACAGTCTCTGGATTCTCCCTCAGTAGCTA TGTAATAAGTTGGGTCCGCCAGGCTCCAGGGAAGGGG CTGGAATGGATCGGAGCCATTGATAGTGATGGTAGTA GCTACTACGCGAGCTGGGCGAAAAGCCGATCCACCAT CACCAGAAACACCAACGAGAACACGGTGACTCTGAA AATGACCAGTCTGACAGCCGCGGACACGGCCACCTAT TTCTGTGCGAGAGGATGGCCTGGTGGTATTAGTGCTA AGGGGGACATCTGGGGCCCAGGCACCCTGGTCACCGT CTCCTCAGGGCAACCTAAGGCTCCATCAGTCTTCCCA CTGGCCCCCTGCTGCGGGGACACACCCAGCTCCACGG TCACCCTGGGTTGTCTTGTGAAGGGATACCTCCCGGA ACCCGTGACCGTGACCTGGAACTCCGGCACCCTGACC AATGGAGTGCGGACCTTCCCGAGCGTCAGGCAGTCCT CCGGGTTGTACAGCTTGTCTAGCGTGGTGTCCGTGAC GTCGTCAAGCCAGCCTGTGACTTGCAATGTGGCCCATCCGGCCACCAACACCAAGGTCGACAAGACCGTGGCGSTDU244218.601(S23-351) CCTTCCACCTGTTCCAAGCCCACTTGCCCGCCGCCTGA GCTCCTGGGAGGACCGTCCGTGTTCATCTTCCCTCCAA AACCCAAGGATACCCTGATGATTAGCCGCACTCCCGA AGTCACTTGCGTGGTCGTGGACGTGTCGCAGGACGAT CCTGAGGTGCAGTTCACTTGGTACATCAACAACGAAC AAGTCCGGACAGCTAGACCACCGCTGCGCGAGCAGC AGTTCAACTCAACTATCCGGGTGGTGTCCACCCTGCC GATCGCGCATCAGGATTGGCTGCGGGGGAAGGAGTTC AAGTGCAAAGTCCACAACAAGGCCCTGCCCGCCCCCA TCGAAAAGACCATCTCCAAGGCTCGGGGCCAGCCTCT GGAGCCCAAAGTGTACACCATGGGCCCGCCTCGCGAG GAGCTCTCCTCACGCTCGGTGTCGCTGACTTGCATGAT TAACGGCTTCTACCCTTCCGACATCTCCGTGGAATGG GAGAAGAACGGAAAAGCCGAAGATAACTACAAGACC ACGCCCGCCGTGCTGGACTCCGACGGAAGCTATTTCC TGTACTCCAAGCTCTCCGTCCCCACTTCGGAATGGCA GAGGGGGGACGTGTTCACTTGCTCCGTGATGCACGAG GCACTCCACAACCACTACACCCAAAAGAGCATTTCGC GGTCACCTGGCAAGTAA VH (amino METGLRWLLLVAVLKGVQCQSVKESEGGLFKPTDTLTL 49 acid) TCTVSGFSLSSYVISWVRQAPGKGLEWIGAIDSDGSSYY ASWAKSRSTITRNTNENTVTLKMTSLTAADTATYFCAR GWPGGISAKGDIWGPGTLVTVSSGQPKAPSVFPLAPCCG DTPSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPS VRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKT VAPSTCSKPTCPPPELLGGPSVFIFPPKPKDTLMISRTPEV TCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFN STIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPIEKTIS KARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDI SVEWEKNGKAEDNYKTTPAVLDSDGSYFLYSKLSVPTS EWQRGDVFTCSVMHEALHNHYTQKSISRSPGK VL (DNA) ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCC 50 TGCTGCTCTGGCTCCCAGGTGCCACATTTGCGCAAGT GCTGACCCAGACTCCAGCCTCCGTGTCTGCGGCTGTT GGAGGCACAGTCACCATCAACTGCCAGTCCAGTCAGA GTGTTTATAAGAACAACTTCTTATCCTGGTTTCAGCAG AAACCAGGGCAGCCTCCCAAGCTCCTGATCTATGGTG CATCCACTCTGGAATCTGGGGTCCCATCGCGGTTCAA AGGCAGTGGATCTGGGTCCCGGTTCACTCTCACCATT AGTGACCTGGAGTGTGACGATGCTGCCACTTATTATT GTGCAGGCGGTTATAGTAGTGATTTCAATGCTTTCGG CGGAGGGACCGAGGTGGTGGTCAAAGGTGATCCAGT TGCACCTACTGTCCTCATCTTCCCACCAGCTGCTGATC AGGTGGCAACTGGAACAGTCACCATCGTGTGCGTGGC TAACAAGTACTTCCCGGACGTGACCGTGACCTGGGAA GTCGACGGAACCACTCAGACCACTGGTATCGAGAACA GCAAGACGCCCCAGAACTCCGCCGATTGTACTTATAA CCTGTCCTCCACACTGACCCTCACCTCGACCCAGTAC AATTCCCACAAGGAGTACACTTGCAAAGTCACCCAGG GAACCACTTCAGTGGTGCAGAGCTTCAACCGGGGGGA TTGCTGA VL (amino MDTRAPTQLLGLLLLWLPGATFAQVLTQTPASVSAAVG 51 acid) GTVTINCQSSQSVYKNNFLSWFQQKPGQPPKLLIYGAST LESGVPSRFKGSGSGSRFTLTISDLECDDAATYYCAGGY SSDFNAFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSSTDU244218.601(S23-351) ADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSF NRGDC HCDR1 SYVIS 52 GFSLSSYVIS 141 HCDR2 AIDSDGSSYASWAKS 53 WIGAIDSDGSSYYASWAKS 142 HCDR3 WPGGISAKGDI 54 ARGWPGGISAKGDI 143 LCDR1 QSSQSVYKNNFLS 55 QSSQSVYKNNFLSWF 144 LCDR2 GASTLES 56 LLIYGASTLES 145 LCDR3 AGGYSSDFNA 57 B8 anti- VH (DNA) ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTG 58 OPN-R TGCTCAAAGGTGTCCAGTGTCAGTCGGTGAAGGAGTC CGAGGGAGGCCTGGTCAAGCCAACGGATACCCTGAC ACTCACCTGCACAGCCTCTGGATTTACCATCAGTAGC TACGACATGAGCTGGGTCCGCCAGGCTCCAGGGAAG GGGCTGGAGTGGCTCGGAATCATTAGTAGTAGTGGTG GCACAGCCTACGCGAACTGGGCGAAAAGCCGATCCA CCATCACCAGAGACACCAATCTGAATATGGTGACTCT AAAAATGACCAGTCTGACAGCCGCGGACACGGCCATT TATTTCTGTGCGAAAGGCTTAAGTAGTGGTGGTGGTT ATAGTGGTGGGTATTACTTTAACATCTGGGGCCCAGG CACCCTGGTCACCGTCTCCTCAGGGCAACCTAAGGCT CCATCAGTCTTCCCACTGGCCCCCTGCTGCGGGGACA CACCCAGCTCCACGGTCACCCTGGGTTGTCTTGTGAA GGGATACCTCCCGGAACCCGTGACCGTGACCTGGAAC TCCGGCACCCTGACCAATGGAGTGCGGACCTTCCCGA GCGTCAGGCAGTCCTCCGGGTTGTACAGCTTGTCTAG CGTGGTGTCCGTGACGTCGTCAAGCCAGCCTGTGACT TGCAATGTGGCCCATCCGGCCACCAACACCAAGGTCG ACAAGACCGTGGCGCCTTCCACCTGTTCCAAGCCCAC TTGCCCGCCGCCTGAGCTCCTGGGAGGACCGTCCGTG TTCATCTTCCCTCCAAAACCCAAGGATACCCTGATGA TTAGCCGCACTCCCGAAGTCACTTGCGTGGTCGTGGA CGTGTCGCAGGACGATCCTGAGGTGCAGTTCACTTGG TACATCAACAACGAACAAGTCCGGACAGCTAGACCA CCGCTGCGCGAGCAGCAGTTCAACTCAACTATCCGGG TGGTGTCCACCCTGCCGATCGCGCATCAGGATTGGCT GCGGGGGAAGGAGTTCAAGTGCAAAGTCCACAACAA GGCCCTGCCCGCCCCCATCGAAAAGACCATCTCCAAG GCTCGGGGCCAGCCTCTGGAGCCCAAAGTGTACACCA TGGGCCCGCCTCGCGAGGAGCTCTCCTCACGCTCGGT GTCGCTGACTTGCATGATTAACGGCTTCTACCCTTCCG ACATCTCCGTGGAATGGGAGAAGAACGGAAAAGCCG AAGATAACTACAAGACCACGCCCGCCGTGCTGGACTC CGACGGAAGCTATTTCCTGTACTCCAAGCTCTCCGTCC CCACTTCGGAATGGCAGAGGGGGGACGTGTTCACTTG CTCCGTGATGCACGAGGCACTCCACAACCACTACACC CAAAAGAGCATTTCGCGGTCACCTGGCAAGTAA VH (amino METGLRWLLLVAVLKGVQCQSVKESEGGLVKPTDTLTL 59 acid) TCTASGFTISSYDMSWVRQAPGKGLEWLGTISSSGGTAYANWAKSRSTITRDTNLNMVTLKMTSLTAADTAIYFCAKGLSSGGGYSGGYYFNIWGPGTLVTVSSGQPKAPSVFPLASTDU244218.601(S23-351) PCCGDTPSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGV RTFPS VRQS S GL YSLS S V VS VTS S S QP VTCN V AHP ATNT KVDKTVAPSTCSKPTCPPPELLGGPSVFIFPPKPKDTLMIS RTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLR EQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAP IEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMING FYPSDISVEWEKNGKAEDNYKTTPAVLDSDGSYFLYSK LSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK VL (DNA) ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCC 60 TGCTGCTCTGGCTCCCAGGTGCCAGATGTGCCAACAT CGTGATGACCCAGACTCCATCCCCCGTGTCTGGAGCT GTGGGAGGCACAGTCACCATCAATTGCCAGGCCAGTC AGAGCATTAGCGATGAATTAGCCTGGTATCAGCAGAA ACCAGGGCAGCCTCCCAAGCTCCTGATCTATCTGGCA TCCAATCTGGAATCTGGGGTCCCATCGCGGTTCAAAG GCAGTGGATCTGGGACACAGTTCACTCTCACCATCAG CGACCTGGAGTGTGACGATGCTGCCACTTACTACTGT CAACAGGGTAATACTGTGATTAATGTTGATAATTCTTT CGGCGGAGGGACCGAGGTGGTGGTCAAAGGTGATCC AGTTGCACCTACTGTCCTCATCTTCCCACCAGCTGCTG ATCAGGTGGCAACTGGAACAGTCACCATCGTGTGCGT GGCTAACAAGTACTTCCCGGACGTGACCGTGACCTGG GAAGTCGACGGAACCACTCAGACCACTGGTATCGAG AACAGCAAGACGCCCCAGAACTCCGCCGATTGTACTT ATAACCTGTCCTCCACACTGACCCTCACCTCGACCCA GTACAATTCCCACAAGGAGTACACTTGCAAAGTCACC CAGGGAACCACTTCAGTGGTGCAGAGCTTCAACCGGG GGGATTGCTGA VL (amino MDTRAPTQLLGLLLLWLPGARCANIVMTQTPSPVSGAV 61 acid) GGTVTINCQASQSISDELAWYQQKPGQPPKLLIYLASNL ESGVPSRFKGSGSGTQFTLTISDLECDDAATYYCQQGNT VINVDNSFGGGTEVVVKGDPVAPTVLIFPPAADQVATGT VTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNS ADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSF NRGDC HCDR1 SYDMS 62 GFTISSYDMS 146 HCDR2 IISSSGGTAYANWAKS 63 WLGILSSSGGTAYANWAKS 147 HCDR3 GLSSGGGYSGGYYFNI 64 AKGLSSGGGYSGGYYFNI 148 LCDR1 QASQSISDELA 65 QASQSISDELAWY 149 LCDR2 LASNLES 66 LLIYLASNLES 150 LCDR3 QQQGNTVINVDNS 67 anti- VH (DNA) ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTG 68 OPN-R TGCTCAAAGGTGTCCGGTGTCAGTCGGTGAAGGAGTC CGAGGGAGGTCTCTTCAAGCCAACGGATACCCTGACA CTCACCTGCACAGCCGCTGGATTCTCCCTCAGCAGAT ACGACATGAGCTGGGTCCGCCAGGCTCCAGGGAACG GGCTGGAATGGATCGGAGCCGTTGGTACGAGCGGCA ACACATACTACGCGAGCTGGGCGAAAAGCCGATCCA CCATCACCAGAAACACCAACGAGAACACGGTGACTCTGAAAATGACCAGTCTGACAGCCGCGGACACGGCCACSTDU244218.601(S23-351) CTATTTCTGTGCGAGAGAGTATCCTGGTCATAGTCCTG GAACTAGCATCTGGGGCCCAGGCACCCTGGTCACCGT CTCCTCAGGGCAACCTAAGGCTCCATCAGTCTTCCCA CTGGCCCCCTGCTGCGGGGACACACCCAGCTCCACGG TCACCCTGGGTTGTCTTGTGAAGGGATACCTCCCGGA ACCCGTGACCGTGACCTGGAACTCCGGCACCCTGACC AATGGAGTGCGGACCTTCCCGAGCGTCAGGCAGTCCT CCGGGTTGTACAGCTTGTCTAGCGTGGTGTCCGTGAC GTCGTCAAGCCAGCCTGTGACTTGCAATGTGGCCCAT CCGGCCACCAACACCAAGGTCGACAAGACCGTGGCG CCTTCCACCTGTTCCAAGCCCACTTGCCCGCCGCCTGA GCTCCTGGGAGGACCGTCCGTGTTCATCTTCCCTCCAA AACCCAAGGATACCCTGATGATTAGCCGCACTCCCGA AGTCACTTGCGTGGTCGTGGACGTGTCGCAGGACGAT CCTGAGGTGCAGTTCACTTGGTACATCAACAACGAAC AAGTCCGGACAGCTAGACCACCGCTGCGCGAGCAGC AGTTCAACTCAACTATCCGGGTGGTGTCCACCCTGCC GATCGCGCATCAGGATTGGCTGCGGGGGAAGGAGTTC AAGTGCAAAGTCCACAACAAGGCCCTGCCCGCCCCCA TCGAAAAGACCATCTCCAAGGCTCGGGGCCAGCCTCT GGAGCCCAAAGTGTACACCATGGGCCCGCCTCGCGAG GAGCTCTCCTCACGCTCGGTGTCGCTGACTTGCATGAT TAACGGCTTCTACCCTTCCGACATCTCCGTGGAATGG GAGAAGAACGGAAAAGCCGAAGATAACTACAAGACC ACGCCCGCCGTGCTGGACTCCGACGGAAGCTATTTCC TGTACTCCAAGCTCTCCGTCCCCACTTCGGAATGGCA GAGGGGGGACGTGTTCACTTGCTCCGTGATGCACGAG GCACTCCACAACCACTACACCCAAAAGAGCATTTCGC GGTCACCTGGCAAGTAA VH (amino METGLRWLLLVAVLKGVRCQSVKESEGGLFKPTDTLTL 69 acid) TCTAAGFSLSRYDMSWVRQAPGNGLEWIGAVGTSGNT YYASWAKSRSTITRNTNENTVTLKMTSLTAADTATYFC AREYPGHSPGTSIWGPGTLVTVSSGQPKAPSVFPLAPCC GDTPSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFP SVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDK TVAPSTCSKPTCPPPELLGGPSVFIFPPKPKDTLMISRTPE VTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQF NSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPIEKTI SKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPS DISVEWEKNGKAEDNYKTTPAVLDSDGSYFLYSKLSVP TSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK VL (DNA) ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCC 70 TGCTGCTCTGGCTCCCAGGTGCAACATTTGCTCAAGT GCTGACCCAGACTCCATCCCTCGTGTCTGCAGCTGTG GGAGGCACAGTCACCATCAGTTGCCAGTCCAGTCAGA GTGTTTATAGTAACAACTGGTTAGCCTGGTATCAGAA GAAACCAGGGCAGCCTCCCAAGCTCCTCATCTATCTG GCATCCAAACTGGCATCTGGGGTCCCATCGCGGTTCA GCGGCAGTGGATCTGGGACACAGTTCACTCTCACCAT CAGCGACCTGGAGTGTGACGATGCTGCCACTTACTAC TGTGCAGGCGGTTATACTGATACTGCTACTTTCGGCG GAGGGACCGAGGTGGTCGTCAAAGGTGATCCAGTTGC ACCTACTGTCCTCATCTTCCCACCAGCTGCTGATCAGG TGGCAACTGGAACAGTCACCATCGTGTGCGTGGCTAA CAAGTACTTCCCGGACGTGACCGTGACCTGGGAAGTCGACGGAACCACTCAGACCACTGGTATCGAGAACAGCSTDU244218.601(S23-351) AAGACGCCCCAGAACTCCGCCGATTGTACTTATAACC TGTCCTCCACACTGACCCTCACCTCGACCCAGTACAA TTCCCACAAGGAGTACACTTGCAAAGTCACCCAGGGA ACCACTTCAGTGGTGCAGAGCTTCAACCGGGGGGATT GCTGA VL (amino MDTRAPTQLLGLLLLWLPGATFAQVLTQTPSLVSAAVG 71 acid) GTVTISCQSSQSVYSNNWLAWYQKKPGQPPKLLIYLAS KLASGVPSRFSGSGSGTQFTLTLSDLECDDAATYYCAGG YTDTATFGGGTEVVVKGDPVAPTVLIFPPAADQVATGT VTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNS ADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSF NRGDC HCDR1 RYDMS 72 GFSLSRYDMS 151 HCDR2 AVGTSGNTYYASWAKS 73 WIGAVGTSGNTYYASWAKS 152 HCDR3 EYPGHSPGTSI 74 AREYPGHSPGTSI 153 LCDR1 QSSQSVYSNNWLA 75 QSSQSVYSNNWLAWY 154 LCDR2 LASKLAS 76 LLIYLASKLAS 155 LCDR3 AGGYTDTAT 77 anti- VH (DNA) ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTG 78 OPN-R TGCTCAAAGGTGTCCAGTGTCAGTCGGTGAAGGAGTC CGAGGGAGGTCTCTTCAAGCCAACGGATACCCTGACA CTCACCTGCACAGCCTCTGGATTCTTCCTCGGTAGCTA CGACATGAGCTGGGTCCGCCAGGCTCCAGGAAACGG GCTGGAATGGATCGGAGCCGTTGGTACGAGCGGCAG GACATACTACGCGAGCTGGGCGAAAAGCCGAGCCAC CATCACCAGAAACACCAACCTGAACACGGTGACTCTG AAAATGACCAGTCTGACAGCCGCGGACACGGCCACCT ATTTCTGTGCGAGAGAATATCCTGGTCATAGTCCTGG AACTAGCATCTGGGGCCCAGGCACCCTGGTCACCGTC TCCTCAGGGCAACCTAAGGCTCCATCAGTCTTCCCAC TGGCCCCCTGCTGCGGGGACACACCCAGCTCCACGGT CACCCTGGGTTGTCTTGTGAAGGGATACCTCCCGGAA CCCGTGACCGTGACCTGGAACTCCGGCACCCTGACCA ATGGAGTGCGGACCTTCCCGAGCGTCAGGCAGTCCTC CGGGTTGTACAGCTTGTCTAGCGTGGTGTCCGTGACG TCGTCAAGCCAGCCTGTGACTTGCAATGTGGCCCATC CGGCCACCAACACCAAGGTCGACAAGACCGTGGCGC CTTCCACCTGTTCCAAGCCCACTTGCCCGCCGCCTGAG CTCCTGGGAGGACCGTCCGTGTTCATCTTCCCTCCAAA ACCCAAGGATACCCTGATGATTAGCCGCACTCCCGAA GTCACTTGCGTGGTCGTGGACGTGTCGCAGGACGATC CTGAGGTGCAGTTCACTTGGTACATCAACAACGAACA AGTCCGGACAGCTAGACCACCGCTGCGCGAGCAGCA GTTCAACTCAACTATCCGGGTGGTGTCCACCCTGCCG ATCGCGCATCAGGATTGGCTGCGGGGGAAGGAGTTCA AGTGCAAAGTCCACAACAAGGCCCTGCCCGCCCCCAT CGAAAAGACCATCTCCAAGGCTCGGGGCCAGCCTCTG GAGCCCAAAGTGTACACCATGGGCCCGCCTCGCGAGG AGCTCTCCTCACGCTCGGTGTCGCTGACTTGCATGATTAACGGCTTCTACCCTTCCGACATCTCCGTGGAATGGGSTDU244218.601(S23-351) AGAAGAACGGAAAAGCCGAAGATAACTACAAGACCA CGCCCGCCGTGCTGGACTCCGACGGAAGCTATTTCCT GTACTCCAAGCTCTCCGTCCCCACTTCGGAATGGCAG AGGGGGGACGTGTTCACTTGCTCCGTGATGCACGAGG CACTCCACAACCACTACACCCAAAAGAGCATTTCGCG GTCACCTGGCAAGTAA VH (amino METGLRWLLLVAVLKGVQCQSVKESEGGLFKPTDTLTL 79 acid) TCTASGFFLGSYDMSWVRQAPGNGLEWIGAVGTSGRTY YASWAKSRATITRNTNLNTVTLKMTSLTAADTATYFCA REYPGHSPGTSIWGPGTLVTVSSGQPKAPSVFPLAPCCG DTPSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPS VRQSSGLYSLSSVVSVTSSSQPVTCNVAIIPATNTKVDKT VAPSTCSKPTCPPPELLGGPSVFIFPPKPKDTLMISRTPEV TCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFN STIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPIEKTIS KARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDI SVEWEKNGKAEDNYKTTPAVLDSDGSYFLYSKLSVPTS EWQRGDVFTCSVMHEALHNHYTQKSISRSPGK VL (DNA) ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCC 80 TGCTGCTCTGGCTCCCAGGTGCCAGATGTGACCCTGT GCTGACCCAGACTGCATCGCCCGTGTCTGCACCTGTG GGAGGCACAGTCACCATCAGTTGCCAGTCCAGTCAGA CTGTTTATAATAACAACTGGATAGCCTGGTATCAGCA GAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATCTG GCATCCACTCTGGCATCTGGGGTCCCATCGCGGTTCA AAGGCAGTGGATTTGGGACACAGTTCACTCTCACCAT CAGCGACCTGGAGTGTGACGATGCTGCCACTTACTAT TGTGCAGGCGGTTATAGTGAGACTGCTATTTTCGGCG GAGGGACCGAGGTGGTCGTCAAAGGTGATCCAGTTGC ACCTACTGTCCTCATCTTCCCACCAGCTGCTGATCAGG TGGCAACTGGAACAGTCACCATCGTGTGCGTGGCTAA CAAGTACTTCCCGGACGTGACCGTGACCTGGGAAGTC GACGGAACCACTCAGACCACTGGTATCGAGAACAGC AAGACGCCCCAGAACTCCGCCGATTGTACTTATAACC TGTCCTCCACACTGACCCTCACCTCGACCCAGTACAA TTCCCACAAGGAGTACACTTGCAAAGTCACCCAGGGA ACCACTTCAGTGGTGCAGAGCTTCAACCGGGGGGATT GCTGA VL (amino MDTR APTQT J, GT J J J. WT. PG A R CDP VT 7TQTASPVS AP VG 81 acid) GTVTISCQSSQTVYNNNWIAWYQQKPGQPPKLLIYLAST LASGVPSRFKGSGFGTQFTLTISDLECDDAATYYCAGGY SETAIFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTI VCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADC TYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRG DC HCDR1 SYDMS 62 GFFLGSYDMS 156 HCDR2 AVGTSGRTYYASWAKS 82 WIGAVGTSGRTYYASWAKS 157 HCDR3 EYPGHSPGTSI 74 AREYPGHSPGTSI 153 LCDR1 QTVYNNNWIA 83 QSSQTVYNNNWIAWY 158 LCDR2 LASTLAS 29LLIYLASTLAS 159STDU244218.601(S23-351) LCDR3 AGGYSETAI 84 E6 anti- VH (DNA) ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTG 85 OPN-R TGCTCAAAGGTGTCCAGTGTCAGTCGGTGAAGGAGTC CGAGGGAGGTCTCTTCAAGCCAACGGATACCCTGACA CTCACCTGCACAGCCTCTGGATTCTCCCTCAGCGCGTA CGACATGAGCTGGGTCCGACAGGCTCCAGGGAATGG GCTGGAATGGATCGGAGGCATCGGTGCTAGTGGTACC ACATACTACGCGAACTGGGCGACAAGCCGATCCACCA TCACCAGAAACACCAACCTGAACACGATGACTCTGAA AATGACCAGTCTGACAGCCGCGGACACGGCCACCTAT TTCTGTGCGAGAGGTGGTACTTTTGGTAATAATCTCTA CGGCACGGACCTCTGGGGCCCAGGGACCCTCGTCACC GTCTCTTCAGGGCAACCTAAGGCTCCATCAGTCTTCCC ACTGGCCCCCTGCTGCGGGGACACACCCAGCTCCACG GTCACCCTGGGTTGTCTTGTGAAGGGATACCTCCCGG AACCCGTGACCGTGACCTGGAACTCCGGCACCCTGAC CAATGGAGTGCGGACCTTCCCGAGCGTCAGGCAGTCC TCCGGGTTGTACAGCTTGTCTAGCGTGGTGTCCGTGA CGTCGTCAAGCCAGCCTGTGACTTGCAATGTGGCCCA TCCGGCCACCAACACCAAGGTCGACAAGACCGTGGC GCCTTCCACCTGTTCCAAGCCCACTTGCCCGCCGCCTG AGCTCCTGGGAGGACCGTCCGTGTTCATCTTCCCTCCA AAACCCAAGGATACCCTGATGATTAGCCGCACTCCCG AAGTCACTTGCGTGGTCGTGGACGTGTCGCAGGACGA TCCTGAGGTGCAGTTCACTTGGTACATCAACAACGAA CAAGTCCGGACAGCTAGACCACCGCTGCGCGAGCAG CAGTTCAACTCAACTATCCGGGTGGTGTCCACCCTGC CGATCGCGCATCAGGATTGGCTGCGGGGGAAGGAGTT CAAGTGCAAAGTCCACAACAAGGCCCTGCCCGCCCCC ATCGAAAAGACCATCTCCAAGGCTCGGGGCCAGCCTC TGGAGCCCAAAGTGTACACCATGGGCCCGCCTCGCGA GGAGCTCTCCTCACGCTCGGTGTCGCTGACTTGCATG ATTAACGGCTTCTACCCTTCCGACATCTCCGTGGAATG GGAGAAGAACGGAAAAGCCGAAGATAACTACAAGAC CACGCCCGCCGTGCTGGACTCCGACGGAAGCTATTTC CTGTACTCCAAGCTCTCCGTCCCCACTTCGGAATGGC AGAGGGGGGACGTGTTCACTTGCTCCGTGATGCACGA GGCACTCCACAACCACTACACCCAAAAGAGCATTTCG CGGTCACCTGGCAAGTAA VH (amino METGLRWLLLVAVLKGVQCQSVKESEGGLFKPTDTLTL 86 acid) TCTASGFSLSAYDMSWVRQAPGNGLEWIGGIGASGTTY YANWATSRSTITRNTNLNTMTLKMTSLTAADTATYFCA RGGTFGNNLYGTDLWGPGTLVTVSSGQPKAPSVFPLAP CCGDTPS STVTLGCL VKG YLPEP VT VTWNS GTLTNG VR TFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTK VDKTVAPSTCSKPTCPPPELLGGPSVFIFPPKPKDTLMISR TPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLRE QQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPI EKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGF YPSDISVEWEKNGKAEDNYKTTPAVLDSDGSYF LYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISR SPGK VL (DNA) ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCC 87 TGCTGCTCTGGCTCCCAGGTGCCAGATGTGCCTATGA TATGACCCAGACTCCAGCCTCCGTGGAGGCAGCTGTGGGAGGCACAGTCACCATCAAGTGCCAGGCCAGTCAGSTDU244218.601(S23-351) AGTATTAGTAGTAGCTACTTATCCTGGTTTCAGCAGA AACCAGGGCAGCGTCCCAAGCCCCTGATCTATGGTGC ATCCACTCTGGCATCTGGGGTCTCATCGCGGTTCAAA GGCAGTGGATCTGGGACACAGTTCGCTCTCACCATCA GCGGCGTGGAGTGTGCCGATGCTGCCACTTACTACTG TCAACAGGATTATAGTTGGACTAATGTTGATAATACT TTCGGCGGAGGGACCGAGGTGGTGGTCAAAGGTGAT CCAGTTGCACCTACTGTCCTCATCTTCCCACCAGCTGC TGATCAGGTGGCAACTGGAACAGTCACCATCGTGTGC GTGGCTAACAAGTACTTCCCGGACGTGACCGTGACCT GGGAAGTCGACGGAACCACTCAGACCACTGGTATCG AGAACAGCAAGACGCCCCAGAACTCCGCCGATTGTAC TTATAACCTGTCCTCCACACTGACCCTCACCTCGACCC AGTACAATTCCCACAAGGAGTACACTTGCAAAGTCAC CCAGGGAACCACTTCAGTGGTGCAGAGCTTCAACCGG GGGGATTGCTGA VL (amino MDTRAPTQLLGLLLLWLPGARCAYDMTQTPASVEAAV 88 acid) GGTVTIKCQASQSISSSYLSWFQQKPGQRPKPLIYGASTL ASGVSSRFKGSGSGTQFALTISGVECADAATYYCQQDYS WTNVDNTFGGGTEVVVKGDPVAPTVLIFPPAADQVATG TVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNS ADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSF NRGDC HCDR1 AYDMS 89 GFSLSAYDMS 160 HCDR2 GIGASGTTYYANWATS 90 WIGGIGASGTTYYANWATS 161 HCDR3 GGTFGNNLYGTDL 91 ARGGTFGNNLYGTDL 162 LCDR1 QASQSISSSYLS 92 QASQSISSSYLSWF 163 LCDR2 GASTLAS 93 PLIYGASTLAS 164 LCDR3 QQDYSWTNVDNT 94 F7 anti- VH (DNA) ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTG 95 OPN-L TGCTCAAAGGTGTCCAGTGTCAGTCGGTGAAGGAGTC CGAGGGAGGTCTCTTCAAGCCAGCGGATACCCTGACA CTCACCTGCACAGCCTCTGGATTCTCCCTCAGTAGCTA TTCAATTAACTGGGTCCGCCAGGCTCCAGGGAACGGG CTGGAATGGATCGGTACCATTGGACGTAGTGGCAGCG CATACTACGCGAGCTGGGCGAAAAGCCGATCCACCAT CACCAGAGACACCAACCTGAACACGGCGACTCTGAA AATGACCAGTCTGACAGCCGCGGACACGGCCACCTAT TTCTGTGCGAGAGGAGTTAATAGTAGTTATGTGTCTA GTATCTGGGGCCCAGGCACCCTGGTCATTGTCTCCTC AGGGCAACCTAAGGCTCCATCAGTCTTCCCACTGGCC CCCTGCTGCGGGGACACACCCAGCTCCACGGTCACCC TGGGTTGTCTTGTGAAGGGATACCTCCCGGAACCCGT GACCGTGACCTGGAACTCCGGCACCCTGACCAATGGA GTGCGGACCTTCCCGAGCGTCAGGCAGTCCTCCGGGT TGTACAGCTTGTCTAGCGTGGTGTCCGTGACGTCGTC AAGCCAGCCTGTGACTTGCAATGTGGCCCATCCGGCC ACCAACACCAAGGTCGACAAGACCGTGGCGCCTTCCA CCTGTTCCAAGCCCACTTGCCCGCCGCCTGAGCTCCTGGGAGGACCGTCCGTGTTCATCTTCCCTCCAAAACCCASTDU244218.601(S23-351) AGGATACCCTGATGATTAGCCGCACTCCCGAAGTCAC TTGCGTGGTCGTGGACGTGTCGCAGGACGATCCTGAG GTGCAGTTCACTTGGTACATCAACAACGAACAAGTCC GGACAGCTAGACCACCGCTGCGCGAGCAGCAGTTCA ACTCAACTATCCGGGTGGTGTCCACCCTGCCGATCGC GCATCAGGATTGGCTGCGGGGGAAGGAGTTCAAGTG CAAAGTCCACAACAAGGCCCTGCCCGCCCCCATCGAA AAGACCATCTCCAAGGCTCGGGGCCAGCCTCTGGAGC CCAAAGTGTACACCATGGGCCCGCCTCGCGAGGAGCT CTCCTCACGCTCGGTGTCGCTGACTTGCATGATTAACG GCTTCTACCCTTCCGACATCTCCGTGGAATGGGAGAA GAACGGAAAAGCCGAAGATAACTACAAGACCACGCC CGCCGTGCTGGACTCCGACGGAAGCTATTTCCTGTAC TCCAAGCTCTCCGTCCCCACTTCGGAATGGCAGAGGG GGGACGTGTTCACTTGCTCCGTGATGCACGAGGCACT CCACAACCACTACACCCAAAAGAGCATTTCGCGGTCA CCTGGCAAGTAA VH (amino METGLRWLLLVAVLKGVQCQSVKESEGGLFKPADTLTL 96 acid) TCTASGFSLSSYSINWVRQAPGNGLEWIGTIGRSGSAYY ASWAKSRSTITRDTNLNTATLKMTSLTAADTATYFCAR G VNS S Y VS SIWGPGTLVI VS S GQPKAPS VFPL APCCGDTP SSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQ SSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTVAP STCSKPTCPPPELLGGPSVFIFPPKPKDTLMISRTPEVTCV VVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIR VVSTLPIAHQDWLRGKEFKCKVHNKALPAPIEKTISKAR GQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVE WEKNGKAEDNYKTTPAVLDSDGSYFLYSKLSVPTSEWQ RGD VFTCS VMHEALHNHYTQKSISRSPGK VL (DNA) ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCC 97 TGCTGCTCTGGCTCCCAGGTGCCAGATGTGCATTCGA GATGACCCAGACTCCATCCTCCGTGGAGGCAGCTGTG GGAGGCACAGTCACCATCAAGTGCCAGGCCAGTCAG AGCATTCGTAGTTACTTAGCCTGGTATCAGCAGAAAC CAGGGCAGCCTCCCAAGCTCCTGATCTATGAAGCATC CAAACTGGCATCTGGGGTCCCATCGCGGTTCAGAGGC AGTGGATCTGCGACAGAGTTCACTCTCGCCATCAGCG ACCTGGAGTGTGCCGATGCTGCCACTTACTACTGTCA AAGCCATGCTATTGATCCTACGCCTGCTTTCGGCGGA GGGACCGAGGTGGTCGTCAAAGGTGATCCAGTTGCAC CTACTGTCCTCATCTTCCCACCAGCTGCTGATCAGGTG GCAACTGGAACAGTCACCATCGTGTGCGTGGCTAACA AGTACTTCCCGGACGTGACCGTGACCTGGGAAGTCGA CGGAACCACTCAGACCACTGGTATCGAGAACAGCAA GACGCCCCAGAACTCCGCCGATTGTACTTATAACCTG TCCTCCACACTGACCCTCACCTCGACCCAGTACAATTC CCACAAGGAGTACACTTGCAAAGTCACCCAGGGAAC CACTTCAGTGGTGCAGAGCTTCAACCGGGGGGATTGC EGA VL (amino MDTRAPTQLLGLLLLWLPGARCAFEMTQTPSSVEAAVG 98 acid) GTVTIKCQASQSIRSYLAWYQQKPGQPPKLLIYEASKLA SGVPSRFRGSGSATEFTLAISDLECADAATYYCQSHAIDP TPAFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIV CVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCT YNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDCSTDU244218.601(S23-351) HCDR1 SYSIN 99 GFSLSSYSIN 165 HCDR2 TIGRSGSAYYASWAKS 100 WIGTIGRSGSAYYASWAKS 166 HCDR3 GVNSSYVSSI 101 ARGVNSSYVSS1 167 LCDR1 QASQSIRSYLA 102 QASQSIRSYLAWY 168 LCDR2 EASKLAS 22 LLIYEASKLAS 128 LCDR3 QSHAIDPTPA 103 F3 anti- VH (DNA) ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTG 104 OPN-L TGCTCAAAGGTGTCCAGTGTCAGTCGGTGAAGGAGTC CGAGGGAGGTCTCTTCAAGCCAACGGATACCCTGACA CTCACCTGCACAGTCTCTGGATTCTCCCTCAGTAGCTA TGCAATAAGTTGGGTCCGCCAGGCTCCAGGGAACGGG CTGGAGTGGATCGGAATCATGGGTAGTAGTGGTAGCG CATACTACGCGAGCTGGGCGAAAAGCCGATCCACCAT CACCAGAAACACCAACCTGAACACGGTGACTCTGAA AATGACCAGTCTGACAGCCGCGGACACGGCCACCTAT TTCTGTGCGAGACATGTTCCTGGAGATGTTGGTCGTC GGTTGGATCTCTGGGGCCAGGGCACCCTGGTCACCGT CTCTTCAGGGCAACCTAAGGCTCCATCAGTCTTCCCA CTGGCCCCCTGCTGCGGGGACACACCCAGCTCCACGG TCACCCTGGGTTGTCTTGTGAAGGGATACCTCCCGGA ACCCGTGACCGTGACCTGGAACTCCGGCACCCTGACC AATGGAGTGCGGACCTTCCCGAGCGTCAGGCAGTCCT CCGGGTTGTACAGCTTGTCTAGCGTGGTGTCCGTGAC GTCGTCAAGCCAGCCTGTGACTTGCAATGTGGCCCAT CCGGCCACCAACACCAAGGTCGACAAGACCGTGGCG CCTTCCACCTGTTCCAAGCCCACTTGCCCGCCGCCTGA GCTCCTGGGAGGACCGTCCGTGTTCATCTTCCCTCCAA AACCCAAGGATACCCTGATGATTAGCCGCACTCCCGA AGTCACTTGCGTGGTCGTGGACGTGTCGCAGGACGAT CCTGAGGTGCAGTTCACTTGGTACATCAACAACGAAC AAGTCCGGACAGCTAGACCACCGCTGCGCGAGCAGC AGTTCAACTCAACTATCCGGGTGGTGTCCACCCTGCC GATCGCGCATCAGGATTGGCTGCGGGGGAAGGAGTTC AAGTGCAAAGTCCACAACAAGGCCCTGCCCGCCCCCA TCGAAAAGACCATCTCCAAGGCTCGGGGCCAGCCTCT GGAGCCCAAAGTGTACACCATGGGCCCGCCTCGCGAG GAGCTCTCCTCACGCTCGGTGTCGCTGACTTGCATGAT TAACGGC1TCTACCCTTCCGACATCTCCGTGGAATGG GAGAAGAACGGAAAAGCCGAAGATAACTACAAGACC ACGCCCGCCGTGCTGGACTCCGACGGAAGCTATTTCC TGTACTCCAAGCTCTCCGTCCCCACTTCGGAATGGCA GAGGGGGGACGTGTTCACTTGCTCCGTGATGCACGAG GCACTCCACAACCACTACACCCAAAAGAGCATTTCGC GGTCACCTGGCAAGTAA VH (amino METGERWET J. VAVTXGVQCQSVKESEGGEFKPTDTETE 105 acid) TCTVSGFSLSSYAISWVRQAPGNGLEWIGIMGSSGSAYY ASWAKSRSTITRNTNLNTVTLKMTSLTAADTATYFCAR HVPGDVGRRLDLWGQGTLVTVSSGQPKAPSVFPLAPCC GDTPSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKSTDU244218.601(S23-351) TVAPSTCSKPTCPPPELLGGPSVFIFPPKPKDTLMISRTPE VTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQF NSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPIEKTI SKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPS DISVEWEKNGKAEDNYKTTPAVLDSDGSYFLYSKLSVP TSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK VL (DNA) ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCC 106 TGCTGCTCTGGCTCCCAGGTGCCACGTTTGCCCTCGAT ATGACCCAGACTGCATCGCCCGTGTCTGCTCCTGTGG GAGGCACAGTCACCATCAATTGCCAGTCCAGTCAGAG TGTTTATAATAACAACGAATTATCTTGGTATCAGCAG AAACCAGGGCAGCCTCCCAAGCTCCTGATCTACAAGG CTTCCACTCTGGCATCTGGGGTCCCATCGCGGTTCGCA GGCAGTGGATCTGGGACACAGTTCACTCTCACCATCA GCGACCTGGAGTGTGACGATGCTGCCACTTACTATTG TGCAGGCTATTATGGCAGTACTAGTGATACTTGGGCT TTCGGCGGGGGGACCGAGGTGGTGGTCAAAGGTGAT CCAGTTGCACCTACTGTCCTCATCTTCCCACCAGCTGC TGATCAGGTGGCAACTGGAACAGTCACCATCGTGTGC GTGGCTAACAAGTACTTCCCGGACGTGACCGTGACCT GGGAAGTCGACGGAACCACTCAGACCACTGGTATCG AGAACAGCAAGACGCCCCAGAACTCCGCCGATTGTAC TTATAACCTGTCCTCCACACTGACCCTCACCTCGACCC AGTACAATTCCCACAAGGAGTACACTTGCAAAGTCAC CCAGGGAACCACTTCAGTGGTGCAGAGCTTCAACCGG GGGGATTGCTGA VL (amino MDTRAPTQLLGLLLLWLPGATFALDMTQTASPVSAPVG 107 acid) GTVTINCQSSQSVYNNNELSWYQQKPGQPPKLLIYKAST LASGVPSRFAGSGSGTQFTLTISDLECDDAATYYCAGYY GSTSDTWAFGGGTEVVVKGDPVAPTVLIFPPAADQVAT GTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQ NSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVV QSFNRGDC HCDR1 SYAIS 108 GFSLSSYAIS 169 HCDR2 IMGSSGSAYYASWAKS 109 WIGIMGSSGSAYYASWAKS 170 HCDR3 HVPGDVGRRLDL 110 ARHVPGDVGRRLDL 171 LCDR1 QSSQSVYNNNELS 111 QSSQSVYNNNELSWY 172 LCDR2 KASTLAS 112 LLIYKASTLAS 173 LCDR3 AGYYGSTSDTWA 113 F6 anti- VH (DNA) ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTG 114 OPN-L TGCTCAAAGGTGTCCAGTGTCAGGAGCAGCTGAAGGA GTCCGAGGGAGGTCTCTTCAAGCCAACGGATACCCTG ACTCTCACCTGCACAGTCTCTGGATTCTCCCTCAGTAC GCATGGAGTGATCTGGGTCCGCCAGGCTCCAGGGAAG GGGCTGGAGTGGATCGGAACCATTGGTAGTAGTGGTA GCGCATACTACGCGAGCTGGGCGAAAAGCCGATCCA CCATCACCAGAAACACCAACCTGAACACGGTGACTCT GAAGATGACCAGTCTGACAGCCGCGGACACGGCCAC CTATTTCTGTGGGAGGAGTTATTATGGTACTCCTGACATCTGGGGCCCAGGCACCCTGGTCACCGTCTCCTCAGGSTDU244218.601(S23-351) GCAACCTAAGGCTCCATCAGTCTTCCCACTGGCCCCC TGCTGCGGGGACACACCCAGCTCCACGGTCACCCTGG GTTGTCTTGTGAAGGGATACCTCCCGGAACCCGTGAC CGTGACCTGGAACTCCGGCACCCTGACCAATGGAGTG CGGACCTTCCCGAGCGTCAGGCAGTCCTCCGGGTTGT ACAGCTTGTCTAGCGTGGTGTCCGTGACGTCGTCAAG CCAGCCTGTGACTTGCAATGTGGCCCATCCGGCCACC AACACCAAGGTCGACAAGACCGTGGCGCCTTCCACCT GTTCCAAGCCCACTTGCCCGCCGCCTGAGCTCCTGGG AGGACCGTCCGTGTTCATCTTCCCTCCAAAACCCAAG GATACCCTGATGATTAGCCGCACTCCCGAAGTCACTT GCGTGGTCGTGGACGTGTCGCAGGACGATCCTGAGGT GCAGTTCACTTGGTACATCAACAACGAACAAGTCCGG ACAGCTAGACCACCGCTGCGCGAGCAGCAGTTCAACT CAACTATCCGGGTGGTGTCCACCCTGCCGATCGCGCA TCAGGATTGGCTGCGGGGGAAGGAGTTCAAGTGCAA AGTCCACAACAAGGCCCTGCCCGCCCCCATCGAAAAG ACCATCTCCAAGGCTCGGGGCCAGCCTCTGGAGCCCA AAGTGTACACCATGGGCCCGCCTCGCGAGGAGCTCTC CTCACGCTCGGTGTCGCTGACTTGCATGATTAACGGC TTCTACCCTTCCGACATCTCCGTGGAATGGGAGAAGA ACGGAAAAGCCGAAGATAACTACAAGACCACGCCCG CCGTGCTGGACTCCGACGGAAGCTATTTCCTGTACTC CAAGCTCTCCGTCCCCACTTCGGAATGGCAGAGGGGG GACGTGTTCACTTGCTCCGTGATGCACGAGGCACTCC ACAACCACTACACCCAAAAGAGCATTTCGCGGTCACC TGGCAAGTAA VH (amino METGLRWLLLVAVLKGVQCQEQLKESEGGLFKPTDTLT 115 acid) LTCTVSGFSLSTHGVIWVRQAPGKGLEWIGTIGSSGSAY YASWAKSRSTITRNTNLNTVTLKMTSLTAADTATYFCG RSYYGTPDIWGPGTLVTVSSGQPKAPSVFPLAPCCGDTP SSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQ S S GE YSES S V VS VTS S S QP VTCN V AHP ATNTK VDKT V AP STCSKPTCPPPELLGGPSVFIFPPKPKDTLMISRTPEVTCV VVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIR VVSTLPIAHQDWLRGKEFKCKVHNKALPAPIEKTISKAR GQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVE WEKNGKAEDNYKTTPAVLDSDGSYFLYSKLSVPTSEWQ RGD VFTCS VMHEALHNHYTQKSISRSPGK VL (DNA) ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCC 116 TGCTGCTCTGGCTCCCAGGTGCCACATTTGCCATCGTG ATGACCCAGACTCCATCGTCCGTGTCTGCAGCTGTGG GAGGCACAGTCAGCATCAGTTGCCAGTCCAGTCAGAG TGTTTATAGTAACTACTTATCCTGGTATCAGCAGAAA CCAGGGCAGCCTCCCAAGCTCCTGATCTATCTGGCAT CCACTCTGGCATCTGGGGTCCCATCGCGGTTCAAAGG CAGTGGATCTGGGACACAGTTCACTCTCACCATCAGC GATGTGGTGTGTGACGATGCTGGCACTTACTACTGTG CAGGATATAAAAGTAGTACTGATGATGGTAGGGCTTT CGGCGGAGGGACCGAGGTGGTGGTCAAAGGTGATCC AGTTGCACCTACTGTCCTCATCTTCCCACCAGCTGCTG ATCAGGTGGCAACTGGAACAGTCACCATCGTGTGCGT GGCTAACAAGTACTTCCCGGACGTGACCGTGACCTGG GAAGTCGACGGAACCACTCAGACCACTGGTATCGAG AACAGCAAGACGCCCCAGAACTCCGCCGATTGTACTTATAACCTGTCCTCCACACTGACCCTCACCTCGACCCASTDU244218.601(S23-351) GTACAATTCCCACAAGGAGTACACTTGCAAAGTCACC CAGGGAACCACTTCAGTGGTGCAGAGCTTCAACCGGG GGGATTGCTGA VL (amino MDTRAPTQLLGLLLLWLPGATFAIVMTQTPSSVSAAVG 117 acid) GTVSLSCQSSQSVYSNYLSWYQQKPGQPPKLLIYLASTL ASGVPSRFKGSGSGTQFTLTISDVVCDDAGTYYCAGYKS STDDGRAFGGGTEVVVKGDPVAPTVLIFPPAADQVATG TVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNS ADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSF NRGDC HCDR1 THGVI 118 GFSLSTHGVI 174 HCDR2 TIGSSGSAYYASWAKS 119 WIGTIGSSGSAYYASWAKS 175 HCDR3 SYYGTPDI 120 GRSYYGTPDI 176 LCDR1 QSSQSVYSNYLS 121 QSSQSVYSNYLSWY 177 LCDR2 LASTLAS 29 LLIYLASTLAS 159LCDR3 AGYKSSTDDGRA 122

[0177] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0178] Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims

STDU244218.601(S23-351) CLAIMSWhat is claimed is:

1. An antibody, or antigen binding fragment thereof, which specifically binds osteopontin or a cleavage fragment thereof, wherein the osteopontin or a cleavage fragment thereof is a polypeptide comprising the amino acid sequence of YGLRSKS (SEQ ID NO: 179), AYGLR (SEQ ID NO: 180), or VYGLR (SEQ ID NO: 181).

2. The antibody, or antigen binding fragment thereof, of claim 1, which exhibits any one or more the following functional characteristics:a. inhibits thrombin cleavage of osteopontin;b. inhibits integrin binding to the thrombin cleavage fragment of osteopontin;c. inhibits chemotactic enhancement of cellular migration of osteopontin;d. binds to thrombin cleaved osteopontin (OPN-R) but not full-length osteopontin (OPN- FL) or carboxypeptidase B cleaved fragment of osteopontin (OPN-L);e. binds to OPN-L but not OPN-FL or OPN-R;f. binds to OPN-FL; andg. binds to human and / or mouse osteopontin or a fragment thereof.

3. The antibody, or antigen binding fragment thereof, of claim 1 or 2, which is monoclonal, optionally recombinant.

4. The antibody, or antigen binding fragment thereof, of any one of claims 1-3, which is human, humanized, or chimeric.

5. The antibody, or antigen binding fragment thereof, of any one of claims 1-4, which is a full length antibody, a single chain antibody, a single chain variable fragment (scFv), a variable fragment (Fv), a fragment antigen binding region (Fab), a Fab-C, a Fab’-SH, a (Fab’)2, a singledomain antibody (sdAb), a VHH antibody, a nanobody, a camelid-derived single-domain antibody, a shark IgNAR-derived single-domain antibody fragment (VNAR), a diabody, a triabody, an anticalin or an aptamer, optionally wherein the antibody is a full length antibody comprising an Fc region such as a human IgGl, IgG2, IgG3 or IgG4 region.STDU244218.601(S23-351)6. The antibody, or antigen binding fragment thereof, binding fragment thereof of any one of claims 1-5, which is conjugated to at least one additional moiety, optionally selected from: a. a therapeutic or cytotoxic moiety;b. a detection moiety;c. a purification moiety; andd. a half-life extension moiety.

7. The antibody, or antigen binding fragment thereof, of any one of claims 1-6, which is a polypeptide comprising:a. one, two or all three HCDRs of any one of the exemplary antibodies the sequences of which are provided in Table 1, and optionally also one, two or all three of the corresponding LCDRs of the exemplary antibody; and / orb. a VH sequence having at least 90% identity to the VH sequence of any one of the exemplary antibodies the sequences of which are provided in Table 1, and optionally also a VL sequence having at least 90% identity to the corresponding VL sequence of the exemplary antibody; and / orc. all six CDRs of any one of the exemplary antibodies the sequences of which are provided in Table 1; and / ord. VH and VL sequences of any one of the exemplary antibodies the sequences of which are provided in Table 1.

8. A polynucleotide encoding an antibody, or antigen binding fragment thereof, of any one of claims 1-7, optionally wherein the polynucleotide comprises or consists of a nucleic acid sequence having at least 70, 80, 90 or 100% identity to a nucleic acid sequence of any one of the exemplary antibodies the sequences of which are provided in Table 1.

9. An expression vector comprising the polynucleotide of claim 8, which is optionally an adeno- associated virus (AAV) vector, a lentiviral (LV) vector, a herpes simplex virus (HSV) vector, or a retrovirus vector.STDU244218.601(S23-351) 10. A pharmaceutical composition comprising an antibody, or antigen binding fragment thereof, of any one of claims 1-7, a polynucleotide of claim 8, or a vector of claim 9, and optionallya. at least one pharmaceutically acceptable carrier, diluent, or preservative; and / or b. at least one additional active ingredient.

11. The antibody, or antigen binding fragment thereof, of any one of claims 1 to 7, the polynucleotide of claim 8, the vector of claim 9, or the composition of claim 10, for use as a medicament, optionally for use in a cancer associated with overexpression of osteopontin or an inflammatory disease or disorder.

12. The antibody, or antigen binding fragment thereof, of any one of claims 1 to 7, the polynucleotide of claim 8, the vector of claim 9, or the composition of claim 10, for use as a medicament, optionally for use in melanoma, glioblastoma, ovarian cancer, breast cancer, or lung cancer.

13. The antibody, or antigen binding fragment thereof, of any one of claims 1 to 7, the polynucleotide of claim 8, the vector of claim 9, or the composition of claim 10, for use as a medicament, optionally for use in cardiac hypertrophy and / or myocardial fibrosis.

14. An antibody, or an antigen binding fragment thereof, directed against osteopontin or a cleavage fragment thereof, comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3, and a light chain variable region (VL) comprising complementarity determining regions (CDRs) LCDR1, LCDR2, and LCDR3, whereina. the HCDR1 comprises an amino acid sequence of any of SEQ ID NOs: 62, 123, 124, 52, 72, or 89; the HCDR2 comprises an amino acid sequence of any of SEQ ID NOs: 18, 25, 33, 40, 44, 53, 63, 73, 82, or 90; and the HCDR3 comprises an amino acid sequence of any of SEQ ID NOs: 126, 130, 134, 54, 64, 74 or 91; and / orthe LCDR1 comprises an amino acid sequence of any of SEQ ID NOs: 21, 28, 36, 46. 55.65, 75, 83, or 92; the LCDR2 comprises an amino acid sequence of any of SEQ ID NOs: 22, 29,STDU244218.601(S23-351) 31, 56, 66, 76, or 93; and the LCDR3 comprises an amino acid sequence of any of SEQ ID NOs: 23, 30, 38, 47, 57, 67, 77, 84, or 94;b. the HCDR1 comprises an amino acid sequence of any of SEQ ID NOs: 2, 6, or 9; the HCDR2 comprises an amino acid sequence of any of SEQ ID NOs: 3, 7, or 10; and the HCDR3 comprises an amino acid sequence of any of SEQ ID NOs: 4 or 11; and / orthe LCDR1 comprises an amino acid sequence of SEQ ID NO: 13; the LCDR2 comprises an amino acid sequence of SEQ ID NO: 14; and the LCDR3 comprises an amino acid sequence of SEQ ID NO: 15; orc. the HCDR1 comprises an amino acid sequence of any of SEQ ID NOs: 99, 108 or 118; the HCDR2 comprises an amino acid sequence of any of SEQ ID NOs: 100, 109 or 119; and the HCDR3 comprises an amino acid sequence of any of SEQ ID NOs: 101, 110, or 120; and / orthe LCDR1 comprises an amino acid sequence of any of SEQ ID NOs: 102, 111 or 121; the LCDR2 comprises an amino acid sequence of any of SEQ ID NO: 22, 29, 112; and the LCDR3 comprises an amino acid sequence of any of SEQ ID NOs: 103, 113, or 122.

15. The antibody, or antigen binding fragment thereof, of claim 14, wherein the antibody, or antigen binding fragment thereof, inhibits thrombin cleavage of osteopontin.

16. The antibody, or antigen binding fragment thereof, of claim 14 or 15, wherein the antibody, or antigen binding fragment thereof, inhibits integrin binding to the thrombin cleavage fragment of osteopontin.

17. The antibody, or antigen binding fragment thereof, of any of 14-16, wherein the antibody, or antigen binding fragment thereof, binds to human and / or mouse osteopontin or a fragment thereof.

18. The antibody, or antigen binding fragment thereof, of any of claims 14-17, wherein the antibody, or antigen binding fragment thereof, binds to thrombin cleaved osteopontin (OPN-R).STDU244218.601(S23-351) 19. The antibody, or antigen binding fragment thereof, of claim 18, wherein the antibody, or antigen binding fragment thereof, does not bind to full-length osteopontin (OPN-FL) or carboxypeptidase B cleaved fragment of osteopontin (OPN-L).

20. The antibody, or antigen binding fragment thereof, of claim 18 or 19, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 62; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 18; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 126.

21. The antibody, or antigen binding fragment thereof, of claim 18 or 19, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 62; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 40; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 126.

22. The antibody, or antigen binding fragment thereof, of any of claims 18-21, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 21; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 22; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 23.

23. The antibody, or antigen binding fragment thereof, of claim 18 or 19, whereina. the HCDR1 comprises the amino acid sequence of SEQ ID NO: 62; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 25: and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 130; and / orb. the LCDR1 comprises the amino acid sequence of SEQ ID NO: 28; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 29; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 30.

24. The antibody, or antigen binding fragment thereof, of claim 18 or 19, whereina. the HCDR1 comprises the amino acid sequence of SEQ ID NO: 123; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 33: and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 134; and / orSTDU244218.601(S23-351) b. the LCDR1 comprises the amino acid sequence of SEQ ID NO: 36; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 37; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 38.

25. The antibody, or antigen binding fragment thereof, of claim 18 or 19, whereina. the HCDR1 comprises the amino acid sequence of SEQ ID NO: 124; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 44; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 134; and / orb. the LCDR1 comprises the amino acid sequence of SEQ ID NO: 46; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 37; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 47.

26. The antibody, or antigen binding fragment thereof, of claim 18 or 19, whereina. the HCDR1 comprises the amino acid sequence of SEQ ID NO: 52; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 53; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 54; and / orb. the LCDR1 comprises the amino acid sequence of SEQ ID NO: 55; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 56; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 57.

27. The antibody, or antigen binding fragment thereof, of claim 18 or 19, whereina. the HCDR1 comprises the amino acid sequence of SEQ ID NO: 62; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 63; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 64; and / orb. the LCDR1 comprises the amino acid sequence of SEQ ID NO: 65; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 66; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 67.

28. The antibody, or antigen binding fragment thereof, of claim 18 or 19, whereinSTDU244218.601(S23-351) a. the HCDR1 comprises the amino acid sequence of SEQ ID NO: 72; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 73; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 74; and / orb. the LCDR1 comprises the amino acid sequence of SEQ ID NO: 75; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 76; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 77.

29. The antibody, or antigen binding fragment thereof, of claim 18 or 19, whereina. the HCDR1 comprises the amino acid sequence of SEQ ID NO: 62; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 82; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 74; and / orb. the LCDR1 comprises the amino acid sequence of SEQ ID NO: 83; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 29; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 84.

30. The antibody, or antigen binding fragment thereof, of claim 18 or 19, whereina. the HCDR1 comprises the amino acid sequence of SEQ ID NO: 89; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 90; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 91; and / orb. the LCDR1 comprises the amino acid sequence of SEQ ID NO: 92; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 93; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 94.

31. The antibody, or antigen binding fragment thereof, of any of claims 18-30, wherein the VH comprises an amino acid sequence having at least 90% identity to any of SEQ ID NOs: 16.24, 31, 39, 42, 49, 59, 69, 79, and 86.

32. The antibody, or antigen binding fragment thereof, of any of claims 18-31, wherein the VL comprises an amino acid sequence having at least 90% identity to any of SEQ ID NOs: 20, 27, 35, 41, 45, 51, 61, 71, 81, and 88.STDU244218.601(S23-351) 33. The antibody, or antigen binding fragment thereof, of any of claims 18-32, wherein a. the VH comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 16 and the VL comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 20;b. the VH comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 24 and the VL comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 27;c. the VH comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 31 and the VL comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 35;d. the VH comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 39 and the VL comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 41;e. the VH comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 42 and the VL comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 45;f. the VH comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 49 and the VL comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 51;g. the VH comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 59 and the VL comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 61;h. the VH comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 69 and the VL comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 71;i. the VH comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 79 and the VL comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 81; orj. the VH comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 86 and the VL comprises an amino acid sequence having at least 90% identity to SEQ ID NO:STDU244218.601(S23-351)34. The antibody, or antigen binding fragment thereof, of any of claims 14-17, wherein the antibody, or antigen binding fragment thereof, binds to OPN-FL.

35. The antibody, or antigen binding fragment thereof, of claim 34, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 2 or 6; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 3 or 7; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 4.

36. The antibody, or antigen binding fragment thereof, of claim 34, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 9; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 10; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 11.

37. The antibody, or antigen binding fragment thereof, of any of claims 34-36, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 13; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 14; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 15.

38. The antibody, or antigen binding fragment thereof, of any of claims 34-37, wherein the VH comprises an amino acid sequence having at least 90% identity to any of SEQ ID NOs: 1, 5 or 8.

39. The antibody, or antigen binding fragment thereof, of any of claims 34-38, wherein the VL comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 12.

40. The antibody, or antigen binding fragment thereof, of any of claims 34-39, wherein the VH comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 1, 5, or 8 and the VL comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 12.STDU244218.601(S23-351) 41. The antibody, or antigen binding fragment thereof, of any of claims 14-17, wherein the antibody, or antigen binding fragment thereof, binds to OPN-L but not OPN-FL or OPN-R.

42. The antibody, or antigen binding fragment thereof, of claim 41, whereina. the HCDR1 comprises the amino acid sequence of SEQ ID NO: 99; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 100; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 101; and / orb. the LCDR1 comprises the amino acid sequence of SEQ ID NO: 102; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 22; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 103.

43. The antibody, or antigen binding fragment thereof, of claim 41, whereina. the HCDR1 comprises the amino acid sequence of SEQ ID NO: 108; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 109; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 110; and / orb. the LCDR1 comprises the amino acid sequence of SEQ ID NO: 111; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 112; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 113.

44. The antibody, or antigen binding fragment thereof, of claim 41, whereina. the HCDR1 comprises the amino acid sequence of SEQ ID NO: 118; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 119; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 120; and / orb. the LCDR1 comprises the amino acid sequence of SEQ ID NO: 121; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 29; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 122.

45. The antibody, or antigen binding fragment thereof, of any of claims 41-44, wherein the VH comprises an amino acid sequence having at least 90% identity to any of SEQ ID NOs: 96, 105 or ll5.STDU244218.601(S23-351) 46. The antibody, or antigen binding fragment thereof, of any of claims 41-45, wherein the VL comprises an amino acid sequence having at least 90% identity to any of SEQ ID NOs: 98, 107, or 117.

47. The antibody, or antigen binding fragment thereof, of any of claims 41-46, wherein a. the VH comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 96 and the VL comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 98;b. the VH comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 105 and the VL comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 107; orc. the VH comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 115 and the VL comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 117.

48. The antibody, or antigen binding fragment thereof, of any of claims 14-47, wherein the antibody is a monoclonal antibody, a human antibody, a humanized antibody, and / or a chimeric antibody.

49. The antibody, or antigen binding fragment thereof, of any of claims 14-48, wherein the antibody is a fragment selected from the group consisting of Fab, Fab-C, Fab'-SH, Fv, scFv, and (Fab')2 fragments.

50. The antibody, or antigen binding fragment thereof, of any of claims 14-49, wherein the antibody is a monospecific antibody.

51. The antibody, or antigen binding fragment thereof, of any of claims 14-50, wherein the antibody comprises a detection moiety, a purification moiety, a half-life extension moiety, or a combination thereof.STDU244218.601(S23-351) 52. A pharmaceutical composition comprising an antibody, or an antigen binding fragment thereof, of any of claims 14-51.

53. A method of treating a disease or disorder comprising administering an antibody, or an antigen binding fragment thereof, of any of claims 14-51 or a pharmaceutical composition comprising thereof to a subject in need thereof.

54. The method of claim 53, wherein the disease or disorder is a cancer associated with overexpression of osteopontin or an inflammatory disease or disorder.

55. The method of claim 53 or 54, wherein the disease or disorder is melanoma, glioblastoma, ovarian cancer, breast cancer, or lung cancer.

56. The method of claim 53 or 54, wherein the disease or disorder is cardiac hypertrophy and / or myocardial fibrosis.

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