Therapeutic antibodies against osteopontin
Inventors
Leung, Lawrence L. K. • Morser, Michael J. • MYLES, TIMOTHY
Assignees
US Department of Veterans Affairs • Leland Stanford Junior University
Publication Number
US-12351625-B2
Publication Date
2025-07-08
Expiration Date
2040-08-07
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Abstract
Therapeutic antibodies specific for osteopontin and methods of using them for treating osteopontin-associated disorders are provided. In particular, antibodies, or antigen-binding fragments thereof, that inhibit thrombin-cleavage of osteopontin or block the activity of thrombin cleavage fragments of osteopontin are provided. Additionally, antibody conjugates and pharmaceutical compositions or formulations comprising the antibodies or antibody conjugates as well as kits including the antibodies, conjugates, or formulations are also provided.
Core Innovation
The invention provides therapeutic antibodies specific for osteopontin (OPN) and methods of using these antibodies for treating disorders associated with osteopontin. Specifically, the antibodies or antigen-binding fragments inhibit thrombin-cleavage of osteopontin or block the activity of thrombin cleavage fragments, such as OPN-R and OPN-CTF, which interact with integrins and other cellular receptors.
The problem addressed is that thrombin cleavage of osteopontin generates fragments that modulate immune and cellular responses, with OPN-R implicated in inflammatory disorders and osteopontin overexpression linked to several cancers. Elevated levels of thrombin-cleaved OPN fragments are associated with diseases like rheumatoid arthritis and possibly tumor progression, but the role of thrombin cleavage in cancers is not well understood. Thus, there is a need for therapeutic agents that inhibit the cleavage or activity of these fragments to treat osteopontin-associated disorders.
Claims Coverage
The patent includes one independent claim describing antibodies with specific binding and functional inhibition properties, covering multiple antibody variants and compositions, as well as therapeutic methods and conjugates. Three main inventive antibody features are claimed.
Antibody comprising specific CDR sequences inhibiting OPN thrombin cleavage or integrin binding
An isolated antibody or antigen-binding fragment specifically binding to osteopontin or a thrombin cleavage fragment thereof, wherein the antibody inhibits thrombin cleavage of osteopontin or integrin binding to the thrombin cleavage fragment of osteopontin, and comprises a set of complementarity-determining regions (CDRs) defined by SEQ ID NOs:29-34, or alternatively SEQ ID NOs:35-40, or SEQ ID NOs:41-46.
Antibody comprising heavy and light chains with specified sequences or homologs
An antibody or antigen-binding fragment comprising a heavy chain amino acid sequence of SEQ ID NO:14 or SEQ ID NO:18 (or at least 80% sequence identity thereto) combined with a light chain amino acid sequence of SEQ ID NO:16 or SEQ ID NO:20 (or at least 80% identity).
Antibody comprising alternative heavy and light chain sequences or homologs
An antibody or antigen-binding fragment comprising a heavy chain with the amino acid sequence of SEQ ID NO:22 (or at least 80% identity) and a light chain with the amino acid sequence of SEQ ID NO:24 (or at least 80% identity).
Antibody comprising another set of heavy and light chain sequences or homologs
An antibody or antigen-binding fragment comprising a heavy chain with the amino acid sequence of SEQ ID NO:26 (or at least 80% identity) and a light chain with the amino acid sequence of SEQ ID NO:28 (or at least 80% identity).
Antibody selected from various immunoglobulin formats
The antibody can be selected from monoclonal, polyclonal, chimeric, humanized, nanobody, Fab, Fab', F(ab′)2, Fv, or single-chain Fv (scFv) fragments.
Pharmaceutical composition comprising the antibodies
A composition comprising the antibody or antigen-binding fragment thereof and a pharmaceutically acceptable excipient or carrier, optionally including B-Raf inhibitors, MEK inhibitors, or their combination.
Method of treating osteopontin-associated disorders with the antibody compositions
A method of treatment comprising administering to a subject a therapeutically effective amount of the antibody compositions to treat osteopontin-associated disorders such as inflammation, cardiac hypertrophy, myocardial fibrosis, and cancers overexpressing osteopontin, including melanoma, glioblastoma, ovarian, breast, and lung cancers, optionally with additional anti-cancer agents.
Conjugates of the antibodies with therapeutic or imaging agents
Conjugates comprising the antibody or antigen-binding fragment thereof linked to agents such as anti-cancer therapeutics, detectable labels, or imaging agents, including cytotoxic agents, toxins, pro-apoptotic agents, photoactive agents, and radioisotopes.
The claims broadly cover isolated antibodies with defined CDRs and heavy/light chain sequences that specifically bind osteopontin or its thrombin cleavage fragments and inhibit cleavage or integrin interactions. These antibodies are provided in various formats, compositions with carriers and inhibitors, therapeutic methods for osteopontin-related disorders, and as conjugates with therapeutic or diagnostic agents.
Stated Advantages
The antibodies provide therapeutic benefit by blocking osteopontin cleavage and activity of thrombin cleavage fragments, helping to treat melanoma and other cancers.
Use of antibodies prevents osteopontin cleavage without the bleeding risk associated with thrombin inhibitors or anticoagulants.
Documented Applications
Treatment of osteopontin-associated disorders including inflammation, cardiac hypertrophy, myocardial fibrosis, and cancers overexpressing osteopontin such as melanoma, glioblastoma, ovarian cancer, breast cancer, and lung cancer.
Use in monotherapy or combined with standard therapies for melanoma and other cancers.
Use in diagnosis and imaging when conjugated with detectable labels or imaging agents.
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