TEM8 antibodies and their use in treatment and detection of tumors
Inventors
Dimitrov, Dimiter • Zhu, Zhongyu • St. Croix, Brad • Zudaire, Enrique • Saha, Saurabh • Zhang, Xiaoyan Michelle • DeCrescenzo, Gary • WELSCH, Dean
Assignees
United Staes Of America Health And Human Services, Secretary of, Department of • Biomed Valley Discoveries Inc • US Department of Health and Human Services
Publication Number
US-9765142-B2
Publication Date
2017-09-19
Expiration Date
2034-10-13
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Abstract
Antibodies that specifically bind TEM8 protein, conjugates thereof, and their use, are disclosed herein. In some examples the conjugates and antibodies are useful for methods of detecting and treating pathogenic angiogenesis. In other examples the conjugates and antibodies are useful for methods of detecting and treating cancer. In additional examples, the conjugates and antibodies are useful for methods of decreasing binding of Anthrax protective antigen to a cell.
Core Innovation
The invention provides isolated human monoclonal neutralizing antibodies that specifically bind TEM8 on the cell surface, antigen binding fragments thereof, conjugates thereof, chimeric antigen receptor (CAR) T cells expressing a CAR including a disclosed antibody or antigen binding fragment thereof, and methods of using these molecules. The antibodies and conjugates include effector molecules or detectable markers linked to monoclonal antibodies that specifically bind TEM8. They are used in methods for detection of endothelial cells expressing TEM8, detection and treatment of pathological angiogenesis and tumors, and for decreasing binding of Anthrax protective antigen (PA) to a cell.
TEM8, also known as Anthrax Toxin Receptor 1 (ANTXR1), is a cell surface glycoprotein over-expressed in endothelial cells of tumor vasculature and functions as a receptor for Anthrax toxin. Unlike many angiogenesis regulators, TEM8 is not required for normal physiological angiogenesis but is up-regulated in tumor vessels and some tumor cells. Hence, there is a need for chemotherapeutic agents targeting TEM8 and high affinity antibodies that specifically bind TEM8 on the cell surface.
The disclosed antibodies and conjugates are useful beyond the specific circumstances described, for instance, to detect endothelial cells expressing TEM8, treat tumors such as carcinomas, reduce pathological angiogenesis, or decrease binding of Anthrax PA to cells. The methods can assist in detecting tumor blood vessels and inhibiting tumor growth and metastasis, as well as decreasing Anthrax toxin cellular entry.
Claims Coverage
The independent claims primarily cover isolated monoclonal antibodies or antigen binding fragments specifically binding TEM8, their compositions, conjugates, nucleic acid molecules encoding them, vectors, host cells, antibody-drug conjugates, kits, and methods of treating tumors, detecting cells expressing TEM8, and decreasing Anthrax PA binding.
Isolated monoclonal antibodies and antigen binding fragments specifically binding TEM8
Antibodies or antigen binding fragments comprising heavy and light chain variable regions including H-CDR1, H-CDR2, H-CDR3, and L-CDR1, L-CDR2, L-CDR3 of SEQ ID NOs: 1 and 2 (m825), 3 and 4 (m822), 5 and 6 (m830), or 7 and 8 (m863) respectively that specifically bind to TEM8 and are neutralizing.
Antibody and antigen binding fragment sequences
Antibodies comprising heavy and light chain variable regions with specific amino acid sequences set forth as SEQ ID NOs: 1 and 2, 3 and 4, 5 and 6, or 7 and 8 corresponding to m825, m822, m830, or m863 antibodies respectively.
Conjugation of antibodies to effector molecules or detectable markers
Antibodies or antigen binding fragments conjugated to effector molecules including anti-angiogenic agents, chemotherapeutic agents, and toxins such as maytansinoid toxins (DM1) or auristatin toxins (MMAE, MMAF), via cleavable or non-cleavable linkers including cathepsin-cleavable or selectively cleavable peptide linkers.
Nucleic acid molecules, vectors, host cells, and chimeric antigen receptors (CARs)
Isolated nucleic acids encoding the antibodies or antigen binding fragments, vectors for their expression, host cells including T cells comprising these sequences, and CAR T cells expressing chimeric antigen receptors derived from the antibodies.
Antibody-drug conjugates with defined formula and properties
Antibody-drug conjugates comprising anti-TEM8 antibodies with specified variable regions conjugated to MMAE toxin via linkers in defined stoichiometric ratios (n being an even integer from 2 to 8).
Compositions and kits with antibodies, nucleic acids, conjugates for diagnosis and treatment
Pharmaceutical compositions containing therapeutically effective amounts of antibodies, antigen binding fragments, nucleic acids, vectors, or antibody-drug conjugates, and kits comprising them with instructions for detecting pathological angiogenesis, treating tumors, or decreasing binding of Anthrax PA.
Methods of treating tumors with TEM8 antibodies or conjugates
Methods for selecting subjects with tumors and administering therapeutically effective amounts of the antibodies or antigen binding fragments or conjugates to treat tumors by forming immune complexes, optionally with co-administration of anti-angiogenic or chemotherapeutic agents.
Methods for detecting cells expressing TEM8
Methods of detecting cells with cell-surface expression of TEM8 in subjects by contacting cells with antibodies or antigen binding fragments or conjugates in vitro or in vivo to form immune complexes, the presence of which indicates pathological angiogenesis or tumors.
Methods for decreasing binding of Anthrax protective antigen
Methods of decreasing binding of Anthrax protective antigen to cells by contacting the cells with effective amounts of TEM8-specific antibodies or antigen binding fragments to form immune complexes, including administration to subjects.
The claims provide broad coverage of isolated monoclonal antibodies and antigen binding fragments specifically targeting TEM8, their molecular sequences, conjugates with therapeutic or diagnostic agents, nucleic acids and vectors encoding them, their use in CAR T cells, antibody-drug conjugates, compositions and kits, and methods of treatment of tumors, detection of cells expressing TEM8, and inhibition of Anthrax PA binding.
Stated Advantages
The antibodies specifically bind TEM8 with high affinity and neutralize its biological function.
The antibodies can be conjugated to therapeutic agents to selectively target TEM8-expressing tumor vasculature and cells, thereby inhibiting tumor growth and metastasis.
The antibodies and conjugates can detect tumor-associated endothelial cells expressing TEM8 via immunofluorescence and imaging assays.
The antibody-drug conjugates show selective cytotoxicity towards TEM8-expressing cells and demonstrate tumor regression in vivo.
Use of antibodies decreases binding of Anthrax protective antigen to cells, providing potential anti-Anthrax utility.
Documented Applications
Methods of detecting endothelial cells expressing TEM8 in subjects for detecting pathological angiogenesis and tumor-associated vasculature.
Treatment of tumors, including carcinomas such as breast carcinoma, colorectal carcinoma, lung carcinoma, and melanoma, by administering TEM8-specific antibodies, conjugates, or CAR T cells.
Decreasing binding of Anthrax protective antigen to cells to potentially prevent Anthrax toxin entry.
Use of antibody-drug conjugates for selective delivery of cytotoxins like MMAE to TEM8-expressing tumor cells in vivo.
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