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
Biomed Valley Discoveries Inc • US Department of Health and Human Services
Publication Number
US-10196443-B2
Publication Date
2019-02-05
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 relates to isolated human monoclonal neutralizing antibodies that specifically bind the Tumor Endothelial Marker 8 (TEM8) protein on the cell surface, antigen binding fragments of such antibodies, conjugates thereof, and chimeric antigen receptor (CAR) T cells expressing a CAR including a disclosed antibody or antigen binding fragment thereof. These molecules can be used for detecting endothelial cells that express TEM8, detecting and treating tumors such as carcinomas, treating pathogenic angiogenesis, and decreasing the binding of Anthrax protective antigen (PA) to cells.
The antibodies or conjugates include human monoclonal antibodies that bind TEM8 with high affinity and are neutralizing, such that they can inhibit TEM8's biological functions including pathological angiogenesis and tumor growth or metastasis. Conjugates comprising an effector molecule or detectable marker linked to such antibodies are provided. The invention also encompasses CAR T cells expressing these antibodies or fragments for targeted immunotherapy. The disclosed antibodies and their derivatives can be used beyond the specific examples described, encompassing a wide range of applications related to pathological angiogenesis, tumor detection and treatment, and Anthrax PA binding inhibition.
The problem being addressed is the need for chemotherapeutic agents that specifically target TEM8, particularly high affinity antibodies that bind selectively to TEM8 on cell surfaces. TEM8 is a tumor-associated endothelial marker overexpressed on tumor vasculature and in some tumor cells, but unlike other angiogenesis regulators, is not essential for normal physiological angiogenesis. Targeting TEM8 offers an opportunity to treat tumors and pathological angiogenesis with potentially fewer side effects because of its limited expression in normal tissues. Additionally, there is a need for agents that reduce binding of Anthrax protective antigen to TEM8, as TEM8 serves as a receptor for Anthrax toxin.
Claims Coverage
The patent includes 33 claims, with independent claims directed to cDNA sequences encoding monoclonal antibodies or antigen binding fragments that specifically bind and neutralize TEM8, as well as methods of treating tumors, detecting TEM8-expressing cells, decreasing Anthrax PA binding, and compositions and kits encompassing these elements. The main inventive features cover antibody coding sequences, specific binding and neutralizing properties, methods of treatment and detection, and use in CAR T cells.
cDNA sequences encoding TEM8-specific human monoclonal antibodies
cDNA sequences encoding heavy and light chain variable regions of monoclonal antibodies or antigen binding fragments thereof that specifically bind and neutralize TEM8 protein, including sequences corresponding to m825, m822, m830, and m863 antibodies.
Antibody or antigen binding fragment with specified complementarity determining regions
The antibodies include heavy and light chain complementarity determining regions (H-CDR1, H-CDR2, H-CDR3 and L-CDR1, L-CDR2, L-CDR3) encoded by cDNAs that correspond to specific amino acid residues of the disclosed SEQ ID NOs.
Vectors and host cells for expression of the antibodies or antigen binding fragments
Vectors comprising the cDNA sequences and host cells (including T cells) transformed with such vectors to express the TEM8-specific antibodies or antigen binding fragments, enabling production and use in therapeutic applications.
Methods of treating tumors using therapeutically effective amounts of the antibodies or antigen binding fragments
Methods comprising selecting subjects with tumors and administering therapeutically effective amounts of the TEM8-specific antibodies or antigen binding fragments to form immune complexes that treat tumors, including colorectal, skin, lung, breast, prostate, or head and neck cancers.
Methods of detecting TEM8-expressing cells
Methods comprising contacting a cell from a subject with the TEM8-specific antibodies or antigen binding fragments under conditions sufficient to form an immune complex and detecting this complex to indicate the presence of TEM8-expressing cells, including endothelial and tumor stromal cells, thereby detecting pathological angiogenesis or tumors.
Methods of decreasing binding of Anthrax protective antigen to cells
Methods comprising contacting cells with TEM8-specific antibodies or antigen binding fragments to form immune complexes that decrease binding of Anthrax protective antigen to the cells, thereby potentially preventing Anthrax toxin entry.
Kits comprising the cDNA sequences, vectors, host cells, and compositions
Kits including components selected from cDNA sequences encoding TEM8-specific antibodies or antigen binding fragments, vectors comprising these sequences, host cells, and compositions thereof, for detecting pathological angiogenesis, treating tumors, or decreasing Anthrax protective antigen binding.
The claims cover TEM8-specific neutralizing human monoclonal antibody coding cDNAs, their expression vectors and host cells, therapeutic and diagnostic methods employing these antibodies or fragments, methods for decreasing Anthrax PA binding, and kits including these compositions. The inventive features focus on antibody sequence specificity, methods of treatment and detection of tumors and pathological angiogenesis, and Anthrax-related applications.
Stated Advantages
The antibodies and conjugates specifically bind TEM8 with high affinity and neutralize biological functions, enabling targeted treatment of pathological angiogenesis and tumors.
The antibodies inhibit tumor growth and metastasis in animal models.
Antibody-drug conjugates demonstrate selective cytotoxicity towards TEM8-expressing cells and enhanced tumor regression compared to antibody alone.
The antibodies can detect TEM8-expressing endothelial cells, facilitating diagnosis and imaging of pathological angiogenesis.
The antibodies can decrease binding of Anthrax protective antigen to TEM8, offering potential for Anthrax toxin inhibition.
Documented Applications
Detection of endothelial cells expressing TEM8 in subjects to identify pathological angiogenesis, including tumor-associated blood vessels.
Treatment of tumors, including carcinomas such as breast, colorectal, lung, and skin cancer, by administration of TEM8-specific antibodies, antibody fragments, conjugates, or CAR T cells.
Use in imaging techniques for in vivo or in vitro detection of TEM8-expressing cells or pathological angiogenesis.
Decreasing binding of Anthrax protective antigen to cells by contacting them with TEM8-specific antibodies or conjugates.
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