TEM8 antibodies, conjugates thereof, and their use
Inventors
St. Croix, Brad • Fleming, Tony • Chaudhary, Amit • Saha, Saurabh • Zhang, Xiaoyan Michelle • Kwong, Rou-fun • Hilton, Mary Beth
Assignees
Novartis AG • US Department of Health and Human Services
Publication Number
US-9181340-B2
Publication Date
2015-11-10
Expiration Date
2032-06-13
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Abstract
Antibodies that specifically bind TEM8 protein, and conjugates thereof, 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 to the Tumor Endothelial Marker 8 (TEM8) protein on the cell surface, antigen binding fragments of such antibodies, conjugates thereof, and methods of using these molecules. The conjugates can include an effector molecule or a detectable marker covalently linked to a monoclonal antibody or antigen binding fragment that specifically binds TEM8. These antibodies and conjugates are useful in methods for the detection of endothelial cells expressing TEM8, detecting pathological angiogenesis, detecting and treating tumors including carcinomas, and for decreasing binding of Anthrax protective antigen (PA) to a cell.
The problem solved by the invention arises from the critical role of angiogenesis in tumor growth and other diseases. TEM8 is over-expressed in endothelial cells lining tumor vasculature but is not required for normal physiological angiogenesis, making it an attractive therapeutic target. Prior to this invention, there was a need for chemotherapeutic agents that target TEM8 and for high affinity antibodies that specifically bind TEM8 on the cell surface. The invention addresses this need by providing such antibodies and conjugates, enabling improved detection and treatment of pathological angiogenesis, tumors, and reduction of Anthrax PA binding.
Claims Coverage
The patent contains multiple independent claims focused on isolated monoclonal antibodies or antigen binding fragments thereof that specifically bind TEM8, their conjugates, encoding nucleic acids, compositions, and methods of treatment and detection. The inventive features cover antibody structure, specificity, conjugation with effector molecules or detectable markers, nucleic acid vectors, therapeutic uses, and diagnostic methods.
TEM8-specific monoclonal antibodies and antigen binding fragments
Isolated monoclonal antibodies or antigen binding fragments comprising heavy and light chain variable regions with defined complementarity determining regions (CDRs) sequences from five antibodies (L1, L2, L3, L5, 1D2) that specifically bind TEM8.
Conjugation of antibodies to effector molecules or detectable markers
Monoclonal antibodies or antigen binding fragments conjugated to chemotherapeutic agents, anti-angiogenic agents, toxins (including maytansinoids like DM1, auristatins like MMAE or MMAF), or detectable markers such as fluorescent, enzymatic, heavy metal, or radioactive markers, with the linker possibly being cleavable.
Nucleic acid molecules encoding the antibodies
Isolated nucleic acid molecules encoding the monoclonal antibodies or antigen binding fragments with specified heavy and light chain variable regions; expression vectors and host cells comprising these nucleic acids.
Methods of treating tumors expressing TEM8
Methods of treating subjects having TEM8-expressing tumors by administering a therapeutically effective amount of the specified monoclonal antibodies or antigen binding fragments to form immune complexes, optionally combined with additional agents such as anti-angiogenic or chemotherapeutic agents.
Methods of detecting endothelial cells expressing TEM8
Methods for detecting endothelial cells expressing TEM8 in a subject by contacting such cells with effective amounts of the monoclonal antibodies or antigen binding fragments and detecting immune complexes, performed in vivo or in vitro, to detect pathological angiogenesis.
Methods of decreasing binding of Anthrax protective antigen to cells
Methods of decreasing Anthrax protective antigen binding to a cell by contacting the cell with effective amounts of the specified antibodies or antigen binding fragments, optionally by administering to a subject.
Kits for detection and treatment
Kits comprising the specified monoclonal antibodies or antigen binding fragments and instructions for use for detecting pathological angiogenesis, treating tumors, or decreasing Anthrax protective antigen binding.
The claims provide comprehensive coverage of monoclonal antibodies specific to TEM8, their conjugates with therapeutic or diagnostic agents, nucleic acid constructs, compositions, and methods of use for treating tumors, detecting TEM8-positive cells, and reducing Anthrax protective antigen binding. This wide-ranging coverage protects the antibodies themselves, their compositions, conjugates, encoding sequences, and applications in therapy and diagnostics related to pathological angiogenesis and Anthrax toxin interference.
Stated Advantages
The antibodies and conjugates specifically bind TEM8 with high affinity and are neutralizing, enabling targeted detection and treatment.
The antibodies inhibit tumor growth and pathological angiogenesis in multiple tumor models without affecting normal wound healing or physiological angiogenesis.
Treatment with the antibodies or conjugates is non-toxic in animal models even at high doses.
The antibodies augment the efficacy of various classes of anti-cancer agents including chemotherapeutics and anti-angiogenic agents without added toxicity.
The antibodies can engage immune effector functions such as antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity.
The conjugates enable specific detection of tumor vasculature over normal tissues, facilitating diagnostic imaging of pathological angiogenesis.
Documented Applications
Methods of detecting endothelial cells expressing TEM8 in a subject for detection of pathological angiogenesis.
Methods for treating tumors, including breast carcinoma, colorectal carcinoma, lung carcinoma, and skin cancer, by administering TEM8-specific antibodies or conjugates.
Decreasing binding of Anthrax protective antigen to cells for potential treatment or prevention of Anthrax infection.
Use of TEM8-specific antibody conjugates in combination with other anti-cancer agents to enhance tumor growth inhibition.
Use of TEM8-specific antibody conjugates labeled with detectable markers for diagnostic imaging of tumor vasculature in vivo.
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