Combination therapies using agents that target tumor-associated stroma or tumor cells and alkylating agents
Inventors
Saha, Saurabh • Zhang, Xiaoyan M. • Dimitrov, Dimiter • Zhu, Zhongyu • St. Croix, Brad • Zudaire, Enrique
Assignees
National Institutes of Health NIH • Biomed Valley Discoveries Inc • US Department of Health and Human Services
Publication Number
US-10799584-B2
Publication Date
2020-10-13
Expiration Date
2035-06-09
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Abstract
The present invention provides, inter alia, methods for treating or ameliorating the effects of a disease, such as cancer, in a subject. The methods include: administering to a subject in need thereof (a) a therapeutically effective amount of an alkylating agent; and (b) a therapeutically effective amount of a monoclonal antibody or antigen binding fragment thereof, wherein the monoclonal antibody contains: (i) a heavy chain variable region (VH), which includes an amino acid sequence selected from SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, and SEQ ID NO:7; and (ii) a light chain variable region (VL), which includes an amino acid sequence selected from SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, and SEQ ID NO:8. Compositions, including pharmaceutical compositions, and kits for treating diseases, such as cancer, are also provided herein.
Core Innovation
The invention provides methods and compositions for treating or ameliorating diseases, such as cancer, by administering to a subject in need thereof a therapeutically effective amount of an alkylating agent together with a therapeutically effective amount of a monoclonal antibody or antigen binding fragment thereof. The monoclonal antibody comprises specific heavy chain variable region (VH) and light chain variable region (VL) amino acid sequences selected from particular SEQ ID NOs.
The problem addressed by the invention arises from the limitations of existing cancer therapies that target tumor-associated stroma and vasculature. Current treatments, including anti-angiogenic and vascular disrupting agents, often cause toxicity and off-target effects on healthy vasculature. Therefore, there is a need for additional therapeutics that are less toxic and that can be used in combination with current agents to better suppress tumor growth by targeting tumor-associated stroma or tumor cells themselves.
The invention utilizes monoclonal antibodies targeting tumor endothelial marker 8 (TEM8), which is differentially expressed, often upregulated, on tumor endothelial cells, tumor cells, and tumor stromal cells compared to healthy cells. When used in combination with alkylating agents such as cyclophosphamide, or with ionizing radiation, these antibodies provide a method and composition for effective treatment against various cancers. The provision of pharmaceutical compositions and kits further facilitates the practical application of these combination therapies.
Claims Coverage
The claims include one independent claim focusing on a method of treating a tumor by administering a combination of ionizing radiation and a specific monoclonal antibody or antigen binding fragment thereof.
Combination of ionizing radiation and monoclonal antibody targeting TEM8
A method of treating a tumor comprising administering ionizing radiation together with a monoclonal antibody or antigen binding fragment that binds human tumor endothelial marker 8 (TEM8). The monoclonal antibody comprises a heavy chain variable region with the amino acid sequence SEQ ID NO:5 and a light chain variable region with the amino acid sequence SEQ ID NO:6.
Specific binding and targeting of TEM8-expressing tumor cells and stromal cells
The monoclonal antibody or antigen binding fragment includes a constant (Fc) region and binds specifically to human TEM8 expressed on one or more of the tumor cells and tumor stromal cells present in the tumor.
Use against various cancers expressing TEM8
The method covers treatment of tumors comprising cancers selected from kidney, colon, lung, liposarcomas, brain, breast, melanoma, liver, head and neck, and prostate cancers.
Monoclonal antibody defined by nucleic acid sequence encoding heavy chain variable region
The antibody or antigen binding fragment comprises the VH polypeptide encoded by the nucleic acid sequence corresponding to SEQ ID NO:15.
The independent claim covers a method of treating TEM8-expressing tumors by combining ionizing radiation with a monoclonal antibody comprising specific heavy and light chain variable regions that target TEM8, optionally covering several cancer types and defined by particular polypeptide sequences.
Stated Advantages
Provides additional therapeutics with reduced toxicity compared to existing anti-angiogenic and vascular disrupting agents.
Enables combination therapy that enhances suppression of tumor growth by targeting tumor-associated stroma or tumor cells.
Offers specific targeting of tumor cells and stromal cells expressing the tumor endothelial marker 8 (TEM8), sparing normal healthy tissue.
Can be formulated into pharmaceutical compositions and kits for practical use in treating cancer.
Documented Applications
Treatment of various cancers including kidney, colon, lung, liposarcomas, brain, breast, melanoma, liver, head and neck, and prostate cancers.
Combination therapies comprising alkylating agents such as cyclophosphamide and monoclonal antibodies targeting TEM8.
Combination therapies comprising ionizing radiation with TEM8-targeting monoclonal antibodies or antigen binding fragments.
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