Combination therapies targeting tumor-associated stroma or tumor cells
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-11033621-B2
Publication Date
2021-06-15
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 agent selected from the group consisting of an anti-angiogenic agent, a vascular disrupting agent (VDA), and combinations thereof; 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.
Core Innovation
The invention provides methods for treating or ameliorating diseases such as cancer in subjects by administering a combination of agents. These agents include an anti-angiogenic agent, a vascular disrupting agent (VDA), or combinations thereof, alongside a monoclonal antibody or antigen binding fragment recognizing tumor endothelial marker 8 (TEM8). The monoclonal antibodies comprise specific heavy chain variable regions (VH) and light chain variable regions (VL) defined by amino acid sequences selected from SEQ ID NOs:1, 3, 5, 7 for VH and SEQ ID NOs:2, 4, 6, 8 for VL.
The problem addressed by the invention is the toxicity and off-target effects associated with current chemotherapeutics directed toward tumor vasculature such as anti-angiogenic agents and vascular disrupting agents. These therapies, while widely used, particularly in metastatic cancer, can harm healthy vasculature. There exists a need for additional therapeutics that are less toxic and that can work in combination with current agents to suppress tumor growth by targeting the tumor-associated stroma or tumor cells.
The invention further encompasses pharmaceutical compositions and kits comprising the combination of (a) anti-angiogenic and/or vascular disrupting agents with (b) TEM8-specific monoclonal antibodies or antigen binding fragments thereof. The antibodies are designed to specifically target TEM8, which is differentially expressed on tumor cells and tumor-associated stroma, including tumor endothelial cells, with limited expression in healthy tissues. This specificity aims to reduce toxicity and improve therapeutic outcomes in cancer treatment.
Claims Coverage
The patent includes three independent claims focusing on compositions and methods involving combination therapies with bevacizumab and TEM8-targeting monoclonal antibodies or antigen binding fragments.
Combination composition comprising bevacizumab and TEM8-targeting monoclonal antibody
A composition for treating human tumors comprising (a) bevacizumab and (b) a monoclonal antibody or antigen binding fragment that includes a heavy chain variable region with the amino acid sequence of SEQ ID NO:5 and a light chain variable region with the amino acid sequence of SEQ ID NO:6. The monoclonal antibody or fragment includes a constant (Fc) region capable of mediating Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) and binds human tumor endothelial marker 8 (TEM8) sequences (SEQ ID NOs:10, 20, and 22). The tumor comprises TEM8-expressing tumor cells and/or tumor stromal cells.
Human tumor characterized by TEM8-expressing tumor or stromal cells
The human tumor targeted by the composition includes tumor cells and/or tumor stromal cells that express TEM8, specifically colon cancer.
Composition further comprising additional anti-angiogenic or vascular disrupting agents
The composition optionally includes one or more additional anti-angiogenic agents selected from a defined group including pegaptanib, ranibizumab, various inhibitors and steroids, and/or one or more vascular disrupting agents from a specified group including ABT-751, AVE8062, and others.
Combination composition comprising bevacizumab, irinotecan, and TEM8-targeting monoclonal antibody
A composition for treating tumors in humans comprising (a) bevacizumab and irinotecan, and (b) a monoclonal antibody or antigen binding fragment with heavy and light chain variable regions of SEQ ID NOs:5 and 6 respectively, capable of mediating ADCC and binding to human TEM8 sequences.
Pharmaceutical composition including the combination composition and pharmaceutically acceptable carrier
A pharmaceutical composition comprising the combination composition defined herein and a pharmaceutically acceptable diluent or carrier.
Kit comprising the combination composition or pharmaceutical composition with instructions
A kit containing the combination composition or pharmaceutical composition packaged together with instructions for use.
The claims cover combination therapies and pharmaceutical compositions involving bevacizumab with TEM8-targeting monoclonal antibodies having defined variable regions, capable of mediating ADCC and binding to TEM8 expressed on tumor and stromal cells. The claims also include use of additional anti-angiogenic and vascular disrupting agents, as well as kits comprising these compositions.
Stated Advantages
The invention provides additional therapeutics that are less toxic and can work synergistically with current agents to suppress tumor growth by specifically targeting tumor-associated stroma or tumor cells.
Combination therapies including the TEM8 antibodies and anti-angiogenic or vascular disrupting agents improve efficacy over monotherapies in xenograft models.
The antibodies target TEM8 with limited expression in normal tissues, reducing off-target effects and toxicity compared to existing therapies.
Pharmaceutical compositions and kits enable convenient and effective treatment regimens.
Documented Applications
Treatment of various cancers including kidney cancer, colon cancer, lung cancer, liposarcomas, brain cancer, breast cancer, melanoma, liver cancer, head and neck cancer, and prostate cancer.
Use in combination therapies with agents such as bevacizumab, paclitaxel, irinotecan, and other chemotherapeutics in xenograft tumor models.
Treatment of tumors expressing tumor endothelial marker 8 (TEM8) on tumor cells and tumor stromal cells including tumor vasculature.
Use of TEM8 antibodies as antibody-drug conjugates for enhanced antitumor effects in multiple cancer xenograft models.
Combination therapy with cyclooxygenase-2 (COX-2) inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), and prostaglandin E2 (PGE2) synthase inhibitors to improve efficacy against cancer.
Use in treatment of tumor-associated stroma or vascular structures associated with tumors to inhibit tumor growth and metastasis.
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