Combination therapies using agents that target tumor-associated stroma or tumor cells and tumor vasculature
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-11034757-B2
Publication Date
2021-06-15
Expiration Date
2035-06-09
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
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 a monoclonal antibody or antigen binding fragment of the present invention, and (b) a therapeutically effective amount of a combination therapy including bevacizumab and at least one additional therapeutic agent; or a therapeutically effective amount of at least one additional therapeutic agent selected from the group consisting of a COX-2 inhibitor (COXIB), a non-steroidal anti-inflammatory drug (NSAID), a prostaglandin E2 (PGE2) synthase inhibitor, and combinations thereof. Compositions, including pharmaceutical compositions, and kits for treating diseases, such as cancer, are also provided herein.
Core Innovation
The invention provides methods for treating or ameliorating the effects of diseases, particularly cancer, in subjects by administering a combination of therapeutic agents. Specifically, the methods include administering (a) a combination therapy comprising bevacizumab and at least one additional therapeutic agent, and (b) a therapeutically effective amount of a monoclonal antibody or antigen binding fragment thereof that targets tumor endothelial marker 8 (TEM8). The monoclonal antibody comprises specified heavy and light chain variable regions with 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 that current therapeutics targeting tumor-associated stroma, especially tumor vasculature, such as anti-angiogenic agents and vascular disrupting agents, are hampered by toxicity and off-target effects against healthy vasculature. There is a need for additional therapeutics that are less toxic and can work in combination with existing agents to suppress tumor growth by targeting tumor-associated stroma or tumor cells themselves.
The invention also includes compositions and pharmaceutical compositions comprising these monoclonal antibodies or antigen binding fragments and the therapeutic agents, as well as kits comprising such compositions with instructions for use. The therapeutic agents encompass a broad range of anti-cancer agents, including COX-2 inhibitors, NSAIDs, prostaglandin E2 synthase inhibitors, and chemotherapeutic drugs such as irinotecan, fluoropyrimidine-irinotecan combinations, and others. The monoclonal antibodies specifically target TEM8, a membrane antigen differentially expressed on tumor endothelial and stromal cells, enabling selective targeting of tumor-associated vasculature while sparing healthy tissues.
Claims Coverage
The patent includes two independent claims focusing on therapeutic compositions combining bevacizumab-based regimens with monoclonal antibodies targeting TEM8.
Combination therapy comprising bevacizumab and a topoisomerase inhibitor with a TEM8 monoclonal antibody
A composition for treating human tumors comprising (a) a combination therapy with bevacizumab and a topoisomerase inhibitor selected from irinotecan, topotecan hydrochloride, etoposide, doxorubicin, epirubicin, idarubicin, and combinations thereof; and (b) a monoclonal antibody or antigen binding fragment thereof. The monoclonal antibody comprises a heavy chain variable region of SEQ ID NO:5 and a light chain variable region of SEQ ID NO:6, and includes an Fc region capable of mediating antibody-dependent cell-mediated cytotoxicity (ADCC). The antibody binds to one or more human TEM8 sequences (SEQ ID NOs: 10, 20, 22), targeting tumor and/or stromal cells expressing TEM8.
The independent claims cover therapeutic compositions combining bevacizumab and specified chemotherapeutic agents with TEM8-targeting monoclonal antibodies, emphasizing sequences of VH and VL regions, Fc-mediated ADCC capability, and tumor targeting based on TEM8 expression.
Stated Advantages
The monoclonal antibodies effectively target TEM8-expressing tumor and tumor stromal cells, sparing normal tissues, thereby potentially reducing toxicity compared to current therapies.
Combination therapies using these antibodies with bevacizumab and other therapeutic agents exhibit enhanced efficacy against various tumor models compared to monotherapies.
Antibody-drug conjugates (ADCs) based on the monoclonal antibodies show significant tumor inhibition and regression, even where cytotoxicity in vitro is weak, indicating targeted potency in vivo.
The combinations with COX-2 inhibitors, NSAIDs, and prostaglandin E2 synthase inhibitors provide further therapeutic potential, showing expected synergy and improved outcomes.
Documented Applications
Treatment of cancers characterized by differential or upregulated expression of TEM8, including kidney, colon, lung, liposarcomas, brain, breast, melanoma, liver, head and neck, and prostate cancers.
Use of monoclonal antibodies against TEM8 in combination with bevacizumab and chemotherapeutic agents such as irinotecan, fluoropyrimidine-irinotecan, and other anti-cancer drugs for enhanced therapeutic outcomes.
Treatment of tumor-associated stroma or tumor vasculature through targeted inhibition using combination therapies comprising TEM8 antibodies and VEGF pathway inhibitors.
Use in pharmaceutical compositions and kits comprising combinations of TEM8 monoclonal antibodies and other therapeutic agents for administration in cancer therapeutics.
Interested in licensing this patent?