Combination therapies using platinum agents and agents that target tumor-associated stroma or tumor cells
Inventors
Saha, Saurabh • Zhang, Xiaoyan M. • Dimitrov, Dimiter • Zhu, Zhongyu • St. Croix, Brad • Zudaire, Enrique
Assignees
Biomed Valley Discoveries Inc • US Department of Health and Human Services
Publication Number
US-10434174-B2
Publication Date
2019-10-08
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
Methods, pharmaceutical compositions, and kits for treating 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 platinum agent; and (b) a therapeutically effective amount of a monoclonal antibody or antigen binding fragment thereof.
Core Innovation
The invention provides methods, pharmaceutical compositions, and kits for treating diseases such as cancer by administering a therapeutically effective amount of a platinum agent together with a therapeutically effective amount of a monoclonal antibody or antigen binding fragment thereof. The monoclonal antibody specifically comprises heavy and light chain variable regions with amino acid sequences selected from SEQ ID NOs:1, 3, 5, 7 for heavy chains and SEQ ID NOs:2, 4, 6, 8 for light chains.
The methods particularly address diseases characterized by differential expression of tumor endothelial marker 8 (TEM8) membrane antigen on tumor cells and/or tumor stromal cells, which includes various cancers such as kidney, colon, lung, liposarcomas, brain, breast, melanoma, liver, head and neck, and prostate cancers. The platinum agents include a variety of compounds such as cisplatin, carboplatin, oxaliplatin and their analogs. The monoclonal antibodies can be full-length or antigen-binding fragments and include chimeric, humanized, or recombinant antibodies with defined variable region sequences.
The problem addressed is the need for effective cancer therapies that can target tumor-associated stroma, particularly tumor vasculature, with reduced toxicity and off-target effects as compared to existing anti-angiogenic and vascular disrupting agents. Current therapies targeting tumor vasculature are limited by their toxicity and effects on healthy vasculature. The invention aims to provide combinational treatments using platinum agents and TEM8-targeting antibodies to suppress tumor growth while minimizing toxicity to normal tissues.
Claims Coverage
The patent contains three independent claims focused on methods and compositions combining platinum agents with TEM8 monoclonal antibodies or fragments for treating TEM8-mediated diseases.
Combination of platinum agents with TEM8 monoclonal antibodies
A method of treating or ameliorating a TEM8-mediated disease by administering therapeutically effective amounts of a platinum agent and a TEM8 monoclonal antibody or antigen binding fragment, wherein the monoclonal antibody comprises a heavy chain variable region and a light chain variable region having amino acid sequences selected from SEQ ID NOs:1 & 2, 3 & 4, 5 & 6, or 7 & 8.
Specific variable region sequences for the TEM8 monoclonal antibody
A method wherein the monoclonal antibody comprises a heavy chain variable region comprising SEQ ID NO:5 and a light chain variable region comprising SEQ ID NO:6.
Combination of carboplatin with TEM8 monoclonal antibodies
A method for treating a TEM8-mediated disease comprising administering carboplatin as the platinum agent and a TEM8 monoclonal antibody or antigen binding fragment comprising heavy and light chain variable regions of SEQ ID NOs:5 and 6, respectively.
Pharmaceutical compositions combining platinum agents and TEM8 antibodies
Compositions comprising therapeutically effective amounts of a platinum agent and a TEM8 monoclonal antibody or antigen binding fragment with specific heavy and light chain variable region sequences selected from the sets indicated in the claims, particularly including carboplatin and antibodies with SEQ ID NOs:5 and 6.
The independent claims cover methods and compositions combining platinum agents, including carboplatin, with specific TEM8-targeting monoclonal antibodies or antigen binding fragments characterized by particular variable region sequences to treat or ameliorate TEM8-mediated diseases, notably cancers characterized by differential TEM8 expression.
Stated Advantages
Combination therapy with platinum agents and TEM8-targeting antibodies offers effective tumor growth suppression by specifically targeting tumor-associated stroma and tumor cells expressing TEM8.
The therapies aim to reduce toxicity and off-target effects compared to existing anti-angiogenic or vascular disrupting agents.
The monoclonal antibodies can achieve tumor specificity due to differential expression of TEM8, thereby sparing normal healthy tissues.
Documented Applications
Treatment of various cancers characterized by differential expression of tumor endothelial marker 8 (TEM8), including kidney cancer, colon cancer, lung cancer, liposarcomas, brain cancer, breast cancer, melanoma, liver cancer, head and neck cancer, and prostate cancer.
Use in xenograft models of colorectal carcinoma, melanoma, ovarian cancer, triple negative breast cancer, non-small cell lung carcinoma, and liver metastasis to inhibit tumor growth and improve survival.
Combination therapies involving platinum agents and TEM8 monoclonal antibodies to enhance anti-tumor efficacy and survival in animal cancer models.
Interested in licensing this patent?