Combination therapies using anti-metabolites 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
National Institutes of Health NIH • Biomed Valley Discoveries Inc • US Department of Health and Human Services
Publication Number
US-10758613-B2
Publication Date
2020-09-01
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 an anti-metabolite agent or analog thereof 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 herein.
Core Innovation
The invention provides methods for treating or ameliorating the effects of diseases such as cancer in a subject by administering a combination of (a) a therapeutically effective amount of an anti-metabolite agent or its analog and (b) 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 SEQ ID NO:1, 3, 5, 7 for VH and SEQ ID NO:2, 4, 6, 8 for VL.
The problem being solved is the toxicity and off-target effects associated with existing chemotherapeutic agents directed toward tumor vasculature, including anti-angiogenic agents and vascular disrupting agents. These conventional therapies often affect healthy vasculature and are limited in their efficacy, especially in metastatic cancer. There is a need for additional therapeutics that are less toxic and can work in combination with current agents to suppress tumor growth by specifically targeting tumor-associated stroma or tumor cells.
The invention addresses this need by providing compositions, pharmaceutical compositions, and kits that combine anti-metabolite agents or analogs with monoclonal antibodies specifically targeting tumor endothelial marker 8 (TEM8), which is differentially expressed on tumor endothelial cells, tumor cells, and tumor stromal cells. This combination is intended to enhance therapeutic efficacy with improved targeting and potentially reduced toxicity compared to existing therapies.
Claims Coverage
The patent contains several independent claims focusing on combination compositions and methods for treating tumors using anti-metabolite agents with TEM8-targeting monoclonal antibodies.
Combination composition comprising anti-metabolite agents and TEM8-specific monoclonal antibodies
A composition for treating human tumors comprising (a) an anti-metabolite agent or analog selected from antifolates, purine inhibitors, pyrimidine inhibitors, and their combinations; and (b) a monoclonal antibody or antigen-binding fragment thereof. The monoclonal antibody comprises 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, includes a constant Fc region, and binds human TEM8 expressed on tumor cells and/or tumor stromal cells.
Monoclonal antibody variable region specificity
The monoclonal antibody or antigen binding fragment comprises a heavy chain variable region with the amino acid sequence from SEQ ID NO:5 and a light chain variable region from SEQ ID NO:6 that specifically binds human tumor endothelial marker 8 (TEM8).
Use of specified anti-metabolite agents in combination treatments
The anti-metabolite agent or analog used in the combination is selected from 5-fluorouracil, tegafur, capecitabine, cladribine, methotrexate, pemetrexed, hydroxyurea, and various other purine and pyrimidine inhibitors, pharmaceutically acceptable salts thereof, and their combinations.
Pharmaceutical composition including the combined agents
A pharmaceutical composition comprising the combination of an anti-metabolite agent or analog and the monoclonal antibody or antigen binding fragment thereof as defined above, formulated with a pharmaceutically acceptable diluent or carrier.
Kit comprising the combination composition with usage instructions
A kit comprising the combination composition or pharmaceutical composition as described, packaged together with instructions for use in treating tumors.
The independent claims cover therapeutic compositions and methods employing a specific anti-metabolite agent or analog combined with a monoclonal antibody targeting TEM8, including defined VH and VL sequences, formulated as pharmaceutical compositions and kits for treating tumors expressing TEM8.
Stated Advantages
The combination therapy using anti-metabolite agents and TEM8-targeting monoclonal antibodies offers effective suppression of tumor growth by specifically targeting tumor-associated stroma and tumor cells.
The invention provides therapeutics that are less toxic and have fewer off-target effects compared to existing anti-angiogenic and vascular disrupting cancer therapies.
The combination approach enhances treatment efficacy, including improved survival and tumor regression as demonstrated in multiple xenograft models.
Documented Applications
Treatment or amelioration of cancer in subjects, including tumor types such as kidney, colon, lung, liposarcomas, brain, breast, melanoma, liver, head and neck, and prostate cancers.
Treatment of tumors expressing human tumor endothelial marker 8 (TEM8) in tumor cells and/or tumor stromal cells.
Combination therapies employing anti-metabolite agents such as 5-fluorouracil and monoclonal antibodies targeting TEM8 to inhibit tumor growth in xenograft models including colorectal carcinoma, melanoma, ovarian cancer, breast cancer, non-small cell lung carcinoma, and colon carcinoma liver metastasis.
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