Combination therapies using agents that target tumor-associated stroma or tumor cells and other pathways
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-10758526-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 a molecularly targeted 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 a combination of (a) a therapeutically effective amount of a molecularly targeted agent and (b) a therapeutically effective amount of a monoclonal antibody or antigen binding fragment thereof. The monoclonal antibody comprises specific heavy chain variable regions selected from SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, and SEQ ID NO:7 and light chain variable regions selected from SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, and SEQ ID NO:8. These methods include use of antibodies targeting tumor endothelial marker 8 (TEM8) which is differentially expressed on tumor cells and tumor-associated stromal cells.
The problem being solved is that current anti-angiogenic and vascular disrupting agents, which target tumor-associated stroma particularly tumor vasculature, suffer from toxicity and off-target effects on healthy vasculature. Thus, there is a need for additional therapeutics that have reduced toxicity and can work in combination with existing agents to more effectively suppress tumor growth by targeting tumor-associated stroma or tumor cells themselves.
Claims Coverage
The claims cover five main inventive features related to compositions for treating tumors using specific antibodies and molecularly targeted agents.
Composition comprising monoclonal antibody with defined heavy and light chain variable regions binding TEM8 and a molecularly targeted agent
A composition for treating a tumor comprising at least one molecularly targeted agent and a monoclonal antibody or antigen binding fragment with heavy chain variable region comprising SEQ ID NO:5 and light chain variable region comprising SEQ ID NO:6. The antibody includes a constant (Fc) region and binds human tumor endothelial marker 8 (TEM8). The molecularly targeted agent is selected from a specified group including trastuzumab, bevacizumab, erlotinib, vemurafenib, gefitinib, and others.
Composition wherein the tumor comprises tumor cells expressing human TEM8
The tumor targeted by the composition comprises tumor cells that express human TEM8.
Composition wherein the tumor comprises stromal cells expressing human TEM8
The tumor targeted comprises tumor stromal cells expressing human TEM8; includes cancers such as kidney, colon, lung, liposarcomas, brain, breast, melanoma, liver, head and neck, and prostate cancer.
Composition comprising monoclonal antibody with specified VH and VL sequences and a molecularly targeted agent
A composition comprising at least one molecularly targeted agent and a monoclonal antibody or antigen binding fragment thereof with heavy chain variable region of SEQ ID NO:5 and light chain variable region of SEQ ID NO:6 that binds human TEM8, with molecularly targeted agents selected from a defined group.
Composition comprising trastuzumab and a monoclonal antibody or fragment binding TEM8
A composition comprising trastuzumab and a monoclonal antibody or antigen binding fragment thereof with heavy chain variable region of SEQ ID NO:5 and light chain variable region of SEQ ID NO:6 that binds human TEM8.
The claims focus on compositions combining molecularly targeted agents, including trastuzumab, with monoclonal antibodies specifically binding TEM8 via defined heavy and light chain variable regions for treatment of tumors expressing TEM8 on tumor cells and/or stromal cells, covering specified cancers.
Stated Advantages
The combination therapies are less toxic compared to current anti-angiogenic agents and have reduced off-target effects on healthy vasculature.
The combination of TEM8 antibodies with molecularly targeted agents is effective at suppressing tumor growth, including complete tumor regressions in xenograft models.
The therapies show enhanced efficacy in combination compared to monotherapies across multiple cancer models, demonstrating potential synergistic effects.
Documented Applications
Treatment of cancers characterized by differential expression of tumor endothelial marker 8 (TEM8) including kidney, colon, lung, liposarcomas, brain, breast, melanoma, liver, head and neck, and prostate cancers.
Use in combination therapy with molecularly targeted agents such as trastuzumab, bevacizumab, irinotecan, paclitaxel, celecoxib, ibuprofen, and sulindac sulphide in various xenograft tumor models.
Treatment of tumor-associated stroma and tumor vasculature to inhibit tumor growth and metastasis, demonstrated in multiple in vivo xenograft models including colorectal carcinoma, melanoma, ovarian cancer, breast cancer, non-small cell lung carcinoma, and liver metastasis models.
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