Combination therapies targeting tumor-associated stroma or tumor cells and microtubules
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-11033620-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 a microtubule inhibitor; 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 by administering a combination of a microtubule inhibitor and a monoclonal antibody or antigen binding fragment thereof targeting tumor endothelial marker 8 (TEM8). The monoclonal antibody comprises specific heavy chain variable regions (VH) and light chain variable regions (VL) with amino acid sequences selected from defined SEQ ID NOs. Pharmaceutical compositions and kits containing these components are also disclosed.
The problem addressed arises from existing therapeutic approaches targeting tumor-associated stroma and vasculature, such as anti-angiogenic and vascular disrupting agents. While these therapies are used, especially in metastatic cancer cases, they suffer from toxicity and off-target effects against healthy vasculature. There is a need for additional therapeutics that are less toxic and that work in combination with current agents to suppress tumor growth by targeting tumor-associated stroma or the tumor cells themselves.
The invention thus addresses this need by providing combination therapies that include a microtubule inhibitor, which disrupts microtubule function, and a monoclonal antibody specifically recognizing the TEM8 antigen that is differentially expressed on tumor cells or tumor stroma. The combination demonstrates enhanced efficacy in multiple xenograft cancer models, including colorectal, melanoma, ovarian, breast, and lung cancers, when compared to monotherapies.
Claims Coverage
The patent presents two independent claims focused on compositions for treating tumors, covering the combination of a taxane-type microtubule inhibitor and a specific anti-TEM8 monoclonal antibody.
Composition comprising a taxane and a TEM8-targeting monoclonal antibody
The composition includes (a) a taxane selected from paclitaxel, docetaxel, cabazitaxel, DJ-927, and combinations thereof; and (b) a monoclonal antibody or antigen binding fragment having: (i) a heavy chain variable region comprising SEQ ID NO:5; (ii) a light chain variable region comprising SEQ ID NO:6; the antibody or fragment also includes a constant Fc region capable of mediating ADCC and binding to human TEM8 sequences (SEQ ID NOs: 10, 20, and 22). The tumor comprises cells expressing TEM8 on tumor or stromal cells.
Composition comprising paclitaxel and a TEM8-targeting monoclonal antibody for human subjects
The composition comprises (a) paclitaxel; and (b) a monoclonal antibody with heavy and light chain variable regions comprising SEQ ID NO:5 and SEQ ID NO:6, respectively, capable of mediating ADCC and binding to human TEM8 sequences (SEQ ID NOs: 10, 20, 22). The tumor contains human TEM8 expressing tumor or stromal cells.
The claims cover compositions combining microtubule inhibitors, especially taxanes like paclitaxel, with monoclonal antibodies targeting TEM8 with defined variable regions and Fc-mediated ADCC capability, for treating tumors expressing TEM8 on tumor or stromal cells, including human subjects.
Stated Advantages
The combination therapy targets tumor-associated stroma and tumor cells with enhanced efficacy compared to monotherapies.
The therapies demonstrate reduced toxicity and off-target effects relative to existing vascular targeting agents.
The compositions and methods enable treatment of a broad range of cancers expressing TEM8, improving survival and tumor regression in preclinical models.
Documented Applications
Treatment of various cancers including kidney, colon, lung, liposarcomas, brain, breast, melanoma, liver, head and neck, and prostate cancer.
Use in xenograft models for colorectal carcinoma, melanoma, ovarian cancer, breast cancer, non-small cell lung carcinoma, and colon carcinoma liver metastasis.
Combination therapy with microtubule inhibitors such as paclitaxel, and anti-TEM8 monoclonal antibodies or antibody-drug conjugates to inhibit tumor growth and improve survival.
Use in combination with molecularly targeted cancer pathway inhibitors such as COX-2 inhibitors, NSAIDs, and PGE2 synthase inhibitors to enhance anti-tumor effects.
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