Combination therapies targeting tumor-associated stroma or tumor cells and topoisomerase
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-10758614-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 topoisomerase 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 and compositions for treating or ameliorating the effects of diseases, such as cancer, in a subject by administering a therapeutically effective amount of a topoisomerase inhibitor together with a therapeutically effective amount of a monoclonal antibody or antigen binding fragment thereof. The monoclonal antibody comprises specific heavy chain variable regions (VH) and light chain variable regions (VL) selected from defined amino acid sequences (SEQ ID NOs: 1, 3, 5, 7 for VH; and SEQ ID NOs: 2, 4, 6, 8 for VL). The compositions include pharmaceutical compositions and kits for treatment.
The problem addressed by the invention is that existing therapies targeting tumor-associated stroma or tumor vasculature, including anti-angiogenic and vascular disrupting agents, have limitations such as 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 current agents to suppress tumor growth by targeting tumor-associated stroma or tumor cells. The invention aims to meet these needs by combining topoisomerase inhibitors with anti-TEM8 monoclonal antibodies.
The invention particularly focuses on diseases characterized by differential expression of tumor endothelial marker 8 (TEM8) membrane antigen on tumor cells and/or tumor stromal cells, including various cancers such as kidney, colon, lung, liposarcomas, brain, breast, melanoma, liver, head and neck, and prostate cancers. The monoclonal antibodies or antigen binding fragments specifically target TEM8, leading to selective targeting of tumor vasculature or cells expressing this marker.
Claims Coverage
The patent includes several independent claims focused on compositions and pharmaceutical compositions for treating tumors using a combination of topoisomerase inhibitors and specific monoclonal antibodies targeting TEM8. Five main inventive features are identified.
Composition comprising a topoisomerase inhibitor and anti-TEM8 monoclonal antibody with specific VH and VL sequences
The composition comprises a topoisomerase inhibitor and a monoclonal antibody or antigen binding fragment thereof that includes a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:5 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:6. The antibody includes a constant (Fc) region and binds human tumor endothelial marker 8 (TEM8). The tumor comprises human TEM8-expressing tumor cells and/or tumor stromal cells. The topoisomerase inhibitor is selected from a specific group of inhibitors including doxorubicin and others.
Composition targeting tumors expressing human TEM8 tumor cells and stromal cells
The composition specifically targets tumors wherein tumor cells and/or tumor stromal cells express human TEM8, utilizing the monoclonal antibody of SEQ ID NOs:5 and 6 and a topoisomerase inhibitor from a listed group.
Inclusion of pharmaceutical compositions with a pharmaceutically acceptable diluent or carrier
The pharmaceutical composition comprises the composition described above combined with a pharmaceutically acceptable diluent or carrier.
Kits comprising the compositions or pharmaceutical compositions packaged with instructions
The invention covers kits comprising the composition or pharmaceutical composition packaged together with instructions for its use for treating tumors.
Combination of topoisomerase inhibitor with monoclonal antibody binding human TEM8 for cancer therapy
The claims cover treatment or compositions comprising a topoisomerase inhibitor and a monoclonal antibody or antigen binding fragment comprising VH of SEQ ID NO:5 and VL of SEQ ID NO:6 where the antibody binds TEM8 expressed on tumor cells or stromal cells, aimed at treating tumors expressing human TEM8.
The independent claims collectively cover therapeutic compositions and methods combining specific anti-TEM8 monoclonal antibodies with selected topoisomerase inhibitors to target TEM8-expressing tumors or tumor stroma, pharmaceutical formulations thereof, and kits including such compositions with instructions for use.
Stated Advantages
The combination therapies employing anti-TEM8 antibodies and topoisomerase inhibitors are more effective than monotherapies in suppressing tumor growth in multiple xenograft cancer models, showing enhanced tumor growth delay, regression, and survival benefits.
The therapies provide selective targeting of tumor-associated stroma or tumor cells expressing TEM8, potentially reducing toxicity and off-target effects associated with current vascular-targeting agents.
The monoclonal antibodies, including Fc-mutant variants, demonstrate enhanced antibody-dependent cell-mediated cytotoxicity (ADCC), potentially improving therapeutic efficacy.
Documented Applications
Treatment of various cancers characterized by TEM8 expression including colorectal carcinoma, melanoma, ovarian cancer, breast cancer (triple negative), non-small cell lung carcinoma, colon carcinoma liver metastasis, and others, using combination therapies of topoisomerase inhibitors with anti-TEM8 monoclonal antibodies.
Use in xenograft models to inhibit tumor growth and regression, demonstrating efficacy in human cancer cell lines implanted in mice.
Combination cancer therapies involving anti-TEM8 antibodies with chemotherapeutic agents such as irinotecan, paclitaxel, doxorubicin, bevacizumab, and COX-2 inhibitors, NSAIDs, or PGE2 synthase inhibitors to enhance anti-tumor efficacy.
Use in kits comprising compositions for cancer treatment packaged with instructions for administration.
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