Triple-negative breast cancers (TNBCs) account for ~25% of breast cancer deaths and lack targeted therapies. Drs. Sonenshein, Mineva and Romagnoli and their co-workers recently identified the non-essential, cell surface protein ADAM8 (A Disintegrin and Metalloprotease 8) as a pivotal promoter of breast tumor growth and metastasis, and validated it as a target of antibody therapy for TNBC. ADAM8 mRNA was highly expressed in TNBCs, and its level correlated with poor patient outcome. ADAM8 protein was present in 34% of primary TNBCs, and half of all breast cancer patient-derived metastases, but absent in adjacent normal breast tissues. Orthotopic tumors from ADAM8 knockdown TNBC cells grew only to a palpable size and generated very few circulating tumor cells and brain metastases. The Metalloproteinase (MP) and Disintegrin (DI) domains of ADAM8 were critical in tumor growth and dissemination through release of pro-angiogenic factors and activation of ?1-integrin on cancer cells, respectively. Treatment with a reagent grade commercial anti-ADAM8 mouse monoclonal antibody (mAb) MAB1031 (R&D), with in vitro antagonist activity against both the MP and DI domains, reduced primary TNBC tumor burden by 70% at 1.5 mg/kg vs control isotype-matched IgG2B in an orthotopic model when started at the time of cell implantation. MAB1031 also profoundly reduced dissemination of pre-existing tumors to the brain and lungs, providing proof-of-concept that a dual antagonist mAb can be prepared and that both domains are accessible to antibody-based therapy in vivo. Thus, we hypothesize that ADAM8 antibody-based treatment constitutes an effective therapy for TNBC patients expressing this transmembrane protein. A PCT patent application PCT/US14/37857 was filed May 13, 2014 by Drs. Sonenshein, Mineva and Romagnoli, and Tufts University, with claims including the targeting of ADAM8 MP and DI domains for treatment of breast and other ADAM8-driven cancers, including pancreatic adenocarcinomas. In October 2014, Adecto Pharmaceuticals, Inc (AP) was founded by the three inventors with the goal of developing ADAM8-specific antibodies for the treatment of TNBC and metastatic breast cancer as the initial indications. In this Phase 1 STTR application, AP will work closely with the Sonenshein lab (SL) to prepare mouse mAbs specific for human ADAM8 that inhibit both its MP and DI domains and perform pilot preclinical testing in mice. The specific aims are to: (1) Isolate a panel of mAbs specific for HuADAM8 with MP and DI domain antagonist activity; (2) Identify the most effective antagonist mAbs using cell based assays; (3) Perform pilot in vivo testing of the ability of the two most effective ADAM8 antagonist mAbs to inhibit growth and metastatic dissemination of pre-existing luciferase-tagged MDA-MB-231 cell-derived tumors. We propose that ADAM8 antibody-based therapy has the potential to revolutionize the treatment of TNBC patients, and reduce the mortality associated with metastatic breast cancer and thus will become a new component of care for TNBC.
Public Health Relevance Statement: Public Health Relevance: Triple-Negative Breast Cancer (TNBC) represents only 15% of breast tumor cases but is highly metastatic, and accounts for more than 25% of the 500,000 breast cancer deaths yearly worldwide. We have identified a protein on the surface of TNBC tumors called ADAM8 and showed that a reagent grade monoclonal antibody that inhibits the two major activities of ADAM8 reduces primary TNBC tumor growth and metastasis in mice. Here we propose to prepare preclinical antagonist monoclonal antibodies that are highly specific for ADAM8 and study their therapeutic potential in mouse models, which if confirmed could revolutionize treatment of TNBC by providing safe, targeted and effective interventions that reduce growth and metastases of these very aggressive tumors.
NIH Spending Category: Biotechnology; Breast Cancer; Cancer
Project Terms: Accounting; Adverse effects; Advisory Committees; Affinity; angiogenesis; Angiogenic Factor; Animal Cancer Model; Animal Model; Antibodies; Antibody Therapy; base; Benchmarking; Binding; Biological Assay; Biology; Blood; Blood Vessels; Brain; Breast; Breast Cancer Cell; Breast Cancer Patient; Budgets; Businesses; cancer cell; Caring; Cell Adhesion; Cell Line; Cell Surface Proteins; Cells; Cessation of life; chemotherapy; Clinic; Cloning; cross reactivity; Data; density; Development; Disease; Disintegrin Domain; Disintegrins; effective intervention; effective therapy; Endothelium; Enzyme-Linked Immunosorbent Assay; Epitopes; Estrogen Receptor Status; Financial compensation; Goals; Growth; Human; Hybridomas; Immunoglobulin G; implantation; improved; In Vitro; in vitro Assay; in vivo; Injection of therapeutic agent; Integral Membrane Protein; Integrins; knock-down; Legal patent; Licensing; Luciferases; Lung; lymph nodes; malignant breast neoplasm; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary Neoplasms; MDA MB 231; Messenger RNA; Metalloproteases; Metastatic breast cancer; Metastatic malignant neoplasm to brain; migration; Modeling; Monoclonal Antibodies; monoclonal antibody production; mortality; mouse model; Multivariate Analysis; Mus; Neoplasm Circulating Cells; Neoplasm Metastasis; outcome forecast; Palpable; Pancreatic Adenocarcinoma; Patient-Focused Outcomes; Patients; Pharmacologic Substance; Phase; Phenotype; Pilot Projects; pre-clinical; Preclinical Testing; promoter; Proteins; public health relevance; Publishing; Quality of life; Radiation; Reagent; Recombinants; Relapse; research and development; Research Contracts; residence; screening; Small Business Technology Transfer Research; standard of care; Surface; targeted treatment; Testing; Therapeutic; Time; triple-negative invasive breast carcinoma; tumor; Tumor Burden; tumor growth; tumor progression; Tumor-Derived; Universities; Work
