Antibody targeting of ADAM for treatment of triple negative breast cancer

DESCRIPTION provided by applicant Triple negative breast cancers TNBCs account for 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 ADAM A Disintegrin and Metalloprotease as a pivotal promoter of breast tumor growth and metastasis and validated it as a target of antibody therapy for TNBC ADAM mRNA was highly expressed in TNBCs and its level correlated with poor patient outcome ADAM protein was present in of primary TNBCs and half of all breast cancer patient derived metastases but absent in adjacent normal breast tissues Orthotopic tumors from ADAM 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 ADAM were critical in tumor growth and dissemination through release of pro angiogenic factors and activation of integrin on cancer cells respectively Treatment with a reagent grade commercial anti ADAM mouse monoclonal antibody mAb MAB Randamp D with in vitro antagonist activity against both the MP and DI domains reduced primary TNBC tumor burden by at mg kg vs control isotype matched IgG B in an orthotopic model when started at the time of cell implantation MAB 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 ADAM antibody based treatment constitutes an effective therapy for TNBC patients expressing this transmembrane protein A PCT patent application PCT US was filed May by Drs Sonenshein Mineva and Romagnoli and Tufts University with claims including the targeting of ADAM MP and DI domains for treatment of breast and other ADAM driven cancers including pancreatic adenocarcinomas In October Adecto Pharmaceuticals Inc AP was founded by the three inventors with the goal of developing ADAM specific antibodies for the treatment of TNBC and metastatic breast cancer as the initial indications In this Phase STTR application AP will work closely with the Sonenshein lab SL to prepare mouse mAbs specific for human ADAM that inhibit both its MP and DI domains and perform pilot preclinical testing in mice The specific aims are to Isolate a panel of mAbs specific for HuADAM with MP and DI domain antagonist activity Identify the most effective antagonist mAbs using cell based assays Perform pilot in vivo testing of the ability of the two most effective ADAM antagonist mAbs to inhibit growth and metastatic dissemination of pre existing luciferase tagged MDA MB cell derived tumors We propose that ADAM 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 Triple Negative Breast Cancer TNBC represents only of breast tumor cases but is highly metastatic and accounts for more than of the breast cancer deaths yearly worldwide We have identified a protein on the surface of TNBC tumors called ADAM and showed that a reagent grade monoclonal antibody that inhibits the two major activities of ADAM reduces primary TNBC tumor growth and metastasis in mice Here we propose to prepare preclinical antagonist monoclonal antibodies that are highly specific for ADAM 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