Triple-negative breast cancers (TNBCs) account yearly for ~25% of all breast cancer deaths. The current Standard-of-Care (SoC), surgery, radiation and chemotherapy (CT), is not curative. More effective, targeted treatments are urgently needed. Recently, we identified the cell surface protein ADAM8 as a critical driver of TNBC tumor growth and metastasis via its Metalloprotease (MP) and Disintegrin (DI) domains, respectively, and showed that treatment with an ADAM8 dual MP/DI antagonist monoclonal antibody (mAb) reduces TNBC primary growth and metastases in mice [1]. Thus, we proposed that ADAM8 dual antagonist antibody therapy will become a new component of care for TNBC and founded Adecto Pharmaceuticals, Inc. (Adecto) to bring this therapy to patients. With Phase I STTR funding, we generated a panel of highly specific anti-human ADAM8 dual antagonist mAbs (termed ADPs) and identified 2 top inhibitors, ADP2 and ADP13, that reduced pre-existing primary tumor growth and metastasis, and improved survival as monotherapies. Addition of ADP13 to the SoC CT Abraxane (ABX) enhanced ABX-mediated tumor inhibition and disease-free and overall survival. Thus, ADAM8 antibody combination therapy could dramatically improve patient outcome. Adecto was recently awarded a Phase II SBIR grant to continued development of this therapy. Of note, high ADAM8 levels correlate with poor patient prognosis, and are seen on 34% of primary TNBCs and 48% of all breast cancer metastases [1]. Thus, to identify patients who can benefit from ADAM8-targeted therapy, a diagnostic assay will be needed. As there is currently no FDA-approved product for diagnosis of ADAM8 cancers, here we propose to begin development using immunohistochemistry (IHC) of formalin-fixed paraffin embedded (FFPE) patient biopsies. As this procedure requires antibodies that recognize ADAM8 protein under fixed conditions following retrieval from paraffin embedding, we propose first to identify an IHC appropriate, clinical-grade, ADAM8 mAb for development using our panel of ADPs as a starting point. Twelve of the 18 ADPs detected ADAM8 on the surface of fixed cells in FACS analysis. ADP2, 3, 4, 13 and 17 showed particularly strong binding and were selected for further studies. Preliminary IHC with FFPE pellets of HEK-293 cells expressing transfected human ADAM8 (HEK-A8) vs empty vector (HEK-EV) support continued assessment of these mAbs. Here, our milestones are to: (1) select a lead ADP for IHC based on both efficacy (using HEK-EV vs HEK-A8) and specificity (using FFPE samples of HEK cells expressing related proteins ADAM9, 12, 15 or 33); (2) develop an IHC scoring system for staining standardization using a control cell microarray (CCM) containing FFPE samples of breast cancer cell lines with a gradient of ADAM8 levels and confirm the range with Patient-Derived Xenograft FFPE and tissue samples; (3) validate our lead ADP and CCM using TNBC primary patient FFPE samples. Identification of an ADAM8 IHC antibody with a strong data package will help us attract Phase II funding and a partner for full development of a diagnostic product for selection of patients who can benefit from ADAM8 targeted therapy.
The ADAM8 cell surface protein has been identified as a critical driver of tumor growth and spread in triple-negative breast cancer (TNBC), a highly aggressive disease which accounts for more than 25% of the 500,000 yearly breast cancer deaths worldwide. A novel antibody-based ADAM8 targeted therapy which inhibits the two extracellular domains of this protein responsible for its cancer promoting functions is under development and has the potential to revolutionize TNBC treatment by significantly enhancing patient survival. Here, we propose to identify an anti-ADAM8 antibody for IHC-based detection of ADAM8-expressing cancers with optimal staining conditions, control panel, scoring system and early patient sample validation, as the first step in the development of an FDA approvable diagnostic assay that will enable selection of patients who can benefit from this important new personalized therapy.
