Development of a Companion Diagnostic Assay for Detection of ADAM8-Positive Cancers

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Breast cancer (BrCa) leads to ~685,000 deaths in women yearly worldwide (WHO). While patients with Hormone Receptor (HR) and Human Epidermal Growth Factor Receptor-2 (HER2)-driven cancers (HR+ and/or HER2+) have benefited from endocrine and HER2-targeted therapies, they still account for the majority of deaths. The HR and HER2 negative (HR-/HER2-) subtype, also known as Triple-negative breast cancer (TNBC), is the most aggressive and even more challenging to treat, leading to ~25% of deaths, despite a much lower incidence. More effective therapies are urgently needed. We identified the cell surface protein ADAM8 as an independent marker of poor BrCa patient outcome and a driver of tumor growth and spread. Using ADAM8-positive (ADAM8+) TNBC mouse models, we showed antibody (Ab)-based targeting of ADAM8 is an effective therapeutic (Tx) strategy [1]. Preliminary immunohistochemistry (IHC) of primary TNBCs revealed only a subset are ADAM8+ (17/50 or 34%), suggesting a diagnostic (Dx) will be needed to identify patients who can benefit from targeted therapy. We launched Adecto Pharmaceuticals to develop Dx and Tx products to improve the outcome of patients with ADAM8+ cancers. ADP2, our top Tx Ab, reduces pre-existing TNBC growth and spread, improves survival, and enhances response to standard-of-care chemotherapy. ADP2 was successfully humanized, and a lead candidate (AD100) selected ahead of IND-enabling studies. AD100 regimens could dramatically improve BrCa treatment. Here, we propose to develop an IHC-based Dx for ADAM8+ cancers as a companion to AD100 or a standalone prognostic for identification of patients at high risk of progressive disease. Currently, there is no Dx for detection of these tumors. Using a panel of highly specific anti-ADAM8 monoclonal Abs (mAbs) and Phase 1 SBIR funds, we (i) optimized IHC conditions and identified ADP2 as lead Dx Ab; (ii) developed a breast staining/scoring control cell line microarray (CCM) with 3 lines expressing low, medium or high ADAM8, and analyzed patient-derived xenograft samples; (iii) validated IHC assay and CCM, and established an ADAM8 scoring system, in primary BrCa samples (which completed all proposed aims). Consistent with earlier findings, ADP2 IHC showed 36.1% of TNBCs (22/61) were ADAM8+, and unexpectedly 32.8% of non-TNBC BrCas (115/351). A 10-year age-adjusted analysis of the HR+/HER2- subtype, with largest sample size, revealed ADAM8 score associated with poor survival, providing early support for a prognostic use of this assay. In this Direct to Phase 2 application, we propose to: 1) refine the ADP2 assay to permit accurate characterization of ADAM8 in any BrCa sample within ASCO/CAP guidelines; 2) verify ADAM8 positivity rates and study the prognostic value of the assay in BrCa; 3) test the predictive value of the assay for AD100 response using TNBC and HR+/HER2- mouse models; 4) complete CLIA validation of the assay by a clinical Dx contractor. Successful completion of the proposed aims will result in an ADAM8 IHC assay with CLIA standard operating protocols ready for testing in future clinical trials.