Abstract 23: Antibody targeting of ADAM8 for treatment of triple-negative breast cancer

Triple-Negative Breast Cancer (TNBC) accounts for 25% of breast cancer deaths. Current therapeutic options are restricted to chemotherapy (CT) and radiation, which fail to block disease progression. Recently, we identified the cell surface protein ADAM8 as a critical driver of TNBC tumor growth and of metastasis in half of all breast cancers (EMBO Mol. Med. 6:278, 2014). Elevated ADAM8 levels correlate with poor breast cancer patient outcome. One third of TNBC patient samples have high ADAM8 levels, while it is undetectable in normal breast tissue. ADAM8 Metalloproteinase (MP) and Disintegrin (DI) domains promote angiogenesis needed for tumor growth, and cancer cell adhesion to and invasion through the endothelium needed for dissemination, respectively. Using a prototype reagent in mice, we validated a unique antibody-based strategy that simultaneously targets ADAM8 MP/DI activities as an effective therapeutic intervention in TNBC. Our group has now prepared a panel of pre-clinical, highly specific anti-human ADAM8 mouse monoclonal antibodies (ADPs) of either IgG1 or IgG2 subclass with dual MP/DI antagonist activity. The top 6 ADPs bind ADAM8 with low dissociation constants of 1.3 x 10-9 M to 7.23 x 10-8 M. The 4 most effective inhibitory ADPs in cell-based assays were screened in a single-dose efficacy study (10 mg/kg 3x/wk) against pre-existing MDA-MB-231 cell-derived tumors (50-75 mm3). ADP2 and ADP13 treatment resulted in significant tumor volume reduction, of 47% and 52%, respectively. Dose-response curves are in progress. ADP13 was also tested in a neo-adjuvant model for its ability to reduce metastases. Antibody treatment was initiated as above and continued for 6 weeks after tumors were resected at a volume of ~200 mm3. Metastases in dissected organs were examined using biophotonic imaging. ADP13 substantially decreased metastasis to multiple organs. Lastly, a neo-adjuvant survival experiment was performed, as above, except that following surgical resection of tumors mice were treated for 12 weeks. Recurrence at the primary site was assessed using palpation. Mice were sacrificed when recurrent tumors reached 900 mm3. ADP13 treatment resulted in significantly improved disease-free survival (P=0.05) and overall survival (P=0.03). More recently, we noted that ADAM8 regulates miRNAs associated with resistance to CT and showed that ADAM8 inhibition sensitizes TNBC cells to Cisplatin, Paclitaxel, and Doxorubicin. In vivo testing of a combinatorial anti-ADAM8 + CT approach is in progress and may present a promising strategy for early entry into the clinic. Conclusions: A new anti-ADAM8 antibody therapeutic shows efficacy against TNBC tumor growth and dissemination, and improves survival in pre-clinical testing. We hypothesize that addition of an anti-ADAM8 antibody to current CT standards of care will enhance tumor killing, reduce metastasis, and increase survival of patients with ADAM8-expressing TNBC. Citation Format: Sonia G. Das, Stefania Pianetti, Gail E. Sonenshein, Nora D. Mineva. Antibody targeting of ADAM8 for treatment of triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 23. doi:10.1158/1538-7445.AM2017-23