Abstract 2212: An antibody drug conjugate targeting activated matriptase, exhibits synergistic cytotoxicity with a PARP inhibitor, olaparib in triple negative breast cancer

Abstract

Abstract Matriptase, is a serine protease type II transmembrane protein. Matriptase forms a cognate pair with its Kunitz type endogenous inhibitor HAI-1 and is commonly deregulated and ubiquitously expressed in a variety of human carcinomas and in particular, breast cancer. This enzyme activity is regulated by binding to its endogenous inhibitors (HAI-1 or 2). Previously, we reported the synthesis and anti-tumor studies of a novel antibody drug conjugate (ADC) targeting activated matriptase of tumor cells (Oncotarget, 2018,9(40):25983). The activated matriptase-specific monoclonal antibody (M69) was conjugated with a potent anti-mitotic toxin, monomethyl auristatin-E (MMAE) via a lysosomal protease (cathepsin B) -cleavable dipeptide linker. The ADC was found to be potent and selective against multiple activated matriptase-positive epithelial carcinoma cell lines including triple negative breast cancer (TNBC), as well as alone and in combination with bortezomib in Mantle cell lymphoma (Frontiers in Oncology, 2019,9:258). In-vivo studies showed that the ADC has potent anti-tumor effects alone or in combination with cisplatin or carboplatin against TNBC xenografts and a primary human TNBC (PDX), respectively. The chimeric ADC (mouse-human chimera) also evoked an immune response against TNBC xenografts in humanized mouse models. Here, we report the sensitivity of TNBC tumors with and without a BRCA mutation to ADC alone or in combination with a PARP inhibitor, Olaparib. We analyzed the mutational status of BRCA1, BRAC2, p53 and activated matriptase expression of four TNBC cell lines (MDA-MB-468, MDA-MB-231, HCC1806 and MDA-MB-436). All of the cell lines had p53 mutations. The MDA-MB-468 cell line with a mutation in BRCA 2, and expression of activated matriptase was the most sensitive cell line to both olaparib and the chimeric MMAE ADC, and the combination of them resulted in marked synergistic cell kill. The MDA-MB-436 cell line with a splice site mutation in BCRA1 was less sensitive to both treatments, but there was modest synergy when the two drugs were combined. In contrast the MDA-MB-231 cell line without a BRCA mutation was much less sensitive to the ADC or olaparib, and the combination did not show synergy. The HCC1806 cell line with wt BRCA was sensitive to the ADC and olaparib, but the combination resulted in antagonistic effects. Triple negative breast cancers with a BRAC2 mutation and overexpression of activated matriptase may be a subset of breast cancers that may benefit from the combination of our novel ADC and a PARP inhibitor. Citation Format: Gulam M. Rather, Zoltan Szekely, Joseph R. Bertino. An antibody drug conjugate targeting activated matriptase, exhibits synergistic cytotoxicity with a PARP inhibitor, olaparib in triple negative breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2212.