Therapeutic efficacy of a MMAE-based anti-DR5 drug conjugate Oba01 in preclinical models of pancreatic cancer

Pancreatic cancer (PC) is among the most aggressive malignancies with a 5-year survival rate of <9%, and treatment options remain limited. Antibody-drug conjugates (ADCs) are a new class of anticancer agents with favorable efficacy and safety. We investigated the antitumor activity and mechanism of Oba01, a monomethyl auristatin E (MMAE)-based anti-DR5 ADC, in preclinical PC models. DR5 was highly expressed on the plasma membrane of PC cells, and Oba01 showed potent in vitro activity in a panel of human DR5-positive PC cell lines. Following receptor-mediated internalization, DR5 was cleaved by lysosomal proteases and MMAE was released into the cytosol, inducing G2/M-phase arrest, apoptosis, and a bystander effect. Oba01 also mediated antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Oba01 combined with gemcitabine exhibited superior antiproliferative activity versus either agent alone. In cell- and patient-derived xenografts, Oba01 showed strong tumoricidal activity as monotherapy or in combination. These data support Oba01 as a novel biotherapeutic and provide a rationale for clinical trials in DR5-expressing PC.