Abstract
Abstract SLC34A2, also known as type II Na/Pi co-transporters NaPi2b or NaPi3b, is a member of solute carrier protein family SLC34. SLC34A2 is highly expressed on cancers of the lung, ovary and thyroid as well as on normal lung pneumocytes, and is a promising target for antigen-directed therapy. Antibody drug conjugates (ADCs) specify the delivery of a cytotoxic drug to cells expressing an accessible antigenic target. Here we have appended monomethyl auristatin E (MMAE) to an antibody recognizing SLC34A2. Anti-SLC34A2-vc-MMAE inhibits tumor growth in multiple ovarian and non-small cell lung cancer xenograft models that express SLC34A2. Anti-SLC34A2 antibody and its conjugate cross-react with both human and monkey, and toxicity studies in monkeys are conducted to identify both target- and MMAE-related effects. Anti-SLC34A2-vc-MMAE was well tolerated in monkeys at efficacious doses and produced dose-related bone marrow suppression and increased apoptosis and mitotic figures consistent with MMAE-related pharmacology. Despite high levels of expression in normal lung of non-human primate, the cross-reactive ADC exhibited an acceptable safety profile with a dose-limiting toxicity unrelated to normal tissue expression. Overall, our preclinical results suggest that the antibody drug conjugate targeting the SLC34A2 may provide an effective new therapy for the treatment of NSCLC and ovarian cancer. Citation Format: Kedan Lin, Crystal Zhang, Eric Harstad, Hajime Hiraragi, Willy Solis, Siao Ping Tsai, Keyang Xu, Maria Hristopoulos, Rayna Venook, Bonnee Rubinfeld, Paul Polakis. Preclinical development of anti-SLC34A2 antibody drug conjugate as a therapeutic for non-small cell lung and ovarian cancers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5619. doi:10.1158/1538-7445.AM2013-5619
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