Abstract ND06: AMG 305, a dual targeting BiTE®molecule with selective activity for solid tumors that co-express CDH3 and MSLN

Abstract T cell engager (TCE) molecules are a targeted immune therapy that redirect a patient’s T cells to kill tumor cells. While several TCE molecules have now advanced to approval, clinical development has been challenging, especially in the solid tumor setting. There are few solid tumor surface antigens that are tumor-specific, and antigens with even low levels of expression in normal tissue can be recognized by a TCE and result in on-target off-tumor toxicity. To overcome this challenge, we have developed AMG 305, a first-in-class, dual targeting BiTE® (bispecific T cell engager) molecule that requires binding to both P-cadherin (CDH3) and mesothelin (MSLN) for potent cytotoxic activity. Immunohistochemistry analysis shows that CDH3 and MSLN are co-expressed in multiple solid tumor types. In normal tissues, immunostaining shows fewer tissues have overlapping co-expression than expression of just one or the other target. AMG 305 relies on an avidity-based approach to engage T cells to preferentially kill CDH3+MSLN+ tumor cells, with limited activity against normal cells that express only one of the target antigens. In vitro, AMG 305 induces potent cytotoxicity against tumor cells co-expressing CDH3 and MSLN, with greatly attenuated activity against cells expressing only CDH3 or MSLN. In vivo, AMG 305 demonstrates dose-dependent antitumor activity in a CDH3+MSLN+ xenograft tumor model. AMG 305 was clinically well-tolerated in a nonclinical safety study in cynomolgus monkey. Data from IND-enabling preclinical studies support initiation of the first-in-human study of AMG 305 in CDH3+MSLN+ solid tumors in 2023. Citation Format: Elizabeth Pham, Petra Lutterbuese, Petra Deegen, Natalie Mariano, Katja Matthes, Joachim Wahl, Pamela Bogner, Joan Lane, Kristin Lewis Wilson, Rodolfo Yabut, Virginie Naegele, Ines Ullrich, Stephanie Everts, Markus Muenz, Thomas Boehm, Sabine Stienen, Angela Coxon, Peter Kufer, Tobias Raum, Julie M. Bailis. AMG 305, a dual targeting BiTE®molecule with selective activity for solid tumors that co-express CDH3 and MSLN [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr ND06.