Abstract
Abstract Advanced gastric cancer remains a disease of high unmet medical need. In the United States, most patients present with symptomatic, incurable disease and prognosis is poor, with a 5-year survival rate of less than 10%. BiTE® (bispecific T cell engager) immune therapy activates a patient's own T cells to kill tumor cells and has the potential to overcome common mechanisms of therapy resistance. We generated fully human, half-life extended (HLE) BiTE® molecules against the tumor antigens MUC17 and CLDN18.2 for the treatment of gastric cancer. The mucin MUC17 is a protein normally found in the mucosal layer of intestinal epithelial cells that is delocalized and expressed in 45% of gastric tumors. The claudin CLDN18.2 is a protein normally found in the cellular tight junctions of gastric mucosa and intestinal epithelium that is delocalized and expressed in >60% of gastric tumors. AMG 199 (MUC17 HLE BiTE®) and AMG 910 (CLDN18.2 HLE BiTE®) show potent cytotoxic activity against gastric cancer cell lines that express MUC17 or CLDN18.2, respectively, in vitro, and promote significant tumor growth inhibition against established gastric tumor xenograft models in vivo. In preclinical non-human primate (NHP) toxicology studies, both molecules show evidence for BiTE® target engagement, including T cell activation and proliferation, but demonstrate different effects on target-expressing tissue. Weekly administration of AMG 199 is well tolerated in NHP with minimal findings in MUC17-expressing normal tissues. In contrast, treatment with AMG 910 led to direct cell killing of CLDN18.2-expressing gastric mucosal cells in NHP, a finding which was fully reversible once treatment was stopped. AMG 199 and AMG 910 may offer the potential to improve outcomes in advanced gastric patients worldwide. Citation Format: Julie M. Bailis, Petra Lutterbuese, Oliver Thomas, Kathrin Locher, John Harrold, Michael Boyle, Joachim Wahl, Shyun Li, Alexander Sternjak, Anja Henn, Christoph Dahlhoff, Virginie Naegele, Benno Rattel, Tobias Raum, Angela Coxon. Preclinical evaluation of BiTE®immune therapy targeting MUC17 or CLDN18.2 for gastric 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 3364.
Published Version
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