Abstract 2628: AM109, a PSMA×CD137 bispecific antibody with target-dependent T cell activation and potent anti-tumor activity in prostate cancer.

Abstract Metastatic castration-resistant prostate cancer (mCRPC) remains a fatal malignancy with limited responsiveness to current immunotherapies. To achieve tumor-restricted immune activation, we developed AM109, a bispecific antibody that links a PSMA-targeting humanized antibody to a CD137 (4-1BB) affibody, designed to activate T cells exclusively in the presence of PSMA-expressing tumor cells. AM109 elicited robust CD8+ T-cell activation and cytokine secretion (IFN-γ, IL-2, and Granzyme B) in PSMA+ LNCaP cells, but not in PSMA- MKN45 cells, confirming its target-dependent mode of action. Cytotoxicity assays demonstrated dose-dependent tumor cell killing that correlated with PSMA expression levels. In vivo efficacy was evaluated using human CD137 transgenic mice bearing hPSMA/MC38 tumors, where AM109 achieved complete tumor regression at doses of 0.1-0.3 mpk, exhibiting superior potency compared with the reference CD137 agonist utomilumab. Structural and functional stability were maintained for at least 12 weeks at 4-40 °C. Pharmacokinetic and single-dose toxicity studies in rodents revealed favorable systemic exposure and good tolerability. Collectively, these findings demonstrate that AM109 selectively activates T cells within the tumor microenvironment, eliciting potent and PSMA-dependent anti-tumor responses with an improved therapeutic window. AM109 therefore represents a promising next-generation immunotherapeutic candidate for the treatment of mCRPC. Citation Format: Dong-Wook Kim, Hyun-Jong Lee, Seong Yeol Kim, Min Yoon, Youngha Lee, In-Sik Hwang, Yoon Lee, Jong-Hoon Kim, Jong-Seo Lee, . AM109, a PSMA×CD137 bispecific antibody with target-dependent T cell activation and potent anti-tumor activity in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2628.