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

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-gamma, 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.