Antibody to CD137 Activated by Extracellular Adenosine Triphosphate Is Tumor Selective and Broadly Effective<i>In Vivo</i>without Systemic Immune Activation

Abstract Agonistic antibodies targeting CD137 have been clinically unsuccessful due to systemic toxicity. Because conferring tumor selectivity through tumor-associated antigen limits its clinical use cancers that highly express such antigens, we exploited extracellular adenosine triphosphate (exATP), which is a hallmark of the microenvironment and elevated in solid tumors, as broadly tumor-selective switch. We generated novel anti-CD137 switch antibody, STA551, exerts agonistic activity only presence exATP. STA551 demonstrated potent broad antitumor efficacy against all mouse human tumors tested wide therapeutic window without immune activation mice. was well tolerated even at 150 mg/kg/week cynomolgus monkeys. These results provide strong rationale for testing variety regardless expression, further application this platform other targets cancer therapy. Significance: Reported agonists suffer from either toxicity or limited antigen-specific cancers. an antibody designed agonize ATP, inhibited growth models any dependence on expression. See related commentary by Keenan Fong, p. 20. This article highlighted In Issue feature, 1