Abstract 1851: Responses of a novel tumor selective anti-CD137 agonist antibody activated by elevated extracellular ATP in tumor microenvironment

Background: CD137 (4-1BB) is a co-stimulatory molecule which exerts activation signals in multiple immune cell subsets. However, agonist antibodies targeting CD137 have not been clinically successful due to severe systemic toxicity. Since conferring tumor selectivity through tumor-associated antigen limits its clinical use to cancers that highly express such antigen, we instead exploited extracellular adenosine triphosphate (exATP), which is known to be elevated in tumor microenvironment (TME) while remaining tightly regulated in normal tissues, as a broadly tumor selective switch. Here we report a novel anti-CD137 switch antibody, STA551, which exerts agonistic activity only in the presence of exATP. Methods & Results: STA551 bound to human CD137 in an ATP dependent manner. Consistent with the binding profile, STA551 induced IFN-γ only in the presence of ATP, whereas urelumab induced IFN-γ regardless of ATP concentration in a human T cell assay. We examined the anti-tumor efficacy of Sta-MB, which has the same variable region as STA551 using a surrogate mouse Fc, in human CD137 knock-in (hCD137-KI) mice. STA551 demonstrated potent and broad anti-tumor efficacy against all the tumors we tested both as a monotherapy and in combination with anti-PD-L1 antibody. To confirm the immune responses in tumors, we evaluated gene expression and analyzed tumor infiltrating lymphocytes by flow cytometry. Immune-related gene expression changed after treatment with Sta-MB. We also confirmed that Sta-MB treatment increased the number of activated CD8+ T cells in tumors. For all tumor responses, Sta-MB tended to be more potent than Ure-MB. Whereas other anti-CD137 conventional antibodies showed significant CD137 mediated clearance and systemic T cell activation in draining lymph node (DLN), spleen, and liver, STA551 demonstrated significant intratumor T cell activation, but not in normal tissues and without CD137 mediated systemic clearance in mice. Furthermore, STA551 was well-tolerated in cynomolgus monkeys in a repeated-dose toxicity study*. Conclusion: These results suggest that STA551, due to its tumor selective agonistic activity, has potent anti-tumor efficacy and a wide therapeutic window, providing a strong rationale for its clinical testing against a broad variety of cancers regardless of antigen expression, and for the further application of this novel platform to other targets in cancer therapy. STA551 is currently being tested in a phase 1 clinical study. We w