Background Agonistic antibodies targeting CD137 in clinic have failed due to severe hepatotoxicity, leading to the development of bispecific approaches that must rely on high tumor-associated antigen expression to crosslink CD137. Here we report on STA551, a novel anti-CD137 agonist antibody which binds to CD137 only in the presence of ATP. Extracellular ATP concentration is well-known to be elevated in tumor tissue while remaining tightly regulated in non-tumor tissue, suggesting that STA551 can activate immune cells only in tumor tissue and not elsewhere. Thus, STA551 has great potential to overcome the limitations of conventional CD137-targeted antibodies.

Methods We evaluated in vitro STA551’s effect on IFN-γ production from human CD8+ T cells. We also evaluated in vivo STA551’s effect on tumor growth, RNAseq-based immune-related gene expression, immunohistochemistry, and T cell activation in tumor and non-tumor tissues in human CD137 knock-in mice treated with mouse surrogate STA551 (Sta-MB) or urelumab (Ure-MB) in combination with anti-PD-L1 antibody.

Results In a human T cell assay, STA551 induced IFN-γ only in the presence of ATP. In contrast, urelumab induced IFN-γ regardless of ATP concentration. In mice with Colon 38 tumors, Sta-MB inhibited tumor growth at least as strongly as Ure-MB, but whereas Ure-MB elicited systemic immune responses in draining lymph node, spleen, and liver, Sta-MB appeared to evade such responses. To confirm immune responses in tumors, we evaluated immune-related gene expression and found changes after treatment with Sta-MB or Ure-MB. These results suggest that STA551 works only in tumor tissue. Furthermore, Sta-MB with anti-PD-L1 antibody synergistically inhibited tumor growth and dramatically changed immune-related gene expression, CD8+ T cell infiltration, and PD-L1 expression without systemic immune responses. Also, it was well-tolerated in cynomolgus monkey in a repeated-dose toxicity study*.

Conclusions STA551 is a novel anti-CD137 agonist antibody that exerts agonistic activity selectively in tumors without on-target toxicity in non-tumor tissues, regardless of tumor-associated antigen expression. These results strongly support the clinical testing of STA551 for the treatment of solid tumors. STA551 is currently being tested in a phase 1 clinical study.

Ethics Approval All animal studies were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC).