Antibody to CD137 Activated by Extracellular Adenosine Triphosphate Is Tumor Selective and Broadly Effective In Vivo 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 to cancers that highly express such antigens, we exploited extracellular adenosine triphosphate (exATP), which is a hallmark of the tumor microenvironment and highly elevated in solid tumors, as a broadly tumor-selective switch. We generated a novel anti-CD137 switch antibody, STA551, which exerts agonistic activity only in the presence of exATP. STA551 demonstrated potent and broad antitumor efficacy against all mouse and human tumors tested and a wide therapeutic window without systemic immune activation in mice. STA551 was well tolerated even at 150 mg/kg/week in cynomolgus monkeys. These results provide a strong rationale for the clinical testing of STA551 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. SIGNIFICANCE: Reported CD137 agonists suffer from either systemic toxicity or limited efficacy against antigen-specific cancers. STA551, an antibody designed to agonize CD137 only in the presence of extracellular ATP, inhibited tumor growth in a broad variety of cancer models without any systemic toxicity or dependence on antigen expression.See related commentary by Keenan and Fong, p. 20.

journal_name

Cancer Discov

journal_title

Cancer discovery

authors

Kamata-Sakurai M,Narita Y,Hori Y,Nemoto T,Uchikawa R,Honda M,Hironiwa N,Taniguchi K,Shida-Kawazoe M,Metsugi S,Miyazaki T,Wada NA,Ohte Y,Shimizu S,Mikami H,Tachibana T,Ono N,Adachi K,Sakiyama T,Matsushita T,Kadono

doi

10.1158/2159-8290.CD-20-0328

subject

Has Abstract

pub_date

2020-08-25 00:00:00

eissn

2159-8274

issn

2159-8290

pii

2159-8290.CD-20-0328

pub_type

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