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

Autor:	Kamata-Sakurai M; Translational Research Division, Chugai Pharmaceutical Co., Ltd., Chuo-ku, Tokyo, Japan. mika.sakurai22@chugai-pharm.co.jp., Narita Y; Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan., Hori Y; Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan., Nemoto T; Translational Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan., Uchikawa R; Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan., Honda M; Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan., Hironiwa N; Chugai Pharmabody Research Pte. Ltd., Synapse, Singapore., Taniguchi K; Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan., Shida-Kawazoe M; Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan., Metsugi S; Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan., Miyazaki T; Clinical Development Division, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan., Wada NA; Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan., Ohte Y; Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan., Shimizu S; Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan., Mikami H; Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan., Tachibana T; Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan., Ono N; Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan., Adachi K; Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan., Sakiyama T; Pharmaceutical Technology Division, Chugai Pharmaceutical Co., Ltd., Kita-ku, Tokyo, Japan., Matsushita T; Translational Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan., Kadono S; Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan., Komatsu SI; Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan.; Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan., Sakamoto A; Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan., Horikawa S; Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan., Hirako A; Translational Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan., Hamada K; Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan., Naoi S; Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan., Savory N; Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan., Satoh Y; Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan., Sato M; Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan., Noguchi Y; Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan., Shinozuka J; Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan., Kuroi H; Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan., Ito A; Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan., Wakabayashi T; Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan., Kamimura M; Chugai Research Institute for Medical Science, Inc., Kamakura, Kanagawa, Japan., Isomura F; Chugai Research Institute for Medical Science, Inc., Gotemba, Shizuoka, Japan., Tomii Y; Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan., Sawada N; Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan., Kato A; Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan.; Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan., Ueda O; Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan., Nakanishi Y; Project & Lifecycle Management Unit, Chugai Pharmaceutical Co., Ltd., Chuo-ku, Tokyo, Japan., Endo M; Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan.; Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan., Jishage KI; Chugai Research Institute for Medical Science, Inc., Kamakura, Kanagawa, Japan.; Chugai Research Institute for Medical Science, Inc., Gotemba, Shizuoka, Japan., Kawabe Y; Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan.; Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan., Kitazawa T; Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan.; Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan., Igawa T; Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan.; Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan.; Chugai Pharmabody Research Pte. Ltd., Synapse, Singapore.
Jazyk:	angličtina
Zdroj:	Cancer discovery [Cancer Discov] 2021 Jan; Vol. 11 (1), pp. 158-175. Date of Electronic Publication: 2020 Aug 25.
DOI:	10.1158/2159-8290.CD-20-0328
Abstrakt:	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 . This article is highlighted in the In This Issue feature, p. 1 . (©2020 American Association for Cancer Research.)
Databáze:	MEDLINE
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