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

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

  • Cancer Discov. 2021 Jan;11(1):158-175. doi: 10.1158/2159-8290.CD-20-0328.
Mika Kamata-Sakurai # 1,  Yoshinori Narita # 2,  Yuji Hori 3,  Takayuki Nemoto 4,  Ryo Uchikawa 2,  Masaki Honda 3,  Naoka Hironiwa 5,  Kenji Taniguchi 2,  Meiri Shida-Kawazoe 3,  Shoichi Metsugi 2,  Taro Miyazaki 6,  Naoko A Wada 3,  Yuki Ohte 2,  Shun Shimizu 3,  Hirofumi Mikami 3,  Tatsuhiko Tachibana 3,  Natsuki Ono 2,  Kenji Adachi 3,  Tetsushi Sakiyama 7,  Tomochika Matsushita 8,  Shojiro Kadono 2,  Shun-Ichiro Komatsu 2 3,  Akihisa Sakamoto 3,  Sayuri Horikawa 2,  Ayano Hirako 8,  Koki Hamada 2,  Sotaro Naoi 3,  Nasa Savory 3,  Yasuko Satoh 2,  Motohiko Sato 3,  Yuki Noguchi 3,  Junko Shinozuka 3,  Haruka Kuroi 3,  Ami Ito 3,  Tetsuya Wakabayashi 3,  Masaki Kamimura 9,  Fumihisa Isomura 10,  Yasushi Tomii 3,  Noriaki Sawada 2,  Atsuhiko Kato 2 3,  Otoya Ueda 3,  Yoshito Nakanishi 11,  Mika Endo 2 3,  Kou-Ichi Jishage 9 10,  Yoshiki Kawabe 2 3,  Takehisa Kitazawa 2 3,  Tomoyuki Igawa 2 3 5
Affiliations

Affiliations

  • 1 Translational Research Division, Chugai Pharmaceutical Co., Ltd., Chuo-ku, Tokyo, Japan. mika.sakurai22@chugai-pharm.co.jp.
  • 2 Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan.
  • 3 Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan.
  • 4 Translational Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan.
  • 5 Chugai Pharmabody Research Pte. Ltd., Synapse, Singapore.
  • 6 Clinical Development Division, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan.
  • 7 Pharmaceutical Technology Division, Chugai Pharmaceutical Co., Ltd., Kita-ku, Tokyo, Japan.
  • 8 Translational Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan.
  • 9 Chugai Research Institute for Medical Science, Inc., Kamakura, Kanagawa, Japan.
  • 10 Chugai Research Institute for Medical Science, Inc., Gotemba, Shizuoka, Japan.
  • 11 Project & Lifecycle Management Unit, Chugai Pharmaceutical Co., Ltd., Chuo-ku, Tokyo, Japan.
  • # Contributed equally.
PMID: 32847940 DOI: 10.1158/2159-8290.CD-20-0328
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.This article is highlighted in the In This Issue feature, p. 1.

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