Exploitation of Elevated Extracellular ATP to Specifically Direct Antibody to Tumor Microenvironment
Futa Mimoto, K. Tatsumi, Shun Shimizu, Shojiro Kadono, Kenta Haraya, Miho Nagayasu, Yuki Suzuki, Etsuko Fujii, Masaki Kamimura, Akira Hayasaka, Hiroki Kawauchi, Kazuhiro Ohara, Masayuki Matsushita, Takeshi Baba, Hiroaki Susumu, Takuya Sakashita, Terushige Muraoka, Kosuke Aso, Hitoshi Katada, Eriko Tanaka, Kenji Nakagawa, Masami Hasegawa, Miho Ayabe, Tessai Yamamoto, Shigero Tanba, Takahiro Ishiguro, Takayuki Kamikawa, Takeru Nambu, Tatsuya Kibayashi, Yumiko Azuma, Yasushi Tomii, Atsuhiko Kato, Kazuhisa Ozeki, Naoaki Murao, Mika Endo, Junichi Kikuta, Mika Kamata‐Sakurai, Masaru Ishii, Kunihiro Hattori, Tomoyuki Igawa
Abstract
The extracellular adenosine triphosphate (ATP) concentration is highly elevated in the tumor microenvironment (TME) and remains tightly regulated in normal tissues. Using phage display technology, we establish a method to identify an antibody that can bind to an antigen only in the presence of ATP. Crystallography analysis reveals that ATP bound in between the antibody-antigen interface serves as a switch for antigen binding. In a transgenic mouse model overexpressing the antigen systemically, the ATP switch antibody binds to the antigen in tumors with minimal binding in normal tissues and plasma and inhibits tumor growth. Thus, we demonstrate that elevated extracellular ATP concentration can be exploited to specifically target the TME, giving therapeutic antibodies the ability to overcome on-target off-tumor toxicity.