Cancer neovasculature-targeted near-infrared photoimmunotherapy (NIR-PIT) for gastric cancer: different mechanisms of phototoxicity compared to cell membrane-targeted NIR-PIT
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Near-infrared photoimmunotherapy (NIR-PIT) constitutes a new class of molecular-targeted theranostics utilizing monoclonal antibody (mAb)-photosensitizer conjugates and NIR light. In this study, we developed a new type of NIR-PIT targeting vascular endothelial growth factor receptor 2 (VEGFR-2) expressed on vascular endothelium in an experimental gastric cancer model and evaluated the feasibility by comparing conventional NIR-PIT targeting cancer cell membrane in vitro and in vivo.
HER2-positive human gastric cancer cells, NCI-N87, were used for the experiments. Anti-HER2 mAb, trastuzumab and anti-VEGFR-2 mAb, DC101 were conjugated to photosensitizer, IR700. Phototoxicity in response to NIR-PIT were investigated in vitro and in vivo. Microvessel densities, as an indicator of angiogenesis, were counted in harvested xenografts after NIR-PIT to elucidate the mechanism.
DC101-IR700 did not induce phototoxic effect in vitro because of the absence of expression of VEGFR-2 in NCI-N87 cancer cells. However, it induced an antitumor effect in NCI-N87 xenograft tumors accompanied with damage in tumor neovasculature as determined by decreasing tumor microvessel density, which represents a different mechanism than that of conventional NIR-PIT targeting antigens expressed on the tumor cell membrane.
We demonstrated a new approach of NIR-PIT utilizing a target on vascular endothelium, such as VEGFR-2, and this treatment might lead to the development of a new therapeutic strategy for human gastric cancer.
KeywordsNear-infrared photoimmunotherapy Monoclonal antibody Photosensitizer VEGFR-2 Cancer neovasculature
Monoclonal antibody photosensitizer conjugate
Immunogenic cell death
Human epidermal growth factor receptor 2
IRDye700DX N-hydroxysuccinimide ester
Mean fluorescence intensity
Vascular endothelial growth factor receptor 2
We would like to thank Mr. Kazuya Sakurai and Ms. Mamiko Ohwada for their pathological assistants with the experiments. This study was supported partly by a Grant-in-Aid for Young Scientists (A) (JSPS KAKENHI 26710010), Grant-in-Aid for Scientific Research (B) (JSPS KAKENHI 18H03523), funding from a research Grant of Bristol-Myers Squibb (M.M.), and funding from the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research (1ZIABC011513).
Conceptualization: MM; data duration: TN, KI and MM; formal analysis: TN, KI and MM; funding acquisition: MM and HK; supervision: HK and MS; writing: TN, MM and HK.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
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