Near-Infrared Photochemoimmunotherapy by Photoactivatable Bifunctional Antibody–Drug Conjugates Targeting Human Epidermal Growth Factor Receptor 2 Positive Cancer

5 years ago

Near-Infrared Photochemoimmunotherapy by Photoactivatable Bifunctional Antibody–Drug Conjugates Targeting Human Epidermal Growth Factor Receptor 2 Positive Cancer

Takashi Nishimura, Hisataka Kobayashi, Hisao Tajiri, Makoto Mitsunaga, Masayuki Saruta, Kimihiro Ito, Takeo Iwamoto

Near-infrared photoimmunotherapy (NIR-PIT) is a new class of molecular targeted cancer therapy based on antibody–photoabsorber conjugates and NIR light irradiation. Recent studies have shown effective tumor control, including that of human epidermal growth factor receptor 2 (HER2)-positive cancer, by selective molecular targeting with NIR-PIT. However, the depth of NIR light penetration limits its use. Trastuzumab emtansine (T–DM1) is an antibody–drug conjugate consisting of the monoclonal antibody trastuzumab linked to the cytotoxic agent maytansinoid DM1. Here, we developed bifunctional antibody–drug–photoabsorber conjugates, T–DM1–IR700, that can work as both NIR-PIT and chemoimmunotherapy agents. We evaluated the feasibility of T–DM1–IR700-mediated NIR light irradiation by comparing the in vitro and in vivo cytotoxic efficacy of trastuzumab–IR700 (T–IR700)-mediated NIR light irradiation in HER2-expressing cells. T–IR700 and T–DM1–IR700 showed almost identical binding to HER2 in vitro and in vivo. Owing to the presence of internalized DM1 in the target cells, NIR-PIT using T–DM1–IR700 tended to induce greater cytotoxicity than that of NIR-PIT using T–IR700 in vitro. In vivo NIR-PIT using T–DM1–IR700 did not show a superior antitumor effect to NIR-PIT using T–IR700 in subcutaneous small-tumor models, which could receive sufficient NIR light. In contrast, NIR-PIT using T–DM1–IR700 tended to reduce the tumor volume and showed significant prolonged survival compared to NIR-PIT using T–IR700 in large-tumor models that could not receive sufficient NIR light. We successfully developed a T–DM1–IR700 conjugate that has a similar immunoreactivity to the parental antibody with increased cytotoxicity due to DM1 and potential as a new NIR-PIT agent for targeting tumors that are large and inaccessible to sufficient NIR light irradiation to activate the photoabsorber IR700.

Publisher URL: http://dx.doi.org/10.1021/acs.bioconjchem.7b00144

DOI: 10.1021/acs.bioconjchem.7b00144