Near-infrared-induced drug release from antibody-drug double conjugates exerts a cytotoxic photo-bystander effect.

Ideal cancer treatments specifically target and eradicate tumor cells without affecting healthy cells. Therefore, antibody-based therapies that specifically target cancer antigens can be considered ideal cancer therapies. Antibodies linked with small-molecule drugs (i.e., antibody-drug conjugates [ADCs]) are widely used in clinics as antibody-based therapeutics. However, because tumors express antigens heterogeneously, greater target specificity and stable binding of noncleavable linkers in ADCs limit their antitumor effects. To overcome this problem, strategies, including decreasing the binding strength, conjugating more drugs, and targeting tumor stroma, have been applied, albeit with limited success. Thus, further technological advancements are required to remotely control the ADCs. Here, we described a drug that is photo-releasable from an ADC created via simple double conjugation and its antitumor effects both on target and nontarget tumor cells. Specifically, noncleavable T-DM1 was conjugated with IR700DX to produce T-DM1-IR700. Although T-DM1-IR700 itself is noncleavable, with NIR-light irradiation, it can release DM1-derivatives which elicited antitumor effect in vitro mixed culture and in vivo mixed tumor model which are mimicking heterogeneous tumor-antigen expression same as real clinical tumors. This cytotoxic photo-bystander effect occurred in various types mixed cultures in vitro, and changing antibodies also exerted photo-bystander effects, suggesting that this technology can be used for targeting various specific cancer antigens. These findings can potentially aid the development of strategies to address challenges associated with tumor expression of heterogeneous antigen.