2 research outputs found
Additional file 1: of Molecular targeted photoimmunotherapy for HER2-positive human gastric cancer in combination with chemotherapy results in improved treatment outcomes through different cytotoxic mechanisms
Figure S1. LIVE/DEAD assay. Figure S2. Caspase-3 activity assay. (DOCX 397 kb
Near-Infrared Photochemoimmunotherapy by Photoactivatable Bifunctional Antibody–Drug Conjugates Targeting Human Epidermal Growth Factor Receptor 2 Positive Cancer
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