Journal
CLINICAL CANCER RESEARCH
Volume 27, Issue 14, Pages 3970-3979Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-21-0397
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Funding
- Daiichi Sankyo Research grant
- National Cancer Center Research and Development Fund
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The study used PID imaging analysis to assess the intratumor pharmacokinetics of T-DXd, a novel HER2-targeted antibody-drug conjugate. The results demonstrated that T-DXd is distributed to tumor tissues via trastuzumab in a HER2-dependent manner and then spreads to adjacent HER2-negative areas. This successful visualization of the intratumoral distribution of T-DXd also illustrated its mechanism of action, known as the bystander effect.
Purpose: We assessed the intratumor pharmacokinetics of [fam-] trastuzumab deruxtecan, T-DXd (known as DS-8201a), a novel HER2-targeted antibody-drug conjugate, using phosphor-integrated dots (PID)-imaging analysis to elucidate its pharmacologic mechanism. Experimental Design: We used two mouse xenograft models administered T-DXd at the concentration of 4 mg/kg: (i) a heterogeneous model in which HER2-positive and HER2-negative cell lines were mixed, and (ii) a homogeneous model in which both cell types were transplanted separately into the same mouse. PID imaging involved immunostaining using novel high-intensity fluorescent nanoparticles. The distribution of T-DXd was assessed by PID imaging targeting the parent antibody, trastuzumab, and the payload, DXd, in serial frozen sections, respectively. Results: After T-DXd administration in the heterogeneous model, HER2 expression tended to decrease in a time-dependent manner. The distribution of trastuzumab and DXd was observed by PID imaging along the HER2- positive area throughout the observation period. A detailed comparison of the PID distribution between trastuzumab and DXd showed that trastuzumab matched almost perfectly with the HER2-positive area. In contrast, DXd exhibited widespread distribution in the surrounding HER2-negative area as well. In the HER2-negative tumor of the homogeneous model, the PID distribution of trastuzumab and DXd remained extremely low throughout the observation period. Conclusions: Our results suggest that T-DXd is distributed to tumor tissues via trastuzumab in a HER2-dependent manner and then to adjacent HER2-negative areas. We successfully visualized the intratumor distribution of T-DXd and its mechanism of action, the so-called bystander effect.
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