Trastuzumab deruxtecan efficacy, FcRn-facilitated penetration of the blood-tumor barrier and distribution to tumor cells in HER2+ brain metastasis model systems.
[BACKGROUND] Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) approved for metastatic HER2+ and HER2-low/ultralow breast cancer.
APA
Khan I, Kumar D, et al. (2026). Trastuzumab deruxtecan efficacy, FcRn-facilitated penetration of the blood-tumor barrier and distribution to tumor cells in HER2+ brain metastasis model systems.. Neuro-oncology. https://doi.org/10.1093/neuonc/noag002
MLA
Khan I, et al.. "Trastuzumab deruxtecan efficacy, FcRn-facilitated penetration of the blood-tumor barrier and distribution to tumor cells in HER2+ brain metastasis model systems.." Neuro-oncology, 2026.
PMID
41501998
Abstract
[BACKGROUND] Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) approved for metastatic HER2+ and HER2-low/ultralow breast cancer. It has shown impressive clinical activity for HER2+ brain metastases. We conducted preclinical brain metastasis experiments to understand T-DXd efficacy.
[METHODS] Nude mice were intracardiacly injected with either JIMT1-BR (HER2-2+) or SUM190-BR (HER2-3+) brain-tropic breast cancer cells and dosed with 3 or 10 mg/kg T-DXd or 10 mg/kg control-ADC, with endpoints of metastasis number and size, in both the metastasis prevention and treatment of established disease settings.
[RESULTS] In the JIMT1-BR model, T-DXd at both doses reduced metastasis number by 48-88% and size by 32-88%; a reduction of HER2 expression by lesions remaining at the experimental endpoint and heterogeneous T-DXd distribution were observed. A distinct dose effect was observed in SUM190-BR with the 3 mg/kg dose inhibiting size and number by 24-39% and 10 mg/kg by 72-79%; HER2 expression was maintained together with heterogeneous T-DXd distribution. In both models widespread reduced tumor Ki-67 was observed, while increased cleaved caspase-3 primarily costained with T-DXd. We used an in vitro model of the blood-brain- and blood-tumor barriers (BBB/BTB) to ask how T-DXd crossed. Data demonstrated T-DXd endocytosis and transcytosis of brain endothelial cells partially reliant on the neonatal Fc receptor (FcRn). BTB transcytosis was accompanied by increased endothelial RAB11FIP5 expression in vitro and in vivo.
[CONCLUSIONS] The data confirm T-DXd activity in HER2+ brain metastases and identify important correlates including heterogeneous uptake, variable HER2 expression at endpoint, tumor cell cytotoxicity, decreased proliferation, and BTB transcytosis.
[METHODS] Nude mice were intracardiacly injected with either JIMT1-BR (HER2-2+) or SUM190-BR (HER2-3+) brain-tropic breast cancer cells and dosed with 3 or 10 mg/kg T-DXd or 10 mg/kg control-ADC, with endpoints of metastasis number and size, in both the metastasis prevention and treatment of established disease settings.
[RESULTS] In the JIMT1-BR model, T-DXd at both doses reduced metastasis number by 48-88% and size by 32-88%; a reduction of HER2 expression by lesions remaining at the experimental endpoint and heterogeneous T-DXd distribution were observed. A distinct dose effect was observed in SUM190-BR with the 3 mg/kg dose inhibiting size and number by 24-39% and 10 mg/kg by 72-79%; HER2 expression was maintained together with heterogeneous T-DXd distribution. In both models widespread reduced tumor Ki-67 was observed, while increased cleaved caspase-3 primarily costained with T-DXd. We used an in vitro model of the blood-brain- and blood-tumor barriers (BBB/BTB) to ask how T-DXd crossed. Data demonstrated T-DXd endocytosis and transcytosis of brain endothelial cells partially reliant on the neonatal Fc receptor (FcRn). BTB transcytosis was accompanied by increased endothelial RAB11FIP5 expression in vitro and in vivo.
[CONCLUSIONS] The data confirm T-DXd activity in HER2+ brain metastases and identify important correlates including heterogeneous uptake, variable HER2 expression at endpoint, tumor cell cytotoxicity, decreased proliferation, and BTB transcytosis.