A rationally designed ICAM1 antibody drug conjugate eradicates late-stage and refractory triple-negative breast tumors in vivo

Triple-negative breast cancer (TNBC) remains the most lethal form of breast cancer, and effective targeted ther-apeutics are in urgent need to improve the poor prognosis of TNBC patients. Here, we report the development of a rationally designed antibody drug conjugate (ADC) for the treatment of late-stage and refractory TNBC. We determined that intercellular adhesion molecule-1 (ICAM1), a cell surface receptor overexpressed in TNBC, effi-ciently facilitates receptor-mediated antibody internalization. We next constructed a panel of four ICAM1 ADCs using different chemical linkers and warheads and compared their in vitro and in vivo efficacies against multiple human TNBC cell lines and a series of standard, late-stage, and refractory TNBC in vivo models. An ICAM1 an-tibody conjugated with monomethyl auristatin E (MMAE) via a protease-cleavable valine-citrulline linker was identified as the optimal ADC formulation owing to its outstanding efficacy and safety, representing an effective ADC candidate for TNBC therapy.

Automated summary

In this study, a rationally designed antibody drug conjugate (ADC) was developed for the treatment of late-stage and refractory triple-negative breast cancer (TNBC). The overexpression of intercellular adhesion molecule-1 (ICAM1) in TNBC was found to efficiently facilitate receptor-mediated antibody internalization. Four ICAM1 ADCs with different chemical linkers and warheads were constructed and their efficacy was evaluated in vitro and in vivo using multiple human TNBC cell lines and TNBC animal models. An ICAM1 antibody conjugated with monomethyl auristatin E (MMAE) via a protease-cleavable valine-citrulline linker was identified as the optimal ADC formulation due to its outstanding efficacy and safety, and could serve as an effective ADC candidate for TNBC therapy.