ICAM1 is highly overexpressed in triple-negative breast cancer (TNBC) cells and facilitates receptor-mediated antibody internalization. Guo et al. developed a rationally designed panel of four ICAM1 antibody–drug conjugates using different chemical linkers and warheads for the treatment of TNBC. IC1–MMAE, which has a protease-cleavable linker and a microtubule inhibitor warhead, showed the highest and most consistent efficacy for complete and durable tumor regression and eradication in a series of standard, late-stage, and refractory TNBC models in vivo. IC1–MMAE did not show liver or renal toxicities in systemic treatment at dosages of 1 to 10 mg/kg.
Contributed by Shishir Pant
ABSTRACT: Triple-negative breast cancer (TNBC) remains the most lethal form of breast cancer, and effective targeted therapeutics 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, efficiently 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 antibody 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.
Author Info: (1) Vascular Biology Program, Boston Children's Hospital, Boston, MA 02115, USA. Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA
Author Info: (1) Vascular Biology Program, Boston Children's Hospital, Boston, MA 02115, USA. Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA. Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China. Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China. (2) Vascular Biology Program, Boston Children's Hospital, Boston, MA 02115, USA. Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA. (3) Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China. Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China. (4) MabPlex International, Yantai, Shandong 264006, China. (5) School of Life Science and Technology, Tongji University, Shanghai 200092, China. (6) School of Life Science and Technology, Tongji University, Shanghai 200092, China. (7) Vascular Biology Program, Boston Children's Hospital, Boston, MA 02115, USA. Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
