A Biparatopic HER2-Targeting Antibody-Drug Conjugate Induces Tumor Regression in Primary Models Refractory to or Ineligible for HER2-Targeted Therapy

Publication date: 11 January 2016
Source:Cancer Cell, Volume 29, Issue 1
Author(s): John Y. Li, Samuel R. Perry, Vanessa Muniz-Medina, Xinzhong Wang, Leslie K. Wetzel, Marlon C. Rebelatto, Mary Jane Masson Hinrichs, Binyam Z. Bezabeh, Ryan L. Fleming, Nazzareno Dimasi, Hui Feng, Dorin Toader, Andy Q. Yuan, Lan Xu, Jia Lin, Changshou Gao, Herren Wu, Rakesh Dixit, Jane K. Osbourn, Steven R. Coats
Antibody-drug conjugate (ADC) which delivers cytotoxic drugs specifically into targeted cells through internalization and lysosomal trafficking has emerged as an effective cancer therapy. We show that a bivalent biparatopic antibody targeting two non-overlapping epitopes on HER2 can induce HER2 receptor clustering, which in turn promotes robust internalization, lysosomal trafficking, and degradation. When conjugated with a tubulysin-based microtubule inhibitor, the biparatopic ADC demonstrates superior anti-tumor activity over ado-trastuzumab emtansine (T-DM1) in tumor models representing various patient subpopulations, including T-DM1 eligible, T-DM1 ineligible, and T-DM1 relapsed/refractory. Our findings indicate that this biparatopic ADC has promising potential as an effective therapy for metastatic breast cancer and a broader patient population may benefit from this unique HER2-targeting ADC.

Graphical abstract

Teaser

Li et al. develop a biparatopic HER2-targeting antibody-drug conjugate that demonstrates therapeutic activity in breast cancer models representing T-DM1 eligible, resistant, and ineligible patient populations and has sufficient safety profile in non-human primates to support its translation into clinical trials.


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