Abstract PD5-08: A biparatopic HER2-targeting antibody-drug conjugate demonstrates potent antitumor activity in primary tumor models that are refractory to or ineligible for HER2-targeted therapies
Authors: Li JY , Perry SR , Muniz-Medina V , Wetzel LK , Rebelatto MC , Bezabeh BZ , Fleming RL , Dimasi N , Gao C , Wu H , Jenkins DW , Osbourn JK , Coats SR 
Published: May 2016

Abstract
Current HER2-targeted drugs are ineffective in killing cancer cells expressing relatively low levels of HER2. Therefore, more than 60% of breast cancer patients are ineligible for HER2-targeted therapies because of lack of HER2 overexpression and the vast majority of eligible patients who initially respond to the treatment will eventually relapse. MedImmune is developing a novel HER2-targeting antibody-drug conjugate (ADC) to address this unmet medical need. We show that a bivalent biparatopic antibody targeting two distinct non-overlapping epitopes on HER2 is able to induce receptor clustering on the tumor cell surface, which in turn facilitates internalization and promotes lysosomal trafficking and degradation. When conjugated with a tubulysin-based microtubule inhibitor, the biparatopic antibody can deliver a greater quantity of cytotoxin into the targeted cancer cells. As a result, it demonstrated superior antitumor activity over Kadcyla® (T-DM1) in HER2-overexpressing (HER2-positive) tumor models. It also induced complete tumor regression in a HER2-positive tumor model that had developed acquired resistance to T-DM1 through chronic exposure. Moreover, to explore the potential clinical applications in treating the HER2 non-overexpressing (HER2-negative) patients the biparatopic ADC was evaluated across 17 primary tumor models derived from HER2-negative breast cancer patients among which 13 were triple-negative. Other criteria were also considered in the selection of these 17 models, including the degree of heterogeneity in HER2 expression, ER/PR status and histopathologic subclass, to maximize the diversity of tumor subtypes in the study. The biparatopic ADC demonstrated potent antitumor activity regardless of the histopathologic subclass and ER/PR status of the tumor. At the dose of 1 mg/kg, 41% of the tumor models (7 out of 17) showed tumor regression and 6% (1 out of 17) showed tumor stasis. At the dose of 3 mg/kg, 71% of the models (12 out of 17) showed tumor regression and 12% (2 out of 17) showed tumor stasis. Overall, our findings underscore the potential use of this novel HER2-targeting ADC to treat a large patient population that is ineligible for or relapsed/refractory to current HER2-targeted therapies, and thus warrant investigation in the clinic.
Citation Format: Li JY, Perry SR, Muniz-Medina V, Wetzel LK, Rebelatto MC, Bezabeh BZ, Fleming RL, Dimasi N, Gao C, Wu H, Jenkins DW, Osbourn JK, Coats SR. A biparatopic HER2-targeting antibody-drug conjugate demonstrates potent antitumor activity in primary tumor models that are refractory to or ineligible for HER2-targeted therapies. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr PD5-08.