Abstract 1682: Development and activity of a novel antibody-drug conjugate for the treatment of P-cadherin expressing cancers

Abstract

The cell surface glycoprotein P-cadherin is an attractive target for an antibody-drug conjugate (ADC) therapy as it is known to be highly expressed in a number of malignancies, including those arising in the epithelium of the breast, lung, bladder, esophagus, stomach, endometrium and colon, among others. In breast cancer, P-cadherin is frequently overexpressed in high grade invasive tumors and is a reliable marker of the basal-like breast cancer molecular subtype, a disease with no effective therapeutic treatment options. Based on the expression profile of P-cadherin in human cancer, a highly selective and potent ADC was developed to target cancer types overexpressing this glycoprotein. This ADC consists of a fully human anti-P-cadherin-specific antibody conjugated to the potent maytansine-derived microtubule-disruptor, DM1, via an SMCC non-cleavable thioether linkage (technology licensed from ImmunoGen, Inc.). In vitro, the ADC was demonstrated to selectively bind P-cadherin expressing cell lines, to rapidly internalize and traffic to lysosomes, and to release a sufficient amount of activated payload to potently induce a cytotoxic response in cell viability assays. Profiling of activity in a cell line panel indicated that this ADC can effectively target and kill P-cadherin-positive cancer cells representing breast, head and neck, and bladder carcinomas. In vivo, the ADC was highly efficacious in numerous relevant xenograft models of P-cadherin expressing cancers, including breast, head and neck, bladder and lung. From this promising cellular and in vivo activity, this ADC may be an effective treatment for patients with P-cadherin positive cancers of high unmet medical need.

Citation Format: Daniel Menezes, Tinya J. Abrams, Christopher Karim, Yan Tang, Chi Ying, Kathy Miller, Christie Fanton, Majid Ghoddusi, Zhen Wang, Montesa Patawaran, Nancy Pryer, Emma Lees, Jason Damiano. Development and activity of a novel antibody-drug conjugate for the treatment of P-cadherin expressing cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1682. doi:10.1158/1538-7445.AM2015-1682