Abstract 213: Development of a probody-drug conjugate targeting EpCAM for the treatment of solid tumors
Authors: Liu Yimao , Wu Rui , Gavrilescu Cristina , Sagert Jason , Tipton Kimberly , Liu Shouchun , Chan Chanty , Boulé Steven , Wilhelm Alan , Lucas Jacquelynn , Matin Bahar , Lecerf Jean-Michel , Themeles Marian , Morneault Ashley , Drake Tara , Yancey Sadiqa , Kohli Neeraj , Espelin Christopher , Follit John , Donahue Kerry A. , Chittenden Tom , Guidi Cynthia , Hicks Stuart W. 
Published: August 2019

Epithelial Cell Adhesion Molecule (EpCAM) is a glycosylated, 40-kDa type I transmembrane protein that plays a role in cell adhesion and cell signaling. EpCAM is an attractive target for antibody drug conjugate (ADC) development due to its overexpression on a variety of tumors of epithelial origin, including lung, colon, breast, ovarian, prostate and pancreatic cancers. In addition, EpCAM is enriched on tumor-initiating cells (TICs), which are often resistant to conventional cancer therapies. As such, EpCAM-targeted therapies may lead to more durable responses. However, EpCAM is also expressed on a variety of normal epithelia, thus limiting its utility as an ADC target due to potential toxicity. We aim to overcome this limitation by developing an EpCAM-targeting Probody™ drug conjugate (PDC). A Probody therapeutic is an antibody engineered with a mask that blocks the antigen binding site. Probody therapeutics can be selectively activated by tumor associated proteases releasing an active antibody with restored antigen binding activity. Therefore, an EpCAM-targeting PDC could have the anti-tumor potency of an ADC, while limiting binding to healthy tissues and minimizing toxicities.

Here, we describe the development of EpCAM-targeted PDCs, based on a novel human/cynomolgus cross-reactive anti-EpCAM antibody. Probody molecules were successfully conjugated to either the maytansine-derived microtubule disruptor, DM4, linked via a hindered disulfide hydrophilic linker (sulfo-SPDB) or the ultra-potent DNA alkylating payload, DGN549. The antigen binding and in vitro cytotoxicity of intact PDCs were dramatically reduced compared to the corresponding ADC, but could be restored following in vitro proteolytic activation. Furthermore, EpCAM-targeting PDCs displayed compelling and specific anti-tumor activity in xenograft mouse models. In addition, the tolerability and pharmacokinetics (PK) of a selection of the EpCAM PDCs were compared to the EpCAM-targeting ADC in cynomolgus monkeys. EpCAM-targeting PDCs were better tolerated than the corresponding EpCAM-targeting ADC even at higher dose levels and displayed longer half-lives and greater exposure. Therefore, EpCAM PDCs showed greatly improved tolerability and PK profiles compared to the EpCAM ADC.

The studies presented herein support an anti-EpCAM PDC as a promising novel therapeutic to target a wide range of EpCAM-expressing cancers with the potential to overcome the associated on-target toxicities.

PROBODY is a trademark of CytomX Therapeutics, Inc.

Citation Format: Yimao Liu, Rui Wu, Cristina Gavrilescu, Jason Sagert, Kimberly Tipton, Shouchun Liu, Chanty Chan, Steven Boulé, Alan Wilhelm, Jacquelynn Lucas, Bahar Matin, Jean-Michel Lecerf, Marian Themeles, Ashley Morneault, Tara Drake, Sadiqa Yancey, Neeraj Kohli, Christopher Espelin, John Follit, Kerry A. Donahue, Tom Chittenden, Cynthia Guidi, Stuart W. Hicks. Development of a probody-drug conjugate targeting EpCAM for the treatment of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 213.