Abstract 212: CD166-DM4 probody drug conjugate (CX-2009) treatment of 198 patient-derived xenograft models (PDX) in a mouse clinical trial format
Authors: Bob Y. Liu, Joel Shen, Matthias Will, Sreeni Yalamanchili, Judi Gordon, Mark Stroh, Jennifer Richardson, Annie Weaver, Luc Desnoyer, Marcia Belvin, Michael Kavanaugh, Siew Schleyer
Journal: Cancer Research (2019)

Abstract Ideal targets for antibody drug conjugates (ADC) are highly and homogeneously expressed on tumor cells in a wide variety of tumor types and in a high proportion of patients. Such targets should also be efficient cellular internalizers and have limited expression on normal tissues. Unfortunately, targets that meet all these criteria are rare. Probody™ drug conjugates (PDCs) are masked antibody prodrugs designed for activation by tumor-associated proteases. PDCs are designed to direct drug activity to the tumor microenvironment by exploiting the dysregulation of tumor protease activity that is the hallmark of most cancers. The Probody platform is designed to minimize interaction with healthy tissues, mitigate “on-target” toxicity regardless of expression outside of the tumor, and greatly expand the number of potential ADC targets. CD166 (ALCAM) is one such novel target. It is expressed at high levels in a high proportion of patients across multiple cancer types, but it is also on healthy tissues, including lung, gastro-intestinal tract, and liver. CX-2009, an investigational SPDB-DM4 PDC targeting CD166, is currently being evaluated in PROCLAIM CX-2009, a clinical phase I/II trial (NCT03149549). CX-2009 exhibited robust preclinical activity against cell-line derived xenograft (CDX) models across various solid tumor indications. Because the DM4 mechanism of action is similar to that of taxane-based chemotherapy, CX-2009 is being evaluated in the clinic for cancer types that respond to microtubule inhibitors and have prevalent CD166 expression. To help further inform patient selection for clinical studies, CX-2009 is being evaluated in 198 PDX models using a murine clinical trial format in collaboration with South Texas Accelerated Research Therapeutics (START). Each mouse is engrafted with a patient’s resected tumor sample that has not been passaged in vitro, and when kept minimally passaged in vivo, may more faithfully recapitulate the tumor biology and response to therapeutics than CDX models. The PDX models are dosed with 5mg/kg of CX-2009 every 2 weeks for 6 weeks via i.v. (q2wX3), and tumor volume is measured twice per week. Currently, we have dosed 66 breast, lung, and ovarian PDX models, obtaining an end-of-study response rate of 21% using clinically defined criteria, e.g. complete response (CR) plus partial response (PR), and a 29% disease-control rate (DCR). Relative to untreated controls, 43% of CX-2009-treated tumors yielded tumor growth inhibition (TGI) of greater than fifty percent. Because of the large cohort data set, this effort can potentially inform patient selection for clinical studies based on correlating efficacy with CD166 expression, tumor subtype, tumor growth rate (doubling time), and taxane sensitivity. PROBODY is a trademark of CytomX Therapeutics, Inc. Citation Format: Bob Y. Liu, Joel Shen, Matthias Will, Sreeni Yalamanchili, Judi Gordon, Mark Stroh, Jennifer Richardson, Annie Weaver, Luc Desnoyer, Marcia Belvin, Michael Kavanaugh, Siew Schleyer. CD166-DM4 probody drug conjugate (CX-2009) treatment of 198 patient-derived xenograft models (PDX) in a mouse clinical trial format [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 212.