Abstract C165: Development of a probody drug conjugate (PDC) against CD166 for the treatment of multiple cancers

Abstract

Abstract Antibody drug conjugates (ADCs) have shown their greatest clinical utility when targeting antigens expressed at very high levels on cancer cells that have coincidentally lower expression in normal tissues. This is exemplified by the approvals of trastuzumab emtansine for her2neu 3+ breast cancer and brentuximab vedotin for Hodgkins Disease and Anaplastic large-cell lymphoma. Both drugs are approved for subsets of specific cancer types where target antigen expression is particularly high relative to expression in normal tissues. There are other cell surface antigens that are highly expressed on cancer cells and normal tissues, but the utility of such antigens as ADC targets is restricted by their corresponding expression in normal tissues. One such target is CD166 (ALCAM), which shows 3+ expression by IHC in most donors of multiple cancer types, e.g., ca. 70% prevalence in breast, prostate, and lung cancers but also expression in multiple normal tissues including lung, GI tissues, and liver. Thus CD166 has not been progressed as a target for ADCs. Probody™ therapeutics are fully recombinant antibody prodrugs that are converted to active antibodies by tumor-associated proteases. Preclinical in vivo studies show that Probody therapeutics remain substantially inactive in normal tissues and in circulation. As such, Probody drug conjugates (PDCs), unlike ADCs, enable targeting of high expression tumor targets that are also expressed in normal tissues. We have developed an anti-CD166 Probody therapeutic selected for specific binding, internalization, and cross reactivity to cynomolgus macaque as a species for toxicology assessments. This therapeutic has been conjugated to spdb-DM4 and tested in preclinical models of efficacy and safety. Treatment with the PDC has led to complete regressions in models of lung and breast cancer at therapeutically relevant doses. These same doses were assessed for safety in cynomolgus monkeys. The safety and efficacy profiles for the anti-CD166 PDC are supportive of progression to clinical development of this anti-CD166 Probody drug conjugate. Citation Format: Annie Yang Weaver, Shweta Singh, Amy DuPage, Jason Sagert, Jeanne Flandez, Elizabeth Menendez, Judi Ford, Michael Krimm, Stephen Moore, Margaret Nguyen, Andrew Jang, Eric Brecht, Yuanhui Huang, Linnea Diep, Nicole Lapuyade, Tereza Sputova, James West, Olga Vasiljeva, Shouchun Liu, Jennifer Richardson, W. Michael Kavanaugh, Jonathan A. Terrett, Luc R. Desnoyers. Development of a probody drug conjugate (PDC) against CD166 for the treatment of multiple cancers. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C165.