Abstract 4752: Preclinical development and translational research on a novel antibody-drug conjugate that targets 5T4, an oncofetal antigen expressed on tumor-initiating cells.

Abstract

Abstract Antibody-drug conjugates (ADCs) represent a promising therapeutic modality for the clinical management of cancer. We sought to develop a novel ADC that targets 5T4 (TPBG), an oncofetal antigen expressed on tumor-initiating cells (TICs), which comprise the most aggressive cell population in the tumor. We optimized an anti-5T4 ADC (A1mcMMAF) by sulfydryl-based conjugation of the humanized A1 antibody to the tubulin inhibitor monomethylauristatin F (MMAF) via a maleimidocaproyl linker. A1mcMMAF exhibited potent in vivo anti-tumor activity in a variety of tumor models and induced long-term regressions for up to 100 days after the last dose. Strikingly, animals showed pathological complete response in each model. In a non-small cell lung cancer patient-derived xenograft in which 5T4 is preferentially expressed on the less differentiated tumor cells, A1mcMMAF treatment resulted in sustained tumor regressions and reduced TIC frequency. These results highlight the potential of ADCs that target the most aggressive cell populations within tumors. An optimized pharmacokinetic/pharmacodynamic (PK/PD) model of tumor growth and drug kill was used to characterize the ADC concentration response relationship in mouse. A holistic secondary parameter, tumor static concentration (TSC), was derived from model parameters to quantify efficacy and support early clinical trial design. Tumor static concentrations [80% confidence] of A1mcMMAF ranged from 1.1[0.9 -1.4] μg/ml to 11.6 [9.6 - 14.1] μg/ml across tumor models. For comparison, in the clinic T-DM1 has an average concentration of 14 μg/ml at an efficacious dose of 3.6 mg/kg Q3wk (HER+ breast cancer) (Krop et al. 2010) and Brentuximab-vedotin has an average concentration of 3.65 μg/ml at an efficacious dose of 1.8 mg/kg Q 3wk (HL/ ALCL) (Younes et al. 2010). Taken together, the preclinical data established a promising therapeutic index that supports clinical testing of A1mcMMAF. Expression analysis profiling using clinical and preclinical data indicated that lung and breast tumors demonstrated differentially high expression of 5T4 in comparison to normal tissues. An IHC assay developed in house confirmed the hypothesis that a broad range of 5T4 expression was measurable in NSCLC patient tumor samples. Additionally, we developed an assay that measures 5T4 expression on circulating tumor cells (CTCs) and used this assay to measure and characterize a broad range of 5T4 expression in CTCs obtained from the blood of NSCLC patients. We intend to deploy these co-developed immunoassays to guide A1mcMMAF clinical development. Citation Format: Puja Sapra, Marc Damelin, Kimberly Marquette, Kenneth G. Geles, Jonathon Golas, Maureen Dougher, Bitha Narayanan, Andreas Giannakou, Kiran Khandke, Russell Dushin, Elana Ernstoff, Judy Lucas, Mauricio Leal, George Hu, Alison Betts, Nahor Haddish-Berhane, Eric Powell, Steven Pirie-Shepherd, Christopher O'Donnell, Lioudmila Tchistiakova, Hans-Peter Gerber, Dena Marrinucci, Eric Tucker. Preclinical development and translational research on a novel antibody-drug conjugate that targets 5T4, an oncofetal antigen expressed on tumor-initiating cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4752. doi:10.1158/1538-7445.AM2013-4752