Development Of An Antibody-Drug Conjugate Targeting Tim-1 For The Treatment Of Ovarian And Renal Cell Carcinoma

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA T cell immunoglobulin and mucin domain 1 (TIM-1) is a type I transmembrane protein that was originally described as kidney injury molecule 1 (KIM-1) due to its elevated expression in kidney and urine after renal injury. Tim-1 expression is also upregulated in several human cancers, most notably in renal cell and ovarian carcinomas, but has very restricted expression in healthy tissues thus representing a promising target for antibody mediated therapy. To this end we have developed a fully human monoclonal IgG1 antibody specific for extracellular domain of TIM-1. This antibody was shown to bind purified recombinant chimeric TIM-1-Fc protein and TIM-1 expressed on a variety of transformed cell lines, including Caki-1 (human renal clear cell carcinoma), IGROV-1 (human ovarian adenocarcinoma) and ACHN (human renal cell adenocarcinoma). Internalization studies using confocal microscopy revealed the antibody was rapidly internalized by cells in vitro, and the internalization was confirmed by quantitative imaging flow cytometry using ImageStream. An antibody-drug conjugate (ADC) was produced with the anti-TIM-1 antibody covalently linked to a potent cytotoxin, monomethyl auristatin E (MMAE), and designated CDX-014. The ADC was shown to exhibit in vitro cytostatic or cytotoxic activity against a variety of TIM-1 expressing cell lines, but not on TIM-1 negative cell lines. Using the Caki-1 and IGROV-1 xenograft models, CDX-014 showed significant anti-tumor activity in the range of 75-300 μg/dose given every four days for a total of four doses. Activities are on-going to support the manufacturing and IND-enabling studies in order to advance CDX-014 towards clinical studies in renal cell carcinomas and potentially other TIM-1 expressing tumors. Citation Format: Lawrence J. Thomas, Laura Vitale, Thomas O'Neill, Ree Dolnick, Paul K. Wallace, Hans Minderman, Lauren E. Gergel, Eric M. Forsberg, James M. Boyer, James R. Storey, Russell A. Hammond, Jennifer Widger, Karuna Sundarapandiyan, Andrea Crocker, Henry C. Marsh, Tibor Keler. Development of an antibody-drug conjugate targeting TIM-1 for the treatment of ovarian and renal cell carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2649. doi:10.1158/1538-7445.AM2014-2649