Abstract 4209: Targeting GPNMB with 89Zr-CR011 for PET imaging of triple negative breast cancer

Abstract

Abstract Glycoprotein non-metastatic melanoma B (GPNMB) is a transmembrane protein overexpressed in 30 - 40% of triple negative breast cancer (TNBC) and has shown to be associated with metastasis and disease recurrence. An anti-GPNMB antibody drug conjugate, Glembatumumab Vedotin (CDX-011), is currently in Phase II clinical trials for the treatment of metastatic TNBC patients, with promising outcomes. Positron Emission Tomography using radiolabeled antibodies could be advantageous in stratifying patients who may benefit from CDX-011, tracking the biodistribution of CDX-011, and assessing GPNMB expression in vivo. To this end, we radiolabeled the naked antibody, Glembatumumab (CR011), with the positron-emitting 89Zr (half life = 3.3 days). We characterized the stability, affinity, rate of cellular internalization, and specificity of 89Zr-CR011 using various cell-binding assays in human TNBC cell lines. We determined that 89Zr-CR011 is stable in serum solution for up to 5 days, binds specifically to GPNMB+ TNBC cells with high affinity (KD = 16 nM), and internalizes rapidly (50% within 30 - 60 min). We conducted a biodistribution study from 1 - 12 days post administration via tail vein in GPNMB+ MDA-MB-468 xenografts to determine the time point at which we achieve the optimal tumor-to-nontarget ratios. A subset of mice was administered a blocking dose of unlabeled CR011 (100-fold excess, 1 mg/mouse), where we observed a 2.5-fold reduction in 89Zr-CR011 tumor uptake, confirming the specificity of 89Zr-CR011 for GPNMB+ TNBC tumors. PET imaging studies and dosimetry calculations are currently in progress. This preliminary study demonstrates that 89Zr-CR011 may be an excellent companion diagnostic agent for CDX-011 therapy and an essential tool to assess the function of GPNMB in vivo. Citation Format: Bernadette V. Marquez, Supum Lee, Tibor Keler, Thomas Hawthorne, Jeremy Hoog, Shunqiang Li, Cynthia Ma, Suzanne E. Lapi. Targeting GPNMB with 89Zr-CR011 for PET imaging of triple negative breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4209.