Abstract 2315: The LGR5 monoclonal antibody BNC101 has anti-tumor and anti-cancer stem cell activity in pancreatic cancer

Abstract

Abstract BNC101 is a humanized monoclonal antibody (mAb) targeting LGR5 that has successfully completed IND-enabling studies for upcoming human clinical trials. LGR5 was originally identified as a cancer stem cell (CSC) specific receptor associated with the Wnt signaling pathway in colorectal cancer (CRC). BNC101 has significant anti-tumor and anti-CSC activity in multiple CRC patient-derived xenografts (PDX), consistent with the hypothesis that LGR5 is a functional CSC target in CRC. Because LGR5 has also been reported to be expressed on regenerating pancreatic stem cells and upregulated in pancreatic cancer, we investigated pancreatic cancer as an additional indication for BNC101 therapy. LGR5 expression was screened in a panel of pancreatic PDX samples by qPCR and RNAscope, and found to be highly expressed in a number of pancreatic samples including JH109. In vivo debulking of JH109 tumors with standard of care (SOC) Gemcitabine and Abraxane combination followed by treatment with BNC101 caused complete tumor regression in 43% (3/7) of mice (compared to 0% (0/7) in control SOC only group). We also screened LGR5 expression in a series of pancreatic cancer cell lines and identified both high-LGR5 expressing lines ASPC1 and PANC1, and an LGR5-negative line, BxPc3. BNC101 monotherapy partially inhibited tumor growth in ASPC1 and PANC1 models. In combination with Gemzar, however, BNC101 significantly inhibited tumor growth in both models. In contrast, BNC101 single agent or in combination with chemotherapy had no anti-tumor activity in the LGR5 negative BxPc3 xenograft tumors. Post-study analysis of BNC101-treated tumors revealed several interesting findings related to mechanism of action and biomarker identification. LGR5 expression was upregulated in chemo-treated tumors, suggesting that BNC101 chemo combination activity was successful due to greater LGR5 target availability. IHC analysis showed an increase in CA19 and Alcian blue expression, consistent with the hypothesis that BNC101 targets CSCs and induces terminal differentiation. BNC101 treatment also significantly reduced LGR5+ HLA+ circulating-tumor-cells (CTCs) in the peripheral blood of tumor-bearing mice, providing a pharmacodynamic (PD) biomarker of target engagement to further evaluate in clinical studies. Altogether, the data support further evaluation of BNC101 in the clinic for the treatment of pancreatic cancer. Additional translational data for future clinical development of BNC101 in pancreatic cancer will also be presented. Citation Format: Farbod Shojaei, Colin Walsh, Kristen Smith, Camino Menendez, Pedro Lopez, John Norton, Jose Iglesias, Manuel Hidalgo, Christopher Reyes, Peter Chu. The LGR5 monoclonal antibody BNC101 has anti-tumor and anti-cancer stem cell activity in pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2315. doi:10.1158/1538-7445.AM2015-2315