Abstract 3894: Targeting colorectal and pancreatic cancer stem cells with the LGR5 monoclonal antibody BNC101
Authors: Chu Peter , Smith Kristen , Norton John , Walsh Colin , Shojaei Farbod , Iglesias Jose , Reyes Christopher 
Published: May 2015

Abstract
BNC101 is a monoclonal antibody (mAb) targeting LGR5 currently undergoing IND-enabling studies in preparation for Phase I clinical studies in 2014. LGR5 is a validated cancer stem cell (CSC) receptor overexpressed in colorectal cancer (CRC), pancreatic cancer and most other solid tumors. Loss and gain-of-function studies indicate that LGR5 is a functional cancer receptor involved in the growth and survival of colon cancer cells in vitro and in vivo. Sorted LGR5+ primary CRC are highly tumorigenic compared to LGR5- cells in limiting dilution in vivo xenograft studies. Using Bionomics' CSC Rx Discovery™ platform, a panel of high affinity LGR5 mAbs were generated and screened for in vitro and in vivo activity against CSCs from patient-derived CRC tumors. LGR5 mAb therapeutic drug candidates were first screened and identified based on their ability to inhibit the formation of CRC CSC colonies in vitro. Top LGR5 mAb candidates were then tested as single agents and in combination with standard of care (SOC) chemotherapy in primary xenograft efficacy studies. Tumors from these studies were also harvested and re-implanted in limiting dilution assays (LDA) to assess in vivo anti-CSC activity of anti-LGR5 mAbs. A number of functional LGR5 mAbs with significant anti-tumor and anti-CSC activity were identified through this process. A lead BNC101 mAb clone was selected for clinical development based on its ability to inhibit CSC growth and key signaling pathways from multiple patient tumors both in vitro and in vivo. In LDA studies using two different CRC patient tumors, 5/8 (63%) and 6/8 (75%) mice implanted with serially diluted cells from BNC101 treated tumors remained tumor free, compared to 1/8 (13%) and 2/8 (25%) in the control groups. Combination with SOC chemotherapy was shown to further improve BNC101 activity in one CRC model, where 8/8 mice re-implanted for LDA remained tumor-free in a 6 month follow-up. BNC101 was also found to be highly active as a single agent and in combination with SOC in multiple pancreatic models and the MDA-MB-231 triple-negative breast cancer (TNBC) xenograft model. In one primary pancreatic model, BNC101 combined with SOC completely eradicated 3/7 established tumors, compared to 0/7 tumors eradicated with control SOC alone. Additional translational data in CRC, pancreatic and TNBC supporting our hypothesis that BNC101 targeting of CSCs will significantly improve survival and increase duration of response in cancer patients will be presented.
Citation Format: Peter Chu, Kristen Smith, John Norton, Colin Walsh, Farbod Shojaei, Jose Iglesias, Christopher Reyes. Targeting colorectal and pancreatic cancer stem cells with the LGR5 monoclonal antibody BNC101. [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 3894. doi:10.1158/1538-7445.AM2014-3894