Abstract A48: Therapeutic targeting of colorectal cancer stem cells with BNC101, a functional anti-LGR5 monoclonal antibody.

Abstract

Abstract BNC101 is a monoclonal antibody that targets LGR5, a validated cancer stem cell (CSC) receptor overexpressed in colorectal cancer (CRC) and most other solid tumors. Loss and gain-of-function studies found 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 cells were 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 was generated and screened for in vitro and in vivo activity against CSCs from patient-derived CRC tumors. In vitro assays initially identified top LGR5 mAb drug candidates based on their ability to inhibit the formation of CSC colonies. In vivo assays tested candidate LGR5 mAbs as single agents and in combination with standard of care (SOC) chemotherapy in primary xenograft efficacy studies. Tumors from these studies were then harvested and re-implanted in limiting dilution assays (LDA) to assess anti-CSC activity. A number of functional LGR5 mAbs with significant anti-tumor and anti-CSC activity were identified through this process. The 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 transplanted 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 active against tumors from additional cancer indications outside of CRC. Current research is focused on advancing BNC101 translational studies to support clinical development. Significant progress and new results in these studies will be presented, in particular the identification of optimal BNC101 chemo combination strategies, biomarkers and mechanism of action. Altogether, the data support our therapeutic hypothesis that anti-LGR5 mAb BNC101 treatment will be part of an effective strategy in combination with SOC therapy to significantly improve survival and increase duration of response for patients with colorectal cancer and other solid tumors. BNC101 is currently undergoing IND-enabling manufacturing and safety studies in preparation for Phase I clinical studies scheduled for 2014. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A48. Citation Format: Peter Chu, Kristen Smith, Farbod Shojaei, Colin Walsh, John Norton, Jose Iglesias, Christopher Reyes. Therapeutic targeting of colorectal cancer stem cells with BNC101, a functional anti-LGR5 monoclonal antibody. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A48.