Preclinical Evaluation And Biomarker Identification For The Anti-Lgr5 Mab Bnc101 In K-Ras Mutant Crc And Other Solid Tumor Indications

Abstract BNC101 is a monoclonal antibody (mAb) targeting LGR5 that has successfully completed IND-enabling studies in preparation for Phase I clinical studies in 2015. 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 tumor growth and survival. Sorted LGR5+ primary CRC are highly tumorigenic compared to LGR5- cells in limiting dilution in vivo xenograft studies. BNC101 was selected as the lead LGR5 candidate for clinical development using Bionomics’ CSC Rx Discovery™ platform. Key lead selection criteria for BNC101 were anti-tumor and anti-CSC activity in vitro and in vivo, in patient-derived xenograft (PDX) tumor models from multiple tumor types. CSC activity was evaluated by functional in vivo limiting dilution assays (LDA) using tumor cells treated with BNC101 +/- standard-of-care chemotherapy (SOC) combinations. In LDA studies with the K-Ras mutant CRC PDX tumors CT1 and CT3, 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 further improved BNC101 activity against CT3 tumors, where 8/8 mice re-implanted for LDA had 6 months progression-free-survival (vs 3/8 in chemo group). In the pancreatic PDX model JH109, BNC101 combined with SOC flat-lined established tumors in 3/7 mice, compared to 0/7 tumors eradicated with control SOC alone. BNC101 is also active in multiple pancreatic, triple-negative breast (TNBC) and small-cell lung (SCLC) cancer xenograft models. Ongoing translational studies have identified a panel of Wnt genes modulated by BNC101 treatment that could potentially be used to identify BNC101 responsive versus resistant patients in the clinic. Furthermore, BNC101 treatment 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 preclinical data package supports our therapeutic hypothesis that BNC101 targeting of LGR5+ CSCs will significantly improve PFS and OS in solid tumor indications. Additional translational biomarker data to support the clinical development of BNC101 will also be presented. Citation Format: Peter Chu, Kristen Smith, Farbod Shojaei, Colin Walsh, John Norton, Jose Iglesias, Christopher Reyes. Preclinical evaluation and biomarker identification for the anti-LGR5 mAb BNC101 in K-Ras mutant CRC and other solid tumor indications. [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 2639. doi:10.1158/1538-7445.AM2015-2639