Abstract 4695: Targeting the LGR5 complex with BNC101 to improve checkpoint inhibitor therapy in colorectal cancer
Authors: Inglis Daniel J. , Beaumont Donna M. , Lavranos Tina C. 
Published: July 2017

LGR5 is a well characterised marker of intestinal stem cells found at the base of intestinal crypts and a receptor for R-spondins, potent Wnt signalling modulators and stem cell growth factors. Overexpression of LGR5 in colorectal tumor cells has been shown to be a predicative marker of higher relapse rates in CRC patients. BNC101 is a first-in-class high affinity anti-LGR5 humanized monoclonal antibody currently in a Phase I clinical trial in patients with recurrent metastatic CRC. BNC101 has been shown pre-clinically to have anti-tumor activity in multiple CRC patient derived xenografts and limiting dilution re-implantation assays consistent with the hypothesis that LGR5 is a functional cancer stem cell (CSC) target in CRC. Recent evidence suggests that CSCs or treatment resistant cells, due to distinct gene and antigen expression profiles, may share the same immune privilege that is afforded to normal stem cells. Immunologic therapies with checkpoint inhibitors directed against whole tumors are largely biased toward differentiated tumor cells which form the bulk of the tumor. CSCs may also have an immunosuppressive phenotype, allowing them to evade and dampen the anti-tumor host immune response. The syngeneic murine MC38 colorectal cancer model was used to explore the potential synergies of BNC101 and anti-PD-1 treatments. The combination of murine versions of both antibodies drove a reduction (35%) in tumoral Tregs (FoxP3+) when BNC101 and anti-PD-1 were used compared to anti-PD-1 treatment alone. This is a significant finding and shows early efficacy in keeping with the notion that CSCs create an immunosuppressive environment which can be targeted in combination for a better immunotherapeutic response. The activation of antibody-dependent cell-mediated cytotoxicity (ADCC) was demonstrated using BNC101 treatment of cells. Membrane dye tracked U-937 monocytes (which express FcR) were able to specifically cross bind with CHO-LGR5 cells but only in the presence of BNC101 (an IgG1). This potentially indicates a further adaptive immune priming mechanism with the ability to complement the action of checkpoint inhibitors. Understanding the role of CSCs in tumor immunity will help guide future clinical applications of immune checkpoint inhibitors in CSC-driven solid tumors. In addition, combination of immune checkpoint therapies with CSC targeting agents may improve the clinical utility of each approach. These findings support clinical evaluation of BNC101 in combination with checkpoint inhibitors. Releasing the immunosuppressive capabilities of CSC with BNC101 driven targeting of the tumor may extend the reach of the immune system, whereby checkpoint inhibitors are able to leverage greater therapeutic benefit to a larger patient population and extend duration of response.

Citation Format: Daniel J. Inglis, Donna M. Beaumont, Tina C. Lavranos. Targeting the LGR5 complex with BNC101 to improve checkpoint inhibitor therapy in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4695. doi:10.1158/1538-7445.AM2017-4695