Development of a first-in-class Arginase 2 inhibitory monoclonal antibody that restores T cell proliferation in vitro


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Stuart W Haynes, Mark Austin, Denise Chan, Lesley Jenkinson, Agata Diamandakis, Daniel Burschowsky, Chitra Seewooruthun, Alexandra Addyman, Sebastian Fiedler, Stephanie Ryman, Jessica Whitehouse, Louise Slater, Ellen Gowans, Yoko Shibata, Michelle Barnard, Robert Wilkinson, Tristan Vaughan, Fiona MCLAUGHLIN, Sarah Holt, Vincenzo Cerundulo, Mark Carr, Maria Groves

Abstract

Background

Active suppression and evasion of the immune system has emerged as a key driver of cancer. Extracellular Arginase 2 (ARG2) has been identified as a potent suppressor of T-cell mediated immune responses in several cancers. ARG2 is primarily a mitochondrial enzyme which catalyses the conversion of L-arginine to L-ornithine and urea.  Depletion of the arginine via increased arginase activity has been well described as a mechanism of tumour mediated immuno-suppression. Reversing the arginine depletion could provide a boost to the immune system which could prove fundamental in cancer treatment. Here we describe the development of novel, fully human monoclonal antibodies which bind to ARG2 with high affinity and inhibit ARG2 function via a novel, non-competitive mechanism of action.

Method

Fully human antibodies were identified by phage display from naïve donor libraries. Lead antibodies inhibit ARG2 enzymatic function completely in cell based assays.

Results

Enzyme kinetic studies confirmed that lead antibodies exhibit a non-competitive mechanism of action, inhibiting ARG2 independently of L-arginine concentrations.  Selectivity for ARG2 vs ARG1 (a closely related hepatic isoenzyme) has also been clearly demonstrated in vitro. The lack of ARG1 binding/inhibition may lead to a better safety profile than dual ARG1/2 inhibitors as ARG1 catalyses the last step of the urea cycle in hepatocytes. Since ARG2 from the blasts of AML patients has been reported to inhibit T cell proliferation in vitro, we show that our lead antibodies can fully restore ARG2 mediated T cell proliferation in vitro.  Initial characterisation of pharmacokinetic properties of several lead candidates has been performed in mice and has identified molecules with acceptable profiles for further in vivo studies in models where ARG2 is upregulated.

Conclusion

Specifically, targeting ARG2 in the tumor microenvironment through the application of the novel ARG2 inhibitory antibody C0021158, potentially in combination with standard chemotherapy regimens or alternate immunotherapies, represents a potential new strategy to target immune cold tumors.

Impact statement

This is the first report of an antibody which can bind to and inhibit the activity of arginase 2 which has been implicated in multiple diseases, in particular those diseases where arginase expression contributes to creating an immune-privileged niche.