Modulation of antigen presentation by first-in-class ERAP1 and ERAP2 inhibitors for the treatment of cancer and autoimmunity

Abstract

The aminopeptidases ERAP1 and ERAP2 play a central role in the processing of antigens for loading onto MHC-I complexes with links to both autoimmunity and cancer. On one hand, genetic variants of each enzyme are associated with the development of several autoimmune disorders with the formation of autoantigens by ERAP1 and ERAP2 as a leading hypothesis for the mechanism behind this association. On the other hand, it is well established that patients with tumors characterized by high antigen diversity have increased response rates to immune checkpoint inhibitors. It follows that modulation of the cancer immunopeptidome offers a new therapeutic strategy to generate de novo anti-tumor T-cell responses and overcome current challenges of existing immuno-oncology (IO) therapeutics. Collectively, this knowledge implies that ERAP1 and ERAP2 represent a novel category of therapeutic targets for autoimmunity and immuno-oncology that can be manipulated to drive changes in antigen repertoire and thereby modulate the detection of cancer cells and self. Here, we present the characterization of our potent and selective First-in-Class ERAP1 and ERAP2 inhibitors both in vitro and in vivo. Importantly, we apply a state-of-the-art immunopeptidomics pipeline to define the qualitative and quantitative effects of these inhibitors. Our data demonstrate that ERAP1 and ERAP2 have overlapping and distinct effects on the antigen repertoire, consistent with their respective substrate specificities.