Novel orally available ERAP1 inhibitor enhances antitumor responses and limits inflammatory autoimmunity in vivo

The Endoplasmic Reticulum Aminopeptidase 1 (ERAP1) plays a critical role in immune regulation by processing peptides for presentation on Major Histocompatibility Complex class I (MHC-I) molecules. This enzyme can either diminish the immunogenicity of cancer cells by degrading tumor-associated antigens or contribute to autoimmune diseases by generating self-antigenic peptides. Consequently, ERAP1 inhibition has emerged as a promising therapeutic strategy for both cancer immunotherapy and specific types of autoimmune diseases, offering a targeted approach to modulate immune responses and restore cellular balance.

Researchers discovered a novel, potent, and selective ERAP1 inhibitor designed to target its regulatory allosteric site. The compound's in vivo pharmacokinetics and oral bioavailability were assessed in preclinical models. Its capacity to modulate the immunopeptidome of cancer cells and enhance tumor antigenicity was evaluated in in vivo tumor growth studies. To investigate its impact on autoimmunity, the inhibitor was administered in a murine collagen-induced arthritis model, observing its effects on disease progression and immune responses. No specific doses or animal numbers were provided in the abstract.

The novel ERAP1 inhibitor exhibited favorable in vivo pharmacokinetics and demonstrated oral bioavailability, a crucial characteristic for drug development. It effectively regulated the immunopeptidome of cancer cells, leading to enhanced tumor antigenicity in vivo, which correlated with controlled tumor growth. This suggests a direct mechanism by which ERAP1 inhibition can bolster the immune system's ability to recognize and attack cancer cells. > Importantly, when tested in the murine collagen-induced arthritis model, the inhibitor did not exacerbate autoimmune responses; instead, it provided a dose-dependent therapeutic benefit. These findings indicate that ERAP1 inhibition offers a tractable approach to modulating immune responses, providing mechanistic insights into its dual role in both cancer and autoimmunity, and serving as a valuable tool for further drug development.