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Myeloid cells can restrain antitumor immunity by metabolic pathways, such as the degradation of l -arginine, whose concentrations are regulated by the arginase 1 (ARG1) enzyme. Results from preclinical studies indicate the important role of arginine metabolism in pancreatic ductal adenocarcinoma (PDAC) progression, suggesting a potential for clinical application; however, divergent evolution in ARG1 expression and function in rodents and humans has restricted clinical translation. To overcome this dichotomy, here, we show that neutrophil extracellular traps (NETs), released by spontaneously activated neutrophils isolated from patients with PDAC, create a microdomain where cathepsin S (CTSS) cleaves human (h)ARG1 into different molecular forms endowed with enhanced enzymatic activity at physiological pH. NET-associated hARG1 suppresses T lymphocytes whose proliferation is restored by either adding a hARG1-specific monoclonal antibody (mAb) or preventing CTSS-mediated cleavage, whereas small-molecule inhibitors are not effective. We show that ARG1 blockade, combined with immune checkpoint inhibitors, can restore CD8 + T cell function in ex vivo PDAC tumors. Furthermore, anti-hARG1 mAbs increase the frequency of adoptively transferred tumor-specific CD8 + T cells in tumor and enhance the effectiveness of immune checkpoint therapy in humanized mice. Thus, this study shows that extracellular ARG1, released by activated myeloid cells, localizes in NETs, where it interacts with CTSS that in turn cleaves ARG1, producing major molecular forms endowed with different enzymatic activity at physiological pH. Once exocytosed, ARG1 activity can be targeted by mAbs, which bear potential for clinical application for the treatment of PDAC and require further exploration.

Increasingly drug discovery programs require the development of orally available and cell permeable classes of drugs derived from the chemical space beyond Lipinski’s rule of 5 (bRO5). The chameleon-like physicochemical properties and differentiated binding modes of bRO5 compounds make them suitable starting points, especially for difficult-to-drug targets beyond traditional small molecule drug discovery. The synthesis of macrocyclic (MC) peptide DNA-Encoded Libraries (DEL) aligns with these efforts and has been an important addition to the rapidly growing field of DNA-encoded small molecule library screening. DEL screening of de novo designed bRO5 compounds will aid the exploration of bRO5 chemical space. X-Chem’s macrocyclic compound libraries apply chemistries beyond traditional peptide formation and extend to the inclusion of diverse building block classes. A case study of a successful screening campaign utilizing these MC DEL for Bcl2 will be presented. Citation Format: Ying Zhang, Anthony Keefe, Paolo Centrella, John Cuozzo, Holly Soutter, Daniel Resnicow, Sevan Habeshian, Matt Clark. DNA-encoded macrocyclic compound libraries for challenging targets. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5331.