NIH Research Festival
Many immunologically cold, solid organ cancers attract and reeducate innate immune cells to promote tumor growth and cancer progression. Tumor-associated macrophages (TAMs) have been increasingly recognized as a de novo target in the field of cancer immunotherapy. Our group has previously shown that targeting the mannose receptor CD206 expressed on tumor-promoting TAMs with the synthetic peptide RP-182 reinvigorates innate and adaptive immune responses for effective tumor control and improved outcome in human and murine preclinical models of cancer. However, due to the linear, unprotected nature of RP-182, it is notoriously prone to enzymatic degradation, and thus not a clinical drug candidate. Here, we designed and synthesized a series of RP-182 derivatives to improve its stability and possibly enhance biological activity. Out of 20 peptide derivatives, three peptides, NCGC00857950, a cyclic analog, NCGC00857001, connecting a lysine-coupled palmitic acid tail, and NCGC00591015 carrying a 10-carbon acyl group, were found to be 5- to 10-fold more potent in cell-based assays than parent peptide RP-182. Liver microsomal study and MetID studies confirmed improved stability, reduced metabolism, and improved pharmacokinetics profiles compared to the parent RP-182. These analogs were further investigated for the induction of apoptosis in CD206high TAMs, TAM reprogramming, reprogramming of the TME, and tumor control. We found that these analogs effectively shifted M2-like TAMs towards a pro-inflammatory phenotype, increased innate and adaptive anti-tumor immunity, and mediated anti-tumor activity in the preclinical model. In particular, the most active, NCGC00857001 appears to be a promising candidate for further preclinical development and clinical translation.
Scientific Focus Area: Immunology
This page was last updated on Monday, September 25, 2023