Fatty Acid Derivatization and Cyclization of the Immunomodulatory Peptide RP-182 Targeting CD206high Macrophages Improve Antitumor Activity.

Autor:	Singh SS; Rare Tumor Initiative, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland., Calvo R; Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland., Kumari A; Rare Tumor Initiative, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland., Sable RV; Rare Tumor Initiative, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland., Fang Y; Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland., Tao D; Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland., Hu X; Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland., Castle SG; Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland., Nahar S; Rare Tumor Initiative, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland., Li D; Rare Tumor Initiative, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland., Major E; Rare Tumor Initiative, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland., Sanchez TW; Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland., Kato R; Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland., Xu X; Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland., Zhou J; LifeTein LLC, Somerset, New Jersey., Liu L; CPC Scientific Inc., San Jose, California., LeClair CA; Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland., Simeonov A; Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland., Baljinnyam B; Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland., Henderson MJ; Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland., Marugan J; Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland., Rudloff U; Rare Tumor Initiative, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2024 Dec 03; Vol. 23 (12), pp. 1827-1841.
DOI:	10.1158/1535-7163.MCT-23-0790
Abstrakt:	As tumor-associated macrophages (TAM) exercise a plethora of protumor and immune evasive functions, novel strategies targeting TAMs to inhibit tumor progression have emerged within the current arena of cancer immunotherapy. Activation of the mannose receptor 1 (CD206) is a recent approach that recognizes immunosuppressive CD206high M2-like TAMs as a drug target. Ligation of CD206 both induces reprogramming of CD206high TAMs toward a proinflammatory phenotype and selectively triggers apoptosis in these cells. CD206-activating therapeutics are currently limited to the linear, 10mer peptide RP-182, 1, which is not a drug candidate. In this study, we sought to identify a better suitable candidate for future clinical development by synthesizing and evaluating a series of RP-182 analogs. Surprisingly, fatty acid derivative 1a [RP-182-PEG3-K(palmitic acid)] not only showed improved stability but also increased affinity to the CD206 receptor through enhanced interaction with a hydrophobic binding motif of CD206. Peptide 1a showed superior in vitro activity in cell-based assays of macrophage activation which was restricted to CD206high M2-polarized macrophages. Improvement in responses was disproportionally skewed toward improved induction of phagocytosis including cancer cell phagocytosis. Peptide 1a reprogrammed the immune landscape in genetically engineered murine KPC pancreatic tumors toward increased innate immune surveillance and improved tumor control and effectively suppressed tumor growth of murine B16 melanoma allografts. (©2024 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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