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Targeting folate receptor beta on monocytes/macrophages renders rapid inflammation resolution independent of root causes.

ABSTRACT: Provoked by sterile/nonsterile insults, prolonged monocyte mobilization and uncontrolled monocyte/macrophage activation can pose imminent or impending harm to the affected organs. Curiously, folate receptor beta (FRβ), with subnanomolar affinity for the vitamin folic acid (FA), is upregulated during immune activation in hematopoietic cells of the myeloid lineage. This phenomenon has inspired a strong interest in exploring FRβ-directed diagnostics/therapeutics. Previously, we have reported that FA-targeted aminopterin (AMT) therapy can modulate macrophage function and effectively treat animal models of inflammation. Our current investigation of a lead compound (EC2319) leads to discovery of a highly FR-specific mechanism of action independent of the root causes against inflammatory monocytes. We further show that EC2319 suppresses interleukin-6/interleukin-1β release by FRβ⁺ monocytes in a triple co-culture leukemic model of cytokine release syndrome with anti-CD19 chimeric antigen receptor T cells. Because of its chemical stability and metabolically activated linker, EC2319 demonstrates favorable pharmacokinetic characteristics and cross-species translatability to support future pre-clinical and clinical development.

SUBMITTER: Lu YJ

PROVIDER: S-EPMC8561236 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Targeting folate receptor beta on monocytes/macrophages renders rapid inflammation resolution independent of root causes.

Lu Yingjuan J YJ Wheeler Leroy W LW Chu Haiyan H Kleindl Paul J PJ Pugh Michael M You Fei F Rao Satish S Garcia Gabriela G Wu Henry Y HY da Cunha Andre P AP Johnson Richard R Westrick Elaine E Cross Vicky V Lloyd Alex A Dircksen Christina C Klein Patrick J PJ Vlahov Iontcho R IR Low Philip S PS Leamon Christopher P CP

Cell reports. Medicine 20211019 10

Provoked by sterile/nonsterile insults, prolonged monocyte mobilization and uncontrolled monocyte/macrophage activation can pose imminent or impending harm to the affected organs. Curiously, folate receptor beta (FRβ), with subnanomolar affinity for the vitamin folic acid (FA), is upregulated during immune activation in hematopoietic cells of the myeloid lineage. This phenomenon has inspired a strong interest in exploring FRβ-directed diagnostics/therapeutics. Previously, we have reported that F ...[more]

PMID: 34755134

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Dataset Information

Targeting folate receptor beta on monocytes/macrophages renders rapid inflammation resolution independent of root causes.

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Targeting folate receptor beta on monocytes/macrophages renders rapid inflammation resolution independent of root causes.

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