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

Yingjuan J. Lu, Leroy W. Wheeler, Haiyan Chu, Paul J. Kleindl, Michael Pugh, Fei You, Satish Rao, Gabriela Garcia, Henry Y. Wu, Andre P. da Cunha, Richard Johnson, Elaine Westrick, Vicky Cross, Alex Lloyd, Christina Dircksen, Patrick J. Klein, Iontcho R. Vlahov, Philip S. Low, Christopher P. Leamon

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Article number100422
JournalCell Reports Medicine
Volume2
Issue number10
DOIs
StatePublished - Oct 19 2021

Keywords

  • adjuvant arthritis
  • aminopterin
  • autoimmune uveitis
  • autoimmunity
  • cytokine release syndrome
  • dihydrofolate reductase inhibitor
  • folate receptor beta
  • glomerulonephritis
  • inflammation
  • monocyte/macrophage activation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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