Influence of the Duffy antigen on pharmacokinetics and pharmacodynamics of recombinant monocyte chemoattractant protein (MCP-1, CCL-2) in vivo

Int J Immunopathol Pharmacol. 2009 Jul-Sep;22(3):615-25. doi: 10.1177/039463200902200307.

Abstract

Monocyte chemoattractant protein-1 (MCP-1, CCL-2) binds to the Duffy antigen (DARC) on red blood cells, which act as a sink for several chemokines including MCP-1. In this study it is hypothesized that DARC may alter the pharmacokinetics of infused recombinant human MCP-1 (rhMCP-1). The primary aim of this first in man trial is to compare the pharmacokinetics of rhMCP-1 in Duffy positive and negative individuals. A randomized, double-blinded, placebo-controlled dose escalation trial was conducted on 36 healthy volunteers. Subjects received infusions of 0.02-2.0 microg/kg rhMCP-1 or placebo for one hour. RhMCP-1 displayed linear pharmacokinetics. Duffy negative individuals reached maximal plasma levels significantly earlier, but overall plasma concentration profiles were not altered. rhMCP-1 markedly increased monocyte counts, and estimated EC50 values were 10-fold higher in Duffy positive than in Duffy negative subjects. Increased monocyte counts were associated with decreased surface expression of intercellular adhesion molecule 1 (ICAM-1, CD54). In contrast, neither CCR-2 or CD11b expression, nor markers of platelet or endothelial activation, inflammation and coagulation were altered. RhMCP-1 is a highly selective chemoattractant for monocytes in humans. The Duffy antigen only minimally alters the pharmacokinetics of rhMCP-1 for doses up to 2 microg/kg.

Publication types

  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Biological Products / administration & dosage
  • Biological Products / blood
  • Biological Products / pharmacokinetics*
  • Biological Products / urine
  • Biomarkers / blood
  • Blood Coagulation / drug effects
  • Blood Platelets / drug effects
  • Blood Platelets / immunology
  • Cell Count
  • Chemokine CCL2 / administration & dosage
  • Chemokine CCL2 / adverse effects
  • Chemokine CCL2 / blood
  • Chemokine CCL2 / pharmacokinetics*
  • Chemokine CCL2 / urine
  • Double-Blind Method
  • Duffy Blood-Group System / genetics
  • Duffy Blood-Group System / immunology*
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / immunology
  • Genotype
  • Humans
  • Infusions, Intravenous
  • Leukocytes / drug effects
  • Leukocytes / immunology
  • Male
  • Middle Aged
  • Monocytes / drug effects
  • Monocytes / immunology
  • Phenotype
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / immunology*
  • Recombinant Proteins / blood
  • Recombinant Proteins / pharmacokinetics
  • Recombinant Proteins / urine
  • Young Adult

Substances

  • ACKR1 protein, human
  • Biological Products
  • Biomarkers
  • CCL2 protein, human
  • Chemokine CCL2
  • Duffy Blood-Group System
  • Receptors, Cell Surface
  • Recombinant Proteins