Impact of erythrocyte Duffy antigen genetic polymorphism on the distribution of GroBeta-T, a novel human CXC chemokine.
OBJECTIVE
Grobeta-T, a human CXC chemokine, has been studied for its potential to mobilize stem cells. Chemokines bind specifically to receptors on target immune cells but also to a homologous erythrocyte blood group antigen, the Duffy Antigen/Receptor for Chemokines (DARC)that is subject to genetic polymorphism in humans.A mutation in the DARC gene is common among African Americans and results in lack of expression of the erythrocyte antigen. We used a combination of in vitro studies of Grobeta-DARC interaction and pharmacokinetic simulation to anticipate the potential impact of this polymorphism on the pharmacokinetics of Grobeta-T.


METHODS
[125I]Grobeta-T was incubated in Caucasian blood to characterize the concentration dependence of the blood to plasma concentration ratio (B/P). Affinity and capacity of binding was estimated by Scatchard analysis; specificity was investigated by competitive displacement with a CC chemokine. The B/P value (7 nM) was then determined in blood from 8 African American subjects. Duffy antigen expression was determined by antibody agglutination. A pharmacokinetic model was developed which accounted for blood-cell binding. Simulations were performed to explore effects of dose regimen and DARC expression on the Grobeta-T plasma concentration-time profile.


RESULTS
Grobeta-T affinity and capacity for DARC (Caucasian blood)were 23.0 +/- 1.2 and 37.7 +/- 0.6 nM, respectively;excess CC chemokine fully displaced [125I]Grobeta-T. Chemokine binding was highly correlated with the presence or absence of the Duffy antigen (p<0.01) in African American blood; the proportion of subjects for which binding was observed (3/8), was consistent with the reported frequency of DARC expression in this population. Counter to intuition,in the terminal disposition phase at low doses,concentrations of free Grobeta-T in the presence of DARC may be substantially higher than in the absence of DARC.


CONCLUSIONS
Dissociation from the erythrocyte antigen may lead to greater persistence, at low doses, of free Grobetabeta-T in the blood of individuals expressing the chemokine sink.
Hepburn
Timothy W
TW
Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania, USA.
Tobia
LeeAnn P
LP
Shi
Wei
W
McIntyre
Timothy A
TA
Davis
Charles B
CB
D054426:Chemokine CXCL2 / Q000097:blood* / Q000235:genetics*; D004375:Duffy Blood-Group System / Q000097:blood* / Q000235:genetics*; D004912:Erythrocytes / Q000276:immunology; D006801:Humans; D011110:Polymorphism, Genetic / Q000235:genetics*
C499706:CXCL2 protein, human; D054426:Chemokine CXCL2; D004375:Duffy Blood-Group System