Erythropoietin receptor: application in drug development.
Erythropoietin (EPO) is the primary hormone responsible for the growth and maturation of red blood cells in mammals. In contrast to many other growth factors, the specificity of EPO for mature erythroid cells has lead to its development as a safe and efficacious therapeutic, EPREX. The medical benefits of EPREX have been well established in the treatment of anaemic chronic renal failure patients, anaemic HIV patients treated with AZT, cancer chemotherapy patients, and patients wishing to donate their own blood prior to elective surgery (autologous predonation). Due to the chronic nature of EPO therapy, it would be desirable to have an orally administered 'second generation' molecule. An understanding of the structural basis of the interaction of EPO with its receptor will aid in the design of an oral anaemia drug. In this study, a series of mutations have been generated in a truncated form of the receptor comprising the extracellular region, termed EPO binding protein (EBP). One mutant, in which alanine replaces phenylalanine at position 93 (F93A) has a 500-fold reduction in binding compared to wild-type EBP. A neutralizing anti-EBP antibody binds poorly to the F93A mutant, while a non-neutralizing anti-EBP antibody binds wild-type and F93A equally well. Information from this mutational analysis can be applied to a receptor 3-D model and ultimately used in drug development.
Jolliffe
L K
LK
R. W. Johnson Pharmaceutical Research Institute, Raritan, NJ 08869, USA.
Middleton
S A
SA
Barbone
F P
FP
Johnson
D L
DL
McMahon
F J
FJ
Lee
W H
WH
Gruninger
R H
RH
Mulcahy
L S
LS
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D004921:Erythropoietin / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011817:Rabbits; D017467:Receptors, Erythropoietin / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
D000911:Antibodies, Monoclonal; D017467:Receptors, Erythropoietin; D004921:Erythropoietin