The Potency of Erythropoietin-Mimic Antibodies Correlates Inversely with Affinity

Preclinical animal studies have shown that Ab12.6, an agonistic human Ab targeting the erythropoietin receptor (EPOR), exhibits several potential dosing and safety features that make it an attractive clinical candidate for the treatment of anemia. Ab12.6 was derived by yeast display affinity maturat...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2008-07, Vol.181 (2), p.1282-1287
Main Authors: Lacy, Susan E, DeVries, Peter J, Xie, Nancy, Fung, Emma, Lesniewski, Richard R, Reilly, Edward B
Format: Article
Language:English
Subjects:
Antibodies - immunology
Antibodies - metabolism
Antibody Affinity
Erythropoiesis
Erythropoietin - immunology
Erythropoietin - metabolism
Humans
Molecular Mimicry
Receptors, Erythropoietin - agonists
Receptors, Erythropoietin - metabolism
Recombinant Fusion Proteins - immunology
Recombinant Fusion Proteins - metabolism
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Summary:Preclinical animal studies have shown that Ab12.6, an agonistic human Ab targeting the erythropoietin receptor (EPOR), exhibits several potential dosing and safety features that make it an attractive clinical candidate for the treatment of anemia. Ab12.6 was derived by yeast display affinity maturation of parental Ab12, a strategy initially intended to improve off-rate and affinity for EPOR, thereby enhancing erythropoietic activity. Analysis of full-length IgGs derived from yeast clones identified sequences within Ab12 CDRH2 that independently influenced both affinity and potency. The Ab12.6 derivative displayed improved in vitro potency and in vivo efficacy, although its binding affinity to the EPOR was lower than that of the parent Ab12. Additional Ab12 derivatives also exhibited an inverse correlation between affinity and potency. These results suggest that for this class of agonistic Abs, faster off-rates may permit continuous receptor stimulation and more efficient erythropoiesis.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.181.2.1282