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The Potency of Erythropoietin-Mimic Antibodies Correlates Inversely with Affinity

Susan E. Lacy^*, Peter J. DeVries, Nancy Xie, Emma Fung^*, Richard R. Lesniewski and Edward B. Reilly^1,

^* Global Pharmaceutical Research and Development, Abbott Bioresearch Center, Worcester, MA 01605; and Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Edward B. Reilly, Abbott Laboratories, Department 4CD AP-31-4, 200 Abbott Park Road, Abbott Park, IL 60064. E-mail address: ed.reilly{at}abbott.com

² Abbreviations used in this paper: EPO, erythropoietin; ECD, extracellular domain; EPOR, erythropoietin receptor; rHu-EPO, recombinant human erythropoietin; scFv, single chain variable fragment.