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Stem Cells, Vol. 17, No. 4, 203-209, July 1999
© 1999 AlphaMed Press

Immunogenicity of Thrombopoietin Mimetic Peptide GW395058 in BALB/c Mice and New Zealand White Rabbits: Evaluation of the Potential for Thrombopoietin Neutralizing Antibody Production in Man

Mark De Serres, Byron Ellis, John E. Dillberger, Sharon K. Rudolph, Jeff T. Hutchins, Christine M. Boytos, Debra L. Weigl, Randolph B. DePrince

Glaxo Wellcome Inc., Research Triangle Park, North Carolina, USA

Key Words. Immunogenicity • Thrombopoietin • Mimetic peptide • GW395058 • Mice • Rabbits • Neutralizing antibody

Mr. Mark de Serres, Glaxo Wellcome Inc., Department of International Development Support, Division of Bioanalysis and Drug Metabolism, 5 Moore Drive, Research Triangle Park, North Carolina 27709, USA.

Administration of exogenous proteins and peptides as therapeutics carries with it the potential for immune system recognition and the development of neutralizing antibodies to endogenous regulatory proteins. PEGylation of proteins typically reduces their immunogenicity in vivo. GW395058 is a PEGylated peptide thrombopoietin receptor (TPOr) agonist being evaluated for the treatment of chemotherapy-induced thrombocytopenia. Although GW395058 shares no homology with TPO, it does compete with TPO for binding to a common receptor, and a similarity in local structure could result in shared epitopes. Thus GW395058 could elicit TPO-neutralizing antibodies. In this study, we evaluated the immunogenicity of GW395058 in mice, the potential of rabbit antibodies elicited by immunizations with the non-PEGylated parent peptide AF15705 to cross-react with recombinant human (rHu) TPO, and the potential of mouse anti-rHuTPO antibodies elicited by repeated dosing with rHuTPO to cross-react with AF15705. GW395058-dosed mice failed to produce antibodies to AF15705 or rHuTPO. Mouse anti-rHuTPO did not cross-react with AF15705 and rabbit anti-AF15705 antibodies failed to cross-react with rHuTPO. GW395058 caused no immune-mediated lesions in mice, but rHuTPO suppressed megakaryocytopoiesis and caused B-lymphocyte hyperplasia in lymphoid tissues consistent with antigenic stimulation. These data suggest that the potential for an immune response to GW395058 in man would be low. Stem Cells 1999;17:203-209




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