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.