IMPACT OF RECEPTOR DOWN-REGULATION ON CLEARANCE OF 2 HUMAN EGFS WITH DIFFERENT RECEPTOR-BINDING ACTIVITY

Human epidermal growth factor [hEGF(1-53)] has been thought to be clea red mainly via an EGF receptor (EGFR) endocytosis pathway. Pretreatmen t of rats with hEGF(1-53) has been shown previously to cause a dramati c reduction in clearance of the peptide contributable to EGFR downregu lation. The impact of receptor downregulation has raised concerns for rational design of dosage regimen for this potential wound-healing the rapeutic peptide. However, following a similar protocol, we could not reproduce the dramatic reduction in clearance reported previously medi ated by an TV bolus acute dose. As EGFR downregulation may be sensitiv e to the length of exposure and to the activation of the receptor tyro sine kinase activity, two other pretreatment protocols were also evalu ated: a 4-h IV infusion (prolonged exposure) of the peptide and an IV bolus of a potent synthetic kinase inhibitor pretreatment were evaluat ed for effects on clearance. However, neither pretreatment affected th e peptide's clearance profile. Further, no effects on clearance and ot her kinetic parameters were observed for any pretreatment paradigms wi th a truncated analogue hEGF(1-48), whose EGF receptor binding activit y is much weaker but plasma clearance is much higher than hEGF(1-53). In addition, a study in a second rat strain showed no difference in cl earance profile of hEGF(1-53) following pretreatment. Results of the p resent investigation suggest that receptor binding does not have a dir ect relationship with plasma clearance, and that the EGF clearance mec hanisms is highly refractory with EGF receptors possibly recovering ra pidly from downregulation through the recycling process. Copyright (C) 1996 Elsevier Science Inc.