PURPOSE: Heparin-binding EGF-like growth factor (HB-EGF) is a member of the EGF family and is an important therapeutic target in some types of human cancers. KHK2866 is a humanized anti-HB-EGF monoclonal antibody IgG that neutralizes HB-EGF activity by inhibiting the binding of HB-EGF to its receptors. The phase I study of KHK2866 was discontinued because of neuropsychiatric toxicity. In this study, the pharmacokinetics of KHK2866 was evaluated by (89)Zr-immuno-PET study and the determination of drug concentrations in serum and cerebrospinal fluid using cynomolgus monkeys was performed in order to predict neurotoxicity in a reverse-translational manner. METHODS: KHK2866 was radiolabeled with (89)Zr for preclinical evaluations in normal cynomolgus monkeys and its distribution was analyzed. Furthermore, as a separate study, KHK2866 concentrations in serum and cerebrospinal fluid were determined after administration of a single dose. RESULTS: PET studies with monkeys revealed (89)Zr-KHK2866 accumulation in the liver, spleen and joints of multiple parts, but not in brain. In addition, the pharmacokinetic analyses in serum and CSF demonstrated a low penetration of KHK2866 into the brain. CONCLUSIONS: These studies indicate the difficulty of prediction for neuropsychiatric toxicity of monoclonal antibodies in human by means of pharmacokinetic evaluations using cynomolgus monkeys.
PURPOSE:Heparin-binding EGF-like growth factor (HB-EGF) is a member of the EGF family and is an important therapeutic target in some types of humancancers. KHK2866 is a humanized anti-HB-EGF monoclonal antibody IgG that neutralizes HB-EGF activity by inhibiting the binding of HB-EGF to its receptors. The phase I study of KHK2866 was discontinued because of neuropsychiatric toxicity. In this study, the pharmacokinetics of KHK2866 was evaluated by (89)Zr-immuno-PET study and the determination of drug concentrations in serum and cerebrospinal fluid using cynomolgus monkeys was performed in order to predict neurotoxicity in a reverse-translational manner. METHODS:KHK2866 was radiolabeled with (89)Zr for preclinical evaluations in normal cynomolgus monkeys and its distribution was analyzed. Furthermore, as a separate study, KHK2866 concentrations in serum and cerebrospinal fluid were determined after administration of a single dose. RESULTS: PET studies with monkeys revealed (89)Zr-KHK2866 accumulation in the liver, spleen and joints of multiple parts, but not in brain. In addition, the pharmacokinetic analyses in serum and CSF demonstrated a low penetration of KHK2866 into the brain. CONCLUSIONS: These studies indicate the difficulty of prediction for neuropsychiatric toxicity of monoclonal antibodies in human by means of pharmacokinetic evaluations using cynomolgus monkeys.
Authors: E C Dijkers; T H Oude Munnink; J G Kosterink; A H Brouwers; P L Jager; J R de Jong; G A van Dongen; C P Schröder; M N Lub-de Hooge; E G de Vries Journal: Clin Pharmacol Ther Date: 2010-03-31 Impact factor: 6.875
Authors: J A Abraham; D Damm; A Bajardi; J Miller; M Klagsbrun; R A Ezekowitz Journal: Biochem Biophys Res Commun Date: 1993-01-15 Impact factor: 3.575
Authors: Iris Verel; Gerard W M Visser; Ronald Boellaard; Marijke Stigter-van Walsum; Gordon B Snow; Guus A M S van Dongen Journal: J Nucl Med Date: 2003-08 Impact factor: 10.057
Authors: Seonwook Kim; Lihua Yang; Seongu Kim; Richard G Lee; Mark J Graham; Judith A Berliner; Aldons J Lusis; Lei Cai; Ryan E Temel; Debra L Rateri; Sangderk Lee Journal: PLoS One Date: 2017-08-09 Impact factor: 3.240