Preclinical Pharmacokinetics Evaluation of Anti-heparin-binding EGF-like Growth Factor (HB-EGF) Monoclonal Antibody Using Cynomolgus Monkeys via89Zr-immuno-PET Study and the Determination of Drug Concentrations in Serum and Cerebrospinal Fluid
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 receptor...
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Veröffentlicht in: | Pharmaceutical research 2016, Vol.33 (2), p.476-486 |
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Format: | Artikel |
Sprache: | eng |
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Zusammenfassung: | 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
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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
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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
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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. |
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ISSN: | 0724-8741 1573-904X |
DOI: | 10.1007/s11095-015-1803-2 |