RESUMO
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.
Assuntos
Anticorpos Monoclonais Humanizados/imunologia , Anticorpos Monoclonais Humanizados/farmacocinética , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacocinética , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/imunologia , Animais , Anticorpos Monoclonais/sangue , Anticorpos Monoclonais/líquido cefalorraquidiano , Anticorpos Monoclonais Humanizados/sangue , Anticorpos Monoclonais Humanizados/líquido cefalorraquidiano , Feminino , Humanos , Macaca fascicularis , Tomografia por Emissão de Pósitrons/métodos , Zircônio/sangue , Zircônio/líquido cefalorraquidiano , Zircônio/farmacocinéticaAssuntos
Anticorpos Monoclonais Humanizados/farmacocinética , Administração Intranasal , Administração Intravenosa , Animais , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/sangue , Anticorpos Monoclonais Humanizados/líquido cefalorraquidiano , Área Sob a Curva , Barreira Hematoencefálica , Meia-Vida , Infusões Intraventriculares , Macaca mulatta , Masculino , Taxa de Depuração MetabólicaAssuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos/administração & dosagem , Biomarcadores Tumorais/análise , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Injeções Espinhais , Neoplasias Meníngeas/tratamento farmacológico , Receptor ErbB-2/análise , Idoso , Anticorpos Monoclonais Humanizados/sangue , Anticorpos Monoclonais Humanizados/líquido cefalorraquidiano , Antineoplásicos/sangue , Antineoplásicos/líquido cefalorraquidiano , Neoplasias Ósseas/secundário , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/secundário , Neoplasias da Mama/química , Irradiação Craniana , Esquema de Medicação , Feminino , Humanos , Neoplasias Meníngeas/secundário , Punção Espinal , Trastuzumab , Resultado do Tratamento , Regulação para CimaRESUMO
GNbAC1 is a humanized IgG4 monoclonal antibody antagonist of Mulitple Sclerosis Retrovirus Envelope (MSRV-Env), a protein that could play a critical role in multiple sclerosis. This randomized placebo-controlled dose-escalation study evaluated the safety and pharmacokinetics of GNbAC1 in 21 healthy volunteers after single intravenous infusion at doses of 6, 18 and 36 mg/kg. Lumbar punctures were performed at days 2, 15 or 29 to measure GNbAC1 concentrations in cerebrospinal fluid (CSF). GNbAC1 was well tolerated. Serum data show a dose-linear pharmacokinetics. A mean CSF/serum ratio of 0.12% was observed at Day 2, increasing to 0.39% at Day 15 and 0.42% at Day 29. Linear regression analysis shows a relationship between GNbAC1 CSF/serum ratio and albumin CSF/serum ratio and a relationship at the limit of statistical significance with the timing of CSF sampling.