Pharmacokinetic-pharmacodynamic relationships of the bispecific antibody MDX-H210 when administered in combination with interferon gamma: a multiple-dose phase-I study in patients with advanced cancer which overexpresses HER-2/neu.

摘要: Abstract Introduction: MDX-H210 is a Fab′×Fab′ bispecific antibody (BsAb) constructed chemically by crosslinking Fab′ mAb 520C9 (anti-HER-2/neu) and mAbH22 (anti-CD64). Study design objectives: This was dose escalation study of intravenous (1–70 mg/m2), preceded 24 h beforehand subcutaneous IFNγ (50 μg/m2 to up-regulate FcγRI) administered three times week for 3 weeks. We investigated the pharmacokinetic–pharmacodynamic relationships between Cmax AUC (i) binding peripheral blood monocytes neutrophils, (ii) peak plasma G-CSF, IL-6, IL-8 TNFα concentrations, (iii) observed clinical toxicity. Results: 23 patients (19F:4M; median age 51.5; range 25–72 y) with advanced HER-2/neu positive cancers (19 breast, prostate one lung) were studied. Plasma concentrations over time, circulating numbers percent saturation monocyte neutrophil FcγRI, time measured toxicity monitored. The Emax pharmacodynamic model best fitted relationship maximum both (Emax=74.6; EC50=0.9 μg/ml) neutrophils (Emax=66.2; EC50=2.3 on first day treatment. On last treatment, 19, these parameters Emax=57.0% EC50=0.46 μg/ml Emax=61.9% EC50=0.26 neutrophils. No defined log TNF or 1. 19 cytokine undetectable post therapy. There no consistent toxicities. Conclusions: These data suggest that could be related FcγRI in After 1, therapy response attenuated desensitization. did not find