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

Abstract

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