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

Introduction: MDX-H210 is a Fab'XFab' bispecific antibody (BsAb) constructe d chemically by crosslinking Fab' mAb 520C9 (anti-HER-2/neu) and Fab' mAbH2 2 (anti-CD64). Study design and objectives: This was a dose escalation stud y of intravenous MDX-H210 (1-70 mg/m(2)), preceded 24 h beforehand by subcu taneous IFN gamma (50 mug/m(2) to up-regulate Fc gamma RI) administered thr ee times a week for 3 weeks. We investigated the pharmacokinetic-pharmacody namic 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 TNF alpha concentrations, and (iii) the observed clinical t oxicity, 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 lun g) were studied. plasma MDX-H210 concentrations over time, circulating numb ers of monocytes and neutrophils, percent saturation of monocyte and neutro phil Fc gamma RI, and plasma concentrations over time of G-CSF, IL-6, IL-8 and TNF alpha were measured and clinical toxicity monitored. The E-max phar macodynamic model best fitted the relationship of MDX-H210 C-max and the ma ximum percent saturation of both monocytes (E-max = 74.6; EC50 = 0.9 mug/ml ) and neutrophils (E-max = 66.2; EC50 = 2.3 mug/ml) on the first day of tre atment. On the last day of treatment, day 19, these parameters were E-max = 57.0% and EC50 = 0.46 mug/ml for monocytes and E-max = 61.9% and EC50 = 0. 26 mug/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 concen trations on day 1. On day 19 these plasma cytokine concentrations were unde tectable post MDX-H210 therapy. There was no consistent relationship betwee n MDX-H210 C-max and the observed clinical toxicities. Conclusions: These d ata suggest that MDX-H210 C-max and AUC could be related by the E-max model to maximum percent Fc gamma RI saturation on circulating monocytes and neu trophils in the patients studied. After day 1, the post MDX-H210 therapy cy tokine response attenuated over time, consistent with desensitization. We d id not find a relationship between log MDX-H210 C-max and peak plasma cytok ine concentrations or clinical toxicities. (C) 2001 Elsevier Science B.V. A ll rights reserved.