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′×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 subcut...
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Veröffentlicht in: | Journal of immunological methods 2001-02, Vol.248 (1), p.149-165 |
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Sprache: | eng |
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Zusammenfassung: | 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
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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. |
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ISSN: | 0022-1759 1872-7905 |
DOI: | 10.1016/S0022-1759(00)00355-0 |