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.
BACKGROUND
MDX-H210 is a Fab'xFab' bispecific antibody (BsAb) constructed chemically by crosslinking Fab' mAb 520C9 (anti-HER-2/neu) and Fab' mAbH22 (anti-CD64).


OBJECTIVE
This was a dose escalation study of intravenous MDX-H210 (1-70 mg/m(2)), preceded 24 h beforehand by subcutaneous IFNgamma (50 microg/m(2) to up-regulate FcgammaRI) 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 TNFalpha 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 FcgammaRI, and plasma concentrations over time of G-CSF, IL-6, IL-8 and TNFalpha 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 microg/ml) and neutrophils (E(max)=66.2; EC(50)=2.3 microg/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 microg/ml for monocytes and E(max)=61.9% and EC(50)=0.26 microg/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 FcgammaRI 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.
Lewis
L D
LD
Department of Medicine, Dartmouth Medical School and The Norris Cotton Cancer Center, Lebanon, NH 03756, USA. lionel.d.lewis@dartmouth.edu
Cole
B F
BF
Wallace
P K
PK
Fisher
J L
JL
Waugh
M
M
Guyre
P M
PM
Fanger
M W
MW
Curnow
R T
RT
Kaufman
P A
PA
Ernstoff
M S
MS
D000328:Adult; D000368:Aged; D018033:Antibodies, Bispecific / Q000008:administration & dosage* / Q000276:immunology / Q000493:pharmacokinetics; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology / Q000493:pharmacokinetics; D061067:Antibodies, Monoclonal, Humanized; D016207:Cytokines / Q000097:blood; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000502:physiology; D009369:Neoplasms / Q000628:therapy*; D009504:Neutrophils / Q000502:physiology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis / Q000276:immunology*; D017452:Receptors, IgG / Q000276:immunology*
D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D016207:Cytokines; D007371:Interferon-gamma; D018719:Erb-b2 Receptor Tyrosine Kinases; D017452:Receptors, IgG; C121360:MDX-H210 antibody