title: Phase I pilot trial of the bispecific antibody MDXH210 (anti-Fc gamma RI X anti-HER-2/neu) in patients whose prostate cancer overexpresses HER-2/neu.
abstract: The goal of this study was to evaluate, in patients with prostate cancer, the toxicity profile and biologic activity of the bispecific antibody MDXH210, which has specificity for the non-ligand-binding site of the high-affinity immunoglobulin G receptor (Fc gamma RI) and the extracellular domain of the HER-2/neu proto-oncogene product. Patients with prostate cancer that expressed HER-2/neu were entered into a phase I dose-escalation trial of MDXH210. Patients received an intravenous infusion MDXH210 during a period of 2 h three times per week for 2 weeks and were monitored for toxicity. Pharmacokinetic and pharmacodynamic parameters were measured and included the biologic end points of monocyte-bound MDXH210, cytokine production, and clinical response. Seven patients were treated with MDXH210 doses ranging from 1 to 8 mg/m2. In general, MDXH210 was well tolerated, with only mild infusion-related malaise, fever, chills, and myalgias. No dose-limiting toxic effects were observed. Biologic effects included induction of low plasma concentrations of tumor necrosis factor-alpha and interleukin-6 observed immediately after MDXH210 infusion and 70% saturation of circulating monocyte-associated Fc gamma RI with MDXH210 at a dose level of 4 to 8 mg/m2. Five of six patients had stable prostate-specific antigen levels during the course of 40 days or more. Circulating plasma HER-2/neu levels decreased by 80% at days 12 and 29 (p = 0.03 and 0.06, respectively, by the Wilcoxon signed rank test). MDXH210 can be given safely to patients with HER-2/neu-positive prostate cancer in doses of at least 8 mg/m2. At the doses studied, biologic activity was demonstrated and characterized by binding of MDXH210 to circulating monocytes, release of monocyte-derived cytokines, a decrease in circulating HER-2/neu, and short-term stabilization of prostate-specific antigen levels.
authors.affiliation: Uro-Oncology Program, Norris Cotton Cancer Center and Section of Urology and Immunology and Immunotherapy Research Programs, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA.
authors.forename: T
authors.initials: T
authors.lastname: Schwaab
authors.forename: L D
authors.initials: LD
authors.lastname: Lewis
authors.forename: B F
authors.initials: BF
authors.lastname: Cole
authors.forename: Y
authors.initials: Y
authors.lastname: Deo
authors.forename: M W
authors.initials: MW
authors.lastname: Fanger
authors.forename: P
authors.initials: P
authors.lastname: Wallace
authors.forename: P M
authors.initials: PM
authors.lastname: Guyre
authors.forename: P A
authors.initials: PA
authors.lastname: Kaufman
authors.forename: J A
authors.initials: JA
authors.lastname: Heaney
authors.forename: A R
authors.initials: AR
authors.lastname: Schned
authors.forename: R D
authors.initials: RD
authors.lastname: Harris
authors.forename: M S
authors.initials: MS
authors.lastname: Ernstoff
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D016207:Cytokines / Q000097:blood; D006801:Humans; D007116:Immunization, Passive; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D010865:Pilot Projects; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D000090063:Proto-Oncogene Mas; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000097:blood / Q000276:immunology*; D017452:Receptors, IgG / Q000096:biosynthesis / Q000276:immunology*
chemical_list: D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D016207:Cytokines; D000090063:Proto-Oncogene Mas; D018719:Erb-b2 Receptor Tyrosine Kinases; D017452:Receptors, IgG; C000715470:MAS1 protein, human; C121360:MDX-H210 antibody