title: Phase Ia/Ib trial of bispecific antibody MDX-210 in patients with advanced breast or ovarian cancer that overexpresses the proto-oncogene HER-2/neu.
abstract: OBJECTIVE
  MDX-210 is a bispecific antibody that binds simultaneously to type I Fc receptors for immunoglobulin G (IgG) (Fc gamma RI) and to the HER-2/neu oncogene protein product. MDX-210 effectively directs Fc gamma RI-positive effector cells such as monocytes and macrophages to phagocytose or kill tumor cells that overexpress HER-2/neu. The goals of this phase Ia/Ib trial were to determine the maximum-tolerated dose (MTD) and/or the optimal biologic dose (OBD) of MDX-210.
  
  
  METHODS
  Patients with advanced breast or ovarian cancer that overexpressed HER-2/neu were eligible for treatment. Cohorts of three patients received a single intravenous (IV) infusion of MDX-210 at increasing dose levels from 0.35 to 10.0 mg/m2.
  
  
  RESULTS
  Treatment was well tolerated, with most patients experiencing transient grade 1 to 2 fevers, malaise, and hypotension only. Two patients experienced transient grade 3 hypotension at 10.0 mg/m2. Transient monocytopenia and lymphopenia developed at 1 to 2 hours, but no other hematologic changes were observed. Doses of MDX-210 > or = 3.5 mg/m2 saturated > or = 80% of monocyte Fc gamma RI and produced peak plasma concentrations > or = 1 microgram/mL, which is greater than the concentration for optimal monocyte/macrophage activation in vitro. Elevated plasma levels of the monocyte products tumor necrosis factor alpha (TNF alpha), interleukin-6 (IL-6), granulocyte colony-stimulating factor (G-CSF), and neopterin were observed with maximal levels at doses > or = 7.0 mg/m2. Localization of MDX-210 in tumor tissue was demonstrated in two patients. One partial and one mixed tumor response were observed among 10 assessable patients.
  
  
  CONCLUSIONS
  MDX-210 is immunologically active at well-tolerated doses. The MTD and OBD is 7 to 10 mg/m2.
authors.affiliation: Department of Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA.
authors.forename: F H
authors.initials: FH
authors.lastname: Valone
authors.forename: P A
authors.initials: PA
authors.lastname: Kaufman
authors.forename: P M
authors.initials: PM
authors.lastname: Guyre
authors.forename: L D
authors.initials: LD
authors.lastname: Lewis
authors.forename: V
authors.initials: V
authors.lastname: Memoli
authors.forename: Y
authors.initials: Y
authors.lastname: Deo
authors.forename: R
authors.initials: R
authors.lastname: Graziano
authors.forename: J L
authors.initials: JL
authors.lastname: Fisher
authors.forename: L
authors.initials: L
authors.lastname: Meyer
authors.forename: M
authors.initials: M
authors.lastname: Mrozek-Orlowski
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001708:Biopterins / Q000031:analogs & derivatives / Q000097:blood; D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D015331:Cohort Studies; D005260:Female; D005334:Fever / Q000209:etiology; D015870:Gene Expression; D018734:Genes, erbB-2; D016179:Granulocyte Colony-Stimulating Factor / Q000097:blood; D006801:Humans; D007022:Hypotension / Q000209:etiology; D007262:Infusions, Intravenous; D015850:Interleukin-6 / Q000097:blood; D008875:Middle Aged; D019798:Neopterin; D010051:Ovarian Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D000090063:Proto-Oncogene Mas; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology* / Q000378:metabolism; D017452:Receptors, IgG / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D001708:Biopterins; D016179:Granulocyte Colony-Stimulating Factor; D015850:Interleukin-6; D019798:Neopterin; D000090063:Proto-Oncogene Mas; D018719:Erb-b2 Receptor Tyrosine Kinases; D017452:Receptors, IgG; D014409:Tumor Necrosis Factor-alpha; C000715470:MAS1 protein, human