title: Specific targeting, biodistribution, and lack of immunogenicity of chimeric anti-GD3 monoclonal antibody KM871 in patients with metastatic melanoma: results of a phase I trial.
abstract: OBJECTIVE
  KM871 is a chimeric monoclonal antibody against the ganglioside antigen GD3, which is highly expressed on melanoma cells. We conducted an open-label, dose escalation phase I trial of KM871 in patients with metastatic melanoma.
  
  
  METHODS
  Seventeen patients were entered onto one of five dose levels (1, 5, 10, 20, and 40 mg/m2). Patients received three infusions of KM871 at 2-week intervals, with the first infusion of KM871 trace-labeled with indium-111 (111In) to enable assessment of biodistribution in vivo. Biopsies of metastatic melanoma sites were performed on days 7 to 10.
  
  
  RESULTS
  Fifteen of 17 patients completed a cycle of three infusions of KM871. No dose-limiting toxicity was observed during the trial; the maximum-tolerated dose was therefore not reached. Three patients (at the 1-, 5-, and 40-mg/m2 dose levels) developed pain and/or erythema at tumor sites consistent with an inflammatory response. No normal tissue uptake of 111In-KM871 was observed, and tumor uptake of 111In-KM871 was observed in all lesions greater than 1.5 cm (tumor biopsy 111KM871 uptake results: range, 0.001% to 0.026% injected dose/g). The ratio of maximum tumor to normal tissue was 15:1. Pharmacokinetic analysis revealed a 111In-KM871 terminal half-life of 7.68 +/- 2.94 days. One patient had a clinical partial response that lasted 11 months. There was no serologic evidence of human antichimeric antibody in any patient, including one patient who received 16 infusions over a 12-month period.
  
  
  CONCLUSIONS
  This study is the first to demonstrate the biodistribution and specific targeting of an anti-GD3 antibody to metastatic melanoma in patients. The long half-life and lack of immunogenicity of KM871 makes this antibody an attractive potential therapy for patients with metastatic melanoma.
authors.affiliation: Ludwig Institute for Cancer Research, Melbourne Tumour Biology Branch, and Department of Nuclear Medicine and Centre for Positron Emission Tomography, Surgery, and Anatomical Pathology, Melbourne, Australia. ams@austin.unimelb.edu.au
authors.forename: A M
authors.initials: AM
authors.lastname: Scott
authors.forename: F T
authors.initials: FT
authors.lastname: Lee
authors.forename: W
authors.initials: W
authors.lastname: Hopkins
authors.forename: J S
authors.initials: JS
authors.lastname: Cebon
authors.forename: J M
authors.initials: JM
authors.lastname: Wheatley
authors.forename: Z
authors.initials: Z
authors.lastname: Liu
authors.forename: F E
authors.initials: FE
authors.lastname: Smyth
authors.forename: C
authors.initials: C
authors.lastname: Murone
authors.forename: S
authors.initials: S
authors.lastname: Sturrock
authors.forename: D
authors.initials: D
authors.lastname: MacGregor
authors.forename: N
authors.initials: N
authors.lastname: Hanai
authors.forename: K
authors.initials: K
authors.lastname: Inoue
authors.forename: M
authors.initials: M
authors.lastname: Yamasaki
authors.forename: M W
authors.initials: MW
authors.lastname: Brechbiel
authors.forename: I D
authors.initials: ID
authors.lastname: Davis
authors.forename: R
authors.initials: R
authors.lastname: Murphy
authors.forename: A
authors.initials: A
authors.lastname: Hannah
authors.forename: M
authors.initials: M
authors.lastname: Lim-Joon
authors.forename: T
authors.initials: T
authors.lastname: Chan
authors.forename: G
authors.initials: G
authors.lastname: Chong
authors.forename: G
authors.initials: G
authors.lastname: Ritter
authors.forename: E W
authors.initials: EW
authors.lastname: Hoffman
authors.forename: A W
authors.initials: AW
authors.lastname: Burgess
authors.forename: L J
authors.initials: LJ
authors.lastname: Old
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000276:immunology* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000918:Antibody Specificity; D001706:Biopsy; D017252:CD3 Complex / Q000276:immunology*; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics; D007205:Indium Radioisotopes; D008297:Male; D008545:Melanoma / Q000000981:diagnostic imaging / Q000276:immunology* / Q000378:metabolism* / Q000628:therapy; D008875:Middle Aged; D011877:Radionuclide Imaging; D011993:Recombinant Fusion Proteins / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use; D014018:Tissue Distribution
chemical_list: D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D018796:Immunoconjugates; D007205:Indium Radioisotopes; D011993:Recombinant Fusion Proteins