title: A phase I biodistribution and pharmacokinetic trial of humanized monoclonal antibody Hu3s193 in patients with advanced epithelial cancers that express the Lewis-Y antigen.
abstract: OBJECTIVE
  We report a first-in-man trial of a humanized antibody (hu3S193) against the Le(y) antigen.
  
  
  METHODS
  Patients with advanced Le(y)-positive cancers received four infusions of hu3S193 at weekly intervals, with four dose levels (5, 10, 20, and 40 mg/m(2)). The first infusion of hu3S193 was trace labeled with Indium-111, and biodistribution, pharmacokinetics, tumor uptake, and immune response were evaluated in all patients.
  
  
  RESULTS
  A total of 15 patients (7 male/8 female; age range, 42-76 years; 6 breast, 8 colorectal cancer, and 1 non-small-cell lung cancer) were entered into the study. Transient grade 1 to 2 nausea and vomiting was observed following infusion of hu3S193 at the 40 mg/m(2) dose level only. There was one episode of dose-limiting toxicity with self-limiting Common Toxicity Criteria grade 3 elevated alkaline phosphatase observed in one patient with extensive liver metastases. The biodistribution of (111)In-hu3S193 showed no evidence of any consistent normal tissue uptake, and (111)In-hu3S193 uptake was observed in cutaneous, lymph node, and hepatic metastases. Hu3S193 displayed a long serum half-life (T(1/2)beta = 189.63 +/- 62.17 h). Clinical responses consisted of 4 patients with stable disease and 11 patients with progressive disease, although one patient experienced a 89% decrease in a lymph node mass, and one patient experienced inflammatory symptoms in cutaneous metastases, suggestive of a biological effect of hu3S193. No immune responses (human anti-human antibody) to hu3S193 were observed.
  
  
  CONCLUSIONS
  Hu3S193 is well tolerated and selectively targets tumors, and the long half-life and biological function in vivo of this antibody makes it an attractive potential therapy for patients with Le(y)-expressing cancers.
authors.affiliation: Ludwig Institute for Cancer Research, Melbourne Tumour Biology Branch, Austin Hospital, Australia. andrew.scott@ludwig.edu.au
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Scott
authors.forename: Niall
authors.initials: N
authors.lastname: Tebbutt
authors.forename: Fook-Thean
authors.initials: FT
authors.lastname: Lee
authors.forename: Tina
authors.initials: T
authors.lastname: Cavicchiolo
authors.forename: Zhanqi
authors.initials: Z
authors.lastname: Liu
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Gill
authors.forename: Aurora M T
authors.initials: AM
authors.lastname: Poon
authors.forename: Wendie
authors.initials: W
authors.lastname: Hopkins
authors.forename: Fiona E
authors.initials: FE
authors.lastname: Smyth
authors.forename: Carmel
authors.initials: C
authors.lastname: Murone
authors.forename: Duncan
authors.initials: D
authors.lastname: MacGregor
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Papenfuss
authors.forename: Bridget
authors.initials: B
authors.lastname: Chappell
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Saunder
authors.forename: Martin W
authors.initials: MW
authors.lastname: Brechbiel
authors.forename: Ian D
authors.initials: ID
authors.lastname: Davis
authors.forename: Roger
authors.initials: R
authors.lastname: Murphy
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Chong
authors.forename: Eric W
authors.initials: EW
authors.lastname: Hoffman
authors.forename: Lloyd J
authors.initials: LJ
authors.lastname: Old
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007205:Indium Radioisotopes / Q000493:pharmacokinetics; D007983:Lewis Blood Group Antigens / Q000096:biosynthesis*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000628:therapy*; D012878:Skin Neoplasms / Q000628:therapy*; D013997:Time Factors; D014018:Tissue Distribution; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C522039:Hu3S193 monoclonal antibody; D007205:Indium Radioisotopes; D007983:Lewis Blood Group Antigens; C094162:Lewis Y antigen