A Phase I Biodistribution and Pharmacokinetic Trial of Humanized Monoclonal Antibody Hu3s193 in Patients with Advanced Epithelial Cancers that Express the Lewis-Y Antigen Academic Article uri icon

abstract

  • Purpose

    We report a first-in-man trial of a humanized antibody (hu3S193) against the Le(y) antigen.

    Experimental design

    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.

    Conclusion

    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

  • Scott, Andrew M
  • Tebbutt, Niall
  • Lee, Fook-Thean
  • Cavicchiolo, Tina
  • Liu, Zhanqi
  • Gill, Sanjeev
  • Poon, Aurora MT
  • Hopkins, Wendie
  • Smyth, Fiona E
  • Murone, Carmel
  • MacGregor, Duncan
  • Papenfuss, Anthony T
  • Chappell, Bridget
  • Saunder, Timothy H
  • Brechbiel, Martin W
  • Davis, Ian D
  • Murphy, Roger
  • Chong, Geoffrey
  • Hoffman, Eric W
  • Old, Lloyd J

publication date

  • June 1, 2007