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

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: Andrew M Scott, Niall Tebbutt, Fook-Thean Lee, Tina Cavicchiolo, Zhanqi Liu, Sanjeev Gill, Aurora M T Poon, Wendie Hopkins, Fiona E Smyth, Carmel Murone, Duncan MacGregor, Anthony T Papenfuss, Bridget Chappell, Timothy H Saunder, Martin W Brechbiel, Ian D Davis, Roger Murphy, Geoffrey Chong, Eric W Hoffman, Lloyd J Old
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 13 Issue 11 Pg. 3286-92 (Jun 01 2007) ISSN: 1078-0432 [Print] United States
• PMID: 17545534 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Hu3S193 monoclonal antibody
• Indium Radioisotopes
• Lewis Blood Group Antigens
• Lewis Y antigen

Topics

• Adult
• Aged
• Antibodies, Monoclonal (adverse effects, pharmacokinetics, therapeutic use)
• Antibodies, Monoclonal, Humanized
• Female
• Humans
• Immunotherapy (methods)
• Indium Radioisotopes (pharmacokinetics)
• Lewis Blood Group Antigens (biosynthesis)
• Male
• Middle Aged
• Neoplasms (therapy)
• Skin Neoplasms (therapy)
• Time Factors
• Tissue Distribution
• Treatment Outcome