A phase I biodistribution and pharmacokinetic trial of humanized monoclonal antibody Hu3s193 in patients with advanced epithelial cancers that express the Lewis-Y antigen.
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.
Scott
Andrew M
AM
Ludwig Institute for Cancer Research, Melbourne Tumour Biology Branch, Austin Hospital, Australia. andrew.scott@ludwig.edu.au
Tebbutt
Niall
N
Lee
Fook-Thean
FT
Cavicchiolo
Tina
T
Liu
Zhanqi
Z
Gill
Sanjeev
S
Poon
Aurora M T
AM
Hopkins
Wendie
W
Smyth
Fiona E
FE
Murone
Carmel
C
MacGregor
Duncan
D
Papenfuss
Anthony T
AT
Chappell
Bridget
B
Saunder
Timothy H
TH
Brechbiel
Martin W
MW
Davis
Ian D
ID
Murphy
Roger
R
Chong
Geoffrey
G
Hoffman
Eric W
EW
Old
Lloyd J
LJ
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
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C522039:Hu3S193 monoclonal antibody; D007205:Indium Radioisotopes; D007983:Lewis Blood Group Antigens; C094162:Lewis Y antigen