A phase I trial of humanized monoclonal antibody A33 in patients with colorectal carcinoma: biodistribution, pharmacokinetics, and quantitative tumor uptake.
OBJECTIVE
To determine the in vivo characteristics of huA33, a CDR-grafted humanized antibody against the A33 antigen, we have conducted an open-label, dose escalation, biopsy-based phase I trial of huA33 in patients with colorectal carcinoma.


METHODS
Patients with colorectal carcinoma were infused with [131I]huA33 (400 MBq: 10 mCi) and [125I]huA33 (40 MBq: 1 mCi) 1 week before surgery. There were four huA33 dose levels (0.25, 1.0, 5.0, and 10 mg/m2). Adverse events, pharmacokinetics, biodistribution, tumor biopsies, and immune responses to huA33 were evaluated.


RESULTS
There were 12 patients entered into the trial (6 males and 6 females; age range, 39-66 years). No dose-limiting toxicity was observed. The biodistribution of huA33 showed excellent uptake of [131I]huA33 in metastatic colorectal carcinoma. Pharmacokinetic analysis showed no significant difference in terminal half-life (T1/2beta) between dose levels (mean +/- SD, 86.92 +/- 22.12 hours). Modeling of colon uptake of huA33 showed a T1/2 of elimination of 32.4 +/- 8.1 hours. Quantitative tumor uptake ranged from 2.1 x 10(-3) to 11.1 x 10(-3) %ID/g, and tumor/normal tissue and tumor/serum ratios reached as high as 16.3:1 and 4.5:1, respectively. Biosensor analysis detected low-level human anti-human antibody responses in four patients following huA33 infusion.


CONCLUSIONS
huA33 shows selective and rapid localization to colorectal carcinoma in vivo and penetrates to the center of large necrotic tumors, and colon elimination half-life of huA33 is equivalent to basal colonocyte turnover. The excellent targeting characteristics of this humanized antibody indicate potential for the targeted therapy of metastatic colorectal cancer in future trials.
Ludwig Institute for Cancer Research, Melbourne Tumour Biology Branch, Melbourne, Victoria, Australia. andrew.scott@ludwig.edu.au
Andrew M
AM
Scott
Fook-Thean
FT
Lee
Robert
R
Jones
Wendie
W
Hopkins
Duncan
D
MacGregor
Jonathan S
JS
Cebon
Anthony
A
Hannah
Geoffrey
G
Chong
Paul
P
U
Anthony
A
Papenfuss
Angela
A
Rigopoulos
Susan
S
Sturrock
Roger
R
Murphy
Veronika
V
Wirth
Carmel
C
Murone
Fiona E
FE
Smyth
Simon
S
Knight
Sydney
S
Welt
Gerd
G
Ritter
Elizabeth
E
Richards
Edouard C
EC
Nice
Antony W
AW
Burgess
Lloyd J
LJ
Old
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007457:Iodine Radioisotopes; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology*; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D014018:Tissue Distribution; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; C104258:GPA33 protein, human; D007457:Iodine Radioisotopes; D008562:Membrane Glycoproteins