A phase I trial of humanized monoclonal antibody A33 in patients with colorectal carcinoma: biodistribution, pharmacokinetics, and quantitative tumor uptake.
Clin Cancer Res
; 11(13): 4810-7, 2005 Jul 01.
Article
in En
| MEDLINE
| ID: mdl-16000578
ABSTRACT
PURPOSE:
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. EXPERIMENTALDESIGN:
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 16.31 and 4.51, 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.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Membrane Glycoproteins
/
Colorectal Neoplasms
/
Antibodies, Monoclonal
Type of study:
Prognostic_studies
Limits:
Adult
/
Aged
/
Female
/
Humans
/
Male
/
Middle aged
Language:
En
Journal:
Clin Cancer Res
Journal subject:
NEOPLASIAS
Year:
2005
Type:
Article
Affiliation country:
Australia