Pilot trial evaluating an 123I-labeled 80-kilodalton engineered anticarcinoembryonic antigen antibody fragment (cT84.66 minibody) in patients with colorectal cancer.
OBJECTIVE
The chimeric T84.66 (cT84.66) minibody is a novel engineered antibody construct (V(L)-linker-V(H)-C(H)3; 80 kDa) that demonstrates bivalent and high affinity (4 x 10(10) m(-1)) binding to carcinoembryonic antigen (CEA). The variable regions (V(L) and V(H)) assemble to form the antigen-combining sites, and the protein forms dimers through self-association of the C(H)3 domains. In animal models, the minibody demonstrated high tumor uptake, approaching that of some intact antibodies, substantially faster clearance than intact chimeric T84.66, and superior tumor-to-blood ratios compared with the cT84.66 F(ab')(2) fragment, making it attractive for further evaluation as an imaging and therapy agent. The purpose of this pilot clinical study was to determine whether (123)I-cT84.66 minibody demonstrated tumor targeting and was well tolerated as well as to begin to evaluate its biodistribution, pharmacokinetics, and immunogenicity in patients with colorectal cancer.


METHODS
Ten patients with biopsy-proven colorectal cancer (6 newly diagnosed, 1 pelvic recurrence, 3 limited metastatic disease) were entered on this study. Each received 5-10 mCi (1 mg) of (123)I-labeled minibody i.v. followed by serial nuclear scans and blood and urine sampling over the next 48-72 h. Surgery was performed immediately after the last nuclear scan.


RESULTS
Tumor imaging was observed with (123)I-labeled minibody in seven of the eight patients who did not receive neoadjuvant therapy before surgery. Two patients received neoadjuvant radiation and chemotherapy, which significantly reduced tumor size before surgery and minibody infusion. At surgery, no tumor was detected in one patient and only a 2-mm focus was seen in the second patient. (123)I-labeled minibody tumor targeting was not seen in either of these pretreated patients. Mean serum residence time of the minibody was 29.8 h (range, 10.9-65.4 h). No drug-related adverse reactions were observed. All 10 patients were evaluated for immune responses to the minibody, with no significant responses observed.


CONCLUSIONS
This pilot study represents one of the first clinical efforts to evaluate an engineered intermediate-molecular-mass radiolabeled antibody construct directed against CEA. cT84.66 minibody demonstrates tumor targeting to colorectal cancer and a faster clearance in comparison with intact antibodies, making it appropriate for further evaluation as an imaging and therapy agent. The mean residence time of the minibody in patients is longer than predicted from murine models. We therefore plan to further evaluate its biodistribution and pharmacokinetic properties with minibody labeled with a longer-lived radionuclide, such as (111)In.
Division of Radiation Oncology, City of Hope National Medical Center and Beckman Research Institute, Duarte, California 91010, USA.
Jeffrey Y C
JY
Wong
David Z
DZ
Chu
Lawrence E
LE
Williams
Dave M
DM
Yamauchi
David N
DN
Ikle
Cheuk S
CS
Kwok
An
A
Liu
Sharon
S
Wilczynski
David
D
Colcher
Paul J
PJ
Yazaki
John E
JE
Shively
Anna M
AM
Wu
Andrew A
AA
Raubitschek
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000906:Antibodies / Q000737:chemistry* / Q000627:therapeutic use*; D002272:Carcinoembryonic Antigen / Q000276:immunology*; D002851:Chromatography, High Pressure Liquid; D015179:Colorectal Neoplasms / Q000628:therapy*; D019281:Dimerization; D005260:Female; D006801:Humans; D007128:Immunoglobulin Fragments / Q000627:therapeutic use*; D007167:Immunotherapy / Q000379:methods*; D007457:Iodine Radioisotopes / Q000627:therapeutic use*; D007700:Kinetics; D008297:Male; D051379:Mice; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010865:Pilot Projects; D017434:Protein Structure, Tertiary; D011874:Radiometry; D013997:Time Factors; D015899:Tomography, Emission-Computed, Single-Photon
D000906:Antibodies; D002272:Carcinoembryonic Antigen; D007128:Immunoglobulin Fragments; D007457:Iodine Radioisotopes