Clinical evaluation of indium-111-labeled chimeric anti-CEA monoclonal antibody.
Chimeric T84.66 (cT84.66) is a high-affinity (1.16 x 10[11] M[-1]) IgG1 monoclonal antibody (MAb) against carcinoembryonic antigen (CEA). This pilot trial evaluated the tumor-targeting properties, biodistribution, pharmacokinetics and immunogenicity of 111In-labeled cT84.66.


METHODS
Patients with CEA-producing metastatic malignancies were administered a single intravenous dose of 5 mCi 111In-diethylenetriaminepentaacetic acid-cT84.66. Serial blood samples, 24-hr urine collections and nuclear images were collected up to 7 days postinfusion. Human antichimeric antibody response was assessed up to 6 mo postinfusion.


RESULTS
Imaging of at least one known tumor site was observed in 14 of 15 (93%) patients. Seventy-four lesions were analyzed with an imaging sensitivity rate of 45.1% and a positive predictive value of 94.1%. In one patient, two additional bone metastases developed within 6 mo of antibody administration at sites initially felt to be falsely positive on scan. One patient developed a human antichimeric antibody response predominantly to the murine portion of the antibody. The antibody cleared serum with a median T(1/2alpha) of 6.53 hr and a T(1/2beta) of 90.87 hr. Interpatient variations in serum clearance rates were observed and were secondary to differences in clearance and metabolic rates of antibody-antigen complexes by the liver. One patient demonstrated very rapid clearance of antibody by the liver, which compromised antibody localization to the primary tumor. Antibody uptake in primary and metastatic tumors ranged from 0.5% to 10.5% injected dose/kg, resulting in estimated radiation doses ranging from 0.97 to 21.3 cGy/mCi 90Y. Antibody uptake in regional lymph nodes ranged from 1.3% to 377% injected dose/kg, resulting in estimated radiation doses ranging from 2.0 to 617 cGy/mCi 90Y.


CONCLUSIONS
Chimeric T84.66 demonstrated tumor targeting that was comparable to that of other radiolabeled intact anti-CEA Mabs. Its immunogenicity after single administration was lower than murine Mabs. These properties make cT84.66 or a lower molecular weight derivative attractive for further evaluation as an imaging agent. These same properties also make it appropriate for future evaluation in Phase I therapy trials. Finally, a wide variation in the rate of antibody clearance was observed, with one patient demonstrating very slow clearance, resulting in the highest estimated marrow dose of the group, and one patient demonstrating unusually rapid clearance, resulting in poor antibody localization to tumor. Data from this study suggest that serum CEA levels, antibody-antigen complex clearance and, therefore, antibody clearance are influenced by both the production and clearance rates of CEA. This underscores the need to further identify, characterize and understand those factors that influence the biodistribution and clearance of radiolabeled anti-CEA antibodies to allow for better selection of patients for therapy and rational planning of radioimmunotherapy.
Wong
J Y
JY
Division of Radiation Oncology, City of Hope National Medical Center and Beckman Research Institute, Duarte, California 91010, USA.
Thomas
G E
GE
Yamauchi
D
D
Williams
L E
LE
Odom-Maryon
T L
TL
Liu
A
A
Esteban
J M
JM
Neumaier
M
M
Dresse
S
S
Wu
A M
AM
Primus
F J
FJ
Shively
J E
JE
Raubitschek
A A
AA
D000328:Adult; D000368:Aged; D000818:Animals; D002272:Carcinoembryonic Antigen / Q000276:immunology*; D005260:Female; D006801:Humans; D007205:Indium Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008875:Middle Aged; D010865:Pilot Projects; D011237:Predictive Value of Tests; D016719:Radioimmunodetection; D016499:Radioimmunotherapy; D011993:Recombinant Fusion Proteins / Q000493:pharmacokinetics / Q000627:therapeutic use; D012680:Sensitivity and Specificity; D014018:Tissue Distribution; D015021:Yttrium Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use
D002272:Carcinoembryonic Antigen; D007205:Indium Radioisotopes; D011993:Recombinant Fusion Proteins; D015021:Yttrium Radioisotopes