Therapeutic advantage of pretargeted radioimmunotherapy using a recombinant bispecific antibody in a human colon cancer xenograft.
OBJECTIVE
To assess if pretargeting, using a combination of a recombinant bispecific antibody (bsMAb) that binds divalently to carcinoembryonic antigen (CEA) and monovalently to the hapten histamine-succinyl-glycine and a (90)Y-peptide, improves therapeutic efficacy in a human colon cancer-nude mouse xenograft compared with control animals given (90)Y-humanized anti-CEA immunoglobulin G (IgG).


METHODS
Clearance and biodistribution were monitored by whole-body readings and necropsy. Animals were monitored for 34 weeks with a determination of residual disease and renal pathology in survivors. Hematologic toxicity was assessed separately in non-tumor-bearing NIH Swiss mice.


RESULTS
Hematologic toxicity was severe at doses of 100 to 200 microCi of (90)Y-IgG, yet mild in the pretargeted animals given 500 or 700 microCi of the (90)Y-peptide. Evidence of end-stage renal disease was found at 900 microCi of the pretargeted (90)Y-peptide whereas animals given 700 microCi showed only mild renal pathology, similar to that seen in control animals given (90)Y-IgG. Biodistribution data indicated that the average amount of tumor radioactivity by a 700-microCi dose of the pretargeted peptide over a 96-hour period was increased 2.5-fold (48 microCi/g) compared with 150 microCi of (90)Y-IgG (18.9 microCi/g). At these doses, survival (i.e., time to progression to 2.5 cm(3)) was significantly improved (P < 0.04) compared with (90)Y-IgG, with ablation of about one third of the tumors, whereas viable tumor was present in all of the (90)Y-IgG-treated animals.


CONCLUSIONS
Pretargeting increases the amount of radioactivity delivered to colorectal tumors sufficiently to improve the therapeutic index and responses as compared with conventional radioimmunotherapy.
Karacay
Habibe
H
Center for Molecular Medicine and Immunology and the Garden State Cancer Center, Belleville, NJ 07109, USA.
Brard
Pierre-Yves
PY
Sharkey
Robert M
RM
Chang
Chien-Hsing
CH
Rossi
Edmund A
EA
McBride
William J
WJ
Ragland
Dan R
DR
Horak
Ivan D
ID
Goldenberg
David M
DM
D000818:Animals; D018033:Antibodies, Bispecific / Q000737:chemistry*; D019540:Area Under Curve; D002272:Carcinoembryonic Antigen / Q000378:metabolism; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000473:pathology* / Q000628:therapy*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry; D007668:Kidney / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010455:Peptides / Q000737:chemistry; D016499:Radioimmunotherapy / Q000379:methods*; D013997:Time Factors
D018033:Antibodies, Bispecific; D002272:Carcinoembryonic Antigen; D007074:Immunoglobulin G; D010455:Peptides