Can antibody galactosylation be used to improve radioimmunotherapy of induced peritoneal carcinomatosis of colonic origin in the rat?
In radioimmunotherapy (RIT), hematologic toxicity is the dose-limiting toxicity due to the long circulatory half-life of the antibody. Although intraperitoneal (i.p.) RIT results in high uptake of i.p. growing tumors, the radiolabeled antibody enters the circulation, resulting in bone marrow toxicity. Carbohydrate modification of antibodies could induce accelerated clearance of the antibody via the hepatic asialoglycoprotein receptor, thereby reducing exposure to normal tissues. In this study, we investigated whether galactosylation of an antibody in a model of peritoneal carcinomatosis (PC) of colonic origin could be used to improve targeting of i.p. growing tumors. Therefore, the biodistribution of the galactosylated and nongalactosylated anti-CC531 antibody, MG1, after i.p. injection was determined in a model of peritoneal carcinomatosis of CC-531 colon tumors in Wag/Rij rats. Uptake of the radiolabeled antibodies in the tumor and relevant organs was determined at 2, 4, 24, and 48 hours after injection. Galactosylation of the antibody did not affect the binding affinity of MG1. Remarkably, the uptake of Gal-MG1 in tumors was higher than that of MG1 at 2 and 4 hours after injection. After 24 and 48 hours, uptake of Gal-MG1 in tumor tissue was lower than that of MG1. Gal-MG1 cleared from the blood within hours after administration. At 2-24 hours after administration, tumor-to-blood ratios obtained with Gal-MG1 were significantly higher than those obtained with unmodified MG1. Antibody galactosylation resulted in improved tumor-non-tumor ratios after i.p. injection in a model of PC. This could improve the efficiency of RIT, especially in combination with short-lived nonresidualizing radionuclides.
Aarts
Frits
F
Department of Surgery, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. F.Aarts@chir.umcn.nl
Hendriks
Thijs
T
Eek
Annemarie
A
Oyen
Wim J G
WJ
Bleichrodt
Robert P
RP
Boerman
Otto C
OC
D000818:Animals; D000906:Antibodies / Q000737:chemistry*; D000911:Antibodies, Monoclonal / Q000737:chemistry; D019540:Area Under Curve; D002277:Carcinoma / Q000628:therapy*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000473:pathology / Q000628:therapy*; D004195:Disease Models, Animal; D005690:Galactose / Q000737:chemistry*; D008297:Male; D051379:Mice; D010534:Peritoneal Neoplasms / Q000556:secondary / Q000628:therapy*; D016499:Radioimmunotherapy / Q000379:methods*; D051381:Rats; D014018:Tissue Distribution
D000906:Antibodies; D000911:Antibodies, Monoclonal; D005690:Galactose