Biodistribution of antibodies after intraperitoneal or intravenous injection and effect of carbohydrate modifications.
These studies were designed to improve the strategy for intraperitoneal immunotherapy of human ovarian carcinoma with monoclonal antibodies (MAbs). Since ovarian tumor cells generally appear to be confined to the peritoneal cavity, regional therapy is appropriate and can reduce the need for strictly tumor-specific MAbs. In normal mice, with the use of radioiodine-labeled MAbs, transfer from peritoneal cavity to blood was found to be very rapid, within hours, and this transfer was delayed slightly by increasing the volume injected. The presence of ascitic fluid in mice greatly delayed the rate of transfer. For reduction of possible toxicity for normal cells outside the peritoneal cavity, the hepatic receptor for desialylated serum glycoproteins was used. Neuraminidase treatment of all major mouse immunoglobulin classes and subclasses, including IgM, IgG1, IgG2a, IgG2b, IgG3, and IgA, did not cause their rapid blood clearance, although similar treatment of fetuin was effective. Conjugation of IgG with galactose, with use of the cyanomethyl derivative, did result in very rapid blood clearance via the hepatic lectin; within 3 minutes clearance was essentially complete. The specificity of uptake was demonstrated by inhibition with desialylated fetuin. Degradation within the liver, release of the radioiodine, and excretion from the animal were also quite rapid, within hours. This conjugation procedure had no effect on the antibody activity of the two MAbs tested. Such modified MAbs, therefore, are degraded almost immediately after entering the blood and would be advantageous in intraperitoneal therapy and in other situations in which regional immunotherapy is appropriate.
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001201:Ascites; D001212:Asialoglycoproteins; D002241:Carbohydrates; D005260:Female; D060748:Fetuins; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy; D008099:Liver / Q000378:metabolism; D051379:Mice; D009439:Neuraminidase / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000628:therapy; D013329:Structure-Activity Relationship; D000509:alpha-Fetoproteins / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D001212:Asialoglycoproteins; D002241:Carbohydrates; D060748:Fetuins; D006023:Glycoproteins; D000509:alpha-Fetoproteins; C017029:asialofetuin; D009439:Neuraminidase