In vivo modulators of antibody kinetics.
The aim of the present study was to summarize the effect of in vivo modulation of antibody kinetics and to present new data on the in vivo effect of the cell membrane active detergent Tween 80 and the cytokine interleukin-2 (IL-2) on the accumulation and clearance of a radioactive antibody. Mice bearing Lewis lung carcinoma xenografts and rats bearing DMBA-induced mammary carcinomas were studied after injecting I-125 labeled IgG1 monoclonal antibody (3c4c7g6) raised against a tyrosine kinase receptor protein Tie. Expression of Tie is known to be abundant in vascular endothelia and possibly related to malignant angiogenesis. Tween 80 was administered intratumorally (0.04% of tumor volume), whereas IL-2 was administered intraperitoneally. In the Lewis lung tumor model, the absolute tumor uptake varied between 2 and 5% ID/g, and maximum uptake was achieved after 24 h with Tween, and after 48 h without Tween. Tween manipulation did not increase the uptake in any normal organ, but it enhanced antibody clearance from the blood. In the DMBA rat model, IL-2 had no effect on blood clearance, but enhanced the uptake of Tie antibody into the tumor from 2.5-0.9 to 4.5-0.4% ID/g at 48 h. These data indicate that antibody biodistribution and pharmacokinetics can be modulated by a surface detergent and a cytokine, giving decreased exposure to critical organs, and increased uptake into the tumor. This type of manipulation provides an opportunity to optimize radioimmunotherapy.
Jekunen
A
A
Department of Oncology, Helsinki University Central Hospital, Helsinki.
Kairemo
K
K
Karnani
P
P
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000009:adverse effects; D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000097:blood / Q000378:metabolism; D002273:Carcinogens / Q000009:adverse effects; D002277:Carcinoma / Q000139:chemically induced / Q000378:metabolism; D004730:Endothelium, Vascular / Q000276:immunology; D005260:Female; D018796:Immunoconjugates / Q000097:blood / Q000187:drug effects / Q000493:pharmacokinetics*; D007074:Immunoglobulin G / Q000097:blood / Q000378:metabolism; D015552:Injections, Intralesional; D007274:Injections, Intraperitoneal; D007376:Interleukin-2 / Q000494:pharmacology*; D007457:Iodine Radioisotopes / Q000097:blood / Q000493:pharmacokinetics; D008175:Lung Neoplasms / Q000378:metabolism / Q000532:radiotherapy; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism; D051379:Mice; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000276:immunology; D011136:Polysorbates / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000276:immunology; D013501:Surface-Active Agents / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors; D014183:Transplantation, Heterologous
D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D002273:Carcinogens; D018796:Immunoconjugates; D007074:Immunoglobulin G; D007376:Interleukin-2; D007457:Iodine Radioisotopes; D011136:Polysorbates; D013501:Surface-Active Agents; D015127:9,10-Dimethyl-1,2-benzanthracene; D020794:Receptor Protein-Tyrosine Kinases