| Autor: |
H, Kobayashi, I S, Kim, D, Drumm, M K, Kim, D S, Paik, N, Le, T A, Waldmann, J A, Carrasquillo, C H, Paik |
| Rok vydání: |
1999 |
| Předmět: |
|
| Zdroj: |
Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 40(5) |
| ISSN: |
0161-5505 |
| Popis: |
One of the major limitations of using intact immunoglobulins for targeting tumors is poor penetration into tissues. Although Fab fragments have been used because of their improved kinetics, they have undesirable high renal accumulation. In this study we tested a new approach to block renal accumulation of Fab.We conjugated humanized antiTac Fab fragments, which are directed against the interleukin-2 receptor, with glycolate. The biodistribution, pharmacokinetics and catabolism of glycolated Fab (glyco-Fab) were evaluated at two different levels of substitution (heavy and light) compared with nonglycolated Fab in Tac-antigen-positive (ATAC4) and -negative (A431) tumor-bearing nude mice. The mice received coinjections of 125I-labeled glyco-Fab (3 microCi/1 microg) and 131I-labeled nonglycolated Fab (5 microCi/1 microg). In addition, groups of mice receiving these reagents were also coinfused with 50 mg L-lysine.Significantly less glyco-Fab than nonglycolated Fab accumulated in the kidney (21 versus 189 %ID/g; P0.001). A higher proportion of glyco-Fab was excreted into the urine in its intact form. The glyco-Fab survived longer in circulation than nonglycolated Fab. The peak tumor accumulation of glyco-Fab was 2.3-fold greater than that of nonglycolated Fab. Furthermore, the ATAC4 tumor-to-normal tissue ratio of glyco-Fab was much higher in all organs than that of nonglycolated Fab. The heavily glyco-Fab accumulated less in the kidney than the lightly glyco-Fab. The coinjected lysine reduced the renal accumulation of both nonglycolated Fab and glyco-Fab.Glyco-Fab is a promising agent because of its lower renal accumulation, higher tumor uptake and higher tumor-to-normal tissue ratio. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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