ISSN:
1573-3904
Keywords:
Carcinoembryonic antigen
;
Colon cancer
;
Lymphoma
;
Monoclonal antibodies
;
Targeting
Source:
Springer Online Journal Archives 1860-2000
Topics:
Chemistry and Pharmacology
Notes:
Abstract The advantages of bivalent hapten-bearing peptides for the detection oftumours pretargeted with bispecific antibodies have been demonstrated. Thistechnology is now considered for radioimmunotherapy and bivalent haptensdesigned to target 131I are needed. We thus synthesised aseries of tyrosine-containing peptides bearing the histamine-hemisuccinatehapten. These molecules were tested for their ability to bind simultaneouslytwo anti-hapten antibody molecules. One of these bivalent haptens, AG3.0,with a lysyl-d-tyrosyl-lysine connecting chain, was found to have optimalbinding characteristics and was thus selected for further investigations.AG3.0 was shown to efficiently deliver radioactive iodine to humancolorectal tumours grafted in nude mice using an anti-carcinoembryonicantigen×anti-histamine-hemisuccinate bispecific antibody. AG3.0 wasalso targeted to human B lymphoma cells pretargeted with a bispecificantibody specific for membrane IgM. In this system, bivalent ligands such asF(ab′)2 or IgG are rapidly internalised and covalentlylinked radioactive iodine is released from target cells as a result ofintracellular catabolism. With the pretargeted iodine-labelled bivalenthapten, a fivefold increase in the intracellular activity retention time ascompared to 125I-labelled F(ab′)2 and IgGwas observed. The radiolabelled hapten did not undergo any degradation afterinternalisation. These results have been confirmed in vivo with ananti-BCL1 IgM idiotype bispecific antibody and131I-labelled AG3.0. These reagents injected as a single 300µCi dose, 7 days after inoculation of 104BCL1 lymphoma cells in BALB/c mice, cured 14/16 of the animalsand the treatment was well tolerated. Comparatively, the same dose oflabelled IgG cured 13/16 of the mice but three mice died of haematologictoxicity. The same dose of labelled F(ab′)2 orFab′ was completely inefficient. was completely inefficient. 131I-labelled bivalenthaptens are now used in phase I radioimmunotherapy clinical trials.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1023/A:1008848905210
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