caa a22 4500 477137768 CHVBK 20180405111723.0 cr unu---uuuuu 170330e19971201xx s 000 0 eng 10.1007/BF02442897 doi (NATIONALLICENCE)springer-10.1007/BF02442897 Pretargeted radioimmunotherapy using131I-labelled bivalent hapten-bearing peptides [Elektronische Daten] [Marc de Boisferon, Corrine Manetti, Olivier Raguin, Emmanuel Gautherot, William Rostène, Jacques Barbet, Anne Gruaz-Guyon] Summary: The advantages of bivalent hapten-bearing peptides for the detection of tumours pretargeted with bispecific antibodies have been demonstrated. This technology is now considered for radioimmunotherapy and bivalent haptens designed to target131I are needed. We thus synthesised a series of tyrosine-containing peptides bearing the histamine-hemisuccinate hapten. These molecules were tested for their ability to bind simultaneously two anti-hapten antibody molecules. One of these bivalent haptens, AG3.0, with a lysyl-d-tyrosyl-lysine connecting chain, was found to have optimal binding characteristics and was thus selected for further investigations. AG3.0 was shown to efficiently deliver radioactive iodine to human colorectal tumours grafted in nude mice using an anti-carcinoembryonic antigen×anti-histamine-hemisuccinate bispecific antibody. AG3.0 was also targeted to human B lymphoma cells pretargeted with a bispecific antibody specific for membrane IgM. In this system, bivalent ligands such as F(ab′)2 or IgG are rapidly internalised and covalently linked radioactive iodine is released from target cells as a result of intracellular catabolism. With the pretargeted iodine-labelled bivalent hapten, a fivefold increase in the intracellular activity retention time as compared to125I-labelled F(ab′)2 and IgG was observed. The radiolabelled hapten did not undergo any degradation after internalisation. These results have been confirmed in vivo with an anti-BCL1 IgM idiotype bispecific antibody and131I-labelled AG3.0. These reagents injected as a single 300 μCi dose, 7 days after inoculation of 104 BCL1 lymphoma cells in BALB/c mice, cured 14/16 of the animals and the treatment was well tolerated. Comparatively, the same dose of labelled IgG cured 13/16 of the mice but three mice died of haematologic toxicity. The same dose of labelled F(ab′)2 or Fab′ was completely inefficient.131I-labelled bivalent haptens are now used in phase I radioimmunotherapy clinical trials. Kluwer Academic Publishers, 1997 Carcinoembryonic antigen nationallicence Colon cancer nationallicence Lymphoma nationallicence Monoclonal antibodies nationallicence Targeting nationallicence de Boisferon Marc Inserm U339, Hôpital and Faculté de Médecine Saint Antoine, 27 Rue Chaligny, F-75012, Paris, France aut Manetti Corrine Immunotech S.A., 130 Avenue de Lattre de Tassigny, BP176, F-13276, Marseille Cedex 9, France aut Raguin Olivier Inserm U339, Hôpital and Faculté de Médecine Saint Antoine, 27 Rue Chaligny, F-75012, Paris, France aut Gautherot Emmanuel Immunotech S.A., 130 Avenue de Lattre de Tassigny, BP176, F-13276, Marseille Cedex 9, France aut Rostène William Inserm U339, Hôpital and Faculté de Médecine Saint Antoine, 27 Rue Chaligny, F-75012, Paris, France aut Barbet Jacques Immunotech S.A., 130 Avenue de Lattre de Tassigny, BP176, F-13276, Marseille Cedex 9, France aut Gruaz-Guyon Anne Inserm U339, Hôpital and Faculté de Médecine Saint Antoine, 27 Rue Chaligny, F-75012, Paris, France aut Letters in Peptide Science Kluwer Academic Publishers 4/4-6(1997-12-01), 331-339 0929-5666 4:4-6<331 1997 4 10989 https://doi.org/10.1007/BF02442897 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/BF02442897 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- de Boisferon Marc Inserm U339, Hôpital and Faculté de Médecine Saint Antoine, 27 Rue Chaligny, F-75012, Paris, France aut NATIONALLICENCE 700 1- Manetti Corrine Immunotech S.A., 130 Avenue de Lattre de Tassigny, BP176, F-13276, Marseille Cedex 9, France aut NATIONALLICENCE 700 1- Raguin Olivier Inserm U339, Hôpital and Faculté de Médecine Saint Antoine, 27 Rue Chaligny, F-75012, Paris, France aut NATIONALLICENCE 700 1- Gautherot Emmanuel Immunotech S.A., 130 Avenue de Lattre de Tassigny, BP176, F-13276, Marseille Cedex 9, France aut NATIONALLICENCE 700 1- Rostène William Inserm U339, Hôpital and Faculté de Médecine Saint Antoine, 27 Rue Chaligny, F-75012, Paris, France aut NATIONALLICENCE 700 1- Barbet Jacques Immunotech S.A., 130 Avenue de Lattre de Tassigny, BP176, F-13276, Marseille Cedex 9, France aut NATIONALLICENCE 700 1- Gruaz-Guyon Anne Inserm U339, Hôpital and Faculté de Médecine Saint Antoine, 27 Rue Chaligny, F-75012, Paris, France aut NATIONALLICENCE 773 0- Letters in Peptide Science Kluwer Academic Publishers 4/4-6(1997-12-01), 331-339 0929-5666 4:4-6<331 1997 4 10989 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer