title: Targeting of indium 111-labeled bivalent hapten to human melanoma mediated by bispecific monoclonal antibody conjugates: imaging of tumors hosted in nude mice.
abstract: Antibody conjugates were prepared by coupling F(ab')2 or Fab' fragments of an antibody specific for the human high molecular weight-melanoma associated antigen to Fab' fragments of an antibody specific for indium-diethylenetriaminepentaacetate complexes. Monovalent and bivalent haptens were synthesized by reacting the dipeptide tyrosyl-lysine with diethylenetriaminepentaacetic cyclic anhydride. In vitro, the antibody conjugate mediated binding of the 111In-labeled haptens to melanoma cells. In vivo, it allowed specific localization of the haptens in A375 tumors. The bivalent hapten exhibited much higher efficiency at targeting 111In onto cells, both in vitro and in vivo. Antibody conjugate and hapten doses (2 micrograms and 1 pmol, respectively) and the delay between antibody conjugate and tracer injections (24 h) were adjusted to maximize tumor uptake (4% injected dose/g) and tumor to normal tissue contrast (greater than 3) obtained 3 h after injection of the 111In-labeled bivalent hapten. This two-step technique, when compared to direct targeting of 111In-labeled F(ab')2 fragments, provided lower localization of injected activity into the tumor (x 0.25), but higher tumor/tissue ratios, especially with respect to liver (x 7), spleen (x 8), and kidneys (x 10). In addition, high contrast images were obtained within 3 hours, instead of days. Thus, antibody conjugate-mediated targeting of small bivalent haptens, labeled with short half-life isotopes, is proposed as a general method for improving tumor radioimmunolocalization.
authors.affiliation: Immunotech S.A., Luminy Case 915, Marseille, France.
authors.forename: J M
authors.initials: JM
authors.lastname: Le Doussal
authors.forename: A
authors.initials: A
authors.lastname: Gruaz-Guyon
authors.forename: M
authors.initials: M
authors.lastname: Martin
authors.forename: E
authors.initials: E
authors.lastname: Gautherot
authors.forename: M
authors.initials: M
authors.lastname: Delaage
authors.forename: J
authors.initials: J
authors.lastname: Barbet
mesh_terms: D000818:Animals; D000906:Antibodies / Q000378:metabolism*; D000918:Antibody Specificity; D000951:Antigens, Neoplasm; D005260:Female; D006241:Haptens / Q000008:administration & dosage*; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000378:metabolism* / Q000493:pharmacokinetics; D000922:Immunotoxins / Q000378:metabolism; D007205:Indium Radioisotopes / Q000276:immunology; D008545:Melanoma / Q000000981:diagnostic imaging / Q000276:immunology / Q000378:metabolism*; D058950:Melanoma-Specific Antigens; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000276:immunology*; D004369:Pentetic Acid / Q000378:metabolism*; D011877:Radionuclide Imaging
chemical_list: D000906:Antibodies; D000951:Antigens, Neoplasm; D006241:Haptens; D007140:Immunoglobulin Fab Fragments; D000922:Immunotoxins; D007205:Indium Radioisotopes; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins; D004369:Pentetic Acid