title: Improved therapy of non-Hodgkin's lymphoma xenografts using radionuclides pretargeted with a new anti-CD20 bispecific antibody.
abstract: A comparison of the therapeutic efficacy of a new bispecific monoclonal antibody (bsMAb)-pretargeting system vs the conventional direct targeting modality was undertaken. A bsMAb was made by coupling the Fab' of a humanized anti-CD20 antibody to the Fab' of a murine antibody directed against the peptide histamine-succinyl-glycine (HSG). The tumor targeting of the bsMAb was separated from the subsequent delivery of the radionuclide-bearing HSG peptide conjugated with (111)In or (90)Y. Nude mice bearing s.c. Ramos human B-cell lymphomas were injected with the bsMAb and then, 48 h later, (111)In/(90)Y-HSG peptide was given. At 3 h postinjection, tumor/blood ratios for pretargeted (111)In-HSG-peptide were similar to that observed with the directly conjugated (111)In-anti-CD20 IgG at its highest level on day 7, but by day 1, tumor/blood ratios were about 10-fold higher than the IgG. Tumors progressed rapidly in animals given 800 microCi of (90)Y-HSG peptide alone, whereas 5/10 animals in the group pretargeted by the anti-CD20 bsMAb were tumor-free 18 weeks later. The antitumor response in animals administered the pretargeted (90)Y-HSG peptide was also significantly superior to treatment with the directly radiolabeled (90)Y-anti-CD20 IgG, whether given as a single injection (P<0.007) or as a divided dose (P=0.016). This bsMAb-pretargeting procedure significantly improves the therapeutic response of targeted radionuclides in non-Hodgkin's lymphoma, warranting further development of this method of radioimmunotherapy.
authors.affiliation: Garden State Cancer Center, Center for Molecular Medicine and Immunology, Belleville, NJ 10709, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Sharkey
authors.forename: H
authors.initials: H
authors.lastname: Karacay
authors.forename: C-H
authors.initials: CH
authors.lastname: Chang
authors.forename: W J
authors.initials: WJ
authors.lastname: McBride
authors.forename: I D
authors.initials: ID
authors.lastname: Horak
authors.forename: D M
authors.initials: DM
authors.lastname: Goldenberg
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D018951:Antigens, CD20 / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D007205:Indium Radioisotopes / Q000494:pharmacology; D008228:Lymphoma, Non-Hodgkin / Q000401:mortality / Q000532:radiotherapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016499:Radioimmunotherapy / Q000379:methods*; D023041:Xenograft Model Antitumor Assays
chemical_list: D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018951:Antigens, CD20; D007074:Immunoglobulin G; D007205:Indium Radioisotopes; C493846:veltuzumab