title: A comparative analysis of conventional and pretargeted radioimmunotherapy of B-cell lymphomas by targeting CD20, CD22, and HLA-DR singly and in combinations.
abstract: Relapsed B-cell lymphomas are currently incurable with conventional chemotherapy and radiation treatments. Radiolabeled antibodies directed against B-cell surface antigens have emerged as effective and safe therapies for relapsed lymphomas. We therefore investigated the potential utility of both directly radiolabeled 1F5 (anti-CD20), HD39 (anti-CD22), and Lym-1 (anti-DR) antibodies (Abs) and of pretargeted radioimmunotherapy (RIT) using Ab-streptavidin (SA) conjugates, followed by an N-acetylgalactosamine dendrimeric clearing agent and radiometal-labeled DOTA-biotin, for treatment of lymphomas in mouse models using Ramos, Raji, and FL-18 human lymphoma xenografts. This study demonstrates the marked superiority of pretargeted RIT for each of the antigenic targets with more complete tumor regressions and longer mouse survival compared with conventional one-step RIT. The Ab-SA conjugate yielding the best tumor regression and progression-free survival after pretargeted RIT varied depending upon the lymphoma cell line used, with 1F5 Ab-SA and Lym-1 Ab-SA conjugates yielding the most promising results overall. Contrary to expectations, the best rates of mouse survival were obtained using optimal single Ab-SA conjugates rather than combinations of conjugates targeting different antigens. We hypothesize that clinical implementation of pretargeted RIT methods will provide a meaningful prolongation of survival for patients with relapsed lymphomas compared with currently available treatment strategies.
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. jpagel@fhcrc.org
authors.forename: John M
authors.initials: JM
authors.lastname: Pagel
authors.forename: Nural
authors.initials: N
authors.lastname: Orgun
authors.forename: Donald K
authors.initials: DK
authors.lastname: Hamlin
authors.forename: D Scott
authors.initials: DS
authors.lastname: Wilbur
authors.forename: Theodore A
authors.initials: TA
authors.lastname: Gooley
authors.forename: Ajay K
authors.initials: AK
authors.lastname: Gopal
authors.forename: Steven I
authors.initials: SI
authors.lastname: Park
authors.forename: Damian J
authors.initials: DJ
authors.lastname: Green
authors.forename: Yukang
authors.initials: Y
authors.lastname: Lin
authors.forename: Oliver W
authors.initials: OW
authors.lastname: Press
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20 / Q000276:immunology*; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D006684:HLA-DR Antigens / Q000276:immunology*; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage*; D016393:Lymphoma, B-Cell / Q000401:mortality / Q000532:radiotherapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016499:Radioimmunotherapy / Q000379:methods*; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000276:immunology*; D016019:Survival Analysis; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D006684:HLA-DR Antigens; D018796:Immunoconjugates; C410509:Lym-1 monoclonal antibody; D051918:Sialic Acid Binding Ig-like Lectin 2