title: Comparison of anti-CD20 and anti-CD45 antibodies for conventional and pretargeted radioimmunotherapy of B-cell lymphomas.
abstract: Radiolabeled anti-CD20 antibodies produce responses in 60% to 95% of patients with relapsed non-Hodgkin lymphoma (NHL); however, absorbed radiation ratios between tumors and normal organs are relatively low, and many patients have relapses. In this study we compared the abilities of anti-CD45 (BC8) and anti-CD20 (1F5) antibodies to target human Ramos lymphoma xenografts in athymic mice. When direct radioiodination was performed with conventional methods, BC8 delivered 2- to 4-fold more radioiodine to tumors than 1F5, with tumor-to-normal organ ratios as high as 20:1 using radiolabeled BC8 compared with a maximal ratio of 9.8:1 using radioiodinated 1F5. To optimize the biodistribution of radioactivity, we performed studies following a pretargeting method using streptavidin (SA)-conjugated BC8 and 1F5. Injection of a synthetic clearing agent decreased the circulating level of conjugates by 80% to 90% within 1 hour. Pretargeting with BC8-SA resulted in a 2- to 4-fold greater tumor uptake of radiolabeled biotin than with 1F5-SA, with maximal tumor-to-normal organ ratios of more than 80:1 and approximately 16:1, respectively. Therapy experiments demonstrated that 400 microCi (14.8 MBq) or more of yttrium-90-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-biotin cured 100% of mice treated with BC8-SA and more than 90% of mice pretargeted with 1F5-SA, with complete remission occurring 8 to 10 days sooner in mice receiving BC8-SA. After treatment with 200 microCi (7.4 MBq) (90)Y-DOTA-biotin, 70% of the mice treated with BC8-SA were cured, but no mice were cured using 1F5-SA. Doses up to 800 microCi (29.6 MBq) (90)Y-DOTA-biotin were delivered with minor toxicity using either antibody conjugate. These lymphoma xenograft data suggest that pretargeted radioimmunotherapy using either anti-CD20 or anti-CD45 conjugates is highly effective and minimally toxic.
authors.affiliation: Fred Hutchinson Cancer Research Center and the Department of Medicine, University of Washington, Seattle 98109, USA. jpagel@fhcrc.org
authors.forename: John M
authors.initials: JM
authors.lastname: Pagel
authors.forename: Nathan
authors.initials: N
authors.lastname: Hedin
authors.forename: Krishnan
authors.initials: K
authors.lastname: Subbiah
authors.forename: Damon
authors.initials: D
authors.lastname: Meyer
authors.forename: Robert
authors.initials: R
authors.lastname: Mallet
authors.forename: Donald
authors.initials: D
authors.lastname: Axworthy
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Theodore
authors.forename: D Scott
authors.initials: DS
authors.lastname: Wilbur
authors.forename: Dana C
authors.initials: DC
authors.lastname: Matthews
authors.forename: Oliver W
authors.initials: OW
authors.lastname: Press
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D018951:Antigens, CD20 / Q000276:immunology*; D001710:Biotin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D007205:Indium Radioisotopes / Q000493:pharmacokinetics; D007457:Iodine Radioisotopes / Q000032:analysis / Q000493:pharmacokinetics; D017493:Leukocyte Common Antigens / Q000276:immunology*; D016393:Lymphoma, B-Cell / Q000532:radiotherapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009942:Organometallic Compounds / Q000493:pharmacokinetics; D016499:Radioimmunotherapy / Q000009:adverse effects / Q000379:methods*; D012074:Remission Induction; D019809:Streptavidin; D014407:Tumor Cells, Cultured; D015021:Yttrium Radioisotopes / Q000493:pharmacokinetics
chemical_list: D000911:Antibodies, Monoclonal; D018951:Antigens, CD20; C405616:DOTA-biotin; D007205:Indium Radioisotopes; D007457:Iodine Radioisotopes; D009942:Organometallic Compounds; D015021:Yttrium Radioisotopes; D001710:Biotin; D019809:Streptavidin; D017493:Leukocyte Common Antigens