title: A comparative evaluation of conventional and pretargeted radioimmunotherapy of CD20-expressing lymphoma xenografts.
abstract: Radioimmunotherapy with anti-CD20 monoclonal antibodies is a promising new treatment approach for patients with relapsed B-cell lymphomas. However, the majority of patients treated with conventional radiolabeled anti-CD20 antibodies eventually have a relapse because the low tumor-to-blood and tumor-to-normal organ ratios of absorbed radioactivity limit the dose that can be safely administered without hematopoietic stem cell support. This study assessed the ability of a streptavidin-biotin "pretargeting" approach to improve the biodistribution of radioactivity in mice bearing Ramos lymphoma xenografts. A pretargeted streptavidin-conjugated anti-CD20 1F5 antibody was infused, followed 24 hours later by a biotinylated N-acetylgalactosamine-containing "clearing agent" and finally 3 hours later by (111)In-labeled DOTA-biotin. Tumor-to-blood ratios were 3:1 or more with pretargeting, compared with 0.5:1 or less with conventional (111)In-1F5. Tumor-to-normal organ ratios of absorbed radioactivity up to 56:1 were observed with pretargeting, but were 6:1 or less with conventional (111)In-1F5. Therapy experiments demonstrated that 400 microCi (14.8 MBq) or more of conventional (90)Y-1F5 was required to obtain major tumor responses, but this dose was associated with lethal toxicity in 100% of mice. In marked contrast, up to 800 microCi (29.6 MBq) (90)Y-DOTA-biotin could be safely administered by the pretargeting approach with only minor toxicity, and 89% of the mice were cured. These data suggest that anti-CD20 pretargeting shows great promise for improving current therapeutic options for B-cell lymphomas and warrants further preclinical and clinical testing.
authors.affiliation: Fred Hutchinson Cancer Research Center, Department of Medicine, University of Washington, Seattle, WA 98109, USA. press@u.washington.edu
authors.forename: O W
authors.initials: OW
authors.lastname: Press
authors.forename: M
authors.initials: M
authors.lastname: Corcoran
authors.forename: K
authors.initials: K
authors.lastname: Subbiah
authors.forename: D K
authors.initials: DK
authors.lastname: Hamlin
authors.forename: D S
authors.initials: DS
authors.lastname: Wilbur
authors.forename: T
authors.initials: T
authors.lastname: Johnson
authors.forename: L
authors.initials: L
authors.lastname: Theodore
authors.forename: E
authors.initials: E
authors.lastname: Yau
authors.forename: R
authors.initials: R
authors.lastname: Mallett
authors.forename: D L
authors.initials: DL
authors.lastname: Meyer
authors.forename: D
authors.initials: D
authors.lastname: Axworthy
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D018951:Antigens, CD20 / Q000276:immunology*; D004195:Disease Models, Animal; D006801:Humans; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016393:Lymphoma, B-Cell / Q000532:radiotherapy*; D051379:Mice; D008819:Mice, Nude; D016499:Radioimmunotherapy / Q000379:methods*; D015996:Survival Rate; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D018951:Antigens, CD20; D007457:Iodine Radioisotopes