A comparative evaluation of conventional and pretargeted radioimmunotherapy of CD20-expressing lymphoma xenografts.
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.
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Fred Hutchinson Cancer Research Center, Department of Medicine, University of Washington, Seattle, WA 98109, USA. press@u.washington.edu
Corcoran
M
M
Subbiah
K
K
Hamlin
D K
DK
Wilbur
D S
DS
Johnson
T
T
Theodore
L
L
Yau
E
E
Mallett
R
R
Meyer
D L
DL
Axworthy
D
D
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
D000911:Antibodies, Monoclonal; D018951:Antigens, CD20; D007457:Iodine Radioisotopes