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Blood, 15 October 2001, Vol. 98, No. 8, pp. 2535-2543
NEOPLASIA
A comparative evaluation of conventional and pretargeted
radioimmunotherapy of CD20-expressing lymphoma xenografts
Oliver W. Press,
Melissa Corcoran,
Krishnan Subbiah,
Don K. Hamlin,
D. Scott Wilbur,
Timothy Johnson,
Louis Theodore,
Eric Yau,
Robert Mallett,
Damon L. Meyer, and
Don Axworthy
From the Fred Hutchinson Cancer Research Center, the
Departments of Medicine, Biological Structure, and Radiation Oncology
of the University of Washington, and NeoRx, Seattle, WA.
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 111In-labeled DOTA-biotin. Tumor-to-blood
ratios were 3:1 or more with pretargeting, compared with 0.5:1 or less
with conventional 111In-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 111In-1F5. Therapy
experiments demonstrated that 400 µCi (14.8 MBq) or more of
conventional 90Y-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 µCi (29.6 MBq)
90Y-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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