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Biodistribution and Dosimetry following Infusion of Antibodies Labeled with Large Amounts of ¹³¹I¹

Division of Clinical Research, Fred Hutchinson Cancer Research Center [C. C. B., J. D., C. N., Z. M. W., H. S., F. R. A., D. C. M., I. D. B.], Seattle, Washington 98104; Departments of Medicine [C. C. B., F. R. A.], Pathology [H. S.], Radiology [J. F. E., K. A. K.], and Pediatrics [D. C. M., I. D. B.], University of Washington, Seattle, Washington 98195; and Battelle Pacific Northwest Laboratories [T. E. H., D. R. F.], Richland, Washington 99352

Dosimetry and treatment planning for therapeutic infusions of radiolabeled antibodies are usually performed by extrapolation from the biodistribution of trace-labeled antibody. This extrapolation assumes that the biodistribution of high specific activity antibody will be similar to that seen with trace-labeled antibody. However, high doses of radiation result in rapid depletion of lymphoid and hematopoietic cells in lymph nodes, spleen, and marrow with replacement by blood and plasma. If radiolabeled antibody is cleared slowly from blood, this replacement may result in increased radionuclide concentrations in these tissues following infusions of antibody labeled with large amounts of radionuclide.

To examine the influence of deposited radiation on the biodistribution of radiolabeled antibody, we treated mice with a constant amount of antibody that was labeled with varying amounts of ¹³¹I. Survival was determined in normal specific pathogen-free AKR/Cum mice (Thy1.2+) after infusion of anti-Thy1.1 antibody labeled with 10 to 6500 µCi of ¹³¹I, to determine an appropriate range of ¹³¹I doses for further study. The dose producing 50% lethality within 30 days following infusion of ¹³¹I-labeled antibody was 530 µCi ¹³¹I. Biodistribution, bone marrow histology, and dosimetry were subsequently determined after infusion of 500 µg of antibody labeled with 10, 250, 500, or 3500 µCi ¹³¹I. The amount of ¹³¹I did not influence uptake or retention of antibody in blood, liver, lung, or kidney. In contrast, infusion of antibody labeled with 250 to 3500 µCi of ¹³¹I led to a dose-related increase in the concentration of ¹³¹I in marrow, spleen, lymph node, and thymus. For example, at 96 h after infusion of antibody labeled with 500 or 3500 µCi ¹³¹I, concentrations in marrow were 3- to 4-fold higher than after infusion of trace-labeled antibody. The increase in marrow ¹³¹I concentrations was associated with depletion of cells and hemorrhage within the marrow space. As a result, estimated mean absorbed doses to marrow, lymph node, spleen, and thymus were 1.2 to 3.1 times higher than would have been predicted from the biodistribution of trace-labeled antibody.

These results suggest that the biodistribution of trace-labeled antibody should be an accurate predictor of the behavior of high specific activity antibody in blood and solid organs such as liver and kidney. In contrast, radiation from antibody labeled with large amounts of radionuclide can result in an alteration of the concentration of radiolabeled antibody in rapidly responding tissues such as marrow. For this reason, in situations in which radiolabeled antibody remains in serum for a prolonged period (many hours to days), extrapolation from the biodistribution of trace-labeled antibody may underestimate the absorbed dose to marrow following infusion of antibody labeled with higher amounts of radionuclide.

¹ This study was supported by Grant CA26386 from the National Cancer Institute, Department of Health and Human Services, and was presented in part at the 80th Annual Meeting of the American Association for Cancer Research, San Francisco, CA, 1989.

² To whom requests for reprints should be addressed, at Fred Hutchinson Cancer Research Center, 1124 Columbia Street, Seattle, WA 98104.

Received 6/ 4/91. Accepted 8/16/91.

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