This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Buchsbaum, D. J. Articles by Kaminski, M. S. Search for Related Content PubMed PubMed Citation Articles by Buchsbaum, D. J. Articles by Kaminski, M. S.

Improved Delivery of Radiolabeled Anti-B1 Monoclonal Antibody to Raji Lymphoma Xenografts by Predosing with Unlabeled Anti-B1 Monoclonal Antibody¹

Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama 35233 [D. J. B.]; Department of Internal Medicine [R. L. W., M. S. K.], and Department of Radiology [R. L. W.], Medical School, and Department of Biostatistics [D. P. N.], School of Public Health, University of Michigan, Ann Arbor, Michigan 48109; and Coulter Immunology, Division of Coulter Corporation, Hialeah, Florida, 33010 [S. D. G.]

A human B-cell lymphoma xenograft model was used to test whether the administration of unlabeled MoAb prior to injection of radiolabeled monoclonal antibody (MoAb) improves delivery of the radiolabeled MoAb to tumor prior to testing in clinical radioimmunotherapy trials. The anti-B1/CD20 pan-B-cell MoAb reactive with human B-cell lymphomas and leukemias but not reactive with mouse B-cells was used in this study. Athymic nude mice bearing human Raji Burkitt lymphoma xenografts were given injections of 2.5 µCi (0.3 µg) ¹³¹I-labeled anti-B1 with or without a 2-h prior single injection of 100 µg of unlabeled anti-B1 antibody. Four days later the animals given injections of ¹³¹I-labeled anti-B1 and the unlabeled anti-B1 predose had a tumor uptake of 12.72 ± 1.17% (SEM) of injected dose/g which was 44% greater than the animals receiving the ¹³¹I-labeled anti-B1 alone (P = 0.014). The uptake in most normal tissues was unchanged, although the blood level of ¹³¹I-labeled anti-B1 appeared to be greater following unlabeled anti-B1 predosing (P = 0.067). Predosing with isotype matched irrelevant MoAb did not result in a greater tumor uptake or blood concentration of ¹³¹I-labeled anti-B1 compared to the administration of ¹³¹I-labeled anti-B1 alone.

In studies using ¹¹¹In-labeled anti-B1, the effect of unlabeled antibody predosing was more pronounced. For animals given injections of 4.5 µCi (0.4 µg) ¹¹¹In-labeled anti-B1 and the unlabeled anti-B1 predose, the uptake in tumor was 12.37 ± 2.07% of injected dose/g which was 162% greater than the animals receiving the ¹¹¹In-labeled anti-B1 alone (P = 0.009). Predosing decreased ¹¹¹In-labeled anti-B1 uptake in spleen, while the blood level was significantly greater.

Predosing was more effective than simultaneous injection in improving tumor delivery. When tumor-bearing mice were either simultaneously given injections of 36 µg of unlabeled anti-B1 and 4 µg ¹¹¹In-labeled anti-B1 or were given preinjections of 36 µg unlabeled anti-B1 3 h prior to injection of 4 µg ¹¹¹In-labeled anti-B1, tumor uptake 3 days later was 1.3-fold higher in the animals which received the preinjection of unlabeled antibody (P = 0.011). As the quantity of unlabeled anti-B1 was increased (36, 96, 996 µg) in the predose, significantly greater uptake in tumor was observed, although this uptake appeared to plateau at the highest predoses. This was accompanied by an increase in ¹¹¹In-labeled anti-B1 in blood and a decrease in uptake in the spleen.

It thus appears that unlabeled pan-B-cell MoAb predosing results in superior targeting of subsequently administered radiolabeled anti-B1 MoAb to tumor. Since it is unlikely that free antigen or tumor cells are present in the circulation in this animal model, it appears that blocking of specific anti-B1 Fc receptor sites by unlabeled anti-B1 predosing is involved in the enhanced tumor uptake. These results may have significant impact on the way in which radiolabeled pan-B-cell MoAbs should be delivered in clinical trials.

¹ This investigation was supported by National Cancer Institute Grants P01 CA42768 and R01 CA43368.

² To whom requests for reprints should be addressed, at Department of Radiation Oncology, University of Alabama at Birmingham, 619 South 19th Street, Birmingham, AL 35233-6832.

Received 6/ 6/91. Accepted 11/11/91.

This article has been cited by other articles:

				N. S. Kapadia, J. M. Engles, and R. L. Wahl In Vitro Evaluation of Radioprotective and Radiosensitizing Effects of Rituximab J. Nucl. Med., April 1, 2008; 49(4): 674 - 678. [Abstract] [Full Text] [PDF]

				R. L. Wahl Tositumomab and 131I Therapy in Non-Hodgkin's Lymphoma J. Nucl. Med., January 1, 2005; 46(1_suppl): 128S - 140S. [Abstract] [Full Text] [PDF]

				R. M. Sharkey, A. Brenner, J. Burton, G. Hajjar, S. P. Toder, A. Alavi, A. Matthies, D. E. Tsai, S. J. Schuster, E. A. Stadtmauer, et al. Radioimmunotherapy of Non-Hodgkin's Lymphoma with 90Y-DOTA Humanized Anti-CD22 IgG (90Y-Epratuzumab): Do Tumor Targeting and Dosimetry Predict Therapeutic Response? J. Nucl. Med., December 1, 2003; 44(12): 2000 - 2018. [Abstract] [Full Text] [PDF]

				R. B. Michel, R. Ochakovskaya, and M. J. Mattes Antibody Localization to B-Cell Lymphoma Xenografts in Immunodeficient Mice: Importance of Using Residualizing Radiolabels Clin. Cancer Res., August 1, 2002; 8(8): 2632 - 2639. [Abstract] [Full Text] [PDF]

				A. Goel, S. Augustine, J. Baranowska-Kortylewicz, D. Colcher, B. J. M. Booth, G. Pavlinkova, M. Tempero, and S. K. Batra Single-Dose versus Fractionated Radioimmunotherapy of Human Colon Carcinoma Xenografts Using 131I-labeled Multivalent CC49 Single-chain Fvs Clin. Cancer Res., January 1, 2001; 7(1): 175 - 184. [Abstract] [Full Text]

				T. M. Illidge, M. S. Cragg, H. M. McBride, R. R. French, and M. J. Glennie The Importance of Antibody-Specificity in Determining Successful Radioimmunotherapy of B-Cell Lymphoma Blood, July 1, 1999; 94(1): 233 - 243. [Abstract] [Full Text] [PDF]