HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH RSS TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Figures Only Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend 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 Google Scholar Google Scholar Articles by Mitchell, P. Articles by Scott, A. M. Search for Related Content PubMed PubMed Citation Articles by Mitchell, P. Articles by Scott, A. M.

Targeting Primary Human Ph⁺ B-Cell Precursor Leukemia-Engrafted SCID Mice Using Radiolabeled Anti-CD19 Monoclonal Antibodies

¹ Ludwig Medical Oncology Unit, Ludwig Institute For Cancer Research, Melbourne Tumour Biology Branch, Austin and Repatriation Medical Centre, Melbourne, Victoria, Australia
² Tumour Targeting Program, Ludwig Institute For Cancer Research, Melbourne Tumour Biology Branch, Austin and Repatriation Medical Centre, Melbourne, Victoria, Australia
³ Department of Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
⁴ Sanquin Research and Landsteiner Laboratory, University of Amsterdam, Amsterdam, The Netherlands
⁵ Leukemia Unit, Royal Marsden Hospital, Surrey, United Kingdom
⁶ Radioimmune and Inorganic Chemistry Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
⁷ Department of Nuclear Medicine and Centre for PET, Austin and Repatriation Medical Centre, Melbourne, Victoria, Australia

The Philadelphia chromosome translocation (Ph⁺) confers a poor prognosis in patients with acute lymphocytic leukemia (ALL). CD19 is highly expressed (CD19⁺) on ALL cells and is an attractive target for antibody-based therapies. CLB-CD19 is an IgG1 murine monoclonal antibody (mAb) directed against an epitope on the CD19 antigen. Methods: Radiolabeled CLB-CD19 antibody was evaluated for targeting ALL in a severe combined immunodeficient (SCID) mouse model engrafted with primary human leukemia cells. Lodgment of CD19⁺ ALL cells in spleen and liver was confirmed using immunohistochemistry analyses. Circulating CD19⁺ ALL cells in blood were also detected by flow cytometry. Results: Antibody was labeled directly with the radiohalogen ¹²⁵I and radiometal ¹¹¹In via the bifunctional metal ion chelate CHX-A''-diethylenetriaminepentaacetic acid (DTPA) with retention of immunoreactivities. After intravenous injection of radioconjugates, biodistribution studies showed rapid localization of the ¹¹¹In-conjugate to leukemia-infiltrated spleen, reaching a maximum (mean ± SD) of 72.78 ± 13.67 % injected dose per gram of tissue (%ID/g) by 24 h after injection. In contrast, peak localization of coinjected ¹²⁵I-CLB-CD19 occurred by 4 h and was significantly lower (11.41 ± 12.79 %ID/g) (P < 0.001). Uptake of ¹¹¹In-conjugate in the liver containing tumor was also evident but not in other normal tissues. Uptake of radiolabeled CLB-CD19 in tumor-bearing organs was specific, as uptake of radiolabeled isotype-matched antibody control was low. Gamma-camera imaging detected the uptake of ¹¹¹In-CHX-A''-DTPA CLB-CD19 in enlarged tumor-bearing spleen of engrafted mice. A single injection of 32 µg CLB-CD19 mAb had a delayed suppressive effect on the level of circulatory leukemia cells in surviving mice and extended the median survival from 48.5 to 58 d (n = 8; P = 0.03). Conclusion: The radiolabeled anti-CD19 antibody showed specific targeting and rapid internalization in ALL cell–engrafted SCID mice and may also be used for selective intracellular delivery of cytotoxic radionuclides with ß-, Auger, or -emissions.

Key Words: monoclonal antibody • CD19 • Philadelphia chromosome–positive acute lympoblastic leukemia • severe combined immunodeficient mouse strain