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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