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

Journal of Nuclear Medicine

Fook-Thean Lee¹  Fiona E. Smyth¹  Gijs M. van Schijndel¹  Angela Rigopoulos¹  Anne-Marie Hekman¹  Martin W. Brechbiel¹  Ray Powles¹  Cathrine Hall¹  Andrew M. Scott¹  Paul Mitchell¹ 

关键词: monoclonal antibody;    CD19;    Philadelphia chromosome–positive acute lympoblastic leukemia;    severe combined immunodeficient mouse strain;   

DOI  :  

学科分类：医学（综合）

来源: Society of Nuclear Medicine

【 摘 要 】

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 IgG1κ 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 β-, Auger, or α-emissions.

【 授权许可】

Unknown