Binding of CD33 antibody and CD33 antibody chelator-conjugate to CD33-positive HL-60 cells by FACS staining in comparison to an isotype control. Bound antibodies were detected using secondary PE-labeled anti-human antibody. Median fluorescence intensity (MFI) was recorded and plotted against antibody concentrations. EC50 values were determined by fitting data using Graph Pad software.
ARTICLE ABSTRACT
The clinical efficacy of the first approved alpha pharmaceutical, Xofigo (radium-223 dichloride, 223RaCl2), has stimulated significant interest in the development of new alpha-particle emitting drugs in oncology. Unlike radium-223 (223Ra), the parent radionuclide thorium-227 (227Th) is able to form highly stable chelator complexes and is therefore amenable to targeted radioimmunotherapy. We describe the preparation and use of a CD33-targeted thorium-227 conjugate (CD33-TTC), which binds to the sialic acid receptor CD33 for the treatment of acute myeloid leukemia (AML). A chelator was conjugated to the CD33-targeting antibody lintuzumab via amide bonds, enabling radiolabeling with the alpha-emitter 227Th. The CD33-TTC induced in vitro cytotoxicity on CD33-positive cells, independent of multiple drug resistance (MDR) phenotype. After exposure to CD33-TTC, cells accumulated DNA double-strand breaks and were arrested in the G2 phase of the cell cycle. In vivo, the CD33-TTC demonstrated antitumor activity in a subcutaneous xenograft mouse model using HL-60 cells at a single dose regimen. Dose-dependent significant survival benefit was further demonstrated in a disseminated mouse tumor model after single dose injection or administered as a fractionated dose. The data presented support the further development of the CD33-TTC as a novel alpha pharmaceutical for the treatment of AML. Mol Cancer Ther; 15(10); 2422–31. ©2016 AACR.
