In vitro and in vivo efficacy of a novel CD33 targeted thorium-227 conjugate for the treatment of acute myeloid leukemia

The clinical efficacy of the first approved alpha pharmaceutical, Xofigo (radium-223 dichloride, 223 RaCl 2 ), has stimulated significant interest in the development of new alpha-particle emitting drugs in oncology. Unlike radium-223 ( 223 Ra), the parent radionuclide thorium-227 ( 227 Th) 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 227 Th. 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 G 2 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 .