CD33- targeted thorium-227 conjugate

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 (RIT). 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 anti-tumor 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.

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