Aussie researchers find chink in AML

Data demonstrating the promising pre-clinical activity of a novel monoclonal antibody in the potential treatment of acute myeloid leukemia (AML), have been published in the international journal Cell Stem Cell.

The novel antibody specifically targets the leukemic stem cell (LSC), which was first identified in the laboratory of Professor John Dick, senior scientist in the Division of Cellular and Molecular Biology at the Toronto General Research Institute, who is one of the key authors of the study.

It is currently thought that the resistance of leukemic stem cells to chemotherapy is a major reason for the inability to cure most AML, and that improving the outlook for patients with AML will require elimination of these cells.

The antibody used in the research, 7G3, was first created by Professor Angel Lopez at the Hanson Centre for Cancer Research in Adelaide, and is being developed further in conjunction with biopharmaceutical company, CSL.

It hones in on CD123 (IL-3 receptor alpha chain) on the surface of the LSC, blocking its function, growth and survival. CD123 is found on the surface of normal blood stem cells much less frequently, and 7G3 should therefore have no effect on normal blood cell development.

The published research paper, describes the results of treatment with 7G3 of irradiated immune-deficient (NOD-SCID) mice with AML.

Two central experiments were undertaken: firstly human AML stem cells were treated with 7G3 and then injected into the mice, which were compared with a control group of mice injected with untreated AML stem cells. The overall survival of treated engrafted mice was significantly improved with the median survival of control group 11.5 weeks versus 24 weeks for the antibody-treated group.

Secondly, 7G3 was administered to mice with established AML. Administration of the antibody to these mice reduced AML dissemination around the body of the mice. The ability of leukaemic stem cells from mice treated in this way to reestablish leukemia as secondary transplants into other animals was markedly reduced.

In contrast, exposure to 7G3 had little effect on normal human bone marrow stem cells.

“These results show that 7G3 is able to target LSCs to prevent them from moving around and proliferating in the mice, while at the same time having little effect on normal blood cells,” Associate Professor Richard Lock at Sydney’s Children’s Cancer Institute Australia for Medical Research, corresponding author for the study, said today.

“This is a very exciting finding because this is one of the first approaches that has been designed to specifically target the LSC, rather than simply attacking the cancer cells proliferating in the blood and bone marrow. Hopefully this means that we can fight leukaemia without many of the side effects of current chemotherapy. This research opens up many exciting new avenues for clinical drug development for the treatment of AML,” he said.

The authors wish to acknowledge the contribution of the University Health Network in Toronto, Canada, The Institute of Medical and Veterinary Science Centre for Cell Biology in South Australia, Children’s Cancer Institute Australia for Medical Research in Sydney, Australia , Queensland Institute for Medical Research, Australia and CSL Limited, key collaborators in this important project.