Feature: Antibody attack on acute myeloid leukaemia

By Susan Willamson

Dr Samantha Busfield, Principal Scientist with CSL in Melbourne, is working on CSL’s newly developed anti-interleukin-3 (IL3) receptor antibody, which is in development with the hope that it will provide a new treatment option for patients with acute myeloid leukaemia (AML), a cancer of the blood and bone marrow characterised by the rapid growth of abnormal immature white blood cells or myeloid cells.

“In patients with this disease, myeloid leukaemic cells circulate in the blood and a large bulk of them reside in the bone marrow, which is where they initiate and continually generate,” says Busfield. “This accumulation of abnormal cells in the bone marrow interferes with the production of normal white blood cells.”

AML is the most common acute leukaemia in adults. The disease is fast-acting and about two months after diagnosis the bone marrow has been taken over, which leads to anaemia, a proneness to infection and bleeding or bruising due to a low platelet count. If left untreated it is fatal. In the US about 12,000 new patients are identified each year, and about 9000 patients with AML die per year. The overall survival rate is about 21 per cent, however, if patients are over 65 years of age their survival rate is about 5 per cent.

Treatment for AML is limited. Chemotherapy and bone-marrow transplant are the standard of care, but many patients do not tolerate high-dose chemotherapy very well because of their age.

The IL3 receptor alpha chain (also known as CD123) is expressed on committed blood progenitor cells in the bone marrow, where it mediates IL-3-induced proliferation, survival and differentiation. CD123 is also expressed in a variety of blood cell malignancies including AML. The majority of AML cells express high levels of CD123 on their cell surface, which is associated with increased leukemic cell proliferation and poor clinical prognosis.

Recently, CD123 was also shown to be expressed on a small subset of leukaemia cells that are resistant to chemotherapy and are able to maintain and reinitiate AML following treatment. These cells have been termed leukaemic stem cells (LSCs).

In contrast to the high level of CD123 expression on LSCs there is very low or undetectable CD123 expression on normal (non-cancerous) stem cells. Targeting LSCs has become a major goal in developing new treatments for AML and CD123 provides an attractive target option for an antibody therapeutic because of its differential expression on normal and leukemic cells.

CSL has been working for several years with an anti-CD123 antibody, originally generated by Professor Angel Lopez in Adelaide in the late 1990s. After licensing the mouse monoclonal antibody from Lopez, a chimeric version of it, called CSL360, was put through a phase I trial that was conducted in six hospitals across Australia.

The antibody specifically targets the alpha chain of the IL3 receptor and is able to inhibit IL-3-mediated activities. The phase I trial results indicated that the antibody was safe and well-tolerated, but neutralisation of IL-3 was not sufficient to provide a therapeutic effect in patients who took part in the trial.

Over the last two years, Busfield and colleagues have been working on improving the ability of the antibody to interact with the immune system and recruit natural killer (NK) cells, which can mediate lysis and death of the tumour cells – so-called antibody-dependent cellular cytotoxicity (ADCC).

“We have engineered the antibody to increase its affinity to receptors on NK cells,” says Busfield. “We are evaluating the antibody pre-clinically and will take it through to further clinical trials.”

The new antibody, called CSL362, retains the same specificity and neutralising ability as CSL360, but has a greater capacity to elicit ADCC. Data from in vitro experiments and xenograft mouse models have demonstrated that CSL362 is substantially more cytotoxic than the original CSL360. A planned phase I trial will be conducted in patients with AML and will examine the antibody’s safety and tolerability.

“Not many advancements have been made over the last 30 years in treating this disease,” says Busfield. “The ultimate aim of this work is to target the LSCs, thus the tumours will be prevented from regenerating and we will have an effective treatment for this disease.”

This feature appeared in the September/October 2010 issue of Australian Life Scientist. To subscribe to the magazine, go here.