A new monoclonal antibody that can treat leukaemia and a few solid tumours, like ovarian cancer, is a step closer. Leukaemia is largely incurable in adults. This is because the cancer-associated proteins — the target of monoclonal antibodies — are safely secured inside cells, and are beyond the reach of currently available drugs.
But according to the results published today (March 14) in Science Translational Medicine journal, researchers have found a way to overcome this hurdle and destroy the cancer cells.
Wilms tumour 1 (WT1) is a cancer protein that is over-expressed in leukaemia. Though found inside cancer cells, there is a chink in WT1’s armour — the degraded fragments of WT1 become present on the surface of the cells. In effect, WT1 becomes a biomarker for leukaemia and other cancers.
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The researchers developed a monoclonal antibody — ESK1— that “recognizes” a peptide fragment of WT1 (RMF) that forms a complex with human leukocyte antigen (HLA A0201).
The antibody’s ability to bind to leukaemia cells — an essential requirement of a therapeutic drug — was tested. It passed the first test — ESK1 was able to bind to WT1 cell lines as well as fresh leukaemia cells taken from patients.
They then progressed to the next stage by testing the antibody’s ability to destroy leukaemia cells in mice. Human acute lymphoblastic leukaemia was first grafted into the mice. A two-pronged approach was adopted to test the therapeutic potential. The monoclonal antibody was either injected alone or combined with “effector” cells (peripheral blood natural killer cells) to improve the binding ability.
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The therapeutic effect was prominently seen in both the approaches, but only one achieved the set goal of improved long-term outcomes and prolonged survival. At the end of 70 days, the tumour burden “markedly reduced” in the mice when the monoclonal antibody drug was given. But as expected, leukaemia relapsed “more quickly” as residual leukaemia cells were present in the mice even at the time of completion of the treatment.
So the researchers tested its ability to “clear” the leukaemia cells completely so it never relapsed. This was done by injecting two doses of the drug using three different strengths. Leukaemia still relapsed, though “slowly” after the treatment was stopped. The relapse time depended on the dosage.
In the second approach, the drug combined with the effector was tested. The animals had “little leukaemia” on the 70 day when treatment was stopped. “One of five mice had still not relapsed,” they write.
The drug was tested for toxicity in transgenic mice. “No evidence of toxicity” was seen when the mice were injected with the same dose as used for testing the drug’s therapeutic potential.
According to the authors, more than one million cancer patients worldwide have WT1+ tumour or leukaemia. Of this huge population, nearly one third who have the HLA-A02 haplotype will stand to benefit. This means that the ESK1 antibody will have a large clinical impact if successful in clinical trials.