Image by Joshua Stokes
Scientists say they have discovered an antibody that can transform leukemic cells into immune cells that target their former “siblings.”
This agonist antibody, which is highly specific for the thrombopoietin receptor, can turn acute myeloid leukemia (AML) cells into dendritic cells.
With extended exposure to the antibody, these dendritic cells can then transform into natural killer (NK)-like cells that target AML cells.
The scientists described these discoveries in PNAS.
“It’s a totally new approach to cancer, and we’re working to test it in human patients as soon as possible,” said study author Richard A. Lerner, MD, of The Scripps Research Institute in La Jolla, California.
Unexpected transformation
Dr Lerner’s lab has pioneered techniques to generate and screen large libraries of antibodies to find therapeutic antibodies that bind to a desired target or activate a desired receptor on cells.
During the course of this work, the team discovered a phenomenon they call “receptor pleiotropism,” in which agonist antibodies against known receptors cause cell fates that are extremely different from those induced by the natural agonist to the receptor.
Why this happens is unclear, but the discovery led the scientists to wonder if they could use the method to convert leukemia cells into non-cancerous cells.
To find out, they tested 20 of their recently discovered receptor-activating antibodies against AML cells from patients. This revealed the transformative properties of the agonist antibody that is highly specific for the thrombopoietin receptor.
When this antibody was applied to healthy, immature bone marrow cells, it caused them to mature into megakaryocytes. However, when the antibody was applied to AML cells, they were converted into dendritic cells.
With longer exposures to the antibody and certain other in vitro conditions, the induced dendritic cells morphed into cells that closely resemble NK cells.
“That antibody could have turned those acute myeloid leukemia cells into a lot of other cell types, but, somehow, we were lucky enough to get NK cells,” Dr Lerner said.
The team examined these induced NK cells with electron microscopy and observed that many of the cells had extended tendrils through the outer membranes of neighboring AML cells. In in vitro tests, a modest number of these NK cells wiped out about 15% of the surrounding AML cell population in 24 hours.
The scientists also noted that the induced NK cells’ cancer-killing effects appeared to be purely “fratricidal.” Unrelated breast cancer cells did not die off in large numbers in the presence of the NK cells.
Fratricidin therapy
Why the induced NK cells appear to target only closely related cells isn’t yet clear. However, the finding suggests there may be antibodies—and even small-molecule compounds—that would turn other cancerous cell types into fratricidal NK cells by activating other receptors expressed on those cells.
Such fratricidal therapies, which Dr Lerner calls “fratricidins,” would have several potential advantages. First, especially if they are antibodies, they could be clinically useful with little or no further modification.
Second, their high specificity for their target receptors, and the resulting NK cells’ specificity for related cancer cells, should reduce the likelihood of adverse effects.
Finally, the peculiar dynamics of fratricidin therapy, in which every cancerous cell is potentially convertible to a cancer-killing NK cell, suggests that—if the strategy works—it might not just reduce the targeted cancer-cell population in a patient but eliminate it altogether.
“We’re in discussions with pharmaceutical companies to take this straight into humans after the appropriate preclinical toxicity studies,” Dr Lerner said.
This research was supported by the JPB Foundation and Zebra Biologics.
