Image by Lance Liotta
New research appears to explain how antibodies that target CD44 fight acute myeloid leukemia (AML).
Previous research showed that anti-CD44 antibodies inhibit proliferation and induce differentiation in AML, but it wasn’t clear how or why this happens.
The new study suggests anti-CD44 antibodies work by inhibiting 2 “major players” of the PI3K/Akt/mTOR pathway—mTORC1 and mTORC2.
Jasmeen Merzaban, PhD, of King Abdullah University of Science and Technology in Thuwal, Saudi Arabia, and her colleagues described this discovery in a letter to Leukemia.
The researchers tested an anti-CD44 antibody known as A3D8 in cell lines representing different AML subtypes (HL60, THP-1, and KG1a) as well as a mouse model of AML.
In these experiments, A3D8 inhibited proliferation and induced differentiation in AML cells. This was accompanied by a decrease in phosphorylation of the mTORC1 and mTORC2 complexes, which was strongly correlated with inhibition of the PI3K/Akt pathway.
The researchers said this finding is important because a complete shutdown of mTOR signaling is probably needed to disrupt the multiple feedback loops that can fuel AML growth, and drugs that only inhibit one of these complexes have, in the past, failed to demonstrate a therapeutic benefit for patients with AML.
“A growing body of evidence suggests that a broader inhibitor would result in a more potent therapeutic effect,” Dr Merzaban said.
She and her colleagues believe an anti-CD44 antibody like A3D8 might just be that type of inhibitor.
They also noted that A3D8 was able to induce differentiation in different subtypes of AML and did not seem to present any toxicity issues.
“We show that the anti-CD44 antibody used for our studies had no effect on normal blood cells,” said Samah Gadhoum, PhD, a research scientist in Dr Merzaban’s lab.
“However, more work is needed to carefully determine the effect of these antibodies on other cells and other cellular functions within the body.”
The researchers are now conducting follow-up experiments, but they believe their results support the use of anti-CD44 antibodies to treat different types of AML.
