Photo courtesy of the
University of California Davis
Researchers say they have developed a targeted conjugate therapy that harnesses a monoclonal antibody to deliver antisense DNA to acute lymphoblastic leukemia (ALL) cells.
Once delivered, the therapeutic DNA reduces levels of MXD3, a protein that helps cancer cells survive.
This conjugate therapy proved cytotoxic in ALL cell lines and showed promise in animal models, destroying ALL cells while limiting other damage.
“We’ve shown, for the first time, that anti-CD22 antibody-antisense conjugates are a potential therapeutic agent for ALL,” said Noriko Satake, MD, of the University of California Davis in Sacramento.
“This could be a new type of treatment that kills leukemia cells with few side effects.”
Dr Satake and her colleagues described the treatment in Molecular Medicine.
To create the therapy, the researchers attached antisense DNA that inhibits the MXD3 protein to an antibody that binds to CD22, a protein receptor expressed almost exclusively on ALL cells and normal B cells.
Once the antibody binds to CD22, the conjugate is drawn inside the cell, allowing the antisense molecule to prevent MXD3 production. Without this anti-apoptotic protein, cells are more prone to death.
The conjugate therapy was effective against ALL cell lines and primary ALL cells in a xenograft mouse model. Animals that received the therapy survived significantly longer than those in the control group.
While the conjugate therapy does target healthy B cells along with ALL cells, it is expected to leave hematopoietic stem cells and other tissues unharmed.
“Our novel conjugate is designed so that it does not harm hair, eyes, heart, kidneys, or other types of cells,” Dr Satake said.
She and her colleagues noted that, although this study shows the conjugate therapy can knock down MXD3, it is not clear exactly how this is accomplished. So the researchers plan to investigate the mechanism.
The team also plans to look into combining the conjugate therapy with other treatments. Because it hastens cell death, the conjugate could make traditional chemotherapy drugs more effective, and it might work against other cancers.
“You can see this as proof of principle,” Dr Satake said. “You could switch the target and substitute the antibody, which could be used to treat other cancers or even other diseases.”
This study was not industry-funded, but 4 study authors are employees and stockholders of Isis Pharmaceuticals.
