A hybrid treatment is being developed by researchers at UC Davis and Ionis Pharmaceuticals, that harnesses a monoclonal antibody to deliver antisense DNA to acute lymphoblastic leukemia (ALL) cells and that may lead to less toxic treatments for the disease.
The study, published in the journal Molecular Medicine, demonstrated that once delivered, the therapeutic DNA reduced levels of MXD3, a protein that helps cancer cells survive. This novel conjugate therapy showed great promise in animal models, destroying ALL cells while limiting other damage.
‘Acute lymphoblastic leukemia is the most common type of childhood cancer in which the bone marrow makes too many immature lymphocytes, a type of white blood cell.’
Advertisement"We've shown, for the first time, that anti-CD22 antibody-antisense conjugates are a potential therapeutic agent for ALL," said Noriko Satake, associate professor in the Department of Pediatrics at UC Davis. "This could be a new type of treatment that kills leukemia cells with few side effects."
ALL is the most common type of childhood cancer. It is a disease in which the bone marrow makes too many immature lymphocytes, a type of white blood cell. While most children survive ALL, many patients suffer late or long-term side effects from treatment, which may include heart problems, growth and development delays, secondary cancers and infertility.
Antisense oligonucleotides are single strands of DNA that can bind to messenger RNA, preventing it from making a protein. While antisense technology has long shown therapeutic potential, getting the genetic material inside target cells has been a problem. In the study, researchers attached antisense DNA that inhibits the MXD3 protein to an antibody that binds to CD22, a protein receptor expressed almost exclusively in ALL cells and normal B cells.
Once the antibody binds to CD22, the conjugate is drawn inside the leukemia cell, allowing the antisense molecule to prevent MXD3 production. Without this anti-apoptotic protein, ALL cells are more prone to cell death. The hybrid treatment was effective against ALL cell lines in vitro and primary (patient-derived) ALL cells in a xenograft mouse model. Animals that received the hybrid therapy survived significantly longer than those in the control group.
Designed to be selective, the treatment only targets cells that express CD22. While it does attack healthy B cells, the therapy is expected to leave blood stem cells and other tissues unscathed. "You really don't want to destroy hematopoietic stem cells because then you have to do a stem cell transplant, which is an extremely intensive therapy," noted Satake. "Our novel conjugate is designed so that it does not harm hair, eyes, heart, kidneys or other types of cells."
While the study shows the conjugate knocked down MXD3, researchers still have to figure out how this was accomplished. In addition, they will investigate combining this treatment with other therapies. Because it hastens cell death, the conjugate could make traditional chemotherapy drugs more effective. In addition, the approach might work against other cancers.
"You can see this as proof of principle," Satake said. "You could switch the target and substitute the antibody, which could be used to treat other cancers or even other diseases." Other authors included Connie Duong, Sakiko Yoshida, Cathy Chen, Yueju Li, Laurel Beckett, Jong Chung, Jan Nolta, Nitin Nitin and Joseph Tuscano, all of UC Davis, and Michael Oestergaard, Rachael Peralta, Shuling Guo and Punit Seth at Ionis Pharmaceuticals.
This research was supported by The Hartwell Foundation, Keaton Rafael Memorial Foundation, National Center for Advancing Translational Sciences, the California Institute for Regenerative Medicine and the National Institutes of Health (grants UL1 418 TR000002, R01GM099688, CTSC-MCRTP) and UC Davis Comprehensive Cancer Center Support Grant P30CA093373.