Abstract
Researchers have developed an antibody–drug conjugate with the potential to treat neuroblastoma. The agent targets ALK, which is found on neuroblastoma cells but not healthy cells, delivering a drug that causes DNA cross-links. Researchers have found that the antibody–drug conjugate kills ALK-expressing cells in vitro and increases survival in mouse models of neuroblastoma.
An antibody–drug conjugate (ADC) that targets ALK may be effective against neuroblastoma, a mouse study suggests.
Researchers are investigating multiple targeted treatments for neuroblastoma, which usually occurs in children younger than 5. The first therapy to receive FDA approval, the monoclonal antibody dinutuximab (Unituxin; United Therapeutics), can cause side effects such as severe pain, likely because it binds to a protein, GD2, which is expressed on healthy nerve cells.
Another potential treatment target is the receptor tyrosine kinase ALK. For example, small-molecule inhibitors of ALK have been developed and tested in clinical trials, but their value may be limited due to the development of resistance. Using an ADC represents a different approach: Most neuroblastoma cells express ALK on their surface—with or without mutations—but healthy cells don't carry the protein at all, says Yael Mossé, MD, of the Children's Hospital of Philadelphia in Pennsylvania, the study's senior author. “That gives us an opportunity to precisely target ALK.”
To deliver a drug payload directly to neuroblastoma cells, she and her colleagues created an ADC, which links an antibody that homes in on cancer cells to a cytotoxic drug. The researchers immunized mice with a section of the human ALK protein and then isolated an antibody, CDX-0125, that binds tightly to ALK. When the antibody attached to neuroblastoma cells in vitro, the cells internalized it.
The team then fused the antibody to the DNA-alkylating agent thienoindole (TEI), which induces cross-links within or between DNA strands and triggers apoptosis. To gauge CDX-0125-TEI's ability to kill tumor cells, the researchers tested it against four human neuroblastoma–derived cell lines with differing amounts of ALK, with and without mutations. The ADC proved cytotoxic in the three cell lines with ALK on their surface, more than doubling the amount of DNA damage and inducing apoptosis. The ADC didn't kill cells in the fourth cell line, which lacked ALK.
To determine if the ADC worked in vivo, the team tested it in two patient-derived xenograft models of neuroblastoma with ALK mutations. They injected each animal with one of three doses once a week for 2 weeks and tracked tumor growth and survival. Because the mice received CDX-0125-TEI for a limited time, they eventually died from their tumors. Compared with untreated mice, however, the animals that received the highest ADC dose survived up to twice as long and showed slower tumor growth. The researchers also evaluated the ADC in two ALK wild-type models. Again, the higher dose of the ADC improved survival in these animals and delayed tumor growth.
The study “is an important step forward,” says Ruth Palmer, PhD, of the University of Gothenburg in Sweden, who wasn't connected to the research. “It says there is space for this approach in neuroblastoma therapy.” Healthy tissues mainly express ALK during embryonic development, so future studies should test the ADC in young mice to ensure that it doesn't cause developmental defects, says Palmer.
Before clinical trials of ALK-targeting antibody can begin, Mossé and her team need to determine what level of ALK expression is “sufficient to elicit ADC-mediated cytotoxicity.” The scientists' in vitro and in vivo experiments revealed that the ADC didn't kill cells that had modest ALK expression, so they may need to develop an assay to identify patients most likely to benefit from the treatment. –Mitch Leslie
