Scientists are working to understand how therapeutic antibodies stimulate the body’s immune cells to kill cells that contribute to a wide range of diseases, including cancer.
“Antibody therapies can be very powerful; however, sometimes the immune cells stop killing the disease-causing cells,” explained South Dakota State University professor Adam Hoppe. He is working with researchers at the University of Southampton in the United Kingdom to examine how specialized immune cells called macrophages recognize and destroy target cells and why they sometimes do not.
“We want to understand the pathways and immune signals that control macrophage activity making them more—or less—potent killers,” said Hoppe, whose research group in the Department of Chemistry and Biochemistry specializes in macrophages.
Work began July 10 on the National Institutes of Health project. It is one of six projects that were funded as part of a focused effort aimed at improving the effectiveness of therapeutic antibodies— and one of the few that involves an international collaboration.
Professor Mark Cragg, alongside professor Stephen Beers, leads the University of Southampton team at the Center for Cancer Immunology. Its research focuses on how antibody therapeutics redirect and activate immune cells to target cancer as well as how to overcome resistance to these treatments.
“They are the world’s experts on therapeutic antibodies that can target autoimmune or malignant B and T cells,” Hoppe said, noting that they recently discovered how immune activation of macrophages is one of the key components for effective antibody therapeutics. Postdoctoral researchers and doctoral students at SDSU and Southampton will work collaboratively on the five-year, $1.78 million project.
What the researchers learn will help increase the effectiveness of antibody therapeutics designed to fight cancer and target autoimmune disorders, such as multiple sclerosis and rheumatoid arthritis.
Tracking genetic pathways
“One of the main ways macrophages recognize target cells is via antibodies on the target cell surface,” Hoppe said. However, “sometimes the macrophages just do not respond or simply clean the antibody off the target cell and let it go—they do not kill it,” he continued. This deactivation makes the antibody therapeutic ineffective.
Hoppe and his group will use the CRISPR gene-editing tool to identify which genes promote or inhibit the macrophages’ ability to use antibodies to destroy target cells. “We want to figure out which genes control this activation and killing process,” Hoppe said. Sequencing of the cellular level screenings will be done at SDSU’s Genome Sequencing Facility.
Analyzing gene expression will require extensive use of bioinformatics, Hoppe noted. Professor Xijin Ge of SDSU’s Department of Mathematics and Statistics will help with bioinformatics analysis using the university’s high-performance computing cluster. Senior research fellow Stephen Thirdborough will work with bioinformatics at the University of Southampton.
The Southampton research group will then study the genes identified through Hoppe’s CRISPR screenings in mice experiments to verify their importance. In addition, they will analyze data from patients who received antibody therapeutics to treat cancer and autoimmune disorders to confirm their results.
“We want to understand what is deactivating the macrophages,” Hoppe said. For instance, a therapeutic to treat B cell malignancies also works for mild lupus but not for more reactive lupus. “We want to know why those antibodies can perform so well in some patients, but fail in others.”