Using a method described as similar to panning for gold, Carbone Cancer Center scientists discovered human antibodies for the cancer stem cells of glioblastoma, one of the most difficult brain cancers to treat.
Patients with glioblastoma (GBM) generally live less than two years after diagnosis; it is the type of brain cancer that killed Beau Biden and Sen. Edward Kennedy.
Dr. John Kuo, a professor of neurosurgery who leads the Carbone brain tumor program, says that a major reason GBM inevitably returns after aggressive surgery, chemotherapy and radiation therapies is because the brain is seeded with treatment-resistant GBM stem cells. Kuo and collaborators have mined a library of bio-engineered yeast expressing millions of human antibodies to identify antibodies that bind and target GBM stem cells, and potentially light them up for imaging and for therapeutic targeting.
The yeast expressing human antibodies were obtained from Kuo’s co-author, Dr. Eric Shusta, a UW professor of chemical and biological engineering. Shusta's laboratory specializes in screening yeast cells that produce millions of different human antibodies, which the Kuo lab used in a method called "bio-panning" to seek the 'needle in a haystack' antibody that sticks to GBM stem cells.
The scientists mixed together known GBM stem cells with millions of yeast expressing human antibodies, enriching for antibodies that stick to cancer stem cells, but not to normal stem cells or to other GBM cells. The 'sticky' bio-engineered yeast expressing candidate antibody clones were grown again and biopanned for multiple rounds to enrich binding of GBM stem cells.
"It's like panning for gold," says Michael Zorniak, PhD, a former UW graduate student in the Kuo lab, describes the technique.
These experiments identified 62 antibody clones that potentially attach to and target GBM stem cells. Their specificity was then confirmed against 12 cells lines derived from patient’s GBM brain cancer cells, normal human stem cells, and normal brain cells.
An antibody named VH-9.7 surprisingly bound to five different cancer stem cell lines.
"VH9.7 was remarkably binding to many different GBM stem cells," Kuo says. "It did not bind to normal brain cells or to other GBM cells. That is what we hoped to find, an antibody that only binds to cancer stem cells."
"If we can tag a therapeutic payload to this antibody, we can potentially target cancer stem cells with immunotherapy," Kuo says.
"This is one of the first human antibodies discovered that specifically targets GBM stem cells, which may limit toxicities compared to current approaches when developed as a therapeutic," says Zorniak, the first author of this paper.
The study was published in Scientific Reports, a Nature journal. The group has filed a U.S. patent application with the assistance of the Wisconsin Alumni Research Foundation.