City of Hope researchers and colleagues have developed a potential method of making monoclonal antibodies more effective and less toxic for cancer patients.
The research, done in collaboration with scientists from Kimmel Cancer Center at Thomas Jefferson University, recently was published online in the journal Cancer Biology & Therapy in advance of the Nov. 15 edition.
|John Williams seeks ways to make monoclonal antibodies more effective. (Photo by Thomas Brown)|
Monoclonal antibody-based therapies have shown uneven effectiveness in treating colorectal and head and neck cancers. Some patients do not respond to them, and those that do may experience serious side effects, such as skin rash, that limit their use in treatment.
“Monoclonal antibodies like cetuximab work by blocking activity of the epidermal growth factor receptor [EGFR], which is critical to the survival of tumor cells, but is also active in normal, healthy noncancerous cells,” said Joshua M. Donaldson, an M.D./Ph.D. student at Jefferson and lead author of the study.
Donaldson conducted the research at Beckman Research Institute of City of Hope under the guidance of John C. Williams, Ph.D., assistant professor in molecular medicine and director of the X-ray Crystallography Core at City of Hope.
The researchers looked at how to keep cetuximab from hurting healthy cells to lessen side effects like skin rashes and gastrointestinal issues. By doing that, they might also be able to concentrate the therapy at the tumor site, making it more effective, said Donaldson.
Williams, in collaboration with Ulrich Rodeck, M.D., Ph.D., professor of dermatology and cutaneous biology at Jefferson Medical College of Thomas Jefferson University, designed a molecule made up of two monoclonal antibodies, matuzumab and cetuximab, linked by a chain that can be broken by an enzyme that is very active in tumors.
“We designed a product that is inactive around healthy tissue in its ‘masked’ state and is only activated at the tumor site into an ‘unmasked’ state by the action of enzymes overproduced by cancer cells,” said Williams.
When linked, the monoclonal antibodies resist the natural attraction to bind to EGFR, but when the cancer-related enzymes break the link between the antibodies, the antibodies become active once again and block EGFR.
“The design has potential to improve the targeted release of therapeutic antibodies at disease sites, sparing healthy tissue and possibly lessening any side effects,” said Williams.
The research team members also included Csaba Kari, M.D., research associate in the Department of Dermatology and Cutaneous Biology at Jefferson, and Ruben Fragoso, M.D., Ph.D., from the Department of Radiation Oncology at Jefferson.