Immunotherapies vs. infections

Breakthrough research identifies a potential vaccine against deadly fungus

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LOS ANGELES—Researchers at the Los Angeles Biomedical Research Institute (LA BioMED) and Vitalex Biosciences announced in June a successful experiment studying a mucormycosis immunization in mice that protected against the fungal infection. The result of the experiment gives hope for the possibility of a comparable immunotherapy for humans against serious infections caused by fungi in the family Mucorales, which are on the rise and often fatal.
LA BioMed’s Dr. Ashraf Ibrahim, a professor of medicine at UCLA and the founder of Vitalex Biosciences, led a team of 12 researchers in the development of several polyclonal and monoclonal antibodies against conserved peptide regions of the CotH3 protein, which is universally present in Mucorales. CotH3 protein allows the fungus to invade host tissues to cause infection.
“This line of research goes back to 2008-2010,” says Ibrahim. “At the time, we identified CotH3 as the fungal component that allows Mucorales to bind to host cells via the GRP78 protein. We were interested in blocking this process from happening, to see if we can help mice overcome the infection.”
“When we looked into the protein sequence of CotH3, two regions were predicted to be surface-exposed, thus accessible to the antigen [GRP78] and highly antigenic,” Ibrahim continues. “Hence, we collaborated with Dr. Michael Yeaman from LA Biomed to map these peptides on a three-dimensional modeled structure for CotH3 while binding to GRP78, and found one of the peptides to reside in the binding site to GRP78.”
The experiment found that one of the monoclonal antibodies, C2, when delivered in a 30-µg dose, significantly reduced mortality in neutropenic or diabetic mice infected with any of the Mucorales organisms that cause mucormycosis. Furthermore, mice treated with a combination of the C2 antibody and a common antifungal drug almost universally survived the infection, and most had recovered and appeared healthy by the end of the study. These recovered mice showed no residual fungi in the lungs or brains.
The researchers are optimistic that their discovery could lead to the development of similar immunotherapies in humans. The antibodies in the study were of mouse origin, and thus will need to be adapted to the human immune system. Ibrahim’s team plans to modify the structure of the antibodies through a process called antibody humanization in order to allow them to function properly in humans.
Mucormycosis is caused by several fungi in the Mucorales family, including Rhizopus, Mucor and Lichtheimia. It has gained attention for its rise in U.S. transplant centers in recent years, as well as for an outbreak of infection in France, in which cases rose by 70 percent in a nine-year period. Infection of these fungi have mortality rates ranging from 50 percent to 100 percent.
“This is mainly a disease of the immunosuppressed patients,” explains Ibrahim, including patients with poorly controlled hyperglycemia, diabetics, hematologic malignancy patients, neutropenic patients due to cancer treatment, and transplant patients.
“All of these patients are increasing in numbers every year due to the advancement in cancer treatment and transplantations, and due to increased cases of diabetes,” he says. “A steady and alarming rise in mucormycosis cases has been noticed over the past two decades, and is predicted to continue increasing.”
Mucormycosis also strikes some patients who suffer severe injuries due to major trauma, such as soldiers injured in combat and vehicle accident victims.
Beyond reversing the underlying predisposing factors for the disease whenever possible, there are currently three small-molecule agents used for treating mucormycosis: lipid formulations of amphotericin B, isavuconazole and posaconazole. Surgical removal of the infected foci is a final option, but can involve a disfiguring surgery to remove necrotic tissues.
This is the first immunotherapy to specifically target mucormycosis and engage the patient’s immune system to recognize and kill the invading fungus, according to Ibrahim.
“Immunotherapies have made real difference in cancer and inflammatory disease management, and it is the time now for them to be used in managing infectious disease more widely than they are used now,” he remarks.

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