Monoclonal Antibody-Based Therapies for Disseminated Candidiasis
Abstract
Hematogenously disseminated candidiasis, or invasive candidiasis, is a fungal infection of Candida species. It usually presents as candidemia (the presence of Candida in the blood) and progresses to several viscera (i.e., liver, kidney, spleen, eyes, brain, and heart). Disseminated candidiasis in humans is the leading cause of hospital-related bloodstream infection in the United States. Despite the availability of appropriate antifungal therapy, crude mortality in the last decade has remained high, ranging from 36% to 90%. As there is no approved antifungal vaccine for use in humans and significant therapeutic challenges remain, disease prevention through active and passive immunization strategies have become critically important. Vaccination represents a particularly promising strategy to prevent invasive fungal infections as easily identifiable risk factors are clearly defined. Treatment with protective antibodies can even protect against severe infection more rapidly than antifungal medication, and they are also effective against antifungal resistance in multiple Candida species. With the aging global and U.S. populations, increasingly intensive medical treatments of critical illnesses, and increasingly aggressive immune-suppressive treatment of patients with cancer, the incidence of invasive fungal infections will continue to rise over the coming decades. Mortality rates associated with these diseases remain high despite the availability of new antifungal agents. Together, these factors make therapeutic antibodies for invasive fungal infection highly desirable. The goal of this proposal is to develop and establish preclinical proof-of-concept for the first universal therapeutic antibodies that protect against disseminated candidiasis caused by all the medically important Candida species. The most common pathogen for invasive candidiasis is C. albicans (41%-65%); however, non-albicans Candida species resistant to conventional treatments have emerged as prevalent causes of candidiasis. The lethal fungus, known as Candida auris, has been identified in at least 98 people in the United States up to April 2017, mostly in New York, New Jersey, and Illinois. The fatality rate appears to be unusually high: About 60% of those who get infected with C. auris have died, the Centers for Disease Control and Prevention (CDC) said. C. auris is multidrug-resistant, meaning that it is resistant to most antifungal drugs commonly used to treat Candida infections. The CDC reported that this type of multidrug resistance has never been seen before in other species of Candida. Given the high mortality rate and significant burden on the healthcare system associated with the disease, novel approaches are needed to supplement or replace current antifungal therapy. Several universal peptide vaccines, which have 100% homology in all the five medically important Candida species, including C. auris, have been developed. Furthermore, a panel of monoclonal antibodies that are specific for these universal peptides has been identified and produced. The protective efficacy of both universal peptide vaccines and related antibodies is now being tested in mouse model of C. auris invasive infection. At the same time, an efficient combination therapy with protective antibody cocktails against invasive candidiasis by all medical important Candida species is being developed. Furthermore, by combining conventional antifungal agents, the novel antibody-based therapy is expected to further improve the efficacy of these antifungal drugs, with the possibility to reduce their toxicities and doses. The milestones established in this proposal will be a significant leap forward in clinical management of invasive fungal infection.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810125
Entities
People
- Hong Xin
Organizations
- LSU Health Sciences Center New Orleans
- United States Army