Human Monoclonal Antibody-Based Therapy in the Treatment of Invasive Candidiasis

Abstract

Invasive candidiasis (IC) represents the leading fungal infection of humans causing life-threatening disease in immunosuppressed and neutropenic individuals including also the intensive care unit patients. Despite progress in recent years in drugs development for the treatment of IC, morbidity and mortality rates still remain very high. Historically, cell-mediated immunity and innate immunity are considered to be the most important lines of defense against candidiasis. Nevertheless recent evidence demonstrates that antibodies with defined specificities could act with different degrees showing protection against systemic and mucosal candidiasis. Mycograb is a human recombinant monoclonal antibody against heat shock protein 90 (Hsp90) that was revealed to have synergy when combined with fluconazole, caspofungin, and amphotericin B against a broad spectrum of Candida species. Furthermore, recent studies have established an important role for Hsp90 in mediating Candida resistance to echinocandins, giving to this antibody molecule even more attractive biological properties. In response to the failure of marketing authorization by the CHMP (Committee for Medicinal Products for Human Use) a new formulation of Mycograb, named Mycograb C28Y variant, with an amino acid substitution was developed in recent years. First data on Mycograb C28Y variant indicate that this monoclonal antibody lacked efficacy in a murine candidiasis model.

Antifungal Therapy: New Advances in the Understanding and Treatment of Mycosis

“…The same antibody was used in a multicenter double-blind placebo-controlled trial of patients with invasive candidiasis, and complete mycological resolution reached 84% in the combination therapy group compared to 48% in the AMB monotherapy group. Moreover, clearance of infections in the combination therapy group was twice that of AMB therapy alone, resulting in 4 and 18% mortality, respectively (Matthews et al, 2003; Bugli et al, 2013; Wang et al, 2015). …”

The antifungal pipeline: a reality check

“…Therefore, blockade of either of these targets could be synergistic with other inhibitors, such as azoles or echinocandins. Much work has been carried out to investigate HSP90 inhibitors, such as the geldanamycin-like agents 38,87 and the monoclonal antibody efungumab 39,88,89 . Notably, the capacity of MGCD290 to synergize with known antifungals is retained even when there is some apparent resistance to the primary, established drug 84 .…”

“…The use of monoclonal antibodies to attack fungi 88,140 or even carry potent antifungal material, such as radiation (radioimmunotherapy), to the fungus has been validated in animal models 141 as a potential treatment strategy. However, it should be noted how carefully these antibodies need to be tested.…”

mRNA mediates passive vaccination against infectious agents, toxins, and tumors

“…Hence, passive immunization, by transferring either serum or purified antibodies, is a potent means to confer immediate protection against various threats. Clinical benefit was demonstrated for invasive bacterial infections (Casadevall & Scharff, 1994), for various viral diseases (Janeway, 1945;Hammon et al, 1953), as well as for anti-fungal therapy (Bugli et al, 2013), and polyclonal antibody products were licensed for several viruses.…”