An Anti-β-Glucan Monoclonal Antibody Inhibits Growth and Capsule Formation of Cryptococcus neoformans In Vitro and Exerts Therapeutic, Anticryptococcal Activity In Vivo

Abstract

In this study we tested the in vitro and in vivo anti-Cryptococcus neoformans activity of an antilaminarin (anti-␤-glucan) monoclonal antibody (MAb 2G8) (immunoglobulin G2b) which was previously shown to inhibit the growth of ␤-glucan-exposing Candida albicans cells. Here we show that MAb 2G8 binds to the cell wall of C. neoformans and inhibits its growth to an extent comparable to that observed for C. albicans. Binding and growth inhibition were detected almost equally for encapsulated and acapsular C. neoformans strains. In addition, at subinhibitory concentrations, MAb 2G8 reduced the capsule thickness without affecting protease or phospholipase production. Acapsular fungal cells, but not encapsulated fungal cells, were opsonized by the antibody and more efficiently phagocytosed and killed by human monocytes and by murine peritoneal macrophages. A single administration of MAb 2G8 resulted in a reduction in the fungal burden in the brains and livers of mice systemically infected with a highly virulent, encapsulated C. neoformans strain. This protective effect was also detected in neutropenic mice. Overall, these findings demonstrate that cell wall ␤-glucan of encapsulated C. neoformans is accessible to antibodies which can exert remarkable anticryptococcal activities in vitro and in vivo.Deep-seated mycoses are a severe clinical problem because of well-known diagnostic difficulties and the partial inability of antifungal drugs to eradicate the infections in immunocompromised hosts, often resulting in toxicity, drug resistance, and associated high costs of supportive treatment. As a consequence, the mortality rate for invasive fungal infections remains high, particularly in severely immunocompromised pa-

Cryptococcal Interactions with the Host Immune System

“…Therapy was well tolerated for antibody concentrations up to 1 mg/kg of body weight, with higher doses showing pharmacological effects (99). A second antibody, 2G8, targeting the cell wall glucan exerts remarkable anticryptococcal activity in vitro and in vivo and might be a good candidate as a new therapeutic agent (156). Thus, there is clear potential for anticryptococcalantibody-mediated therapy.…”

The protective role of immunoglobulins in fungal infections and inflammation

“…Therefore, authors further performed the experiments by using antibody concentrations that closely mimics in vivo situation and found that IgG1 was more effective than IgA in conferring the protection against challenge [15]. In addition, other reports also confirmed the therapeutic potential of murine IgG1 MAb to capsular polysaccharide (CNPS), IgM MAb that binds to melanin and murine IgG2b MAb to glucosylceramide and β-glucan (laminarin) of C. neoformans [58][59][60][61].…”

Immunization with Pneumocystis Cross-Reactive Antigen 1 (Pca1) Protects Mice against Pneumocystis Pneumonia and Generates Antibody to Pneumocystis jirovecii

“…The extent of protection that resulted from immunization with Pca1 was unexpected, since partial protection after immunization appears to be the typical outcome of immunization against fungal pathogens such as Candida, Aspergillus, and Cryptococcus (18)(19)(20)(21)(22). A number of potential vaccine candidates have been evaluated in animal models of PcP as well, but at best, they achieved only partial protection (15,(23)(24)(25)(26)(27).…”