Monoclonal Immunoglobulin G1 Directed againstAspergillus fumigatusCell Wall Glycoprotein Protects against Experimental Murine Aspergillosis

Abstract

Most of the biological functions related to pathogenicity and virulence reside in the fungal cell wall, which, being the outermost part of the cell, mediates the host-fungus interplay. For these reasons much effort has focused on the discovery of useful inhibitors of cell wall glucan, chitin, and mannoprotein biosynthesis. In the absence of a wide-spectrum, safe, and potent antifungal agent, a new strategy for antifungal therapy is directed towards the development of monoclonal antibodies (MAbs). In the present study the MAb A9 (immunoglobulin G1 [IgG1]) was identified from hybridomas raised in BALB/c mice immunized with cell wall antigen of Aspergillus fumigatus. The immunoreactive epitopes for this IgG1 MAb appeared to be associated with a peptide moiety, and indirect immunofluorescence microscopy revealed its binding to the cell wall surface of hyphae as well as with swollen conidia. MAb A9 inhibited hyphal development as observed by MTT [3-(4,5-dimethythiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay (25.76%), reduced the duration of spore germination, and exerted an in vitro cidal effect against Aspergillus fumigatus. The in vivo protective efficacy of MAb A9 was also evaluated in a murine model of invasive aspergillosis, where a reduction in CFU (>4 log 10 units) was observed in kidney tissue of BALB/c mice challenged with A. fumigatus (2 ؋ 10 5 CFU/ml) and where enhanced mean survival times (19.5 days) compared to the control (7.1 days) and an irrelevant MAb (6.1 days) were also observed.

CD4+T Cells Mediate the Protective Effect of the Recombinant Asp f3-Based Anti-Aspergillosis Vaccine

“…Several studies have suggested a possible protective role for antibodies in immunity against fungal diseases, in particular for yeast infections such as cryptococcosis (35) and candidiasis (11,27,35,39,48,49) and a few for aspergillosis, a mold infection (12,13). Interestingly, most studies were conducted in vitro or used animal models of systemic disease, in which fungal spores were intravenously injected, which is quite different from the respiratory route of naturally occurring aspergillosis.…”

Monoclonal Antibody to Fungal Glucosylceramide Protects Mice against LethalCryptococcus neoformansInfection

“…Antibodies to GXM have been characterized as potential therapeutic agents (6) and are in clinical trials for individuals with cryptococcosis (18). In other models, passively administered MAbs have protected mice against lethal infections with Histoplasma capsulatum (26), Candida albicans (15), and Aspergillus fumigatus (7). The mechanisms of MAb-mediated protection are complex and heterogeneous, but it appears that passively administered antibodies enhance the effectiveness of host immune cells (5,13) or are directly antifungal (23,35).…”

Therapy of Murine Pulmonary Aspergillosis with Antibody-Alliinase Conjugates and Alliin

“…It is noteworthy that the new monoclonal antibody against A. fumigatus, MAb MPS5.44, was found to have in itself some protective effect, as had previously been reported for other monoclonal antibodies (9). Our MAb was also found to crossreact with other Aspergillus species, such as A. niger, A. flavus, and A. terreus, though it did not recognize C. albicans, C. krusei, or a Mucor mold.…”

“…Most are based on azoles, such as voriconazole (52), or on formulations and applications of AMB (6,31,41) or echinocandins (12,16,23). Recent studies of animal models have demonstrated the therapeutic potential of monoclonal antibodies (9,53) as well as of ultrashort synthetic lipopeptides (54) with several types of fungal infections. Another report indicated that anti-idiotypic antibodies administered intranasally could effectively control A. fumigatus infection in neutropenic mice (8).…”