Therapeutic monoclonal antibody for sporotrichosis

Abstract

Sporotrichosis is a chronic subcutaneous mycosis that affects both humans and animals worldwide. This subcutaneous mycosis had been attributed to a single etiological agent, Sporothrix schenckii. S. schenckii exhibits considerable genetic variability, and recently, it was suggested that this taxon consists of a complex of species. Sporotrichosis is caused by traumatic inoculation of the fungus, which is a ubiquitous environmental saprophyte that can be isolated from soil and plant debris. The infection is limited to cutaneous forms, but recently, more severe clinical forms of this mycosis have been described, especially among immunocompromised individuals. The immunological mechanisms involved in the prevention and control of sporotrichosis are not well understood. Some studies suggest that cell-mediated immunity plays an important role in protecting the host against S. schenckii. In contrast, the role of the humoral immune response in protection against this fungus has not been studied in detail. In a previous study, we showed that antigens secreted by S. schenckii induced a specific humoral response in infected animals, primarily against a 70-kDa molecule, indicating a possible role of specific antibodies against this molecule in infection control. In another study by our group, we produced a mAb against a 70-kDa glycoprotein of S. schenckii to better understand the effect of the passive immunization of mice infected with S. schenckii. The results showed a significant reduction in the number of CFUs in various mice organs when the mAb was injected before or during S. schenckii infection. Similar results were observed when T-cell-deficient mice were used. The drugs of choice in the treatment of sporotrichosis require long periods, and relapses are frequently observed, primarily in immunocompromised patients. The strong protection induced by the mAb against a 70-kDa glycoprotein makes it a strong candidate as a therapeutic vaccine against sporotrichosis.

A cell wall protein-based vaccine candidate induce protective immune response against Sporothrix schenckii infection

“…For many years, the protective role of antibody-mediated immunity in fungal infections was controversial, whereas cell-mediated immunity was considered the fundamental mechanism of host defense. However, in the last two decades, a role for antibodies in host defense against different pathogenic fungi (Casadevall and Pirofski, 2012b), including S. schenckii (Almeida, 2012), has been shown in various forms, including opsonization and inhibi-tion of fungus adherence onto host cells, complement activation, and antibody-dependent cellular cytotoxicity (ADCC) (Casadevall and Pirofski, 2012a). It is thus expected that an effective antifungal vaccine would be able to induce antibodies against the fungus' cell wall components in order to trigger some of the abovementioned mechanisms.…”

“…This therapy is often associated with sometimes severe adverse effects and frequent fungal resistance (Rodrigues et al, 2014). Therefore, vaccination has been proposed as a viable alternative for both therapeutic and prophylactic purposes (Almeida, 2012;Lacerda et al, 2011). For decades, a variety of cell wall proteins (CWPs) from many different pathogenic fungi have been evaluated in mouse models of vaccination for assessment of their immunogenicity, safety and protection-affording potential (Edwards, 2012).…”

Differences in Cell Morphometry, Cell Wall Topography and Gp70 Expression Correlate with the Virulence of Sporothrix brasiliensis Clinical Isolates

“…A clear correlation was observed, as a reduced level of gp70 expression was found in all virulent S. brasiliensis isolates. This finding could represent a misbalance in the immune response, as this antigen induces a protective host response [44]. Accordingly, the S. schenckii clinical reference strains of different geographical origins (IPEC 15383 and 1099-18), which were both less virulent in the subcutaneous murine model, presented high expression of gp70.…”

Vaccines and immunotherapy against fungi: the new frontier

“…The utility of antibody based therapeutic approaches is presented against a specific fungus, Histoplasma capsulatum (Nosanchuk et al, 2012), and as a broad-spectrum therapeutic using antibody labeled with fungicidal nuclides (Nosanchuk and Dadachova, 2012). A therapeutic monoclonal antibody in early phase research for sporotrichosis is also detailed (Almeida, 2012). Moreover, the broad potential of antibody-derived “killer peptides” is presented (Magliani et al, 2012).…”