Plant production of anti-β-glucan antibodies for immunotherapy of fungal infections in humans.
There is an increasing interest in the development of therapeutic antibodies (Ab) to improve the control of fungal pathogens, but none of these reagents is available for clinical use. We previously described a murine monoclonal antibody (mAb 2G8) targeting β-glucan, a cell wall polysaccharide common to most pathogenic fungi, which conferred significant protection against Candida albicans, Aspergillus fumigatus and Cryptococcus neoformans in animal models. Transfer of this wide-spectrum, antifungal mAb into the clinical setting would allow the control of most frequent fungal infections in many different categories of patients. To this aim, two chimeric mouse-human Ab derivatives from mAb 2G8, in the format of complete IgG or scFv-Fc, were generated, transiently expressed in Nicotiana benthamiana plants and purified from leaves with high yields (approximately 50 mg Ab/kg of plant tissues). Both recombinant Abs fully retained the β-glucan-binding specificity and the antifungal activities of the cognate murine mAb against C. albicans. In fact, they recognized preferentially β1,3-linked glucan molecules present at the fungal cell surface and directly inhibited the growth of C. albicans and its adhesion to human epithelial cells in vitro. In addition, both the IgG and the scFv-Fc promoted C. albicans killing by isolated, human polymorphonuclear neutrophils in ex vivo assays and conferred significant antifungal protection in animal models of systemic or vulvovaginal C. albicans infection. These recombinant Abs represent valuable molecules for developing novel, plant-derived immunotherapeutics against candidiasis and, possibly, other fungal diseases.
ENEA, UT BIORAD, Laboratory of Biotechnology, Research Center Casaccia, Rome, Italy.
Cristina
C
Capodicasa
Paola
P
Chiani
Carla
C
Bromuro
Flavia
F
De Bernardis
Marcello
M
Catellani
Angelina S
AS
Palma
Yan
Y
Liu
Ten
T
Feizi
Antonio
A
Cassone
Eugenio
E
Benvenuto
Antonella
A
Torosantucci
D000818:Animals; D000908:Antibodies, Fungal / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D000946:Antigens, Fungal / Q000276:immunology; D001232:Aspergillus fumigatus / Q000276:immunology; D002176:Candida albicans / Q000254:growth & development / Q000276:immunology* / Q000502:physiology; D002177:Candidiasis / Q000382:microbiology / Q000628:therapy*; D002448:Cell Adhesion / Q000276:immunology; D002460:Cell Line; D002473:Cell Wall / Q000276:immunology; D003455:Cryptococcus neoformans / Q000276:immunology; D005260:Female; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000378:metabolism; D007074:Immunoglobulin G / Q000235:genetics / Q000378:metabolism; D007167:Immunotherapy; D051379:Mice; D023421:Models, Animal; D009181:Mycoses / Q000382:microbiology / Q000628:therapy; D018515:Plant Leaves / Q000235:genetics / Q000378:metabolism; D046549:Plantibodies / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000378:metabolism; D057127:Single-Chain Antibodies / Q000235:genetics / Q000378:metabolism; D014026:Nicotiana / Q000235:genetics / Q000276:immunology*; D047071:beta-Glucans / Q000276:immunology* / Q000378:metabolism
D000908:Antibodies, Fungal; D000911:Antibodies, Monoclonal; D000946:Antigens, Fungal; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D046549:Plantibodies; D011993:Recombinant Fusion Proteins; D057127:Single-Chain Antibodies; D047071:beta-Glucans