Human domain antibodies against virulence traits of Candida albicans inhibit fungus adherence to vaginal epithelium and protect against experimental vaginal candidiasis.
Antibody variable domains (domain antibodies [DAbs]) are genetically engineered antibody fragments that include individual heavy-chain (VH) or kappa-chain (Vkappa) variable domains and lack the Fc region. Human DAbs against the 65-kDa mannoprotein (MP65) or the secretory aspartyl proteinase (SAP)-2 of Candida albicans (monospecific DAbs) or against both fungal antigens (heterodimeric, bispecific DAbs) were generated from phage expression libraries. Both monospecific and bispecific DAbs inhibited fungus adherence to the epithelial cells of rat vagina and accelerated the clearance of vaginal infection with the fungus. When heterodimeric DAbs were used, the clearance of infection was at least equivalent to treatment with fluconazole. The in vivo protective effects of DAbs were demonstrated by both pre- and postchallenge schedules of DAb administration and with both fluconazole-susceptible and fluconazole-resistant strains of C. albicans. This is the first demonstration that human DAbs lacking the Fc constituent can efficiently control an infection and can act largely by inhibiting adherence.
De Bernardis
Flavia
F
Department of Infectious, Parasitic and Immune-Mediated Diseases, Istituto Superiore di Sanità, Viale Regina Elena, 00161 Rome, Italy.
Liu
Haiqun
H
O'Mahony
Rachel
R
La Valle
Roberto
R
Bartollino
Silvia
S
Sandini
Silvia
S
Grant
Steven
S
Brewis
Neil
N
Tomlinson
Ian
I
Basset
Rachel C
RC
Holton
John
J
Roitt
Ivan M
IM
Cassone
Antonio
A
D000818:Animals; D000908:Antibodies, Fungal / Q000276:immunology*; D016282:Aspartic Acid Endopeptidases / Q000276:immunology; D002176:Candida albicans / Q000201:enzymology / Q000472:pathogenicity / Q000502:physiology*; D002181:Candidiasis, Vulvovaginal / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004848:Epithelium / Q000382:microbiology* / Q000473:pathology; D005260:Female; D005656:Fungal Proteins / Q000276:immunology; D006801:Humans; D050440:Immunoglobulin Subunits / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000276:immunology; D051381:Rats; D014621:Vagina / Q000276:immunology* / Q000473:pathology; D014774:Virulence
D000908:Antibodies, Fungal; D005656:Fungal Proteins; D050440:Immunoglobulin Subunits; D008562:Membrane Glycoproteins; C025363:mannoproteins; D016282:Aspartic Acid Endopeptidases; C090753:SAP2 protein, Candida