Combination immunotherapy of MAb B6.1 with fluconazole augments therapeutic effect to disseminated candidiasis

Abstract

We recently reported that IgM MAb B6.1, specific for β-1, 2-mannotriose on the cell wall of Candida albicans, is therapeutic to disseminated candidiasis due to C. albicans. In the current study, we examined if MAbB6.1 enhances therapeutic effect of fluconazole (FLC) to the disseminated disease. To assess the combination effect, determination by the kidneys-colony forming unit and survival times were used. Results showed that the therapeutic effect of FLC on mice with disseminated candidiasis was dose-dependent, but a FLC dose at 0.8 mg/kg body weight of mice was ineffective. To determine combination effect, mice treated intraperitoneally with a combination of FLC plus MAb B6.1 at 1 h post-infection - a condition of developing partial therapeutic activity - enhanced survival times beyond the effect by only antibody (p < 0.05). The resulting MST (mean survival times) value from the combination-received mice was almost the same as MST value from 3.2 mg FLC dose-given animals (p < 0.05). Another combination of 1.6 mg FLC dose and B6.1 reduced severity of the disseminated disease at almost the same rate as combination efficacy of 0.8 mg FLC dose plus B6.1. This data indicates that B6.1 acts in concert with FLC and that this combination therapy augments protection, which suggests a possibility of reducing FLC dose. The augmentation response was specific because an irrelevant IgM MAb S9 was not effective to the disseminated disease. Thus, our present studies demonstrate that this combination immunotherapy may be a way of solving the problem of limited antifungal drug choices caused by drug-resistant C. albicans.

Immunochemistry of pathogenic yeast, <i>Candida</i> species, focusing on mannan

“…64) Moreover, Cutler and coworkers 65,66) demonstrated that the monoclonal antibody against β-1,2-linked mannooligosaccharides protects against disseminated candidiasis and vaginal infection. Recently, Lee et al 67) showed the effectiveness of a monoclonal antibody against β-1,2-linked mannooligosaccharides, in combination with fluconazole, against candidiasis.…”

Demonstration of b-1,2 Mannan Structures Expressed on the Cell Wall of Candida albicans Yeast Form But Not on the Hyphal Form by Using Monoclonal Antibodies

“…β-1,2 bağlı mannoz ünitelerinin daha antijenik yapıda olması nedeniyle buna karşı üreti-len antikorların koruyuculuğu da yüksektir 6 . Bu durum, kandida enfeksiyonlarının önlen-mesinde monoklonal antikorların kullanımını gündeme getirmiştir [18][19][20][21][22] . Nitekim Han ve arkadaşlarının 18 çalışmasında, β-1,2 bağlı mannanlara karşı elde edilen monoklonal antikorların deneysel kandidiyaz ve vajinal enfeksiyonu önlediği gösterilmiştir.…”

“…Kavishwar ve Shukla 21 elde ettikleri G5 monoklonal antikorlarının, in vivo deney koşulları altında tedavi ve profilaktik kullanım için faydalı olduğunu bildirmişlerdir. Lee ve arkadaşları 22 , β-1,2 mannana özgül olarak geliştirilen IgM tipindeki monoklonal antikorlar ile flukonazol kombinasyonunun, sistemik kandidiyaza karşı etkili olduğunu göstermişlerdir.…”

Monoclonal Antibodies and Antibody Like Fragments Derived from Immunised Phage Display Libraries

“…In combination immunotherapy a chemical antifungal drug is administered along with an antibody. For example, mAb B6.1 is synergistic with amphotericin B [39] and augments the therapeutic effect of fluconazole in a mouse model of disseminated candidiasis [59]. These examples demonstrate the potential for antifungal mAbs in clinical settings and the use of drug combinations as a powerful strategy to enhance antifungal efficacy and abolish drug resistance.…”