Systemic candidiasis causes significant mortality in patients despite
amphotericin B (AMB)
therapy.
Mycograb C28Y variant, a human recombinant
antibody fragment to
heat shock protein 90, is closely related to
Mycograb, which showed a survival advantage in combination with AMB in a phase III human trial. The
Mycograb C28Y variant could potentially increase the antifungal effect of AMB. In our study, the interaction between AMB-desoxycholate (DAMB) and the
Mycograb C28Y variant was characterized in vitro by using a checkerboard method. Quantitative cultures of kidneys, livers, and spleens of neutropenic mice with systemic Candida albicans
infections were used to assess the in vivo interaction between 1.4 mg/kg of
body weight/day of DAMB and 0.15, 1.5, and 15 mg/kg/day of the
Mycograb C28Y variant after 1, 3, and 5 days of
therapy. DAMB and
Mycograb C28Y variant monotherapies, vehicle, and a no-treatment arm served as controls. Also, single- and multidose pharmacokinetics for the
Mycograb C28Y variant were determined. Indifference or synergy between DAMB and the
Mycograb C28Y variant was seen in two trials by the checkerboard method. The pharmacokinetics of the
Mycograb C28Y variant was best described by a 2-compartment model with a median serum t(1/2)(α) of ~0.198 h and a t(1/2)(β) of ~1.77 h. In mice, DAMB together with the
Mycograb C28Y variant was no more effective than AMB alone (P > 0.05 by analysis of variance). The
Mycograb C28Y variant alone had no antifungal activity. We therefore conclude that the
Mycograb C28Y variant in combination with DAMB offered no benefit over DAMB monotherapy in a neutropenic murine model of
systemic candidiasis.