Dose Range Evaluation of Mycograb C28Y Variant (MYC123 C28Y), a Human Recombinant Antibody Fragment to Heat Shock Protein 90, In Combination with Amphotericin B-Desoxycholate for the Treatment of Murine Systemic Candidiasis

Abstract

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 3 human trial. The Mycograb C28Y variant could potentially increase the antifungal effect of AMB. Method: The interaction between AMB-desoxycholate (DAMB) and the Mycograb C28Y variant was characterized in vitro by 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/d of DAMB and 0.15, 1.5, and 15 mg/kg/d 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 multi-dose pharmacokinetics for the Mycograb C28Y variant were determined. Results: 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 t1/2α of ~0.198 h and a t1/2β of ~1.77 h. In mice, DAMB together with the Mycograb C28Y variant was no more effective than AMB alone (p > 0.05 by ANOVA). The Mycograb C28Y variant alone had no antifungal activity. Conclusion: The Mycograb C28Y variant in combination with DAMB offered no benefit over DAMB monotherapy in a neutropenic murine model of systemic candidiasis