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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

Louie, Arnold and Stein, Daniel and Zack, Julia and Liu, Weiguo and Conde, Haley and Fregeau, Christine and VanScoy, Brian and Drusano, George (2011) 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. Antimicrobial Agents and Chemotherapy, 55 (7). pp. 3295-3304. ISSN 0066-4804

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.

Item Type: Article
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Keywords: Mycograb, neutropenic mouse, candida
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Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15
URI: https://oak.novartis.com/id/eprint/3669

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