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Experimental Therapeutics

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

Arnold Louie, Daniel S. Stein, Julia Z. Zack, Weiguo Liu, Haley Conde, Christine Fregeau, Brian D. VanScoy, George L. Drusano
Arnold Louie
1Ordway Research Institute, Albany, New York
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  • For correspondence: alouie@ordwayresearch.org
Daniel S. Stein
2Translational Sciences, Novartis Institute for Biomedical Research, East Hanover, New Jersey
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Julia Z. Zack
2Translational Sciences, Novartis Institute for Biomedical Research, East Hanover, New Jersey
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Weiguo Liu
1Ordway Research Institute, Albany, New York
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Haley Conde
1Ordway Research Institute, Albany, New York
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Christine Fregeau
1Ordway Research Institute, Albany, New York
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Brian D. VanScoy
1Ordway Research Institute, Albany, New York
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George L. Drusano
1Ordway Research Institute, Albany, New York
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DOI: 10.1128/AAC.01324-10
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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 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 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 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.

  • Copyright © 2011, American Society for Microbiology
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Dose Range Evaluation of Mycograb C28Y Variant, a Human Recombinant Antibody Fragment to Heat Shock Protein 90, in Combination with Amphotericin B-Desoxycholate for Treatment of Murine Systemic Candidiasis
Arnold Louie, Daniel S. Stein, Julia Z. Zack, Weiguo Liu, Haley Conde, Christine Fregeau, Brian D. VanScoy, George L. Drusano
Antimicrobial Agents and Chemotherapy Jun 2011, 55 (7) 3295-3304; DOI: 10.1128/AAC.01324-10

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Dose Range Evaluation of Mycograb C28Y Variant, a Human Recombinant Antibody Fragment to Heat Shock Protein 90, in Combination with Amphotericin B-Desoxycholate for Treatment of Murine Systemic Candidiasis
Arnold Louie, Daniel S. Stein, Julia Z. Zack, Weiguo Liu, Haley Conde, Christine Fregeau, Brian D. VanScoy, George L. Drusano
Antimicrobial Agents and Chemotherapy Jun 2011, 55 (7) 3295-3304; DOI: 10.1128/AAC.01324-10
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