title: 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.
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 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.
authors.affiliation: Ordway Research Institute, Albany, New York 12208, USA. alouie@ordwayresearch.org
authors.forename: Arnold
authors.initials: A
authors.lastname: Louie
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Stein
authors.forename: Julia Z
authors.initials: JZ
authors.lastname: Zack
authors.forename: Weiguo
authors.initials: W
authors.lastname: Liu
authors.forename: Haley
authors.initials: H
authors.lastname: Conde
authors.forename: Christine
authors.initials: C
authors.lastname: Fregeau
authors.forename: Brian D
authors.initials: BD
authors.lastname: Vanscoy
authors.forename: George L
authors.initials: GL
authors.lastname: Drusano
mesh_terms: D000666:Amphotericin B / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology* / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000935:Antifungal Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D002177:Candidiasis / Q000188:drug therapy*; D003840:Deoxycholic Acid / Q000008:administration & dosage / Q000627:therapeutic use*; D004338:Drug Combinations; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000276:immunology*; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000935:Antifungal Agents; D004338:Drug Combinations; D018841:HSP90 Heat-Shock Proteins; D003840:Deoxycholic Acid; D000666:Amphotericin B; C059765:amphotericin B, deoxycholate drug combination; C512268:efungumab