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JAC Advance Access published online on February 25, 2008
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkn075
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

Efungumab and caspofungin: pre-clinical data supporting synergy

Samantha Hodgetts1, Lucy Nooney1, Raid Al-Akeel2, Alan Curry3, Sawsan Awad1, Ruth Matthews1,2 and James Burnie1,2,*

1 NeuTec Pharma Ltd, a wholly owned subsidiary of Novartis Pharma AG, Williams House, Lloyd Street North, Manchester M15 6SE, UK; 2 The University of Manchester, 2nd Floor, Clinical Sciences Building, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, UK; 3 Electron Microscopy Unit, Ground Floor, Clinical Sciences Building, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, UK

Received 21 November 2007; returned 23 January 2008; revised 8 January 2008; accepted 2 February 2008

* Corresponding author. Tel: +44-161-232-2900; Fax: +44-161-232-2901; E-mail: james.burnie{at}neutecpharma.com

Objectives: Heat shock protein 90 (hsp90) is targeted by the humoral response in invasive candidiasis. This paper tests for synergy between caspofungin and efungumab—a human antibody fragment against hsp90.

Methods: The MIC-0, MIC-2 values and FICI were determined for a range of yeasts against efungumab and caspofungin. These yeasts were injected intravenously into mice with: 100 µL of saline plus 100 µL of formulation buffer; 100 µL of caspofungin (1 or 4 mg/kg) plus 100 µL of formulation buffer; or 100 µL of caspofungin (1 or 4 mg/kg) plus 100 µL of efungumab 2 mg/kg. Yeast counts were determined for kidney, liver and spleen. Electron microscopy was performed on efungumab-stained Candida grown with and without caspofungin.

Results: The FICIs of efungumab and caspofungin at MIC-0 and MIC-2, respectively, were: fluconazole-susceptible Candida albicans: 0.5, 0.52; fluconazole-resistant C. albicans, Candida tropicalis and Candida krusei: 0.5, 0.5; Candida parapsilosis: 2, 0.5; Candida glabrata: 0.26, 0.28; and Candida guilliermondii: 2, 0.27. A statistically significant reduction in colony counts or increase in the number of negative biopsies (P < 0.05) was seen in mice on combination therapy at 1 mg/kg caspofungin for the renal biopsies of C. glabrata, liver biopsies of fluconazole-resistant C. albicans, C. krusei and C. guilliermondii and spleen biopsies of C. guilliermondii, and at 4 mg/kg for the renal biopsies of C. tropicalis, the liver biopsies of C. parapsilosis and the spleen biopsies of C. guilliermondii and C. glabrata. Electron microscopy confirmed extracellular hsp90 up-regulated by growth in caspofungin.

Conclusions: Efungumab increased the susceptibility of Candida to caspofungin.

Key Words: hsp90 , combination therapies , antibodies , echinocandins , yeasts


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