Efungumab and caspofungin: pre-clinical data supporting synergy.
OBJECTIVE
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 microL of saline plus 100 microL of formulation buffer; 100 microL of caspofungin (1 or 4 mg/kg) plus 100 microL of formulation buffer; or 100 microL of caspofungin (1 or 4 mg/kg) plus 100 microL 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.
Hodgetts
Samantha
S
NeuTec Pharma Ltd, Williams House, Lloyd Street North, Manchester M15 6SE, UK.
Nooney
Lucy
L
Al-Akeel
Raid
R
Curry
Alan
A
Awad
Sawsan
S
Matthews
Ruth
R
Burnie
James
J
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000935:Antifungal Agents / Q000494:pharmacology; D002175:Candida / Q000145:classification / Q000187:drug effects; D002177:Candidiasis / Q000188:drug therapy*; D000077336:Caspofungin; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D054714:Echinocandins / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000494:pharmacology*; D055666:Lipopeptides; D051379:Mice; D008826:Microbial Sensitivity Tests; D013045:Species Specificity
D000911:Antibodies, Monoclonal; D000935:Antifungal Agents; D054714:Echinocandins; D007135:Immunoglobulin Variable Region; D055666:Lipopeptides; D000077336:Caspofungin