Efungumab and caspofungin: pre-clinical data supporting synergy.
Abstract
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. 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. 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. Efungumab increased the susceptibility of Candida to caspofungin. Invasive candidiasis remains a costly, life-threatening disease with a high attributable mortality rate, despite advances in the formulation and diversification of therapeutic agents.1 There is a growing medical need for new agents and therapeutic strategies, especially combination therapy.2 Conventional antifungal therapies target the fungus directly and leave the host exposed to potentially toxic molecules such as proteinases, hydrolases and heat shock proteins released by the fungus.3 Their neutralization by antibody would be a further way of improving clinical outcome, especially if it included a molecule critical to fungal pathogenesis and the development of resistance to currently licensed antifungal agents.4 Previous work established a correlation between recovery from invasive candidiasis and the production of antibody to heat shock protein 90 (hsp90).5,6 Efungumab (Mycograb®) has been developed as a human recombinant antibody fragment against hsp90 that incorporates the dominant paratope found in patients who recovered from invasive candidiasis, mimicking this humoral immune response.7 The presence of extracellular hsp90 has been demonstrated in Candida albicans and Cryptococcus neoformans, in Campylobacter jejuni, where it acts as a binding protein for surface lipoprotein JlpA, and in dengue, where it interacts with the viral envelope glycoprotein.8–11 In cancer, antibody-mediated neutralization of hsp90 has blocked metastasis formation and impacted on the functioning of the multiple molecules involved in tumour progression.12,13 Efungumab and other hsp90 inhibitors, such as geldanamycin, have an antifungal effect in vitro and, in the case of efungumab, in an animal model of fungal infection.7,14–16 Geldanamycin can block the development of resistance to caspofungin and fluconazole in Aspergillus terreus, Saccharomyces cerevisiae and C. albicans, respectively.14–16 In a randomized, double-blind study in patients with invasive candidiasis, the combination of efungumab and lipid-associated amphotericin B was superior to monotherapy with lipid-associated amphotericin B, demonstrating a higher clinical response rate [86% versus 52% (P < 0.001)], a higher mycological response rate [89% versus 54% (P < 0.001)], a faster rate of culture-confirmed clearance (hazard ratio, 2.3; 95% CI, 1.4–3.8; P = 0.001) and less Candida-attributable mortality [18% versus 4% (P = 0.025)].17 Echinocandins have recently become popular as an alternative to amphotericin B in the treatment of fungal infection. A systematic review of comparative studies in fungal infections, primarily those due to Candida, has reported an overall treatment success rate of 52.6% in caspofungin-treated patients and 44.7% for amphotericin B and lipid-associated amphotericin B-treated patients.18 Caspofungin demonstrated a more favourable safety profile than amphotericin B, with significantly fewer discontinuations due to drug toxicity (odds ratio, 0.25; 95% CI, 0.07–0.85) and significantly less nephrotoxicity, hypokalaemia and fever.18 These findings support the use of caspofungin as an alternative treatment to amphotericin B, but underline the need to improve clinical outcome. Resistance to caspofungin has been increasingly reported and hsp90 is implicated in this process.14,15,19 This raises the qu
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The recombinant antibody against C. albicans Hsp90 demonstrated synergy with caspofungin in a murine model.
“This antibody also demonstrated synergy with the echinocandin caspofungin in a murine model [53].”
From Hsp90 Governs Echinocandin Resistance in the Pathogenic Yeast Candida albicans via Calcineurin (2009) · cites this paper as [53]
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- Authors
- Hodgetts, S., Nooney, L., Al-Akeel, R., Curry, A., Awad, S., Matthews, R., & Burnie, J.
- Affiliations
- Manchester Royal Infirmary (GB)
- Corresponding author
- Burnie, J.
- Venue
- Journal of Antimicrobial Chemotherapy
- Publisher
- Oxford University Press (OUP)
- Published
- 2008-03-06
- Volume
- 61
- Issue
- 5
- Pages
- 1132-1139
- ISSN
- 0305-7453 (ISSN-L)
- 1460-2091
- OpenAlex
- W2170911130
- Cited by
- 51
- References
- 37
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 2 · 2022: 1 · 2021: 1 · 2020: 4 · 2018: 2 · 2017: 5 · 2016: 1 · 2015: 3 · 2014: 7 · 2013: 7 · 2012: 3
- FWCI
- 2.80
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Antimicrobial Chemotherapy (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Keywords
- caspofungin, invasive candidiasis, Candida, HSP90, antibody-drug conjugates, combination therapy, synergistic effect, fluconazole resistance, Candida glabrata, Candida tropicalis, Candida krusei, Candida parapsilosis, Candida albicans, Candida guilliermondii, antifungal susceptibility
- MeSH terms
- Caspofungin, Animals, Antibodies, Monoclonal, Antifungal Agents, Candida, Candidiasis, Dose-Response Relationship, Drug, Drug Synergism, Female, Humans, Immunoglobulin Variable Region, Microbial Sensitivity Tests, Species Specificity, Mice, Echinocandins, Lipopeptides
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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