Efungumab is also known as Mycograb (trade name) as an anti-fungal drug intended to treat invasive Candida infection in combination with amphotericin B. It is a recombinant human single-chain variable antibody fragment drug developed by NeuTec Pharma, which is a subsidiary of Novartis. Efungumab was designed as scFv-fragment to “grabs” onto fungal heat shock protein 90 (Hsp90) better. Invasive candidiasis is different with oral candidiasis and candidal vulvovaginitis as it can induced a serious infection that can affect the blood, heart, brain, eyes, bones, and other parts of the body. Invasive candidiasis can be induced by multiple species of Candida. Of which, C. albicans has been responsible for 95% of infections over the last 20-30 years. While C. glabrata, C. parapsilosis, C. tropicalis, and C. krusei is the main pathogen of the majority of the remaining cases. The type and dose of antifungal drugs are usually selected according to the patient's condition. The initial study reported that efungumab against Candida synergize with amphotericin B (AMB) in vitro. And it was developed as an adjunctive agent in the treatment of invasive candidiasis. However, due to some unsolved technical problems, such as high immunogenicity, aggregation trend of active substances, etc., the Committee for Medicinal Products for Human Use (CHMP) did not approve it in March 2007. Although it has been awarded the title of orphan drug by the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA). The recently Phase-III research of efungumab was discontinued in 2010.
Efungumab was designed as an antifungals which works by inhibiting the activity of yeast antigen heat shock protein hsp90 (rhMAB-hsp90). Hsp90 is one of the common heat shock proteins (HSPs), which plays important roles in regulating the balance of protein synthesis and degradation and protein localization. The main function of HSPs is to maintain the correct folding of its client proteins, making that proteins can form the conformation required for physiological function. Hsp90 can participate in protein activation and maturation by binding to the client protein which has formed a tertiary structure. In addition, hsp90 is also found to stabilize a number of proteins required for tumor growth. Thus, it is considered to be a potential target for tumor therapy. Hsp90 is also essential for the viability of the yeast. Efungumab in combination with amphotericin-B and showed significantly repress to all five species of Candida. The antifungal mechanism of efungumab might prevent the conformational changes of proteins needed for fungal activity by binding to hsp90, effecting the survival of fungal.
Fig.1 Mechanism of Action of Efungumab