Breaking the mould – novel diagnostic and therapeutic strategies for invasive pulmonary aspergillosis in the immune deficient patient

Abstract

Invasive pulmonary aspergillosis (IPA) caused by the ubiquitous environmental fungus Aspergillus is a frequently fatal lung disease of immunocompromised humans accounting for more than 200,000 infections each year, with an associated mortality rate of 30–90%. This review addresses the current status of IPA diagnosis and treatment and the urgent need to develop accurate, non-invasive strategies for identifying pulmonary infections in the ever-expanding population of immune deficient patients at risk of acquiring opportunistic fungal infections including hematological malignancy and hematopoetic stem cell transplant patients. Recent advances in the use of an Aspergillus-specific monoclonal antibody, JF5, for point-of-care diagnosis of IPA using lateral-flow technology is examined, as is its use in PET/MRI bioimaging and radio-immunotherapy using radionuclide-labeled single chain antibody fragments, Fab fragments, and a fully humanized JF5 derivative.

Keywords::

• bioimaging
• hematological malignancy
• invasive pulmonary aspergillosis
• monoclonal antibody
• PET/MRI
• radioimmunotherapy
• stem cell transplant
• vaccine

Financial & competing interests disclosure

The funding for this article is supported by a grant from the European Commission FP7 program HEALTH.2013.12-1 (MATHIAS – New Molecular-Functional Imaging Technologies and Therapeutic Strategies for Theranostic of Invasive Aspergillosis, Project No. 602820). The author is an Associate Professor of Fungal Immunology at the University of Exeter and CEO of the University spin-out company Isca Diagnostics Ltd., manufacturer of the Aspergillus LFD described in this review. The author is also the named inventor of the JF5 monoclonal antibody. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• In the absence of a ‘gold standard' test for diagnosis, invasive pulmonary aspergillosis (IPA) detection is multifaceted relying on data from patient history, radiology and microbiology.

• Treatment of IPA is biased toward antifungal prophylaxis, with toxicities and high costs associated with mould-active drugs.

• Non-invasive and highly accurate methods of detection that are compatible with routine hospital diagnostic procedures are needed to drive timely and efficacious antifungal treatment.

• Antibody-guided bioimaging using PET/MRI and radioimmunotherapy holds enormous potential for the non-invasive identification of IPA in the immunodeficient patient.

• The Aspergillus-specific monoclonal antibody JF5, currently incorporated into a diagnostic lateral-flow device, is being used to develop antibody fragments (single-chain variable fragments and Fab) and a fully humanized antibody derivative to develop radionuclide tracers for bioimaging and radioimmunotherapy of IPA.

Notes