Single human B cell-derived monoclonal anti-Candida antibodies enhance phagocytosis and protect against disseminated candidiasis

Fiona M Rudkin; Ingrida Raziunaite; Hillary Workman; Sosthene Essono; Rodrigo Belmonte; Donna M MacCallum; Elizabeth M Johnson; Lisete M Silva; Angelina S Palma; Ten Feizi; Allan Jensen; Lars P Erwig; Neil A. R. Gow

doi:10.1038/s41467-018-07738-1

Single human B cell-derived monoclonal anti-Candida antibodies enhance phagocytosis and protect against disseminated candidiasis

Fiona M Rudkin, Ingrida Raziunaite, Hillary Workman, Sosthene Essono, Rodrigo Belmonte, Donna M MacCallum, Elizabeth M Johnson, Lisete M Silva, Angelina S Palma, Ten Feizi, Allan Jensen, Lars P Erwig, Neil A. R. Gow^* (Corresponding Author)

^*Corresponding author for this work

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Abstract

The high global burden of over one million annual lethal fungal infections reflects a lack of protective vaccines, late diagnosis and inadequate chemotherapy. Here, we have generated a unique set of fully human anti-Candida monoclonal antibodies (mAbs) with diagnostic and therapeutic potential by expressing recombinant antibodies from genes cloned from the B cells of patients suffering from candidiasis. Single class switched memory B cells isolated from donors serum-positive for anti-Candida IgG were differentiated in vitro and screened against recombinant Candida albicans Hyr1 cell wall protein and whole fungal cell wall preparations. Antibody genes from Candida-reactive B cell cultures were cloned and expressed in Expi293F human embryonic kidney cells to generate a panel of human recombinant anti-Candida mAbs that demonstrate morphology-specific, high avidity binding to the cell wall. The species-specific and pan-Candida mAbs generated through this technology display favourable properties for diagnostics, strong opsono-phagocytic activity of macrophages in vitro, and protection in a murine model of disseminated candidiasis.

Original language	English
Article number	5288
Number of pages	16
Journal	Nature Communications
Volume	9
DOIs	https://doi.org/10.1038/s41467-018-07738-1
Publication status	Published - 11 Dec 2018

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Single human B cell-derived monoclonal anti-Candida antibodies enhance phagocytosis and protect against disseminated candidiasis
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Fiona Rudkin
- School of Medicine, Medical Sciences & Nutrition, Medical Sciences - Research Fellow
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Iain Fraser Cytometry Centre
Andrea Holme (Manager), Linda Duncan (Senior Application Scientist), Ailsa Laird (Technician) & Kate Burgoyne (Technician)
Institute of Medical Sciences
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Microscopy and Histology
Debbie Wilkinson (Manager) & Gillian Milne (Manager)
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Rudkin, F. M., Raziunaite, I., Workman, H., Essono, S., Belmonte, R., MacCallum, D. M., Johnson, E. M., Silva, L. M., Palma, A. S., Feizi, T., Jensen, A., Erwig, L. P., & Gow, N. A. R. (2018). Single human B cell-derived monoclonal anti-Candida antibodies enhance phagocytosis and protect against disseminated candidiasis. Nature Communications, 9, [5288]. https://doi.org/10.1038/s41467-018-07738-1

Rudkin, FM, Raziunaite, I, Workman, H, Essono, S, Belmonte, R, MacCallum, DM, Johnson, EM, Silva, LM, Palma, AS, Feizi, T, Jensen, A, Erwig, LP & Gow, NAR 2018, 'Single human B cell-derived monoclonal anti-Candida antibodies enhance phagocytosis and protect against disseminated candidiasis', Nature Communications, vol. 9, 5288. https://doi.org/10.1038/s41467-018-07738-1

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title = "Single human B cell-derived monoclonal anti-Candida antibodies enhance phagocytosis and protect against disseminated candidiasis",

abstract = "The high global burden of over one million annual lethal fungal infections reflects a lack of protective vaccines, late diagnosis and inadequate chemotherapy. Here, we have generated a unique set of fully human anti-Candida monoclonal antibodies (mAbs) with diagnostic and therapeutic potential by expressing recombinant antibodies from genes cloned from the B cells of patients suffering from candidiasis. Single class switched memory B cells isolated from donors serum-positive for anti-Candida IgG were differentiated in vitro and screened against recombinant Candida albicans Hyr1 cell wall protein and whole fungal cell wall preparations. Antibody genes from Candida-reactive B cell cultures were cloned and expressed in Expi293F human embryonic kidney cells to generate a panel of human recombinant anti-Candida mAbs that demonstrate morphology-specific, high avidity binding to the cell wall. The species-specific and pan-Candida mAbs generated through this technology display favourable properties for diagnostics, strong opsono-phagocytic activity of macrophages in vitro, and protection in a murine model of disseminated candidiasis.",

author = "Rudkin, {Fiona M} and Ingrida Raziunaite and Hillary Workman and Sosthene Essono and Rodrigo Belmonte and MacCallum, {Donna M} and Johnson, {Elizabeth M} and Silva, {Lisete M} and Palma, {Angelina S} and Ten Feizi and Allan Jensen and Erwig, {Lars P} and Gow, {Neil A. R.}",

note = "We thank the BBSRC, SULSA BioSKAPE and Pfizer Inc. for funding for a studentship for F.M.R. and the Wellcome Trust (086827, 075470, 099215, 099197 and 101873) and a Wellcome Trust ISSF award (105625), MRC CiC (MC_PC_14114) and MRC Centre for Medical Mycology and University of Aberdeen for funding and a Wellcome Trust Strategic Award (097377) and a Wellcome Trust grant 099197MA to T.F. and FCT Investigator IF/00033/2012 and PTDC/QUI-QUI/112537/2009 to A.S.P. We thank Ian Broadbent, Angus McDonald and Ron Gladue for constructive discussions; Chris Boston and Amanda Fitzgerald for advice on antibody expression and purification; Ed Lavallie and Wayne Stochaj for design and expression of the recombinant Hyr1; Louise Walker for high-pressure freezing of samples for TEM analysis; Jeanette Wagener for endotoxin testing of mAbs for in vivo experiments; Yan Liu of the Glycosciences laboratory for insight in the analysis with N-glycan array; Rebecca Hall and Mark Gresnigt for providing fungal strains; Andrew Limper and Theodore J. Kottom for providing Pneumocystis infected lung tissue extracts; David Williams for C. albicans mannoprotein; Christopher Thornton for A. fumigatus mannoprotein; Katie J. Doores for mAb PGT 128; and Gordon Brown for the murine Fc-Dectin-1. We are grateful to Lucinda Wight, Debbie Wilkinson and Kevin MacKenzie in the Microscopy and Histology Core Facility (Aberdeen University) and Raif Yuecel in the Iain Fraser Cytometry Centre (Aberdeen University) for their expert help with microscopy and cytometry experiments. We are also grateful to the staff at the University of Aberdeen Medical Research Facility for assistance with in vivo experiments and members of the Glycosciences Laboratory for their support of the Carbohydrate Microarray Facility. 18 January 2019 - Author Correction: Single human B cell-derived monoclonal anti-Candida antibodies enhance phagocytosis and protect against disseminated candidiasis F. M. Rudkin, I. Raziunaite, H. Workman, S. Essono, R. Belmonte, D. M. MacCallum, E. M. Johnson, L. Silva, A. S. Palma, T. Feizi, A. Jensen, L. P. Erwig & N. A. R. Gow Nature Communicationsvolume 10, Article number: 394 (2019) ",

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T1 - Single human B cell-derived monoclonal anti-Candida antibodies enhance phagocytosis and protect against disseminated candidiasis

AU - Rudkin, Fiona M

AU - Raziunaite, Ingrida

AU - Workman, Hillary

AU - Essono, Sosthene

AU - Belmonte, Rodrigo

AU - MacCallum, Donna M

AU - Johnson, Elizabeth M

AU - Silva, Lisete M

AU - Palma, Angelina S

AU - Feizi, Ten

AU - Jensen, Allan

AU - Erwig, Lars P

AU - Gow, Neil A. R.

N1 - We thank the BBSRC, SULSA BioSKAPE and Pfizer Inc. for funding for a studentship for F.M.R. and the Wellcome Trust (086827, 075470, 099215, 099197 and 101873) and a Wellcome Trust ISSF award (105625), MRC CiC (MC_PC_14114) and MRC Centre for Medical Mycology and University of Aberdeen for funding and a Wellcome Trust Strategic Award (097377) and a Wellcome Trust grant 099197MA to T.F. and FCT Investigator IF/00033/2012 and PTDC/QUI-QUI/112537/2009 to A.S.P. We thank Ian Broadbent, Angus McDonald and Ron Gladue for constructive discussions; Chris Boston and Amanda Fitzgerald for advice on antibody expression and purification; Ed Lavallie and Wayne Stochaj for design and expression of the recombinant Hyr1; Louise Walker for high-pressure freezing of samples for TEM analysis; Jeanette Wagener for endotoxin testing of mAbs for in vivo experiments; Yan Liu of the Glycosciences laboratory for insight in the analysis with N-glycan array; Rebecca Hall and Mark Gresnigt for providing fungal strains; Andrew Limper and Theodore J. Kottom for providing Pneumocystis infected lung tissue extracts; David Williams for C. albicans mannoprotein; Christopher Thornton for A. fumigatus mannoprotein; Katie J. Doores for mAb PGT 128; and Gordon Brown for the murine Fc-Dectin-1. We are grateful to Lucinda Wight, Debbie Wilkinson and Kevin MacKenzie in the Microscopy and Histology Core Facility (Aberdeen University) and Raif Yuecel in the Iain Fraser Cytometry Centre (Aberdeen University) for their expert help with microscopy and cytometry experiments. We are also grateful to the staff at the University of Aberdeen Medical Research Facility for assistance with in vivo experiments and members of the Glycosciences Laboratory for their support of the Carbohydrate Microarray Facility. 18 January 2019 - Author Correction: Single human B cell-derived monoclonal anti-Candida antibodies enhance phagocytosis and protect against disseminated candidiasis F. M. Rudkin, I. Raziunaite, H. Workman, S. Essono, R. Belmonte, D. M. MacCallum, E. M. Johnson, L. Silva, A. S. Palma, T. Feizi, A. Jensen, L. P. Erwig & N. A. R. Gow Nature Communicationsvolume 10, Article number: 394 (2019)

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Y1 - 2018/12/11

N2 - The high global burden of over one million annual lethal fungal infections reflects a lack of protective vaccines, late diagnosis and inadequate chemotherapy. Here, we have generated a unique set of fully human anti-Candida monoclonal antibodies (mAbs) with diagnostic and therapeutic potential by expressing recombinant antibodies from genes cloned from the B cells of patients suffering from candidiasis. Single class switched memory B cells isolated from donors serum-positive for anti-Candida IgG were differentiated in vitro and screened against recombinant Candida albicans Hyr1 cell wall protein and whole fungal cell wall preparations. Antibody genes from Candida-reactive B cell cultures were cloned and expressed in Expi293F human embryonic kidney cells to generate a panel of human recombinant anti-Candida mAbs that demonstrate morphology-specific, high avidity binding to the cell wall. The species-specific and pan-Candida mAbs generated through this technology display favourable properties for diagnostics, strong opsono-phagocytic activity of macrophages in vitro, and protection in a murine model of disseminated candidiasis.

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JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

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Single human B cell-derived monoclonal anti-Candida antibodies enhance phagocytosis and protect against disseminated candidiasis

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