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Professor Sir Mark Brian Pepys MA MD PhD FRCP FRCPath FRS FMedSci is the Director of University College London’s Wolfson Drug Discovery Unit, which he founded in 2011, and he is Honorary Consultant Physician at the Royal Free London NHS Foundation Trust. From 1999 until 2011 he was Professor and Head of the Department of Medicine at the Royal Free Campus of University College London, and Director of the UCL Centre for Amyloidosis and Acute Phase Proteins. He established the UK National Health Service National Amyloidosis Centre at the Royal Free Campus in 1999. He was created Knight Bachelor for Services to Biomedicine in the 2012 New Year Honours.

= Education =

Mark Pepys was born in Cape Town, South Africa and came to the UK in 1948. He was educated at Trinity College Cambridge, where he was a Senior Scholar, and took a double first in the Natural Sciences Tripos. After qualifying in medicine at University College Hospital Medical School, he obtained the Membership of the Royal College of Physicians (London). He then returned to Cambridge for his PhD in immunology and was elected to a Fellowship at Trinity in 1973 for his discovery of the role of complement in induction of antibody production. = Career appointments =

After training in clinical medicine and continued immunology research at the Royal Postgraduate Medical School, Pepys was appointed Head of the Department of Immunology at the Royal Free Hospital School of Medicine in 1976. In 1977 he returned to the Royal Postgraduate Medical School as Senior Lecturer/Consultant Physician and established the Immunological Medicine Unit, which became one of the world’s leading centers for basic and clinical research on the acute phase response and amyloidosis. He was appointed Professor of Immunological Medicine in 1984. In 1999 he was appointed Professor and Head of the Department of Medicine at the Royal Free Campus of University College London, and moved his whole Department there to establish the UCL Centre for Amyloidosis and Acute Phase Proteins. He also set up the UK National Health Service National Amyloidosis Centre in 1999 at the Royal Free. It is funded by the UK Department of Health to provide diagnostic and management advisory services for the whole national caseload and also sees many patients from abroad. His research has been continuously supported by the UK Medical Research Council since 1969 and he has also received generous support from the Wolfson Foundation, the Wellcome Trust and other medical charities.

He has been a member of the Medical Research Council Molecular and Cell Medicine Board (2000‑2004), the Council of the Royal Society (2003‑2005), the Council of the Academy of Medical Sciences (2004‑2006), and the Lister Institute Scientific Advisory Committee (2006‑2011). He is a member of the Wolfson Foundation Science and Medicine Panel (since 2007), the Scientific Council of le Centre Cardio-Thoracique de Monaco (since 2008) and is Chair of the Royal Society Temporary Nominating Group for Clinical Science (since 2013).

= Awards and honors =

Royal College of Physicians

Goulstonian Lecture                           1982

“C-reactive protein, amyloidosis and the acute phase response”

Lumleian Lecture                           1998

“C-reactive protein and amyloidosis: from proteins to drugs?”

Moxon Trust Medal for Clinical Research               1999

Harveian Oration                           2007

“Science and Serendipity”

Royal College of Pathologists

Kohn Lecture                               1991

“Serum amyloid P component: molecular interactions and

clinical applications”

Royal College of Surgeons of England

Sir Arthur Sims Commonwealth Travelling Professorship        1991

Royal Society of London

Fellow                                    1998

GlaxoSmithKline Prize and Lecture                    2007

https://royalsociety.org/events/2008/proteins-drugs/.

Academy of Medical Sciences

Founder Fellow                            1998

Keynote Lecture, New Fellows’ Admissions Day           2009

“Therapeutic targeting: a tale of three proteins”

Renal Association

Chandos Lecture                           2000

“Prognostic and pathogenetic significance of C-reactive protein”

British Society for Rheumatology

Heberden Medal and Oration                       2002

“Pentraxins in rheumatology: physiology, pathology and new drugs”

University College London

Fellow                                    2003

American Society of Nephrology

State of the Art Lecture                       2003

“Recent advances in systemic amyloidosis”

Israel Society for Rheumatology

Gerald Loewi Memorial Lecture                   2004

“Amyloidosis and C-reactive protein: from old molecules to new drugs” 

Imperial College London

Fellow, Faculty of Medicine                        2004

Ernst Chain Prize for Medical Discovery and Lecture        2008

“Towards curing amyloidosis”

Royal Society of Medicine

Richard Kovacs Lecture                       2009

“C-reactive protein and inflammation”

Michael Feiwel Memorial Lecture                   2010

“Progress in amyloidosis”

Medical Research Society

Gordon Cumming Memorial Lecture                   2010

“Designer drugs for deadly diseases”

University of Dundee

Adam Neville Lecture                           2010

“Designer drugs for plasma protein targets”

International Society for Amyloidosis

Enno Mandema Memorial Lecture                   2012

“Amyloidosis 1979-2012…..”

Trinity College, Cambridge

Fellow                                   1973

Honorary Fellow                           2014

= Research =

After his seminal 1972 discovery of the role of complement in the induction of antibody production, and his subsequent studies in this field, Mark Pepys has mostly worked on amyloid and acute phase proteins. He has illuminated the pathogenesis and natural history of systemic amyloidosis, transforming diagnosis of this fatal disease, and improving management and survival. He has also elucidated the structural properties, function and clinical significance of serum amyloid P component (SAP) and C-reactive protein (CRP). He first identified these proteins as therapeutic targets, and has developed new drugs aimed at them.

His invention of in vivo scintigraphy with radiolabelled SAP enabled systemic amyloidosis for the first time to be safely, non-invasively diagnosed and quantitatively monitored. This revolutionized understanding of the natural history of amyloidosis and its response to therapy, and has guided radical therapeutic developments, especially by focusing attention on the crucial importance of reducing the abundance of the protein precursors of amyloid fibrils. Some of the fatal hereditary amyloidoses are now curable by liver transplantation, and the prognosis of acquired disease has been greatly improved. Pepys has discovered many of the mutations responsible for hereditary amyloidosis, including the first mutations in the human lysozyme gene. These enabled his team to show that the amyloidogenic lysozyme variants are less stable than wild type lysozyme and to develop the widely accepted general model of amyloid fibrillogenesis. His detailed characterizations of the phenotypes of hereditary amyloidosis have greatly improved investigation and management of systemic amyloid in general.

Pepys first suggested a small molecule therapy for amyloidosis in 1984. His novel SAP targeting drug, hexanoyl bis(D-proline), CPHPC, reported in Nature in 2002, was recognized by the American Chemical Society as one of the medicinal chemistry highlights of that year. It is a small molecule palindromic ligand which cross-links pairs of circulating SAP molecules, thereby uniquely triggering their immediate clearance from the circulation, and it thus depletes SAP from systemic amyloid deposits and from the brain in Alzheimer’s disease. He has demonstrated that the drug may stabilize organ function in some amyloidosis patients. The capacity of CPHPC to deplete SAP from the brain offers an exciting new therapeutic prospect for Alzheimer’s disease which is about to be tested in the DESPIAD clinical trial starting in 2016. His invention of the combination of CPHPC and antibody to serum amyloid P component for treatment of systemic amyloidosis is being developed in collaboration with GlaxoSmithKline. The very encouraging first in human study in systemic amyloidosis patients, showing unprecedented clinically beneficial clearance of visceral amyloid deposits, was published in the New England Journal of Medicine in 2015. The intervention has received Orphan Drug status from the FDA and the European Medicines Agency, which has also adopted it as a leading candidate for adaptive licensing and a phase 2 study is scheduled for 2016.

Pepys’s demonstration that CRP increases ischaemic myocardial and cerebral damage in vivo, was the first validation of CRP as a potential therapeutic target. His success in targeting SAP enabled his rational design of bis(phosphocholine)-hexane, the first specific inhibitor of CRP, reported in Nature in 2006. Ongoing development of more medicinal CRP inhibitor compounds for treatment of conditions associated with greatly increased CRP production has been supported by the UK Medical Research Council and the British Heart Foundation. Pepys identified the first definite in vivo function of autologous CRP, contributing to innate host defense against pneumococcal infection, and also showed that human CRP is not pro-inflammatory or otherwise pathogenic in healthy individuals. He played a leading role in establishing the routine use of CRP testing in clinical practice, and produced the World Health Organization’s International Immunoassay Reference Standards for CRP , serum amyloid A protein , and thyroxine binding globulin.

= References =