Pentraxins and amyloidosis: from molecular mechanisms to medicines

Lead Research Organisation: University College London
Department Name: Unlisted

Abstract

We have invented a platform technology for creation of drugs to target any blood protein that causes disease and are using it to develop new medicines.  Our most advanced drug compound targets serum amyloid P component (SAP) and is undergoing clinical testing in amyloidosis, Alzheimer’s disease and osteoarthritis.  It may also be useful in type 2, maturity onset, diabetes.  Other drugs are being designed to treat and prevent hitherto untreatable lethal forms of inherited and acquired amyloidosis.  Our drug which targets C?reactive protein (CRP) is beneficial in rat models of heart attack and stroke, and will be developed for clinical trials.
 
The MRC has funded, continuously since 1979, our research on CRP and SAP, which are related human blood proteins, and our work on amyloidosis, a usually fatal disease.  We study the individual proteins, their interactions with each other and with cells, and animal models of human disease, and we also perform clinical testing in patients.
 
We have introduced new methods of diagnosis and treatment that improve quality and duration of life for most patients who attend the world leading NHS National Amyloidosis Centre in our Department.  We will continue to refine and develop these methods.

Technical Summary

We have elucidated much of the molecular pathogenesis, natural history and response to treatment of amyloidosis, as well as the structures and functions of the pentraxins and their roles in disease, but effective therapies are still urgently required. Our discoveries have enabled us to develop a powerful new drug, CPHPC, with a novel pharmacological mechanism of action that both inhibits ligand binding by serum amyloid P component (SAP) and depletes it from the circulation. Clinical testing of CPHPC in amyloidosis is providing promising results, has revealed an unexpected possible application in osteoarthritis, and has informed our rational design of other new drug compounds to target C-reactive protein (CRP) and amyloid fibril precursor proteins. We now aim:
1] to implement this translational research to create new medicines and treatments, including: the continued evaluation and development of CPHPC in systemic amyloidosis; clinical evaluation of CPHPC in Alzheimer?s disease and osteoarthritis; proof of principle demonstration that inhibitors of CRP binding abrogate the tissue damaging effects of human CRP in vivo, opening the way to development of cardioprotective and neuroprotective drugs for clinical use; and continued design, synthesis and experimental evaluation of our novel compounds targeting amyloid fibril precursor proteins, successful outcomes of which will lead swiftly to their clinical development.
2] to continue exploring the roles of pentraxins in health and disease, including: the role of human CRP in experimental murine atherosclerosis and atherothrombosis in vivo, and in human foam cell formation and tissue factor production in vitro; further epidemiological studies of CRP in cardiovascular disease; the role of SAP in the islet amyloid and clinical expression of experimental murine type 2 diabetes; the role of human SAP in the normal glomerular basement membrane and in host defence against Shiga toxins.
3] to vigorously pursue our collaborative studies of the structures of CRP, SAP and their complexes with low molecular weight ligands, peptides, proteins and amyloid fibrils that invaluably subtend all our work on drug design and development as well as providing critical fundamental knowledge of these important molecules.
4] to sustain our very productive and wide ranging clinical research programme on the causes, pathogenesis, diagnosis and treatment of human amyloidosis and the hereditary periodic fever syndromes.

Publications

10 25 50
 
Guideline Title Guidelines on the diagnosis and management of AL amyloidosis. Guidelines Working Group of UK Myeloma Forum; British Committee for Standards in Haematology, British Society for Haematology.
Description Amyloidosis Diagnostics
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical guidelines
Impact The National Amyloidosis Centre sees more than 3,000 patients per year. The diagnostic service provided by the Centre is based on radiolabelled scintigraphy, a safe, non-invasive diagnostic and monitoring technique invented by Mark Pepys and developed into a routine clinical test by Philip Hawkins during his PhD (1986-89). Due to its complexity, sophistication and cost, the method is available only in the National Amyloidosis Centre and in one other Centre, in Groningen, Holland, which is collaboratively supported by the National Amyloidosis Centre. However the test is the envy of the world and has enabled the National Amyloidosis Centre to develop world leading experience and expertise in all aspects of amyloidosis, involving the largest and most diverse cohort of patients with this disease in the world. The Centre has delivered both new fundamental scientific knowledge and substantial improvements in clinical management leading to greatly improved patient survival, the best for this disease in the world.
 
Description British Heart Foundation
Amount £677,715 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2012 
End 06/2015
 
Description MRC Biomarkers Grant
Amount £1,034,631 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 05/2007 
End 05/2010
 
Description MRC Strategic Skills Award
Amount £201,353 (GBP)
Funding ID MR/K000187/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 01/2012 
End 01/2015
 
Description NC3R's Project Grant
Amount £377,634 (GBP)
Organisation National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) 
Sector Public
Country United Kingdom
Start 03/2009 
End 02/2012
 
Description NIHR Strategic Award via UCLH/UCL BRC
Amount £2,750,798 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start  
End 11/2021
 
Description NIHR UCLH/UCL BRC Core Support for Wolfson Drug Discovery Unit
Amount £125,000 (GBP)
Organisation National Institute for Health Research 
Department UCLH/UCL Biomedical Research Centre
Sector Academic/University
Country United Kingdom
Start 09/2016 
End 03/2017
 
Description NIHR UCLH/UCL BRC Core Support for Wolfson Drug Discovery Unit
Amount £1,000,000 (GBP)
Organisation National Institute for Health Research 
Department UCLH/UCL Biomedical Research Centre
Sector Academic/University
Country United Kingdom
Start 03/2017 
End 03/2022
 
Description NIHR UCLH/UCL BRC Core Support for Wolfson Drug Discovery Unit (Supplement)
Amount £150,000 (GBP)
Organisation National Institute for Health Research 
Department UCLH/UCL Biomedical Research Centre
Sector Academic/University
Country United Kingdom
Start 11/2018 
End 03/2022
 
Description UCL Technology Fund Licensing Project Investment
Amount £1,280,000 (GBP)
Organisation University College London 
Sector Academic/University
Country United Kingdom
Start 03/2018 
End 02/2021
 
Description UCL/UCLH BRC
Amount £900,000 (GBP)
Organisation National Institute for Health Research 
Department UCLH/UCL Biomedical Research Centre
Sector Academic/University
Country United Kingdom
Start 06/2012 
End 07/2016
 
Description UCL/UCLH BRC
Amount £1,000,000 (GBP)
Organisation National Institute for Health Research 
Department UCLH/UCL Biomedical Research Centre
Sector Academic/University
Country United Kingdom
Start 08/2013 
End 11/2014
 
Description Wellcome Seeding Drug Discovery Strategic Award
Amount £3,891,205 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2007 
End 09/2010
 
Description Wolfson Foundation Equipment Grant for proteomic mass spectrometry facility
Amount £330,000 (GBP)
Organisation The Wolfson Foundation 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Title Anti-SAP mAbs 
Description monoclonal antibodies to SAP - designed to bind to SAP and clear amyloid 
Type Of Material Antibody 
Year Produced 2009 
Provided To Others? Yes  
Impact In 2009 GSK licensed Pepys's patents on his invention of the obligate therapeutic partnership of CPHPC and monoclonal anti-SAP antibodies for treatment of systemic amyloidosis. The invention was published in Nature 4 November 2010. It has now been developed for human use and is in its first in human clinical trial with very encouraging results. Orphan drug status has been conferred by the EMA and it is their flagship candidate for adaptive licensing. 
 
Title Anti-serum amyloid P component antibodies 
Description A range of novel antibodies to human serum amyloid P component have been developed and characterised for use in in vitro and in vivo experimental, therapeutic and diagnostic studies. 
Type Of Material Antibody 
Provided To Others? No  
Impact Publication of a novel assay method and unique clinical research results. 
 
Title Assays for human SAP 
Description IRMA assay to measure SAP levels in serum, plasma and CSF at the ng level 
Type Of Material Technology assay or reagent 
Year Produced 2010 
Provided To Others? Yes  
Impact Ability to sensitively measure the amount of SAP present in samples of serum, plasma and CSF. 
 
Title GMP SAP and CRP 
Description The human pentraxin proteins, serum amyloid P component (SAP) and C reactive protein (CRP) are important in routine clinical diagnosis, SAP for systemic amyloidosis and CRP for monitoring the non-specific acute phase response. They are also targets for novel therapies currently in development but their roles in health and disease are controversial. Thus, both for clinical use and to rigorously elucidate their functions, structurally and functionally intact, pharmaceutical grade preparations of the natural, authentic proteins are required. Prof Sir Mark Pepys's group has produced and characterised the first such preparations from normal human donor plasma. 
Type Of Material Technology assay or reagent 
Year Produced 2012 
Provided To Others? Yes  
Impact These structurally and functionally intact, pharmaceutical grade preparations of the natural, authentic proteins will enable rigourous elucidation of their functions as well as being suitable for clinical use. 
 
Title SAA transgenic mouse model of amyloidosis 
Description Transgenic mouse capable of overexpressing SAA on ingestion of tetracycline, and forming amyloid 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact New mouse model that develops amyloidosis without having to induce inflammation. This is kinder to the mice and also more closely resembles the human disease 
 
Description Brain SAP content and cognition in the elderly at death 
Organisation University of Cambridge
Department MRC Cognitive Function and Ageing Study (CFAS)
Country United Kingdom 
Sector Academic/University 
PI Contribution Pepys is investigating the role of human serum amyloid P component (SAP) in neurodegeneration and seeks a relationship between the presence, distribution and amount of SAP in different brain regions of elderly individuals whose cognitive status at the time fo death is well established. Pepys has world leading expertise in all aspects of the study of SAP.
Collaborator Contribution The MRC CFAS Tissue Resource is unique and uniquely able to provide the large number of samples required for this study.
Impact The study is just starting.
Start Year 2012
 
Description CPHPC and anti SAP antibody collaboration with GSK 
Organisation GlaxoSmithKline (GSK)
Country Global 
Sector Private 
PI Contribution We have invented a new treatment for systemic amyloidosis and licensed the relevant IP and proprietary knowledge to GSK for full scale clinical development to be conducted in collaboration with our team, each party contributing their particular expertise and resource in a synergistic programme aimed at the earliest possible clinical testing and commercial development.
Collaborator Contribution GSK have fully humanised our mouse optimal monoclonal antibody, conducted animal toxicology with it in mice treated with our small molecule drug CPHPC and conducted phase I studies of CPHPC in healthy volunteers and patients with systemic amyloidosis. The entirely favourable results have enabled progression to a phase I study of the obligate therapeutic partnership of CPHPC and anti-SAP antibody in amyloidosis patients, which is now giving favourable results. All this development work is absolutely dependent on very close and continuous interactions between the unique expertise of our group and that of GSK.
Impact A full scale clinical development programme is in progress in which GSK are progressing our small molecule drug, CPHPC, and have already humanised our mouse monoclonal antibodies to human serum amyloid P component. We continue, now without MRC support, to conduct the essential experimental component of the programme. A Phase 1, Open Label, Dose Characteristic Study to Investigate the pharmacokinetics, pharmacodynamics, safety, and tolerability of Intravenous and subcutaneous doses of CPHPC in patients with systemic amyloidosis was conducted by GSK in 2012 enabling progression to a single dose first in human study of anti-SAP antibodies co-administered with CPHPC in patients with systemic amyloidosis. This started in Q3 2013 and is providing very encouraging results which are currently being written up for publication. GSK have recognised achievement of Clinical Proof of Mechanism and have accordingly paid a substantial milestone payment to Pentraxin Therapeutics Ltd. The European Medicines Agency have awarded Orphan Drug Status to the potential product and furthermore have adopted it as their flagship candidate for adaptive licensing. The original patent applications, licensed to GSK for this programme, have been granted and GSK have filed new patents as the work proceeds.
Start Year 2009
 
Description CRP CFH interaction (Prof Paul Morgan) 
Organisation Cardiff University
Department School of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution We provided expertise, reagents and experiments for a very productive collaboration leading to novel and important results. We showed that human CRP is bound by CFH only when the CRP is denatured, with important implications for speculation about the possible pathogenic role of these proteins in AMD.
Collaborator Contribution Morgan and his team provided expertise, reagents and experiments for a very productive collaboration leading to novel and important results.
Impact 18786923.
Start Year 2006
 
Description CRP is not immunomodulatory in vivo (Prof Marina Botto) 
Organisation University of Oxford
Department Kennedy Institute of Rheumatology
Country United Kingdom 
Sector Academic/University 
PI Contribution We provided world leading expertise in all aspects of CRP, including provision of highly purified authentic functionally fully active protein, as well as contributing to experimental design and writing the paper.
Collaborator Contribution Synergistic collaboration enabled us to demonstrate that published reports of potent in vivo immunomodulation by human C-reactive protein were not reproducible. The Botto team are expert in the relevant animal models.
Impact Publication: Carlucci, F., Cook, H.T., Garg, A., Pepys, M.B. and Botto, M. (2009) Single injection of human C-reactive protein has no effect on murine lupus or nephrotoxic nephritis. Arth. Rheum. (in press).
Start Year 2007
 
Description DNA Vaccination (Prof Thomas Hanke) 
Organisation University of Oxford
Department Nuffield Department of Clinical Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution The goal of the project is to demonstrate that DNA vaccination of normal human volunteers in whom circulating human serum amyloid P component (SAP) has been depleted by the drug, (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxohexanoyl] pyrrolidine-2-carboxylic acid (CPHPC), induces an enhanced immune response compared to the same vaccination in control subjects with normal circulating SAP values. The vaccine to be used is directed at conserved epitopes of the HIV-1 virus. The objectives are: 1. Demonstrate that the T cell immune response to the three priming doses of DNA vaccine is significantly enhanced in SAP depleted subjects compared to identically vaccinated SAP sufficient control subjects. 2. Demonstrate that the T cell immune response to subsequent boosting by the cognate protein antigen, is significantly enhanced in subjects who were primed by DNA vaccination whilst SAP depleted, compared to identically vaccinated SAP sufficient control subjects. 3. Determine whether the enhanced T cell responses which may be observed after SAP depletion are more potent than the responses in controls in suppressing HIV-1 virus replication in vitro, and thus, (a) support the general concept that SAP depletion can be used to enhance the protective immunity inducible by DNA vaccination in humans, and (b) encourage further vaccination studies against conserved regions of HIV-1 in order to develop an effective protective and potentially therapeutic vaccine against this pathogen. The study will also confirm safety and tolerability of 3 courses of 24 h intravenous infusion of CPHPC, to produce maximal depletion of plasma SAP, immediately before intramuscular injection of DNA vaccine. Prof Sir Mark Pepys developed the drug CPHPC which uniquely depletes circulating SAP to extremely low concentrations and he originated the concept for the present trial. He is the inventor on the key patents covering CPHPC which are owned by his UCL spin out company. Some of the patents are licensed to GSK and they have helpfully provided the drug for the present study.
Collaborator Contribution Hanke and the Oxford team have a long track record in designing novel vaccine immunogens and vaccination regimens. They have great expertise in translational studies, comprising eleven studies involving candidate HIV-1 vaccines over the past 10 years (reviewed in ref 38 and unpublished), coupled with high level specialist expertise in measuring and characterizing vaccine-induced T cells. They are providing the unique GMP DNA vaccine for this study.
Impact MRC DCS award to fund the study which covers the disciplines of immunology and drug development.
Start Year 2012
 
Description Depletion of SAP in Alzheimer's disease by CPHPC (Prof Martin Rossor) 
Organisation University College London
Department Institute of Neurology
Country United Kingdom 
Sector Academic/University 
PI Contribution Development of CPHPC as an SAP depleting drug from conception to human studies in amyloidosis. We contributed substantially to the design and analysis of this first clinical study of CPHPC in patients with Alzheimer's disease.
Collaborator Contribution The positive findings of our exploratory clinical study provide compelling support for proceeding to a large randomised controlled trial of CPHPC in Alzheimer's disease.
Impact 19372378.
 
Description Development of canakinumab as a treatment for CAPS (Dr Thomas Jung) 
Organisation Novartis
Country Global 
Sector Private 
PI Contribution Design and execution of clinical and in vitro studies of canakinumab, a human monoclonal anti-IL-1 antibody, in patients with cryopyrin associated periodic fever syndrome.
Collaborator Contribution Publications.
Impact Launching of canakinumab as a highly effective treatment for CAPS in the EU in 2009. 19364880, 19494217.
 
Description Development of serum free light chain assays in amyloidosis (Prof Arthur Bradwell) 
Organisation The Binding Site
Country Global 
Sector Private 
PI Contribution Clinical studies to determine the utility of serum free light chain measurements in the diagnosis and management of AL amyloidosis.
Collaborator Contribution Publications.
Impact Widespread adoption throughout the world of the serum free light chain assay in the diagnosis and management of AL amyloidosis. 16822290, 18708629.
 
Description Development of serum free light chain assays in amyloidosis (Prof Arthur Bradwell) 
Organisation University of Birmingham
Department College of Medical and Dental Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Clinical studies to determine the utility of serum free light chain measurements in the diagnosis and management of AL amyloidosis.
Collaborator Contribution Publications.
Impact Widespread adoption throughout the world of the serum free light chain assay in the diagnosis and management of AL amyloidosis. 16822290, 18708629.
 
Description Development of transthyretin superstabilisers 
Organisation GlaxoSmithKline (GSK)
Country Global 
Sector Private 
PI Contribution Transthyretin is an inherently amyloidogenic protein and forms microscopic amyloid deposits in all individuals over the age of 80 years. In some aged individuals massive transthyretin amyloid deposition in the heart causes fatal senile cardiac amyloidosis, a condition which is rarely diagnosed but is almost certainly much more prevalent than currently recognised. Most of the >100 rare mutations in the human transthyretin gene increase the amyloidogenicity of the respective variant proteins and cause autosomal dominant adult onset hereditary transthyretin amyloidosis, usually presenting as familial amyloid polyneuropathy. There is currently no effective treatment for this uniformly fatal disease. Since transthyretin amyloidogenesis involves misfolding and dissociation of the native tetrameric structure of the protein, a rational therapeutic approach is the use of small molecule ligands which are specifically bound by transthyretin and stabilise its native structure and assembly. Prof Sir Mark Pepys and his research group are world leaders in the study of transthyretin misfolding and amyloid fibrillogenesis. They contribute both intellectually and practically to the design and evaluation of novel TTR stabilising ligands.
Collaborator Contribution GlaxoSmithkline are providing medicinal chemistry, drug development and Intellectual Property expertise and practical support to the programme. They are designing and synthesising novel compounds, are running a full, early stage, drug development programme and are preparing to file a patent to protect arising IP.
Impact The development programme is still at an early stage. Novel transthyretin stabilising compounds have been identified. These are being evaluated and refined for eventual clinical testing. New Intellectual Property has arisen and is being protected appropriately.
Start Year 2010
 
Description EURAMY collaboration (Prof Per Westermark and others) 
Organisation Uppsala University
Country Sweden 
Sector Academic/University 
PI Contribution This is an EU FP6 funded collaboration of 17 amyloidosis groups accross the EU. Major contribution to experimental and clinical studies.
Collaborator Contribution Improved collaboration with virtually all prominent groups working within the field of amyloidosis in Europe
Impact Improved collaboration with virtually all prominent groups working within the field of amyloidosis in Europe
Start Year 2006
 
Description Epidemiological studies of CRP in CHD (Prof John Danesh) 
Organisation University of Cambridge
Department Department of Public Health and Primary Care
Country United Kingdom 
Sector Academic/University 
PI Contribution We provide our world leading knowledge, experience and expertise in all aspects of C-reactive protein to the design, conduct and reporting of the collaborative studies.
Collaborator Contribution The combination of our world leading knowledge, experience and expertise in all aspects of C-reactive protein with the exceptional epidemiological skills deployed by Professor John Danesh, his team and his huge international set of collaborators, especially under the umbrella of the Emerging Risk Factors Collaboration (ERFC) that he established and directs, is making a unique contribution to knowledge in cardiovascular disease and more widely.
Impact The compelling results of the Emerging Risk Factors Collaboration (ERFC) observational study with 126,338 subjects and 23,587 first-ever incident vascular disease outcomes or nonvascular deaths during 1.1 million person-years of follow-up are published online in the Lancet on 22 Dec 2009. The largest ever Mendelian randomisation epidemiology study of CRP and CVD was published in BMJ in 2011. The defnitive observational study of all available data on CRP and CHD was published in the New England Journal of Medicine in 2012.
 
Description Exclusion of role for prions in systemic amyloidosis (Prof Ironside) 
Organisation University of Edinburgh
Department School of Molecular and Clinical Medicine Edinburgh
Country United Kingdom 
Sector Academic/University 
PI Contribution A collaborative study that excluded involvement of prions in the pathogenesis of systemic amyloidosis.
Collaborator Contribution Publication.
Impact 17955450.
Start Year 2006
 
Description Genetic studies of CRP and factor H (Prof Aroon Hingorani) 
Organisation University College London
Department Centre for Clinical Pharmacology & Therapeutics
Country United Kingdom 
Sector Academic/University 
PI Contribution We provide our world leading knowledge, experience and expertise in all aspects of C-reactive protein, and our expertise in complement and plasma protein immunoassay.
Collaborator Contribution Collaborative exchange of ideas, samples sets and information leading to new knowledge in the field.
Impact We developed a high throughput automated immunoassay for complement factor H (CFH) enabling the Hingorani lab to assat CFH in large scale epidemiological series of CHD and AMD patients. These important methods and results are currently being prepared for publication.
 
Description Investigation of CRP-ligand interactions by NMR 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Our work has centred on the development of palindrominic ligands as inhibitors of CRP binding to damaged and dead cells in order to prevent the exacerbation of CRP-mediated complement activation and subsequent tissue injury. We have prepared highly purified endotoxin free human CRP together with our patented CRP-crosslinking palindromic ligands for NMR analysis. This is part of our ongoing programme of rational design of novel CRP inhibitors.
Collaborator Contribution The partner and his group will undertake these high resolution NMR studies using our materials in order to gain new insights into the factors controlling CRP-ligand and CRP-CRP interactions.
Impact N/a as still very early
Start Year 2013
 
Description Islet amyloid and type 2 diabetes (Dr Gunilla Westermark) 
Organisation Linkoping University
Country Sweden 
Sector Academic/University 
PI Contribution We have shown that in human SAP transgenic mice, the human protein localises to islet amyloid deposits just as it does in man, and is therefore a valid target for treatment with our new invention for clearance of systemic amyloid deposits that is being developed with GSK. We will use our reagents to determine whether this treatment clears islet amyloid in the Westermark mice and affects their clinical diabetes.
Collaborator Contribution Westermark has created ob/ob mice expressing transgenic human IAPP which develop both clinical type 2 diabetes and islet amyloid deposits. These are ideal models for study of the role of SAP in islet amyloidosis and type 2 diabetes and especially the possible utility of such SAP as a therapeutic target for the new approaches to treatment of amyloid that we have invented.
Impact SAP is always present in the islet amyloid of human type 2 diabetes. A key positive finding in our long term collaborative study, with Dr Gunilla Westermark, of islet amyloid and type 2 diabetes in ob/ob mice expressing transgenic human IAPP with either mouse SAP deficiency or transgenic human SAP expression, is the presence of human SAP in the islet amyloid. This validates the model for testing our potent new approach to clearance of established amyloid in vivo using CPHPC plus anti SAP antibody.
 
Description Islet amyloid and type 2 diabetes (Dr Jo Hoeppener) 
Organisation Utrecht University
Country Netherlands 
Sector Academic/University 
PI Contribution We have shown that in human SAP transgenic mice, the human protein localises to islet amyloid deposits just as it does in man, and is therefore a valid target for treatment with our new invention for clearance of systemic amyloid deposits that is being developed with GSK. We will use our reagents to determine whether this treatment clears islet amyloid in the Hoeppener mice and affects their clinical diabetes.
Collaborator Contribution Hoeppener has created ob/ob mice expressing transgenic human IAPP which develop both clinical type 2 diabetes and islet amyloid deposits. These are ideal models for study of the role of SAP in islet amyloidosis and type 2 diabetes and especially the possible utility of such SAP as a therapeutic target for the new approaches to treatment of amyloid that we have invented.
Impact SAP is always present in the islet amyloid of human type 2 diabetes. A key positive finding in our long term collaborative study, with Dr Jo Hoeppener, of islet amyloid and type 2 diabetes in ob/ob mice expressing transgenic human IAPP with either mouse SAP deficiency or transgenic human SAP expression, is the presence of human SAP in the islet amyloid. This validates the model for testing our potent new approach to clearance of established amyloid in vivo using CPHPC plus anti SAP antibody.
 
Description Macrophage biology 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution Histology, immunocytochemistry and electron microscopy analyses of in vivo anti-SAP therapy experiments in mice.
Collaborator Contribution Analyses in vitro of the properties of monocytes and multinucleated giant cells.
Impact Collaborative research paper ready for submission.
Start Year 2013
 
Description Monoclonal light chain structure (Sir Gregory Winter) 
Organisation Medical Research Council (MRC)
Department MRC Laboratory of Molecular Biology (LMB)
Country United Kingdom 
Sector Academic/University 
PI Contribution We providced amyloid expertise to show that although the aggregates had a vey intersting structure they were not in fact genuine amyloid fibrils
Collaborator Contribution The Winter lab undertook studies of an interesting amyloid-like light chain aggregate that they had identified.
Impact 17292396
Start Year 2006
 
Description Quantification and treatment of amyloidosis (Dr Bouke Hazenberg) 
Organisation University Medical Center Gronigen
Country Netherlands 
Sector Hospitals 
PI Contribution Methodology and collaborative clinical study of patients.
Collaborator Contribution Publications on improved methods for quantifying and treating amyloidosis.
Impact 16564782, 17554116, 17577686.
 
Description SAP in normal human brain 
Organisation Medical Research Council (MRC)
Department MRC UK Brain Banks Network
Country United Kingdom 
Sector Academic/University 
PI Contribution Pepys is investigating the role of human serum amyloid P component (SAP) in neurodegeneration and is characterising the presence, distribution and amount of SAP in different brain regions of individuals dying over the whole age range represented in the Brain Bank. Pepys has world leading expertise in all aspects of the study of SAP.
Collaborator Contribution The MRC Brain Bank is a unique resource, uniquely able to supply the material required for this study.
Impact The project has just started
Start Year 2012
 
Description SAP neurotoxicity (Dr Frances Edwards, Prof Sebastian Brandner) 
Organisation University College London
Department Neuroscience, Physiology & Pharmacology
Country United Kingdom 
Sector Academic/University 
PI Contribution The objectives of the work are to: 1. Characterise the toxic effects of human serum amyloid P component (SAP) on cerebral neurones in organotypic hippocampal slices in vitro with respect to time and dose dependence of abnormalities in synaptic transmission, paired pulse ratio, long term potentiation, necrotic and apoptotic neuronal cell death, binding and entry of SAP in cells and nuclear localisation. 2. Establish that the adverse effects of human SAP are specific, by comparison with the very closely related human C reactive protein and SAP from mice rats and mice, and demonstrate abrogation of human SAP toxicity by CPHPC, our specific SAP binding and inhibitory drug. 3. Investigate the time and dose dependence of abnormalities of synaptic transmission in the brains of human SAP transgenic mice, characterise these abnormalities precisely and identify and characterise any associated neuropathological changes in the brain in comparison with age and sex matched wild type litter mate controls. 4. Investigate cognitive performance of human SAP transgenic mice in comparison with age and sex matched wild type littermate controls in relation to age and level of human SAP expression in different strains. 5. Investigate effects of human SAP expression in TASTPM mice, which carry variant human PS1 and APP transgenes associated with hereditary Alzheimer's disease. In particular we will seek modulation by human SAP of the time of onset and severity of abnormalities of synaptic transmission, cognition and neuropathology. 6. Investigate the capacity of sustained depletion of human SAP, produced by life long treatment with CPHPC, to abrogate any or all of the neurological abnormalities observed in human SAP transgenic mice. Human SAP likely contributes to formation and persistence of cerebral amyloid deposits and neurofibrillary tangles, and is therefore already an attractive therapeutic target in AD. The results of the present work will compellingly strengthen the case for clinical trials of CPHPC and SAP depletion in AD and possibly also other neurodegenerative causes of cognitive loss. Pepys has worked on SAP since 1974, supported throughout by the MRC, and with his collaborators has contributed most of what is known about this protein in humans and other species. He discovered the role of SAP in amyloidosis, validated it as a therapeutic target and developed CPHPC with Roche.
Collaborator Contribution Edwards is a neuroscientist, specialised in CNS electrophysiology for study of fast synaptic transmission. She and her collaborators pioneered the application of patch clamp techniques to brain slices. In recent years she has optimised methods for detailed characterisation of plasticity and structure of individual synapses in acute and organotypic brain slices. Brandner is the Head of Neuropathology at the UCL Institute of Neurology and one of the world's leading experts on murine neuropathology.
Impact Award of MRC research grant "Neurotoxicity of human serum amyloid P component" to Edwards, Brandner, Dr Paul Simons (a member of the Pepys group) and Pepys in Jan 2012
Start Year 2011
 
Description Structures of CRP and SAP (Prof Steve Wood) 
Organisation University College London
Department Division of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution We have provided the isolated, purified and highly characterised proteins that Wood and his team have crystallised for X-ray analysis and other structural studies. Together we have designed and developed small molecule ligands for these proteins which are now in development as drugs. We have held and have under consideration many grants which have brought very substantial sums of money to support our collaborative work but your rigid form does not allow us to enter this information!
Collaborator Contribution The more than 25 years of close and highly productive collaboration with the powerful structural biology expertise of Steve Wood and his colleagues has underpinned a large part of our world leading discoveries and inventions in the field of pentraxins and amyloid proteins.
Impact The outstanding structural biology studies of Professor Steve Wood and his team have been essential for our successful work on pentraxins and drug design, and enabled their recruitment to UCL, with two tenured chairs (Wood, Jon Cooper), one senior lecturer post (Alun Coker) and 6 others on soft money. A new Laboratory of Protein Crystallography led by Wood has been established in the Centre for Amyloidosis and Acute Phase Proteins and has greatly increased the speed and efficiency of our extensive collaboration. This critical development was made possible by generous MRC support throughout the 20 years that Wood and I have collaborated. In the present quinquennium they have solved 18 crystal structures of human and animal pentraxins and their ligand complexes, elucidating protein structure and function and indispensably aiding drug design.
 
Title ?????????? SAP-?????????? ??????? ? ????-SAP ??????? 
Description ??????????? ????????? ?????????? ??????????, ??????? ????????? ???????????? ?????????? ?-????????? ?? ??????????, ? ?????????? ? ?????????, ??????????? ? ????????? ????????????? ??????????? ?-??????????, ??? ??????? ??? ???????????? ??????????. 
IP Reference EA201070063 
Protection Patent granted
Year Protection Granted 2010
Licensed Yes
Impact Potential therapy in development in collaboration with GlaxoSmithKline.
 
Title COMBINACIONES DE AGENTES QUE DISMINUYEN SAP Y ANTICUERPOS. 
Description The invention describes the use of a compound which depletes serum amyloid P component from the circulation, in combination with an antibody specific for serum amyloid P component, for the treatment or prophylaxis of amyloidosis. 
IP Reference MX2009013840 
Protection Patent granted
Year Protection Granted 2013
Licensed Yes
Impact Potential therapy in development in collaboration with GlaxoSmithKline.
 
Title COMBINATIONS OF SAP DEPLETING AGENTS AND ANTI-SAP ANTIBODIES 
Description The invention describes the use of a compound which depletes serum amyloid P component from the circulation, in combination with an antibody specific for serum amyloid P component, for the treatment or prophylaxis of amyloidosis. 
IP Reference WO2009000926 
Protection Patent application published
Year Protection Granted 2008
Licensed Yes
Impact Potential therapy in development in collaboration with GlaxoSmithKline. First in human patient studies in progress 2013.
 
Title COMBINATIONS OF SAP DEPLETING AGENTS AND ANTI-SAP ANTIBODIES 
Description The invention describes the use of a compound which depletes serum amyloid P component from the circulation, in combination with an antibody specific for serum amyloid P component, for the treatment or prophylaxis of amyloidosis. 
IP Reference WO2009000926 
Protection Patent application published
Year Protection Granted 2008
Licensed Yes
Impact Licensing and collaboration agreement with GSK for full scale clinical development of this novel treatment is now in active progress, including humanisation of monoclonal antibodies. Phase 1 study conducted in 2012.. Further clinical trial in patients in progress 2013.
 
Title COMBINATIONS OF SAP DEPLETING AGENTS AND ANTI-SAP ANTIBODIES 
Description The invention describes the use of a compound which depletes serum amyloid P component from the circulation, in combination with an antibody specific for serum amyloid P component, for the treatment or prophylaxis of amyloidosis. 
IP Reference EP2173341 
Protection Patent granted
Year Protection Granted 2010
Licensed Yes
Impact Potential therapy in development in collaboration with GlaxoSmithKline.
 
Title COMBINATIONS OF SAP DEPLETING AGENTS AND ANTI-SAP ANTIBODIES 
Description The invention describes the use of a compound which depletes serum amyloid P component from the circulation, in combination with an antibody specific for serum amyloid P component, for the treatment or prophylaxis of amyloidosis. 
IP Reference KR20100050495 
Protection Patent granted
Year Protection Granted 2010
Licensed Yes
Impact Potential therapy in development in collaboration with GlaxoSmithKline.
 
Title COMBINATIONS OF SAP DEPLETING AGENTS AND ANTI-SAP ANTIBODIES 
Description The invention describes the use of a compound which depletes serum amyloid P component from the circulation, in combination with an antibody specific for serum amyloid P component, for the treatment or prophylaxis of amyloidosis. 
IP Reference WO2009000926 
Protection Patent granted
Year Protection Granted 2008
Licensed Yes
Impact Potential therapy in development in collaboration with GlaxoSmithKline.
 
Title COMPOUNDS INHIBITING THE BINDING OF SAP FOR TREATING OSTEOARTHRITIS 
Description Use of an agent capable of inhibiting serum amyloid P component (SAP) ligand binding activity or depleting SAP from the plasma of a subject for the production of a medicament for treatment or prevention of osteoarthritis in the subject. 
IP Reference EP1633345 
Protection Patent granted
Year Protection Granted 2006
Licensed No
Impact Therapy in development.
 
Title Combinations of SAP depleting agents and anti-SAP antibodies 
Description The invention describes the use of a compound which depletes serum amyloid P component from the circulation, in combination with an antibody specific for serum amyloid P component, for the treatment or prophylaxis of amyloidosis. 
IP Reference JP2010531338 
Protection Patent granted
Year Protection Granted 2010
Licensed Yes
Impact Potential therapy in development in collaboration with GlaxoSmithKline.
 
Title Combinations of SAP depleting agents and anti-SAP antibodies 
Description The invention describes the use of an antibody specific for serum amyloid P component, for the treatment or prophylaxis of amyloidosis, and the use of a compound which depletes serum amyloid P component from the circulation in combination with an antibody specific for serum amyloid P component. 
IP Reference US2011166329 
Protection Patent granted
Year Protection Granted 2011
Licensed Yes
Impact Potential therapy in development in collaboration with GlaxoSmithKline.
 
Title Combinations of sap depleting agents and anti-sap antibodies 
Description The invention describes the use of a compound which depletes serum amyloid P component from the circulation, in combination with an antibody specific for serum amyloid P component, for the treatment or prophylaxis of amyloidosis. 
IP Reference AU2008267148 
Protection Patent granted
Year Protection Granted 2008
Licensed Yes
Impact Potential therapy in development in collaboration with GlaxoSmithKline.
 
Title Compounds Inhibiting the Binding of Sap for Treating Osteoarthritis 
Description Use of an agent capable of inhibiting SAP ligand binding activity or depleting SAP from the plasma of a subject for the production of a medicament for treatment or prevention of osteoarthritis in the subject. 
IP Reference US2008249003 
Protection Patent granted
Year Protection Granted 2008
Licensed No
Impact Potential therapy.
 
Title Compounds inhibiting the binding of SAP for treating osteoarthritis 
Description Use of an agent capable of inhibiting serum amyloid P component (SAP) ligand binding activity or depleting SAP from the plasma of a subject for the production of a medicament for treatment or prevention of osteoarthritis in the subject. 
IP Reference AU2004244815 
Protection Patent granted
Year Protection Granted 2004
Licensed No
Impact Potential therapy.
 
Title Compounds inhibiting the binding of sap for treating osteoarthritis 
Description Use of an agent capable of inhibiting serum amyloid P component (SAP) ligand binding activity or depleting SAP from the plasma of a subject for the production of a medicament for treatment or prevention of osteoarthritis in the subject. 
IP Reference GB2420498 
Protection Patent granted
Year Protection Granted 2006
Licensed No
Impact Potential therapy.
 
Title Screening assays to identify therapeutic agents for amyloidosis 
Description PCT No. PCT/GB94/01802 Sec. 371 Date Aug. 22, 1996 Sec. 102(e) Date Aug. 22, 1996 PCT Filed Aug. 17, 1994 PCT Pub. No. WO95/05394 PCT Pub. Date Feb. 23, 1995Therapeutical and diagnostic agents for amyloidosis comprise molecules that inhibit the binding of serum amyloid P component to amyloid fibrils or analogues or homologues of the amyloid binding site on serum amyloid P component. The resolution of the complete three dimensional structure of serum amyloid P component enables inhibitors, binding site analogues and homologues to be designed by computer-aided molecular modelling. 
IP Reference US6126918 
Protection Patent granted
Year Protection Granted 2000
Licensed No
Impact Enabling the development of potential therapies.
 
Title THERAPEUTIC AGENT 
Description Provided are agents and methods for use in depleting serum amyloid P component (SAP) from a patient in need thereof. 
IP Reference US2010173969 
Protection Patent granted
Year Protection Granted 2010
Licensed No
Impact Potential therapy in development.
 
Title THERAPEUTIC AGENT 
Description The invention relates to an agent for the depletion of unwanted proteins from plasma comprising a plurality of ligands covalently co-linked to produce a complex with a plurality of proteins wherein at least two of the ligands are capable of being bound by ligand binding sites on the proteins and wherein the non-protein access agent excludes certain D-proline derivatives. 
IP Reference US2006014665 
Protection Patent granted
Year Protection Granted 2006
Licensed No
Impact Potential therapy.
 
Title THERAPEUTIC AGENT FOR DEPLETION OF AN UNWANTED PROTEIN POPULATION FROM PLASMA 
Description Use of a non-proteinaceous agent for the preparation of a composition for the treatment of a subject having a disorder caused by a pathogenic protein, by therapeutic depletion of the pathogenic protein from the plasma of the subject; wherein the treatment comprises administering to the subject a dosage of the agent sufficient for therapeutic depletion; wherein the agent comprises a plurality of ligands covalently co-linked so as to form a complex with a plurality of the proteins in the presence 
IP Reference EP1418905 
Protection Patent granted
Year Protection Granted 2004
Licensed No
Impact Potential therapy.
 
Title THERAPEUTIC AND DIAGNOSTIC AGENTS FOR AMYLOIDOSIS 
Description Therapeutical and diagnostic agents for amyloidosis comprise molecules that inhibit the binding of serum amyloid P component to amyloid fibrils or analogues or homologues of the amyloid binding site on serum amyloid P component. The resolution of the complete three dimensional structure of serum amyloid P component enables inhibitors, binding site analogues and homologues to be designed by computer-aided molecular modelling. 
IP Reference EP0714405 
Protection Patent granted
Year Protection Granted 1996
Licensed No
Impact Potential therapy in development.
 
Title TREATMENT AND PREVENTION OF TISSUE DAMAGE 
Description A method for the treatment or prevention of tissue damage in a subject having an inflammatory and/or tissue damaging condition, which comprises administering to the subject an effective amount of a compound capable of inhibiting the binding of C-reactive protein (CRP) to an autologous or extrinsic ligand. 
IP Reference US2009074745 
Protection Patent granted
Year Protection Granted 2009
Licensed No
Impact Potential therapy.
 
Title TREATMENT AND PREVENTION OF TISSUE DAMAGE 
Description An agent for use in medicine, which agent comprises a plurality of ligands covalently co-linked so as to form a complex with a plurality of C-reactive protein (CRP) molecules in the presence thereof, wherein (i) at least two of the ligands are the same or different and are capable of being bound by ligand binding sites present on the CRP molecules; or (ii) at least one of the ligands is capable of being bound by a ligand binding site present on a CRP molecule, and at least one other of the ligands is capable of being bound by a ligand binding site present on a serum amyloid P component (SAP) molecule. 
IP Reference WO03097104 
Protection Patent granted
Year Protection Granted 2003
Licensed No
Impact Potential therapy.
 
Title TREATMENT AND PREVENTION OF TISSUE DAMAGE ASSOCIATED WITH INCREASED C-REACTIVE PROTEIN PRODUCTION 
Description An agent for use in medicine, which agent comprises a plurality of ligands covalently co-linked so as to form a complex with a plurality of C-reactive protein (CRP) molecules in the presence thereof, wherein (i) at least two of the ligands are the same or different and are capable of being bound by ligand binding sites present on the CRP molecules; or (ii) at least one of the ligands is capable of being bound by a ligand binding site present on a CRP molecule, and at least one other of the ligan 
IP Reference EP1503800 
Protection Patent granted
Year Protection Granted 2005
Licensed No
Impact Potential therapy.
 
Title Therapeutic agent 
Description Agent for the depletion of an unwanted protein population from the plasma of a subject, which agent comprises a plurality of ligands covalently co-linked so as to form a complex with a plurality of the proteins in the presence thereof, wherein at least two of the ligands are the same or different and are capable of being bound by ligand binding sites present on the proteins, wherein the agent is a non-proteinaceous agent other than a D-proline of the formula wherein R is the group R<1 >is hydrogen or halogen; X is -(CH2)n-; -CH(R<2>)(CH2)n-; -CH2O(CH2)n-; -CH2NH-; benzyl, -C(R<2>)-CH-; -CH2CH(OH)-; or thiazol-2,5-diyl; Y is -S-S-; -(CH2)n-; -O-; -NH-; -N(R<2>); -CH-CH-; -NHC(O)NH-; -N(R<2>)C(O)N(R<2>)-; -N[CH2C6H3(OCH3)2]-; -N(CH2C6H5)-; -N(CH2C6H5)C(O)N(CH2C6H5)-; -N(alkoxyalkyl)-; N(cycloalkyl-methyl)-; 2,6-pyridyl; 2,5-furanyl; 2,5-thienyl; 1,2-cyclohexyl; 1,3-cyclohexyl; 1,4-cyclohexyl; 1,2-naphthyl; 1,4-naphthyl; 1,5-naphthyl; 1,6-naphthyl; biphenylen; or 1,2-phenylen, 1,3-phenylen and 1,4-phenylen, wherein the phenylen groups are optionally substituted by 1-4 substituents, selected from halogen, lower alkyl, lower alkoxy, hydroxy, carboxy, -COO-lower alkyl, nitrilo, 5-tetrazol, (2-carboxylic acid pyrrolidin-1-yl)-2-oxo-ethoxy, N-hydroxycarbamimidoyl, 5-oxo[1,2,4]oxadiazolyl, 2-oxo-[1,2,3,5]oxathiadiazolyl, 5-thioxo[1,2,4]oxadiazolyl and 5-tert-butylsulfanyl-[1,2,4]oxadiazolyl; X' is -(CH2)n-; -(CH2)nCH(R<2>)-; -(CH2)nOCH2-; -NHCH2-; benzyl, -CH-C(R<2>)-; -CH(OH)CH2; or thiazol-2,5-diyl; R<2 >is lower alkyl, lower alkoxy or benzyl and n is 0-3, or a pharmaceutically acceptable salt or mono- or diester thereof. 
IP Reference US2006122124 
Protection Patent granted
Year Protection Granted 2006
Licensed No
Impact Therapy in development.
 
Title Therapeutic agent for depletion of an unwanted protein population from plasma 
Description Agent for the depletion of an unwanted protein population from the plasma of a subject, which agent comprises a plurality of ligands covalently co-linked so as to from a complex with a plurality of the proteins in the presence thereof, wherein at least two of the ligands are the same or different and are capable of being bound by ligand binding sites present on the proteins, wherein the agent is a non-proteinaceous agent other than a D-proline of the formula (I-A) or (I-B) wherein R is formula ( 
IP Reference JP2005501071 
Protection Patent granted
Year Protection Granted 2005
Licensed No
Impact Potential therapy.
 
Title Therapeutic agent for depletion of an unwanted protein population from plasma 
Description Use of a non-proteinaceous agent for the preparation of a composition for the treatment of a subject having a disorder caused by a pathogenic protein, by therapeutic depletion of the pathogenic protein from the plasma of the subject; wherein the treatment comprises administering to the subject a dosage of the agent sufficient for therapeutic depletion; wherein the agent comprises a plurality of ligands covalently co-linked so as to form a complex with a plurality of the proteins in the presence thereof; and wherein at least two of the ligands are the same or different and are capable of being bound by ligand binding sites present on the proteins. 
IP Reference EP1820501 
Protection Patent granted
Year Protection Granted 2007
Licensed No
Impact Therapy in development.
 
Title Treatment and prevention of tissue damage 
Description A method for the treatment or prevention of tissue damage in a subject having an inflammatory and/or tissue damaging condition, which comprises administering to the subject an effective amount of a compound capable of inhibiting the binding of C-reactive protein (CRP) to an autologous or extrinsic ligand. 
IP Reference US2003171251 
Protection Patent granted
Year Protection Granted 2003
Licensed No
Impact Potential therapy.
 
Title Treatment and prevention of tissue damage 
Description An agent for use in medicine, which agent comprises a plurality of ligands covalently co-linked so as to form a complex with a plurality of C-reactive protein (CRP) molecules in the presence thereof, wherein (i) at least two of the ligands are the same or different and are capable of being bound by ligand binding sites present on the CRP molecules; or (ii) at least one of the ligands is capable of being bound by a ligand binding site present on a CRP molecule, and at least one other of the ligands is capable of being bound by a ligand binding site present on a serum amyloid P component (SAP) molecule. 
IP Reference US2006019930 
Protection Patent granted
Year Protection Granted 2006
Licensed No
Impact Potential therapy.
 
Title USE 
Description The invention describes the use of an antibody specific for serum amyloid P component, for the treatment or prophylaxis of amyloidosis, and the use of a compound which depletes serum amyloid P component from the circulation in combination with an antibody specific for serum amyloid P component. 
IP Reference US2009191196 
Protection Patent granted
Year Protection Granted 2009
Licensed Yes
Impact Combination is in full development with GSK with clinical trial in progress 2013.
 
Title Use 
Description The invention describes the use of an antibody specific for serum amyloid P component, for the treatment or prophylaxis of amyloidosis, and the use of a compound which depletes serum amyloid P component from the circulation in combination with an antibody specific for serum amyloid P component. 
IP Reference AU2008358292 
Protection Patent granted
Year Protection Granted 2009
Licensed Yes
Impact Potential therapy in development in collaboration with GlaxoSmithKline.
 
Title CPHPC 
Description My research supported by the MRC Programme Grant since 1979 first identified serum amyloid P component as a potential therapeutic target in amyloidosis and Alzheimer's disease. I designed a high throughput screen for inhibitors of ligand binding by serum amyloid P component and, in collaboration with Roche, 100,000 compounds in their library were screened. The best lead was developed into a drug which was eventually licensed exclusively to myself and UCL for clinical testing in humans. I discovered that it had a completely novel pharmacological mechanism of action which caused rapid and almost total depletion of circulating serum amyloid P component. This was reported in Nature in 2002 and received major coverage in the scientific and lay media, including mainstream BBC, ITV, US and European television and radio. It was identified by the American Chemical Society as one of the medicinal chemistry highlights of 2002. My invention of the mechanism responsible is covered by granted patents. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2006
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Our first into man open label phase 2 study in systemic amyloidosis showed promising signs of clinical efficacy. Our open label first clinical study in Alzheimer's disease showed complete safety and dramatic biochemical efficacy in depleting SAP from the CSF. We have now out licensed CPHPC to GSK as part of the package for treatment of systemic amyloidosis by my newly invented approach detailed separately. Other workers have used my approach to design drugs targeting cholera and shiga toxins, while I have used it to design successfully the first inhibitor of human C-reactive protein, as reported in another entry in this form. The same strategy also led to our novel drugs targeting transthyretin for treatment and prevention of transthyretin amyloidosis. 
URL http://clinicaltrials.gov/show/NCT01406314
 
Title Clinical trials of CPHPC for Alzheimer's and other neurodegenerative diseases 
Description The 30 years of MRC support for this programme, 1979-2009, led to development of the CPHPC drug. This was ready for clinical trials in 2000 but the prolonged battle for funding support from the MRC and pharma was unsuccessful until 2009 when some of the IP was licensed to GSK for treatment of systemic amyloidosis. Five years later the clinical trial of that treatment has been shown to be successful, winning major milestone awards, Orphan Drug status, etc. The MRC completely failed to either understand the need for studies in Alzheimer's disease and dementia, or to provide funding for these. However the NIHR first provided core support for the Pepys team in 2012, followed by £1 million for trial preparations in 2013, and finally a Strategic Award in 2014 of £2.571 million to fund the clinical trial. Pepys has now also been invited by the Alzheimer's Society-Alzheimer's Drug Discovery Foundation to apply for two new grants of $1.5 million each for trials of his drug in cerebral amyloid angiopathy and traumatic brain injury respectively. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2014
Development Status Under active development/distribution
Impact In addition to the generous funding from the NIHR, contrasting sharply with the failure of the MRC to support one of the major outputs from its previous continuous funding of Pepys's research since 1969, the work on CPHPC for Alzheimer's and related diseases is also strongly supported by GSK. They are critically important partners in development at all levels in a synergistic relationship which is a paradigm of collaboration between academia and the pharma industry. 
 
Title Combination of CPHPC and anti SAP mAb 
Description The tissue damage in systemic amyloidosis which is responsible for disease and death is caused by accumulation of amyloid deposits in the tissues and organs. There are currently no clinical treatments which directly target amyloid deposits for elimination. The Pepys team first identified and validated human serum amyloid P component (SAP) as a therapeutic target in amyloidosis in the mid 1990s. In vitro, SAP both enhances amyloid fibril formation and protects amyloid fibrils from proteolytic degradation by macrophages. In collaboration with Roche they developed the novel palindromic bis-D-proline compound (R)-1-[6-[(R)-2-Carboxy-Pyrrolidin-1-yl]-6-oxo-Hexanoyl]Pyrrolidine-2-Carboxylic acid (CPHPC), which was intended to prevent SAP from binding to amyloid fibrils in vivo and dissociate bound SAP from amyloid deposits (Nature 2002). CPHPC is avidly bound by human SAP in a complex composed of two native pentameric SAP molecules cross linked by 5 bivalent CPHPC molecules. The complex is perceived as abnormal by the liver and instantly cleared, leading to profound depletion of SAP from the circulation which persists for as long as the drug is administered (PNAS 2009). Targeted depletion of a pathogenic protein by a small molecule drug constitutes a potent, novel pharmacological mechanism. The depletion of plasma SAP also clears most of the SAP from amyloid deposits but the affinity of SAP for CPHPC is insufficient to produce complete dissociation of all SAP from amyloid deposits in the face of the continuous production of 50-100 mg of new SAP per day and the avid binding of SAP to amyloid fibrils. CPHPC is well tolerated by patients and has been administered to more than 60 subjects for a total of more than 50 patient years without any adverse effects. But up to about 10% of the amyloid associated SAP remains in major visceral amyloid deposits even after months of continuous CPHPC treatment. Nevertheless we have not observed any new amyloid accumulation in patients on CPHPC, even those in whom there was progressive deposition before and after CPHPC exposure. Furthermore there were encouraging signs of prolonged renal and possibly patient survival in subjects receiving CPHPC. However we have not detected any amyloid regression. Thus while CPHPC may be a useful adjunct to other therapy for amyloidosis it does not itself promote elimination of the deposits. Pentraxin acquired full ownership of CPHPC from Roche in December 2008. The capacity of CPHPC to clear essentially all SAP from the circulation, while leaving significant amounts of SAP specifically bound in the amyloid deposits, suggested the possibility of using the residual SAP as an amyloid-specific target for antibodies which can invoke physiological clearance of amyloid from the tissues. Depletion of circulating SAP crucially allows such antibodies to be administered safely and effectively. This approach is unrelated to the function of SAP itself and simply uses SAP as a passive amyloid-specific target. It has been remarkably successful in experimental models (Nature 2010) and should be applicable to all forms of amyloidosis although its safety and efficacy, especially for amyloid in different organs and tissues, will have to be, and is being, carefully evaluated. GlaxoSmithKline licensed the invention of this first in class combination of a small molecule drug and a monoclonal antibody from Pentraxin in February 2009. They have already fully humanised one of our optimal mouse monoclonal anti-human SAP antibodies and clinical testing is currently underway. In 2012 they conducted a Phase 1, Open Label, Dose Characteristic Study to Investigate the pharmacokinetics, pharmacodynamics, safety, and tolerability of intravenous and subcutaneous doses of CPHPC in patients with systemic amyloidosis (http://www.clinicaltrials.gov/ct2/show/NCT01406314?term=amyloid+gsk&rank=4), enabling progression to a single dose first in human study of anti-SAP antibodies co-administered with CPHPC in patients with systemic amyloidosis, which is currently underway http://www.clinicaltrials.gov/ct2/show/NCT01777243?term=amyloid+gsk&rank=2. Meanwhile our original patent applications, licensed to GSK for this programme, are progressing and GSK are filing new patents as the work proceeds. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2012
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Combination currently in clinical trials with very encouraging results and a first publication being prepared for submission. The intervention has already been granted Orphan Drug status by the EMA and been adopted as their flagship candidate for adaptive licensing. 
URL http://www.clinicaltrials.gov/show/NCT01777243
 
Title Depletion of serum amyloid P component to enhance the immune response to DNA vaccination 
Description Successful immunisation induces a protective immune response against particular component(s) of the target pathogen, the so-called immunogen(s). For some diseases the immunogens are not known and for others they are difficult and expensive to produce, transport and administer, for example influenza vaccine must be produced in millions of chicken eggs. A very attractive potential solution is to inject the DNA gene encoding the immunogen rather than the immunogen itself. In this process, known as DNA vaccination, the DNA enters cells, predominantly at the site of injection, and causes them to produce the immunogen locally within the body. DNA vaccination works well and stimulates excellent protective immunity against a variety of different infections, and even some cancers, in mice, horses, dogs, rabbits and pigs. But in humans and other primates, and in cows and sheep, the immune response to DNA vaccination is very feeble. Despite enormous academic and pharmaceutical industry efforts, the reasons for this failure have not been understood or overcome. We previously discovered, in work funded by the MRC, that a protein in human plasma, known as serum amyloid P component (SAP), is the only normal plasma protein which binds avidly to DNA. We have now found that, in each of the animal species in which DNA vaccination is effective, this protein is either absent or, if it is present, it binds only weakly to DNA. In contrast, non-human primates, cows and sheep share with humans the presence of SAP proteins which strongly bind to DNA. We believe that binding of DNA by SAP may be responsible for blocking induction of immune responses by DNA and that removal of SAP may overcome this inhibition. SAP contributes to important human diseases, amyloidosis and Alzheimer's disease, and, in MRC funded work towards treatment for these conditions, we have previously developed a drug, CPHPC, which safely removes almost all SAP from the blood in humans. Another laboratory has recently reported that the presence of human SAP inhibits DNA vaccination in mice and that this effect is reversed by our drug, CPHPC. These observations confirm our hypothesis. We are now undertaking the first human clinical study of DNA vaccination after SAP depletion, funded by an MRC DCS award. We will measure the immune responses to HIV-1 in normal adult men, comparing a group in whom SAP has been completely depleted at the time of DNA vaccination and a control group vaccinated without SAP depletion. We predict that SAP depletion at the time of vaccination will enhance the immune response. The DNA vaccine to be tested is a promising new vaccine against HIV-AIDS, developed and manufactured with previous MRC awards. A positive result, consistent with improved protective immunity against HIV-1, will be very encouraging. Furthermore, proof of the concept that SAP depletion can enhance immune responses to DNA vaccination in humans will open up this approach for the many other diseases for which effective vaccination does not yet exist and in which it could have therapeutic as well as prophylactic benefits. Success in the clinical trial undertaken here with an HIV-1 vaccine will establish a critical proof of concept, opening the way to general application of our new approach. The clinical trial has begun. The first two subjects have been successfully screened and randomised and have been admitted to the CRF. CPHPC infusion has taken place and they have now received the first DNA vaccination. The programme is funded by MRC DCS award MR/J008605/1. 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2014
Development Status Under active development/distribution
Clinical Trial? Yes
Impact The intervention is still in early stage clinical assessment. 
URL http://public.ukcrn.org.uk/Search/StudyDetail.aspx?StudyID=14680
 
Title Inhibitors of C-reactive protein 
Description Prof Sir Mark Pepys identified C-reactive protein (CRP) as a therapeutic target in clinical situations in which there is pre-existing tissue damage and high level production of CRP. Novel CRP inhibitor compounds are currently in pre-clinical development. After extensive evaluation the original compound, BPC8, for the development of which the DCS award was given in 2010, was found not be optimal for further development. In 2012 the MRC awarded Sir Mark additional funds for a back up chemistry programme to rationally design and synthesise new candidate molecules drawing on the results so far with BPC8. This programme continues and two promising candidate molecules are currently being synthesised by a CRO. In a progress report to the MRC Sir Mark described the novel molecules which have been designed, synthesised and tested so far. Unsurprisingly for such a novel programme none evaluated so far have been optimal for development, however the results of these evaluations have provided important knowledge for the design of subsequent compounds. Two promising compounds are currently being synthesised by a CRO and are due for delivery early November. Unfortunately the MRC have deemed the programme to now be too different from the original plan and have decided to terminate the award. A termination plan has been submitted and we await approval. In the meantime evaluation of the newest compounds will continue with a view to seeking further funds if one or more of these should prove worthy of full scale pre-clinical evaluation. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Initial development
Year Development Stage Completed 2013
Development Status Under active development/distribution
Impact The work was published in Nature in 2006 and was the subject of the cover illustration and additional material in the journal. It was recognised by commentaries in the New England Journal of Medicine and Nature Structural Biology as a seminally important piece of work. 
 
Title Transthyretin superstabilisers 
Description Transthyretin is an inherently amyloidogenic protein and forms microscopic amyloid deposits in all individuals over the age of 80 years. In some aged individuals massive transthyretin amyloid deposition in the heart causes fatal senile cardiac amyloidosis, a condition which is rarely diagnosed but is almost certainly much more prevalent than currently recognised. Most of the >100 rare mutations in the human transthyretin gene increase the amyloidogenicity of the respective variant proteins and cause autosomal dominant adult onset hereditary transthyretin amyloidosis, usually presenting as familial amyloid polyneuropathy. There is currently no effective treatment for this uniformly fatal disease. Since transthyretin amyloidogenesis involves misfolding and dissociation of the native tetrameric structure of the protein, a rational therapeutic approach is the use of small molecule ligands which are specifically bound by transthyretin and stabilise its native structure and assembly. Prof Sir Mark Pepys and his research group are developing novel transthyretin superstabiliser compounds in collaboration with GlaxoSmithKline. The compounds are currently at medicinal chemistry/ early non-clinical testing and refinement stage. As GSK licensed this programme in 2010 they are now the principle source of funding. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Initial development
Year Development Stage Completed 2012
Development Status Under active development/distribution
Impact The development programme is still at an early stage. Novel transthyretin stabilising compounds have been identified. These are being evaluated and refined for eventual clinical testing. New Intellectual Property has arisen and is being protected appropriately. 
 
Company Name Pentraxin Therapeutics Limited 
Description The Company was set up by UCL Business (the commercial arm of UCL) to hold and commercialise all intellectual property arising from Professor Sir Mark's work at UCL. Pentraxin has been financed by UCL Business and the current shareholdings are held as 45% by Professor Sir Mark Pepys, 45% by UCL Business, 5% each by Professor Philip Hawkins and Professor Steve Wood. There are four Directors, Professor Sir Mark Pepys and Mr Cengiz Tarhan (representing UCL Business), Professor Hawkins and Professor Wood. The majority of Pentraxin's research work is carried out at UCL with certain aspects being out-sourced to third parties. The company has three main programmes under development: 1) CPHPC, a small molecule compound, in combination with an anti- Serum amyloid P component (SAP) mAb for the treatment of systemic amyloidosis. This programme was licensed by GSK in 2009 2) Inhibitors of C-reactive protein (CRP), developed for the treatment and prevention of tissue damage; and 3) a compound for the treatment of hereditary systemic and senile cardiac amyloidosis targeting depletion of transthyretin. This programme was licensed by GSK in 2010. Sir Mark is also preparing to trial his drug CPHPC in three different studies in patients with Alzheimer's disease, cerebral amyloid angiopathy and traumatic brain injury respectively . The company's website can be found at www.pentraxin.com 
Year Established 2004 
Impact The company has supported Professor Sir Mark's research work for many years and facilitated the licensing of CPHPC from Roche and proceeded with the GMP manufacture of CPHPC - for use in clinical trials on patients with systemic amyloidosis at UCL. A licence deal was signed with GSK in February 2009 to enable GSK to develop an application combining a humanised antibody with CPHPC to eliminate amyloid deposits. Clinical trials with the combination are currently in progress (see URLs http://www.clinicaltrials.gov/ct2/show/NCT01406314?term=amyloid+gsk&rank=4 and http://www.clinicaltrials.gov/ct2/show/NCT01777243?term=amyloid+gsk&rank=2.). In November 2010 GSK also licensed Prof Sir Mark Pepys's transthyretin superstabiliser programme. Sir Mark's group worked closely with GSK on this programme. Sir Mark's group also collaborated closely with GSK's scientific advisory arm, Scinovo, on his CRP inhibitor molecule programme.
Website http://pentraxin.wordpress.com/
 
Description Articles in The Times and The Financial Times 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Articles published in The Times and The Financial Times - outcome was greater public awareness of amyloidosis and Prof Mark Pepys's research to develop treatments for it

Publications were very recent
Year(s) Of Engagement Activity 2010,2011
URL http://pentraxin.wordpress.com/news/
 
Description BBC and many other national and international radio interviews 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Interviews on BBC Today programme & other multiple national and international radio shows, regarding various high impact publications of our work on drug development for amyloidosis, Alzheimer's disease and cardiovascular disease in Nature, PNAS, etc. Also in relation to my Harveian Oration at the RCP in 2007.

Much public interest, especially from potential patients and some investors.
Year(s) Of Engagement Activity 2006,2007,2008,2009