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Cited by 67Biomarkers in Disease MechanismsAmyloidosis: Diagnosis, Treatment, OutcomesSepsis Diagnosis and Treatment

The Pentraxins 1975–2018: Serendipity, Diagnostics and Drugs

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Pepys, Mark. B.·2018·Frontiers in Immunology
DOI 10.3389/fimmu.2018.02382PMC PMC6232782
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Abstract

The phylogenetically ancient, pentraxin family of plasma proteins, comprises C-reactive protein (CRP) and serum amyloid P component (SAP) in humans and the homologous proteins in other species. They are composed of five, identical, non-covalently associated protomers arranged with cyclic pentameric symmetry in a disc-like configuration. Each protomer has a calcium dependent binding site that mediates the particular specific ligand that mediates all the rigorously established functional properties of these proteins. No genetic deficiency of either human CRP or SAP has been reported, nor even any sequence polymorphism in the proteins themselves. Although their actual functions in humans are therefore unknown, gene deletion studies in mice demonstrate that both proteins can contribute to innate immunity. CRP is the classical human acute phase protein, routinely measured in clinical practice worldwide to monitor disease activity. Human SAP, which is not an acute phase protein, is a universal constituent of all human amyloid deposits as a result of its avid specific binding to amyloid fibrils of all types. SAP thereby contributes to amyloid formation and persistence in vivo. Whole body radiolabelled SAP scintigraphy safely and non-invasively localises and quantifies systemic amyloid deposits, and has transformed understanding of the natural history of amyloidosis and its response to treatment. Human SAP is also a therapeutic target, both in amyloidosis and Alzheimer’s disease. Our drug, miridesap, depletes SAP from the blood and the brain and is currently being tested in the DESPIAD clinical trial in Alzheimer’s disease. Meanwhile, the obligate therapeutic partnership of miridesap, to deplete circulating SAP, and dezamizumab, a humanised monoclonal anti-SAP antibody that targets residual SAP in amyloid deposits, produces unprecedented removal of amyloid from the tissues and improves organ function. Human CRP binds to dead and damaged cells in vivo and activates complement and this can exacerbate pre-existing tissue damage. The adverse effects of CRP are completely abrogated by compounds that block its binding to autologous ligands and we are developing CRP inhibitor drugs. The present personal and critical perspective on the pentraxins reports, for the first time, the key role of serendipity in our work since 1975.

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  • CPHPC efficiently binds to SAP, leading to the dissociation of SAP from bound amyloids and subsequent depletion of SAP levels in the body.

    “This compound efficiently binds to SAP, leading to the dissociation of SAP from bound amyloids and subsequent depletion of SAP levels in the body24,62–68.”

    From Serum amyloid P secreted by bone marrow adipocytes drives skeletal amyloidosis (2025) · cites this paper as [63]

    In “SAP and amyloidosis,” the paper says CPHPC forms a stable complex with SAP and rapidly depletes circulating SAP through liver clearance of that complex. It also says circulating SAP depletion removes much, but never all, SAP bound to amyloid deposits; complete elution requires a CPHPC concentration unattainable in vivo. The claim overstates dissociation from amyloid and presents it as the step leading to systemic depletion. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • CPHPC (miridesap) at a concentration of 5 mg ml−1 in drinking water is an established dose for SAP depletion from the body.

    “To examine the effects of CPHPC on age-associated bone changes, male and female mice aged 18 months were treated with CPHPC (miridesap) at a concentration of 5 mg ml−1 in drinking water, which is an established dose for SAP depletion from the body62–65,67,68,84.”

    From Serum amyloid P secreted by bone marrow adipocytes drives skeletal amyloidosis (2025) · cites this paper as [63]

    The “SAP and amyloidosis” section reports that CPHPC depletes circulating SAP in humans and describes SAP depletion with CPHPC in transgenic mice. The “Functions of human serum amyloid P component” section also reports sustained depletion during treatment. Neither section specifies 5 mg ml−1 in drinking water or establishes that concentration as a dose for mice; page numbers are unavailable in our copy. (LLM, conf=0.88)

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References 161 · Cited by 67

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Authors
Pepys, M. B.
Affiliations
National Institute for Health and Care Research (GB)
Corresponding author
Pepys, Mark. B.
ORCID
Pepys, Mark. B.
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2018-10-16
Volume
9
Pages
2382-2382
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2018.02382
PMC
PMC6232782
OpenAlex
W2896076612
Cited by
67
References
161
Citations by year
2026: 3 · 2025: 9 · 2024: 8 · 2023: 12 · 2022: 10 · 2021: 12 · 2020: 7 · 2019: 5 · 2018: 1
FWCI
0.64
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Immunology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • UCL Discovery (University College London) (submittedVersion)
Funders
  • Dana Foundation
  • GlaxoSmithKline
  • Wellcome Trust
  • NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research
  • National Institute for Health and Care Research
  • British Heart Foundation
  • University College London
  • Wolfson Foundation
  • University College London Hospitals NHS Foundation Trust
  • Medical Research Council
  • UCLH Biomedical Research Centre
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Biomarkers in Disease Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Amyloidosis: Diagnosis, Treatment, Outcomes
  • Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
Keywords
pentraxins, C-reactive protein, serum amyloid P component, acute phase proteins, amyloidosis, Alzheimer's disease, innate immunity, complement activation, serendipity in research, plasma proteins
MeSH terms
Alzheimer Disease, Serum Amyloid P-Component, Amyloidosis, Animals, C-Reactive Protein, Humans, Protein Binding, Structure-Activity Relationship, Biomarkers, Molecular Targeted Therapy, Protein Aggregation, Pathological, Protein Aggregates

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