Abstract
Accumulation of amyloid fibrils in the viscera and connective tissues causes systemic amyloidosis, which is responsible for about one in a thousand deaths in developed countries1. Localized amyloid can also have serious consequences; for example, cerebral amyloid angiopathy is an important cause of haemorrhagic stroke. The clinical presentations of amyloidosis are extremely diverse and the diagnosis is rarely made before significant organ damage is present1. There is therefore a major unmet need for therapy that safely promotes the clearance of established amyloid deposits. Over 20 different amyloid fibril proteins are responsible for different forms of clinically significant amyloidosis and treatments that substantially reduce the abundance of the respective amyloid fibril precursor proteins can arrest amyloid accumulation1. Unfortunately, control of fibril-protein production is not possible in some forms of amyloidosis and in others it is often slow and hazardous1. There is no therapy that directly targets amyloid deposits for enhanced clearance. However, all amyloid deposits contain the normal, non-fibrillar plasma glycoprotein, serum amyloid P component (SAP)2,3. Here we show that administration of anti-human-SAP antibodies to mice with amyloid deposits containing human SAP triggers a potent, complement-dependent, macrophage-derived giant cell reaction that swiftly removes massive visceral amyloid deposits without adverse effects. Anti-SAP-antibody treatment is clinically feasible because circulating human SAP can be depleted in patients by the bis-d-proline compound CPHPC4, thereby enabling injected anti-SAP antibodies to reach residual SAP in the amyloid deposits. The unprecedented capacity of this novel combined therapy to eliminate amyloid deposits should be applicable to all forms of systemic and local amyloidosis.
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Acknowledgements
The study was supported by Medical Research Council Programme Grant G97900510 to M.B.P. and P.N.H. and by the University College London Amyloidosis Research Fund. K.B. was supported by the Erik and Edith Fernströms Foundation for Medical Research and a Postdoctoral Fellowship from the Swedish Research Council. K.B. dedicates his work to his late father, Gunnar Bodin. We thank S. Gordon, S. Wood, S. Kolstoe, J. Raynes, P. Simons and R. Al-Shawi for information, advice, reagents and support, and B. Jones for processing the manuscript.
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The study was conceived, designed and supervised by M.B.P. K.B., M.C.K. and S.E. performed all the experimental animal work. G.A.T., A.L., J.A.G., S.M. and A.P.D. performed or contributed to the histological studies. Amyloid scoring was performed by K.B., M.C.K., S.E., J.D.G. and M.B.P. W.L.H., P.P.M., J.R.G., D.J.M., G.W.T. and V.B. conducted the immunochemical, radiochemical and immunoassay studies. A.P. undertook the statistical analyses. A.R.B. produced the sheep anti-human SAP and control antisera. M.B. supplied the complement knockout mice. J.D.G. and P.N.H. contributed to experimental design. The paper was written by M.B.P. and reviewed and approved by all co-authors.
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M.B.P. is the inventor on patents covering SAP as a therapeutic target in amyloidosis and amyloid-associated diseases, and the use of CPHPC for SAP depletion, owned by Pentraxin Therapeutics Ltd, a University College London spinout company in which he and P.N.H. own shares. Pentraxin Therapeutics Ltd owns the patents on CPHPC itself and has licensed the intellectual property relevant to the present work to GlaxoSmithKline.
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Supplementary Information
This file contains Supplementary Information 1-12 including a schematic of the main findings and Supplementary Tables 1-3. Supplementary Materials and Methods and additional references are also included. (PDF 926 kb)
Supplementary Movie 1
This file contains a QTVR interactive movie of confocal microscopy imaging of a splenic marginal zone AA amyloid deposit from a mouse 4 days after treatment with anti SAP antibody. The amyloid fibril protein is stained green with antibodies to mouse AA. Macrophage phagolysosomes are stained red with antibody to CD68, a marker of phagolysosome fusion. Cell nuclei are counterstained blue with Hoechst 33342. The images confirm the close co-localisation of amyloid and phagolysosome fusion in macrophages and giant cells as they ingest and destroy the amyloid deposits that have been opsonised by anti SAP antibody and complement. (MOV 29912 kb)
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Bodin, K., Ellmerich, S., Kahan, M. et al. Antibodies to human serum amyloid P component eliminate visceral amyloid deposits. Nature 468, 93–97 (2010). https://doi.org/10.1038/nature09494
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DOI: https://doi.org/10.1038/nature09494
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