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Targeted pharmacological depletion of serum amyloid P component for treatment of human amyloidosis

Abstract

The normal plasma protein serum amyloid P component (SAP) binds to fibrils in all types of amyloid deposits, and contributes to the pathogenesis of amyloidosis. In order to intervene in this process we have developed a drug, R-1-[6-[R-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid, that is a competitive inhibitor of SAP binding to amyloid fibrils. This palindromic compound also crosslinks and dimerizes SAP molecules, leading to their very rapid clearance by the liver, and thus produces a marked depletion of circulating human SAP. This mechanism of drug action potently removes SAP from human amyloid deposits in the tissues and may provide a new therapeutic approach to both systemic amyloidosis and diseases associated with local amyloid, including Alzheimer's disease and type 2 diabetes.

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Figure 1: Inhibitors of SAP binding.
Figure 2: The structure of the complex of CPHPC with SAP.
Figure 3: Effects of CPHPC on human and mouse SAP in mice in vivo.
Figure 4: Effect of intravenous infusion of CPHPC on plasma SAP values in patients with systemic amyloidosis.
Figure 5: Whole-body 123I-labelled SAP scintigraphy before and 6-h after starting infusion of CPHPC.

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References

  1. Pepys, M. B. in Protein Misfolding and Disease (eds Dobson, C. M., Ellis, R. J. & Fersht, A. R.) Phil. Trans. R. Soc. Lond. B 356, 203–211 (The Royal Society, London, 2001)

    Google Scholar 

  2. Pepys, M. B. & Hawkins, P. N. in Samter's Immunologic Diseases (eds Austen, K. F., Frank, M. M., Atkinson, J. P. & Cantor, H.) 401–412 (Lippincott Williams, Philadelphia, 2001)

    Google Scholar 

  3. Holmgren, G. et al. Clinical improvement and amyloid regression after liver transplantation in hereditary transthyretin amyloidosis. Lancet 341, 1113–1116 (1993)

    Article  CAS  PubMed  Google Scholar 

  4. Gillmore, J. D., Hawkins, P. N. & Pepys, M. B. Amyloidosis: a review of recent diagnostic and therapeutic developments. Brit. J. Haematol. 99, 245–256 (1997)

    Article  CAS  Google Scholar 

  5. Gillmore, J. D. et al. Curative hepatorenal transplantation in systemic amyloidosis caused by the Glu526Val fibrinogen α-chain variant in an English family. Q. J. Med. 93, 269–275 (2000)

    Article  CAS  Google Scholar 

  6. Gillmore, J. D., Lovat, L. B., Persey, M. R., Pepys, M. B. & Hawkins, P. N. Amyloid load and clinical outcome in AA amyloidosis in relation to circulating concentration of serum amyloid A protein. Lancet 358, 24–29 (2001)

    Article  CAS  PubMed  Google Scholar 

  7. Pepys, M. B. et al. Amyloid P component. A critical review. Int. J. Exp. Clin. Invest. 4, 274–295 (1997)

    CAS  Google Scholar 

  8. Tennent, G. A., Lovat, L. B. & Pepys, M. B. Serum amyloid P component prevents proteolysis of the amyloid fibrils of Alzheimer's disease and systemic amyloidosis. Proc. Natl Acad. Sci. USA 92, 4299–4303 (1995)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  9. Pepys, M. B. et al. Human serum amyloid P component is an invariant constituent of amyloid deposits and has a uniquely homogeneous glycostructure. Proc. Natl Acad. Sci. USA 91, 5602–5606 (1994)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hind, C. R. K., Collins, P. M., Caspi, D., Baltz, M. L. & Pepys, M. B. Specific chemical dissociation of fibrillar and non-fibrillar components of amyloid deposits. Lancet ii, 376–378 (1984)

    Article  Google Scholar 

  11. Botto, M. et al. Amyloid deposition is delayed in mice with targeted deletion of the serum amyloid P component gene. Nature Med. 3, 855–859 (1997)

    Article  CAS  PubMed  Google Scholar 

  12. Pepys, M. B. & Blundell, T. L. Screening assays to identify therapeutic agents for amyloidosis. US patent 6126918 (2000).

  13. Hohenester, E., Hutchinson, W. L., Pepys, M. B. & Wood, S. P. Crystal structure of a decameric complex of human serum amyloid P component with bound dAMP. J. Mol. Biol. 269, 570–578 (1997)

    Article  CAS  PubMed  Google Scholar 

  14. Ashton, A. W., Boehm, M. K., Gallimore, J. R., Pepys, M. B. & Perkins, S. J. Pentameric and decameric structures in solution of serum amyloid P component by X-ray and neutron scattering and molecular modelling analyses. J. Mol. Biol. 272, 408–422 (1997)

    Article  CAS  PubMed  Google Scholar 

  15. Hertel, C., Norcross, R. D., Jakob-Roetne, R. & Hoffmann, T. D-proline derivatives. US patent 6262089 (2001).

  16. Emsley, J. et al. Structure of pentameric human serum amyloid P component. Nature 367, 338–345 (1994)

    Article  ADS  CAS  PubMed  Google Scholar 

  17. Hawkins, P. N., Tennent, G. A., Woo, P. & Pepys, M. B. Studies in vivo and in vitro of serum amyloid P component in normals and in a patient with AA amyloidosis. Clin. Exp. Immunol. 84, 308–316 (1991)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Hawkins, P. N., Wootton, R. & Pepys, M. B. Metabolic studies of radioiodinated serum amyloid P component in normal subjects and patients with systemic amyloidosis. J. Clin. Invest. 86, 1862–1869 (1990)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hutchinson, W. L., Noble, G. E., Hawkins, P. N. & Pepys, M. B. The pentraxins, C-reaction protein and serum amyloid P component, are cleared and catabolized by hepatocytes in vivo. J. Clin. Invest. 94, 1390–1396 (1994)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Pepys, M. B. Therapeutic protein depletion. GB Patent application No. 0119370.5 (filed 2001).

  21. Hawkins, P. N., Myers, M. J., Epenetos, A. A., Caspi, D. & Pepys, M. B. Specific localization and imaging of amyloid deposits in vivo using 123I-labeled serum amyloid P component. J. Exp. Med. 167, 903–913 (1988)

    Article  CAS  PubMed  Google Scholar 

  22. Schenk, D. et al. Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400, 173–177 (1999)

    Article  ADS  CAS  PubMed  Google Scholar 

  23. Bard, F. et al. Peripherally administered antibodies against amyloid β-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nature Med. 6, 916–919 (2000)

    Article  CAS  PubMed  Google Scholar 

  24. Pepys, M. B. Isolation of serum amyloid P component (protein SAP) in the mouse. Immunology 37, 637–641 (1979)

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Pepys, M. B., Baltz, M., Gomer, K., Davies, A. J. S. & Doenhoff, M. Serum amyloid P-component is an acute-phase reactant in the mouse. Nature 278, 259–261 (1979)

    Article  ADS  CAS  PubMed  Google Scholar 

  26. Nelson, S. R. et al. Serum amyloid P component in chronic renal failure and dialysis. Clin. Chim. Acta 200, 191–200 (1991)

    Article  CAS  PubMed  Google Scholar 

  27. Hutchinson, W. L., Hohenester, E. & Pepys, M. B. Human serum amyloid P component is a single uncomplexed pentamer in whole serum. Mol. Med. 6, 482–493 (2000)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wiseman, T., Williston, S., Brandts, J. F. & Lin, L. N. Rapid measurement of binding constants and heats of binding using a new titration calorimeter. Anal. Biochem. 179, 131–137 (1989)

    Article  CAS  PubMed  Google Scholar 

  29. Otwinowski, Z. & Minor, W. Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol. 276, 307–326 (1997)

    Article  CAS  PubMed  Google Scholar 

  30. Vagin, A. & Teplyakov, A. MOLREP: an automated program for molecular replacement. J. Appl. Cryst. 30, 1022–1025 (1997)

    Article  CAS  Google Scholar 

  31. Brünger, A. T. et al. Crystallography & NMR system: a new software suite for macromolecular structure determination. Acta Crystallogr. D 54, 905–921 (1998)

    Article  PubMed  Google Scholar 

  32. Vriend, G. WHAT IF: a molecular modeling and drug design program. J. Mol. Graph. 8, 52–56 (1990)

    Article  CAS  PubMed  Google Scholar 

  33. Laskowski, R. A., MacArthur, M. W., Moss, D. S. & Thornton, J. M. PROCHECK: a program to check the stereochemical quality of protein structures. J. Appl. Crystallogr. 26, 283–291 (1993)

    Article  CAS  Google Scholar 

  34. Iwanaga, T. et al. Liver-specific and high-level expression of human serum amyloid P component gene in transgenic mice. Dev. Genet. 10, 365–371 (1989)

    Article  CAS  PubMed  Google Scholar 

  35. Hawkins, P. N., Myers, M. J., Lavender, J. P. & Pepys, M. B. Diagnostic radionuclide imaging of amyloid: biological targeting by circulating human serum amyloid P component. Lancet i, 1413–1418 (1988)

    Article  Google Scholar 

  36. Hawkins, P. N., Lavender, J. P. & Pepys, M. B. Evaluation of systemic amyloidosis by scintigraphy with 123I-labeled serum amyloid P component. N. Engl. J. Med. 323, 508–513 (1990)

    Article  CAS  PubMed  Google Scholar 

  37. Jager, P. L. et al. Kinetic studies with iodine-123-labeled serum amyloid P component in patients with systemic AA and AL amyloidosis and assessment of clinical value. J. Nucl. Med. 39, 699–706 (1998)

    CAS  PubMed  Google Scholar 

  38. Rydh, A. et al. Serum amyloid P component scintigraphy in familial amyloid polyneuropathy: regression of visceral amyloid following liver transplantation. Eur. J. Nucl. Med. 25, 709–713 (1998)

    Article  CAS  PubMed  Google Scholar 

  39. Esnouf, R. M. An extensively modified version of MolScript that includes greatly enhanced coloring capabilities. J. Mol. Graphics Mod. 15, 132–134 (1997)

    Article  CAS  Google Scholar 

  40. Merritt, E. A. & Murphy, M. E. P. Raster3D Version 2.0. A program for photorealistic molecular graphics. Acta Crystallogr. D 50, 869–873 (1994)

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by grants from the Medical Research Council and The Wellcome Trust to M.B.P., P.N.H. and S.P.W., by National Health Service R & D Funds, and by many donations of patients, relatives and friends to the Amyloidosis Research Fund. M.B.P. conceived the idea of inhibition of SAP binding for therapy of amyloidosis, devised the screening assay, originated and directed the project and wrote the paper; J.H., W.L.H., G.A.T., J.R.G. and L.B.L. performed the experimental work and protein assays in the Pepys laboratory; T.B. and J.A.K. supervised the project within Roche; R.J.-R., R.D.N., A.A., C.H. and T.H. designed and synthesized the inhibitor molecules and evaluated them in vitro; K.Y. and M.S. provided the human SAP transgenic mouse line; G.W.T. and S.M. performed the ex vivo drug assays; S.P.W., D.T., S.K. and A.P. crystallized the SAP–drug complex and solved its structure; P.N.H. contributed to all aspects of the work in the Pepys laboratory and devised and supervised the clinical study, which was conducted by H.J.L. We thank R. Zell, C. Jenny (kilolab), A. FerRo, P. Keller (galenics), R. Strobel, E. Gocke, B. Schläppi (toxicology), D. Schwab, B. Levet-Trafit, J. Huwyler, S. Poli (pharmacokinetics), P. Williams, U. Widmer, Q. Branca and G. Adam for their contributions, S. Madhoo and D. Gopaul for care of the patients and the SAP scintigraphy studies, M. Botto for help in breeding transgenic mice, and E. Jones for preparation of the manuscript.

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Correspondence to M. B. Pepys.

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Competing interests

Funding: Work conducted within Roche was funded entirely by F. Hoffmann-La Roche Ltd, which also provided minor running costs and loan of the gamma camera to the Pepys laboratory.

Employment: Authors identified as Roche personnel were employed by Roche while engaged in the project.

Personal financial interests: M.B.P. was consultant to Roche regarding SAP and amyloidosis for the duration of the project, prior to the clinical studies. M.B.P. is the inventor on the patent, cited in the paper, regarding inhibitors of SAP for treatment of amyloidosis. This patent is now owned by UCL. The patents on CPHPC and related compounds are held by Roche with some of their employees named as inventors. Roche retain all rights to commercial exploitation of CPHPC for treatment of Alzheimer's disease and diabetes but has granted an exclusive licence to FreeMedic PLC, the commercial arm of the Royal Free Campus of Royal Free and University College Medical School, for development of CPHPC for other indications.

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Pepys, M., Herbert, J., Hutchinson, W. et al. Targeted pharmacological depletion of serum amyloid P component for treatment of human amyloidosis. Nature 417, 254–259 (2002). https://doi.org/10.1038/417254a

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