Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing
Patent
1996-08-22
2000-10-03
Duffy, Patricia A.
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
424 92, 435 78, 436503, G01N 3353, A61K 4900
Patent
active
061269182
DESCRIPTION:
BRIEF SUMMARY
The present application is a nationalization of International Application No. PCT/GB 94/01802, filed Aug. 17, 1994; which has a priority date of Aug. 17, 1993.
1. Field of the Invention
The present invention relates to therapeutic and diagnostic agents for amyloidosis. The invention also relates to the three-dimensional structure of human serum amyloid P component and to the use of that structure in the production of therapeutic and diagnostic agents.
2. Description of the Related Art
Amyloidosis is the abnormal deposit of autologous proteins as insoluble fibrils in tissues. There are many different forms, each associated with a different fibril protein. Although microscopic amyloid deposition is always present in the elderly, and rarely causes clinical problems, more substantial amyloidosis, especially in the vital organs, is associated with progressive, untreatable and usually fatal disease. The most common disorders associated with amyloidosis are Alzheimer's disease and maturity onset diabetes mellitus. Other forms of acquired and hereditary amyloidosis are rarer but cause serious morbidity and are generally fatal.
Serum amyloid P component (SAP), a normal human plasma protein, is a universal constituent of amyloid deposits in all forms of amyloidosis, including the cerebral amyloid of Alzheimer's disease [1], as a result of its specific calcium-dependent binding affinity for amyloid fibrils [2]. The role, if any, of SAP in the pathogenesis or persistence of amyloid in vivo is not known and amyloid fibrils can be generated in vitro from suitable precursor proteins in the absence of SAP. However, SAP in amyloid is identical to its normal circulating form, it is not catabolised in the deposits in contrast to its normal rapid uptake from the circulation and catabolism in hepatocytes, and it is itself highly resistant to proteolytic degradation.
Human serum amyloid P component is a decameric plasma glycoprotein composed of identical subunits non-covalently associated in two pentameric rings interacting face-to-face. Although SAP is not required for amyloid fibrillogenesis in vitro, it may protect the fibrils from degradation in vivo [3]. SAP is also the major DNA and chromatin binding protein of plasma [4,5] and other autologous ligands for SAP include fibronectin, C4-binding protein [6] and glycosamino-lycans [7]; SAP is also a normal tissue matrix constituent associated with elastic fibres [8] and the glomerular basement membrane [9]. Finally, SAP is a calcium-dependent lectin, the best characterised ligand of which is the 4,6-cyclic pyruvate acetal of .beta.-D-galactose (MO.beta.DG) [10].
Human SAP shows no polymorphism or heterogeneity of its protein or its glycan [11] and no individual deficient in SAP has yet been described, suggesting that the molecule has important functions. Furthermore, SAP and C-reactive protein (CRP), the classical acute phase protein with which it shares over 50% sequence identity, belong to the pentraxin family of plasma proteins which have been stably conserved throughout vertebrate evolution [12,13]. The structure and structure-function relationships of SAP are thus of considerable fundamental interest, in addition to their clinical importance which arises from the invaluable new information provided by use of radio-labelled SAP as a specific quantitative in vivo tracer for amyloid deposits [14]. The speed and specificity with which SAP from the circulation localises to amyloid deposits and its prolonged retention there make SAP an interesting targeting agent. As indicated above, however, in spite of various observations and speculations, the role if any of SAP in the pathogenesis and persistence of amyloid in vivo was not known.
SUMMARY OF THE INVENTION
The present invention is based on our complete resolution of the three-dimensional structure of SAP, and also on our demonstration that the binding of SAP in vitro to amyloid fibrils at a specific binding site protects those fibrils from proteolytic degradation in the presence of proteinases. Results obtained on amyloid
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Blundell Thomas L.
Pepys Mark B.
Duffy Patricia A.
Imperial College Innovations Limited
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