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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 countries (1). 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 present (1). 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 accumulation (1). Unfortunately, control of fibril-protein production is not possible in some forms of amyloidosis and in others it is often slow and hazardous (1). 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., SAP is selectively concentrated in amyloid deposits by its avid binding to all amyloid fibril types (2,3). SAP binding stabilizes amyloid fibrils, protects them from proteolysis in vitro (5) and [...]

The transformation of soluble autologous proteins into insoluble amyloid fibrils as tissue deposits is linked with Alzheimer's disease, systemic amyloidosis, transmissible spongiform encephalopathy and other serious diseases. The two naturally occurring human lysozyme variants, which both cause autosomal dominant hereditary amyloidosis, are analyzed in terms of their structure, stability, fibrillogenic properties and conformational dynamics.