Antibodies to human serum amyloid P component eliminate visceral amyloid deposits

Systemic amyloidosis is a serious disease caused by accumulation of amyloid fibrils in the viscera and connective tissues. Serum amyloid P (SAP) is a normal plasma protein that concentrates within the amyloid deposits. Working in a mouse model of the disease, Mark Pepys and colleagues find that a combination of a drug that depletes circulating SAP and an antibody that targets residual SAP within the deposits results in clearance of amyloid deposits. A humanized version of the anti-SAP antibody has been developed with a view to clinical evaluation of this dual approach. Systemic amyloidosis is a serious disease caused by accumulation of amyloid fibrils in the viscera and connective tissues. Serum amyloid P component (SAP) is a normal plasma protein that concentrates within the amyloid deposits. These authors find that a combination of a drug that depletes circulating SAP and an antibody that targets residual SAP within the deposits results in clearance of amyloid deposits in a mouse model of the disease. 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.