Therapeutic Clearance of Amyloid by Antibodies to Serum Amyloid P Component

Abstract

Treatment with CPHPC followed by an anti-SAP antibody safely triggered clearance of amyloid deposits from the liver and some other tissues. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01777243.).

Repeat doses of antibody to serum amyloid P component clear amyloid deposits in patients with systemic amyloidosis

“…We have recently reported safety and clinical proofofconcept results for miridesap followed by the fully humanized monoclonal antihuman SAP antibody, dezamizumab, in patients with different forms of systemic amyloidosis, including the following types: monoclonal immunoglobulin light chain (AL), reactive systemic amyloid A protein (AA), apolipoprotein AI (AApoAI), and fibrinogen A αchain (AFib) (3). Infusion of antiSAP antibody triggered transient early inflammatory cytokine production and an acute phase response, followed by substantial plasma C3 depletion, but there was no new or increased renal or other organ dysfunction (3).…”

“…The residual SAP acts as a specific antigen target for therapeutic antiSAP antibodies that can bind to it and thereby trigger amyloid removal (2,3). Plasma SAP depletion by miridesap is essential before antiSAP antibody administration to avoid formation of potentially proinflammatory circulating immune complexes.…”

Improved outcomes for newly diagnosed AL amyloidosis between 2000 and 2014: cracking the glass ceiling of early death

“…12,13 Moreover, monoclonal antibodies targeting amyloid deposits are undergoing studies with promising results. 14,15 The survival of patients with AL amyloidosis has improved over time, but 6-month mortality had largely remained unchanged over multiple decades. 16,17 In light of major advances in recent years, we aimed to study the trends in patients and disease characteristics, treatment use, and outcome in 1551 newly diagnosed AL amyloidosis patients seen in our institution between 2000 and 2014.…”

Amyloid-β and lysozyme proteotoxicity in Drosophila : Beneficial effects of lysozyme and serum amyloid P component in models of Alzheimer’s disease and lysozyme amyloidosis

“…Using the same mouse model for AA, administration of the organic molecule R-1-[6-[R-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid, CPHPC, decreased the endogenous level of mouse SAP in amyloid deposits by binding of the molecule to circulating SAP and inducing clearance of the complex by the liver (Pepys et al, 2002). In a phase I clinical trial, which included systemic amyloid light chain and apolipoprotein AI amyloidosis patients, a combinatorial treatment involving the drug CPHPC and an anti-SAP antibody reduced the level of SAP circulating in plasma and removed SAP from amyloid aggregates, leading to a decrease in amyloid load (Richards et al, 2015). A phase II clinical trial is now pending.…”

“…However, in lysozyme amyloidosis, the main pathological event is the huge accumulation of amyloid aggregates, which eventually cause organ failure, implying that SAP promotes disease progression and that reduced SAP levels could be beneficial in patients suffering from systemic amyloidosis. Indeed, in an on-going clinical trial, the organic molecule CPHPC in combination with an anti-SAP antibody is used as a potential treatment strategy for systemic amyloidosis, targeting, and lowering the levels of, SAP both in plasma and in the amyloid aggregates (Richards et al, 2015). Positive results have been observed in a clinical phase I trial, where two injections of anti-SAP antibody in combination with CPHPC dramatically reduced the amyloid load in patients suffering from light chain and apolipoprotein AI amyloidosis.…”