Sustained pharmacological depletion of serum amyloid P component in patients with systemic amyloidosis

Abstract

SummarySerum amyloid P component (SAP) is a universal constituent of amyloid deposits and contributes to their formation and/or persistence. We therefore developed CPHPC ((R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2 carboxylic acid), a novel bis(D-proline) drug, to specifically target SAP and report here a first, exploratory, open label proof of principle study in systemic amyloidosis. CPHPC produced sustained, >95% depletion of circulating SAP in all patients and c. 90% reduction in the SAP content of the two amyloidotic organs that became available. There were no significant adverse effects of either SAP depletion or CPHPC itself. No accumulation of amyloid was demonstrable by SAP scintigraphy in any patient on the drug. In hereditary fibrinogen amyloidosis, which is inexorably progressive, proteinuria was reduced in four of five patients receiving CPHPC and renal survival was prolonged compared to a historical control group. These promising clinical observations merit further study.

Light-chain amyloidosis: SCT, novel agents and beyond

“…76 Subcutaneous CPHPC has been studied in amyloid patients and effectively reduced serum SAP levels. 75 Following treatment with CPHPC, residual SAP remains bound to amyloid deposited in organs. 75,77 In murine studies, after eliminating circulating SAP, targeting the residual tissue-bound SAP with anti SAP IgG induced an inflammatory response and promoted amyloid clearance.…”

“…75 Following treatment with CPHPC, residual SAP remains bound to amyloid deposited in organs. 75,77 In murine studies, after eliminating circulating SAP, targeting the residual tissue-bound SAP with anti SAP IgG induced an inflammatory response and promoted amyloid clearance. 78 Based on these studies, CPHPC in combination with monoclonal antihuman SAP is currently being studied in humans.…”

“…Amyloid fibrils share constituent non-fibrillary proteins including serum amyloid P (SAP), 75 which stabilizes amyloid fibrils and promotes fibrillogenesis. A novel compound, CPHPC ((R) À 1-[6-[(R)-2-carboxy -pyrrolidin-1 yl]-6-oxo-hexanoyl] pyrrolidine-2 carboxylic acid) binds to circulating SAP to form complexes that are cleared by the liver.…”

Amyloidosis

“…85 This mechanism possibly stops accumulation of amyloid and may be useful for all types of systemic amyloidosis, although fibrinogen-derived amyloidosis seems to respond best. 86 Vaccination against amyloid has been attempted in the past with poor results. Early vaccination research was primarily focused on the induction of antibodies against conformational epitopes that were believed to be present in all types of amyloid.…”

Pursuing an underdiagnosed disease: a simple imaging test for increasing suspicion of cardiac amyloidosis

“…Significant advances in treatment have been made over the past decade, particularly in AL amyloidosis in which the precursor protein is derived from immunoglobulin light chain fragments [2]. Transthyretin (TTR)-derived amyloidosis has also been the subject of intensive investigation, and several new therapeutic approaches have completed, or are approaching, preliminary clinical testing [3][4][5][6][7]. Refinements in immunohistochemical and proteomic techniques have permitted precise definition of the amyloid type, a prerequisite for initiating appropriate (and avoiding inappropriate) therapies [8].…”