ReportSYSTEMIC AMYLOIDOSIS

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

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Science Translational Medicine  03 Jan 2018:
Vol. 10, Issue 422, eaan3128
DOI: 10.1126/scitranslmed.aan3128

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Making amyloid vanish

Fatal systemic amyloidosis is caused by extracellular amyloid deposition that disrupts tissue structure and function. The normal plasma protein, serum amyloid P component (SAP), is always present within amyloid deposits. Richards et al. now show that previous depletion of circulating SAP by the drug, miridesap, uniquely enables subsequent administration of the humanized anti-SAP antibody, dezamizumab, to patients with systemic amyloidosis. Dezamizumab bound to residual SAP in the amyloid deposits and triggered their removal. Repeat cycles of miridesap followed by dezamizumab progressively removed amyloid from the liver, spleen, and kidneys of the patients. Evidence of clinical benefit suggests that this new approach has potential to improve management and outcome for patients with systemic amyloidosis.

Abstract

Systemic amyloidosis is a fatal disorder caused by pathological extracellular deposits of amyloid fibrils that are always coated with the normal plasma protein, serum amyloid P component (SAP). The small-molecule drug, miridesap, [(R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC)] depletes circulating SAP but leaves some SAP in amyloid deposits. This residual SAP is a specific target for dezamizumab, a fully humanized monoclonal IgG1 anti-SAP antibody that triggers immunotherapeutic clearance of amyloid. We report the safety, pharmacokinetics, and dose-response effects of up to three cycles of miridesap followed by dezamizumab in 23 adult subjects with systemic amyloidosis (ClinicalTrials.gov identifier: NCT01777243). Amyloid load was measured scintigraphically by amyloid-specific radioligand binding of 123I-labeled SAP or of 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid. Organ extracellular volume was measured by equilibrium magnetic resonance imaging and liver stiffness by transient elastography. The treatment was well tolerated with the main adverse event being self-limiting early onset rashes after higher antibody doses related to whole body amyloid load. Progressive dose-related clearance of hepatic amyloid was associated with improved liver function tests. 123I-SAP scintigraphy confirmed amyloid removal from the spleen and kidneys. No adverse cardiac events attributable to the intervention occurred in the six subjects with cardiac amyloidosis. Amyloid load reduction by miridesap treatment followed by dezamizumab has the potential to improve management and outcome in systemic amyloidosis.

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