• Duncan B Richards, Louise M Cookson, Alienor C Berges, Sharon V Barton, Thirusha Lane, James M Ritter, Marianna Fontana, James C Moon, Massimo Pinzani, Julian D Gillmore, Philip N Hawkins, and Mark B Pepys.
• From GlaxoSmithKline Research and Development, Stevenage (D.B.R., L.M.C., A.C.B., S.V.B.), and National Health Service National Amyloidosis Centre, Centre for Amyloidosis and Acute Phase Proteins, University College London (UCL) and Royal Free Hospital (T.L., M.F., J.D.G., P.N.H., M.B.P.), Quintiles Drug Research Unit at Guy's Hospital (J.M.R.), and UCL Division of Medicine (M.F.), UCL Institute of Cardiovascular Science and Barts Heart Centre (J.C.M.), UCL Institute for Liver and Digestive Health (M.P.), and UCL Wolfson Drug Discovery Unit (M.B.P.), University College London, London - all in the United Kingdom.
• N. Engl. J. Med. 2015 Sep 17; 373 (12): 1106-14.

BackgroundThe amyloid fibril deposits that cause systemic amyloidosis always contain the nonfibrillar normal plasma protein, serum amyloid P component (SAP). The drug (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC) efficiently depletes SAP from the plasma but leaves some SAP in amyloid deposits that can be specifically targeted by therapeutic IgG anti-SAP antibodies. In murine amyloid A type amyloidosis, the binding of these antibodies to the residual SAP in amyloid deposits activates complement and triggers the rapid clearance of amyloid by macrophage-derived multinucleated giant cells.MethodsWe conducted an open-label, single-dose-escalation, phase 1 trial involving 15 patients with systemic amyloidosis. After first using CPHPC to deplete circulating SAP, we infused a fully humanized monoclonal IgG1 anti-SAP antibody. Patients with clinical evidence of cardiac involvement were not included for safety reasons. Organ function, inflammatory markers, and amyloid load were monitored.ResultsThere were no serious adverse events. Infusion reactions occurred in some of the initial recipients of larger doses of antibody; reactions were reduced by slowing the infusion rate for later patients. At 6 weeks, patients who had received a sufficient dose of antibody in relation to their amyloid load had decreased liver stiffness, as measured with the use of transient elastography. These patients also had improvements in liver function in association with a substantial reduction in hepatic amyloid load, as shown by means of SAP scintigraphy and measurement of extracellular volume by magnetic resonance imaging. A reduction in kidney amyloid load and shrinkage of an amyloid-laden lymph node were also observed.ConclusionsTreatment 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.).

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