Back to Search
Start Over
Therapeutic Clearance of Amyloid by Antibodies to Serum Amyloid P Component
- Source :
- The New England journal of medicine. 373(12)
- Publication Year :
- 2015
-
Abstract
- The 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.We 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.There 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.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.).
- Subjects :
- Adult
Pathology
medicine.medical_specialty
Pyrrolidines
Amyloid
Carboxylic Acids
Immunoglobulin G
Immunoglobulin Light-chain Amyloidosis
chemistry.chemical_compound
medicine
AL amyloidosis
Humans
Serum amyloid A
Infusions, Intravenous
Radionuclide Imaging
Serum amyloid P component
Aged
biology
Dose-Response Relationship, Drug
business.industry
Amyloidosis
Antibodies, Monoclonal
General Medicine
Middle Aged
medicine.disease
Serum Amyloid P-Component
chemistry
Liver
CPHPC
biology.protein
business
Subjects
Details
- ISSN :
- 15334406
- Volume :
- 373
- Issue :
- 12
- Database :
- OpenAIRE
- Journal :
- The New England journal of medicine
- Accession number :
- edsair.doi.dedup.....50d87603b362d15749ed0af64a070c06