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2A4 binds soluble and insoluble light chain aggregates from AL amyloidosis patients and promotes clearance of amyloid deposits by phagocytosis † .
- Source :
-
Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis [Amyloid] 2016 Sep; Vol. 23 (3), pp. 168-177. Date of Electronic Publication: 2016 Aug 05. - Publication Year :
- 2016
-
Abstract
- Amyloid light chain (AL) amyloidosis is characterized by misfolded light chain (LC) (amyloid) deposition in various peripheral organs, leading to progressive dysfunction and death. There are no regulatory agency-approved treatments for AL amyloidosis, and none of the available standard of care approaches directly targets the LC protein that constitutes the amyloid. NEOD001, currently in late-stage clinical trials, is a conformation-specific, anti-LC antibody designed to specifically target misfolded LC aggregates and promote phagocytic clearance of AL amyloid deposits. The present study demonstrated that the monoclonal antibody 2A4, the murine form of NEOD001, binds to patient-derived soluble and insoluble LC aggregates and induces phagocytic clearance of AL amyloid in vitro. 2A4 specifically labeled all 21 fresh-frozen organ samples studied, which were derived from 10 patients representing both κ and λ LC amyloidosis subtypes. 2A4 immunoreactivity largely overlapped with thioflavin T-positive labeling, and 2A4 bound both soluble and insoluble LC aggregates extracted from patient tissue. Finally, 2A4 induced macrophage engagement and phagocytic clearance of AL amyloid deposits in vitro. These findings provide further evidence that 2A4/NEOD001 can effectively clear and remove human AL-amyloid from tissue and further support the rationale for the evaluation of NEOD001 in patients with AL amyloidosis.
- Subjects :
- Amyloidogenic Proteins chemistry
Amyloidogenic Proteins isolation & purification
Amyloidosis metabolism
Amyloidosis pathology
Animals
Antibodies, Monoclonal biosynthesis
Benzothiazoles
Cell Line
Humans
Immunoglobulin Light Chains isolation & purification
Mice
Monocytes cytology
Monocytes immunology
Protein Aggregates immunology
Protein Binding
Staining and Labeling methods
Thiazoles chemistry
Amyloidogenic Proteins immunology
Amyloidosis immunology
Antibodies, Monoclonal chemistry
Antigen-Antibody Complex chemistry
Immunoglobulin Light Chains chemistry
Phagocytosis
Subjects
Details
- Language :
- English
- ISSN :
- 1744-2818
- Volume :
- 23
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis
- Publication Type :
- Academic Journal
- Accession number :
- 27494229
- Full Text :
- https://doi.org/10.1080/13506129.2016.1205974