Novel conformation-specific monoclonal antibodies against amyloidogenic forms of transthyretin. (2nd April 2016)

• Record Type: Journal Article
• Authors: Higaki, Jeffrey N.; Chakrabartty, Avi; Galant, Natalie J.; Hadley, Kevin C.; Hammerson, Bradley; Nijjar, Tarlochan; Torres, Ronald; Tapia, Jose R.; Salmans, Joshua; Barbour, Robin; Tam, Stephen J.; Flanagan, Ken; Zago, Wagner; Kinney, Gene G.
• Is Part Of: Amyloid. Volume 23:Number 2(2016:Jun.)
• Page Start: 86
• Page End: 97
• Publication Date: 2016-04-02
• Subjects: Aggregation -- cardiac -- clearance -- cryptotope -- fibrils -- immunotherapy -- protein misfolding; Amyloidosis -- Periodicals; 616.3995
• DOI: 10.3109/13506129.2016.1148025
• Languages: English
• ISSNs: 1350-6129

Abstract

Abstract: Introduction : Transthyretin amyloidosis (ATTR amyloidosis) is caused by the misfolding and deposition of the transthyretin (TTR) protein and results in progressive multi-organ dysfunction. TTR epitopes exposed by dissociation and misfolding are targets for immunotherapeutic antibodies. We developed and characterized antibodies that selectively bound to misfolded, non-native conformations of TTR. Methods : Antibody clones were generated by immunizing mice with an antigenic peptide comprising a cryptotope within the TTR sequence and screened for specific binding to non-native TTR conformations, suppression of in vitro TTR fibrillogenesis, promotion of antibody-dependent phagocytic uptake of mis-folded TTR and specific immunolabeling of ATTR amyloidosis patient-derived tissue. Results : Four identified monoclonal antibodies were characterized. These antibodies selectively bound the target epitope on monomeric and non-native misfolded forms of TTR and strongly suppressed TTR fibril formation in vitro . These antibodies bound fluorescently tagged aggregated TTR, targeting it for phagocytic uptake by macrophage THP-1 cells, and amyloid-positive TTR deposits in heart tissue from patients with ATTR amyloidosis, but did not bind to other types of amyloid deposits or normal tissue. Conclusions : Conformation-specific anti-TTR antibodies selectively bind amyloidogenic but not native TTR. These novel antibodies may be therapeutically useful in preventing deposition and promoting clearance of TTR amyloid and in diagnosing TTR amyloidosis.