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Amyloid. 2016 Jun;23(2):86-97. doi: 10.3109/13506129.2016.1148025. Epub 2016 Mar 16.

Novel conformation-specific monoclonal antibodies against amyloidogenic forms of transthyretin.

Author information

1
a Prothena Biosciences Inc , South San Francisco , CA , USA .
2
b Princess Margaret Cancer Centre, University Health Network , Toronto , Ontario , Canada , and.
3
c Seattle Genetics , Bothell , WA , USA.

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.

KEYWORDS:

Aggregation; cardiac; clearance; cryptotope; fibrils; immunotherapy; protein misfolding

PMID:
26981744
PMCID:
PMC4898150
DOI:
10.3109/13506129.2016.1148025
[Indexed for MEDLINE]
Free PMC Article

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