title: Novel conformation-specific monoclonal antibodies against amyloidogenic forms of transthyretin.
abstract: BACKGROUND
  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.
authors.affiliation: a Prothena Biosciences Inc , South San Francisco , CA , USA .
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Higaki
authors.affiliation: b Princess Margaret Cancer Centre, University Health Network , Toronto , Ontario , Canada , and.
authors.forename: Avi
authors.initials: A
authors.lastname: Chakrabartty
authors.affiliation: b Princess Margaret Cancer Centre, University Health Network , Toronto , Ontario , Canada , and.
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Galant
authors.affiliation: b Princess Margaret Cancer Centre, University Health Network , Toronto , Ontario , Canada , and.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Hadley
authors.affiliation: c Seattle Genetics , Bothell , WA , USA.
authors.forename: Bradley
authors.initials: B
authors.lastname: Hammerson
authors.affiliation: a Prothena Biosciences Inc , South San Francisco , CA , USA .
authors.forename: Tarlochan
authors.initials: T
authors.lastname: Nijjar
authors.affiliation: a Prothena Biosciences Inc , South San Francisco , CA , USA .
authors.forename: Ronald
authors.initials: R
authors.lastname: Torres
authors.affiliation: a Prothena Biosciences Inc , South San Francisco , CA , USA .
authors.forename: Jose R
authors.initials: JR
authors.lastname: Tapia
authors.affiliation: a Prothena Biosciences Inc , South San Francisco , CA , USA .
authors.forename: Joshua
authors.initials: J
authors.lastname: Salmans
authors.affiliation: a Prothena Biosciences Inc , South San Francisco , CA , USA .
authors.forename: Robin
authors.initials: R
authors.lastname: Barbour
authors.affiliation: a Prothena Biosciences Inc , South San Francisco , CA , USA .
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Tam
authors.affiliation: a Prothena Biosciences Inc , South San Francisco , CA , USA .
authors.forename: Ken
authors.initials: K
authors.lastname: Flanagan
authors.affiliation: a Prothena Biosciences Inc , South San Francisco , CA , USA .
authors.forename: Wagner
authors.initials: W
authors.lastname: Zago
authors.affiliation: a Prothena Biosciences Inc , South San Francisco , CA , USA .
authors.forename: Gene G
authors.initials: GG
authors.lastname: Kinney
mesh_terms: D000595:Amino Acid Sequence; D028227:Amyloid Neuropathies, Familial / Q000150:complications / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis / Q000737:chemistry* / Q000302:isolation & purification; D000936:Antigen-Antibody Complex / Q000737:chemistry*; D009202:Cardiomyopathies / Q000150:complications / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002999:Clone Cells; D000939:Epitopes / Q000737:chemistry*; D006801:Humans; D051379:Mice; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D010586:Phagocytes / Q000166:cytology / Q000276:immunology; D010587:Phagocytosis; D011228:Prealbumin / Q000737:chemistry* / Q000276:immunology; D066329:Protein Aggregates / Q000276:immunology; D011487:Protein Conformation; D017510:Protein Folding; D011994:Recombinant Proteins / Q000737:chemistry / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; D000939:Epitopes; D011228:Prealbumin; D066329:Protein Aggregates; D011994:Recombinant Proteins
keywords: Aggregation; cardiac; clearance; cryptotope; fibrils; immunotherapy; protein misfolding