The Basis for an Antibody Therapy to Treat Transthyretin Amyloidosis


Misfolded transthyretin accumulates with age, forming solid amyloid deposits in tissues, particularly in the cardiovascular system. Amyloid disrupts proper function of cells and organs, and this is likely the majority cause of death in supercentenarians, the oldest humans. In recent years evidence has emerged for transthyretin amyloid to be involved in heart failure and a range of other conditions in younger old age, as well. There are a number of different approaches to clearing transthyretin amyloid under development, one of which has had a successful human trial, but progress towards the clinic is nonetheless exceedingly slow. This is disappointing, as this sort of therapy is a form of narrow rejuvenation, beneficial to every adult, and should not be locked up within the regulatory system in this way. Those developing and funding these treatments have to date failed to appreciate the true scope of success, or they would be far more eager to move ahead.

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. 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 misfolded TTR and specific immunolabeling of ATTR amyloidosis patient-derived tissue.

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. These novel antibodies may be therapeutically useful in preventing deposition and promoting clearance of TTR amyloid and in diagnosing TTR amyloidosis.


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