Transthyretin aggregate-specific antibodies recognize cryptic epitopes on patient-derived amyloid fibrils

Monichan Phay, Veronika Blinder, Sallie Macy, Michael J. Greene, Daniel C. Wooliver, Wen Liu, Antoni Planas, Dominic M. Walsh, Lawreen H. Connors, Stanley R. Primmer, Stephanie A. Planque, Sudhir Paul, Brian O'Nuallain

Research output: Indexed journal article Articlepeer-review

19 Citations (Scopus)

Abstract

Amyloidosis involves the extracellular deposition of proteinaceous amyloid fibrils and accessory molecules in organ(s) and/or tissue(s), and is associated with a host of human diseases, including Alzheimer disease, diabetes, and heart disease. Unfortunately, the amyloidoses are currently incurable, and there is an urgent need for less invasive diagnostics. To address this, we have generated 22 monoclonal antibodies (mAbs) against aggregates formed by a blood transport protein, transthyretin (TTR), which primarily forms amyloid fibrils in a patient's heart and/or peripheral nerves. Four of the mAbs, 2T5C9, 2G9C, T1F11, and TB2H7, demonstrated diagnostic potential in enzyme-linked immunosorbent assays (ELISA) by their low to sub-nanomolar cross-reactivity with recombinant wild-type (WT) and mutant TTR aggregates and lack of binding to native TTR or amyloid fibrils formed by other peptides or proteins. Notably, in the presence of normal human sera, three of the four mAbs, 2T5C9, 2G9C, and T1F11, retained low nM binding to TTR amyloid fibrils derived from two patients with familial amyloidotic polyneuropathy (FAP). The two most promising mAbs, 2T5C9 and 2G9C, were also shown by immunohistochemistry to have low nM binding to TTR amyloid deposits in cardiac tissue sections from two FAP patients. Taken together, these findings strongly support further investigations on the diagnostic utility of TTR aggregate specific mAbs for patients with TTR amyloidoses.

Original languageEnglish
Pages (from-to)97-104
Number of pages8
JournalRejuvenation Research
Volume17
Issue number2
DOIs
Publication statusPublished - 1 Apr 2014

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