Transthyretin stabilizer therapy increases naturally-occurring antibodies in ATTR cardiomyopathy

Background Amyloid transthyretin cardiomyopathy (ATTR-CM) results from extracellular deposition of misfolded transthyretin (TTR), causing progressive heart failure. Naturally-occurring antibodies (nAbs) targeting misfolded proteins exist in neurodegenerative disease, but their presence in ATTR-CM is unknown. The objective of this study is to determine whether nAbs against TTR (nAbsTTR) exist in humans and whether they are influenced by disease or its treatment.Methods Serum from healthy donors, umbilical cord blood (UCB), and patients with ATTR-CM - both untreated and receiving TTR-stabilizing therapy - was analyzed for nAbsTTR using immunoassays, blotting, and binding studies. Functional activity was evaluated in a fibril formation assay.Results nAbsTTR binding both native and amyloid TTR (ATTR) with high affinity (KD 30 nM/7 nM) were detected in healthy serum and UCB. NAbsTTR levels were significantly altered in ATTR-CM compared to controls: nAbsTTR (IgG) were higher while nAbsTTR (IgM) were lower. nAbsTTR of both subtypes significantly increased by 22% (p ≤ 0.05) in patients receiving TTR-stabilizing therapy. In vitro, nAbsTTR suppressed TTR fibril aggregation.Conclusions Naturally-occurring TTR-targeting antibodies are present from birth, modulated by disease and therapy, and inhibit fibril formation. These findings reveal an unrecognized immune mechanism with potential relevance for ATTR-CM pathogenesis and treatment.