Transthyretin stabilizer therapy increases naturally-occurring antibodies in ATTR cardiomyopathy

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 (nAbs_TTR) exist in humans and whether they are influenced by disease or its treatment.

Serum from healthy donors, umbilical cord blood (UCB), and patients with ATTR-CM - both untreated and receiving TTR-stabilizing therapy - was analyzed for nAbs_TTR using immunoassays, blotting, and binding studies. Functional activity was evaluated in a fibril formation assay.

nAbs_TTR binding both native and amyloid TTR (ATTR) with high affinity (KD 30 nM/7 nM) were detected in healthy serum and UCB. NAbs_TTR 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, nAbs_TTR suppressed TTR fibril aggregation.

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.