Transthyretin Stabilizer Therapy increases naturally-occurring Antibodies in ATTR Cardiomyopathy

S. Settelmeier (Essen)¹, D. Agranovski (Essen)², M. Steinhardt (Würzburg)³, S. Waydhas (Essen)¹, I. Gering (Jülich)⁴, V. Cejka (Würzburg)⁵, C. Morbach (Würzburg)⁶, S. Störk (Würzburg)⁵, D. Willbold (Jülich)⁷, R. Küppers (Essen)⁸, J. Vogel (Essen)¹, L. Michel (Essen)¹, A. Carpinteiro (Essen)⁹, H. C. Reinhardt (Essen)¹⁰, R. Dodel (Essen)², T. Rassaf (Essen)¹, A. J. Ross (Essen)², U. Hendgen-Cotta (Essen)^1
1Universitätsklinikum Essen Klinik für Kardiologie und Angiologie Essen, Deutschland; ²Universität Duisburg-Essen Lehrstuhl für Geriatrie Essen, Deutschland; ³University Hospital Würzburg nterdisciplinary Amyloidosis Center of Northern Bavaria Würzburg, Deutschland; ⁴Forschungszentrum Jülich Institute of Biological Information Processing Jülich, Deutschland; ⁵Universitätsklinikum Würzburg Deutsches Zentrum für Herzinsuffizienz/DZHI Würzburg, Deutschland; ⁶Universitätsklinikum Würzburg Medizinische Klinik I, Kardiologie Würzburg, Deutschland; ⁷Forschungszentrum Jülich Jülich, Deutschland; ⁸Universitätsklinikum Essen Institut für Zellbiologie (Tumorforschung) Essen, Deutschland; ⁹Universitätsklinik Essen Klinik für Hämatologie und Stammzelltransplantation Essen, Deutschland; ¹⁰Universitätsklinikum Essen Klinik für Hämatologie und Stammzelltransplantation Essen, Deutschland

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

 

Methods & Results:

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 spectroscopic binding studies. Functional activity was evaluated in a TTR fibril formation assay. nAbs_TTR binding both native and amyloid TTR (aTTR) were detected in healthy serum and UCB, with high affinity (K_d 30 nM / 7 nM). nAbs_TTR levels were altered in ATTR-CM compared with controls but increased in patients receiving TTR-stabilizing therapy. In vitro, nAbs_TTR suppressed TTR fibril aggregation.

 

Conclusion:

Naturally-occurring TTR-specific antibodies are present in humans, are modulated by disease and therapy, and functionally inhibit fibril formation. These findings reveal an unrecognized immune mechanism with potential relevance for ATTR-CM pathogenesis and treatment.