A human antibody selective for transthyretin amyloid removes cardiac amyloid through phagocytic immune cells

• Published in: Nature communications 2021-05, Vol.12 (1), p.3142-3142, Article 3142
• Main Authors: Michalon, Aubin, Hagenbuch, Andreas, Huy, Christian, Varela, Evita, Combaluzier, Benoit, Damy, Thibaud, Suhr, Ole B., Saraiva, Maria J., Hock, Christoph, Nitsch, Roger M., Jan Grimm
• Format: Article
• Language: English
• Subjects: 101/28; 13/105; 14/63; 49/1; 631/154/51/1568; 631/45/470/2284; 631/61/490; 64/60; 692/4019/592/1540; 82/103; 82/29; 82/47; 82/51; Amyloid; Antibodies; Biological activity; Cardiomyopathy; Cell activation; Congestive heart failure; Coronary artery disease; Fibrils; Hereditary diseases; Humanities and Social Sciences; Immune system; Immunoglobulin G; Immunological memory; Macrophages; multidisciplinary; Myocardium; Older people; Phagocytes; Science; Science (multidisciplinary); Transthyretin
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-23274-x

Transthyretin amyloid (ATTR) cardiomyopathy is a debilitating disease leading to heart failure and death. It is characterized by the deposition of extracellular ATTR fibrils in the myocardium. Reducing myocardial ATTR load is a therapeutic goal anticipated to translate into restored cardiac function and improved patient survival. For this purpose, we developed the selective anti-ATTR antibody NI301A, a recombinant human monoclonal immunoglobulin G1. NI301A was cloned following comprehensive analyses of memory B cell repertoires derived from healthy elderly subjects. NI301A binds selectively with high affinity to the disease-associated ATTR aggregates of either wild-type or variant ATTR related to sporadic or hereditary disease, respectively. It does not bind physiological transthyretin. NI301A removes ATTR deposits ex vivo from patient-derived myocardium by macrophages, as well as in vivo from mice grafted with patient-derived ATTR fibrils in a dose- and time-dependent fashion. The biological activity of ATTR removal involves antibody-mediated activation of phagocytic immune cells including macrophages. These data support the evaluation of safety and tolerability of NI301A in an ongoing phase 1 clinical trial in patients with ATTR cardiomyopathy. Analyzing memory B cell repertoires of the healthy elderly enabled Michalon et al. to develop a recombinant human antibody selective for transthyretin amyloid. This antibody removes cardiac amyloid through recruitment of phagocytic immune cells.