Clinical Epidemiology and Ageing

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

Michalon A, Hagenbuch A, Huy C, Varela E, Combaluzier B, Damy T, Suhr OB, Saraiva MJ, Hock C, Nitsch RM Nat Commun. 2021;12(1):3142.

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.

MeSH terms: Aged, 80 and over; Amyloid Neuropathies, Familial; Animals; Antibodies, Monoclonal; Cardiomyopathies; Clinical Trials, Phase I as Topic; Disease Models, Animal; Female; Humans; Macrophages; Male; Mice; Mutation; Myocardium; Phagocytosis; Prealbumin; Protein Aggregates; Recombinant Proteins; Transplantation, Heterologous
DOI: 10.1038/s41467-021-23274-x