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.
A human antibody selective for transthyretin amyloid removes cardiac amyloid through phagocytic immune cells.
Nat Commun. 2021;12(1):3142.
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