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

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. ; We thank the patients and their relatives who donated the biospecimens used in this study, and acknowledge partial funding through a Eurostars grant (E! 9036). We also thank the National Disease Research Interchange for providing biospecimens; Dr. Fab-rice Heitz, Neurimmune, and Gery Barmettler, Center for Microscopy and Image Analysis University of Zurich, for electron microscopy imaging; Dr. Stefan Schauer, Functional Genomics Center ETH and University of Zurich, for his support with kinetic binding experiments using SPR; and the Antibody Technology Group at Neurimmune for antibody cloning and expression.