Systemic amyloidosis is caused by misfolding and aggregation of globular proteins in vivo for which
effective treatments are urgently needed. Inhibition of protein self-aggregation represents an attractive
therapeutic strategy. Studies on the amyloidogenic variant of \u3b22-microglobulin, D76N, causing
hereditary systemic amyloidosis, have become particularly relevant since fibrils are formed in vitro in
physiologically relevant conditions. Here we compare the potency of two previously described inhibitors
of wild type \u3b22-microglobulin fibrillogenesis, doxycycline and single domain antibodies (nanobodies).
The \u3b22-microglobulin -binding nanobody, Nb24, more potently inhibits D76N \u3b22-microglobulin
fibrillogenesis than doxycycline with complete abrogation of fibril formation. In \u3b22-microglobulin knock
out mice, the D76N \u3b22-microglobulin/ Nb24 pre-formed complex, is cleared from the circulation at the
same rate as the uncomplexed protein; however, the analysis of tissue distribution reveals that the
interaction with the antibody reduces the concentration of the variant protein in the heart but does
not modify the tissue distribution of wild type \u3b22-microglobulin. These findings strongly support the
potential therapeutic use of this antibody in the treatment of systemic amyloidosis
