Kidney dysfunction increases the blood levels of β2-microglobulin (β2-m), triggering dialysis-related amyloidosis. Previously, we developed a navigator molecule, consisting of a fusion protein of the N-terminal domain of apolipoprotein E (ApoE NTD) and the α3 domain of the major histocompatibility complex class I (MHC α3), for switching the metabolic processing pathway of β2-m from the kidneys to the liver. However, the β2-m binding of ApoE NTD-MHC α3 was impaired in the blood. In the current study, we replaced the β2-m binding part of the navigator protein (MHC α3) with an anti-β2-m single-chain variable fragment (scFv) antibody. The resultant ApoE NTD-scFv exhibited better β2-m binding than ApoE NTD-MHC α3 in buffer, and even in serum. Similar to ApoE NTD-MHC α3, in the mice model ApoE NTD-scFv bound to the liver cells' surfaces in vitro and accumulated mainly in the liver, when complexed with 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC). Both ApoE NTD-MHC α3 + DMPC and ApoE NTD-scFv + DMPC significantly switched the β2-m accumulation in mice from the kidneys to the liver, but only the ApoE NTD-scFv + DMPC group showed a significantly higher ratio of β2-m accumulation in the liver versus the kidneys, compared with the control group. These results suggest that the enhanced β2-m binding activity of the navigator molecule increased the efficiency of switching the metabolic processing pathway of the etiologic factor.
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