Enhanced β2-microglobulin binding of a "navigator" molecule bearing a single-chain variable fragment antibody for artificial switching of metabolic processing pathways. (6th July 2021)

• Record Type: Journal Article
• Authors: Kambe, Yusuke; Kuwahara, Ken; Sato, Mitsuru; Nakaoki, Takahiko; Yamaoka, Tetsuji
• Is Part Of: Biomaterials science. Volume 9:Number 16(2021)
• Page Start: 5551
• Page End: 5558
• Publication Date: 2021-07-06
• Subjects: Biomedical materials -- Periodicals; 610.28
• DOI: 10.1039/d1bm00385b
• Languages: English
• ISSNs: 2047-4830

Abstract

Abstract : Replacement of the β2-microglobulin-binding part of the "navigator" with scFv improved the β2-microglobulin-binding activity in the blood, resulting in better switching of the metabolic processing pathway of the etiologic factor in mice. Abstract : 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.