Anti-sortilin1 Antibody Up-Regulates Progranulin via Sortilin1 Down-Regulation

Area of Science:

• Neuroscience
• Immunology
• Genetics

Background:

• Progranulin (PGRN) deficiency due to GRN mutations causes frontotemporal dementia (FTD).
• Increasing PGRN levels presents a potential therapeutic strategy for FTD.
• Sortilin1 (SORT1) acts as a clearance receptor for PGRN, making it a potential therapeutic target.

Purpose of the Study:

• To explore the therapeutic potential of targeting SORT1 to increase PGRN levels.
• To generate and characterize monoclonal antibodies against SORT1.
• To investigate the mechanism by which anti-SORT1 antibodies modulate PGRN levels.

Main Methods:

• Generation of monoclonal antibodies against SORT1 using Sort1 knockout mice.
• Epitope binning of antibodies based on competitive binding assays.
• Assessment of antibody effects on SORT1-PGRN interaction, SORT1 expression, and PGRN levels in vitro and in vivo.
• Characterization of antibody K1-67 in mouse models.

Main Results:

• Monoclonal antibodies against SORT1 were generated and classified into 7 epitope bins.
• A positive correlation was observed between PGRN up-regulation and SORT1 down-regulation.
• Antibody K1-67 demonstrated in vivo efficacy, significantly increasing PGRN levels in mouse plasma and brain interstitial fluid.
• SORT1 down-regulation was confirmed as a key mechanism for PGRN level increase.

Conclusions:

• Down-regulation of SORT1 using anti-SORT1 antibodies is an effective strategy to increase PGRN levels.
• Anti-SORT1 antibodies, particularly K1-67, show therapeutic potential for conditions with PGRN deficiency, such as GRN-related FTD.
• SORT1 represents a promising therapeutic target for restoring PGRN levels in neurological disorders.