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

Abstract

Progranulin (PGRN) haploinsufficiency associated with loss-of-function mutations in the granulin gene causes frontotemporal dementia (FTD). This suggests that increasing PGRN levels could have promising therapeutic implications for patients carrying GRN mutations. In this study, we explored the therapeutic potential of sortilin1 (SORT1), a clearance receptor of PGRN, by generating and characterizing monoclonal antibodies against SORT1. Anti-SORT1 monoclonal antibodies were generated by immunizing Sort1 knockout mice with SORT1 protein. The antibodies were classified into 7 epitope bins based on their competitive binding to the SORT1 protein and further defined by epitope bin-dependent characteristics, including SORT1-PGRN blocking, SORT1 down-regulation, and binding to human and mouse SORT1. We identified a positive correlation between PGRN up-regulation and SORT1 down-regulation. Furthermore, we also characterized K1-67 antibody via SORT1 down-regulation and binding to mouse SORT1 in vivo and confirmed that K1-67 significantly up-regulated PGRN levels in plasma and brain interstitial fluid of mice. These data indicate that SORT1 down-regulation is a key mechanism in increasing PGRN levels via anti-SORT1 antibodies and suggest that SORT1 is a potential target to correct PGRN reduction, such as that in patients with FTD caused by GRN mutation.

Regulation of lysosomal trafficking of progranulin by sortilin and prosaposin

“… 48 Thus, sortilin has become a hot target for FTLD- GRN therapeutics to boost circulating PGRN levels. Small molecules and anti-sortilin antibodies have been developed to inhibit PGRN–sortilin interaction and anti-sortilin antibodies are currently in clinical trials for FTLD- GRN 49–51 (NCT04111666, NCT04374136, NCT03987295). Recent studies have shown that anti-sortilin antibodies not only block PGRN–sortilin interaction but also downregulate sortilin levels.…”

“…Recent studies have shown that anti-sortilin antibodies not only block PGRN–sortilin interaction but also downregulate sortilin levels. 49 However, given the critical role of PGRN and granulin peptides in the lysosome 10 , 22 and the fact that GRN mutations in FTLD also cause haploinsufficiency of granulin peptides, 33 restoration of both extracellular and lysosomal pools of PGRN in the brain of FTLD- GRN patients will be needed to have better therapeutic outcomes.…”

Progranulin in neurodegenerative dementia

“…SORT1 is a potential target to correct PGRN reduction (Miyakawa et al., 2020). The therapeutic potential of SORT1 was developed by generating and characterizing monoclonal antibodies that downregulate SORT1.…”

Progranulin as a Potential Therapeutic Target in Immune-Mediated Diseases

“…70 Similarly, down-regulation of sortilin 1 (SORT1) expression is a pivotal mechanism of PGRN elevation and a prospective target for PGRN to promote arthritis and other diseases, as indicated by PGRN KO mice phenotype. 98 As for the protection of PGRN from proteolytic degradation, some proteins, such as the secretory leukocyte protease inhibitor (SLPI) and apolipoprotein A1 can bind to it to protect it against proteolytic degradation. 34 Besides, an engineered protein consisted of the FAC domain of PGRN was constructed, which retains comparable TNFR binding affinity of PGRN referred as Atsttrin.…”