Fc-Engineering Improves PET Imaging of Anti-Mesothelin VH-Fc across Multiple Tumor Mouse Models and Reveals Sex-Specific Renal Clearance.

ABSTRACT: Mesothelin (MSLN) is overexpressed in various malignancies, making it a promising target for molecular imaging and therapeutic strategies. Anti-MSLN VH-Fc fusion proteins show high tumor uptake as compared with monoclonal antibodies; however, elevated accumulation in Fc-rich organs (liver, spleen) can compromise tumor-to-background ratios and limit clinical applicability. To overcome this, we developed Fc mutant anti-MSLN VH-Fc fusion proteins incorporating G236R/L328R (GRLR) and L234A/L235A/P329G (LALAPG) mutations to eliminate FcγRs interactions. Engineered mutants exhibited high purity (>95%), retained strong MSLN binding (KD 2.2-3.7 nM), and effectively silenced FcγR binding by ex vivo and in vivo analyses. Following zirconium-89 radiolabeling, PET imaging was conducted a

SUBMITTER: Bhise A 

PROVIDER: S-EPMC12828721 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature