Engineering a single-chain immunoglobulin scaffold loaded with a latent-releasable cytotoxic pore-forming peptide.

ABSTRACT: Pore-forming peptides (PFPs) hold strong anti-tumor potential but require delivery systems to ensure stability and prevent off-target effects. In this study, we develop a strategy to transport a PFP in a biologically latent, precursor-like state. Specifically, based on the therapeutic antibody atezolizumab, which targets the tumor-associated programmed death-ligand 1, we engineered a single-chain IgG (scIgG) construct with flexible linkers embedding the melittin sequence. To further enable tumor-specific activation, melittin was flanked by regions cleavable by matriptase/ST14 (MT), a protease overexpressed in carcinomas. Initial constructs failed due to cytotoxicity during expression, prompting the redesign of melittin into a variant named Pmod2-2. This peptide retained potent pore-forming

SUBMITTER: Morillo I 

PROVIDER: S-EPMC12647727 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature