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<p>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 ability and was compatible with IgG fusion. The resulting scIgG-Pmod2-2 hybrid preserved Fab and Fc functionalities of the atezolizumab IgG, displayed favorable pharmacokinetics and released the active peptide in response to MT. These results highlight the potential of integrating cytolytic PFPs into antibody-based therapeutics.</p><p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月25日

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  • Izaskun Morillo,
  • Joao Zulaica,
  • Asier R. Caballero,
  • Jaione Auzmendi-Iriarte,
  • Eneko Largo,
  • Beatriz Apellaniz,
  • Arkaitz Carracedo,
  • Marco Piva,
  • José L. Nieva,
  • Edurne Rujas

摘要

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 ability and was compatible with IgG fusion. The resulting scIgG-Pmod2-2 hybrid preserved Fab and Fc functionalities of the atezolizumab IgG, displayed favorable pharmacokinetics and released the active peptide in response to MT. These results highlight the potential of integrating cytolytic PFPs into antibody-based therapeutics.