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Antibody-mediated neutralization of perfringolysin o for intracellular protein delivery

Nicole J Yang1,2, David V Liu1,2, Demetra Sklaviadis3

  • 1†Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.

Molecular Pharmaceutics
|April 18, 2015
PubMed

Insights

Engineered antibodies neutralize perfringolysin O (PFO), a bacterial toxin, enabling targeted protein delivery into cells. This innovation significantly enhances PFO

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Immunology

Background:

  • Perfringolysin O (PFO) is a potent bacterial pore-forming protein.
  • PFO's cytotoxicity limits its use for intracellular delivery.
  • Cholesterol-dependent cytolysins (CDCs) are a family of bacterial proteins.

Purpose of the Study:

  • To engineer a bispecific antibody to neutralize PFO.
  • To develop a targeted intracellular delivery system using attenuated PFO.
  • To improve the safety and efficacy of PFO as a delivery vehicle.

Main Methods:

  • Design and engineering of a bispecific, neutralizing antibody against PFO.
  • Targeting reversibly attenuated PFO to endocytic compartments via receptor-mediated internalization.
  • Co-targeting a gelonin construct with the PFO-antibody system for endosomal release.

Main Results:

  • The PFO-based system achieved efficient endosomal release of a gelonin construct.
  • High specificity and minimal toxicity were observed in vitro.
  • The therapeutic window of PFO was improved by over 5 orders of magnitude.

Conclusions:

  • Antibody-mediated neutralization can control the activity of pore-forming proteins.
  • This strategy enables the safe and effective use of PFO for intracellular delivery.
  • The engineered system presents a novel approach for targeted protein delivery.
Keywords:
cholesterol-dependent cytolysinendosomal releaseintracellular deliveryneutralizing antibodyperfringolysin Oprotein delivery

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