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Split-Protein Therapeutic Platforms: Identifying Binder Pairs.

Christine S Nervig1, James R Gustat2, Shawn C Owen3,4,5

  • 1Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT, USA.

Methods in Molecular Biology (Clifton, N.J.)
|September 29, 2023
PubMed
Summary
This summary is machine-generated.

Researchers developed methods to create safer therapeutic proteins. By splitting proteins and using antibody binders, they enable conditional activation, reducing off-target effects for improved disease treatment.

Keywords:
AntibodyComplementationComputational modelingConditionally activeProtein engineeringProtein switchSplit-enzyme

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Area of Science:

  • Biotechnology
  • Protein Engineering
  • Immunotherapy

Background:

  • Therapeutic proteins offer advanced treatment options for diseases resistant to small molecule drugs.
  • Off-target or systemic activity poses a significant challenge in protein-based therapies.
  • Conditional activation strategies are crucial for enhancing the safety and efficacy of protein therapeutics.

Purpose of the Study:

  • To describe methods for identifying antibody pairs that facilitate the reconstitution of active therapeutic proteins.
  • To provide computational and empirical approaches for developing conditionally active protein constructs.
  • To enable the design of targeted protein therapies using only protein sequence data.

Main Methods:

  • Splitting therapeutic proteins into inactive fragments.
  • Fusing protein fragments to binders targeting distinct cell surface epitopes.
  • Utilizing computational and empirical strategies to identify functional antibody pairs.
  • Assessing antibody-mediated proximity-induced protein reconstitution.

Main Results:

  • Demonstrated approaches to determine suitable antibody pairs for protein reconstitution.
  • Provided general methods applicable to various therapeutic proteins.
  • Facilitated the identification of antibody pairs starting from protein sequence data.

Conclusions:

  • Conditionally active protein constructs can mitigate toxicity associated with therapeutic proteins.
  • Antibody-mediated targeting and reconstitution offer a promising strategy for localized protein activation.
  • The described methods support the development of safer and more effective protein-based medicines.