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Related Experiment Video

Updated: Sep 19, 2025

Homogeneous Glycoconjugate Produced by Combined Unnatural Amino Acid Incorporation and Click-Chemistry for Vaccine Purposes
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Machine-guided dual-objective protein engineering for deimmunization and therapeutic functions.

Eric Wolfsberg1, Jean-Sebastien Paul2, Josh Tycko3

  • 1Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA.

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This study introduces a workflow to reduce immune responses to cell and gene therapies by optimizing protein domains. It uses machine learning to minimize immunogenic peptides, enhancing therapy safety and effectiveness.

Keywords:
protein designsynthetic biology

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Area of Science:

  • Biotechnology
  • Immunology
  • Genomic Medicine

Background:

  • Cell and gene therapies can trigger immune responses due to nonhuman proteins.
  • Modified human protein domains may still contain immunogenic peptides, posing a challenge for therapy development.

Purpose of the Study:

  • To develop a modular workflow for optimizing protein function and minimizing immunogenicity in therapeutic proteins.
  • To create safer and more effective cell and gene therapies by reducing anti-therapy immune responses.

Main Methods:

  • Utilized machine learning models to predict protein function and peptide-MHC presentation.
  • Applied workflow to remove immunogenic MHC II epitopes from transcriptional activation and RNA-binding domains.
  • Developed deimmunized zinc-finger arrays for targeted gene upregulation.

Main Results:

  • Successfully removed potentially immunogenic MHC II epitopes from protein domains.
  • Generated small-molecule-controllable transcription factors with human-derived DNA-binding domains.
  • Demonstrated upregulation of utrophin (UTRN) and SCN1A genes using deimmunized zinc-finger arrays.

Conclusions:

  • The presented modular workflow offers a strategy to enhance the safety and efficacy of cell and gene therapies.
  • Integration of machine learning for immunogenicity prediction and protein engineering is a promising approach for next-generation therapeutics.