MHCEpitopeEnergy, a Flexible Rosetta-Based Biotherapeutic Deimmunization Platform.

Area of Science:

• Biochemistry
• Immunology
• Computational Biology

Background:

• Biotherapeutics, as non-self macromolecules, can elicit immune responses, leading to reduced efficacy, treatment cessation, or severe adverse events.
• T-cell epitopes are key drivers of immunogenicity in protein-based drugs.

Purpose of the Study:

• To integrate a novel scoring term into the Rosetta protein design suite to facilitate the design of deimmunized protein biotherapeutics.
• To enable the reduction of T-cell epitopes during protein design while maintaining desirable physicochemical properties.

Main Methods:

• Developed and integrated a flexible scoring term into the Rosetta protein design suite.
• The scoring term accounts for predicted or experimentally identified epitopes within the objective function.
• Applied the scoring term across various Rosetta design trajectories and targeted specific protein regions.
• Validated the approach using three case study proteins and a diverse benchmark set.

Main Results:

• Demonstrated the effective exploration of deimmunized sequence space using the new scoring term.
• Identified diverse protein designs with potentially reduced immunogenicity.
• Showcased that deimmunized designs retained physical and chemical qualities comparable to non-deimmunized counterparts.
• The scoring term proved adaptable to various epitope predictors and design strategies.

Conclusions:

• The integrated scoring term offers a powerful tool for designing safer and more effective protein biotherapeutics.
• This computational approach aids in mitigating immune responses against therapeutic proteins.
• Facilitates the discovery of novel protein therapeutics with enhanced safety profiles and sustained efficacy.