Function-preserving CD8⁺ T Cell Immunogenicity minimization through protein design
6 affiliations
- 1Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
- 2Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
- 3Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
- 4Department of Biotechnology and Biomedicine, Technical University of Denmark, Kongens Lyngby, 9 Denmark
- 5Massachusetts General Hospital Cancer Center, Boston, MA 02129, USA.
- 6Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA.
Abstract
Rapid advances in protein design enable new approaches in adoptive cell therapy, but foreign proteins can elicit cytotoxic T cell responses, and hence there is considerable need for approaches which reduce immunogenicity without compromising protein function. Here, we develop a computational framework integrating structure-guided sequence design with MHC class I epitope prediction to efficiently tune protein immunogenicity while preserving function. Using a de novo-designed luciferase as a model, we demonstrate epitope elimination while preserving function across 5 common mouse alleles and extend our computational optimization to 25 common human MHC-I alleles. In mice immunized with mRNA-lipid nanoparticles, variants designed to have few MHC-I epitopes elicited little detectable CD8 T cell response, whereas variants designed to include multiple epitopes induced robust responses. Together, these results demonstrate that the CD8 T cell immunogenicity of designed proteins can be tuned while preserving function, opening the door to incorporation of designed proteins in a next generation of adoptive cell therapies.
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BibTeX
@misc{liu2026functionpreserving,
title = {{Function-preserving CD8⁺ T Cell Immunogenicity minimization through protein design}},
author = {Bingxu Liu and Tianyang Mao and Max H Witwer and Oliver Morell and Nir Hacohen and David Baker},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.24.761497},
url = {https://www.biorxiv.org/content/10.64898/2026.10.24.761497v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Function-preserving CD8⁺ T Cell Immunogenicity minimization through protein design
AU - Bingxu Liu
AU - Tianyang Mao
AU - Max H Witwer
AU - Oliver Morell
AU - Nir Hacohen
AU - David Baker
PY - 2026
DA - 2026/10/24
PB - bioRxiv
DO - 10.64898/2026.10.24.761497
UR - https://www.biorxiv.org/content/10.64898/2026.10.24.761497v1
AB - Rapid advances in protein design enable new approaches in adoptive cell therapy, but foreign proteins can elicit cytotoxic T cell responses, and hence there is considerable need for approaches which reduce immunogenicity without compromising protein function. Here, we develop a computational framework integrating structure-guided sequence design with MHC class I epitope prediction to efficiently tune protein immunogenicity while preserving function. Using a de novo-designed luciferase as a model, we demonstrate epitope elimination while preserving function across 5 common mouse alleles and extend our computational optimization to 25 common human MHC-I alleles. In mice immunized with mRNA-lipid nanoparticles, variants designed to have few MHC-I epitopes elicited little detectable CD8 T cell response, whereas variants designed to include multiple epitopes induced robust responses. Together, these results demonstrate that the CD8 T cell immunogenicity of designed proteins can be tuned while preserving function, opening the door to incorporation of designed proteins in a next generation of adoptive cell therapies.
SN - 2692-8205
ER -