Engineered receptors for soluble cellular communication and disease sensing

Dan I Piraner; Mohamad H Abedi; Maria J Duran Gonzalez; Adam Chazin-Gray; Annie Lin; Iowis Zhu; Pavithran T Ravindran; Thomas Schlichthaerle; Buwei Huang; Tyler H Bearchild; David Lee; Sarah Wyman; Young-Wook Jun; David Baker; Kole T Roybal

doi:10.1038/s41586-024-08366-0

Engineered receptors for soluble cellular communication and disease sensing

Nature. 2024 Nov 14. doi: 10.1038/s41586-024-08366-0. Online ahead of print.

Authors

Dan I Piraner^#¹, Mohamad H Abedi^#², Maria J Duran Gonzalez^#¹, Adam Chazin-Gray^#², Annie Lin³, Iowis Zhu¹, Pavithran T Ravindran^{1

4}, Thomas Schlichthaerle², Buwei Huang², Tyler H Bearchild¹, David Lee², Sarah Wyman¹, Young-Wook Jun^{5

6

7}, David Baker^{8

9

10

11}, Kole T Roybal^{12

13

14

15

16}

Affiliations

¹ Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA, USA.
² Department of Biochemistry, University of Washington, Seattle, WA, USA.
³ Joint Graduate Program in Bioengineering, University of California San Francisco and University of California Berkeley, San Francisco, CA, USA.
⁴ Penn Medical Scientist Training Program, University of Pennsylvania, Philadelphia, PA, USA.
⁵ Department of Otolaryngology, University of California San Francisco, San Francisco, CA, USA.
⁶ Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA.
⁷ Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
⁸ Department of Biochemistry, University of Washington, Seattle, WA, USA. dabaker@uw.edu.
⁹ Institute for Protein Design, University of Washington, Seattle, WA, USA. dabaker@uw.edu.
¹⁰ Graduate Program in Biological Physics, Structure and Design, University of Washington, Seattle, WA, USA. dabaker@uw.edu.
¹¹ Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA. dabaker@uw.edu.
¹² Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA, USA. kole.roybal@ucsf.edu.
¹³ Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. kole.roybal@ucsf.edu.
¹⁴ Chan Zuckerberg Biohub, San Francisco, CA, USA. kole.roybal@ucsf.edu.
¹⁵ Gladstone UCSF Institute for Genetic Immunology, San Francisco, CA, USA. kole.roybal@ucsf.edu.
¹⁶ UCSF Cell Design Institute, San Francisco, CA, USA. kole.roybal@ucsf.edu.

^# Contributed equally.

PMID: 39542025
DOI: 10.1038/s41586-024-08366-0

Abstract

Despite recent advances in mammalian synthetic biology, there remains a lack of modular synthetic receptors that can robustly respond to soluble ligands and, in turn, activate bespoke cellular functions. Such receptors would have extensive clinical potential to regulate the activity of engineered therapeutic cells, but so far only receptors against cell-surface targets have approached clinical translation¹. To address this gap, here we adapt a receptor architecture called the synthetic intramembrane proteolysis receptor (SNIPR) for activation by soluble ligands. Our SNIPR platform can be activated by both natural and synthetic soluble factors, with notably low baseline activity and high fold activation, through an endocytic, pH-dependent cleavage mechanism. We demonstrate the therapeutic capabilities of the receptor platform by localizing the activity of chimeric antigen receptor (CAR) T cells to solid tumours in which soluble disease-associated factors are expressed, bypassing the major hurdle of on-target off-tumour toxicity in bystander organs. We further apply the SNIPR platform to engineer fully synthetic signalling networks between cells orthogonal to natural signalling pathways, expanding the scope of synthetic biology. Our design framework enables cellular communication and environmental interactions, extending the capabilities of synthetic cellular networking in clinical and research contexts.

Grants and funding

R35 GM134948/GM/NIGMS NIH HHS/United States