Immune receptor inhibition through enforced phosphatase recruitment

Ricardo A. Fernandes, Leon Su, Yoko Nishiga, Junming Ren, Aladdin M. Bhuiyan, Ning Cheng, Calvin J. Kuo, Lora K. Picton, Shozo Ohtsuki, Robbie G. Majzner, Skyler P. Rietberg, Crystal L. Mackall, Qian Yin, Lestat R. Ali, Xinbo Yang, Christina S. Savvides, Julien Sage, Michael Dougan and K. Christopher Garcia ()
Additional contact information
Ricardo A. Fernandes: Stanford University School of Medicine
Leon Su: Stanford University School of Medicine
Yoko Nishiga: Stanford University
Junming Ren: Stanford University School of Medicine
Aladdin M. Bhuiyan: Massachusetts General Hospital
Ning Cheng: Stanford University School of Medicine
Calvin J. Kuo: Stanford University School of Medicine
Lora K. Picton: Stanford University School of Medicine
Shozo Ohtsuki: Stanford University School of Medicine
Robbie G. Majzner: Stanford University
Skyler P. Rietberg: Stanford University School of Medicine
Crystal L. Mackall: Stanford University
Qian Yin: Stanford University School of Medicine
Lestat R. Ali: Harvard Medical School
Xinbo Yang: Stanford University School of Medicine
Christina S. Savvides: Stanford University School of Medicine
Julien Sage: Stanford University
Michael Dougan: Massachusetts General Hospital
K. Christopher Garcia: Stanford University School of Medicine

Nature, 2020, vol. 586, issue 7831, 779-784

Abstract: Abstract Antibodies that antagonize extracellular receptor–ligand interactions are used as therapeutic agents for many diseases to inhibit signalling by cell-surface receptors1. However, this approach does not directly prevent intracellular signalling, such as through tonic or sustained signalling after ligand engagement. Here we present an alternative approach for attenuating cell-surface receptor signalling, termed receptor inhibition by phosphatase recruitment (RIPR). This approach compels cis-ligation of cell-surface receptors containing ITAM, ITIM or ITSM tyrosine phosphorylation motifs to the promiscuous cell-surface phosphatase CD452,3, which results in the direct intracellular dephosphorylation of tyrosine residues on the receptor target. As an example, we found that tonic signalling by the programmed cell death-1 receptor (PD-1) results in residual suppression of T cell activation, but is not inhibited by ligand-antagonist antibodies. We engineered a PD-1 molecule, which we denote RIPR-PD1, that induces cross-linking of PD-1 to CD45 and inhibits both tonic and ligand-activated signalling. RIPR-PD1 demonstrated enhanced inhibition of checkpoint blockade compared with ligand blocking by anti-PD1 antibodies, and increased therapeutic efficacy over anti-PD1 in mouse tumour models. We also show that the RIPR strategy extends to other immune-receptor targets that contain activating or inhibitory ITIM, ITSM or ITAM motifs; for example, inhibition of the macrophage SIRPα ‘don’t eat me’ signal with a SIRPα–CD45 RIPR molecule potentiates antibody-dependent cellular phagocytosis beyond that of SIRPα blockade alone. RIPR represents a general strategy for direct attenuation of signalling by kinase-activated cell-surface receptors.

Date: 2020
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DOI: 10.1038/s41586-020-2851-2

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