| First Author | Fernandes RA | Year | 2020 |
| Journal | Nature | Volume | 586 |
| Issue | 7831 | Pages | 779-784 |
| PubMed ID | 33087934 | Mgi Jnum | J:297388 |
| Mgi Id | MGI:6472569 | Doi | 10.1038/s41586-020-2851-2 |
| Citation | Fernandes RA, et al. (2020) Immune receptor inhibition through enforced phosphatase recruitment. Nature 586(7831):779-784 |
| abstractText | Antibodies that antagonize extracellular receptor-ligand interactions are used as therapeutic agents for many diseases to inhibit signalling by cell-surface receptors(1). 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 CD45(2,3), 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 SIRPalpha 'don't eat me' signal with a SIRPalpha-CD45 RIPR molecule potentiates antibody-dependent cellular phagocytosis beyond that of SIRPalpha blockade alone. RIPR represents a general strategy for direct attenuation of signalling by kinase-activated cell-surface receptors. |
