Identification of Glutaminyl Cyclase isoenzyme isoQC as a regulator of SIRPα-CD47 axis

Regulation of CD47 expression in cancer cells

“…Enzymes are typically involved in the post-translational modification level of a target protein. To date, at the post-translational modification level, only QPCTL was validated and shown to modify the N-terminal pyroglutamate formation early in the CD47 protein life cycle, thereby influencing the binding of CD47-SIRPα [ 65 , 68 ].…”

“…Notably, the presence of N-terminal pyroglutamate formation of CD47 protein, which is considered to be the post-translational modification of CD47, could be specifically recognized by SIRPα and contributed to the binding of CD47 to SIRPα [ 65 , 66 ]. QPCTL has been recently reported as an enzymatic modifier which can catalyze the pyroglutamate modification of CD47 protein [ 65 , 67 , 68 ]. Inhibiting the formation of CD47 N-terminal pGlu by the QPCTL inhibitor SEN177 or knockout of QPCTL significantly reduced the binding of CC2C6, an anti-CD47 antibody which has the same recognition site (pGlu) of SIRPα [ 65 ].…”

“…Inhibiting the formation of CD47 N-terminal pGlu by the QPCTL inhibitor SEN177 or knockout of QPCTL significantly reduced the binding of CC2C6, an anti-CD47 antibody which has the same recognition site (pGlu) of SIRPα [ 65 ]. Similarly, the post-translational modification of CD47 by QPCTL had also been identified in DLD1 colorectal cancer and HCT116 colonic carcinoma cancer cells [ 68 ].…”

Patent Highlights December 2020–January 2021

“…Instead of blocking CD47 the present inventors have exploited the fact that binding of SIRPα to CD47 depends on the conversion of the N-terminal glutamine moiety of CD47 into pyroglutamate by the secreted glutaminyl-peptide cyclotransferase (QPCT), but to a higher extent by the closely related isoQC enzyme located in the Golgi apparatus. Inhibition or genetic deletion of these enzymes increases phagocytosis of antibody opsonized cells in vitro and clearance of opsonized tumor cells in vivo [40,41]. The inventors' novel 'FRPPO compounds' are, in part, loosely derived from a series of known compounds with anticancer activity that had been described as bromodomain and Bet inhibitors in WO2014/191894, WO2014/191896, WO/2014/191906, WO/2014/191911 and WO/2015/075665.…”

CD47 (Cluster of differentiation 47): an anti-phagocytic receptor with a multitude of signaling functions

“…Surprisingly, co-incubation with 2D3 was found to significantly inhibit CD47-mediated cell death induced by 1F7 and Ad22, which suggests a requirement for a flexible extracellular domain (Pettersen et al 1999 ). Importantly, clone CC2C6, but not B6H12, can only bind CD47 containing an N-terminal pyroglutamate, a post-translational modification that is catalyzed by the enzyme glutaminyl cyclase (Hatherley et al 2008 ; Logtenberg et al 2019 ; Wu et al 2019 ). In addition, binding of SIRPα to CD47 also requires the pyroglutamate epitope.…”