An evolutionary T119R substitution in the macaque T-cell immunoreceptor TIGIT enables proteolytic shedding and reveals clinical antibody vulnerabilities.

Despite being a promising target for cancer immunotherapy, several TIGIT (T-cell immunoreceptor with immunoglobulin and ITIM domain) antibodies have been largely disappointing in human trials. As TIGIT antibodies demonstrated a preclinical profile in macaque studies similar to that of clinically successful PD-1 and PD-L1 antibodies, we sought to investigate whether the differential species-specific regulation of TIGIT in lymphocytes might predict the mechanistic complexity of the TIGIT signaling pathway. Here, we discover that, unlike human TIGIT, the macaque TIGIT is a direct target of proteolytic plasmin cleavage. When tested, unlike human PBMCs, the rhesus macaque PBMCs released soluble TIGIT in the presence of plasmin. Furthermore, saturation with clinical anti-TIGIT antibodies does not interfere with the plasmin cleavage of rhesus TIGIT. In addition, the shed ectodomain of TIGIT maintains binding to CD155 and the tested clinical anti-TIGIT antibody, tiragolumab. Given the significant anti-TIGIT failures, these unexpected findings reveal potential saturation vulnerabilities of macaque CD155 and preclinical TIGIT antibodies by soluble shedded TIGIT ectodomain, contrary to the intended mechanism of action on the lymphocyte membrane. These results caution against extrapolation and question the suitability of cynomolgus and rhesus macaques for preclinical safety and dose estimation of TIGIT-targeted therapies.