The study was led by Jogender Tushir-Singh at UC Davis, with collaborators including Eric Pirillo and others, and supported by NIH/NCI funding and the ovarian cancer alliance of Greater Cincinnati.

A UC Davis-led study reports TIGIT behaves differently in rhesus macaques than in humans, highlighting the need for human-relevant models and cautioning against relying on macaque data to predict human outcomes in TIGIT-targeted cancer therapies.

The researchers emphasize improving human-relevant models and call for additional studies to confirm findings and reassess TIGIT-targeted drug development strategies.

In rhesus macaques, exposure to plasmin causes TIGIT to shed from immune cell surfaces, generating a soluble TIGIT that can still bind anti-TIGIT antibodies like tiragolumab, potentially diluting drug efficacy.

A new study shows macaque TIGIT, when exposed to plasmin, is shed into a soluble form that can capture anti-TIGIT therapies, potentially soaking up the drug.

This plasmin-mediated shedding in macaques creates soluble TIGIT that remains bindable by cancer therapies, unlike human TIGIT under the same conditions.

TIGIT is an immune checkpoint that acts as a brake on T cells and NK cells, and blocking TIGIT is a strategy currently pursued in cancer immunotherapy.

Researchers engineered lab versions of human and macaque TIGIT and found that only macaque TIGIT is shed by plasmin and remains capable of binding cancer therapies.

Context: Anti-TIGIT antibodies have shown limited success in Phase III trials for solid tumors, prompting questions about underlying mechanisms and the adequacy of current model systems.

Implications for preclinical testing: Macaque models may misrepresent human safety and dosing due to drug dilution away from T cells, challenging the predictive value of macaque data for humans.

Humans do not exhibit the same plasmin-induced TIGIT shedding, indicating a species-specific difference that could limit the translational relevance of macaque preclinical data.

A single amino acid difference at position 119 between human and macaque TIGIT underlies the susceptibility of macaque TIGIT to plasmin cleavage.