Unlocking the Potential of AB154: Advancing Combination Cancer Immunotherapies with a Humanized Anti-TIGIT Antibody

TIGIT is an inhibitory receptor on NK cells, CD8+ T-cells, and Treg cells, which competes with the activating receptor DNAM-1 for binding to shared ligands CD155 and CD112 expressed on tumor and antigen-presenting cells. High TIGIT expression is associated with immune suppression and is often seen alongside upregulation of other immune checkpoint proteins and T-cell exhaustion markers like PD-1 in progressing malignancies.

AB154 is a fully humanized antibody developed to inhibit TIGIT, thereby promoting a more effective anticancer immune response. It has been shown to block human TIGIT with high affinity and, when combined with anti-PD-1 or anti-PD-L1 in mixed lymphocyte reactions, significantly increased IFN-gamma secretion, indicating a synergistic effect.

Data from TCGA indicates co-expression of TIGIT and PD-1 in various tumor types, with upregulation compared to normal tissue. Immunophenotyping of human tumor-infiltrating lymphocytes revealed a strong correlation between TIGIT and PD-1 co-expression on CD8+ T-cells and Treg cells.

A multicolor flow cytometry-based assay was developed to evaluate the pharmacodynamic effects of AB154, demonstrating complete inhibition of TIGIT in human whole blood and suitable target engagement by AB154 in blood mononuclear cells. Additionally, TIGIT receptor occupancy by AB154 in NSCLC patients treated with pembrolizumab was comparable to that in healthy donors.

The findings support the combination of AB154 with the in-house anti-PD-1 antibody AB122 for upcoming clinical trials and provide a methodology for evaluating TIGIT receptor occupancy in AB154 dose escalation studies. AB154 is anticipated to enter clinical trials in 2018.