TIGIT (T-cell immunoreceptor with Ig and ITIM domains) is an inhibitory receptor that is expressed on NK and CD8+ T cells, as well as immunosuppressive Tregs. TIGIT binds to CD155 and CD112, both of which are expressed by tumors and antigen-presenting cells, resulting in immune suppression. These ligands also bind the costimulatory molecule CD226 resulting in NK and T cell activation. Shifting the balance within the tumor from one that favors TIGIT binding with CD155 / CD112 towards the more productive CD226 interaction induces a strong anti-tumor immune response. Thus, TIGIT blockade represents an attractive approach to the treatment of cancer.
AB154 is a humanized antibody that binds human TIGIT with sub-nanomolar affinity thus inhibiting the ability of CD155 and TIGIT to interact. Functional T-cell responses to TIGIT inhibition were evaluated using either Staphylococal enterotoxin B (SEB)-stimulated human whole blood or an antigen-specific recall response to Tetanus Toxin (TT). Inhibition of TIGIT in the SEB assay resulted in increased IL-2, TNF-a, IFN-g and Granzyme A secretion. In the TT assay, inhibition of TIGIT increased IL-2 secretion and the frequency of proliferating CD8+ T cells. AB154-mediated inhibition of TIGIT on freshly isolated human NK cells resulted in a significant increase in their ability to kill target K562 cells. Cynomolgus monkeys that received a single dose of AB154 did not exhibit any ill effects. Analysis of the peripheral CD4+ and CD8+ T-cell compartments revealed target engagement by AB154 without any reduction in the overall CD4+ and CD8+ populations. In the same animals, ex vivo stimulation of whole blood with SEB after AB154 dosing confirmed TIGIT inhibition as determined by a significant increase in IL-2 relative to pre-dose levels. AB154 is undergoing preclinical development and is expected to enter into the clinic in the coming months.
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