Development of an optimized TIGIT and CD155 receptors as precursors for a new bispecific, non-antibody biologic drug

TIGIT and CD226 are two immunoreceptor molecules that interact with the polio virus receptors (PVR) CD155 and CD112, which are expressed on a vast range of cancer cells. The interaction of PVR with TIGIT and CD226 propagate to an inhibitory and stimulatory T-cell signal, respectively.

CD155 interaction with TIGIT is known to shutdown T-cell response, enabling cancer cells to evade immune response and proliferate, while CD155 interaction with CD226 co-stimulates T-cells activation. Hence, specific interference of the TIGIT-CD155 while maintaining the CD226-CD155 interaction is a promising therapeutic approach. Herein, we designed novel TIGIT variants that will specifically interfere with the TIGIT-CD155 interaction without affecting the CD226-CD155 complex.

In addition to the therapeutic potential of TIGIT-CD155 inhibition it is well-established that a combination treatment with TIGIT- and PD1-blocking antibodies have synergism in the subsequent anti-tumor response as opposed to the use of anti-TIGIT antibodies alone, which showed a milder anti-tumor response. Given that some cancer cells expressing both the PD-L1 and CD155 ligands which are interacting with PD1 and TIGIT receptors, our long-term vision is to generate a library of fused optimized PD-L1 and CD155 variants. The fused dual biomolecule will simultaneously target specific TIGIT/PD1 presenting cells and selectively interfere with their PD-L1/CD155 interaction with cancer cells. Unlike antibodies, this method can be generalized towards set of agonists and antagonists to disrupt the inhibitory interaction between tumor and immune cells, or exert a stimulatory effect. Thus, this novel approach will generate new, non-antibody, dual-target biological drugs with improved activity and specificity.