Mode of Action

T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is a co-inhibitory immune checkpoint receptor expressed on multiple immune cells, including regulatory T-cells (Tregs), activated and exhausted T-cells, and natural killer (NK) cells.³

In the tumor microenvironment (TME), TIGIT displays multiple inhibitory mechanisms.⁴ Highly expressed on Tregs⁵, TIGIT signaling enhances their immunosuppressive functions leading to T-cell exhaustion.^4,5 When expressed on T-cells and NK-cells, TIGIT binds to two ligands, CD155 (PVR, nectin-like protein-5) and CD112 (PVRL-2, nectin-2), expressed by tumor cells which leads to inhibitory signaling in T-cells and promotes functional exhaustion of tumor-infiltrating lymphocytes.^4,6,7 The immune-activating co-stimulatory receptor CD226 (DNAM-1) is also expressed on T-cells and NK-cells. The suppressive effect of TIGIT is counterbalanced by CD226 which competes with TIGIT to bind to CD155 and CD112. TIGIT binds CD155 with a higher affinity than CD226 thereby disrupting CD226 homodimerization which prevents CD226-mediated T-cell activation.^4,8,9

Ociperlimab exerts its effects by multiple mechanisms^1,2:

• Binding of ociperlimab to TIGIT led to a reduction of Tregs by inducing potential antibody-dependent cellular cytotoxicity, but not a reduction in cytotoxic T-cells.
• Ociperlimab blocked the interaction between TIGIT and CD155 and CD112 on tumor cells and increased ligand availability for the CD226 co-stimulatory receptor resulting in reactivation of T-cells and NK cells and anti-tumor immune responses.
• TIGIT expression was reduced on T-cell surfaces through Fc-dependent trogocytosis, while CD226 was upregulated in a Fc-dependent manner.
• Fc/FcүR engagement resulted in a proinflammatory TME through myeloid cell and NK-cell activation.

Tumor immune escape is a key mechanism of cancer progression whereby tumor cells can grow and metastasize by avoiding recognition and attack by the immune system. In solid tumors, TIGIT is highly co-expressed with PD-1 on CD8+ T cells. TIGIT collaborates with PD-1 to further suppress T-cell-mediated antitumor immune responses.⁴ Dual targeting of the TIGIT/CD155/CD112 and PD-1/PD-L1 pathways may overcome tumor immune escape and enhance anti-tumor response in patients with advanced solid tumors.⁴

Ociperlimab in clinical trials

Ociperlimab is currently being investigated in a pivotal global Phase 3 trial in combination with tislelizumab (anti-PD-1) in first-line (1L) PD-L1 positive advanced/metastatic non-small cell lung cancer (NSCLC) and in a global Phase 3 trial in locally advanced NSCLC in combination with concurrent chemoradiation. Ociperlimab plus tislelizumab is further investigated in pivotal global Phase 2 trials in combination with chemotherapy in 1L NSCLC irrespective of PD-L1 expression as well as in combination with tislelizumab and concurrent chemoradiotherapy in previously untreated limited-stage small cell lung cancer (LS-SCLC).

For an exhaustive list of ociperlimab in combination clinical trials, view the development program.

Ociperlimab is not authorized for use in the EU. 

References

1. Chen, et al. AACR 2021, Abstract 1854.
2. Chen X, et al. An Fc-Competent Anti-Human TIGIT Blocking Antibody Ociperlimab (BGB-A1217) Elicits Strong Immune Responses and Potent Anti-Tumor Efficacy in Pre-Clinical Models. Front Immunol 2022; 22(13):828319.
3. Zhou XM, et al. Intrinsic Expression of Immune Checkpoint Molecule TIGIT Could Help Tumor Growth in vivo by Suppressing the Function of NK and CD8+ T Cells Front Immunol 2018; 9(2821).
4. Chauvin, J.-M. & Zarour, H. M. TIGIT in cancer immunotherapy. J. Immunother. Cancer 2020;8, e000957.
5. Joller N, et al. Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell responses. Immunity 2014; 40(4):569-81.
6. Yu X, et al. The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells. Nat Immunol 2009;10(1):48-57.
7. Joller N, et al. Cutting Edge: TIGIT Has T Cell-Intrinsic Inhibitory Functions. J Immunol 2011;186 (3) 1338-1342.
8. Bottino C, et al. Identification of PVR (CD155) and Nectin-2 (CD112) as cell surface ligands for the human DNAM-1 (CD226) activating molecule. J Exp Med 2003;198(4):557-67.
9. Ge Z, et al. TIGIT, the Next Step Towards Successful Combination Immune Checkpoint Therapy in Cancer. Front Immunol 2021; 22(12):699895.