Ociperlimab (BGB-A1217) is an investigational humanized monoclonal antibody designed to bind to TIGIT with high specificity and affinity. Ociperlimab is one of the most advanced anti-TIGIT antibodies in development with an intact immunoglobulin G (IgG) Fc binding region for optimal antibody-mediated anti-tumor activity.^1,2

Ociperlimab is currently being investigated in combination with the anti-PD-1 monoclonal antibody tislelizumab in Phase 2 and 3 trials across a broad range of advanced or metastatic solid tumors in a robust late-stage development program, which covers more than 25 countries/regions with over 1,000 enrolled patients.

References

1. Chen, et al. A Fc-competent anti-human TIGIT blocking antibody BGB-A1217 elicits strong immune responses and potent anti-tumor efficacy in pre-clinical models. 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 Immunol2022; 22(13):828319.

Mechanism 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.¹

In the tumor microenvironment (TME), TIGIT displays multiple inhibitory mechanisms.² Highly expressed on Tregs³, TIGIT signaling enhances their immunosuppressive functions leading to T-cell exhaustion.^2,3 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.^2,4,5 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.^2,6,7

Ociperlimab exerts its effects by multiple mechanisms^8,9:

• 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.² 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.²

References

1. 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 Immunol2018; 9(2821).
2. Chauvin, J.-M. & Zarour, H. M. TIGIT in cancer immunotherapy.  Immunother. Cancer2020;8, e000957.
3. Joller N, et al. Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell responses. Immunity2014; 40(4):569-81.
4. Yu X, et al. The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells. Nat Immunol2009;10(1):48-57.
5. Joller N, et al. Cutting Edge: TIGIT Has T Cell-Intrinsic Inhibitory Functions. J Immunol2011;186 (3) 1338-1342.
6. 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 Med2003;198(4):557-67.
7. Ge Z, et al. TIGIT, the Next Step Towards Successful Combination Immune Checkpoint Therapy in Cancer. Front Immunol2021; 22(12):699895.
8. Chen, et al. A Fc-competent anti-human TIGIT blocking antibody BGB-A1217 elicits strong immune responses and potent anti-tumor efficacy in pre-clinical models. AACR 2021, Abstract 1854.
9. 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 Immunol2022; 22(13):828319.

Approval status

Ociperlimab is an investigational compound for which safety and efficacy have not been established. Because of the uncertainty of clinical trials, there is no guarantee that ociperlimab will receive regulatory approval and become commercially available for the uses being investigated.

For a complete list of ociperlimab in combination clinical trials, view the pipeline.