Tislelizumab (BGB-A317) is a humanized IgG4 anti–PD-1 monoclonal antibody specifically designed to minimize binding to FcγR on macrophages to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy.^1,2

Tislelizumab is being developed internationally as a monotherapy and in combination with other therapies for the treatment of a broad array of solid tumor and hematologic cancers. BeiGene has initiated or completed over 20 potentially registration-enabling clinical trials in 35 countries and regions, including 17 Phase 3 trials and 4 pivotal Phase 2 trials.

References

1. Zhang T et al. The binding of an anti-PD-1 antibody to FcγRΙ has a profound impact on its biological functions. Cancer Immunol Immunother. 2018;67:1079–1090.
2. Lu, S. et al. Tislelizumab Plus Chemotherapy as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC (RATIONALE 304): A Randomized Phase 3 Trial.  Thorac. Oncol.2021;16:1512–1522.

Immune surveillance is a mechanism by which the immune system identifies cancer cells and eliminates them via cytotoxic T-cells (CTLs). Tumors have developed strategies to escape immune surveillance including an altered expression of various immune checkpoints leading to the suppression of CTL function.¹ In normal tissues the PD-1/PD-L1 axis acts as a ‘brake’ in immune function preventing sustained T-cell activity and tissue damage.² T-cells are activated via binding of the TCR to the MHC/antigen complex on an APC or tumor cell.³ Upon T-cell activation, PD-1 expression is induced.⁴ A tumor cell can upregulate PD-L1 expression to mimic normal cells and “turn off” T-cells to escape immune surveillance.^3,4

Blocking the PD-1/PD-L1 signaling pathway by an anti-PD-1 antibody allows T-cells to maintain their effector functions.⁵ The Fc portion of the anti-PD-1 antibody and its limited interaction with FcγR are important for its therapeutic activities.⁶ Activated tumor-specific T-cells mediate the destruction of tumor cells and secrete cytokines that activate and recruit other immune cells to participate in the antitumor response.⁷ Anti-PD-1 antibodies, which bind to FcγRs, likely mediate the crosslinking between PD-1+ T cells and FcγR+ macrophages. Such crosslinking could potentially induce macrophages to phagocytize PD-1+ T cells and possibly diminish antitumor responses.⁶

Tislelizumab is a humanized IgG4 mAb with high affinity and binding specificity for PD-1.⁸ Tislelizumab was specifically engineered to minimize binding to FcγR on macrophages.⁶ Minimal binding of anti-PD-1 antibodies to FcγR abrogates antibody-dependent cellular phagocytosis, a potential mechanism of T-cell clearance.^9,10 Binding surface of tislelizumab on PD-1 overlapped largely with that of PD-L1, leading to the complete blockade of PD-1/PD-L1 interaction (>99%).¹¹

References

1. Zhang T et al. The binding of an anti-PD-1 antibody to FcγRΙ has a profound impact on its biological functions. Cancer Immunol Immunother. 2018;67:1079–1090.
2. Lu, S. et al. Tislelizumab Plus Chemotherapy as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC (RATIONALE 304): A Randomized Phase 3 Trial.  Thorac. Oncol.2021;16:1512–1522.
3. Ribatti D. The concept of immune surveillance against tumors: The first theories. Oncotarget2017; 8:7175-7180.
4. LaFleur MW, et al. Inhibitors of the PD-1 Pathway in Tumor Therapy. J Immunol2018 Jan 15; 200(2):375-383.
5. Tsai KK et al. PD-1 and PD-L1 antibodies for melanoma. Human Vaccines & Immunotherapeutics2014; 10:3111–3116
6. Zhang T et al. The binding of an anti-PD-1 antibody to FcγRΙ has a profound impact on its biological functions. Cancer Immunol Immunother. 2018;67:1079–1090.
7. Mahoney KM et al. The Next Immune-Checkpoint Inhibitors: PD-1/PD-L1 Blockade in Melanoma  Ther2015; 37:764–782.
8. Sznol M. Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the treatment of advanced human cancer. Clin Cancer Res.2013;1 9:1021–1034.
9. Waldman AD, et al. A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat Rev Immunol2020; 20:651-668.
10. Desai J et al. Preliminary results from subsets of patients (pts) with advanced gastric cancer (GC) and esophageal carcinoma (EC) in a dose-escalation/expansion study of BGB-A317, an anti-PD-1 monoclonal antibody (mAb). Ann Oncol 2017; 28(suppl_5):v122–v141.
11. Arlauckas SP et al. In vivo imaging reveals a tumor-associated macrophage–mediated resistance pathway in anti–PD-1 therapy. Sci Transl Med 2017; 9:eaal3604.

Tislelizumab is indicated:

• In combination with pemetrexed and platinum‑containing chemotherapy for the first-line treatment of adult patients with non-squamous non-small cell lung cancer (NSCLC) whose tumors have PD-L1 expression on ≥50% of tumor cells with no EGFR or ALK positive mutations and who have:
  • locally advanced NSCLC and are not candidates for surgical resection or platinum-based chemoradiation, or
  • metastatic NSCLC.
• In combination with carboplatin and either paclitaxel or nab-paclitaxel for the first-line treatment of adult patients with squamous NSCLC who have:
  • locally advanced NSCLC and are not candidates for surgical resection or platinum-based chemoradiation, or
  • metastatic NSCLC.
• As monotherapy for the treatment of adult patients with locally advanced or metastatic NSCLC after prior platinum-based therapy. Patients with EGFR mutant or ALK positive NSCLC should also have received targeted therapies before receiving tislelizumab.
• In combination with platinum and fluopyrimidine-based chemotherapy for the first-line treatment of adult patients with HER2-negative locally advanced unresectable or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma whose tumors express PD-L1 with a tumor area positivity (TAP) score ≥5%.
• In combination with platinum-based chemotherapy for the first-line treatment of adult patients with unresectable, locally advanced or metastatic esophageal squamous cell carcinoma (ESCC) whose tumors express PD-L1 with a tumor area positivity (TAP) score ≥5%.
• As monotherapy for the treatment of adult patients with unresectable, locally advanced or metastatic ESCC after prior platinum-based chemotherapy.

Please see the Summary of Product Characteristics for important information on approved uses.

For a complete list of tislelizumab monotherapy and combination clinical trials, view the pipeline.