An Fc-Competent Anti-Human TIGIT Blocking Antibody Ociperlimab (BGB-A1217) Elicits Strong Immune Responses and Potent Anti-Tumor Efficacy in Pre-Clinical Models

Abstract

TIGIT (T-cell immunoglobulin and ITIM domain) has emerged as a promising target in cancer immunotherapy. It is an immune “checkpoint” inhibitor primarily expressed on activated T cells, NK cells and Tregs. Engagement of TIGIT to its ligands PVR and PVR-L2 leads to inhibitory signaling in T cells, promoting functional exhaustion of tumor-infiltrating T lymphocytes. Here, we described the pre-clinical characterization of Ociperlimab (BGB-A1217), a novel humanized IgG1 anti-TIGIT antibody (mAb), and systemically evaluated the contribution of Fc functions in the TIGIT mAb-mediated anti-tumor activities. BGB-A1217 binds to the extracellular domain of human TIGIT with high affinity (KD = 0.135 nM) and specificity, and efficiently blocks the interaction between TIGIT and its ligands PVR or PVR-L2. Cell-based assays show that BGB-A1217 significantly enhances T-cell functions. In addition, BGB-A1217 induces antibody dependent cellular cytotoxicity (ADCC) against Treg cells, activates NK cells and monocytes, and removes TIGIT from T cell surfaces in an Fc-dependent manner, In vivo, BGB-A1217, either alone or in combination with an anti-PD-1 mAb elicits strong immune responses and potent anti-tumor efficacy in pre-clinical models. Moreover, the Fc effector function is critical for the anti-tumor activity of BGB-A1217 in a syngeneic human TIGIT-knock-in mouse model. The observed anti-tumor efficacy is associated with a pharmacodynamic change of TIGIT down-regulation and Treg reduction. These data support the selection of BGB-A1217 with an effector function competent Fc region for clinical development for the treatment of human cancers.

LIGHT (TNFSF14) Costimulation Enhances Myeloid Cell Activation and Antitumor Immunity in the Setting of PD-1/PD-L1 and TIGIT Checkpoint Blockade

“…If a TIGIT-blocking Ab has the ability to engage Fcg receptors, then it is possible that Ab-dependent cellular cytotoxicity could lead to depletion of the TIGIT-expressing cells that are bound by the Fc-competent anti-TIGIT Ab. Indeed, depletion of CD8 1 T cells was recently reported in human clinical studies with such an Ab (42,43). In contrast, CD4 1 Tregs also express TIGIT, which led to the hypothesis that perhaps anti-TIGIT Abs could lead to depletion of Tregs and enhance antitumor immunity; however, reasoning behind the selective depletion of CD4 1 Tregs versus CD8 1 effector T cells other than the surface expression of TIGIT on these cell types has not been clearly presented (44,45).…”

Cutting-Edge: Preclinical and Clinical Development of the First Approved Lag-3 Inhibitor

“…Ociperlimab is a fully humanized IgG1 antibody developed by BeiGene that binds TIGIT with high affinity and specificity thanks to its intact IgG Fc function [ 165 ]. The combination of ociperlimab plus the anti-PD-1 antibody tislelizumab (BGB-A317) is currently under evaluation in patients diagnosed with distinct advanced or metastatic tumors, including NSCLC, esophageal squamous cell carcinoma, and cervical cancer.…”

Natural killer cells: the next wave in cancer immunotherapy

“…Another shared checkpoint between T cells and NK cells, TIGIT, is constitutively expressed on PBMC-derived NK cells as well as in vitro activated human NK cells ( 40 – 43 ). In a recent publication, we have demonstrated the direct activation of NK cells by the therapeutic TIGIT blocking antibody ociperlimab (BGB-A1217) in an in vitro NK-cancer cell co-culture assay ( 44 ). Remarkably, the full Fc effector function of ociperlimab further elevated NK cell function in addition to checkpoint blockade ( 44 ), probably through the synergy between FcγRIIIa (CD16a) signaling and release of TIGIT mediated suppression on NK cells ( 45 ).…”

“…In a recent publication, we have demonstrated the direct activation of NK cells by the therapeutic TIGIT blocking antibody ociperlimab (BGB-A1217) in an in vitro NK-cancer cell co-culture assay ( 44 ). Remarkably, the full Fc effector function of ociperlimab further elevated NK cell function in addition to checkpoint blockade ( 44 ), probably through the synergy between FcγRIIIa (CD16a) signaling and release of TIGIT mediated suppression on NK cells ( 45 ). Another immune checkpoint, TIM3, has been found to be up-regulated on NK cells from patients with melanoma ( 46 ), gastric cancer ( 47 ) and lung adenocarcinoma ( 48 ), and blockade of TIM3 has been reported to release the exhaustion of NK cells from advanced melanoma patients in vitro ( 46 ).…”

“…Direct evidence for this hypothesis comes from the Fc-competent TIGIT antibody Ociperlimab. TIGIT expression is highly expressed on Treg cells, relative to effector T cells, and is further elevated on Tregs in tumor microenvironment ( 44 , 54 ). Our data have shown that the ligation of TIGIT on Tregs and Fcγ receptors on NK cells by Ociperlimab directly promoted NK cell activation and induced ADCC against cancer patient PBMC derived Tregs in vitro .…”