Co-blocking TIGIT and PVRIG Using a Novel Bispecific Antibody Enhances Antitumor Immunity

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Immune checkpoints T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) and poliovirus receptor-related immunoglobulin domain (PVRIG) are co-expressed on T and NK cells, contributing to tumor immune evasion.
• Simultaneous blockade of TIGIT and PVRIG presents a promising strategy for enhancing cancer immunotherapy efficacy.
• TIGIT and PVRIG expression is observed in tumor-infiltrating lymphocytes across various cancers, including non-small cell lung cancer and colorectal cancer.

Purpose of the Study:

• To develop and characterize a bispecific antibody (BsAb) designed to co-target the TIGIT and PVRIG immune checkpoints.
• To evaluate the therapeutic potential of this dual-targeting BsAb in preclinical cancer models.

Main Methods:

• Engineered a BsAb by fusing anti-PVRIG nanobodies to anti-TIGIT antibodies.
• Assessed TIGIT and PVRIG expression on tumor-infiltrating lymphocytes from cancer patients.
• Conducted in vitro and in vivo functional characterization, including T- and NK-cell activation, cytotoxicity assays, and pharmacokinetic/safety studies in cynomolgus monkeys.

Main Results:

• The BsAb effectively blocked TIGIT and PVRIG interactions with their ligands (CD155 and CD112), significantly increasing T-cell activation (2.8-fold) and NK-cell cytotoxicity (1.8-fold).
• Demonstrated potent antitumor activity in preclinical models, both as monotherapy and in combination with anti-PD-1/PD-L1 therapies.
• Exhibited a favorable pharmacokinetic profile and no dose-limiting toxicities in cynomolgus monkeys.

Conclusions:

• The developed bispecific antibody targeting the TIGIT-PVRIG axis shows significant preclinical efficacy in enhancing antitumor immunity.
• This dual-targeting approach holds therapeutic promise for cancer immunotherapy.
• Further clinical investigation is warranted to validate the safety and efficacy of this BsAb.