Innovative Bispecific Nanobody Targeting PVRIG and TIGIT for Cancer Immunotherapy

VHH-P232 is a cutting-edge bispecific antibody fusion construct featuring a monoclonal antibody targeting T cell immunoreceptor with Ig and ITIM domains (TIGIT), fused to a single-domain antibody (nanobody) against PVR related immunoglobulin domain containing (PVRIG). This molecule, expressed in human embryonic kidney cells, is advancing through biological testing and is designed to disrupt immune checkpoint pathways implicated in cancer immune evasion. By simultaneously engaging PVRIG and TIGIT, VHH-P232 offers a new therapeutic strategy to overcome resistance in cancer treatment and restore anti-tumor immunity. Its unique dual-targeting modality positions it as a highly promising candidate in the development pipeline for cancer immunotherapy.

Licensing Opportunity

VHH-P232 is now available for out-licensing opportunities. We welcome collaboration with industry partners seeking to advance innovative bispecific nanobody immunotherapies and expand their oncology pipelines.

Development Phase

Modality

VHH-P232 leverages a modular bispecific architecture, composed of a monoclonal antibody against TIGIT, each heavy chain N-terminus fused via a flexible (G4S)2 peptide linker to a nanobody that targets PVRIG. This construct maximizes the unique benefits of nanobodies—namely, their single-domain structure, reduced molecular size, and exceptional tissue penetration—while retaining the effector functions of a conventional antibody. The bispecific format enables precise and simultaneous checkpoint blockade, which is increasingly recognized as a superior approach for cancer therapies. Expression in human embryonic kidney cells ensures human compatibility and manufacturability, enhancing its clinical translation potential.

Target

PVRIG and TIGIT are cell surface immune checkpoint proteins crucially involved in the regulation of T cell and natural killer (NK) cell functions within the tumor microenvironment. PVRIG, a transmembrane molecule of the immunoglobulin superfamily, and TIGIT, another inhibitory receptor widely expressed on lymphocytes, both act to dampen anti-tumor responses. PVRIG and TIGIT are predominantly found on various immune cell subsets, including T cells and NK cells, particularly in tumor-infiltrating lymphocytes in cancer patients. Targeting PVRIG and TIGIT offers a rational strategy to disrupt immunosuppressive signaling in tumors, thereby enhancing immune-mediated tumor elimination. The dual blockade of PVRIG and TIGIT by VHH-P232 is strategically attractive, as it addresses redundant checkpoint pathways often co-opted by cancers to evade immune surveillance, representing a significant step forward in the development of next-generation immunotherapies.

Mechanism of Action

VHH-P232 exerts its function as an immune checkpoint inhibitor by specifically binding to both PVRIG and TIGIT, blocking their respective inhibitory pathways on T cells and NK cells. Through its bispecific binding, VHH-P232 counteracts the suppressive signals mediated by these checkpoints in cancer, leading to the restoration of immune cell cytotoxic activity and the enhancement of anti-tumor immune responses. This dual-targeting approach is designed to address compensatory mechanisms that often limit the efficacy of single-agent checkpoint inhibitors. Furthermore, the nanobody platform employed in VHH-P232 could enable diverse therapeutic configurations, including bispecifics, antibody-drug conjugates, and other multifunctional biologics, expanding its clinical application spectrum.

Cancer

Cancer remains one of the leading causes of morbidity and mortality worldwide, with global incidence rising due to aging populations and lifestyle factors. It encompasses a heterogeneous group of diseases characterized by uncontrolled cell proliferation and the ability to invade surrounding tissues and metastasize. The mainstays of current cancer therapy include surgery, radiation, chemotherapy, and an expanding category of targeted and immunological treatments. While significant progress has been made, many forms of cancer develop resistance to existing therapies or fail to respond to single-modality treatment, resulting in poor long-term outcomes for many patients. Major challenges include immune evasion by tumor cells and the emergence of immunosuppressive microenvironments. VHH-P232, by simultaneously blocking PVRIG and TIGIT checkpoints, represents a novel immunotherapeutic approach with the potential to enhance anti-tumor immunity, overcome resistance mechanisms, and address substantial unmet needs in cancer treatment.