Next-Generation Nanobody-Based Bispecific Antibody Targeting TIGIT and TNFRSF9 for Colorectal Cancer Immunotherapy

VHH-P821 is an innovative bispecific, fully humanized nanobody currently in biological testing, designed to simultaneously target T cell immunoreceptor with Ig and ITIM domains (TIGIT) and TNF receptor superfamily member 9 (TNFRSF9). By harnessing advanced single-domain antibody technology, VHH-P821 offers a novel immunomodulatory approach with significant potential for the treatment of colorectal cancer. The unique molecular design and dual-targeting capability of this antibody provide a strategic advantage to enhance antitumor immune responses, aiming to address key challenges in effective colorectal cancer therapy.

Licensing Opportunity

VHH-P821 is currently available for out-licensing and partnership opportunities. We invite collaboration with pharmaceutical and biotechnology companies seeking to expand their immuno-oncology portfolios through this advanced bispecific nanobody platform.

Development Phase

Modality

VHH-P821 is a bispecific antibody that integrates two nanobody domains directed against TIGIT, fused to an IgG1 Fc domain for optimized stability and half-life, and further linked to single-chain variable fragments targeting TNFRSF9. The nanobody format endows the molecule with small size, high tissue penetration, and superior stability compared to conventional antibodies, allowing for efficient targeting of tumor microenvironments. The bispecific architecture enhances its functional versatility in activating multiple immune pathways. These structural features make VHH-P821 especially advantageous for overcoming the barriers associated with solid tumors such as colorectal cancer, potentially improving immune cell infiltration and cytotoxic activity within tumor tissues.

Target

TIGIT and TNFRSF9 are both key immune modulators with critical roles in tumor immunology. TIGIT is an inhibitory receptor predominantly expressed on T cells and NK cells, negatively regulating immune responses. TNFRSF9 is a co-stimulatory molecule primarily found on activated T cells and NK cells, critically involved in enhancing anti-tumor immunity. Both TIGIT and TNFRSF9 are established immunotherapeutic targets in colorectal cancer, as modulation of these checkpoints can potentiate anti-tumor responses while overcoming immune suppression in the tumor microenvironment. Strategic targeting of TIGIT enables VHH-P821 to inhibit immune evasion by the tumor, while engagement of TNFRSF9 amplifies T cell activation and persistence. Combining these complementary mechanisms positions VHH-P821 as a highly attractive asset for immuno-oncology pipelines focused on colorectal cancer.

Mechanism of Action

VHH-P821 exerts its therapeutic action through dual modulation of immune checkpoints and co-stimulatory signaling. By antagonizing TIGIT, VHH-P821 blocks inhibitory signals that dampen T cell and NK cell activation within the tumor milieu. Concurrently, agonistic engagement of TNFRSF9 provides co-stimulatory signals that enhance the proliferation, survival, and cytotoxic function of effector lymphocytes. This synergistic mechanism aims to restore and amplify anti-tumor immunity in colorectal cancer, offering a compelling approach for overcoming immune resistance. The nanobody-based format of VHH-P821 also provides a modular platform suitable for further engineering into antibody-drug conjugates or multispecific agents in the future, broadening its clinical and commercial potential in oncology.

Colorectal Cancer

Colorectal cancer is among the most prevalent malignancies worldwide, posing a significant health burden with substantial mortality and morbidity. Current standard treatments include surgical resection, chemotherapy, radiotherapy, and targeted therapies. Although these interventions have improved patient outcomes, there remains a considerable proportion of patients who either do not respond or relapse, particularly in advanced disease settings. Immune checkpoint inhibitors have emerged as a promising class; however, their efficacy is frequently limited by tumor-mediated immune evasion and a highly suppressive microenvironment. There is a pressing unmet need for novel immunotherapeutics capable of overcoming these barriers. VHH-P821’s bispecific targeting of TIGIT and TNFRSF9 offers an innovative strategy, leveraging both immune inhibition blockade and co-stimulation to drive more effective and durable anti-tumor activity. This approach holds promise for transforming the treatment paradigm for colorectal cancer patients, particularly those unresponsive to existing therapies.