Innovative Tri-Specific Nanobody Engaging CD3E and EGFR for Advanced Cancer Immunotherapy

VHH-P754 is a humanized tri-specific nanobody construct designed to target both CD3 epsilon subunit of the T-cell receptor complex (CD3E) and epidermal growth factor receptor (EGFR). Currently in the Biological Testing stage of development, VHH-P754 leverages advanced single-domain antibody technology for precise engagement with these clinically relevant targets. This program holds significant promise for the treatment of cancer, harnessing the immune system and tumor-selective targeting to address unmet needs in oncology.

Licensing Opportunity

VHH-P754 is available for out-licensing opportunities. We invite partners interested in advancing this tri-specific nanobody immunotherapy for cancer to collaborate on its development and commercialization.

Development Phase

Modality

VHH-P754 is a tri-specific nanobody-based T cell engager, consisting of a N-terminal single domain antibody against EGFR, a domain targeting human serum albumin, and a C-terminal V-domain fragment engaging CD3E. These domains are connected via flexible glycine-serine-rich linkers to provide structural stability and optimal spatial arrangement. The single-domain antibody format endows VHH-P754 with a small molecular size and high stability, contributing to deeper tumor penetration and reduced immunogenicity compared to conventional antibodies. Expression in Expi293 cells supports scalable production and post-translational fidelity. This modular structure can potentially enhance the therapeutic index for cancer treatment by improving targeting precision and minimizing off-tumor effects.

Target

CD3E and EGFR are both pivotal molecular targets in cancer immunotherapy. CD3E is a T-cell surface receptor component involved in antigen recognition and T-cell activation, predominantly expressed on T lymphocytes. EGFR is a transmembrane receptor tyrosine kinase widely overexpressed in various tumors, including epithelial malignancies. Its aberrant activation drives tumor cell proliferation and survival. The simultaneous targeting of CD3E redirects cytotoxic T cells toward EGFR-expressing tumor cells, promoting tumor cell killing. EGFR-specific engagement enables selective recognition of tumor cells, while CD3E ensures potent immune activation. This dual targeting strategy by VHH-P754 offers unique strategic value for cancer therapy by combining immunomodulation with precise tumor targeting.

Mechanism of Action

VHH-P754 mediates anti-tumor activity through simultaneous engagement of EGFR on tumor cells and CD3E on T cells. By binding to EGFR, VHH-P754 selectively localizes to cancer cells overexpressing this receptor, while engagement of CD3E on T cells initiates T-cell activation and cytotoxicity. The tri-specific design facilitates immune synapse formation, enhancing the recruitment and activation of immune effector cells at the tumor site. In addition, the serum albumin-binding domain prolongs systemic exposure. The nanobody platform underlying VHH-P754 enables the development of versatile next-generation therapeutics, including antibody-drug conjugates and multispecific immune engagers for cancer and other indications.

Cancer

Cancer comprises a broad group of diseases characterized by uncontrolled cell proliferation and the potential for local invasion and distant metastasis. It remains a foremost global health challenge, contributing substantially to morbidity and mortality worldwide. Common treatment modalities include surgery, radiotherapy, chemotherapy, immunotherapy, and targeted therapies, each with varying degrees of effectiveness and associated adverse effects. While targeted therapies and immune checkpoint inhibitors have significantly improved outcomes in certain cancers, many patients still face resistance, relapse, or toxicity. Unmet clinical needs include more selective approaches to minimize off-tumor toxicity, drive durable responses, and overcome tumor immune evasion. VHH-P754, by directing T cells specifically to EGFR-positive tumor cells, offers substantial potential to augment anti-cancer immunity and address limitations of existing therapies, positioning it as a promising candidate for cancer treatment.