Transforming Cancer Immunotherapy: Dual EGFR and NCR3 Nanobody-Enabled NK Cell Engager

VHH-P818 is a next-generation, humanized nanobody-based bispecific molecule designed to target two critical cancer antigens: epidermal growth factor receptor (EGFR) and natural cytotoxicity triggering receptor 3 (NCR3). Currently in the Biological Testing stage, VHH-P818 combines specificity for EGFR, highly expressed on many tumor cells, with engagement of NCR3 on natural killer (NK) cells, offering a potent approach for cancer immunotherapy. This advanced construct aims to bridge and potentiate anti-tumor immune responses, establishing a promising therapeutic strategy against cancer.

Licensing Opportunity

VHH-P818 is available for out-licensing and collaboration opportunities. We welcome partners seeking innovative bispecific immunotherapy candidates with unique mechanisms and significant commercial potential in oncology.

Development Phase

Modality

VHH-P818 is engineered as a bispecific IgG-based NK cell engager that harnesses the unique advantages of nanobody technology. The molecule features two humanized antigen-binding fragments directed against EGFR, fused to the IgG Fc domain for optimal immune effector function. At each CH3 region C-terminus, it incorporates a single-domain nanobody targeting NCR3. This compact and stable structure enhances tumor tissue penetration due to its small molecular size and single-domain architecture. The robust design offers improved stability and manufacturability, making it highly suitable for cancer treatment where efficient tumor targeting and immune activation are essential.

Target

EGFR and NCR3 are central to tumor cell biology and immune modulation, respectively. EGFR is a receptor tyrosine kinase frequently overexpressed in various epithelial cancers, where it drives proliferation and survival. It is predominantly found on tumor cells of lung, colorectal, and head and neck cancers. NCR3 is a key activating receptor present on NK cells and plays an essential role in immune surveillance by mediating direct cytotoxicity against malignant cells. The dual targeting of EGFR and NCR3 enables VHH-P818 to precisely recognize cancer cells while simultaneously activating innate immune responses via NK cell engagement. Selecting EGFR and NCR3 as therapeutic targets leverages their established roles in cancer biology, providing strategic value for the development of effective anti-cancer modalities.

Mechanism of Action

VHH-P818 functions through a dual mechanism: it binds EGFR on tumor cells while simultaneously engaging NCR3 on NK cells. By bridging these targets, VHH-P818 acts as an NK cell engager that redirects and activates the cytolytic activity of NK cells towards EGFR-positive cancer cells. This dual engagement triggers signal transduction cascades leading to NK cell degranulation and apoptosis of tumor cells. Furthermore, the modular nanobody format of VHH-P818 allows for versatile applications, such as future adaptation into antibody-drug conjugates or bispecific constructs with alternative immune effectors. This multi-faceted approach ensures a robust and selective anti-tumor immune response.

Cancer

Cancer remains a leading cause of morbidity and mortality worldwide, affecting millions of individuals and presenting significant healthcare challenges. Cancer encompasses a heterogeneous group of diseases characterized by uncontrolled cellular proliferation and the ability to invade surrounding tissues and metastasize. Standard treatment options include surgery, chemotherapy, radiotherapy, targeted therapies, and immunotherapies. However, drug resistance, tumor heterogeneity, and immune evasion continue to limit the long-term effectiveness of current treatments. There remains a high unmet need for therapies that improve selectivity, overcome resistance mechanisms, and safely boost anti-tumor immunity. By selectively targeting EGFR-expressing tumor cells and simultaneously activating NCR3-positive NK cells, VHH-P818 offers the potential to enhance tumor cell killing, minimize off-target effects, and improve clinical outcomes for patients with various malignancies.