Next-Generation Trifunctional Nanobody Targeting GPC3 and NCR3 for Innovative Cancer Immunotherapy

VHH-P548 is a novel nanobody-based therapeutic candidate currently at the Biological Testing stage, designed to target glypican 3 (GPC3) and natural cytotoxicity triggering receptor 3 (NCR3) for the treatment of cancer. This molecule harnesses the specificity and versatility of nanobody technology, integrating a humanized single-domain antibody approach to enhance selectivity and immune activation. By combining anti-GPC3 and anti-NCR3 functionalities within a trifunctional structure, VHH-P548 aims to address important unmet needs in cancer immunotherapy, providing a new strategy for effective and selective tumor cell targeting.

Licensing Opportunity

VHH-P548 is currently available for out-licensing and partnering opportunities. We welcome collaboration with biopharmaceutical companies and research institutions interested in advancing novel immunotherapeutic solutions for cancer.

Development Phase

Modality

VHH-P548 is a trifunctional antibody modality, featuring an anti-GPC3 monoclonal antibody fused at the N-terminus with an anti-NCR3 single-domain nanobody. Additionally, interleukin-15 and its receptor variant sequences are inserted within the antibody scaffold, all expressed recombinantly in E. coli. The nanobody component, characterized by its small molecular weight and unique single-domain structure, offers superior tissue penetration, stability, and decreased immunogenicity compared to traditional antibodies. For cancer therapy, these structural attributes enable more effective tumor infiltration and enhance multi-faceted immune engagement, promising improved therapeutic outcomes in challenging solid and hematological malignancies.

Target

GPC3 and NCR3 represent two highly relevant molecular targets in oncology. GPC3 is a cell surface proteoglycan frequently overexpressed in diverse cancer types, including hepatocellular carcinoma, serving as a tumor-associated antigen. NCR3, a member of the natural cytotoxicity receptor family, is primarily expressed on natural killer cells and is pivotal for immune-mediated tumor cell lysis. Both GPC3 and NCR3 play crucial roles in tumor biology—GPC3 in supporting cancer cell growth and immune evasion, and NCR3 in orchestrating innate immune responses. Targeting GPC3 allows precise tumor localization, while engaging NCR3 leverages the immune system's cytotoxic arm. By dually targeting GPC3 and NCR3, VHH-P548 is strategically positioned to deliver synergistic anti-tumor activity and offers unique competitive advantages for cancer drug development.

Mechanism of Action

VHH-P548 exerts its anti-cancer effects through simultaneous targeting of GPC3 on tumor cells and engagement of NCR3 on natural killer cells. By binding to GPC3, VHH-P548 selectively accumulates within the tumor microenvironment, while its anti-NCR3 domain activates and directs NK cells toward malignant cells. The inclusion of interleukin-15 and its receptor component further potentiates immune cell proliferation and persistence. This multi-modal engagement is designed to drive robust tumor cell lysis via direct cytotoxicity and immune modulation. The flexible nanobody platform also opens avenues for advanced therapeutic formats, such as antibody-drug conjugates and bispecific molecules, expanding its translational potential for future cancer immunotherapy innovations.

Cancer

Cancer remains one of the leading causes of morbidity and mortality worldwide, encompassing a diverse group of diseases characterized by uncontrolled cell growth and metastasis. Globally, the incidence of cancer continues to rise, presenting significant healthcare and socio-economic challenges. Current standard treatment modalities include surgery, chemotherapy, radiotherapy, immunotherapy, and molecularly targeted therapies. Despite advances, many cancer types still exhibit poor prognosis, significant toxicity, and limited durable responses, especially in advanced or resistant cases. The unmet need for therapies that offer greater selectivity, efficacy, and immune activation remains substantial. VHH-P548 addresses these gaps by combining tumor-specific targeting (GPC3) and immune effector engagement (NCR3), with the added benefit of enhanced tissue penetration and potentially lower immunogenicity inherent in its nanobody-based design. This innovative approach holds promise for improving response rates, minimizing off-target effects, and broadening applicability across multiple cancer types.