Innovative Bispecific Nanobody Targeting NT5E and ENTPD1 for Pancreas Cancer Immunotherapy
VHH-P450 is a fully humanized nanobody-based therapeutic candidate currently in biological testing, developed for the treatment of pancreas cancer. This bispecific antibody fusion construct targets both 5'-nucleotidase ecto (NT5E) and ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1), two immunoregulatory ectoenzymes with established roles in tumor immune escape. Designed to precisely modulate the tumor microenvironment by simultaneously inhibiting these key immune checkpoints, VHH-P450 seeks to unlock new therapeutic avenues for patients with limited options. The molecule’s unique bispecific configuration is anticipated to enhance anti-tumor immune responses in the pancreatic cancer setting.
| Candidate | VHH-P450 |
| Target | 5'-nucleotidase ecto (NT5E) ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1) |
| Modality | humanized bispecific VHH |
| Indication | Pancreas Cancer |
Licensing Opportunity
VHH-P450 is now open for out-licensing and collaborative development opportunities. Partners are invited to engage and accelerate the advancement of this promising bispecific nanobody program for unmet needs in pancreas cancer.
Contact UsDevelopment Phase
| Program | Research | Preclinical | Phase 1 |
|---|---|---|---|
| VHH-P450 |
Modality
VHH-P450 utilizes a bispecific antibody fusion modality, comprising an anti-CD39 single domain antibody (nanobody) fused to the N-terminus of both heavy chains of an anti-CD73 IgG backbone. This format leverages the advantageous properties of nanobodies, including small molecular size and enhanced tissue penetration, combined with the effector functions and half-life extension typical of IgG molecules. Manufactured in Chinese hamster ovary cells to ensure clinical-grade quality, the design promotes dual checkpoint blockade. The structural attributes of the construct can facilitate deep tumor infiltration and robust target engagement within the pancreatic tumor microenvironment, offering a promising approach for challenging solid tumors such as pancreas cancer.
Target
NT5E and ENTPD1 are cell surface ectoenzymes serving as pivotal immunoregulatory mediators. NT5E, also referred to as CD73, functions in the hydrolysis of extracellular AMP to adenosine, while ENTPD1, also known as CD39, catalyzes the conversion of extracellular ATP and ADP to AMP. Both NT5E and ENTPD1 are highly expressed on numerous immune and tumor cells within the pancreas cancer microenvironment, contributing to immunosuppression via adenosine accumulation. Targeting NT5E and ENTPD1 is scientifically rational for pancreas cancer, as both enzymes foster tumor growth and hinder anti-tumor immunity. By focusing on NT5E and ENTPD1, VHH-P450 presents a compelling asset for strategic immune modulation and next-generation oncology therapeutics.
Mechanism of Action
VHH-P450 exerts its therapeutic effect through dual inhibition of NT5E and ENTPD1, two enzymes critical to adenosine-mediated immunosuppression. The anti-CD39 single domain antibody component selectively blocks ENTPD1 activity, reducing extracellular AMP production, while the anti-CD73 IgG component interferes with NT5E, limiting the conversion of AMP to immunosuppressive adenosine. This bispecific blockade interrupts a central immune checkpoint axis exploited by tumors, thereby enhancing anti-tumor immune responses. Furthermore, the nanobody platform employed by VHH-P450 offers future opportunities for modality expansion, including the development of next-generation antibody-drug conjugates or multi-specific constructs for additional oncology applications.
Pancreas Cancer
Pancreas cancer is among the most lethal forms of cancer globally, distinguished by poor prognosis and high mortality rates. It is often diagnosed at an advanced stage due to subtle early symptoms and lack of effective screening methods. The mainstay treatments currently include surgical resection, chemotherapy, and, for select cases, radiotherapy and immunotherapy. Despite these approaches, five-year survival rates remain low, largely due to aggressive tumor biology and resistance to conventional therapies. There is a critical need for innovative therapies that specifically address immune evasion in the pancreas cancer microenvironment. VHH-P450, by targeting NT5E and ENTPD1, has the potential to overcome significant barriers associated with immunosuppression, providing new hope for improved clinical outcomes in this challenging disease.