Innovative Bispecific Nanobody Targeting CD274 and ENTPD1 for Advanced Colorectal Cancer Immunotherapy
VHH-P303 is a novel, humanized nanobody-based bispecific antibody currently in the Biological Testing stage. It is engineered to target both CD274 molecule (CD274) and ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1), two key immune modulators implicated in tumor immune evasion. Leveraging advanced antibody engineering, VHH-P303 is designed with the potential to enhance immune responses against colorectal cancer. Its dual-targeting mechanism offers a promising approach for addressing the complex microenvironment of colorectal cancer, potentially enabling improved therapeutic outcomes compared to single-target agents.
| Candidate | VHH-P303 |
| Target | CD274 molecule (CD274) ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1) |
| Modality | humanized bispecific VHH |
| Indication | Colorectal Cancer |
Licensing Opportunity
VHH-P303 is open for external licensing and partnering opportunities. Companies and organizations interested in advancing innovative immuno-oncology solutions are welcome to engage in collaboration discussions.
Contact UsDevelopment Phase
| Program | Research | Preclinical | Phase 1 |
|---|---|---|---|
| VHH-P303 |
Modality
VHH-P303 features a modular bispecific structure, comprising a monoclonal IgG4 antibody directed against CD274 and a humanized nanobody specific for ENTPD1, fused to the Fc region using a (G4S)3 linker. Expressed in human embryonic kidney cells, this arrangement enhances protein stability and ensures human compatibility. The nanobody component, characterized by its single-domain structure and reduced molecular weight, provides superior tumor penetration and stability, which are particularly advantageous for targeting the challenging microenvironment of colorectal cancer. The combination of these features supports effective tumor targeting and immune modulation.
Target
CD274 and ENTPD1 are critical molecular targets in immuno-oncology. CD274, an immune checkpoint protein, is widely expressed on tumor cells and immune regulatory cells, playing a vital role in suppressing T cell activity within the tumor microenvironment. ENTPD1 is an ectoenzyme expressed on various immune and stromal cells, where it regulates extracellular ATP and adenosine levels, contributing to immunosuppression. Both CD274 and ENTPD1 are overexpressed in colorectal cancer, promoting immune escape and tumor progression. Targeting both CD274 and ENTPD1 addresses complementary immunosuppressive pathways, making VHH-P303 a strategically differentiated candidate for colorectal cancer treatment.
Mechanism of Action
VHH-P303 is designed as an immune checkpoint inhibitor and immune cell engager, simultaneously targeting CD274 and ENTPD1. By blocking CD274, it disrupts inhibitory signaling between tumor cells and T lymphocytes, thereby reactivating anti-tumor immune responses. The anti-ENTPD1 nanobody blocks adenosine-mediated immunosuppression, further enhancing the activation of cytotoxic immune cells within the tumor microenvironment. This dual mechanism amplifies anti-tumor immunity at multiple checkpoints. The nanobody platform of VHH-P303 also provides a basis for further development of advanced modalities, such as bispecific and antibody-drug conjugates, increasing its future therapeutic versatility.
Colorectal Cancer
Colorectal cancer is one of the most prevalent malignancies worldwide, representing a leading cause of cancer-related morbidity and mortality. It affects both men and women and is associated with diverse risk factors, genetic mutations, and environmental exposures. The primary modalities for managing colorectal cancer include surgical resection, radiation therapy, chemotherapy, and targeted therapies, with immunotherapy emerging as a new option for certain patient populations. However, significant limitations remain, such as treatment resistance, disease recurrence, and lack of durable response in advanced stages. Current therapies may be associated with serious adverse effects, and a substantial proportion of patients exhibit limited benefit from existing immune checkpoint inhibitors. VHH-P303 addresses unmet needs by employing a bispecific approach that targets two non-redundant immunosuppressive pathways, offering the potential to overcome resistance, broaden patient eligibility for immunotherapy, and enhance therapeutic outcomes for individuals with colorectal cancer.