Next-Generation Bispecific Nanobody Targeting SLC34A2 and TNFRSF9 for Advanced Colon Cancer Therapy
VHH-P239 is a humanized nanobody-based therapeutic candidate engineered to target solute carrier family 34 member 2 (SLC34A2) and tumor necrosis factor receptor superfamily member 9 (TNFRSF9). Now in the Biological Testing phase, VHH-P239 represents a novel approach for the potential treatment of colon cancer. By simultaneously engaging SLC34A2, implicated in phosphate transport and tumor proliferation, and TNFRSF9, a key costimulatory immune receptor, this bispecific biologic offers a mechanistically differentiated strategy for intervening in the complex pathophysiology of colon cancer. Its unique structure and mechanism support development as a next-generation immunotherapeutic.
| Candidate | VHH-P239 |
| Target | solute carrier family 34 member 2 (SLC34A2) TNF receptor superfamily member 9 (TNFRSF9) |
| Modality | humanized bispecific VHH |
| Indication | Colon Cancer |
Licensing Opportunity
VHH-P239 is currently available for out-licensing and collaborative development. We welcome inquiries from partners seeking to advance innovative nanobody-based therapies for oncology, especially those targeting colon cancer.
Contact UsDevelopment Phase
| Program | Research | Preclinical | Phase 1 |
|---|---|---|---|
| VHH-P239 |
Modality
VHH-P239 is a tetravalent bispecific antibody fusion construct comprising two antigen-binding fragments that target SLC34A2, each fused to the N-terminus of an IgG1 Fc domain with an N297A mutation, and at each Fc heavy chain C-terminus, a single-domain nanobody against TNFRSF9 via a flexible G4S linker. Expressed in Chinese hamster ovary cells, the molecule leverages the small size and high stability of nanobodies to optimize tissue penetration and tumor accessibility in colon cancer. This architecture combines potent immune agonism with specific tumor targeting, potentially enhancing efficacy while minimizing off-target effects compared to conventional antibody modalities.
Target
SLC34A2 is a membrane transporter involved in phosphate regulation, prominently expressed in certain epithelial tissues and upregulated in various cancers including colon cancer. TNFRSF9 is an inducible co-stimulatory molecule predominantly found on activated immune cells. SLC34A2 is associated with aberrant cellular metabolism and tumorigenesis in colon cancer, while TNFRSF9 modulates immune activation, enhancing anti-tumor responses. Targeting SLC34A2 disrupts tumor metabolism and microenvironment, and co-engagement of TNFRSF9 potentiates immune cell function. The combination of SLC34A2 and TNFRSF9 as dual targets in VHH-P239 provides strategic therapeutic advantage—enabling direct anti-tumor activity and immune-mediated tumor eradication, which reinforces VHH-P239's value for the evolving treatment landscape in colon cancer.
Mechanism of Action
VHH-P239 exerts its action through dual engagement: it targets SLC34A2 on tumor cells to interfere with phosphate transport and cell growth, while simultaneously agonizing TNFRSF9 on immune cells to enhance co-stimulatory signaling. By binding SLC34A2, VHH-P239 may limit tumor progression and survival signals. Activation of TNFRSF9, a member of the tumor necrosis factor receptor superfamily, stimulates effector T cell expansion and activity within the tumor microenvironment. This bifunctional approach intends to suppress tumor cell viability and stimulate robust anti-tumor immunity. The construct’s nanobody platform is well-suited to support future development of additional multi-specific or conjugated therapeutics, broadening its translational and commercial potential.
Colon Cancer
Colon cancer, also known as colorectal carcinoma, is among the most common and deadly malignancies worldwide. Its incidence continues to rise globally, representing a significant portion of all gastrointestinal cancers. Current therapeutic paradigms include surgical resection, cytotoxic chemotherapy, targeted agents, and immunotherapeutic approaches. While advances in diagnosis and treatment have improved outcomes for some, many patients experience disease recurrence or progression, underscoring unmet clinical needs for more effective and durable therapies. Limitations of existing interventions include resistance mechanisms, lack of lasting immune surveillance, and off-target toxicity. VHH-P239, by targeting tumor-specific SLC34A2 and activating immune effector cells via TNFRSF9, introduces a novel and rationally designed strategy with potential to overcome prevailing barriers in colon cancer treatment, offering promise for more precise and potent disease control.