Dual Targeting Nanobody Innovation for CD47 and TNFRSF9 in Colon Cancer Immunotherapy
VHH-P359 is a humanized nanobody-based bispecific antibody construct in the biological testing stage, designed to simultaneously target CD47 molecule (CD47) and TNF receptor superfamily member 9 (TNFRSF9). By incorporating a mutant SIRPgamma specific for CD47 fused to an IgG1 Fc domain, and a humanized single domain antibody recognizing TNFRSF9, VHH-P359 offers a highly selective therapeutic approach. Its modular structure enables efficient engagement of relevant immune mechanisms, providing a novel strategy with significant potential in the treatment of colon cancer by modulating immune checkpoints and T cell co-stimulation.
| Candidate | VHH-P359 |
| Target | CD47 molecule (CD47) TNF receptor superfamily member 9 (TNFRSF9) |
| Modality | humanized bispecific VHH |
| Indication | Colon Cancer |
Licensing Opportunity
VHH-P359 is available for out-licensing opportunities. We welcome partnership discussions with biotechnology companies and pharmaceutical organizations seeking best-in-class, innovative immunotherapeutic assets for colon cancer and related indications.
Contact UsDevelopment Phase
| Program | Research | Preclinical | Phase 1 |
|---|---|---|---|
| VHH-P359 |
Modality
VHH-P359 utilizes a unique bispecific antibody architecture, combining a CD47-binding SIRPgamma variant on the N-terminus of a human IgG1 Fc domain with an alpaca-derived humanized single domain antibody targeting TNFRSF9 attached via a (G4S)2 linker to the Fc's C-terminus. The nanobody component offers the advantage of a small molecular size, allowing improved tissue penetration and stability, which is particularly advantageous in solid tumor contexts such as colon cancer. F99Y mutation is incorporated to reduce T-cell epitope content, potentially improving safety and immunogenicity profile. This sophisticated modality allows for dual immune-targeting within the tumor microenvironment, maximizing therapeutic reach and immune cell recruitment.
Target
CD47 is a cell surface glycoprotein broadly expressed on hematopoietic and many solid tumor cells, where it functions as a 'don't eat me' signal inhibiting macrophage-mediated phagocytosis. TNFRSF9 is a co-stimulatory receptor primarily found on activated T cells and natural killer cells, modulating immune activation and persistence. Both CD47 and TNFRSF9 have been validated as attractive immuno-oncology targets, playing distinct but complementary roles in the evasion and activation of anti-tumor responses in colon cancer. Targeting CD47 can overcome tumor-induced immune suppression, while engagement of TNFRSF9 enhances cytotoxic immune cell activity. The dual specificity of VHH-P359 for CD47 and TNFRSF9 positions it as a strategically differentiated asset in the immunotherapy landscape, enabling both removal of inhibitory signals and robust immune activation.
Mechanism of Action
VHH-P359 exerts its therapeutic effects in colon cancer by simultaneously binding to CD47 and TNFRSF9. Interaction with CD47 disrupts its inhibitory signaling, promoting phagocytosis of cancer cells by innate immune elements such as macrophages. Concurrent targeting of TNFRSF9 acts as a potent signal transduction modulator, enhancing adaptive immune responses through increased T cell activation and survival. As a nanobody-based bispecific antibody, VHH-P359 offers modular potential for future derivations, with possibilities including antibody-drug conjugates and multi-specific agents. This approach leverages both blocking of immune evasion and upregulation of anti-tumor immunity, addressing key mechanisms of immune resistance in colon cancer.
Colon Cancer
Colon cancer is a major global malignancy, with substantial incidence and mortality across diverse populations. Standard treatments typically include surgical resection, chemotherapy, radiation, and more recently, targeted therapies and immune checkpoint inhibitors. Despite these advances, the prognosis for metastatic or refractory disease remains limited, with significant unmet medical needs due to therapeutic resistance, off-target toxicity, and inadequate immune engagement. Many patients experience disease recurrence or progression, underlining the need for novel immunotherapeutic approaches. VHH-P359 represents a promising strategy, as its dual targeting of immune suppressive and stimulatory pathways could enhance the effectiveness of current regimens while potentially overcoming resistance mechanisms and minimizing adverse effects associated with broader immunosuppression.