Innovative Bispecific Nanobody Targeting CD274 and TNFRSF9 for Colorectal Cancer Immunotherapy

VHH-P608 is a humanized bispecific nanobody fusion antibody currently in the Biological Testing stage, developed for the treatment of colorectal cancer. This novel molecule targets both CD274 molecule (CD274) and TNF receptor superfamily member 9 (TNFRSF9), two critical immunoregulatory proteins implicated in tumor immune evasion and activation. By simultaneously engaging CD274 and TNFRSF9, VHH-P608 is designed to disrupt immune checkpoint pathways and potentiate antitumor immunity. Engineered for high specificity and functional versatility, it holds the potential to address unmet clinical needs in colorectal cancer therapy.

Licensing Opportunity

VHH-P608 is open for out-licensing and partnership opportunities. We welcome inquiries from organizations seeking strategic collaboration or access to this innovative bispecific nanobody technology for colorectal cancer immunotherapy.

Development Phase

Modality

VHH-P608 is an advanced bispecific fusion antibody composed of single-domain nanobodies targeting human CD274 and human 4-1BB, both fused via optimized linkers to a human IgG1 Fc domain with specific mutations to fine-tune effector functions. This nanobody-based construct leverages the small molecular weight and structural simplicity of single-domain antibodies, supporting deeper tumor penetration and high tissue stability. Produced in Chinese hamster ovary cells, its distinctive architecture allows for dual-targeting while maintaining manufacturability and stability, providing a promising approach for treating colorectal cancer by enhancing tumor microenvironment modulation and immune system engagement.

Target

CD274 and TNFRSF9 are transmembrane proteins with pivotal roles in immune modulation. CD274 acts as an immune checkpoint molecule, expressed mainly on tumor and immune cells, suppressing T cell activity to promote immune escape. TNFRSF9 is a co-stimulatory receptor predominantly found on activated T cells and natural killer cells, crucial for enhancing immune responses. In colorectal cancer, CD274 upregulation enables tumor evasion of immune surveillance, while TNFRSF9 activation supports potent antitumor activity. The dual targeting of CD274 and TNFRSF9 by VHH-P608 strategically combines immune checkpoint inhibition and immune activation, creating a synergistic therapeutic modality. The bispecific approach positions VHH-P608 as a competitive asset in the evolving immunotherapy landscape, expanding options beyond single-target interventions for colorectal cancer.

Mechanism of Action

VHH-P608 exerts its action by simultaneously binding to CD274 and TNFRSF9, blocking inhibitory signals mediated by the CD274 pathway while activating stimulatory pathways through TNFRSF9. This dual mechanism disrupts tumor-induced immune suppression and promotes robust T cell-mediated antitumor responses, distinguishing it as both an immune checkpoint inhibitor and a signal transduction modulator. The nanobody platform facilitates the design of multifunctional formats, supporting further development as antibody-drug conjugates or next-generation bispecifics. Through its combined action, VHH-P608 is poised to overcome therapeutic resistance associated with conventional checkpoint inhibitors and has broad potential in immuno-oncology.

Colorectal Cancer

Colorectal cancer is one of the most common malignancies globally, presenting a significant health challenge due to its high prevalence and mortality rates. Risk factors include dietary habits, genetic predisposition, and lifestyle influences. Standard treatment regimens encompass surgical resection, chemotherapy, radiation therapy, and targeted biologics. Despite these interventions, many patients with advanced or metastatic disease experience limited long-term survival, stemming from resistance to existing therapies and immune escape within the tumor microenvironment. Innovative immunomodulators, including immune checkpoint inhibitors, have shown clinical potential but efficacy in colorectal cancer remains constrained, especially in immunologically 'cold' tumors. VHH-P608 offers a promising therapeutic avenue by engaging both immune checkpoint blockade and T cell co-stimulation, aiming to convert non-responsive tumors into immunologically active sites and address the inadequacies of current treatments.