Innovative Bispecific Nanobody Targeting CLDN18 and TNFRSF9 for Advanced Colon Cancer Immunotherapy

VHH-P290 is a bispecific, humanized nanobody therapeutic candidate designed to simultaneously target claudin 18 (CLDN18) and TNF receptor superfamily member 9 (TNFRSF9). Currently in the Biological Testing phase, this molecule incorporates advanced engineering for selective binding to CLDN18 and immune modulation through TNFRSF9 activation. Its innovative dual-targeting mechanism addresses critical signaling pathways implicated in colon cancer progression, with the aim of enhancing anti-tumor immune responses. Expressed in Chinese hamster ovary cells, VHH-P290 demonstrates the potential to become a therapeutically valuable option for colon cancer patients, especially in clinical contexts where alternative treatments remain limited.

Licensing Opportunity

VHH-P290 is available for global out-licensing and collaborative development. We invite industry partners and investors to join us in advancing this promising bispecific nanobody program for novel colon cancer therapies.

Development Phase

Modality

VHH-P290 is a homodimeric bispecific antibody fusion construct, consisting of two polypeptides. Each polypeptide features a nanobody—a single-domain antibody—targeting human CLDN18. This domain is fused via flexible (G4S)4 linkers to a human IgG1 Fc region, and via (G4S)3 linkers to a single-chain variable fragment directed at human TNFRSF9. The nanobody format ensures a compact molecular size, granting improved tissue penetration and stability over conventional antibodies. The unique bivalent structure enables simultaneous engagement of tumor cell antigens and immune co-stimulatory receptors, optimizing T cell recruitment and activity within the tumor microenvironment, vital for achieving enhanced efficacy in colon cancer therapy.

Target

CLDN18 and TNFRSF9 are key molecular targets in the context of colon cancer immunotherapy. CLDN18 is a tight junction protein primarily involved in cell adhesion and barrier function, and shows aberrant overexpression in various gastrointestinal malignancies, including colon cancer. TNFRSF9, a co-stimulatory receptor predominantly expressed on activated T cells and natural killer (NK) cells, plays an essential role in promoting cellular immune responses. Targeting CLDN18 enables selective recognition of tumor cells, while engagement of TNFRSF9 amplifies immune cell activation and persistence in the tumor milieu. The dual targeting strategy with VHH-P290 leverages both tumor selectivity (via CLDN18) and immune activation (via TNFRSF9), creating synergistic therapeutic potential. This approach underscores the program’s unique competitive position and strategic appeal for colon cancer treatment.

Mechanism of Action

VHH-P290 exerts its anti-tumor effect through simultaneous engagement of CLDN18 on tumor cells and TNFRSF9 on immune effector cells. By binding CLDN18, the nanobody moiety enables selective targeting of colon cancer cells, facilitating localized immune modulation. Concurrently, the anti-TNFRSF9 activity induces co-stimulatory signaling, augmenting T cell and NK cell responses critical for effective tumor eradication. This bispecific architecture allows for precise modulation of immune pathways at the tumor site, reducing potential off-target immune effects. The nanobody platform further supports versatile drug development, offering options for engineering next-generation antibody-drug conjugates, multispecific formats, or immune cell engagers, broadening its therapeutic impact in oncology.

Colon Cancer

Colon cancer remains a leading cause of cancer incidence and mortality worldwide, with high prevalence in both developed and developing regions. Standard therapies encompass surgery, radiation, cytotoxic chemotherapy, and targeted biological agents. Despite advances, significant challenges persist, including resistance to conventional drugs, limited durability of response, and the frequent emergence of metastatic disease. Immuno-oncology has shown promise, yet not all patients benefit from current immunotherapies due to tumor heterogeneity and immunosuppressive microenvironments. There is a critical unmet need for innovative treatments that effectively combine tumor specificity with potent immune activation. VHH-P290, by co-targeting CLDN18 and TNFRSF9, aims to overcome these barriers, offering new hope through its dual-pronged mechanism. Its design is poised to address gaps in efficacy and broaden the scope of effective immunotherapies for colon cancer.