Next-Generation Bispecific Nanobody Targeting CLDN6 and TNFRSF9 for Colorectal Cancer Immunotherapy

VHH-P474 is a fully humanized nanobody-based bispecific antibody designed to target both claudin 6 (CLDN6) and TNF receptor superfamily member 9 (TNFRSF9). Currently in the Biological Testing stage, this innovative therapeutic candidate harnesses the dual-specificity approach to enhance anti-tumor efficacy in colorectal cancer. By simultaneously engaging CLDN6 and TNFRSF9, VHH-P474 aims to provide targeted tumor cell recognition and potent immune activation, offering new prospects for patients with colorectal cancer.

Licensing Opportunity

VHH-P474 is available for licensing and strategic collaborations. We invite partners seeking innovative immuno-oncology assets for co-development, out-licensing, or joint commercialization to contact us regarding collaborative opportunities.

Development Phase

Modality

VHH-P474 is a bispecific antibody constructed by fusing an agonistic single-domain nanobody against 4-1BB to the C-terminus of the heavy chain of an anti-CLDN6 monoclonal IgG1 antibody. This nanobody format retains the advantages of single-domain antibodies—such as compact molecular size, high tissue penetration, and excellent stability—while preserving IgG-like effector functions. In the context of colorectal cancer, the structural attributes of VHH-P474 enhance its ability to reach tumor cells within dense tissue matrices and facilitate robust immune cell recruitment and activation, improving the potential for durable therapeutic responses.

Target

CLDN6 is a tight junction protein that is not typically expressed in adult normal tissues but is aberrantly upregulated in various tumor types, making CLDN6 an attractive target for cancer therapy. TNFRSF9, a member of the TNF receptor superfamily, delivers costimulatory signals critical for T cell activation and survival. In colorectal cancer, CLDN6 expression enables selective targeting of malignant cells, while TNFRSF9 is primarily found on the surface of activated T cells and NK cells within the tumor microenvironment. Targeting both CLDN6 and TNFRSF9 enables VHH-P474 to direct immune activation specifically to the tumor site, maximizing therapeutic benefit and reducing off-target effects. This dual-targeting approach of CLDN6 and TNFRSF9 represents a strategic advantage for colorectal cancer immunotherapy.

Mechanism of Action

VHH-P474 exerts its anti-tumor effects by specifically binding to CLDN6 on colorectal cancer cells and simultaneously activating TNFRSF9 on immune effector cells. The anti-CLDN6 arm mediates precise tumor localization, ensuring that immune engagement occurs predominantly at cancer sites. The anti-TNFRSF9 agonistic component stimulates T cells and NK cells via costimulatory signaling, promoting their proliferation, survival, and cytotoxic activity against tumor cells. This dual mechanism results in focused immune activation within the tumor, minimizing systemic toxicity. The nanobody-based design also provides a modular platform, enabling further therapeutic innovation such as antibody–drug conjugates or additional multispecific formats.

Colorectal Cancer

Colorectal cancer is one of the most prevalent malignancies worldwide, with significant morbidity and mortality. Incidence rates have been rising in many regions, particularly in younger populations. Current standard care includes a combination of surgery, chemotherapy, radiotherapy, and biologics targeting specific pathways. While advances in immunotherapy and targeted agents have improved outcomes in some patients, resistance, relapse, and adverse side effects remain major challenges. There is a substantial need for novel therapies that deliver selective tumor targeting and enhanced anti-tumor immunity. By addressing these critical gaps, VHH-P474 offers promising potential for more effective and safer treatment options in colorectal cancer.