Dual Target CTLA4/TNFRSF4 Bispecific Nanobody for Advanced Bladder Cancer Immunotherapy

VHH-P492 is a bispecific, humanized nanobody-based antibody fusion construct designed to target both cytotoxic T-lymphocyte associated protein 4 (CTLA4) and tumor necrosis factor receptor superfamily member 4 (TNFRSF4). Developed at the biological testing stage, VHH-P492 aims to harness the complementary roles of these key immune regulators to enhance anti-tumor immunity. The construct leverages single-domain antibodies derived from llama, fused to a human IgG1 monoclonal antibody backbone, offering a novel strategy for treating bladder cancer. Its dual targeting of CTLA4 and TNFRSF4 positions VHH-P492 as a promising therapeutic approach for overcoming immune evasion in urothelial malignancies.

Licensing Opportunity

VHH-P492 is available for out-licensing partnerships. We welcome inquiries from biopharmaceutical companies and academic collaborators interested in developing first-in-class immunotherapies for bladder cancer and related indications.

Development Phase

Modality

VHH-P492 utilizes a bispecific antibody fusion modality, featuring agonistic, humanized single-domain nanobodies that target TNFRSF4. These nanobodies are genetically fused to both N-termini of a monoclonal human IgG1 antibody specific for CTLA4 via GS-rich linkers, and are expressed using ExpiCHO cells for scalable production. The single-domain nanobody elements provide small molecular size and high tissue penetration, while the IgG1 scaffold supports improved pharmacokinetics and effector functions. This rationally engineered format offers enhanced stability and manufacturability, which can be particularly advantageous for addressing the complex immune environment in bladder cancer.

Target

Both CTLA4 and TNFRSF4 are immune regulatory molecules critically involved in T cell function. CTLA4, primarily expressed on regulatory and activated T cells, functions as an immune checkpoint that downregulates immune responses. TNFRSF4, known as OX40, is predominantly found on activated T cells and serves as a potent co-stimulatory receptor, enhancing T cell survival and proliferation. In bladder cancer, CTLA4 inhibition can alleviate T cell suppression in the tumor microenvironment, while TNFRSF4 activation further drives robust anti-tumor immunity. Dual targeting of CTLA4 and TNFRSF4 with VHH-P492 uniquely positions this molecule to simultaneously release inhibitory brakes and stimulate effector functions of T cells, providing a differentiated immunotherapeutic strategy. The bispecific approach maximizes the immune response potential against bladder cancer, reflecting significant strategic value for cancers characterized by immune evasion.

Mechanism of Action

VHH-P492 exerts its antitumor activity through dual modulation of immune pathways. By antagonizing CTLA4, VHH-P492 acts as an immune checkpoint inhibitor, blocking the inhibitory signaling that dampens T cell activation. Concurrently, the nanobody-based agonism of TNFRSF4 stimulates co-stimulatory pathways, supporting T cell expansion and effector function. This dual mechanism amplifies T cell-mediated cytotoxicity against tumor cells in bladder cancer, effectively overcoming immune suppression within the tumor microenvironment. The bispecific, nanobody-based architecture allows for versatile engineering, supporting not only checkpoint blockade but also other modalities such as antibody-drug conjugates or additional multispecific designs, broadening VHH-P492's therapeutic potential.

Bladder Cancer

Bladder cancer is a prevalent malignancy arising from the urinary bladder epithelium, representing a significant global health burden. Its incidence is notably higher in certain populations and risk increases with age, exposure to carcinogens, and chronic inflammation. The mainstays of therapy include surgery, chemotherapy, radiotherapy, and immune checkpoint blockade. Despite these advances, many patients with advanced or metastatic disease face poor long-term outcomes and high rates of recurrence. Challenges include limited efficacy of conventional therapies in refractory settings and the immune-suppressive tumor microenvironment that impairs anti-tumor immune responses. There remains a compelling need for innovative immunotherapies that can circumvent immune evasion and provide durable responses. By simultaneously targeting both CTLA4 and TNFRSF4 pathways, VHH-P492 offers a rational approach to enhancing immune activation and surveillance against bladder cancer, with the potential to address critical gaps left by current treatments.