Next-Generation Bispecific Nanobody Targeting CD274 and CD28 for Cancer Immunotherapy

VHH-P641 is a humanized nanobody-based therapeutic candidate designed to target CD274 molecule (CD274) and CD28 molecule (CD28). Currently in the biological testing phase, this molecule demonstrates significant promise in the treatment of cancer by modulating key immune pathways. VHH-P641 leverages advanced biotherapeutics engineering to direct a bispecific, tetravalent nanobody towards these two pivotal immunoregulatory targets, providing a novel approach for overcoming immune evasion in cancer. Its fully humanized structure and strategic dual-targeting of CD274 molecule (CD274) and CD28 molecule (CD28) set the foundation for potentially transformative effects in oncology therapeutics.

Licensing Opportunity

VHH-P641 is available for out-licensing and collaborative development opportunities. Partners interested in advancing next-generation bispecific nanobody therapeutics for cancer immunotherapy are encouraged to engage in discussions for strategic collaboration.

Development Phase

Modality

VHH-P641 employs a tetravalent, bispecific nanobody structure, integrating two single-domain antibodies specific for programmed death-ligand 1 with two single-domain antibodies targeting CD28. These are fused via flexible linkers and capped with a human IgG1 Fc domain, enhancing the molecule's half-life and immune effector functions. The single-domain antibody (nanobody) characteristics provide several advantages, including smaller molecular size for improved tissue penetration, increased stability, and reduced aggregation tendency, which are especially valuable in the tumor microenvironment. This rationally engineered modularity supports the development of robust anti-cancer therapeutics by harnessing both checkpoint inhibition and co-stimulation in a single therapeutic entity.

Target

CD274 and CD28 are central immunological targets in oncology. CD274, a membrane-bound ligand expressed on tumor and immune cells, acts as a key immune checkpoint by binding to receptors and attenuating T cell responses. CD28 is a critical co-stimulatory receptor located primarily on T lymphocytes; its activation is required for full T cell stimulation and sustained antitumor immunity. Both CD274 and CD28 are strategically relevant in cancer, where CD274 expression disrupts immune detection and CD28 signaling promotes immune cell activation. VHH-P641 simultaneously targets CD274 and CD28, addressing both immune suppression and T cell activation, which underscores the program’s strategic value in enabling robust and selective antitumor responses.

Mechanism of Action

VHH-P641 exerts its therapeutic effects through dual mechanisms. By antagonizing CD274, it disrupts immune checkpoint signaling, thereby releasing the inhibitory brakes on T cell activity that tumors exploit for immune evasion. Simultaneously, VHH-P641 acts as an agonist of CD28, providing necessary co-stimulatory signals that enhance the activation and proliferation of T cells. This dual modulation not only restores immune surveillance but also enhances the breadth and durability of antitumor responses. The nanobody platform underlying VHH-P641 also offers versatile design potential, supporting future development into antibody-drug conjugates or multispecific formats for expanded oncologic applications.

Cancer

Cancer encompasses a diverse group of diseases characterized by uncontrolled cell growth and the potential to invade or spread beyond the primary tissue. It remains one of the leading causes of mortality globally, with incidence rates continuing to rise as populations age and risk factors accumulate. Standard treatments include surgery, radiation, chemotherapy, immunotherapy, and molecularly targeted agents, each addressing different aspects of tumor biology. However, many patients experience limited efficacy, relapse, or significant side effects. Unmet medical needs persist, particularly in the context of therapeutic resistance, tumor heterogeneity, and immune evasion. By concurrently blocking immune checkpoints and activating T cells via CD274 and CD28, VHH-P641 is positioned to overcome intrinsic and acquired resistance mechanisms, providing innovative therapeutic solutions for patients with cancer.