Next-Generation Bispecific Nanobody Targeting CD274 and TNFRSF4 for Cancer Immunotherapy

VHH-P590 is a fully human bispecific antibody-based nanobody candidate designed to target two critical immunomodulatory proteins: CD274 molecule (CD274) and TNF receptor superfamily member 4 (TNFRSF4). Currently in the Biological Testing phase, VHH-P590 uniquely combines a monoclonal IgG1 domain that binds CD274 with a variable region (VHH) nanobody moiety directed against TNFRSF4, fused to the N-terminal of the IgG1 Fc domain. This innovative therapeutic modality is being developed to address the unmet need for more effective and durable immunotherapies for cancer.

Licensing Opportunity

VHH-P590 is available for out-licensing opportunities. We welcome partnerships and collaborations to accelerate its clinical development and commercialization globally. Interested parties are encouraged to engage with us for further discussion.

Development Phase

Modality

VHH-P590 leverages a bispecific format, comprising a full-length human IgG1 targeting CD274 fused with a nanobody domain recognizing TNFRSF4 at the Fc N-terminus. The nanobody, or single-domain antibody, offers distinct advantages such as small molecular size, high tissue penetration, and strong stability, which can facilitate better tumor penetration and target engagement in cancer microenvironments. The modularity of the structure enables simultaneous dual pathway modulation, providing opportunities to synergistically enhance immune activation and tumor eradication.

Target

CD274 and TNFRSF4 are both pivotal immunological checkpoints involved in the regulation of antitumor immunity. CD274, widely overexpressed on many tumor cells and within the tumor microenvironment, inhibits T cell activation when engaged, thus allowing cancer cells to evade immune surveillance. TNFRSF4, predominantly expressed on activated T cells, acts as an immune costimulatory molecule, enhancing T cell proliferation and survival when engaged. Targeting CD274 disrupts inhibitory signaling, reviving exhausted T cells, while TNFRSF4 agonism fosters further immune stimulation. Thus, the strategic dual targeting of CD274 and TNFRSF4 by VHH-P590 harnesses checkpoint blockade with immune enhancement, positioning it as a potentially transformative cancer immunotherapy.

Mechanism of Action

VHH-P590 functions through simultaneous engagement of CD274 and TNFRSF4, combining immune checkpoint inhibition with signal transduction modulation. By blocking CD274, VHH-P590 interrupts the inhibitory PD-1/PD-L1 axis, thereby restoring T cell activation and immune-mediated tumor clearance. Concurrently, the nanobody-mediated activation of TNFRSF4 provides an additional costimulatory signal to T cells, amplifying their proliferation and cytotoxic activity against tumor cells. This dual mechanism orchestrates a robust, multi-faceted antitumor response. Furthermore, the bispecific nanobody platform lends itself to future innovations, such as antibody-drug conjugates (ADC) or multispecific formats, extending its potential across oncology applications.

Cancer

Cancer encompasses a heterogenous group of diseases marked by uncontrolled cell growth and the ability to invade or metastasize to distant organs. It is a leading cause of morbidity and mortality worldwide, with incidence increasing globally due to population aging and lifestyle factors. Standard treatments include surgery, radiotherapy, chemotherapy, immunotherapies, and targeted modalities, yet many patients experience relapse or demonstrate resistance, and non-specific side effects remain a significant challenge. The advent of immunotherapies, notably those modulating immune checkpoints, has revolutionized treatment but not all patients benefit, highlighting the continued need for more effective and tolerable options. VHH-P590 introduces an innovative approach by dual targeting of immune checkpoints CD274 and TNFRSF4, aiming to overcome immune resistance and deliver more sustained, potent antitumor responses for diverse cancer types.