Innovative Bispecific Nanobody Targeting CD28 and TNFRSF4 for Advancing Graft-versus-host Disease Therapy

VHH-P380 is a next-generation bispecific antibody engineered to target the CD28 molecule (CD28) and the TNF receptor superfamily member 4 (TNFRSF4). Harnessing dual targeting capabilities, this fully humanized molecule is being developed through advanced biological testing and is designed for the treatment of graft-versus-host disease. With its unique architecture, combining a single-chain variable fragment against OX40 and a llama-derived nanobody specific for CD28, VHH-P380 offers the potential for enhanced therapeutic benefits by precisely modulating two critical immune checkpoints involved in the pathogenesis of graft-versus-host disease.

Licensing Opportunity

VHH-P380 is available for out-licensing and collaborative development. We welcome inquiries from partners interested in advancing this innovative bispecific nanobody program for graft-versus-host disease and immunotherapy applications.

Development Phase

Modality

VHH-P380 leverages a bispecific antibody modality, combining a single-chain variable fragment and a nanobody to simultaneously target two immune co-stimulatory receptors. The nanobody component, characterized by its compact size and robust stability, promotes superior tissue penetration and resilience under physiological conditions. The fusion to a human IgG1 Fc domain harboring specific mutations further optimizes pharmacokinetics and effector function. Produced using knobs-into-holes technology in FREESTYLE HEK293-FS cells, this format enables highly specific, bivalent engagement with both CD28 and TNFRSF4, offering a versatile and modular approach ideal for addressing the complex immunological dysregulation observed in graft-versus-host disease.

Target

CD28 and TNFRSF4 are pivotal co-stimulatory molecules essential to T cell activation and immune regulation. CD28, a key receptor on T lymphocytes, plays a crucial role in T cell proliferation and cytokine secretion, while TNFRSF4, primarily expressed on activated T cells, regulates cell survival and immune response modulation. Both CD28 and TNFRSF4 are predominantly found on lymphoid tissues and peripheral blood immune cells. Targeting these molecules in the context of graft-versus-host disease is supported by substantial research evidencing their role in driving pathogenic T cell responses after allogeneic transplantation. By directly engaging CD28 and TNFRSF4, VHH-P380 strategically modulates pathological immune activation, positioning these targets at the forefront of next-generation immunotherapeutic strategies for graft-versus-host disease.

Mechanism of Action

VHH-P380 exerts its effect by simultaneously binding to CD28 and TNFRSF4, functioning as a signal transduction modulator for these vital co-stimulatory receptors. By modulating CD28-mediated costimulation, it influences T-cell activation thresholds and immune response magnitude. Concurrent engagement of TNFRSF4 allows for additional control over T-cell proliferation and survival signals. This dual mechanism offers the potential to rebalance hyperactive alloimmune responses characteristic of graft-versus-host disease. The bispecific nanobody format enables versatile therapeutic innovation, supporting potential platform expansion as antibody–drug conjugates (ADC) or additional bispecific constructs for broader immunological indications.

Graft-versus-host Disease

Graft-versus-host disease (GVHD) is a severe immunological complication frequently observed following allogeneic hematopoietic stem cell transplantation. GVHD arises when donor-derived immune cells mount a misguided attack against recipient tissues, leading to significant morbidity and mortality. While the global incidence reflects the growing use of allogeneic transplants, current mainstay treatments such as systemic immunosuppressants—alongside newer approaches including targeted biologics and cellular therapies—often fail to achieve long-term remissions and can result in significant adverse effects and infection risk. There remains a pronounced need for therapies offering improved specificity and immune modulation with fewer off-target consequences. By specifically targeting CD28 and TNFRSF4, VHH-P380 introduces a novel immunotherapeutic strategy that directly addresses core mechanisms of GVHD pathogenesis, presenting substantial potential to fill critical gaps in patient care and outcome improvement.