Innovative Bispecific Nanobody Targeting CD19 and TNFRSF9 for B-cell Lymphoma Therapy

VHH-P799 is a cutting-edge humanized nanobody therapeutic specifically designed to target both CD19 molecule (CD19) and TNF receptor superfamily member 9 (TNFRSF9). Currently in the Biological Testing phase of development, VHH-P799 is engineered to address significant unmet needs in the treatment of B-cell lymphoma. By combining dual antigen targeting with the unique properties of nanobodies, this program represents a promising new approach in hematologic oncology. The novel fusion architecture underscores high specificity and potential adaptability in B-cell lymphoma intervention strategies, supporting further investigation and collaborative development.

Licensing Opportunity

VHH-P799 is available for out-licensing and strategic partnership. We welcome collaboration with industry partners interested in innovative immunotherapy for B-cell lymphoma, supported by robust scientific rationale and potential for broad clinical application.

Development Phase

Modality

VHH-P799 is a bispecific antibody fusion construct consisting of two separate antigen-binding fragments (Fab) directed against CD19, each fused to the N-terminus of an IgG1 Fc domain. The Fc C-terminus is further extended with two single domain antibodies (nanobodies) specific for 4-1BB (also known as TNFRSF9). This modular structure offers several advantages: the inclusion of nanobodies provides reduced molecular size, superior tissue penetration, and robust stability under physiological conditions. The bispecificity enables simultaneous engagement of B-cell targets and immune costimulatory pathways, presenting a rational strategy for the effective treatment of B-cell lymphoma and enhanced T-cell mediated cytotoxicity within the tumor microenvironment.

Target

CD19 and TNFRSF9 are pivotal immunotherapeutic targets in hematologic malignancies. CD19 is a B-lineage surface molecule broadly expressed throughout B-cell development and retained on most malignant B cells, making CD19 an essential marker for B-cell lymphoma detection and intervention. TNFRSF9, also known as 4-1BB, is an inducible costimulatory receptor predominantly found on activated T cells and natural killer cells, with a crucial role in amplifying immune responses. Targeting CD19 enables selective depletion or modulation of malignant B cells, while engagement of TNFRSF9 potentiates anti-tumor immunity by enhancing T cell activation and persistence. The dual targeting of CD19 and TNFRSF9 in VHH-P799 brings synergistic effects in the elimination of B-cell lymphoma cells, promoting durable therapeutic outcomes and providing a strategic edge in immune-based cancer treatments.

Mechanism of Action

VHH-P799 functions as a bispecific immunomodulator by binding to CD19 on B cells and TNFRSF9 on activated T cells. Through its high-affinity anti-CD19 Fab arms, VHH-P799 achieves selective recognition and targeting of malignant B cells in lymphoma. The appended nanobody domains against TNFRSF9 serve to cluster and activate the 4-1BB receptor on immune effector cells, thereby stimulating potent anti-tumor signaling cascades. This dual engagement bridges tumor cells with cytotoxic lymphocytes, fostering effective immune synapse formation and promoting tumor cell elimination. The modular nanobody platform of VHH-P799 allows further expansion into antibody-drug conjugate (ADC) developments or advanced bispecific modalities, maximizing therapeutic flexibility and translational value across oncology indications.

B-cell Lymphoma

B-cell lymphoma comprises a diverse group of hematological malignancies derived from B lymphocytes. It represents a significant proportion of non-Hodgkin lymphoma cases worldwide. While advances in immunochemotherapy and targeted approaches have improved survival, many patients still face relapse or refractory disease, highlighting the need for novel therapies. Current standards include combination chemotherapy, radiation, anti-CD20 antibodies, and, for select cases, cellular therapies like CAR-T. However, resistance, toxicity, and accessibility remain substantial obstacles. The emergence of agents like VHH-P799, engineered for dual targeting of CD19 and TNFRSF9, addresses critical gaps—specifically, boosting selective tumor recognition while directly enhancing anti-tumor immune responses. This approach offers the promise of greater efficacy, improved tolerability, and potential synergy with existing treatment paradigms, responding to the clear unmet medical needs in B-cell lymphoma care.