Next-Generation Bispecific Nanobody Targeting CD276 and TNFRSF1B for Novel Colon Cancer Therapy

VHH-P418 is an innovative humanized bispecific nanobody currently in the Biological Testing development stage, designed to target CD276 molecule (CD276) and TNF receptor superfamily member 1B (TNFRSF1B). This program leverages a dual-targeting approach to address critical tumor biology in colon cancer. By incorporating domains that specifically recognize CD276 and provide agonistic activity towards TNFRSF1B, VHH-P418 is positioned to modulate both the tumor and immune microenvironments. The targeted and selective mechanism, combined with advanced nanobody engineering, positions VHH-P418 as a promising candidate for the treatment of colon cancer.

Licensing Opportunity

VHH-P418 is currently available for out-licensing and collaboration opportunities. We invite partners interested in advancing innovative oncology immunotherapies to connect and explore commercial or research alliances.

Development Phase

Modality

VHH-P418 is a bispecific IgG4 kappa antibody featuring two polypeptide chains. One chain contains a single-chain variable fragment (scFv) against B7H3, while the second chain fuses B7H3’s variable heavy region and constant domains to an agonistic nanobody targeting TNFR2, joined by a (G4S)3 linker. Its nanobody (VHH) format allows for a significantly smaller molecular size compared to conventional antibodies, offering improved tumor penetration, high stability, and the potential for greater tissue accessibility. The IgG4 backbone confers reduced immune effector activation, desirable for modulating immune checkpoints in colon cancer. Expression in CHO cells ensures scalable manufacturability and consistent quality, supporting future clinical development.

Target

CD276 and TNFRSF1B are both cell-surface molecules integral to tumor biology and immune regulation. CD276, a member of the B7 immune checkpoint family, is broadly expressed in various cancers, including colon cancer, and is associated with immune evasion and tumor progression. TNFRSF1B, part of the tumor necrosis factor receptor superfamily, is primarily found on regulatory T cells and certain tumor cells, contributing to immune suppression within the tumor microenvironment. By co-targeting CD276 and TNFRSF1B, VHH-P418 addresses key resistance mechanisms in colon cancer therapy. The dual targeting of CD276 and TNFRSF1B has strategic value, as it enables simultaneous immune checkpoint inhibition and immune modulation, reflecting a rational approach to overcoming tumor escape and enhancing anti-tumor efficacy.

Mechanism of Action

VHH-P418 is designed to utilize a dual mechanism of action: inhibition of CD276 and agonistic activation of TNFRSF1B. The anti-CD276 component blocks immune checkpoint signals that facilitate tumor cell evasion of immune surveillance, while the agonistic anti-TNFRSF1B nanobody stimulates TNFR2 signaling, enhancing the activity of immune effector cells within the tumor microenvironment. This combined approach is intended to suppress tumor growth, promote anti-tumor immunity, and disrupt tolerogenic signals. The bispecific nanobody architecture supports expansion into modular antibody formats, such as bispecific T-cell engagers or antibody-drug conjugates, providing additional therapeutic versatility for colon cancer and potentially other malignancies.

Colon Cancer

Colon cancer is among the most common malignancies globally, contributing significantly to cancer-associated morbidity and mortality. Epidemiologically, the burden of colon cancer continues to rise due to aging populations and environmental risk factors. Current standard treatments include surgical resection, chemotherapy, radiation therapy, and targeted therapeutics, with immunotherapy becoming an emerging approach for select patients. However, challenges remain, such as limited responses to immune checkpoint inhibitors, recurrence after treatment, and poor prognosis in advanced stages. Critical unmet needs include the development of more effective, selective, and durable therapies, particularly for patients with refractory or relapsed disease. VHH-P418 introduces a novel immunotherapeutic strategy by simultaneously targeting immune checkpoints and modulating the tumor microenvironment, offering the potential to address these medical gaps and improve patient outcomes in colon cancer.