Innovative Bispecific Nanobody Targeting CD274 and ERBB2 for Advanced Stomach Cancer Therapy

VHH-P449 is a fully humanized nanobody-based bispecific antibody that specifically targets both CD274 molecule (CD274) and erb-b2 receptor tyrosine kinase 2 (ERBB2). Currently in the Biological Testing stage, this fusion protein is designed for investigational use in the treatment of stomach cancer. By combining two clinically validated tumor-associated antigens, VHH-P449 holds potential to address therapeutic resistance and improve treatment outcomes in gastric oncology. Its unique structure, comprising nanobody and IgG1 elements, aims to deliver potent antitumor activity and immune modulation, making VHH-P449 a promising addition to future targeted cancer immunotherapies.

Licensing Opportunity

VHH-P449 is available for out-licensing and partnership. We welcome inquiries from pharmaceutical companies and research institutions interested in advancing innovative bispecific nanobody therapeutics for stomach cancer.

Development Phase

Modality

VHH-P449 is a bispecific antibody fusion construct composed of two identical first polypeptide chains incorporating an anti-human programmed cell death ligand-1 single domain nanobody and the variable heavy chain of an anti-human epidermal growth factor receptor 2 antibody, capable of recognizing both targets simultaneously. These are fused via a flexible polypeptide linker to a human IgG1 constant region, paired with two identical light chains derived from the variable and constant regions of the trastuzumab light chain. Expressed in ExpiCHO cells, the single domain antibody structure (nanobody) endows the molecule with a compact size and enhanced tissue penetration, crucial for overcoming the dense tumor microenvironment typical of stomach cancer, while maintaining high specificity and stability essential for therapeutic development.

Target

CD274 and ERBB2 are high-value targets in oncology. CD274 is a transmembrane protein pivotal in immune checkpoint regulation, commonly expressed in various tumor cells, including those of stomach cancer, facilitating immune evasion. ERBB2 is a receptor tyrosine kinase involved in cell proliferation and survival, frequently overexpressed in gastric tumors, contributing to aggressive disease phenotypes and poor prognosis. Targeting CD274 interrupts tumor-mediated immunosuppression, while inhibition of ERBB2 disrupts oncogenic signaling. The co-targeting of CD274 and ERBB2 by VHH-P449 leverages the critical pathways driving stomach cancer, positioning this approach as a strategically attractive asset for novel combination immunotherapies that may enhance response rates and overcome resistance mechanisms.

Mechanism of Action

VHH-P449 exerts antitumor activity by simultaneously targeting CD274 and ERBB2, capitalizing on two distinct yet complementary mechanisms. Its anti-CD274 component disrupts immune checkpoint-mediated inhibition, fostering T cell–mediated tumor cell recognition and response. The anti-ERBB2 segment blocks receptor-mediated growth signals, exerting anti-proliferative effects and potentially enabling direct cell killing. This dual action is designed to both reinvigorate the immune microenvironment and shut down critical oncogenic pathways. As a nanobody-based bispecific molecule, VHH-P449 exemplifies the platform's versatility, offering avenues for further development into antibody-drug conjugates or multi-specific immunotherapies to address complex tumor biology and resistance patterns in stomach cancer.

Stomach Cancer

Stomach cancer is among the leading causes of cancer morbidity and mortality worldwide, particularly prevalent in regions such as East Asia and Eastern Europe. While early-stage cases may be curable with surgery, the majority present at an advanced stage requiring systemic therapy. Standard treatments include chemotherapy and a growing number of targeted and immunotherapies; however, survival rates remain modest due to disease heterogeneity and the rapid development of resistance. Current therapies are often limited by toxicity, incomplete response, and relapse, highlighting an urgent need for novel modalities. The overexpression of CD274 and ERBB2 in significant subsets of stomach cancer patients underscores the rationale for dual-targeted approaches. VHH-P449, by inhibiting both immune escape and oncogenic signaling reservoirs, represents a next-generation strategy with the potential to improve long-term outcomes, address resistance, and support combination regimens in gastric cancer therapy.