Innovative Bi-Functional Nanobody Targeting CD274 and TGF-β Pathways for Cancer Therapy

VHH-P653 is a highly specialized, fully human bi-functional nanobody designed to target both CD274 molecule (CD274) and transforming growth factor beta (TGF-β). Currently in the Biological Testing stage, this therapeutic candidate combines a single domain antibody against CD274 with an IgG Fc domain and the extracellular domain of human TGF-β receptor 2, creating a versatile platform for cancer intervention. VHH-P653 leverages the unique immune-modulating and tumor-microenvironmental regulatory roles of CD274 molecule (CD274) and transforming growth factor beta (TGF-β), offering a promising new approach to cancer therapy.

Licensing Opportunity

VHH-P653 is currently available for out-licensing and collaborative development opportunities. Partners interested in advancing this innovative cancer immunotherapy asset are welcome to initiate discussions to explore strategic collaboration and commercialization.

Development Phase

Modality

VHH-P653 is a bi-functional fusion protein consisting of a single domain nanobody targeting human programmed cell death ligand 1, fused via a (G4S)4 linker to an IgG Fc domain and the extracellular portion of TGF-β receptor 2. The nanobody structure of VHH-P653 confers several key advantages: small molecular size, enhanced tissue penetration, and robust thermal and chemical stability. The modular design enables simultaneous blockade of immune checkpoints and neutralization of TGF-β–driven immunosuppressive signaling within the tumor microenvironment. These attributes position VHH-P653 as a versatile and innovative modality in the treatment of cancer, ideally suited for overcoming resistance and achieving sustained antitumor responses.

Target

CD274 and TGF-β are immune regulatory molecules critically involved in the pathogenesis and progression of cancer. CD274, also recognized as PD-L1, is a transmembrane protein frequently upregulated on tumor cells and tumor-infiltrating immune cells, facilitating immune evasion. TGF-β is a multifunctional cytokine abundantly found in the tumor microenvironment, where it modulates immune cell function and supports tumor growth, invasion, and metastasis. Both CD274 and TGF-β are strongly implicated in mechanisms of resistance to standard therapies and immune checkpoint inhibitors. By targeting CD274 and TGF-β, VHH-P653 offers dual inhibition of key immunosuppressive pathways. The strategic value of dual targeting CD274 and TGF-β resides in its potential to amplify antitumor immune responses and alter the malignant microenvironment, making it a compelling asset for cancer therapy development.

Mechanism of Action

VHH-P653 exerts its therapeutic activity through dual inhibition of immune-suppressive pathways by binding to CD274 and TGF-β. By blocking CD274, VHH-P653 functions as an immune checkpoint inhibitor, preventing the interaction between tumor-expressed CD274 and PD-1 on immune cells, thereby restoring T-cell activation and promoting antitumor immunity. Simultaneously, the nanobody neutralizes TGF-β by sequestering this cytokine via the extracellular domain of its receptor, counteracting TGF-β–driven immune evasion and fibrosis within tumors. This integrated mechanism enables a multifaceted approach to cancer therapy, disrupting the tumor's ability to suppress immune surveillance. The nanobody platform of VHH-P653 also paves the way for future innovation, including conjugation with cytotoxic payloads or the development of multi-valent constructs for broader oncologic applications.

Cancer

Cancer encompasses a group of malignant diseases characterized by uncontrolled cell growth and the capacity to invade or spread to other parts of the body. It remains a leading cause of morbidity and mortality worldwide, impacting millions of lives annually. Current mainstream treatment options include surgery, chemotherapy, radiotherapy, immunotherapy, and targeted therapies, each with distinct mechanisms and indications. However, limitations such as treatment resistance, relapse, adverse effects, and limited efficacy in certain subtypes present significant challenges. In particular, the immunosuppressive nature of the tumor microenvironment and adaptive resistance mechanisms often diminish the success of existing therapies. The dual targeting strategy embodied by VHH-P653 aims to address these unmet needs by combining immune checkpoint blockade with modulation of the TGF-β pathway. This approach holds promise for enhancing treatment efficacy, overcoming resistance, and improving clinical outcomes for diverse cancer patients.