A Next-Generation Bispecific Nanobody Targeting CD274 and VEGF for Melanoma Immunotherapy

VHH-P424 is an innovative bispecific humanized nanobody fusion construct directed against CD274 molecule (CD274) and vascular endothelial growth factors (VEGF). Currently in the Biological Testing phase, VHH-P424 is engineered for the potential treatment of melanoma by leveraging dual mechanisms of immune checkpoint inhibition and angiogenesis suppression. This construct combines high-affinity binding domains for CD274 and VEGF, aiming to address key pathophysiological pathways in melanoma progression. The advanced design and targeted approach position VHH-P424 as a promising new modality for enhancing therapeutic benefit in melanoma management.

Licensing Opportunity

VHH-P424 is available for out-licensing opportunities. We invite partners interested in collaborative development, commercialization, or co-development of this bispecific nanobody platform for melanoma and other oncology applications.

Development Phase

Modality

VHH-P424 utilizes a bispecific antibody fusion modality, featuring an affinity matured, humanized single domain nanobody against VEGF, fused via a flexible linker to the C-terminus of heavy chains from a humanized monoclonal antibody targeting CD274. Expressed in ExpiCHO cells, this design harnesses the unique properties of nanobodies, such as their small molecular size and increased tissue penetration. The fusion architecture supports robust stability and precise targeting, advantages particularly relevant in the challenging tumor microenvironment of melanoma. By simultaneously blocking key molecules with a compact, penetrant structure, VHH-P424 is optimized for dual pathway interference and enhanced anticancer efficacy.

Target

CD274 is an immune regulatory protein expressed on various tumor and immune cells, playing a central role in modulating immune responses through checkpoint pathways. VEGF is a growth factor crucial for angiogenesis and is commonly overexpressed in tumor cells to support neovascularization. In melanoma, CD274 enables tumor immune evasion, while VEGF promotes tumor vascularization and growth. Both CD274 and VEGF are widely expressed in melanoma lesions and associated with disease progression. By co-targeting CD274 and VEGF, VHH-P424 strategically disrupts both immune suppression and angiogenesis, underscoring its scientific and therapeutic value in addressing malignant melanoma. The dual-action approach is designed to tackle melanoma aggressiveness and resistance mechanisms.

Mechanism of Action

VHH-P424 exerts its antitumor effects through dual mechanisms: inhibition of angiogenesis and modulation of immune checkpoints. By binding to CD274, the construct blocks key inhibitory signals that limit antitumor immune activity, thereby restoring T cell function in the tumor environment. Simultaneously, specific engagement of VEGF by the nanobody domain hampers angiogenic signaling, curtailing tumor vascularization required for growth and metastasis. This multifaceted mechanism is reinforced by the nanobody platform, which enables further innovation such as antibody-drug conjugate (ADC) and advanced bispecific formats. VHH-P424 is thus designed to comprehensively interfere with melanoma’s survival strategies and stimulate a potent antitumor response.

Melanoma

Melanoma is an aggressive form of skin cancer originating in melanocytes, with rising global incidence and significant mortality if unresectable or metastatic. It is particularly prevalent among fair-skinned individuals and those with excessive ultraviolet exposure. Management options have evolved from conventional chemotherapies to targeted therapies and immune checkpoint inhibitors. Despite advances, challenges remain such as resistance to monotherapies, limited durable responses, and high rates of disease progression in advanced cases. Current approaches do not fully address the complexity of immune suppression and tumor angiogenesis in melanoma. VHH-P424 offers a novel strategy by targeting both CD274 and VEGF, potentially overcoming major treatment limitations and offering improved, multifactorial therapeutic benefit for patients with advanced melanoma.