Next-Generation Bispecific Nanobody Targeting CD47 and TIGIT for Cancer Immunotherapy

VHH-P675 is an innovative, fully humanized nanobody-based antibody currently in the Biological Testing stage, designed to target both the CD47 molecule (CD47) and T cell immunoreceptor with Ig and ITIM domains (TIGIT). By simultaneously engaging these two key immune checkpoint regulators, VHH-P675 is positioned as a promising candidate for the treatment of cancer. This technology leverages dual binding specificities to modulate both the innate and adaptive immune response, providing a novel approach for cancer immunotherapy that addresses multi-faceted aspects of tumor immune evasion.

Licensing Opportunity

VHH-P675 is currently open for out-licensing opportunities. Collaboration and partnership proposals are welcome to advance this innovative bispecific nanobody for cancer immunotherapy.

Development Phase

Modality

VHH-P675 utilizes a bispecific IgG4 antibody modality, combining a monoclonal antibody targeting CD47 with a single-domain antibody (nanobody) fused at the N-terminal of the heavy chain to recognize TIGIT, linked via a flexible G9 linker and expressed in Chinese hamster ovary cells. The nanobody component confers advantages of small molecular size, high tissue penetration, and desirable stability, enhancing the agent’s ability to access solid tumor microenvironments. This structural configuration allows simultaneous blockade of two immune checkpoints, potentially resulting in improved anti-tumor efficacy and minimized immune escape critical for cancer therapy.

Target

CD47 and TIGIT are both important immunomodulatory proteins. CD47 is a transmembrane protein broadly expressed on hematopoietic and many tumor cells, functioning as a 'don’t eat me' signal to inhibit phagocytosis by macrophages. TIGIT is an inhibitory receptor found predominantly on T cells and natural killer (NK) cells involved in dampening immune responses. Both CD47 and TIGIT are overexpressed or dysregulated in various cancers, contributing to immune evasion and tumor progression. By co-targeting CD47 and TIGIT, VHH-P675 can enhance anti-tumor immunity through dual modulation of both innate and adaptive responses, offering strategic advantages by disrupting tumor-associated immune suppression and potentially overcoming resistance to single-target immunotherapies.

Mechanism of Action

VHH-P675 acts by binding to CD47, thereby disrupting the interaction between CD47 and SIRPα on macrophages, relieving the phagocytosis inhibition and reactivating tumor-associated macrophages (TAMs) for tumor cell clearance. Simultaneously, its targeting of TIGIT on T cells blocks inhibitory signaling, thereby promoting T cell activation and enhancing adaptive immune responses against cancer cells. Through this dual mechanism, VHH-P675 is positioned as an immune checkpoint inhibitor with the potential to synergistically stimulate both macrophage and lymphocyte-mediated anti-tumor activity. The nanobody-based bispecific platform also provides opportunities for future adaptation into bispecific formats, antibody–drug conjugates, or other multi-modal immunotherapeutic strategies.

Cancer

Cancer comprises a diverse group of diseases characterized by uncontrolled cellular growth and the ability to invade or spread to distant tissues. As one of the leading causes of morbidity and mortality worldwide, cancer encompasses numerous types affecting nearly all organs. Current treatment regimens include surgery, chemotherapy, radiation therapy, immunotherapy, and targeted therapies. While advancements in these modalities have improved outcomes, significant challenges persist, such as therapy resistance, tumor relapse, adverse side effects, and the development of immune evasion mechanisms by tumors. Immune checkpoint inhibition has emerged as a promising avenue yet is frequently limited by partial responsiveness and acquired resistance. There remains a substantial unmet clinical need for more effective, durable, and broadly applicable cancer therapies. VHH-P675, with its unique dual targeting of CD47 and TIGIT, addresses these gaps by leveraging mechanisms that engage both innate and adaptive immunity, providing potential for improved clinical benefit in diverse cancer populations.