Next-Generation Bispecific Nanobody Targeting CD47 and CTLA4 for Innovative Cancer Immunotherapy

VHH-P672 is a novel humanized nanobody therapeutic candidate specifically engineered to target both CD47 molecule (CD47) and cytotoxic T-lymphocyte associated protein 4 (CTLA4). Designed as a bispecific monoclonal antibody, VHH-P672 is currently at the Biological Testing stage of development, showcasing its potential as an advanced therapeutic approach for cancer. By simultaneously engaging two well-validated immune checkpoint molecules, CD47 and CTLA4, VHH-P672 aims to enhance antitumor immune responses, offering a promising addition to current immuno-oncology strategies.

Licensing Opportunity

VHH-P672 is available for out-licensing opportunities. We welcome collaborations with industry partners and research organizations interested in the development and commercialization of this promising bispecific nanobody immunotherapy for cancer.

Development Phase

Modality

VHH-P672 is a bispecific monoclonal antibody constructed with two distinct polypeptide chains. The first chain features a highly stable single-domain antibody targeting CTLA4, fused to the C-terminus of an anti-CD47 heavy chain through a flexible G15-linker. The second chain comprises the anti-CD47 light chain. Expressed in Chinese hamster ovary cells, this format incorporates nanobody elements, conferring excellent tissue penetration, small molecular size, and favorable pharmacokinetics. The nanobody structure of VHH-P672 contributes to its enhanced tumor accessibility and robust stability, addressing challenges often seen with larger, conventional antibodies. These characteristics offer significant therapeutic advantages in cancer treatment, such as improved tumor infiltration and reduced immunogenicity.

Target

CD47 and CTLA4 are critical immune checkpoint molecules playing pivotal roles in immune regulation, particularly in cancer. CD47 is a transmembrane protein broadly expressed on various cell types, including tumor cells, where it transmits a "don't eat me" signal to macrophages, thereby enabling immune evasion. CTLA4 is an inhibitory receptor expressed primarily on activated T cells and regulatory T cells, negatively regulating T-cell activation. The overexpression of CD47 and CTLA4 has been closely linked with immune suppression in the tumor microenvironment, contributing to cancer progression and resistance to immune therapies. Simultaneous targeting of CD47 and CTLA4 with VHH-P672 offers strategic value by disrupting multiple immunosuppressive pathways, potentially maximizing antitumor immune responses and providing a compelling therapeutic strategy in oncology.

Mechanism of Action

VHH-P672 functions through dual checkpoint inhibition by binding to both CD47 and CTLA4 on immune and tumor cells. By targeting CD47, VHH-P672 blocks the interaction with SIRPα on macrophages, promoting the phagocytosis of tumor cells and enhancing the innate immune response. Concurrently, blockade of CTLA4 prevents negative signaling in T cells, leading to increased T cell activation and proliferation. This synergistic mechanism not only disrupts tumor-associated macrophage-mediated immune escape but also stimulates adaptive immunity to combat cancer cells more effectively. The nanobody-based bispecific format of VHH-P672 exemplifies the next generation in immune checkpoint modulators, with potential for further platform extensions such as the development of antibody-drug conjugates or multi-specific modalities.

Cancer

Cancer remains one of the most significant public health challenges globally, with a continually growing incidence across all demographics. It encompasses a spectrum of malignant diseases characterized by uncontrolled cell growth and the ability to metastasize to distant organs. Common treatment modalities include surgery, chemotherapy, radiotherapy, targeted therapies, and more recently, immune checkpoint blockade. Despite advances in these areas, many patients experience limited efficacy, drug resistance, and adverse effects. Current immunotherapies have shown promise but are often hampered by compensatory immune escape mechanisms and incomplete response rates. There remains a substantial unmet need for innovative therapies capable of overcoming tumor immune evasion and improving patient outcomes. VHH-P672, through its dual targeting of CD47 and CTLA4, is poised to deliver enhanced immune activation and tumor clearance, representing a potentially transformative advancement in cancer immunotherapy.