Next-Generation Bispecific Nanobody Targeting CD274 and CTLA4 for Colon Cancer Immunotherapy

VHH-P738 is an innovative, humanized nanobody program designed to target two critical immune checkpoints: CD274 molecule (CD274) and cytotoxic T-lymphocyte associated protein 4 (CTLA4). Leveraging a unique bispecific antibody structure, this molecule is currently in the Biological Testing development stage. VHH-P738 aims to address unmet therapeutic needs in colon cancer by modulating key pathways that allow tumors to evade immune surveillance. Through selective dual engagement of CD274 molecule (CD274) and cytotoxic T-lymphocyte associated protein 4 (CTLA4), VHH-P738 offers a promising strategy for enhancing anti-tumor immune responses in the clinical management of colon cancer.

Licensing Opportunity

VHH-P738 is available for out-licensing and partnership opportunities. We welcome collaborations with biopharmaceutical firms interested in advancing next-generation immuno-oncology therapeutics targeting CD274 and CTLA4.

Development Phase

Modality

VHH-P738 is a bispecific antibody construct, comprising a humanized non-glucosylated IgG1 backbone that targets PD-L1, fused at the N-terminus of the heavy chain to a pair of humanized single-domain nanobodies directed against CTLA4 through a mutated human IgG1 hinge. Produced in CHO-3E7 cells, this modular architecture offers high stability, small molecular size, and improved tissue penetration compared to conventional antibodies. The nanobody components enable superior access to tumor microenvironments, while the bispecific design allows simultaneous blockade of two immune suppression pathways within the colon cancer setting. This advanced modality is anticipated to maximize immune activation with enhanced safety and pharmacokinetic profiles.

Target

CD274 and CTLA4 are pivotal immune checkpoint molecules that regulate T cell activity. Both CD274 and CTLA4 are immunomodulatory proteins; CD274 is commonly expressed on tumor and antigen-presenting cells, acting to inhibit T cell activation, while CTLA4 is predominantly found on regulatory and activated T cells and functions to dampen immune responses. In colon cancer, overexpression of CD274 and CTLA4 facilitates immune escape by tumor cells. Bispecific antibodies like VHH-P738 that target CD274 and CTLA4 have strategic value, as simultaneous inhibition disrupts these immunosuppressive signals, potentially enhancing anti-tumor immunity and improving patient outcomes. Targeting both CD274 and CTLA4 is supported by robust preclinical evidence for effective immune checkpoint blockade in diverse cancer contexts.

Mechanism of Action

VHH-P738 acts as a dual immune checkpoint inhibitor, binding specifically to CD274 and CTLA4. By engaging CD274, it prevents its interaction with PD-1 on T cells, thereby restoring T cell activation and anti-tumor function. Concurrently, VHH-P738 binds CTLA4 on T cells, blocking this negative regulator and further enhancing immune responses against tumor cells. This mechanism positions VHH-P738 to surmount tumor immune evasion in colon cancer. The nanobody-based bispecific platform also offers opportunities to generate related molecules tailored for additional mechanisms of action, including antibody-drug conjugates and other multispecific formats, broadening future therapeutic impact.

Colon Cancer

Colon cancer is among the most prevalent malignancies worldwide and a major cause of cancer-related morbidity and mortality. Patients often present with advanced or metastatic disease, with disease burden influenced by genetic, environmental, and lifestyle factors. Standard therapies include surgery, chemotherapy, radiation, and targeted biological agents, though recurrence and resistance remain significant issues. Immunotherapy has emerged as a transformative approach, particularly for patients with molecular profiles predictive of response. Despite advances, a substantial unmet need persists for more effective and safer treatments. Bispecific nanobodies such as VHH-P738 offer promising potential by simultaneously targeting dual immune checkpoints implicated in tumor immune evasion, providing a novel therapeutic approach for improving clinical outcomes in colon cancer.