Innovative Bispecific Nanobody Targeting CD40 and CD47 for Next-Generation Colorectal Cancer Therapy
VHH-P813 is a humanized bispecific tetravalent nanobody currently in the Biological Testing phase, designed to target CD40 molecule (CD40) and CD47 molecule (CD47) for the potential treatment of colorectal cancer. This advanced molecule combines blocking anti-CD47 single-domain antibodies with agonistic anti-CD40 VHHs within an optimized antibody framework. By leveraging both immune activation and checkpoint inhibition, VHH-P813 aims to reshape antitumor immunity in colorectal cancer. Its novel design holds promise for addressing key resistance mechanisms and enhancing the efficacy of existing therapeutic strategies. Ongoing preclinical evaluation supports its application across diverse colorectal cancer contexts.
| Candidate | VHH-P813 |
| Target | CD40 molecule (CD40) CD47 molecule (CD47) |
| Modality | humanized bispecific VHH |
| Indication | Colorectal Cancer |
Licensing Opportunity
VHH-P813 is currently available for partnering and out-licensing. Organizations interested in collaborative development or commercialization are invited to explore this distinctive opportunity within the next-generation immunotherapy landscape.
Contact UsDevelopment Phase
| Program | Research | Preclinical | Phase 1 |
|---|---|---|---|
| VHH-P813 |
Modality
VHH-P813 is based on an innovative modular architecture: a humanized, bispecific, tetravalent antibody platform. It features an inactivated human IgG1 Fc region fused to two anti-CD47 single-domain antibodies at the CH2 terminal and two agonistic anti-CD40 VHHs at the CH3 terminal. The use of nanobody (single-domain antibody) technology reduces molecular size, enhances tissue penetration, and confers high stability, which are critical advantages for targeting deeply embedded colorectal tumors. In addition, the tetravalent design increases binding valency and functional potency. The absence of effector function from the inactivated Fc domain further optimizes the safety profile for therapeutic applications in solid tumors like colorectal cancer.
Target
CD40 and CD47 are pivotal targets in cancer immunotherapy. CD40 is a co-stimulatory molecule predominantly expressed on antigen-presenting cells such as dendritic cells and B cells, playing an essential role in immune system activation. CD47, a transmembrane protein, is widely expressed on both normal and tumor cells, where it functions as a ‘don’t eat me’ signal by interacting with SIRPα on macrophages to inhibit phagocytosis. In colorectal cancer, upregulation of CD47 contributes to immune evasion, while modulation of CD40 enhances antigen presentation and T cell activation. Targeting both CD40 and CD47 with VHH-P813 enables dual modulation of tumor immunity: blockade of CD47 facilitates tumor cell clearance, and CD40 agonism promotes robust antitumor immune responses. The simultaneous engagement of CD40 and CD47 by VHH-P813 represents a strategically attractive approach for overcoming tumor immune escape mechanisms in colorectal cancer.
Mechanism of Action
VHH-P813 combines immune checkpoint inhibition and immunostimulatory signaling by simultaneously targeting CD47 and CD40. Its anti-CD47 moieties block the interaction between CD47 on tumor cells and SIRPα on macrophages, enhancing phagocytosis and promoting innate immune clearance of malignant cells. The agonistic anti-CD40 VHHs stimulate CD40-positive antigen-presenting cells, supporting dendritic cell activation, improved antigen presentation, and efficient T cell priming. Together, these mechanisms orchestrate an amplified antitumor response through both the innate and adaptive immune systems. The nanobody-based engineering platform also provides flexibility for further functionalization, such as constructing antibody-drug conjugates or creating additional bispecific formats for broader immunotherapeutic applications.
Colorectal Cancer
Colorectal cancer is among the most prevalent malignancies worldwide, representing a significant health burden across both developed and developing regions. The disease is typically categorized by its anatomical location and molecular characteristics, with risk factors including age, lifestyle, and genetic predisposition. Standard treatments encompass surgery, chemotherapy, radiotherapy, and more recently, targeted and immunotherapeutic approaches. While major advances have been made, prognosis for advanced or metastatic colorectal cancer remains challenging due to tumor heterogeneity, therapeutic resistance, and immune evasion. Existing therapies often fail to deliver durable responses, underscoring the need for innovative modalities. Bispecific nanobodies like VHH-P813, which simultaneously modulate immune activation (via CD40) and disrupt immune checkpoint barriers (via CD47), represent a promising solution to increase response rates, overcome resistance, and address substantial unmet needs in colorectal cancer therapy.