Tri-Specific Nanobody Therapeutic Targeting CD33 and FCGR3A for Innovative Cancer Immunotherapy

VHH-P575 is a humanized nanobody-based therapeutic currently in the Biological Testing stage, designed to target both CD33 molecule (CD33) and Fc gamma receptor IIIa (FCGR3A). This highly innovative program presents a promising new approach for cancer treatment by integrating three functional modules into a single agent: a camelid-derived single-domain antibody specific for human CD16, human interleukin-12, and a CD33-targeting single-chain variable fragment. Through precise engagement of both CD33 molecule (CD33) on malignant myeloid cells and FCGR3A on natural killer cells, VHH-P575 is strategically positioned to enhance anti-tumor immune responses and address critical unmet needs in the cancer field.

Licensing Opportunity

VHH-P575 is currently available for out-licensing and collaborative partnership opportunities. Organizations interested in innovative immuno-oncology assets are encouraged to discuss potential collaborations to accelerate the clinical translation and commercialization of this advanced tri-specific nanobody program.

Development Phase

Modality

VHH-P575 is a tri-specific killer cell engager constructed from a single-domain nanobody targeting human CD16, which is genetically fused to human interleukin-12 and a CD33-targeting scFv. The unique modular architecture leverages the favorable properties of nanobodies, including small molecular size, high stability, and strong tissue penetration. This enables effective recruitment of effector immune cells to the tumor microenvironment and efficient activation of anti-cancer pathways. The molecular design supports prolonged circulation and robust immune activation, making it a promising strategy for treating cancers that resist conventional therapies or possess immune-evasive phenotypes.

Target

CD33 and FCGR3A are critical molecular targets for cancer immunotherapy. CD33 is a myeloid cell surface receptor commonly expressed on malignant leukemia cells, especially in acute myeloid leukemia, while FCGR3A is a receptor primarily found on natural killer cells that regulates antibody-dependent cellular cytotoxicity. Both CD33 and FCGR3A play essential roles in the tumor microenvironment—CD33 as a marker of malignant myeloid populations, and FCGR3A as an activator of cytotoxic immune responses. Therapeutic engagement of both CD33 and FCGR3A provides a dual-pronged approach for selectively targeting tumor cells while concurrently stimulating anti-tumor immunity. VHH-P575’s dual-targeting of CD33 and FCGR3A addresses a pressing need in oncology by potentially increasing therapeutic specificity and efficacy through immune cell redirection.

Mechanism of Action

The mechanism of action of VHH-P575 involves simultaneous targeting of CD33 and FCGR3A to orchestrate a potent anti-cancer immune response. By binding CD33 on malignant myeloid cells and engaging FCGR3A on natural killer cells, VHH-P575 functions as a molecular bridge that brings effector immune cells into close proximity with tumor targets. The inclusion of interleukin-12 further amplifies immune cell activation, promoting robust cytotoxic activity. Through this NK-cell engagement strategy, VHH-P575 seeks to overcome cancer immune evasion. The nanobody platform’s flexible design also creates opportunities for future modalities—including bispecifics, multispecifics, and antibody-drug conjugates—enabling a modular pipeline for cancer immunotherapy development.

Cancer

Cancer remains a leading cause of morbidity and mortality worldwide, characterized by the uncontrolled growth and spread of abnormal cells. Epidemiologically, cancer encompasses a broad spectrum of malignancies involving various tissues and organs, with significant impact on healthcare systems globally. Current treatment modalities include surgery, radiation therapy, chemotherapy, immunotherapy, and targeted therapy. While these approaches have improved patient outcomes, many cancers still present challenges including drug resistance, toxicity, and insufficient specificity. Conventional therapies often lack the ability to precisely distinguish between malignant and normal cells, leading to adverse effects and incomplete disease eradication. There is an urgent need for innovative treatments that can engage the immune system with higher selectivity and potency. VHH-P575 holds significant potential to transform the standard of care by precisely targeting CD33 and FCGR3A, thus leveraging the body’s own immune surveillance mechanisms against cancer cells and addressing many of the unmet needs in current oncology practice.