Innovative Bispecific Nanobody Immunotherapy Targeting CD274 and LAG3 for Cancer Treatment

VHH-P540 is a novel humanized bispecific nanobody-based therapeutic candidate in biological testing, designed to target CD274 molecule (CD274) and lymphocyte activating 3 (LAG3). By simultaneously engaging these two immune checkpoint proteins, VHH-P540 aims to modulate tumor immune evasion pathways and restore anti-tumor immunity in cancer. The bispecific fusion format, consisting of a monoclonal IgG1 antibody against LAG3 fused with an anti-CD274 humanized nanobody via a flexible linker and expressed in HEK293 cells, ensures high specificity and potential therapeutic versatility for cancer indications. This modular and humanized approach positions VHH-P540 as a promising avenue for next-generation immunotherapy development.

Licensing Opportunity

VHH-P540 is available for out-licensing and strategic collaborations. Partners interested in advancing innovative bispecific nanobody immunotherapies for cancer are encouraged to inquire about partnership opportunities.

Development Phase

Modality

VHH-P540 utilizes a bispecific antibody modality in which a humanized monoclonal IgG1 targeting LAG3 is fused at its C-terminus to a humanized nanobody specific for CD274 via a flexible GGGGSPGGGSPGGGS linker. Expressed in HEK293 cells, this configuration combines the structural benefits of IgG1—such as immune effector engagement and stability—with the unique properties of the nanobody domain, including small molecular size, enhanced tissue penetration, and robust stability. The nanobody’s single-domain architecture provides improved access to tumor microenvironments and difficult-to-reach epitopes, offering strategic advantages in treating cancer by potentially maximizing immune checkpoint blockade at the tumor site.

Target

CD274 and LAG3 are critical immune checkpoint regulators. CD274, a membrane-bound ligand often expressed on tumor cells and antigen-presenting cells, inhibits T cell function by engaging with its receptor, thereby enabling tumor immune escape. LAG3 is an inhibitory receptor predominantly found on activated T cells and regulatory T cells, contributing to T cell exhaustion and suppression of anti-tumor activity. Both CD274 and LAG3 are upregulated in various cancer types, playing pivotal roles in modulating anti-tumor immunity. Targeting both CD274 and LAG3 with VHH-P540 leverages the complementary mechanisms of these checkpoints, providing a strategic therapeutic approach that may overcome resistance associated with monotherapies. The dual targeting of CD274 and LAG3 exemplifies innovative immunotherapy strategies aiming to reinvigorate immune responses against cancer.

Mechanism of Action

VHH-P540 mediates its anti-cancer effects by simultaneously blocking immune checkpoints CD274 and LAG3, both of which are central to tumor immune evasion. The IgG1 antibody portion binds LAG3 on T cells, preventing its inhibitory signal and promoting T cell activation. Meanwhile, the nanobody domain targets CD274, disrupting its interaction with immune cell receptors and further removing immunosuppressive barriers within the tumor microenvironment. This dual blockade synergistically restores and enhances anti-tumor immunity. The nanobody platform underlying VHH-P540 also paves the way for further therapeutic innovations, including the development of bispecific constructs and antibody-drug conjugates, broadening its applicability in oncological indications.

Cancer

Cancer encompasses a diverse group of diseases characterized by uncontrolled cell growth and potential for metastasis. Globally, cancer remains one of the leading causes of morbidity and mortality, affecting millions of individuals each year. Standard therapeutic approaches include surgery, radiotherapy, chemotherapy, immunotherapy, and molecularly targeted agents. Despite these advances, many cancers remain difficult to treat due to factors such as tumor heterogeneity, resistance development, limited efficacy, and adverse side effects. Immune checkpoint inhibitors have transformed cancer treatment, yet responses are often variable and not durable for all patients. By targeting both CD274 and LAG3, VHH-P540 addresses key mechanisms of immune suppression in the tumor microenvironment, representing a promising strategy to enhance and sustain immune-mediated tumor regression, and to fill unmet clinical needs in oncology.