Unlocking New Possibilities in Breast Cancer Therapy with Bispecific Nanobody Targeting AXL and CD274

VHH-P828 is a humanized bispecific nanobody construct specifically engineered to target AXL receptor tyrosine kinase (AXL) and CD274 molecule (CD274), two pivotal molecules implicated in tumor progression and immune evasion. Currently in the Biological Testing development stage, VHH-P828 offers a novel approach for the treatment of breast cancer. By simultaneously addressing both AXL and CD274, this agent aims to overcome key resistance mechanisms, setting the stage for next-generation immunotherapy strategies. Its unique design and mechanism position VHH-P828 as a promising investigational molecule in the fight against breast cancer.

Licensing Opportunity

VHH-P828 is available for out-licensing and collaborative development opportunities. Partners seeking innovative and differentiated therapies for breast cancer are welcome to engage in discussions for global or regional rights.

Development Phase

Modality

VHH-P828 is a humanized bispecific, tetravalent, biparatopic antibody fusion construct, incorporating single-domain antibody fragments (VHH) derived from llama sources and engineered to bind both CD274 and AXL. The nanobody format provides notable structural advantages, including small molecular size, increased stability, and superior tumor penetration compared to conventional antibodies. The molecule is assembled by fusing a humanized VHH targeting CD274 to an IgG1 Fc domain, with an additional humanized VHH against AXL attached in tandem. Its expression in human embryonic kidney 293 cells ensures human-compatible glycosylation patterns, enhancing its therapeutic potential. This structural versatility offers pronounced benefits for breast cancer therapy by enabling enhanced blocking of immune checkpoints and tumor signaling pathways within the tumor microenvironment.

Target

AXL and CD274 are critical molecular targets in breast cancer. AXL is a type of receptor tyrosine kinase extensively involved in cellular processes such as survival, proliferation, and metastasis. CD274 is an immune checkpoint modulator, predominantly expressed on tumor cells and infiltrating immune cells, facilitating tumor immune evasion. In breast cancer, overexpression of both AXL and CD274 has been associated with aggressive tumor behavior, therapy resistance, and poor prognosis. VHH-P828’s dual targeting of AXL and CD274 leverages their significance as drivers of malignancy: blocking AXL disrupts tumor cell signaling and metastatic potential, while inhibiting CD274 restores anti-tumor immune responses. This strategic dual targeting heightens the therapeutic value and differentiation of VHH-P828 in the competitive landscape of breast cancer therapeutics.

Mechanism of Action

VHH-P828 functions by simultaneously binding and inhibiting AXL and CD274. Targeting AXL with a nanobody impedes key pathways that promote tumor cell survival, invasion, and metastasis. In parallel, blockade of CD274 interrupts interactions with immune checkpoint receptors, thereby facilitating the activation and proliferation of cytotoxic T cells against tumor cells. The bispecific, tetravalent structure of VHH-P828 allows effective engagement of both targets without compromising binding selectivity or affinity. Further, the nanobody platform employed in VHH-P828 offers a versatile basis for future extensions, such as antibody-drug conjugates or combination immunotherapies, enhancing its applicability in precision oncology settings.

Breast Cancer

Breast cancer is among the most prevalent and life-threatening malignancies affecting women worldwide, representing a significant proportion of global cancer incidence. Disease subtypes vary by genetic and molecular markers, leading to heterogeneity in progression, prognosis, and therapeutic response. Standard treatment approaches include surgery, chemotherapy, radiation, endocrine therapy, and targeted agents. However, many patients eventually develop resistance or relapse, underscoring persistent unmet medical needs—especially in aggressive and refractory subtypes. Immunomodulatory approaches, including immune checkpoint inhibition, have begun to transform the treatment landscape, yet durable responses remain limited in a large subset of patients. VHH-P828, by targeting both AXL and CD274 pathways, presents a potentially transformative approach to breast cancer therapy, aiming to address tumor cell-intrinsic resistance mechanisms and enhance anti-tumor immune activity. Its bispecific design aligns with growing demands for multi-targeted precision therapies in this challenging indication.