Innovative Bispecific Nanobody Targeting CD274 and SIRPA for Colorectal Cancer Immunotherapy

VHH-P361 is a next-generation humanized nanobody therapeutic targeting both CD274 molecule (CD274) and signal regulatory protein alpha (SIRPA), currently in the Biological Testing development stage. Designed to address critical immunosuppressive pathways, VHH-P361 has the potential to offer novel treatment options for colorectal cancer. As a bispecific antibody fusion format, it simultaneously targets these key immune checkpoints, making it an exciting asset in the pipeline of immuno-oncology therapeutics. The interplay between CD274 molecule (CD274) and signal regulatory protein alpha (SIRPA) highlights VHH-P361’s scientific rationale and potential to meet significant clinical needs in colorectal cancer.

Licensing Opportunity

VHH-P361 is available for out-licensing opportunities. Partners interested in collaborating on further development or commercialization of this innovative colorectal cancer immunotherapy are encouraged to contact us for detailed discussions.

Development Phase

Modality

VHH-P361 features a bispecific antibody fusion architecture consisting of a single-domain nanobody directed at the programmed death-ligand 1 (extracellular domain), fused to the N-terminus of a human IgG1 Fc region, with an additional antibody-derived fragment targeting signal regulatory protein alpha at the C-terminus, linked via a flexible (G4S)4 sequence. Expressed in CHO-K1 cells, the nanobody's small size and single-domain structure facilitate enhanced tissue penetration and stability, potentially overcoming tumor microenvironment barriers in colorectal cancer. The modular, bispecific format also enables dual checkpoint targeting in one molecule, increasing immune activation opportunities and catering to diverse patient profiles.

Target

CD274 is an immune checkpoint molecule broadly expressed on tumor and immune cells, acting as a negative regulator of T-cell activation. SIRPA, a regulatory receptor found predominantly on myeloid cells, serves a critical inhibitory role in 'do not eat me' signaling by interacting with its ligand, often leading to immune evasion by tumor cells. In colorectal cancer, overexpression of CD274 and SIRPA contributes to an immunosuppressive microenvironment, allowing tumor cells to escape immune surveillance. VHH-P361’s bispecific nature, capable of concurrently targeting CD274 and SIRPA, provides strategic therapeutic leverage by disrupting multiple immune evasion pathways. This dual approach is highly attractive scientifically and commercially, positioning VHH-P361 as a valuable asset in the competitive field of oncology therapeutics.

Mechanism of Action

VHH-P361 is designed as an immune checkpoint inhibitor with dual specificity for CD274 and SIRPA. By binding to CD274, VHH-P361 blocks the interaction of this checkpoint molecule with T cells, thereby reinvigorating T-cell-mediated antitumor activity. Simultaneously, its engagement with SIRPA interferes with inhibitory signaling on myeloid cells, promoting macrophage-mediated phagocytosis of tumor cells and further relieving immunosuppression within the tumor microenvironment. The nanobody platform’s flexibility also supports the generation of advanced therapeutic formats, such as antibody-drug conjugates and additional bi- or multi-specific constructs, broadening potential applications within immuno-oncology.

Colorectal Cancer

Colorectal cancer is a major global health challenge and one of the most prevalent forms of cancer, especially in developed regions. It is characterized by malignant transformation of epithelial cells lining the colon or rectum. Standard clinical approaches include surgical intervention, chemotherapy, radiation, and more recently, targeted therapies and immunotherapies. However, significant limitations persist, such as treatment resistance, recurrence, and adverse effects from existing regimens. Current immunotherapies targeting immune checkpoints offer meaningful benefits, yet a substantial proportion of patients do not respond or develop acquired resistance. Thus, a need exists for novel therapeutics that can more effectively modulate the tumor immune microenvironment. VHH-P361, with its bispecific mechanism targeting both CD274 and SIRPA, addresses these unmet needs by offering a potentially superior method to overcome immune escape and improve patient outcomes in colorectal cancer.