Innovative Bi-Specific Nanobody Targeting ROR1 and TNFRSF9 for Colorectal Cancer Therapy
VHH-P412 is an affinity matured, humanized nanobody currently advancing through Biological Testing, designed to target receptor tyrosine kinase like orphan receptor 1 (ROR1) and TNF receptor superfamily member 9 (TNFRSF9). As a multi-component antibody construct, VHH-P412 aims to provide a novel therapeutic approach for colorectal cancer, leveraging its humanized structure and optimized binding to two validated targets involved in malignant transformation and immune regulation. Its rationally engineered format addresses critical disease pathways, reflecting significant potential for the clinical management of colorectal cancer in future development.
| Candidate | VHH-P412 |
| Target | receptor tyrosine kinase like orphan receptor 1 (ROR1) TNF receptor superfamily member 9 (TNFRSF9) |
| Modality | humanized bispecific VHH |
| Indication | Colorectal Cancer |
Licensing Opportunity
VHH-P412 is now available for out-licensing and partnership opportunities. We welcome collaboration inquiries from biopharmaceutical companies seeking to expand their oncology pipelines with innovative, next-generation biologics for colorectal cancer.
Contact UsDevelopment Phase
| Program | Research | Preclinical | Phase 1 |
|---|---|---|---|
| VHH-P412 |
Modality
VHH-P412 utilizes an advanced nanobody-based modality, integrating a bi-paratopic and bi-specific architecture. This design includes a single-chain variable fragment and an antigen-binding fragment targeting two distinct epitopes of human receptor tyrosine kinase, fused to an IgG1 Fc domain for increased half-life and immune effector function. Additionally, it is fused via a flexible linker to a single-domain antibody specific for 4-1BB, facilitating T cell activation. The nanobody format confers unique benefits such as small molecular size, superior stability, deep tissue penetration, and high binding specificity—all critical for enhancing the therapeutic impact in colorectal cancer where solid tumor architecture requires efficient intratumoral delivery.
Target
ROR1 and TNFRSF9 are pivotal targets in colorectal cancer therapy. ROR1 is a transmembrane protein implicated in aberrant signal transduction in tumor cells and is preferentially expressed in malignant tissues with limited (not detected in the majority of adult normal tissues) normal expression, making it an attractive oncologic target. TNFRSF9, an immune costimulatory receptor, is mainly found on activated T cells and NK cells, and plays a crucial role in modulating anti-tumor immune responses. Targeting ROR1 with VHH-P412 may disrupt oncogenic signaling, while simultaneous engagement of TNFRSF9 can potentiate immune-mediated tumor clearance. The dual-targeting capability of VHH-P412 against ROR1 and TNFRSF9 addresses tumor cell survival and the tumor microenvironment, offering strategic value in colorectal cancer treatment and highlighting its potential for combination and multimodal immunotherapeutic strategies.
Mechanism of Action
VHH-P412 exerts its antitumor effect by selectively binding two independent epitopes of ROR1 and concurrently engaging TNFRSF9. By antagonizing ROR1, VHH-P412 can interfere with tumor-promoting signal transduction pathways critical for cancer cell proliferation and survival. Simultaneously, the engagement of TNFRSF9 on immune effector cells acts as a costimulatory signal, enhancing T cell activation and augmenting anti-tumor immune responses within the tumor microenvironment. The modular nanobody platform used for VHH-P412 supports adaptation for further biotherapeutic innovations, including the development of ADCs, bispecifics, or additional immune cell engagers, thus expanding its translational potential for next-generation cancer therapy.
Colorectal Cancer
Colorectal cancer is among the most prevalent malignancies worldwide, with high morbidity and mortality rates. It ranks among the top diagnosed cancers in both men and women and is a leading cause of cancer-related deaths globally. Standard of care typically involves surgical resection, chemotherapy, radiotherapy, and targeted biological agents. However, these approaches may be limited by resistance, toxicity, and insufficient long-term efficacy in advanced settings. Unmet medical needs include improved efficacy in metastatic disease, overcoming immune escape, and reducing treatment-associated adverse effects. VHH-P412, with its dual targeting of ROR1 and TNFRSF9, offers a promising avenue to address these gaps by both directly impeding tumor cell viability and potentiating immune responses, thus representing a potential new strategy for refractory colorectal cancer.