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Proof-of-Concept of a nanobody targeting Osteopontin to inhibit colorectal cancer development

Periodic Reporting for period 1 - POCON (Proof-of-Concept of a nanobody targeting Osteopontin to inhibit colorectal cancer development)

Reporting period: 2019-04-01 to 2021-03-31

The problem: CRC is a significant challenge to the healthcare system. An estimated ~210,000 EU citizens are yearly diagnosed with CRC and the disease accounts for ~10% of all cancers worldwide. This makes CRC the 3rd most common cancer and the 4th leading cause of cancer death. Overall 5-year survival of CRC is around 60%, with metastatic CRC (m CRC) having the lowest survival rate, even below 20%. For m CRC, chemotherapy is the cornerstone treatment, but acquired chemoresistance is common in patients and constitutes the main reason for treatment failure. Over the last 15 years, treatment options for CRC have been static, with the exception of immunotherapy which is successful but only suitable for a very small number of patients. Therefore, new treatment options are urgently needed.

The solution: molecular targeted therapies that interfere with specific molecules to block cancer pathways, are an attractive alternatives of cancer treatment next to chemotherapeutic agents that target dividing cells. Many molecular targeted therapies approved by EMA/FDA, demonstrated remarkable clinical success in the treatment of various cancer types including breast, leukemia, and ovarian cancers. However, identification of key targets is essential for a successful development of molecular targeted therapies in cancer. With OPN we identified such a key target with a role in clonogenicity and cancer stem cell functionality. Now, we aim to demonstrate the feasibility of an OPN-targeting therapy forCRC. Monoclonal antibodies (mabs) are commonly used targeting agents. However, the full potential of mab for cancer therapy is hampered by the size of mabs, as this limits access to the tumour tissue. But now there is an attractive minimal-sized alternative for mabs, the nanobody. Since their discovery, nanobodies have been used extensively in the fields of research and therapy. Nanobodies possess unusual hallmarks in terms of (small) size, stability, solubility and specificity, hence allowing cost-effective production. Interestingly, nanobodies do not interfere with the therapeutic effects of the host antibodies since nanobodies recognize epitopes which are not immunogenic to conventional antibodies.

This project: in this project we aimed to demonstrate feasibility of targeting OPN using a blocking nanobody to inhibit tumour growth in CRC. Tumour cell surface receptors found to bind to OPN will be targeted. This first set of nanobodies that we generated and studied failed to block OPN. Then, we set-up an OPN adhesion assay to functionally assess a selection of anti-OPN nanobodies for a second generated batch of nanobodies. Out of the 31 nanobodies that were able to recognize human OPN, 13 significantly inhibited the attachment of cells. Of the murine OPN recognizing nanobodies, 2 nanobodies significantly reduced the cell attachment to murine recombinant OPN. We now derived a set of anti-OPN nanobodies that can be used to selectively inhibit cellular interaction with either human or murine OPN. Follow-up studies need to further explore the potential of the generated nanobodies to inhibit tumour growth.