LGR5 antibody drug conjugate for the treatment of neuroblastoma

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Neuroblastoma (NB) is a cancer of the nervous system outside the brain that occurs in children under 15 years of age. It is the most frequently diagnosed cancer during infancy, accounting for ~12% of all-cancer related death in children. It is considered a rare cancer since its overall incidence is significantly less than 6 per 100,000 people in the U.S. Approximately half of NB cases are cured with minimal and sometimes no chemotherapy while the other half are high-risk patients who only have a long-term survival of ~50% despite intensive multimodal treatment that is quite toxic. Antibody–drug conjugates (ADCs) are monoclonal antibodies (mAbs) that are covalently linked to cell-killing cytotoxins to deliver the payloads into cancers cells. Multiple ADCs have now been approved by FDA for cancer treatment, including leukemia, breast cancer, and bladder cancer. LGR5 (leucine-rich repeat containing, G protein-coupled receptor 5) is a membrane receptor that is associated with formation and metastasis of cancers in the gastrointestinal system. Therapeutic agents targeting LGR5 and its associated pathway are being developed for gastrointestinal cancers driven by this mechanism. Remarkably, high levels of LGR5 are found in NB tumor cells, and more LGR5 expression is correlated with poor survival. However, whether LGR5 can also be targeted for the treatment of high-risk NBs remains unknown. We have found that ablation of LGR5 from NB cancer cells led to drastic decrease in cancer cell growth in cell cultures and tumor formation in animals. We also generated an ADC using an anti-LGR5 antibody and found that the LGR5 ADC is highly effectively in killing NB cancer cells with high level of LGR5. The goals of this project are to validate LGR5 as a potential target for the treatment of high-risk NBs using the ADC approach and further improve the potency and efficacy of LGR5 ADC. We will generate a series of ADCs with different payloads and determine their activities in blocking tumor growth in animal models. The project, if successful, may lead to the validation of a new approach for the discovery and development of treatments of high-risk NBs and drug candidates for further development.