Over the last two decades, the realm of cancer treatment has witnessed revolutionary progress in targeted therapies, such as the development of anti-HER2 monoclonal antibody (mAbs) trastuzumab. However, soon after trastuzumab entered clinical practice, the occurrence of brain metastases has increased substantially. Each year in USA, > 200,000 patients, mainly with advanced lung cancer, breast cancer, and melanoma, are diagnosed with metastatic brain cancer, outnumbering the incidence of primary brain tumors by several-fold. The reason for this HER2 paradigm – improvement of systemic disease control on one hand and outbreak of brain metastases on the other, is that the central nervous system (CNS) is considered as a sanctuary site for metastatic tumor growth. In fact, many therapeutics highly effective outside of the CNS do not work well once the cancer spreads to brains. Particularly, the blood-brain barrier (BBB) stands as a major obstacle preventing drugs including mAbs and antibody-drug conjugates (ADCs) to efficiently accumulate at their pharmacological concentrations in brains. Built on our expertise in antibody engineering, this project aims to develop brain penetrating ADCs able to efficiently cross BBB and thus significantly improve treatment efficacy of brain metastases. Inspired by Nature, the key to our unique design is to achieve a unidirectional and sustained brain delivery of ADCs. Preliminary data strongly demonstrated the promises of our novel bispecific antibody design, and we plan to further develop, optimize, and evaluate ADCs for brain metastatic HER2+ breast cancer, as it has high risks to develop brain metastases in patients. Overall, millions of Americans suffer from brain metastases, but the effective treatment remains as an unmet and urgent medical need. This project, if successful, will collect key preliminary data and open the door to develop BBB penetrating ADCs with improved therapeutic efficacy and less side effects.