Antibody-Drug Conjugates to Treat Triple Negative Breast Cancers
Dr. Margaret Liu
Triple negative breast cancer (TNBC) is characterized by rapid growth, metastasis, and high recurrence. The severe adverse effects and drug resistance associated with standard cytotoxic chemotherapies minimize their clinical benefits. The anti-epidermal growth factor receptor (EGFR) monoclonal antibody had been developed and tested to treat TNBC, but no significant efficiency was demonstrated in clinical trials. The goal of this study was to develop novel antibody-drug conjugates (ADCs) to treat TNBC. Specifically, multiple surface receptors overexpressed in TNBC and the specific targeting of their antibodies were evaluated. We established a platform to conjugate mAbs with multiple small molecules, and also improved the conjugation efficiency by optimizing the linker and drug-to-antibody ratio. The generated ADCs can specifically bind to multiple TNBC subtypes, be effectively internalized, and release potent drug intracellularly. The IC50 study showed that two ADCs killed >90% TNBC cells with dose of 5-10 nM. The TNBC xenograft mouse model also showed that the constructed ADCs had high anticancer efficacy and successfully inhibited tumor growth. Moreover, the live-animal imaging using In Vivo Imaging System and the tissue microarray samples with immunohistochemical analysis of TNBC and organs indicated that our ADC specifically target TNBC in vivo.
Finally, the maximal tolerated dose, pharmacokinetics, and biodistribution data were collected. To summarize, we developed a TNBC targeted therapy, which could provide an effective targeted therapy to treat TNBC and improve the life quality and survival rate of patients.
Dr. Margaret Liu is an Associate Professor in the Department of Biomedical Engineering at The University of Alabama at Birmingham (UAB). Dr. Liu’s research group has established several projects to develop novel targeted therapies and drug delivery vehicles (5 provisional patents filed). 1) Several surface receptors in TNBC, NET and malignant meningioma were identified and fully evaluated. The glycosylated immunogen was designed to develop monoclonal antibody using hybridoma technology. High-productivity, high-quality and high-affinity mAbs were screened and characterized in vitro and in vivo in cell line xenograft animal model and patient tissue derived xenograft model. The cancer specific targeting, biodistribution and possible immune responses were evaluated. 2) The antibody-drug conjugates (ADCs) platform was established to targeting deliver multiple highly potent small molecule drugs. 3) Two targeted mitochondrial gene therapies were developed and validated in animal models, which completely eliminated cancers in vivo. 4) Surface tagging technology and scalable biomanufacturing platform were developed to deliver cytotoxic drugs, siRNA and AAV to treat heart diseases and cancers via exosome.
Dr. Liu had worked in Biopharmaceutical and Biotechnology industries for seven years before joining academia research. She accomplished her Ph.D. research in the Department of Chemical and Biomolecular at The Ohio State University in 2005.