7月20日“绿色制药前沿论坛”第十五讲预告

　　题目：Antibacterial Drug Discovery: deimmunizing a big antibiotic as a green treatment against MRSA infections（抗菌药物的研发：以降低免疫原性的“大”抗生素作为针对多重耐药葡萄球菌感染的绿色疗法）
　　主讲人：Prof. Karl Griswold （美国常春藤盟校达特茅斯学院赛亚工学院）
　　时间：7月20日 10：00
　　地点：协同创新大楼1006会议室
    
　　讲座内容简介：Multidrug-resistant Staphylococcus aureus (MRSA) is a deadly pathogen that is responsible for nearly half of all US deaths associated with drug-resistant bacteria. Given the weak pipeline of antibiotics under development, there is a critical need for new therapeutic options to combat this threat to public health. Lysostaphin is an antibacterial enzyme with extraordinary potency against MRSA both in vitro and in vivo. Since it can be fully degraded in nature, lysostaphin will not contribute to the spread of antibiotic resistance through bioaccumulation effects. Despite its promising therapeutic properties, lysostaphin has been found to be highly immunogenic in animals, including human subjects. These undesirable immune reactions run the risk of undermining the enzyme’s efficacy and even threatening patients’ safety. To conquer this barrier, Prof. Karl Griswold and his co-workers at Dartmouth College (Hanover, NH) designed and developed deimmunizedlysostaphin variants that retain the wild type enzyme’s anti-MRSA potency. By utilizing an iterative directed evolution strategy, they have isolated a highly engineered variant that exhibits significantly reduced anti-drug antibody responses following administration to transgenic mice bearing the human DRB1*0401 MHC II allele. They have shown that wild-type lysostaphin rescues humanized mice from the first infection with a MRSA clinical isolate, but it fails to treat subsequent recurrent infections that are coincident with escalating anti-drug antibody titers. In contrast, the deimmunizedlysostaphin variant successfully rescued mice from as many as three recurrent MRSA challenges. This work provides the first controlled demonstration that depletion of T cell epitopes from a biotherapeutic agent results in enhanced efficacy in an immunocompetent disease model. Moreover, their broadly applicable protein design and deimmunizaiton tools may also facilitate safer translation of the rising tide of biologics in the development pipeline.

　　主讲人简介： Karl Griswold is a tenured Associate Professor of Bioengineering in the Thayer School of Engineering at Dartmouth. His work in the field of protein engineering has resulted in the development of new tools for protein deimmunization, enhanced microbial production systems, novel strategies for gene library construction, and new approaches to high throughput screening of recombinant protein libraries. At the Thayer School, his research group is seeking to develop and utilize tools for protein design and engineering while placing a priority on therapeutic applications. He studied as a DOW Foundation Scholar at Texas State University, receiving a B.S. in chemistry with summa cum laude honors in 1995. He received his Ph.D. from the University of Texas at Austin in 2005 under Professor George Georgiou and Prof. Brent Iverson. Following a postdoctoral fellowship under Professor George Georgiou in the University of Texas department of chemical engineering, he joined the faculty of the Thayer School of Engineering at Dartmouth where he continues to teach and maintain an interdisciplinary research group. Dr. Griswold’s recent honors include a “Teacher of the Year” award from the Thayer School of Engineering and a “Young Investigator Award in Translational Biomedical Engineering” from the Coulter Foundation. To date, Dr. Griswold has received $4.4 million grants (2.1 million active and 2.3 million completed) to directly support his research group and coauthored 42 peer-reviewed articles. In September of 2013, he co-founded the biotechnology startup Stealth Biologics LLC, where he serves as the CEO.