Title：Molecular Engineering of WMD (Weapons of Microbial Destruction): deimmunizing a big antibiotic to treat fatal infections by MRSA super bugs.

Speaker：Dr. Karl Griswold, Associate Professor, Thayer School of Engineering, Dartmouth College.

Time: 10:00 a.m. Wednesday, March 17th , 2016

Place: Room 412, Building 5, School of Pharmacy

Host : Professor Jianwei Zhu

Lecture abstracts：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 lysostaphin variants that retain the wild type enzyme’s anti-MRSA potency, exhibit reduced immunogenicity in cellular immunoassays, and significantly reduced anti-drug antibody responses following administration to mice bearing humanized immune systems. They have shown that wild-type lysostaphin rescues humanized mice from an initial infection by a MRSA clinical isolate, but it fails to treat subsequent recurrent infections that are coincident with escalating anti-drug antibody titers. In contrast, the deimmunized lysostaphin variant successfully rescued mice from multiple 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 immune competent disease model. Thus, their broadly applicable protein design and deimmunizaiton tools may facilitate safer translation of the rising tide of biologics in the development pipeline.