Protein therapeutics are the fastest growing segment of the pharmaceutical market, accounting for one-third of the overall late stage drug development pipeline, and anticipated to represent 20% of the total pharmaceuticals market value by 2017. However, two significant challenges must be overcome to maximize patient benefit and access to biologic drugs: Patient immunogenicity remains a significant problem for biologic drugs, resulting in patient non-response rates of up to 70% or more over the course of long term treatment. Denatured and aggregated proteins in biologic drugs are a known cause for immunogenicity, so maintaining their 3D structure is therefore critical for ensuring patient safety and drug efficacy. Lack of low cost generic competition looms as a pressing issue with biologic drug patents worth more than $26 billion in annual US sales expiring before 2020. However, one challenge slowing FDA approval of biosimilar drug applications is the inability to ensure that the 3D structures of proposed biosimilars are the same as the original branded drug. Unfortunately, current analytical strategies are inadequate for delivering easy to obtain, high-resolution analyses of protein 3D structure. In response, ReclaimRx and its research partners at Indiana University and University of Massachusetts propose to develop a mass spectrometry method that uses labeling to detect changes in protein 3D structure. This method will be quick, easy to use, and high resolution. Preliminary studies have demonstrated the strong potential for success of the proposed labeling approach by detecting changes in the 3D structure of 3 proteins (?-2-microglobulin, human growth hormone, and immunoglobulin G1) in response to forced degradation conditions. Phase I efforts will build upon this work by demonstrating the feasibility of the proposed technology. This will be achieved through the following Specific Aims: 1) Demonstrate effective detection of the structural degradation of 3 proteins (EPO, human growth hormone, and an IgG1 mAb) in response to thermal and oxidative forced degradation conditions; and 2) Develop a software pipeline specifically designed for protein covalent labeling studies. The simplicity of this approach allows ReclaimRx, an Indiana-based small business, to commercialize this method via a fee-for-service offering, where client will send samples to be analyzed in ReclaimRx's facilities. This service will include data analysis via software that converts the MS files into user-friendly formats. Phase II efforts will focus on developing the technology as a kit that can be purchased to allow researchers to perform the analysis in their own lab, and further refining the software pipeline for commercial use and test conditions relevant to potential customers.
High resolution measurements of the 3D structure of therapeutic proteins is essential for ensuring the safety and efficacy of biotech drugs, and is a key element in enabling the introduction of generic competition for offpatent branded drugs via biosimilars. Unfortunately, current analytical strategies are inadequate for delivering easy to obtain, high resolution analyses of protein 3D structure. In this SBIR project, ReclaimRx, LLC will develop a mass spectrometry method that uses labeling to detect changes in protein 3D structure, providing high resolution protein structure analyses without the limitations of existing methods.
| Limpikirati, Patanachai; Liu, Tianying; Vachet, Richard W (2018) Covalent labeling-mass spectrometry with non-specific reagents for studying protein structure and interactions. Methods 144:79-93 |
