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Recent Scientific Case Studies

Advanced Analytical Approaches for Accelerated Development of Gene Therapy Products

Advanced therapeutic platforms like gene and cell therapies offer tremendous potential for treating unmet medical needs, but have remained extremely challenging to develop successfully, largely because their molecular platforms and clinical delivery systems are highly complex. Obtaining a better understanding of specific structural attributes that influence clinical delivery and outcomes is essential for advancing both individual gene therapy candidates, as well as the emerging vector/gene platforms on which they are based. In particular, identifying and controlling specific molecular attributes of a vector, quantifying vector delivery to the target therapeutic site and correlating therapeutic protein expression in vivo with clinical response are all now beginning to emerge as important underpinnings in leading gene therapy development programs. Concurrently, advances in high-resolution LC-MS based vector characterization, in situ quantification and in vivo expression profiling approaches are increasingly being applied to enable improved program understanding, controls and clinical outcomes. This White Paper describes leading approaches in detailed characterization and quantitation of gene therapy vectors, delivery to target tissues and therapeutic protein expression from development through regulatory package submission. It conveys how understanding the relationship between specific molecular attributes identified through high-resolution analyses and quantification of related in vivo expression influences efficacy, and can guide, de-risk and improve development of complex gene therapy products. The primary focus is on AAV systems with inclusion of related aspects of LVV, however the methods reviewed may be applied to other related platforms for advanced therapeutic medicinal products as well.


Advanced HDX-MS and Native-MS for Improved Biologic Candidate Selection and Development

Despite substantial efforts utilizing a diverse set of biologic evaluation and high-throughput techniques to select candidates with the best chance of success in preclinical development, the vast majority of biologic drug molecules fail in clinical trials. With most biologic drugs, including gene therapies, failures are realized in late-stage development, after substantial investment has been made in a candidate. Here, we discuss the potential for improving identification of potentially successful biologic drugs and de-risking CMC and clinical designs earlier through strategic application of advanced mass spectrometry, and specifically, how detailed assessment of target engagement using HDX-MS and Native-MS analyses may provide understanding to guide biologic development decisions.


LC-MS Based Host Cell Protein Analysis

Host cell proteins (HCPs) are common impurities in biologic drug products and are an obligatory critical quality attribute (CQA). The individual protein contaminants that make up the HCP profile, however, may vary significantly among individual biologic products and expression systems. As such, the HCP profile must be analyzed to identify even low levels of potentially concerning species in a biologic drug to ensure safety and efficacy. This whitepaper reviews fundamental aspects of HCPs pertaining to biologic drug development and current and emerging approaches to HCP analysis.


In Vivo CQA Mapping/Biotransformation Analysis

Historically, only general biologic drug PK levels have been assessed in clinical subjects, while related drug sub-structures and post translational modifications (PTMs) have rarely been examined in vivo. Recent advances in mass spectrometry and related sample preparations are enabling detailed characterization of biologic drugs extracted from biologic tissues including serum and plasma PK samples. This letter highlights how “In Vivo CQA Mapping” can be used to understand the relationship between specific drug structures and clinical parameters to accelerate and de-risk advanced biologic drug development programs.

Related Content: In Vivo Peer Reviewed Publications

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