PT  - JOURNAL ARTICLE
AU  - Markus Walles
AU  - Michael Berna
AU  - Wenying Jian
AU  - Simon Hauri
AU  - Shawna Hengel
AU  - Lloyd King
AU  - John C. Tran
AU  - Cong Wei
AU  - Keyang Xu
AU  - Xiaochun Zhu
TI  - A Cross Company Perspective on the Assessment of Therapeutic Protein Biotransformation
AID  - 10.1124/dmd.121.000462
DP  - 2022 Jun 01
TA  - Drug Metabolism and Disposition
PG  - 846--857
VI  - 50
IP  - 6
4099  - http://dmd.aspetjournals.org/content/50/6/846.short
4100  - http://dmd.aspetjournals.org/content/50/6/846.full
SO  - Drug Metab Dispos2022 Jun 01; 50
AB  - Unlike with new chemical entities, the biotransformation of therapeutic proteins (TPs) has not been routinely investigated or included in regulatory filings. Nevertheless, there is an expanding pool of evidence suggesting that a more in-depth understanding of biotransformation could better aid the discovery and development of increasingly diverse modalities. For instance, such biotransformation analysis of TPs affords important information on molecular stability, which in turn may shed light on any potential impact on binding affinity, potency, pharmacokinetics, efficacy, safety, or bioanalysis. This perspective summarizes the current practices in studying biotransformation of TPs and related findings in the biopharmaceutical industry. Various TP case studies are discussed, and a fit-for-purpose approach is recommended when investigating their biotransformation. In addition, we provide a decision tree to guide the biotransformation characterization for selected modalities. By raising the awareness of this important topic, which remains relatively underexplored in the development of TPs (Bolleddula et al., 2022), we hope that current and developing practices can pave the way for establishing a consensus on the biotransformation assessment of TPs.SIGNIFICANCE STATEMENT This article provides a comprehensive perspective of the current practices for exploring the biotransformation of therapeutic proteins across the drug development industry. We, the participants of the Innovation and Quality therapeutic protein absorption distribution metabolism excretion working group, recommend and summarize appropriate approaches for conducting biotransformation studies to support internal decision making based on the data generated in discovery and development.