Abstract

Unlike with new chemical entities (NCEs), 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 the TP 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 case studies are discussed and a fit-for-purpose approach is recommended when dealing with the uniqueness in biotransformation investigation. 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 could 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 IQ therapeutic protein ADME 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.