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Antibody Disulfide Bond Reduction and Recovery during Biopharmaceutical Process Development - A Review
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  • Tingwei Ren,
  • Zhijun Tan,
  • Vivekh Ehamparanathan,
  • Angela Lewandowski,
  • Sanchayita Ghose,
  • Zheng Jian Li
Tingwei Ren
Bristol Myers Squibb
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Zhijun Tan
Bristol Myers Squibb
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Vivekh Ehamparanathan
Bristol-Myers Squibb Co
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Angela Lewandowski
Bristol Myers Squibb
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Sanchayita Ghose
Bristol Myers Squibb
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Zheng Jian Li
Bristol-Myers Squibb Company
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Abstract

Disulfide bond reduction has been a challenging issue in antibody manufacturing, as it leads to reduced product purity, failed product specifications and more importantly, impacting drug safety and efficacy. Scientists across industry have been examining the root causes and developing mitigation strategies to address the challenge. In recent years, with the development of high-titer mammalian cell culture processes to meet the rapidly growing demand for antibody biopharmaceuticals, disulfide bond reduction has been observed more frequently. Thus, it is necessary to continue evolving the disulfide reduction mitigation strategy and development of novel approaches to achieve high product quality. Additionally, in recent years as more complex molecules emerge such as bispecific and trispecific antibodies, the molecular heterogeneity due to incomplete formation of the interchain disulfide bonds becomes a more imperative issue. Given the disulfide reduction challenges that our industry are facing, in this review, we provide a comprehensive contemporary scientific insight into the root cause analysis of disulfide reduction during process development of antibody therapeutics, mitigation strategies and recovery based on our expertise in commercial and clinical manufacturing of biologics. First, this paper intended to highlight different aspects of the root cause for disulfide reduction. Secondly, to provide a broader understanding of the disulfide bond reduction in downstream process, this paper discussed disulfide bond reduction impact to product stability and process performance, analytical methods for detection and characterization, process control strategies and their manufacturing implementation. In addition, brief perspectives on development of future mitigation strategies will also be reviewed, including platform alignment, mitigation strategy application for bi- and tri-specific antibodies and using machine learning to identify molecule susceptibility of disulfide bond reduction. The data in this review are originated from both the published papers and our internal development work.

Peer review status:ACCEPTED

16 Dec 2020Submitted to Biotechnology and Bioengineering
17 Dec 2020Submission Checks Completed
17 Dec 2020Assigned to Editor
19 Dec 2020Reviewer(s) Assigned
15 Jan 2021Review(s) Completed, Editorial Evaluation Pending
15 Jan 2021Editorial Decision: Revise Major
20 Mar 20211st Revision Received
22 Mar 2021Assigned to Editor
22 Mar 2021Submission Checks Completed
22 Mar 2021Reviewer(s) Assigned
02 Apr 2021Editorial Decision: Revise Minor
02 Apr 2021Review(s) Completed, Editorial Evaluation Pending
07 Apr 20212nd Revision Received
08 Apr 2021Assigned to Editor
08 Apr 2021Submission Checks Completed
08 Apr 2021Review(s) Completed, Editorial Evaluation Pending
08 Apr 2021Editorial Decision: Accept