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Article: Ligand-Bound Forced Degradation as a Strategy to Generate Functionally Relevant Analytical Challenge Materials for Assessment of CQAs.

Giddens, John P / Schiel, John E

2022 Volume 9, Page(s) 789973

Abstract: Therapeutic monoclonal antibodies (mAbs) contain a variety of amino acids that are susceptible to enzymatic, chemical, and physical modifications. These modifications can happen throughout production, purification, formulation, and storage and many are ... ...

Abstract	Therapeutic monoclonal antibodies (mAbs) contain a variety of amino acids that are susceptible to enzymatic, chemical, and physical modifications. These modifications can happen throughout production, purification, formulation, and storage and many are known to affect the biological activity of a mAb. Methods that are able to characterize and evaluate these attributes are critical in order to understand how they might alter biological activity. Methods capable of site-specific monitoring of these critical quality attributes are extremely valuable to biopharmaceutical research but also require well-defined materials with site-specific attribute modifications. Here, we describe the development and application of a strategy to generate functionally relevant analytical challenge materials that have unique site-specific attributes. This method involves the use of a ligand that is bound to the mAb during oxidative stress resulting in unique oxidation patterns with some methionine residues protected while others are exposed to oxidation. These unique materials were used to develop a rapid surface plasmon resonance (SPR) assay that could detect methionine oxidation in both the Fab and Fc regions using specific molecular probes. The addition of uniquely oxidized materials to our data set enabled us to determine specific methionine residues vital to binding. Further analysis showed that antibody oxidation could also be rapidly detected in multiple domains from qualitative thermal melting using intrinsic tryptophan fluorescence. Methionine oxidation of an antibody was explored in this study, but we envision this method could be useful to explore structure function relationships of a variety of antibody modifications and modifications to other biologically relevant protein drugs.
Language	English
Publishing date	2022-04-11
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2814330-9
ISSN	2296-889X
ISSN	2296-889X
DOI	10.3389/fmolb.2022.789973
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Article ; Online: Managing integrated continuous bioprocesses in real time: Deviations in product quality.

Grampp, Gustavo / Bosley, Allen / Qadan, Maen / Schiel, John / Spasoff, Andy / Valax, Pascal / Schaefer, Gene

Biotechnology progress

2023 Volume 40, Issue 2, Page(s) e3414

Abstract: The N-mAb case study was produced by the National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL) to support teaching and learning for both industry and regulators around adoption of advanced manufacturing process technologies such ... ...

Abstract	The N-mAb case study was produced by the National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL) to support teaching and learning for both industry and regulators around adoption of advanced manufacturing process technologies such as integrated continuous bioprocesses (ICB) for monoclonal antibodies (mAbs). N-mAb presents the evolution of an integrated control strategy, from early clinical through process validation and commercial manufacturing with a focus on elements that are unique to ICB. The entire N-mAb case study is quite comprehensive, therefore this publication presents a summary of the chapter on managing deviations from a state of control in real time. This topic is of critical importance to ICB and is also applicable to batch processes operated at a rapid cadence.
MeSH term(s)	Technology, Pharmaceutical ; Antibodies, Monoclonal ; Biological Products
Chemical Substances	Antibodies, Monoclonal ; Biological Products
Language	English
Publishing date	2023-11-28
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	165657-0
ISSN	1520-6033 ; 8756-7938
ISSN (online)	1520-6033
ISSN	8756-7938
DOI	10.1002/btpr.3414
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Article ; Online: Qualification of NISTmAb charge heterogeneity control assays.

Turner, Abigail / Schiel, John E

Analytical and bioanalytical chemistry

2018 Volume 410, Issue 8, Page(s) 2079–2093

Abstract: The NISTmAb is a monoclonal antibody Reference Material from the National Institute of Standards and Technology; it is a class-representative IgG1κ intended serve as a pre-competitive platform for harmonization and technology development in the ... ...

Abstract	The NISTmAb is a monoclonal antibody Reference Material from the National Institute of Standards and Technology; it is a class-representative IgG1κ intended serve as a pre-competitive platform for harmonization and technology development in the biopharmaceutical industry. The publication series of which this paper is a part describes NIST's overall control strategy to ensure NISTmAb quality and availability over its lifecycle. In this paper, the development and qualification of methods for monitoring NISTmAb charge heterogeneity are described. Capillary zone electrophoresis (CZE) and capillary isoelectric focusing (CIEF) assays were optimized and evaluated as candidate assays for NISTmAb quality control. CIEF was found to be suitable as a structural characterization assay yielding information on the apparent pI of the NISTmAb. CZE was found to be better suited for routine monitoring of NISTmAb charge heterogeneity and was qualified for this purpose. This paper is intended to provide relevant details of NIST's charge heterogeneity control strategy to facilitate implementation of the NISTmAb as a test molecule in the end user's laboratory. Graphical Abstract Representative capillary zone electropherogram of the NIST monoclonal antibody (NISTmAb). The NISTmAb is a publicly available research tool intended to facilitate advancement of biopharmaceutical analytics.
MeSH term(s)	Animals ; Antibodies, Monoclonal/chemistry ; Antibodies, Monoclonal, Humanized/chemistry ; Biosimilar Pharmaceuticals/chemistry ; Electrophoresis, Capillary/methods ; Electrophoresis, Capillary/standards ; Humans ; Immunoglobulin G/chemistry ; Isoelectric Focusing/methods ; Isoelectric Focusing/standards ; Mice ; Models, Molecular ; Quality Control ; Reference Standards ; Static Electricity
Chemical Substances	Antibodies, Monoclonal ; Antibodies, Monoclonal, Humanized ; Biosimilar Pharmaceuticals ; Immunoglobulin G
Language	English
Publishing date	2018-03
Publishing country	Germany
Document type	Journal Article
ZDB-ID	201093-8
ISSN	1618-2650 ; 0016-1152 ; 0372-7920
ISSN (online)	1618-2650
ISSN	0016-1152 ; 0372-7920
DOI	10.1007/s00216-017-0816-6
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Article ; Online: The NISTmAb Reference Material 8671 lifecycle management and quality plan.

Schiel, John E / Turner, Abigail

Analytical and bioanalytical chemistry

2018 Volume 410, Issue 8, Page(s) 2067–2078

Abstract: Comprehensive analysis of monoclonal antibody therapeutics involves an ever expanding cadre of technologies. Lifecycle-appropriate application of current and emerging techniques requires rigorous testing followed by discussion between industry and ... ...

Abstract	Comprehensive analysis of monoclonal antibody therapeutics involves an ever expanding cadre of technologies. Lifecycle-appropriate application of current and emerging techniques requires rigorous testing followed by discussion between industry and regulators in a pre-competitive space, an effort that may be facilitated by a widely available test metric. Biopharmaceutical quality materials, however, are often difficult to access and/or are protected by intellectual property rights. The NISTmAb, humanized IgG1κ Reference Material 8671 (RM 8671), has been established with the intent of filling that void. The NISTmAb embodies the quality and characteristics of a typical biopharmaceutical product, is widely available to the biopharmaceutical community, and is an open innovation tool for development and dissemination of results. The NISTmAb lifecyle management plan described herein provides a hierarchical strategy for maintenance of quality over time through rigorous method qualification detailed in additional submissions in the current publication series. The NISTmAb RM 8671 is a representative monoclonal antibody material and provides a means to continually evaluate current best practices, promote innovative approaches, and inform regulatory paradigms as technology advances. Graphical abstract The NISTmAb Reference Material (RM) 8671 is intended to be an industry standard monoclonal antibody for pre-competitive harmonization of best practices and designing next generation characterization technologies for identity, quality, and stability testing.
MeSH term(s)	Animals ; Antibodies, Monoclonal/analysis ; Antibodies, Monoclonal, Humanized/analysis ; Biosimilar Pharmaceuticals/analysis ; Chemistry Techniques, Analytical/methods ; Chemistry Techniques, Analytical/standards ; Drug Stability ; Humans ; Immunoglobulin G/analysis ; Mice ; Models, Molecular ; Quality Control ; Reference Standards
Chemical Substances	Antibodies, Monoclonal ; Antibodies, Monoclonal, Humanized ; Biosimilar Pharmaceuticals ; Immunoglobulin G
Language	English
Publishing date	2018-02-12
Publishing country	Germany
Document type	Journal Article
ZDB-ID	201093-8
ISSN	1618-2650 ; 0016-1152 ; 0372-7920
ISSN (online)	1618-2650
ISSN	0016-1152 ; 0372-7920
DOI	10.1007/s00216-017-0844-2
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Article ; Online: Ligand-Bound Forced Degradation as a Strategy to Generate Functionally Relevant Analytical Challenge Materials for Assessment of CQAs

John P. Giddens / John E. Schiel

Frontiers in Molecular Biosciences, Vol

2022 Volume 9

Abstract	Therapeutic monoclonal antibodies (mAbs) contain a variety of amino acids that are susceptible to enzymatic, chemical, and physical modifications. These modifications can happen throughout production, purification, formulation, and storage and many are known to affect the biological activity of a mAb. Methods that are able to characterize and evaluate these attributes are critical in order to understand how they might alter biological activity. Methods capable of site-specific monitoring of these critical quality attributes are extremely valuable to biopharmaceutical research but also require well-defined materials with site-specific attribute modifications. Here, we describe the development and application of a strategy to generate functionally relevant analytical challenge materials that have unique site-specific attributes. This method involves the use of a ligand that is bound to the mAb during oxidative stress resulting in unique oxidation patterns with some methionine residues protected while others are exposed to oxidation. These unique materials were used to develop a rapid surface plasmon resonance (SPR) assay that could detect methionine oxidation in both the Fab and Fc regions using specific molecular probes. The addition of uniquely oxidized materials to our data set enabled us to determine specific methionine residues vital to binding. Further analysis showed that antibody oxidation could also be rapidly detected in multiple domains from qualitative thermal melting using intrinsic tryptophan fluorescence. Methionine oxidation of an antibody was explored in this study, but we envision this method could be useful to explore structure function relationships of a variety of antibody modifications and modifications to other biologically relevant protein drugs.
Keywords	methionine oxidation ; NISTmAb ; mass spectrometry ; surface plasmon resonance ; analytical materials ; Biology (General) ; QH301-705.5
Subject code	540
Language	English
Publishing date	2022-04-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Development of an LC-MS/MS peptide mapping protocol for the NISTmAb.

Mouchahoir, Trina / Schiel, John E

Analytical and bioanalytical chemistry

2018 Volume 410, Issue 8, Page(s) 2111–2126

Abstract: Peptide mapping is a component of the analytical toolbox used within the biopharmaceutical industry to aid in the identity confirmation of a protein therapeutic and to monitor degradative events such as oxidation or deamidation. These methods offer the ... ...

Abstract	Peptide mapping is a component of the analytical toolbox used within the biopharmaceutical industry to aid in the identity confirmation of a protein therapeutic and to monitor degradative events such as oxidation or deamidation. These methods offer the advantage of providing site-specific information regarding post-translational and chemical modifications that may arise during production, processing or storage. A number of such variations may also be induced by the sample preparation methods themselves which may confound the ability to accurately evaluate the true modification levels. One important focus when developing a peptide mapping method should therefore be the use of sample preparation conditions that will minimize the degree of artificial modifications induced. Unfortunately, the conditions that are amenable to effective reduction, alkylation and digestion are often the same conditions that promote unwanted modifications. Here we describe the optimization of a tryptic digestion protocol used for peptide mapping of the NISTmAb IgG1κ which addresses the challenge of balancing maximum digestion efficiency with minimum artificial modifications. The parameters on which we focused include buffer concentration, digestion time and temperature, as well as the source and type of trypsin (recombinant vs. pancreatic; bovine vs porcine) used. Using the optimized protocol we generated a peptide map of the NISTmAb which allowed us to confirm its identity at the level of primary structure. Graphical abstract Peptide map of the NISTmAb RM 8671 monoclonal antibody. Tryptic digestion was performed using an optimized protocol and followed by LC-UV-MS analysis. The trace represents the total ion chromatogram. Each peak was mapped to peptides identified using mass spectrometry data.
MeSH term(s)	Animals ; Antibodies, Monoclonal/chemistry ; Antibodies, Monoclonal, Humanized/chemistry ; Cattle ; Chromatography, Liquid/methods ; Chromatography, Liquid/standards ; Humans ; Immunoglobulin G/chemistry ; Mice ; Models, Molecular ; Peptide Mapping/methods ; Peptide Mapping/standards ; Peptides/analysis ; Reference Standards ; Swine ; Tandem Mass Spectrometry/methods ; Tandem Mass Spectrometry/standards ; Trypsin/chemistry
Chemical Substances	Antibodies, Monoclonal ; Antibodies, Monoclonal, Humanized ; Immunoglobulin G ; Peptides ; Trypsin (EC 3.4.21.4)
Language	English
Publishing date	2018-02-07
Publishing country	Germany
Document type	Journal Article
ZDB-ID	201093-8
ISSN	1618-2650 ; 0016-1152 ; 0372-7920
ISSN (online)	1618-2650
ISSN	0016-1152 ; 0372-7920
DOI	10.1007/s00216-018-0848-6
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Article ; Online: Bioindustrial manufacturing readiness levels (BioMRLs) as a shared framework for measuring and communicating the maturity of bioproduct manufacturing processes.

Smanski, Michael J / Aristidou, Aristos / Carruth, Ryan / Erickson, John / Gordon, Mark / Kedia, Sandeep B / Lee, Kelvin H / Prather, Darcy / Schiel, John E / Schultheisz, Heather / Treynor, Thomas P / Evans, Steven L / Friedman, Douglas C / Tomczak, Melanie

Journal of industrial microbiology & biotechnology

2022 Volume 49, Issue 5

Abstract: Readiness level (RL) frameworks such as technology readiness levels and manufacturing readiness levels describe the status of a technology/manufacturing process on its journey from initial conception to commercial deployment. More importantly, they ... ...

Abstract	Readiness level (RL) frameworks such as technology readiness levels and manufacturing readiness levels describe the status of a technology/manufacturing process on its journey from initial conception to commercial deployment. More importantly, they provide a roadmap to guide technology development and scale-up from a ''totality of system'' approach. Commercialization risks associated with too narrowly focused R&D efforts are mitigated. RLs are defined abstractly so that they can apply to diverse industries and technology sectors. However, differences between technology sectors make necessary the definition of sector specific RL frameworks. Here, we describe bioindustrial manufacturing readiness levels (BioMRLs), a classification system specific to bioindustrial manufacturing. BioMRLs will give program managers, investors, scientists, and engineers a shared vocabulary for prioritizing goals and assessing risks in the development and commercialization of a bioindustrial manufacturing process.
MeSH term(s)	Industry ; Technology
Language	English
Publishing date	2022-09-21
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1482484-X
ISSN	1476-5535 ; 1367-5435
ISSN (online)	1476-5535
ISSN	1367-5435
DOI	10.1093/jimb/kuac022
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Article: Qualification of NISTmAb charge heterogeneity control assays

Turner, Abigail / John E. Schiel

Analytical and bioanalytical chemistry. 2018 Mar., v. 410, no. 8

2018

Abstract	The NISTmAb is a monoclonal antibody Reference Material from the National Institute of Standards and Technology; it is a class-representative IgG1κ intended serve as a pre-competitive platform for harmonization and technology development in the biopharmaceutical industry. The publication series of which this paper is a part describes NIST’s overall control strategy to ensure NISTmAb quality and availability over its lifecycle. In this paper, the development and qualification of methods for monitoring NISTmAb charge heterogeneity are described. Capillary zone electrophoresis (CZE) and capillary isoelectric focusing (CIEF) assays were optimized and evaluated as candidate assays for NISTmAb quality control. CIEF was found to be suitable as a structural characterization assay yielding information on the apparent pI of the NISTmAb. CZE was found to be better suited for routine monitoring of NISTmAb charge heterogeneity and was qualified for this purpose. This paper is intended to provide relevant details of NIST’s charge heterogeneity control strategy to facilitate implementation of the NISTmAb as a test molecule in the end user’s laboratory. Graphical Abstract Representative capillary zone electropherogram of the NIST monoclonal antibody (NISTmAb). The NISTmAb is a publicly available research tool intended to facilitate advancement of biopharmaceutical analytics.
Keywords	biopharmaceutical industry ; biopharmaceuticals ; capillary zone electrophoresis ; immunoglobulin G ; isoelectric focusing ; monitoring ; monoclonal antibodies ; quality control
Language	English
Dates of publication	2018-03
Size	p. 2079-2093.
Publishing place	Springer Berlin Heidelberg
Document type	Article
ISSN	1618-2642
DOI	10.1007/s00216-017-0816-6
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Mass Spectrometry Advances and Perspectives for the Characterization of Emerging Adoptive Cell Therapies.

Lombard-Banek, Camille / Schiel, John E

Molecules (Basel, Switzerland)

2020 Volume 25, Issue 6

Abstract: Adoptive cell therapy is an emerging anti-cancer modality, whereby the patient's own immune cells are engineered to express T-cell receptor (TCR) or chimeric antigen receptor (CAR). CAR-T cell therapies have advanced the furthest, with recent approvals ... ...

Abstract	Adoptive cell therapy is an emerging anti-cancer modality, whereby the patient's own immune cells are engineered to express T-cell receptor (TCR) or chimeric antigen receptor (CAR). CAR-T cell therapies have advanced the furthest, with recent approvals of two treatments by the Food and Drug Administration of Kymriah (trisagenlecleucel) and Yescarta (axicabtagene ciloleucel). Recent developments in proteomic analysis by mass spectrometry (MS) make this technology uniquely suited to enable the comprehensive identification and quantification of the relevant biochemical architecture of CAR-T cell therapies and fulfill current unmet needs for CAR-T product knowledge. These advances include improved sample preparation methods, enhanced separation technologies, and extension of MS-based proteomic to single cells. Innovative technologies such as proteomic analysis of raw material quality attributes (MQA) and final product quality attributes (PQA) may provide insights that could ultimately fuel development strategies and lead to broad implementation.
MeSH term(s)	Antigens, CD19/therapeutic use ; Biological Products ; Humans ; Immunotherapy, Adoptive/methods ; Mass Spectrometry ; Neoplasms/immunology ; Neoplasms/therapy ; Proteomics/methods ; Receptors, Antigen, T-Cell/therapeutic use ; Single-Cell Analysis
Chemical Substances	Antigens, CD19 ; Biological Products ; Receptors, Antigen, T-Cell ; tisagenlecleucel (Q6C9WHR03O) ; axicabtagene ciloleucel (U2I8T43Y7R)
Language	English
Publishing date	2020-03-19
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules25061396
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Article ; Online: A Sensitive and Controlled Data-Independent Acquisition Method for Proteomic Analysis of Cell Therapies.

Lombard-Banek, Camille / Pohl, Kerstin I / Kwee, Edward J / Elliott, John T / Schiel, John E

Journal of proteome research

2022 Volume 21, Issue 5, Page(s) 1229–1239

Abstract: Mass spectrometry (MS)-based proteomic measurements are uniquely poised to impact the development of cell and gene therapies. With the adoption of rigorous instrumental performance qualifications (PQs), large-scale proteomics can move from a research to ... ...

Abstract	Mass spectrometry (MS)-based proteomic measurements are uniquely poised to impact the development of cell and gene therapies. With the adoption of rigorous instrumental performance qualifications (PQs), large-scale proteomics can move from a research to a manufacturing control tool. Especially suited, data-independent acquisition (DIA) approaches have distinctive qualities to extend multiattribute method (MAM) principles to characterize the proteome of cell therapies. Here, we describe the development of a DIA method for the sensitive identification and quantification of proteins on a Q-TOF instrument. Using the improved acquisition parameters, we defined a control strategy and highlighted some metrics to improve the reproducibility of SWATH acquisition-based proteomic measurements. Finally, we applied the method to analyze the proteome of Jurkat cells that here serves as a model for human T-cells. Raw and processed data were deposited in PRIDE (PXD029780).
MeSH term(s)	Data Accuracy ; Humans ; Mass Spectrometry/methods ; Proteome/analysis ; Proteomics/methods ; Reproducibility of Results
Chemical Substances	Proteome
Language	English
Publishing date	2022-04-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2078618-9
ISSN	1535-3907 ; 1535-3893
ISSN (online)	1535-3907
ISSN	1535-3893
DOI	10.1021/acs.jproteome.1c00887
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