Risk-Based Control Strategies of Recombinant Monoclonal Antibody Charge Variants
Abstract
:1. Introduction
2. Modifications of Acidic and Basic Species
2.1. Modifications in Acidic Species
2.2. Modifications in Basic Species
3. Impact of Acidic and Basic Species on mAb Structure, Stability, and Biological Activity
4. In Vivo Modifications
4.1. Animal Model Studies
4.2. Human Studies
5. Control Strategies
5.1. Upstream Control
5.2. Down-Stream Control
5.3. Formulation and Storage
5.4. Phase-Appropriate Specification for Acidic and Basic Species
5.5. Critical Quality Attribute Assessment
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
ADCC | Antibody-dependent cellular cytotoxicity |
Asn | Asparagine |
Asp | Aspartate |
BLA | Biologics license application |
CDC | Complement-dependent cytotoxicity |
CDR | Complementarity-determining region |
CHO | Chinese hamster ovary |
CEX | Cation exchange chromatography |
cIEF | Capillary isoelectric focusing |
CMC | Chemistry, manufacturing, and controls |
CQA | Critical quality attribute |
Cys | Cysteine |
DOE | Design of experiment |
Fab | Fragment antigen binding |
Gln | Glutamine |
Glu | Glutamate |
ICH | The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use |
IND | Investigational New Drug |
IEF | Isoelectric focusing |
IEX | Ion exchange chromatography |
LC-MS | Liquid chromatography-mass spectrometry |
Lys | Lysine |
Met | Methionine |
NGNA | N-Glycolylneuraminic acid |
PAM | Peptidyl glycine α-amidating monooxygenase |
PD | Pharmacodynamics |
PK | Pharmacokinetics |
PPQ | Process performance qualification |
PyroGlu | Pyroglutamate |
WCX | Weak cation exchange |
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Modifications | References |
---|---|
Common | |
Asn deamidation | [9,13,14,15,16,17,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42] |
Sialylation | [9,27,30,36,39,43,44,45,46] |
Glycation | [9,14,29,34,36,37,39,47,48] |
Oxidation | [14,29,30,44] |
Cysteine-related modifications | |
Unformed disulfide bond | [9,33,39,49] |
Non-reducible disulfide bond | [9] |
Trisulfide bond | [32,50] |
IgG2 disulfide bond isoforms | [24,32,34,50] |
Cysteinylation and glutathionylation | [39] |
Fragmentation | [9,14,33,39,44,45] |
Rare | |
Asp more acidic than isoAsp | [26,28] |
Succinimide intermediate of Asp isomerization | [34] |
IsoAsp from Asp isomerization | [32] |
Maleuric acid modification | [51] |
Tyrosine sulfation | [52] |
Citric acid modification | [53] |
Xylosone modification | [54] |
Leader sequence | [38] |
Sequence variant from Gly to Asp | [29] |
Arginine modification by methylglyoxal | [55] |
Aggregates | [33] |
Modifications | References |
---|---|
Common | |
C-terminal Lys | [9,13,27,28,30,32,34,36,39,40,43,45,63,64,65,66,67] |
C-terminal amidation | [32,34,67,68,69] |
Succinimide intermediate | [26,44,57,59] |
IsoAsp as Asp isomerization | [16,26,34,42] |
Leader sequence | [9,27,32,34,38,45,64,69] |
Aggregates | [9,10,33,40] |
N-terminal uncyclized Gln | [27,62,64,65] |
Oxidation | [36,46,60,61] |
IgG2 isoforms | [24,32,34,50] |
Rare | |
Sequence variant Ser to Arg or Glu to Lys | [70,71] |
Unformed disulfide bonds | [33,62] |
Cysteinylation | [38] |
Cyclization of N-terminal Glu to pyroGlu | [39,69] |
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Beck, A.; Nowak, C.; Meshulam, D.; Reynolds, K.; Chen, D.; Pacardo, D.B.; Nicholls, S.B.; Carven, G.J.; Gu, Z.; Fang, J.; et al. Risk-Based Control Strategies of Recombinant Monoclonal Antibody Charge Variants. Antibodies 2022, 11, 73. https://doi.org/10.3390/antib11040073
Beck A, Nowak C, Meshulam D, Reynolds K, Chen D, Pacardo DB, Nicholls SB, Carven GJ, Gu Z, Fang J, et al. Risk-Based Control Strategies of Recombinant Monoclonal Antibody Charge Variants. Antibodies. 2022; 11(4):73. https://doi.org/10.3390/antib11040073
Chicago/Turabian StyleBeck, Alain, Christine Nowak, Deborah Meshulam, Kristina Reynolds, David Chen, Dennis B. Pacardo, Samantha B. Nicholls, Gregory J. Carven, Zhenyu Gu, **g Fang, and et al. 2022. "Risk-Based Control Strategies of Recombinant Monoclonal Antibody Charge Variants" Antibodies 11, no. 4: 73. https://doi.org/10.3390/antib11040073