Nucleation, Aggregation, and Conformational Distortion

Roberts, Christopher J.

doi:10.1002/9781118354698.ch5

Cited by 4 publications

(6 citation statements)

References 71 publications

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“…Non-native protein aggregation, or the assembly of proteins into conformationally altered agglomerates, is a multistep process that can occur by different mechanisms through various molecular and colloidal steps. − In the biopharmaceutical industry, non-native aggregation of therapeutic proteins is a highly undesirable phenomenon because the presence of protein aggregates can compromise drug efficacy by decreasing potency and/or by increasing product immunogenicity potential (i.e., formation of antidrug antibodies). − The process of non-native, irreversible protein aggregation (hereafter referred to as aggregation) can result in aggregates ranging in size from soluble dimers to insoluble macroscopic particles . The extent of protein aggregation is largely determined by the sequence and structure of the protein itself, , solution environment (e.g., pH, ionic strength, cosolutes), − and stress condition applied to induce aggregation (e.g., temperature, mechanical agitation, light, etc.)…”

Section: Introductionmentioning

confidence: 99%

Effects of Protein Conformation, Apparent Solubility, and Protein–Protein Interactions on the Rates and Mechanisms of Aggregation for an IgG1Monoclonal Antibody

et al. 2016

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Non-native protein aggregation is a key degradation pathway of immunoglobulins. In this work, the aggregation kinetics of an immunoglobulin gamma-1 monoclonal antibody (IgG1 mAb) in different solution environments was monitored over a range of incubation temperatures for up to seven months using size exclusion chromatography. Histidine and citrate buffers with/without sodium chloride were employed to modulate the mAb's conformational stability, solubility (in the presence of polyethylene glycol, PEG), and protein-protein interactions as measured by differential scanning calorimetry, PEG precipitation, and static light scattering, respectively. The effect of these parameters on the mechanism(s) of mAb aggregation during storage at different temperatures was determined using kinetic models, which were used to fit aggregation data to determine rate constants for aggregate nucleation and growth processes. This approach was used to investigate the effects of colloidal protein-protein interactions and solubility values (in PEG solutions) on the mechanisms and rates of IgG1 mAb aggregation as a function of temperature-induced structural perturbations. Aggregate nucleation and growth pathways for this IgG1 mAb were sensitive to temperature and overall conformational stability. Aggregate growth, on the other hand, was also sensitive to conditions affecting the solubility of the mAb, particularly at elevated temperatures.

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Section: Introductionmentioning

confidence: 99%

Effects of Protein Conformation, Apparent Solubility, and Protein–Protein Interactions on the Rates and Mechanisms of Aggregation for an IgG1Monoclonal Antibody

et al. 2016

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“…When a PTS container hits the wall in the receptacle, there is tremendous mechanical shock to IV bag and solution within it. The mechanical shock can lead to protein particles in the IV solutions through several different mechanisms, all of which can be operative simultaneously [116][117][118] . The particle formation may occur immediately and/or after exposure of the protein molecules to stressful conditions generated by the mechanical shock 119 .…”

Section: Potential Mechanisms For Protein Particle Formation During Pts Transportation Of IV Bagsmentioning

confidence: 99%

Effects of Transportation of IV Bags Containing Protein Formulations Via Hospital Pneumatic Tube System: Particle Characterization by Multiple Methods

Linkuvienė

Ross

Crawford

et al. 2022

Journal of Pharmaceutical Sciences

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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“…27,28 In general, aggregation is considered a multistep process that occurs as a result of changes in various conformational and colloidal properties. 29,30 Subtle changes to the primary sequence of the C H 2 and C H 3 domains can dramatically alter the conformational stability and aggregation propensity of mAbs. 31,32 Rose et al 32 reported that a point mutation in the C H 3 domain (Y407E) of an IgG1 and IgG4 not only caused conformational changes in the C H 3 domain but also led to remarkable structural changes in the C H 2 domain and caused significant conformational changes via allosteric effects.…”

Section: Introductionmentioning

confidence: 99%

Characterization of a Novel Bispecific Antibody With Improved Conformational and Chemical Stability

Manikwar

Mulagapati

Kasturirangan

et al. 2020

Journal of Pharmaceutical Sciences

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Bispecific antibodies containing single-chain variable fragment (scFv) appended to immunoglobulins G offer unique development challenges. Here, we describe the stability of a novel bispecific format, BiS5, where the scFv is tethered to the C H 3 domain. BiS5 showed an improved conformational and chemical stability compared with that of BiS4 in which the scFv is appended in the hinge region between the F ab and F c. By switching the location of the scFv from hinge region to the C H 3, there was an improved stabilization of C H 2 and scFv domains. Interestingly, no noticeable impact was observed on the conformational stability of C H 3 and F ab domains. BiS4 and BiS5 showed different aggregation and fragmentation rates under accelerated temperature stress conditions. BiS4 showed higher fragmentation rates compared with BiS5 likely owing to fragmentation in the linker region on either side of the scFv while BiS5 is more resistant toward fragmentation owing to tethering of scFv to the C H 3 domain at its N and C terminus. In conclusion, the location of scFv affects both aggregation and fragmentation kinetics. These insights into the molecular structure and correlations with their physical and chemical stability will help formulation development of these novel bispecific antibodies.

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Nucleation, Aggregation, and Conformational Distortion

Cited by 4 publications

References 71 publications

Effects of Protein Conformation, Apparent Solubility, and Protein–Protein Interactions on the Rates and Mechanisms of Aggregation for an IgG1Monoclonal Antibody

Effects of Protein Conformation, Apparent Solubility, and Protein–Protein Interactions on the Rates and Mechanisms of Aggregation for an IgG1Monoclonal Antibody

Effects of Transportation of IV Bags Containing Protein Formulations Via Hospital Pneumatic Tube System: Particle Characterization by Multiple Methods

Characterization of a Novel Bispecific Antibody With Improved Conformational and Chemical Stability

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