Stability assessment of antibody-drug conjugate Trastuzumab emtansine in comparison to parent monoclonal antibody using orthogonal testing protocol

Mohamed, H. E.; Mohamed, Abeer A.; Al‐Ghobashy, Medhat A.; Fathalla, Faten A.; Abbas, Samah S.

doi:10.1016/j.jpba.2017.12.022

Cited by 38 publications

(29 citation statements)

References 39 publications

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“…Adjustments to the pH of ADC formulations compared with the native mAb formulation have been shown to be a stabilizing tool to prevent or reduce aggregate formation. 59 Because changes in charge can alter thermal and colloidal stabilities of the protein as well as impact viscosity of the formulation, PKs, or tissue distribution of the protein or protein conjugate, a deeper understanding of charge heterogeneity after conjugation is essential.…”

Section: Chargementioning

confidence: 99%

Alteration of Physicochemical Properties for Antibody-Drug Conjugates and Their Impact on Stability

Buecheler

Winzer

Weber

et al. 2020

Journal of Pharmaceutical Sciences

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a b s t r a c tAntibody conjugates, in particular antibody-drug conjugates (ADCs), are a fast-growing area in research and in the pharmaceutical industry. The covalent attachment of an antibody to a chemical moiety can be an effective measure for drug targeting or can also positively impact pharmacokinetics of small molecular compounds by serum half-life extension. Stability, physicochemical properties, and degradation pathways of biotherapeutics or small molecule therapeutics are often not totally known and understood. However, ADCs represent a hybrid of small molecular and macromolecular components, and their properties are still not fully understood and described. This review discusses the alteration of the physicochemical properties of antibodies upon conjugation of chemical moieties to its surface and the resulting impact on ADC stability.

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Section: Chargementioning

confidence: 99%

Alteration of Physicochemical Properties for Antibody-Drug Conjugates and Their Impact on Stability

Buecheler

Winzer

Weber

et al. 2020

Journal of Pharmaceutical Sciences

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“…The peaks of the oxidized forms were detected at shorter migration time than adalimumab. This was attributed to the increased polarity of the oxidized forms (Figure S4) (Mohamed et al, ; Shaltout et al, ). In the literature, the aromatic amino acids tryptophan, tyrosine and phenylalanine were the most affected.…”

Section: Resultsmentioning

confidence: 99%

“…Formulation at such high concentrations may lead to aggregate formation in the final formulation (Shire, Shahrokh, & Liu, ; Thiagarajan, Semple, James, Cheung, & Shameem, ; Warne, ). Thus, the quality assessment of these products is challenging in order to assure purity and stability (Mohamed, Mohamed, Al‐Ghobashy, Fathalla, & Abbas, ; Shaltout, Al‐Ghobashy, Fathalla, & Salem, ).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the pattern and kinetics of degradation of adalimumab using a stability‐indicating orthogonal testing protocol

Hassan

Al‐Ghobashy

Abbas

2019

Biomedical Chromatography

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Forced degradation studies are crucial for the evaluation of the stability and biosimilarity. Here, adalimumab was subjected to oxidation, pH, temperature, agitation and repeated freeze-thaw in order to generate all possible degradation products. An orthogonal stability-indicating testing protocol comprising SE-HPLC, RP-HPLC, TapeStation gel electrophoresis, dynamic light scattering (DLS), and functional receptor binding assay was developed and validated. The assay protocol was used for the assessment of the pattern and kinetics of aggregation/degradation of adalimumab. SE-HPLC and DLS were used to show the formation of aggregates/fragments of adalimumab under nondenaturing conditions. TapeStation electrophoresis was performed under denaturing conditions to reveal the nature of aggregates. Results of the receptor binding assay agreed to those of SE-HPLC and DLS which indicated that it can be used as an activity-indicating assay for adalimumab. RP-HPLC demonstrated excellent selectivity for adalimumab in the presence of its oxidized forms. The kineticsof degradation was studied in each case and the results showed that it followed the first-order reaction kinetics. Correlation between the results supported the quality assessment of the tested product in industrial and clinical settings. This orthogonal protocol is a useful tool in stability assessment of monoclonal antibodies and a key criterion for the biosimilarity assessment.

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“…SEC is effectively separating low molecular weight and high molecular weight species in mAbs [63]. SEC has found many applications like stability testing [64], quality control during manufacturing [65], in depth characterization of antibody-drug-conjugates (ADC's) [66] and assessing aggregate content in biosimilarity studies [67]. However, resolution of SEC is rather poor to clearly distinguish individual size variants.…”

Section: Separation Of Proteoforms Of Therapeutic Proteins 41 Separamentioning

confidence: 99%

Preparing Proteoforms of Therapeutic Proteins for Top-Down Mass Spectrometry

Hidayah¹,

Gaikwad²,

Heikaus³

et al. 2020

Proteoforms - Concept and Applications in Medical Sciences

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A characteristic of many proteoforms, derived from a single gene, is their similarity regarding the composition of atoms, making their analysis very challenging. Many overexpressed recombinant proteins are strongly associated with this problem, especially recombinant therapeutic glycoproteins from large-scale productions. In contrast to small molecule drugs, which consist of a single defined molecule, therapeutic protein preparations are heterogenous mixtures of dozens or even hundreds of very similar species. With mass spectrometry, currently highquality spectra of intact proteoforms can be obtained only, if the complexity of the mixture of individual proteoform-ions, entering the gas phase at the same time is low. Thus, prior to mass spectrometric analysis, an effective separation is required for getting fractions with a low number of individual proteoforms. This is especially true not only for recombinant therapeutic proteins, because of their huge heterogeneity, but also relevant for top-down proteomics. Purification of proteoforms is the bottleneck in analyzing intact proteoforms with mass spectrometry. This review is focusing on the current state of the art, especially of liquid chromatography for preparing proteoforms for mass spectrometric top-down analysis. The topic of therapeutic proteins has been chosen, because this group of proteins is most challenging regarding their proteoform analysis.

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Stability assessment of antibody-drug conjugate Trastuzumab emtansine in comparison to parent monoclonal antibody using orthogonal testing protocol

Cited by 38 publications

References 39 publications

Alteration of Physicochemical Properties for Antibody-Drug Conjugates and Their Impact on Stability

Alteration of Physicochemical Properties for Antibody-Drug Conjugates and Their Impact on Stability

Evaluation of the pattern and kinetics of degradation of adalimumab using a stability‐indicating orthogonal testing protocol

Preparing Proteoforms of Therapeutic Proteins for Top-Down Mass Spectrometry

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