Forced Degradation of Monoclonal Antibodies After Compounding: Impact on Routine Hospital Quality Control

Jaccoulet, Emmanuel; Daniel, Thomas; Prognon, Patrice; Caudron, Éric

doi:10.1016/j.xphs.2019.06.004

Cited by 12 publications

(7 citation statements)

References 38 publications

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“…Consequently, following the recommendations of the NHS protocol, these pertuzumab preparations would still be considered stable. [28] Interestingly, several studies have already shown significant instability of monoclonal antibodies when stored at 40-50°C, [31][32][33] which speaks for the pronounced stability profile of Perjeta ® .…”

Section: Discussionmentioning

confidence: 99%

Combined physicochemical and functional assessment of pertuzumab integrity supports extended in‐use stability

Jirschitzka

Längle

Lück

et al. 2023

Archiv der Pharmazie

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Pertuzumab (Perjeta®) is a monoclonal antibody approved for the treatment of HER2‐positive breast cancer. Before treatment, the concentrate must be diluted to obtain the ready‐to‐use infusion solution. Data on the storage stabilities of these preparations are lacking but important for all healthcare professionals in the area of outpatient chemotherapy. The aim of this study was to investigate the storage stability of the ready‐to‐use infusion bags and the concentrates from once‐opened vials over a period of up to 42 days. For a comprehensive and unambiguous assessment of pertuzumab's integrity, a panel of orthogonal analytical methods was employed, including a newly established mass spectrometry‐based peptide mapping procedure along with a reporter gene assay for monitoring cellular bioactivity. The herein presented data showed that the ready‐to‐use infusion solutions stored at 4 ± 2°C and at 20 ± 3°C without light protection, as well as the undiluted Perjeta® concentrates stored at 4 ± 2°C, were physicochemically stable and biologically active for 28 days. These results might eventually allow for infusion preparations in advance, thus improving the quality of patient care as well as the economic usage of pertuzumab.

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Section: Discussionmentioning

confidence: 99%

Combined physicochemical and functional assessment of pertuzumab integrity supports extended in‐use stability

Jirschitzka

Längle

Lück

et al. 2023

Archiv der Pharmazie

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“…Like all mAbs, nivolumab consists of a large, highly complex molecule and is extremely sensitive to its environment [6]. Before administration to patients, mAbs may be subject to environmental stress conditions such as exposure to light, and mechanical or thermal stresses, among others [7,8]. These stresses can have a negative impact on the structure of the protein, leading to its chemical or physical degradation [9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

“…Routine handling prior to administration-e.g., for sample preparation-or inadvertent mishandling-e.g., incorrect storage-can expose mAbs to these environmental stress conditions, so giving rise to the aforementioned forms of degradation [8]. These forms of degradation alter the quality of mAb-based products and can have a significant effect on their therapeutic efficacy, by limiting their bioactivity or increasing their immunogenicity [6,7]. One of the main concerns with therapeutic proteins is the increase of aggregation in clinical samples, a form of degradation that could modify the ability of the mAb to correctly interact with its specific target, and could lead to immunogenicity.…”

Section: Introductionmentioning

confidence: 99%

“…One of the main concerns with therapeutic proteins is the increase of aggregation in clinical samples, a form of degradation that could modify the ability of the mAb to correctly interact with its specific target, and could lead to immunogenicity. Detecting degraded mAbs before administration to patients is therefore crucial for ensuring high quality, efficacy, and safety [7].…”

Section: Introductionmentioning

confidence: 99%

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Comprehensive Analysis of Nivolumab, A Therapeutic Anti-Pd-1 Monoclonal Antibody: Impact of Handling and Stress

et al. 2022

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Nivolumab, formulated in the medicine Opdivo® (10 mg/mL), is a therapeutic monoclonal antibody (mAb) used in the treatment of different types of cancer. Currently, there is insufficient knowledge about the behaviour of this protein with regards to the risk associated with its routine handling or unintentional mishandling, or when subjected to stress conditions in hospitals. These conditions can be simulated in forced degradation studies, which provide an in-depth understanding of the biophysical and biochemical properties of mAbs. In this study, we carried out a physicochemical and functional characterisation of nivolumab, which was subjected to various stress conditions: heat, freeze/thaw cycles, agitation, light exposure and high hypertonic solution. We used a wide range of analytical techniques: Far-UV CD, IT-FS, DLS, SE/UHPLC(UV)-[Native]MS, and ELISA. The results show that exposure to light was the stress test with the greatest impact on the samples, revelling the formation of non-natural dimers and a different isoform profile. In addition, nivolumab (Opdivo®) demonstrated stability up to 60 °C (1 h). As regards functionality all the nivolumab (Opdivo®) stressed samples were found to be stable except for those subjected to light and agitation, and to a lesser extent, those subjected to FTC 5 and NaCl stresses.

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“…These studies are essential in that they are an integral part of biotherapeutics research and development and serve a variety of objectives ranging from early stage manufacturability evaluation to supporting comparability assessments both prior to and after approval for sale 11 . Forced degradation studies are also of great importance for quality control of these drugs after compounding in routine hospital use before administration, as they can test the impact of handling of the drug on its stability from the time it is released by the manufacturer up until its administration to patients 12 . In the most similar previously published paper, researchers studied AFL (Eylea) under physiological conditions as well as when incorporated into drug delivery systems 13 , and analysed the changes it undergoes when submitted to different temperatures and pH values.…”

mentioning

confidence: 99%

Comprehensive biophysical and functional study of ziv-aflibercept: characterization and forced degradation

Hermosilla

Pérez-Robles

Salmerón-García

et al. 2020

Sci Rep

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Bones 4 & natalia navas 1* Aflibercept (AFL) is an Fc fusion protein used in the treatment of colorectal cancers and different ophthalmological diseases. There are two medicines in which AFL is the active substance: Zaltrap and Eylea, referred as ziv-AFL and AFL respectively. No proper accelerated degradation studies were published on either AFL or ziv-AFL. These studies are essential during research, development and manufacturing stages. Here, we characterized ziv-AFL and submitted it to different stress conditions: light, 60 °C, freeze-thaw cycles, changes in pH, high hypertonic solution and strong denaturing conditions. We used an array of techniques to detect aggregation (SE-HPLC/DAD and DLS), changes in secondary structure (Far-UV circular dichroism), changes in conformation or tertiary structure (Intrinsic tryptophan fluorescence) and alterations in functionality (ELISA). Results indicate that aggregation is common degradation pathway. Two different types of aggregates were detected: dimers and high molecular weight aggregates attributed to β-amyloid-like structures. Secondary structure was maintained in most of the stress tests, while conformation was altered by almost all the tests except for the freeze-thaw cycles. Functionality, evaluated by its immunochemical reaction with VEGF, was found to be stable but with decrease when exposed to light and with likely partial inactivation of the drug when pH was altered. Fc-fusions proteins are a well-established class of biotherapeutics. They are composed of the Fc region of the IgG antibody (Hinge-CH2-CH3) and a desired linked protein. Although the top-selling biotherapeutics are monoclonal antibodies (mAbs), there is increasing use of therapeutic Fc-fusion proteins in medicine today 1. One of these is aflibercept (AFL), a recombinant human Fc-fusion protein that-as indicated in the assessment report of Zaltrap of the European Medicine Agency 2-"acts as a high-affinity soluble decoy receptor that preferentially binds to vascular endothelial growth factor A (VEGF-A), VEGF-B and placenta growth factor (PlGF) and prevents these factors from activating their endogenous receptors. By blocking this pathway, AFL exerts direct anti-cancer activity and boosts the anti-cancer activity of chemotherapy agents by preventing new tumour vessel growth, regressing existing tumour vessels, normalizing vasculature, negatively affecting tumour cell function, offsetting the effects of chemotherapy induction of VEGF levels and potentially inhibiting VEGF repression of dendritic cell function" 2. As a VEGF inhibitor, AFL is also classified as a VEGF-trap together with bevacizumab and ranibizumab. Cancer therapy is not the only field of medicine to benefit from AFL, which is also being used to treat several ophthalmological diseases characterized by neovascularization. As the administration to patient varies depending on the particular illness they are suffering, two different medicines are currently available, Zaltrap (Sanofi-Aventis US, LLC, Bridgewater, New Jersey, USA and Regeneron...

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Forced Degradation of Monoclonal Antibodies After Compounding: Impact on Routine Hospital Quality Control

Cited by 12 publications

References 38 publications

Combined physicochemical and functional assessment of pertuzumab integrity supports extended in‐use stability

Combined physicochemical and functional assessment of pertuzumab integrity supports extended in‐use stability

Comprehensive Analysis of Nivolumab, A Therapeutic Anti-Pd-1 Monoclonal Antibody: Impact of Handling and Stress

Comprehensive biophysical and functional study of ziv-aflibercept: characterization and forced degradation

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