scholarly journals Monoclonal antibody stability can be usefully monitored using the excitation-energy-dependent fluorescence edge-shift

2020 ◽  
Vol 477 (18) ◽  
pp. 3599-3612
Author(s):  
Michael J. Knight ◽  
Rachel E. Woolley ◽  
Anthony Kwok ◽  
Stuart Parsons ◽  
Hannah B. L. Jones ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Structural Heterogeneity ◽  
Forced Degradation ◽  
Degradation Study ◽  
Highly Active ◽  
Extreme Sensitivity ◽  
The Stability ◽  
Energy Dependent ◽  
Stable Molecule

Among the major challenges in the development of biopharmaceuticals are structural heterogeneity and aggregation. The development of a successful therapeutic monoclonal antibody (mAb) requires both a highly active and also stable molecule. Whilst a range of experimental (biophysical) approaches exist to track changes in stability of proteins, routine prediction of stability remains challenging. The fluorescence red edge excitation shift (REES) phenomenon is sensitive to a range of changes in protein structure. Based on recent work, we have found that quantifying the REES effect is extremely sensitive to changes in protein conformational state and dynamics. Given the extreme sensitivity, potentially this tool could provide a ‘fingerprint’ of the structure and stability of a protein. Such a tool would be useful in the discovery and development of biopharamceuticals and so we have explored our hypothesis with a panel of therapeutic mAbs. We demonstrate that the quantified REES data show remarkable sensitivity, being able to discern between structurally identical antibodies and showing sensitivity to unfolding and aggregation. The approach works across a broad concentration range (µg–mg/ml) and is highly consistent. We show that the approach can be applied alongside traditional characterisation testing within the context of a forced degradation study (FDS). Most importantly, we demonstrate the approach is able to predict the stability of mAbs both in the short (hours), medium (days) and long-term (months). The quantified REES data will find immediate use in the biopharmaceutical industry in quality assurance, formulation and development. The approach benefits from low technical complexity, is rapid and uses instrumentation which exists in most biochemistry laboratories without modification.

scholarly journals Monoclonal antibody stability can be usefully monitored using the excitation-energy-dependent fluorescence edge-shift

2020 ◽  
Author(s):  
MK Knight ◽  
RE Woolley ◽  
A Kwok ◽  
S Parsons ◽  
HBL Jones ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Structural Heterogeneity ◽  
Forced Degradation ◽  
Degradation Study ◽  
Highly Active ◽  
Extreme Sensitivity ◽  
The Stability ◽  
Energy Dependent ◽  
Stable Molecule

AbstractAmong the major challenges in the development of biopharmaceuticals are structural heterogeneity and aggregation. The development of a successful therapeutic monoclonal antibody (mAb) requires both a highly active and also stable molecule. Whilst a range of experimental (biophysical) approaches exist to track changes in stability of proteins, routine prediction of stability remains challenging. The fluorescence red edge excitation shift (REES) phenomenon is sensitive to a range of changes in protein structure. Based on recent work, we have found that quantifying the REES effect is extremely sensitive to changes in protein conformational state and dynamics. Given the extreme sensitivity, potentially this tool could provide a ‘fingerprint’ of the structure and stability of a protein. Such a tool would be useful in the discovery and development of biopharamceuticals and so we have explored our hypothesis with a panel of therapeutic mAbs. We demonstrate that the quantified REES data show remarkable sensitivity, being able to discern between structurally identical antibodies and showing sensitivity to unfolding and aggregation. The approach works across a broad concentration range (μg–mg/ml) and is highly consistent. We show that the approach can be applied alongside traditional characterisation testing within the context of a forced degradation study (FDS). Most importantly, we demonstrate the approach is able to predict the stability of mAbs both in the short (hours), medium (days) and long-term (months). The quantified REES data will find immediate use in the biopharmaceutical industry in quality assurance, formulation and development. The approach benefits from low technical complexity, is rapid and uses instrumentation which exists in most biochemistry laboratories without modification.

The Stability of the WHO Reference Thromboplastin NIBS & C 67/40

1979 ◽  
Vol 42 (04) ◽  
pp. 1135-1140 ◽  
Author(s):  
G I C Ingram
Keyword(s):  
Human Brain ◽  
Collaborative Study ◽  
Calibration Constant ◽  
Long Term Stability ◽  
Freeze Dried ◽  
Show Evidence ◽  
Human Material ◽  
Reference Preparation ◽  
The Stability

SummaryThe International Reference Preparation of human brain thromboplastin coded 67/40 has been thought to show evidence of instability. The evidence is discussed and is not thought to be strong; but it is suggested that it would be wise to replace 67/40 with a new preparation of human brain, both for this reason and because 67/40 is in a form (like Thrombotest) in which few workers seem to use human brain. A �plain� preparation would be more appropriate; and a freeze-dried sample of BCT is recommended as the successor preparation. The opportunity should be taken also to replace the corresponding ox and rabbit preparations. In the collaborative study which would be required it would then be desirable to test in parallel the three old and the three new preparations. The relative sensitivities of the old preparations could be compared with those found in earlier studies to obtain further evidence on the stability of 67/40; if stability were confirmed, the new preparations should be calibrated against it, but if not, the new human material should receive a calibration constant of 1.0 and the new ox and rabbit materials calibrated against that.The types of evidence available for monitoring the long-term stability of a thromboplastin are discussed.

Antiretroviral Treatment-Associated Labia Majora Lipohypertrophy: A Rare Case and Plastic Surgical Treatment Options

2017 ◽  
Vol 2 (1) ◽  
pp. 43
Author(s):  
Akmal Hisham ◽  
Devananthan Ilenghoven ◽  
Wan Syazli Wan Ahmad Kamal ◽  
Salina Ibrahim ◽  
Shah Jumaat Mohd Yussof
Keyword(s):  
Highly Active Antiretroviral Therapy ◽  
Daily Living ◽  
Treatment Options ◽  
Hiv Positive ◽  
Highly Active ◽  
Labia Majora ◽  
The Face ◽  
Central Fat

The emergence of highly active antiretroviral therapy (HAART) has revolutionized the prognosis of HIV-infected patients. However, the extended use of HAART is associated with a disfiguring complication termed lipodystrophy, a disorder of body fat maldistribution causing peripheral fat loss (lipoatrophy) and central fat accumulation (lipohypertrophy). Lipoatrophy commonly affects the face, legs, buttocks and arm, whilst lipohypertrophy frequently favours the abdomen, breast and dorsocervical region. To our knowledge, we present only the second documented case in the literature of a labia majora lipohypertrophy in a HIV-positive patient receiving long-term HAART. The severity of labial abnormality caused significant physical and functional morbidities. Labiaplasty with dermolipectomy of the labia majora and excisional lipectomy of the mons pubis was successfully performed. At a 6-month follow-up, patient had no recurrence with resolution of symptoms and resumption of normal activities of daily living (ADL).

Application of the method of mathematical modeling for forecasting channel deformations at the underwater crossing of the main pipeline

2020 ◽  
Vol 10 (6) ◽  
pp. 599-609
Author(s):  
Valery А. Gruzdev ◽  
◽  
Georgy V. Mosolov ◽  
Ekaterina A. Sabayda ◽  
◽  
...  
Keyword(s):  
Mathematical Modeling ◽  
Mathematical Model ◽  
Roughness Coefficient ◽  
Computational Domain ◽  
Channel Deformations ◽  
Geological Surveys ◽  
Kuban River ◽  
The Stability ◽  
Protective Structures

In order to determine the possibility of using the method of mathematical modeling for making long-term forecasts of channel deformations of trunk line underwater crossing (TLUC) through water obstacles, a methodology for performing and analyzing the results of mathematical modeling of channel deformations in the TLUC zone across the Kuban River is considered. Within the framework of the work, the following tasks were solved: 1) the format and composition of the initial data necessary for mathematical modeling were determined; 2) the procedure for assigning the boundaries of the computational domain of the model was considered, the computational domain was broken down into the computational grid, the zoning of the computational domain was performed by the value of the roughness coefficient; 3) the analysis of the results of modeling the water flow was carried out without taking the bottom deformations into account, as well as modeling the bottom deformations, the specifics of the verification and calibration calculations were determined to build a reliable mathematical model; 4) considered the possibility of using the method of mathematical modeling to check the stability of the bottom in the area of TLUC in the presence of man-made dumping or protective structure. It has been established that modeling the flow hydraulics and structure of currents, making short-term forecasts of local high-altitude reshaping of the bottom, determining the tendencies of erosion and accumulation of sediments upstream and downstream of protective structures are applicable for predicting channel deformations in the zone of the TLUC. In all these cases, it is mandatory to have materials from engineering-hydro-meteorological and engineering-geological surveys in an amount sufficient to compile a reliable mathematical model.

Influence of internal and external risks on sustainability of financial system of Аltai krai

2018 ◽  
Vol 35 (4) ◽  
pp. 133-136
Author(s):  
R. N. Ibragimov
Keyword(s):  
Sustainable Development ◽  
Financial Stability ◽  
Management Strategy ◽  
Financial System ◽  
Risk Management Strategy ◽  
The Sustainable Development ◽  
The Stability ◽  
The Impact

The article examines the impact of internal and external risks on the stability of the financial system of the Altai Territory. Classification of internal and external risks of decline, affecting the sustainable development of the financial system, is presented. A risk management strategy is proposed that will allow monitoring of risks, thereby these measures will help reduce the loss of financial stability and ensure the long-term development of the economy of the region.

Synthesis and Characterization of Potential and Degraded Impurities of Regadenoson

2020 ◽  
Vol 16 (8) ◽  
pp. 1130-1139
Author(s):  
Singaram Sathiyanarayanan ◽  
Chidambaram Subramanian Venkatesan ◽  
Senthamaraikannan Kabilan
Keyword(s):  
Mass Spectra ◽  
Degradation Products ◽  
Hplc Method ◽  
Forced Degradation ◽  
Spectroscopic Techniques ◽  
A2a Adenosine Receptor ◽  
Degradation Study ◽  
Related Substances ◽  
Adenosine Receptor Agonist

Background: Regadenoson is an A2A adenosine receptor agonist that is a coronary vasodilator and commonly used as a pharmacologic cardiac stressing agents. Methods: HPLC method was used for the analysis of related substances. The degraded impurities during the process were isolated and characterized by IR, Mass and NMR spectral analysis. Results: Forced degradation study of regadenoson under conditions of hydrolysis (neutral, acidic and alkaline) and oxidations suggested in the ICH Q1A(R2) was accomplished. The drug showed significant degradation under all the above conditions. On the whole, five novel degradation products were found under diverse conditions along with process related impurities which were not reported earlier. Conclusion: All the degradation products were well characterized by using advanced spectroscopic techniques like IR, 1H NMR, 13C NMR and Mass spectra. The identification of these impurities will be productive for the quality control during the production and stability behavior of the regadenoson drug substance.

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