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Karakterizacija mikronskih in vidnih proteinskih delcev v bioloških zdravilih.
ID Belko Parkel, Kaja (Author), ID Narat, Mojca (Mentor) More about this mentor... This link opens in a new window, ID Kuzman, Drago (Co-mentor)

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Abstract
Monoklonska protitelesa so beljakovinske molekule, ki so nagnjene k agregaciji, kar za biološko zdravilo ni sprejemljivo, saj lahko poveča imunogenost končnega produkta. Dolgoročno stabilnost proteina ocenimo z merjenjem proteinske agregacije v vzorcih, ki so izpostavljeni povišanim temperaturam in kasnejšo ekstrapolacijo podatkov z uporabo različnih modelov. Glede na različne mehanizme nastajanja agregatov, kinetiko agregacije ter adhezije delcev na površino vial lahko pri dejanskih dolgoročnih pogojih shranjevanja pride do višje koncentracije delcev v raztopini, ki je ni mogoče napovedati na tak način. V nalogi smo preučevali vpliv površine viale, temperature shranjevanja in prisotnosti soli na kinetiko procesa agregacije na več velikostnih skalah agregatov za dve različni monoklonski protitelesi. Pri obeh smo določili, da so pri koncentracijah, značilnih za biološka zdravila, omejujoč korak hitrosti agregacije bimolekularni trki. Hitrost agregacije lahko pri poljubni temperaturi in koncentraciji napovemo le za enega od testiranih monoklonskih protiteles, medtem ko pri drugem dodaten neznan proces povzroča odstopanje dejanskih rezultatov od napovedi. To predstavlja povečano tveganje pri izbiri formulacije na podlagi presejalnih testov pri povišani temperaturi in nizki koncentraciji, ki pa ga lahko zmanjšamo z dodatnimi temperaturnimi in koncentracijskimi pogoji testiranja.

Language:Slovenian
Keywords:agregacija, monoklonska protitelesa, biološka zdravila, napovedovanje agregacije
Work type:Master's thesis/paper
Typology:2.09 - Master's Thesis
Organization:BF - Biotechnical Faculty
Place of publishing:Ljubljana
Publisher:[K. Belko Parkel]
Year:2021
PID:20.500.12556/RUL-129111 This link opens in a new window
UDC:606:661.12:616-097.3:544.77.052.2(043.2)
COBISS.SI-ID:74560515 This link opens in a new window
Publication date in RUL:27.08.2021
Views:1052
Downloads:98
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Secondary language

Language:English
Title:Characterization of visible and subvisible protein particles in biopharmaceuticals
Abstract:
Monoclonal antibodies are protein molecules that are prone to aggregation, which is not acceptable for biopharmaceuticals, since it can increase the immunogenicity of the final product. Long-term protein stability can be assessed by measuring protein aggregation in samples exposed to elevated temperatures and subsequent extrapolation of data using different models. Due to different mechanisms of aggregate formation, aggregation kinetics and particle adhesion to the vial surface, higher particle concentrations in solution may occur under actual long-term storage conditions, which cannot be predicted from accelerated studies. We studied the effect of vial surface, temperature and presence of salt on the kinetics of aggregation process on multiple size ranges of aggregates for two monoclonal antibodies. Bimolecular collisions were found to be the limiting step of aggregation at concentrations specific to biologics. The rate of aggregation can be predicted at any temperature or concentration for only one of the tested monoclonal antibodies, while the other is likely to undergo an additional unknown process, which causes a deviation of prediction from the actual results. This poses an increased risk when selecting a formulation based on screening tests at elevated temperatures and low concentrations, which can be mitigated by additional temperature and concentration conditions.

Keywords:aggregation, monoclonal antibodies, biopharmaceuticals, aggregation propensity

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