Predviđanje imunogeničnosti bioloških lijekova

professional thesis

• Author: Petra Lazarić Bošnjak
• Mentor: Jelena Filipović-Grčić (mentor)
• Committee member: Jelena Filipović-Grčić
• Committee member: Jasmina Lovrić
• Committee member: Biserka Cetina Čižmek
• Granter: University of Zagreb; Faculty of Pharmacy and Biochemistry; Zagreb
• Defense date and country: 2016, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Pharmacy; Pharmacy

Abstract

Biološki lijekovi se zbog porijekla i kompleksne strukture razlikuju od kemijski sintetiziranih molekula. Procjena imunogeničnosti važna je za biološke lijekove, a radi se prema važećim smjernicama u pretkliničkim i kliničkim studijama te je uključena u farmakovigilancijski Plan upravljanja rizicima. U ovom radu obrađuju se uzroci, kliničke posljedice i mogućnosti predviđanja imunogeničnosti terapijskih proteina. Mrežnom pretragom literature s ključnim riječima immunogenicity, biopharmaceuticals, biosimilars odabrani su znanstveni radovi, smjernice, preporuke i knjige na tu temu. Terapijski proteini se proizvode pomoću genetski modificiranih staničnih linija ili transgeničnih životinja. Zaostala procesna onečišćenja mogu biti uzrok imunogeničnosti. Glikozilacija ili pegilacija molekule mogu maskirati imunogenične epitope. Tvari koje migriraju iz primarne ambalaže mogu potaknuti stvaranje agregata većeg imunogeničnog potencijala. Produkcija protutijela kreće nakon podražaja imunosnog sustava iz diferenciranih limfocita B. Ona se selektivno vežu na komplementarni antigen tvoreći imunokompleks koji se neutralizira ili precipitira. Specijalizirane predočne stanice prerađuju strane antigene i na svojoj površini izlažu njihove dijelove (epitope) limfocitima T. Jačina imunoreakcije ovisi o imunogeničnosti, veličini, količini, filogenetskoj udaljenosti i putu unosa antigena te stanju organizma. Klinički je beznačajna prolazna pojava protutijela na rekombinantni somatropin. Stvaranje veznih protutijela dovodi do promijenjene farmakokinetike inzulina, gubitka učinkovitosti rekombinantnih interferona α i β ili inihibitora TNF-α i natalizumaba i pojačanih nuspojava (najčešće alergijskih reakcija). Neutralizirajuća protutijela u križnoj reakciji mogu neutralizirati endogeni protein s važnom fiziološkom funkcijom i ugroziti život bolesnika (eritropoetin ili
trombopoetin). Nadomjesna terapija u bolesnika s genskim defektima može u potpunosti propasti zbog stvaranja protutijela (čimbenik VIII ili IX). Probir uzoraka u kojima su protutijela prisutna i njihova karakterizacija na neutralizirajući učinak provode se kombinirano s pregledima pacijenata. Modeli ograničene vrijednosti kojima se predviđa imunogeničnost postojećih ili novih proteina su pokusne životinje, in vitro testovi otkrivanja epitopa koje prepoznaju limfociti i računalni alati za analizu proteina.

Abstract (english)

Biopharmaceuticals differ from chemical drugs due to their origin and complex structure. Immunogenicity assessment is important for all biopharmaceuticals and is a part of preclinical and clinical studies and pharmacovigilance Risk Management Plan. This paper discusses about causes, clinical consequences and ways of predicting immunogenicity of therapeutic proteins. References (papers, guidelines, recommendations and books) were found by web search that included key words immunogenicity, biopharmaceuticals, biosimilars. Therapeutic proteins are produced by genetically modified cell lines or transgenic animals. Process-related impurities can induce drug immunogenicity. Glycosilation and PEGilation of a molecule can hide immunogenic epitopes. Leachables can induce formation of more immunogenic aggregates. B lymphocytes produce antibodies after immune system stimulation. They complementarly bind with antigenes to an immunocomplex that is then neutralized or precipitated. Epitopes of the foreign antigenes are presented to the T lymphocytes by the antigene presenting cells. Intensity of an immunoreaction depends on immunogenic potential, size, amount and phylogenetic diversity of an antigene, route of administration and some patient-related characteristics. Transient antibody formation has no apparent clinical relevance in a case of recombinant somatotropine. Formation of binding antibodies alters insulin pharmacokinetics. Loss of drug efficacy is noted for recombinant interferons α and β or for the TNF-α inhibitors and natalizumab. Side effects such as allergic reactions are more common. Neutralizing antibodies can cross-react with an endogenous protein which is life-threatening condition.
Replacement therapy in gene deficient patients can fail completely due to antibody formation (factor VIII or IX).
Screening tests and in vitro characterization of found antibodies (their neutralizing effect is analyzed in cell-based tests) are performed together with the physical exams of the patients. Models for predicting immunogenicity (animals, in vitro epitope recognition by lymphocytes and bioinfirmatics, tools for structure analysis) have limited value but are used and combined.

• Keywords: biološki lijekovi; biofarmaceutici; imunogeničnost
• Keywords (english): biological drugs; biopharmaceuticals; immunogenicity; biosimilars
• Language: croatian
• URN:NBN: urn:nbn:hr:163:808724
• Study programme: Title: Clinical pharmacy; Study programme type: university; Study level: postgraduate specialist; Academic / professional title: sveučilišni/a magistar/sveučilišna magistra kliničke farmacije (sveučilišni/a magistar/sveučilišna magistra kliničke farmacije)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2016-03-22 13:41:25