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Therapeutic Proteins: Innovations in Medical Biotechnology Programs

Explore the advancements in protein-based therapies and the utilization of therapeutic proteins in medical biotechnology programs. Learn about protein replacement therapies and examples of proteins used in therapy. Discover the origins and production techniques of therapeutic proteins.

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Therapeutic Proteins: Innovations in Medical Biotechnology Programs

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  1. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat theUniversity of Pécs and at the University of Debrecen Identificationnumber: TÁMOP-4.1.2-08/1/A-2009-0011

  2. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat theUniversity of Pécs and at the University of Debrecen Identificationnumber: TÁMOP-4.1.2-08/1/A-2009-0011 József Tőzsér MolecularTherapies-Lectures 5-6 Protein replacementtherapies

  3. Protein-basedtherapies • Replacement of missingorabnormalproteins (e.g. Insulin) • Influencingsignaltransductionpathways (e.g. interferons) • Supplementation of growthhormones (e.g. PDGF) • Influencingthehaemostaticsystem (e.g. tPA) • Degradation of moleculeswithenzymes (e.g. Asparaginase • Use of protein vaccines (e.g. recombinant HPV vaccine)

  4. Examples of proteinsreplacedintherapy • Insulin (diabetes) • Albumin (hypoalbuminaemia) • Lactate (lactoseintolerance) • Factor VIII. (haemophilia) • Factor IX. (haemophilia) • Protein C (protein C deficiency) • Beta-glucocerebrosidase (Gaucher’sdisease)

  5. Examples of protein therapeuticproducts • Humulin (insulin) • Novolin (insulin) • Flexbumin 25% (albumin) • Lactaid (lactose) • ReFacto (F VIII) • BeneFix (F IX) • Ceprotin (aktivált protein C)

  6. Therapeuticproteins • The firsttherapeutic protein usewastheutilization of cowpox „protein vaccine" againstsmallpoxby Jenner (1796) • The firsttherapeutic protein usedwasinsulinbyBantingand Best (1922) • More than 200 peptideor protein has beenapprovedin USA foruseintherapy • Therapeuticproteinsmaycomefromdifferentsources

  7. Therapeuticproteins – sources ProteinOriginalsource • Albumin Human blood • InsulinPig, bovinepancreas • Factor VIII Human blood • Factor IX Human blood • KalcitoninSalmon • Anti-venom Horse, dunkeyblood • β-glucorerebrosidase Human placenta

  8. Therapeuticproteins – sources • Naturalsourse is usuallysparse and expensive • It is difficulttosatisfydemands • Hardtoisolatetheproduct • May lead toimmuneintolerance (e.g. incase of animanproteins) • Potentialviral and pathogencontaminations • Nowadays most of the protein drugsare made byrecombinanttechniques • Cheaper, safer, unlimitedsource

  9. Insulin, thefirst protein replacementdrug • InJanuary1922, Bantingand Bestusedfirstinsulintotreat a 14-years-old patientnamed Leonard Thomson • He became more illastheconsequence of theinjection, buthisbloodglucoseleveldecreased, thereforetheimprovement of thepreparationtechniquewasdecided • 6 weekslater a betterextractwasabletodecreasethebloodglucoselevelfrom520 mg/dLto120 mg/dL within 24 hours. • Leonard livedforadditional 13 years, he died of pneumonisaattheage 27

  10. Structure of insulin Twopolypeptidchains, A.chain: 21 aminoacidresidues B-chain: 30 aminoacidresidues Chainsareheldtogetherby a disulfidebridge Insulingene is locatedat chromosome 11

  11. Protein therapeutics – fromblood • The human body containsapprox. 6 liters of blood • 60-70% of blood is plasma, 8-9%- proteins. Therefore • it is an important protein source • Human plasmacontainsabout10,000 different • proteins • About 20 proteinsmakeupthe99% of thetotal protein • content of plasma • Annuallyseveralmillionliters of outdated • transfusionplasma is genereated, thereforeit is an • excellent and relativelyabundant protein source

  12. Examples of blood protein products • Factor VIII (correction of haemophilia) • Factor IX (correction of haemophilia) • Albumin (correction of hypoalbuminaemia) • IntravenousIgG(ininfections) • Antithrombin III (correction of coagulationdisorder) • Alpha I-PI (correction of emphysema)

  13. Cohnfractionation • Cohnfractionationwasoriginallydevelopedin 1946. • InCohnfractionationplasmaproteinsareselectivelyprecipitatedbyusingethanol, salt, temperaturechange. • Separation of thefractions is achievedbycentrifugation.

  14. Recombinanttechnologies • Theyweredevelopedinthe 1970s and 1980s • Paul Berg (1973): discovery of restrictionenzymes • Herbert Boyer (1978): cloning of the human insulingeneinto E. coli - Genentech • Fundamentallytwo major approaches • Expressin inisolatedcells • Expressionintransgenicplantsoranimals

  15. Hemostaticcascade XII XIIa XIa Ca2+ XI Extrinsic pathway IX IXa, VIII PL Ca2+ Intrinsic pathway VII + TF, Ca2+ VIIa TF, Ca2+ X Xa V PL Ca2+ Common pathway XIII prothrombin thrombin fibrinogen fibrin XIIIa + Ca2+ Allcomponents of theintrinsicpathwayareinthebloodstream. Extrinsicpathway is initiatedbythe TF that is normallyexclodedfromthe Bloodstream. Cascade (avalange) model. crosslinked fibrin

  16. Haemophilias A and B • Hemophilias A and B are caused by deficiencies in factors VIII or IX, respectively • Affect ~1 in 5,000 males in Hemophilia A, • ~1 in 30,000 males in Hemophilia B • Inherited as a recessive X-linked trait in both cases (Mother would be an unaffected carrier) • Treated by administration of factor VIII or factor IX concentrates • Recombinant factor VIII or IX • Gene therapy trials

  17. Haemophilia A – genetherapy • Only FVIII level is  1 % of normalcausesseveresymptoms (spontaneousbleedingintojoints, vital • organs), thereforeevenlowlevels of proteinsare • beneficial • Tightcontrol of FVIII production is notrequired • Broadtherapeutic index minimizestherisk of • overdose • Deliverytobloodstreamdoesnotrequireexpression • intheliver • Domain B is notrequiredforfunction, initsabsencetheexpressionlevelsarehigher

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