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KV 8.31 Passive Immunisierung und Antikörpertherapien Konteptvorlesung 3 Themenblock 8 Beda M. Stadler Institut für Immunologie Diese Folien stehen auch.

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Präsentation zum Thema: "KV 8.31 Passive Immunisierung und Antikörpertherapien Konteptvorlesung 3 Themenblock 8 Beda M. Stadler Institut für Immunologie Diese Folien stehen auch."—  Präsentation transkript:

1 KV 8.31 Passive Immunisierung und Antikörpertherapien Konteptvorlesung 3 Themenblock 8 Beda M. Stadler Institut für Immunologie Diese Folien stehen auch als PPT Files zum download bereit unter:

2 Protein Pharmaceutika FDA-zugelassene biotechnologisch hergestellte (Proteine/Peptide) Medikamente Protein Pharmaceutika kosten derzeit ca. $50 Milliarden/Jahr 2

3 3

4 Top Ten Monoclonal Antibodies 2009/2010 Generic NameBrands®Indications Sales $ billion 2009 / 2010 InfliximabRemicadeRA,UC,CD,Ps,PsA,AS BevacizumabAvastinColon cancer RituximabRituxanNHL,RA AdalimumabHumiraRA,Ps,JIA,PsA,AS,CD TrastuzumabHerceptinBreast Cancer CetuximabErbituxColon, head and neck cancer RanibizumabLucentisWet macular degeneration NatalizumabTysabriMultiple sclerosis OmalizumabXolairAllergic Asthma PalivizumabSynagisRSV Thearapeutische Antikörper auch zu teuer für uns?

5 KV 8.35 Übersicht / Lernziele Antikörper Produktion einst Passive Immuntherapie einst Monoklonale / rekombinante Antikörper Antikörper als Therapie für: Immunsuppression Krebs Therapie Immunmodulation Anti-Adhäsionstherapien Rückblick und Zukunft Paul Ehrlich vor 100 Jahren

6 KV 8.36 Passive Immuntherapie einst

7 KV 8.37 Passive Immuntherapie mit polyklonalen Antikörpern Multispender human Gammaglobulin oder Pferd Antitoxin Tetanus Pferd AntiveninSchlangenbiss Multispender human GammaglobulinTollwut Multispender human GammaglobulinMasern Multispender human GammaglobulinHepatitis A and B Pferd AntitoxinDiphtherie Pferd AntitoxinBotulismus Pferd AntiveninSchwarze Spinnenbiss TherapeutikumKrankheit

8 KV 8.38 Monoklonale Antikörper Hybridoma Technologie

9 KV 8.39 Therapeutische Maus Antikörper Probleme Immunogenizität (humane anti-Maus AK, HAMA) keine Effektor Mechanismen (Maus Fc) Unerwartete Toxizität (Reaktivitiät mit normalem Gewebe, Kreuzreaktion mit anderen Antigenen) Verlust von Tumorantigen (z.B. anti-idiotyp Behandlung von Lymphomen)

10 KV Immunogenicität von Infliximab (chimärer monokl. Ak gegen TNFα) Human anti-mouse Ab Human/mouse chimeric Ab (Infliximab) 61% of patients had detectable antibodies after the fifth infusion of Infliximab Incidence of the formation of antibodies to Infliximab is reduced with immuno- suppressive therapy

11 KV Diversity of Antibodies is Generated by Gene Rearrangement Dank Wissen um Grundlagen rekombinante Antikörper

12 Die Domänenstruktur hilft zum Umbau von Antikörpern KV Fab Fv Fc Hinge VLVL VHVH CLCL CHCH CH2CH2 CH3CH3 VHVH VLVL scFvIgG

13 KV Ezzell, Scientific American Humanisierung von Maus Antikörpern HumanMausChimäreHumanisiert

14 Therapeutische Antikörper KV Generic nameTrade name Target Type MuromonabOrthoclone OKT3CD3Murine AbciximabReoProPlatelet GP IIb/IIIaMurine RituximabRituxanCD20Chimeric DaclizumabZenapax IL2R Humanized BasiliximabSimulectIL2RChimeric PalivizumabSynagisRSVHumanized InfliximabRemicade TNF Chimeric TrastuzumabHerceptinHer2/neu/ErbB2Humanized GemtuzumabMylotargCD33Humanized AlemtuzumabCampath-1HCD52Humanized EndrecolomabPanorex17A-1Humanized Ibritumomab tiuxetanZevalinCD20Chimeric AdalimumabHumira TNF Human OmalizumabXolairIgEHumanized CentuximabErbituxEGFR/ErbB1/Her1Humanized BevacisumabAvastinVEGFHumanized EfalizumabRaptivaCD11aHumanized

15 KV FabscFvFvdsFvVHVH Mono- & plurivalente Ak-Fragmente scFv DiabodyTriabodyTetrabody

16 KV Transgene Humanisation humane Antikörper in human Ig transgenenen Mäusen

17 KV Der Wunsch nach humanen AK mRNA von B Zellen mRNA cDNA PCR of H&L chain genes PCR of H&L chain genes Blut Antikörper (Fab) Expression auf p3 des M13 Phagen Klonierung und Rekombination Humane Antikörper mittels Repertoire Klonierung

18 KV Expression von Antikörpern Antikörper DNA Antikörper Vektor Transfektion Zellkultur Expression

19 KV Industrielle Antikörper Produktion FlaskSpinner Bioreaktor (Bench scale) Bio Reactor (Plant) SubkulturProduktion 1mL 100mL 1L 1Lx3 12L 100L 300L 2000L 10000L

20 KV Ersatz von passivem IgG durch rekombinante anti-RhD RhD + Erythrozyten rekombinante Antikörper mittels phage display

21 KV Neue Therapeutische Antikörper

22 KV Immunsuppressive Anikörper (anti-T Zell Antikörper) Lymphocyte immune globulin (Atgam®) lytic to human thymic lymphocytes; blocks T-cell responding Anti-CD3: (OKT3®, muromonab-CD3) binds CD3, blocks antigen binding; depletes T-cells Anti-CD3: huOKT3 Humanized version of OKT3 Anti-CD4: OKT4 less infusion-related reaction Anti-Tac monoclonal antibody (Zenopax®) binds IL-2 receptor of activated T-cells causing their inactivation

23 KV OKT3 Campath-1H CD3 CD52 Polyclonal Anti-Thymocyte Globulin Lymphocyte Depleting Antibody Therapies

24 KV Immunsuppressive Anikörper (anti B-Zell Antikörper) Anti-CD20: Rituxan® (Rituximab) results in mature B-cell depletion and induces apoptosis (B-cell mediated vascular rejection) for B- cell Non Hodgkins Lymphoma anti-CD52: Campath-1H (Alemtuzumab) depletes T and B lymphocytes, NK cells, monocytes and macrophages slg DR CD19 CD20 CD22

25 KV Side effects fever chills weakness headache nausea vomiting diarrhea low blood pressure rashes

26 KV Complement pathway Tumor cell ADCC Anti-Idiotyp IL-1 TNF Mac NK -Tox -Tox -Tox -Tox -Y-90 -Drug - Drug -Drug Antikörper Krebs Therapie Strategien 5 Anti Angiogenese

27 KV Antikörper-abhängige Zytotoxizität (ADCC) Apoptosis via Induktion von intrazellulären Signal-Pathways Complement-abhängige Zytotoxizität (CDC) Ziel Zelle NK Zelle Strategie 1 Antikörper vermittelte Zytotoxizität

28 KV Binds HER-2 (human epidermal growth factor receptor 2), a growth factor receptor found on some tumor cells (some breast cancers, lymphomas). Over-expression of HER2 causes increased cell growth and reproduction. HER2 protein over-expression affects approximately 25% to 30% of breast cancer patients z.B. Herceptin® (Trastuzumab) normal celltumor celltreatment

29 KV HLA-DR TDT CD19 CD10 CD20 CD22 CD21 CD38 Stem cell Pro- B cell Pre- B cells Immature B cell Mature B cell Activated B cell Plasma cell Neoplasias: Leukemias from B-cell Precursors (B-ALL) B-cell Lymphomas (NHL, CLL) Multiple Myeloma Antigen independentAntigen dependent Strategie 1: maligne B-Zellen

30 KV Strategie 1 anti idiotypische Antikörper (B-Zell Lymphome)

31 KV Strategie 2: Verschiedene Isotope Nackter AntikörperRadiomarkierter Antikörper

32 KV Isotopen markierte Antikörper LymphoCide (anti CD22, found on some B-cell leukemias. Tositumomab (Anti-CD20) Lym-1 (Oncolym). Anti- HLA-DR expressed at high levels on lymphoma cells.

33 KV A conjugate of a monoclonal antibody that binds CD33 (cell-surface molecule expressed by the cancerous cells in acute myelogenous leukemia (AML) but not found on the normal stem cells needed to repopulate the bone marrow) and calicheamicin, an oligosaccharide that blocks the binding of transcription factors (proteins) to DNA and thus inhibits transcription. Strategie 3: Mylotarg® (anti CD-33)

34 KV Strategie 4: Enzym markierte Antikörper Antibody directed enzyme prodrug therapy (ADEPT) Tumor antigen Tumorzelle Zytotoxischer Wirkstoff Prodrug Enzym Antikörper

35 KV Strategie 5: Anti-Angiogenes

36 KV Recombinant humanized monoclonal antibody against VEGF; prevents binding with its receptor. Blocks stimulation of angiogenesis stops tumor growth. Anti-VEGF: Avastin ®

37 KV Immunmodulatorische Antikörper Anti-TNF Therapie Infliximab Etanercept Humira etc (Biosimilarika) Anti-IgE Therapie Xolair

38 KV Anti-TNF- : Infliximab Binds specifically to TNF-, neutralizing its activity Used for Crohns disease and rheumatoid arthritis Side-effect: can convert a latent case of tuberculosis into active disease Chimeric monoclonal antibody

39 KV Infliximab: Mechanism of Action Binds and neutralizes soluble and membrane bound TNF TNFR2 Nucleus NF B transcription No Signal TNF

40 KV Other Postulated Mechanisms of Action… Antibody dependent cell-mediated cytotoxicity (ADCC) Lysis of TNF -expressing cells through complement (C) activation Complement Activation C Complement Receptor Phagocyte T Cell Phagocytosis

41 KV EtanerceptInfliximab TNF- : Rezeptor oder Antikörper

42 KV Biosimilarika: z.B. anti-TNF Generic Name Brand name (source) Molecular Derivation Development status Infliximab Remicade ® Human/mouse chimeric anti-human TNF monoclonal Ab Approved in US & Europe for CD & RA Etanercept Enbrel ® Human recombinant p75 (TNF receptor fusion protein) Good for RA CDP-571 Humicade Humanised anti- human TNF mAb Trials ongoing for CD & ulcerative colitis CDP-870 N/A (Celltech) Humanised anti-TNF mAb fragment Phase III trials ongoing Adalimumab Humira ® Human anti-human TNF mAb Approved for RA

43 Omalizumab (Xolair®) B MC free IgE FcεRI Degranulation Inflammation Symptoms IgE FcεRI Mediator Release Allergic Inflammation Holgate S. et al., J Allergy Clin Immunol 2005 vol. 115 (3) pp anti-IgE Omalizumab Reduces IgE and FcεRI Levels

44 KV Anti-IgE: Omalizumab (Xolair ® )

45 KV Anti Adhäsionstherapie Efalizumab (Raptiva®) Anti-CD11a (subunit of LFA-1) inhibits activation of T cells Alefacept (Amevive®) binds to CD2 on memory effector T lymphocytes, inhibiting their activation Abciximab (Reopro®) Anti-Gp IIb/IIIa

46 KV Efalizumab (Raptiva) Interactions between leukocyte-function associated antigen type 1 (LFA-1) and intercellular adhesion molecules are important in the pathogenesis of psoriasis. Efalizumab, a humanized monoclonal antibody, binds to the subunit (CD11a) of LFA-1 and inhibits the activation of T cells

47 KV Alefacept (Amevive®) CD2 Anti-CD2

48 KV Anti-GpIIb/IIIa Inhibits the clumping of platelets by binding the receptors on their surface that normally are linked by fibrinogen. Abciximab (Reopro®) Helpful in preventing reclogging of the coronary arteries in patients who have undergone angioplasty.

49 KV Ausblick: mehr Antikörper für… Transplantation Knochenmark, Niere, Leber und Pancreas Insel Zellen. Krebs Metastatic Brust Krebs, CLL, non-Hodgkins Lymphome. Autoimmunkrankheiten Rheumatoide Arthritis, Psoriasis, Multiple Sclerosis, Crohns Krankheit. Infektionskrankheiten Respiratory syncytial virus, Cytomegalovirus, Septikämien. Allergien: Mehr als 150 weitere Ak in der Pipeline…


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