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![Page 1: Medical biotechnology - an overview Maria Judit Molnar Institute of Medical Genomics and Rare Diseases Semmelweis University Budapest, Hungary.](https://reader030.fdocuments.us/reader030/viewer/2022033023/56649da75503460f94a92e74/html5/thumbnails/1.jpg)
Medical biotechnology- an overview
Maria Judit Molnar
Institute of Medical Genomics and Rare Diseases
Semmelweis University
Budapest, Hungary
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Conclusions
2
Biotechnology in medicine
Milestones in medical biotechnology
Achievements, paradigm shifts
Current trends and research
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Biotechnology in medicine
3
Biologic medicinal product
Biologicalproduct Biologic
Biologicaldrug
Biotech drug
Biotech
product
=
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Definition of biologics
4
„A biological medicinal product is a product, the active substance of which is a biological substance. A biological substance is a substance that is produced by or extracted from a biological source and that needs for its characterisation and the determination of its quality a combination of physico-chemical-biological testing, together with the production process and its control.”
COMMISSION DIRECTIVE 2003/63/EC, 3.2.1.1. b,
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Types of biologics
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Biologics
Advanced therapymedicinal products
Somatic cell therapy
Somatic cell therapy
Gene therapyGene therapy
Tissue engineeringTissue engineering
VaccinesVaccines
Blood or blood componentsBlood or blood components
Allergenic productsAllergenic products
Recombinant DNAproducts
Therapeutic proteinsTherapeutic proteins
Monoclonal antibodiesMonoclonal antibodies
Fusion proteinsFusion proteins
XenotransplantationXenotransplantation
COMMISSION DIRECTIVE 2003/63/EC, 3.2.1.1. b,
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Biologics vs. Small molecule drugs
6Source: Cecil Nick, TOPRA 2010
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Biologics vs. Small molecule drugs
7
IN SUMMARY, biologics are protein-like macromolecules. Potential risk: immunogenicity Parenteral administration
Small molecule drugs Biologics
Production Chemical synthesis Extracted from biological source or recombinant DNA techology
Molecular weight < 10 kDa > 10 kDa
Administration route Mainly oral route Mainly parenteral route
Immunogenicity Not an issue Could elicit immunological response
Follow-up molecules Generics Biosimilars
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Milestones in medical biotechnology
Conclusions
Biotechnology in medicine
Achievements, paradigm shifts
Current trends and research
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Major milestones in medical biotechnology
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1855
1973
1975
1977
1982
1986
2009
2012
Escherichia coli (E. coli) bacterium discovered (later becomes a major tool for biotechnology).
Genentech scientists and their collaborators produce the first human protein (somatostatin) in a bacterium (E. coli).
Eli Lilly and Company markets recombinant human insulin - the first such product on the market.
Cohen and Boyer develop genetic engineering techniques to "cut and paste" DNA and reproduce the new DNA in bacteria.
First therapeutic monoclonal antibody approved by FDA (muromonab for organ transplant rejection prevention).
Köhler and Milstein: hybridoma technology (Nobel prize 1984).
First tissue engineered product approved in the EU (ChondroCelect).
First gene therapy approved in the EU (Glybera).
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Recombinant DNA products
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CLONED CELLS WORK LIKE A FACTORY,
PRODUCING THE DESIRED PROTEIN BESIDES THEIR
OWN PROTEINS.E. coli
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Recombinant DNA products manufacturing process
11
Multi-step manufacturing process
1. Cell line genetic cloning and selection2. Upscale (= fermentation)3. Downscale (= purification)4. Formulation5. Fill and finish
Cell lines•Prokaryotic (e.g. E. coli)•Eukaryotic (e.g. Chinese Hamster Ovary)
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12
Milestones in medical biotechnology
Conclusions
Biotechnology in medicine
Achievements, paradigm shifts
Current trends and research
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Important therapeutic fields of recombinant DNA products
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Endocrinology
Cardiology
Ophtalmology
Infectious diseases
Transplantation medicine Haematology
Intensive care
Asthma
Oncology
Inflammatory bowel diseases
Neurology
Psoriasis
RheumatologyAutoimmune diseases
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ENDOCRINOLOGYInsulin
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From the 1920’sinsulin was derived from porcine / cattle pancreas for therapeutic use (organotherapy)
1982first recombinant insulin on the European market
2014multiple recombinant insulin products on the market
Rapid-actingShort-actingIntermediate-actingLong-actingPre-mixed
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ENZYMESGaucher’s disease and
imiglucerase
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Gaucher’s disease• lysosomal disease• deficit of the enzyme glucocerebrosidase • accumulation of glucocerebrosides• autosomal recessive trait
Therapy of Gaucher’s disease• enzyme substitution therapy• e.g. imiglucerase
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Pompe Disease
Muscle weakness, atrophyAlpha glycosidase deficiencyAutosomal recessiv
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Source: International Society for Mannosidosis & Related Diseases
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Monoclonal antibodies(abbreviated as mAbs)
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„…like a key in a keyhole”
TARGETED TARGETED THERAPYTHERAPY
„bind to a corresponding antigen in a highly specific manner…”
Schneider, Curr Pharm Biotechnol., 2008
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Monoclonal antibodiesmechanism of action
19
antagonism apoptosis CDC ADCC transporter
Complement dependent cytotoxicity
Antigen dependent cellular cytotoxicity
Lutterotti & Martin, Lancet Neurol, 2008
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ONCOLOGYTrastuzumab
20
Conventional chemotherapy• like „carpet bombing” –> frequent adverse events
Monoclonal antibodies (mAbs)• targeted therapy
better outcomes less adverse events
An example from oncology: Trastuzumab• indication: HER2 positive metastatic breast cancer• HER2 is a type of growth factor receptor• HER2 positive histology: in approx. ¼ of the cases• trastuzumab targets HER2 and kills cancer cells
Source: Herceptin®, European Public Assessment Report
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ONCOLOGY + AUTOIMMUNE DISEASE
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CD20• antigen present on mature B cells• not present on pre-B cells and plasma cells• B cells are key players in immune responses more specifically in
humoral immunity
Rituximab• monoclonal antibody (mAb)• targeting CD20 with high specificity, and depletes B cells
Indications of rituximab• Oncological diseases
• non-Hodgkin’s lymphoma• chronic lymphocytic leukemia
• Autoimmune diseases• rheumatoid arthritis• specific types of vasculitis
Source: MabThera®, European Public Assessment Report
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AUTOIMMUNE DISEASE
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Etanercept• fusion protein• Fc part of a mAb + 2 pieces of TNF-receptors• targeting TNF-alfa
TNF-alfa• cytokine• plays important role in inflammatory processes
Source: Enbrel®, European Public Assessment Report
Indications of etanercept• rheumatoid arthritis• juvenile idiopathic arthritis• ankylosing spondylitis• psoriatic arthritis• plaque psoriasis• paediatric plaque psoriasis
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Vaccines
23
Prophylactic vaccines against infectious diseases e.g. Hepatitis B vaccination
Therapeutic vaccines
e.g. cancer vaccines intensive research is ongoing
Production derived from natural source recombinant DNA technology
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Blood and blood components
24
For the treatment of anaemia thrombocytopenia clotting deficiencies
Blood components red blood cells white blood cells plasma clotting factors platelets
Whole blood
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Allergenic products
25
Application
used for specific immunotherapy (SIT)
in vivo diagnosis of immunoglobulin E (IgE)-mediated allergic diseases
E.g. Prick skin allergy test
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Gene therapy
26
• First gene therapy approved in EU• Recurrent pancreatitis (lipoprotein lipase deficiency)• Vector: adeno-associated virus
Source: European Medicines Agency homepage
„contain genes that lead to a therapeutic effect. They work by inserting 'recombinant' genes into cells, usually to treat a variety of diseases, including genetic disorders, cancer or long-term diseases. A recombinant gene is a stretch of DNA that is created in the laboratory, bringing together DNA from different sources”
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The history of the gene therapyThe history of the gene therapy
1977 - A gene was successfully delivered into mammalian cells1990 - First human gene therapy was approved: SCID1999 - J. Gelsinger with OTC deficiency died from organ failure
after gene therapy2000 - A. Fischer cured children with SCID using retroviral
vector, 2 of the children developed leukemia. FDA halted the use of retroviruses in the US
2006 - Patients was successfully treated with metastatic melanoma using killer T cells genetically retargeted to attack the cancer cells
2006 - Succesfull gene-based th. for the treatment of HIV: lentiviral vector for delivery of an antisense gene
againts HIV envelope2009 - Researchers succeeded at halting
adrenoleukodystrophy, using a vector derived from HIV to deliver the gene for the missing enzyme
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The number of gene therapeutical clinical trials The number of gene therapeutical clinical trials
2012 N:3398
2006 N:1064
Phase I N:1023
Phase I/I N:342
Phase II N:1237
Phase II/III N:214
Phase III N:562
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General applications ofGeneral applications of therapeutictherapeutic gene transfergene transfer
1. Molecular therapy for genetic diseases 2. Establishment of a stable gene reservoir as a source of therapeutic proteins in non - genetic diseases
3.. Destruction of malignant cells in neoplasias
4. DNA vaccines
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23.04.19.
Vectors
Viral Nonviral
PlasmidArteficial Chr
LiposomesDNAsomes
Nanoparticlees
RetroHerpesAdenoAAVLenti
Strategies
Gene delivery
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Molecular therapiesMolecular therapies
DNA modulating therapies Gene replacement – to replace the defected gene Gene transfer – to upregulate therapeutic protein Gene editing – to correct the defected gene Gene shifting – to upregulate healthy mtDNA molecules, change ratio of
heteroplasmy
RNA modulating therapies Exon skipping by antisense oligonucleotides Exon inclusion by antisense oligonucletotides Mutant RNA removal Inactivation of the mutant mRNA by RNAi Destruction of the mutant mRNA by ribozymes
Protein modulating therapies Neutralization of the mutant protein Regulating the level of the haploinsufficient protein Upregulating compensatory molecule
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TheThe Kaplitt Kaplitt ExperimentExperiment
Tp Tp “calm down” the overactive neurons of the subthalamic nucleus which “calm down” the overactive neurons of the subthalamic nucleus which gives rise to signals that cause bradykinesia and tremor in Parkinson’s gives rise to signals that cause bradykinesia and tremor in Parkinson’s
diseasedisease
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• A mutation-specific therapy Providing personalized medicine Simultaneously may correct all isoforms Maintains the original tissue-specific gene regulation The antisense compounds inducing exon skipping are small
synthetic, and highly sequence-specific
EXON SKIPPINGEXON SKIPPING
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Exon skipping in Duchenne MDExon skipping in Duchenne MD13% of DMD patients: correct deletions of 50, 52, 45-50, 48-50, 49-50exons13% of DMD patients: correct deletions of 50, 52, 45-50, 48-50, 49-50exons
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Progress in AON exon skipping therapy in DMDProgress in AON exon skipping therapy in DMD
TimelinesTimelines 2007 2008 2009 2010 2011 2012 20132007 2008 2009 2010 2011 2012 2013
PRO051Prosensa/GSK
2OME AON
EteplirsenAVI
PMO AON
Ph IIm.
Ph I/IISystemic adm, iv, weekly
Ph I/IIStudy extension.
Ph INon ambulant
Ph IIDosing
Ph IIIEfficacy
Ph IIm.
Ph I/IISyst. admin. sc, 3 w
Ph I/IIDosing
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P15 P17 P18
P19
Pre
Post
Post Pre Post Pre Post Pre Post Pre
Results: Lancet 2011 Aug 13; 378(9791):595-605
P15 P17 P18
• 7 patients responded to treatment dose higher than 2 mg/kg• Mean dystrophin fluorescence intensity changed from 8·9% to 16·4%• The cytotoxic T cells in the post-treatment muscle biopsies decresed in the two high-dose cohorts• In future studies higher doses of eteplirsen for longer periods of time will be administered
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Somatic cell therapy
37
• approved in the EU (2013)• autologous peripheral blood mononuclear cells activated with PAP-GM-CSF
Sources: European Medicines Agency homepage; Barar & Omidi, BioImpacts, 2012
„contain cells or tissues that have been manipulated to change their biological characteristics. They can be used to cure, diagnose or prevent diseases”
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Stem cells
38
Embryonic stem cells
Adult or somatic stem cells• Bone marrow (hematopoietic) stem cells• Mesenchymal stromal / stem cells• Tissue-specific progenitor cells with a more restricted differentiation capacity responsible for normal tissue renewal and turnover (neurons, intestine, skin, lung and muscle)
Induced pluripotent stem cells
Genetically modified stem cells
Source: EMA/CAT/571134/2009
„cells with self-renewing capacity i.e. the capability to generate daughter cells
and multi-lineage differentiation capacity. Stem cells are capable of proliferation as stem cells in an undifferentiated form”
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Stem cells
39
e.g. ReNeuron’s ReN001
Phase 1 trial is ongoing, phase 2 trial application submitted
For the treatment of ischemic stroke
Potential applications of stem cells
metabolic, degenerative and inflammatory diseases
repair and regeneration of damaged or lost tissues
treatment of cancer
Source: EMA/CAT/571134/2009; ReNeuron homepage
Umbilical cord stem cell preservation
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Tissue engineered products
40
ChondroCelecto first advanced therapy medicinal product in the EU in 2009
MACI o matrix autologous chondrocyte implantationo approved in EU in 2013
Source: European Medicines Agency homepage
„contain cells or tissues that have been modified so they can be used to
repair, regenerate or replace tissue”
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Regenerative medicine
41
3D printing
Bone grafts
Blood vessels
Ear printing
Printing of a kidney
Liver printing with hepatocytes (awaited for 2014)
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42
Milestones in medical biotechnology
Conclusions
Biotechnology in medicine
Achievements, paradigm shifts
Current trends and research
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Personalized medicine
43
To date more than 100 drugs approved by FDA have information on pharmacogenetic biomarkers in the labelling.
Examples of individualized / tailored therapies
Metastatic breast cancer• Drug: trastuzumab (Herceptin®)• Biomarker: HER2 positivity of tumor
Duchenne muscular dystrophy• exon skipping
"the right patient with the right drug at the right dose at the right time."
Source: FDA homepage
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Market potential
44
In 20124 of the 10 top selling pharmaceuticals were biologics
What is projectedfor 2016?
Source: Elena Wolff-Holz, European Antibody Congress, 2012; IMS Health Top 20 Global Products 2012
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Trends in marketing authorizations in the US
45
NOTE: Approvals by the Center for Biologics Evaluation and Research (CBER) are not included in this drug count.
Mullard, Nature Reviews Drug Discovery, 2014
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Trends in marketing authorizations in the US / 2
46Dowden et al., Clinical Pharmacology & Therapeutics, 2013
NOTE: Approvals by the CBER are included in the figures.
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Costs and risks associated to biotech drug development
47
Approx. $ 1 billion out-of-pocket money for 1 new drug.
Biotech product development is somewhat more expensive than small molecule development ($1241 vs $899
million).
DiMasi et al., Manage. Decis. Econ. 2007; DiMasi et al., Nature, 2010; goldengatebridge.org (USD currency in 2003)
≈
Average research success rate for clinical development: 1:6.
Biotech products are somewhat better in terms of pre-market success rate compared to small molecules.
Golden Gate bridge, San Francisco
Approx. 8-12 years of research for 1 new drug.
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Recent metrics on biotech Research & Development
48CSDD, Impact Report, November/December 2013
In 2012, the 21 largest pharmaceutical companies had 429 biotech products in clinical development, of which 58% were monoclonal antibody products.
From 2001 to 2012 (11 years)… the number of biotech products in clinical development grew 155%, from 355 to 907. financing of biotech research increased 10-fold, from $10.5 billion to $103 billion. worldwide growth in biotechnology product sales grew 353%, from $36 billion to $163 billion.
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49
Milestones in medical biotechnology
Conclusions
Biotechnology in medicine
Achievements, paradigm shifts
Current trends and research
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Conclusions
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• Some diseases can now be cured / controlled effectively with biologics, and become part of the standard of care.
• Biologics are important tools of targeted therapy and help to fulfil the principles of personalized medicine.
• Intensive research is ongoing for new biotech therapies.
• Hungary is strong in the research and production of biotechnological treatments.
• Further innovative products are expected in the future especially in the field of the regenerative medicine.
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Thank you for your attention!
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Questions & Answers