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giovedi 20 Aprile Lezione generale sui principi della microscopia - Gabriele Baj Giovedi 27 aprile Che cosa può fare un biologo/biotecnologo dopo la laurea ? Tiziano Gaiotto (UK)
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now require 7.6 years on average to complete the clinical development process and receive marketing approval, Total development and approval times for mAbs, one of today's premier biotech tools, compare favorably with small molecule drugs, which require an average of 7.5 years to follow the same path, and with all biotech products, which require an average of 8 years.
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Antibody revenue over the past few years
In 2000 antibody revenue was billion USD Between 2001 and 2002, the market grew by 37% per year, reaching 5.4 billion USD in 2002 It is estimated that 2008 sales will be 16.7 billion USD
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Global Monoclonal Antibodies Market Review 2008 (World Top Ten mAbs)
Monoclonal antibodies is one of the current success story of the modern biotechnology R&D. Thirty therapeutic mAbs have been approved around the world, including 23 in the United States. The global sales of monoclonal antibodies were $33 billion in 2008 as compared to $27 billion in 2007. Remicade was the market leader with sales of $6.5 billion in 2008, followed by Rituxan, Herceptin, Avastin and Humira. There were 8 monoclonal antibodies with sales of $1 billion or more in 2008.
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Monoclonal Antibodies (mAbs) Market Size Worth $245 Billion By 2024
November 2016 | Report Format: Electronic (PDF) The global monoclonal antibodies (mAbs) market was valued at USD 85.4 billion in 2015 and is expected to reach a value of USD 245 billion by 2024. the global market is expected to rise at a CAGR of 12.6%. Increasing R&D pertaining to the development of therapeutic mAbs coupled with supportive government initiatives is expected to drive the monoclonal antibodies market growth over the forecast period.
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2012 global sales of antibody-based therapeutics exceeded USD50 billion 6 of the top 12 selling drugs in 2012 were antibody-based. The 6 products are: #1 adalimumab (Humira®), with sales of USD9.265 b #3 rituximab (Rituxan®), with sales of USD b; #5 trastuzumab (Herceptin®), with sales of USD b; #7 infliximab (Remicade®), with sales of USD b; #8 bevacizumab (Avastin®), with sales of USD b; #11 etanercept (Enbrel®) with sales of USD b.
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Trade name Company Target Source Year Indication Orthoclone® Ortho Biotech, Inc. (subsidiary of J&J) CD3 all rodent 1986 Transplantation rejection ReoProTM Centocor, Inc. (subsidiary of Johnson & Johnson) and Eli Lilly GPIIb, IIIa chimeric 1994 High risk angioplasty RituxanTM Biogen Idec and Genentech, Inc. CD20 Non-Hodgkin’s lymphoma, rheumatoid arthritis REMICADE® Centocor, Inc. (subsidiary of Johnson & Johnson) TNF-a 1998 Crohn's disease Simulect® Novartis CD25 SynagisTM Medimmune RSV F protein humanized RSV infection Zenapax® Hoffmann-La Roche Inc., Protein Design Labs 1997 Herceptin® Genentech HER-2 Breast cancer MylotargTM UCB and Wyeth CD33 2000 Acute Myeloid Leukemia Campath® Millenium Pharmaceuticals, Inc. and Berlex Laboratories, Inc. CD52 2001 Chronic lymphotic leucemia, T-cell lymphoma Zevalin® Idec Pharmaceuticals Corporation murine â with yttrium-90 or indium-111 2002 Non-Hodgkin's lymphoma HUMIRATM Abbott Laboratories/Cambridge Antibody Technology human Inflammatory diseases – mostly autoimmune disorders like rheumatoid arthritis, psoriadic arthritis, Morbus Chron Bexxar® Corixa Corp. and GlaxoSmithKline murine — covalentely bound to Iodine 131 2003 Non-Hodgkin’s lymphoma Xolair® Genentech, Tanox, Inc., Novartis Pharmaceuticals IgE Severe (allergic) asthma Avastin TM VEGF 2004 Metastatic colorectal cancer, non-small cell lung cancer, metastatic breast bancer TYSABRI® Biogen Idec and Elan Corp. α4 subunit of a4ß1 Multiple Sclerosis, Chron´s disease ErbituxTM Merck KG aA / Bristol-Myers Squibb / ImClone Systems EGFR Colorectal cancer, head and neck cancer Vectibix ™ Amgen 2006 Metastatic colorectal carcinoma LUCENTIS™ VEGF-A humanized Fab Wet Macular Degeneration Soliris® Alexion Pharmaceuticals, Inc. CD59 2007 Paroxysmmal nocturnal hemoglobinuria CIMZIA® UCB Humanized (Fab) 2008 Morbus Chron, rheumatoid arthritis SimponiTM Centocor (subsidiary of Johnson & Johnson) 2009 Rheumatoid & psoriatic arthritis, active ankylosing spondylitis
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Marketed Antibody Products
Company Name Name of Product(1) Indications Date of FDA Approval Antibody Type (2) Ortho Biotech Orthoclone-OKT® Organ Transplant Rejection 1986 M J&J/Eli Lilly ReoPro® Acute Cardiac Conditions 1994 C BiogenIdec/Genentech/Roche Rituxan® Non-Hodgkin’s Lymphoma 1997 BiogenIdec Zevalin™ 2002 PDLI Zenapax® Acute Transplant Rejection H MedImmune/Abbott Synagis® Viral Respiratory Disease 1998 Genentech/Roche Herceptin® Avastin ® Breast Cancer Colorectal Cancer 2004 J & J Remicade® Crohn’s, Rheumatoid Arthritis Novartis Simulect® Wyeth Mylotarg™ Acute Myleoid Leukemia 2000 Schering /ILEX Oncology Campath® Chronic Lymphocytic Leukemia 2001 Abbott/CAT Humira™ Rheumatoid Arthritis PD Novartis/Genentech/Tanox Xolair® Asthma 2003 Genentech/Xoma Raptiva™ Psoriasis Corixa/GlaxoSmithKline Bexxar® BMS/ImClone Systems Erbitux ™
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Why only 23 approved monoclonals after 35 years?
How do you make human antibodies Transgenic animals Phage display Ribosome RNA display Microbial cell / yeast display Development takes time Approval takes time We want safe drugs
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MAbs approved for human therapy
Sponsor company Generic name US trade name mAb type Therapeutic category US approval Johnson & Johnson Muromonab-CD3 Orthoclone OKT3 Murine Immunological Centocor Abciximab ReoPro Chimeric Hemostasis Biogen IDEC Rituximab Rituxan Antineoplastic Protein Design Daclizumab Labs | Zenapax Humanized Novartis Basiliximab Simulect MedImmune Palivizumab Synagis Anti-infective Infliximab Remicade Genentech Trastuzumab Herceptin Wyeth Gemtuzumab ozogamicin Mylotarg Millennium/ILEX Alemtuzumab Campath Ibritumomab tiuxetan Zevalin Abbott Adalimumab Humira Human Omalizumab Xolair Corixa Tositumomab-I131 BEXXAR Efalizumab Raptiva Imclone Systems Cetuximab Erbitux Bevacizumab Avastin Transplantation Stroke Lymphoma IL-2, immunosupressant Transplantation Respiratory infection Synciitial Virus Arthritis HER-2/neu (EGF2) breast cancer CD leukemia (AML) Leukemia Lymphoma Arthritis IgE asthma Lymphoma Psoriasis EGF-R colon cancer VEGF colon cancer
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Why not mouse antibodies?
Made relatively easily by hybridoma technology Main problem is “Human Anti-Mouse Antibodies” HAMA The mouse antibodies are seen as foreign and induce an immune response Anti-mouse antibodies are made Endanger the patient Enhance the clearance of the Ab Reduce the therapeutic effect Create immune complexes Mouse antibodies do not activate human effector functions Complement Antibody mediated cytotoxicity
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Anticorpi monoclonali
Anticorpi monoclonali murini mediante la tecnologia dell’ibridoma Human immune response to mouse antibodies HAMA = Human Anti-Mouse Antibodies - Endanger the patient enhance the clearance of the Ab reduce its therapeutic effect. CDR murini chimerici umanizzati umani Regione V murina murini
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The general trend for antibody approvals
Murine monoclonals Chimeric monoclonals Humanized monoclonals Human monoclonals Mouse CDRs chimeric Humanized Human Mouse V regions mouse
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MAbs approved for human therapy
Sponsor company Generic name US trade name mAb type Therapeutic category US approval Johnson & Johnson Muromonab-CD3 Orthoclone OKT3 Murine Immunological Centocor Abciximab ReoPro Chimeric Hemostasis Biogen IDEC Rituximab Rituxan Antineoplastic Protein Design Daclizumab Labs | Zenapax Humanized Novartis Basiliximab Simulect MedImmune Palivizumab Synagis Anti-infective Infliximab Remicade Genentech Trastuzumab Herceptin Wyeth Gemtuzumab ozogamicin Mylotarg Millennium/ILEX Alemtuzumab Campath Ibritumomab tiuxetan Zevalin Abbott Adalimumab Humira Human Omalizumab Xolair Corixa Tositumomab-I131 BEXXAR Efalizumab Raptiva Imclone Systems Cetuximab Erbitux Bevacizumab Avastin Transplanation Stroke Lymphoma IL-2, immunosupressant Transplanation Respiratory infection Synciitial Virus Arthritis HER-2/neu (EGF2) breast cancer CD leukemia (AML) Leukemia Lymphoma Arthritis IgE asthma Lymphoma Psoriasis EGF-R colon cancer VEGF colon cancer
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Chimera
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How to make a chimeric antibody
Human Murine Chimeric
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Anticorpi monoclonali
Anticorpi monoclonali murini mediante la tecnologia dell’ibridoma Anticorpi chimerici (70% DNA umano solo la regione V è murina) #3 rituximab (Rituxan®), with sales of USD b; #7 infliximab (Remicade®), with sales of USD b; CDR murini chimerici umanizzati umani Regione V murina murini
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Humanized
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What about a humanized antibody?
Murine Chimeric gene Pick human gene that most resembles the murine gene Informatically insert the murine CDRs into the human V gene Synthesize the humanized gene
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Anticorpi umanizzati (95% DNA umano solo i CDR3 sono murini)
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Nature Reviews Cancer 1; 118-129 (2001)
IMPROVING THE EFFICACY OF ANTIBODY-BASED CANCER THERAPIES
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MAbs approved for human therapy
Sponsor company Generic name US trade name mAb type Therapeutic category US approval Johnson & Johnson Muromonab-CD3 Orthoclone OKT3 Murine Immunological Centocor Abciximab ReoPro Chimeric Hemostasis Biogen IDEC Rituximab Rituxan Antineoplastic Protein Design Daclizumab Labs | Zenapax Humanized Novartis Basiliximab Simulect MedImmune Palivizumab Synagis Anti-infective Infliximab Remicade Genentech Trastuzumab Herceptin Wyeth Gemtuzumab ozogamicin Mylotarg Millennium/ILEX Alemtuzumab Campath Ibritumomab tiuxetan Zevalin Abbott Adalimumab Humira Human Omalizumab Xolair Corixa Tositumomab-I131 BEXXAR Efalizumab Raptiva Imclone Systems Cetuximab Erbitux Bevacizumab Avastin Transplanation Stroke Lymphoma IL-2, immunosupressant Transplanation Respiratory infection Synciitial Virus Arthritis HER-2/neu (EGF2) breast cancer CD leukemia (AML) Leukemia Lymphoma Arthritis IgE asthma Lymphoma Psoriasis EGF-R colon cancer VEGF colon cancer
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2012 global sales of antibody-based therapeutics exceeded USD50 billion 6 of the top 12 selling drugs in 2012 were antibody-based. The 6 products are: #1 adalimumab (Humira®), with sales of USD9.265 b #3 rituximab (Rituxan®), with sales of USD b; #5 trastuzumab (Herceptin®), with sales of USD b; #7 infliximab (Remicade®), with sales of USD b; #8 bevacizumab (Avastin®), with sales of USD b; #11 etanercept (Enbrel®) with sales of USD b.
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Although the MRC is not primarily concerned with making money from inventions, the scale of LMB’s contribution to the field of therapeutic antibodies has led to significant revenues back to the MRC. For example, from 2000 to 2006 the MRC received approximately £84M from humanized antibodies £127M from human antibodies (share sales and royalties), of which the LMB and the inventors and associated co-workers have received a share through the MRC’s Awards to Inventors Scheme.
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MAbs approved for human therapy
Sponsor company Generic name US trade name mAb type Therapeutic category US approval Johnson & Johnson Muromonab-CD3 Orthoclone OKT3 Murine Immunological Centocor Abciximab ReoPro Chimeric Hemostasis Biogen IDEC Rituximab Rituxan Antineoplastic Protein Design Daclizumab Labs | Zenapax Humanized Novartis Basiliximab Simulect MedImmune Palivizumab Synagis Anti-infective Infliximab Remicade Genentech Trastuzumab Herceptin Wyeth Gemtuzumab ozogamicin Mylotarg Millennium/ILEX Alemtuzumab Campath Ibritumomab tiuxetan Zevalin Abbott Adalimumab Humira Human Omalizumab Xolair Corixa Tositumomab-I131 BEXXAR Efalizumab Raptiva Imclone Systems Cetuximab Erbitux Bevacizumab Avastin Transplanation Stroke Lymphoma IL-2, immunosupressant Transplanation Respiratory infection Synciitial Virus Arthritis HER-2/neu (EGF2) breast cancer CD leukemia (AML) Leukemia Lymphoma Arthritis IgE asthma Lymphoma Psoriasis EGF-R colon cancer VEGF colon cancer
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Anticorpi monoclonali
Anticorpi monoclonali murini mediante la tecnologia dell’ibridoma Anticorpi chimerici (70% DNA umano) Anticorpi umanizzati (95% DNA umano solo i CDR3 sono murini) ANTICORPI COMPLETAMENTE UMANI CDR murini chimerici umanizzati umani Regione V murina murini
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Monoclonal antibodies
Murine monoclonals Made using hybridoma technology - everything is mouse Chimeric antibodies All constant regions are human, variable are mouse: 70% human Humanized antibodies Only the antibody binding loops (CDRs - complementarity determining regions) are mouse, the rest is human: % human Human antibodies Everything is human
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What they really look like
Mouse Human Chimeric Humanized The participation in regulatory review allows the researcher reviewer a reality check for the real regulatory impact of the MOA data 35
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MAbs in Action Technology MAb Approved Hybridoma Zenapax Rituxan
Herceptin Remicade Synagis Simulect Mylotarg Campath Chimerization Humanization Phage Display Transgenic Mice ReoPro 2001 2000 1998 1997 1994 1986 1985 1975 OKT3 2002 Zevalin Yeast Display 2003 Humira Xolair Bexxar Ribosome Display Technology MAb Approved 2004 Avastin Erbitux
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Making human antibodies
Transgenic animals Phage display Ribosome RNA display Microbial cell / yeast display
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Transgenic Mouse H k l VH1 VH65 VH2 DH JH Cg
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Grafting human heavy- and light-chain miniloci into mice & producing human mAb
( 80 kb )
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What they really look like
Mouse Human Humanized Chimeric The participation in regulatory review allows the researcher reviewer a reality check for the real regulatory impact of the MOA data 44
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XenoMouse®- Strains
IgG1 IgG2 IgG4 IgG1 IgG2 IgG4 Today, XenoMouse technology consists of a collection of strains of mice. We have different strains with the different heavy-chain isotypes IgG1, IgG2 and IgG4. We also have introduced both light-chain loci – the kappa and the lamda light chains.
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The TC Mouse™ was developed through the use of Kirin's proprietary microcell mediated chromosome transfer (MMCT) technology which has the capability to introduce large portions of the human chromosome into mice. The TC Mouse™ carries human chromosomal fragments which contain the complete human immunoglobulin loci. Therefore, the TC Mouse™ Technology is distinguished from other antibody producing transgenic mice by being a Transchromosomic mouse, carrying the full human immunoglobulin repertoire.
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Ci sono 3 ditte che dispongono di topi –mAb-human
Ci sono più di 35 anticorpi umani in trials clinici avanzati
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Transgenic mice These produce human antibodies following immunization
The creation of monoclonal antibodies is the same as normal mice using hybridoma technology This technology is not used to produce large amounts of antibody Antibody production is still required after selection
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Making human antibodies
Transgenic animals Phage display Ribosome RNA display Microbial cell / yeast display
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