Molekular- Biologie Verfahrens- technik Zell- Biologie Mikrobiologie

Präsentation zum Thema: "Molekular- Biologie Verfahrens- technik Zell- Biologie Mikrobiologie"—  Präsentation transkript:

1 Viele wissenschaftliche Disziplinen leisten einen Beitrag zur Biotechnologie
Molekular- Biologie Verfahrens- technik Zell- Biologie Mikrobiologie Biochemie Genetik Biotechnologie Biotechnology is employed in the discovery, development and delivery of medicines, vaccines and diagnostics. Biotechnology focuses on products of living systems, but uses research methodologies from many scientific disciplines including molecular biology, microbiology, biochemistry, genetics, chemical engineering, and cell biology.1 As of 2006, 165 biopharmaceutical products are available worldwide.2 Grace ES. Biotechnology Unzipped. Promises and Realities. 2nd edition. Washington, DC: Joseph Henry Press; 2006. Walsh G. Nat Biotechnol. 2006;24: Arzneimittel Impfstoffe Diagnostika Grace ES. Biotechnology Unzipped. Promises and Realities. 2nd edition Amgen Corporate Template

2 Die biotechnologische Medikamentenentwicklung
Definition des Stoffwechselweges1-3 Identifikation eines Ziel-Proteins1-3 proteinbasierte zielgerichtete Therapie Zielgerichteter Wirkmechanismus Wirksubstanz Key Point Traditional medications and biopharmaceuticals differ in how they are identified and developed.1 Supplemental Information Traditional approaches to drug discovery are grounded in medicinal chemistry and use high-throughput screening of randomly generated compounds to identify potential drug candidates.1-4 In general, these small molecule drugs have less specificity for desired targets than biopharmaceuticals.1-3 With biotechnology, specific targets whose function or dysfunction are involved in disease, are identified, and protein- or peptide-based therapies are designed to specifically interact with these targets.1 Avidor Y et al. Urology 2002; 59: 643–651. Emerging biotechnology brings change to pharmaceutical industry. Accessed 10 August 2007. Bleicher KH et al. Nat Rev Drug Discov 2003; 2: 369–378. Macarron R. Drug Discov Today 2006; 11: 277–279. 1. Avidor Y, et al. South Med J 2003; 96: 1174–1186; 2. Avidor Y, et al. Urology 2002; 59: 643–651; 3. Bleicher KH, et al. Nature Rev Drug Discov 2003; 2: 369–378 Amgen Corporate Template

3 Traditionelle Arzneimittel
Biopharmazeutika sind große, komplexe Moleküle mit spezifischen Zielstrukturen Traditionelle Arzneimittel Biopharmazeutika Aspirin (180.2 Da1) Etanercept (150,000 Da4) Insulin (~5808 Da2) Paclitaxel (853.9 Da1) Filgrastim (20,000 Da3) Biopharmaceuticals are large molecules with molecular weights many times higher than traditional medicines such as aspirin.1-4 Because biopharmaceuticals are complex peptides or proteins and would be digested in the gastrointestinal system, most are administered by injection rather than via the oral route.5 Biopharmaceuticals are available for the treatment of many conditions, including cancer, heart disease, and rheumatoid arthritis. Vaccines and recombinant human insulin are used routinely in primary health care.5 1. Chemfinder.com. Available at: Accessed August 10, 2007. 2. Exubera® (insulin human [rDNA origin]) inhalation powder prescribing information, Pfizer. 3. Neupogen® (filgrastim) prescribing information, Amgen. 4. Enbrel® (etanercept) prescribing information, Amgen. 5. Walsh G. Nat Biotechnol. 2006;24: Ibuprofen (206.3 Da1) 1. Verfügbar auf: Zugriff am 10. August 2007. 2. Verfügbar auf: 3. Filgrastim scientific discussion (Homepage EMA) 4. Etanercept scientific discussion (Homepage EMA) 3 Amgen Corporate Template

4 Entwicklung therapeutischer Antikörper4
Murin Chimär Humanisiert 100% Mäuseprotein Denosumab1 34% Mäuseprotein Beispiel: Orthoclon OKT®32 (Muromonab-CD3) Vollhuman Beispiel: ReoPro® 3,4 (Abciximab) 5%–10% Mäuseprotein Denosumab is the first fully human monoclonal antibody in clinical development that specifically targets RANK Ligand.1 Therapeutic monoclonal antibodies were first introduced in 1986 with the approval of muromonab-CD3 (Orthoclone OKT®3), a product consisting of 100% mouse protein indicated for treating acute organ transplant rejection.2 Murine monoclonal antibodies are associated with limitations such as immunogenicity, short elimination half-life, and decreased treatment response due to the development of human antimurine antibodies (HAMAs).2-5 Efforts were undertaken to develop new types of monoclonal antibodies to address the limitations associated with murine monoclonal antibodies. The first step was development of chimeric monoclonal antibodies such as abciximab (ReoPro®), which consist of mouse variable regions and human constant regions (34% mouse protein).4,5 Chimeric monoclonal antibodies have a decreased risk of immunogenicity compared with mouse antibodies; however, human antichimeric antibodies (HACAs) may occur.4 “Humanization” was the next step in the evolution of monoclonal antibodies, including products such as trastuzumab (Herceptin®). With “humanization,” all rodent sequences are replaced with human sequences except the complementarity-determining regions (5%–10% mouse protein).4,5 Human antihuman antibodies (HAHAs) may be observed, but to a lesser extent than HAMAs or HACAs.4 A new strategy involves developing fully human monoclonal antibodies from transgenic mice. These transgenic mice are generated by disrupting and replacing the murine Ig genes with human Ig gene clusters. Theoretically, fully human monoclonal antibodies may have a lower propensity for antiantibody responses than other types of monoclonal antibodies.2,4 Bekker PJ, et al. J Bone Miner Res. 2004;19: Lonberg N. Nat Biotechnol. 2005;23: Ternant D, et al. Expert Opin Biol Ther. 2005;5(suppl 1):S37-47. Weiner LM. J Immunother. 2006;29:1-9. Yang X-D, et al. Crit Rev Oncol Hematol. 2001;38:17-23. Beispiel: Herceptin® (Trastuzumab) 100% Humanes Protein Orthoclone OKT®3: registriertes Warenzeichen von Johnson & Johnson; ReoPro®: registriertes Warenzeichen von Eli Lilly and Company; Herceptin® : registriertes Warenzeichen von Genentech, Inc. 1. Bekker PJ, et al. J Bone Miner Res. 2004;19: ; 2. Lonberg N. Nat Biotechnol. 2005;23: ; 3. Weiner LM. J Immunother ;29:1-9;4. Yang X-D, et al. Crit Rev Oncol Hematol. 2001;38:17-23. Amgen Corporate Template

5 Herstellung vollhumaner monoklonaler Antikörper in transgenen Mäusen
Deletion der murinen Immunglobulin-Gene Gentransfer humaner Immunglobulin-Gene Mouse antibody genes inactivated Human antibody genes introduced The XenoMouse® is a transgenic mouse strain engineered to lack functional murine immunoglobulin (Ig) genes, while expressing human Ig genes that have been introduced into the germ line.1-2 Preclinical data demonstrate that the XenoMouse® is able to produce high affinity, fully human antibodies of the IgG2 isotype to multiple antigens, including human proteins. Thus, as a therapeutic protein, MAbs produced by the XenoMouse® are anticipated to be nonimmunogenic, allowing multiple and repeat administrations without eliciting an immune response. Yang XD, Jia XC, Corvalan JR, Wang P, Davis CG. Development of ABX-EGF, a fully human anti-EGF receptor monoclonal antibody, for cancer chemotherapy. Crit Rev Oncol Hematol. 2001;38:17-23. Foon KA, et al. Preclinical and clinical evaluations of ABX-EGF, a fully human anti-epidermal growth factor receptor antibody. Int J Radiation Oncology Biol Phys 2004; 58(3): YYang XD, et al. Crit Rev Oncol Hematol. 2001;38:17-23. Amgen Corporate Template

6 Herstellung vollhumaner monoklonaler Antikörper in transgenen Mäusen
Immunisierung gegen das gewünschte Antigen Production of fully human antibodies Transgenic Mouse Produktion des gewünschten Antikörpers über Hybridomzellen The XenoMouse® is a transgenic mouse strain engineered to lack functional murine immunoglobulin (Ig) genes, while expressing human Ig genes that have been introduced into the germ line.1-2 Preclinical data demonstrate that the XenoMouse® is able to produce high affinity, fully human antibodies of the IgG2 isotype to multiple antigens, including human proteins. Thus, as a therapeutic protein, MAbs produced by the XenoMouse® are anticipated to be nonimmunogenic, allowing multiple and repeat administrations without eliciting an immune response. Yang XD, Jia XC, Corvalan JR, Wang P, Davis CG. Development of ABX-EGF, a fully human anti-EGF receptor monoclonal antibody, for cancer chemotherapy. Crit Rev Oncol Hematol. 2001;38:17-23. Foon KA, et al. Preclinical and clinical evaluations of ABX-EGF, a fully human anti-epidermal growth factor receptor antibody. Int J Radiation Oncology Biol Phys 2004; 58(3): YYang XD, et al. Crit Rev Oncol Hematol. 2001;38:17-23. Amgen Corporate Template

7 Produktion von Biopharmazeutika
Anzucht der Zellen in Bioreaktoren Expression des gewünschten Proteins Insertion eines Gens in einen DNA-Vektor Transfer in eine Wirtszelle Production of biopharmaceuticals is a complex process involving living systems. DNA is isolated and inserted into a host cell. The cells expressing the protein of interest are grown in large quantities to generate or express sufficient quantities of the therapeutic protein. A final step in production is the extraction and purification of the raw protein into pharmaceutical grade product. Manufacturing a protein-based therapeutic is a multifaceted process; each step impacts the final quality of the end product.1 1. Kleinberg M and Mosdell KM. Am J Health-Syst Pharm. 2004;61: Extraktion, Aufreinigung, Verdünnung Kleinberg M, et al. Am J Health-Syst Pharm. 2004;61: 7 Amgen Corporate Template

8 Nomenklatur Monoklonaler Antikörper (mAb)
Präfix Zielorgan bzw. Krankheit Quelle Suffix varies -o(s)- bone -u- human -mab -vi(r)- viral -o- mouse -ba(c)- bacterial -a- rat -li(m)- immune -e- Hamster -le(s)- infectious lesions -i- Primate -ci(r)- cardiovascular -xi- Chimeric -mu(l)- musculoskeletal -zu- Humanized -ki(n)- interleukins -axo- rat/murine hybrid -co(l)- colonic tumor ä -me(l)- melanoma -ma(r)- mammary tumor -go(t)- testicular tumor -go(v)- ovarian tumor -pr(o)- prostate tumor -tu(m)- miscellaneous tumor -ne(r)- nervous system -tox(a)- toxin as target -fu(ng)- fungal Beispiel: den / os / u / mab A naming convention exists for monoclonal antibodies.1 Each generic name for therapeutic monoclonal antibodies consists of 4 sections: the variable prefix, an acronym representing the target or disease state, an acronym for the species source, and the root -mab for monoclonal antibody.1 For example, zanolimumab [zano- (variable prefix), lim- (immune), u-(human), mab (monoclonal antibody)] is an investigational fully human monoclonal antibody against the T-cell differentiation antigen, CD4.2 Monoclonal antibodies. Available at: Accessed August 10, 2007. Lonberg N. Nat Biotechnol. 2005;23: Prefix: Variable Target: bone Source: Human Suffix: Monoclonal antibody Available at: Accessed August 10, 2007. Amgen Corporate Template

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