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2. Helpful Agents. Prior to the appearance of atomic biotechnology most human proteins were accessible in just little (constrained) quantities.Today many qualities (~1000) for human proteins have been cloned, sequenced, communicated in the host cells and are being tried as remedial specialists (drugs) in humans.Over 140 biopharmaceuticals available; more than 400 in clinical trialsBiopharmaceuticals incl
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Restorative AGENTS Introduction Recombinant Proteins Nucleic Acids

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Therapeutic Agents Introduction Before the approach of atomic biotechnology most human proteins were accessible in just little (constrained) amounts. Today several qualities (~1000) for human proteins have been cloned, sequenced, communicated in the host cells and are being tried as restorative specialists (drugs) in people. More than 140 biopharmaceuticals available; more than 400 in clinical trials Biopharmaceuticals include: Proteins (made in bacterial, contagious or mammalian cell society) erythropoietin (EPO) insulin interferon ( Intron A) granulocyte-state animating variable (G-CSF) human development hormone (HGH, human somatotropin ) tissue plasminogen activator ( tPA ) Monoclonal antibodies (made in mammalian cell society) Vaccines live and inactivated infections and microscopic organisms subunit immunizations recombinant immunizations Gene Therapy Products (viral and non-viral)

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Therapeutic Agents Introduction Process of Drug Production Formulation/Filling Transfection Cell society Purification + Drug item - (sterile) Cells and plasmid Cell line Drug substance (rough) Drug substance (unadulterated) Cell line make Medium advancement Bioreactor process improvement & scale-up Downstream filtration Analytical portrayal

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Therapeutic Agents Development of the Process Introduction Biological Assay Development and Support Cell/Virus Culture Development/Media Optimization Purification Process Dev. Cell Line/Viral Vector/Construction Formulation Design/Drug Delivery Design Facility/Equipment Design Technology Transfer Process Validation Pilot-Scale cGMP Production Commercial-Scale Production

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Therapeutic Agents Recombinant Proteins Human Interferons - > to battle viral contaminations - > Scientists found an antiviral protein in 1957 that hindered development of flu infection in chicken fetuses. It was named interferon since it meddled with the development of flu infection. Hostile to viral proteins discharged by host cells (part of the resistant system) Interfere with viral duplication Host cell particular yet not infection particular Different sorts of cells in creatures produce distinctive interferons

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Therapeutic Agents Recombinant Proteins Human Interferons - > to battle viral contaminations 3 sorts of human interferon: alpha interferon (13 qualities) beta interferon (2 qualities) gamma interferon (1 quality) Alpha & beta typically delivered right on time in viral diseases (infections or viral RNA) - Gamma seems later - > Presence of twofold stranded RNA demonstrates cell is tainted - > Viral tainted cells discharge alpha and beta interferons Diffuse to neighboring cells - > Virus can\'t imitate

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Therapeutic Agents Antiviral Treatment: Recombinant Proteins Human Interferons - > to battle viral contaminations Interferon treatment Limited lifetime, short enduring impact Recombinant interferons Pure and quick Hybrid qualities for improved/new movement Oral organization

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Therapeutic Agents Why is Oral Interferon Different? Recombinant Proteins Human Interferons - > to battle viral contaminations Why are Side Effects Common and Severe for Injectable Interferon? Injectable interferon (beta) is endorsed around the world (FDA) for the treatment of different tumors and viral maladies. Interferon is a protein promptly wiped out from the blood by the kidney. To neutralize the kidney\'s freedom of interferon from the blood injectable interferon must be given in measurements much higher than what happen actually. Reactions incorporate influenza like indications, poor results on liver capacity tests, and platelet variations from the norm. More genuine symptoms incorporate melancholy, epileptic seizures, or liver issues. Low-measurements oral interferon is given in dosages 10 thousand times not exactly injectable interferon. Consequently, reactions are drastically diminished. Oral interferon is human interferon alpha managed in a little tablet (capsule) to people or in powder to creatures. Oral interferon ties to surface (mucosal) cells in the mouth and throat bringing about incitement of white platelets and initiates several qualities influencing the insusceptible framework in the fringe blood of man, dairy cattle and mice. Thinks about show oral interferon is successful against scatters, for example, malignancy, viral infections and autoimmunity.

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Therapeutic Agents Mechanism of Action Recombinant Proteins Human Interferons - > to battle viral diseases Oral Epithelial Cells Tonsil IFN a Mandibular Lymph Nodes Activation of Perioral Lymphoid Cells and Peripheral Lymphoid Tissues Activation of Humoral Immunity (Antibody) Activation of Cell Mediated Immunity Virus Interferon put in the mouth ties to receptors in the mucosal coating and starts systemic consequences for the insusceptible framework in creatures and man. These immunomodulatory impacts are protected and powerful in controlling viral and immune system ailments and malignancy.

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Therapeutic Agents Recombinant Proteins Human Interferons - > to battle viral contaminations Manufacturing Steps for Interferon:

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Therapeutic Agents Recombinant Proteins Human Interferons - > to battle viral diseases Human sicknesses in which oral interferon has been tried and answered to be protected

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Efficacy of Human Leukocyte Interferon as Prophylaxis Against Influenza 25 20 15 Percent of Patients Sick Interferon 10 Placebo 5 0 Adults Children 7-12 yr 2-6 yr Population (14,000 subjects all out) Therapeutic Agents Recombinant Proteins Human Interferons - > to battle viral contaminations Human Study – Influenza and Interferon 14,000 individuals took an interest in controlled investigations of fake treatment versus interferon treatment amid a characteristic flare-up of Hong Kong flu. Interferon (around 128 units) or fake treatment was trickled into the nose day by day for 5 days beginning about the season of the initially reported flu cases. Interferon fundamentally (P<0.01) diminished the quantity of flu cases. Soloviev, Bull. WHO 41:683-688, 1969.

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Therapeutic Agents Strategies for Optimization of Recombinant Production Recombinant Proteins Screening libraries of recombinant qualities (IFNs, human development hormone, TNF-a… ) Screening of recombinant expression frameworks (E coli, parasites, Mammalian cells… ) Delivery by intestinal microscopic organisms (lactobacilli)

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Therapeutic Agents Enzymes – Treating Cystic Fibrosis Recombinant Proteins Cystic fibrosis (CF) - > ~30,000 cases in the US and 23,000 in Canada. Europe: it happens in 1 in 2,500 live birth and 1 in 25 are transporters. Brought on by more than 500 unique changes in the cystic fibrosis transmembrane conductance controller (CFTR) quality. People with CF are very helpless to bacterial contamination and anti-infection treatment regularly brings about safe strains. Manifestations: - > little conduits (exceptional channels) get to be stopped up with a thick bodily fluid Clogging and contamination of lungs connecting of little bile pipes to liver (hinders processing) stopping of pipes of pancreas (blocks assimilation) impediment of small digestive tract guys are barren breaking down sweat organs

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Enzymes – Treating Cystic Fibrosis Therapeutic Agents Recombinant Proteins Gene in charge of illness: CF is for the most part brought on by a 3 base pair cancellation in Cystic Fibrosis Transmembrane Regulator (CTFR) - > F508 erased CTFR - > ABC transporter coupled to a channel

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Enzymes – Treating Cystic Fibrosis Therapeutic Agents Recombinant Proteins - > It transports Cl-particles in the wake of being phosphorylated and restricting two ATP atoms - > It has an expansive administrative area that is phosphorylated by a cAMP ward protein kinase

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Enzymes – Treating Cystic Fibrosis Therapeutic Agents Recombinant Proteins A typical lung Chloride into aviation route; sodium out - keeps bodily fluid wet and thin Normal CFTR controls the sodium channel (inactivates it) A CF lung Chloride does not get into aviation route; more sodium leaves; More salt in cell - > water comes in - >This makes the bodily fluid thick

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Enzymes – Treating Cystic Fibrosis Therapeutic Agents Recombinant Proteins Treatments: Chloride conveyance - actuate other chloride bearers Viscous bodily fluid - beating, DNase treatment, gelosin repetitive diseases – anti-microbials tissue harm because of safe reaction - calming drugs (ibuprofen)

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Enzymes – Treating Cystic Fibrosis Therapeutic Agents Recombinant Proteins DNase 1 (GeneTech) A thick bodily fluid which is a consequences of: Alignate created by microscopic organisms DNA from lysed cells Leucocytes which gather because of the disease Makes breathing troublesome. Researcher at Genentech separated the quality for DNase1 The purged compound was conveyed as an airborne to the lung where it hydrolysed the DNA into short oligonucleotides. This abatement the thickness in the lungs and made breathing less demanding. Alginate Lyase Alginate is a polysaccharide polymer that is created by microscopic organisms. The discharge of alginate by Pseudomonas aeruginosa of patients with CF adds to the thickness in the lung. The compound alginate lyase can condense microbes alginate. Alginate lyase was seclude from Flavobacterium sp. furthermore, cloned into E. coli . - > Combined with DNase1, alginate lyse can diminish the bodily fluid in the lungs of patients with CF.

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Monoclonal Antibodies Therapeutic Agents Recombinant Proteins Clinical Applications Transplantation – muronomab (OKT3) 1986, basiliximab 1998 Cardiovascular ailment – abciximab 1994 Cancer – rituximab 1997, trastuzumab 1998 Viral contamination – palivizumab 1998 Inflammatory sicknesses – infliximab 1998, etanercept 1999 Side impacts: Transfusion responses ( any antagonistic occasion which happens in light of a blood transfusion) Infections, immunosuppression Cardiac, respiratory capture ( suspension of breathing) Pharmacological danger

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Monoclonal Antibodies Therapeutic Agents Recombinant Proteins Productio

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