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    美國生物制藥研究進(jìn)展與國家生物經(jīng)濟(jì)藍(lán)圖*

    2014-09-10 01:16:56GeorgeBolger
    關(guān)鍵詞:拜爾生物制藥維爾

    George R.Bolger,張 泓

    (美國拜爾麥德生物醫(yī)藥公司,美國洛克維爾 20855)

    Ever since the synthesis of the B-chain of insulin by Chinese scientists in 1964[1],the discovery of the first restriction enzyme in 1968[2]and the developmentofrecombinantDNA technology in 1973[3]by U.S.scientists,biotechnology and biopharmaceuticals have dramatically changed the pharmaceutical industry,and become economic growth engines and the best hope for fighting many lifethreatening illnesses such as cancers,cardiovascular diseases and HIV/AIDS.Hundreds of biopharmaceuticals and vaccines have been approved by regulatory agencies since the first recombinant protein,human insulin(Humulin),was approved by U.S.Food and Drug Administration(FDA)in 1982,which have helped millions of people worldwide.The top three worldwide best-selling drugs of 2012 were all biopharmaceuticals[4-5]and the stock market values for some big biopharmaceutical companies are already higher than some big pharmaceutical companies.According to Pharmaceutical Research and Manufacturers of America's 2013 Report,U.S.biopharmaceutical companies are currently developing 907 biopharmaceuticals through biological manufacturing processes which target more than 100 diseases including cancers,autoimmune diseases and infectious diseases[6-7].The current progresses in U.S.biopharmaceutical development and the National Bioeconomy Blueprint of the U.S.government are discussed in this minireview.

    1 Major milestones in biopharmaceutical development

    Many scientific events have shaped biotechnology and biopharmaceutical development through the past 60 years which included the following major milestones[8]:

    1953 Three-dimensional structure of DNA reported by Watson and Crick[9].

    1957 Amino acid sequence of insulin reported by Sanger and Thompson[10].

    1965 First total synthesis of crystalline bovine insulin by Chinese scientists[11].

    1968 First restriction enzyme discovered by Meselsom and Yuan[2].

    1973 First cloning of biologically functional DNA molecules by Cohen et al[3].

    1977 DNA sequencing method developed by Sanger's group[12-13].

    1982 First recombinant protein-h(huán)uman insulin(Eli Lilly & Co.'s Humulin)approved by U.S.FDA.

    1983 Polymerase chain reaction(PCR)invented.

    1986 First monoclonal antibody(Mab),Muromonab CD3,approved by US FDA[14].

    1997 First humanized Mab(Zenapax)and first chimeric Mab(Rituxan)approved by US FDA.

    2001 Sequence of the human genome published[15].

    2002 Fully-h(huán)uman Mab(Humira,adalimumab)approved by U.S.FDA to treat rheumatoid arthritis.

    2009 First insect cell cultured biopharmaceutical,the Cervarix vaccine for HPV,approved by U.S.FDA.

    2012 First cultured plant cell-expressed therapeutic enzyme,Elelyso(taliglucerase alfa),approved by US FDA to treat a form of Gaucher disease[16].

    2013 Genomes of CHO(Chinese hamster ovary)cell lines mapped[17].

    2 Many biopharmaceuticals are natural protein factors

    There are about 25,000 genes and 200,000 proteins encoded by the human genome[6].More than 100 biologics license applications(BLAs)have been approved by U.S.FDA since 1995,and most of them are natural protein factors.These natural protein factors can be divided into different categories such as growth factors,hormones,cytokins,therapeutic enzymes,blood factors,antibodies,anticoagulants et al.Currently,U.S.pharmaceutical companies are developing 907 biopharmaceuticals through biological manufacturing processes using living cells or organisms[6-7].These 907 biopharmaceuticals in human clinical trials or under review by U.S.FDA include 338 cancer therapeutics that treat different types of cancers(170 of them are monoclonal antibodies),250 vaccines,176 candidate biopharmaceuticals targeting infectious diseases,71 biopharmaceuticals for autoimmune diseases,and 58 biopharmaceutical treatments for cardiovascular diseases[6-7].

    3 Some biopharmaceutical companies are more efficient and profitable than big pharmaceutical companies

    The manufacturing process for biopharmaceuticals is far more complex than that for small molecule drugs because recombinant proteins are often much larger and more complex than chemical drugs,undergo various kinds of post-translational modifications and are produced in living cells or organisms.In addition,the same biopharmaceuticals could be produced and purified from different expression systems such as bacteria,yeast,or cultured mammalian cells,and therefore,the impurities/contaminants may vary extensively which could be clinically significant.Despite the complexity of manufacturing processes and the high development cost associated with biopharmaceuticals,some big biopharmaceutical companies are more efficient and profitable than some big pharmaceutical companies.As shown in Table 1,numbers of employees who work at big biopharmaceutical companies such as Amgen(18,000),Biogen(5,950)and Alexion(1,373)are normally smaller than those who work at big pharmaceutical companies such as Pfizer(78,400),Merck(83,000)and Bristol- Myers Squibb(28,000).However,when 2012 income statements of these six companies were compared,it is clear that employees who work at big biopharmaceutical companies generated higher average revenues and net incomes than those who work at big pharmaceutical companies,which support the conclusion that some big biopharmaceutical companies are more efficient and profitable than some big pharmaceutical companies(Table 1).

    Table 1 Comparison between biopharmaceutical and pharmaceutical companies based on their income statements of December 31,2012

    4 Eight of top 20 worldwide bestselling drugs of 2012 were biopharmaceuticals

    Based on an article published by the Genetic Engineering & Biotechnology News[4],8 of the top 20 best- selling drugs of 2012 in the world and 3 bestselling drugs(all involved in the treatment of rheumatoid arthritis)were biopharmaceuticals(Table 2).Details about these 8 biopharmaceuticals including trade name,generic name,U.S.FDA approval date,expression system,dosage form,administration route,pharmaceutical class and approved indication were listed in Table 2.As indicated in Table 2,five of the eight best-selling biopharmaceuticals(Humira,Enbrel,Rituxan,Herceptin and Avastin)were manufactured in Chinese hamster ovary(CHO)cells,and two of them(Lantus and Neulasta)were manufactured in E.coli bacteria.Administration routes for these biopharmaceuticals were either intravenous or subcutaneous injections with the lowest concentration of 10mg/ml(Remicade,Rituxan,and Neulasta)and the highest concentration of 50mg/ml(Humira and Enbrel).

    Table 2 Top eight worldwide best-selling biopharmaceuticals of 2012

    5 National Bioeconomy Blueprint of the U.S.government

    Because biotechnology and biopharmaceuticals have become economic engines with tremendous potential for growth,the U.S.government(the White House)released the National Bioeconomy Blueprint on April 26,2012[18]which defined bioeconomy as“economic activity that is fueled by research and innovation in the biological sciences and is a large and rapidly growing segment of the world economy that provides substantial public benefit”.The National Bioeconomy Blueprint remarks that“The growth of today’s U.S.bioeconomy is due in large part to the development of three foundational technologies:genetic engineering,DNA sequencing,and automated high-throughput manipulations of biomolecules”and“It can allow Americans to live longer,healthier lives,reduce our dependence on oil,address key environmental challenges,transform manufacturing processes,and increase the productivity and scope of the agricultural sector while growing new jobs and industries”[18].

    The Bioeconomy Blueprint of the U.S.government called on Federal agencies to accelerate their efforts to utilize the biological sciences and illustrated five strategic objectives for a bioeconomy with the potential to generate future U.S.economic growth:1)to support research and development investments;2)to facilitate the transition of bioinventions from research lab to market;3)to develop and reform government regulations to reduce barriers,increase the speed as well as predictability of regulatory processes,and reduce costs while protecting human and environmental health;4)to update training programs and align academic institution incentives with student training for national workforce needs;and 5)to identify and support opportunities for the development of public-private partnerships and precompetitive collaborations[18].

    6Summary

    Biotechnology and biopharmaceuticals have dramatically changed the pharmaceutical industry and become economic growth engines and the best hope for fighting many life-threatening diseases such as cancers,autoimmune diseases, and cardiovascular diseases.Despite the complexity of manufacturing processes and the high cost associated with biopharmaceutical development,some big biopharmaceutical companies are more efficient and profitable than some big pharmaceutical companies.Currently,U.S.biopharmaceutical companies are developing 907 biopharmaceuticals and vaccines which target more than 100 diseases.Because of its tremendous potential for economic growth and many other societal benefits it offers,the U.S.government defined the bioeconomy as a large and rapidly growing segment of the world economy,and therefore,released the National Bioeconomy Blueprint in April 2012 for the purposes of presenting strategic objectives that would help realize the full potential of the U.S.bioeconomy and highlighting early achievements toward those objectives[18].

    [1]Niu C I,Kung Y T,Huang W T,et al.Synthesis of peptide fragments of the B-chain of insulin.IX.Synthesis of the B-chain of insulin and its reconstitution with natural A -chain to regenerate insulin activity[J].Sci Sin,1964,13:1343-1345.

    [2]Meselson M,Yuan R.DNA restriction enzyme from E.coli[J].Nature,1968,217(5134):1110 - 1114.

    [3]Cohen S N,Chang A C Y,Boyer H W,et al.Construction of biologically functional bacterial plasmids in vitro[J].Proc Natl Acad Sci USA,1973,70(11):3240 –3244.

    [4]Top 20 best selling-drugs of 2012.Genetic Engineering News.Insights and Intelligence.March 5,2013.http://www.genengnews.com/insight- and - intelligence/top -20-best-selling-drugs-of-2012/77899775/?page=1.

    [5]Pohlscheidt M,Kiss R.Recent advances and trends in the biotechnology industry-development and manufacturing of recombinant proteins and antibodies[J].American Pharmaceutical Review,2013,16(6):48-53.

    [6]Pharmaceutical Research and Manufacturers of America PhRMA.Medicine in Development:Biologics 2013 Report[EB/OL].http://phrma.org/sites/default/files/2488/biologics2013.pdf.

    [7]Pharmaceutical Research and Manufacturers of America PhRMA.Medicine in Development- Overview:Biologics 2013 Report[EB/OL].http://phrma.org/sites/default/files/pdf/biologicsoverview2013.pdf.

    [8]BioPlan Associates,Inc.The bioprocessing timeline:A note[J].American Pharmaceutical Review,2013,16(6):112.

    [9]Watson J D,Crick F H.Genetical implications of the structure of deoxyribonucleic acid [J].Nature,1953,171(4361):964-967.

    [10]Sanger F,Thompson E O.The amino-acid sequence in the glycyl chain of insulin.I.The identification of lower peptides from partial hydrolysates [J].Biochem J,1953,53(3):353-366.

    [11]Kung Y T,Du Y C,Huang W T,et al.Total synthesis of crystalline bovine insulin[J].Sci Sin,1965,14:1710-1716.

    [12]Sanger F,Nicklen S,Coulson A R.DNA sequencing with chain-terminating inhibitors[J].Proc Natl Acad Sci USA,1977,74(12):5463-5467.

    [13]Air G M,Sanger F,Coulson A R.Nucleotide and amino acid sequences of gene G of omegaX174[J].J Mol Biol,1976,108(3):519 -533.

    [14]Todd PA,Brogden RN.Muromonab CD3.A review of its pharmacology and therapeutic potential[J].Drugs,1989,37(6):871-899.

    [15]Venter J C,Adams M D,Myers E W,et al.The sequence of the human genome[J].Science,2001,291(5507):1304-1351.

    [16]U.S.Food and Drug Administration.FDA News Release[EB/OL].http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/reproductivehealthdrugsadvisorycommittee/ucm176595.pdf

    [17]Lewis N E,Liu X,Li Y,et al.Genomic landscapes of Chinese hamster ovary cell lines as revealed by the Cricetulus griseus draft genome [J].Nat Biotechnol,2013,31(8):759 -765.doi:10.1038/nbt.2624.

    [18]The White House.National Bioeconomy Blueprint.April 2012.http://www.whitehouse.gov/sites/default/files/microsites/ostp/national_bioeconomy_blueprint_april_2012.pdf.

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