ZMapp

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ZMapp(ジーマップ。ズィーマップとも)[1]は、タバコの近縁種であるNicotiana benthamianaの葉の遺伝子へ組み込んで作られる、3種類のヒト化モノクローナル抗体を混合した抗エボラウイルス薬である[2][3]。2014年現在、サルに対する非臨床試験しか実施されていない未承認薬であるが、2014年8月4日に2人のエボラ出血熱患者に投与され、実験的な治療が行われた。その結果、2人とも症状が改善されるポジティブな結果を示した[4]。しかしながらその翌週ごろに投与された6名のうち2名は一定の効果を見せた後に容態悪化で死亡しており、死因が用法用量の不適切か副作用か病状悪化か患者の体力由来かなどの詳細なソースも不明であり、薬効については不透明のままである[5]。なお2名死者のうちスペイン人司祭は後期高齢者であった[6]。この薬は、米国のベンチャー企業、マップ・バイオファーマシューティカル社が開発中である[7]

元々は生物兵器から身を守るために開発されたもので、国立衛生研究所国防脅威削減局が開発を支援している[8]

脚注[編集]

  1. ^ エボラ、欧州初の死者…新薬治療のスペイン司祭(読売新聞 2014年8月12日 同日閲覧)
  2. ^ Larry Zeitlin, James Pettitt, Corinne Scully, Natasha Bohorova, Do Kim, Michael Pauly, Andrew Hiatt, Long Ngo, Herta Steinkellner, Kevin J. Whaley, and Gene G. Olinger (2011). “Enhanced potency of a fucose-free monoclonal antibody being developed as an Ebola virus immunoprotectant”. PNAS. doi:10.1073/pnas.1108360108. http://www.pnas.org/content/108/51/20690.abstract?sid=a570a830-ca93-4cd2-aa8c-47de89fe0327. 
  3. ^ Gene Garrard Olinger Jr, James Pettitt, Do Kim, Cara Working, Ognian Bohorov, Barry Bratcher, Ernie Hiatt, Steven D. Hume, Ashley K. Johnson, Josh Morton, Michael Pauly, Kevin J. Whaley, Calli M. Lear, Julia E. Biggins, Corinne Scully, Lisa Hensley, and Larry Zeitlin (2012). “Delayed treatment of Ebola virus infection with plant-derived monoclonal antibodies provides protection in rhesus macaques”. PNAS. doi:10.1073/pnas.1213709109. http://www.pnas.org/content/109/44/18030.full?sid=ec334f96-1b52-465b-aad9-25b716b3f669. 
  4. ^ "Mystery Ebola virus serum manufactured by San Diego firm". Los Angeles Times. August 4, 2014.
  5. ^ エボラ出血熱:未承認薬投与の医師死亡 リベリア 毎日新聞 2014年8月25日
  6. ^ エボラ熱感染のスペイン人神父、マドリードの病院で死亡 ロイター 2014年8月12日
  7. ^ http://medicalware.org/wiki/ZMapp
  8. ^ “実験用エボラ治療剤「ZMapp」、生体武器防御目的で開発”. 中央日報. (2014年8月6日). http://japanese.joins.com/article/613/188613.html 2014年11月1日閲覧。 

関連項目[編集]


Schematic representation of how monoclonal antibodies are generally made from hybridomas. To make ZMapp, the genes encoding for the antibodies were extracted from the hybridomas, genetically engineered to replace mouse components with human components, and transfected into tobacco plants.[1]

ZMapp is an experimental biopharmaceutical drug comprising three chimeric monoclonal antibodies under development as a treatment for Ebola virus disease. The drug was first tested in humans during the 2014 West Africa Ebola virus outbreak, but has not been subjected to a randomized controlled trial to determine whether it works, and whether it is safe enough to allow on the market.

Medical use[編集]

ZMapp is under development as a treatment for Ebola virus disease.[2] It was first used experimentally to treat some people with Ebola virus disease during the 2014 West African Ebola outbreak, but as of August 2014 it had not yet been tested in a clinical trial to support widespread usage in humans; it is not known whether it is effective to treat the disease, nor if it is safe. [3] [4] [5]

Mechanism of action[編集]

Like intravenous immunoglobulin therapy, ZMapp contains neutralizing antibodies [6] that provide passive immunity to the virus by directly and specifically reacting with it in a "lock and key" fashion.[7]

Physical and chemical properties[編集]

The drug is composed of three monoclonal antibodies (mAbs) that have been chimerized by genetic engineering.[8] The components are chimeric monoclonal antibody c13C6 from a previously existing antibody cocktail called "MB-003" and two chimeric mAbs from a different antibody cocktail called ZMab, c2G4 and c4G7.[2]

ZMapp is manufactured in the tobacco plant Nicotiana benthamiana in the bioproduction process known as "pharming" by Kentucky BioProcessing, a subsidiary of Reynolds American.[1][9][10]

green plant being injected by a needle
The Nicotiana benthamiana tobacco plant

History[編集]

The composite drug is being developed by Leaf Biopharmaceutical (LeafBio, Inc.), a San Diego based arm of Mapp Biopharmaceutical.[11] LeafBio created ZMapp in collaboration with its parent and Defyrus Inc., each of which had developed its own cocktail of antibodies, called MB-003 and ZMab.

MB-003[編集]

MB-003 is a cocktail of three humanized or human–mouse chimeric mAbs: c13C6, h13F6 and c6D8.[2] A study published in September 2012 found that rhesus macaques infected with Ebola virus (EBOV) survived when receiving MB-003 (mixture of 3 chimeric monoclonal antibodies) one hour after infection. When treated 24 or 48 hours after infection, four of six animals survived and had little to no viremia and few, if any, clinical symptoms.[12]

MB-003 was created by Mapp Biopharmaceutical, based in San Diego, with years of funding from US government agencies including the National Institute of Allergy and Infectious Disease, Biomedical Advanced Research and Development Authority, and the Defense Threat Reduction Agency.[1][13]

ZMAb[編集]

ZMAb is a mixture of three mouse mAbs: m1H3, m2G4 and m4G7.[2] A study published in November 2013 found that EBOV-infected macaque monkeys survived after being given a therapy with a combination of three EBOV surface glycoprotein (EBOV-GP)-specific monoclonal antibodies (ZMAb) within 24 hours of infection. The authors concluded that post-exposure treatment resulted in a robust immune response, with good protection for up to 10 weeks and some protection at 13 weeks.[14]

ZMab was created by Defyrus, a Toronto-based biodefense company, funded by the Public Health Agency of Canada.[15] The identification of the optimal components from MB-003 and ZMab was carried out at the Public Health Agency of Canada’s National Microbiology Laboratory in Winnipeg.[16]

ZMapp[編集]

A 2014 paper described how Mapp and its collaborators, including investigators at Public Health Agency of Canada, Kentucky BioProcessing, and the National Institute of Allergy and Infectious Diseases, first chimerized the three antibodies comprising ZMAb, then tested combinations of MB-003 and the chimeric ZMAb antibodies in guinea pigs and then primates to determine the best combination, which turned out to be c13C6 from MB-003 and two chimeric mAbs from ZMAb, c2G4 and c4G7. This is ZMapp.[2]

In an experiment also published in the 2014 paper, 21 rhesus macaque primates were infected with the Kikwit Congolese variant of EBOV. Three primates in the control arm were given a non-functional antibody, and the 18 in the treatment arm were divided into three groups of six. All primates in the treatment arm received three doses of ZMapp, spaced 3 days apart. The first treatment group received its first dose on 3rd day after being infected; the second group on the 4th day after being infected, and the third group, on the 5th day after being infected. All three primates in the control group died; all 18 primates in the treatment arm survived.[2] Mapp then went on to show that ZMapp inhibits replication of a Guinean strain of EBOV in cell cultures.[17]

Mapp remains involved in the production of the drug through its contracts with Kentucky BioProcessing, a subsidiary of Reynolds American.[1] To produce the drug, genes coding for the chimeric mAbs were inserted into viral vectors, and tobacco plants are infected with the viral vector encoding for the antibodies, using Agrobacterium cultures.[18][19][20] Subsequently, antibodies are extracted and purified from the plants. Once the genes encoding the chimeric mAbs are in hand, the entire tobacco production cycle is believed to take a few months.[21] The development of these production methods was funded by the U.S. Defense Advanced Research Projects Agency as part of its bio-defense efforts following the 9/11 terrorist attacks.[22][23]

Use during the 2014 Ebola outbreak[編集]

The FDA allowed two drugs, ZMapp and an RNA interference drug called TKM-Ebola, to be used in Americans who had contracted Ebola virus disease.[24] Other countries have similar programs to allow early access through named patient programs.[25][26] 2014年10現在, ZMapp had been used to treat 7 individuals infected with the Ebola virus.[27] Although some of them have recovered, the outcome is not considered to be statistically significant.[5] Mapp announced on August 11, 2014, that its supplies of ZMapp had been exhausted.[28]

Controversy[編集]

The lack of drugs and unavailability of experimental treatment in the most affected regions of the West African Ebola virus outbreak spurred some controversy.[21] The fact that the drug was first given to Americans and a European and not to Africans, according to the Los Angeles Times, "provoked outrage, feeding into African perceptions of Western insensitivity and arrogance, with a deep sense of mistrust and betrayal still lingering over the exploitation and abuses of the colonial era".[29] Salim S. Abdool Karim, the director of an AIDS research center in South Africa, placed the issue in the context of the history of exploitation and abuses. Responding to a question on how people may have reacted if ZMapp and other drugs would have been used first on Africans, said, "It would have been the front-page screaming headline: 'Africans used as guinea pigs for American drug company’s medicine'".[21]

In early August, the World Health Organization called for convening a panel of medical authorities "to consider whether experimental drugs should be more widely released." In a statement, Peter Piot (co-discoverer of the Ebola virus); Jeremy Farrar, the director of the Wellcome Trust; and David Heymann of the Chatham House Center on Global Health Security, called for the release of experimental drugs for affected African nations.[29]

At an August 6, 2014 press conference, Barack Obama, the President of the United States, was questioned regarding whether the cocktail should be fast-tracked for approval or be made available to sick patients outside of the United States. He responded, “I think we’ve got to let the science guide us. I don't think all the information's in on whether this drug is helpful."[30]

See also[編集]

References[編集]

  1. ^ a b c d Kroll, David (2014年8月5日). “Ebola 'Secret Serum': Small Biopharma, The Army, And Big Tobacco”. Forbes. http://www.forbes.com/sites/davidkroll/2014/08/05/ebola-secret-serum-small-biopharma-the-army-and-big-tobacco/ 
  2. ^ a b c d e f Qiu X, Wong G, Audet J, et al. (August 2014). “Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp”. Nature 514 (7520): 47–53. doi:10.1038/nature13777. PMID 25171469. 
  3. ^ WHO Experts Give Nod to Using Untested Ebola Drugs” (2014年8月12日). 2014年11月8日閲覧。
  4. ^ WHO – Ethical considerations for use of unregistered interventions for Ebola virus disease”. World Health Organization. 2014年10月8日閲覧。
  5. ^ a b How Will We Know If The Ebola Drugs Worked?”. Forbes. 2014年9月10日閲覧。
  6. ^ Ebola 'cocktail' developed at Canadian and U.S. labs”. CBC News (2014年8月5日). 2014年11月8日閲覧。
  7. ^ Keller MA, Stiehm ER (October 2000). “Passive immunity in prevention and treatment of infectious diseases”. Clin. Microbiol. Rev. 13 (4): 602–14. doi:10.1128/CMR.13.4.602-614.2000. PMC 88952. PMID 11023960. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=88952. 
  8. ^ Pollack, Andrew (2014年8月29日). “Experimental Drug Would Help Fight Ebola if Supply Increases, Study Finds”. The New York Times. http://www.nytimes.com/2014/08/30/world/africa/study-says-zmapp-works-against-ebola-but-making-it-takes-time.html?_r=0 2014年9月1日閲覧。 
  9. ^ Parshley, Lois (2014年8月8日). “ZMapp: The Experimental Ebola Treatment Explained”. Popular Science. http://www.popsci.com/article/science/zmapp-experimental-ebola-treatment-explained 
  10. ^ Daniel, Fran (2014年8月12日). “Ebola drug provided for two Americans by Reynolds American subsidiary”. Winston-Salem Journal. http://www.journalnow.com/news/local/ebola-drug-provided-for-two-americans-by-reynolds-american-subsidiary/article_144fb3ce-1cb3-11e4-9f1b-0017a43b2370.html 
  11. ^ Monoclonal antibody-based filovirus therapeutic licensed to Leaf Biopharmaceutical” (2014年7月15日). 2014年11月8日閲覧。
  12. ^ Olinger GG, Pettitt J, Kim D, et al. (October 2012). “Delayed treatment of Ebola virus infection with plant-derived monoclonal antibodies provides protection in rhesus macaques”. Proc. Natl. Acad. Sci. U.S.A. 109 (44): 18030–5. doi:10.1073/pnas.1213709109. PMC 3497800. PMID 23071322. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=3497800. 
  13. ^ Questions and answers on experimental treatments and vaccines for Ebola”. Centers for Disease Control and Prevention (2014年8月29日). 2014年11月8日閲覧。
  14. ^ Qiu X, Audet J, Wong G, et al. (2013). “Sustained protection against Ebola virus infection following treatment of infected nonhuman primates with ZMAb”. Sci Rep 3: 3365. doi:10.1038/srep03365. PMC 3842534. PMID 24284388. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=3842534. 
  15. ^ Branswell, Helen (2014年8月5日). “Experimental Ebola drug based on research discoveries from Canada's national lab”. Canadian Press. http://www.brandonsun.com/business/breaking-news/experimental-ebola-drug-based-on-research-discoveries-from-canadas-national-lab-269910211.html 
  16. ^ Branswell, Helen (2014年8月29日). “Scientists at Canada’s national lab created, tested Ebola drug ZMapp”. Canadian Press. Macleans. http://www.macleans.ca/society/health/scientists-at-canadas-national-lab-created-tested-ebola-drug-zmapp/ 
  17. ^ Geisbert TW (August 2014). “Medical research: Ebola therapy protects severely ill monkeys”. Nature 514 (7520): 41–3. doi:10.1038/nature13746. PMID 25171470. 
  18. ^ Magnifection – mass-producing drugs in record time”. National Geographic. 2014年9月11日閲覧。
  19. ^ Whaley KJ et al. (2014). “Emerging antibody-based products”. Curr Top Microbiol Immunol 375: 107–26. doi:10.1007/82_2012_240. PMID 22772797. 
  20. ^ Giritch A et al. (2006). “Rapid high-yield expression of full-size IgG antibodies in plants coinfected with noncompeting viral vectors”. Proc Natl Acad Sci USA 40 (40): 14701–14706. doi:10.1073/pnas.0606631103. PMID 16973752. 
  21. ^ a b c Pollack, Andrew (2014年8月8日). “In Ebola outbreak, who should get experimental drug?”. The New York Times. http://www.nytimes.com/2014/08/09/health/in-ebola-outbreak-who-should-get-experimental-drug.html 
  22. ^ Till, Brian (2014年9月9日). “DARPA may have a way to stop Ebola in its tracks”. New Republic. http://www.newrepublic.com/article/119376/ebola-drug-zmapp-darpa-program-could-get-it-africa 
  23. ^ Shannon Pettypiece for Bloomberg News. 23, October 2014. Cheney in Post 9/11 Era May Be to Thank on Ebola Vaccine
  24. ^ Pollack, Andrew (2014年8月7日). “Second drug is allowed for treatment of Ebola”. The New York Times. http://www.nytimes.com/2014/08/08/health/second-experimental-drug-allowed-for-treating-ebola.html?_r=0 2014年8月8日閲覧。 
  25. ^ Helene S (2010). “EU Compassionate Use Programmes (CUPs): Regulatory Framework and Points to Consider before CUP Implementation”. Pharm Med 24 (4): 223–229. doi:10.1007/bf03256820. http://adisonline.com/pharmaceuticalmedicine/Fulltext/2010/24040/EU_Compassionate_Use_Programmes__CUPs___Regulatory.4.aspx. 
  26. ^ Spain imports US experimental Ebola drug to treat priest evacuated from Liberia with disease”. First Word Pharma (2014年8月11日). 2014年11月8日閲覧。
  27. ^ “US signs contract with ZMapp maker to accelerate development of the Ebola drug”. BMJ. BMJ. (2014年). http://dx.doi.org/10.1136/bmj.g5488 2014年10月9日閲覧。 
  28. ^ Lenny M. Bernstein, Brady Dennis (2014年8月11日). “Ebola test drug’s supply ‘exhausted’ after shipments to Africa, U.S. company says”. Washington Post. http://www.washingtonpost.com/national/health-science/ebola-test-drugs-supply-exhausted-after-shipments-to-africa-us-company-says/2014/08/11/020cefc0-2199-11e4-958c-268a320a60ce_story.html 
  29. ^ a b Dixon, Robyn (2014年8月6日). “Three leading Ebola experts call for release of experimental drug”. Los Angeles Times. http://www.latimes.com/world/africa/la-fg-three-ebola-experts-release-drugs-20140806-story.html 
  30. ^ “Obama: 'Premature' to say U.S. should green-light new Ebola drug”. NBC News. (2014年8月6日). http://www.nbcnews.com/storyline/ebola-virus-outbreak/obama-premature-say-u-s-should-green-light-new-ebola-n174461 

External links[編集]

Template:Ebola Template:Engineered antibodies Template:Monoclonals for infectious disease and toxins