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WO1990010078A1 - Systeme ameliore d'expression de baculovirus capable de produire des proteines de genes etrangers en grande quantite - Google Patents

Systeme ameliore d'expression de baculovirus capable de produire des proteines de genes etrangers en grande quantite Download PDF

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Publication number
WO1990010078A1
WO1990010078A1 PCT/CA1990/000061 CA9000061W WO9010078A1 WO 1990010078 A1 WO1990010078 A1 WO 1990010078A1 CA 9000061 W CA9000061 W CA 9000061W WO 9010078 A1 WO9010078 A1 WO 9010078A1
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WO
WIPO (PCT)
Prior art keywords
gene
protein
foreign gene
foreign
polyhedrin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CA1990/000061
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English (en)
Inventor
C. Yong Kang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Ottawa
Original Assignee
University of Ottawa
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from CA000591908A external-priority patent/CA1330425C/fr
Priority claimed from US07/316,768 external-priority patent/US5194376A/en
Application filed by University of Ottawa filed Critical University of Ottawa
Publication of WO1990010078A1 publication Critical patent/WO1990010078A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C12N15/86—Viral vectors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
    • C12N2710/00011—Details
    • C12N2710/14011—Baculoviridae
    • C12N2710/14111—Nucleopolyhedrovirus, e.g. autographa californica nucleopolyhedrovirus
    • C12N2710/14141—Use of virus, viral particle or viral elements as a vector
    • C12N2710/14143—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16111—Human Immunodeficiency Virus, HIV concerning HIV env
    • C12N2740/16122—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16111—Human Immunodeficiency Virus, HIV concerning HIV env
    • C12N2740/16134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein

Definitions

  • An object of the present invention is to provide a method of genetic engineering which provides high level expression of genes formerly expressing at only low or intermediate levels in the bacul.ovirus-cellular expression system.
  • Another object of the invention is to provide refined site-directed utagenesis methods with synthetic oligonucleotide linkers which can be used to engineer transfer vectors for the preparation of recombinant baculoviruses suitable for high level expression of foreign genes in the baculovirus-cellular expression system.
  • Fig. 1 is a schematic diagram showing a procedure according to a preferred embodiment of the invention in whic a modified rev gene of HIV-1 is inserted into a pAcYMl vecto to form a transfer vector pAcYMl-rev suitable for forming a recombinant baculovirus AcNPV-HIVYKrev capable of producing rev at high levels;
  • the present invention is based on the introduction of a putative insect cell ribosome binding site immediately upstream of the foreign gene without intervening sequences under the polyhedrin gene promoter in the baculovirus transfer vector.
  • the invention also involves the elimination of any non-coding flanking sequences at preferably both the 3' and 5 1 ends of the foreign gene using a uniquely modified crossover linker mutagenesis method. This modification of the baculovirai vector overcomes any tendency of the viral-cellular system to resist expression of the foreign gene.
  • the crossover linker mutagenesis procedure can be described as follows.
  • the foreign gene is synthesized or isolated from a suitable DNA or RNA source (e.g. a commercially available plasmid having suitable restriction sites bracketing the foreign gene) and is inserted into a small plasmid using standard techniques. If isolated from a natural source, the gene is normally accompanied by non-coding flanking sequences and, to the extent possible, these are partially removed by standard digestion and ligation techniques.
  • the plasmid containing the modified foreign gene resulting from the previous crossover linker mutagenesis is then linearized at a site downstream of the 3' end of the foreign gene, the oligonucleotide linker is ligated and the resulting DNA structure is transfected into a competent microorganism, again preferably E_ ⁇ Coli, which deletes the unwanted flanking sequences, adds a desired restriction enzyme site and recircularizes the plasmid.
  • the plasmid pUC19-rev 2 contained the desired sequence upstream of the rev gene but also contained unwanted non-coding sequences downstream of the rev gene and these were removed by the following technique:
  • the second strand comprised the Hind III sticky end and the complementary sequences of the first strand, except for the final three nucleotides.
  • the double stranded linker thus was as follows: translation termination
  • the present invention can be used as a system for expressing foreign genes at high levels in a eukaryotic cell system, and the resulting proteins can be used for a variety of purposes, e.g. in vaccines and in medical diagnostic and prognostic tests.

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  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Virology (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Biomedical Technology (AREA)
  • General Health & Medical Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Biochemistry (AREA)
  • Physics & Mathematics (AREA)
  • Microbiology (AREA)
  • Plant Pathology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Medicinal Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

Le système d'expression de baculovirus décrit, qui est capable de produire des protéines de gènes étrangers en grande quantité, consiste à produire un baculovirus recombinant contenant un gène étranger modifié entre la région promotrice du gène de polyhédrine et le signal de terminaison de transcription du gène structurel de polyhédrine. Le gène étranger modifié comprend un site de liaison de ribosome supposé immédiatement en amont de la séquence de codage du gène étranger, c'est-à-dire sans aucune intervention de la part de séquences non codantes. Le site de liaison de ribosome supposé est de préférence positionné de façon approprié, sans les séquences intervenantes, par un processus de mutagenèse par agent de liaison de chevauchement, avant que le gène étranger modifié soit introduit dans le virus. Le site de liaison de ribosome supposé comprend de préférence au moins les quatre nucléotides finals de la séquence ACCTATAAAT immédiatement en amont du codon d'initiation de translation (ATG) du gène étranger. Ce système est capable de produire des protéines de gènes étrangers (lorsque des cellules d'insecte sont infectées par le virus recombinant) à des niveaux élevés, même dans le cas des gènes qui ne pouvaient être exprimés qu'à des niveaux faible ou intermédiaire dans les systèmes de baculovirus recombinants antérieurs.
PCT/CA1990/000061 1989-02-23 1990-02-23 Systeme ameliore d'expression de baculovirus capable de produire des proteines de genes etrangers en grande quantite Ceased WO1990010078A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CA591,908 1989-02-23
CA000591908A CA1330425C (fr) 1989-02-23 1989-02-23 Systeme d'expression dans baculovirus permettant de produire des proteines etrangeres en grande quantite
US07/316,768 US5194376A (en) 1989-02-28 1989-02-28 Baculovirus expression system capable of producing foreign gene proteins at high levels
US316,768 1989-02-28

Publications (1)

Publication Number Publication Date
WO1990010078A1 true WO1990010078A1 (fr) 1990-09-07

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Country Status (2)

Country Link
AU (1) AU5187190A (fr)
WO (1) WO1990010078A1 (fr)

Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5244805A (en) * 1989-05-17 1993-09-14 University Of Georgia Research Foundation, Inc. Baculovirus expression vectors
RU2156300C2 (ru) * 1991-03-22 2000-09-20 Руссель-Юклаф Рекомбинантный стабильный окклюдированный вирус ядерного полиэдроза (варианты), инсектицидная композиция и способ борьбы с насекомыми на участке
WO2006069246A2 (fr) 2004-12-22 2006-06-29 Ambrx, Inc. Compositions contenant des acides amines non naturels et des polypeptides, procedes impliquant ces acides amines non naturels et polypeptides, et utilisations desdits acides amines non naturels et polypeptides
WO2008030558A2 (fr) 2006-09-08 2008-03-13 Ambrx, Inc. Polypeptide plasmatique humain modifié ou squelettes de fc et leurs utilisations
WO2009067636A2 (fr) 2007-11-20 2009-05-28 Ambrx, Inc. Polypeptides d'insuline modifiés et leurs utilisations
US7632823B2 (en) 2005-08-18 2009-12-15 Ambrx, Inc. Compositions of tRNA and uses thereof
US7632924B2 (en) 2004-06-18 2009-12-15 Ambrx, Inc. Antigen-binding polypeptides and their uses
US7638299B2 (en) 2004-07-21 2009-12-29 Ambrx, Inc. Biosynthetic polypeptides utilizing non-naturally encoded amino acids
WO2010011735A2 (fr) 2008-07-23 2010-01-28 Ambrx, Inc. Polypeptides g-csf bovins modifiés et leurs utilisations
WO2010037062A1 (fr) 2008-09-26 2010-04-01 Ambrx, Inc. Vaccins et micro-organismes dépendant de la réplication d'acide aminé non naturels
US7736872B2 (en) 2004-12-22 2010-06-15 Ambrx, Inc. Compositions of aminoacyl-TRNA synthetase and uses thereof
US7816320B2 (en) 2004-12-22 2010-10-19 Ambrx, Inc. Formulations of human growth hormone comprising a non-naturally encoded amino acid at position 35
EP2284191A2 (fr) 2004-12-22 2011-02-16 Ambrx, Inc. Procédé de préparation de hGH
US7947473B2 (en) 2004-12-22 2011-05-24 Ambrx, Inc. Methods for expression and purification of pegylated recombinant human growth hormone containing a non-naturally encoded keto amino acid
EP2327724A2 (fr) 2004-02-02 2011-06-01 Ambrx, Inc. Polypeptides d'hormone de croissance humaine et leur utilisations
US8012931B2 (en) 2007-03-30 2011-09-06 Ambrx, Inc. Modified FGF-21 polypeptides and their uses
US8093356B2 (en) 2005-06-03 2012-01-10 Ambrx, Inc. Pegylated human interferon polypeptides
US8114630B2 (en) 2007-05-02 2012-02-14 Ambrx, Inc. Modified interferon beta polypeptides and their uses
WO2012024452A2 (fr) 2010-08-17 2012-02-23 Ambrx, Inc. Polypeptides de relaxine modifiés et leurs utilisations
US8278418B2 (en) 2008-09-26 2012-10-02 Ambrx, Inc. Modified animal erythropoietin polypeptides and their uses
US8420792B2 (en) 2006-09-08 2013-04-16 Ambrx, Inc. Suppressor tRNA transcription in vertebrate cells
EP2805964A1 (fr) 2009-12-21 2014-11-26 Ambrx, Inc. Polypeptides modifiés de somatotrophine bovine et leurs utilisations
EP2805965A1 (fr) 2009-12-21 2014-11-26 Ambrx, Inc. Polypeptides modifiés de somatotrophine bovine et leurs utilisations
US9133495B2 (en) 2006-09-08 2015-09-15 Ambrx, Inc. Hybrid suppressor tRNA for vertebrate cells
US9434778B2 (en) 2014-10-24 2016-09-06 Bristol-Myers Squibb Company Modified FGF-21 polypeptides comprising an internal deletion and uses thereof
US9488660B2 (en) 2005-11-16 2016-11-08 Ambrx, Inc. Methods and compositions comprising non-natural amino acids
EP3103880A1 (fr) 2008-02-08 2016-12-14 Ambrx, Inc. Polypeptides d'insuline modifiés et utilisations de ceux-ci
US9567386B2 (en) 2010-08-17 2017-02-14 Ambrx, Inc. Therapeutic uses of modified relaxin polypeptides
US10266578B2 (en) 2017-02-08 2019-04-23 Bristol-Myers Squibb Company Modified relaxin polypeptides comprising a pharmacokinetic enhancer and uses thereof
US11273202B2 (en) 2010-09-23 2022-03-15 Elanco Us Inc. Formulations for bovine granulocyte colony stimulating factor and variants thereof

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2033070A1 (fr) * 1989-05-17 1990-11-18 Lois K. Miller Vecteurs d'expression du baculovirus

Citations (1)

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EP0265785A2 (fr) * 1986-10-16 1988-05-04 Microgenesys, Inc. Polypeptides dérivés du gène d'enveloppe du virus d'immuno-dépression acquise, dans des cellules d'insectes infectées par un baculovirus recombinant

Patent Citations (1)

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Non-Patent Citations (2)

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Title
Agricultural & Biological Chemistry, Volume 51, No. 6, June 1987, (Tokyo, JP), T. HORIUCHI et al.: "High-Level Expression of the Human-alpha-Interferon Gene Through the use of an Improved Baculovirus Vector in the Silkworm, Bombyx Mori", pages 1573-1580 *
The Journal of General Virology, Volume 68, No. 5, May 1987, SGM, (GB), Y. MATSUURA et al.: "Baculovirus Expression Vectors: the Requirements for High Level Expression of Proteins, Including Glycoproteins", pages 1233-1250 *

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5244805A (en) * 1989-05-17 1993-09-14 University Of Georgia Research Foundation, Inc. Baculovirus expression vectors
RU2156300C2 (ru) * 1991-03-22 2000-09-20 Руссель-Юклаф Рекомбинантный стабильный окклюдированный вирус ядерного полиэдроза (варианты), инсектицидная композиция и способ борьбы с насекомыми на участке
US8907064B2 (en) 2004-02-02 2014-12-09 Ambrx, Inc. Modified human four helical bundle polypeptides and their uses
US8097702B2 (en) 2004-02-02 2012-01-17 Ambrx, Inc. Modified human interferon polypeptides with at least one non-naturally encoded amino acid and their uses
US9260472B2 (en) 2004-02-02 2016-02-16 Ambrx, Inc. Modified human four helical bundle polypeptides and their uses
US8232371B2 (en) 2004-02-02 2012-07-31 Ambrx, Inc. Modified human interferon polypeptides and their uses
EP2327724A2 (fr) 2004-02-02 2011-06-01 Ambrx, Inc. Polypeptides d'hormone de croissance humaine et leur utilisations
US8906676B2 (en) 2004-02-02 2014-12-09 Ambrx, Inc. Modified human four helical bundle polypeptides and their uses
US9175083B2 (en) 2004-06-18 2015-11-03 Ambrx, Inc. Antigen-binding polypeptides and their uses
US7632924B2 (en) 2004-06-18 2009-12-15 Ambrx, Inc. Antigen-binding polypeptides and their uses
US7638299B2 (en) 2004-07-21 2009-12-29 Ambrx, Inc. Biosynthetic polypeptides utilizing non-naturally encoded amino acids
US7939496B2 (en) 2004-12-22 2011-05-10 Ambrx, Inc. Modified human growth horomone polypeptides and their uses
US7959926B2 (en) 2004-12-22 2011-06-14 Ambrx, Inc. Methods for expression and purification of recombinant human growth hormone mutants
US7838265B2 (en) 2004-12-22 2010-11-23 Ambrx, Inc. Compositions of aminoacyl-tRNA synthetase and uses thereof
US7846689B2 (en) 2004-12-22 2010-12-07 Ambrx, Inc. Compositions of aminoacyl-tRNA synthetase and uses thereof
US7858344B2 (en) 2004-12-22 2010-12-28 Ambrx, Inc. Compositions of aminoacyl-tRNA synthetase and uses thereof
US7883866B2 (en) 2004-12-22 2011-02-08 Ambrx, Inc. Compositions of aminoacyl-tRNA synthetase and uses thereof
EP2284191A2 (fr) 2004-12-22 2011-02-16 Ambrx, Inc. Procédé de préparation de hGH
US7816320B2 (en) 2004-12-22 2010-10-19 Ambrx, Inc. Formulations of human growth hormone comprising a non-naturally encoded amino acid at position 35
US8143216B2 (en) 2004-12-22 2012-03-27 Ambrx, Inc. Modified human growth hormone
US7947473B2 (en) 2004-12-22 2011-05-24 Ambrx, Inc. Methods for expression and purification of pegylated recombinant human growth hormone containing a non-naturally encoded keto amino acid
US7736872B2 (en) 2004-12-22 2010-06-15 Ambrx, Inc. Compositions of aminoacyl-TRNA synthetase and uses thereof
US7829310B2 (en) 2004-12-22 2010-11-09 Ambrx, Inc. Compositions of aminoacyl-tRNA synthetase and uses thereof
US8163695B2 (en) 2004-12-22 2012-04-24 Ambrx Formulations of human growth hormone comprising a non-naturally encoded amino acid
US8178108B2 (en) 2004-12-22 2012-05-15 Ambrx, Inc. Methods for expression and purification of recombinant human growth hormone
US8178494B2 (en) 2004-12-22 2012-05-15 Ambrx, Inc. Modified human growth hormone formulations with an increased serum half-life
US8080391B2 (en) 2004-12-22 2011-12-20 Ambrx, Inc. Process of producing non-naturally encoded amino acid containing high conjugated to a water soluble polymer
EP2399893A2 (fr) 2004-12-22 2011-12-28 Ambrx, Inc. Compositions contenant des acides aminés et des polypeptides non naturels, procédés les impliquant et leurs utilisations
WO2006069246A2 (fr) 2004-12-22 2006-06-29 Ambrx, Inc. Compositions contenant des acides amines non naturels et des polypeptides, procedes impliquant ces acides amines non naturels et polypeptides, et utilisations desdits acides amines non naturels et polypeptides
US8093356B2 (en) 2005-06-03 2012-01-10 Ambrx, Inc. Pegylated human interferon polypeptides
US7632823B2 (en) 2005-08-18 2009-12-15 Ambrx, Inc. Compositions of tRNA and uses thereof
US9488660B2 (en) 2005-11-16 2016-11-08 Ambrx, Inc. Methods and compositions comprising non-natural amino acids
US8022186B2 (en) 2006-09-08 2011-09-20 Ambrx, Inc. Modified human plasma polypeptide or Fc scaffolds and their uses
US8420792B2 (en) 2006-09-08 2013-04-16 Ambrx, Inc. Suppressor tRNA transcription in vertebrate cells
US9133495B2 (en) 2006-09-08 2015-09-15 Ambrx, Inc. Hybrid suppressor tRNA for vertebrate cells
US8053560B2 (en) 2006-09-08 2011-11-08 Ambrx, Inc. Modified human plasma polypeptide or Fc scaffolds and their uses
WO2008030558A2 (fr) 2006-09-08 2008-03-13 Ambrx, Inc. Polypeptide plasmatique humain modifié ou squelettes de fc et leurs utilisations
US7919591B2 (en) 2006-09-08 2011-04-05 Ambrx, Inc. Modified human plasma polypeptide or Fc scaffolds and their uses
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US8383365B2 (en) 2007-03-30 2013-02-26 Ambrx, Inc. Methods of making FGF-21 mutants comprising non-naturally encoded phenylalanine derivatives
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US9975936B2 (en) 2007-03-30 2018-05-22 Ambrx, Inc. Nucleic acids encoding modified FGF-21 polypeptides comprising non-naturally occurring amino acids
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US10961291B2 (en) 2007-03-30 2021-03-30 Ambrx, Inc. Modified FGF-21 polypeptides and their uses
US8114630B2 (en) 2007-05-02 2012-02-14 Ambrx, Inc. Modified interferon beta polypeptides and their uses
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US10138283B2 (en) 2008-07-23 2018-11-27 Ambrx, Inc. Modified bovine G-CSF polypeptides and their uses
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US8278418B2 (en) 2008-09-26 2012-10-02 Ambrx, Inc. Modified animal erythropoietin polypeptides and their uses
US9156899B2 (en) 2008-09-26 2015-10-13 Eli Lilly And Company Modified animal erythropoietin polypeptides and their uses
US9121024B2 (en) 2008-09-26 2015-09-01 Ambrx, Inc. Non-natural amino acid replication-dependent microorganisms and vaccines
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US9121025B2 (en) 2008-09-26 2015-09-01 Ambrx, Inc. Non-natural amino acid replication-dependent microorganisms and vaccines
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