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WO1993025698A9 - Particules vecteurs resistantes a l'inactivation par le serum humain - Google Patents

Particules vecteurs resistantes a l'inactivation par le serum humain

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Publication number
WO1993025698A9
WO1993025698A9 PCT/US1993/004706 US9304706W WO9325698A9 WO 1993025698 A9 WO1993025698 A9 WO 1993025698A9 US 9304706 W US9304706 W US 9304706W WO 9325698 A9 WO9325698 A9 WO 9325698A9
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WO
WIPO (PCT)
Prior art keywords
amino acid
protein
changed
vector particle
mutated
Prior art date
Application number
PCT/US1993/004706
Other languages
English (en)
Other versions
WO1993025698A1 (fr
Filing date
Publication date
Application filed filed Critical
Priority to JP6501479A priority Critical patent/JPH09507741A/ja
Priority to EP93913964A priority patent/EP0644946A4/fr
Publication of WO1993025698A1 publication Critical patent/WO1993025698A1/fr
Publication of WO1993025698A9 publication Critical patent/WO1993025698A9/fr

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Definitions

  • This invention relates to "injectable" vector particles. More particularly, this invention relates to vector particles, such as retroviral vector particles, wherein such vector particles are resistant to inactivation by human serum.
  • Vector particles are useful agents for introducing gene(s) or DNA (RNA) into a cell, such as a eukaryotic cell.
  • the gene(s) is controlled by an appropriate promoter.
  • vectors which may be employed to generate vector particles include prokaryotic vectors, such as bacterial vectors; eukaryotic vectors,' including fungal vectors such as yeast vectors; and viral vectors such as DNA virus vectors, RNA virus vectors, and retroviral vectors.
  • Retroviruses which have been employed for generating vector particles for introducing genes or DNA (RNA) into a cell include Moloney Murine Leukemia Virus, Spleen Necrosis Virus, Rous Sarcoma Virus and Harvey Sarcoma Virus.
  • the term "introducing” as used herein encompasses a variety of methods of transfering genes or DNA (RNA) into a cell. Such methods include transformation, transduction, transfection, and infection.
  • Vector particles have been used for introducing DNA (RNA) into cells for gene therapy purposes.
  • RNA DNA
  • such a procedure involves obtaining cells from a patient and using a vector particle to introduce desired DNA (RNA) into the cells and then providing the patient with the engineered cells for a therapeutic purpose.
  • RNA desired DNA
  • Such an alternative procedure would involve genetically engineering cells in vivo.
  • a vector particle which includes the desired DNA (RNA) would be administered to a patient for in vivo delivery to the cells of a patient.
  • a vector particle such as, for example, a retroviral vector particle
  • a vector particle which is resistant to inactivation by human serum.
  • the vector particle is a viral vector particle, and more preferably the viral vector particle is a retroviral vector particle.
  • retroviruses include a protein known as p15E, and Applicants have found that retroviruses are susceptible to inactivation by human serum as a result of the action of complement protein(s) present in serum on the p15E protein portion of the retrovirus. Applicants have further found that such retroviruses can be made resistant to inactivation by human serum by mutating such p15E protein.
  • a retroviral vector wherein a portion of the DNA encoding p15E protein (shown in the accompanying sequence listing), has been mutated to render the vector particle resistant to inactivation by human serum.
  • mutated and mutation as used herein mean that the DNA encoding p15E protein has been changed such that at least one but not all of the amino acids of p15E protein have been changed (such changes can include point mutations, deletions, and/or insertions).
  • p15E protein is a viral protein having 196 amino acid residues. In viruses, sometimes all 196 amino acid residues are present, and other times, amino acid residues 181 to 196 (known as the "r" peptide), are not present, and the resulting protein is the "mature" form of p15E known as p12E. Thus, viruses can contain both the p15E and p12E proteins.
  • p15E protein is anchored in the viral membrane such that amino acid residues 1 to 134 are present on the outside of the virus.
  • the p15E protein includes two regions, amino acid residues 39 to 61 (sometimes hereinafter referred to as region 1), and amino acid residues 101 to 123 (sometimes hereinafter referred to as region 2), which Applicants believe have an external location in the three-dimensional structure of the p15E protein; i.e., such regions are directly exposed to human serum.
  • Region 2 is a highly conserved region in many retroviruses, even though the amino acid sequences of this region are not identical in all retroviruses.
  • Such regions are complement binding regions. Examples of complement proteins which may bind to the complement binding regions are CIS and ClQ, which bind to regions 1 and 2.
  • complement proteins bind to both region 1 and region 2.
  • at least one portion of DNA encoding a complement binding region of p15E protein has been mutated.
  • Such a mutation results in a change of at least one amino acid residue of a complement binding region of p15E protein.
  • the change in at least one amino acid residue of a complement binding region of p15E protein prevents binding of a complement protein to the complement binding region, thereby preventing complement inactivation of the retrovirus.
  • at least one amino acid residue in both complement binding regions of p15E protein is changed, whereas in another embodiment, at least one amino acid residue in one of the complement binding regions is changed.
  • the at least one portion of DNA encoding p15E protein is mutated such that at least one positively charged amino acid residue or negatively charged amino acid residue is changed to an amino acid residue having the opposite charge.
  • the positively charged' amino acids are His, Lys, and Arg.
  • the negatively charged amino acids are Asp and Glu.
  • the at least one portion of DNA encoding p15E protein is mutated such that at least one positively charged amino acid or negatively charged amino acid is changed to a noncharged amino acid.
  • the at least one portion of DNA encoding a complement binding region of p15E protein which is mutated, encodes one or more of amino acid residues 101 to 123 of p15E protein. In one embodiment, the at least one portion of DNA encoding p15E protein is mutated such that amino acid residue 122 is changed.
  • the at least one portion of DNA encoding p15E protein is mutated such that at least one of amino acid residues 117 and 122 are changed.
  • amino acid residue 117 is changed from Arg to Glu
  • amino acid residue 122 is changed from Glu to Gln.
  • the at least one portion of DNA encoding p15E protein is mutated such that amino acid residues 104, 105, 109, and 111 are changed.
  • amino acid residue 104 is changed from Arg to His
  • amino acid residue 105 is changed from Asp to Asn
  • amino acid residue 109 is changed from Lys to Gln
  • amino acid residue 111 is changed from Arg to Gln.
  • the at least one portion of DNA encoding p15E protein is mutated such that amino acid residues 104, 105, 109, 111, 117, and 122 are changed.
  • the at least one portion of DNA is mutated such that amino acid residue 104 is changed from Arg to His, amino acid residue 105 is changed from Asp to Asn, amino acid residue 109 is changed from Lys to Gln, amino acid residue 111 is changed from' Arg to Gln, amino acid residue 117 is changed from Arg to Glu, and amino acid residue 122 is changed from Glu to Gln.
  • the mutation of DNA encoding p15E protein may be effected by deleting a portion of the p15E gene, and replacing the deleted portion of the p15E gene, with fragment(s) or portion(s) of a gene encoding another viral protein.
  • one portion of DNA encoding the p15E protein is replaced with a fragment of the gene encoding the p21 protein, which is an HTLV-I transmembrane protein.
  • HTLV-I virus has been found to be resistant to binding by complement proteins and thus HTLV-I is resistant to inactivation by human serum (Hoshino, et al., Nature, Vol. 310, pgs. 324-325 (1984)).
  • p15E protein is a protein having 176 amino acid residues, and which, in relation to p15E, has significant amino acid sequence homology.
  • at least amino acid residues 39 to 61, and 101 to 123 are deleted from p15E protein, and replaced with amino acid residues 34 to 56 and 96 to 118 of p21 protein.
  • at least amino acid residues 39 to 123 of p15E protein are deleted and replaced with amino acid residues 34 to 118 of p21 protein.
  • amino acid residues 39 to 69 of p15E protein are deleted and replaced with amino acid residues 34 to 64 of p21 protein, and amino acid residues 96 to 123 of p15E protein are deleted and replaced with amino acid residues 91 to 118 of p21 protein.
  • Vector particles thus generated, and which are resistant to inactivation by human serum may be engineered such that the vector particles may, when introduced into a patient, travel directly to a target cell or tissue.
  • the vector particle further includes a protein which contains a receptor binding region that binds to a receptor of a human target cell, such as, for example, but not limited to, the amphotropic cell receptor.
  • retroviral vectors hereinabove described may be constructed by genetic engineering techniques known to those skilled in the art.
  • the retroviral vector may be of the LN series of vectors, as described in Bender, et al., J.Virol., Vol. 61, pgs. 1639-1649 (1987) and Miller, et al., Biotechniques, Vol. 7, pgs. 980-990 (1989).
  • the retroviral vector includes a multiple restriction enzyme site, or multiple cloning site.
  • the multiple cloning site includes at least four cloning, or restriction enzyme sites, wherein at least two of the sites have an average frequency of appearance in eukaryotic genes of less than once in 10,000 base pairs; i.e., the restriction product has an average size of at least 10,000 base pairs.
  • restriction sites also sometimes hereinafter referred to as "rare" sites, which have an average frequency of appearance in eukaryotic genes of less than once in 10,000 base pairs, contain a CG doublet within their recognition sequence, such doublet appearing particularly infrequently in the mammalian genome.
  • Another measure of rarity or scarcity of a restriction enzyme site in mammals is its representation in mammalian viruses, such as SV40.
  • an enzyme whose recognition sequence is absent in SV40 may be a candidate for being a "rare" mammalian cutter.
  • restriction enzyme sites having an average frequency of appearance in eukaryotic genes of less than once in 10,000 base pairs include, but are not limited to the NotI, SnaBI, Sall, Xhol, Clal, Sad, EagI, and Smal sites.
  • Preferred cloning sites are selected from the group consisting of NotI, SnaBI, Sall, and Xhol.
  • the multiple cloning site has a length no greater than about 70 base pairs, and preferably no greater than about 60 base pairs.
  • the multiple restriction enzyme site, or multiple cloning site is located between the 5'LTR and 3'LTR of the retroviral vector.
  • the 5' end of the multiple cloning site is no greater than about 895 base pairs from the 3' end of the 5' LTR, and preferably at least about 375 base pairs from the 3' end of the 5' LTR.
  • the 3' end of the multiple cloning site is no greater than about 40 base pairs from the 5' end of the 3' LTR, and preferably at least 11 base pairs from the 5' end of the 3 ' LTR.
  • Such vectors may be engineered from existing retroviral vectors through genetic engineering techniques known in the art such that the resulting retroviral vector includes at least four cloning sites wherein at least two of the cloning sites are selected from the group consisting of the NotI, SnaBI, Sall, and Xhol cloning sites.
  • the retroviral vector includes each of the NotI, SnaBI, Sall, and Xhol cloning sites.
  • Such a retroviral vector may serve as part of a cloning system for the transfer of genes to eukaryotic cells.
  • a cloning system for the manipulation of genes in a retroviral vector which includes a retroviral vector including a multiple cloning site of the type hereinabove described, and a shuttle cloning vector which includes at least two cloning sites which are compatible with at least two cloning sites selected from the group consisting of NotI, SnaBI, Sall, and Xhol located on the retroviral vector.
  • the shuttle cloning vector also includes at least one desired gene which is capable of being transferred from said shuttle cloning vector to said retroviral vector.
  • the shuttle cloning vector may be constructed from a basic "backbone" vector or fragment to which are ligated one or more linkers which include cloning or restriction enzyme recognition sites. Included in the cloning sites are the compatible, or complementary cloning sites hereinabove described. Genes and/or promoters having ends corresponding to the restriction sites of the shuttle vector may be ligated into the shuttle vector through techniques known in the art.
  • the shuttle cloning vector can be employed to amplify DNA sequences in prokaryotic systems.
  • the shuttle cloning vector may be prepared from plasmids generally used in prokaryotic systems and in particular in bacteria. Thus, for example, the shuttle cloning vector may be derived from plasmids such as pBR322; pUC18; etc.
  • the DNA encoding p15E protein which has been mutated to render a vector particle resistant to inactivation by human serum may be contained in an expression vehicle other than a retroviral vector.
  • expression vehicles include, for example, viral vectors other than retroviral vectors, or any expression plasmid which is capable of being transferred into a cell line which is capable of producing vector particles which include the mutated p15E protein.
  • Such vectors or expression vehicles which contain DNA encoding a mutated env protein such as the mutated p15E protein hereinabove described, are transferred into a pre-packaging cell line to generate vector particles.
  • the pre-packaging cell line contains the gag and pol proteins of the virus, plus a retroviral vector lacking the structural gag, pol, and env proteins.
  • An example of such a pre-packaging cell line is the GPL pre-packaging cell line which consists of an NIH 3T3 mouse fibroblast cell line which contains an expression plasmid for MoMuLV gag-pol protein as well as the retroviral vector LNL6 (Miller, et al., Biotechniques, Vol. 7, pgs. 980-990 (1989)). It is to be understood, however, that the scope of the present invention is not to be limited to any particular pre-packaging cell line.
  • the pre-packaging cell line Upon transfection of the pre-packaging cell line with an expression vehicle containing DNA encoding a mutated env protein, the pre-packaging cell line will generate vector particles. The vector particles are then tested for complement resistance. The vector particles which are shown to be complement resistant (i.e., not inactivated by human serum), therefore, contain complement resistant envelope proteins encoded by a specific envelope expression vehicle.
  • Such an expression vehicle can then be used, by techniques known to those skilled in the art, to produce a packaging cell line which contains an expression vehicle encoding the retroviral gag and pol proteins, and an expression vehicle containing a gene encoding the mutated env protein (such as, for example, an expression vehicle or expression plasmid containing a mutated p15E protein such as hereinabove described), whereby such packaging cell line may be employed to generate vector particles which are resistant to inactivation by human serum.
  • a retroviral vector which lacks the structural gag, pol, and env genes, but includes a desired gene of interest, may be transferred into such a packaging cell line.
  • the packaging cell line may generate vector particles which contain a desired gene(s) of interest, and which are resistant to inactivation by human serum.
  • the vector particles generated from the packaging cell line will not be inactivated when contacted with human serum; and in addition, such vector particles, when engineered with protein containing a receptor binding region for a human receptor, are targetable, whereby the receptor binding region for a human receptor enables the vector particles to bind to a target cell.
  • retroviral vector particles may be directly introduced into the body (e.g., by intravenous, intramuscular, or subcutaneous injection, intranasally, orally, rectally or vaginally), and travel to a desired target cell.
  • Such vector particles therefore, are useful for the introduction of desired heterologous genes into target cells in vivo as a gene therapy procedure.
  • the vectors of the present invention further include at least one heterologous gene.
  • Heterologous or foreign genes which may be placed into the vector or vector particles include, but are not limited to, genes which encode cytokines or cellular growth factors, such as lymphokines, which are growth factors for lymphocytes.
  • Other examples of foreign genes include, but are not limited to, genes encoding Factor VIII, Factor IX, tumor necrosis factors (TNF's), ADA, ApoE, ApoC, and Protein C.
  • the vectors of the present invention include one or more promoters.
  • Suitable promoters which may be employed include, but are not limited to, the retroviral LTR; the SV40 promoter; and the human cytomegalovirus (CMV) promoter described in Miller, et al., Biotechniques, Vol. 7, No. 9, pgs. 980-990 (1989), or any other promoter (eg., cellular promoters such as eukaryotic cellular promoters including, but not limited to, the histone, pol III, and ⁇ -actin promoters).
  • Other viral promoters which may be employed include, but are not limited to adenovirus promoters, TK promoters, and B19 parvovirus promoters. The selection of a suitable promoter will be apparent to those skilled in the art from the teachings contained herein.
  • the vectors of the present invention may contain regulatory elements, where necessary, to ensure tissue specific expression of the desired heterologous gene(s), and/or to regulate expression of the heterologous gene(s) in response to cellular or metabolic signals.
  • retroviral vector particles other viral vector particles (such as, for example, adenovirus and adeno-associated virus particles), or synthetic particles may be constructed wherein a region of the envelope protein in the vector particle may be mutated such that the vector particle becomes resistant to inactivation by human serum, thereby making such vector particles suitable for in vivo administration.
  • viral vector particles such as, for example, adenovirus and adeno-associated virus particles
  • synthetic particles may be constructed wherein a region of the envelope protein in the vector particle may be mutated such that the vector particle becomes resistant to inactivation by human serum, thereby making such vector particles suitable for in vivo administration.
  • Plasmid pCE2 was constructed from pBR322 such that the resulting plasmid pCE2 includes genes encoding the envelope proteins gp70 and p15E.
  • pBR322 ( Figure 1) was cut with EcoRI and filled in to destroy the EcoRI site to give pBR322 Rl .
  • pBR322 R1 was then cut with Ndel and filled in to destroy the Ndel site to give pBR322 R N.
  • pBR322 R N was digested with HindIII and EcoRV, and cloned into the Hindlll/EcoRV fragment was a Hindlll/Fspl cassette containing the gp70 and p15E genes under the control of a cytomegalovirus (CMV) intermediate early promoter with a polyA (adenine) tail from SV40 ( Figure 2) from plasmid pCEE. ( Figure 3).
  • CMV cytomegalovirus
  • the Hindlll/Fspl cassette obtained from plasmid pCEE contains a CMV intermediate early promoter in which the Ball/SacII (bp 21 to bp 766) was converted to an Hindlll/Sall fragment by linker addition; the ecotropic envelope Bglll/Nhel fragment (bp 5408 to bp 7847 of MoMuLV, encoding gp70 and p15E) was filled and EcoRI linkers were added; and the SV40 poly A signal from Bel l to BamHI (bp 2770 to bp 2533 ) was cloned into a BamHI site (thereby destroying the Bell site). A Bglll site was added at the 3' end of the gp70 gene. (This addition does not alter any amino acids).
  • the resulting plasmid is pCE2 ( Figure 4. )
  • pUC-E2 plasmid
  • This plasmid is pUC18 ( Figure 5) with the PvuII fragment removed and replaced with EcoRI linkers. Such was accomplished by digesting pUC18 with PvuII to remove a 322 bp PvuII fragment, and EcoRI linkers were then added.
  • the MoMuLV ecotropic envelope gene i.e., the gp70 and p15E genes from pCE2
  • Bglll site gp70 and p15E genes from pCE2
  • Nhel site 7847
  • PCR primers are then synthesized to encode the following mutations in the p15E protein (using pCE2 as a template):
  • Amino acid residue 117 is changed from Arg to Glu, and amino acid residue 122 is changed from Glu to Gln;
  • Amino acid residue 104 is changed from Arg to His
  • amino acid residue 105 is changed from Asp to Asn
  • amino acid residue 109 is changed from Lys to Gln
  • amino acid residue 111 is changed from Arg to Gln
  • Amino acid residue 104 is changed from Arg to His
  • amino acid residue 105 is changed from Asp to Asn
  • amino acid residue 109 is changed from Lys to Gln
  • amino acid residue 111 is changed from Arg to Gln
  • amino acid residue 117 is changed from Arg to Glu
  • amino acid residue 122 is changed from Glu to Gln.
  • Each PCR product is digested with Spel and PvuII, and cloned into pUC-E2 at the unique Spel and PvuII sites.
  • the resulting plasmids are then sequenced to confirm the point mutations. DNA fragments bearing these mutations are then subcloned into the expression plasmid pCE2.
  • pCE2 is digested with EcoRI and the envelope DNA fragment is removed and replaced with the EcoRI envelope fragment from the pUC-E2 plasmids.
  • the resulting pCE2 plasmids are then checked for orientation of the EcoRI fragment and sequenced again (only at the cloning site junctions and at the regions bearing the point mutations) to confirm the presence of the newly created mutated p15E genes.
  • the resulting expression plasmids are identified as follows:
  • pCR68 - includes mutations in which amino acid residue 117 is changed from Arg to Glu, and amino acid residue 122 is changed from Glu to Gln;
  • pCR69 - includes mutations in which amino acid residue 104 is changed from Arg to His, amino acid residue 105 is changed from Asp to Asn, amino acid residue 109 is changed from Lys to Gln, and amino acid residue 111 is changed from Arg to Gln; and
  • pCR70 - includes mutations in which amino acid residue 104 is changed from Arg to His, amino acid residue 105 is changed from Asp to Asn, amino acid residue 109 is changed from Lys to Gln, amino acid residue 111 is changed from Arg to Gln, amino acid residue 117 is changed from Arg to Glu, and amino acid residue 122 is changed from Glu to Gln.
  • Plasmids pCR68, pCR69, and pCR70 are transfected separately into the GPL pre-packaging cell line.
  • the GPL pre-packaging cell line consists of an NIH 3T3 mouse fibroblast cell line which contains an expression plasmid for MoMuLV gag-pol protein as well as the retroviral vector LNL6 (Miller, et al., 1989).
  • the GPL packaging cell line produces vector particles. Transiently expressed vector particles are collected with cell supernatant at 48-72 hrs. post-transfection.
  • the vector particles generated as hereinabove described may then be assayed for vector titer by techniques known to those skilled in the art.
  • the vector particles may also be collected in viral supernatant and concentrated, if necessary, according to procedures known to those skilled in the art in order to employ such vector particles in assays or in therapeutic procedures.
  • Advantages of the present invention include the ability to introduce vector particles directly into a human patient whereby the vector particle is not lysed or inactivated by human serum upon such introduction.
  • the vector particles of the present invention enable one to deliver desired genes to a patient in vivo.
  • Such vector particles may also be engineered such that they are "targetable”, as well as injectable, thereby enabling the vector particles to travel directly to a target cell or tissue without being lysed or inactivated by human serum.
  • ADDRESSEE Carella, Byrne, Bain,

Abstract

Particule vecteur rétrovirale résistante à l'inactivation par le sérum humain. Les particules vecteurs comprennent de préférence la protéine p15E, au moins une partie de l'ADN codant la protéine p15E étant mutée de sorte que la particule vecteur devienne résistante à l'inactivation par le sérum humain. Les particules vecteurs peuvent comprendre en outre une protéine contenant une région de liaison de récepteur qui se lie au récepteur d'une cellule cible humaine, ce qui permet l'introduction directe in vivo de gènes hétérologues requis, de sorte que la particule vecteur comprenant le gène hétérologue se dirige directement vers une cellule ou des tissus cibles.
PCT/US1993/004706 1992-06-10 1993-05-14 Particules vecteurs resistantes a l'inactivation par le serum humain WO1993025698A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP6501479A JPH09507741A (ja) 1992-06-10 1993-05-14 ヒト血清による不活性化に耐性のあるベクター粒子
EP93913964A EP0644946A4 (fr) 1992-06-10 1993-05-14 Particules vecteurs resistantes a l'inactivation par le serum humain.

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US89660392A 1992-06-10 1992-06-10
US896,603 1992-06-10

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WO1993025698A9 true WO1993025698A9 (fr) 1994-06-09

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