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WO1997032026A1 - Molecules d'adapteur pour cibler les particules virales sur les cellules - Google Patents

Molecules d'adapteur pour cibler les particules virales sur les cellules Download PDF

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Publication number
WO1997032026A1
WO1997032026A1 PCT/GB1997/000570 GB9700570W WO9732026A1 WO 1997032026 A1 WO1997032026 A1 WO 1997032026A1 GB 9700570 W GB9700570 W GB 9700570W WO 9732026 A1 WO9732026 A1 WO 9732026A1
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WO
WIPO (PCT)
Prior art keywords
molecule
amino acid
adapter
acid sequence
viral
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/GB1997/000570
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English (en)
Inventor
Alan John Kingsman
Susan Mary Kingsman
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Oxford Biomedica UK Ltd
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Oxford Biomedica UK Ltd
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Filing date
Publication date
Application filed by Oxford Biomedica UK Ltd filed Critical Oxford Biomedica UK Ltd
Priority to GB9817903A priority Critical patent/GB2326415B/en
Priority to JP09530724A priority patent/JP2000511401A/ja
Priority to AU22236/97A priority patent/AU2223697A/en
Priority to EP97905310A priority patent/EP0883688A1/fr
Publication of WO1997032026A1 publication Critical patent/WO1997032026A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/70542—CD106
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2812—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD4
    • 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
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/62—DNA sequences coding for fusion proteins
    • C12N15/625—DNA sequences coding for fusion proteins containing a sequence coding for a signal sequence
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
    • C07K2319/036—Fusion polypeptide containing a localisation/targetting motif targeting to the medium outside of the cell, e.g. type III secretion
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/32—Fusion polypeptide fusions with soluble part of a cell surface receptor, "decoy receptors"
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/33—Fusion polypeptide fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
    • 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
    • C12N2799/00—Uses of viruses
    • C12N2799/02—Uses of viruses as vector
    • C12N2799/021—Uses of viruses as vector for the expression of a heterologous nucleic acid
    • C12N2799/027—Uses of viruses as vector for the expression of a heterologous nucleic acid where the vector is derived from a retrovirus

Definitions

  • This invention relates to adapter molecules which facilitate the binding of virus particles to cell surface molecules.
  • the invention also relates to nucleic acids encoding the adapter molecules, to cell lines expressing the adapter molecules and to the use of the adapter molecules in gene therapy.
  • a common goal of gene therapy is to be able to deliver genes in vivo rather than using the cumbersome ex vivo strategies most often used to date.
  • This invention describes a new strategy for achieving targeted gene delivery using retroviral vectors.
  • retroviral vectors used for human applications, are promiscuous in that they carry the amphotropic envelope protein that permits infection of a wide range of cell types from diverse species. This is in contrast to the other main type of retroviral vector that is used in the laboratory which carries the ecotropic envelope which only permits infection of rodent cells. In an attempt to achieve efficient and selective gene transfer in vivo, considerable effort is now being directed towards producing retroviral vectors that are targeted to specific human cell types.
  • chimaeric envelopes require either co-expression of the unmodified envelope protein or deglycosylation of the virus or treatment of the cells with endosome modifying agents (e.g. chloroquine) to effect any gene transfer at all.
  • endosome modifying agents e.g. chloroquine
  • an alternative, novel approach is described for targeting the ecotropic receptor to a specific cell type, and then using unmodified ecotropic vectors to deliver genes to those cells.
  • This has the considerable advantage that the envelope proteins go through the same binding and fusion events as they do when infecting a murine cell.
  • the invention provides in one aspect an adapter molecule comprising a first amino acid sequence having binding affinity for a cell surface molecule and a second amino acid sequence having binding affinity for a viral surface molecule, which adapter molecule is capable of mediating infection of a cell expressing the cell surface molecule by a viral particle having the viral surface molecule.
  • the second amino acid sequence is derived from a viral receptor, and most preferably it consists essentially of the extracellular portion of the viral receptor to which the viral particle binds.
  • the first amino acid sequence in the adapter molecule according to the invention may be any amino acid sequence that has a specific affinity for a cell surface molecule.
  • it could be an antibody or antibody derivative, a natural ligand or a derivative of a natural ligand, or a peptide selected by any of various known affinity selection systems such as phage display.
  • An example of an antibody derivative suitable for use in the adapter molecule is a single chain antibody (scFv).
  • An scFv could be used for targeting any specific cell surface molecule.
  • scFv's would be those having binding affinity to tumour- specific cell surface antigens and tissue specific cell surface proteins. It will be understood that the first and second amino acid sequences as described herein may have the usual modifications associated with proteins and peptides, such as glycosylation.
  • the first amino acid sequence may be at the carboxy terminus and the second amino acid sequence at the amino terminus, or vice versa.
  • An adapter molecule according to the invention is capable of mediating infection of a cell by a viral particle as described.
  • infection means attachment of the viral particle to the cell surface and introduction of genetic material from the viral particle into the cell.
  • the adapter molecule may thus aid the process of transduction i.e. virus mediated gene transfer.
  • the first and second amino acid sequences are linked in the adapter molecule either covalently or non-covalently. If covalently linked, the adapter molecule could be produced from a single fusion gene or by chemical cross-linking. If the association is non-covalent the components may be attached by streptavidin-biotin bridges or by means of other binding partners.
  • the invention provides a nucleic acid coding for an adapter molecule as described herein.
  • the nucleic acid may or may not also contain a secretion signal coding region.
  • the secretion signal coding region could be for example a yeast or an E.coli or a mammalian signal for expression and secretion in yeast or E.coli or mammalian cells.
  • the viral surface molecule to which the adapter molecule according to the invention binds is preferably but not necessarily an unmodified ecotropic viral protein.
  • the invention thus permits targeting of viral vectors to specific cell surface molecules with a minimum of modification to the viral envelope. However, it may be necessary or advantageous to modify part of the viral envelope e.g. the particular viral surface molecule involved.
  • the invention provides genetically engineered cells containing nucleic acids as herein described and capable of expressing adapter molecules as herein described.
  • adapter molecules described herein would be administered to the target cells either in vivo or in vitro, just prior to the administration of corresponding ecotropic vector particles.
  • One aspect of the invention also provides the use of an adapter molecule as described herein in the manufacture of a medicament for use in gene therapy.
  • Figure 1 is a schematic illustration of a basic amino acid transporter in a membrane.
  • FIG. 2 shows the principle of the targeting molecular adapters according to the invention.
  • FIG 3 shows a scheme for constructing one embodiment of a targeting adapter according to the invention.
  • the receptor for all murine ecotropic viruses is the murine cationic amino acid transporter (Albritten et al., 1989 Cell 57, 659; Kim et al., 1991 Nature 352, 725; Wang et al., 1991 Nature 352, 729). It will be referred to here at the Ecotropic Retrovirus Receptor (ERR).
  • ERR Ecotropic Retrovirus Receptor
  • This is an integral membrane protein related to the yeast transporters for arginine, histidine and choline. By analogy with other transporters and by using membrane protein prediction programmes putative membrane spanning regions can be identified in the amino acid sequence of the transporter. These are shown schematically in Figure 1.
  • VKGSIKNWQLTEEDFGCNNNDTNVKYGEGGFMP [SEQ ID NO: 1]
  • the tyrosine and glutamate residues shown in bold have been specifically implicated in virus infection (Eiden et al., 1993 J.Virol. 67, 4056; Yoshimoto et al., 1993 J.Virol. 67, 1310; Kavanaugh et al., 1994 JBC 269, 15445; Yoshimoto et al., 1993 J.Virol.67, 1310; MacLeod et al.,1990 MCB 10, 3663).
  • This region of the protein will be referred to here as ERRed3.
  • ERRed3 is linked to a second molecule that targets it to a specific cell surface molecule.
  • the combination molecule is known as a targeting adapter. This would achieve, for example, the specific targeting of the third domain to a specific cell type. Once attached to the specific cell type the 3rd domain is used as a receptor for ecotropic retroviral vector particles. This would achieve the selective delivery of genes carried by the retroviral vector to specific cell types. The system would be of general use in gene therapy.
  • a single chain antibody (scFv) directed against the cell surface marker CD4 is fused to ERRed3 in order to target the receptor fragment to CD4+ cells.
  • This adapter molecule is useful in delivering an anti-HIV gene to HIV susceptible cells.
  • scFv's The technology for making scFv's is well established and generally available through kits supplied by commercial organisations such as Pharmacia Biotech and Novagen.
  • An scFv coding fragment is produced from RNA from a hybridoma expressing the OKT4 monoclonal antibody using the Pharmacia Biotech kit. This fragment is then linked, using standard genetic manipulation techniques, to a coding sequence for ERRed3. This latter fragment is produced by PCR using the following primers:
  • the fragment encodes amino acids 210-243 with an additional cysteine residue on each end to provide a constrained loop analogous to the authentic extracellular domain.
  • a short coding sequence encoding a secretion signal sequence is then added to the 5' end of this coding sequence to produce the coding sequence shown in Figure 3b.
  • Figure 3b This will produce a fragment ( Figure 3b) that encodes an adapter, designated OKT4sc-ERRed3 that is secreted from mammalian cells.
  • This fragment is then inserted into a mammalian expression vector such as pCI-neo (Promega) and the resulting plasmid designated pCln- ADAPT-OKT4.
  • This plasmid is then used to transiently transfect 293T cells. 48 hours later the cell supernatant is harvested. This supernatant contains the secreted adapter.
  • the supernatant sample is filter sterilised and then 1 ml is placed in a dish with HeLa-CD4 cells, in a control experiment 1 ml of supernatant from untransfected 293T cells is also placed in a dish with HeLa-CD4 cells.
  • the cells are left exposed to the supematants for 1 hour and then 1ml of ecotropic retroviral vector preparation containing 10 6 transducing particles/ml are added to both dishes.
  • the retroviral vector particles are prepared using the HIT vector system (Soneoka et al., 1995 NAR 23, 628) and they carry the vector genome HIT111 which contains the E.coli lacZ gene. After 48 hours the dishes are stained with X-gal and blue cells that have received the vector are counted.
  • the adapter molecules could be produced by a variety of gene fusions that are subtly different at the junctions between the scFv and ERRed3.
  • Example 3 A similar strategy to that described in Example 1 can be used except that the targeting molecule is not an antibody but any other ligand that binds to a cell surface molecule.
  • the first three extracellular immunoglobulin domains of VCAM are fused to ERRed3 using standard recombinant DNA procedures.
  • the VCAM-ERRed3 protein is made in mammalian, yeast or E.coli expression systems and then used, as described above for the OKT4svERRed3 protein, to target retroviral vectors to VLA4-bearing cells.
  • EXAMPLE 3 EXAMPLE 3

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Abstract

L'invention concerne des molécules d'adaptateur pour cibler des particules virales, en particulier des particules rétrovirales, sur des cellules. Les molécules d'adaptateur comprennent une première séquence d'aminoacides ayant une affinité pour une molécule de surface cellulaire et une seconde séquence d'aminoacides ayant une affinité pour une molécule de surface virale. Les molécules d'adaptateur sont utiles en thérapie génique pour cibler des vecteurs rétroviraux transporteurs sur des types cellulaires spécifiques.
PCT/GB1997/000570 1996-02-29 1997-02-28 Molecules d'adapteur pour cibler les particules virales sur les cellules Ceased WO1997032026A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
GB9817903A GB2326415B (en) 1996-02-29 1997-02-28 Adapter molecules for targeting viral particles to cells
JP09530724A JP2000511401A (ja) 1996-02-29 1997-02-28 ウィルス粒子を細胞にターゲッティングするアダプター分子
AU22236/97A AU2223697A (en) 1996-02-29 1997-02-28 Adapter molecules for targeting viral particles to cells
EP97905310A EP0883688A1 (fr) 1996-02-29 1997-02-28 Molecules d'adapteur pour cibler les particules virales sur les cellules

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9604354.2A GB9604354D0 (en) 1996-02-29 1996-02-29 Targeting adapters
GB9604354.2 1996-02-29

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WO1997032026A1 true WO1997032026A1 (fr) 1997-09-04

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PCT/GB1997/000570 Ceased WO1997032026A1 (fr) 1996-02-29 1997-02-28 Molecules d'adapteur pour cibler les particules virales sur les cellules

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EP (1) EP0883688A1 (fr)
JP (1) JP2000511401A (fr)
AU (1) AU2223697A (fr)
GB (2) GB9604354D0 (fr)
WO (1) WO1997032026A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000018240A1 (fr) * 1998-10-01 2000-04-06 University Of Southern California Systeme de transport de gene et procedes d'utilisation associes
US11065311B2 (en) 2012-10-25 2021-07-20 Denovo Biopharma Llc Retroviral vector with mini-promoter cassette

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995023846A1 (fr) * 1994-03-04 1995-09-08 University Of Medicine & Dentistry Of New Jersey Transfert genique specifique de types de cellules a l'aide de vecteurs retroviraux contenant des proteines de fusion d'enveloppe d'anticorps et d'enveloppe de type sauvage

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995023846A1 (fr) * 1994-03-04 1995-09-08 University Of Medicine & Dentistry Of New Jersey Transfert genique specifique de types de cellules a l'aide de vecteurs retroviraux contenant des proteines de fusion d'enveloppe d'anticorps et d'enveloppe de type sauvage

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
ALBRITTON ET AL.: "A putative murine ecotropic retrovirus receptor gene encodes a multiple membrane-spanning protein and confers susceptibility to virus infection", CELL, vol. 57, 1989, pages 659 - 666, XP002036212 *
KASAHARA N ET AL: "TISSUE-SPECIFIC TARGETING OF RETROVIRAL VECTORS THROUGH LIGAND-RECEPTOR INTERACTIONS", SCIENCE, vol. 266, no. 5189, 25 November 1994 (1994-11-25), pages 1373 - 1376, XP000541772 *
MARIN ET AL.: "Cell targeting by murine recombinant retroviruses", GENE THERAPY, vol. 1, no. suppl.2, 1994, pages S15 - A59, XP002036213 *
MILLER N ET AL: "TARGETED VECTORS FOR GENE THERAPY", FASEB JOURNAL, vol. 9, no. 2, February 1995 (1995-02-01), pages 190 - 199, XP000616414 *
ROUX P ET AL: "A VERSATILE AND POTENTIALLY GENERAL APPROACH TO THE TARGETING OF SPECIFIC CELL TYPES BY RETROVIRUSES: APPLICATION TO THE INFECTION OF HUMAN CELLS BY MEANS OF MAJOR HISTOCOMPATIBILITY COMPLEX MURINE LEUKEMIA VIRUS-DERIVED VIRUSES", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF USA, vol. 86, no. 23, 1 December 1989 (1989-12-01), pages 9079 - 9083, XP000081882 *
TE-HUA TEARINA CHU ET AL: "CELL TARGETING WITH RETROVIRAL VECTOR PARTICLES CONTAINING ANTIBODY-ENVELOPE FUSION PROTEINS", GENE THERAPY, vol. 1, no. 5, September 1994 (1994-09-01), pages 292 - 299, XP000646936 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000018240A1 (fr) * 1998-10-01 2000-04-06 University Of Southern California Systeme de transport de gene et procedes d'utilisation associes
US8741279B2 (en) 1998-10-01 2014-06-03 University Of Southern California Gene delivery system and methods of use
US11065311B2 (en) 2012-10-25 2021-07-20 Denovo Biopharma Llc Retroviral vector with mini-promoter cassette

Also Published As

Publication number Publication date
GB2326415B (en) 2000-08-02
JP2000511401A (ja) 2000-09-05
GB2326415A (en) 1998-12-23
AU2223697A (en) 1997-09-16
GB9604354D0 (en) 1996-05-01
EP0883688A1 (fr) 1998-12-16
GB9817903D0 (en) 1998-10-14

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