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WO1999029864A1 - Vaccins de recombinaison exprimant l'interleukine 2 (il-2) feline, compositions et procedes d'utilisation - Google Patents

Vaccins de recombinaison exprimant l'interleukine 2 (il-2) feline, compositions et procedes d'utilisation Download PDF

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Publication number
WO1999029864A1
WO1999029864A1 PCT/US1998/025207 US9825207W WO9929864A1 WO 1999029864 A1 WO1999029864 A1 WO 1999029864A1 US 9825207 W US9825207 W US 9825207W WO 9929864 A1 WO9929864 A1 WO 9929864A1
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Prior art keywords
recombinant
feline
cells
animal
poxvims
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PCT/US1998/025207
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English (en)
Inventor
Russell R. Gettig
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Virogenetics Corporation
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Filing date
Publication date
Application filed by Virogenetics Corporation filed Critical Virogenetics Corporation
Priority to AU16067/99A priority Critical patent/AU1606799A/en
Publication of WO1999029864A1 publication Critical patent/WO1999029864A1/fr

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    • 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
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/54—Interleukins [IL]
    • C07K14/55—IL-2
    • 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
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • 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
    • C12N2710/24011—Poxviridae
    • C12N2710/24041—Use of virus, viral particle or viral elements as a vector
    • C12N2710/24043—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector

Definitions

  • IL-2 is necessary for complete activation of the immune response to a foreign antigen. The inclusion of exogenous IL-2 at the time of immunization ensures adequate amounts of IL-2 are present locally for a complete and efficient activation of the immune system.
  • IL-2 has demonstrated varying levels of modulation of antitumor activity. However, further improvements are necessary if this strategy is to be applied in the veterinary clinic. In order to circumvent toxicity issues associated with the systemic administration of cytokines, a method of localized delivery of cytokines to the tumor microenvironment at appropriate concentrations is required. Therefore, the delivery system employed to achieve this goal is a key to success.
  • a recombinant poxvirus containing therein a nucleic acid sequence encoding a biological response modifier or immunomodulating fragment thereof in a non-essential region of the recombinant virus genome.
  • the poxvirus may be an avipox virus, particularly a canarypox virus, for example, an
  • the poxvirus may be a vaccinia virus, for example, a NYVAC virus expressing the biological response modifier.
  • the recombinant poxvirus used herein generally has non-essential virus-encoded genetic function inactivated therein.
  • the biological response modifier preferably is a cytokine or a chemokine, such as a feline cytokine. Examples of cytokines useful in the present invention, include interleukins, such as IL-2 or IL-12, or granulocyte macrophage colony stimulating factor (GM-CSF).
  • the present invention includes use of the recombinant poxvirus described herein to augment or enhance the immune response of an animal, preferably a feline, to an antigen.
  • the antigen may be co-administered with the recombinant poxvirus.
  • the recombinant poxvirus may be engineered to contain, in addition to the biological response modifier of the present invention, a foreign gene sequence encoding an antigen of interest, such that the biological response modifier and the antigen are co-expressed.
  • the antigen may be administered, by conventional means known to those having skill in the art, to an animal that has been previously or contemporaneously infected with the recombinant poxvirus of the present invention. By administering to an animal in this way the biological response modifier together with the antigen of interest, an enhanced immune response to the antigen of interest may be obtained relative to that observed were the antigen of interest to be administered without the biological response modifier.
  • the present invention further includes, in another aspect thereof, cells infected by a recombinant poxvirus as provided herein and wherein the biological response modifier is expressed in the cells.
  • the cells usually are tumor cells including feline tumor cells.
  • the biological response modifier that is expressed in the cells preferably is a cytokine or chemokine.
  • a biological response modifier-susceptible condition in an animal preferably a feline
  • a method of treatment of a biological response modifier-susceptible condition in an animal preferably a feline, which comprises administering to the animal an effective amount of a recombinant poxvirus provided herein, which may be in the form of the infected cells provided herein.
  • the susceptible condition generally is presence of, or susceptibility to, infectious agents or the presence of tumor cells in the animal.
  • the biological response modifier may be delivered in conjunction with a conventional vaccine.
  • the recombinant poxvirus or infected cells may be administered intratumorally in vivo.
  • the recombinant virus may be administered by removing tumor cells from the animal, infecting the tumor cells with the recombinant virus and administering the infected tumor cells to the animal.
  • the biological response modifier may be a cytokine or a chemokine, preferably an interleukin, and more preferably IL-2.
  • Tumor cells which have been infected with the recombinant virus of the present invention may be used, in a non-replicating form, to protect an animal against tumor formation.
  • a method of protecting an animal against tumor formation which comprises administering to the animal an effective amount of non-replicating tumor cells which have been infected by a recombinant poxvirus as provided herein.
  • Non-replicating tumor cells may be prepared by irradiating cells as provided herein.
  • the invention extends to the recombinant poxvirus provided herein when used as a medicament, as well as to the use of the recombinant poxvirus provided herein in the manufacture of a medicament for the treatment of a biological response modifier-susceptible condition in an animal.
  • the invention extends to the cells provided herein when used as a medicament, as well as to the use of the cells in the manufacture of a medicament for the treatment of a biological response modifier-susceptible condition in an animal.
  • Recombinant poxvirus expressing a biological response modifier such as cytokine and chemokines, augment or enhance an immune response to an antigen or antigens.
  • the antigens can be provided independently of the recombinant poxvirus or, preferably, they are encoded by the recombinant poxvirus to ensure optimal spatial and temporal delivery of the antigen together with the biological response modifier.
  • Figure 1 demonstrates expression of functional feline IL-2 from the recombinant virus vCP1338.
  • Patents Nos. 5,453,364, 5,225,336 and 5,155,020 relate to attenuated recombinant vaccinia virus constructs.
  • U.S. Patents Nos. 5,174,993 and 5,505,941 relate to recombinant avipox vims constructs and methods of use thereof.
  • the NYVAC strain was derived from the vaccinia virus Copenhagen strain by the precise deletion of 18 ORFs encoding functions implicated in the pathogenicity of orthopoxviruses, as well as host-range regulatory functions governing the replication competency of these viruses on cells from certain species (Tartaglia et al, 1992).
  • NYVAC General biological properties include: 1) a highly debilitated replicative capacity on cells derived from mice, swine, equids, and humans; 2) the ability to replicate with wildtype efficiency on primary chick embryo fibroblasts; and 3) a highly attenuated phenotype in immunocompetent and immunocompromised animal systems used historically to assess the virulence of vaccinia virus strains (Tartaglia et al, 1992). These attributes are described in detail in U.S. Patent No. 5,494,807. Despite these highly attenuated properties, NYVAC has been shown to function effectively as an immunization vehicle (Tartaglia et al, 1992; Konishi et al, 1992).
  • NYVAC provides a safer alternative to existing vaccinia virus vaccine strains for developing vector-based vaccine candidates. Due to the attenuation profile of NYVAC, the Recombinant DNA Advisory Committee of the National Institutes of Health has reduced the biological containment level of this virus from BSL-2 to
  • BSL-1 It is the only member of the Orthopoxvirus genus accorded a BSL-1 biocontainment level.
  • the basic vaccinia virus vector technology has been extended to other members of the poxvirus family.
  • Extension to the Avipoxvirus genus, in particular fowlpoxvirus (FPV) was targeted for species-specific applications in the poultry industry (Taylor et al, 1988a).
  • ALVAC like NYVAC
  • NYVAC has demonstrated a highly attenuated phenotype in a number of animal systems comparing existing vaccinia virus vaccine strains (Tartaglia et al, 1992).
  • the Recombinant DNA Advisory Committee has reduced the biological containment for ALVAC to BSL-1.
  • the concept of using a non-replicating vector in humans was supported by the results of phase I clinical trials using an ALVAC-based rabies G (Cadoz et al, 1992) and an ALVAC- HIV-1 MN env (Pialoux et al, 1995) recombinant.
  • the poxvirus vectors are used in a novel manner to modulate an immune response.
  • Several biological response modifiers have been cloned and assessed in the treatment of various conditions including cancer, autoimmunity and transplantation. The effectiveness of many of these treatments has been limited by the large doses required and the associated toxicity.
  • the recombinant poxvirus vector, particularly the ALVAC vector is used to deliver immunomodulatory molecules, such as cytokines or chemokines, to the appropriate environment in an animal, particularly a feline, at appropriate concentrations.
  • immunomodulatory molecules such as cytokines or chemokines
  • NYVAC expressing immunomodulatory molecules is a new and useful approach for the treatment of certain conditions, particularly cancer, where the use of biological response modifiers has shown promise.
  • the present invention employs recombinant poxvirus as the delivery system for cytokines in tumor therapy.
  • a canarypox (ALVAC) virus encoding Interleukin-2 (IL-2) as a candidate cancer immunotherapeutic.
  • ALVAC-feline IL-2 expresses functional feline IL-2 which can be used to treat biological response-modifier susceptible conditions such as infection or tumor formation in animals.
  • ALVAC-feline IL-2 may be used as an anticancer immuno therapeutic in cats.
  • the recombinant pox virus that is described and referred to herein has been deposited with the American Type Culture Collection (ATCC) located at 12301 Parklawn Drive, Rockville, Maryland 20852, USA pursuant to the Budapest Treaty and prior to the filing of this application. Samples of the deposited plasmid will become available to the public and all restrictions imposed on access to the deposit will be removed upon grant of a patent on this application.
  • the invention described and claimed herein is not to be limited in scope by recombinant virus deposited, since the deposited embodiment is intended only as an illustration of the invention. Any equivalent or similar recombinant virus is within the scope of the invention.
  • This Example illustrates construction of the pNVQH6C5LSP insertion plasmid (C5 locus).
  • a genomic library of canarypox DNA was constructed in the cosmid vector pVK102 (Knauf and Nester, 1982)probed with pRW764.5 (a pUC9 based plasmid containing an 880 bp canarypox PvuII fragment which includes the C5 ORF) and a cosmid clone containing a 29 kb insert was identified (pHCOSl).
  • pHCOSl cosmid clone containing a 29 kb insert was identified (pHCOSl).
  • a 3.3 kb Clal fragment from pHCOSl containing the C5 region was identified (SEQ ID NO: 1).
  • the C5 ORF is initiated at position 1537 and terminated at position 1857.
  • the C5 insertion vector was constructed in two steps.
  • the 1535 bp upstream sequence was generated by PCR amplification from purified genomic canarypox DNA using oligonucleotide primers C5A (SEQ ID NO: 2)(5'- ATCATCGAATTCTGAATGTTAAATGTTATACTTTG-3') and C5B (SEQ ID NO: 3)(5'- GGGGGTACCTTTGAGAGTACCACTTCAG-3'). This fragment was digested with EcoRI and ligated into pUC8 digested with EcoRI/Smal to yield pC5LAB.
  • the 404 bp arm was generated by PCR amplification using oligonucleotides C5C (SEQ ID NO: 4)(5'- GGGTCTAGAGCGGCCGCTTATAAAGATCTAAAATGCATAATTTC-3') and C5DA (SEQ ID NO: 5)(5'-ATCATCCTGCAGGTATTCTAAACTAGGAATAGATG-3'). This fragment was digested with PstI and cloned into Smal/PstI digested pC5LAB to yield pC5L.
  • pC5L was digested within the MCS with Asp718/NotI and ligated to kinased and annealed oligonucleotides CP26 (SEQ ID NO: 6)(5'- GTACGTGACTAATTAGCTATAAAAAGGATCCGGTACCCTCGAGTCTAGAATCGAT CCCGGGTTTTTATGACTAGTTAATCAC-3') and CP27 (SEQ ID NO: 7)(5'-
  • the vaccinia H6 promoter (Guo et al., 1989; Perkus et al., 1989) was derived by PCR using pRW823 as template (a plasmid containing the H6 promoter linked to an irrelevant gene) and oligonucleotides CP30 (SEQ ID NO: 8) (5'-TCGGGATCCGGG-TTAATTAATTAGTCATCAGGCAGGGCG-3') and CP31 (SEQ ID NO: 9) (5'--
  • TAGCTCGAGGGTACCTACGATACAAACTTAACGGATATCG-3' The PCR product was digested with BamHI and Xhol (sites present at the 5'end of CP30 and CO31, respectively) and ligated to BamHI/XhoI digested pC5LSP generating plasmid pVQH6C5LSP.
  • This plasmid was digested with EcoRI, ligated with kinased and self- annealed oligonucleotide CP29 (SEQ ID NO: 10)(5'-AATTGCGGCCGC-3') and digested with Notl.
  • the linearized plasmid was purified and self-ligated to generate pNVQH6C5LSP- 5.
  • This C5 insertion plasmid contains 1535 bp of canarypox DNA upstream of the C5 ORF, translation stop codons in six reading frames, vaccinia early transcription termination signal, an MCS with BamHI, vaccinia H6 promoter, Kpnl, Xhol, Clal and Smal restriction sites, vaccinia early termination signal, translation stop codons in six reading frames and 404 bp of downstream canarypox sequence (31 bp of C5 coding sequence and 373 bp of downstream canarypox sequence).
  • Example 2 This Example illustrates the preparation of ALVAC-feline IL-2 recombinant canarypox vims.
  • PHA phytohemagglutinin
  • PBMCs feline peripheral blood mononuclear cells
  • TRI reagent Molecular Research Center, Inc. Cincinnati, OH
  • AMV reverse transcriptase Life Sciences, St. Russia, FL
  • random hexamer primers random hexamer primers
  • pNVQH6C5LSP is an ALVAC insertion plasmid which contains the H6 promoter.
  • the sequence of the IL-2 gene (SEQ ID NO. 14) was identical to that published by Cozzi et al, 1993.
  • This donor plasmid, pC5FIL2H6 was used in in vivo recombination (Piccini et al, 1987) with the ALVAC vims vector to generate the recombinant virus vCP1338.
  • EXAMPLE 3 This Example illustrates expression of functional feline IL-2 from vCP1338.
  • IL-2 activity was determined by the maintenance of proliferation of the IL-2 dependent cell line CTLL-2 of serial dilutions of each supematent fluid. Proliferation of the CTLL2 cell line was assessed by measuring [3H]-thymidine incorporation.
  • One unit of IL-2 activity is defined as being capable of sustaining 50% of maximum proliferation of the cell line.
  • NIH IL-2 standards human and murine
  • CTLL2 cells are also capable of proliferating in response to murine IL-4
  • the presence of IL-4 was ruled out by assessing IL-4 activity against the IL-4 dependent cell line CT.4S.
  • the results show that a significant level of functional IL-2 is present in the vCP1338 supematent, while no activity was detected in uninfected or ALVAC infected cell supernatents ( Figure 1).
  • the present invention provides a novel manner of augmenting or enhancing the immune response of a feline to antigens as components of vaccines.
  • the present invention also provides a novel therapy for tumors or infectious agents in felines as well as a novel delivery system employing cytokines and other biological response modifiers, specifically feline IL-2. Modifications are possible within the scope of the invention.
  • Nonrephcating viral vectors as potential vaccines recombinant canarypox vims expressing measles vims fusion (F) and hemagglutinin (HA) glycoproteins.

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Abstract

L'invention concerne un poxvirus de recombinaison, spécifiquement un poxvirus aviaire et de préférence un poxvirus des canaris, renfermant une molécule d'acide nucléique codant un modificateur de réponse biologique, en particulier une cytokine féline ou un fragment immunomodulateur de cette cytokine, dans une région non essentielle des cellules de génome infectées par le virus de recombinaison pour exprimer le modificateur de réponse immunitaire biologique. Le poxvirus de recombinaison codant une cytokine féline peut être utilisé pour améliorer ou accroître la réponse immunitaire féline aux composants antigéniques des agents ou des tumeurs de type infectieux. On peut utiliser les cellules infectées pour traiter le cancer chez des animaux, par administration intratumorale, ou par traitement in vivo des cellules tumorales, et par réintroduction des cellules tumorales traitées. Les cellules considérées sont également utilisées, hors réplication, pour protéger les félins contre la formation de tumeurs.
PCT/US1998/025207 1997-12-09 1998-12-07 Vaccins de recombinaison exprimant l'interleukine 2 (il-2) feline, compositions et procedes d'utilisation WO1999029864A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU16067/99A AU1606799A (en) 1997-12-09 1998-12-07 Recombinant vaccinia constructs expressing feline il-2, compositions and methodsof use thereof

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US98720497A 1997-12-09 1997-12-09
US08/987,204 1997-12-09

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WO1999029864A1 true WO1999029864A1 (fr) 1999-06-17

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2918598B1 (fr) * 2007-02-28 2019-01-30 The Govt. Of U.S.A. As Represented By The Secretary Of The Department Of Health And Human Services Polypeptides brachyury et procédés d'utilisation

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994016716A1 (fr) * 1993-01-21 1994-08-04 Virogenetics Corporation Immunotherapie par virus recombine
WO1996007433A1 (fr) * 1994-09-09 1996-03-14 Japanese Foundation For Cancer Research Substance de therapie genique contre le cancer, composition medicale et methode therapeutique

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994016716A1 (fr) * 1993-01-21 1994-08-04 Virogenetics Corporation Immunotherapie par virus recombine
WO1996007433A1 (fr) * 1994-09-09 1996-03-14 Japanese Foundation For Cancer Research Substance de therapie genique contre le cancer, composition medicale et methode therapeutique

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
COZZI P.J. ET AL.: "Sequence and functional characterization of feline Interleukin 2", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 194, no. 3, 16 August 1993 (1993-08-16), pages 1038 - 1043, XP002096600 *
DATABASE WPI Section Ch Week 9617, Derwent World Patents Index; Class B04, AN 96-171400, XP002096601 *
KARUPIAH G. ET AL.: "Recombinant vaccine vector-induced protection of athymic, nude mice from influenza A virus infection. Analysis of protective mechanism", SCANDINAVIAN JOURNAL OF IMMUNOLOGY, vol. 36, no. 1, July 1992 (1992-07-01), pages 99 - 105, XP002097308 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2918598B1 (fr) * 2007-02-28 2019-01-30 The Govt. Of U.S.A. As Represented By The Secretary Of The Department Of Health And Human Services Polypeptides brachyury et procédés d'utilisation

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