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WO2004015098A2 - Molecule d'adhesion cellulaire epitheliale rhesus, nucleotides codant cette molecule et utilisations associees - Google Patents

Molecule d'adhesion cellulaire epitheliale rhesus, nucleotides codant cette molecule et utilisations associees Download PDF

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Publication number
WO2004015098A2
WO2004015098A2 PCT/EP2003/008504 EP0308504W WO2004015098A2 WO 2004015098 A2 WO2004015098 A2 WO 2004015098A2 EP 0308504 W EP0308504 W EP 0308504W WO 2004015098 A2 WO2004015098 A2 WO 2004015098A2
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Prior art keywords
cam
vector
protein
nucleic acid
rhep
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WO2004015098A3 (fr
Inventor
Gennaro Ciliberto
Nicola Lamonica
Fabio Palombo
Valentina Salucci
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Istituto di Ricerche di Biologia Molecolare P Angeletti SpA
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Istituto di Ricerche di Biologia Molecolare P Angeletti SpA
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Priority to AU2003251679A priority Critical patent/AU2003251679A1/en
Publication of WO2004015098A2 publication Critical patent/WO2004015098A2/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
    • 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
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A61K39/001166—Adhesion molecules, e.g. NRCAM, EpCAM or cadherins
    • 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
    • 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
    • A61K2039/53—DNA (RNA) vaccination
    • 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
    • C12N2710/10011—Adenoviridae
    • C12N2710/10311—Mastadenovirus, e.g. human or simian adenoviruses
    • C12N2710/10341—Use of virus, viral particle or viral elements as a vector
    • C12N2710/10343—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector

Definitions

  • the present invention relates generally to the detection and therapy of cancer. More specifically, the present invention relates to the rhesus monkey homologue ofthe tumor associated polypeptide epithelial cell adhesion molecule, herein designated rhEp-CAM, to isolated nucleic acid molecules which encode this protein, and to recombinant vectors and hosts comprising DNA encoding this protein. This invention also relates to adenoviral vector constructs carrying rhEp-CAM and to their use in vaccines and pharmaceutical compositions for preventing and treating cancer.
  • rhEp-CAM tumor associated polypeptide epithelial cell adhesion molecule
  • Cancer is one ofthe leading causes of mortality in the United States and is a leading health concern worldwide. Despite an abundance of cancer-related research, conventional therapies that combine surgery, radiation, and chemotherapy, fail to effectively treat many established cancers. Reliable methods of prevention also remain unavailable.
  • Cancer typically involves the malfunction of genes that contribute to the regulation ofthe cell cycle or cell proliferation, such as growth factors and their receptors, oncogenes and tumor suppressor genes.
  • the products of many of these genes are expressed on the surface of a wide variety of tumor cells and, hence, were designated tumor-associated antigens.
  • Recent evidence supports the existence of tumor-associated antigens that are capable of eliciting an immune response, making these molecules a target for vaccine therapy.
  • Many of these gene products are also expressed in normal cells, albeit at lower levels, many cancer vaccines targeting tumor-associated antigens have proven ineffective due to self-tolerance.
  • Ep-CAM epithelial cell adhesion molecule
  • Ep- CAM has been alternatively known as epithelial glycoprotein 40 (EGP40), GA 733-2, ESA, KSA, and the 17-1 A antigen. Recently, the human gene was renamed tumor- associated calcium signal transducer 1 (TACSTD1). The Ep-CAM gene encodes a 40 KDa transmembrane glycoprotein, which participates in epithelial-specific, Ca2+ independent, cell-cell adhesions.
  • Ep-CAM Ep-CAM cDNA encoding Ep-CAM was cloned from human colon carcinoma cell lines and from a human lung adenocarcinoma cell line (Simon et al., Proc. Natl Acad. Sci. USA ' 87:2755-59 (1990); Szala et al., Proc. Natl. Acad. Sci. USA 87:3542-46 (1990); Perez and Walker, J. Immunol. 142(10): 3662-3667 (1989); Strnad et al, Cancer Res. 49: 314-317 (1989); see also U.S. Patent 5,348,887; WO 93/08298; and WO 99/54466).
  • Ep-CAM Ep-CAM binds to human Ep-CAM.
  • sequences with homology to the human Ep-CAM gene were detected in other species by Southern blot hybridization (Linnenbach et al., Mol Cell Biol. 13: 1507-1515 (1993)). No simian homologs ofthe human Ep-CAM encoding gene are available to date.
  • Ep-CAM In the human, expression ofthe gene that encodes Ep-CAM is normally restricted to adult epithelial cells, although expression levels vary according to specific tissue type. In vivo Ep-CAM expression has been correlated with an increase in epithelial proliferation and a decrease in cell differentiation. Ep-CAM expression has also been detected at various stages of normal embryonic development (for review, see Balzar et al., J. Mol. Med. 77: 699-712 (1999)). Several observations have lead researchers to propose Ep-CAM as an immunological target for the development of cancer therapies for various cancers, including colorectal cancer. Among these observations is the common association of Ep-CAM expression with the development of human carcinomas, all of which are derived from epithelial tissue. See Balzar et al., supra.
  • Ep-CAM While high levels of Ep-CAM expression can be detected in the majority of epithelial-derived carcinomas, other tumor types have not been found to express this tumor antigen.
  • the present invention relates to isolated or purified nucleic acid molecules (polynucleotides) comprising a sequence of nucleotides that encode a novel rhesus monkey epithelial cell adhesion molecule (hereinafter rhEp-CAM) as set forth in SEQ ID NO:2.
  • rhEp-CAM novel rhesus monkey epithelial cell adhesion molecule
  • the DNA molecules disclosed herein may be transfected into a host cell of choice wherein the recombinant host cell provides a source for substantial levels of an expressed functional rhEp-CAM protein (SEQ ID NO:2).
  • the present invention further relates to an isolated nucleic acid molecule which encodes mRNA that expresses a novel rhesus monkey Ep-CAM protein; this DNA molecule comprising the nucleotide sequence disclosed herein as SEQ ID NO:l.
  • FIGURE 1 shows a DNA molecule (SEQ ID NO: 1) that encodes a novel rhEp-CAM protein (SEQ ID NO:2).
  • Another aspect of this invention is an isolated nucleic acid molecule which encodes a novel rhesus monkey Ep-CAM protein (SEQ ID NO:2), said nucleic acid molecule comprising a sequence of nucleotides as set forth in SEQ ID NO: 15.
  • the present invention also relates to recombinant vectors and recombinant host cells, both prokaryotic and eukaryotic, which contain the nucleic acid molecules disclosed throughout this specification.
  • the present invention further relates to a process for expressing a rhesus monkey Ep-CAM protein in a recombinant host cell, comprising: (a) introducing a vector comprising a nucleic acid as set forth in SEQ ID NO: 1 or SEQ ID NO: 15 into a suitable host cell; and, (b) culturing the host cell under conditions which allow expression of said rhesus monkey Ep-CAM protein.
  • Another aspect ofthe present invention is a method of protecting or a mammal from cancer or treating a mammal suffering from cancer comprising: (a) introducing into the mammal a first vector comprising: i) a polynucleotide encoding a rhesus monkey Ep-CAM protein; and ii) a promoter operably linked to the polynucleotide; (b) allowing a predetermined amount of time to pass; and (c) introducing into the mammal a second vector comprising: i) a polynucleotide encoding a rhesus monkey Ep-CAM protein; and ii) a promoter operably linked to the polynucleotide.
  • rhEp-CAM refers to a -rhesus monkey epithelial cell adhesion molecule--
  • mammalian refers to any mammal, including a human being.
  • Ep-CAM epithelial cell adhesion molecule
  • the present invention relates to compositions and methods to elicit or enhance immunity to the protein product expressed by the Ep-CAM tumor-associated antigen, wherein aberrant Ep-CAM expression is associated with the carcinoma or its development. Association of aberrant Ep-CAM expression with a carcinoma does not require that the Ep-CAM protein be expressed in tumor tissue at all timepoints of its development, as abnormal Ep-CAM expression may be present at tumor initiation and not be detectable late into tumor progression.
  • the rhesus Ep-CAM expression cassette is inserted into a vector.
  • the vector is preferably an adenoviral vector, although linear DNA linked to a promoter, or other vectors, such as adeno-associated virus or a modified vaccinia virus vector may also be used.
  • the instant invention further relates to an adenovirus vaccine vector comprising an adenoviral genome with a deletion in the El region, and an insert in the El region, wherein the insert comprises an expression cassette comprising: (a) a polynucleotide encoding a rhesus monkey Ep-CAM protein; and (b) a promoter operably linked to the polynucleotide.
  • the adenovirus vector is an Ad 5 vector.
  • an adenoviral vector vaccine and a plasmid vaccine may be administered to a vertebrate as part of a single therapeutic regime to induce an immune response.
  • the present invention relates to a method of protecting a mammal from cancer comprising: (a) introducing into the mammal a first vector comprising: i) a polynucleotide encoding a rhesus monkey Ep-CAM protein; and ii) a promoter operably linked to the polynucleotide; (b) allowing a predetermined amount of time to pass; and (c) introducing into the mammal a second vector comprising: i) a polynucleotide encoding a rhesus monkey Ep-CAM protein; and ii) a promoter operably linked to the polynucleotide.
  • booster vaccinations may be provided.
  • Parentaeral administration such as intravenous, intramuscular, subcutaneous or other means of administration with adjuvants such as interleukin 12 protein, concurrently with or subsequent to parenteral introduction ofthe vaccine of this invention is also advantageous.
  • the vaccine vectors of this invention may be naked, i.e., unassociated with any proteins, adjuvants or other agents which impact on the recipient's immune system.
  • an immunostimulant such as an adjuvant, cytokine, protein, or other carrier with the vaccines or immunogenic compositions ofthe present invention. Therefore, this invention includes the use of such immunostimulants in conjunction with the compositions and methods ofthe present invention.
  • libraries as well as libraries constructed from other cell types-or species types, may be useful for isolating a rhEp-CAM-encoding DNA or a rhEp-CAM homologue.
  • Other types of libraries include, but are not limited to, cDNA libraries derived from other cells.
  • suitable cDNA libraries may be prepared from cells or cell lines which have rhEp-CAM activity, such as various epithelial-derived cells.
  • the selection of cells or cell lines for use in preparing a cDNA library to isolate a cDNA encoding rhEp-CAM may be done by first measuring cell-associated rhEp-CAM activity using any known assay available for such a purpose.
  • the DNA molecules, RNA molecules, and recombinant protein ofthe present invention may be used to screen and measure levels of rhEp-CAM.
  • the recombinant proteins, DNA molecules, and RNA molecules lend themselves to the formulation of kits suitable for the detection and typing of rhEp-CAM.
  • a kit would comprise a compartmentalized carrier suitable to hold in close confinement at least one container.
  • the carrier would further comprise reagents such as recombinant rhEp-CAM or anti-rhEp-CAM antibodies suitable for detecting rhEp-CAM.
  • the carrier may also contain a means for detection such as labeled antigen or enzyme substrates or the like.
  • oligonucleotide primers were designed based on the alignment ofthe 5' and 3' conserved non-translated regions of the human (Accession No. NM_002354), mouse (Accession No. NM_008532) and rat (Accession No. AJ001044) Ep-CAM genes (see FIGURE 5): (EpcamA, 5' - G G A A GATCTCGCGCGCAGCATGGCG-3' (SEQ ID NO: 11); and EpcamB, 5'-ACGCGTCGACGAGTACAGGTTTCACTATTACAAAT- 3' (SEQ ID NO: 12)).
  • the primer sequences were modified to introduce the cloning sites BgRl and Sail.
  • PCR was carried out in a Perkin Elmer 2400 thermocycler (Perkin Elmer, Inc., Wellesley, MA). Cycling conditions consisted of 40 cycles of 94°C for 15 sec, 50°C for 30 sec, and 72°C for 1 min, followed by an extensive elongation step of 7 min at 72°C. The amplification product was analyzed by agarose gel electrophoresis and the expected band isolated with JetSorb (Genomed, Bad Oeynhausen, Germany).
  • JetSorb Geneomed, Bad Oeynhausen, Germany.
  • Purified DNA bands obtained by RT-PCR were cloned into plasmid vectors for further analysis.
  • the purified DNA bands were treated with Klenow in the presence of 200 ⁇ M dNTPs and subcloned in the EcoRV site of pBluescript vector for sequence analysis.
  • a second cloning experiment was performed in which PCR products were digested with BgR ⁇ and Sail and inserted in the corresponding sites ofthe pMRK plasmid. Both pBluescript and pVl J ⁇ p-CAM clones were sequenced to confirm the rh ⁇ p-CAM sequence, as described below.
  • the open reading frame ofthe Rhesus monkey Ep-CAM gene was found to contain 34 base changes compared to the published sequence of human Ep- CAM.
  • RT-PCR was performed essentially as described above (see EXAMPLE 1) utilizing total RNA isolated from the intestine of a different monkey.
  • PCR primers were used from the conserved 5' and 3' ends ofthe Ep-CAM coding region: EpcamC; -5'-GGAAGA TCTAGCCATCGCGCCCCCGCAGGTCCTCG-3' (SEQ ID NO:13) andEpcamD; 5'-ACGCGTCGACTTATGCATTGAGTTCC CTAT-3' (SEQ ID NO: 14).
  • PCR products were digested with Bgl ⁇ l and Sail and inserted in the corresponding sites ofthe pMRK plasmid.
  • the plasmid was recombined with the adenoviral backbone vector p ⁇ El ⁇ E3-Ad5, which contains all Ad5 sequences except those encompassing the El and E3 regions, using E. coli BJ5183 cells (Chartier et al, J. Virol. 70: 4805- 10 (1996)).
  • pMRK- ⁇ El ⁇ E3-Ad5 -Ep-CAM was linearized by digestion with Pad and transfected in PerC.6 cells using Lipofectamine (Life Technologies, Rockville, MD). 5-6 viral passages were performed to amplify viral titer and a large viral amplification was carried out with a final production of 1.3x1012 physical particles (pp).
  • expression vectors pVU/rhEp-CAM and pVU-liEp-CAM comprising expression cassettes containing Rhesus monkey Ep-CAM and human Ep-CAM, respectively, were constructed. Construction of pVl J/rhEp-CAM is described in EXAMPLE 3. To obtain pVl J/hEp-CAM, which comprises the human Ep-CAM coding region, total RNA was extracted from human CaCo2 cells. RT-PCR experiments were carried out using primers EpcamC and EpcamD (SEQ ID NOs: 13 and 14). The resulting PCR product was digested with BglR and Sail and inserted in the corresponding sites of pVU vector. Sequence analysis of single positive colonies showed that the correct human sequence was obtained.
  • FACS analysis was performed using the human Ep-CAM Ab-3 monoclonal antibody (clone 323/A), which was obtained from Lab Vision Corp. (Fremont, CA). Cells were detached with a mild trypsin treatment and collected in complete medium. 10e6 cells were washed with PBS 1% FCS and incubated for 30 minutes in 100 ⁇ l containing 5 ⁇ g/ml of Ab-3 monoclonal antibody. After one wash with PBS 1% FCS, buffer cells were incubated with anti-mouse IG1 antibody diluted 1:500. Cells were washed once and analyzed in the FACScalibur (Becton Dickinson, San Jose, CA) using cellquest software (Becton Dickinson).
  • mice were injected in the quadriceps with 109 pp of MRK-Ad5-rhEp-CAM and with the same dose ofthe control construct MRK-Ad5-hEp-CAM, which expresses the human Ep- CAM cDNA. Mice were treated with l ⁇ 9 p ⁇ of either construct. Three weeks after this injection, mice received a single booster injection of 109 pp.
  • Antigen-specific IFN ⁇ -secreting cells were detected using a standard enzyme-linked immunospot (ELISPOT) assay.
  • Spleen cells were prepared from immunized mice and resuspended in RIO medium (RPMI 1640 supplemented with 10% fetal calf serum, 2 mM L-glutamine, 50 U of penicillin per ml, 50 mg of streptomycin per ml, 10 mMHEPES, 50 mM 2-mercaptoethanol).
  • Multiscreen 96- well filtration plates catalog number MAIPS4510; Millipore Corp., Bedford, Mass.
  • were coated with purified rat anti-mouse IFN ⁇ antibody catalog. N. 18118 ID; Pharmingen; San Diego, CA).
  • mice C57BL/6 (B6) mice were injected with either pMRK-Ad5 -rhEp-CAM or the control construct pMRK-Ad5-hEp-CAM, or mock injected. Mice were treated with 10 pp both in priming and boosting at 3 -week intervals (as described in EXAMPLE 5).
  • mice were challenged with 3x105 MC38 cells by subcutaneous injection into the dorsum.
  • MC38 cells comprise a syngeneic cell line that expresses human Ep-CAM.
  • the MC38 cell line was generated by transfecting the pVl J-Zeo-hEpCAM in MC38-CEA cells and selecting with zeocyne. FACS analysis indicated that this cell line expressed hEp-CAM in more than 90% ofthe cells. Results indicated that 90%> (9/10) of B6 mice immunized with pMRK-
  • Ad5-rhEp-CAM and challenged with hEp-CAM-expressing cells remained tumor free 46 days after tumor challenge.
  • 90% (9/10) of B6 mice immunized with pMRK-Ad5-hEp-CAM and challenged with hEp-CAM expressing cells also remained tumor free.
  • Only 1/9 mice in the mock injected control group remained tumor free after the challenge protocol described above.
  • the pulse length is 2 msec/phase with a pulse frequency and amplitude of 100 Hz and 100 mA, respectively (constant current mode).
  • animals are injected with either the pVl J-rhEp-CAM plasmid DNA construct + EGT or with a dose of 10l 1 physical particles ofthe adenovirus construct pMRK-Ad5 -rhEp-CAM.
  • PBMC peripheral mononuclear cells
  • IFN ⁇ Elispot assay will show that the immunization protocol discussed above is effective in inducing a specific immune response against rhEp-CAM in rhesus monkeys.

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Abstract

L'invention concerne une molécule d'adhésion cellulaire épithéliale de singe rhésus codant des ADN (rhEp-CAM) ayant été isolée, clonée et séquencée. Le gène codant Ep-CAM est généralement associé au développement de carcinomes humains dérivés de l'épithélium. L'invention concerne des compositions et des méthodes permettant de provoquer ou d'améliorer l'immunité par rapport au produit protéinique exprimé par l'antigène associé à la tumeur Ep-CAM, l'expression de Ep-CAM aberrante étant associée à un carcinome ou à son développement. L'invention concerne en particulier des constructions de vecteur adénoviral portant rhEp-CAM, et leur utilisation dans des vaccins et dans des compositions pharmaceutiques pour prévenir et pour traiter le cancer.
PCT/EP2003/008504 2002-08-07 2003-07-31 Molecule d'adhesion cellulaire epitheliale rhesus, nucleotides codant cette molecule et utilisations associees Ceased WO2004015098A2 (fr)

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AU2003251679A AU2003251679A1 (en) 2002-08-07 2003-07-31 Rhesus epithelial cell adhesion molecule, nucleic acid encoding the same, and uses thereof

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US40169102P 2002-08-07 2002-08-07
US60/401,691 2002-08-07

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WO2004015098A3 WO2004015098A3 (fr) 2004-03-18

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DE69232395T2 (de) * 1991-11-26 2002-11-14 Jenner Technologies, Walworth Antitumorvakzine

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