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Title:  Ctage gene family
United States Patent: 
7,314,922
Issued: 
January 1, 2008

Inventors: 
Eichmuller; Stefan (Edingen-Neckarhausen, DE), Schadendorf; Dirk (Mannheim, DE), Usener; Dirk (Mainz, DE)
Assignee: 
Deutsches Krebsforschungszentrum (Heidelberg, DE)
Appl. No.: 
10/110,807
Filed: 
October 13, 2000
PCT Filed: 
October 13, 2000
PCT No.: 
PCT/DE00/03628
371(c)(1),(2),(4) Date: 
September 06, 2002
PCT Pub. No.: 
WO01/27255
PCT Pub. Date: 
April 19, 2001


 

Executive MBA in Pharmaceutical Management, U. Colorado


Abstract

The present invention relates to a novel gene family for "cutaneous T-cell lymphoma associated genes" (CTAGE). The present invention describes two members of said family, CTAGE-1 and CTAGE-2, the underlying genes thereof and the use thereof for diagnosis and treatment of tumoral diseases.

Description of the Invention

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is filed under the provisions of 35 U.S.C. .sctn.371 and claims the priority of International Patent Application No. PCT/DE00/03628 filed Oct. 13, 2000, which in turn claims priority of German Patent Application No. 199 49 595.5 filed Oct. 14, 1999.

FIELD OF THE INVENTION

The present invention relates to a novel gene family for "cutaneous T-cell lymphoma associated genes" (CTAGE). The present invention describes two members of this family, CTAGE-1 and CTAGE-2, the underlying cDNA thereof (ctage-1 and ctage-2), and the use thereof for diagnosis and therapy of tumoral diseases.

1. Background of the Invention

The cutaneous T-cell lymphoma (CTCL) is a tumor of the skin which is based on T-lymphocytes and difficult to treat in an advanced stage. The cutaneous T-cell lymphomas are generally counted among the group of non-Hodgkin's lymphomas. The cutaneous T-cell lymphomas comprise inter alia the diseases mycosis fungoides, Sezary syndrome and pagetoid reticulosis. After removing the primary tumor, conventional therapies (irradiation, chemotherapy) often have only little effectiveness in the metastasizing stage of the disease or as a preventive therapy and are also accompanied by the known major side-effects. The tumor has often grown and spread to such an extent that operative treatment is of no use. The measure of a possible immunotherapy (vaccination against tumors) has recently been considered in particular for tumors of the skin. However, the application of such therapy forms requires tumor-specific antigens which have not been found for many tumor types thus far.

2. Description of the Invention

Thus, the invention is substantially based on the problem of discovering tumor-specific antigens which are suited inter alia for cutaneous T-cell lymphomas and can be used for a vaccination therapy.

The solution to this technical problem was obtained by providing the embodiments characterized in the claims.

The inventors were able to isolate a DNA molecule family which in addition to expression in testis tissues is only expressed in different tumor tissues, in particular in the case of T-cell lymphomas (such as the Sezary syndrome), tumors of the HNO region or ovarian cancers (see Examples 4 and 5). They belong to what is called "cancer-testis antigens". The identification of such genes (CTAGE-1 and CTAGE-2) is of interest, since the proteins encoded by them and peptides derived therefrom serve as target structures, e.g. for cytotoxic cells, and can be used as antigens for the production of diagnostic or therapeutic antibodies. For tumor therapy, the peptides encoded by CTAGE-1 or CTAGE-2 or fragments thereof can be either applied directly or loaded on antigen-presenting cells. Peptides presenting the antigens can also be expressed by means of vectors in different cells (e.g. dendritic cells as antigen-presenting cells). Furthermore, cloning of one or more representatives of the CTAGE gene family forms the foundation for developing diagnostic tests to ensure a more reliable and early diagnosis in affected persons in the future. Functional analyses of the protein will no doubt add to the insight into the development of tumors. Thus, they have to be regarded as candidate genes for studying the pathomechanisms on which different tumoral diseases are based.

The present invention therefore relates to a DNA molecule coding for a tumor-associated antigen, comprising: (a) the nucleic acid of FIG. 1 (SEQ ID NO: 1, see Original Patent) or FIG. 2 (SEQ ID NO: 4, see Original Patent) or a DNA differing therefrom by one or more base pairs or a fragment thereof, (b) a DNA hybridizing with the nucleic acid from (a), or (c) a DNA related to the nucleic acid from (a) or (b) via the degenerated genetic code.

The nucleic acid molecules defined in items (a) and (c) code for proteins, polypeptides or peptides, which still have at least one of the below described biological activities of the protein encoded by the nucleic acid according to FIG. 1 or FIG. 2, e.g. represent a tumor-specific antigen.

The DNA molecules defined in (a) also comprise DNA molecules differing from the sequence indicated in FIGS. 1 and/or 2 by deletion(s), insertion(s), substitution(s) and/or other modifications known in the art, e.g. alternative splicing, or comprise a fragment of the original nucleic acid molecule, the protein encoded by these DNA molecules additionally having one or more of the above described biological activities. Allele variants are also counted thereamong. Methods of producing the above modifications in the nucleic acid sequence are known to a person skilled in the art and are described in standard manuals of molecular biology, e.g. in Sambrook et al., Molecular Cloning: A Laboratory Manual, 2.sup.nd edition, Cold Spring Harbor Laboratory Press, Cold Spring Harbor N.Y. (1989). In this connection, the variants have a homology of at least 70%, preferably 80%, more preferably 90%, and most preferably 95, 96, 97, 98 or 99%, with the sequences according to FIG. 1 or 2.

The term "hybridizing DNA" refers to a DNA which hybridizes under common conditions, in particular at 20.degree. C. below the melting point of the DNA, with a DNA from (a) In this connection, the term "hybridize" refers to conventional hybridization conditions, preferably to hybridization conditions in which 5.times.SSPE, 1% SDS, 1.times. Denhardt's solution is used as the solution and the hybridization temperatures are between 35.degree. C. and 70.degree. C., preferably at 65.degree. C. Following hybridization, it is preferred to first carry out a wash step with 2.times.SSC, 1% SDS and then with 0.2.times.SSC at temperatures between 35.degree. C. and 70.degree. C., preferably at 65.degree. C. (for the definitions of SSPE, SSC and Denhardt's solution see Sambrook et al., supra). Stringent hybridization conditions as described in Sambrook et al., supra, for example, are preferred.

In a particularly preferred embodiment the DNA molecule according to the invention is a cDNA.

In another preferred embodiment, the DNA molecule according to the invention is a genomic DNA which is derived preferably from a mammal, e.g. a human being. Screening methods based on nucleic acid hybridization enable the isolation of the genomic DNA molecules according to the invention from any organism or derived genomic DNA libraries, probes being used which contain the nucleic acid sequence indicated in FIG. 1 or 2 or a part thereof.

A nucleic acid according to the invention is particularly suited as an antigen-coding structure for therapeutic purposes. Here, the objective is to stimulate the immune system and/or eliminate tumor cells identified via a member of the CTAGE family, particularly CTAGE-1 or CTAGE-2. There are various possibilities to do so, e.g. giving the patient the naked DNA by way of injection. For this purpose, a plasmid having a very active promoter and a member of the CTAGE family, in particular CTAGE-1 or CTAGE-2, are given by intramuscular or intradermal injection, for example. What is aimed at is that the cells take up the plasmid, produce antigens, present individual peptides via HLA molecules and thus evoke a cytotoxic T-cell immunoresponse which shall then serve for warding off tumor cells. This procedure is described generally in Conry et al., Clinical Cancer Research, Vol. 4, pages 2903-2912 (1998). The gene-gun method is an alternative. It is described in Fynan et al., Proc. Natl. Acad. Sci, U.S.A., Vol. 90, pages 11478-11482 (1993).

The nucleic acids according to the invention can also be inserted in a vector or expression vector. Hence the present invention also comprises vectors containing the nucleic acid molecules. Examples thereof are known to the person skilled in the art. In the case of an expression vector for E. coli these are pGEMEX, pUC derivatives (e.g. pUC8), pBR322, pBLueScript, pGEX-2T, pET3b and pQE-8, for example. For expression in yeast e.g. pY100 and Ycpad1 have to be mentioned while e.g. pKCR, pEFBOS, cDM8 and pCEV4 have to be indicated for expression in animal cells. The baculovirus expression vector pAcSGHisNT-A is particularly suited for expression in insect cells. In a preferred embodiment the nucleic acid molecule according to the invention is functionally linked in the vector with regulatory elements which enable the expression thereof in prokaryotic or eukaryotic host cells. Along with the regulatory elements, e.g. a promoter, such vectors contain typically a replication origin and specific genes which enable the phenotypic selection of a transformed host cell. The regulatory elements for expression in prokaryotes, e.g. E. coli, comprise the lac-, trp promoter or T7 promoter, and those for expression in eukaryotes comprise the AOX1 or GAL1 promoter in yeast, and those for expression in animal cells include the CMV, SV40, RVS-40 promoter and/or CMV or SV40 enhancer. Further examples of suitable promoters are the metallothionein I and polyhedrin promoters.

Suitable vectors are in particular T7-based expression vectors for expression in bacteria (Rosenberg et al., Gene 56 (1987), 125) or pMSXND for expression in mammalian cells (Lee and Nathans, J. Biol. Chem. 263 (1988), 3521).

The DNA according to the invention can be inserted in a vector not only for the purpose of recombinant production but also to inject using vectors this DNA into patients where it codes for an antigen for therapeutic purposes. In this connection, the DNA is attached in vivo by means of a vector to antigen-presenting cells (APCs), e.g. dendritic cells, for HLA presentation of CTAGE. Here, the vector containing the DNA according to the invention can be injected in different ways: a) lipid-packed or liposome-packed DNA or RNA, e.g. generally described by Nabel et al., Proc. Natl. Acad. Sci. U.S.A., Vol. 93, pages 15388-15393 (1996); b) by means of a bacterium as a transport vehicle for the expression vector. Suitable bacteria are e.g. (attenuated) listerias [e.g. Listeria monocytogenes], salmonella strains [e.g. Salmonella spp.]. This method is described generally by Medina et al., Eur. J. Immunol., 29, pages 693-699 (1999) and Guzman et al., Eur. J. Immunol. 28, pages 1807-1814 (199). Reference is also made to WO 96/14087; Weiskirch et al., Immunological Reviews, Vol. 158, pages 159-169 (1997) and U.S. Pat. No. 5,830,702; c) by means of gene gun (Williams et al., Proc. Natl. Acad. Sci. U.S.A., Vol. 88, pages 2726-2730, 1991).

In a preferred embodiment, the vector containing the DNA molecules according to the invention is a virus, e.g. an adenovirus, vaccinia virus or an AAV virus, which is of use for a gene therapy. Retroviruses are particularly preferred. Examples of suitable retroviruses are MoMuLV, HaMuSV, MuMTV, RSV or GaLV. The above-mentioned viruses and the fowlpox virus, canarypox virus, influenza virus or sindbis virus are also suited as a basis for a vaccine. Such new vaccines, which after being administered give the patient immunity against tumors, are described in N. Restifo, Current Opinion in Immunology, 8, pages 658-663 1996), or Ying et al., Nature Medicine, Vol. 5, No. 7, page 823 et seq., (1999), for example. For the purpose of gene therapy the DNA molecules according to the invention can also be transported to the target cells in the form of colloidal dispersions. These comprise e.g. liposomes or lipoplexes (Mannino et al., Biotechniques 6 (1988), 682).

General methods known in the art can be used to design vectors or plasmids which contain the DNA molecules according to the invention and suitable control sequences. These methods comprise e.g. in vitro recombination techniques, synthetic methods and in vivo recombination methods, as described in Sambrook et al., supra, for example.

The present invention also relates to host cells containing the above described vectors. These host cells comprise bacteria, yeast, insect and animal cells, preferably mammalian cells. The E. coli strains HB101, DH1, x1776, JM101, JM109, BL21, XL1Blue and SG13009, the yeast strain Saccharomyces cerevisiae and the animal cells L, 3T3, FM3A, CHO, COS, Vero, HeLa, and the insect cells sf9 are preferred. Methods of transforming these host cells, of phenotypically selecting transformants and expressing the DNA molecules according to the invention using the above described vectors are known in the art.

In order to produce immunity against tumors, it is also preferred to transfect the DNA according to the invention into antigen-presenting cells and give the patient these cells by way of injection. Here, a plasmid is introduced in vitro into an antigen presenting cell (APCs), e.g. dendritic cells, which then produce antigens and present individual peptides via HLA molecules. In this connection, the plasmid DNA can be introduced into the antigen-presenting cells in different ways: (a) as a naked DNA, e.g. by means of gene gun or electroporation, (b) lipid-packed or liposome-packed DNA or RNA (Nair et al., Nature Biotechnology, Vol. 16, page 364 et seq. (1998)), (c) by means of a virus as a vector (Kim et al., J. of Immunotherapy, 20(4), pages 276-286 (1997)), (d) by means of a bacterium as a transport vehicle for the expression vector (Medina et al., Eur. J. Immunol., 29, pages 693-699 (1999); Guzman et al., Eur. J. Immunol. 28, pages 1807-1814 (1998)).

A clone which codes for a nucleic acid according to the invention (CTAGE-1) was deposited with DSMZ, Deutsche Sammlung von Mikroorganismen und Zellkulturen CmbH [German-type collection of microorganisms and cell cultures], Mascheroder Weg 1b, 38124 Braunschweig, Germany, in accordance with the Budapest Treaty under accession number DSM 13079 (=Escherichia coli XL2-Blue pCTAGE-1) on Oct. 7, 1999.

The present invention also relates to a method of producing a protein which is encoded by the above nucleic acids, comprising culturing the above described host cells under conditions enabling the expression of the protein (preferably stable expression) and obtaining the protein from the culture. Suitable methods of recombinantly producing the protein are generally known (see e.g. Holmgren, Annu. Rev. Biochem. 54 (1985), 237; LaVallie et al., Bio/Technology 11 (1993), 187; Wong, Curr. Opin. Biotech. 6 (1995), 517; Romanos, Curr. Opin. Biotech. 6 (1995), 527; Williams et al., Curr. Opin. Biotech. 6 (1995), 538; and Davies, Curr. Opin Biotech. 6 (1995), 543). Suitable purification methods (e.g. preparative chromatography, affinity chromatography, e.g. immunoaffinity chromatography, HPLC, etc.) are also generally known.

In another embodiment, the present invention relates to a protein encoded by the DNA molecules according to the invention (CTAGE-1 or CTAGE-2) or obtained according to the above method. The protein coding for CTAGE-2 is shown in FIG. 3 (see Original Patent). In this connection, it is pointed out that the protein according to the invention can be modified according to common methods known in the art. The modifications comprise substitutions, insertions or deletions of amino acids, which modify the structure of the protein, its biological activity being substantially maintained. The substitutions comprise particularly "conservative" substitution of amino acid residues, i.e. substitutions for biologically similar residues, e.g. the substitution of a hydrophobic residue (isoleucine, valine, leucine, methionine, for example) for another hydrophobic residue, or the substitution of a polar residue for another polar residue (e.g. arginine for lysine, glutamic acid for aspartic acid, etc.). Deletions may result in the production of molecules markedly reduced in size, i.e. they lack amino acids at the N-terminus or C-terminus, for example. In this connection, the variants have a homology of at least 70%, preferably 80%, more preferably 90%, most preferably 95, 96, 97, 98 or 99%, with the amino acid sequence derived from the nucleotide sequence according to FIG. 1 or with the amino acid sequence according to FIG. 3.

For the desired anti-tumor vaccination, it is also suited to give the protein or one or more peptides derived therefrom by way of injection. For this purpose, HLA-dependent peptide fragments are determined from the sequence of the protein according to the invention by either corresponding computer programs or experiments (e.g. phagocytotic uptake of the entire protein, then analysis of the presenting peptides). They are produced artificially by methods known to the person skilled in the art and then given to the patient by way of injection (if necessary, with factors stimulating the immune system, e.g. interferons, interleukins etc.). This treatment shall effect that the APCs take up the peptides, present them and thus stimulate in vivo the production of tumor-specific cytotoxic T-cells. This principle is described generally by Melief et al., Current Opinion in Immunology, 8, pages 651-657 (1996).

As described above, the protein according to the invention or fragments thereof can be loaded in vitro on APCs in place of the vector. The loaded cells are then injected into the patient's lymph nodes and provide directly for the stimulation and replication of tumor-specific cytotoxic T-cells (Nestle et al., Nature Medicine, Vol. 4, No. 3, page 328 et seq. (1998); Schadendorf et al., in: Burg, Dummer, Strategies for Immunointerventions in Dermatology, Springer Verlag, Berlin Heidelberg, pages 399-409, 1997). For the purpose of vaccination it may be favorable to modify individual amino acids, as described above, vis-a-vis the wild-type antigen, since under certain circumstances it is in this way possible to increase binding and improve effectiveness (Clay et al., The Journal of Immunology 162: pages 1749-1755, 1999).

The present invention also relates to antibodies which recognize specifically the above described protein CTAGE-1 or CTAGE-2. The antibodies may be monoclonal, polyclonal or synthetic antibodies or fragments thereof, e.g. Fab, Fv or scFv fragments. They are preferably monoclonal antibodies. For the production it is favorable to immunize animals, in particular rabbits or chickens for a polyclonal antibody and mice for a monoclonal antibody, with an above (fusion) protein or with fragments thereof. Further boosters of the animals can be made with the same (fusion) protein or with fragments thereof. The polyclonal antibody can then be obtained from the animal serum or egg yolk. The antibodies according to the invention can be produced according to standard methods, the protein encoded by the DNA molecules according to the invention or a synthetic fragment thereof serving as an immunogen Monoclonal antibodies can be prepared by the method described by Kohler and Milstein (Nature 256 (1975), 495) and Galfre (Meth. Enzymol. 73 (1981), 3), murine myeloma cells being fused with spleen cells originating from immunized mammals. These antibodies can be used e.g. for the immunoprecipitation of the above discussed proteins or for isolating of related proteins from cDNA expression libraries. The antibodies can be bound e.g. in immunoassays in liquid phase or to a solid carrier. Here, the antibodies can be labeled in different ways. Suitable markers and labeling methods are known in the art. Examples of immunoassays are ELISA and RIA. The antibodies can also be used therapeutically along with their diagnostic suitability. In this connection, e.g. a protein of the CTAGE family, e.g. CTAGE-1 or CTAGE-2, serves as a target for bispecific antibodies. Reference is made to Kastenbauer et al. Laryngorhinootologie, 78(1), pages 31-35 (1999) and Cao et al., Bioconj. Chem. 9(6), pages 635-644 (1998). As a result of antibody administration, it is possible to counteract the effect of the CTAGE proteins, which supports tumor growth and metastasis.

Furthermore, the use of CTAGE-1 or CTAGE-2 antisense DNA can serve for inhibiting the translation of CTAGE-1 or CTAGE-2 and a therapeutic effect can thus be exerted specifically to this gene. RNA/DNA hybrids form in the corresponding tumor cells, preventing transcription in this way and simultaneously degrading the hybrids (and thus the RNA) by RNaseH (Scanlon et al., The Faseb Journal, Vol. 9, pages 1288-1296, 1995).

The present invention also relates to the use of the above described DNA molecules, vectors, proteins and/or antibodies. They are used preferably for producing a medicament for the diagnosis or treatment of tumoral diseases in which CTAGE-1 or CTAGE-2 plays a role. The provision of a vaccine which as described above is based on either the DNA or the protein/peptide, is preferred.

These medicaments also contain, where appropriate, a pharmaceutically compatible carrier. Suitable carriers and the formulation of such medicaments are known to the person skilled in the art. Suitable carriers comprise e.g. phosphate-buffered common salt solutions, water, emulsions, e.g. oil/water emulsions, wetting agents, sterile solutions, etc. The medicaments can be administered orally or parenterally. The methods of parenteral administration comprise the topical, intra-arterial, intramuscular, subcutaneous, intramedullary, intrathecal, intraventricular, intravenous, intraperitoneal or intranasal administration. The suitable dosage is determined by the attending physician and depends on various factors, e.g. the patient's age, sex and weight, the stage of the disease, the kind of administration, etc.

The present invention also relates to a diagnostic composition which contains the above-described DNA molecule or the antibody or to combinations thereof with a suitable analytical agent, where appropriate. The diagnostic composition is suited on the one hand to detect a tumoral disease but also to carry out a follow-up.

The DNA molecule according to the invention, which is defined as outlined above, can also be used as a probe to isolate DNA molecules which are derived e.g. from another species or another organism and code for a protein having an equal biological activity. For this purpose, the probe has preferably a length of at least 10, more preferably at least 15 bases. Suitable detection methods based on hybridization are known to the person skilled in the art, e.g. Southern or Northern blot. Suitable labeling for the probe is also known to the person skilled in the art and comprises e.g. labeling with radioisotopes, bioluminescence, chemiluminescence, fluorescent markers, metal chelates, enzymes, etc.

In addition, this can also be effected by PCR (Wiedemann et al., PCR Methods Appl. 3, pages 551-564 (1994); Saiki et al., Nature 324, pages 163-166 (1986)) or "ligase chain reaction" (LCR) (Taylor et al., Curr. Opin. Biotechnol. 6, pages 24-29 (1995); Rouwendal et al., Methods Mol. Biol., pages 149-156 (1996)), the primers being derived from the sequence in FIG. 1 or FIG. 2 and the person skilled in the art being able to design suitable primers (as regards length, complementarity with respect to the template, the area to be amplified, etc.) by common methods.

The present invention also relates to a method of diagnosing tumoral diseases in vitro, comprising the steps of: isolating nucleic acid from the patient, carrying out LCR or PCR with suitable primers or a hybridization analysis with one or more suitable probes based on the coding sequence of FIG. 1 or FIG. 2, detecting an amplified product or a hybridization as a reference to the presence of a tumoral disease.

In connection with the above-mentioned method, it is possible to use methods known to the person skilled in the art with respect to the preparation of DNA or RNA from biological samples, the restriction digestion of the DNA, the application of the restriction fragments onto gels separating according to size, e.g. agarose gels, the production and labeling of the probe and the detection of hybridization, e.g. via "Southern blot" or in situ hybridization.

The above detection can also be carried out via PCR or LCR. Here, primers are used, flanking the sequence according to the invention or suitable partial regions. In this connection, amplification products of DNA from the tissue in question, which differ from the amplification products of DNA from healthy tissue as regards the occurrence of CTAGE-1 or CTAGE-2-specific bands, are of diagnostic significance.

In an alternative embodiment, a method can be used which comprises the steps of. isolating RNA from the patient, carrying out a Northern blot analysis with one or more suitable probes, comparing the concentration and/or length of CTAGE-1 or CTAGE-2 mRNA of the patient's sample with an mRNA from a healthy person, the occurrence of CTAGE-1 or CTAGE-2 mRNA referring to a tumoral disease as compared to control mRNA from normal tissue.

In connection with this method, it is possible to use procedures known to the person skilled in the art with respect to the preparation of whole RNA or poly(A)+RNA from biological samples, the application of RNAs onto gels separating according to size, e.g. denaturing agarose gels, the production and labeling of the probe and the detection via "Northern blot".

In another alternative embodiment, a possible disease can also be diagnosed by a method comprising the steps of: obtaining a cell sample from a patient, contacting the resulting cell sample with the above described antibody according to the invention as a probe under conditions enabling binding of the antibody, binding of the antibody referring to an existing expression of CTAGE-1 or CTAGE-2, which is a reference to a tumoral disease.

This detection can also be carried out using standard techniques known to the person skilled in the art. He is also familiar with cell breaking-up methods which enable the isolation of the protein such that it can be contacted with the antibody. The bound antibody is detected preferably via immunoassays, e.g. Western blot, ELISA, FACS or RIA or immunohistochemical methods. The antibodies are also suited to catch CTAGE-1 or CTAGE-2 overexpressed in tumors so as to inhibit the growth of the tumor, since there is reference to the fact that the occurrence of CTAGE-1 or CTAGE-2 does not only show the presence of tumors but also supports tumor growth actively.

The present invention also relates to kits for carrying out the diagnostic method according to the invention, which contain the antibody according to the invention or a fragment thereof, a DNA molecule according to the invention as a probe or a primer pair suitable for PCR or LCR and based on the sequence of the DNA molecule according to the invention, optionally in combination with a suitable detection means.

Depending on the design of the diagnostic method to be carried out with the kit according to the invention, the DNA molecules, antibodies or fragments thereof, which are contained in the kit, can be immobilized on a suitable carrier.
 

Claim 1 of 8 Claims

1. An isolated nucleic acid which codes for a protein of the CTAGE family and has expression in malignant tumors and in ordinary testis tissue, wherein the nucleic acid consists of the nucleic acid of SEQ ID NO: 1.

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