Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Reexamination Certificate
1997-01-31
2001-03-20
Draper, Garnette D. (Department: 1647)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
C435S069100, C435S252300, C435S320100, C435S006120, C536S023500, C536S024300
Reexamination Certificate
active
06204021
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to nucleic acid and amino acid sequences of novel human cytokines and to the use of these sequences in the diagnosis, prevention, and treatment of cancers, inflammation, allograft rejection, neurodegenerative diseases, and conditions affecting pregnancy, growth and development.
BACKGROUND OF THE INVENTION
Cytokines are active in cell proliferation and differentiation and affect such activities as leukocyte migration and function, hematopoietic cell numbers, temperature regulation, acute response to infections, tissue remodeling and cell survival. Since cytokines are produced in groups and in patterns characteristic of the particular stimulus or disease, studies using antibodies or other drugs that modify the activity of a particular cytokine are beginning to elucidate the roles of individual cytokines in pathology and physiology. For purposes of example, two cytokines which are rapidly expressed in response to fibroblast growth factor (FGF) and inflammatory response (AIF-1), respectively, will be described.
FIN 14 is an inducible gene which was expressed in cells transfected with a genomic fragment of the FGF-4, a growth factor known to play a crucial role in mouse and Xenopus embryonic growth and development (Feldman, B et al. (1995) Science 267:246-9; Amaya, E. et al. (1991) Cell 66:257-70). The transcript for FIN 14 was originally isolated using subtractive hybridization between the transformed 15 cell line and untransfomed mouse NIH3T3 cells, the line from which A15 was derived. FIN 14 is maximally induced 12-18 hours after FGF-4 treatment and is considered to be a delayed or late response transcript when compared to intermediate-early response genes such as transcription factors. Further studies showed that FIN 14 maps to the distal arm of mouse chromosome 6 and is also expressed in response to mitogenic stimulation (serum; Guthridge, M. A. (1996) Oncogene 12:1267-78).
AIF-1, allograft inflammatory factor-1, was first cloned and characterized from rat cardiac allografts. AIF-1 is a 17 kD hydrophillic protein which is selectively expressed in macrophages and neutrophils, and when stimulated by T-cell interferon-gamma, AIF-1 expression increases six-fold. AIF-1 transcripts are lacking in cardiac syngrafts and in host hearts, and transcript levels can be reduced in allografts by introducing CTLA-4 immunoglobulin (Utans, U. et al. (1995) J. Clin. Invest. 95:2954-62).
AIF-1 has 77% overall amino acid identity with IBA1; however, most of the variability is in the first 9 and in the last 20 residues. Both of these molecules share a calcium binding domain, D
58
LNGNGDIDIMSL
70
. Imai, Y et al. (Biochem. Biophys. Res. Comm. 224:855-862) report that IBA1 is highly expressed in spleen, testes, and microglia where the protein may mediate calcium signaling.
The discovery of novel cytokines and the molecules encoding them provides a means to investigate cell proliferation, leukocyte migration and function, response to infections and tissue remodeling under normal and disease conditions. Such novel cytokines satisfy a need in the art by providing new compositions useful in diagnosing and treating cancers, inflammation, allograft rejection, neurodegenerative diseases, and conditions affecting pregnancy, growth and development
SUMMARY OF THE INVENTION
The present invention features two novel cytokines, designated individually as NHC-1 and NHC-2 and collectively as NHC, and characterized as having similarity to mouse FIN14 and AIF-1, respectively
Accordingly, the invention features substantially purified NHC proteins NHC-1 and NHC-2 having the amino acid sequences shown in SEQ ID NO:1 and SEQ ID NO:4, respectively.
One aspect of the invention features isolated and substantially purified polynucleotides that encode NHC proteins—NHC-1 and NHC-2. In a particular aspect, the polynucleotides are the nucleotide sequences of SEQ ID NO:2 and SEQ ID NO:5, respectively.
The invention also features a polynucleotide sequence comprising the complement of SEQ ID NO:2 and SEQ ID NO:5, or variants thereof. In addition, the invention features polynucleotide sequences which hybridize under stringent conditions to SEQ ID NO:2 and SEQ ID NO:5.
The invention additionally features nucleic acid sequences encoding polypeptides, oligonucleotides, peptide nucleic acids (PNA), fragments, portions or antisense molecules thereof, and expression vectors and host cells comprising polynucleotides that encode NHC. The present invention also features antibodies which bind specifically to NHC, and pharmaceutical compositions comprising substantially purified NHC. The invention also features the use of agonists and antagonists of NHC.
REFERENCES:
patent: 5527886 (1996-06-01), Russell et al.
Feldman, B., et al., “Requirement of FGF-4 for Postimplantation Mouse Development”,Science, 267: 246-249 (1995).
Amaya, E., et al., “Expression of a Dominant Negative Mutant of the FGF Receptor Disrupts Mesoderm Formation in Xenopus Embryos”,Cell, 66: 257-270 (1991).
Guthridge, M.A., et al., “Induction of expression of growth-related genes by FGF-4 in mouse fibroblasts”,Oncogene, 12: 1267-1278 (1996).
Utans U., et al., “Cloning and characterization of allograft inflammatory factor-1: a novel macrophage factor identified in rat cardiac allografts with chronic rejection”,J. Clin. Invest.95: 2954-2962 (1995).
Imai, Y., et al., “A novel gene ibal in the major histocompatibility complex class III region encoding an EF hand protein expressed in a monocytic lineage”,Biochem Biophys Res Commun, 224: 855-862 (1996).
Guthridge, M.A., et al., (GI 1353711) GenBank Sequence Database (Accession U42386), National Center for Biotechnology Information: National Library of Medicine, Bethesda, Maryland 2084.
Guthridge, M.A., et al., (GI 1353710) GenBank Sequence Database (Accession U42386), National Center for Biotechnology Information: National Library of Medicine, Bethesda, Maryland 2084.
Utans, U., et al., (GI 1229022) GenBank Sequence Database (Accession U49392), National Center for Biotechnology Information: National Library of Medicine, Bethesda, Maryland 2084.
Utans, U., et al., (GI 1229021) GenBank Sequence Database (Accession U49392), National Center for Biotechnology Information: National Library of Medicine, Bethesda, Maryland 2084.
Imai, Y., et al., (GI 1514968) GenBank Sequence Database (Accession D82069), National Center for Biotechnology Information: National Library of Medicine, Bethesda, Maryland 2084.
Imai, Y., et al., (GI 1514969) GenBank Sequence Database (Accession D82069), National Center for Biotechnology Information: National Library of Medicine, Bethesda, Maryland 2084.
Utans, U., et al., (GI 1122909) GenBank Sequence Database (Accession U19713), National Center for Biotechnology Information: National Library of Medicine, Bethesda, Maryland 2084.
Utans, U., et al., (GI 1703217) GenBank Sequence Database (Accession P55008), National Center for Biotechnology Information: National Library of Medicine, Bethesda, Maryland 2084.
Utans, U., et al., “Allograft Inflammatory Factor-1”,Transplantation, 61: 1387-1392 (1996).
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Hillier et al, EST No. AA046385, 1995.*
Hillier et al EST No. AA 245272, 1996.*
Hillier et al EST N. N32593, 1995.*
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Bandman Olga
Goli Surya K.
Hawkins Phillip R.
Murry Lynn E.
Draper Garnette D.
Incyte Genomics Inc.
Incyte Genomics, Inc.
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