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
2000-03-17
2001-11-06
Kemmerer, Elizabeth (Department: 1646)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
C435S320100, C435S325000, C435S070500, C435S252800, C435S254110, C435S348000, C435S349000, C435S419000, C536S023520, C536S023100, C514S002600, C530S351000
Reexamination Certificate
active
06312924
ABSTRACT:
TECHNICAL FIELD
The present invention relates generally to a new cytokine having diagnostic and therapeutic uses. In particular, the present invention relates to a novel murine interferon-&agr;, and to nucleic acid molecules encoding interferon-&agr;.
BACKGROUND OF THE INVENTION
Cellular differentiation of multicellular organisms is controlled by hormones and polypeptide growth factors. These difflusable molecules allow cells to communicate with each other and act in concert to form tissues and organs, and to repair and regenerate damaged tissue. Examples of hormones and growth factors include the steroid hormones, parathyroid hormone, follicle stimulating hormone, the interferons, the interleukins, platelet derived growth factor, epidermal growth factor, and granulocyte-macrophage colony stimulating factor, among others.
Hormones and growth factors influence cellular metabolism by binding to receptor proteins. Certain receptors are integral membrane proteins that bind with the hormone or growth factor outside the cell, and that are linked to signaling pathways within the cell, such as second messenger systems. Other classes of receptors are soluble intracellular molecules.
Of particular interest, from a therapeutic standpoint, are the interferons (reviews on interferons are provided by De Maeyer and De Maeyer-Guignard, “Interferons,” in
The Cytokine Handbook
3
rd
Edition,
Thompson (ed.), pages 491-516 (Academic Press Ltd. 1998), and by Walsh,
Biopharmaceuticals: Biochemistry and Biotechnology,
pages 158-188 (John Wiley & Sons 1998)). Interferons exhibit a variety of biological activities, and are useful for the treatment of certain autoimmune diseases, particular cancers, and the enhancement of the immune response against infectious agents, including viruses, bacteria, fungi, and protozoa. To date, six forms of interferon have been identified, which have been classified into two major groups. The so-called “type I” interferons include interferon-&agr;, interferon-&bgr;, interferon-&ohgr;, interferon-&dgr;, and interferon-&tgr;. Currently, interferon-&ggr; and one subclass of interferon-&agr; are the only type II interferons.
Type I interferons, which are thought to be derived from the same ancestral gene, have retained sufficient similar structure to act by the same cell surface receptor. The &agr;-chain of the human interferon-&agr;/&bgr; receptor comprises an extracellular N-terminal domain, which has the characteristics of a class II cytokine receptor. Interferon-&ggr; does not share significant homology with the type I interferons or with the type II interferon-&agr; subtype, but shares a number of biological activities with the type I interferons.
In humans, at least 16 non-allelic genes code for different subtypes of interferon-&agr;, while interferons &bgr; and &ohgr; are encoded by single genes. Type I interferon genes are clustered in the short arm of chromosome 9. Unlike typical structural human genes, interferon-&agr;, interferon-&bgr;, and interferon-&ohgr; lack introns. A single gene for human interferon-&ggr; is localized on chromosome 12 and contains three introns. To date, interferon-&tgr; has been described only in cattle and sheep, while interferon-&dgr; has been described only in pigs.
At least 12 non-allelic murine interferon-&agr; genes have been identified so far (for a review, see De Maeyer and De Maeyer-Guignard, “Interferons,” in
The Cytokine Handbook,
3
rd
Edition,
Thompson (ed.), pages 491-516 (Academic Press Ltd. 1998)). In general, the structure of murine interferon-&agr; genes is similar to that of corresponding human genes. The mouse also appears to have a single interferon-&bgr; gene. Murine interferon-&agr; and -&bgr; genes are clustered on chromosome 4, although the interferon-&bgr; gene is distal from the interferon-&agr; cluster.
Clinicians are taking advantage of the multiple activities of interferons by using the proteins to treat a wide range of conditions. For example, one form of interferon-&agr; has been approved for use in more than 50 countries for the treatment of medical conditions such as hairy cell leukemia, renal cell carcinoma, basal cell carcinoma, malignant melanoma, AIDS-related Kaposi's sarcoma, multiple myeloma, chronic myelogenous leukemia, non-Hodgkin's lymphoma, laryngeal papillomatosis, mycosis fungoides, condyloma acuminata, chronic hepatitis B, hepatitis C, chronic hepatitis D, and chronic non-A, non-B/C hepatitis. The U.S. Food and Drug Administration has approved the use of interferon-&bgr; to treat multiple sclerosis, a chronic disease of the nervous system. Interferon-&ggr; is used to treat chronic granulomatous diseases, in which the interferon enhances the patient's immune response to destroy infectious bacterial, fungal, and protozoal pathogens. Clinical studies also indicate that interferon-&ggr; may be useful in the treatment of AIDS, leishmaniasis, and lepromatous leprosy.
Although new uses of known interferons may be discovered, a need exists for the provision of new interferons for biopharmaceuticals.
BRIEF SUMMARY OF THE INVENTION
The present invention provides a novel murine interferon-&agr;, designated “Zcyto13.” The present invention also provides Zcyto13 polypeptides and Zcyto13 fusion proteins, as well as nucleic acid molecules encoding such polypeptides and proteins, and methods for using these nucleic acid molecules and amino acid sequences.
DETAILED DESCRIPTION OF THE INVENTION
1. Overview
A nucleic acid molecule containing a sequence that encodes murine interferon-&agr;, initially designated as “Zcyto13,” has the following nucleotide sequence:
ATACTAAGCA CCAGGGTTGA GAATGACTCC AAAGTTTTTA TGGCTGGTGG
[SEQ ID NO:1].
CCCTTGTGGC TCTATACATT CCGCCCATCC AATCTCTGAA CTGTGTTTAC
CTGGATGATA GCATCTTGGA AAATGTGAAA CTTCTGGGCA GTACCATGAC
CGGCTTTCCC TTAAGATGTC TAAAAGATAT CACAGATTTT AAGTTTCCTA
AAGAGATTTT GCCATACATC CAGCATATGA AAAGGGAGAT AAACGCCGTC
TCCTATCGTA TATCCTCTCT GGCACTAACT ATCTTCAATC TTAAAGGCTC
CATCCCTCCA GTGACAGAGG AACACTGGGA ACGTATCAGA TCGGGACTTT
TCAAACAAGT GCGGCAAGCT CAAGAGTGCT TCATGGACGA GGAGAAAGAG
AACAGGGAAC ATCCTCACTC CGAGGACTTC CTGACAGTCT ACCTGGAGTT
GGGCAAGTAT TTCTTCAGAA TCAAAAAGTT CCTGATAAAT AAGAAATACA
GTTTCTGTGC ATGGAAGATT GTCACAGTGG AAATAAGAAG ATGTTTCATT
ATATTTTCCA AGTCCAGAAA ACTACTCAAA ATGATATCAG AATCACCCAC
CTTCAAGCAA GAACTTAAAT AGAAGCTGCA ATTGCTCAAA TGTCTCCAAG
AACGCTTTAT TCTAAAGCCA TTACCAGGAT GCTGCTAATG CTACCTTCAG
ATGCAAGACT TTTCAAGTTC AGGGTTCAAG GCAGTGCAGT CAAAGAAAGT
CTTAAGCAAA AGATGAAC
The encoded polypeptide has the following amino acid sequence: MTPKFLWLVA LVALYIPPIQ SLNCVYLDDS ILENVKLLGS TMTGFPLRCL KDITDFKFPK EILPYIQHMK REINAVSYRI SSLALTIFNL KGSIPPVTEE HWERIRSGLF KQVRQAQECF MDEEKENREH PHSEDFLTVY LELGKYFFRI KKFLINKKYS FCAWKIVTVE IRRCFIIFSK SRKLLKMISE SPTFKQELK (SEQ ID
NO:2). The Zcyto13 form of an interferon-&agr; gene encodes a polypeptide of 199 amino acids, as shown in SEQ ID NO:2. The signal sequence for Zcyto13 can be predicted as comprising Met
1
through Ser
21
of SEQ ID NO:2. The mature peptide for Zcyto13 begins at Leu
22
. Additional structural features of Zcyto13 are summarized in Table 4.
Hybridization analyses indicate that the Zcyto13 gene is strongly expressed in murine heart and liver tissue, and to a lesser extent, in murine brain, kidney, uterine, spleen, and seven-day embryo tissues. Zcyto13 RNA was also detected in lung, skeletal muscle, and testis tissues, as well as in the tissues of 11-, 15-, and 17-day embryos. Typically, Zcyto13 mRNA appeared as bands of about 2.8 and 6.6 kilobases. These results show that the interferon-&agr; sequences can be used differentiate among various tissues.
Southern analyses revealed that a Zcyto13 probe bound with rat and mouse genomic DNA. When incubated with EcoRI-digested DNA, the probe hybridized with fragments of 4.8 and 5.65 kilobases in murine genomic DNA, and 2.1 and 5.2 kilobases in rat genomic DNA.
The Zcyto13 gene has been mapped to mouse chromosome 4 (framework marker D4Mit94, located at 4.6 centimorgans)
Feldhaus Andrew L.
Gao Zeren
Presnell Scott R.
Andres Janet L.
Jones Phillip B. C.
Kemmerer Elizabeth
ZymoGenetics Inc.
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