Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Blood proteins or globulins – e.g. – proteoglycans – platelet...
Reexamination Certificate
2002-02-28
2004-09-28
Mertz, Prema (Department: 1646)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Blood proteins or globulins, e.g., proteoglycans, platelet...
C530S387100, C530S389100, C530S388100, C530S387300, C530S388150, C530S389200, C424S001110, C424S001490
Reexamination Certificate
active
06797813
ABSTRACT:
FIELD OF THE INVENTION
The present invention pertains to compositions related to proteins which function in controlling biology and physiology of mammalian cells, e.g., cells of a mammalian immune system. In particular, it provides purified genes, proteins, antibodies, and related reagents useful, e.g., to regulate activation, development, differentiation, and function of various cell types, including hematopoietic cells.
BACKGROUND OF THE INVENTION
AK155 is a cytokine that is structurally related to interleukin-10 (IL-10). A number of cytokines have been classed as IL-10-like, based on their structure. The IL-10-like cytokines include IL-20, IL-22, and mda-7, as well as AK155 (Moore, et al., (2001)
Annu. Rev. Immunol.
19:683-765; Moore, et al. (1993)
Annu. Rev. Immunol.
11:165-190). Cytokines are signaling molecules that mediate communication between cells, e.g., between cells of the immune system. Once secreted, cytokines travel to a different or identical cell, bind to a membrane-bound receptor, and provoke a series of events such as protein phosphorylation or gene activation, where these events result in changes in phagocytic or secretory activity, or changes in migration, differentiation state, and proliferation activity.
The cytokines may be classed into those associated with increased inflammation (Th1-type response) and decreased inflammation (Th2-type response). The Th1-type response is characterized by increases in production of interferon-&ggr; (IFN-&ggr;), tumor necrosis factor-&agr; (TNF-&agr;), TNF-&bgr;, IL-12, IL-18, and other pro-inflammatory cytokines (Sallusto, et al. (1998)
Immunol. Today
19:568-574). IL-17 is generally a pro-inflammatory cytokine (Fort, et al. (2001)
J. Immunol.
15:985-995). Th2-type response is characterized by increases in production of cytokines that suppress inflammation, e.g., IL-4, IL-5, IL-10, and IL-13 (Liu, et al. (2001)
Nature Immunol.
2:585-589). IL-25 appears to suppress inflammation (Fort, et a. (2001)
J. Immunol.
15:985-995).
Within one interleukin family, such as the IL-1 family, different interleukins may be functionally related to each other in that they influence the course of one event, but exert opposite effects on that event. For example, 1L-1&egr; has a pro-inflammatory effect, while IL-1&dgr; has an anti-inflammatory effect (Debets, et al. (2001)
J. Immunol.
167:1440-1446). IL-17 and IL-25 are examples of two other cytokines which are structurally similar, but produce opposite biological effects. The structure of any particular cytokine therefore serves as a guide to determining its physiological function.
An analysis of cell signaling proteins can also help determine a cytokine's role in physiology. For example, signaling involving signal transducers and activators of transcription-4 (STAT4) may indicate an inflammatory response, while signaling via STAT6 may indicate an anti-inflammatory response or Th2-type response (Romagnani (1997)
Immunol. Today
18:263-266). Hence, the identities of the proteins that are phosphorylated, of the particular amino acid residues that become phosphorylated, and of the relevant transcription factors and genes that become activated, are all relevant to determining the function of the cytokine of interest. Other powerful techniques for determining the functions of cytokines and related signaling proteins include use of genetically altered animals where a specific gene is altered in all cells, e.g., IL-10
−/−
mice (Scheerens, et al., (2001)
Eur. J. Immunol.
31:1465-1474), or where the genetic alteration is targeted to only one type of cell in the animal, e.g., liver cells, epithelial cells, cells of lymphoid lineage (Blumberg, et al., (2001)
Cell
104:9-19), or macrophages and neutrophils (Takeda, et al. (1999)
Immunity
10:39-49).
SUMMARY OF THE INVENTION
The present invention is directed to mammalian, e.g., rodent, canine, feline, primate, AK155 (interleukin-XX; IL-XX) and its biological activities. It includes nucleic acids coding for polypeptides themselves and methods for their production and use. The nucleic acids of the invention are characterized, in part, by their homology to cloned complementary DNA (cDNA) sequences enclosed herein, or by functional assays for IL-10-like activities of the polypeptides encoded by these nucleic acids. Methods for modulating, inhibiting, or stimulating an immune response are provided.
The present invention is based, in part, upon the discovery of a new cytokine exhibiting a sequence similarity to cellular IL-10. In particular, it provides a gene encoding a protein whose mature size is about 150 amino acids, which is expressed in virally transformed cells, and in certain tissues, e.g., kidney, and possibly lung and liver. Functional equivalents exhibiting significant sequence homology will be available from various mammalian species, i.e., human, mouse, rat.
More particularly, the present invention provides a substantially pure or recombinant AK155 protein or peptide fragment thereof. Various embodiments include an antigenic protein or peptide selected from a protein or peptide from a warm blooded animal selected from the group of birds and mammals, including a primate; a protein or peptide comprising at least one polypeptide segment of SEQ ID NO:2 or a fragment thereof; a protein or peptide which exhibits a post-translational modification pattern distinct from natural AK155; or a protein or peptide which is capable of co-stimulating a T cell with another signal. The protein or peptide can comprise a fusion protein. Another embodiment is a composition comprising an AK155 protein or peptide and a pharmaceutically acceptable carrier.
The invention also embraces an antibody which specifically binds a AK155 protein or peptide, e.g., wherein the AK155 is a mammalian protein, including a primate; the antibody is raised against a purified AK155 peptide sequence of SEQ ID NO:2; the antibody is a monoclonal antibody; or the antibody is labeled. The antibodies also make available a method of purifying an AK155 protein or peptide from other materials in a mixture comprising contacting the mixture to an anti-AK155 antibody, and separating bound AK155 from other materials.
Another aspect of the invention is an isolated or recombinant nucleic acid capable of encoding a full length or mature AK155 polypeptide, including a nucleic acid which encodes a sequence of SEQ ID NO:2; which includes a sequence of SEQ ID NO:1; or which encodes a sequence from a natural AK155. Such nucleic acid embodiments also include an expression vector.
The invention also provides a kit containing a substantially pure AK155 or fragment; an antibody or receptor which specifically binds AK155; or a nucleic acid, or its complement, encoding AK155 or a fragment thereof. This kit also provides methods for detecting in a sample the presence of a nucleic acid, protein, or antibody, comprising testing said sample with such a kit.
The invention also supplies methods of modulating the physiology of a cell comprising contacting said cell with a substantially pure AK155 or fragment; an antibody or binding partner which specifically binds an AK155; or a nucleic acid encoding an AK155 or peptide. Certain preferred embodiments include a method where the cell is a T cell and the modulating of physiology is activation of the T cell or apoptosis of the T cell; or where the cell is in a tissue or in an organism.
Also provided are methods of expressing an AK155 peptide by expressing a nucleic acid encoding an AK155 polypeptide. The invention also provides a cell, tissue, organ, or organism comprising a nucleic acid encoding an AK155 peptide.
The invention also provides a recombinant nucleic acid comprising sequence at least about 70% identity over a stretch of at least about 30 nucleotides to an AK155 nucleic acid sequence of SEQ ID NO:1, useful, e.g., as a probe or PCR primer for a related gene. Another embodiment further encodes a polypeptide comprising at least about 60% identity over a stretch of at least about 20 amino acids to an AK155 sequence of SEQ ID NO:2.
Th
de Waal Malefyt Rene
Fleckenstein Bernhard
Flickensher Helmut
Knappe Andrea
Ching Edwin P.
Mertz Prema
Mohan-Peterson Sheela
Schering Corporation
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