Mammalian chemokine reagents

Details Mammalian chemokine reagents Mammalian chemokine reagents

1995-12-08

2003-01-28

Eyler, Yvonne (Department: 1646)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C435S007210, C435S069100, C435S069500, C435S252300, C435S320100, C436S501000, C514S002600, C530S300000, C530S350000, C530S351000

Reexamination Certificate

active

06512103

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to compositions related to proteins which function in controlling development and differentiation of mammalian cells, e.g., cells of a mammalian immune system. In particular, it provides proteins and mimetics which regulate development, differentiation, and function of various cell types, including hematopoietic cells. It also provides receptor reagents for such proteins.
BACKGROUND OF THE INVENTION
The circulating component of the mammalian circulatory system comprises various cell types, including red and white blood cells of the erythroid or the myeloid cell lineages. See, e.g., Rapaport (1987)
Introduction to Hematology
(2d ed.) Lippincott, Philadelphia, Pa.; Jandl (1987)
Blood: Textbook of Hematology,
Little, Brown and Co., Boston, Mass.; and Paul (ed.) (1993)
Fundamental Immunology
3d ed, Raven Press, N.Y. Progression through various stages of differentiation are regulated by various signals provided to the cells, often mediated through a class of proteins known as the cytokines. Within this group of molecules are a further group known as the chemoattractant cytokines, or chemokines. See, e.g., Schall (1994) “The Chemokines” in
The Cytokine Handbook
(2d ed.) Academic Press; Schall and Bacon (1994)
Current Opinion in Immunology
6:865-873.
Although the full spectrum of biological activities of the chemokines has not been extensively investigated, chemoattractant effects are recognized. The best known biological functions of these molecules relate to chemoattraction of leukocytes. However, new chemokines are being discovered, and their biological effects on the various cells responsible for immunological responses are topics of continued study. Mouse CCF18 has been reported by a Japanese Group, and also published by the present inventors in Hara, et al. (1995)
J. Immunol.
155:5352-5358.
These observations indicate that other factors exist whose functions in hematopoiesis, immune development, and leukocyte trafficking were heretofore unrecognized. These factors provide for biological activities whose spectra of effects are distinct from known differentiation, activation, or other signaling factors. The absence of knowledge about the structural, biological, and physiological properties of the regulatory factors which regulate hematopoietic cell physiology in vivo prevents the modification of the effects of such factors. Thus, medical conditions where regulation of the development or physiology of relevant cells is required remain unmanageable.
SUMMARY OF THE INVENTION
The present invention is based, in part, upon the discovery of new genes encoding CC chemokines, and new genes encoding various receptors for chemokines. It embraces agonists and antagonists of the chemokine designated CCF18, e.g., mutations (muteins) of the natural sequences, fusion proteins, chemical mimetics, antibodies, and other structural or functional analogs. It is also directed to isolated genes encoding proteins of the invention. Various uses of these different protein or nucleic acid compositions are also provided. Likewise for the receptor described herein.
The present invention provides a substantially pure CCF18 chemokine; a fusion protein comprising CCF18 chemokine sequence; an antibody specific for binding to a CCF18 chemokine; and a nucleic acid encoding a CCF18 chemokine or fusion protein thereof.
In CCF18 chemokine embodiments, the chemokine may be from a warm blooded animal selected from the group of birds and mammals, including a mouse or human; may comprise a sequence of Table 1 or 3; may exhibit a post-translational modification pattern distinct from natural CCF18 chemokine; or may exhibit the features disclosed in Table 2. The invention also embraces a composition comprising the chemokine and a pharmaceutically acceptable carrier.
In fusion protein embodiments, the protein may comprise either sequence of Table 1 or 3; and/or sequence of another cytokine or chemokine.
In antibody embodiments, the CCF18 chemokine can be a mammalian protein, including a mouse or human; or the antibody may be raised against a peptide sequence of Table 1 or 3; may be monoclonal antibody; or the antibody may be labeled.
In nucleic acid embodiments, the chemokine may be from a warm blooded animal selected from the group of birds and mammals, including a mouse or human. The nucleic acid may comprise a sequence of Table 1 or 3; be an expression vector; or comprise a deoxyribonucleic acid nucleotide.
The invention also provides a kit comprising a substantially pure CCF18 chemokine, or fragment thereof; an antibody which specifically binds a mammalian CCF18 chemokine; or a nucleic acid encoding a CCF18 chemokine or peptide. The kit may also be capable of making a qualitative or quantitative analysis.
In another embodiment, the invention provides methods of modulating physiology or development of a cell comprising contacting the cell with an agonist or antagonist of a mammalian CCF18 chemokine. The antagonist may be an antibody against a mammalian CCF18 chemokine. The cell may be a hematopoietic cell, including a lymphoid cell; a placenta cell; a gonad cell; or a neural cell, including neuronal or non-neuronal cells. Various of the physiological effects include effecting a cellular calcium flux; a chemoattractant response; cellular morphology modification responses; phosphoinositide lipid turnover; or an antiviral response.
The present invention also provides reagents related to a chemokine receptor, designated CCKR3. In particular embodiments, the invention provides a substantially pure CCKR3 chemokine receptor; a fusion protein comprising CCKR3 chemokine receptor sequence; an antibody specific for binding to a CCKR3 chemokine receptor; and a nucleic acid encoding a CCKR3 chemokine receptor or fusion protein thereof.
The CCKR3 may be from a warm blooded animal selected from the group of birds and mammals, including a mouse or human; may comprise a sequence of Table 4; or may exhibit a post-translational modification pattern distinct from natural CCKR3 chemokine receptor.
In receptor fusion embodiments, the protein may comprise sequence of Table 4; and/or sequence of another receptor for a chemokine.
In receptor antibody embodiments, the CCKR3 chemokine receptor may be a mammalian protein, including a mouse or human. The antibody may be raised against a peptide sequence of Table 4; may be a monoclonal antibody; or may be labeled.
In receptor nucleic acid embodiments, the chemokine receptor may be from a warm blooded animal selected from the group of birds and mammals, including a mouse or human. Alternatively, the nucleic acid may comprise a sequence of Table 4; may be an expression vector; or may comprise a deoxyribonucleic acid nucleotide.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Outline
I. General
II. Purified Chemokine
A. physical properties
B. biological properties
III. Physical Variants
A. sequence variants, fragments
B. post-translational variants
1. glycosylation
2. others
IV. Functional Variants
A. analogs; fragments
1. agonists
2. antagonists
B. mimetics
1. protein
2. chemicals
C. species variants
V. Antibodies
A. polyclonal
B. monoclonal
C. fragments, binding compositions
VI. Nucleic Acids
A. natural isolates; methods
B. synthetic genes
C. methods to isolate
VII. Making Chemokine; Mimetics
A. recombinant methods
B. synthetic methods
C. natural purification
VIII. Uses
A. diagnostic
B. therapeutic
IX. Kits
A. nucleic acid reagents
B. protein reagents
C. antibody reagents
X. Receptor
I. General
The present invention provides DNA sequences encoding various mammalian proteins which exhibit structural properties characteristic of a chemotactic cytokine, or chemokine. See, e.g., Lodi, et al. (1994)
Science
263:1762-1767; Gronenborn and Clore (1991)
Protein Engineering
4:263-269; Miller and Kranger (1992)
Proc. Nat'l Acad. Sci. USA
89:2950-2954; Matsushima and Oppenheim (1989)
Cytokine
1:2-13; Stoeckle and Baker (1990)
New Biol.
2:313-323; Oppenheim, et al. (1991)
Ann. Rev. Immunol.
9:617-648; Schall (1991)
Cytokine
3:165

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