Drug – bio-affecting and body treating compositions – Lymphokine – Interleukin
Reexamination Certificate
1994-05-27
2003-05-13
Nolan, Patrick J. (Department: 1644)
Drug, bio-affecting and body treating compositions
Lymphokine
Interleukin
C530S351000
Reexamination Certificate
active
06562333
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to compositions related to proteins which function in controlling physiology, development, and differentiation of mammalian cells, e.g., cells of a mammalian immune system. In particular, it provides proteins and mimetics which regulate cellular physiology, development, differentiation, or function of various cell types, including hematopoietic cells.
BACKGROUND OF THE INVENTION
The immune system of vertebrates consists of a number of organs and several different cell types. Two major cell types include the myeloid and lymphoid lineages: Among the lymphoid cell lineage are B cells, which were originally characterized as differentiating in fetal liver or adult bone marrow, and T cells, which were originally characterized as differentiating in the thymus. See, e.g., Paul (ed.) (1993)
Fundamental Immunology
(3d ed.) Raven Press, New York.
In many aspects of the development of an immune response or cellular differentiation, soluble proteins known as cytokines play a critical role in regulating cellular interactions. These cytokines apparently mediate cellular activities in many ways. They have been shown, in many cases, to modulate proliferation, growth, and differentiation of hematopoietic stem cells into the vast number of progenitors composing the lineages responsible for an immune response.
However, the cellular molecules which are expressed by different developmental stages of cells in these maturation pathways are still incompletely identified. Moreover, the roles and mechanisms of action of signaling molecules which induce, sustain, or modulate the various physiological, developmental, or proliferative states of these cells is poorly understood. Clearly, the immune system and its response to various stresses had relevance to medicine, e.g., infectious diseases, cancer related responses and treatment, allergic and transplantation rejection responses. See, e.g., Thorn, et al.
Harrison's Principles of Internal Medicine
McGraw/Hill, New York.
Medical science relies, in large degree, to appropriate recruitment or suppression of the immune system in effecting cures for insufficient or improper physiological responses to environmental factors. However, the lack of understanding of how the immune system is regulated or differentiates has blocked the ability to advantageously modulate the normal defensive mechanisms to biological challenges. Medical conditions characterized by abnormal or inappropriate regulation of the development or physiology of relevant cells thus remain unmanageable. The discovery and characterization of specific cytokines will contribute to the development of therapies for a broad range of degenerative or other conditions which affect the immune system, hematopoietic cells, as well as other cell types. The present invention provides solutions to some of these and many other problems.
SUMMARY OF THE INVENTION
The present invention is based, in part, upon the discovery of a cDNA clone encoding a cytokine-like protein. This protein has been designated CTLA-8. The invention embraces isolated genes encoding the proteins of the invention, variants of the encoded protein, e.g., mutations (muteins) of the natural sequence, species and allelic variants, fusion proteins, chemical mimetics, antibodies, and C other structural or functional analogs. Various uses of these different nucleic acid or protein compositions are also provided.
The present invention provides a nucleic acid encoding a CTLA-8 protein or fragment thereof; a substantially pure CTLA-8 or peptide thereof, or a fusion protein comprising CTLA-8 sequence; and an antibody raised to a CTLA-8 protein.
In nucleic acid embodiments, the nucleic acid can comprise a sequence of Table 1, 2, or 3.
In substantially pure CTLA-8 protein or peptide thereof embodiments, the protein or peptide can be from a warm blooded animal selected from the group of birds and mammals, including a mouse or a primate; comprise at least one polypeptide segment of Table 1, 2, or 3; or exhibit a post-translational modification pattern distinct from natural CTLA-8 protein. A further embodiment is a composition comprising such a protein and a pharmaceutically acceptable carrier.
In antibody embodiments, the antigen can be a mammalian protein, including a mouse or a primate; the antibody is raised against a protein sequence of Table 1, 2, or 3; the antibody is a monoclonal antibody; or the antibody is labeled.
The invention also embraces a kit comprising a substantially pure nucleic acid encoding a CTLA-8 protein or peptide; a substantially pure CTLA-8 protein or fragment, e.g., as a positive control; or an antibody or receptor which specifically binds a CTLA-8 protein.
The availability of these reagents also provides methods of modulating physiology or development of a cell comprising contacting said cell with an agonist or antagonist of a CTLA-8 protein. For example, the antagonist might be an antibody against a mammalian CTLA-8 protein or the cell may be a hematopoietic cell, including a lymphoid cell.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
OUTLINE
I. General
II. Nucleic Acids
A. natural isolates; methods
B. synthetic genes
C. methods to isolate
III. Purified CTLA-8 protein
A. physical properties
B. biological properties
IV. Making CTLA-8 protein; Mimetics
A. recombinant methods
B. synthetic methods
C. natural purification
V. Physical Variants
A. sequence variants, fragments
B. post-translational variants
1. glycosylation
2. others
VI. Functional Variants
A. analogs; fragments
1. agonists
2. antagonists
B. mimetics
1. protein
2. chemicals
C. species variants
VII. Antibodies
A. polyclonal
B. monoclonal
C. fragments, binding compositions
VIII. Uses
A. diagnostic
B. therapeutic
IX. Kits
A. nucleic acid reagents
B. protein reagents
C. antibody reagents
I. General
The present invention provides DNA sequence encoding various mammalian proteins which exhibit properties characteristic of functionally significant T cell expressed molecules. The cDNA sequence exhibits various features which are characteristic of mRNAs encoding cytokines, growth factors, and oncogenes. The mouse gene described herein contains an open reading frame encoding a putative 150 amino acid protein. This protein is 57% homologous to a putative protein encoded by a viral genome, the herpesvirus Saimiri ORF13. The message was isolated using a subtraction hybridization method applied to T cells.
These proteins are designated CTLA-8 proteins. The natural proteins should be capable of mediating various physiological responses which would lead to biological or physiological responses in target cells. Initial studies had localized the message (mRNA) encoding this protein to various cell lines of hematopoietic cells. Genes encoding the antigen have been mapped to mouse chromosome 1A and human chromosome 2q31. The best characterized embodiment was initially described in mouse. Similar sequences for proteins in other mammalian species, e.g., rat and human, should also be available. The descriptions below are directed, for exemplary purposes, to a mouse CTLA-8 protein, but are likewise applicable to related embodiments from other species, including primate species, such as human.
II. Nucleic Acids
Table 1 discloses the nucleotide and amino acid sequences of a mouse CTLA-8 protein. The described nucleotide sequences and the related reagents are useful in constructing a DNA clone useful for expressing CTLA-8 protein, or, e.g., isolating a homologous gene from another natural source. Typically, the sequences will be useful in isolating other genes, e.g., allelic variants, from mouse, and similar procedures will be applied to isolate genes from other species, e.g., warm blooded animals, such as birds and mammals. Cross hybridization will allow isolation of genes from other species. A number of different approaches should be available to successfully isolate a suitable nucleic acid clone from other sources.
Table 1 Seq. ID Nos. 1 and 2, Nucleotide and predicted amino acid sequences of murine CTLA-8 submitted to GenBank/
Fossiez François
Golstein Pierre
Lebecque Serge J. E.
Rouvier Eric
Ching Edwin P.
Mohan-Peterson Sheela
Nolan Patrick J.
Schering Corporation
Weber Kenneth A.
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