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
1995-06-06
2001-05-29
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, C530S388100, C530S389100, C530S389200, C435S325000, C435S326000, C435S331000, C435S335000
Reexamination Certificate
active
06239260
ABSTRACT:
FIELD OF THE INVENTION
The invention relates generally to methods and compositions for treating diseases associated with immune system imbalances, particularly imbalances involving humoral and cell-mediated immune responses. The invention also includes proteins and antagonists thereof capable of modulating the synthesis of certain cytokines involved in immune system to achieve therapeutic effects.
BACKGROUND
Immune responses to antigen are classified as being predominantly either cell-mediated, exemplified by the phenomena of delayed-type hypersensitivity (DTH), or humoral, exemplified by the production of antibodies. Cell-mediated immunity is of paramount importance for the rejection of tumors and for recovery from many viral, bacterial, protozoan, and fungal infections. In contrast, a humoral immune response is the most effective form of immunity for eliminating toxins and invading organisms from circulation. It has been observed that for different antigens one or the other of these two responses often predominates in a mutually exclusive fashion, and that the severity of some diseases, e.g. leprosy, leishmaniasis, and some types of autoimmunity, may be due the inappropriate dominance of one class of response over the other, Mosmann et al, Immunol. Today, Vol 8, pgs. 223-227 (1987); Mosmann et al, Ann. Rev. Immunol., Vol. 7, pgs. 145-173 (1989); Parish, Transplant. Rev, Vol. 13, pgs. 35-66 (1972); and Liew, Immunol. Today, Vol. 10, pgs. 40-45 (1989). It has further been observed that sets of cytokines are separately associated with DTH reactions and humoral immune responses, Cher et al, J. Immunol., Vol. 138, pgs. 3688-3694 (1987); and Mosmann et al (1987 and 1989, cited above), and it is thought that diseases associated with these classes of response are caused by the inappropriate production of the associated sets of cytokines.
For example, a large body of evidence suggests that excessive production of gamma interferon (IFN-&ggr;) is responsible for major histocompatibility complex (MHC) associated autoimmune diseases: Hooks et al,
New England J. Med
., Vol. 301, pgs. 5-8 (1979) (elevated serum levels of IFN-&ggr; correlated with autoimmunity); Basham et al,
J. Immunol
., Vol. 130, pgs. 1492-1494 (1983) (IFN-&ggr; can increase MHC gene product expression); Battazzo et al,
Lancet
, pgs. 1115-1119 (Nov. 12, 1983) (aberrant MHC gene product expression correlated with some forms of autoimmunity); Hooks et al,
Ann. N.Y. Acad. Sci
., Vol., pgs. 21-32 (1980) (higher IFN-&ggr; levels correlated to greater severity of disease in SLE patients, and histamine-release enhancing activity of interferon can be inhibited by anti-interferon sera); and Iwatani et al,
J. Clin. Endocrin, and Metabol
., Vol. 63, pgs. 695-708 (1986) (anti-IFN-&ggr; monoclonal antibody eliminated the ability of leucoagglutinin-stimulated T cells to induce HLA-DR expression). It is hypothesized that excess IFN-&ggr; causes the inappropriate expression of MHC gene products which, in turn, causes autoimmune reactions against the tissues whose cells are inappropriately expressing the MHC products and displaying autoantigens in the context of the products.
In the area of clinical parasitology, it has recently been observed that the levels of IFN-&ggr; and IL-2 are important factors in the progression and/or resolution of the protozoan infection, leishmaniasis. In particular, the presence of adequate levels of IFN-&ggr; appears to be essential for the activation of infected macrophages to eliminate intracellular amastigotes, Mauel and Behin, in Cohen et al, eds., Immunology of Parasitic Infections (Blackwell, London, 1982). And, in murine models of the disease, it has been shown that high levels of IFN-&ggr; and low levels of IL-4 are associated with resolution, whereas low levels of IFN-&ggr; and high levels of IL-4 are associated with progression of leishmaniasis, Heinzel et al, J. Exp. Med., Vol. 169, pgs. 59-72 (1989).
In view of the above, it would be advantageous to have available agents that could shift the dominance of one class of immune response to the other, and in particular that could suppress or increase the synthesis of IFN-&ggr; and/or other cytokines, respectively, as required for therapy. Such agents would be highly advantageous for treatment of diseases associated with inappropriate or inadequate immune responses, such as tissue rejection, leishmaniasis and other parasitic diseases, and MHC associated immune disorders including rheumatoid arthritis, systemic lupus erythematosus (SLE), myasthenia gravis, insulin-dependent diabetes mellitus, thyroiditis, and the like.
SUMMARY OF THE INVENTION
The present invention is directed to mammalian cytokine synthesis inhibitory factor (CSIF), CSIF analogs, CSIF peptides, and CSIF antagonists. It includes nucleic acids coding for polypeptides exhibiting CSIF activity, as well as the polypeptides themselves, their agonistic and/or antagonistic analogs, methods for their production, and methods of using them to treat disorders associated with cytokine imbalances, particularly those leading to an inappropriate class of immune response. The invention also includes the use of CSIF or its antagonists, alone or as vaccine adjuvants, to selectively induce a predominantly cell-mediated immune response or a predominantly humoral immune response, respectively. Preferably, antagonists of CSIF are derived from monoclonal antibodies capable of blocking the biological activity of CSIF. The nucleic acids of the invention are defined (1) by their homology to, or their ability to form detectable hybrids with, the cloned complementary DNA (cDNA) sequences disclosed herein, and (2) by functional assays for CSIF activity applied to the polypeptides encoded by the nucleic acids. As used herein, the term “CSIF activity” in reference to a protein or a polypeptide means that the protein or polypeptide is capable of inhibiting or substantially reducing the level of production of at least one of the following cytokines in the assays described below: IFN-&ggr;, interleukin-2 (IL-2), lymphotoxin, interleukin-3 (IL-3), or granulocyte-macrophage colony stimulating factor (GM-CSF).
A preferred embodiment of the invention is a mature human CSIF of the open reading frame defined by the following amino acid sequence:
MHSSALLCCLVLLTGVRASPGQGTQSENSCTHFPGNLPNM-
LRDLRDAFSRVKTFFQMKDQLDNLLLKESLLEDFKGYLGC-
QALSEMIQFYLEEVMPQAENQDPDIKAHVNSLGENLKTLR-
LRLRRCHRFLPCENKSKAVEQVKNAFNKLQEKGIYKAMSE-
FDIFINYIEAYMTMKIRN
wherein the standard one-letter symbols for L-amino acids are listed left to right starting from the N-terminal methionine. More preferably, the mature human CSIF is defined by the following amino acid sequence:
SPGQGTQSENSCTHFPGNLPNMLRDLRDAFSRVKTFFQMKDQLD-
NLLLKESLLEDFKGYLGCQALSEMIQFYLEEVMPQAENQDPDIKA-
HVNSLGENLKTLRLRLRRCHRFLPCENKSKAVEQVKNAFNKLQ-
EKGIYKAMSEFDIFINYIEAYMTMKIRN
The invention is based in part on the discovery and cloning of cDNAs which are capable of expressing proteins having CSIF activity. Accordingly, several such clones designated pcD(SR&agr;)-F115 (carrying a mouse CSIF gene), and pH5C and pH15C (each carrying a human CSIF gene) have been deposited with the American Type Culture Collection (ATCC), 10801 University Boulevard, Manassas, Va., USA, under the accession numbers 68027, 68191, and 68192, respectively.
REFERENCES:
patent: 2194240 (1988-03-01), None
Salgaller et al. Cancer Immunol. Immunotherapy 39:105-116, 1994.*
Burgess et al. J. Cell Biology 111:2129-38, Nov. 1990.*
Kumar et al. PNAS 87:1337-1341, Feb. 1990.*
Fiorentino et al. J. Exp. Med. 170:2081-2095, Dec. 1989.*
Paul, W.E. (ed.) “Fundamental Immunology”, Third Edition, published by Raven Press (New York), see p. 741, 1993.
Bond Martha W.
Moore Kevin W.
Mosmann Timothy R.
Vieira Paulo J. M.
Foulke Cynthia Lee
Mertz Prema
Schering Corporation
Schram David B.
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