Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Structurally-modified antibody – immunoglobulin – or fragment...
Reexamination Certificate
1999-11-09
2002-09-17
Eyler, Yvonne (Department: 1646)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Structurally-modified antibody, immunoglobulin, or fragment...
C424S278100, C536S023500, C536S023400, C435S007100, C435S069520, C435S069700, C435S252300
Reexamination Certificate
active
06451308
ABSTRACT:
FIELD OF THE INVENTION
The field of the invention is cytokine-mediated therapeutics.
BACKGROUND OF THE INVENTION
An effective immune response begins when an antigen or mitogen triggers the activation of T cells. In the process of T cell activation, numerous cellular changes occur, which include the expression of cytokines and cytokine receptors. One of the cytokines involved in the immune response is interleukin-15 (IL-15). IL-15 is a T cell growth factor that stimulates the proliferation and differentiation of B cells, T cells, natural killer (NK) cells, and lymphocyte-activated killer (LAK) cells in vitro. In vivo, the proliferation of these cell types enhances the immune response.
IL-15 binds to a heterotrimeric receptor that consists of the IL-2R&bgr; subunit, the IL-2R&ggr; subunit, and a unique IL-15R&agr; subunit.
Patients benefit from suppression of the immune response in a number of circumstances, for example, in the event of organ transplantation or autoimmune disease. In other circumstances, for example when select immune cells have become malignant or autoaggressive, it is beneficial to actively destroy them.
SUMMARY OF THE INVENTION
The invention features mutants of the cytokine IL-15. Preferably, these mutants bind the IL-15 receptor complex with an affinity similar to wild-type IL-15, but fail to activate signal transduction. The mutant polypeptides of the invention therefore compete effectively with wild-type IL-15 and, when they do so, they block one or more of the events that normally occur in response to IL-15 signalling, such as cellular proliferation. By modulating the events mediated by the IL-15 receptor complex, mutant IL-15 polypeptides can modulate the immune response, and thus are therapeutically useful.
Mutant IL-15 polypeptides can have several characteristics that are advantageous in the context of treatment regimes. First, they are unlikely to be immunogenic because they can differ from wild type IL-15 by only a few substituted residues. Second, IL-15 mutants can bind IL-15R&agr; with the same high affinity as wild type IL-15 and thus, can compete effectively for the receptor. Third, IL-15 mutants can be easily modified to remain active in the circulation for a prolonged period of time, or to produce a lytic response in cells to which they bind. In addition, the IL-15 receptor alpha (IL-15R&agr;) polypeptide is expressed by activated or malignant immune cells, but not on resting immune cells. Thus, the mutant polypeptide of the invention can be used to specifically target activated or malignant immune cells.
Other features and advantages of the invention will be apparent from the following detailed description, and from the claims. Although materials and methods similar or equivalent to those described herein can be used in the practice or testing of the invention, the preferred materials and methods are described below.
REFERENCES:
patent: 5011684 (1991-04-01), Strom
patent: 5116964 (1992-05-01), Capon et al.
patent: 5262522 (1993-11-01), Gearing
patent: WO 88/07089 (1988-09-01), None
patent: WO 95/27722 (1995-10-01), None
patent: WO 96/04306 (1996-02-01), None
patent: WO 96/26274 (1996-08-01), None
Fox RI. Expert Opin Investig Drugs. 200 Sep. 9(9):2007-16. Sjogren's syndrome:current therapies remain inadequate for a common disease.*
Akatsuka et al., “Synovial Mononuclear Cells Consist with T Cells Which Produce High Level . . . ”Microbiol. Immunol., 41:4, 367-370 (1997).
Anderson et al., Functional Characterization of the Human Interleukin-15 Receptor. . . J. Bio. Chem. 270:29862-29869 (1995).
Armitage et al., IL-15 Has Stimulatory Activity for the Induction of B Cell Proliferation and Differentiation, J. Immunology, 154:483-490 (1995).
Bamford et al., The Interleukin (IL) 2 receptor &bgr; chain is shared by IL-2 and a cytokine, provisionally designated IL-T . . . Proc. Nat. Acad. Sciences 91:4940-4944 (1994).
Blanar et al., “Interaction Cloning: Identification of a Helix-Loop-Helix Zipper Protein That Interacts with c-Fos”, Science 256:1014-1018 (1992).
Brekke et al., Structure-Function Relationships of Human IgG, The Immunologist 2:125-130 (1994).
Burger et al., “Imbalance between intersitital collagenase and tissue inhibitor of metalloproteinase 1 . . . ”, Arthritis & Rheumatism 41:10 (1998).
Burton et al., A lymphokine, provisionally designated interleukin T and produced by a human adult T-cell leukemia line . . . Proc. Nat. Acad. Sciences 91:4935-4939 (1994).
Carson et al., Interleukin (IL) 15 Is a Novel Cytokine That Activates Human Natural Killer Cells via Components of the IL-2 Receptor, J. Exper. Medicine 180: 1395-1403 (1994).
Chae et al., “Mutant IL-15 Protein Exerting Antagonistic Effects on IL-15 Triggered Cell Proliferation”, J. American Society of Nephrology 7: 1654 (1996).
Courtenay et al., “Immunisation against heterologous type II collagen induces arthritis in mice”, Nature 283:5748 (1980).
Cunningham et al., “High-Resoluction Epitope Mapping of HGH-Receptor . . . ” Science 244, 1081-1085 (1989).
Elliott et al., “Repeated therapy with monoclonal antibody to tumour necrosis factor . . .”Lancet 344:8930 (1994).
Elliott et al., “Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor . . .” Lancet 344:8930 (1994).
George et al., “Current methods in sequence comparison and analysis”, Macromolecular Sequencing and Synthesis Selected methods and Applications, p127-149 (1988).
Giri et al., “IL-15, A Novel T Cell Growth Factor That Shares Activities and Receptor Components with IL-2”, J. Leukocyte Biology, 57:763-766 (1995).
Giri et al., “Identification and cloning of a novel IL-15 binding protein that is structurally related to . . . ” EMBO Journal 14:3654-3663 (1995).
Giri et al., Utilization of the &bgr; and &ggr; chains of the IL-2 receptor by the novel cytokine IL-15, EMBO Journal 13:2822-2830 (1994).
Grabstein et al., Cloning of a T Cell Growth Factor That Interacts . . . Science 264:965-968 (1994).
Hatakeyama et al., A Restricted Cytoplasmic Region of IL-2 Receptor . . . Cell 59:837-845 (1989).
Kim et al., Targeting the Il-15 Receptor with an Antagonist IL-15 Mutant/Fc&ggr;2a Protein Blocks Delayed-type Hypersensitivity Journal of Immunology 160:5742-5748 (1998).
Isler et al., “Cell surface glycoproteins expressed on activated human T cells induce production of interleukin-1 beta by monocytic cells: a possible role of CD69” Eur. Cytokine Netw., 4:1 15-23, (1993).
Knight et al., “Construction and initial characterization of a mouse-human chimeric anti-TNF antibody” Molecular Immunology 30:16, 1443-1453 (1993).
LeClair et al., The p50 subunit of NF-&kgr;B associates with the NF-IL6 transcription factor, Proc. Nat. Acad. Sciences 89:8145-8149 (1992).
Lin et al., The Role of Shared Receptor Motifs and Common Stat Proteins in the Generation of Cytokine. Immunity 2:331-339 (1995).
Maslinski et al., Interleukin-2 (IL-2) Induces Tyrosine Kinase-dependent Translocation of Active. J. Biological Chemistry 267:15281-15284 (1992).
Maslinski et al., Intoxication of high affinity IL-2 receptor positive thymocytes blocks early stages of T cell maturation, International Immunology 4:509-517 (1992).
Moreland et al., Treatment of Rheumatoid Arthritis with A Recombinant Human Tumor Necrosis Factor Receptor (p75)-Fc Fusion Protein NEJM 337:3, 141-147 (1997).
Miltenburg et al., “Immobilized Anti-CD3 Antibody Activates T Cell Clones to Induce the Production of Interstitial Collagenase, but Not Tissue Inhibitor . . . ” The Journal of Immunology 154:6 (1995).
Morrison et al., Structural Determinants of Human IgG Function, The Immunologist 2:119-124 (1994).
Nickerson et al., Prolonged Islet Allograft Acceptance in the Absence of Interleukin 4 Extression; Transplant Immunology, 4:81-85 (1996).
Pettit et al., Structure-Function Studies of Interleukin 15 using Site-specific Mutagenesis, Polyethylene Glycol . . . J. Biological Chemistry, 2312-2318 (1997).
Pettit et al., “Polyethylene Glycol Conjugation to Lysine Residues of Recombinant IL-15 Generates a Specific IL-15 Antagonist”, Pro. of the Int. Symp. on Cont.
Maslinski Wlodzimierz
Strom Terry B.
Beth Israel Deaconess Medical Center
Eyler Yvonne
Fish & Richardson P.C.
Prasad Sarada
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