Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Lymphokines – e.g. – interferons – interlukins – etc.
Reexamination Certificate
1999-04-23
2002-01-01
Kunz, Gary L. (Department: 1647)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Lymphokines, e.g., interferons, interlukins, etc.
C530S350000, C514S002600, C424S085200
Reexamination Certificate
active
06335426
ABSTRACT:
BACKGROUND
1. Field of the Invention
The invention is generally related to the fields of pharmacology and immunology. More specifically, the invention is directed to novel compositions of matter for selectively activating T cells, and having reduced activation of Endothelial cells or fibroblasts. The novel compositions include variants of the cytokine family, and in particular human Interleukin-4 (IL-4).
2. Description of Related Art
Interleukin 4 (IL-4) is a pleiotropic cytokine, having activities on cells of the immune system, endothelium, and those of fibroblastic nature. Reported in vitro effects of IL-4 administration include proliferation of B cells, immunoglobulin class switching in B cells. In T cells, IL-4 stimulates T cell proliferation after preactivation with mitogens and down-regulates IFN-&ggr; production. In monocytes, IL-4 induces class II MHC molecules expression, release of lipopolysaccharide-induced tPA, and CD23 expression. In Endothelial cells (EC), IL4 induces expression of VCAM-1 and IL-6 release, and decreases ICAM-1 expression (Maher, D W, et al., Human Interleukin-4: An Immunomodulator with Potential Therapeutic Applications,
Progress in Growth Factor Research
, 3:43-56 (1991)).
Because of its ability to stimulate proliferation of T cells activated by exposure to IL-2, IL-4 therapy has been pursued. For instance, IL-4 has demonstrated anti-neoplastic activity in animal models of renal carcinomas, and has induced tumor regression in mice (Bosco, M., et al., Low Doses of IL-4 Injected Perilymphatically in Tumor-bearing Mice Inhibit the Growth of Poorly and Apparently Nonimmunogenic Tumors and Induce a Tumor Specific Immune Memory,
J. Immunol
., 145:3136-43 (1990)). However, its toxicity limits dosage in humans (Margolih, K., et al., Phase II Studies of Human Recombinant Interleukin-4 in Advanced Renal Cancer and Malignant Melanoma,
J. Immunotherapy
, 15:147-153 (1994)).
Because of its immunoregulatory activity, a number of clinical applications are suggested for IL-4. Among these clinical applications are disorders caused by imbalances of the immune system, particularly those caused by imbalances of T helper (Th) cell responses to antigen. These diseases include certain autoimmune diseases, rheumatic diseases, dermatological diseases, and infectious diseases. A large body of experimental work has established that Th cells fall into two broad classes, designated Th1 and Th2 (Mosmann, T. R., Cherwinski, H., Bond, M. W., Giedlin, M. A. and Coffinan, R. L., Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins,
J. Immunol
., 136:2348-2357(1986); Mosmann, T. R., Cytokines, differentiation and functions of subsets of CD4 and CD8 T cells,
Behring Inst. Mitt
., 1-6 (1995)). These T cell classes are defined by the cytokines they express: Th1 cells make IL-2, INF-&ggr;, and TNF-&agr;, while Th2 i cells make IL-4 and IL-5. Th1 and Th2 cells are formed from naive CD4+ T cells. Differentiation into Th1 or Th2 subsets depends on the cytokine present during antigen stimulation: IFN-&ggr; and IL-12 direct differentiation of naive cells to the Th1 phenotype, while IL-4 directs differentiation to the Th2 phenotype. While the Th1 and Th2 subsets may represent extremes along a continuum of Th cell phenotypes (for example, Th0 cells, which express low levels of both INF-&ggr; and IL-4, have been described), this classification nevertheless is the major paradigm in the field of immunology for describing the character of the immune response.
It has been observed that certain organ-specific autoimmune diseases are associated with a predominantly Th1 T cell response against autoantigen (Liblau R S; Singer S M; McDevitt H O, Th1 and Th2 CD4
+
T cells in the pathogenesis of organ-specific autoimmune diseases,
Immunol. Today
, 16:34-38 (1995)). One such autoimmune disease is insulin-dependent diabetes (IDDM), a disorder characterized by T cell-mediated destruction of pancreatic &bgr; cells. Several lines of evidence suggest that Th1-type cells are primarily responsible for the pancreatic &bgr; cell destruction (reviewed in Tisch, R. et al., Review: Insulin-dependent Diabetes Mellitus,
Ceil
, 85:291-297 (1996)). Administration of IL-4 to NOD mice, which serves as an animal model of IDDM, down-regulates the Th1 cell population and significantly delays the onset of diabetes (Rapoport, et al., IL-4 Reverses T cell Proliferation Unresponsiveness and Prevents the Onset of Diabetes in NOD Mice,
J. Exp. Med
., 178:87-99 (1993)). Another such autoimmune disease is multiple sclerosis (MS), a disease which is characterized by an autoiimune attack upon the myelin sheath surrounding nerve cells. Studies in humans with MS have demonstrated that exacerbation of MS is associated with the presence of autoantigen-specific Th1 and Th0 cells and that remission is associated with the presence of autoantigen-specific Th2 and Th0 cells (Correale, J. et al., Patterns of cytokine secretion by autoreactive proteolipid protein-specific T cell clones during the course of multiple sclerosis,
J. Immunol
., 154:2959-2968 (1995)). Mice with experimental autoimmune encephalomyelitis (EAE), an animal model for MS, also exhibit the Th1 cell polarization (Cua, D J, Hinton, D R, and Stohlmarn S A,
J. Immunol
., 155:4052-4059 (1995)). Indirect evidence from a study in the EAE model suggests that IL-4 plays a critical role in disease attenuation resulting from treatment with a tolerogenic peptide (Brocke, S. et al. Treatment of experimental encephalomyelitis with a peptide analogue of myelin basic protein,
Nature
, 379:343-346 (1996)).
Other autoimmune diseases such as Rheumatoid Arthritis (RA) are also targets for IL-4 based therapies. Animal models of RA have shown a disequilibrium of cell profiles tilting towards Th1 cells, and in mice that overexpress TNF-&agr;, anti-TNF-&agr; antibodies have demonstrated disease attenuation, suggesting that IL4 therapies that result in down-regulation of Th1 cell populations may have an anti-TNF-&agr; effect also. (See Feldmann, M, et al., Review: Rheumatoid Arthritis,
Cell
, 85:307-310 (1996)).
Psoriasis vulgaris is a chronic dermatologic disorder characterized by infiltration of affected skin with monocytes and T cells. Several reports indicate that psoriatic skin lesional T cells and PBL are predominantly of the Th1 phenotype (Uyemura K; Yamamura M; Fivenson D F; Modlin R L; Nickoloff B J, The cytokine network in lesional and lesion-free psoriatic skin is characterized by a T-helper type 1 cell-mediated response,
J Invest Dermatol
., 101:701-705 (1993); Schlaak J F; Buslau M; Jochum W; Hermann E; Girndt M; Gallati H; Meyer zum Buschenfelde K H; Fleischer B, T cells involved in psoriasis vulgaris belong to the Th1 subset,
J Invest Dermatol
, 102:145-149 (1994)). Furthermore, monomethylfumarate, a drug which has been reported to be of clinical benefit to patients with psoriasis, has been shown to selectively stimulate Th2 cytokine secretion from PBMC (de Jong R; Bezemer A C; Zomerdyik T P; van de Pouw-Kraan T; Ottenhoff T H, Nibbering PH, Selective stimulation of T helper 2 cytokine responses by the anti-psoriasis agent monomethylfimarate,
Eur J Immunol
, 26:2067-2074 (1996)). Therefore, IL-4 would be expected to reverse the Th polarization and be of clinical benefit in psoriasis.
Certain infectious diseases are associated with polarized Th cell responses to the infectious agent. Th2 responses have in some cases been associated with resistance to the infectious agent. An example is
Borrelia burgdorfei
, the infectious agent for Lyme disease. Humans infected with
B. burgdorferi
exhibit a predominantly Th1-like cytokine profile (Oksi J, Savolainen J; Pene J, Bousquet J; Laippala P; Viljanen M K, Decreased interleukin-4 and increased gamma interferon production by peripheral blood mononuclear cells of patients with Lyme borreliosis,
Infect. Immun
., 64:3620-3623 (1996)). In a mouse model of
B. burgdoreri
-induced arthritis, resistance to disease is associated with IL-4 production wh
Greve Jeffrey M.
Gundel Robert
Shanafelt Armen B.
Bayer Corporation
Kunz Gary L.
Landsman Robert S.
Mahoney John W.
Shaw Melissa A.
LandOfFree
T-cell selective interleukin-4 agonists does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with T-cell selective interleukin-4 agonists, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and T-cell selective interleukin-4 agonists will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2863961