Drug – bio-affecting and body treating compositions – Lymphokine – Interleukin
Reexamination Certificate
2002-05-14
2004-08-03
Mertz, Prema (Department: 1646)
Drug, bio-affecting and body treating compositions
Lymphokine
Interleukin
C514S002600, C514S008100, C514S012200, C514S866000, C530S402000
Reexamination Certificate
active
06770272
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to chimeric proteins including interleukin-10, and therapeutic uses thereof.
Interleukin-10 (IL-10) is a cytokine produced by activated Th2 cells, B cells, keratinocytes, monocytes and macrophages (Moore et al., Annu. Rev. Immunol. 11:165 (1993)). In vitro, murine and human IL-10 inhibit cytokine synthesis by Th1 cells, natural killer cells, monocytes, and macrophages (Fiorentino et al., J. Exp. Med., 170:2081-2095 (1989); Fiorentino et al., J. Immunol. 146:3444 (1991); Hsu et al., Int. Immunol. 4:563 (1992); Hsu et al., Int. Immunol. 4:563 (1992); D'Andrea et al., J. Exp. Med. 178:1041 (1993); de Waal Malefyt et al., J. Exp. Med. 174:915 (1991); Fiorentino et al., J. Immunol. 147:3815 (1991)).
Gram-negative septicemia in hospitalized patients is invariably associated with high morbidity and mortality (Bone, Ann. Intern. Med. 115:457 (1991)). Case fatality rates of 20-60% reflect the frequent development of acute lung injury (Byrne et al., Acute Care 13:206 (1987)) and multiple organ failure (Abrams et al., Surg. Rounds 12:44 (1989)), as well as the lack of effective therapies. Endotoxin (LPS), a product of gram-negative bacteria, is a major causative agent in the pathogenesis of septic shock (Glausner et al., Lancet 338:732 (1991)). A septic shock-like syndrome can be induced experimentally by a single injection of LPS into animals. Injection of IL-10 into mice inhibits secretion of tumor necrosis factor (TNF) in vivo and protects against the lethal effects of endotoxin (Gerard et al., J. Exp. Med. 177(2):547 (1993)); (de Waal Malefyt et al., J. Exp. Med. 174:915 (1991); Fiorentino et al., J. Immunol. 147:3815 (1991); Moore et al., Science 248:1230 (1990)). Naturally-occurring cytokines have short circulating half-lives; naturally-occurring IL-10 is therapeutically effective for approximately 30 minutes following administration (Gerard et al., J. Exp. Med. 177(2):547 (1993)).
SUMMARY OF THE INVENTION
I have discovered that the in vivo half-life of IL-10 can be increased by bonding IL-10 to an enzymatically inactive polypeptide, and I have discovered that the chimeric IL-10 protein is useful for treating septic shock, Type I diabetes, and multiple myeloma in mammals.
Accordingly, in one aspect, the invention features a chimeric protein having IL-10 bonded to an enzymatically inactive polypeptide which increases the circulating half-life of IL-10 in vivo by a factor of at least 10.
In one embodiment, the enzymatically inactive polypeptide includes the Fc region of an IgG molecule and lacks an IgG variable region of a heavy chain. The Fc region can include a mutation which inhibits complement fixation and Fc receptor binding by the protein, or it can be lytic, i.e., able to bind complement. The protein can alsoe be used in a therapeutic composition formed by admixture of the chimeric protein with a pharmaceutically acceptable carrier. The therapeutic composition is administered to a mammal to treat septic shock, to inhibit the development of Type I diabetes, or to treat multiple myeloma. Where the Fc region of the chimeric protein is lytic, the chimeric protein is particularly useful for treating multiple myeloma.
The invention offers several features and advantages: (1) the chimeric proteins of the invention have an extended circulating half life and provides long term protection; (2) the chimeric protein can be easily purified; and (3) some of the chimeric proteins are mutated such that they are defective for antibody-dependent cell-mediated cytotoxicity (ADCC) and complement directed cytolysis (CDC), thus making them useful for treating septic shock, type I diabetes or multiple myeloma without destroying the target cells.
Useful enzymatically inactive polypeptides are those which, when fused to IL-10, extend the circulating half-life of IL-10 by a factor of at least 10. Preferred inactive polypeptides include human serum albumin and the Fc region of IgG minus an IgG heavy chain variable region.
Other features and advantages of the invention will be apparent from the follwing description of the preferred embodiments thereof, and from the claims.
REFERENCES:
patent: 5116964 (1992-05-01), Capon et al.
patent: 5196321 (1993-03-01), Bachmair et al.
patent: 5231012 (1993-07-01), Mosmann et al.
patent: 5428130 (1995-06-01), Capon et al.
patent: 5447851 (1995-09-01), Beutler et al.
patent: 2045869 (1991-06-01), None
patent: WO 90 07932 (1990-07-01), None
patent: 0 464 533 (1992-01-01), None
patent: 0 464 533 (1992-01-01), None
patent: WO 94 04180 (1994-03-01), None
patent: 8807089 (1988-09-01), None
patent: WO 88/07089 (1988-09-01), None
patent: WO 90/07932 (1990-07-01), None
patent: WO 92/12725 (1992-08-01), None
patent: WO 94/04180 (1994-03-01), None
The Merck Manual of Diagnosis Therapy—17th. edition. Beers & Beskow.*
Bowie et al. (1990) Science, vol. 247 pp. 1306-1310.*
Capon et al. (1989) Nature vol. 337 pp. 525-531.*
Bone, R.; “The Pathogenesis of Sepsis,”Annals of Internal Medicine, 115:457-469 (1991).
Byrne, et al.; “Adult Respiratory Distress Syndrome”,Acute Care, 13:206-234 (1987).
D'Andrea, et al.; “Interleukin 10 (IL-10) Inhibits Human Lymphocyte Interferon &ggr;-Production by Suppressing Natural Killer Cell Stimulatory Factor/IL—12 Synthesis . . . ”,J. Exp. Med. 178:1041-1048 (1993).
de Waal Malefyt, et al.; “Interleukin 10 (IL-10) and Viral IL-10 Strongly Reduce Antigen-specific Human T-Cell Proliferation by Diminishing the Antigen-presenting . . . ”,J. Exp. Med. 174:915-924 (1991).
Duncan, et al.; “Localization of the binding site for the human high-affinity Fc receptor on IgC”,Nature332:563-564 (1988).
Duncan, et al.; “The binding site for Clq on IgG”, Nature 332:738-740 (1988).
Fiorentino, et al.; “IL-10 Acts on the Antigen-Presenting Cell to Inhibit Cytokine Production by Th1 Cells,”The Journal of Immunology146;3444-3451 (1991).
Fiorentino, et al.; “IL-10 Inhibits Cytokine Production by Activated Macrophages,”The Journal of Immunology147:3815-3822 (1991).
Gerard, et al.; “Interleukin 10 Reduces the Release of Tumor Necrosis Factor and Prevents Lethality in Experimental Endotoxemia,”J. Exp. Med.177:547-550 (1993).
Glauser, et al.; “Septic shock: pathogenesis,”The Lancet338:732-736 (1991).
Hsu, et al.; “Different effects of IL-4 and IL-10 on IL-2-induced IFN-&ggr; synthesis and lymphokine-activated killer activity,” International Immunology 4:563-569 (1992).
Lee, et al., “Pancreatic Islet Production of Murine Interleukin-10 Does Not Inhibit Immune-Mediated Tissue Destruction,”The Journal of Clinical Investigation, 93:1332-1338 (1994).
Mathison, et al., “Participation of TUmor Necrosis Factor in the Mediation of Gram Negative Bacterial Lipopolysaccharide-induced Injury in Rabbits,”The Journal of Clinical Investigation, 81:1925-1937 (1988).
Moore, et al., “Homology of Cytokine Synthesis Inhibitory Factor (IL-10) to the Epstein-Barr Virus Gene BCRFI,”Science248:1230-1234 (1990).
Moore, et al., “Interleukin-10,”Annu. Rev. Immunol.11:165-190 (1993).
Thompson-Snipes, et al., “Interleukin-10: A Novel Stimulatory Factor for Mast Cells and Their Progenitors”J. Exp. Med.173:507-510 (1991).
Steele, Alan W. et al., “Structure and function in vitro and in vitro and in in vivo of a family of murine interleukin-2Fc . . . ”, J. American Soc. of Nephr., vol. 4, p. 636 (1993).
Traub A. et al., “Interferon albumin conjugate with conserved biological activity”, J. of General Virology 53: 389-92 (1981).
Steele, et al.Structure and function in vitro and in vivo of a family of murine interleukin-10. . . J. American Soc. of Nephro. 4:636, 1993.
Traub, e tal.Interleukin albumin conjugate with conserved biological activity. J. of General Virology 53:389-392, 1981.
Steele Alan
Strom Terry B.
Zheng Xin Xiao
Beth Israel Hospital Association
Mertz Prema
LandOfFree
Treatment of diabetes does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Treatment of diabetes, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Treatment of diabetes will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3341262