Drug – bio-affecting and body treating compositions – Lymphokine – Interferon
Reexamination Certificate
1999-03-19
2001-02-13
Fitzgerald, David L. (Department: 1646)
Drug, bio-affecting and body treating compositions
Lymphokine
Interferon
C435S069510
Reexamination Certificate
active
06187304
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to the effects of IFN-&ggr; on cardiac hypertrophy. More particularly, the invention concerns the use of IFN-&ggr; for the prevention and treatment of cardiac hypertrophy and associated pathological conditions.
BACKGROUND OF THE INVENTION
Interferon-gamma (IFN-&ggr;)
Interferons are relatively small, single-chain glycoproteins released by cells invaded by viruses or certain other substances. Interferons are presently grouped into three major classes, designated leukocyte interferon (interferon-alpha, &agr;-interferon, IFN-&agr;), fibroblast interferon (interferon-beta, &bgr;-interferon, IFN-&bgr;), and immune interferon-gamma, &ggr;-interferon, IFN-&ggr;). In response to viral infection, lymphocytes synthesize primarily &agr;-interferon (along with a lesser amount of a distinct interferon species, commonly referred to as omega interferon), while infection of fibroblasts usually induces &bgr;-interferon. &agr;- and &bgr;-interferons share about 20-30 percent amino acid sequence homology. The gene for human IFN-&bgr; lacks introns, and encodes a protein possessing 29% amino acid sequence identity with human IFN-&agr;I, suggesting that IFN-&agr; and IFN-&bgr; genes have evolved from a common ancestor (Taniguchi et al., Nature 285, 547-549 [1980]). By contrast, IFN-&ggr; is not induced by viral infection, but rather, is synthesized by lymphocytes in response to mitogens, and is scarcely related to the other two types of interferons in amino acid sequence. Interferons-&agr; and -&bgr; are known to induce MHC Class I antigens, while IFN-&ggr; induces MHC Class II antigen expression, and also increases the efficiency with which target cells present viral peptide in association with MHC Class I molecules for recognition by cytotoxic T cells.
IFN-&ggr; is a member of the interferon family, which exhibits the antiviral and anti-proliferative properties characteristic of interferons-&agr; and -&bgr; (IFN-&agr; and IFN-&bgr;), but, in contrast to those interferons, is pH 2 labile. IFN-&ggr; was originally produced upon mitogenic induction of lymphocytes. The recombinant production of human IFN-&ggr; was first reported by Gray, Goeddel and co-workers (Gray et al.,
Nature
295, 503-508 [1982]), and is subject of U.S. Pat. Nos. 4,762,791, 4,929,544, 4,727,138, 4,925,793, 4,855,238, 5,582,824, 5,096,705, 5,574,137, and 5,595,888. The recombinant human IFN-&ggr; of Gray and Goeddel as produced in
E. coli
, consisted of 146 amino acids, the N-terminal position of the molecule commencing with the sequence CysTyrCys. It has later been found that the native human IFN-&ggr; (i.e., that arising from mitogen induction of human peripheral blood lymphocytes and subsequent purification) is a polypeptide which lacks the CysTyrCys N-terminus assigned by Gray et al., supra. More recently, the crystal structure of
E. coli
-derived recombinant human IFN-&ggr; (rhIFN-&ggr;) was determined (Ealick et al.,
Science
252, 698-702 [1991]), showing that the protein exists as a tightly intertwined non-covalent homodimer, in which the two identical polypeptide chains are oriented in an antiparallel manner.
IFN-&ggr; is known to exhibit a broad range of biological activities, including antitumor, antimicrobial and immunoregulatory activities. A particular form of recombinant human IFN-&ggr; (rhIFN-&ggr;-1b, Actimmune®, Genentech, Inc. South San Francisco, Calif.) is commercially available as an immunomodulatory drug for the treatment of chronic granulomatous disease characterized by severe, recurrent infections of the skin, lymph nodes, liver, lungs, and bones due to phagocyte dysfunction (Baehner, R. L.,
Pediatric Pathol.
10, 143-153 [1990]). IFN-&ggr; has also been proposed for the treatment of atopic dermatitis, a common inflammatory skin disease characterized by severe pruritus, a chronically relapsing course with frequent periods of exacerbation, a distinctive clinical morphology and distribution of skin lesions (see PCT Publication No. WO 91/07984 published Jun. 13, 1991), vascular stenosis, including the treatment of restenosis following angioplasty and/or vascular surgery (PCT Publication No. WO 90/03189 published Apr. 5, 1990), various lung conditions, including respiratory distress syndromes (RDS), such as adult respiratory distress syndrome (ARDS) and a neonatal form, termed variously as idiopathic RDS or hyaline membrane disease (PCT Publication No. WO 89/01341, published Feb. 23, 1989). In addition, IFN-&ggr; has been proposed for use in the treatment of various allergies, e.g. asthma, and HIV-infection-related conditions, such as opportunistic infections, e.g.
Pneumocystis carinii
pneumonia, and trauma-associated sepsis. Impaired IFN-&ggr; production has been observed in multiple-sclerosis (MP) patients, and it has been reported that the production of IFN-&ggr; is greatly suppressed in suspensions of mitogen-stimulated mononuclear cells derived from AIDS patients. For a review see, for example, Chapter 16, “The Presence of Possible Pathogenic Role of Interferons in Disease”, In:
Interferons and other Regulatory Cytokines
, Edward de Maeyer (1988, John Wiley and Sons Publishers).
Interferon-&ggr;, along with other cytokines, has been implicated as an inducer of inducible nitric oxide (iNOS) which, in turn, has been described as an important mediator of the inflammatory mechanism underlying heart failure, of the cardiac response to sepsis or allograft rejection, as well as of the progression of dilated cardiomyopathies of diverse etiologies. Ungureanu-Longrois et al.,
Circ. Res.
77, 494-502 (1995); Pinsky et al.,
J. Clin. Invest.
95, 677-685 (1995); Singh et al.,
J. Biol. Chem.
270, 28471-8 (1995); Birks and Yacoub,
Coronary Artery Disease
8, 389-402 (1997); Hattori et al.,
J. Mol. Cell. Cardiol.
29, 1585-92 (1997). Indeed, IFN-&ggr; has been reported to be the most potent single cytokine with regard to myocyte iNOS induction (Watkins et al.,
J. Mol
. &
Cell. Cardiol.
27, 2015-29 [1995]).
Cardiac Hypertrophy
Hypertrophy is generally defined as an increase in size of an organ or structure independent of natural growth that does not involve tumor formation. Hypertrophy of an organ or tissue is due either to an increase in the mass of the individual cells (true hypertrophy), or to an increase in the number of cells making up the tissue (hyperplasia), or both.
Cardiac hypertrophy is the enlargement of heart that is activated by both mechanical and hormonal stimuli and enables the heart to adapt to demands for increased cardiac output or to injury. Morgan and Baker,
Circulation
83, 13-25 (1991). This response is frequently associated with a variety of distinct pathological conditions, such as hypertension, aortic stenosis, myocardial infarction, cardiomyopathy, valvular regurgitation, cardiac shunt, congestive heart failure, etc.
On a cellular level, the heart functions as a syncytium of myocytes and surrounding support cells, called non-myocytes. While non-myocytes are primarily fibroblast/mesenchymal cells, they also include endothelial and smooth muscle cells. Indeed, although myocytes make up most of the adult myocardial mass, they represent only about 30% of the total cell numbers present in heart.
The enlargement of embryonic heart is largely dependent on an increase in myocyte number, which continues until shortly after birth, when cardiac myocytes lose their proliferative capacity. Further growth occurs through hypertrophy of the individual cells. Hypertrophy of adult cardiac ventricular myocytes is a response to a variety of conditions which lead to chronic hemodynamic overload. Thus, in response to hormonal, physiological, hemodynamic, and pathological stimuli, adult ventricular muscle cells can adapt to increased workloads through the activation of a hypertrophic process. This response is characterized by an increase in myocyte cell size and contractile protein content of individual cardiac muscle cells, without concomitant cell division and activation of embryonic
Jin Hongkui
Lu Hsienwie
Paoni Nicholas F.
Yang Renhui
Fitzgerald David L.
Genentech Inc.
Knobbe Martens Olson & Bear LLP
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