Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1996-12-17
2001-05-29
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S012200, C530S350000
Reexamination Certificate
active
06239099
ABSTRACT:
The invention relates to a method of treating viral infections with modified C-reactive protein (mCRP), mutant CRP and recombinant mCRP (r
m
CRP).
Viral infections are serious human and veterinary health problems. Since the advent of AIDS (acquired immunodeficiency syndrome), the need for effective treatments for viral infections has become urgent. AIDS is caused by human immunodeficiency virus 1 (HIV-1). The initial pathogenic event is the binding of HIV-1 to the CD4 receptor on a subset of T cells and monocyte-macrophages. Fauci et al. (1991). The virus interacts with the human immune system, and the ultimate consequence of this interaction is a profound immunosuppression resulting from the quantitative depletion and functional abnormalities of the CD4 T-cell subset Mononuclear phagocytes may play a role in the pathogenesis of HIV-1 infection by serving as reservoirs of the virus. Of note is the fact that monocytes in the peripheral blood of HIV-1-infected individuals are rarely infected in vivo, whereas infected tissue macrophages may play a role in organ-specific HIV-1-related pathogenesis.
One drug that has been approved by the Food and Drug Administration (FDA) for the treatment of AIDS is 3′-azido-2′,3′-dideoxy-thymidine (zidovudine, azidothymidine, AZT) which inhibits HIV-1 replication by acting at the level of reverse transcriptase. However AZT causes serious side effects, such as bone marrow suppression, and it is poorly tolerated in a high proportion of patients. (Yarchoan et al., 1990) Also, the beneficial effects of AZT have been reported to abate in 12-18 months. (Chase, 1988)
The FDA has also approved 2′,3′-dideoxyinosine (DDI) for the treatment of AIDS in patients who cannot tolerate AZT or for whom AZT is no longer effective. DDI has been found efficacious and safe in the short-term, but its long term effects are not yet known.
Another drug for the treatment of AIDS is ampligen. Ampligen is a mispaired double-stranded RNA. It increases antiviral activity by stimulating interferon production, activating natural killer cells, and augmenting an internal cellular antiviral mechanism. (Montefiori et al., 1987; Dagani, 1987)
Other possible therapeutic approaches for the treatment of AIDS are discussed in Yarchoan et al. (1990); Dagani, (1987).
C-reactive protein (CRP) was first described by Tillett and Francis (1930) who observed that sera from acutely ill patients precipitated with the C-polysaccharide of the cell wall of
Streptococcus pneumoniae.
Others subsequently identified the reactive serum factor as protein, hence the designation “C-reactive protein.”
In addition to binding to pneumococcal C-polysaccharide, CRP binds to: 1) phosphate monoesters including particularly phosphorylcholine; 2) other cell wall polysaccharides containing phosphorylcholine; 3) phosphatidyl choline (lecithin); 4) fibronectin; 5) chromatin; 6) histones; and 7) the 70 kDa polypeptide of the U1 small nuclear ribonucleoprotein. (Kilpatrick and Volanakis, 1991) Several laboratories have also reported the binding of CRP to galactose-containing polysaccharides. However, one laboratory has reported that CRP binds to trace phosphate groups that are minor constituents of one particular galactan, making it is unclear whether CRP binding to other galactans is also directed to phosphate residues or to carbohydrate determinants.
Atono (1989) teaches that the level of serum CRP is markedly increased in patients with acute hepatitis type A and type B, especially in type A, but decreases rapidly during the convalescent phase. The article also reports that the CRP level is generally low in non-A, non-B hepatitis in both the acute and convalescent phases.
Putto et al (1986) reports the results of measurements of the level of CRP in febrile children suffering from bacterial and viral infections. If the duration of the illness was more than 12 hours and the CRP level was less than 20 &mgr;g/ml, all children investigated had viral or probable viral infections. Some children with CRP levels of 20 &mgr;g/ml or less had invasive bacterial infections, but they had been sick for 12 hours or less. CRP levels between 20 &mgr;g/ml and 40 &mgr;g/ml were recorded in children with both viral and bacterial infections. A CRP value greater than, or equal to, 40 &mgr;g/ml detected 79% of bacterial infections with 90% specificity.
There have been no reports of CRP binding to viruses, contributing to the phagocytosis of viruses, or otherwise being able to neutralize viruses. CRP is not being used to treat viral infections.
Much of the study of CRP has been directed to determining its role in bacterial infections. For example, Xia et al. (1991) describes experiments designed to explore the role of CRP in endotoxin shock. A chimeric gene coding for rabbit CRP under the control of an inducible promoter (inducible in response to demand for gluconeogenesis) was introduced into mice. In contrast to most other vertebrates, mice synthesize only trace amounts of endogenous CRP, even during an acute phase response. When the chimeric gene was introduced into the mice, rabbit CRP was expressed in response to demand for gluconeogenesis. Further, it was found that 75% of mice expressing high levels of rabbit CRP following induction of gluconeogenesis survived treatment with 350-400 &mgr;g of endotoxin, as compared to 27% survival for animals in which rabbit CRP synthesis had been suppressed by inhibiting gluconeogenesis. The authors speculate that CRP may play a role in natural defense against endotoxin shock, although CRP is not known to bind endotoxin.
Mold et al. (1982) report that CRP binding can lead to complement activation and, in the presence of complement, enhancement of opsonization of C-polysaccharide-sensitized erythrocytes and type 27
S. pneumoniae.
The article further reports that injections of CRP increased survival in mice challenged with type 3 or type 4
S. pneumoniae.
Finally, the authors describe test results from which they conclude that CRP binds to a small group of potentially pathogenic gram-positive bacteria (
S. pneumoniae Streptococcus viridians,
and one isolate of
Staphylococcus aureus
), but does not bind to gram-negative bacteria or to other gram-positive bacteria. They, therefore, postulate that the ability of CRP to enhance opsonization and contribute to host defense may be specific for infection with
S. pneumoniae.
Similarly, Mold et al (1982) report that CRP can act as an opsonin in the presence of complement. However, the article teaches that CRP does not bind to gram-negative bacteria and binds to only some gram-positive organisms. For those gram-positive bacteria to which CRP binds, the effectiveness of CRP as an opsonin varied depending on the species. Finally, the article reports that CRP protected mice from type 3 and type 4
S. pneumoniae
infection.
Nakayama et al. (1983) also teach that CRP protects against lethal infection with type 3 or type 4
S. pneumoniae.
The article further teaches that CRP did not protect against a similar dose of
Salmonella typhimunium
LT2.
Horowitz et al. (1987) describes the effects of CRP in mice with a X-linked immunodeficiency (“xid mice”) which prevents the mice from making antibodies to polysaccharide antigens. In these mice, CRP provided protection against infection with type 3
S. pneumonia
and acted by clearing the bacteria from the blood. However, CRP was not completely protective at higher doses of
S. pneumoniae.
Since CRP provides complete protection against these doses in normal mice, the authors speculated that the function of CRP is to slow the development of pneumococcal bacteremia until protective antibodies to capsular polysaccharide can be produced. C3 depletion decreased or abrogated the protective effects of CRP in xid mice, but not in normal mice.
Nakayama et al. (1984) reports the results of injecting mice with CRP and then immunizing them with type 3
S. pneumococci.
The result was a diminished antibody response to the phosphorylcholine determinants on the bacteria which varied with the dose of CR
Delacroix-Muirheid C.
Immtech International Inc.
Jones Dwayne C.
Sheridan & Ross P.C.
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