Drug – bio-affecting and body treating compositions – Nonspecific immunoeffector – per se ; or nonspecific...
Reexamination Certificate
2000-09-19
2004-04-06
Saunders, David (Department: 1644)
Drug, bio-affecting and body treating compositions
Nonspecific immunoeffector, per se ; or nonspecific...
C424S531000, C514S002600, C514S012200, C514S021800, C514S885000, C530S830000
Reexamination Certificate
active
06716434
ABSTRACT:
BACKGROUND OF THE INVENTION
It has long been known that mammals, when confronted with bacterial or viral infections, exhibit efforts at self-healing which are initiated by a complex physiological network referred to as the immune system. The immune system operates in response to a challenge to the mammal by initially recognizing the presence of a foreign organism or pathogen within the animal's body. In mammals, this is followed by an attack on the foreign organism by the neutrophils, macrophages and other “killer” cells of the immune system. This immune response functions or is “turned on” by a variety of immune system regulators which activate the various aspects of the immune system depending upon the type of insult confronting the subject animal.
A substantial component of the immune system is a group of structurally related glycoproteins, collectively known as immunoglobulins, contained within blood and extra cellular fluids. Five immunoglobulin classes have been identified: immunoglobulin G (IgG), IgM, IgA, IgD and IgE. The basic structural unit of each immunoglobulin class consists of two pairs of polypeptide chains joined by disulfide bonds. The five classes of immunoglobulins have different biological properties and different distributions in the body. The structure responsible for the biological properties of each immunoglobulin class is located on that part of the immunoglobulin molecule which is unique for each class-the Fc fragment. While some antibodies are produced at all times in normal animals, other antibodies are produced only in response to specific antigenic stimulation (e.g., when pathogenically challenged).
IgG is the major antibody class in normal mammalian systems and forms about 70% of the total immunoglobulin. IgG is evenly distributed between intra- and extra vascular pools. It is the first major antibody of the secondary immune response and belongs to the exclusive antitoxin class. IgG is a monomeric protein which can be divided into four sub-chains—two heavy chains “H” and two light chains “L”. Taking the four sub-chains together each IgG molecule consists of one H
2
L
2
unit with a molecular weight of proximately 140,000 Daltons. Molecules of the IgG class are actively transported across the placenta and provide passive immunity to newborns at a time when the infant's immune mechanisms are not developed.
The remaining four immunoglobulin classes are more narrow components of the immune system.
IgM is the first immunoglobulin class produced by the maturing fetus. IgM does not normally cross the placenta from the mother to fetus, but may be produced actively by the fetus prior to birth, especially if the fetus has been exposed to antigens by infection. IgA is found in relatively small amounts in serum and tissue fluids, but is present in high concentrations in external secretion such as saliva, tears, and bronchial secretions. IgE is also present in very low concentrations and appears to be associated with the histamine response. The last immunoglobulin class, IgD, is present in very low concentrations in secretions. IgD stimulates immature lymphocytes to multiply and differentiate thereby causing the production and secretion of other antibodies. Therefore, all immunoglobulin classes are important in immune system responses.
Modulation of the immune system to effect greater response to foreign agents has been an area of interest for some years. The development of specific antibodies through vaccination has long been utilized to provide mammals with long term immune defense mechanisms to specific microorganism forms.
Ansley, U.S. Pat. No. 5,219,578,Jun. 15, 1993 discloses a non-adjuvanted IgG containing caprine serum fraction. This fraction is useful as an immunostimulant in mammals when challenged by specified diseases.
Recent efforts in immunology have been directed towards the utilization of immune system regulating molecules, rather than one of the five classes of immunoglobulins, to provide increased immune system activity. It is believed that, through the use of immune regulating or immune modulating molecules, a state of general immune system hyperactivity can be induced which may help combat challenges to the immune system (e.g., pathogenic infection). Infection may arise from a wound site or may arise from an opportunistic blooming when the host organism is simply deprived of sufficient sleep. It is believed that an induced state of general immune hyperactivity would result in a therapeutic response to the challenge. This might be viewed as the opposite of the vaccination type response that produces a specific long-term immunity. If such a non-specific immune response could be initiated at will it could be utilized to either act alone or in conjunction with a conventional treatment directed towards the etiological agents,
Such a mechanism could be based upon activation of phagocytic cells that are capable of responding to a wide range of infectious agents. It may also be that the T-lymphocytes, which are major mediators of the overall immune response, may act to enhance the operation of non-specific cellular immunity even though the T-lymphocytes themselves are a part of the specific immune response.
The search for agents which potentiate the immune response is a driving force in drug research. Cytokines and cationic peptides are two classes of “relativel” low molecular weight compounds which have shown promise in this area of research. At least nine immuno-defense peptide products are commercially available with annual sales of over $4 billion (Latham, P. W., 1999, Therapeutic peptides revisited
Nature Biotechnology
17:755-757).
Bio-active peptides (such as “cationic peptides”) are emerging as promising alternatives for combating antibiotic-resistant bacteria with minimum inhibitory concentrations reported from 1-100 &mgr;g/ml (Martin, E., T. Ganz, and R. I. lehrer, 1995. Defensins and other endogenous peptide antibiotics of vertebrates,
J. Leukoc. Biol,
58:128-136; Hancock, R. E. W., 1997, Peptide antibiotics,
Lancet,
349:418-422). Cationic peptides range from 16-18 amino acid residues for the protegrins (Ganz, T., and R. Lehrer, 1998. Antimicrobial peptides of vertebrates,
Curr. Opin. Immunol.,
10:41-44.) to 29-35 residues for mammalian defensins (Sawa, T., and K. Turahashi, 1999, Antimicrobial peptides/proteins—application to the therapy of sepsis (article in Japanese), Masui, 48:1186-1193.). Due to a compositional prominence of lysine and arginine, they possess a net positive charge of at least 2, and usually 4, 5, or 6 (Hancock, R. E. W., 1997, Peptide antibiotics
Lancet,
349:418-422).
Interleukin-1 (IL-1), tumor necrosis factor-&agr; (TNF-&agr;) and interferon (IFN) are three cytokines which participate in the immune response. IL-1 is involved in the host's response to antigenic challenge and tissue injury, and has been shown to increase the resistance of mice to pathogenic organisms such as Listeria,
Escherichia coli
, and
Candida albicans
(Czuprynski, C. J., and Brown, J. F., 1987, Recombinant murine interleukin-1&agr; enhancement of nonspecific antibacterial resistance,
Infection and Immunity
55:2061-2065; Cross, A. S., Sadoff, J. C., Kelly, N, Bernton, F., and Genski, P., 1989, Pretreatment with recombinant murine tumor necrosis factor &agr;/cachectin and murine interleukin 1&agr; protects mice from lethal bacterial infection
The Journal of Experiment Medicine
169:2021-2027; Pecyk, R. A., Fraser-Smith, E. B., and Matthews, T. R., 1989, Efficacy of interleukin-1&bgr; against systemic
Candida albicans
in normal and immunosuppressed mice,
Infection and Immunity
57:3257-3258.). TNF-&agr; and &ggr;-IFN were able to increase the resistance of mice to
Salmonella typhimurium
(Morrissey, P. J., and Charrier, K, 1994, Treatment of mice with IL-1 before infection with increases resistance to a lethal challenge with
Salmonella typhimurium, The journal of Immunolgy
153:212-219). Human &agr; IFN's have potent antiviral and antiproliferative activities, and are currently being utilized as anticance
Ansley Daniel R.
Willeford Kenneth O.
Mosoff Serle Ian
Saunders David
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