Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1996-05-07
2003-01-21
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S008100, C514S012200, C514S885000, C424S085100, C424S085200, C424S184100, C424S198100
Reexamination Certificate
active
06509313
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to the field of immunotherapy, and more particularly immunotherapy with low doses of cytokines.
The present method and products are suitable for the treatment of diseases or conditions such as microbial infections, cancer and the like.
2. Description of the Background
In the immune system, there are three major types of lymphocytes: B cells, T cells, and natural killer (NK) cells. B-cells are derived from bone marrow, and comprise about 10% of the lymphocytes found circulating in blood. When stimulated by a specific antigen, each B-cell differentiates into a plasma cell that secretes antibodies of a single specificity. T-cells mature in the thymus and, make up about 80% of circulating lymphocytes. Although not producing antibodies, T-cells bear on their surfaces specific antigen receptors resembling antibody molecules. T-cells react to antigen stimulation by secreting immunomediator molecules or cytokines (helper T-cells), and toxic molecules (cytotoxic T-cells). Cytotoxic T-cells act directly on infected cells, and by secreting toxic molecules kill them and any foreign particles, such as microorganisms, they may contain. NK cells, make up about 10% of the lymphocyte population, and are not antigen specific, but recognize and kill cells infected with microbes. Monocytes and macrophages are large scavenger cells that ingest foreign particles and present antigens to the T-cells, which trigger specific immune responses. When an antigen is introduced, it is initially ingested by macrophages and other antigen presenting cells. After digestion, short segments thereof are presented on their cell surfaces. Only a few of all circulating T-cells have receptors that specifically bind to the antigen, and this binding stimulates the T-cells to secrete cytokines.
Cytokines are small proteins secreted primarily, but not exclusively, by cells of the immune system that promote the proliferation and/or differentiative functions of other cells. Examples of cytokines include interleukins, interferons, hematopoietic colony stimulating factors (CSF), and proinflammatory factors such as tumor necrosis factor (TNF). The therapeutic stimulation of the immune system has yet to find broad applications because of the difficulty in avoiding toxicity, which is part and parcel of immune-mediated inflammation. The toxicity associated with immunoreactivity is familiar to everyone as the signs and symptoms that occur during microbial infections, such as fever, fatigue, malaise and myalgia. These toxic symptoms were originally thought to be caused by substances, such as toxins, released or produced by the microbes themselves. Within the past decade, however, it has gradually become appreciated that the toxic signs and symptoms associated with microbial infection are attributable to molecules termed cytokines released, upon activation, by the immune system. When stimulated, for example, by microbes, the immune system produces the cytokines, which themselves, i.e. not the microbial toxins, produce the recognizable unpleasant and harmful effects. This was proven when the cytokines themselves were isolated, purified and injected into experiential animals and humans.
Despite producing toxic symptoms, the cytokines are primarily responsible for regulating the immune system. They determine the onset, magnitude, and duration of the immune response by stimulating the proliferation and differentiation of various types of cells comprising the immune system, including all of the white blood cells (leukocytes) that are recognizable as lymphocytes, monocytes/macrophages, polymorphonuclear leukocytes (PMN), and specialized antigen-presenting cells (APCs). When it was realized that cytokines regulate the immune system, it was hoped that they could be used therapeutically, to boost or augment immune reactivity in the treatment of microbial infections, malignancies, and for various immunodeficient states, such as the Acquired Immune Deficiency Syndrome (AIDS). However, the high and sometimes intolerable toxicities associated with cytokine administration have precluded their widespread use, especially in asymptomatic individuals afflicted with an infection or illness without signs or symptoms, such as infection with the Human Immunodeficiency Virus (HIV).
The toxicities associated with the administration of various cytokines at high doses are severe. For example, one of the first cytokines to be discovered, interleukin 2 (IL-2), was used initially to treat cancer in very high doses, up to 150×10
6
IU/day (10 mg/day). This resulted in extremely toxic side effects, including capillary leak with hypotension and high fever (>39° C.). This limited the duration of IL-2 therapy to only a few days, and restricted its use to solely patients hospitalized in the intensive care unit.
Over the past several years, lower doses of cytokines have been administered in attempts to circumvent most of the toxicities, while hoping to still retain at least some of the immune enhancing effects. For example, Caliguri and co-workers, including the inventor, found that ambulatory cancer patients could tolerate IL-2 administered as a continuous intravenous (IV) infusion for up to 90 days with minimal toxicities (WHO Grade 1, see table) provided the dose was in the range of 2.5-5.0×10
5
IU/m
2
body surface area per day. Most importantly, even though the dose was lowered about 600-fold from the original dose used earlier in the treatment of cancer, there were still detectable augmenting effects on the immune system, notably a gradual increase in the concentration of circulating Natural Killer (NK) cells. Similar results were recently reported by Bernstein and co-workers, who administered IL-2 subcutaneously (s.q.) to patients suffering from AIDS-associated malignancies, in doses ranging from 0.5-1.0×10
6
IU for 3 months. In a separate study, Teppler and co-workers, including the present inventor, injected IL-2 daily for 30 days intradermally (i.d.) into asymptomatic HIV+ individuals. At a dose of 0.18×10
6
IU/day given for this short interval, no untoward toxic effects were noted, but neither was there an increase in circulating leukocytes.
Thus far, the following four (4) families of cytokines that regulate the immune system, are recognizable according to their structures.
1) The interleukin family includes cytokines such as IL-2, 3, 4, 5, 6, 7, 9, 12, 13, and 15. These cytokines are small (10-20 kDaltons) proteins that all share a 3 dimensional structure of 4 antiparallel alpha helices. The receptors of this cytokine family share amino acid sequence homologies, especially in their extracellular domains.
2) The tumor necrosis factor (TNF) family includes compounds such as TNF-&agr;, TNF-&bgr; (lymphotoxin), nerve growth factor (NGF), and the CD40, Fas, CD27, and CD30 ligands. The ligands of this family are either secreted or remain membrane anchored, and function as homotrimers of about 15 kDalton monomers. The receptors of this family share amino acid sequence homologies.
3) The interferon (IFN) family includes compounds such as IFN-&agr;, IFN-&bgr;, and IFN-&ggr;, and is distinguished by the unique biologic property of stimulating cells to prevent viral replication.
4) The chemokine family includes molecules such as IL-8, macrophage inhibiting protein (MIP), and Rantes. These cytokines are small (about 10 kDaltons), and bind to a distinct family of receptors that have 7 membrane spanning alpha helices, and that are coupled to guanine nucleotide binding proteins (G proteins).
Even though these distinct cytokine families may be classified based upon their structure, they have in common the properties of being produced in, and/or being active on, the mammalian immune system.
Interleukin 2 (IL-2), for example, was one of the first cytokines to be identified and characterized. It is produced exclusively by T-lymphocytes in response to stimulation by antigens. IL-2 acts on the three major types of lymphocytes, including T cells, B cells, and NK cell
Cornell Research Foundation Inc.
Delacroix-Muirheid C.
Jones Dwayne C.
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