Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing
Reexamination Certificate
1999-06-15
2003-12-23
Schwadron, Ronald B. (Department: 1644)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
C424S009200, C424S093700, C424S278100, C435S002000, C435S029000, C514S885000
Reexamination Certificate
active
06667025
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to the chemistry and biology of compounds with immunosuppressive and lymphocyte homing activities and, more specifically, this invention relates to methods and comprises compositions for accelerating lymphocyte homing in a mammal.
2. Description of Related Art
In general, compounds used to suppress the immune response attack certain immune cells. By either removing these cells from the immune system or hampering their ability to respond to chemical messengers, the number of cells participating in any immune response decreases. With fewer cells responding, the immune system cannot mount the same response reaction. The result is immunosuppression.
The use of these compounds follows directly from our understanding of the immune response and the function of immune cells. Numerous publications in the art describe the molecular and cellular aspects of the immune response. Generally, the immune system responds to an antigen first by processing and presenting the antigen through antigen presenting cells (APCs). Over the last decade, intensive research has resulted in a deep and detailed knowledge of this process at the molecular level (1-3). Following the APCs action are the T lymphocytes or T cells. Activated by a process involving antigen presentation by the APC, T cells then initiate the development of a variety of effector immune cells. The activities of phagocytes, natural killer cells, cytotoxic T cells, and B cells and other effector cells each arise from the cytokines secreted from activated T cells. The cytokines, then, are the chemical messengers that trigger the immune response mechanisms that the effector cells perform.
By killing or modifying the cells or messengers of the immune system, certain compounds can be used as treatments and therapies for suppressing the immune response. Our understanding of the immune response has led to two general groups of immunosuppressive compounds, those compounds effecting cytokine action and those directly effecting immune cell metabolism and activity.
In the first group are cyclosporin A (CsA), tacrolimus (TRL) and rapamycin (4-5). CsA, a cyclic peptide, is produced from the Trichoderma polysporum fungus (6-7). TRL, or FK-506, is a macrolide from
Streptomyces tsukubaensis
(8-10). These compounds cut out the cytokine messengers of the immune response by preventing their synthesis. The immune effector cells, therefore, cannot be recruited to complete the immune response. Rapamycin, on the other hand, blocks the cytokine signal from effecting the immune cells (34).
More specifically, CsA suppresses the immune response by inhibiting production of the cytokine interleukin 2 (IL-2) in antigen-stimulated helper T cells, a subset of T cells. TRL inhibits antigen-induced T cell proliferation by inhibiting IL-2 production in helper T cells. CsA and TRL act by binding to two different proteins (11), called cyclophilin and FKBP respectively. After the binding, both of the CsA/cyclophilin and TRL/FKBP complexes inhibit the phosphatase activity of a protein called calcineurin, which activates nuclear factor (NF-AT) in activated T cells. NF-AT promotes IL-2 gene transcription and thus IL-2 production. However, when the CsA/cyclophilin and TRUFKBP complexes inhibit activation of NF-AT, production of IL-2 is also inhibited.
Since CsA and TRL have almost the same mechanism of action, these drugs also show quite similar side effects, such as renal and liver toxicity (12). Multiple drug therapies with either CsA or TRL, using steroids or other immunosuppressants such as azathioprine and mizoribine (13-14), were widely used in order to reduce the side effects of individual immunosuppressants. However, the similar side effects of CsA and TRL prohibits their use together. New immunosuppressant compounds should not only be highly safe but should also possess a mechanism of action distinct from CsA and TRL so that they can be concomitantly administered.
Compounds from the second group of similarly-acting chemicals each interfere with nucleoside synthesis in the immune cells, arresting their metabolism and their immune activity. The group includes azathioprine (35), mizoribine (36), mycophenolic acid (37), and brequinar sodium (38). These compounds can also result in toxic side effects.
Researchers and clinicians use these compounds in human therapies. Those employing CsA have made great contributions to the prevention of acute rejection in human organ transplantation. Immunosuppressants are also used to treat autoimmune diseases, such as rheumatoid arthritis, and diseases such as psoriasis, atopic dermatitis, bronchial asthma, and pollinosis. However, because of the toxic side effects of the currently used compounds, new, more effective and less toxic methods to suppress the immune response are needed in the art.
SUMMARY OF THE INVENTION
The instant invention involves compositions and methods that suppress the immune response in mammals in a novel way. This immunosuppression results from accelerating lymphocyte homing, for example to any of the mesenteric or peripheral lymph tissues or Peyer's patches. This new activity, accelerated lymphocyte homing immunosuppression (ALH-immunosuppression), can be used in conjunction with other immunosuppressive therapies or compounds while avoiding dangerous or toxic side effects. The present invention provides new and useful methods, therapies, treatments, and compositions wherever immunosuppression is desired or manipulating lymphocyte populations is desired. For example, the invention can be used in therapies or treatments for preventing rejection in organ or cell transplantation, genetically modified cell therapy, ex vivo gene therapy, or other cell therapy methods. Research and development may provide additional or related uses directed to the intestinal immune system and the maintenance or manipulation of intestinal intraepithelial lymphocyte function. Thus, the ALH-immunosuppressive compositions of the invention can be used to direct or redirect lymphocytes within a mammal. Such uses do not necessarily require an immunosuppressive action.
In one embodiment, the invention provides a method of suppressing the immune response by accelerating lymphocyte homing to any of the mesenteric or peripheral lymph tissues or Peyer's patches. This embodiment can be used to suppress the immune response in a mammal and comprises administering an ALH-immunosuppressive compound. The ALH-immunosuppressive compounds of this invention functionally act by directing lymphocytes to specific locations or lymphoid tissues. This lymphocyte homing activity can be reversible, so that suspending treatment restores normal lymphocyte populations. The compounds may also act to selectively decrease populations of certain lymphocytes in blood or lymph tissue, such as specifically decreasing populations of circulating lymphocytes or spleen lymphocytes.
Structurally, the class of ALH-immunosuppressive compounds derives from myriocin or ISP-1, a natural product of
Isaria sinclairii
(15). Myriocin is depicted below.
Numerous homologs, analogs or derivatives of these compounds can be prepared by methods known in the art, such as described in the references, particularly (17), which is specifically incorporated herein by reference. In general, for this invention, the ALH-immunosuppressive compounds can be 2-aminopropane-1,3-diol compounds, according to the following formula:
wherein R is an optionally substituted straight or branched carbon chain, an optionally substituted aryl, an optionally substituted cycloalkyl or the like;
and R2, R3, R4, and R5 are the same or different and each is a hydrogen, an alkyl, an acyl, or an alkoxycarbonyl, or R4 and R5 may be bonded to form an alkylene chain, which may be substituted by alkyl, aryl, or an alkoxycarbonyl.
Also, for this invention, the ALH-immunosuppressive compounds can be bezene compounds, of the formula:
wherein W is hydrogen; a straight or branched chain alkyl having 1 to 6 carbon atoms; a straight or branched ch
Adachi Kunitomo
Chiba Kenji
Crowell & Moring LLP
Mitsubishi Pharma Corporation
Schwadron Ronald B.
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