Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2003-01-02
2004-06-08
Wilson, James O. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S061000, C536S017900, C536S018700, C424S093710, C424S579000, C424S580000, C435S372000
Reexamination Certificate
active
06747010
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to NKT cell-activating agents, therapeutic agents for autoimmune diseases and agents for inducing abortion.
2. Background Art
It has been revealed that intermediate TCR cells (TCR
int
cells), which express T-cell receptors (TCRs) intermediately, are related to natural killer (NK) cells in terms of their features, for example, showing a large granular lymphocyte (LGL)-like morphology, constantly expressing IL-2R &bgr;-chains, and having perforin granules, but they are clearly different from NK cells in terms of having TCRs (Watanabe, H. et al., J. Immunol., 155, 2972 (1995)). Furthermore, among the TCR
int
cells activated by interleukin 12 (IL-12), NK 1.1-expressing NK 1.1
+
TCR
int
(NKT) cells have been shown to be important effector cells in controlling hematogenous metastases of tumors to the liver and lung in mice (Hashimoto, W. et al., J. Immunol., 154, 4333 (1995); Anzai, R. et al., Immunol., 88, 82 (1996)). These data suggest that the NKT cells may play an important role in eradicating cancer cells, parasites, protozoans, and intracellular infectious bacteria such as
Listeria monocytogenes
and
Micobacterium tubeculosis
(Seki, S. et al., Clin. Immunol., 28, 1069 (1996)).
The NKT cells are also known to be closely associated with acute rejection in bone marrow transplantation (Yankelevich, B. et al., J. Immunol., 142, 3423 (1989)) and with controlling of IgE antibody production by controlling Th1/Th2 differentiation of helper T cells (Yoshimoto, T. et al., J. Exp. Med., 179, 1285 (1994)). Thus, the NKT cells are a group of new cells that are currently attracting enormous attention.
V&agr;14
+
NKT cells are a subset of the above-mentioned NKT cells. Many V&agr;14
+
NKT cells express V&agr;14J&agr;281 mRNA and have this as a TCR &agr;-chain. Recently, the V&agr;14
+
NKT cells were shown to be closely associated with the onset of autoimmune diseases. The number of V&agr;14
+
NKT cells was revealed to selectively decrease prior to the onset of an autoimmune disease in MRL 1pr/1pr mice, model mice for an autoimmune disease (human systemic lupus erythematosus) in which abnormal lymphocytes accumulate at 17-20 weeks old (Mieza, M. A. et al., J. Immunol., 156, 4035 (1996)).
Similar phenomena were also observed in model mice for other autoimmune diseases, such as gld mice and (NZB×NZW) F1 mice, revealing that the V&agr;14
+
NKT cells are closely associated with the onset of autoimmune diseases (Makino, Y. et al., Clin. Immunol., 28, 1487 (1996)).
More interestingly, similar phenomena were also observed in humans. The V&agr;24J&agr;Q&agr; chain, a human homologue to the mouse V&agr;14J&agr;281 chain, was found in peripheral blood CD4
−
/CD8
−
T cells at a level of 20-50% in healthy humans but not at all in sclerosis patients (Sumida, T. et al., J. Exp. Med., 182, 1163 (1995)).
Thus, the mouse V&agr;14
+
NKT cells and human V&agr;24J&agr;Q&agr; T cells are known to be involved in various autoimmune diseases which are caused by different causative genes or genetic background. Therefore, IL-12 having an NKT cell-activating activity as mentioned above was expected to be a therapeutic agent for autoimmune diseases such as human systemic lupus erythematosus (SLE) and systemic sclerosis (SSc). However, a marked increase in the number of abnormal lymphocytes (CD3
+
B220
+
double negative T cells) in the spleen and lymph nodes was observed in MRL 1pr/1pr mice to which IL-12 was administered as compared with the control mice (Takenori Tsutsui et al., Proceedings of Annual Meeting of the Japanese Society for Immunology, 347 (1996)).
&bgr;-Galactosylceramides or &bgr;-glucosylceramides, in which various sugars bound to ceramides in a &bgr;-configuration, are present in the mammal body (Svennerholm, L. et al., Biochim. Biophys. Acta, 280, 626 (1972); Karlsson, K. -A. et al., Biochim. Biophys. Acta, 316, 317 (1973)). On the other hand, it is known that &agr;-galactosylceramides have marked immunostimulatory activity and antitumor activity (Morita, M. et al., J. Med. Chem., 38, 2176 (1995)) and such activities by &agr;-galactosylceramides or &agr;-glucosylceramides are known to be much stronger than those by &bgr;-galactosylceramides or &bgr;-glucosylceramides (Motoki, K. et al., Biol. Pharm. Bull., 18, 1487 (1995)). It is also known that administration of compounds having an &agr;-glucosylceramide structure protects the body from radiation (Motoki, K. et al., Bioorg. Med. Chem. Lett., 5, 2413 (1995)), suppresses the metastasis of mouse melanoma B16 to the lung (Kobayashi, E. et al., Oncology Res., 7, 529 (1995)) and metastasis of mouse colon adenocarcinoma, Colon 26, and mouse T lymphoma EL-4 to the liver (Kazuhiro Motoki et al., Proceedings of Annual Meeting of the Japanese Cancer Association, 523 (1996)), and increases the number of platelets and leukocytes (Motoki, K. et al., Biol. Pharm. Bull., 19, 952 (1996)).
However, there are no reports to date that compounds having an &agr;-glucosylceramide structure are effective on autoimmune diseases, that such compounds would induce abortion, or that such compounds could even affect NKT cells.
SUMMARY OF THE INVENTION
The present inventors have now found that &agr;-glycosylceramides enhance antitumor cytotoxic activity against tumor cells of NKT cells in RAG-1KO/V&agr;14tg/V&bgr;8.2tg mice (mice having a large number of NKT cells but neither B cells, T cells nor NK cells in the lymphocyte fraction), markedly increase the number of NKT cells, in particular, mouse V&agr;14
+
NKT cells and human V&agr;24
+
NKT cells, suppress abnormal swelling of axillary and inguinal lymph nodes (accumulation of abnormal lymphocytes) in MRL 1pr/1pr mice which are considered model mice for human systemic lupus erythematosus, and control the progression of mouse colitis induced with 4% DSS.
The present inventors have also found that &agr;-glycosylceramides suppress the onset of experimental autoimmune encephalomyelitis. This experimental autoimmune encephalomyelitis in mice is a model for human multiple sclerosis. The present inventors have also found that &agr;-glycosylceramides suppress the spontaneous onset of diabetes in NOD mice which are model animals for human type I diabetes.
The present inventors have further found that &agr;-glycosylceramides have an aborting effect on pregnant mice.
An objective of the present invention is to provide an agent for activating an NKT cell and an activated NKT cell.
Another objective of the present invention is to provide a therapeutic agent for autoimmune diseases such as systemic lupus erythematosus, systemic sclerosis, ulcerative colitis, encephalomyelitis, multiple sclerosis, or type I diabetes.
Further objective of the present invention is to provide an agent for inducing abortion.
The NKT cell-activating agent, the therapeutic agent for autoimmune diseases and the agent for inducing abortion according to the present invention comprise a compound of formula (I) or a salt or a solvate thereof:
wherein
R
1
represents H or OH,
X represents an integer between 7 and 27,
R
2
represents a substituent selected from the group consisting of the following (a) to (e) (wherein Y represents an integer between 5 and 17):
(a) —CH
2
(CH
2
)
Y
CH
3
(b) —CH(OH)(CH
2
)
Y
CH
3
(c) —CH(OH)(CH
2
)
Y
CH(CH
3
)
2
(d) —CH═CH(CH
2
)
Y
CH
3
(e) —CH(OH)(CH
2
)
Y
CH(CH
3
)CH
2
CH
3
, and
R
3
to R
9
represent substituents as defined in any one of the following i) to v):
i) when R
3
, R
6
and R
8
represent H,
R
4
represents H, OH, NH
2
, NHCOCH
3
, or a substituent selected from the group consisting of the following groups (A) to (D):
R
5
represents OH or a substituent selected from the group consisting of the following groups (E) and (F):
R
7
represents OH or a substituent selected from the group consisting of the following groups (A) to (D):
R
9
represents H, CH
3
, CH
2
OH or a substituent selected from the group consisting of the following groups (A′) t
Kawano Tetsu
Koezuka Yasuhiko
Taniguchi Masaru
Foley & Lardner
Khare Devesh
Kirin Beer Kabushiki Kaisha
Wilson James O.
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