Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1998-04-15
2001-05-15
Kemmerer, Elizabeth (Department: 1646)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S012200, C514S008100
Reexamination Certificate
active
06232288
ABSTRACT:
This application is a national stage application of PCT application Serial No. PCT/JP96/03277, filed Nov. 8, 1996.
TECHNICAL FIELD
The present invention relates to a composition for improving pancreatic function, a composition for promoting differentiation of undifferentiated pancreatic stem cells to pancreatic beta cells, or a composition for preventing or treating undifferentiated pancreatic cancer, which comprises a betacellulin protein or a mutein thereof.
BACKGROUND ART
A betacellulin protein (hereinafter also referred to as BTC protein) is a peptide factor produced by pancreatic beta tumor cells derived from a transgenic mouse, and its full amino acid sequence has been clarified by cDNA analysis [Shing et al., Science, 259:1604 (1993); Sasada et al., Biochemical and Biophysical Research Communications, 190:1173 (1993)]. Although BTC protein was first discovered as a factor possessing mouse 3T3 cell growth-promoting activity, it was later found to exhibit growth-promoting activity against vascular smooth muscle cells and retinal pigment epithelial cells [Shing et al., Science, 259:1604 (1993)].
A human BTC protein naturally occurs in very trace amounts, and attempts to obtain it from human tissue has been very difficult by various limitations. In recent years, however, gene engineering techniques have been successfully used to produce highly purified human BTC protein in large amounts and at relatively low costs (EP-A-0555785). Also, it has been reported that BTC protein can be used in the treatment of diseases such as wounds, tumors and vascular malformations, and preparation of competitive agents such as an antibodies or false peptides which can be used in the treatment of such diseases attributable to smooth muscle growth as atherosclerosis and diabetic retinopathy (EP-A-0482623, EP-A-0555785).
In addition, the mRNA of BTC protein has been detected in non-brain organs, e.g., liver, kidney and pancreas, suggesting that BTC protein exhibits some function in these organs as well, but much remains to be known in detail.
DISCLOSURE OF THE INVENTION
Diabetes mellitus is a disease characterized by the onset of various complications associated with persistent hyperglycemia. This disease is classified into insulin-dependent, insulin-independent and other types, and is thought to be associated with diverse causes, but basically it develops when insulin action is diminished. Insulin-dependent diabetes mellitus, in particular, is caused by an absolute lack of insulin production. Against this background is there a need for the development of a medicine which improves pancreatic function to prevent or treat diabetes mellitus etc.
In view of the above problems, the present inventors made extensive investigation and found that known BTC protein acts on cells derived from the pars exocrina pancreatis capable of multiple differentiation to allow them to differentiate to beta cells etc. The present inventors made further investigation based on this finding, and developed the present invention.
Accordingly, the present invention provides:
(1) A composition for improving pancreatic function which comprises a betacellulin protein or a mutein thereof;
(2) The composition according to (1), wherein the betacellulin protein is a protein having the amino acid sequence shown by at least one SQ ID NO. selected from the group consisting of SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6;
(3) The composition according to (1), wherein the betacellulin protein is a protein having the amino acid sequence shown by SEQ ID NO:1 or a protein having the amino acid sequence shown by SEQ ID NO:2;
(4) The composition according to (1), wherein the mutein of the betacellulin protein is a protein having (i) an amino acid sequence resulting from deletion of about 1 to 40 amino acids from the amino acid sequence shown by SEQ ID NO:1 or SEQ ID NO:2, (ii) an amino acid sequence resulting from replacement of about 1 to 40 amino acids in the amino acid sequence shown by SEQ ID NO:1 or SEQ ID NO:2 by other amino acid sequences, or (iii) an amino acid sequence resulting from addition of about 1 to 40 amino acids to the amino acid sequence shown by SEQ ID NO:1 or SEQ NO:2;
(5) The composition according to (1), wherein the mutein of the betacellulin protein is a protein having an amino acid sequence resulting from deletion of 12 or 30 amino acids from the N-terminus of the amino acid sequence shown by SEQ ID NO:1;
(6) The composition according to (1) to (5), which further contains an activin;
(7) The composition according to (6), wherein the content ratio of the activin to the betacellulin protein or a mutein thereof is about 1:10 to 10:1;
(8) The composition according to (1) to (7), which is a composition for preventing or treating diabetes mellitus.
(9) The composition according to (1) to (7), which is a composition for preventing or treating pancreatic dysfunction in diabetes mellitus or pancreatic hypofunction associated with senile insulin secretion reduction;
(10) A composition for promoting differentiation of undifferentiated pancreatic stem cells to pancreatic beta cells, which comprises a betacellulin protein or a mutein thereof;
(11) A composition for preventing or treating undifferentiated type of pancreatic cancer, which comprises a betacellulin protein or a mutein thereof;
(12) A method for improving pancreatic function of human or mammal, which comprises administering an effective amount of a betacellulin protein or a mutein thereof to human or mammal;
(13) A method for promoting differentiation of undifferentiated pancreatic stem cells to pancreatic beta cells of human or mammal, which comprises administering an effective amount of a betacellulin protein or a mutein thereof to human or mammal;
(14) A method for preventing or treating undifferentiated type of pancreatic cancer of human or mammal, which comprises administering an effective amount of a betacellulin protein or a mutein thereof to human or mammal;
(15) A use of a betacellulin protein or a mutein thereof for the manufacture of a composition for improving pancreatic function;
(16) A use of a betacellulin protein or a mutein thereof for the manufacture of a composition for promoting differentiation of undifferentiated pancreatic stem cells to pancreatic beta cells;
(17) A use of a betacellulin protein or a mutein thereof for the manufacture of a composition for preventing or treating undifferentiated pancreatic cancer.
Also, the present invention further provides:
(18) A composition for improving pancreatic function which comprises a DNA coding for a betacellulin protein or a mutein thereof;
(19) A composition for promoting differentiation of undifferentiated pancreatic stem cells to pancreatic beta cells, which comprises a DNA coding for a betacellulin protein or a mutein thereof;
(20) A composition for preventing or treating undifferentiated pancreatic cancer, which comprises a DNA coding for a betacellulin protein or a mutein thereof;
(21) A method for improving pancreatic function of human or mammal, which comprises administering an effective amount of a betacellulin protein or a mutein thereof to human or mammal;
(22) A method for promoting differentiation of undifferentiated pancreatic stem cells to pancreatic beta cells of human or mammal, which comprises administering an effective amount of a betacellulin protein or a mutein thereof to human or mammal;
(23) A method for preventing or treating undifferentiated pancreatic cancer;
(24) A use of a DNA coding for a betacellulin protein or a mutein thereof for the manufacture of a composition for improving pancreatic function;
(25) A use of a DNA coding for a betacellulin protein or a mutein thereof for the manufacture of a composition for promoting differentiation of undifferentiated pancreatic stem cells to pancreatic beta cells; and
(26) A use of a DNA coding for a betacellulin protein or a mutein thereof for the manufacture of a composition for preventing or treating undifferentiated type of pancreatic cancer.
REFERENCES:
patent: 0 555 785 A1 (1893-08-01), None
Bow
Conlin David G.
Dike Bronstein Roberts & Cushman
Kemmerer Elizabeth
Lowen Cara Z.
Takeda Chemical Industries Ltd.
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