Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Reexamination Certificate
1999-06-25
2002-12-31
Low, Christopher S. F. (Department: 1653)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
C435S069700, C435S069600, C435S006120, C435S320100, C435S325000, C435S252300, C530S324000, C530S350000, C530S380000, C530S383000, C530S384000, C424S009321, C424S450000, C514S012200, C514S002600, C514S04400A
Reexamination Certificate
active
06500646
ABSTRACT:
TECHNICAL FIELD
This invention relates to drugs in which peptides having affinity specific for phospholipids, preferably those which are contained in the constituents of lipid bilayers forming the surface layers of cells and of which the proportion in the outer part of each lipid bilayer increases when the cell is not normal, for example, in the case where it is damaged, denatured or activated, and biologically active substances bind to each other, deoxyribonucleic acid (DNA) which codes for the amino acid sequence of the drug in the case where the biologically active substance is a peptide, and processes for producing such drugs.
The invention also relates to a novel peptide having affinity specific for a phospholipid, preferably one which is contained in the constituents of lipid bilayers forming the surface layers of cells and of which the proportion in the outer part of each lipid bilayer increases when the cell is not normal, for example, in the case where it is damaged, denatured or activated, more preferably phosphatidylserine or phosphatidylethanolamine, further preferably phosphatidylserine, and DNA coding for the peptide.
The drugs and novel peptides of the invention are useful as preventives and therapeutics of diseases involving coagulopathy, inflammations and immune response.
BACKGROUND ART
Active studies are conducted today in connection with the creation of new drugs of high utility and as one of such studies an attempt is known that is directed to enhance the proportion in which a drug administered in vivo is delivered to the site for effective action while reducing the amount in which it becomes ineffective. This is an attempt at delivery of the drug in a site-specific manner, or an attempt of the so-called “targeting”. A representative method of targeting is one that utilizes an antigen-antibody reaction. A method that may be mentioned as an example of this approach is one in which an F(ab′)
2
fragment of a tumor cell specific antibody (21B2) is bound to liposomes containing adriamycin (ADM) to prepare immunoliposomes such that ADM is delivered on tumor cells [I. Uyama et al., Jpn. J. Cancer Res., Vol. 85, 434 (1994)]. Another representative method of targeting is one that utilizes the interaction between a polypeptide-composed receptor and its ligand. A method that may be mentioned as an example of this approach is one in which an RGD polypeptide sequence having an ability to bind to a GPIIb/GPIIIa receptor is attached to the C terminus of phospholipase A
2
(PLA
2
), whereby the PLA
2
is delivered on the membrane surface of platelets (A.C.A.P.A. Bekkers et al., Thrombosis and Haemostasis, Vol. 74, 1138 (1995)). Other examples that have so far been reported include one in which a peptide having affinity for heparin present on the surface of cells is bound to superoxide dismutase (SOD) or complement regulatory proteins such that the SOD is delivered on the cell surface (M. Inoue et al., J. Biol. Chem., Vol. 266, 16409 (1991)) or the complement regulatory proteins is delivered on the cell surface (International Patent Publication WO/96/34965).
Peptides are known which themselves have no biological activity but which have selective affinity to the target site, whereby the binding of a biologically active substances to the target site of action is inhibited through a competitive reaction. An example of such peptides is a polypeptide that binds to a receptor on the surface of cells selectively, thereby inhibiting a ligand from binding to the receptor. An example of such polypeptides is a polypeptide fragment derived from the antigen recognizing site (or complementary determining region: CDR) of an anti-TNF&agr; monoclonal antibody, which inhibits TNF&agr; from binding to a receptor [E. Doring et al., Molecular Immunology, Vol. 31, 1059 (1994)]. Another example is a polypeptide which, by selective binding to a phospholipid, phosphatidylserine, inhibits a factor involved in the progress of a blood coagulation from binding to the phospholipid and which is composed of 30 amino acids at the terminus of the C2 region of a human factor VIII (International Patent Publication WO/90/15615) or 12 amino acids derived from the CDR of a phosphatidylserine recognizing antibody (Japanese Patent Public Disclosure KOKAI No. 92992/1993).
Another example that concerns the creation of new drugs of high utility is an attempt at imparting a new biologically active function to an already biologically active peptide by genetic engineering techniques. As regards TM which is known to suppress a blood clotting reaction, reports have been made of a TM derivative which has a fibrinolytic enzyme such as a tissue plasminogen activator (tPA) bound to a TM peptide (Japanese Patent Domestic Announcement KOHYO 505554/1992) and a TM derivative which has a specified amino acid sequence bound to the C terminus of a TM peptide so as to impart its action in enhancing the activity of antithrombin III and suppressing platelet aggregation (Japanese Patent Public Disclosure KOKAI No. 279497/1994).
DISCLOSURE OF INVENTION
There are known many drugs today that must be used in limited doses because of the side effects they have. For example, heparin and antithrombin III are used as anticoagulants but the use of these substances must occasionally be limited since they have side effects such as the tendency to cause bleeding.
When administering drugs, it is generally required to administer more than a certain dose in order to attain a specified efficacy and side effects to the patient are sometimes a serious problem. In addition, it is by no means rare that administering high doses of drugs will eventually often increase the economic burden on the part of the patient. Therefore, it is desired to develop drugs that have high enough activity to exhibit satisfactory efficacy in low doses such that the side effects from drug administration can be reduced and which can be used more extensively without increasing the economic burden on the patient.
Under the circumstances, the present inventors conducted intensive studies with a view to attaining the stated object. As a result, they found that a drug having affinity for a specified phospholipid that was created by binding a biologically active substance to a substance having affinity for the specified phospholipid had an improved ability to localize on the specified phospholipid, thereby achieving a marked enhancement of its action and efficacy. The inventors further found that this marked enhancement of the action and efficacy of the drug was dependent on the specified phospholipid, which led to the accomplishment of the present invention.
Thus, a first aspect of the present invention is a drug that contains both a substance having affinity for a phospholipid and a biologically active substance. The drug is preferably one having a novel substance that possesses both a portion having affinity for a desired phospholipid and a portion having biologically activity; since the drug is obtained as a different form than it inherently occurs in nature, it is a drug having a chimeric substance or a substance produced by fusion of different proteins. Herein, said affinity for a phospholipid or said portion having affinity for a phospholipid preferably originates from the substance having affinity for a phospholipid, whereas the biological activity or the portion having biological activity preferably originates from the biologically active substance. Specifically, the drug is one that contains both a substance having affinity for a specified phospholipid, preferably phosphatidylserine or phosphatidylethanolamine, more preferably phosphatidylserine, and a biologically active substance. Herein, the substance having affinity for a specified phospholipid is preferably a peptide or a peptide-containing substance. Said peptide has a sequence represented by the following general formula; preferably, it is composed of said sequence. It should be noted that all of the sequences to be described in this specification permit substitution, deletion, addition, ins
Hasegawa Takashi
Kuriyama Shinichi
Birch Stewart Kolasch & Birch, LLP.
Kam Chih-Min
Low Christopher S. F.
Mochida Pharmaceutical Co. Ltd.
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