# US 7,745,396 B2 · Use of SERP-1 as an antiplatelet agent

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- Number: US 7,745,396 B2
- Document ID: US7745396B2
- Status: Granted
- Kind: B2
- Application number: 11/899,680
- Filed: 2007-09-07
- Published: 2008-03-20
- Granted: 2010-06-29
- Earliest claimed: 2004-10-21
- Assignees: Viron Therapeutics, Inc.
- Inventors: Alexandra Lucas
- Web page: https://patentgrep.com/patent/US7745396B2

## CPC

- A61K 38/55: Protease inhibitors
- A61K 31/4743: condensed with ring systems having sulfur as a ring hetero atom
- A61K 31/60: Salicylic acid; Derivatives thereof
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Compositions and methods for antiplatelet/anti-thrombotic therapy in a mammalian subject are provided. The method involves administering a therapeutically effective amount of SERP-1 admixed with a pharmaceutically acceptable carrier to a subject in need of such therapy. Methods of administering SERP-1 with at least one other antiplatelet agent are also provided. The compositions and methods of the present invention are useful for treating and preventing recurrence of numerous cardiovascular diseases and injuries.

## Claims

### Claim 1

A method of treating a cardiovascular disease-related thrombosis or embolism in a mammalian subject undergoing stent placement, said method comprising administering a therapeutically effective amount of serine proteinase inhibitor-1 (SERP-1), SERP-1 analog, or biologically active fragment thereof and a pharmaceutically acceptable carrier to said subject, wherein said SERP-1, SERP-1 analog, or biologically active fragment thereof inhibits thrombolytic proteases urokinase-type plasminogen activator, tissue-type plasminogen activator, and plasmin in vitro.

### Claim 2 (depends on 1)

The method of claim 1, wherein said mammalian subject is human.

### Claim 3 (depends on 1)

The method of claim 1, wherein said SERP-1, SERP-1 analog, or biologically active fragment thereof is delivered by oral administration, intravenous, intra-arterial, intra-articular, subcutaneous, intraperitoneal, intraspinal, intrarectal, or intramuscular infusion, or aerosol inhalant.

### Claim 4 (depends on 1)

The method of claim 1, comprising administering a therapeutically effective amount of said SERP-1 or biologically active fragment thereof and a pharmaceutically acceptable carrier to said subject.

### Claim 5 (depends on 4)

The method of claim 4, wherein said SERP-1 or biologically active fragment thereof is mature, processed SERP-1.

### Claim 6 (depends on 5)

The method of claim 5, wherein said therapeutically effective amount of said mature, processed SERP-1 is about 5 μg/kg to about 50 mg/kg per dose.

### Claim 7

A method of treating a cardiovascular abnormal condition-related thrombosis or embolism in a mammalian subject undergoing stent placement, said method comprising administering a therapeutically effective amount of serine proteinase inhibitor-1 (SERP-1), SERP-1 analog, or biologically active fragment thereof and a pharmaceutically acceptable carrier to said subject, wherein said SERP-1, SERP-1 analog, or biologically active fragment thereof inhibits thrombolytic proteases urokinase-type plasminogen activator, tissue-type plasminogen activator, and plasmin in vitro.

### Claim 8 (depends on 7)

The method of claim 7, wherein said mammalian subject is human.

### Claim 9 (depends on 7)

The method of claim 7, wherein said SERP-1, SERP-1 analog, or biologically active fragment thereof is delivered by oral administration, intravenous, intra-arterial, intra-articular, subcutaneous, intraperitoneal, intraspinal, intrarectal, or intramuscular infusion, or aerosol inhalant.

### Claim 10 (depends on 7)

The method of claim 7, comprising administering a therapeutically effective amount of said SERP-1 or biologically active fragment thereof and a pharmaceutically acceptable carrier to said subject.

### Claim 11 (depends on 10)

The method of claim 10, wherein said SERP-1 or biologically active fragment thereof is mature, processed SERP-1.

### Claim 12 (depends on 11)

The method of claim 11, wherein said therapeutically effective amount of said mature, processed SERP-1 is about 5 μg/kg to about 50 mg/kg per dose.

### Claim 13

A method of treating a cardiovascular disease-related thrombosis or embolism in a mammalian subject in need thereof, comprising administering a therapeutically effective amount of serine proteinase inhibitor-1 (SERP-1), SERP-1 analog, or biologically active fragment thereof and at least one other antiplatelet agent and a pharmaceutically acceptable carrier to said subject, wherein said SERP-1, SERP-1 analog, or biologically active fragment thereof inhibits thrombolytic proteases urokinase-type plasminogen activator, tissue-type plasminogen activator, and plasmin in vitro.

### Claim 14 (depends on 13)

The method of claim 13, wherein said mammalian subject is human.

### Claim 15 (depends on 13)

The method of claim 13, wherein said SERP-1, SERP-1 analog, or biologically active fragment thereof and said other antiplatelet agent are delivered by oral administration, intravenous, intra-arterial, intra-articular, subcutaneous, intraperitoneal, intraspinal, intrarectal, or intramuscular infusion, or aerosol inhalant.

### Claim 16 (depends on 13)

The method of claim 13, comprising administering a therapeutically effective amount of said SERP-1 or biologically active fragment thereof and said other antiplatelet agent and said pharmaceutically acceptable carrier to said subject.

### Claim 17 (depends on 16)

The method of claim 16, wherein said SERP-1 or biologically active fragment thereof is mature, processed SERP-1.

### Claim 18 (depends on 17)

The method of claim 17, wherein said therapeutically effective amount of said mature, processed SERP-1 is about 5 μg/kg to about 50 mg/kg per dose.

### Claim 19 (depends on 13)

The method of claim 13, wherein said other antiplatelet agent comprises a compound selected from the group consisting of aspirin, clopidogrel, ridogrel, ticlopidine, and glycoprotein IIb/IIIa inhibitors.

### Claim 20 (depends on 19)

The method of claim 19, wherein said other antiplatelet agent comprises a glycoprotein IIb/IIIa inhibitor selected from the group consisting of abciximab, integrilin, lamifiban, tirofiban, and xemlofiban.

### Claim 21 (depends on 13)

The method of claim 13, wherein said other antiplatelet agent comprises Plavix™.

### Claim 22

A method of treating a cardiovascular abnormal condition-related thrombosis or embolism in a mammalian subject in need thereof, comprising administering a therapeutically effective amount of serine proteinase inhibitor-1 (SERP-1), SERP-1 analog, or biologically active fragment thereof and at least one other antiplatelet agent and a pharmaceutically acceptable carrier to said subject, wherein said SERP-1, SERP-1 analog, or biologically active fragment thereof inhibits thrombolytic proteases urokinase-type plasminogen activator, tissue-type plasminogen activator, and plasmin in vitro.

### Claim 23 (depends on 22)

The method of claim 22, wherein said mammalian subject is human.

### Claim 24 (depends on 22)

The method of claim 22, wherein said SERP-1, SERP-1 analog, or biologically active fragment thereof and said other antiplatelet agent are delivered by oral administration, intravenous, intra-arterial, intra-articular, subcutaneous, intraperitoneal, intraspinal, intrarectal, or intramuscular infusion, or aerosol inhalant.

### Claim 25 (depends on 22)

The method of claim 22, comprising administering a therapeutically effective amount of said SERP-1 or biologically active fragment thereof and said other antiplatelet agent and said pharmaceutically acceptable carrier to said subject.

### Claim 26 (depends on 25)

The method of claim 25, wherein said SERP-1 or biologically active fragment thereof is mature, processed SERP-1.

### Claim 27 (depends on 26)

The method of claim 26, wherein said therapeutically effective amount of said mature, processed SERP-1 is about 5 μg/kg to about 50 mg/kg per dose.

### Claim 28 (depends on 22)

The method of claim 22, wherein said other antiplatelet agent comprises a compound selected from the group consisting of aspirin, clopidogrel, ridogrel, ticlopidine, and glycoprotein IIb/IIIa inhibitors.

### Claim 29 (depends on 28)

The method of claim 28, wherein said other antiplatelet agent comprises a glycoprotein IIb/IIIa inhibitor selected from the group consisting of abciximab, integrilin, lamifiban, tirofiban, and xemlofiban.

### Claim 30 (depends on 22)

The method of claim 22, wherein said other antiplatelet agent comprises Plavix™.

### Claim 31

A method of reducing the occurrence of a cardiovascular disease-related thrombosis or embolism in a mammalian subject undergoing stent placement, said method comprising administering a therapeutically effective amount of serine proteinase inhibitor-1 (SERP-1), SERP-1 analog, or biologically active fragment thereof and a pharmaceutically acceptable carrier to said subject, wherein said SERP-1, SERP-1 analog, or biologically active fragment thereof inhibits thrombolytic proteases urokinase-type plasminogen activator, tissue-type plasminogen activator, and plasmin in vitro.

### Claim 32 (depends on 31)

The method of claim 31, wherein said mammalian subject is human.

### Claim 33 (depends on 31)

The method of claim 31, wherein said SERP-1, SERP-1 analog, or biologically active fragment thereof is delivered by oral administration, intravenous, intra-arterial, intra-articular, subcutaneous, intraperitoneal, intraspinal, intrarectal, or intramuscular infusion, or aerosol inhalant.

### Claim 34 (depends on 31)

The method of claim 31, comprising administering a therapeutically effective amount of said SERP-1 or biologically active fragment thereof and a pharmaceutically acceptable carrier to said subject.

### Claim 35 (depends on 34)

The method of claim 34, wherein said SERP-1 or biologically active fragment thereof is mature, processed SERP-1.

### Claim 36 (depends on 35)

The method of claim 35, wherein said therapeutically effective amount of said mature, processed SERP-1 is about 5 μg/kg to about 50 mg/kg per dose.

### Claim 37

A method of reducing the occurrence of a cardiovascular abnormal condition-related thrombosis or embolism in a mammalian subject undergoing stent placement, said method comprising administering a therapeutically effective amount of serine proteinase inhibitor-1 (SERP-1), SERP-1 analog, or biologically active fragment thereof and a pharmaceutically acceptable carrier to said subject, wherein said SERP-1, SERP-1 analog, or biologically active fragment thereof inhibits thrombolytic proteases urokinase-type plasminogen activator, tissue-type plasminogen activator, and plasmin in vitro.

### Claim 38 (depends on 37)

The method of claim 37, wherein said mammalian subject is human.

### Claim 39 (depends on 37)

The method of claim 37, wherein said SERP-1, SERP-1 analog, or biologically active fragment thereof is delivered by oral administration, intravenous, intra-arterial, intra-articular, subcutaneous, intraperitoneal, intraspinal, intrarectal, or intramuscular infusion, or aerosol inhalant.

### Claim 40 (depends on 37)

The method of claim 37, comprising administering a therapeutically effective amount of said SERP-1 or biologically active fragment thereof and a pharmaceutically acceptable carrier to said subject.

### Claim 41 (depends on 40)

The method of claim 40, wherein said SERP-1 or biologically active fragment thereof is mature, processed SERP-1.

### Claim 42 (depends on 41)

The method of claim 41, wherein said therapeutically effective amount of said mature, processed SERP-1 is about 5 μg/kg to about 50 mg/kg per dose.

### Claim 43

A method of reducing the occurrence of a cardiovascular disease-related thrombosis or embolism in a mammalian subject in need thereof, comprising administering a therapeutically effective amount of serine proteinase inhibitor-1 (SERP-1), SERP-1 analog, or biologically active fragment thereof and at least one other antiplatelet agent and a pharmaceutically acceptable carrier to said subject, wherein said SERP-1, SERP-1 analog, or biologically active fragment thereof inhibits thrombolytic proteases urokinase-type plasminogen activator, tissue-type plasminogen activator, and plasmin in vitro.

### Claim 44 (depends on 43)

The method of claim 43, wherein said mammalian subject is human.

### Claim 45 (depends on 43)

The method of claim 43, wherein said SERP-1, SERP-1 analog, or biologically active fragment thereof and said other antiplatelet agent are delivered by oral administration, intravenous, intra-arterial, intra-articular, subcutaneous, intraperitoneal, intraspinal, intrarectal, or intramuscular infusion, or aerosol inhalant.

### Claim 46 (depends on 43)

The method of claim 43, comprising administering a therapeutically effective amount of said SERP-1 or biologically active fragment thereof and said other antiplatelet agent and said pharmaceutically acceptable carrier to said subject.

### Claim 47 (depends on 46)

The method of claim 46, wherein said SERP-1 or biologically active fragment thereof is mature, processed SERP-1.

### Claim 48 (depends on 47)

The method of claim 47, wherein said therapeutically effective amount of said mature, processed SERP-1 is about 5 μg/kg to about 50 mg/kg per dose.

### Claim 49 (depends on 43)

The method of claim 43, wherein said other antiplatelet agent comprises a compound selected from the group consisting of aspirin, clopidogrel, ridogrel, ticlopidine, and glycoprotein IIb/IIIa inhibitors.

### Claim 50 (depends on 49)

The method of claim 49, wherein said other antiplatelet agent comprises a glycoprotein IIb/IIIa inhibitor selected from the group consisting of abciximab, integrilin, lamifiban, tirofiban, and xemlofiban.

### Claim 51 (depends on 43)

The method of claim 43, wherein said other antiplatelet agent comprises Plavix™.

### Claim 52

A method of reducing the occurrence of a cardiovascular abnormal condition-related thrombosis or embolism in a mammalian subject in need thereof, comprising administering a therapeutically effective amount of serine proteinase inhibitor-1 (SERP-1), SERP-1 analog, or biologically active fragment thereof and at least one other antiplatelet agent and a pharmaceutically acceptable carrier to said subject, wherein said SERP-1, SERP-1 analog, or biologically active fragment thereof inhibits thrombolytic proteases urokinase-type plasminogen activator, tissue-type plasminogen activator, and plasmin in vitro.

### Claim 53 (depends on 52)

The method of claim 52, wherein said mammalian subject is human.

### Claim 54 (depends on 52)

The method of claim 52, wherein said SERP-1, SERP-1 analog, or biologically active fragment thereof and said other antiplatelet agent are delivered by oral administration, intravenous, intra-arterial, intra-articular, subcutaneous, intraperitoneal, intraspinal, intrarectal, or intramuscular infusion, or aerosol inhalant.

### Claim 55 (depends on 52)

The method of claim 52, comprising administering a therapeutically effective amount of said SERP-1 or biologically active fragment thereof and said other antiplatelet agent and said pharmaceutically acceptable carrier to said subject.

### Claim 56 (depends on 55)

The method of claim 55, wherein said SERP-1 or biologically active fragment thereof is mature, processed SERP-1.

### Claim 57 (depends on 56)

The method of claim 56, wherein said therapeutically effective amount of said mature, processed SERP-1 is about 5 μg/kg to about 50 mg/kg per dose.

### Claim 58 (depends on 52)

The method of claim 52, wherein said other antiplatelet agent comprises a compound selected from the group consisting of aspirin, clopidogrel, ridogrel, ticlopidine, and glycoprotein IIb/IIIa inhibitors.

### Claim 59 (depends on 58)

The method of claim 58, wherein said other antiplatelet agent comprises a glycoprotein IIb/IIIa inhibitor selected from the group consisting of abciximab, integrilin, lamifiban, tirofiban, and xemlofiban.

### Claim 60 (depends on 52)

The method of claim 52, wherein said other antiplatelet agent comprises Plavix™.

### Claim 61 (depends on 5)

The method of claim 5, wherein said mature, processed SERP-1 comprises the mature, processed form of a polypeptide having the amino acid sequence of SEQ ID NO: 1.

### Claim 62 (depends on 61)

The method of claim 61, wherein said mature, processed SERP-1 consists of the mature, processed form of a polypeptide having the amino acid sequence of SEQ ID NO: 1.

### Claim 63 (depends on 11)

The method of claim 11, wherein said mature, processed SERP-1 comprises the mature, processed form of a polypeptide having the amino acid sequence of SEQ ID NO: 1.

### Claim 64 (depends on 63)

The method of claim 63, wherein said mature, processed SERP-1 consists of the mature, processed form of a polypeptide having the amino acid sequence of SEQ ID NO: 1.

### Claim 65 (depends on 17)

The method of claim 17, wherein said mature, processed SERP-1 comprises the mature, processed form of a polypeptide having the amino acid sequence of SEQ ID NO: 1.

### Claim 66 (depends on 65)

The method of claim 65, wherein said mature, processed SERP-1 consists of the mature, processed form of a polypeptide having the amino acid sequence of SEQ ID NO: 1.

### Claim 67 (depends on 26)

The method of claim 26, wherein said mature, processed SERP-1 comprises the mature, processed form of a polypeptide having the amino acid sequence of SEQ ID NO: 1.

### Claim 68 (depends on 67)

The method of claim 67, wherein said mature, processed SERP-1 consists of the mature, processed form of a polypeptide having the amino acid sequence of SEQ ID NO: 1.

### Claim 69 (depends on 35)

The method of claim 35, wherein said mature, processed SERP-1 comprises the mature, processed form of a polypeptide having the amino acid sequence of SEQ ID NO: 1.

### Claim 70 (depends on 69)

The method of claim 69, wherein said mature, processed SERP-1 consists of the mature, processed form of a polypeptide having the amino acid sequence of SEQ ID NO: 1.

### Claim 71 (depends on 41)

The method of claim 41, wherein said mature, processed SERP-1 comprises the mature, processed form of a polypeptide having the amino acid sequence of SEQ ID NO: 1.

### Claim 72 (depends on 71)

The method of claim 71, wherein said mature, processed SERP-1 consists of the mature, processed form of a polypeptide having the amino acid sequence of SEQ ID NO: 1.

### Claim 73 (depends on 47)

The method of claim 47, wherein said mature, processed SERP-1 comprises the mature, processed form of a polypeptide having the amino acid sequence of SEQ ID NO: 1.

### Claim 74 (depends on 73)

The method of claim 73, wherein said mature, processed SERP-1 consists of the mature, processed form of a polypeptide having the amino acid sequence of SEQ ID NO: 1.

### Claim 75 (depends on 56)

The method of claim 56, wherein said mature, processed SERP-1 comprises the mature, processed form of a polypeptide having the amino acid sequence of SEQ ID NO: 1.

### Claim 76 (depends on 75)

The method of claim 75, wherein said mature, processed SERP-1 consists of the mature, processed form of a polypeptide having the amino acid sequence of SEQ ID NO: 1.