Therapeutic methods employing sialylated glycoforms of soluble complement receptor 1 (SCR 1)

• US 5,858,969 A
• Filed: 06/06/1995
• Issued: 01/12/1999
• Est. Priority Date: 08/07/1992
• Status: Expired due to Term

• Current Assignee: Celldex Therapeutics Incorporated
• Original Assignee: T Cell Sciences, Inc. (Celldex Therapeutics Incorporated)
• Inventors: Lifter, John, Gosselin, Michael L., Smith, Richard A.G., Marsh, Henry C. Jr., Freeman, Anne Mary, Yeh, Chang-Jing Grace
• Primary Examiner(s): Fitzgerald, David L.
• Application Number:
  US08/470,867
• Time in Patent Office: 1,316 Days
• Field of Search: 530/350, 514/2, 514/8, 424/94.63, 424/94.64
• US Class Current: 514/1.5
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 38/166 Streptokinase
• CPC Class Codes: A61K 38/49 Urokinase; Tissue plasminogen activator
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: C07K 14/705 Receptors; Cell surface antigens; Cell surface determinants tumour specific antigens C07K14/4748

Abstract

Provided are therapeutic methods employing preparations of recombinant soluble Complement Receptor type 1 (sCR1) defined with respect to the distribution of sCR1 glycoforms. The methods are suitable for treatment of disease involving inflammation, inappropriate complement activation, and in thrombotic or shock state conditions. Preferred methods employ sCR1 glycoforms that are sialylated, have a pI of ≦5.1, or have a sialic acid:mannose molar ratio of ≧0.25.

Claims

1. A method of treating a disease or disorder associated with inflammation or inappropriate complement activation comprising administering to a subject in need of such treatment a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a therapeutically effective amount of sCR1 glycoprotein molecules, in which said composition exhibits dominant isoforms of sCR1 glycoprotein molecules which have an isoelectric point, pI, less than or equal to 5.1 as determined by chromatofocusing, and wherein the pI of said dominant isoforms increases after neuraminidase treatment.

2. A method of treating a disease or disorder associated with inflammation or inappropriate complement activation comprising administering to a subject in need of such treatment a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a therapeutically effective amount of sCR1 glycoprotein molecules, wherein substantially all of the sCR1 glycoprotein molecules in said composition contain one or more complex oligosaccharide structures, wherein at least about 40% of said oligosaccharide structures are terminated with one or more sialic acid residues per oligosaccharide structure.

3. The method of claim 2, wherein at least about 70% of said oligosaccharide structures are terminated with one or more sialic acid residues per oligosaccharide structure.

4. A method of treating a disease or disorder associated with inflammation or inappropriate complement activation comprising administering to a subject in need of such treatment a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a therapeutically effective amount of sCR1 glycoprotein molecules, in which 70% of all of said sCR1 glycoprotein molecules have an isoelectric point, pI, less than or equal to 5.1 as determined by chromatofocusing, and wherein the pI of said dominant isoforms increases after neuraminidase treatment.

5. A method of treating a disease or disorder associated with inflammation or inappropriate complement activation comprising administering to a subject in need of such treatment a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a therapeutically effective amount of sCR1 glycoprotein molecules, wherein all of the sCR1 glycoprotein molecules in said composition form a population of sCR1 glycoprotein molecules having a molar ratio of sialic acid to mannose of greater than or equal to 0.25.

6. A method of treating a thrombotic condition in a subject, comprising administering to a subject in need of such treatment a pharmaceutical composition comprising (a) a pharmaceutically acceptable carrier or excipient;

(b) a therapeutically effective amount of a thrombolytic agent; and

(c) a therapeutically effective amount of sCR1 glycoprotein molecules, in which said composition exhibits dominant isoforms of sCR1 glycoprotein molecules which have an isoelectric point, pI, less than or equal to 5.1 as determined by chromatofocusing, and wherein the pI of said dominant isoforms increases after neuraminidase treatment.

7. A method of treating a thrombotic condition in a subject, comprising administering to a subject in need of such treatment a pharmaceutical composition comprising (a) a pharmaceutically acceptable carrier or excipient;

(b) a therapeutically effective amount of a thrombolytic agent; and

(c) a therapeutically effective amount of sCR1 glycoprotein molecules, wherein substantially all of the sCR1 glycoprotein molecules in said composition contain one or more complex oligosaccharide structures, wherein at least about 40% of said oligosaccharide structures are terminated with one or more sialic acid residues per oligosaccharide structure.

8. The method of claim 7, wherein at least about 70% of said oligosaccharide structures are terminated with one or more sialic acid residues per oligosaccharide structure.

9. A method of treating a thrombotic condition in a subject, comprising administering to a subject in need of such treatment a pharmaceutical composition comprising (a) a pharmaceutically acceptable carrier or excipient;

(b) a therapeutically effective amount of a thrombolytic agent; and

(c) a therapeutically effective amount of sCR1 glycoprotein molecules, in which 70% of all of said sCR1 glycoprotein molecules have an isoelectric point, pI, less than or equal to 5.1 as determined by chromatofocusing, and wherein the pI of said dominant isoforms increases after neuraminidase treatment.

10. A method of treating a thrombotic condition in a subject, comprising administering to a subject in need of such treatment a pharmaceutical composition comprising (a) a pharmaceutically acceptable carrier or excipient;

(b) a therapeutically effective amount of a thrombolytic agent; and

(c) a therapeutically effective amount of sCR1 glycoprotein molecules, wherein all of the sCR1 glycoprotein molecules in said composition form a population of sCR1 glycoprotein molecules having a molar ratio of sialic acid to mannose of greater than or equal to 0.25.

11. The method according to claim 6, 7, 8, 9, or 10 wherein said thrombolytic agent is selected from the group consisting of:

(a) a plasminogen activator or a mutein thereof;

(b) anisoylated plasminogen-streptokinase-activator complex;

(c) single-chain urokinase;

(d) two-chain urokinase;

(e) streptokinase;

(f) a fibrinolytically active hybrid protein which comprises one chain of a first two-chain protease linked to one chain of a second two-chain protease, at least one of said first or second protease having fibrinolytic activity, such that said hybrid protein has a catalytic site essential for fibrinolytic activity which is optionally blocked by a removable blocking group; and

(g) a reversibly blocked in vivo fibrinolytic enzyme wherein the catalytic site essential for fibrinolytic activity in said enzyme is blocked by a group which is removable by hydrolysis at a rate such that the pseudo first order rate constant for hydrolysis is in the range 10^-6 sec^-1 to 10^-3 sec^-1 in an isotonic aqueous solution at pH 7.4 at 37°

C.

12. A method of treating adult respiratory distress syndrome in a subject, comprising administering to a subject in need of such treatment a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a therapeutically effective amount of sCR1 glycoprotein molecules, in which said composition exhibits dominant isoforms of sCR1 glycoprotein molecules which have an isoelectric point, pI, less than or equal to 5.1 as determined by chromatofocusing, and wherein the pI of said dominant isoforms increases after neuraminidase treatment.

13. A method of treating adult respiratory distress syndrome in a subject, comprising administering to a subject in need of such treatment a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a therapeutically effective amount of sCR1 glycoprotein molecules, wherein substantially all of the sCR1 glycoprotein molecules in said composition contain one or more complex oligosaccharide structures, wherein at least about 40% of said oligosaccharide structures are terminated with one or more sialic acid residues per oligosaccharide structure.

14. The method of claim 13, wherein at least about 70% of said oligosaccharide structures are terminated with one or more sialic acid residues per oligosaccharide structure.

15. A method of treating adult respiratory distress syndrome in a subject, comprising administering to a subject in need of such treatment a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a therapeutically effective amount of sCR1 glycoprotein molecules, in which 70% of all of said sCR1 glycoprotein molecules have an isoelectric point, pI, less than or equal to 5.1 as determined by chromatofocusing, and wherein the pI of said dominant isoforms increases after neuraminidase treatment.

16. A method of treating adult respiratory distress syndrome in a subject, comprising administering to a subject in need of such treatment a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a therapeutically effective amount of sCR1 glycoprotein molecules, wherein all of the sCR1 glycoprotein molecules in said composition form a population of sCR1 glycoprotein molecules having a molar ratio of sialic acid to mannose of greater than or equal to 0.25.