Tissue plasminogen activator antibodies and methods of use

Patent metadata

Field	Value
Publication number	US-10160813-B2
Application number	US-201414762601-A
Country	US
Kind code	B2
Filing date	Jan 22, 2014
Priority date	Jan 22, 2013
Publication date	Dec 25, 2018
Grant date	Dec 25, 2018

Abstract

A molecule that binds specifically to a human tissue plasminogen activator (TPA) or a TPA mutant is provided. The molecule having sub-nanomolar affinity to inhibit fibrin-dependent plasminogen activation with an IC50<5 nM, to inhibit degradation of human fibrin clots without affecting TPA amidolytic activity or non-fibrin-dependent activation, and the amino acid sequence of the TPA mutant is at least 65% identical to SEQ ID NO: 1 or SEQ ID NO: 2. Further provided is a method for treating systemic bleeding and brain hemorrhage after TPA treatment in a patient in need of such treatment. The method comprises administering to said patient an effective amount of the molecule, wherein the molecule selectively inhibits fibrin-augmented plasminogen activation in the patient.

First claim

What is claimed is:

1. An antibody that binds specifically to a human tissue plasminogen activator (TPA) or a TPA mutant to inhibit degradation of human fibrin clots, wherein said antibody having sub-nanomolar affinity to inhibit fibrin-dependent plasminogen activation with an IC50<5 nM, and wherein the amino acid sequence of said TPA mutant has at least 65% identity to SEQ ID NO: 1 or SEQ ID NO: 2; and wherein said antibody is a monoclonal antibody identified as TPAi-14 (ECACC accession number 18042001) or TPAi-23 (ECACC accession number 18042002) that selectively inhibits fibrin-augmented plasminogen activation.

2. The antibody of claim 1 , wherein the antibody does not affect TPA amidolytic activity or non-fibrin-dependent activation.

3. The antibody of claim 1 wherein the amino acid sequence of human TPA is SEQ ID NO: 1 or SEQ ID NO: 2.

4. The antibody of claim 1 , wherein monoclonal antibody TPAi-14 and TPAi-23 bind to different epitopes of the TPA.

5. A monoclonal antibody identified as TPAi-14 (ECACC accession number 18042001) or TPAi-23 (ECACC accession number 18042002) that selectively inhibits fibrin-augmented plasminogen activation.

6. A method for treating TPA-induced hemorrhage in a patient in need of such treatment, which comprises administering to said patient an effective amount of the antibody of claim 1 , wherein said antibody selectively inhibits fibrin-augmented plasminogen activation in said patient.

7. The method of claim 6 , wherein the patient suffers from ischemic stroke.

8. The method of claim 6 , wherein the patient suffers from acute myocardial infarction.

9. The method of claim 6 , wherein the antibody reduces TPA-induced cerebral hemorrhage and surgical bleeding.

10. The method of claim 6 , wherein the antibody inhibits fibrinolysis induced by TPA.

11. The method of claim 10 , wherein said antibody inhibits the initiation of fibrinolysis.

12. The method of claim 6 , wherein said antibody is identified as TPAi-14.

13. The method of claim 6 , wherein said antibody is identified as TPAi-23.

14. The method of claim 6 , wherein TPAi-14 and TPAi23 are used together and synergistically inhibit fibrinolysis induced by TPA.

15. The method of claim 6 , wherein the TPA-induced hemorrhage comprises systemic bleeding, brain hemorrhage, and/or stroke.

Assignees

• Univ Tennessee Res Found

Inventors

• Reed Guy

Classifications

• A61P7/04

  Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents · CPC title

• C07K2317/92

  Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value · CPC title

• G01N33/573

  for enzymes or isoenzymes · CPC title

• C07K16/40 Primary

  against enzymes · CPC title

• C07K2317/33

  Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity · CPC title