Reduced side-effect hemoglobin compositions

• US 7,211,560 B2
• Filed: 12/29/2003
• Issued: 05/01/2007
• Est. Priority Date: 11/12/1999
• Status: Expired due to Fees

• Current Assignee: Baxter Healthcare SA (Baxter International Inc.), Baxter International Inc.
• Original Assignee: Baxter Healthcare SA (Baxter International Inc.), Baxter International Inc.
• Inventors: Pereira, David, Lee, Geoffrey F., Doyle, Michael P., Burhop, Kenneth E., Foster, David L., Hai, Ton-That, Looker, Douglas L., Hartman, James C., Richards, Jane P., Lemon, Douglas D., Brucker, Eric A., Schick, Michael R., Moore, Edwin G., Apostol, Izydor Z., Trimble, Stephen P., Glascock, Christopher B.
• Primary Examiner(s): CARLSON, KAREN C
• Application Number:
  US10/747,580
• Publication Number:
  US 20040259769A1
• Time in Patent Office: 1,219 Days
• Field of Search: 514/6, 530/385
• US Class Current: 514/13.4
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 39/00 General protective or antinoxious agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/06 Antianaemics
• CPC Class Codes: A61P 7/08 Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock artificial tears A61P27/04
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07K 14/805 Haemoglobins; Myoglobins

Abstract

The invention relates to novel hemoglobin compositions, particularly novel recombinant mutant hemoglobin compositions, which eliminate or substantially reduce 1) the creation of heart lesions, 2) gastrointestinal discomfort, 3) pressor effects, and 4) endotoxin hypersensitivity associated with the administration of extracellular hemoglobin compositions in various therapeutic applications. Applications described include treatments for anemia, head injury, hemorrhage or hypovolemia, ischemia, cachexia, sickle cell crisis and stroke; enhancing cancer treatments; stimulating hematopoiesis; improving repair of physically damaged tissues; alleviating cardiogenic shock; and shock resuscitation.

Claims

1. A pharmaceutical composition for transporting and releasing oxygen comprising a suspension of from about 5 to about 20 grams of reduced lesion hemoglobin per deciliter of a pharmaceutically acceptable carrier, wherein the hemoglobin is polymerized.

2. The pharmaceutical composition of claim 1 wherein the hemoglobin is reduced gastrointestinal effect hemoglobin, low gastrointestinal effect hemoglobin, low pressor effect hemoglobin, or hemoglobin which exhibits decreased aggregate formation when stored in solution in deoxygenated form for prolonged periods.

3. The pharmaceutical composition of claim 1 wherein the composition:

a) is substantially free of red blood cell stroma, b) is substantially free of pyrogens, and c) comprises less than about 10% methemoglobin.

4. The pharmaceutical composition of claim 1 wherein the hemoglobin has an average molecular weight between 65 and 650 kilodaltons.

5. The pharmaceutical composition of claim 1 wherein the hemoglobin is further characterized in that the hemoglobin comprises at least one heme pocket mutation which reduces the rate of NO scavenging when compared to the same molecule without the heme pocket mutation.

6. The pharmaceutical composition of claim 1 wherein the reduced lesion hemoglobin is an oligomeric hemoglobin with a molecular weight distribution of greater than about 50% in the range of 130 to 500 kilodaltons, wherein at least 80% of the oligomeric hemoglobin comprises two or more hemoglobin-like proteins.

7. The pharmaceutical composition of claim 1 wherein the reduced lesion hemoglobin includes about 40 to about 60% derivatized monomeric hemoglobin with an average molecular weight between 65 and less than about 130 kilodaltons, and about 40 to about 60% oligomeric hemoglobin with an average molecular weight between 130 and 650 kilodaltons, wherein the oligomeric hemoglobin comprises two or more hemoglobin-like proteins.

8. A pharmaceutical composition for transporting and releasing oxygen comprising a suspension of from about 5 to about 20 grams of lesion free hemoglobin per deciliter of a pharmaceutically acceptable carrier, wherein the hemoglobin is polymerized.

9. A pharmaceutical composition for transporting and releasing oxygen comprising a suspension of from about 5 to about 20 grams of reduced gastrointestinal effect hemoglobin per deciliter of a pharmaceutically acceptable carrier, wherein the hemoglobin is polymerized.

10. The pharmaceutical composition of claim 9 wherein the hemoglobin is lesion free hemoglobin or reduced lesion hemoglobin.

11. A pharmaceutical composition for transporting and releasing oxygen comprising a suspension of from about 5 to about 20 grams of low gastrointestinal effect hemoglobin per deciliter of a pharmaceutically acceptable carrier, wherein the hemoglobi is polymerized.

12. The pharmaceutical composition of claim 11 wherein the hemoglobin is lesion free hemoglobin or reduced lesion hemoglobin.

13. A pharmaceutical composition for transporting and releasing oxygen comprising a suspension of from about 5 to about 20 grams of reduced pressor effect hemoglobin per deciliter of a pharmaceutically acceptable carrier, wherein the hemoglobin is polymerized and is reduced lesion hemoglobin, low gastrointestinal effect hemoglobin, reduced gastrointestinal effect hemoglobin, lesion free hemoglobin, or hemoglobin which exhibits decreased aggregate formation when stored in solution in deoxygenated form for prolonged periods.

14. A pharmaceutical composition for transporting and releasing oxygen comprising a suspension of from about 5 to about 20 grams of low pressor effect hemoglobin per deciliter of a pharmaceutically acceptable carrier, wherein the hemoglobin is polymerized.

15. The pharmaceutical composition of claim 14 wherein the hemoglobin is reduced lesion hemoglobin or lesion free hemoglobin.

16. A polymerized recombinant hemoglobin which is a reduced lesion hemoglobin.

17. The hemoglobin of claim 16 wherein the hemoglobin exhibits decreased aggregate formation when stored in solution in deoxygenated form for prolonged periods.

18. The hemoglobin of claim 16 wherein the hemoglobin is further characterized in that the hemoglobin comprises at least one heme pocket mutation which reduces the rate of NO scavenging when compared to the same molecule without the heme pocket mutation.

19. A polymerized recombinant hemoglobin which is a lesion free hemoglobin.

20. A polymerized recombinant hemoglobin which is a reduced gastrointestinal effect hemoglobin.

21. The hemoglobin of claim 20 wherein the hemoglobin is lesion free hemoglobin or reduced lesion hemoglobin.

22. A polymerized recombinant hemoglobin which is a low gastrointestinal effect hemoglobin.

23. The hemoglobin of claim 22 wherein the hemoglobin is lesion free hemoglobin or reduced lesion hemoglobin.

24. A polymerized recombinant hemoglobin which is a reduced pressor effect hemoglobin, and which is reduced lesion hemoglobin, lesion free hemoglobin low gastrointestinal effect hemoglobin, reduced gastrointestinal effect hemoglobin, or hemoglobin which exhibits decreased aggregate formation when stored in solution in deoxygenated form for prolonged periods.

25. A polymerized recombinant hemoglobin which is a low pressor effect hemoglobin.

26. The hemoglobin of claim 25 wherein the hemoglobin is lesion free hemoglobin or reduced lesion hemoglobin.

27. A polymerized recombinant hemoglobin which is a reduced endotoxin effect hemoglobin, and which is a lesion free hemoglobin or a reduced lesion hemoglobin.

28. A polymerized recombinant mutant hemoglobin which exhibits decreased aggregate formation when stored in solution in deoxygenated form for prolonged periods, with the proviso that said hemoglobin does not include the mutation β

6 Glu→

Val.

29. A chemically crosslinked polymerized hemoglobin which comprises at least one heme pocket mutation which reduces the rate of NO scavenging by the polymerized hemoglobin when compared to the same molecule without the heme pocket mutation.

30. The polymerized hemoglobin of claim 29 wherein the hemoglobin is reduced lesion hemoglobin, lesion free hemoglobin, or reduced pressor effect hemoglobin.

31. A pharmaceutical composition for transporting and releasing oxygen comprising a suspension of from about 5 to about 20 grams of reduced endotoxin effect hemoglobin per deciliter of a pharmaceutically acceptable carrier, wherein the hemoglobin is polymerized and is reduced lesion hemoglobin or lesion free hemoglobin.