Anti-CD18 antibodies in stroke

• US 5,914,112 A
• Filed: 01/22/1997
• Issued: 06/22/1999
• Est. Priority Date: 01/23/1996
• Status: Expired due to Term

• Current Assignee: Genentech, Inc. (Roche Holding AG), University of Vermont & State Agricultural College
• Original Assignee: Genentech, Inc. (Roche Holding AG), University of Vermont & State Agricultural College
• Inventors: Thomas, G. Roger, Bednar, Martin M., Gross, Cordell E.
• Primary Examiner(s): Chan, Christina Y.
• Assistant Examiner(s): Gambel, Phillip
• Application Number:
  US08/788,800
• Time in Patent Office: 881 Days
• Field of Search: 424/130.1, 424/134.1, 424/141.1, 424/153.1, 530/387.1, 530/388.22, 530/388.73
• US Class Current: 424/144.1
• 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 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 16/2845 against integrin beta2-subunit-containing molecules, e.g. CD11, CD18
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered

Abstract

A method for improving clinical outcome in focal ischemic stroke in a mammal by increasing cerebral blood flow and/or reducing infarct size is described which involves administering an effective amount of an anti-CD18 antibody to the mammal, in the absence of removal of the arterial obstruction.

Claims

1. A method for treating focal ischemic stroke caused by obstruction of a main cerebral artery in a human mammal comprising administering an amount of an anti-CD18 antibody to the mammal which is effective for increasing cerebral blood flow or reducing infarct size, in the absence of removal of the arterial obstruction, wherein at least one of the following conditions is present:

(a) the antibody binds to an extracellular domain of CD18 and inhibits or reduces the ability of a cell expressing CD18 to bind to endothelium,

(b) the antibody binds CD18 with an affinity of 4 nm or less, or

(c) the antibody dissociates a CD11b/CD18 complex.

2. The method of claim 1 which increases cerebral blood flow and reduces infarct size in the mammal.

3. The method of claim 1 wherein the anti-CD18 antibody fragment.

4. The method of claim 3 wherein the anti-CD18 antibody fragment is a F(ab'"'"')₂.

5. The method of claim 1 wherein the anti-CD18 antibody is humanized.

6. The method of claim 1 wherein the anti-CD18 antibody is administered to the mammal by bolus dosage.

7. The method of claim 1 wherein the anti-CD18 antibody is administered intravenously.

8. The method of claim 1 wherein the anti-CD18 antibody is administered via continuous infusion.

9. The method of claim 1 wherein the anti-CD18 antibody is administered to the mammal at a time between about 15 minutes to about 20 hours from the onset of focal ischemic stroke.

10. The method of claim 9 wherein the anti-CD18 antibody is administered to the mammal at a time between about 45 minutes to about 5 hours from the onset of focal ischemic stroke.

11. The method of claim 1 wherein the anti-CD18 antibody is humanized H52 antibody comprising heavy chain sequence of SEQ ID NO:

10 and light chain sequence of SEQ ID NO;

11.

12. The method of claim 11 wherein the H52 antibody is a F(ab'"'"')₂.

13. The method of claim 1, wherein the anti-CD18 antibody binds to an extracellular domain of CD18 and inhibits or reduces the ability of a cell expressing CD18 to bind to endothelium.

14. The method of claim 1, wherein the anti-CD18 antibody binds CD18 with an affinity of 4 nm or less.

15. The method of claim 1, wherein the anti-CD18 antibody binds CD18 with an affinity of 3 nm or less.

16. The method of claim 1, wherein the anti-CD18 antibody binds CD18 with an affinity of 1 nm or less.

17. The method of claim 1, wherein the anti-CD18 antibody dissociates the CD11b/CD18 complex.

18. The method of claim 1, wherein the anti-CD18 antibody binds to the epitope bound by H52 antibody.