Method of treating stroke by administering a compound that inhibits VEGF-B signaling in combination with a thrombolytic agent

1. A method of reducing an effect of stroke in a subject, the method comprising administering to the subject a compound that inhibits VEGF-B signaling, wherein the compound that inhibits VEGF-B signaling is: an antibody or antigen binding fragment thereof that binds to or specifically binds to VEGF-B and neutralizes VEGF-B signaling, the antibody or antigen binding domain thereof comprising complementarity determining regions (CDRs) of a heavy chain variable region (V H ) comprising a sequence set forth in SEQ ID NO: 3, and CDRs of a light chain variable region (V L ), comprising a sequence set forth in SEQ ID NO: 4; and is administered after the stroke and in combination with a thrombolytic compound.

2. The method of claim 1 , wherein the subject suffers from diabetes and/or obesity.

3. The method of claim 2 , wherein the diabetes is type 2 diabetes.

4. The method of claim 1 , wherein the subject has one or more of the following characteristics:

(a) has already suffered from a stroke and/or a transient ischemic attack;

(b) has a family history of stroke;

(c) suffers from heart disease;

(d) has high blood pressure;

(e) has high plasma low density lipoprotein levels;

(f) has metabolic syndrome

(g) has a cardiac abnormality; and/or

(h) has undergone cardiac surgery or hip replacement surgery.

5. The method of claim 1 , wherein the compound that inhibits VEGF-B signaling is administered before the thrombolytic compound.

6. The method of claim 5 , wherein administration of the compound that inhibits VEGF-B signaling extends the time in which the thrombolytic compound can safely be administered to the subject.

7. The method of claim 1 , wherein the thrombolytic compound is administered more than two hours after onset of symptoms of a stroke.

8. The method of claim 1 , wherein the subject has blood glucose levels greater than 400 mg/dL.

9. The method of claim 1 , wherein the thrombolytic compound is selected from the group consisting of a tissue plasminogen activator, lanetoplase, reteplase, staphylokinase, streptokinase, anistreplase, desmoteplase or a urokinase.

10. The method of claim 1 , wherein the compound that inhibits VEGF-B and/or the thrombolytic compound is administered in an amount sufficient to have one or more of the following effects:

(a) reducing infarct size in the subject;

(b) reducing the hemorrhage score as assessed by the intracerebral hemorrhage score in the subject;

(c) reducing incidence of a hemorrhage in a subject;

(d) reducing the likelihood of lethal hemorrhage in a subject;

(e) reducing brain edema in the subject following stroke; and/or

(f) reducing blood-brain-barrier breakdown or leakage in the subject following stroke.

11. The method of claim 1 , wherein the stroke is an ischemic stroke.

12. The method of claim 1 , wherein the compound that inhibits VEGF-B signaling comprises an Fv.

13. The method of claim 12 , wherein the compound that inhibits VEGF-B signaling is selected from the group consisting of:

(i) a single chain Fv fragment (scFv);

(ii) a dimeric scFv (di-scFv);

(iii) a diabody;

(iv) a triabody;

(v) a tetrabody;

(vi) a Fab;

(vii) a F(ab′) 2 ;

(viii) one of (i) to (vii) linked to a constant region of an antibody, Fc or a heavy chain constant domain (C H )2 and/or C H 3; and

(ix) an antibody.

14. The method of claim 13 , wherein the antibody:

(i) comprises a humanized variable region of the V H comprising a sequence set forth in SEQ ID NO: 3 and V L comprising a sequence set forth in SEQ ID NO: 4; or

(ii) comprises a V H comprising a sequence set forth in SEQ ID NO: 5 and a V L comprising a sequence set forth in SEQ ID NO:6.

15. The method of claim 1 , wherein the compound that inhibits VEGF-B signaling is an antibody or antigen binding fragment thereof comprising:

(i) a V H comprising:

(a) a CDR1 comprising a sequence set forth in SEQ ID NO: 21;

(b) a CDR2 comprising a sequence set forth in SEQ ID NO: 22; and

(c) a CDR3 comprising a sequence set forth in SEQ ID NO: 23; and

(ii) a V L comprising:

(a) a CDR1 comprising a sequence set forth in SEQ ID NO: 18;

(b) a CDR2 comprising a sequence set forth in SEQ ID NO: 19; and

(c) a CDR3 comprising a sequence set forth in SEQ ID NO: 20.

16. The method of claim 1 , wherein the thrombolytic compound is administered between two and six hours after onset of symptoms of a stroke.