Methods of treating dementia using a GM-CSF antagonist
View Patent ↗The invention is based on the discovery that GM-CSF antagonists can be used for the treatment of a patient that has Alzheimer's disease or vascular dementia, or is at risk for developing Alzheimer's disease. Accordingly, the invention provides methods of administering a GM-CSF antagonist, e.g., a GM-CSF antibody and pharmaceutical compositions comprising such antagonists.
1. A method for treating a patient suffering from Alzheimer's disease, the method comprising administering a recombinant neutralizing anti-GM-CSF antibody to the patient, wherein the anti-GM-CSF antibody has a heavy chain variable (V H ) region and a light chain variable (V L ) region and is provided in a therapeutically effective amount.
2. The method of claim 1 , wherein the anti-GM-CSF antibody is provided in a therapeutically effective amount to treat cognitive decline.
3. The method of claim 1 , wherein the anti-GM-CSF antibody is administered intravenously or subcutaneously.
4. The method of claim 3 , wherein the patient has mild to moderate Alzheimer's disease.
5. The method of claim 1 , wherein the patient has both Alzheimer's disease and vascular dementia.
6. The method of claim 1 , wherein the patient has both Alzheimer's disease and cerebral amyloid angiopathy.
7. The method of claim 1 , wherein the patient has a family history of familial Alzheimer's disease.
8. The method of claim 1 , further comprising administering an anti-amyloidβ antibody or administering an amyloidβ vaccine.
9. The method of claim 1 , further comprising administering an acetylcholinesterase inhibitor or an NMDA receptor antagonist.
10. The method of claim 1 , wherein the patient has elevated levels of GM-CSF in the cerebrospinal fluid or serum.
11. The method of claim 1 , wherein the anti-GM-CSF antibody is a polyclonal antibody.
12. The method of claim 1 , wherein the anti-GM-CSF antibody is a monoclonal antibody.
13. The method of claim 1 , wherein the anti-GM-CSF antibody is an antibody fragment that is a Fab, a Fab′, a F(ab′) 2 , a scFv, or a dAB.
14. The method of claim 13 , wherein the antibody fragment is conjugated to polyethylene glycol.
15. The method of claim 1 , wherein the anti-GM-CSF antibody has an affinity ranging from about 5 pM to about 50 pM.
16. The method of claim 1 , wherein the anti-GM-CSF antibody is a chimeric antibody.
17. The method of claim 1 , wherein the anti-GM-CSF antibody is a human antibody.
18. The method of claim 1 , wherein the anti-GM-CSF antibody comprises a human variable region.
19. The method of claim 1 , wherein the anti-GM-CSF antibody comprises a human light chain constant region and/or a human heavy chain constant region.
20. The method of claim 19 , wherein the human heavy chain constant region is a gamma chain.
21. The method of claim 1 , wherein the anti-GM-CSF antibody binds to the same epitope as chimeric 19/2.
22. The method of claim 1 , wherein the anti-GM-CSF antibody comprises the V H region CDR3 and V L region CDR3 of chimeric 19/2; or wherein the anti-GM-CSF antibody comprises the V H region and V L region CDR1, CDR2, and CDR3 of chimeric 19/2.
23. The method of claim 1 , wherein the anti-GM-CSF antibody comprises the CDR1, CDR2, and CDR3 of a V H region of SEQ ID NO8, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, or SEQ ID NO:13; and the CDR1, CDR2, and CDR3 of a V L region of SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, or SEQ ID NO:18.
24. The method of claim 23 , wherein the V-segment sequence has a V H V segment sequence.
25. The method of claim 23 , wherein the V H has the sequence of SEQ ID NO8, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, or SEQ ID NO:13.
26. The method of claim 23 , wherein the V L region has the sequence of SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, or SEQ ID NO:18.
27. The method of claim 1 wherein the anti-GM-CSF antibody has a V H region sequence of SEQ ID NO8, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, or SEQ ID NO:13 and a V L region sequence of SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, or SEQ ID NO:18.
28. A method for treating a patient suffering from Alzheimer's disease who has an elevated level of GM-CSF in the cerebrospinal fluid or serum, the method comprising administering a therapeutically effective amount of a neutralizing anti-GM-CSF antibody intravenously or subcutaneously, wherein the anti-GM-CSF antibody comprises a human engineered Fab′ with the binding specificity of chimeric 19/2 and has an affinity ranging from about 5 to about 50 pM.
29. A method for treating a patient suffering from Alzheimer's disease, the method comprising administering a therapeutically effective amount of a neutralizing anti-GM-CSF antibody intravenously or subcutaneously to the patient.
30. The method of claim 29 , further comprising administering an antibody to amyloidβ, an amyloidβ vaccine, an acetylcholinesterase inhibitor, an NMDA antagonist, or IVIG.