Regulation of glucose metabolism using anti-CGRP antibodies
The present disclosure provides methods for the prevention or treatment of metabolic disorders. In exemplary embodiments, methods of administering an anti-CGRP antibody are provided, optionally in combination with a second agent, wherein peripheral and/or hepatic glucose utilization is increased, thereby preventing or treating diseases and disorders associated with insulin resistance. Compositions comprising an anti-CGRP antibody are also provided, optionally in combination with a second agent, which are suitable for administration to increase peripheral and/or hepatic glucose utilization and thereby prevent or treat diseases and disorders associated with insulin resistance.
1. A method of decreasing insulin resistance in a subject in need thereof, comprising administrating an effective amount of (I) a composition comprising an anti-human CGRP antibody or antigen-binding antibody fragment and (II) a composition comprising biguanide to said subject,
wherein said antibody or antigen-binding antibody fragment comprises (i) a V L chain comprising CDR1, CDR2 and CDR3 polypeptides having the amino acid sequences of SEQ ID NOS: 55, 56 and 57, respectively; and (ii) a V H chain comprising complementarity CDR1, CDR2 and CDR3 polypeptides having the amino acid sequences of SEQ ID NOS: 58, 59 and 60, respectively,
and wherein the subject is diagnosed with prediabetes and/or exhibits one or more of: (a) fasting blood glucose level of between 100 mg/dl and 125 mg/dL; (b) blood sugar level of between 140 mg/dL and 199 mg/dl two hours after ingesting a 75 g glucose solution or a glucose solution of 1.75 g of glucose per kg of body weight, to a maximum dose of 75 g; and/or (c) glycated hemoglobin of between 5.7 percent and 6.4 percent.
2. The method of claim 1 , wherein
(I) the composition comprising the anti-CGRP antibody or antigen-binding antibody fragment and (II) the composition comprising biguanide are administered separately.
3. The method of claim 2 , wherein the (I) composition comprising the anti-human CGRP antibody or antigen-binding antibody fragment is administered intravenously and the (II) composition comprising biguanide is administered orally.
4. The method of claim 1 , wherein said biguanide is metformin.
5. The method of claim 1 , wherein either of said composition (I) or composition (II) further comprises a pharmaceutically acceptable carrier.
6. The method of claim 1 , wherein said composition (I) is administered to said subject at an anti-human CGRP antibody or antibody fragment dosage between about 0.1 and 100.0 mg/kg of body weight of recipient subject.
7. The method of claim 1 , wherein said anti-human CGRP antibody or antibody fragment is humanized or chimeric.
8. The method of claim 1 , wherein said antibody fragment is a Fab, F(ab′) 2 or scFv fragment.
9. The method of claim 1 , wherein: (i) the V L chain is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 51 and (ii) the V H chain is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 53.
10. The method of claim 1 , wherein: (i) the V L chain has the amino acid sequence of SEQ ID NO: 51, and (ii) the V H chain has the amino acid sequence of SEQ ID NO: 53.
11. The method of claim 1 , wherein the anti-human CGRP antibody comprises (i) a light chain polypeptide that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 52 and (ii) a heavy chain polypeptide that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 54.
12. The method of claim 1 , wherein the anti-human CGRP antibody comprises (i) a light chain polypeptide having the amino acid sequence of SEQ ID NO: 52 and (ii) a heavy chain polypeptide having the amino acid sequence of SEQ ID NO: 54.
13. The method of claim 1 , wherein said anti-human CGRP antibody comprises an Fc region that has been modified to alter effector function, half-life, proteolysis, and/or glycosylation.
14. The method of claim 1 , wherein said anti-human CGRP antibody or antibody fragment is aglycosylated or if glycosylated only comprises mannose residues.
15. A method of reducing insulin resistance in a subject in need thereof, comprising administering an effective amount of a composition comprising an anti-human CGRP antibody or antigen-binding antibody fragment to said subject,
wherein said antibody or antigen-binding antibody fragment comprises (i) a V L chain comprising CDR1, CDR2 and CDR3 polypeptides having the amino acid sequences of SEQ ID NOS: 55, 56 and 57, respectively; and (ii) a V H chain comprising complementarity CDR1, CDR2 and CDR3 polypeptides having the amino acid sequences of SEQ ID NOS: 58, 59 and 60, respectively,
and wherein the subject is diagnosed with prediabetes and/or exhibits one or more of: (a) fasting blood glucose level of between 100 mg/dl and 125 mg/dL; (b) blood sugar level of between 140 mg/dl and 199 mg/dl two hours after ingesting a 75 g glucose solution or a glucose solution of 1.75 g of glucose per kg of body weight, to a maximum dose of 75 g; and/or (c) glycated hemoglobin of between 5.7 percent and 6.4 percent.
16. The method of claim 15 , wherein:
(a) the method further comprises administering to said subject a biguanide; or
(b) the composition further comprises a biguanide.
17. The method of claim 16 , wherein said biguanide is metformin.
18. The method of claim 15 , wherein: (i) the V L chain of said anti-human CGRP antibody or antibody fragment has the amino acid sequence of SEQ ID NO: 51, and (ii) the V H chain of said anti-human CGRP antibody or antibody fragment has the amino acid sequence of SEQ ID NO: 53.
19. The method of claim 15 , wherein the anti-human CGRP antibody comprises (i) a light chain polypeptide having the amino acid sequence of SEQ ID NO: 52 and (ii) a heavy chain polypeptide having the amino acid sequence of SEQ ID NO: 54.
20. The method of claim 15 , wherein the composition is administered intravenously.