Methods for increasing immunoglobulin A levels
View Patent ↗Methods for increasing immunoglobulin A (IgA) levels in a subject having a deficiency thereof are provided herein by administering to the subject an agent that inhibits CXCL13 activity, such as an anti-CXCL13 or an anti-CXCR5 antibody. Further provided are methods for treating an inflammatory disorder in a subject deficient for IgA by administering to the subject an agent that inhibits CXCL13 activity.
1. A method for increasing immunoglobulin A (IgA) levels in a subject having a deficiency thereof, said method comprising administering to said subject an effective amount of an antibody or antigen-binding fragment thereof that specifically binds CXCL13 and inhibits CXCL13 activity, wherein the antibody or antigen-binding fragment thereof
a) comprises a variable heavy (VH) domain having three complementarity determining regions (CDRs) of SEQ ID NO: 10 and a variable light (VL) domain having three CDRs of SEQ ID NO: 15;
b) comprises a variable heavy (VH) domain having three complementarity determining regions (CDRs) of SEQ ID NO: 14 and a variable light (VL) domain having three CDRs of SEQ ID NO: 19; or
c) comprises a variable heavy (VH) domain having three complementarity determining regions (CDRs) of SEQ ID NO: 14 and a variable light (VL) domain having three CDRs of SEQ ID NO: 21.
2. The method of claim 1 , wherein said IgA deficiency is secondary to an infection or exposure to a drug.
3. The method of claim 2 , wherein said infection is a mucosal infection.
4. The method of claim 2 , wherein said infection is a bacterial infection.
5. The method of claim 4 , wherein said bacterial infection is a Helicobacter infection.
6. The method of claim 5 , wherein said Helicobacter is selected from the group consisting of Helicobacter pylori, Helicobacter heilmannii , and Helicobacter suis.
7. The method of claim 1 , wherein said IgA deficiency is a primary IgA deficiency.
8. The method of claim 1 , wherein secretory IgA levels are increased in said subject upon administration of said antibody or antigen-binding fragment thereof.
9. The method of claim 8 , wherein gastric IgA levels are increased in said subject upon administration of said antibody or antigen-binding fragment thereof.
10. The method of claim 1 , wherein said method increases IgA antibody responses in a mucosal tissue of said subject.
11. The method of claim 1 , wherein said antibody is chimeric, human, or humanized.
12. The method of claim 1 , wherein said antibody is selected from the group consisting of MAb 5261, MAb 5378, MAb 5080, MAb 1476, and MAb 3D2.
13. The method of claim 1 , wherein said antibody or antigen-binding fragment thereof inhibits the interaction of CXCL13 with a CXCL13 receptor.
14. The method of claim 13 , wherein said CXCL13 receptor is CXCR5.
15. The method of claim 1 , wherein said antibody or antigen-binding fragment thereof inhibits CXCR5 receptor internalization.
16. The method of claim 1 , wherein said antibody or antigen-binding fragment thereof is administered with a pharmaceutically acceptable carrier.
17. The method of claim 1 , wherein said subject is an animal.
18. The method of claim 17 , wherein said animal is a mammal.
19. The method of claim 18 , wherein said mammal is a human.
20. The method of claim 1 , wherein the VH domain of said antibody or antigen-binding fragment thereof comprises a CDR1 comprising amino acid residues 31-35 of SEQ ID NO: 10, a CDR2 comprising amino acid residues 50-65 of SEQ ID NO: 10, and a CDR3 comprising amino acid residues 95-102 of SEQ ID NO: 10, and the VL domain of said antibody or antigen-binding fragment thereof comprises a CDR1 comprising amino acid residues 24-34 of SEQ ID NO: 15, a CDR2 comprising amino acid residues 50-56 of SEQ ID NO: 15, and a CDR3 comprising amino acid residues 89-97 of SEQ ID NO: 15, wherein the CDR residues are numbered according to Kabat.
21. The method of claim 1 , wherein the VH domain of said antibody or antigen-binding fragment thereof comprises a CDR1 comprising amino acid residues 26-32 of SEQ ID NO: 10, a CDR2 comprising amino acid residues 52-58 of SEQ ID NO: 10, and a CDR3 comprising amino acid residues 95-102 of SEQ ID NO: 10, and the VL domain of said antibody or antigen-binding fragment thereof comprises a CDR1 comprising amino acid residues 26-32 of SEQ ID NO: 15, a CDR2 comprising amino acid residues 50-52 of SEQ ID NO: 15, and a CDR3 comprising amino acid residues 91-96 of SEQ ID NO: 15, wherein the CDR residues are numbered according to Chothia.
22. The method of claim 1 , wherein the VH domain of said antibody or antigen-binding fragment thereof has the amino acid sequence set forth as SEQ ID NO: 10 and the VL domain of said antibody or antigen-binding fragment thereof has the amino acid sequence set forth as SEQ ID NO: 15.
23. The method of claim 1 , wherein the VH domain of said antibody or antigen-binding fragment thereof comprises a CDR1 comprising amino acid residues 31-35 of SEQ ID NO: 14, a CDR2 comprising amino acid residues 50-65 of SEQ ID NO: 14, and a CDR3 comprising amino acid residues 95-102 of SEQ ID NO: 14, and the VL domain of said antibody or antigen-binding fragment thereof comprises a CDR1 comprising amino acid residues 24-34 of SEQ ID NO: 19, a CDR2 comprising amino acid residues 50-56 of SEQ ID NO: 19, and a CDR3 comprising amino acid residues 89-97 of SEQ ID NO: 19, wherein the CDR residues are numbered according to, according to Kabat.
24. The method of claim 1 , wherein the VH domain of said antibody or antigen-binding fragment thereof comprises a CDR1 comprising amino acid residues 26-32 of SEQ ID NO: 14, a CDR2 comprising amino acid residues 52-58 of SEQ ID NO: 14, and a CDR3 comprising amino acid residues 95-102 of SEQ ID NO: 14, and the VL domain of said antibody or antigen-binding fragment thereof comprises a CDR1 comprising amino acid residues 26-32 of SEQ ID NO: 19, a CDR2 comprising amino acid residues 50-52 of SEQ ID NO: 19, and a CDR3 comprising amino acid residues 91-96 of SEQ ID NO: 19, wherein the CDR residues are numbered according to Chothia.
25. The method of claim 1 , wherein the VH domain of said antibody or antigen-binding fragment thereof has the amino acid sequence set forth as SEQ ID NO: 14 and the VL domain of said antibody or antigen-binding fragment thereof has the amino acid sequence set forth as SEQ ID NO: 19.
26. The method of claim 1 , wherein the VH domain of said antibody or antigen-binding fragment thereof comprises a CDR1 comprising amino acid residues 31-35 of SEQ ID NO: 14, a CDR2 comprising amino acid residues 50-65 of SEQ ID NO: 14, and a CDR3 comprising amino acid residues 95-102 of SEQ ID NO: 14, and the VL domain of said antibody or antigen-binding fragment thereof comprises a CDR1 comprising amino acid residues 24-34 of SEQ ID NO: 21, a CDR2 comprising amino acid residues 50-56 of SEQ ID NO: 21, and a CDR3 comprising amino acid residues 89-97 of SEQ ID NO: 21, wherein the CDR residues are numbered according to Kabat.
27. The method of claim 1 , wherein the VH domain of said antibody or antigen-binding fragment thereof comprises a CDR1 comprising amino acid residues 26-32 of SEQ ID NO: 14, a CDR2 comprising amino acid residues 52-58 of SEQ ID NO: 14, and a CDR3 comprising amino acid residues 95-102 of SEQ ID NO: 14, and the VL domain of said antibody or antigen-binding fragment thereof comprises a CDR1 comprising amino acid residues 26-32 of SEQ ID NO: 21, a CDR2 comprising amino acid residues 50-52 of SEQ ID NO: 21, and a CDR3 comprising amino acid residues 91-96 of SEQ ID NO: 21, wherein the CDR residues are numbered according to Chothia.
28. The method of claim 1 , wherein the VH domain of said antibody or antigen-binding fragment thereof has the amino acid sequence set forth as SEQ ID NO: 14 and the VL domain of said antibody or antigen-binding fragment thereof has the amino acid sequence set forth as SEQ ID NO: 21.
29. The method of claim 1 , wherein said antibody or antigen-binding fragment thereof comprises a variable heavy (VH) domain comprising a CDR1 having the sequence set forth in SEQ ID NO: 11, a CDR2 having the sequence set forth in SEQ ID NO: 12, and a CDR3 having the sequence set forth in SEQ ID NO: 13; and a variable light (VL) domain comprising a CDR1 having the sequence set forth in SEQ ID NO: 16 or 20, a CDR2 having the sequence set forth in SEQ ID NO: 17, and a CDR3 having the sequence set forth in SEQ ID NO: 18.
30. The method of claim 29 , wherein said CDR1 of said VL domain has the sequence set forth in SEQ ID NO: 20.