Methods and compositions for inhibiting CD32B expressing cells
The present invention relates to immunoglobulins that bind FcγRIIb+ cells and coengage the antigen on the cell's surface and an FcγRIIb on the cell's surface, methods for their generation, and methods for using the immunoglobulins.
1. A method of inhibiting BCR activation of at least one B cell comprising contacting the B cell with an anti-CD19 antibody comprising:
an Fc region that binds FcγRIIb on the cell surface with enhanced affinity as compared to a parent antibody comprising the amino acid sequence of SEQ ID NO:4;
a light chain comprising an amino acid sequence of SEQ ID NO: 7;
a heavy chain comprising an amino acid sequence of SEQ ID NO: 2; and
at least one amino acid substitution in the Fc region selected from: L235Y, L235R, G236D, S267D, S267E, and L328F as compared to SEQ ID NO: 4, wherein the numbering is according to the EU index, as in Kabat.
2. The method of claim 1 , wherein the amino acid substitution(s) in the Fc region are selected from L235D/S267E, L235Y/S267E, L235D/S267D, L235I/S267E, L235I/S267D, L235Y/S267D, G236D/S267E, G236D/S267D, S267E/L328F, S267D/L328F, H268D/S267E, H268D/S267D, H268E/S267E, H268E/S267D, G236D/S267E/L328F, and G236N/S267E/L328F.
3. The method of claim 1 , wherein the amino acid substitution(s) in the Fc region are selected from L235D/S267E, L235Y/S267E, L235Y/S267D, G236D/S267E, S267E/L328F, H268D/S267E, H268E/S267E, H268E/S267D, G236D/S267E/L328F, and G236D/S267E/L328F.
4. The method of claim 1 , wherein the amino acid substitution in the Fc region is S267E.
5. The method of claim 1 , wherein the amino acid substitution in the Fc region is L328F.
6. The method of claim 1 , wherein the antibody comprises Fc substitutions S267E/L328F.
7. The method of claim 1 , wherein the amino acid substitution(s) in the Fc region are selected from L235D/S267E, L235Y/S267E, L235Y/S267D, G236D/S267E, S267E/L328F, H268D/S267E, H268E/S267E, H268E/S267D, G236D/S267E/L328F, and G236D/S267E/L328F.
8. A method of treating an indication selected from systemic Sjogren's syndrome, multiple sclerosis, lupus erythematosus (SLE), discoid lupus, and lupus erythematosis, in a patient in need of such treatment, comprising administering to said patient an anti-CD19 antibody comprising:
an Fc region that binds FcγRIIb on the cell surface with enhanced affinity as compared to a parent antibody comprising the amino acid sequence of SEQ ID NO:4;
a light chain comprising an amino acid sequence of SEQ ID NO: 7;
a heavy chain comprising an amino acid sequence of SEQ ID NO: 2; and
at least one amino acid substitution in the Fc region selected from
L235Y, L235R, G236D, S267D, S267E, and L328F
as compared to SEQ ID NO: 4, wherein the numbering is according to the EU index, as in Kabat.
9. The method of claim 8 , wherein the amino acid substitution(s) in the Fc region are selected from L235D/S267E, L235Y/S267E, L235D/S267D, L235I/S267E, L235I/S267D, L235Y/S267D, G236D/S267E, G236D/S267D, S267E/L328F, S267D/L328F, H268D/S267E, H268D/S267D, H268E/S267E, H268E/S267D, G236D/S267E/L328F, and G236N/S267E/L328F.
10. The method of claim 8 , wherein the indication is selected from discoid lupus, lupus erythematosis, and systemic lupus erythematosus.
11. The method of claim 8 , wherein said antibody has reduced binding affinity for FcγRIIIa as compared to a parent antibody.
12. The method of claim 8 , wherein the antibody comprises Fc substitution S267E.
13. The method of claim 8 , wherein the antibody comprises Fc substitution L328F.
14. The method of claim 8 , wherein the antibody comprises Fc substitutions S267E and L328F.
15. A method of treating an indication selected from systemic Sjogren's syndrome, multiple sclerosis, lupus erythematosus (SLE), discoid lupus, and lupus erythematosis, in a patient in need of such treatment, comprising administering to said patient an anti-CD19 antibody comprising:
an Fc region that binds FcγRIIb on the cell surface with enhanced affinity as compared to a parent antibody comprising the amino acid sequence of SEQ ID NO:4;
a light chain comprising an amino acid sequence of SEQ ID NO: 7; and
a heavy chain comprising an amino acid sequence of SEQ ID NO: 2 and amino acid substitution(s) in the Fc region selected from
L235Y, L235R, G236D, S267D, S267E, and L328F
as compared to SEQ ID NO: 4, wherein the numbering is according to the EU index, as in Kabat;
wherein the antibody inhibits said at least one B cell to treat the indication.
16. The method of claim 15 , wherein the amino acid substitution(s) in the Fc region are selected from L235D/S267E, L235Y/S267E, L235D/S267D, L235I/S267E, L235I/S267D, L235Y/S267D, G236D/S267E, G236D/S267D, S267E/L328F, S267D/L328F, H268D/S267E, H268D/S267D, H268E/S267E, H268E/S267D, G236D/S267E/L328F, and G236N/S267E/L328F.
17. The method of claim 15 , wherein the indication is selected from discoid lupus, lupus erythematosis, and systemic lupus erythematosus.
18. The method of claim 15 , wherein said antibody has reduced binding affinity for FcγRIIIa as compared to a parent antibody.
19. The method of claim 15 , wherein the antibody comprises Fc substitution S267E.
20. The method of claim 15 , wherein the antibody comprises Fc substitution L328F.
21. The method of claim 15 , wherein the antibody comprises Fc substitutions S267E and L328F.
22. The method of claim 15 , wherein the indication is selected from discoid lupus, lupus erythematosis, and systemic lupus erythematosus.