Methods of treating GVHD and transplant rejection with anti-PSGL-1 antibodies
Immunoglobulin chains or antibodies having light or heavy chain complementarity determining regions of antibodies that bind to P-Selectin Glycoprotein Ligand-1. Also disclosed are methods of inducing death of an activated T-cell and of modulating a T cell-mediated immune response in a subject.
1. A method for treating graft-versus-host disease (GVHD) in a subject, the method comprising administering to the subject an isolated antibody that binds specifically to human P-Selectin Glycoprotein Ligand 1 (PSGL-1), wherein the antibody comprises:
(i) a light chain comprising SEQ ID NO: 1-3, and a heavy chain comprising SEQ ID NO: 4-6; (ii) a light chain comprising SEQ ID NO: 7-9 and a heavy chain comprising SEQ ID NO: 10-12;
(iii) a light chain comprising SEQ ID NO: 13-15 and a heavy chain comprising SEQ ID NO: 16-18;
(iv) a light chain variable region of SEQ ID NO: 19 and a heavy chain variable region of SEQ ID NO: 20;
(v) a light chain variable region of SEQ ID NO: 25 and a heavy chain variable region of SEQ ID NO: 26;
(vi) a light chain variable region of SEQ ID NO: 21 and a heavy chain variable region of SEQ ID NO: 22; or
(vii) a light chain variable region of SEQ ID NO: 23 and a heavy chain variable region of SEQ ID NO: 24.
2. A method for treating graft-versus-host disease (GVHD) in a subject, the method comprising administering to the subject an isolated antibody that binds specifically to human P-Selectin Glycoprotein Ligand 1 (PSGL-1) without interfering with binding between PSGL-1 and P-Selectin, wherein the antibody, upon binding to human PSGL-1 expressed on an activated T cell, induces death of the activated T cell.
3. A method for treating graft-versus-host disease (GVHD) in a subject, the method comprising administering to the subject an antibody that binds specifically to amino acid residues 115-126 of mature human P-Selectin Glycoprotein Ligand 1 (PSGL-1).
4. The method of claim 1 , wherein the antibody comprises a light chain comprising SEQ ID NO: 7-9 and a heavy chain comprising SEQ ID NO: 10-12 or a light chain comprising SEQ ID NO: 13-15 and a heavy chain comprising SEQ ID NO: 16-18, and
wherein the antibody binds specifically to amino acid residues 50-60 of mature human P-Selectin Glycoprotein Ligand 1 (PSGL-1).
5. The method of claim 1 , wherein the antibody is a chimeric antibody.
6. The method of claim 1 , wherein the antibody is a humanized antibody.
7. A method for treating graft-versus-host disease (GVHD) in a subject, the method comprising administering to the subject an isolated antibody that binds specifically to human P-Selectin Glycoprotein Ligand 1 (PSGL-1), wherein the antibody comprises (i) a light chain variable region of SEQ ID NO: 19 linked to a human kappa light chain constant region, and a heavy chain variable region of SEQ ID NO: 20 linked to a human IgG4 heavy chain constant region; (ii) a light chain variable region of SEQ ID NO: 25 linked to a human kappa light chain constant region, and a heavy chain variable region of SEQ ID NO: 26 linked to a human IgG4 heavy chain constant region; (iii) a light chain variable region of SEQ ID NO: 21 linked to a human kappa light chain constant region, and a heavy chain variable region of SEQ ID NO: 22 linked to a human IgG4 heavy chain constant region; or (iv) a light chain variable region of SEQ ID NO: 23 linked to a human kappa light chain constant region, and a heavy chain variable region of SEQ ID NO: 24 linked to a human IgG4 heavy chain constant region.
8. The method of claim 1 , wherein the subject has received or is contemplated to receive an allogeneic or xenogeneic transplant.
9. The method of claim 8 , wherein the transplant comprises bone marrow, liver, organ or tissue.
10. A method for treating transplant rejection in a subject, the method comprising administering to the subject an isolated antibody that binds specifically to human P-Selectin Glycoprotein Ligand 1 (PSGL-1), wherein the antibody comprises
(i) a light chain comprising SEQ ID NO: 1-3, and a heavy chain comprising SEQ ID NO: 4-6; (ii) a light chain comprising SEQ ID NO: 7-9 and a heavy chain comprising SEQ ID NO: 10-12; (iii) a light chain comprising SEQ ID NO: 13-15 and a heavy chain comprising SEQ ID NO: 16-18;
(iv) a light chain variable region of SEQ ID NO: 19 and a heavy chain variable region of SEQ ID NO: 20;
(v) a light chain variable region of SEQ ID NO: 25 and a heavy chain variable region of SEQ ID NO: 26;
(vi) a light chain variable region of SEQ ID NO: 21 and a heavy chain variable region of SEQ ID NO: 22; or
(vii) a light chain variable region of SEQ ID NO: 23 and a heavy chain variable region of SEQ ID NO: 24.
11. A method for treating transplant rejection in a subject, the method comprising administering to the subject an isolated antibody that binds specifically to human P-Selectin Glycoprotein Ligand 1 (PSGL-1) without interfering with binding between PSGL-1 and P-Selectin, wherein the antibody, upon binding to human PSGL-1 expressed on an activated T cell, induces death of the activated T cell.
12. A method for treating transplant rejection in a subject, the method comprising administering to the subject an antibody that binds specifically to amino acid residues 115-126 of mature human P-Selectin Glycoprotein Ligand 1 (PSGL-1).
13. The method of claim 10 , wherein the antibody comprises a light chain comprising SEQ ID NO: 7-9 and a heavy chain comprising SEQ ID NO: 10-12 or a light chain comprising SEQ ID NO: 13-15 and a heavy chain comprising SEQ ID NO: 16-18, and
wherein the antibody binds specifically to amino acid residues 50-60 of mature human P-Selectin Glycoprotein Ligand 1 (PSGL-1).
14. The method of claim 10 , wherein the antibody is a chimeric antibody.
15. The method of claim 10 , wherein the antibody is a humanized antibody.
16. A method for treating transplant rejection in a subject, the method comprising administering to the subject an isolated antibody that binds specifically to human P-Selectin Glycoprotein Ligand 1 (PSGL-1), wherein the antibody comprises (i) a light chain variable region of SEQ ID NO: 19 linked to a human kappa light chain constant region, and a heavy chain variable region of SEQ ID NO: 20 linked to a human IgG4 heavy chain constant region; (ii) a light chain variable region of SEQ ID NO: 25 linked to a human kappa light chain constant region, and a heavy chain variable region of SEQ ID NO: 26 linked to a human IgG4 heavy chain constant region; (iii) a light chain variable region of SEQ ID NO: 21 linked to a human kappa light chain constant region, and a heavy chain variable region of SEQ ID NO: 22 linked to a human IgG4 heavy chain constant region; or (iv) a light chain variable region of SEQ ID NO: 23 linked to a human kappa light chain constant region, and a heavy chain variable region of SEQ ID NO: 24 linked to a human IgG4 heavy chain constant region.
17. The method of claim 10 , wherein the subject has received or is contemplated to receive an allogeneic or xenogeneic transplant.
18. The method of claim 17 , wherein the transplant comprises bone marrow, liver, organ or tissue.