Monoclonal antibodies to human FLT3/FLK2 receptor protein
The described invention provides compositions containing bi-specific antibodies that bind to human tyrosine kinase receptor FLT3/FLK2 receptor protein and to CD3 receptor protein expressed on T-cells and use of the compositions containing the bispecific antibodies in the preparation of a medicament for eliminating hematopoietic stem cells/hematopoietic progenitors (HSC/HP) in a patient.
1. A monoclonal antibody or antigen binding fragment thereof, wherein an amino acid sequence of a light chain of an antigen-binding portion of the antibody or fragment thereof that binds to human FLT3/FLK2 receptor protein is selected from the group consisting of SEQ ID NO: 5, SEQ ID NO: 9, SEQ ID NO: 13, SEQ ID NO: 17, SEQ ID NO: 21, and SEQ ID NO: 25, and an amino acid sequence of a heavy chain of the antigen-binding portion of the antibody or fragment thereof that binds to human FLT3/FLK2 receptor protein is selected from the group consisting of SEQ ID NO: 7, SEQ ID NO: 11, SEQ ID NO: 15, SEQ ID NO: 19, SEQ ID NO: 23, and SEQ ID NO: 27.
2. The monoclonal antibody or antigen binding fragment thereof according to claim 1 , wherein the amino acid sequence of a light chain of an antigen-binding portion of the antibody or fragment thereof that binds to human FLT3/FLK2 receptor protein is SEQ ID NO: 5 and the amino acid sequence of a heavy chain of the antigen-binding portion of the antibody or fragment thereof that binds to human FLT3/FLK2 receptor protein is SEQ ID NO: 7.
3. The monoclonal antibody or antigen binding fragment thereof according to claim 2 , wherein a half maximal effective concentration (EC50) of the antibody or antigen-binding fragment thereof is between 1 ng/mL (6.25 pM) and 2,000 ng/mL (12.5 nM).
4. The monoclonal antibody or antigen binding fragment thereof according to claim 3 , wherein the half maximal effective concentration (EC50) of the antibody or antigen-binding fragment thereof is between 10 ng/mL (62.5 pM) and 200 ng/mL (1.25 nM).
5. The monoclonal antibody or antigen binding fragment thereof according to claim 2 , wherein binding of the antibody or antigen binding fragment thereof to human FLT3/FLK2 receptor protein on a cell is effective for the cell to internalize the bound antibody or antigen-binding fragment.
6. The monoclonal antibody or antigen binding fragment thereof according to claim 1 , wherein the amino acid sequence of a light chain of an antigen-binding portion of the antibody or fragment thereof that binds to human FLT3/FLK2 receptor protein is SEQ ID NO: 9 and the amino acid sequence of a heavy chain of the antigen-binding portion of the antibody or fragment thereof that binds to human FLT3/FLK2 receptor protein is SEQ ID NO: 11.
7. The monoclonal antibody or antigen binding fragment thereof according to claim 6 , wherein a half maximal effective concentration (EC 50 ) of the antibody or fragment thereof is between 1 ng/mL (6.25 pM) and 2,000 ng/mL (12.5 nM).
8. The monoclonal antibody or antigen binding fragment thereof according to claim 7 , wherein the half maximal effective concentration (EC 50 ) of the antibody or antigen-binding fragment thereof is between 10 ng/mL (62.5 pM) and 200 ng/mL (1.25 nM).
9. The monoclonal antibody or antigen binding fragment thereof according to claim 6 , wherein binding of the antibody or antigen binding fragment thereof to human FLT3/FLK2 receptor protein on a cell is effective for the cell to internalize the bound antibody or antigen-binding fragment.
10. The monoclonal antibody or antigen binding fragment thereof according to claim 1 , wherein the amino acid sequence of a light chain of an antigen-binding portion of the antibody or fragment thereof that binds to human FLT3/FLK2 receptor protein is SEQ ID NO: 13 and the amino acid sequence of a heavy chain of the antigen-binding portion of the antibody or fragment thereof that binds to human FLT3/FLK2 receptor protein is SEQ ID NO: 15.
11. The monoclonal antibody or antigen binding fragment thereof according to claim 10 , wherein a half maximal effective concentration (EC 50 ) of the antibody or antigen-binding fragment thereof is between 1 ng/mL (6.25 pM) and 2,000 ng/mL (12.5 nM).
12. The monoclonal antibody or antigen binding fragment thereof according to claim 11 , wherein the half maximal effective concentration (EC 50 ) of the antibody or antigen-binding fragment thereof is between 10 ng/mL (62.5 pM) and 200 ng/mL (1.25 nM).
13. The monoclonal antibody or antigen binding fragment thereof according to claim 11 , wherein binding of the antibody or antigen binding fragment thereof to human FLT3/FLK2 receptor protein on a cell is effective for the cell to internalize the bound antibody or antigen-binding fragment.
14. The monoclonal antibody or antigen binding fragment thereof according to claim 1 , wherein the amino acid sequence of a light chain of an antigen-binding portion of the antibody or fragment thereof that binds to human FLT3/FLK2 receptor protein is SEQ ID NO: 17 and the amino acid sequence of a heavy chain of the antigen-binding portion of the antibody or fragment thereof that binds to human FLT3/FLK2 receptor protein is SEQ ID NO: 19.
15. The monoclonal antibody or antigen binding fragment thereof according to claim 14 , wherein a half maximal effective concentration (EC 50 ) of the antibody or antigen-binding fragment thereof is between 1 ng/mL (6.25 pM) and 2,000 ng/mL (12.5 nM).
16. The monoclonal antibody or antigen binding fragment thereof according to claim 15 , wherein the half maximal effective concentration (EC 50 ) of the antibody or antigen-binding fragment thereof is between 10 ng/mL (62.5 pM) and 200 ng/mL (1.25 nM).
17. The monoclonal antibody or antigen binding fragment thereof according to claim 14 , wherein binding of the antibody or antigen binding fragment thereof to human FLT3/FLK2 receptor protein on a cell is effective for the cell to internalize the bound antibody or antigen-binding fragment.
18. A monoclonal antibody or antigen binding fragment thereof, wherein the amino acid sequence of a light chain of an antigen-binding portion of the antibody or fragment thereof that binds to human FLT3/FLK2 receptor protein is SEQ ID NO: 21 and the amino acid sequence of a heavy chain of the antigen-binding portion of the antibody or fragment thereof that binds to human FLT3/FLK2 receptor protein is SEQ ID NO: 23, wherein the monoclonal antibody or antigen binding fragment thereof does not compete with FLT3 ligand (FLT3L) when bound to FLT3/FLK2.
19. The monoclonal antibody or antigen binding fragment thereof according to claim 18 , wherein a half maximal effective concentration (EC 50 ) of the antibody or fragment thereof is between 1 ng/mL (6.25 pM) and 2,000 ng/mL (12.5 nM).
20. The monoclonal antibody or antigen binding fragment thereof according to claim 19 , wherein the half maximal effective concentration (EC 50 ) of the antibody or antigen-binding fragment thereof is between 10 ng/mL (62.5 pM) and 200 ng/mL (1.25 nM).
21. The monoclonal antibody or antigen binding fragment thereof according to claim 18 , wherein binding of the antibody or antigen binding fragment thereof to human FLT3/FLK2 receptor protein on a cell is effective for the cell to internalize the bound antibody or antigen-binding fragment.
22. A monoclonal antibody or antigen binding fragment thereof, wherein the amino acid sequence of a light chain of an antigen-binding portion of the antibody or fragment thereof that binds to human FLT3/FLK2 receptor protein is SEQ ID NO: 25 and the amino acid sequence of a heavy chain of the antigen-binding portion of the antibody or fragment thereof that binds to human FLT3/FLK2 receptor protein is SEQ ID NO: 27, wherein the monoclonal antibody or antigen binding fragment thereof does not compete with FLT3 ligand (FLT3L) when bound to FLT3/FLK2.
23. The monoclonal antibody or antigen binding fragment thereof according to claim 22 , wherein a half maximal effective concentration (EC 50 ) of the antibody or fragment thereof is between 1 ng/mL (6.25 pM) and 2,000 ng/mL (12.5 nM).
24. The monoclonal antibody or antigen binding fragment thereof according to claim 23 , wherein the half maximal effective concentration (EC 50 ) of the antibody or antigen-binding fragment thereof is between 10 ng/mL (62.5 pM) and 200 ng/mL (1.25 nM).
25. The monoclonal antibody or antigen binding fragment thereof according to claim 22 , wherein binding of the antibody or antigen binding fragment thereof to human FLT3/FLK2 receptor protein on a cell is effective for the cell to internalize the bound antibody or antigen-binding fragment.