Destruction of tumor cells by trifunctional bispecific antibodies with low to medium expression levels of tumor-associated target antigens
The use of trifunctional bispecific antibodies for the preparation of a pharmaceutical composition for the prophylaxis and treatment of tumor diseases is provided. Trifunctional bispecific antibodies bind to tumor-associated antigens including Her2/neu, CD20, EpCAM, G250, proteoglycans, GD3. GD2, MHC II, EGF-R and CEA expressed on tumor cells at low to medium expression levels. Also provided are methods for the treatment or prophylaxis of tumor diseases by administering a pharmaceutically effective amount of a trifunctional bispecific antibody to a patient in need thereof.
1. A method for the treatment of tumor diseases in a patient, comprising:
(a) providing a patient with a tumor cell expressing a tumor-associated antigen selected from the group consisting of Her2/neu, CD20, EpCam, GD2, and GD3, wherein the tumor-associated antigen is expressed on said tumor cell:
(i) in an amount of about 5,000-150,000 tumor-associated antigens/tumor cell for Her2/neu; or
(ii) in an amount of about up to 500,000 tumor-associated antigens/tumor cell for Her2/neu in tumor cells tested FISH negative; or
(iii) in an amount of about 1,000 to about 350,000 tumor-associated antigens/tumor cell for CD20; or
(iv) in an amount of about 1,000 to about 350,000 tumor-associated antigens/tumor cell for EpCAM, GD2, and GD3; and
(b) administering to said patient a pharmaceutically effective amount of a trifunctional bispecific antibody having the following properties:
1. a first binding arm that binds to a T cell;
2. a second binding arm that binds to said tumor-associated antigen expressed on said tumor cell; and
3. an Fc-portion that binds to Fcγ-receptor type I or III positive cells, or a combination thereof.
2. The method according to claim 1 , wherein said tumor-associated antigen is Her2/neu or CD20.
3. The method according to claim 1 or 2 , wherein said tumor-associated antigen is expressed on the tumor cells in amount of at least about 5,000, 20,000, 50,000 or 80,000 tumor-associated antigens/tumor cell and at a maximum of about 150,000, 110,000 or 100,000 tumor-associated antigens/tumor cell.
4. The method according to claim 1 , wherein said trifunctional antibody is selected from the group consisting of an anti-CD3×anti-tumor-associated antigen antibody, anti-CD4×anti-tumor-associated antigen antibody, anti-CD5×anti-tumor-associated antigen antibody, anti-CD6×anti-tumor-associated antigen antibody, anti-CD8 anti-tumor-associated antigen antibody, anti-CD2×anti-tumor-associated antigen antibody, anti-CD28×anti-tumor-associated antigen antibody, anti-CD44×anti-tumor-associated antigen antibody or a combination thereof.
5. The method according to claim 1 , wherein said trifunctional antibody is a heterologous bispecific antibody.
6. The method according to claim 5 , wherein said antibody is a heterologous rat/mouse bispecific antibody.
7. The method according to claim 1 , wherein said trifunctional antibody is selected from at least one member of the following group of isotype combinations in its Fc-region: rat-IgG2b/mouse-IgG2a, rat-IgG2b/mouse-IgG2b, rat-IgG2b/human-IgG, rat-IgG2b/human-IgG2.
8. The method according to claim 1 , wherein said trifunctional antibody is administered in an amount of 0.05-15 μg/kg body weight.
9. The method according to claim 1 , wherein said trifunctional bispecific antibody is an anti-Her2/neu×anti-CD3 antibody binding to Fcγ-type I/III-receptors.
10. The method according to claim 9 , wherein said antibody has the isotype combination rat-IgG2b/mouse-IgG2a.
11. The method according to claim 1 , wherein said Her2/neu antigen is expressed in an amount of about 5,000-150,000.
12. The method according to claim 11 , wherein said Her-2/neu antigen is expressed in an amount of about 20,000-100,000 on breast tumor cells.
13. The method according to claim 1 , wherein said Her2/neu antigen is expressed in an amount of up to 500,000 and the tumor cells are FISH negative.
14. The method according to claim 13 , wherein the cancer is a breast cancer.
15. The method according to claim 1 , wherein said trifunctional bispecific antibody is an anti-CD20×anti-CD3 antibody binding to Fcγ-type I/III-receptor.
16. The method according to claim 15 , wherein said antibody has the isotype combination rat-IgG2b/mouse-IgG2a.
17. The method according to claim 1 , wherein said tumor-associated antigen is CD20 and is expressed on said tumor cell in an amount of up to 300,000 tumor-associated antigens/tumor cell.
18. The methods according to claim 1 , wherein said tumor-associated antigen is EpCAM, GD2, or GD3, and is expressed on said tumor cell in an amount of about 1,000 to about 300,000 tumor-associated antigens/tumor cell.