Destruction of tumor cells by trifunctional bispecific antibodies with low to medium expression levels of tumor-associated target antigens

• US 9,017,676 B2
• Filed: 02/15/2007
• Issued: 04/28/2015
• Est. Priority Date: 02/15/2006
• Status: Active Grant

• Current Assignee: Horst Lindhofer
• Original Assignee: Horst Lindhofer
• Inventors: Lindhofer, Horst
• Primary Examiner(s): Goddard, Laura B
• Application Number:
  US12/224,010
• Publication Number:
  US 20100178298A1
• Time in Patent Office: 2,994 Days
• Field of Search: None
• US Class Current: 424/136.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/55 characterised by the host/recipient, e.g. newborn with maternal antibodies
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: C07K 16/2809 against the T-cell receptor (TcR)-CD3 complex
• CPC Class Codes: C07K 16/2887 against CD20
• CPC Class Codes: C07K 16/3084 against tumour-associated gangliosides
• CPC Class Codes: C07K 16/32 against translation products of oncogenes
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/31 multispecific
• CPC Class Codes: C07K 2317/73 Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation

Abstract

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.

Claims

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 μ

g/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.