Humanized immunomodulatory monoclonal antibodies for the treatment of neoplastic disease or immunodeficiency

• US 7,332,582 B2
• Filed: 11/19/2004
• Issued: 02/19/2008
• Est. Priority Date: 05/23/2002
• Status: Expired due to Term

• Current Assignee: CureTech Ltd. (Clal Biotechnology Industries Ltd.), Mor Research Applications Ltd. (Clalit Health Services)
• Original Assignee: CureTech Ltd. (Clal Biotechnology Industries Ltd.), Mor Research Applications Ltd. (Clalit Health Services)
• Inventors: Jones, Steven Tarran, Hardy, Britta, Klapper, Leah
• Primary Examiner(s): Blanchard; David J.
• Application Number:
  US10/994,091
• Publication Number:
  US 20050180969A1
• Time in Patent Office: 1,187 Days
• Field of Search: 530/387.3, 530/388.8, 424/133.1
• US Class Current: 530/387.3
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/28 against receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/56 variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/73 Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation

Abstract

The present invention provides to a humanized monoclonal antibody having immunostimulatory effects. This antibody binds specifically to B lymphoblastoid cells, induces proliferation and activation of peripheral blood lymphocytes, and is capable of eliciting an anti-tumor effect upon administration to subjects suffering from cancer.

Claims

1. A humanized antibody comprising the complementarity-determining regions (CDRs) of murine monoclonal antibody BAT-1 (mBAT-1), wherein the humanized antibody comprises:

a light chain variable region selected from the group consisting of;

BATRKA (SEQ. ID NO.

     15), BATRKB (SEQ. ID NO.

     16), BATRKC (SEQ. ID NO.

     17), and BATRKD (SEQ. ID NO.

     18), and

a heavy chain variable region selected from the group consisting of;

BATRHA (SEQ. ID NO.

     20), BATRHB (SEQ. ID NO.

     21), BATRHC (SEQ. ID NO.

     22), BATRHD (SEQ. ID NO.

     23) and BATRHE (SEQ. ID NO.

     24);

wherein the humanized antibody retains the anti-tumor activity of mBAT-1 and is less immunogenic in a human subject than mBAT-1.

2. The humanized antibody of claim 1, wherein the variable regions are selected from the group consisting of:

BATRHA/BATRKA (SEQ. ID NO. 20/SEQ. ID NO.

     15), BATRHB/BATRKA (SEQ. ID NO. 21/SEQ. ID NO.

     15), BATRHB/BATRKB (SEQ. ID NO. 21/SEQ. ID NO.

     16), BATRHC/BATRKB (SEQ. ID NO. 22/SEQ. ID NO.

     16), BATRHB/BATRKD (SEQ. ID NO. 21/SEQ. ID NO.

     18), and BATRHC/BATRKD (SEQ. ID NO. 22/SEQ. ID NO.

     18).

3. An antibody fragment of the humanized antibody of claim 1, wherein the antibody fragment is selected from the group consisting of:

Fv, F(ab′

), F(ab′

)2, and a single chain antibody.

4. A pharmaceutical composition comprising the humanized antibody according to claim 1, and a physiologically acceptable carrier, diluent, or stabilizer.

5. A method for treating cancer cells that express the BAT-1 antigen in a subject in need of such treatment which comprises the step of treating the subject with a therapeutically effective amount of a pharmaceutical composition containing as an active ingredient the humarized antibody of claim 1 and optionally including a physiologically acceptable carrier, diluent, or stabilizer.

6. The method of claim 5 further comprising treating the subject with an additional therapeutic agent.

7. The method of claim 6 wherein the additional therapeutic agent is selected from IL-1, IL-2, IL-6, IFN-α

(interferon-α

), T-cell stimulatory antibody, or anti-tumor therapeutic antibody.

8. The method of claim 6, wherein the humarized antibody and the additional agent is administered substantially at the same time in a single composition or sequentially in separate compositions.

9. The method of claim 6, further comprising applying a cell therapy treatment to the subject.

10. The method of claim 9, wherein the cells are autologous or allogeneic cells.

11. The method of claim 6 wherein the cancer is selected from the group consisting of melanoma, a lung tumor, colorectal cancer and hepatic metastasis.

12. A method for producing the humanized antibody of claim 1, which comprises:

a) transfecting a host cell with a vector comprising a polynucleotide sequence encoding the humanized antibody, or co-transfecting the host cell with 2 vectors each comprising a polynucleotide sequence encoding the heavy or light chain regions of the humanized antibody;

b) culturing the host cell so that said humanized antibody is expressed; and

c) recovering the humanized antibody from the host cell culture.