VARIANTS OF HUMANIZED IMMUNOMODULATORY MONOCLONAL ANTIBODIES

• US 20130022595A1
• Filed: 07/23/2012
• Published: 01/24/2013
• Est. Priority Date: 07/24/2011
• Status: Active Grant

• Current Assignee: CureTech Ltd. (Clal Biotechnology Industries Ltd.)
• Original Assignee: CureTech Ltd. (Clal Biotechnology Industries Ltd.)
• Inventors: Rotem-Yehudar, Rinat, Schickler, Michael
• Granted Patent: US 8,686,119 B2
• Time in Patent Office: Days
• US Class Current: 424/133.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: C07K 16/3061 Blood cells
• CPC Class Codes: C07K 2317/56 variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/75 Agonist effect on antigen
• CPC Class Codes: C07K 2317/94 Stability, e.g. half-life, pH, temperature or enzyme-resistance

Abstract

The present invention relates to humanized monoclonal antibodies, pharmaceutical compositions that include the same, and use thereof for the treatment of a variety of indications, particularly cancer and immunodeficiency disorders. In particular, the present invention provides modified antibodies or fragments thereof having specific amino acid modifications compared to the humanized monoclonal immunomodulatory antibody termed hBAT-1.

Claims

1. An antibody or antigen binding fragment thereof comprising a light chain variable region selected from the group consisting of SEQ ID NO:

1, 2, 3, and 4, and a heavy chain variable region selected from the group consisting of SEQ ID NO;

5, 6, 7, 8, and 9, wherein the antibody or antigen binding fragment thereof comprises at least one amino acid substitution at a position selected from;

Phe 97 and Phe 93 of the light chain variable region to Ala, Leu or Val, or a substitution of Trp 107 of the heavy chain variable region to Ala, Leu, Val or Tyr.

2. The antibody or antigen binding fragment thereof of claim 1, comprising an amino acid substitution of Phe 97 of the light chain variable region and an amino acid substitution of Trp 107 of the heavy chain variable region.

3. The antibody or antigen binding fragment thereof of claim 1, comprising an amino acid substitution of Phe 93 of the light chain variable region and an amino acid substitution of Trp 107 of the heavy chain variable region.

4. The antibody or antigen binding fragment thereof of claim 1, wherein the light chain variable region comprises the amino acid sequence selected from the group consisting of:

SEQ ID NO;

14, 15, 16, 17, 18, 19, 20 and 21.

5. The antibody or antigen binding fragment thereof of claim 1, wherein the light chain variable region comprises the amino acid sequence as set forth in any one of SEQ ID NO:

14 or 15.

6. The antibody or antigen binding fragment thereof of claim 1, wherein the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:

29.

7. The antibody or antigen binding fragment thereof of claim 1, wherein the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:

30.

8. The antibody or antigen binding fragment thereof of claim 1, wherein the heavy chain variable region comprises the amino acid sequence selected from the group consisting of:

SEQ ID NO;

24, 25, 26, 27 and 28.

9. The antibody or antigen binding fragment thereof of claim 1, wherein the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:

24.

10. The antibody or antigen binding fragment thereof of claim 1, wherein the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:

31.

11. The antibody or antigen binding fragment thereof of claim 1, further comprising at least one amino acid modification at a position selected from the group consisting of:

Thr 5, Thr 20, Cys 71, Asn 75 and Ser 76 of the light chain variable region and Asp 54 and Ser 55 of the heavy chain variable region.

12. The antibody or antigen binding fragment thereof of claim 1, comprising a combination of a heavy chain variable region and a light chain variable region, the combination is selected from the group consisting of:

SEQ ID NO;

5/SEQ ID NO;

1, SEQ ID NO;

6/SEQ ID NO;

2, SEQ ID NO;

7/SEQ ID NO;

2, SEQ ID NO;

7/SEQ ID NO;

3, SEQ ID NO;

8/SEQ ID NO;

3, and SEQ ID NO;

7/SEQ ID NO;

1.

13. The antibody or antigen binding fragment thereof of claim 1, comprising variable regions corresponding to SEQ ID NO:

5/SEQ ID NO;

1.

14. The antibody or antigen binding fragment thereof of claim 1 having an antitumor activity of similar, or greater than, mBAT-1.

15. The antibody or antigen binding fragment thereof of claim 1 having an antitumor activity of similar, or greater than, hBAT-1.

16. The antibody or antigen binding fragment thereof of claim 1, wherein the fragment of the humanized antibody is selected from the group consisting of:

Fv, F(ab′

), F(ab′

)2, and a single chain antibody.

17. A polynucleotide sequences encoding the antibody or fragments thereof according to claim 1.

18. A vector comprising the polynucleotide sequence of claim 17.

19. A host cells containing a vector comprising the polynucleotide sequence of claim 18.

20. A pharmaceutical composition comprising as an active ingredient the antibody of claim 1 or an antigen binding fragment thereof, and a pharmaceutically acceptable carrier, diluent or stabilizer.

21. A method for treating cancer or an immunodeficiency disorder in a subject in need thereof, comprising administering to the subject an effective amount of a pharmaceutical composition according to claim 20.

22. The method of claim 21 wherein the subject has a non-solid tumor.

23. The method of claim 22 wherein the subject has a hematologic malignancy.

24. The method of claim 23 wherein the cancer is selected from the group consisting of a colorectal carcinoma, a non-small lung cancer (NSCLC), a small cell lung cancer (SCLC), a breast carcinoma;

a melanoma;

an ovarian carcinoma, a cervical carcinoma, a pancreatic cancer, a head and neck carcinoma, a gastrointestinal carcinoma, an esophageal tumor, a hepatocellular carcinoma, multiple myeloma, a renal cell carcinoma, a prostate tumor, non-Hodgkin'"'"'s lymphoma, Hodgkin'"'"'s disease, mantle cell lymphoma, Kaposi'"'"'s sarcoma, a squamous cell carcinoma, a basal cell carcinoma, acute myeloid leukemia (AML), chronic myelocytic leukemia (CML), acute lymphocytic leukemia (ALL), and chronic lymphocytic leukemia (CLL).

25. The method of claim 24 wherein the cancer is selected from the group consisting of:

colorectal carcinoma, melanoma, pancreatic cancer, head and neck carcinoma, esophageal tumor, multiple myeloma, renal cell carcinoma, non-Hodgkin'"'"'s lymphoma and Hodgkin'"'"'s disease.