Humanized Antibodies To LIV-1 And Use Of Same To Treat Cancer

• US 20130259860A1
• Filed: 12/06/2011
• Published: 10/03/2013
• Est. Priority Date: 12/06/2010
• Status: Active Grant

• Current Assignee: Seagen Inc.
• Original Assignee: Seattle Genetics Incorporated
• Inventors: Sussman, Django, Smith, Maria Leia, Arthur, William, Nesterova, Albina
• Granted Patent: US 9,228,026 B2
• Time in Patent Office: Days
• US Class Current: 424/133.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 47/6865 the tumour determinant being from skin, nerves or brain cancer cell
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 16/28 against receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: C07K 16/3015 Breast
• CPC Class Codes: C07K 16/3053 Skin, nerves, brain
• CPC Class Codes: C07K 16/3069 Reproductive system, e.g. ovaria, uterus, testes, prostate
• CPC Class Codes: C07K 16/465 with additional modified FR-residues
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/52 Constant or Fc region; Isotype
• CPC Class Codes: C07K 2317/56 variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/732 Antibody-dependent cellular cytotoxicity [ADCC]
• CPC Class Codes: C07K 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Abstract

The invention provides humanized antibodies that specifically bind to LIV-1. The antibodies are useful for treatment and diagnoses of various cancers as well as detecting LIV-1.

Claims

1. A humanized antibody comprising a mature heavy chain variable region having an amino acid sequence at least 90% identical to SEQ ID NO:

53 provided that position H27 is occupied by L, position H29 is occupied by I, H30 by E and H94 by V and a mature light chain variable region at least 90% identical to SEQ ID NO;

60 provided position L36 is occupied by Y and position L46 by P.

2. The humanized antibody of claim 1, comprising three CDRs of SEQ ID NO:

53 and three CDRs of SEQ ID NO;

60.

3. The humanized antibody of claim 1, further provided position H76 is occupied by N.

4. The humanized antibody of claim 1, comprising a mature heavy chain variable region having an amino acid sequence at least 95% identical to SEQ ID NO:

53 and a mature light chain variable region at least 95% identical to SEQ ID NO;

60.

5. The humanized antibody of claim 1 wherein the mature heavy chain variable region is fused to a heavy chain constant region and the mature light chain variable region is fused to a light chain constant region.

6. The humanized antibody of any claim 1, wherein the heavy chain constant region is a mutant form of natural human constant region which has reduced binding to an Fcgamma receptor relative to the natural human constant region.

7. The humanized antibody of claim 1, wherein the heavy chain constant region is of IgG1 isotype.

8. The humanized antibody of claim 1, wherein the heavy chain constant region has an amino acid sequence comprising SEQ ID NO:

44 and the light chain constant region has an amino acid sequence comprising SEQ ID NO;

42.

9. The humanized antibody of claim 1, wherein the heavy chain constant region has an amino acid sequence comprising SEQ ID NO:

46 (S239C) and the light chain constant region has an amino acid sequence comprising SEQ ID NO;

42.

10. The humanized antibody of claim 1, provided any differences in CDRs of the mature heavy chain variable region and mature light variable region from SEQ ID NOS. 52 and 60 respectively reside in positions H60-H65.

11. The humanized antibody of claim 1, wherein the mature heavy chain variable region has an amino acid sequence designated SEQ ID NO:

52 or 53 and the mature light chain variable region has an amino acid sequence designated SEQ ID NO;

59 or 60.

12. The humanized antibody of claim 1, wherein the mature heavy chain variable region has an amino acid sequence designated SEQ ID NO:

53 and the mature light chain variable region has an amino acid sequence designated SEQ ID NO;

60.

13. The humanized antibody of claim 1, wherein the antibody is conjugated to a cytotoxic or cytostatic agent.

14. The humanized antibody of claim 1 having an association constant for human or cynomolgus monkey LIV-1 of 0.5 to 2×

10⁹ M<sup>−

1</sup>.

16. A nucleic acid encoding a mature heavy chain variable region and/or a mature light chain variable region as defined by claim 1.

17. A method of treating a patient having or at risk of cancer, comprising administering to the patient an effective regime of a humanized antibody of claim 1.

18. The method of claim 17, wherein the cancer is a breast cancer, a prostate cancer, a cervical cancer or a melanoma.

19. A pharmaceutical composition comprising a humanized antibody of claim 1.

15. A humanized antibody comprising a mature heavy chain variable region comprising the three Kabat CDRs of SEQ ID NO:

52, wherein position H27 is occupied by L, position H29 is occupied by I, H30 by E, H76 by N, and H94 by V and a mature light chain variable region comprising the three Kabat CDRs of SEQ ID NO;

60 provided position L36 is occupied by Y and position L46 by P.

20. A humanized antibody comprising a mature heavy chain variable region having an amino acid sequence at least 90% identical to HB (SEQ ID NO:

10) and a mature light chain variable region at least 90% identical to LB (SEQ ID NO;

5).

21-42. -42. (canceled)