Anti-CD38 human antibodies and uses thereof

• US 8,263,746 B2
• Filed: 02/07/2005
• Issued: 09/11/2012
• Est. Priority Date: 02/06/2004
• Status: Active Grant

• Current Assignee: Morphosys Ag
• Original Assignee: Morphosys Ag
• Inventors: Tesar, Michael, Jager, Ute
• Primary Examiner(s): GUSSOW, ANNE
• Application Number:
  US10/588,568
• Publication Number:
  US 20100285004A1
• Time in Patent Office: 2,773 Days
• Field of Search: None
• US Class Current: 530/387.9
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: C07K 16/005 constructed by phage libraries
• CPC Class Codes: C07K 16/2896 against molecules with a "CD"-designation, not provided for elsewhere
• CPC Class Codes: C07K 16/3061 Blood cells
• CPC Class Codes: C07K 16/40 against enzymes
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/33 Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
• CPC Class Codes: C07K 2317/34 Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• CPC Class Codes: C07K 2317/52 Constant or Fc region; Isotype
• CPC Class Codes: C07K 2317/55 Fab or Fab'
• 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 2317/567 Framework region [FR]
• CPC Class Codes: C07K 2317/732 : Antibody-dependent cellular cytotoxicity [ADCC]
• CPC Class Codes: C07K 2317/734 : Complement-dependent cytotoxicity [CDC]
• CPC Class Codes: C07K 2317/74 : Inducing cell proliferation
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: C07K 2319/30 : Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
• CPC Class Codes: C12N 9/2497 : hydrolysing N- glycosyl compounds (3.2.2)
• CPC Class Codes: C12Y 302/02024 : ADP-ribosyl-[dinitrogen reductase] hydrolase (3.2.2.24)

Abstract

The present invention provides recombinant antigen-binding regions and antibodies and functional fragments containing such antigen-binding regions that are specific for CD38, which plays an integral role in various disorders or conditions. These antibodies, accordingly, can be used to treat, for example, hematological malignancies such as multiple myeloma. Antibodies of the invention also can be used in the diagnostics field, as well as for investigating the role of CD38 in the progression of disorders associated with malignancies. The invention also provides nucleic acid sequences encoding the foregoing antibodies, vectors containing the same, pharmaceutical compositions and kits with instructions for use. The invention also provides isolated novel epitopes of CD38 and methods of use therefore.

Claims

1. An isolated human antibody that specifically binds an epitope of CD38 (SEQ ID NO:

22),

wherein said antibody mediates killing of a CD38+ target cell by antibody dependent cellular cytotoxicity with at least five-fold better efficacy than chimeric OKT10 antibody (SEQ ID NOS;

23 and

     24) under the same or substantially the same conditions when a human PBMC cell is employed as the effector cell,

wherein said CD38+ target cell is selected from the group consisting of LP-1 (DSMZ;

ACC41) and RPMI-8226 (ATCC;

CCL-155), and

wherein the ratio of effector cells to target cells is between about 30;

1 and about 50;

1.

2. An isolated antibody according to claim 1, comprising an H-CDR1, H-CDR2 and H-CDR3 depicted in SEQ ID NO:

5 and an L-CDR1, L-CDR2 and L-CDR3 depicted in SEQ ID NO;

13.

3. An isolated antibody according to claim 1, comprising an H-CDR1, H-CDR2 and H-CDR3 depicted in SEQ ID NO:

6 and an L-CDR1, L-CDR2 and L-CDR3 depicted in SEQ ID NO;

14.

4. An isolated antibody according to claim 1, comprising an H-CDR1, H-CDR2 and H-CDR3 depicted in SEQ ID NO:

7 and an L-CDR1, L-CDR2 and L-CDR3 depicted in SEQ ID NO;

15.

5. An isolated antibody according to claim 1, comprising an H-CDR1, H-CDR2 and H-CDR3 depicted in SEQ ID NO:

8 and an L-CDR1, L-CDR2 and L-CDR3 depicted in SEQ ID NO;

16.

6. An isolated antibody to according to claim 1, which is an IgG.

7. An isolated antibody to according to claim 6, which is an IgG1.

8. An isolated human antibody that specifically binds to an epitope of CD38 (SEQ ID NO:

22),

wherein said antibody mediates killing of a CD38-transfected CHO cell by cell dependent cytotoxicity with at least two-fold better efficacy than chimeric OKT10 antibody (SEQ ID NOS;

23 and

     24) under the same or substantially the same conditions.

9. An isolated antibody according to claim 8, comprising an H-CDR1, H-CDR2 and H-CDR3 depicted in SEQ ID NO:

5 and an L-CDR1, L-CDR2 and L-CDR3 depicted in SEQ ID NO;

13.

10. An isolated antibody according to claim 8, comprising an H-CDR1, H-CDR2 and H-CDR3 depicted in SEQ ID NO:

6 and an L-CDR1, L-CDR2 and L-CDR3 depicted in SEQ ID NO;

14.

11. An isolated antibody according to claim 8, comprising an H-CDR1, H-CDR2 and H-CDR3 depicted in SEQ ID NO:

7 and an L-CDR1, L-CDR2 and L-CDR3 depicted in SEQ ID NO;

15.

12. An isolated antibody to according to claim 8, which is an IgG.

13. An isolated antibody to according to claim 12, which is an IgG1.

14. An isolated human or humanized antibody or antibody fragment thereof containing an antigen-binding region which specifically binds within amino acids 44 to 206 of CD38 (SEQ ID NO:

22).

15. An isolated antibody or antibody fragment thereof containing an antigen-binding region of claim 14, which specifically binds within amino acids 44-66, 82-94, 142-154, 148-164, 158-170, or 192-206 of CD38 (SEQ ID NO:

22).

16. An isolated antibody or antibody fragment thereof containing an antigen-binding region of claim 15, which specifically binds within amino acids 44-66 or 148-164 of CD38 (SEQ ID NO:

22).

17. An isolated antibody or antibody fragment thereof containing an antigen-binding region of claim 16, which specifically binds within amino acids 44-66 and 148-164 of CD38 (SEQ ID NO:

22).

18. An isolated antibody or antibody fragment thereof containing an antigen-binding region of claim 15, which specifically binds within amino acids 192-206 of CD38 (SEQ ID NO:

22).

19. An isolated antibody or antibody fragment thereof containing an antigen-binding region of claim 15, which specifically binds within amino acids 82-94 or 158-170 of CD38 (SEQ ID NO:

22).

20. An isolated antibody or antibody fragment thereof containing an antigen-binding region of claim 19, which specifically binds within amino acids 82-94 and 158-170 of CD38 (SEQ ID NO:

22).

21. An isolated antibody or antibody fragment thereof containing an antigen-binding region of claim 15, which specifically binds within amino acids 82-94 or 142-154 of CD38 (SEQ ID NO:

22).

22. An isolated antibody or antibody fragment thereof containing an antigen-binding region of claim 21, which specifically binds within amino acids 82-94 and 142-154 of CD38 (SEQ ID NO:

22).

23. An isolated antibody or antibody fragment thereof containing an antigen-binding region according to claim 14, comprising an H-CDR1, H-CDR2 and H-CDR3 depicted in SEQ ID NO:

5 and an L-CDR1, L-CDR2 and L-CDR3 depicted in SEQ ID NO;

13.

24. An isolated antibody or antibody fragment thereof containing an antigen-binding region according to claim 14, comprising an H-CDR1, H-CDR2 and H-CDR3 depicted in SEQ ID NO:

6 and an L-CDR1, L-CDR2 and L-CDR3 depicted in SEQ ID NO;

14.

25. An isolated antibody or antibody fragment thereof containing an antigen-binding region according to claim 14, comprising an H-CDR1, H-CDR2 and H-CDR3 depicted in SEQ ID NO:

7 and an L-CDR1, L-CDR2 and L-CDR3 depicted in SEQ ID NO;

15.

26. An isolated antibody or antibody fragment thereof containing an antigen-binding region according to claim 14, comprising an H-CDR1, H-CDR2 and H-CDR3 depicted in SEQ ID NO:

8 and an L-CDR1, L-CDR2 and L-CDR3 depicted in SEQ ID NO;

16.

27. An isolated antibody according to claim 14, which is an IgG.

28. An isolated antibody according to claim 27, which is an IgG1.