Antibodies against CD38 for treatment of multiple myeloma

• US 7,829,673 B2
• Filed: 03/23/2006
• Issued: 11/09/2010
• Est. Priority Date: 03/23/2005
• Status: Active Grant

• Current Assignee: Genmab A/S
• Original Assignee: Genmab A/S
• Inventors: Oprins, Judith, Parren, Paul, Graus, Yvo, Van Vugt, Martine, Van De Winkel, Jan, De Weers, Michel
• Primary Examiner(s): GUSSOW, ANNE
• Application Number:
  US11/886,932
• Publication Number:
  US 20090148449A1
• Time in Patent Office: 1,692 Days
• Field of Search: None
• US Class Current: 530/387.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 49/0004 Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/16 Otologicals
• 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 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 14/70596 Molecules with a "CD"-designation not provided for elsewhere
• CPC Class Codes: C07K 16/2896 against molecules with a "CD"-designation, not provided for elsewhere
• CPC Class Codes: C07K 16/40 against enzymes
• CPC Class Codes: C07K 2317/21 : from primates, e.g. man
• 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 2317/56 : 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 2317/734 : Complement-dependent cytotoxicity [CDC]
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/77 : Internalization into the cell
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: C12N 15/63 : Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
• CPC Class Codes: C12N 5/10 : Cells modified by introduction of foreign genetic material
• CPC Class Codes: G01N 2333/70596 : Molecules with a "CD"-designation not provided for elsewhere in G01N2333/705
• CPC Class Codes: G01N 33/566 : using specific carrier or receptor proteins as ligand binding reagents where possible specific carrier or receptor proteins are classified with their target compounds

Abstract

Isolated human monoclonal antibodies which bind to human CD38, and related antibody-based compositions and molecules, are disclosed. Also disclosed are pharmaceutical compositions comprising the human antibodies, and therapeutic and diagnostic methods for using the human antibodies.

Claims

1. An isolated full-length antibody which binds to human CD38, wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:

7 or encoded by the nucleotide sequence set forth in SEQ ID NO;

6.

2. An isolated full-length antibody which binds to human CD38, wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:

17 or encoded by the nucleotide sequence set forth in SEQ ID NO;

16.

3. An isolated full-length antibody which binds to human CD38, wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:

27 or encoded by the nucleotide sequence set forth in SEQ ID NO;

26.

4. An isolated full-length antibody which binds to human CD38, wherein the antibody comprises a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:

2 or encoded by the nucleotide sequence set forth in SEQ ID NO;

1.

5. An isolated full-length antibody which binds to human CD38, wherein the antibody comprises a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:

12 or encoded by the nucleotide sequence set forth in SEQ ID NO;

11.

6. An isolated full-length antibody which binds to human CD38, wherein the antibody comprises a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:

22 or encoded by the nucleotide sequence set forth in SEQ ID NO;

21.

7. An isolated full-length antibody which binds to human CD38, wherein the antibody comprises heavy and light chain variable region amino acid sequences as set forth in (a) SEQ ID NOs:

7 and 2, respectively;

(b) SEQ ID NOs;

17 and 12, respectively;

or (c) SEQ ID NOs;

27 and 22, respectively.

9. An isolated full-length antibody which binds an epitope on human CD38 recognized by the antibody of claim 7.

10. The antibody of claim 9, wherein the antibody binds to the region SKRNIQFSCKNIYR (SEQ ID NO:

35) and the region EKVQTLEAWVIHGG (SEQ ID NO;

     36) of human CD38 (SEQ ID No;

     31).

20. A hybridoma which produces the antibody of claim 7.

8. An isolated full-length antibody which binds to human CD38, wherein the antibody comprises heavy and light chain variable regions encoded by the nucleotide sequence as set forth in (a) SEQ ID NOs:

6 and 1, respectively;

(b) SEQ ID NOs;

16 and 11, respectively;

or (c) SEQ ID NOs;

26 and 21, respectively.

21. A hybridoma which produces the antibody of claim 8.

11. An isolated full-length antibody which binds to human CD38, wherein the antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences set forth in SEQ ID NOs:

8, 9, and 10, respectively, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences set forth in SEQ ID NOs;

3, 4, and 5, respectively.

14. The antibody of any one of claims 9, 11, 12, or 13, wherein the antibody possesses one or more of the following characteristics:

(i) acts as an antagonist of CD38;

(ii) does not induce significant proliferation of peripheral blood mononuclear cells;

(iii) does not induce release of significant IL-6 by human monocytes or peripheral blood mononuclear cells;

(iv) does not induce release of detectable IFN-gamma by human T cells or peripheral blood mononuclear cells;

(v) is internalized by CD38 expressing cells;

(vi) induces ADCC;

(vii) induces CDC in the presence of complement;

(viii) inhibits the synthesis of cGDPR;

(ix) inhibits the synthesis of cADPR;

(x) binds to human CD38 with an affinity (K_D) of below 10<sup>−

8</sup> M;

(xi) binds to a mutant human CD38 with an EC₅₀ that is less than 50% compared to the EC₅₀ of the binding of the antibody to human CD38 (SEQ ID No;

     31), wherein the serine residue in position 274 of the mutant human CD38 has been substituted with a phenylalanine residue (SEQ ID No;

     34);

(xii) binds to a mutant human CD38 with an EC₅₀ that is less than 50% compared to the EC₅₀ of the binding of the antibody to human CD38 (SEQ ID No;

     31), wherein the glutamine residue in position 272 of the mutant human CD38 has been substituted with an arginine residue (SEQ ID No;

     33);

or

(xiii) binds to a mutant human CD38 with an EC₅₀ that is 75%-125% of the EC₅₀ of the binding of the antibody to human CD38 (SEQ ID No;

     31), wherein the threonine residue in position 237 of the mutant human CD38 has been substituted with an alanine residue (SEQ ID No;

     32).

15. The antibody of any one of claims 9, 11, 12, or 13, which is a human monoclonal antibody.

16. The antibody of any one of claims 9, 11, 12, or 13, wherein the antibody is a full-length IgG1, IgG2, IgG3, IgG4, IgD, IgA, IgE, or IgM antibody.

17. The antibody of any one of claims 9, 11, 12, or 13, wherein the antibody is glycosylated in a eukaryotic cell.

18. The antibody of any one of claims 9, 11, 12, or 13, which is an antibody fragment or a single chain antibody.

19. The antibody of any one of claims 9, 11, 12, or 13, further comprising a chelator linker for attaching a radioisotope.

22. An immunoconjugate comprising the antibody of any one of claims 9, 11, 12, or 13.

23. A bispecific or multispecific molecule comprising the antibody of any one of claims 9, 11, 12, or 13.

24. The bispecific or multispecific molecule of claim 23, which comprises a binding specificity for CD3, CD4, CD 138, IL-15R, membrane bound TNFα

, receptor bound TNFα

, a human Fc receptor, membrane bound IL-15, or receptor bound IL-15.

25. A pharmaceutical composition comprising the antibody of any one of claims 9, 11, 12, or 13 and a pharmaceutically acceptable carrier.

26. The pharmaceutical composition according to claim 25 comprising one or more further therapeutic agents.

27. A method of inhibiting growth and/or proliferation of a cell expressing CD38, comprising administration of the antibody of any one of claims 9, 11, 12, or 13, such that the growth and/or proliferation of the cell is inhibited.

28. A kit comprising the antibody of any one of claims 9, 11, 12, or 13 for detecting the presence of CD38 antigen, or a cell expressing CD38 antigen, in a sample.

29. An anti-idiotypic antibody which binds to the antibody of any one of claims 9, 11, 12, or 13.

12. An isolated full-length antibody which binds to human CD38, wherein the antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences set forth in SEQ ID NOs:

18, 19, and 20, respectively, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences set forth in SEQ ID NOs;

13, 14, and 15, respectively.

13. An isolated full-length antibody which binds to human CD38, wherein the antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences set forth in SEQ ID NOs:

28, 29, and 30, respectively, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences set forth in SEQ ID NOs;

23, 24, and 25, respectively.