Anti-IgE antibodies

• US 20090117124A1
• Filed: 04/01/2008
• Published: 05/07/2009
• Est. Priority Date: 04/02/2007
• Status: Active Grant

• Current Assignee: Amgen Fremont Inc. (Amgen Inc.), Pfizer Inc.
• Original Assignee: Amgen Fremont Inc. (Amgen Inc.)
• Inventors: Yeadon, Mike, de Mendez, Isabelle, Logan, Alison, Moffat, Mark A., Diaz-Collier, Judith, Liao, Wei, Kellermann, Sirid-Aimee, Liu, Wai, Rajpal, Arvind, Brown, Caroline, Beyaz-Kavuncu, Nurten, Casperson, Gerald F.
• Granted Patent: US 7,867,494 B2
• Time in Patent Office: Days
• US Class Current: 424/141.100
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• 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 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 7/04 Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: C07K 16/4291 against IgE
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• 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 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: Y10S 424/805 involving IgE or IgD

Abstract

The present invention relates to novel human antibodies specifically directed against human immunoglobulin E (anti-IgE). The present invention also relates to pharmaceutical compositions and methods for treating asthma, in particular allergic asthma, as well as other IgE-mediated disorders including allergic rhinitis and food allergies.

Claims

1. A human monoclonal antibody or antigen-binding portion thereof directed against human IgE, the antibody or portion having at least one additional property selected from the group consisting of:

a) has an IC₅₀ of 0.5 μ

g/mL or less as measured by its ability to reduce IgE cell binding assay using an RBL-2H3 cell line transfected with the human Fcε

R1;

b) has an IC₅₀ of 0.5 μ

g/mL or less as measured by its ability to inhibit IgE-mediated degranulation of a RBL-2H3 cell line transfected with the human Fcε

R1;

c) does not crosslink receptor-bound IgE and does not stimulate IgE-dependent degranulation of RBL-2H3 (Fcε

R1) cells cultured with human IgE;

d) does not crosslink receptor-bound IgE and does not stimulate IgE-dependent degranulation of human blood basophils;

e) is highly selective for IgE over human IgA, IgG1 and IgG3;

f) binds to the full length of human IgE with an Affinity Constant, K_D, of 15 nM or less as measured by surface plasmon resonance;

g) has an off rate (kOff) for human IgE of 2×

10<sup>−

4</sup> s<sup>−

1</sup> or smaller as measured by surface plasmon resonance; and

h) binds to the same epitope of human IgE as an antibody selected from the group consisting of recombinant 5.396.1;

5.396.1 Hc-S103N Lc-K61R;

recombinant 6.605.1;

6.605.1 (H3Q, M13K, D82E-T25A, T53S);

recombinant 5.948.1; and

5.948.1H100Y.

4. The antibody or portion thereof according to claim 1 or 2, wherein said antibody comprises a H-CDR3 having a sequence selected from the group consisting of SEQ ID NO:

10, 30, 50, 70, 90 and 130.

5. The antibody or portion thereof according to claim 1 or 2, wherein said antibody is selected from the group consisting of:

an antibody comprising a H-CDR set of H-CDRs (H-CDR1, H-CDR2, H-CDR3) respectively having the sequences of SEQ ID NO;

6, 8, 10; and

a L-CDR set of L-CDRs (L-CDR1, L-CDR2, L-CDR3) respectively having the sequences of SEQ ID NO;

16, 18, 20;

an antibody comprising a H-CDR set of H-CDRs (H-CDR1, H-CDR2, H-CDR3) respectively having the sequences of SEQ ID NO;

26, 28, 30; and

a L-CDR set of L-CDRs (L-CDR1, L-CDR2, L-CDR3) respectively having the sequences of SEQ ID NO;

36, 38, 40;

an antibody comprising a H-CDR set of H-CDRs (H-CDR1, H-CDR2, H-CDR3) respectively having the sequences of SEQ ID NO;

46, 48, 50; and

a L-CDR set of L-CDRs (L-CDR1, L-CDR2, L-CDR3) respectively having the sequences of SEQ ID NO;

56, 58, 60;

an antibody comprising a H-CDR set of H-CDRs (H-CDR1, H-CDR2, H-CDR3) respectively having the sequences of SEQ ID NO;

66, 68, 70; and

a L-CDR set of L-CDRs (L-CDR1, L-CDR2, L-CDR3) respectively having the sequences of SEQ ID NO;

76, 78, 80;

an antibody comprising a H-CDR set of H-CDRs (H-CDR1, H-CDR2, H-CDR3) respectively having the sequences of SEQ ID NO;

86, 88, 90; and

a L-CDR set of L-CDRs (L-CDR1, L-CDR2, L-CDR3) respectively having the sequences of SEQ ID NO;

96, 98, 100; and

an antibody comprising a H-CDR set of H-CDRs (H-CDR1, H-CDR2, H-CDR3) respectively having the sequences of SEQ ID NO;

126, 128, 130; and

a L-CDR set of L-CDRs (L-CDR1, L-CDR2, L-CDR3) respectively having the sequences of SEQ ID NO;

136, 138, 140.

6. The antibody or portion thereof according to claim 1 or 2, wherein said antibody is of the IgG1 or IgG2 subtype.

7. The antibody or portion thereof according to claim 1 or 2, wherein said antibody is selected from the group consisting of:

an antibody comprising a H-variable domain having the sequence of SEQ ID NO;

4; and

a L-variable domain having the sequence of SEQ ID NO;

14;

an antibody comprising a H-variable domain having the sequence of SEQ ID NO;

24; and

a L-variable domain having the sequence of SEQ ID NO;

34;

an antibody comprising a H-variable domain having the sequence of SEQ ID NO;

44; and

a L-variable domain having the sequence of SEQ ID NO;

54;

an antibody comprising a H-variable domain having the sequence of SEQ ID NO;

64; and

a L-variable domain having the sequence of SEQ ID NO;

74;

an antibody comprising a H-variable domain having the sequence of SEQ ID NO;

84; and

a L-variable domain having the sequence of SEQ ID NO;

94; and

an antibody comprising a H-variable domain having the sequence of SEQ ID NO;

124; and

a L-variable domain having the sequence of SEQ ID NO;

134.

8. The antibody or portion thereof according to claim 1 or 2, wherein said antibody is selected from the group consisting of:

an antibody comprising a H-chain having the sequence of SEQ ID NO;

2; and

a L-chain having the sequence of SEQ ID NO;

12;

an antibody comprising a H-chain having the sequence of SEQ ID NO;

22; and

a L-chain having the sequence of SEQ ID NO;

32;

an antibody comprising a H-chain having the sequence of SEQ ID NO;

42; and

a L-chain having the sequence of SEQ ID NO;

52;

an antibody comprising a H-chain having the sequence of SEQ ID NO;

62; and

a L-chain having the sequence of SEQ ID NO;

72;

an antibody comprising a H-chain having the sequence of SEQ ID NO;

82; and

a L-chain having the sequence of SEQ ID NO;

92; and

an antibody comprising a H-chain having the sequence of SEQ ID NO;

122; and

a L-chain having the sequence of SEQ ID NO;

132.

9. The antibody or portion thereof according to claim 1 or 2, wherein said antibody is selected from the group consisting of:

an antibody comprising a H-chain sequence encoded by a nucleic acid sequence of SEQ ID NO;

1; and

a L-chain sequence encoded by a nucleic acid sequence of SEQ ID NO;

11;

an antibody comprising a H-chain sequence encoded by a nucleic acid sequence of SEQ ID NO;

21; and

a L-chain sequence encoded by a nucleic acid sequence of SEQ ID NO;

31;

an antibody comprising a H-chain sequence encoded by a nucleic acid sequence of SEQ ID NO;

41; and

a L-chain sequence encoded by a nucleic acid sequence of SEQ ID NO;

51;

an antibody comprising a H-chain sequence encoded by a nucleic acid sequence of SEQ ID NO;

61; and

a L-chain sequence encoded by a nucleic acid sequence of SEQ ID NO;

71;

an antibody comprising a H-chain sequence encoded by a nucleic acid sequence of SEQ ID NO;

81; and

a L-chain sequence encoded by a nucleic acid sequence of SEQ ID NO;

91; and

an antibody comprising a H-chain sequence encoded by a nucleic acid sequence of SEQ ID NO;

121; and

a L-chain sequence encoded by a nucleic acid sequence of SEQ ID NO;

131.

10. A variant of an antibody or portion thereof according to claim 1 or 2, wherein said variant differs from the antibody or portion thereof by 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions.

11. A nucleic acid sequence encoding one of the chains of an antibody or portion thereof according to claim 1 or 2.

12. A vector comprising a nucleic acid sequence according to claim 11.

13. A vector suitable for expressing one of the chains of an antibody or portion thereof according to claim 1 or 2.

14. A cell expressing one of the chains of an antibody or portion thereof according to claim 1 or 2.

15. A method for making an antibody or portion thereof according to claim 1 or 2, comprising culturing a cell according to claim 14, and retrieving said antibody or portion thereof.

18. A pharmaceutical composition comprising an antibody or portion thereof according to claim 1 or 2.

19. The pharmaceutical composition according to claim 18, for the treatment of an IgE-mediated disorder selected from the group consisting of asthma, allergic asthma, allergic rhinitis and food allergies.

20. A method for treating an IgE-mediated disorder selected from the group consisting of asthma, allergic asthma, allergic rhinitis and food allergies in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of an antibody or portion thereof according to claim 1 or 2.

46. A method for reducing IgE binding to Fcε

R1 comprising contacting the IgE with an anti-IgE antibody or antigen binding portion according to claim 1 or 23.

47. A method for reducing IgE-mediated degranulation by a cell comprising contacting the cell with an anti-IgE antibody or antigen binding portion according to claim 1 or 23.

2. An isolated human antibody or antigen-binding portion thereof directed against human IgE, wherein said antibody has an IC_{25 ng/mL}(100-5000 ng/mL) of about 0.1-30 μ

g/mL, wherein the IC_{25 ng/mL}(100-5000 ng/mL) is defined as the in vitro concentration of antibody required to reduce the free IgE concentration in a serum sample from an initial concentration in the range of about 100-5000 ng/mL to a concentration of about 25 ng/mL.

3. The antibody or portion thereof according to claim 2, wherein said antibody has an IC_{25 ng/mL}(500-1500 ng/mL) of about 1-30 μ

g/mL, wherein the IC_{25 ng/mL}(500-1500 ng/mL) is defined as the in vitro concentration of antibody required to reduce the free IgE concentration in a serum sample from an initial concentration in the range of about 500-1500 ng/mL to a concentration of about 25 ng/mL.

16. (canceled)

17. (canceled)

21. (canceled)

22. A nucleic acid sequence selected from the group consisting of SEQ ID NOs:

1, 3, 11, 13, 21, 23, 31, 33, 41, 43, 51, 53, 61, 63, 71, 73, 81, 83, 91, 93, 101, 103, 105, 107, 109, 111, 121, 123, 131 and 133.

23. An antibody or antigen-binding portion thereof directed against human IgE, wherein said antibody is selected from the group consisting of:

an antibody comprising a H-variable domain having the sequence of SEQ ID NO;

4; and

a L-variable domain having the sequence of SEQ ID NO;

14;

an antibody comprising a H-variable domain having the sequence of SEQ ID NO;

24; and

a L-variable domain having the sequence of SEQ ID NO;

34;

an antibody comprising a H-variable domain having the sequence of SEQ ID NO;

44; and

a L-variable domain having the sequence of SEQ ID NO;

54;

an antibody comprising a H-variable domain having the sequence of SEQ ID NO;

64; and

a L-variable domain having the sequence of SEQ ID NO;

74;

an antibody comprising a H-variable domain having the sequence of SEQ ID NO;

84; and

a L-variable domain having the sequence of SEQ ID NO;

94;

an antibody comprising a H-variable domain having the sequence of SEQ ID NO;

124; and

a L-variable domain having the sequence of SEQ ID NO;

134;

an antibody comprising a H-chain having the sequence of SEQ ID NO;

2; and

a L-chain having the sequence of SEQ ID NO;

12;

an antibody comprising a H-chain having the sequence of SEQ ID NO;

22; and

a L-chain having the sequence of SEQ ID NO;

32;

an antibody comprising a H-chain having the sequence of SEQ ID NO;

42; and

a L-chain having the sequence of SEQ ID NO;

52;

an antibody comprising a H-chain having the sequence of SEQ ID NO;

62; and

a L-chain having the sequence of SEQ ID NO;

72;

an antibody comprising a H-chain having the sequence of SEQ ID NO;

82; and

a L-chain having the sequence of SEQ ID NO;

92;

an antibody comprising a H-chain having the sequence of SEQ ID NO;

122; and

a L-chain having the sequence of SEQ ID NO;

132;

an antibody comprising a H-chain encoded by the insert of ATCC deposit PTA-7977; and

a L-chain encoded by the insert of ATCC deposit PTA-7982;

an antibody comprising a H-chain encoded by the insert of ATCC deposit PTA-7981; and

a L-chain encoded by the insert of ATCC deposit PTA-7980;

an antibody comprising a H-chain encoded by the insert of ATCC deposit PTA-7985; and

a L-chain encoded by the insert of ATCC deposit PTA-7984;

an antibody comprising a H-chain encoded by the insert of ATCC deposit PTA-7983; and

a L-chain encoded by the insert of ATCC deposit PTA-7978; and

an antibody comprising a H-chain encoded by the insert of ATCC deposit PTA-7979; and

a L-chain encoded by the insert of ATCC deposit PTA-7986.

37. A pharmaceutical composition comprising an antibody or portion thereof according to claim 23.

38. The pharmaceutical composition according to claim 37, for the treatment of an IgE-mediated disorder selected from the group consisting of asthma, allergic asthma, allergic rhinitis and food allergies.

39. A method for treating an IgE-mediated disorder selected from the group consisting of asthma, allergic asthma, allergic rhinitis and food allergies in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of an antibody or portion thereof according to claim 23.

41. A nucleic acid sequence encoding one of the chains of an antibody or portion thereof according to claim 23.

42. A vector comprising a nucleic acid sequence according to claim 41.

43. A vector suitable for expressing one of the chains of an antibody or portion thereof according to claim 23.

44. A cell expressing one of the chains of an antibody or portion thereof according to claim 23.

45. A method for making an antibody or portion thereof according to claim 23, comprising culturing a cell according to claim 43, and retrieving said antibody or portion thereof.

24-36. -36. (canceled)

40. (canceled)