Dual specific binding proteins directed against IL-1 and/or IL-17

• US 9,062,108 B2
• Filed: 03/14/2014
• Issued: 06/23/2015
• Est. Priority Date: 03/15/2013
• Status: Active Grant

• Current Assignee: Abbvie Incorporated
• Original Assignee: Abbvie Incorporated
• Inventors: Ghayur, Tariq, Gu, JiJie, Harris, Maria, Goodreau, Carrie, Saluja, Sonal
• Primary Examiner(s): DAHLE, CHUN WU
• Application Number:
  US14/211,604
• Publication Number:
  US 20140271458A1
• Time in Patent Office: 466 Days
• Field of Search: None
• US Class Current: 1/1
• 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 47/6845 the antibody targeting a cytokine, e.g. growth factors, VEGF, TNF, a lymphokine or an interferon
• CPC Class Codes: A61K 47/6879 the immunoglobulin having two or more different antigen-binding sites, e.g. bispecific or multispecific immunoglobulin
• 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 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• 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 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• 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 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/24 : Antidepressants
• CPC Class Codes: A61P 25/28 : for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 25/32 : Alcohol-abuse
• CPC Class Codes: A61P 27/02 : Ophthalmic agents
• 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 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/02 : Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 3/08 : for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/08 : for leprosy
• CPC Class Codes: A61P 31/10 : Antimycotics
• CPC Class Codes: A61P 31/16 : for influenza or rhinoviruses
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 33/00 : Antiparasitic agents
• CPC Class Codes: A61P 33/06 : Antimalarials
• 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 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 5/00 : Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 5/18 : of the parathyroid hormones
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07K 16/244 : Interleukins [IL]
• CPC Class Codes: C07K 16/245 : IL-1
• CPC Class Codes: C07K 16/468 : Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies
• CPC Class Codes: C07K 2317/31 : multispecific
• CPC Class Codes: C07K 2317/626 : Diabody or triabody
• CPC Class Codes: C07K 2317/64 : comprising a combination of variable region and constant region components
• 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: C07K 2317/94 : Stability, e.g. half-life, pH, temperature or enzyme-resistance
• CPC Class Codes: C07K 2319/00 : Fusion polypeptide
• CPC Class Codes: G01N 2333/54 : Interleukins [IL]
• CPC Class Codes: G01N 2333/545 : IL-1
• CPC Class Codes: G01N 33/6869 : Interleukin

Abstract

Engineered multivalent and multispecific binding proteins that bind IL-1β and/or IL-17 are provided, along with methods of making and uses in the prevention, diagnosis, and/or treatment of disease.

Claims

1. A method of treating a subject for an inflammatory disorder, comprising administering a binding protein to the subject, wherein the binding protein comprises first and second polypeptide chains, each independently comprising VD1-(X1)n-VD2-C-X2, wherein

VD1 is a first variable domain;

VD2 is a second variable domain;

C is a constant domain;

X1 is a linker;

X2 is an Fc region that is either present or absent; and

n is 0 or 1;

wherein the VD1 domains on the first and second polypeptide chains form a first functional target binding site and the VD2 domains on the first and second polypeptide chains form a second functional target binding site, and wherein the binding protein is capable of binding IL-1β and

IL-17, wherein

(i) the variable domains that form a functional target binding site for IL-1β

comprise;

CDRs 1-3 from SEQ ID NO;

32 and CDRs 1-3 from SEQ ID NO;

33,

CDRs 1-3 from SEQ ID NO;

34 and CDRs 1-3 from SEQ ID NO;

35,

CDRs 1-3 from SEQ ID NO;

36 and CDRs 1-3 from SEQ ID NO;

37,

CDRs 1-3 from SEQ ID NO;

38 and CDRs 1-3 from SEQ ID NO;

39, or

CDRs 1-3 from SEQ ID NO;

40 and CDRs 1-3 from SEQ ID NO;

41;

and

(ii) the variable domains that form a functional target binding site for IL-17 comprise

CDRs 1-3 from SEQ ID NO;

44 and CDRs 1-3 from SEQ ID NO;

45.

2. The method of claim 1, wherein the binding protein has a first polypeptide chain comprising SEQ ID NO:

104 and a second polypeptide chain comprising SEQ ID NO;

105.

4. The method of claim 1, wherein the binding protein comprises a first polypeptide chain comprising VD1-(X1)n-VD2-C-X2, wherein

VD1 is a first heavy chain variable domain;

VD2 is a second heavy chain variable domain;

C is a heavy chain constant domain;

X1 is a linker;

X2 is an Fc region that is either present or absent;

n is 0 or 1, and

a second polypeptide chain comprising VD1-(X1)n-VD2-C, wherein

VD1 is a first light chain variable domain;

VD2 is a second light chain variable domain;

C is a light chain constant domain;

X1 is a linker;

n is 0 or 1,

wherein the VD1 domains on the first and second polypeptide chains form a first functional target binding site and the VD2 domains on the first and second polypeptide chains form a second functional target binding site.

5. The method of claim 1, wherein

(i) the binding protein is capable of binding IL-1β

with a K_D of about 5.1×

10<sup>−

11</sup> M, as measured by surface plasmon resonance, or capable of inhibiting IL-1β

with an IC50 of about 2.563 nM, as measured in an IL-1β

neutralization assay, and/or

(ii) the binding protein is capable of binding IL-17 with a K_D of about 4.8×

10<sup>−

12</sup> M, as measured by surface plasmon resonance, or capable of inhibiting IL-17 with an IC50 of about 1.7 nM, as measured in an IL-17 neutralization assay.

6. The method of claim 1, wherein the binding protein comprises

(i) variable domains that form a functional target binding site for IL-1β

comprising;

(1) SEQ ID NO;

32 and SEQ ID NO;

33,

(2) SEQ ID NO;

34 and SEQ ID NO;

35,

(3) SEQ ID NO;

36 and SEQ ID NO;

37,

(4) SEQ ID NO;

38 and SEQ ID NO;

39, or

(5) SEQ ID NO;

40 and SEQ ID NO;

41;

and

(ii) variable domains that form a functional target binding site for IL-17 comprising;

SEQ ID NO;

44 and SEQ ID NO;

45.

7. The method of claim 1, wherein the binding protein comprises two first polypeptide chains and two second polypeptide chains and four functional target binding sites.

8. The method of claim 1, wherein X1 is any one of SEQ ID NO:

1-31.

9. The method of claim 1, wherein the Fc region of the binding protein is a variant sequence Fc region.

10. The method of claim 1, wherein the Fc region of the binding protein is an Fc region from an IgG1, IgG2, IgG3, IgG4, IgA, IgM, IgE, or IgD.

11. The method of claim 1, wherein the binding protein comprises

(a) a heavy chain constant region comprising a wild type human IgG1 heavy chain sequence;

and

(b) a light chain constant region comprising a wild type human kappa light chain constant region sequence.

12. The method of claim 1, wherein the binding protein comprises

(a) a heavy chain constant region comprising a human IgG1 heavy chain sequence modified by one or more amino acid changes, wherein the changes comprise substitution of leucines at positions 234 and 235 with alanines, wherein the amino acid positions are numbered using EU index numbering;

and

(b) a light chain constant region comprising a wild type human kappa light chain constant region sequence.

13. The method of claim 1, wherein the binding protein is a crystallized binding protein.

14. The method of claim 1, wherein the binding protein comprises

(i) variable domains that form a functional target binding site for IL-1β

comprising CDRs 1-3 from SEQ ID NO;

32 and CDRs 1-3 from SEQ ID NO;

33, and

(ii) variable domains that form a functional target binding site for IL-17 comprising CDRs 1-3 from SEQ ID NO;

44 and CDRs 1-3 from SEQ ID NO;

45.

15. The method of claim 1, wherein the binding protein comprises

(i) variable domains that form a functional target binding site for IL-1β

comprising SEQ ID NO;

32 and SEQ ID NO;

33, and

(ii) variable domains that form a functional target binding site for IL-17 comprising SEQ ID NO;

44 and SEQ ID NO;

45.

16. The method of claim 1, wherein the first polypeptide chain of the binding protein comprises SEQ ID NO:

98 and the second polypeptide chain of the binding protein comprises SEQ ID NO;

99.

17. The method of claim 16, wherein the binding protein comprises

(a) a heavy chain constant region on the first polypeptide chain comprising a human IgG1 heavy chain sequence modified by one or more amino acid changes, wherein the changes comprise substitution of leucines at positions 234 and 235 with alanines, wherein the amino acid positions are numbered using EU index numbering;

and

(b) a light chain constant region on the second polypeptide chain comprising a human kappa light chain constant region sequence.

18. The method of claim 16, wherein:

(i) the binding protein is capable of binding IL-1β

with a K_D of about 5.1×

10<sup>−

11</sup> M, as measured by surface plasmon resonance, or capable of inhibiting IL-1β

with an IC50 of about 0.027 nM, as measured in an IL-1β

neutralization assay, and/or

(ii) the binding protein is capable of binding IL-17 with a K_D of about 4.8×

10<sup>−

12</sup> M, as measured by surface plasmon resonance, or capable of inhibiting IL-17 with an IC50 of about 0.091 nM, as measured in an IL-17 neutralization assay.

19. The method of claim 1, wherein the binding protein comprises

(i) variable domains that form a functional target binding site for IL-1β

comprising CDRs 1-3 from SEQ ID NO;

34 and CDRs 1-3 from SEQ ID NO;

35, and

(ii) variable domains that form a functional target binding site for IL-17 comprising CDRs 1-3 from SEQ ID NO;

44 and CDRs 1-3 from SEQ ID NO;

45.

20. The method of claim 1, wherein the binding protein comprises

(i) variable domains that form a functional target binding site for IL-1β

comprising SEQ ID NO;

34 and SEQ ID NO;

35, and

(ii) variable domains that form a functional target binding site for IL-17 comprising SEQ ID NO;

44 and SEQ ID NO;

45.

21. The method of claim 19, wherein X1 on the first polypeptide chain comprises SEQ ID NO:

29 and X1 on the second polypeptide chain comprises SEQ ID NO;

30.

22. The method of claim 2, wherein the binding protein comprises

(a) a heavy chain constant region on the first polypeptide chain comprising a human IgG1 heavy chain sequence modified by one or more amino acid changes, wherein the changes comprise substitution of leucines at positions 234 and 235 with alanines, wherein the amino acid positions are numbered using EU index numbering;

and

(b) a light chain constant region on the second polypeptide chain comprising a human kappa light chain constant region sequence.

23. The method of claim 2, wherein:

(i) the binding protein is capable of binding IL-1β

with a K_D of about 3.4×

10<sup>−

11</sup> M, as measured by surface plasmon resonance, or capable of inhibiting IL-1β

with an IC50 of about 0.018 nM, as measured in an IL-1β

neutralization assay, and/or

(ii) the binding protein is capable of binding IL-17 with a K_D of about 4.8×

10<sup>−

12</sup> M, as measured by surface plasmon resonance, or capable of inhibiting IL-17 with an IC50 of about 0.068 nM, as measured in an IL-17 neutralization assay.

24. The method of claim 1, wherein the binding protein comprises any one of:

DVD2423 (comprising SEQ ID NOs;

48 and

     49);

DVD2424 (comprising SEQ ID NOs;

50 and

     51);

DVD2425 (comprising SEQ ID NOs;

52 and

     53);

DVD2426 (comprising SEQ ID NOs;

54 and

     55);

DVD2427 (comprising SEQ ID NOs;

56 and

     57);

DVD2428 (comprising SEQ ID NOs;

58 and

     59);

DVD2429 (comprising SEQ ID NOs;

60 and

     61);

DVD2430 (comprising SEQ ID NOs;

62 and

     63);

DVD2431 (comprising SEQ ID NOs;

64 and

     65);

DVD2432 (comprising SEQ ID NOs;

66 and

     67);

DVD2433 (comprising SEQ ID NOs;

68 and

     69);

DVD2434 (comprising SEQ ID NOs;

70 and

     71);

DVD2435 (comprising SEQ ID NOs;

72 and

     73);

DVD2436 (comprising SEQ ID NOs;

74 and

     75);

DVD2437 (comprising SEQ ID NOs;

76 and

     77);

DVD2438 (comprising SEQ ID NOs;

78 and

     79);

DVD2439 (comprising SEQ ID NOs;

80 and

     81);

DVD2440 (comprising SEQ ID NOs;

82 and

     83);

DVD2441 (comprising SEQ ID NOs;

84 and

     85);

DVD2442 (comprising SEQ ID NOs;

86 and

     87);

DVD3415 (comprising SEQ ID NOs;

98 and

     99); and

DVD3418 (comprising SEQ ID NOs;

104 and

     105).

25. The method of claim 1, further comprising administering a second agent.

34. The method of claim 2, wherein the disorder is keratoconjunctivitis sicca.

3. A method of treating a subject for a disorder selected from the group consisting of asthma, rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, psoriasis, plaque psoriasis, keratoconjunctivitis sicca, blepharitis, keratitis, uveitis, Crohn'"'"'s disease, ulcerative colitis, inflammatory bowel disease (IBD), insulin dependent diabetes mellitus, ankylosing spondylitis, spondyloarthropathy, chronic obstructive pulmonary disease (COPD), cystic fibrosis, urticaria, ectopic eczema, osteoarthritis, and multiple sclerosis, the method comprising administering a binding protein to the subject, wherein the binding protein comprises first and second polypeptide chains, each independently comprising VD1-(X1)n-VD2-C-X2, wherein

VD1 is a first variable domain;

VD2 is a second variable domain;

C is a constant domain;

X1 is a linker;

X2 is an Fc region that is either present or absent; and

n is 0 or 1;

wherein the VD1 domains on the first and second polypeptide chains form a first functional target binding site and the VD2 domains on the first and second polypeptide chains form a second functional target binding site, and wherein the binding protein is capable of binding IL-1β and

IL-17, wherein

(i) the variable domains that form a functional target binding site for IL-16 comprise;

CDRs 1-3 from SEQ ID NO;

32 and CDRs 1-3 from SEQ ID NO;

33,

CDRs 1-3 from SEQ ID NO;

34 and CDRs 1-3 from SEQ ID NO;

35,

CDRs 1-3 from SEQ ID NO;

36 and CDRs 1-3 from SEQ ID NO;

37,

CDRs 1-3 from SEQ ID NO;

38 and CDRs 1-3 from SEQ ID NO;

39, or

CDRs 1-3 from SEQ ID NO;

40 and CDRs 1-3 from SEQ ID NO;

41;

and

(ii) the variable domains that form a functional target binding site for IL-17 comprise

CDRs 1-3 from SEQ ID NO;

44 and CDRs 1-3 from SEQ ID NO;

45.

26. The method of claim 3, wherein the disorder is rheumatoid arthritis.

27. The method of claim 3, wherein the disorder is psoriatic arthritis.

28. The method of claim 3, wherein the disorder is keratoconjunctivitis sicca.

29. The method of claim 3, wherein the disorder is Crohn'"'"'s disease, ulcerative colitis, or inflammatory bowel disease (IBD).

30. The method of claim 3, wherein the disorder is osteoarthritis.

31. The method of claim 3, wherein the disorder is ankylosing spondylitis.

32. The method of claim 3, wherein the disorder is uveitis.

33. The method of claim 3, wherein the disorder is psoriasis or plaque psoriasis.