Dual variable domain immunoglobulins and uses thereof

• US 9,035,027 B2
• Filed: 06/03/2009
• Issued: 05/19/2015
• Est. Priority Date: 06/03/2008
• Status: Active Grant

• Current Assignee: Abbvie Incorporated
• Original Assignee: Abbvie Incorporated
• Inventors: Ghayur, Tariq, Isakson, Peter C., Olson, Lisa M., Wu, Chengbin, Hugunin, Margaret, Kamath, Rajesh V., Cuff, Carolyn A., Allen, Hamish J.
• Primary Examiner(s): Yu, Misook
• Assistant Examiner(s): Moseley, II, Nelson B
• Application Number:
  US12/477,711
• Publication Number:
  US 20090311253A1
• Time in Patent Office: 2,176 Days
• Field of Search: None
• US Class Current: 530/387.3
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/70 Multivalent vaccine
• 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: 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 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• 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 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• 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 25/00 Drugs for disorders of the nervous system
• 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 25/28 : 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 27/14 : Decongestants or antiallergics
• 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 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 33/00 : Antiparasitic agents
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• 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 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07K 16/22 : against growth factors ; against growth regulators
• CPC Class Codes: C07K 16/241 : Tumor Necrosis Factors
• CPC Class Codes: C07K 16/244 : Interleukins [IL]
• CPC Class Codes: C07K 16/245 : IL-1
• CPC Class Codes: C07K 16/247 : IL-4
• CPC Class Codes: C07K 16/248 : IL-6
• CPC Class Codes: C07K 16/2866 : against receptors for cytokines, lymphokines, interferons
• CPC Class Codes: C07K 16/2887 : against CD20
• CPC Class Codes: C07K 16/468 : Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies
• CPC Class Codes: C07K 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/31 : multispecific
• CPC Class Codes: C07K 2317/35 : Valency
• CPC Class Codes: C07K 2317/64 : comprising a combination of variable region and constant region components
• CPC Class Codes: C07K 2317/73 : Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• 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 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: G01N 2333/545 : IL-1
• CPC Class Codes: G01N 33/6869 : Interleukin
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention relates to engineered multivalent and multispecific binding proteins, methods of making, and specifically to their uses in the prevention, diagnosis, and/or treatment of disease.

Claims

1. A binding protein capable of binding at least IL-1α

and IL-1β

, comprising first and second polypeptide chains, wherein said first polypeptide chain comprises a first VD1-(X1)n-VD2-C-(X2)n, wherein

VD1 is a first heavy chain variable domain comprising CDRs 1-3 from SEQ ID NO;

52;

VD2 is a second heavy chain variable domain comprising CDRs 1-3 from SEQ ID NO;

68;

C is a heavy chain constant domain;

X1 is a linker;

X2 is an Fc region; and

n is 1; and

wherein said second polypeptide chain comprises a second VD1-(X1)n-VD2-C-(X2)n, wherein

VD1 is a first light chain variable domain comprising CDRs 1-3 from SEQ ID NO;

53;

VD2 is a second light chain variable domain comprising CDRs 1-3 from SEQ ID NO;

69;

C is a light chain constant domain;

X1 is a linker;

n is 1 for (X1)n; and

(X2)n is absent.

2. The binding protein according to claim 1, wherein the first polypeptide chain comprises the VD1 sequence of SEQ ID NO:

52 and the VD2 sequence of SEQ ID NO;

68, and the second polypeptide chain comprises the VD1 sequence of SEQ ID NO;

53 and the VD2 sequence of SEQ ID NO;

69.

3. The binding protein according to claim 1, wherein X1 is at least one of SEQ ID NOs:

1-27.

4. The binding protein according to claim 1, wherein the binding protein comprises two first polypeptide chains and two second polypeptide chains and forms four functional binding sites.

5. The binding protein according to claim 1, wherein the Fc region is a variant sequence Fc region.

6. The binding protein according to claim 1, wherein the Fc region is an Fc region from an IgG1, IgG2, IgG3, IgG4, IgA, IgM, IgE, or IgD.

7. The binding protein according to claim 1, wherein said VD1 and said VD2 are a human antibody or a CDR grafted antibody.

8. A binding protein conjugate comprising the binding protein according to claim 1, said binding protein conjugate further comprising an immunoadhesion molecule, an imaging agent, a therapeutic agent, or a cytotoxic agent.

9. The binding protein conjugate according to claim 8, wherein said imaging agent is a radiolabel, an enzyme, a fluorescent label, a luminescent label, a bioluminescent label, a magnetic label, or biotin.

10. The binding protein according to claim 1, wherein said binding protein is a crystallized binding protein.

11. A pharmaceutical composition comprising the binding protein according to claim 1, and a pharmaceutically acceptable carrier.

12. The pharmaceutical composition according to claim 11 further comprising at least one additional therapeutic agent.

13. The pharmaceutical composition according to claim 12, wherein said additional therapeutic agent is an imaging agent, a cytotoxic agent, an angiogenesis inhibitor, a kinase inhibitor, a co-stimulation molecule blocker, an adhesion molecule blocker, an anti-cytokine antibody or functional fragment thereof, methotrexate, cyclosporin, rapamycin, FK506, a detectable label or reporter, a TNF antagonist, an antirheumatic, a muscle relaxant, a narcotic, a non-steroid anti-inflammatory drug (NSAID), an analgesic, an anesthetic, a sedative, a local anesthetic, a neuromuscular blocker, an antimicrobial, an antipsoriatic, a corticosteroid, an anabolic steroid, an erythropoietin, an immunization, an immunoglobulin, an immunosuppressive, a growth hormone, a hormone replacement drug, a radiopharmaceutical, an antidepressant, an antipsychotic, a stimulant, an asthma medication, a beta agonist, an inhaled steroid, an epinephrine or analog, a cytokine, or a cytokine antagonist.

14. A method of determining the presence of at least one target or fragment thereof in a test sample by an immunoassay,

wherein the immunoassay comprises contacting the test sample with at least one binding protein and at least one detectable label,

wherein the at least one binding protein comprises the binding protein according to claim 1.

15. A method of determining the amount or concentration of an target or fragment thereof in a test sample by an immunoassay,

wherein the immunoassay (a) employs at least one binding protein and at least one detectable label and (b) comprises comparing a signal generated by the detectable label with a control or calibrator comprising the antigen or fragment thereof,

wherein the calibrator is optionally part of a series of calibrators in which each calibrator differs from the other calibrators in the series by the concentration of the antigen or fragment thereof,

and wherein the at least one binding protein comprises the binding protein according to claim 1.

16. A kit for assaying a test sample for the presence, amount, or concentration of an target or fragment thereof, said kit comprising

(a) instructions for assaying the test sample for the antigen or fragment thereof and

(b) at least one binding protein comprising the binding protein according to claim 1.

17. The binding protein according to claim 1, wherein the binding protein is capable of binding:

IL-1alpha and IL-1beta, wherein the binding protein comprises;

SEQ ID NO;

210 and 211;

SEQ ID NO;

214 and 215;

or

SEQ ID NO;

218 and 219.

18. The binding protein according to claim 1, wherein X1 is SEQ ID NO:

13, 14, 21, or 22.