# US 2015/0147327 A1 · Dual Variable Domain Immunoglobulin and Uses Thereof

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- Number: US 2015/0147327 A1
- Document ID: US20150147327A1
- Status: Published application
- Kind: A1
- Application number: 14/551,792
- Filed: 2014-11-24
- Published: 2015-05-28
- Earliest claimed: 2005-08-19
- Assignees: AbbVie Inc.
- Applicants: Abbvie Inc.
- Inventors: Chengbin WU; Tariq GHAYUR; Richard W. DIXON; Jochen G. SALFELD
- Web page: https://patentgrep.com/patent/US20150147327A1

## CPC

- C07K 16/468: {Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies}
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/42: Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein (oligopeptides having up to five amino acids {A61K47/183}; polyamino acids A61K47/34)
- A61K 51/1093: {conjugates with carriers being antibodies}
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/06: Antianaemics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 13/12: of the kidneys
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/04: for non-specific disorders of the connective tissue
- A61P 19/10: for osteoporosis
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 21/02: Muscle relaxants, e.g. for tetanus or cramps
- A61P 23/00: Anaesthetics
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/06: Antimigraine agents
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/24: Antidepressants
- 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
- A61P 25/32: Alcohol-abuse
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/04: Antibacterial agents
- A61P 31/12: Antivirals
- A61P 31/18: for HIV
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 41/00: Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
- C07K 16/22: against growth factors {; against growth regulators}
- C07K 16/24: against cytokines, lymphokines or interferons
- C07K 16/241: {Tumor Necrosis Factors}
- C07K 16/244: {Interleukins [IL]}
- C07K 16/245: {IL-1}
- C07K 16/2809: {against the T-cell receptor (TcR)-CD3 complex}
- C07K 16/2887: {against CD20}
- C07K 16/2896: {against molecules with a "CD"-designation, not provided for elsewhere}
- C07K 16/40: against enzymes
- C07K 16/46: Hybrid immunoglobulins (hybrids of an immunoglobulin with a peptide not being an immunoglobulin C07K19/00)
- C07K 16/467: {Igs with modifications in the FR-residues only}
- A61K 2039/505: {comprising antibodies}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/31: multispecific
- C07K 2317/51: Complete heavy chain or Fd fragment, i.e. VH + CH1
- C07K 2317/522: CH1 domain
- C07K 2317/56: variable (Fv) region, i.e. VH and/or VL
- C07K 2317/64: comprising a combination of variable region and constant region components
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- 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
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- Y02A: TECHNOLOGIES FOR ADAPTATION TO 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 and/or treatment of acute and chronic inflammatory and other diseases.

## Claims

### Claim at position 1

1-75. (canceled)

### Claim 76

A multispecific binding protein comprising functional antigen binding sites for tumor necrosis factor (TNF) and interleukin 17 (IL-17).

### Claim 77 (depends on 76)

The binding protein of claim 76, wherein the binding protein is capable of simultaneously binding TNF and IL-17.

### Claim 78 (depends on 76)

The binding protein of claim 76, wherein the binding protein is capable of simultaneously neutralizing TNF and IL-17.

### Claim 79 (depends on 76)

The binding protein of claim 76, wherein the binding protein comprises an antigen-binding portion of an anti-TNF antibody and an antigen-binding portion of an anti-IL-17 antibody.

### Claim 80 (depends on 76)

The binding protein of claim 76, wherein the antigen binding sites for TNF and IL-17 are joined by a linker.

### Claim 81 (depends on 80)

The binding protein of claim 80, wherein the linker comprises any one of: SEQ ID NO:38; SEQ ID NO:40; SEQ ID NO:42; SEQ ID NO:44; SEQ ID NO:48; SEQ ID NO:50; SEQ ID NO:88; SEQ ID NO:92; SEQ ID NO:99; SEQ ID NO: 103; and SEQ ID NOs: 118-133.

### Claim 82 (depends on 76)

The binding protein of claim 76, wherein the binding protein is a single-chain multispecific binding protein, tandem single-chain Fv molecule, a bispecific antibody, a multispecific antibody, a dual-specific antibody, a diabody, a bispecific diabody, a single-chain diabody, a diabody fused to an Fc molecule, a dual variable domain binding protein, a chemical conjugation of two or more antibodies, two or more cross-linked antibodies, or a derivative thereof.

### Claim 83 (depends on 76)

The binding protein of claim 76, wherein the binding protein is affinity-matured, chimeric, humanized, CDR-grafted, back-mutated, or framework modified.

### Claim 84 (depends on 76)

The binding protein of claim 76, wherein the TNF binding site comprises an antigen-binding portion of adalimumab (HUMIRA®), infliximab (REMICADE®), HUMICADE®, ONTO 148 (Medarex/Centocor), or etanercept (ENBREL®).

### Claim 85 (depends on 76)

The binding protein of claim 76, wherein the TNF binding site comprises an antigen-binding portion of adalimumab (HUMIRA®).

### Claim 86 (depends on 76)

The binding protein of claim 76, wherein the TNF is TNF-alpha.

### Claim 87 (depends on 76)

The binding protein of claim 76, wherein the IL-17 is IL-17A.

### Claim 88 (depends on 76)

A method of treating a subject for a disease or a disorder by administering the binding protein of claim 76 to the subject.

### Claim 89 (depends on 88)

The method of claim 88, wherein the disorder is an autoimmune disorder, an inflammatory disorder, an allergic disorder, a neurodegenerative disorder, or an oncological disorder.

### Claim 90 (depends on 88)

The method of claim 88, wherein the disorder is rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriatic arthritis, psoriasis, plaque psoriasis, pain, keratoconjunctivitis sicca, blepharitis, keratitis, Crohn's disease, ulcerative colitis, inflammatory bowel disease (IBD), insulin-dependent diabetes mellitus, systemic lupus erythematosus (SLE), multiple sclerosis, ankylosing spondylitis, asthma, chronic obstructive pulmonary disease (COPD), eosinophilia, fibrosis, cystic fibrosis, dermatitis, urticaria, eczema, or sepsis.

### Claim 91 (depends on 88)

The method of claim 88, wherein the disorder is rheumatoid arthritis, psoriatic arthritis, or osteoarthritis.

### Claim 92 (depends on 88)

The method of claim 88, wherein the binding protein is formulated for parenteral, subcutaneous, intramuscular, intravenous, intrarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracerebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, bolus, vaginal, rectal, buccal, sublingual, intranasal, or transdermal administration.

### Claim 93

A multispecific binding protein comprising functional antigen binding sites for interleukin 1 alpha (IL-1A) and interleukin 1 beta (IL-1B).

### Claim 94 (depends on 93)

The binding protein of claim 93, wherein the binding protein is capable of simultaneously binding IL-1A and IL-1B.

### Claim 95 (depends on 93)

The binding protein of claim 93, wherein the binding protein is capable of simultaneously neutralizing IL-1A and IL-1B.

### Claim 96 (depends on 93)

The binding protein of claim 93, wherein the binding protein comprises an antigen-binding portion of an anti-IL-1A antibody and an antigen-binding portion of an anti-IL-1B antibody.

### Claim 97 (depends on 93)

The binding protein of claim 93, wherein the antigen binding sites for IL-1A and IL-1B are joined by a linker.

### Claim 98 (depends on 97)

The binding protein of claim 97, wherein the linker comprises any one of: SEQ ID NO:38; SEQ ID NO:40; SEQ ID NO:42; SEQ ID NO:44; SEQ ID NO:48; SEQ ID NO:50; SEQ ID NO:88; SEQ ID NO:92; SEQ ID NO:99; SEQ ID NO: 103; and SEQ ID NOs: 118-133.

### Claim 99 (depends on 93)

The binding protein of claim 93, wherein the binding protein is a single-chain multispecific binding protein, tandem single-chain Fv molecule, a bispecific antibody, a multispecific antibody, a dual-specific antibody, a diabody, a bispecific diabody, a single-chain diabody, a diabody fused to an Fc molecule, a dual variable domain binding protein, a chemical conjugation of two or more antibodies, two or more cross-linked antibodies, or a derivative thereof.

### Claim 100 (depends on 93)

The binding protein of claim 93, wherein the binding protein is affinity-matured, chimeric, humanized, CDR-grafted, back-mutated, or framework modified.

### Claim 101 (depends on 93)

A method of treating a subject for a disease or a disorder by administering the binding protein of claim 93 to the subject.

### Claim 102 (depends on 101)

The method of claim 101, wherein the disorder is an autoimmune disorder, an inflammatory disorder, an allergic disorder, a neurodegenerative disorder, or an oncological disorder.

### Claim 103 (depends on 101)

The method of claim 101, wherein the disorder is rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriatic arthritis, psoriasis, plaque psoriasis, pain, keratoconjunctivitis sicca, blepharitis, keratitis, Crohn's disease, ulcerative colitis, inflammatory bowel disease (IBD), insulin-dependent diabetes mellitus, systemic lupus erythematosus (SLE), multiple sclerosis, ankylosing spondylitis, asthma, chronic obstructive pulmonary disease (COPD), eosinophilia, fibrosis, cystic fibrosis, dermatitis, urticaria, eczema, or sepsis.

### Claim 104 (depends on 101)

The method of claim 101, wherein the disorder is rheumatoid arthritis, osteoarthritis, or pain.

### Claim 105 (depends on 101)

The method of claim 101, wherein the binding protein is formulated for parenteral, subcutaneous, intramuscular, intravenous, intrarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracerebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, bolus, vaginal, rectal, buccal, sublingual, intranasal, or transdermal administration.

### Claim 106

A multispecific binding protein comprising functional antigen binding sites for interleukin 1 beta (IL-1B) and interleukin 17 (IL-17).

### Claim 107 (depends on 106)

The binding protein of claim 106, wherein the binding protein is capable of simultaneously binding IL-1B and IL-17.

### Claim 108 (depends on 106)

The binding protein of claim 106, wherein the binding protein is capable of simultaneously neutralizing IL-1B and IL-17.

### Claim 109 (depends on 106)

The binding protein of claim 106, wherein the binding protein comprises an antigen-binding portion of an anti-IL-1B antibody and an antigen-binding portion of an anti-IL-17 antibody.

### Claim 110 (depends on 106)

The binding protein of claim 106, wherein the antigen binding sites for IL-1B and IL-17 are joined by a linker.

### Claim 111 (depends on 110)

The binding protein of claim 110, wherein the linker comprises any one of: SEQ ID NO:38; SEQ ID NO:40; SEQ ID NO:42; SEQ ID NO:44; SEQ ID NO:48; SEQ ID NO:50; SEQ ID NO:88; SEQ ID NO:92; SEQ ID NO:99; SEQ ID NO: 103; and SEQ ID NOs: 118-133.

### Claim 112 (depends on 106)

The binding protein of claim 106, wherein the binding protein is a single-chain multispecific binding protein, tandem single-chain Fv molecule, a bispecific antibody, a multispecific antibody, a dual-specific antibody, a diabody, a bispecific diabody, a single-chain diabody, a diabody fused to an Fc molecule, a dual variable domain binding protein, a chemical conjugation of two or more antibodies, two or more cross-linked antibodies, or a derivative thereof.

### Claim 113 (depends on 106)

The binding protein of claim 106, wherein the binding protein is affinity-matured, chimeric, humanized, CDR-grafted, back-mutated, or framework modified.

### Claim 114 (depends on 106)

The binding protein of claim 106, wherein the IL-17 is IL-17A.

### Claim 115 (depends on 106)

A method of treating a subject for a disease or a disorder by administering the binding protein of claim 106 to the subject.

### Claim 116 (depends on 115)

The method of claim 115, wherein the disorder is an autoimmune disorder, an inflammatory disorder, an allergic disorder, a neurodegenerative disorder, or an oncological disorder.

### Claim 117 (depends on 115)

The method of claim 115, wherein the disorder is rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriatic arthritis, psoriasis, plaque psoriasis, pain, keratoconjunctivitis sicca, blepharitis, keratitis, Crohn's disease, ulcerative colitis, inflammatory bowel disease (IBD), insulin-dependent diabetes mellitus, systemic lupus erythematosus (SLE), multiple sclerosis, ankylosing spondylitis, asthma, chronic obstructive pulmonary disease (COPD), eosinophilia, fibrosis, cystic fibrosis, dermatitis, urticaria, eczema, or sepsis.

### Claim 118 (depends on 115)

The method of claim 115, wherein the disorder is rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, or keratoconjunctivitis sicca.

### Claim 119 (depends on 115)

The method of claim 115, wherein the binding protein is formulated for parenteral, subcutaneous, intramuscular, intravenous, intrarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracerebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, bolus, vaginal, rectal, buccal, sublingual, intranasal, or transdermal administration.

### Claim 120

A multispecific binding protein comprising functional antigen binding sites for a first target and a second target, wherein the first and/or second target is interleukin 17 (IL-17), tumor necrosis factor (TNF), interleukin 1 alpha (IL-1A), or interleukin 1 beta (IL-1B).

### Claim 121 (depends on 120)

The binding protein of claim 120, wherein the binding protein is capable of neutralizing IL-17, TNF, IL-1A, and/or IL-1B.

### Claim 122 (depends on 120)

The binding protein of claim 120, wherein the binding protein comprises an antigen-binding portion of an anti-TNF antibody, an antigen-binding portion of an anti-IL-1A antibody, an antigen-binding portion of an anti-IL-1B antibody, and/or an antigen-binding portion of an anti-IL-17 antibody.

### Claim 123 (depends on 120)

The binding protein of claim 120, wherein the first and second binding sites are joined by a linker.

### Claim 124 (depends on 123)

The binding protein of claim 123, wherein the linker comprises any one of: SEQ ID NO:38; SEQ ID NO:40; SEQ ID NO:42; SEQ ID NO:44; SEQ ID NO:48; SEQ ID NO:50; SEQ ID NO:88; SEQ ID NO:92; SEQ ID NO:99; SEQ ID NO: 103; and SEQ ID NOs: 118-133.

### Claim 125 (depends on 120)

The binding protein of claim 120, wherein the binding protein is a single-chain multispecific binding protein, tandem single-chain Fv molecule, a bispecific antibody, a multispecific antibody, a dual-specific antibody, a diabody, a bispecific diabody, a single-chain diabody, a diabody fused to an Fc molecule, a dual variable domain binding protein, a chemical conjugation of two or more antibodies, two or more cross-linked antibodies, or a derivative thereof.

### Claim 126 (depends on 120)

The binding protein of claim 120, wherein the binding protein is affinity-matured, chimeric, humanized, CDR-grafted, back-mutated, or framework modified.

### Claim 127 (depends on 120)

The binding protein of claim 120, wherein the binding protein is capable of binding TNF and the TNF binding site comprises an antigen-binding portion of adalimumab (HUMIRA®), infliximab (REMICADE®), HUMICADE®, ONTO 148 (Medarex/Centocor), or etanercept (ENBREL®).

### Claim 128 (depends on 120)

The binding protein of claim 120, wherein the binding protein is capable of binding TNF and the TNF binding site comprises an antigen-binding portion of adalimumab (HUMIRA®).

### Claim 129 (depends on 120)

The binding protein of claim 120, wherein the TNF is TNF-alpha.

### Claim 130 (depends on 120)

The binding protein of claim 120, wherein the IL-17 is IL-17A.

### Claim 131 (depends on 120)

A method of treating a subject for a disease or a disorder by administering the binding protein of claim 120 to the subject.

### Claim 132 (depends on 131)

The method of claim 131, wherein the disorder is an autoimmune disorder, an inflammatory disorder, an allergic disorder, a neurodegenerative disorder, or an oncological disorder.

### Claim 133 (depends on 131)

The method of claim 131, wherein the disorder is rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriatic arthritis, psoriasis, plaque psoriasis, pain, keratoconjunctivitis sicca, blepharitis, keratitis, Crohn's disease, ulcerative colitis, inflammatory bowel disease (IBD), insulin-dependent diabetes mellitus, systemic lupus erythematosus (SLE), multiple sclerosis, ankylosing spondylitis, asthma, chronic obstructive pulmonary disease (COPD), eosinophilia, fibrosis, cystic fibrosis, dermatitis, urticaria, eczema, or sepsis.

### Claim 134 (depends on 131)

The method of claim 131, wherein the disorder is rheumatoid arthritis, psoriatic arthritis, or osteoarthritis.

### Claim 135 (depends on 131)

The method of claim 131, wherein the binding protein is formulated for parenteral, subcutaneous, intramuscular, intravenous, intrarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracerebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, bolus, vaginal, rectal, buccal, sublingual, intranasal, or transdermal administration.