Dual Variable Domain Immunoglobulin and Uses Thereof

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.

1 - 75 . (canceled) 
     
     
         76 . A multispecific binding protein comprising functional antigen binding sites for tumor necrosis factor (TNF) and interleukin 17 (IL-17). 
     
     
         77 . The binding protein of  claim 76 , wherein the binding protein is capable of simultaneously binding TNF and IL-17. 
     
     
         78 . The binding protein of  claim 76 , wherein the binding protein is capable of simultaneously neutralizing TNF and IL-17. 
     
     
         79 . 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. 
     
     
         80 . The binding protein of  claim 76 , wherein the antigen binding sites for TNF and IL-17 are joined by a linker. 
     
     
         81 . 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. 
     
     
         82 . 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. 
     
     
         83 . The binding protein of  claim 76 , wherein the binding protein is affinity-matured, chimeric, humanized, CDR-grafted, back-mutated, or framework modified. 
     
     
         84 . 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®). 
     
     
         85 . The binding protein of  claim 76 , wherein the TNF binding site comprises an antigen-binding portion of adalimumab (HUMIRA®). 
     
     
         86 . The binding protein of  claim 76 , wherein the TNF is TNF-alpha. 
     
     
         87 . The binding protein of  claim 76 , wherein the IL-17 is IL-17A. 
     
     
         88 . A method of treating a subject for a disease or a disorder by administering the binding protein of  claim 76  to the subject. 
     
     
         89 . 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. 
     
     
         90 . 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. 
     
     
         91 . The method of  claim 88 , wherein the disorder is rheumatoid arthritis, psoriatic arthritis, or osteoarthritis. 
     
     
         92 . 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. 
     
     
         93 . A multispecific binding protein comprising functional antigen binding sites for interleukin 1 alpha (IL-1A) and interleukin 1 beta (IL-1B). 
     
     
         94 . The binding protein of  claim 93 , wherein the binding protein is capable of simultaneously binding IL-1A and IL-1B. 
     
     
         95 . The binding protein of  claim 93 , wherein the binding protein is capable of simultaneously neutralizing IL-1A and IL-1B. 
     
     
         96 . 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. 
     
     
         97 . The binding protein of  claim 93 , wherein the antigen binding sites for IL-1A and IL-1B are joined by a linker. 
     
     
         98 . 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. 
     
     
         99 . 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. 
     
     
         100 . The binding protein of  claim 93 , wherein the binding protein is affinity-matured, chimeric, humanized, CDR-grafted, back-mutated, or framework modified. 
     
     
         101 . A method of treating a subject for a disease or a disorder by administering the binding protein of  claim 93  to the subject. 
     
     
         102 . 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. 
     
     
         103 . 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. 
     
     
         104 . The method of  claim 101 , wherein the disorder is rheumatoid arthritis, osteoarthritis, or pain. 
     
     
         105 . 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. 
     
     
         106 . A multispecific binding protein comprising functional antigen binding sites for interleukin 1 beta (IL-1B) and interleukin 17 (IL-17). 
     
     
         107 . The binding protein of  claim 106 , wherein the binding protein is capable of simultaneously binding IL-1B and IL-17. 
     
     
         108 . The binding protein of  claim 106 , wherein the binding protein is capable of simultaneously neutralizing IL-1B and IL-17. 
     
     
         109 . 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. 
     
     
         110 . The binding protein of  claim 106 , wherein the antigen binding sites for IL-1B and IL-17 are joined by a linker. 
     
     
         111 . 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. 
     
     
         112 . 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. 
     
     
         113 . The binding protein of  claim 106 , wherein the binding protein is affinity-matured, chimeric, humanized, CDR-grafted, back-mutated, or framework modified. 
     
     
         114 . The binding protein of  claim 106 , wherein the IL-17 is IL-17A. 
     
     
         115 . A method of treating a subject for a disease or a disorder by administering the binding protein of  claim 106  to the subject. 
     
     
         116 . 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. 
     
     
         117 . 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. 
     
     
         118 . The method of  claim 115 , wherein the disorder is rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, or keratoconjunctivitis sicca. 
     
     
         119 . 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. 
     
     
         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). 
     
     
         121 . The binding protein of  claim 120 , wherein the binding protein is capable of neutralizing IL-17, TNF, IL-1A, and/or IL-1B. 
     
     
         122 . 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. 
     
     
         123 . The binding protein of  claim 120 , wherein the first and second binding sites are joined by a linker. 
     
     
         124 . 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. 
     
     
         125 . 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. 
     
     
         126 . The binding protein of  claim 120 , wherein the binding protein is affinity-matured, chimeric, humanized, CDR-grafted, back-mutated, or framework modified. 
     
     
         127 . 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®). 
     
     
         128 . 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®). 
     
     
         129 . The binding protein of  claim 120 , wherein the TNF is TNF-alpha. 
     
     
         130 . The binding protein of  claim 120 , wherein the IL-17 is IL-17A. 
     
     
         131 . A method of treating a subject for a disease or a disorder by administering the binding protein of  claim 120  to the subject. 
     
     
         132 . 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. 
     
     
         133 . 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. 
     
     
         134 . The method of  claim 131 , wherein the disorder is rheumatoid arthritis, psoriatic arthritis, or osteoarthritis. 
     
     
         135 . 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.