Prostaglandin e2 dual variable domain immunoglobulins 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, diagnosis, and/or treatment of disease.

1 .- 76 . (canceled) 
     
     
         77 . A method for treating a subject for a disease or a disorder, comprising administering to the subject a binding protein comprising first and second polypeptide chains, each independently comprising VD1-(X1)n-VD2-C-(X2)n, 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; 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 VD 2 domains on the first and second polypeptide chains form a second functional target binding site, wherein the binding protein binds to PGE2, and wherein the variable domains that form a functional binding site for PGE2 comprise CDRs 1-3 from SEQ ID NO; 110 or CDRs 1-3 from SEQ ID NO: 111.   
     
     
         78 . A method for treating a subject for a disease or a disorder, comprising administering to the subject a binding protein comprising first and second polypeptide chains, each independently comprising VD1-(X1)n-VD2-C-(X2)n, 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 Fe region; 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 binds
 (a) TNF and PGE2, wherein
 (1) the variable domains that form a functional binding site for TNF comprise CDRs 1-3 from SEQ ID NO: 112 or CDRs 1-3 from SEQ ID NO: 113; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise CDRs 1-3 from SEQ ID NO: 110 or CDRs 1-3 from SEQ ID NO: 111; 
 
 (b) NGF and PGE2, wherein
 (1) the variable domains that form a functional binding site for NGF comprise CDRs 1-3 from SEQ ID NO: 32 or CDRs 1-3 from SEQ ID NO: 33; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise CDRs 1-3 from SEQ ID NO: 48 or CDRs 1-3 from SEQ ID NO: 49; 
 
 (c) IL-17A and PGE2; wherein
 (1) the variable domains that form a functional binding site for IL-17A comprise CDRs 1-3 from SEQ ID NO: 34 or CDRs 1-3 from SEQ ID NO: 35; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise CDRs 1-3 from SEQ ID NO: 48 or CDRs 1-3 from SEQ ID NO: 49; 
 
 (d) IL-1b and PGE2, wherein
 (1) the variable domains that form a functional binding site for comprise CDRs 1-3 from SEQ ID NO: 36 or CDRs 1-3 from SEQ ID NO: 37; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise CDRs 1-3 from SEQ ID NO: 48 or CDRs 1-3 from SEQ ID NO: 49; 
 
 (e) IL-6R and PGE2, wherein
 (1) the variable domains that form a functional binding site for IL 6R comprise CDRs 1-3 from SEQ ID NO: 54 or CDRs 1-3 from SEQ ID NO: 55; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise CDRs 1-3 from SEQ ID NO: 48 or CDRs 1-3 from SEQ ID NO: 49; 
 
 (f) VEGF and PGE2, wherein
 (1) the variable domains that form a functional binding site for VEGF comprise CDRs 1-3 from SEQ ID NO: 28 or CDRs 1-3 from SEQ. ID NO: 29; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise CDRs 1-3 from SEQ ID NO: 48 or CDRs 1-3 from SEQ ID NO: 49; 
 
 (g) Abeta and PGE2, wherein
 (1) the variable domains that form a functional binding site for Abeta comprise CDRs 1-3 from SEQ ID NO: 40 or CDRs 1-3 from SEQ ID NO: 41; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise CDRs 1-3 from SEQ ID NO: 48 or CDRs 1-3 from SEQ ID NO: 49; 
 
 or 
 (h) IL-15 and PGE2, wherein
 (1) the variable domains that form a functional binding site for IL-15 comprise CDRs 1-3 from SEQ ID NO: 50 or CDRs 1-3 from SEQ ID NO: 51; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise CDRs 1-3 from SEQ ID NO: 48 or CDRs 1-3 from SEQ ID NO: 49. 
 
 
     
     
         79 . The method of  claim 78 , wherein the binding protein is capable of binding to
 (a) TNF and PGE2, wherein
 (1) the variable domains that form a functional binding site for TNF comprise CDRs 1-3 from SEQ ID NO: 112 and CDRs 1-3 from SEQ ID NO: 113; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise CDRs 1-3 from SEQ ID NO: 110 and CDRs 1-3 from SEQ ID NO: 111; 
   (b) NGF and PGE2, wherein
 (1) the variable domains that form a functional binding site for NGF comprise CDRs 1-3 from SEQ ID NO: 32 and CDRs 1-3 from SEQ ID NO: 33; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise CDRs 1-3 from SEQ ID NO: 48 and CDRs 1-3 from SEQ ID NO: 49; 
   (c) IL-17A and PGE2, wherein
 (1) the variable domains that form a functional binding site for IL-17A comprise CDRs 1-3 from SEQ ID NO: 34 and CDRs 1-3 from SEQ ID NO: 35; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise CDRs 1-3 from SEQ ID NO: 48 and CDRs 1-3 from SEQ ID NO: 49; 
   (d) IL-1b and PGE2, wherein
 (1) the variable domains that form a functional binding site for IL-1b comprise CDRs 1-3 from SEQ ID NO: 36 and CDRs 1-3 from SEQ ID NO: 37; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise CDRs 1-3 from SEQ ID NO: 48 and CDRs 1-3 from SEQ D NO: 49; 
   (e) IL-6R and PGE2, wherein
 (1) the variable domains that form a functional binding site for IL-6R comprise CDRs 1-3 from SEQ ID NO: 54 and CDRs 1-3 from SEQ ID NO: 55; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise CDRs 1-3 from SEQ ID NO: 48 and CDRs 1-3 from SEQ ID NO: 49; 
   (f) VEGF and PGE2, wherein
 (1) the variable domains that form a functional binding site for VEGF comprise CDRs 1-3 from SEQ ID NO; 28 and CDRs 1-3 from SEQ D NO: 29; and 
 (2) the variable domains that form a functional binding site, for PGE2 comprise CDRs 1-3 from SEQ ID NO: 48 and CDRs 1-3 from SEQ ID NO: 49; 
   (g) Abeta and PGE2, wherein
 (1) the variable domains that form a functional binding site for Abeta comprise CDRs 1-3 from SEQ ID NO: 40 and CDRs 1-3 from SEQ ID NO: 41; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise CDRs 1-3 from SEQ ID NO: 48 and CDRs 1-3 from SEQ ID NO: 49; 
   or   (h) IL-15 and PGE2, wherein
 (1) the variable domains that form a functional binding site for IL-15 comprise CDRs 1-3 from SEQ ID NO: 50 and CDRs 1-3 from SEQ ID NO: 51; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise CDRs 1-3 from SEQ ID NO: 48 and CDRs 1-3 from SEQ ID NO: 49. 
   
     
     
         80 . The method of  claim 78 , wherein the binding protein is capable of binding to
 (a) TNF and PGE2, wherein
 (1) the variable domains that form a functional binding site for TNF comprise SEQ ID NO: 112 or 113; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise SEQ ID NO: 110 or 111; 
   (b) NGF and PGE2, wherein
 (1) the variable domains that form a functional binding site for NSF comprise SEQ ID NO: 32 or 33; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise SEQ ID NO 48 or 49; 
   (c) IL-17A and PGE2, wherein
 (1) the variable domains that form a functional binding site for IL-17A comprise SEQ ID NO: 34 or 35; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise SEQ ID NO: 48 or 49; 
   (d) IL-1b and PGE2, wherein
 (1) the variable domains that form a functional binding site for IL-1b comprise SEQ ID NO: 36 or 37; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise SEQ ID NO: 48 or 49; 
   (e) IL-6R and PGE2, wherein
 (1) the variable domains that form a functional binding site for IL-6R comprise SEQ ID NO: 54 or 55; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise SEQ ID NO: 48 or 49; 
   (f) VEGF and PGE2, wherein
 (1) the variable domains that form a functional binding site for VEGF comprise SEQ ID NO: 28 or 29; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise SEQ ID NO: 48 or 49; 
   (g) Abeta and PGE2, wherein
 (1) the variable domains that form a functional binding site for Abeta comprise SEQ ID NO: 40 or 41; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise SEQ ID NO: 48 or 49; 
   or   (h) IL-15 and PGE2, wherein
 (1) the variable domains that form a functional binding site for IL-15 comprise SEQ ID NO: 50 or 51; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise SEQ ID NO: 48 or 49. 
   
     
     
         81 . The method of  claim 80 , wherein the binding protein is capable of binding to
 (a) TNF and PGE2, wherein
 (1) the variable domains that form a functional binding site for TNF comprise SEQ ID NOs: 112 and 113; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise SEQ ID NOs: 110 and 111; 
   (b) NGF and PGE2, wherein
 (1) the variable domains that form a functional binding site for NGF comprise SEQ ID NOs: 32 and 33; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise SEQ ID NOs: 48 and 49; 
   (c) IL-17A and PGE2, wherein
 (1) the variable domains that form a functional binding site for IL-17A comprise SEQ ID NOs: 34 and 35; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise SEQ ID NOs: 48 and 49; 
   (d) IL-1b and PGE2, wherein
 (1) the variable domains that form a functional binding site for IL-1b comprise SEQ ID NOs: 36 and 37; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise SEQ ID NOs: 48 and 49; 
   (e) IL-6R and PGE2, wherein
 (1) the variable domains that form a functional binding site for IL-6R comprise SEQ ID NOs: 54 and 55; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise SEQ ID NOs: 48 and 49; 
   (f) VEGF and PGE2, wherein
 (1) the variable domains that form a f motional binding site for VEGF comprise SEQ ID NOs: 28 and 29; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise SEQ ID NOs: 48 and 49; 
   (g) Abeta and PGE2, wherein
 (1) the variable domains that form a functional binding site for Abets comprise SEQ ID NOs: 40 and 41; and 
 (2) the variable domains that for a functional binding site for PGE2 comprise SEQ ID NOs: 48 and 49; 
   or   (h) IL-15 and PGE2, wherein
 (1) the variable domains that form a functional binding site for IL-15 comprise SEQ ID NOs: 50 and 51; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise SEQ ID NOs; 48 and 49. 
   
     
     
         82 . The method of  claim 78 , wherein the binding protein that is capable of binding to
 (a) TNF and PGE2
 (1) inhibits TNF with an IC 50  of at least 14×10 −12  M, as measured by direct bind ELISA and/or binds TNF with a dissociation constant (K D ) of at most 806×10 −12 M, as measured by surface plasmon resonance; and 
 (2) inhibits PGE2 with an IC 50  of at least 45×10 −12  M, as measured by direct bind ELISA and/or binds PGE2 with a dissociation constant (K D ) of at most 261×10 −12  M, as measured by surface plasmon resonance; 
   (b) NGF and PGE2
 (1) inhibits NGF with an EC 50  of at most 1.21×10 −9  M, as measured by direct bind ELISA and/or binds NGF with a dissociation constant (K D ) of at most 2.48×10 −10  M, as measured by surface plasmon resonance; and 
 (2) inhibits PGE2 with an EC 50  of at most 1.3×10 −9  M, as measured by direct in ELISA and/or neutralizes PGE2 with an EC 50  of at most 0.079×10 −9  M, as measured by a PGE2 neutralization assay; 
   (c) IL-17A and PGE2
 (1) inhibits IL-17A with an EC 50  of at most 248.1×10 −9  M, as measured by direct bind ELISA and/or binds IL-17A with a dissociation constant (K D ) of at most 3.37×10 −9  M as measured by surface plasmon resonance; and 
 (2) inhibits PGE2 with an EC 50  of at most 1.55×10 −9  M, as measured by direct hind ELISA and/or neutralizes PGE2 with an EC 50  of at most 0.025×10 −9  M, as measured by a PGE2 neutralization assay; 
   (d) IL-1b and PGE2
 (1) inhibits IL-1b with an EC 50  of at most 2480.71×10 −9  M, as measured by direct bind ELISA, binds IL-1b with a dissociation constant (K D ) of at most 3.87×10 −11  M as measured by surface plasmon resonance, and/or neutralizes IL-1b with an EC 50  of at most 3.22×10 −9  M, as measured by an IL-1b neutralization assay; and 
 (2) inhibits PGE2 with an EC 50  of at most 1.23×10 −9  M, as measured by direct bind ELISA and/or neutralizes PGE2 with an EC 50  of at most 0.217×10 −9  M, as measured by a PGE2 neutralization assay; 
   (e) IL-6R and PGE2
 (1) inhibits IL-6R with an EC 50  of at most 26,452.34×10 −9  M, as measured by direct bind ELISA, binds IL-6R with a dissociation constant (K D ) of at most 4.48×10 −10  M, as measured by surface plasmon resonance, and/or binds IL-6R with a FACS geometric mean of at least 0.21, as measured by flow cytometry; and 
 (2) inhibits PGE2 with an EC 50  of at most 1.65×10 −9  M, as measured by direct bind ELISA and/or neutralizes PGE2 with an EC 50  of at most 0.036×10 −9  M, as measured by a PGE2 neutralization assay; 
   (f) VEGF and PGE2
 (1) inhibits VEGF with an EC of at most 391.23×10 −9  M, as measured by direct bind ELISA and/or binds VEGF with a dissociation constant (K D ) of at most 7.55×10 −10  M, as measured by surface plasmon resonance; and 
 (2) inhibits PGE2 with an EC 50  of at most 1.32×10 −9  M, as measured by direct bind ELISA and/or neutralizes PGE2 with an EC 50  of at most 0.193×10 −9  M, as measured by a PGE2 neutralization assay; 
   (g) Abets and PGE2
 inhibits PGE2 an EC 50  of at most 1.21×10 −9  M, as measured by direct bind ELISA and/or neutralizes PGE2 with an EC 50  of at most 0.049×10 −9  M, as measured by a PGE2 neutralization assay; 
   or   (h) IL-15 and PGE2
 (1) binds IL-15 with a dissociation constant (K D ) of at most 4.89×10 −9  M, as measured by surface plasmon resonance; and 
 (2) inhibits PGE2 with an EC 50  of at most 1.54×10 −9  M, as measured by direct bind ELISA and/or neutralizes PGE2 with an EC 50  of at most 0.048×10 −9  M, as measured by a PGE2 neutralization assay. 
   
     
     
         83 . The method of  claim 78 , wherein
 the first polypeptide chain comprises VD1-(X1)n-VD2-C-(X2)n, 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; 
 X1 is a linker; and 
 n is 0 or 1; 
   and the second polypeptide chain comprises 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; 
 n is 1 for (X1)n; and 
 n is 0 for (X2)n. 
   
     
     
         84 . The method of  claim 78 , wherein the binding protein comprises two first polypeptide chains and two second polypeptide chains and four functional target binding sites. 
     
     
         85 . The method of  claim 78 , wherein
 (a) X1 comprises one or more of SEQ ID NOs: 1-27;   (b) the binding protein is a crystalized binding protein;   (c) the Fc region is a native sequence Fc region or a variant sequence Fc region; and/or   (d) the Fc region is an Fc region from an IgG1, IgG2, IgG3, IgG4, IgA, IgM, IgE, or IgD.   
     
     
         86 . A method for treating a subject for a disease or a disorder, comprising administering to the subject a binding protein comprising first and second of peptide chains, wherein the binding protein binds to a target pair selected from:
 (a) TNF and PGE2, wherein the binding protein comprises
 DVD HU2B5.7SLD2E7 (comprising SEQ ID NOs: 114 and 115), 
 DVD HU2B5.7LLD2E7 (comprising SEQ ID NOs: 116 and 117), 
 DVD D2E7SLHU2B5.7 (comprising SEQ ID NOs: 118 and 119), or 
 DVD D2E7LLHU2B5.7 (comprising SEQ ID NOs: 120 and 121); 
   (b) NGF and PGE2, wherein the binding protein comprises
 DVD 164 (comprising SEQ ID NOs: 132 and 133), or 
 DVD 163 (comprising SEQ ID NOs: 134 and 135); 
   (c) IL-17A and PGE2, wherein the binding protein comprises
 DVD 156 (comprising SEQ ID NOs: 136 and 137), or 
 DVD 155 (comprising SEQ ID NOs: 138 and 139); 
   (d) IL-1b and PGE2, wherein the binding protein comprises
 DVD 158 (comprising SEQ ID NOs: 140 and 141), or 
 DVD 157 (comprising SEQ ID NOs: 142 and 143); 
   (e) IL-6R and PGE2, wherein the binding protein comprises
 DVD 152 (comprising SEQ ID NOs: 172 and 173), or 
 DVD 151 (comprising SEQ ID NOs: 174 and 175); 
   (f) VEGF and PGE2, wherein the binding protein comprises
 DVD 162 (comprising SEQ ID NOs: 128 and 129), or 
 DVD 161 (comprising SEQ ID NOs: 130 and 131); 
   (g) Abets and PGE2, wherein the binding protein comprises
 DVD 227 (comprising SEQ ID NOs: 148 and 149), or 
 DVD 228 (comprising SEQ ID NOs: 150 and 151); 
   and   (h) IL-15 and PGE2, wherein the binding protein comprises
 DVD 154 (comprising SEQ ID NOs: 164 and 165), or 
 DVD 153 (comprising SEQ ID NOs: 166 and 167). 
   
     
     
         87 . The method of  claim 78 , wherein the binding protein binds TNF and PGE2, wherein the first polypeptide chain comprises SEQ ID NO: 114 and the second polypeptide chain comprises SEQ ID NO: 115. 
     
     
         88 . The method of  claim 78 , wherein the binding protein binds TNF and PGE2, wherein the first polypeptide chain comprises SEQ ID NO: 116 and the second polypeptide chain comprises SEQ ID NO: 117. 
     
     
         89 . The method of  claim 78 , wherein the binding protein binds TNF and PGE2, wherein the first polypeptide chain comprises SEQ ID NO: 118 and the second polypeptide chain comprises SEQ ID NO: 119. 
     
     
         90 . The method of  claim 78 , wherein the binding protein binds TNF and PGE2, wherein the first polypeptide chain comprises SEQ ID NO: 120 and the second polypeptide chain comprises SEQ ID NO: 121. 
     
     
         91 . The method of  claim 78 , wherein the binding protein binds NGF and PGE2, wherein the first polypeptide chain comprises SEQ ID NO: 132 and the second polypeptide chain comprises SEQ ID NO: 133. 
     
     
         92 . The method of  claim 78 , wherein the binding protein binds NGF and PGE2, wherein the first polypeptide chain comprises SEQ ID NO: 134 and the second polypeptide chain comprises SEQ ID NO: 135. 
     
     
         93 . The method of  claim 78 , wherein the binding protein binds IL-17A and PGE2, wherein the first polypeptide chain comprises SEQ ID NO: 136 and the second polypeptide chain comprises SEQ ID NO: 137. 
     
     
         94 . The method of  claim 78 , wherein the binding protein binds IL-17A and PGE2, wherein the first polypeptide chain comprises SEQ ID NO: 138 and the second polypeptide chain comprises SEQ ID NO: 139. 
     
     
         95 . The method of  claim 78 , wherein the binding protein binds IL-1b and PGE2, wherein the first polypeptide chain comprises SEQ ID NO: 140 and the second polypeptide chain comprises SEQ ID NO: 141. 
     
     
         96 . The method of  claim 78 , wherein the binding protein binds IL-1b and PGE2, wherein the first polypeptide chain comprises SEQ ID NO: 142 and the second polypeptide chain comprises SEQ ID NO: 143. 
     
     
         97 . The method of  claim 78 , wherein the binding protein binds IL-6R and PGE2, wherein the first polypeptide chain comprises SEQ ID NO: 172 and the second polypeptide chain comprises SEQ ID NO: 173. 
     
     
         98 . The method of  claim 78 , wherein the binding protein binds IL-6R and PGE2, wherein the first polypeptide chain comprises SEQ ID NO: 174 and the second poi peptide chain comprises SEQ ID NO: 175. 
     
     
         99 . The method of  claim 78 , wherein the binding protein binds VEGF and PGE2, wherein the first polypeptide chain comprises SEQ ID NO: 128 and the second polypeptide chain comprises SEQ ID NO: 129. 
     
     
         100 . The method of  claim 78 , wherein the binding protein binds VEGF and PGE2, wherein the first polypeptide chain comprises SEQ ID NO: 130 and the second polypeptide chain comprises SEQ ID NO: 131. 
     
     
         101 . The method of  claim 78 , wherein the binding protein binds Abets and PGE2, wherein the first polypeptide chain comprises SEQ ID NO: 148 and the second polypeptide chain comprises SEQ ID NO: 149. 
     
     
         102 . The method of  claim 78 , wherein the binding protein binds Abets and PGE2, wherein the first polypeptide chain comprises SEQ ID NO: 150 and the second polypeptide chain comprises SEQ ID NO: 151. 
     
     
         103 . The method of  claim 78 , wherein the binding protein binds IL-15 and PGE2, wherein the first polypeptide chain comprises SEQ ID NO: 164 and the second polypeptide chain comprises SEQ ID NO: 165. 
     
     
         104 . The method of  claim 78 , wherein the binding protein binds IL-15 and PGE2, wherein the first polypeptide chain comprises SEQ ID NO: 166 and the second polypeptide chain comprises SEQ ID NO: 167. 
     
     
         105 . The method of  claim 78 , wherein the disease or the disorder is selected from the group consisting of rheumatoid arthritis, osteoarthritis, juvenile chronic arthritis, septic arthritis, Lyme arthritis, psoriatic arthritis, reactive arthritis, spondyloarthropathy, systemic lupus erythematosus, Crohn's disease, ulcerative colitis, inflammatory bowel disease, insulin dependent diabetes mellitus, thyroiditis, asthma, allergic diseases, psoriasis, dermatitis  scleroderma , graft versus host disease, organ transplant rejection, acute or chronic immune disease associated with organ transplantation, sarcoidosis, atherosclerosis, disseminated intravascular coagulation, Kawasaki's disease, Grave's disease, nephrotic syndrome, chronic fatigue syndrome, Wegener's granulomatosis, Henoch-Schoenlein purpurea, microscopic vasculitis of the kidneys, chronic active hepatitis, uveitis, septic shock, toxic shock syndrome, sepsis syndrome, cachexia, infectious diseases, parasitic diseases, acquired immunodeficiency syndrome, acute transverse myelitis, Huntington's chorea, Parkinson's disease, Alzheimer's disease, stroke, primary biliary cirrhosis, hemolytic anemia, malignancies, heart failure, myocardial infarction, Addison's disease, sporadic, polyglandular deficiency type I and polyglandular deficiency type H, Schmidt's syndrome, adult (acute) respiratory distress syndrome, alopecia, alopecia areata, seronegative arthropathy, arthropathy, Reiter's disease, psoriatic arthropathy, ulcerative oolitic arthropathy, enteropathic synovitis,  chlamydia, Yersinia  and  salmonella  associated arthropathy, spondyloarthropathy, atheromatous disease/arteriosclerosis, atopic allergy, autoimmune bullous disease,  pemphigus vulgaris, pemphigus foliaceus , pemphigoid, linear IgA disease, autoimmune haemolytic anaemia, Coombs positive haemolytic anaemia, acquired pernicious anaemia, Juvenile pernicious anaemia, myalgic encephalitis Royal Free Disease, chronic mucocutaneous candidiasis, giant cell arteritis, primary sclerosing hepatitis, cryptogenic autoimmune hepatitis, acquired immunodeficiency disease syndrome, acquired immunodeficiency related diseases, hepatitis B, hepatitis C, common varied immunodeficiency (common variable hypogammaglobulinaemia), dilated cardiomyopathy, female infertility, ovarian failure, premature ovarian failure, fibrotic lung disease, cryptogenic fibrosing alveolitis, post-inflammatory interstitial lung disease, interstitial pneumonitis, connective tissue disease associated interstitial lung disease, mixed connective tissue disease associated lung disease, systemic sclerosis associated interstitial lung disease, rheumatoid arthritis associated interstitial lung disease, systemic lupus erythematosus associated lung disease, dermatomyositis/polymyositis associated lung disease, Sjögren's disease associated lung disease, ankylosing spondylitis associated lung disease, vasculitic diffuse lung disease, haemosiderosis associated lung disease, drug-induced interstitial lung disease, fibrosis, radiation fibrosis, bronchiolitis obliterans, chronic eosinophilic pneumonia, lymphocytic infiltrative lung disease, postinfectious interstitial lung disease, gouty arthritis, autoimmune hepatitis, type-1 autoimmune hepatitis (classical autoimmune or lupoid hepatitis), type-2 autoimmune hepatitis (anti-LKM antibody hepatitis), autoimmune mediated hypoglycaemia, type B insulin resistance with acanthosis  nigricans , hypoparathyroidism, acute immune disease associated with organ transplantation, chronic immune disease associated with organ transplantation, osteoarthrosis, primary sclerosing cholangitis, psoriasis type 1, psoriasis type 2, idiopathic leucopaenia, autoimmune neutropaenia, renal disease NOS, glomerulonephritides, microscopic vasulitis of the kidneys, lyme disease, discoid lupus erythematosus, male infertility idiopathic or NOS, sperm autoimmunity, multiple sclerosis (all subtypes), sympathetic ophthalmia, pulmonary hypertension secondary to connective tissue disease, Goodpasture's syndrome, pulmonary manifestation of polyarteritis nodosa, acute rheumatic fever, rheumatoid spondylitis, Still's disease, systemic sclerosis, Sjörgren's syndrome, Takayasu's disease/arteritis, autoimmune thrombocytopaenia, idiopathic thrombocytopaenia, autoimmune thyroid disease, by goitrous autoimmune by (Hashimoto's disease), atrophic autoimmune hypothyroidism, primary myxoedema, phacogenic uveitis, primary vasculitis, vitiligo acute liver disease, chronic over diseases, alcoholic cirrhosis, alcohol-induced over injury, cholestasis, idiosyncratic liver disease, Drug-Induced hepatitis, non-alcoholic steatohepatitis, allergy and asthma, group B streptococci (GBS) infection, mental disorders, depression, schizophrenia, Th2 Type and Th1 Type mediated diseases, acute pain, chronic pain, cancer, lung cancer, breast cancer, stomach cancer, bladder cancer, colon cancer, pancreatic cancer, ovarian cancer, prostate cancer, rectal cancer, hematopoietic malignancies, leukemia, lymphoma, abetalipoprotemia, acrocyanosis, acute and chronic parasitic or infectious processes, acute leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute or chronic bacterial infection, acute pancreatitis, acute renal failure, adenocarcinomas, aerial ectopic beats, AIDS dementia complex, alcohol-induced hepatitis, allergic conjunctivitis, allergic contact dermatitis, all rhinitis, allograft rejection, alpha-1-antitrypsin deficiency, amyotrophic lateral sclerosis, anemia, angina pectoris, anterior horn cell degeneration, anti-CD3 therapy, antiphospholipid syndrome, anti-receptor hypersensitivity reactions, aortic and peripheral aneuryisms, aortic dissection, arterial hypertension, arteriosclerosis, arteriovenous fistula, ataxia, atrial fibrillation (sustained or paroxysmal), atrial flutter, atrioventricular block, B cell lymphoma, bone graft rejection, bone marrow transplant (BMT) rejection, bundle branch block, Burkitt's lymphoma, burns, cardiac arrhythmias, cardiac stun syndrome, cardiac tumors, cardiomyopathy, cardiopulmonary bypass inflammation response, cartilage transplant rejection, cerebellar cortical degenerations, cerebellar disorders, chaotic or multifocal atrial tachycardia, chemotherapy associated disorders, chronic myelocytic leukemia (CML), chronic alcoholism, chronic inflammatory pathologies, chronic lymphocytic leukemia (CLL), chronic obstructive pulmonary disease (COPD), chronic salicylate intoxication, colorectal carcinoma, congestive heart failure, conjunctivitis, contact dermatitis, cor pulmonale, coronary artery disease, Creutzfeldt-Jakob disease, culture negative sepsis, cystic fibrosis, cytokine therapy associated disorders, Dementia pugilistica, demyelinating diseases, dengue hemorrhagic fever, dermatitis, dermatologic conditions, diabetes, diabetes mellitus, diabetic ateriosclerotic disease, diffuse Lewy body disease, dilated congestive cardiomyopathy, disorders of the basal ganglia, Down's syndrome in middle age, drug-induced movement disorders induced by drugs which block CNS dopamine receptors, drug sensitivity, eczema, encephalomyelitis, endocarditis, endocrinopathy, epiglottitis, epstein-barr virus infection, erythromelalgia, extrapyramidal and cerebellar disorders, hematophagocytic lymphohistiocytosis, fetal thymus implant rejection, Friedreich's ataxia, functional peripheral arterial disorders, fungal sepsis, gas gangrene, gastric ulcer, glomerular nephritis, graft rejection of any organ or tissue, gram negative sepsis, gram positive sepsis, granulomas due to intracellular organisms, hairy cell leukemia, Hallervorden-Spatz disease, Hashimoto's thyroiditis, hay fever, heart transplant rejection, hemachromatosis, hemodialysis, hemolytic uremic syndrome/thrombolytic thrombocytopenic purpura, hemorrhage, hepatitis A, His bundle arrythmias, HIV infection/HIV neuropathy, Hodgkin's disease, hyperkinetic movement disorders, hypersensitivity reactions, hypersensitivity pneumonitis, hypertension, hypokinetic movement disorders, hypothalamic-pituitary-adrenal axis evaluation, idiopathic Addison's disease, idiopathic pulmonary fibrosis, antibody mediated cytotoxicity, asthenia, infantile spinal muscular atrophy, inflammation of the aorta, influenza A, ionizing radiation exposure, iridocyclitis/uveitis/optic neuritis, schema reperfusion injury, ischemic stroke, juvenile rheumatoid arthritis, juvenile spinal muscular atrophy, Kaposi's sarcoma, kidney transplant rejection,  legionella , leishmaniasis, leprosy, lesions of the corticospinal system, lipedema, liver transplant rejection, lymphedema, malaria, malignant lymphoma, malignant histiocytosis, malignant melanoma, meningitis, meningococcemia, metabolic/idiopathic, migraine headache, mitochondrial multi system disorder, mixed connective tissue disease, monoclonal gammopathy, multiple myeloma, multiple systems degenerations, Mencel Dejerine-Thomas Shi-Drager degeneration, Machado-Joseph degeneration, myasthenia gravis,  mycobacterium avium intracellulare, mycobacterium tuberculosis , myelodyplastic syndrome, myocardial infarction, myocardial ischemic disorders, nasopharyngeal carcinoma, neonatal chronic lung disease, nephritis, nephrosis, neurodegenerative diseases, neurogenic muscular atrophies, neutropenic fever, non-Hodgkin's lymphoma, occlusion of the abdominal aorta and its branches, occlusive arterial disorders, OKT3 therapy, orchitis/epidydimitis, orchitis/vasectomy reversal procedures, organomegaly, osteoporosis, pancreas transplant rejection, pancreatic carcinoma, paraneoplastic syndrome/hypercalcemia of malignancy, parathyroid transplant rejection, pelvic inflammatory disease, perennial rhinitis, pericardial disease, peripheral arteriosclerotic disease, peripheral vascular disorders, peritonitis, pernicious anemia,  pneumocystis carinii  pneumonia, pneumonia, POEMS syndrome, polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes syndrome, post perfusion syndrome, post pump syndrome, post-MI cardiotomy syndrome, preeclampsia, progressive supranuclear palsy, primary pulmonary hypertension, radiation therapy, Raynaud's phenomenon and disease, Raynoud's disease, Refsum's disease, regular narrow QRS tachycardia, renovascular hypertension, reperfusion injury, restrictive cardiomyopathy, sarcomas,  scleroderma , senile chorea, senile dementia of Lewy body type, seronegative arthropathies, shock, sickle cell anemia, skin allograft rejection, skin changes syndrome, small bowel transplant rejection, solid tumors, specific arrythmias, spinal ataxia, spinocerebellar degenerations, streptococcal myositis, structural lesions of the cerebellum, subacute sclerosing panencephalitis, Syncope, syphilis of the cardiovascular system, systemic anaphalaxis, systemic inflammatory response syndrome, systemic onset juvenile rheumatoid arthritis, T-cell or FAB ALL, telangiectasia, thromboangitis obliterans, thrombocytopenia, toxicity, transplants, trauma/hemorrhage, type ill hypersensitivity reactions, type IV hypersensitivity, unstable angina, uremia, urosepsis, urticaria, valvular heart diseases, varicose veins, vasculitis, venous diseases, venous thrombosis, ventricular fibrillation, viral and fungal infections, viral encephalitis/aseptic meningitis, viral-associated hemaphagocytic syndrome, Wernicke-Korsakoff syndrome, Wilson's disease, xenograft rejection of any organ or tissue, acute coronary syndromes, acute idiopathic polyneuritis, acute inflammatory demyelinating polyradiculoneuropathy, acute ischemia, adult Still's disease, alopecia areata, anaphylaxis, anti-phospholipid antibody syndrome, aplastic anemia, arteriosclerosis, atopic eczema, atopic dermatitis, autoimmune dermatitis, autoimmune disorder associated with  streptococcus  infection, autoimmune enteropathy, autoimmune hearing loss, autoimmune lymphoproliferative syndrome (ALPS), autoimmune myocarditis, autoimmune premature ovarian failure, blepharitis, bronchiectasis, bullous pemphigoid, cardiovascular disease, catastrophic antiphospholipid syndrome, celiac disease, cervical spondylosis, chronic ischemia, cicatricial pemphigoid, clinically isolated syndrome (cis) with risk for multiple sclerosis, conjunctivitis, childhood onset psychiatric disorder, chronic obstructive pulmonary disease (COPD), dacryocystitis, dermatomyositis, diabetic retinopathy, diabetes mellitus, disk herniation, disk prolapse, drug induced immune hemolytic anemia, endocarditis, endometriosis, endophthalmitis, episcleritis, erythema mulfiforme, erythema multiforme major, gestational pemphigoid, Guillain-Barré syndrome (GBS), hay fever, Hughes syndrome, idiopathic Parkinson's disease, idiopathic interstitial pneumonia, IgE-mediated allergy, immune hemolytic anemia, inclusion body myositis, infectious ocular inflammatory disease, inflammatory demyelinating disease, inflammatory heart disease, inflammatory kidney disease, IPF/UIP, iritis, keratitis, keratoconjunctivitis sicca, Kussmaul disease or Kussmaul-Meier disease, Landry's paralysis, Langerhan's cell histiocytosis, livedo  reticularis , macular degeneration, microscopic, polyanglitis, morbus bechterev, motor neuron disorders, mucous membrane pemphigoid, multiple organ failure, myasthenia gravis, myelodysplastic syndrome, myocarditis, nerve root disorders, neuropathy, non-A non-B hepatitis, optic neuritis, osteolysis, pauciarticular JRA, peripheral artery occlusive disease (PAOD), peripheral vascular disease (PVD), peripheral artery, disease (PAD), phlebitis, polyarteritis nodosa, periarteritis, nodosa, polychondritis, polymyalgia rheumatica, poliosis, polyarticular JRA, polyendocrine deficiency syndrome, polymyositis, polymyalgia rheumatica (PMR), post-pump syndrome, primary Parkinsonism, prostatitis, pure red cell aplasia, primary adrenal insufficiency, recurrent neuromyelitis optica, restenosis, rheumatic heart disease, sapho (synovitis, acne, pustulosis, hyperostosis, and osteitis),  scleroderma , secondary amyloidosis, shock lung, scleritis, sciatica, secondary adrenal in silicone associated connective tissue disease, sneddon-wilkinson dermatosis, spondilitis ankylosans, Stevens-Johnson syndrome (SJS), systemic inflammatory response syndrome, temporal arteritis, toxoplasmic retinitis, toxic epidermal necrolysis, transverse myelitis, TRAPS (tumor necrosis factor receptor, type 1 allergic reaction, type II diabetes, urticaria, usual interstitial pneumonia (UP), vasculitis, vernal conjunctivitis, viral retinitis, Vogt-Koyanagi-Harada syndrome (VKH syndrome), wet macular degeneration, wound healing,  Yersinia , and  salmonella  associated arthropathy. 
     
     
         106 . The method of  claim 78 , wherein the disease or the disorder is an inflammatory disorder or an immune disorder. 
     
     
         107 . The method of  claim 106 , wherein the disease or the disorder is selected from the group consisting of rheumatoid arthritis, osteoarthritis, juvenile chronic arthritis, septic arthritis, Lyme arthritis, psoriatic arthritis, reactive arthritis, spondyloarthropathy, gouty arthritis, osteoarthrosis, spondilitis ankylosans, systemic lupus erythematosus, Crohn's disease, ulcerative colitis, inflammatory bowel disease, diabetes mellitus, thyroiditis, asthma, psoriasis, dermatitis, sarcoidosis, Kawasaki's disease, Wegener's granulomatosis, Henoch-Schoenlein  purpurea , vasculitis, hepatitis, uveitis, temporal arteritis, toxoplasmic retinitis, toxic epidermal necrolysis, transverse myelitis, Vogt-Koyanagi-Harada syndrome (VKH syndrome), eczema, autoimmune lymphoproliferative syndrome (ALPS), autoimmune myocarditis, autoimmune premature ovarian failure, blepharitis, celiac disease, Gulllain-Barré syndrome (GBS), Hughes syndrome, SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis),  scleroderma , scleritis) Sneddon-Wilkinson dermatosis, Schmidt's syndrome, Reiter's disease, enteropathic synovitis, autoimmune bullous disease, giant cell arteritis, Goodpasture's syndrome, Still's disease, Sjörgren's syndrome, Takayasu's disease, and multiple sclerosis. 
     
     
         108 . The method of  claim 78 , wherein the binding protein is adapted 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. 
     
     
         109 . A method for treating a subject for a disease or a disorder, comprising administering to the subject a binding protein conjugate comprising a binding protein, wherein the binding protein comprises first and second polypeptide chains, each independently comprising VD1-(X1)n-VD2-C-(X2)n, 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; 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 binds
 (a) TNF and PGE2, wherein
 (1) the variable domains that form a functional binding site for TNF comprise CDRs 1-3 from SEQ ID NO: 112 or CDRs 1-3 from SEQ ID NO: 113; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise CDRs 1-3 from SEQ ID NO: 110 or CDRs 1-3 from SEQ ID NO: 111; 
 
 (b) NGF and PGE2, wherein
 (1) the variable domains that form a functional binding site for NGF comprise CDRs 1-3 from SEQ ID NO: 32 or CDRs 1-3 from SEQ ID NO: 33; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise CDRs 1-3 from SEQ ID NO: 48 or CDRs 1-3 from SEQ ID NO: 49; 
 
 (c) IL-17A and PGE2, wherein
 (1) the variable domains that form a functional binding site for IL-17A comprise CDRs 1-3 from SEQ ID NO: 34 or CDRs 1-3 from SEQ ID NO: 35; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise CDRs 1-3 from SEQ ID NO: 48 or CDRs 1-3 from SEQ ID NO: 49; 
 
 (d) IL-1b and PGE2, wherein
 (1) the variable domains that form a functional binding site for IL-1 b comprise CDRs 1-3 from SEQ ID NO: 36 or CDRs 1-3 from SEQ ID NO: 37; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise CDRs 1-3 from SEQ ID NO: 48 or CDRs 1-3 from SEQ ID NO: 49; 
 
 (e) IL-6R and PGE2, wherein
 (1) the variable domains that form a functional binding site for IL-6R comprise CDRs 1-3 from SEQ ID NO: 54 or CDRs 1-3 from SEQ ID NO: 55; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise CDRs 1-3 from SEQ ID NO: 48 or CDRs 1-3 from SEQ ID NO: 49; 
 
 (f) VEGF and PGE2, wherein
 (1) the variable domains that form a functional binding site for VEGF comprise CDRs 1-3 from SEQ 1D NO: 28 or CDRs 1-3 from SEQ ID NO: 29; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise CDRs 1-3 from SEQ ID NO: 48 or CDRs 1-3 from SEQ ID NO: 49; 
 
 (g) Abeta and PGE2, wherein
 (1) the variable domains that form a functional binding site for Abeta comprise CDRs 1-3 from SEQ ID NO: 40 or CDRs 1-3 from SEQ ID NO: 41; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise CDRs 1-3 from SEQ ID NO: 48 or CDRs 1-3 from SEQ ID NO: 49; 
 
 or 
 (h) IL-15 and PGE2, wherein
 (1) the variable domains that form a functional binding site for IL-15 comprise CDRs 1-3 from SEQ ID NO: 50 or CDRs 1-3 from SEQ ID NO: 51; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise CDRs 1-3 from SEQ ID NO: 48 or CDRs 1-3 from SEQ ID NO: 49; 
 
 wherein the binding protein conjugate further comprises an immunoadhesion molecule, an imaging agent, a therapeutic agent, or a cytotoxic agent; 
 wherein the imaging agent is optionally selected from the group consisting of a radiolabel, an enzyme, a fluorescent label, a luminescent label, a bioluminescent label, a magnetic label, and biotin; 
 wherein the radiolabel is optionally selected from the group consisting of  3 H,  14 C,  35 S,  90 Y,  98 Y,  99 Tc,  111 In,  125 I,  131 I,  177 Lu,  166 Ho, and  153 Sm; or 
 wherein the therapeutic or cytotoxic agent is optionally selected from the group consisting of an anti-metabolite, alkylating agent, an antibiotic, a growth factor, a cytokine, anti-angiogenic agent, an anti-mitotic agent, an anthracycline, toxin, and an apoptotic agent. 
 
     
     
         110 . An isolated nucleic acid encoding a binding protein, wherein the binding protein comprises first and second polypeptide chains, each independently comprising VD1-(X1)n-VD2-C-(X2)n, 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; 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 binds
 (a) TNF and PGE2, wherein
 (1) the variable domains that form a functional binding site for TNF comprise CDRs 1-3 from SEQ ID NO: 112 or CDRs 1-3 from SEQ ID NO: 113; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise CDRs 1-3 from SEQ ID NO: 110 or CDRs 1-3 from SEQ ID NO: 111; 
 
 (b) NGF and PGE2, wherein
 (1) the variable domains that form a functional binding site for NGF comprise CDRs 1-3 from SEQ ID NO: 32 or CDRs 1-3 from SEQ ID NO 33; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise CDRs 1-3 from SEQ ID NO: 48 or CDRs 1-3 from SEQ ID NO: 49; 
 
 (C) IL-17A and PGE2, wherein
 (1) the variable domains that form a functional binding site for IL-17A comprise CDRs 1-3 from SEQ ID NO: 34 or CDRs 1-3 from SEQ ID NO: 35; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise CDRs 1-3 from SEQ ID NO: 48 or CDRs 1-3 from SEQ ID NO: 49; 
 
 (d) IL-1b and PGE2, wherein
 (1) the variable domains that form a functional binding site for IL-1b comprise CDRs 1-3 from SEQ ID NO: 36 or CDRs 1-3 from SEQ ID NO: 37; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise CDRs 1-3 from SEQ ID NO: 48 or CDRs 1-3 from SEQ ID NO: 49; 
 
 (e) IL-6R and PGE2, wherein
 (1) the variable domains that form a functional binding site for IL-6R comprise CDRs 1-3 from SEQ ID NO: 54 or CDRs 1-3 from SEQ ID NO: 55; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise CDRs 1-3 from SEQ ID NO; 48 or CDRs 1-3 from SEQ ID NO: 49; 
 
 (f) VEGF and PGE2, wherein
 (1) the variable domains that form a functional binding site for VEGF comprise CDRs 1-3 from SEQ ID NO: 28 or CDRs 1-3 from SEQ ID NO: 29; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise CDRs 1-3 from SEQ ID NO: 48 or CDRs 1-3 from SEQ ID NO: 49; 
 
 (g) Abeta and PGE2, wherein
 (1) the variable domains that form a functional binding site for Abeta comprise CDRs 1-3 from SEQ ID NO: 40 or CDRs 1-3 from SEQ ID NO: 41; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise CDRs 1-3 from SEQ ID NO: 48 or CDRs 1-3 from SEQ ID NO: 49; 
 
 or 
 (h) IL-15 and PGE2, wherein
 (1) the variable domains that form a functional binding site for IL-15 comprise CDRs 1-3 from SEQ ID NO: 50 or CDRs 1-3 from SEQ ID NO: 51; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise CDRs 1-3 from SEQ ID NO: 48 or CDRs 1-3 from SEQ ID NO: 49. 
 
 
     
     
         111 . The nucleic; acid of  claim 110 , wherein
 (a) X1 comprises one or more of SEQ ID NOs: 1-27;   (b) the Fc region is a native sequence Fc region or a variant sequence Fc region;   (c) the Fc region is an Fc region from an IgG1, IgG2, IgG3, IgG4, IgA, IgM, IgE, or IgD; or   (d) the binding protein comprises two first polypeptide chains and two second polypeptide chains and four functional target binding sites.   
     
     
         112 . A vector comprising the isolated nucleic acid of  claim 110 . 
     
     
         113 . The vector of  claim 112 , wherein the vector is selected from the group consisting of pcDNA™, pTT, pTT3, pEFBOS, pBV, pJV, pcDNA3.1™ TOPO™, pEF6 TOPO™, and pBJ. 
     
     
         114 . A host cell comprising the vector of  claim 112 . 
     
     
         115 . The host cell of  claim 114 , wherein the host cell is selected from the group consisting of a prokaryotic cell, an  Escherichia coli  cell, a eukaryotic cell, an animal cell, a plant cell, a fungal cell, a mammalian cell, an avian cell, an insect cell, a CHO cell, a COS cell, a yeast cell, a  Saccharomyces cerevisiae  cell, and an Sf9 cell. 
     
     
         116 . A method of producing a binding protein, comprising culturing the host cell of  claim 114  under conditions sufficient to produce the binding protein. 
     
     
         117 . A method of determining the presence, amount, or concentration of at least one target selected from the group consisting of PGE2, TNF, NOF, IL-17A, IL-1b, IL-6R, VEGF, Abeta, and IL-15 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, and   wherein the at least one binding protein comprises first and second polypeptide chains, each independently comprising VD1-(X)n-VD2-C-(X2)n, 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; 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 binds
 (a) TNF and PGE2, wherein
 (1) the variable domains that form a functional binding site for TNF comprise CDRs 1-3 from SEQ ID NO: 112 or CDRs 1-3 from SEQ ID NO: 113; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise CDRs 1-3 from SEQ ID NO: 110 or CDRs 1-3 from SEQ ID NO; 111; 
 
 (b) NGF and PGE2, wherein
 (1) the variable domains that form a functional binding site for NGF comprise CDRs 1-3 from SEQ ID NO: 32 or CDRs 1-3 from SEQ ID NO: 33; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise CDRs 1-3 from SEQ ID NO: 48 or CDRs 1-3 from SEQ ID NO: 49; 
 
 (c) IL-17A and PGE2wherein
 (1) the variable domains that form a functional binding site for IL-17A comprise CDRs 1-3 from SEQ ID NO: 34 or CDRs 1-3 from SEQ ID NO: 35; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise CDRs 1-3 from SEQ ID NO: 48 or CDRs 1-3 from SEQ ID NO: 49; 
 
 (d) IL-1 b and PGE2, wherein
 (1) the variable domains that form a functional binding site for IL-1b comprise CDRs 1-3 from SEQ ID NO: 36 or CDRs 1-3 from SEQ ID NO: 37; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise CDRs 1-3 from SEQ ID NO: 48 or CDRs 1-3 from SEQ ID NO: 49; 
 
 (e) IL-6R and PGE2, wherein
 (1) the variable domains that form a functional binding site for IL-6R comprise CDRs 1-3 from SEQ ID NO: 54 or CDRs 1-3 from SEQ ID NO: 55; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise CDRs 1-3 from SEQ 1D NO: 48 or CDRs 1-3 from SEQ ID NO: 49; 
 
 (f) VEGF and PGE2, wherein
 (1) the variable domains that form a functional binding site for VEGF comprise CDRs 1-3 from SEQ ID NO: 28 or CDRs 1-3 from SEQ ID NO: 29; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise CDRs 1-3 from SEQ ID NO: 48 or CDRs 1-3 from SEQ NO: 49; 
 
 (g) Abets and PGE2, wherein
 (1) the variable domains that form a functional binding site for Abets comprise CDRs 13 from SEQ ID NO: 40 or CDRs 1-3 from SEQ ID NO: 41; and 
 (2) the variable domains that form a functional binding site for PGE2 comprise CDRs 1-3 from SEQ ID NO: 48 or CDRs 1-3 from SEQ ID NO: 49; 
 
 or 
 (h) IL-15 and PGE2, wherein
 (1) the variable domains that form a functional binding site for IL-15 comprise CDRs 1-3 from SEQ ID NO: 50 or CDRs 1-3 from SEQ ID NO: 51; and) 
 (2) the variable domains that form a functional binding site for PGE2 comprise CDRs 1-3 from SEQ ID NO: 48 or CDRs 1-3 from SEQ ID NO: 49. 
 
   
     
     
         118 . The method of  claim 117 , further comprising:
 (a) contacting the test sample with the at least one binding protein, wherein the binding protein binds to an epitope on the target or fragment thereof so as to form a first complex;   (b) contacting the complex with the at least one detectable label, wherein the detectable label binds to the binding protein or an epitope on the target or fragment thereof that is not bound by the binding protein to form a second complex; and   (c) detecting the presence, amount, or concentration of the target or fragment thereof in the test sample based on the signal generated by the detectable label in the second complex, wherein the presence, amount, or concentration of the target or fragment thereof is directly correlated with the signal generated by the detectable label.   
     
     
         119 . The method of  claim 117 , further comprising:
 (a) contacting the test sample with the at least one binding protein, wherein the binding protein binds to an epitope on the target or fragment thereof so as to form a first complex;   (b) contacting the complex with the at least one detectable label, wherein the detectable label competes with the target or fragment thereof for binding to the binding protein so as to form a second complex; and   (c) detecting the presence, amount, or concentration of the target or fragment thereof in the test sample based on the signal generated by the detectable label in the second complex, wherein the presence, amount, or concentration of the target or fragment thereof is indirectly correlated with the signal generated by the detectable label.   
     
     
         120 . The method of  claim 117 , wherein
 (a) X1 comprises one or more of SEQ ID NOs: 1-27;   (b) the Fe region is a native sequence Fc region or a variant sequence Fc region;   (c) the Fc region is an Fe region from an IgG1, IG2, IgG3, IgG4, IgA, IgM, IgE, or IgD;   (d) the binding protein comprises two first polypeptide chains and two second polypeptide chains and four functional target binding sites; or   (e) the binding protein is a crystallized binding protein.