Dual Variable Domain Immunoglobulins and Uses Thereof

Abstract

Engineered multivalent and multispecific binding proteins, methods of making, and their uses in the prevention, diagnosis, and/or treatment of disease are provided.

1 - 90 . (canceled) 
     
     
         91 . A pharmaceutical composition 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;   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, wherein the binding protein is capable of binding IL-17 and TNFα, and wherein the variable domains that form a functional target binding site for IL-17 comprise CDRs 1-3 from SEQ ID NO: 40 and CDRs 1-3 from SEQ ID NO: 41.   
     
     
         92 . The pharmaceutical composition of  claim 91 , wherein the variable domains that form a functional target binding site for IL-17 comprise SEQ ID NO: 40 and SEQ ID NO: 41. 
     
     
         93 . The pharmaceutical composition of  claim 91 , wherein
 (a) X1 comprises any one of SEQ ID NOs: 1-29;   (b) the binding protein is a crystallized binding protein;   (c) the Fc region is a variant sequence Fc region;   (d) the Fc region is from an IgG1, IgG2, IgG3, IgG4, IgA, IgM, IgE, or IgD; and/or   (e) the binding protein comprises two first polypeptide chains and two second polypeptide chains and four functional target binding sites.   
     
     
         94 . The pharmaceutical composition of  claim 91 , further comprising a pharmaceutically acceptable carrier. 
     
     
         95 . The pharmaceutical composition of  claim 91 , further comprising at least one additional therapeutic agent. 
     
     
         96 . An isolated nucleic acid encoding a binding protein amino acid sequence, 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 F c region;   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, wherein the binding protein is capable of binding IL-17 and TNFα, and wherein the variable domains that form a functional target binding site for IL-17 comprise CDRs 1-3 from SEQ ID NO: 40 and CDRs 1-3 from SEQ ID NO: 41.   
     
     
         97 . A vector comprising the isolated nucleic acid of  claim 96 . 
     
     
         98 . A host cell comprising the vector of  claim 97 . 
     
     
         99 . The host cell of  claim 98 , wherein the host cell is selected from the group consisting of a eukaryotic cell, an animal cell, a mammalian cell, a CHO cell, and a COS cell. 
     
     
         100 . A method of producing a binding protein, comprising culturing the host cell of  claim 98  under conditions sufficient to produce the binding protein. 
     
     
         101 . The nucleic acid of  claim 96 , wherein the variable domains that form a functional target binding site for IL-17 comprise SEQ ID NO: 40 and SEQ ID NO: 41. 
     
     
         102 . The nucleic acid of  claim 96 , wherein
 (a) X1 comprises any one of SEQ ID NOs: 1-29;   (b) the Fc region is a variant sequence Fc region;   (c) the Fc region is from an IgG1, IgG2, IgG3, IgG4, IgA, IgM, IgE, or IgD; and/or   (d) the binding protein comprises two first polypeptide chains and two second polypeptide chains and four functional target binding sites.   
     
     
         103 . A method of determining the presence, amount, or concentration of IL-17 and/or TNFα 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-(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; 
 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, wherein the binding protein is capable of binding IL-17 and TNFα, and wherein the variable domains that form a functional target binding site for IL-17 comprise CDRs 1-3 from SEQ ID NO: 40 and CDRs 1-3 from SEQ ID NO: 41. 
 
     
     
         104 . The method of  claim 103  further comprising:
 (a) contacting the test sample with 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 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 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 of the target or fragment thereof is directly correlated with the signal generated by the detectable label. 
 
     
     
         105 . The method of  claim 103  further comprising:
 (a) contacting the test sample with 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 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 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 of the target or fragment thereof is indirectly correlated with the signal generated by the detectable label. 
 
     
     
         106 . The method of  claim 103 , wherein the variable domains that form a functional target binding site for IL-17 comprise SEQ ID NO: 40 and SEQ ID NO: 41. 
     
     
         107 . The method of  claim 103 , wherein
 (a) X1 comprises any one of SEQ ID NOs: 1-29;   (b) the binding protein is a crystallized binding protein;   (c) the Fc region is a variant sequence Fc region;   (d) the Fc region is from an IgG1, IgG2, IgG3, IgG4, IgA, IgM, IgE, or IgD; and/or   (e) the binding protein comprises two first polypeptide chains and two second polypeptide chains and four functional target binding sites.   
     
     
         108 . A kit for assaying a test sample for the presence, amount, or concentration of IL-17 and/or TNFα, the kit comprising
 (a) instructions for assaying the test sample for IL-17 and/or TNFα and 
 (b) at least one 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 F c region; 
 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, wherein the binding protein is capable of binding IL-17 and TNFα, and wherein the variable domains that form a functional target binding site for IL-17 comprise CDRs 1-3 from SEQ ID NO: 40 and CDRs 1-3 from SEQ ID NO: 41. 
 
     
     
         109 . The kit of  claim 108 , wherein the variable domains that form a functional target binding site for IL-17 comprise SEQ ID NO: 40 and SEQ ID NO: 41. 
     
     
         110 . The kit of  claim 108 , wherein
 (a) X1 comprises any one of SEQ ID NOs: 1-29;   (b) the binding protein is a crystallized binding protein;   (c) the Fc region is a variant sequence Fc region;   (d) the Fc region is from an IgG1, IgG2, IgG3, IgG4, IgA, IgM, IgE, or IgD; and/or   (e) the binding protein comprises two first polypeptide chains and two second polypeptide chains and four functional target binding sites.