Anti-cd38 antibodies and methods of use

Abstract

The disclosure provides binding proteins that bind CD38 polypeptides, e.g., human and cynomolgus monkey CD38 polypeptides. For example, the binding proteins can be monospecific, bispecific, or trispecific binding proteins with at least one antigen binding domain that binds a CD38 polypeptide. The disclosure also provides methods for making binding proteins that bind CD38 polypeptides and uses of such binding proteins.

What is claimed is: 
     
         1 . A binding protein comprising an antigen binding site that binds a CD38 polypeptide, wherein the antigen binding site comprises:
 (a) an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GYTFTSFN (SEQ ID NO:31) or GYTFTSYA (SEQ ID NO:37), a CDR-H2 sequence comprising the amino acid sequence of IYPGNGGT (SEQ ID NO:32) or IYPGQGGT (SEQ ID NO:38), and a CDR-H3 sequence comprising the amino acid sequence of ARTGGLRRAYFTY (SEQ ID NO:33); and   (b) an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of ESVDSYGNGF (SEQ ID NO:34) or QSVSSYGQGF (SEQ ID NO:39), a CDR-L2 sequence comprising the amino acid sequence of LAS (SEQ ID NO:35) or GAS (SEQ ID NO:40), and a CDR-L3 sequence comprising the amino acid sequence of QQNKEDPWT (SEQ ID NO:36).   
     
     
         2 . The binding protein of  claim 1 , wherein the antigen binding site comprises:
 (a) an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GYTFTSFN (SEQ ID NO:31), a CDR-H2 sequence comprising the amino acid sequence of IYPGNGGT (SEQ ID NO:32), and a CDR-H3 sequence comprising the amino acid sequence of ARTGGLRRAYFTY (SEQ ID NO:33); and   (b) an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of ESVDSYGNGF (SEQ ID NO:34), a CDR-L2 sequence comprising the amino acid sequence of LAS (SEQ ID NO:35), and a CDR-L3 sequence comprising the amino acid sequence of QQNKEDPWT (SEQ ID NO:36).   
     
     
         3 . The binding protein of  claim 1  or  claim 2 , wherein the VH domain comprises the sequence, from N-terminus to C-terminus, FR1-CDR-H1-FR2-CDR-H2-FR3-CDR-H3-FR4; wherein FR1 comprises the sequence QVQLVQSGAEVVKPGASVKVSCKAS (SEQ ID NO:86), QVQLVQSGAEVVKSGASVKVSCKAS (SEQ ID NO:87), or QVQLVQSGAEVVKPGASVKMSCKAS (SEQ ID NO:88); wherein FR2 comprises the sequence MHWVKEAPGQRLEWIGY (SEQ ID NO:90) or MHWVKEAPGQGLEWIGY (SEQ ID NO:91); wherein FR3 comprises the sequence NYNQKFQGRATLTADTSASTAYMELSSLRSEDTAVYFC (SEQ ID NO:93) or NYNQKFQGRATLTADTSASTAYMEISSLRSEDTAVYFC (SEQ ID NO:94); and wherein FR4 comprises the sequence WGQGTLVTVSS (SEQ ID NO:96). 
     
     
         4 . The binding protein of  claim 1  or  claim 2 , wherein the VH domain comprises the amino acid sequence of SEQ ID NO:5, and the VL domain comprises the amino acid sequence of SEQ ID NO:6. 
     
     
         5 . The binding protein of  claim 4 , wherein the binding protein comprises an antibody heavy chain comprising the amino acid sequence of SEQ ID NO:7 and an antibody light chain comprising the amino acid sequence of SEQ ID NO:8. 
     
     
         6 . The binding protein of  claim 1  or  claim 2 , wherein the VH domain comprises the amino acid sequence of SEQ ID NO:17, and the VL domain comprises the amino acid sequence of SEQ ID NO:18. 
     
     
         7 . The binding protein of  claim 6 , wherein the binding protein comprises an antibody heavy chain comprising the amino acid sequence of SEQ ID NO:19 and an antibody light chain comprising the amino acid sequence of SEQ ID NO:20. 
     
     
         8 . The binding protein of  claim 1  or  claim 2 , wherein the VH domain comprises the amino acid sequence of SEQ ID NO:21, and the VL domain comprises the amino acid sequence of SEQ ID NO:18. 
     
     
         9 . The binding protein of  claim 8 , wherein the binding protein comprises an antibody heavy chain comprising the amino acid sequence of SEQ ID NO:22 and an antibody light chain comprising the amino acid sequence of SEQ ID NO:20. 
     
     
         10 . The binding protein of  claim 1  or  claim 2 , wherein the VH domain comprises the amino acid sequence of SEQ ID NO:23, and the VL domain comprises the amino acid sequence of SEQ ID NO:18. 
     
     
         11 . The binding protein of  claim 10 , wherein the binding protein comprises an antibody heavy chain comprising the amino acid sequence of SEQ ID NO:24 and an antibody light chain comprising the amino acid sequence of SEQ ID NO:20. 
     
     
         12 . The binding protein of  claim 1 , wherein the antigen binding site comprises:
 (a) an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GYTFTSYA (SEQ ID NO:37), a CDR-H2 sequence comprising the amino acid sequence of IYPGQGGT (SEQ ID NO:38), and a CDR-H3 sequence comprising the amino acid sequence of ARTGGLRRAYFTY (SEQ ID NO:33); and   (b) an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of QSVSSYGQGF (SEQ ID NO:39), a CDR-L2 sequence comprising the amino acid sequence of GAS (SEQ ID NO:40), and a CDR-L3 sequence comprising the amino acid sequence of QQNKEDPWT (SEQ ID NO:36).   
     
     
         13 . The binding protein of  claim 1  or  claim 12 , wherein the VH domain comprises the sequence, from N-terminus to C-terminus, FR1-CDR-H1-FR2-CDR-H2-FR3-CDR-H3-FR4; wherein FR1 comprises the sequence QVQLVQSGAEVVKPGASVKVSCKAS (SEQ ID NO:86), QVQLVQSGAEVVKSGASVKVSCKAS (SEQ ID NO:87), or QVQLVQSGAEVVKPGASVKMSCKAS (SEQ ID NO:88); wherein FR2 comprises the sequence MHWVKEAPGQRLEWIGY (SEQ ID NO:90) or MHWVKEAPGQGLEWIGY (SEQ ID NO:91); wherein FR3 comprises the sequence NYNQKFQGRATLTADTSASTAYMELSSLRSEDTAVYFC (SEQ ID NO:93) or NYNQKFQGRATLTADTSASTAYMEISSLRSEDTAVYFC (SEQ ID NO:94); and wherein FR4 comprises the sequence WGQGTLVTVSS (SEQ ID NO:96). 
     
     
         14 . The binding protein of  claim 1  or  claim 12 , wherein the VH domain comprises the amino acid sequence of SEQ ID NO:13, and the VL domain comprises the amino acid sequence of SEQ ID NO:14. 
     
     
         15 . The binding protein of  claim 14 , wherein the binding protein comprises an antibody heavy chain comprising the amino acid sequence of SEQ ID NO:15 and an antibody light chain comprising the amino acid sequence of SEQ ID NO:16. 
     
     
         16 . A binding protein comprising an antigen binding site that binds a CD38 polypeptide, wherein the antigen binding site comprises:
 (a) an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GFTFSSYG (SEQ ID NO:41), a CDR-H2 sequence comprising the amino acid sequence of IWYDGSNK (SEQ ID NO:42), and a CDR-H3 sequence comprising the amino acid sequence of ARMFRGAFDY (SEQ ID NO:43); and   (b) an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of QGIRND (SEQ ID NO:44), a CDR-L2 sequence comprising the amino acid sequence of AAS (SEQ ID NO:45), and a CDR-L3 sequence comprising the amino acid sequence of LQDYIYYPT (SEQ ID NO:46).   
     
     
         17 . The binding protein of  claim 16 , wherein the VH domain comprises the amino acid sequence of SEQ ID NO:9, and the VL domain comprises the amino acid sequence of SEQ ID NO:10. 
     
     
         18 . The binding protein of  claim 16  or  claim 17 , wherein the binding protein comprises an antibody heavy chain comprising the amino acid sequence of SEQ ID NO:11 and an antibody light chain comprising the amino acid sequence of SEQ ID NO:12. 
     
     
         19 . The binding protein of any one of  claims 1 - 18 , wherein the antigen binding site cross-reacts with an extracellular domain of a human CD38 polypeptide and an extracellular domain of a cynomolgus monkey CD38 polypeptide. 
     
     
         20 . The binding protein of  claim 19 , wherein the antigen binding site binds a human CD38 polypeptide comprising the amino acid sequence of SEQ ID NO:1. 
     
     
         21 . The binding protein of  claim 20 , wherein the antigen binding site binds the human CD38 polypeptide comprising the amino acid sequence of SEQ ID NO:1 with an equilibrium dissociation constant (K D ) of 2.1 nM or less. 
     
     
         22 . The binding protein of  claim 19 , wherein the antigen binding site binds a human isoform E CD38 polypeptide comprising the amino acid sequence of SEQ ID NO:105. 
     
     
         23 . The binding protein of any one of  claims 19 - 22 , wherein the antigen binding site binds a cynomolgus monkey CD38 polypeptide comprising the amino acid sequence of SEQ ID NO:30. 
     
     
         24 . The binding protein of  claim 23 , wherein the antigen binding site binds the cynomolgus monkey CD38 polypeptide comprising the amino acid sequence of SEQ ID NO:30 with an equilibrium dissociation constant (K D ) of 1.3 nM or less. 
     
     
         25 . The binding protein of any one of  claims 1 - 24 , wherein the binding protein is a chimeric or humanized antibody. 
     
     
         26 . The binding protein of any one of  claims 16 - 24 , wherein the binding protein is a human antibody. 
     
     
         27 . The binding protein of any one of  claims 1 - 24 , wherein the binding protein is a monoclonal antibody. 
     
     
         28 . The binding protein of any one of  claims 1 - 24 , wherein the binding protein comprises one or more full-length antibody heavy chains comprising an Fc region. 
     
     
         29 . The binding protein of  claim 28 , wherein the Fc region is a human Fc region comprising one or more mutations that reduce or eliminate Fc receptor binding and/or effector function of the Fc region. 
     
     
         30 . The binding protein of  claim 28 , wherein the Fc region is a human IgG1 Fc region. 
     
     
         31 . The binding protein of  claim 30 , wherein the human IgG1 Fc region comprises amino acid substitutions at positions corresponding to positions 234, 235, and 329 of human IgG1 according to EU Index, wherein the amino acid substitutions are L234A, L235A, and P329A. 
     
     
         32 . The binding protein of  claim 30 , wherein the human IgG1 Fc region comprises amino acid substitutions at positions corresponding to positions 298, 299, and 300 of human IgG1 according to EU Index, wherein the amino acid substitutions are S298N, T299A, and Y300S. 
     
     
         33 . The binding protein of  claim 28 , wherein the Fc region is a human IgG4 Fc region. 
     
     
         34 . The binding protein of  claim 33 , wherein the human IgG4 Fc region comprises amino acid substitutions at positions corresponding to positions 228 and 409 of human IgG4 according to EU Index, wherein the amino acid substitutions are S228P and R409K. 
     
     
         35 . The binding protein of  claim 33  or  claim 34 , wherein the human IgG4 Fc region comprises amino acid substitutions at positions corresponding to positions 234 and 235 of human IgG4 according to EU Index, wherein the amino acid substitutions are F234A and L235A. 
     
     
         36 . The binding protein of  claim 33  or  claim 34 , wherein the human IgG4 Fc region comprises amino acid substitutions at positions corresponding to positions 233-236 of human IgG4 according to EU Index, wherein the amino acid substitutions are E233P, F234V, L235A, and a deletion at 236. 
     
     
         37 . The binding protein of any one of  claims 1 - 24 , wherein the binding protein comprises an antibody F(ab), F(ab′)2, Fab′-SH, Fv, or scFv fragment. 
     
     
         38 . The binding protein of any one of  claims 1 - 37 , wherein the binding protein is conjugated to a cytotoxic agent or label. 
     
     
         39 . The binding protein of any one of  claims 1 - 37 , wherein the binding protein is a bispecific binding protein comprising the first antigen binding site that binds the CD38 polypeptide and a second antigen binding site. 
     
     
         40 . The binding protein of any one of  claims 1 - 37 , wherein the binding protein is a trispecific binding protein comprising the first antigen binding site that binds the CD38 polypeptide, a second antigen binding site, and a third antigen binding site. 
     
     
         41 . The binding protein of  claim 40 , wherein the first antigen binding site binds the extracellular domain of a human CD38 polypeptide, and wherein the second and third antigen binding sites each bind a T-cell surface protein. 
     
     
         42 . The binding protein of  claim 41 , wherein the first antigen binding site binds the extracellular domain of a human CD38 polypeptide, and wherein (a) the second antigen binding site binds a human CD28 polypeptide, and the third antigen binding site binds a human CD3 polypeptide, or (b) the second antigen binding site binds a human CD3 polypeptide, and the third antigen binding site binds a human CD28 polypeptide. 
     
     
         43 . A binding protein comprising three antigen binding sites that each bind one or more target proteins, wherein at least one of the three antigen binding sites cross-reacts with an extracellular domain of a human CD38 polypeptide and an extracellular domain of a cynomolgus monkey CD38 polypeptide. 
     
     
         44 . The binding protein of  claim 43 , wherein the binding protein cross-reacts with a human CD38 polypeptide comprising the amino acid sequence of SEQ ID NO:1 or SEQ ID NO:105. 
     
     
         45 . The binding protein of  claim 43  or  claim 44 , wherein the binding protein cross-reacts with a cynomolgus monkey CD38 polypeptide comprising the amino acid sequence of SEQ ID NO:30. 
     
     
         46 . The binding protein of any one of  claims 43 - 45 , wherein the binding protein comprises an antigen binding site that cross-reacts with an extracellular domain of a human CD38 polypeptide and an extracellular domain of a cynomolgus monkey CD38 polypeptide and two antigen binding sites that each bind a T-cell surface protein. 
     
     
         47 . The binding protein of  claim 46 , wherein the binding protein comprises an antigen binding site that cross-reacts with an extracellular domain of a human CD38 polypeptide and an extracellular domain of a cynomolgus monkey CD38 polypeptide, an antigen binding site that binds a human CD28 polypeptide, and an antigen binding site that binds a human CD3 polypeptide. 
     
     
         48 . The binding protein of any one of  claims 43 - 47 , wherein the binding protein comprises four polypeptide chains that form the three antigen binding sites, wherein a first polypeptide chain comprises a structure represented by the formula:
   V L2 -L 1 -V L1 -L 2 -C L   [I]
   and a second polypeptide chain comprises a structure represented by the formula:
   V H1 -L 3 -V H2 -L 4 -C H1 -hinge-C H2 -C H3   [II]
 
   and a third polypeptide chain comprises a structure represented by the formula:
   V H3 -C H1 -hinge-C H2 -C H3   [III]
 
   and a fourth polypeptide chain comprises a structure represented by the formula:
   V L3 -C L   [IV]
 
   wherein:
 V L1  is a first immunoglobulin light chain variable domain; 
 V L2  is a second immunoglobulin light chain variable domain; 
 V L3  is a third immunoglobulin light chain variable domain; 
 V H1  is a first immunoglobulin heavy chain variable domain; 
 V H2  is a second immunoglobulin heavy chain variable domain; 
 V H3  is a third immunoglobulin heavy chain variable domain; 
 C L  is an immunoglobulin light chain constant domain; 
 C H1  is an immunoglobulin C H1  heavy chain constant domain; 
 C H2  is an immunoglobulin C H2  heavy chain constant domain; 
 C H3  is an immunoglobulin C H3  heavy chain constant domain; 
 hinge is an immunoglobulin hinge region connecting the C H1  and C H2  domains; and 
 L 1 , L 2 , L 3  and L 4  are amino acid linkers; 
 wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair, and 
 wherein: 
 (a) the V H1  domain comprises a CDR-H1 sequence comprising the amino acid sequence of GYTFTSFN (SEQ ID NO:31) or GYTFTSYA (SEQ ID NO:37), a CDR-H2 sequence comprising the amino acid sequence of IYPGNGGT (SEQ ID NO:32) or IYPGQGGT (SEQ ID NO:38), and a CDR-H3 sequence comprising the amino acid sequence of ARTGGLRRAYFTY (SEQ ID NO:33), and the V L1  domain comprises a CDR-L1 sequence comprising the amino acid sequence of ESVDSYGNGF (SEQ ID NO:34) or QSVSSYGQGF (SEQ ID NO:39), a CDR-L2 sequence comprising the amino acid sequence of LAS (SEQ ID NO:35) or GAS (SEQ ID NO:40), and a CDR-L3 sequence comprising the amino acid sequence of QQNKEDPWT (SEQ ID NO:36); 
 (b) the V H2  domain comprises a CDR-H1 sequence comprising the amino acid sequence of GYTFTSFN (SEQ ID NO:31) or GYTFTSYA (SEQ ID NO:37), a CDR-H2 sequence comprising the amino acid sequence of IYPGNGGT (SEQ ID NO:32) or IYPGQGGT (SEQ ID NO:38), and a CDR-H3 sequence comprising the amino acid sequence of ARTGGLRRAYFTY (SEQ ID NO:33), and the V L2  domain comprises a CDR-L1 sequence comprising the amino acid sequence of ESVDSYGNGF (SEQ ID NO:34) or QSVSSYGQGF (SEQ ID NO:39), a CDR-L2 sequence comprising the amino acid sequence of LAS (SEQ ID NO:35) or GAS (SEQ ID NO:40), and a CDR-L3 sequence comprising the amino acid sequence of QQNKEDPWT (SEQ ID NO:36); or 
 (c) the V H3  domain comprises a CDR-H1 sequence comprising the amino acid sequence of GYTFTSFN (SEQ ID NO:31) or GYTFTSYA (SEQ ID NO:37), a CDR-H2 sequence comprising the amino acid sequence of IYPGNGGT (SEQ ID NO:32) or IYPGQGGT (SEQ ID NO:38), and a CDR-H3 sequence comprising the amino acid sequence of ARTGGLRRAYFTY (SEQ ID NO:33), and the V L3  domain comprises a CDR-L1 sequence comprising the amino acid sequence of ESVDSYGNGF (SEQ ID NO:34) or QSVSSYGQGF (SEQ ID NO:39), a CDR-L2 sequence comprising the amino acid sequence of LAS (SEQ ID NO:35) or GAS (SEQ ID NO:40), and a CDR-L3 sequence comprising the amino acid sequence of QQNKEDPWT (SEQ ID NO:36). 
   
     
     
         49 . The binding protein of  claim 48 , wherein
 (a) the V H1  domain comprises a CDR-H1 sequence comprising the amino acid sequence of GYTFTSFN (SEQ ID NO:31), a CDR-H2 sequence comprising the amino acid sequence of IYPGNGGT (SEQ ID NO:32), and a CDR-H3 sequence comprising the amino acid sequence of ARTGGLRRAYFTY (SEQ ID NO:33), and the V L1  domain comprises a CDR-L1 sequence comprising the amino acid sequence of ESVDSYGNGF (SEQ ID NO:34), a CDR-L2 sequence comprising the amino acid sequence of LAS (SEQ ID NO:35), and a CDR-L3 sequence comprising the amino acid sequence of QQNKEDPWT (SEQ ID NO:36);   (b) the V H1  domain comprises a CDR-H1 sequence comprising the amino acid sequence of GYTFTSYA (SEQ ID NO:37), a CDR-H2 sequence comprising the amino acid sequence of IYPGQGGT (SEQ ID NO:38), and a CDR-H3 sequence comprising the amino acid sequence of ARTGGLRRAYFTY (SEQ ID NO:33), and the V L1  domain comprises a CDR-L1 sequence comprising the amino acid sequence of QSVSSYGQGF (SEQ ID NO:39), a CDR-L2 sequence comprising the amino acid sequence of GAS (SEQ ID NO:40), and a CDR-L3 sequence comprising the amino acid sequence of QQNKEDPWT (SEQ ID NO:36);   (c) the V H2  domain comprises a CDR-H1 sequence comprising the amino acid sequence of GYTFTSFN (SEQ ID NO:31), a CDR-H2 sequence comprising the amino acid sequence of IYPGNGGT (SEQ ID NO:32), and a CDR-H3 sequence comprising the amino acid sequence of ARTGGLRRAYFTY (SEQ ID NO:33), and the V L2  domain comprises a CDR-L1 sequence comprising the amino acid sequence of ESVDSYGNGF (SEQ ID NO:34), a CDR-L2 sequence comprising the amino acid sequence of LAS (SEQ ID NO:35), and a CDR-L3 sequence comprising the amino acid sequence of QQNKEDPWT (SEQ ID NO:36);   (d) the V H2  domain comprises a CDR-H1 sequence comprising the amino acid sequence of GYTFTSYA (SEQ ID NO:37), a CDR-H2 sequence comprising the amino acid sequence of IYPGQGGT (SEQ ID NO:38), and a CDR-H3 sequence comprising the amino acid sequence of ARTGGLRRAYFTY (SEQ ID NO:33), and the V L2  domain comprises a CDR-L1 sequence comprising the amino acid sequence of QSVSSYGQGF (SEQ ID NO:39), a CDR-L2 sequence comprising the amino acid sequence of GAS (SEQ ID NO:40), and a CDR-L3 sequence comprising the amino acid sequence of QQNKEDPWT (SEQ ID NO:36);   (e) the V H3  domain comprises a CDR-H1 sequence comprising the amino acid sequence of GYTFTSFN (SEQ ID NO:31), a CDR-H2 sequence comprising the amino acid sequence of IYPGNGGT (SEQ ID NO:32), and a CDR-H3 sequence comprising the amino acid sequence of ARTGGLRRAYFTY (SEQ ID NO:33), and the V L3  domain comprises a CDR-L1 sequence comprising the amino acid sequence of ESVDSYGNGF (SEQ ID NO:34), a CDR-L2 sequence comprising the amino acid sequence of LAS (SEQ ID NO:35), and a CDR-L3 sequence comprising the amino acid sequence of QQNKEDPWT (SEQ ID NO:36); or   (h) the V H3  domain comprises a CDR-H1 sequence comprising the amino acid sequence of GYTFTSYA (SEQ ID NO:37), a CDR-H2 sequence comprising the amino acid sequence of IYPGQGGT (SEQ ID NO:38), and a CDR-H3 sequence comprising the amino acid sequence of ARTGGLRRAYFTY (SEQ ID NO:33), and the V L3  domain comprises a CDR-L1 sequence comprising the amino acid sequence of QSVSSYGQGF (SEQ ID NO:39), a CDR-L2 sequence comprising the amino acid sequence of GAS (SEQ ID NO:40), and a CDR-L3 sequence comprising the amino acid sequence of QQNKEDPWT (SEQ ID NO:36).   
     
     
         50 . The binding protein of  claim 49 , wherein
 (a) the V H3  domain comprises a CDR-H1 sequence comprising the amino acid sequence of GYTFTSFN (SEQ ID NO:31), a CDR-H2 sequence comprising the amino acid sequence of IYPGNGGT (SEQ ID NO:32), and a CDR-H3 sequence comprising the amino acid sequence of ARTGGLRRAYFTY (SEQ ID NO:33), and the V L3  domain comprises a CDR-L1 sequence comprising the amino acid sequence of ESVDSYGNGF (SEQ ID NO:34), a CDR-L2 sequence comprising the amino acid sequence of LAS (SEQ ID NO:35), and a CDR-L3 sequence comprising the amino acid sequence of QQNKEDPWT (SEQ ID NO:36); or   (b) the V H3  domain comprises a CDR-H1 sequence comprising the amino acid sequence of GYTFTSYA (SEQ ID NO:37), a CDR-H2 sequence comprising the amino acid sequence of IYPGQGGT (SEQ ID NO:38), and a CDR-H3 sequence comprising the amino acid sequence of ARTGGLRRAYFTY (SEQ ID NO:33), and the V L3  domain comprises a CDR-L1 sequence comprising the amino acid sequence of QSVSSYGQGF (SEQ ID NO:39), a CDR-L2 sequence comprising the amino acid sequence of GAS (SEQ ID NO:40), and a CDR-L3 sequence comprising the amino acid sequence of QQNKEDPWT (SEQ ID NO:36).   
     
     
         51 . The binding protein of  claim 50 , wherein
 (a) the V H3  domain comprises the amino acid sequence of SEQ ID NO:5, and the V L3  domain comprises the amino acid sequence of SEQ ID NO:6;   (b) the V H3  domain comprises the amino acid sequence of SEQ ID NO:17, and the V L3  domain comprises the amino acid sequence of SEQ ID NO:18;   (c) the V H3  domain comprises the amino acid sequence of SEQ ID NO:21, and the V L3  domain comprises the amino acid sequence of SEQ ID NO:18;   (d) the V H3  domain comprises the amino acid sequence of SEQ ID NO:23, and the V L3  domain comprises the amino acid sequence of SEQ ID NO:18; or   (e) the V H3  domain comprises the amino acid sequence of SEQ ID NO:13, and the V L3  domain comprises the amino acid sequence of SEQ ID NO:14.   
     
     
         52 . The binding protein of any one of  claims 43 - 47 , wherein the binding protein comprises four polypeptide chains that form the three antigen binding sites, wherein a first polypeptide chain comprises a structure represented by the formula:
   V L2 -L 1 -V L1 -L 2 -C L   [I]
   and a second polypeptide chain comprises a structure represented by the formula:
   V H1 -L 3 -V H2 -L 4 -C H1 -hinge-C H2 -C H3   [II]
 
   and a third polypeptide chain comprises a structure represented by the formula:
   V H3 -C H1 -hinge-C H2 -C H3   [III]
 
   and a fourth polypeptide chain comprises a structure represented by the formula:
   V L3 -C L   [IV]
 
   wherein:
 V L1  is a first immunoglobulin light chain variable domain; 
 V L2  is a second immunoglobulin light chain variable domain; 
 V L3  is a third immunoglobulin light chain variable domain; 
 V H1  is a first immunoglobulin heavy chain variable domain; 
 V H2  is a second immunoglobulin heavy chain variable domain; 
 V H3  is a third immunoglobulin heavy chain variable domain; 
 C L  is an immunoglobulin light chain constant domain; 
 C H1  is an immunoglobulin C H1  heavy chain constant domain; 
 C H2  is an immunoglobulin C H2  heavy chain constant domain; 
 C H3  is an immunoglobulin C H3  heavy chain constant domain; 
 hinge is an immunoglobulin hinge region connecting the C H1  and C H2  domains; and 
 L 1 , L 2 , L 3  and L 4  are amino acid linkers; 
 wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair, and 
 wherein: 
 (a) the V H1  domain comprises a CDR-H1 sequence comprising the amino acid sequence of GFTFSSYG (SEQ ID NO:41), a CDR-H2 sequence comprising the amino acid sequence of IWYDGSNK (SEQ ID NO:42), and a CDR-H3 sequence comprising the amino acid sequence of ARMFRGAFDY (SEQ ID NO:43), and the V L1  domain comprises a CDR-L1 sequence comprising the amino acid sequence of QGIRND (SEQ ID NO:44), a CDR-L2 sequence comprising the amino acid sequence of AAS (SEQ ID NO:45), and a CDR-L3 sequence comprising the amino acid sequence of LQDYIYYPT (SEQ ID NO:46); 
 (b) the V H2  domain comprises a CDR-H1 sequence comprising the amino acid sequence of GFTFSSYG (SEQ ID NO:41), a CDR-H2 sequence comprising the amino acid sequence of IWYDGSNK (SEQ ID NO:42), and a CDR-H3 sequence comprising the amino acid sequence of ARMFRGAFDY (SEQ ID NO:43), and the V L2  domain comprises a CDR-L1 sequence comprising the amino acid sequence of QGIRND (SEQ ID NO:44), a CDR-L2 sequence comprising the amino acid sequence of AAS (SEQ ID NO:45), and a CDR-L3 sequence comprising the amino acid sequence of LQDYIYYPT (SEQ ID NO:46); or 
 (c) the V H3  domain comprises a CDR-H1 sequence comprising the amino acid sequence of GFTFSSYG (SEQ ID NO:41), a CDR-H2 sequence comprising the amino acid sequence of IWYDGSNK (SEQ ID NO:42), and a CDR-H3 sequence comprising the amino acid sequence of ARMFRGAFDY (SEQ ID NO:43), and the V L3  domain comprises a CDR-L1 sequence comprising the amino acid sequence of QGIRND (SEQ ID NO:44), a CDR-L2 sequence comprising the amino acid sequence of AAS (SEQ ID NO:45), and a CDR-L3 sequence comprising the amino acid sequence of LQDYIYYPT (SEQ ID NO:46). 
   
     
     
         53 . The binding protein of  claim 52 , wherein the V H3  domain comprises a CDR-H1 sequence comprising the amino acid sequence of GFTFSSYG (SEQ ID NO:41), a CDR-H2 sequence comprising the amino acid sequence of IWYDGSNK (SEQ ID NO:42), and a CDR-H3 sequence comprising the amino acid sequence of ARMFRGAFDY (SEQ ID NO:43), and the V L3  domain comprises a CDR-L1 sequence comprising the amino acid sequence of QGIRND (SEQ ID NO:44), a CDR-L2 sequence comprising the amino acid sequence of AAS (SEQ ID NO:45), and a CDR-L3 sequence comprising the amino acid sequence of LQDYIYYPT (SEQ ID NO:46). 
     
     
         54 . The binding protein of  claim 53 , wherein the V H3  domain comprises the amino acid sequence of SEQ ID NO:9, and the V L3  domain comprises the amino acid sequence of SEQ ID NO:10. 
     
     
         55 . The binding protein of any one of  claims 48 - 54 , wherein
 (a) the V H1  domain comprises the amino acid sequence of SEQ ID NO:49, the V L1  domain comprises the amino acid sequence of SEQ ID NO:50, the V H2  domain comprises the amino acid sequence of SEQ ID NO:53, and the V L2  domain comprises the amino acid sequence of SEQ ID NO:54;   (b) the V H2  domain comprises the amino acid sequence of SEQ ID NO:49, the V L2 domain comprises the amino acid sequence of SEQ ID NO:50, the V H1  domain comprises the amino acid sequence of SEQ ID NO:53, and the V L1  domain comprises the amino acid sequence of SEQ ID NO:54;   (c) the V H1  domain comprises the amino acid sequence of SEQ ID NO:51, the V L1  domain comprises the amino acid sequence of SEQ ID NO:52, the V H2  domain comprises the amino acid sequence of SEQ ID NO:53, and the V L2  domain comprises the amino acid sequence of SEQ ID NO:54;   (d) the V H2  domain comprises the amino acid sequence of SEQ ID NO:51, the V L2  domain comprises the amino acid sequence of SEQ ID NO:52, the V H1  domain comprises the amino acid sequence of SEQ ID NO:53, and the V L1  domain comprises the amino acid sequence of SEQ ID NO:54   (e) the V H1  domain comprises the amino acid sequence of SEQ ID NO:49, the V L1  domain comprises the amino acid sequence of SEQ ID NO:50, the V H2  domain comprises the amino acid sequence of SEQ ID NO:84, and the V L2  domain comprises the amino acid sequence of SEQ ID NO:85;   (f) the V H2  domain comprises the amino acid sequence of SEQ ID NO:49, the V L2  domain comprises the amino acid sequence of SEQ ID NO:50, the V H1  domain comprises the amino acid sequence of SEQ ID NO:84, and the V L1  domain comprises the amino acid sequence of SEQ ID NO:85;   (g) the V H1  domain comprises the amino acid sequence of SEQ ID NO:51, the V L1  domain comprises the amino acid sequence of SEQ ID NO:52, the V H2  domain comprises the amino acid sequence of SEQ ID NO:84, and the V L2  domain comprises the amino acid sequence of SEQ ID NO:85; or   (h) the V H2  domain comprises the amino acid sequence of SEQ ID NO:51, the V L2  domain comprises the amino acid sequence of SEQ ID NO:52, the V H1  domain comprises the amino acid sequence of SEQ ID NO:84, and the V L1  domain comprises the amino acid sequence of SEQ ID NO:85.   
     
     
         56 . The binding protein of  claim 55 , wherein
 (a) the V H1  domain comprises the amino acid sequence of SEQ ID NO:49, the V L1  domain comprises the amino acid sequence of SEQ ID NO:50, the V H2  domain comprises the amino acid sequence of SEQ ID NO:53, the V L2  domain comprises the amino acid sequence of SEQ ID NO:54, the V H3  domain comprises the amino acid sequence of SEQ ID NO:13, and the V L3  domain comprises the amino acid sequence of SEQ ID NO:14; or   (b) the V H1  domain comprises the amino acid sequence of SEQ ID NO:49, the V L1  domain comprises the amino acid sequence of SEQ ID NO:50, the V H2  domain comprises the amino acid sequence of SEQ ID NO:53, the V L2  domain comprises the amino acid sequence of SEQ ID NO:54, the V H3  domain comprises the amino acid sequence of SEQ ID NO:9, and the V L3  domain comprises the amino acid sequence of SEQ ID NO:10.   
     
     
         57 . The binding protein of any one of  claims 48 - 56 , wherein at least one of L 1 , L 2 , L 3  or L 4  is independently 0 amino acids in length. 
     
     
         58 . The binding protein of any one of  claims 48 - 56 , wherein L 1 , L 2 , L 3  or L 4  are each independently at least one amino acid in length. 
     
     
         59 . The binding protein of any one of  claims 48 - 56 , wherein (a) L 1 , L 2 , L 3  and L 4  each independently are zero amino acids in length or comprise a sequence selected from the group consisting of GGGGSGGGGS (SEQ ID NO:55), GGGGSGGGGSGGGGS (SEQ ID NO:56), S, RT, TKGPS (SEQ ID NO:57), GQPKAAP (SEQ ID NO: 58), and GGSGSSGSGG (SEQ ID NO:59); or (b) L 1 , L 2 , L 3  and L 4  each independently comprise a sequence selected from the group consisting of GGGGSGGGGS (SEQ ID NO:55), GGGGSGGGGSGGGGS (SEQ ID NO:56), S, RT, TKGPS (SEQ ID NO:57), GQPKAAP (SEQ ID NO: 58), and GGSGSSGSGG (SEQ ID NO:59). 
     
     
         60 . The binding protein of any one of  claims 48 - 56 , wherein
 (a) L 1  comprises the sequence GQPKAAP (SEQ ID NO: 58), L 2  comprises the sequence TKGPS (SEQ ID NO:57), L 3  comprises the sequence S, and L 4  comprises the sequence RT;   (b) L 1  comprises the sequence GGGGSGGGGS (SEQ ID NO:55), L 2  comprises the sequence GGGGSGGGGS (SEQ ID NO:55), L 3  is 0 amino acids in length, and L 4  is 0 amino acids in length;   (c) L 1  comprises the sequence GGSGSSGSGG (SEQ ID NO:59), L 2  comprises the sequence GGSGSSGSGG (SEQ ID NO:59), L 3  is 0 amino acids in length, and L 4  is 0 amino acids in length; or   (d) L 1  comprises the sequence GGGGSGGGGSGGGGS (SEQ ID NO:56), L 2  is 0 amino acids in length, L 3  comprises the sequence GGGGSGGGGSGGGGS (SEQ ID NO:56), and L 4  is 0 amino acids in length.   
     
     
         61 . The binding protein of any one of  claims 48 - 60 , wherein the hinge-C H2 -C H3  domains of the second and the third polypeptide chains are human IgG4 hinge-C H2 -C H3  domains, and wherein the hinge-C H2 -C H3  domains each comprise amino acid substitutions at positions corresponding to positions 234 and 235 of human IgG4 according to EU Index, wherein the amino acid substitutions are F234A and L235A. 
     
     
         62 . The binding protein of any one of  claims 48 - 60 , wherein the hinge-C H2 -C H3  domains of the second and the third polypeptide chains are human IgG4 hinge-C H2 -C H3  domains, and wherein the hinge-C H2 -C H3  domains each comprise amino acid substitutions at positions corresponding to positions 233-236 of human IgG4 according to EU Index, wherein the amino acid substitutions are E233P, F234V, L235A, and a deletion at 236. 
     
     
         63 . The binding protein of any one of  claims 48 - 62 , wherein the hinge-C H2 -C H3  domains of the second and the third polypeptide chains are human IgG4 hinge-C H2 -C H3  domains, and wherein the hinge-C H2 -C H3  domains each comprise amino acid substitutions at positions corresponding to positions 228 and 409 of human IgG4 according to EU Index, wherein the amino acid substitutions are S228P and R409K. 
     
     
         64 . The binding protein of any one of  claims 48 - 60 , wherein the hinge-C H2 -C H3  domains of the second and the third polypeptide chains are human IgG1 hinge-C H2 -C H3  domains, and wherein the hinge-C H2 -C H3  domains each comprise amino acid substitutions at positions corresponding to positions 234, 235, and 329 of human IgG1 according to EU Index, wherein the amino acid substitutions are L234A, L235A, and P329A. 
     
     
         65 . The binding protein of any one of  claims 48 - 60 , wherein the hinge-C H2 -C H3  domains of the second and the third polypeptide chains are human IgG1 hinge-C H2 -C H3  domains, and wherein the hinge-C H2 -C H3  domains each comprise amino acid substitutions at positions corresponding to positions 298, 299, and 300 of human IgG1 according to EU Index, wherein the amino acid substitutions are S298N, T299A, and Y300S. 
     
     
         66 . The binding protein of any one of  claims 48 - 65 , wherein the hinge-C H2 -C H3  domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 or IgG4 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the hinge-C H2 -C H3 domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 or IgG4 according to EU Index, wherein the amino acid substitutions are S354C and T366W. 
     
     
         67 . The binding protein of any one of  claims 48 - 65 , wherein the hinge-C H2 -C H3  domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 or IgG4 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the hinge-C H2 -C H3  domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 or IgG4 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V. 
     
     
         68 . The binding protein of  claim 48  or  claim 52 , wherein the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:61, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:60, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:62, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:63. 
     
     
         69 . The binding protein of  claim 48  or  claim 52 , wherein the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:61, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:64, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:65, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:63. 
     
     
         70 . The binding protein of  claim 48  or  claim 52 , wherein the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:61, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:66, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:67, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:63. 
     
     
         71 . The binding protein of  claim 48  or  claim 52 , wherein the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:61, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:60, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:68, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:69. 
     
     
         72 . The binding protein of  claim 48  or  claim 52 , wherein the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:61, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:64, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:70, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:69. 
     
     
         73 . The binding protein of  claim 48  or  claim 52 , wherein the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:61, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:66, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:71, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:69. 
     
     
         74 . A binding protein comprising three antigen binding sites that each bind one or more target proteins, wherein the binding protein comprises four polypeptide chains that form the three antigen binding sites, wherein a first polypeptide chain comprises a structure represented by the formula:
   V L2 -L 1 -V L1 -L 2 -C L   [I]
   and a second polypeptide chain comprises a structure represented by the formula:
   V H1 -L 3 -V H2 -L 4 -C H1 -hinge-C H2 -C H3   [II]
 
   and a third polypeptide chain comprises a structure represented by the formula:
   V H3 -C H1 -hinge-C H2 -C H3   [III]
 
   and a fourth polypeptide chain comprises a structure represented by the formula:
   V L3 -C L   [IV]
 
   wherein:
 V L1  is a first immunoglobulin light chain variable domain; 
 V L2  is a second immunoglobulin light chain variable domain; 
 V L3  is a third immunoglobulin light chain variable domain; 
 V H1  is a first immunoglobulin heavy chain variable domain; 
 V H2  is a second immunoglobulin heavy chain variable domain; 
 V H3  is a third immunoglobulin heavy chain variable domain; 
 C L  is an immunoglobulin light chain constant domain; 
 C H1  is an immunoglobulin C H1  heavy chain constant domain; 
 C H2  is an immunoglobulin C H2  heavy chain constant domain; 
 C H3  is an immunoglobulin C H3  heavy chain constant domain; 
 hinge is an immunoglobulin hinge region connecting the C H1  and C H2  domains; and 
 L 1 , L 2 , L 3  and L 4  are amino acid linkers; 
 wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair; and 
 wherein:
 (a) the hinge-C H2 -C H3  domains of the second and the third polypeptide chains are human IgG1 hinge-C H2 -C H3  domains, and wherein the hinge-C H2 -C H3  domains each comprise amino acid substitutions at positions corresponding to positions 298, 299, and 300 of human IgG1 according to EU Index, wherein the amino acid substitutions are S298N, T299A, and Y300S; or 
 (b) the hinge-C H2 -C H3  domains of the second and the third polypeptide chains are human IgG4 C H3  domains, and wherein the hinge-C H2 -C H3  domains each comprise amino acid substitutions at positions corresponding to positions 233-236 of human IgG4 according to EU Index, wherein the amino acid substitutions are E233P, F234V, L235A, and a deletion at 236. 
 
   
     
     
         75 . The binding protein of  claim 74 , wherein at least one pair of V H1  and V L1 , V H2  and V L2 , and V H3  and V L3  forms an antigen binding site that binds a CD38 polypeptide. 
     
     
         76 . The binding protein of  claim 74 , wherein one, two, or three pairs of V H1  and V L1 , V H2  and V L2 , and V H3  and V L3  form an antigen binding site that binds an antigen target selected from the group consisting of A2AR, APRIL, ATPDase, BAFF, BAFFR, BCMA, BlyS, BTK, BTLA, B7DC, B7H1, B7H4, B7H5, B7H6, B7H7, B7RP1, B7-4, C3, C5, CCL2, CCL3, CCL4, CCL5, CCL7, CCL8, CCL11, CCL15, CCL17, CCL19, CCL20, CCL21, CCL24, CCL25, CCL26, CCR3, CCR4, CD3, CD19, CD20, CD23, CD24, CD27, CD28, CD38, CD39, CD40, CD70, CD80, CD86, CD122, CD137, CD137L, CD152, CD154, CD160, CD272, CD273, CD274, CD275, CD276, CD278, CD279, CDH1, chitinase, CLEC9, CLEC91, CRTH2, CSF-1, CSF-2, CSF-3, CX3CL1, CXCL12, CXCL13, CXCR3, DNGR-1, ectonucleoside triphosphate diphosphohydrolase 1, EGFR, ENTPD1, FCER1A, FCER1, FLAP, FOLH1, Gi24, GITR, GITRL, GM-CSF, Her2, HHLA2, HMGB1, HVEM, ICOSLG, IDO, IFNα, IgE, IGF1R, IL2Rbeta, IL1, IL1A, IL1B, IL1F10, IL2, IL4, IL4Ra, IL5, IL5R, IL6, IL7, IL7Ra, IL8, IL9, IL9R, IL10, rhIL10, IL12, IL13, IL13Ra1, IL13Ra2, IL15, IL17, IL17Rb, IL18, IL22, IL23, IL25, IL27, IL33, IL35, ITGB4, ITK, KIR, LAG3, LAMP1, leptin, LPFS2, MHC class II, NCR3LG1, NKG2D, NTPDase-1, OX40, OX40L, PD-1H, platelet receptor, PROM1, S152, SISP1, SLC, SPG64, ST2, STEAP2, Syk kinase, TACI, TDO, T14, TIGIT, TIM3, TLR, TLR2, TLR4, TLR5, TLR9, TMEF1, TNFa, TNFRSF7, Tp55, TREM1, TSLP, TSLPR, TWEAK, VEGF, VISTA, Vstm3, WUCAM, and XCR1. 
     
     
         77 . The binding protein of  claim 74 , wherein a first pair of V H1  and V L1 , V H2  and V L2 , and V H3  and V L3  forms an antigen binding site that binds a human CD3 polypeptide, a second pair of V H1  and V L1 , V H2  and V L2 , and V H3  and V L3  forms an antigen binding site that binds a human CD28 polypeptide, and a third pair of V H1  and V L1 , V H2  and V L2 , and V H3  and V L3  forms an antigen binding site that binds a human antigen target selected from the group consisting of A2AR, APRIL, ATPDase, BAFF, BAFFR, BCMA, BlyS, BTK, BTLA, B7DC, B7H1, B7H4, B7H5, B7H6, B7H7, B7RP1, B7-4, C3, C5, CCL2, CCL3, CCL4, CCL5, CCL7, CCL8, CCL11, CCL15, CCL17, CCL19, CCL20, CCL21, CCL24, CCL25, CCL26, CCR3, CCR4, CD3, CD19, CD20, CD23, CD24, CD27, CD28, CD38, CD39, CD40, CD70, CD80, CD86, CD122, CD137, CD137L, CD152, CD154, CD160, CD272, CD273, CD274, CD275, CD276, CD278, CD279, CDH1, chitinase, CLEC9, CLEC91, CRTH2, CSF-1, CSF-2, CSF-3, CX3CL1, CXCL12, CXCL13, CXCR3, DNGR-1, ectonucleoside triphosphate diphosphohydrolase 1, EGFR, ENTPD1, FCER1A, FCER1, FLAP, FOLH1, Gi24, GITR, GITRL, GM-CSF, Her2, HHLA2, HMGB1, HVEM, ICOSLG, IDO, IFNα, IgE, IGF1R, IL2Rbeta, IL1, IL1A, IL1B, IL1F10, IL2, IL4, IL4Ra, IL5, IL5R, IL6, IL7, IL7Ra, IL8, IL9, IL9R, IL10, rhIL10, IL12, IL13, IL13Ra1, IL13Ra2, IL15, IL17, IL17Rb, IL18, IL22, IL23, IL25, IL27, IL33, IL35, ITGB4, ITK, KIR, LAG3, LAMP1, leptin, LPFS2, MHC class II, NCR3LG1, NKG2D, NTPDase-1, OX40, OX40L, PD-1H, platelet receptor, PROM1, S152, SISP1, SLC, SPG64, ST2, STEAP2, Syk kinase, TACI, TDO, T14, TIGIT, TIM3, TLR, TLR2, TLR4, TLR5, TLR9, TMEF1, TNFa, TNFRSF7, Tp55, TREM1, TSLP, TSLPR, TWEAK, VEGF, VISTA, Vstm3, WUCAM, and XCR1. 
     
     
         78 . A kit of polynucleotides, comprising:
 (a) a first polynucleotide comprising the sequence of SEQ ID NO:73, a second polynucleotide comprising the sequence of SEQ ID NO:72, a third polynucleotide comprising the sequence of SEQ ID NO:74, and a fourth polynucleotide comprising the sequence of SEQ ID NO:75;   (b) a first polynucleotide comprising the sequence of SEQ ID NO:73, a second polynucleotide comprising the sequence of SEQ ID NO:76, a third polynucleotide comprising the sequence of SEQ ID NO:77, and a fourth polynucleotide comprising the sequence of SEQ ID NO:75;   (c) a first polynucleotide comprising the sequence of SEQ ID NO:73, a second polynucleotide comprising the sequence of SEQ ID NO:78, a third polynucleotide comprising the sequence of SEQ ID NO:79, and a fourth polynucleotide comprising the sequence of SEQ ID NO:75;   (d) a first polynucleotide comprising the sequence of SEQ ID NO:73, a second polynucleotide comprising the sequence of SEQ ID NO:72, a third polynucleotide comprising the sequence of SEQ ID NO:80, and a fourth polynucleotide comprising the sequence of SEQ ID NO:81;   (e) a first polynucleotide comprising the sequence of SEQ ID NO:73, a second polynucleotide comprising the sequence of SEQ ID NO:76, a third polynucleotide comprising the sequence of SEQ ID NO:82, and a fourth polynucleotide comprising the sequence of SEQ ID NO:81; or   (f) a first polynucleotide comprising the sequence of SEQ ID NO:73, a second polynucleotide comprising the sequence of SEQ ID NO:78, a third polynucleotide comprising the sequence of SEQ ID NO:83, and a fourth polynucleotide comprising the sequence of SEQ ID NO:81.   
     
     
         79 . A polynucleotide encoding the binding protein of any one of  claims 1 - 77 . 
     
     
         80 . A vector comprising the polynucleotide of  claim 79 . 
     
     
         81 . A host cell comprising the kit of polynucleotides of  claim 78 , the polynucleotide of  claim 79 , or the vector of  claim 80 . 
     
     
         82 . A method of producing a binding protein, the method comprising culturing the host cell of  claim 81  such that the binding protein is produced. 
     
     
         83 . The method of  claim 82 , further comprising recovering the binding protein from the host cell. 
     
     
         84 . A pharmaceutical composition comprising the binding protein of any one of  claims 1 - 77  and a pharmaceutically acceptable carrier. 
     
     
         85 . A method of preventing and/or treating cancer in a patient comprising administering to the patient a therapeutically effective amount of at least one binding protein of any one of  claims 1 - 73  or the pharmaceutical composition of  claim 84 . 
     
     
         86 . The method of  claim 85 , wherein the binding protein comprises one antigen binding site that binds a T-cell surface protein and another antigen binding site that binds the extracellular domain of a human CD38 polypeptide. 
     
     
         87 . The method of  claim 86 , wherein the binding protein is a trispecific binding protein comprising a first antigen binding site that binds CD3, a second antigen binding site that binds CD28, and a third antigen binding site that binds the extracellular domain of a human CD38 polypeptide. 
     
     
         88 . The method of any one of  claims 85 - 87 , wherein the at least one binding protein is co-administered with a chemotherapeutic agent. 
     
     
         89 . The method of any one of  claims 85 - 88 , wherein the cancer is multiple myeloma. 
     
     
         90 . The method of any one of  claims 85 - 88 , wherein the cancer is acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), or a B cell lymphoma. 
     
     
         91 . The method of any one of  claims 85 - 90 , wherein the patient is a human. 
     
     
         92 . The method of any one of  claims 85 - 91 , wherein the patient is selected for treatment because cells of the cancer express a human CD38 isoform E polypeptide on their cell surface.