Antibody constructs for flt3 and cd3

Abstract

The present invention relates to a bispecific antibody construct comprising a first binding domain which binds to human FLT3 on the surface of a target cell and a second binding domain which binds to human CD3 on the surface of a T cell. Moreover, the invention provides a polynucleotide encoding the antibody construct, a vector comprising said polynucleotide and a host cell transformed or transfected with said polynucleotide or vector. Furthermore, the invention provides a process for the production of the antibody construct of the invention, a medical use of said antibody construct and a kit comprising said antibody construct.

1 - 21 . (canceled) 
     
     
         22 . A method for treating or ameliorating a cancer in a subject comprising administering to the subject an effective amount of a bispecific antibody construct comprising a first binding domain which binds to human and macaque Fms-like tyrosine kinase 3 (FLT3) on the surface of a target cell and a second binding domain which binds to human CD3 on the surface of a T cell, wherein the first binding domain comprises a VH region comprising CDR-H1, CDR-H2 and CDR-H3 and a VL region comprising CDR-L1, CDR-L2 and CDR-L3, wherein said CDR-HI, CDR-H2, CDR-H3, CDR-LI, CDR-L2, and CDR-L3 comprise the amino acid sequences selected from the group consisting of:
 SEQ ID NOs: 181-186, SEQ ID NOs: 201-206, SEQ ID NOs: 211-216, SEQ ID NOs: 221-226, SEQ ID NOs: 251-256, SEQ ID NOs: 261-266, SEQ ID NOs: 281-286, SEQ ID NOs: 291-296, SEQ ID NOs: 301-306, SEQ ID NOs: 311-316, SEQ ID NOs: 331-336, SEQ ID NOs: 341-346, SEQ ID NOs: 431-436, SEQ ID NOs: 451-456, SEQ ID NOs: 461-466, SEQ ID NOs: 471-476, SEQ ID NOs: 491-496, SEQ ID NOs: 531-536, SEQ ID NOs: 541-546, SEQ ID NOs: 561-566, SEQ ID NOs: 591-596, SEQ ID NOs: 611-616, SEQ ID NOs: 631-636, and SEQ ID NOs: 701-706.   
     
     
         23 . The method of  claim 22 , wherein the antibody construct is in a format selected from the group consisting of: (scFv) 2 , scFv-single domain mAb, diabodies and oligomers of those formats. 
     
     
         24 . The method of  claim 22 , wherein the first binding domain comprises a VH region comprising the amino acid sequence selected from the group consisting of: SEQ ID NO: 187, SEQ ID NO: 207, SEQ ID NO: 217, SEQ ID NO: 227, SEQ ID NO: 257, SEQ ID NO: 267, SEQ ID NO: 277, SEQ ID NO: 287, SEQ ID NO: 297, SEQ ID NO: 307, SEQ ID NO: 317, SEQ ID NO: 337, SEQ ID NO: 347, SEQ ID NO: 437, SEQ ID NO: 457, SEQ ID NO: 467, SEQ ID NO: 477, SEQ ID NO: 497, SEQ ID NO: 537, SEQ ID NO: 547, SEQ ID NO: 567, SEQ ID NO: 597, SEQ ID NO: 617, SEQ ID NO: 637, and SEQ ID NO: 707. 
     
     
         25 . The method of  claim 22 , wherein the first binding domain comprises a VL region comprising the amino acid sequence selected from the group consisting of: SEQ ID NO: 188, SEQ ID NO: 208, SEQ ID NO: 218, SEQ ID NO: 228, SEQ ID NO: 258, SEQ ID NO: 268, SEQ ID NO: 278, SEQ ID NO: 288, SEQ ID NO: 298, SEQ ID NO: 308, SEQ ID NO: 318, SEQ ID NO: 338, SEQ ID NO: 348, SEQ ID NO: 438, SEQ ID NO: 458, SEQ ID NO: 468, SEQ ID NO: 478, SEQ ID NO: 498, SEQ ID NO: 538, SEQ ID NO: 548, SEQ ID NO: 568, SEQ ID NO: 598, SEQ ID NO: 618, SEQ ID NO: 638, and SEQ ID NO: 708. 
     
     
         26 . The method of  claim 22 , wherein the first binding domain comprises a VH region and a VL region comprising the pair of amino acid sequences, respectively, selected from the group consisting of: SEQ ID NOs: 187 and 188, SEQ ID NOs: 207 and 208, SEQ ID NOs: 217 and 218, SEQ ID NOs: 227 and 228, SEQ ID NOs: 257 and 258, SEQ ID NOs: 267 and 268, SEQ ID NOs: 277 and 278, SEQ ID NOs: 287 and 288, SEQ ID NOs: 297 and 298, SEQ ID NOs: 307 and 308, SEQ ID NOs: 317 and 318, SEQ ID NOs: 337 and 338, SEQ ID NOs: 347 and 348, SEQ ID NOs: 437 and 438, SEQ ID NOs: 457 and 458, SEQ ID NOs: 467 and 468, SEQ ID NOs: 477 and 478, SEQ ID NOs: 497 and 498, SEQ ID NOs: 537 and 538, SEQ ID NOs: 547 and 548, SEQ ID NOs: 567 and 568, SEQ ID NOs: 597 and 598, SEQ ID NOs: 617 and 618, SEQ ID NOs: 637 and 638, and SEQ ID NOs: 707 and 708. 
     
     
         27 . The method of  claim 22 , wherein the first binding domain comprises the amino acid sequence selected from the group consisting of: SEQ ID NO: 189, SEQ ID NO: 209, SEQ ID NO: 219, SEQ ID NO: 229, SEQ ID NO: 259, SEQ ID NO: 269, SEQ ID NO: 279, SEQ ID NO: 289, SEQ ID NO: 299, SEQ ID NO: 309, SEQ ID NO: 319, SEQ ID NO: 339, SEQ ID NO: 349, SEQ ID NO: 439, SEQ ID NO: 459, SEQ ID NO: 469, SEQ ID NO: 479, SEQ ID NO: 499, SEQ ID NO: 539, SEQ ID NO: 549, SEQ ID NO: 569, SEQ ID NO: 599, SEQ ID NO: 619, SEQ ID NO: 639, and SEQ ID NO: 709. 
     
     
         28 . The method of  claim 22 , wherein the second binding domain binds to human CD3 epsilon and to  Callithrix jacchus, Saguinus oedipus  or  Saimiri sciureus  CD3 epsilon. 
     
     
         29 . The method of  claim 22 , wherein the second binding domain comprises a VL region comprising CDR-H1, CDR-H2 and CDR-H3 and a VH region comprising CDR-L1, CDR-L2 and CDR-L3 selected from the group consisting of:
 a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 11, CDR-L2 comprising the amino acid sequence of SEQ ID NO: 12, CDR-L3 comprising the amino acid sequence of SEQ ID NO: 13; CDR-H1 comprising the amino acid sequence of SEQ ID NO:   14, CDR-H2 comprising the amino acid sequence of SEQ ID NO: 15, and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 16;   b) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 20, CDR-L2 comprising the amino acid sequence of SEQ ID NO: 21, CDR-L3 comprising the amino acid sequence of SEQ ID NO: 22; CDR-H1 comprising the amino acid sequence of SEQ ID NO: 23, CDR-H2 comprising the amino acid sequence of SEQ ID NO: 24, and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 25;   c) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 29, CDR-L2 comprising the amino acid sequence of SEQ ID NO: 30, CDR-L3 comprising the amino acid sequence of SEQ ID NO: 31; CDR-H1 comprising the amino acid sequence of SEQ ID NO: 32, CDR-H2 comprising the amino acid sequence of SEQ ID NO: 33, and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 34;   d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 38, CDR-L2 comprising the amino acid sequence of SEQ ID NO: 39, CDR-L3 comprising the amino acid sequence of SEQ ID NO: 40; CDR-H1 comprising the amino acid sequence of SEQ ID NO: 41, CDR-H2 comprising the amino acid sequence of SEQ ID NO: 42, and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 43;   e) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 47, CDR-L2 comprising the amino acid sequence of SEQ ID NO: 48, CDR-L3 comprising the amino acid sequence of SEQ ID NO: 49; CDR-H1 comprising the amino acid sequence of SEQ ID NO: 50, CDR-H2 comprising the amino acid sequence of SEQ ID NO: 51, and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 52;   f) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 56, CDR-L2 comprising the amino acid sequence of SEQ ID NO: 57, CDR-L3 comprising the amino acid sequence of SEQ ID NO: 58; CDR-H1 comprising the amino acid sequence of SEQ ID NO: 59, CDR-H2 comprising the amino acid sequence of SEQ ID NO: 60, and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 61;   g) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 65, CDR-L2 comprising the amino acid sequence of SEQ ID NO: 66, CDR-L3 comprising the amino acid sequence of SEQ ID NO: 67; CDR-H1 comprising the amino acid sequence of SEQ ID NO: 68, CDR-H2 comprising the amino acid sequence of SEQ ID NO: 69, and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 70;   h) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 74, CDR-L2 comprising the amino acid sequence of SEQ ID NO: 75, CDR-L3 comprising the amino acid sequence of SEQ ID NO: 76; CDR-H1 comprising the amino acid sequence of SEQ ID NO: 77, CDR-H2 comprising the amino acid sequence of SEQ ID NO: 78, and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 79; and   i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 83, CDR-L2 comprising the amino acid sequence of SEQ ID NO: 84, CDR-L3 comprising the amino acid sequence of SEQ ID NO: 85; CDR-H1 comprising the amino acid sequence of SEQ ID NO: 86, CDR-H2 comprising the amino acid sequence of SEQ ID NO: 87, and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 88; and   j) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 92, CDR-L2 comprising the amino acid sequence of SEQ ID NO: 93, CDR-L3 comprising the amino acid sequence of SEQ ID NO: 94; CDR-H1 comprising the amino acid sequence of SEQ ID NO: 95, CDR-H2 comprising the amino acid sequence of SEQ ID NO: 96, and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 97.   
     
     
         30 . The method of  claim 22 , wherein the second binding domain comprises a VH region comprising the amino acid sequence selected from the group consisting of: SEQ ID NO: 17, SEQ ID NO: 26, SEQ ID NO: 35, SEQ ID NO: 44, SEQ ID NO: 53, SEQ ID NO: 62, SEQ ID NO: 71, SEQ ID NO: 80, SEQ ID NO: 89, and SEQ ID NO: 98. 
     
     
         31 . The method of  claim 22 , wherein the second binding domain comprises a VL region comprising the amino acid sequence selected from the group consisting of: SEQ ID NO: 18, SEQ ID NO: 27, SEQ ID NO: 36, SEQ ID NO: 45, SEQ ID NO: 54, SEQ ID NO: 63, SEQ ID NO: 72, SEQ ID NO: 81, SEQ ID NO: 90, and SEQ ID NO: 99. 
     
     
         32 . The method of  claim 22 , wherein the second binding domain comprises a VH region and a VL region comprising the pair of amino acid sequences, respectively, selected from the group consisting of: SEQ ID NOs: 17 and 18; SEQ ID NOs: 26 and 27; SEQ ID NOs: 35 and 36; SEQ ID NOs: 44 and 45; SEQ ID NOs: 53 and 54; SEQ ID NOs: 62 and 63; SEQ ID NOs: 71 and 72; SEQ ID NOs: 80 and 81; SEQ ID NOs: 89 and 90; and SEQ ID NOs: 98 and 99. 
     
     
         33 . The method of  claim 22 , wherein the second binding domain comprises an amino acid sequence selected from the group consisting of: SEQ ID NO: 19, SEQ ID NO: 28, SEQ ID NO: 37, SEQ ID NO: 46, SEQ ID NO: 55, SEQ ID NO: 64, SEQ ID NO: 73, SEQ ID NO: 82, SEQ ID NO: 91, and SEQ ID NO: 100. 
     
     
         34 . The method of  claim 22 , wherein the antibody construct comprises:
 (a) an amino acid sequence comprising at least 80% identity to the amino acid sequence set forth in SEQ ID NO: 862; or   (b) the amino acid sequence set forth in SEQ ID NO: 862.   
     
     
         35 . The method of  claim 22 , wherein the antibody construct comprises:
 (a) a polypeptide comprising in the following order starting from the N-terminus:
 a polypeptide comprising the amino acid sequence selected from the group consisting of: SEQ ID NO: 189, SEQ ID NO: 209, SEQ ID NO: 219, SEQ ID NO: 229, SEQ ID NO: 259, SEQ ID NO: 269, SEQ ID NO: 279, SEQ ID NO: 289, SEQ ID NO: 299, SEQ ID NO: 309, SEQ ID NO: 319, SEQ ID NO: 339, SEQ ID NO: 349, SEQ ID NO: 439, SEQ ID NO: 459, SEQ ID NO: 469, SEQ ID NO: 479, SEQ ID NO: 499, SEQ ID NO: 539, SEQ ID NO: 549, SEQ ID NO: 569, SEQ ID NO: 599, SEQ ID NO: 619, SEQ ID NO: 639, and SEQ ID NO: 709; 
 a peptide linker comprising the amino acid sequence selected from any one of SEQ ID NOs: 1-9; and 
 a polypeptide comprising the amino acid sequence selected from the group consisting of: SEQ ID NO: 19, SEQ ID NO: 28, SEQ ID NO: 37, SEQ ID NO: 46, SEQ ID NO: 55, SEQ ID NO: 64, SEQ ID NO: 73, SEQ ID NO: 82, SEQ ID NO: 91, SEQ ID NO: 100, and SEQ ID NO: 103; and 
 optionally a His-tag comprising the amino acid sequence of SEQ ID NO: 10; 
   (b) a polypeptide comprising in following order starting from the N-terminus:
 a polypeptide comprising the amino acid sequence selected from the group consisting of: SEQ ID NO: 189, SEQ ID NO: 209, SEQ ID NO: 219, SEQ ID NO: 229, SEQ ID NO: 259, SEQ ID NO: 269, SEQ ID NO: 279, SEQ ID NO: 289, SEQ ID NO: 299, SEQ ID NO: 309, SEQ ID NO: 319, SEQ ID NO: 339, SEQ ID NO: 349, SEQ ID NO: 439, SEQ ID NO: 459, SEQ ID NO: 469, SEQ ID NO: 479, SEQ ID NO: 499, SEQ ID NO: 539, SEQ ID NO: 549, SEQ ID NO: 569, SEQ ID NO: 599, SEQ ID NO: 619, SEQ ID NO: 639, and SEQ ID NO: 709; 
 a peptide linker comprising the amino acid sequence selected from any one of SEQ ID NOs: 1-9; 
 a polypeptide comprising the amino acid sequence selected from the group consisting of: SEQ ID NO: 19, SEQ ID NO: 28, SEQ ID NO: 37, SEQ ID NO: 46, SEQ ID NO: 55, SEQ ID NO: 64, SEQ ID NO: 73, SEQ ID NO: 82, SEQ ID NO: 91, SEQ ID NO: 100, and SEQ ID NO: 103; 
 optionally peptide linker comprising the amino acid sequence selected from any one of SEQ ID NOs: 1-9; 
 a polypeptide comprising the amino acid sequence selected from the group consisting of: SEQ ID NOs: 104-134; and 
 optionally a His-tag comprising the amino acid sequence of SEQ ID NO: 10; 
   (c) a polypeptide comprising in the following order starting from the N-terminus:
 a polypeptide comprising the amino acid sequence QRFVTGHFGGLX 1 PANG (SEQ ID NO: 135), wherein X 1  is Y or H; 
 a polypeptide having an amino acid sequence selected from the group consisting of: SEQ ID NO: 189, SEQ ID NO: 209, SEQ ID NO: 219, SEQ ID NO: 229, SEQ ID NO: 259, SEQ ID NO: 269, SEQ ID NO: 279, SEQ ID NO: 289, SEQ ID NO: 299, SEQ ID NO: 309, SEQ ID NO: 319, SEQ ID NO: 339, SEQ ID NO: 349, SEQ ID NO: 439, SEQ ID NO: 459, SEQ ID NO: 469, SEQ ID NO: 479, SEQ ID NO: 499, SEQ ID NO: 539, SEQ ID NO: 549, SEQ ID NO: 569, SEQ ID NO: 599, SEQ ID NO: 619, SEQ ID NO: 639, and SEQ ID NO: 709; 
 a peptide linker having an amino acid sequence selected from the group consisting of: SEQ ID NOs: 1-9; 
 a polypeptide having an amino acid sequence selected from the group consisting of: SEQ ID NO: 19, SEQ ID NO: 28, SEQ ID NO: 37, SEQ ID NO: 46, SEQ ID NO: 55, SEQ ID NO: 64, SEQ ID NO: 73, SEQ ID NO: 82, SEQ ID NO: 91, SEQ ID NO: 100, and SEQ ID NO: 103; 
 a polypeptide having the amino acid sequence QRFVTGHFGGLHPANG (SEQ ID NO: 137) or QRFCTGHFGGLHPCNG (SEQ ID NO: 139); and 
 optionally a His-tag comprising the amino acid sequence of SEQ ID NO: 10; 
   (d) a polypeptide comprising in the following order starting from the N-terminus:
 a polypeptide having an amino acid sequence selected from the group consisting of: SEQ ID NO: 17, SEQ ID NO: 26, SEQ ID NO: 35, SEQ ID NO: 44, SEQ ID NO: 53, SEQ ID NO: 62, SEQ ID NO: 71, SEQ ID NO: 80, SEQ ID NO: 89, SEQ ID NO: 98, and SEQ ID NO: 101; 
 a peptide linker comprising the amino acid sequence of SEQ ID NO: 8; 
 a polypeptide comprising the amino acid sequence selected from the group consisting of: SEQ ID NO: 188, SEQ ID NO: 208, SEQ ID NO: 218, SEQ ID NO: 228, SEQ ID NO: 258, SEQ ID NO: 268, SEQ ID NO: 278, SEQ ID NO: 288, SEQ ID NO: 298, SEQ ID NO: 308, SEQ ID NO: 318, SEQ ID NO: 338, SEQ ID NO: 348, SEQ ID NO: 438, SEQ ID NO: 458, SEQ ID NO: 468, SEQ ID NO: 478, SEQ ID NO: 498, SEQ ID NO: 538, SEQ ID NO: 548, SEQ ID NO: 568, SEQ ID NO: 598, SEQ ID NO: 618, SEQ ID NO: 638, and SEQ ID NO: 708, and a serine residue at the C-terminus; 
 a polypeptide comprising the amino acid sequence of SEQ ID NO: 140; and 
 a polypeptide comprising in the following order starting from the N-terminus: 
 a polypeptide comprising the amino acid sequence selected from the group consisting of: SEQ ID NO: 187, SEQ ID NO: 207, SEQ ID NO: 217, SEQ ID NO: 227, SEQ ID NO: 257, SEQ ID NO: 267, SEQ ID NO: 277, SEQ ID NO: 287, SEQ ID NO: 297, SEQ ID NO: 307, SEQ ID NO: 317, SEQ ID NO: 337, SEQ ID NO: 347, SEQ ID NO: 437, SEQ ID NO: 457, SEQ ID NO: 467, SEQ ID NO: 477, SEQ ID NO: 497, SEQ ID NO: 537, SEQ ID NO: 547, SEQ ID NO: 567, SEQ ID NO: 597, SEQ ID NO: 617, SEQ ID NO: 637, and SEQ ID NO: 707; 
 a peptide linker comprising the amino acid sequence of SEQ ID NO: 8; 
 a polypeptide comprising the amino acid sequence selected from the group consisting of: SEQ ID NO: 18, SEQ ID NO: 27, SEQ ID NO: 36, SEQ ID NO: 45, SEQ ID NO: 54, SEQ ID NO: 63, SEQ ID NO: 72, SEQ ID NO: 81, SEQ ID NO: 90, SEQ ID NO: 99, and SEQ ID NO: 102 and a serine residue at the C-terminus; and 
 a polypeptide comprising the amino acid sequence of SEQ ID NO: 141; 
   (e) a polypeptide comprising in the following order starting from the N-terminus:
 a polypeptide comprising the amino acid sequence selected from the group consisting of: SEQ ID NO: 17, SEQ ID NO: 26, SEQ ID NO: 35, SEQ ID NO: 44, SEQ ID NO: 53, SEQ ID NO: 62, SEQ ID NO: 71, SEQ ID NO: 80, SEQ ID NO: 89, SEQ ID NO: 98, and SEQ ID NO: 101; 
 a peptide linker comprising the amino acid sequence of SEQ ID NO: 8; 
 a polypeptide comprising the amino acid sequence selected from the group consisting of: SEQ ID NO: 188, SEQ ID NO: 208, SEQ ID NO: 218, SEQ ID NO: 228, SEQ ID NO: 258, SEQ ID NO: 268, SEQ ID NO: 278, SEQ ID NO: 288, SEQ ID NO: 298, SEQ ID NO: 308, SEQ ID NO: 318, SEQ ID NO: 338, SEQ ID NO: 348, SEQ ID NO: 438, SEQ ID NO: 458, SEQ ID NO: 468, SEQ ID NO: 478, SEQ ID NO: 498, SEQ ID NO: 538, SEQ ID NO: 548, SEQ ID NO: 568, SEQ ID NO: 598, SEQ ID NO: 618, SEQ ID NO: 638, and SEQ ID NO: 708; 
 a polypeptide comprising the amino acid sequence of SEQ ID NO: 142; and 
 a polypeptide comprising in the following order starting from the N-terminus: 
 a polypeptide comprising the amino acid sequence selected from the group consisting of: SEQ ID NO: 187, SEQ ID NO: 207, SEQ ID NO: 217, SEQ ID NO: 227, SEQ ID NO: 257, SEQ ID NO: 267, SEQ ID NO: 277, SEQ ID NO: 287, SEQ ID NO: 297, SEQ ID NO: 307, SEQ ID NO: 317, SEQ ID NO: 337, SEQ ID NO: 347, SEQ ID NO: 437, SEQ ID NO: 457, SEQ ID NO: 467, SEQ ID NO: 477, SEQ ID NO: 497, SEQ ID NO: 537, SEQ ID NO: 547, SEQ ID NO: 5671 SEQ ID NO: 617, SEQ ID NO: 637, and SEQ ID NO: 707; 
 a peptide linker comprising the amino acid sequence of SEQ ID NO: 8; 
 a polypeptide comprising the amino acid sequence selected from the group consisting of: SEQ ID NO: 18, SEQ ID NO: 27, SEQ ID NO: 36, SEQ ID NO: 45, SEQ ID NO: 54, SEQ ID NO: 63, SEQ ID NO: 72, SEQ ID NO: 81, SEQ ID NO: 90, SEQ ID NO: 99, and SEQ ID NO: 102, and a serine residue at the C-terminus; and 
 a polypeptide comprising the amino acid sequence of SEQ ID NO: 143; 
   (f) a polypeptide comprising in the following order starting from the N-terminus:
 a polypeptide comprising the amino acid sequence selected from the group consisting of: SEQ ID NO: 189, SEQ ID NO: 209, SEQ ID NO: 219, SEQ ID NO: 229, SEQ ID NO: 259, SEQ ID NO: 269, SEQ ID NO: 279, SEQ ID NO: 289, SEQ ID NO: 299, SEQ ID NO: 309, SEQ ID NO: 319, SEQ ID NO: 339, SEQ ID NO: 349, SEQ ID NO: 439, SEQ ID NO: 459, SEQ ID NO: 469, SEQ ID NO: 479, SEQ ID NO: 499, SEQ ID NO: 539, SEQ ID NO: 549, SEQ ID NO: 569, SEQ ID NO: 599, SEQ ID NO: 619, SEQ ID NO: 639, and SEQ ID NO: 709; 
 a peptide linker comprising the amino acid sequence selected from any one of SEQ ID NOs: 1-9; 
 a polypeptide comprising the amino acid sequence selected from the group consisting of: SEQ ID NO: 19, SEQ ID NO: 28, SEQ ID NO: 37, SEQ ID NO: 46, SEQ ID NO: 55, SEQ ID NO: 64, SEQ ID NO: 73, SEQ ID NO: 82, SEQ ID NO: 91, SEQ ID NO: 100, and SEQ ID NO: 103; 
 a polypeptide comprising the amino acid sequence of SEQ ID NO: 144; and 
 a polypeptide comprising the amino acid sequence of SEQ ID NO: 145; 
   (g) a polypeptide comprising in the following order starting from the N-terminus:
 a polypeptide comprising the amino acid sequence selected from the group consisting of: SEQ ID NO: 189, SEQ ID NO: 209, SEQ ID NO: 219, SEQ ID NO: 229, SEQ ID NO: 259, SEQ ID NO: 269, SEQ ID NO: 279, SEQ ID NO: 289, SEQ ID NO: 299, SEQ ID NO: 309, SEQ ID NO: 319, SEQ ID NO: 339, SEQ ID NO: 349, SEQ ID NO: 439, SEQ ID NO: 459, SEQ ID NO: 469, SEQ ID NO: 479, SEQ ID NO: 499, SEQ ID NO: 539, SEQ ID NO: 549, SEQ ID NO: 569, SEQ ID NO: 599, SEQ ID NO: 619, SEQ ID NO: 639, and SEQ ID NO: 709; and 
 a polypeptide comprising the amino acid sequence of SEQ ID NO: 146; and 
 a polypeptide comprising in the following order starting from the N-terminus: 
 a polypeptide comprising the amino acid sequence selected from the group consisting of: SEQ ID NO: 19, SEQ ID NO: 28, SEQ ID NO: 37, SEQ ID NO: 46, SEQ ID NO: 55, SEQ ID NO: 64, SEQ ID NO: 73, SEQ ID NO: 82, SEQ ID NO: 91, SEQ ID NO: 100, and SEQ ID NO: 103; and 
 a polypeptide comprising the amino acid sequence of SEQ ID NO: 147; 
   (h) a polypeptide comprising in the following order starting from the N-terminus:
 a polypeptide comprising the amino acid sequence selected from the group consisting of: SEQ ID NO: 189, SEQ ID NO: 209, SEQ ID NO: 219, SEQ ID NO: 229, SEQ ID NO: 259, SEQ ID NO: 269, SEQ ID NO: 279, SEQ ID NO: 289, SEQ ID NO: 299, SEQ ID NO: 309, SEQ ID NO: 319, SEQ ID NO: 339, SEQ ID NO: 349, SEQ ID NO: 439, SEQ ID NO: 459, SEQ ID NO: 469, SEQ ID NO: 479, SEQ ID NO: 499, SEQ ID NO: 539, SEQ ID NO: 549, SEQ ID NO: 569, SEQ ID NO: 599, SEQ ID NO: 619, SEQ ID NO: 639, and SEQ ID NO: 709; and 
 a polypeptide comprising the amino acid sequence of SEQ ID NO: 148; and 
 a polypeptide comprising in the following order starting from the N-terminus: 
 a polypeptide comprising the amino acid sequence selected from the group consisting of: SEQ ID NO: 19, SEQ ID NO: 28, SEQ ID NO: 37, SEQ ID NO: 46, SEQ ID NO: 55, SEQ ID NO: 64, SEQ ID NO: 73, SEQ ID NO: 82, SEQ ID NO: 91, SEQ ID NO: 100, and SEQ ID NO: 103; and 
 a polypeptide comprising the amino acid sequence of SEQ ID NO: 149; 
   (i) a polypeptide comprising in the following order starting from the N-terminus:
 a polypeptide comprising the amino acid sequence selected from the group consisting of: SEQ ID NO: 189, SEQ ID NO: 209, SEQ ID NO: 219, SEQ ID NO: 229, SEQ ID NO: 259, SEQ ID NO: 269, SEQ ID NO: 279, SEQ ID NO: 289, SEQ ID NO: 299, SEQ ID NO: 309, SEQ ID NO: 319, SEQ ID NO: 339, SEQ ID NO: 349, SEQ ID NO: 439, SEQ ID NO: 459, SEQ ID NO: 469, SEQ ID NO: 479, SEQ ID NO: 499, SEQ ID NO: 539, SEQ ID NO: 549, SEQ ID NO: 569, SEQ ID NO: 599, SEQ ID NO: 619, SEQ ID NO: 639, and SEQ ID NO: 709; 
 a peptide linker comprising the amino acid sequence selected from any one of SEQ ID NOs: 1-9; 
 a polypeptide comprising the amino acid sequence selected from the group consisting of: SEQ ID NO: 19, SEQ ID NO: 28, SEQ ID NO: 37, SEQ ID NO: 46, SEQ ID NO: 55, SEQ ID NO: 64, SEQ ID NO: 73, SEQ ID NO: 82, SEQ ID NO: 91, SEQ ID NO: 100, and SEQ ID NO: 103; and 
 a polypeptide comprising the amino acid sequence of SEQ ID NO: 150; or 
   (j) a polypeptide comprising in the following order starting from the N-terminus:
 a polypeptide comprising the amino acid sequence selected from the group consisting of: SEQ ID NO: 189, SEQ ID NO: 209, SEQ ID NO: 219, SEQ ID NO: 229, SEQ ID NO: 259, SEQ ID NO: 269, SEQ ID NO: 279, SEQ ID NO: 289, SEQ ID NO: 299, SEQ ID NO: 309, SEQ ID NO: 319, SEQ ID NO: 339, SEQ ID NO: 349, SEQ ID NO: 439, SEQ ID NO: 459, SEQ ID NO: 469, SEQ ID NO: 479, SEQ ID NO: 499, SEQ ID NO: 539, SEQ ID NO: 549, SEQ ID NO: 569, SEQ ID NO: 599, SEQ ID NO: 619, SEQ ID NO: 639, and SEQ ID NO: 709; 
 a peptide linker comprising the amino acid sequence selected from any one of SEQ ID NOs: 1-9; 
 a polypeptide comprising the amino acid sequence selected from the group consisting of: SEQ ID NO: 19, SEQ ID NO: 28, SEQ ID NO: 37, SEQ ID NO: 46, SEQ ID NO: 55, SEQ ID NO: 64, SEQ ID NO: 73, SEQ ID NO: 82, SEQ ID NO: 91, SEQ ID NO: 100, and SEQ ID NO: 103; 
 a peptide linker having an amino acid sequence selected from the group consisting of: SEQ ID NOs: 1-9; and 
 the third domain comprising the amino acid sequence selected from any one of SEQ ID NOs: 843-850. 
   
     
     
         36 . The method of  claim 22 , wherein the antibody construct comprises the amino acid sequence of any one of SEQ ID NOs: 856, 857, and 862-865. 
     
     
         37 . The method of  claim 22 , wherein binding of the first binding domain to human FLT3 is reduced by FLT3-ligand by ≤2%. 
     
     
         38 . The method of  claim 22 , wherein the cancer is a hematological cancer. 
     
     
         39 . The method of  claim 23 , wherein the hematological cancer is acute myeloid leukemia. 
     
     
         40 . The method of  claim 22 , wherein the cancer is breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, head and neck cancer, mesothelioma, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, renal cancer or stomach cancer. 
     
     
         41 . The method of  claim 22 , wherein the cancer is a metastatic cancer.