Anti-phosphorylcholine antibodies and methods of use thereof

Abstract

The present disclosure provides polypeptides that specifically bind to phosphorylcholine (PC). Also provided are pharmaceutical compositions comprising the polypeptides, nucleic acids encoding the polypeptides, expression vectors and host cells for making the polypeptides, and methods of using the polypeptides to treat subjects.

Description

[0001] This application claims priority to U.S. Provisional Patent Application Serial No. 63 / 452,798, filed March 17, 2023, the entire disclosure of which is hereby incorporated by reference.

[0002] This application contains a sequence list electronically submitted in ST.26 format, the entire contents of which are hereby incorporated by reference. The ST.26 copy created on March 15, 2024, is named “208485_seqlist.xml” and is 644,762 bytes in size. Technical Field

[0003] This disclosure relates to antibodies specific to phosphoric acid choline (PC) and methods of using them. Background Technology

[0004] Phospholipids containing polyunsaturated fatty acids are highly susceptible to modification by reactive oxygen species (ROS) and non-free radical oxidants. Oxidized lipids in cell membranes and circulation can have both beneficial and harmful effects on the human body. Endogenous oxidized phospholipids (OxPL) have been shown to act as stress signals, prompting phagocytes (such as macrophages) to respond by triggering inflammatory programs and eliminating stressors. However, excessive oxidized phospholipid products are associated with the pathogenesis of chronic inflammation and various cardiopulmonary diseases, such as atherosclerosis and thrombosis, acute lung injury, and neurodegenerative processes.

[0005] Oxidized low-density lipoprotein (OxLDL) contains many types of OxPL and is found in atherosclerotic lesions, and is detected in high concentrations in the serum of patients with hyperlipidemia, diabetes, and liver disease. The phosphocholine (PC) head group of OxPL has been shown to be important for the binding of phospholipids to integrated membrane proteins such as CD36 and the innate defense molecule C-reactive protein (CRP) (Boullier et al., J Lipid Res May 2005; 46(5): 969-76; Gershov et al., J Exp Med .November 6, 2000; 192(9): 1353-64).

[0006] Therefore, there is a need to combine PC with therapies that target OxPL across a wide range of diseases, including antibodies. Summary of the Invention

[0007] This disclosure provides a polypeptide that specifically binds to PC ( For example(Antibodies). This disclosure also provides pharmaceutical compositions comprising these antibodies, nucleic acids encoding these antibodies, expression vectors and host cells for preparing these antibodies, and methods for treating subjects using these antibodies. The peptides provided herein are particularly advantageous because they bind to PCs with high affinity, exhibit good stability, stress resistance and immunogenicity, and can be produced in high yields. The peptides provided herein are particularly useful for treating inflammatory or degenerative diseases in subjects.

[0008] Therefore, in one aspect, this disclosure provides an antibody that specifically binds to phosphorycholine (PC), the antibody comprising: VH, the VH comprising the CDRH1, CDRH2 and CDRH3 amino acid sequences of any one of the VH amino acid sequences shown in SEQ ID NO: 1-180; and VL, which comprises the CDRL1, CDRL2 and CDRL3 amino acid sequences of any one of the VL amino acid sequences shown in SEQ ID NO: 181-368.

[0009] In one embodiment, the antibody comprises the amino acid sequences CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, respectively, as shown in the VH and VL amino acid sequences in the following: SEQ ID NO: 1 and 181; 2 and 182; 3 and 183; 4 and 184; 5 and 185; 1 and 184; 6 and 184; 1 and 186; 7 and 187; 8 and 188; 9 and 189; 10 and 190; 4 and 191; 11 and 192; 12 and 193; 13 and 194; 14 and 195; 15 and 196 ;16 and 184; 17 and 197; 18 and 198; 1 and 199; 19 and 200; 20 and 201; 21 and 202; 22 and 203; 23 and 204; 24 and 205; 25 and 184; 4 and 206; 26 and 207; 27 and 208; 28 and 209; 9 and 210; 29 and 2 11; 30 and 212; 31 and 213; 32 and 214; 33 and 215; 34 and 216; 17 and 217; 1 and 218; 35 and 184; 36 and 184; 35 and 219; 35 and 220; 37 and 184; 38 and 221; 39 and 222; 9 and 223; 9 and 224; 40 and 184; 41 and 225; 8 and 226; 42 and 227; 35 and 228; 43 and 229; 4 and 230; 9 and 231; 8 and 232; 1 and 233; 8 and 234; 44 and 184; 1 and 235; 45 and 236; 30 and 237; 46 and 184; 47 and 238; 48 and 2 39; 1 and 230; 49 and 190; 44 and 240; 50 and 184; 51 and 241; 52 and 242; 53 and 243; 54 and 184; 55 and 244; 56 and 245; 57 and 246; 58 and 247; 59 and 248; 60 and 249; 8 and 250; 61 and 184; 3 5 and 251; 62 and 252; 1 and 253; 63 and 254; 64 and 181; 65 and 255; 66 and 256; 67 and 257; 68 and 198; 35 and 258; 69 and 259; 70 and 260; 71 and 261; 72 and 262; 73 and 263; 74 and 264; 75 and 2 65; 76 and 266; 77 and 267; 4 and 205; 78 and 268; 1 and 269; 27 and 269; 79 and 269; 80 and 270; 81 and 269; 22 and 269; 82 and 269; 83 and 271; 84 and 272; 1 and 273; 8 and 274; 8 and 275; 22 and 2 76; 8 and 277; 85 and 278; 86 and 279; 87 and 269; 88 and 280; 89 and 269; 60 and 281; 90 and 269; 91 and 282; 22 and 283; 92 and 269; 93 and 284; 94 and 285; 95 and 286; 96 and 269; 73 and 287;97 and 288; 68 and 289; 98 and 269; 99 and 290; 100 and 291; 4 and 292; 4 and 289; 101 and 284; 66 and 289; 89 and 293; 102 and 294; 103 and 269; 22 and 295; 104 and 296; 105 and 297; 106 and 270; 107 and 269; 67 and 269; 62 and 298; 66 and 269; 108 and 299; 109 and 300; 110 and 301; 111 and 302; 112 and 269; 113 and 303; 1 and 304; 72 and 305; 114 and 306; 115 and 307; 116 and 269; 1 17 / 308; 118 / 269; 110 / 309; 119 / 310; 120 / 311; 121 / 269; 122 / 312; 123 / 289; 9 / 313; 124 / 314; 120 / 289; 125 / 315; 110 / 316; 126 / 317; 127 / 318; 49 / 319; 128 / 320; 9 / 321; 22 / 322; 129 / 323; 130 / 269; 131 / 324; 132 / 325; 133 / 326; 134 / 327; 53 / 328; 135 / 272; 136 / 329; 4 / 301; 137 / 330; 13 8 / 269; 1 / 284; 22 / 331; 139 / 269; 140 / 332; 141 / 269; 142 / 333; 143 / 334; 144 / 335; 101 / 298; 1 / 336; 145 / 269; 146 / 337; 147 / 269; 17 / 338; 22 / 320; 4 / 339; 148 / 340; 149 / 341; 150 / 342; 151 / 343; 152 / 344; 94 / 289; 153 / 345; 154 / 346; 155 / 347; 22 / 348; 89 / 282; 156 / 349; 157 / 296; 158 / 35 0; 159 and 329; 24 and 351; 160 and 352; 161 and 269; 162 and 353; 163 and 269; 1 and 354; 164 and 355; 165 and 269; 1 and 356; 166 and 357; 167 and 358; 110 and 334; 87 and 359; 168 and 360; 169 and 269; 170 and 269; 171 and 269; 172 and 361; 8 and 362; 173 and 304; 174 and 269; 1 and 363; 175 and 364; 176 and 365; 177 and 269; 178 and 366; 179 and 269; 180 and 367; or 89 and 368.

[0010] In one embodiment, the antibody comprises the amino acid sequences of CDRH1, CDRH2, and CDRH3 as shown in the following items: SEQ ID NO: 369, 428 and 484; 370, 429 and 485; 371, 428 and 486; 372, 428 and 484; 373, 429 and 48 4; 374, 430 and 484; 375, 428 and 487; 376, 428 and 484; 377, 428 and 484; 378, 428 and 4 84; 379, 428 and 484; 372, 428 and 488; 376, 431 and 484; 380, 432 and 484; 372, 428 and 489; 381, 428 and 490; 382, ​​428 and 484; 381, 428 and 491; 377, 428 and 492; 376, 43 3 and 484; 383, 434 and 484; 383, 428 and 484; 384, 435 and 484; 369, 436 and 484; 372, 437 and 487; 385, 428 and 493; 386, 428 and 484; 372, 437 and 484; 387, 428 and 484; 385 , 428 and 484; 372, 438 and 484; 388, 428 and 494; 369, 439 and 484; 389, 428 and 484; 3 81, 428 and 484; 376, 440 and 495; 390, 441 and 484; 370, 442 and 484; 391, 428 and 484; 392, 432 and 484; 377, 443 and 484; 393, 428 and 484; 383, 444 and 489; 394, 428 and 48 4; 383, 444 and 496; 376, 434 and 484; 395, 445 and 497; 396, 446 and 487; 392, 428 and 4 84; 393, 428 and 498; 376, 428 and 495; 369, 440 and 484; 397, 428 and 484; 389, 447 and 484; 398, 448 and 492; 373, 449 and 490; 399, 428 and 484; 400, 450 and 484; 401, 42 8 and 484; 390, 428 and 484; 400, 428 and 499; 384, 429 and 484; 402, 436 and 484; 381, 451 and 484; 403, 428 and 484; 369, 429 and 484; 404, 429 and 484; 372, 429 and 484; 388 , 428 and 484; 405, 451 and 484; 406, 428 and 484; 400, 428 and 484; 404, 428 and 484; 3 84, 432 and 500; 376, 452 and 501; 407, 428 and 484; 375, 428 and 484; 408, 428 and 484;369, 428 and 497; 403, 453 and 484; 402, 454 and 484; 383, 434 and 500; 376, 455 and 502; 383, 435 and 484; 376, 428 and 490; 369, 428 and 503; 409, 428 and 484; 383, 428 and 504; 369, 434 and 484; 369, 456 and 484; 370, 457 and 484; 404, 458 and 499; 410, 428 and 484; 383, 459 and 484; 407, 428 and 489; 374, 434 and 484; 411, 460 and 505; 383, 428 and 485; 386, 460 and 4 90; 412, 455 and 493; 383, 461 and 484; 376, 437 and 484; 383, 462 and 500; 400, 463 and 484; 376, 464 and 484; 400, 434 and 506; 369, 436 and 507; 377, 465 and 484; 413, 459 and 484; 3 69, 452 and 484; 414, 466 and 484; 373, 428 and 484; 415, 428 and 489; 369, 428 and 491; 403, 458 and 508; 392, 467 and 484; 369, 452 and 509; 388, 468 and 490; 377, 440 and 484; 370, 42 8 and 484; 384, 467 and 487; 392, 469 and 510; 378, 464 and 484; 416, 434 and 484; 370, 428 and 511; 376, 428 and 502; 417, 428 and 484; 376, 428 and 512; 381, 428 and 493; 383, 470 and 50 1; 404, 471 and 484; 418, 428 and 484; 383, 472 and 513; 419, 428 and 484; 372, 473 and 484; 383, 474 and 484; 420, 434 and 484; 370, 428 and 514; 369, 475 and 484; 421, 436 and 484; 378 , 452 and 484; 376, 476 and 515; 376, 428 and 504; 422, 469 and 484; 369, 428 and 516; 405, 460 and 484; 413, 431 and 484; 406, 429 and 484; 383, 428 and 517; 377, 437 and 518; 369, 477 Japanese 487; 403, 464 Japanese 484; 369, 454 Japanese 484; 372, 478 Japanese 519; 423, 429 Japanese 484; 382, ​​434 Japanese 484; 424, 479 Japanese 484; 376, 429 Japanese 484; 425, 428 Japanese 484; 403, 428 Japanese 520; 417, 460 Japanese 484;409, 460 and 484; 404, 452 and 484; 383, 428 and 521; 372, 480 and 493; 369, 477 and 484; 369, 481 and 484; 384, 452 and 484; 377, 482 and 484; 410, 483 and 484; 384, 428 and 489; 426, 429 and 484; 427, 428 and 484; 373, 452 and 506; 369, 429 and 521; 405, 428 and 522; 376, 428 and 510; 384, 428 and 484; 410, 429 and 484; or 400, 452 and 484.

[0011] In the embodiments, the antibody comprises the amino acid sequences CDRL1, CDRL2, and CDRL3 shown in the following items, respectively: SEQ ID NO: 523, 591 and 656; 523, 592 and 657; 523, 593 and 658; 523, 591 and 659; 523, 594 and 65 9; 523, 595 and 660; 523, 596 and 659; 524, 591 and 659; 523, 591 and 661; 523, 591 and 6 62; 523, 597 and 658; 523, 598 and 662; 525, 599 and 659; 523, 600 and 663; 523, 591 and 664; 523, 601 and 659; 526, 597 and 665; 523, 602 and 659; 527, 591 and 661; 528, 59 1 and 662; 529, 603 and 662; 523, 604 and 666; 523, 605 and 667; 530, 606 and 659; 523, 607 and 659; 523, 608 and 659; 523, 609 and 662; 531, 591 and 663; 523, 608 and 661; 523 , 610 and 659; 523, 611 and 668; 523, 611 and 658; 523, 596 and 662; 523, 612 and 667; 5 23, 613 and 668; 523, 591 and 669; 523, 591 and 663; 523, 614 and 659; 532, 615 and 662; 523, 616 and 670; 523, 591 and 668; 523, 617 and 671; 533, 595 and 659; 523, 618 and 65 9; 534, 619 and 662; 535, 620 and 659; 536, 621 and 659; 537, 603 and 671; 523, 622 and 6 59; 523, 617 and 659; 523, 623 and 659; 538, 607 and 672; 523, 616 and 671; 523, 624 and 659; 523, 620 and 659; 523, 625 and 660; 523, 602 and 671; 523, 611 and 663; 523, 62 6 and 670; 523, 606 and 673; 523, 627 and 671; 523, 628 and 671; 539, 591 and 662; 523, 591 and 670; 523, 611 and 659; 537, 613 and 671; 540, 598 and 659; 541, 591 and 659; 542 , 629 and 659; 523, 591 and 671; 523, 630 and 667; 543, 631 and 659; 523, 632 and 664; 5 23, 597 and 661; 523, 633 and 659; 544, 607 and 659; 523, 630 and 659; 523, 591 and 665;523, 610 and 674; 523, 634 and 671; 545, 591 and 661; 523, 635 and 667; 546, 591 and 659; 523, 636 and 664; 547, 591 and 663; 548, 619 and 659; 523, 637 and 659; 523, 638 and 659; 549, 591 and 659; 550, 591 and 675; 551, 591 and 659; 552, 591 and 659; 553, 591 and 676; 554, 591 and 659; 523, 591 and 676; 555, 606 and 659; 556, 591 and 659; 523, 637 and 677; 557, 591 and 6 59; 558, 591 and 659; 523, 591 and 677; 553, 639 and 659; 549, 591 and 667; 559, 617 and 666; 523, 591 and 672; 523, 606 and 659; 523, 592 and 670; 560, 591 and 667; 530, 591 and 659; 5 61, 603 and 666; 562, 591 and 659; 523, 616 and 660; 523, 602 and 677; 523, 616 and 659; 523, 630 and 660; 563, 591 and 659; 523, 640 and 659; 564, 591 and 659; 523, 641 and 677; 565, 59 1 and 662; 523, 642 and 664; 566, 643 and 659; 523, 644 and 667; 567, 606 and 659; 568, 591 and 659; 569, 645 and 659; 523, 603 and 659; 570, 628 and 678; 571, 630 and 663; 572, 591 and 66 4; 573, 591 and 670; 523, 646 and 659; 574, 591 and 670; 523, 647 and 667; 575, 591 and 659; 537, 591 and 659; 523, 635 and 670; 576, 591 and 659; 577, 606 and 659; 523, 648 and 679; 523 , 592 and 659; 523, 595 and 659; 523, 600 and 659; 523, 649 and 664; 578, 641 and 659; 523, 591 and 667; 523, 606 and 660; 523, 650 and 656; 579, 621 and 671; 580, 591 and 660; 527, 591 Japanese 659; 581, 595 Japanese 659; 582, 640 Japanese 664; 583, 651 Japanese 659; 534, 591 Japanese 659; 584, 591 Japanese 671; 523, 591 Japanese 680; 523, 591 Japanese 681; 585, 591 Japanese 659; 523, 649 Japanese 659; 586, 591 Japanese 666;587, 652 and 659; 588, 638 and 659; 523, 623 and 664; 523, 591 and 682; 553, 653 and 659; 523, 654 and 659; 523, 648 and 659; 560, 591 and 659; 580, 606 and 659; 589, 593 and 661; 523, 637 and 676; 590, 622 and 659; 555, 591 and 661; 523, 615 and 672; 523, 626 and 668; 523, 655 and 659; or 523, 606 and 680.

[0012] In one embodiment, the antibody comprises the amino acid sequences of CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 as shown in the following: SEQ ID NO: 369, 428, 484, 523, 591 and 656; 370, 429, 485, 523, 592 and 657; 371, 428, 486, 523, 593 and 658; 372, 428, 484, 523, 591 and 659; 373, 429, 484, 523, 59 4 and 659; 369, 428, 484, 523, 591 and 659; 374, 430, 484, 523, 591 and 659; 369, 428, 484, 523, 595 and 660; 375, 428, 487, 523, 596 and 659; 376, 428, 484, 524, 591 and 659; 377, 428, 484, 523, 591 and 661; 378, 428, 484, 523, 591 and 662; 372, 428, 484, 523, 597 and 658; 379, 428, 484, 523, 598 and 662; 372, 42 8, 488, 525, 599 and 659; 376, 431, 484, 523, 600 and 663; 380, 432, 484, 523, 591 and 664; 372, 428, 489, 523, 601 and 659; 381, 428, 490, 523, 591 and 659; 382, 428, 484, 526, 597 and 665; 381, 428, 491, 523, 602 and 659; 369, 428, 484, 527, 591 and 661; 377, 428, 492, 528, 591 and 662; 376, 433, 484, 529, 60 3 and 662; 383, 434, 484, 523, 604 and 666; 383, 428, 484, 523, 605 and 667; 384, 435, 484, 530, 606 and 659; 369, 436, 484, 523, 607 and 659; 372, 437, 487, 523, 591 and 659; 372, 428, 484, 523, 608 and 659; 385, 428, 493, 523, 609 and 662; 386, 428, 484, 531, 591 and 663; 372, 437, 484, 523, 608 and 661; 377, 42 8, 484, 523, 610 and 659; 387, 428, 484, 523, 611 and 668; 385, 428, 484, 523, 611 and 658; 372, 438, 484, 523, 596 and 662; 388, 428, 494, 523, 612 and 667;369, 439, 484, 523, 613 and 668; 389, 428, 484, 523, 591 and 669; 382, ​​428, 484, 523, 591 and 663; 369, 428, 484, 523, 614 and 659; 381, 428, 484, 523, 591 and 659; 37 6, 440, 495, 523, 591 and 659; 381, 428, 484, 532, 615 and 662; 381, 428, 484, 523, 616 and 670; 390, 441, 484, 523, 591 and 659; 370, 442, 484, 523, 591 and 668; 391, 4 28, 484, 523, 617 and 671; 377, 428, 484, 533, 595 and 659; 377, 428, 484, 523, 618 and 659; 392, 432, 484, 523, 591 and 659; 377, 443, 484, 534, 619 and 662; 376, 428, 484, 535, 620 and 659; 393, 428, 484, 536, 621 and 659; 381, 428, 484, 537, 603 and 671; 383, 444, 489, 523, 622 and 59; 372, 428, 484, 523, 617 and 659; 377, 428, 484, 523, 623 and 659; 376, 428, 484, 538, 607 and 672; 369, 428, 484, 523, 616 and 671; 376, 428, 484, 523, 624 and 659; 394, 428, 484, 523, 591 and 659; 369, 428, 484, 523 , 620 and 659; 383, 444, 496, 523, 625 and 660; 385, 428, 484, 523, 602 and 671; 376, 434, 484, 523, 591 and 659; 395, 445, 497, 523, 611 and 663; 396, 446, 487, 523, 62 6 and 670; 369, 428, 484, 523, 617 and 659; 392, 428, 484, 523, 591 and 662; 394, 428, 484, 523, 606 and 673; 393, 428, 498, 523, 591 and 659; 376, 428, 495, 523, 627 and 6 71; 369, 440, 484, 523, 628 and 671; 397, 428, 484, 539, 591 and 662; 389, 447, 484, 523, 591 and 659; 398, 448, 492, 523, 591 and 670; 373, 449, 490, 523, 611 and 659;399, 428, 484, 537, 613 and 671; 400, 450, 484, 540, 598 and 659; 401, 428, 484, 541, 591 and 659; 390, 428, 484, 542, 629 and 659; 376, 428, 484, 523, 591 and 671; 400 , 428, 499, 523, 591 and 659; 381, 428, 484, 523, 630 and 667; 384, 429, 484, 543, 631 and 659; 369, 428, 484, 523, 632 and 664; 402, 436, 484, 523, 597 and 661; 381, 45 1, 484, 523, 591 and 656; 403, 428, 484, 523, 633 and 659; 369, 429, 484, 544, 607 and 659; 404, 429, 484, 523, 630 and 659; 372, 429, 484, 523, 602 and 659; 381, 428, 4 84, 523, 591 and 665; 388, 428, 484, 523, 610 and 674; 405, 451, 484, 523, 634 and 671; 406, 428, 484, 545, 591 and 661; 400, 428, 484, 523, 635 and 667; 404, 428, 484, 546, 591 and 659; 384, 432, 500, 523, 636 and 664; 376, 452, 501, 547, 591 and 663; 407, 428, 484, 548, 619 and 659; 375, 428, 484, 523, 637 and 659; 372, 428, 484, 523 , 607 and 659; 408, 428, 484, 523, 638 and 659; 386, 428, 484, 523, 591 and 659; 369, 428, 497, 523, 591 and 659; 403, 453, 484, 549, 591 and 659; 402, 454, 484, 523, 59 1 W659; 383, 428, 484, 523, 591 W659; 383, 434, 500, 523, 591 W659; 376, 455, 502, 550, 591 W675; 383, 435, 484, 523, 591 W664; 369, 428, 484, 523, 602 W6 59; 376, 428, 484, 551, 591 and 659; 376, 428, 484, 552, 591 and 659; 383, 428, 484, 553, 591 and 676; 376, 428, 484, 554, 591 and 659; 376, 428, 490, 523, 591 and 676;369, 428, 503, 555, 606 and 659; 409, 428, 484, 523, 591 and 659; 383, 428, 504, 556, 591 and 659; 369, 434, 484, 523, 591 and 659; 390, 428, 484, 523, 637 and 677; 369 , 456, 484, 523, 591 and 659; 370, 457, 484, 557, 591 and 659; 383, 428, 484, 558, 591 and 659; 404, 458, 499, 523, 591 and 659; 410, 428, 484, 523, 591 and 677; 383, 45 9, 484, 553, 639 and 659; 407, 428, 489, 549, 591 and 667; 374, 434, 484, 523, 591 and 659; 404, 428, 484, 559, 617 and 666; 411, 460, 505, 523, 591 and 672; 372, 429, 4 84, 523, 606 and 659; 383, 428, 485, 523, 591 and 659; 386, 460, 490, 523, 601 and 659; 412, 455, 493, 523, 592 and 670; 372, 428, 484, 560, 591 and 667; 372, 428, 484, 523, 606 and 659; 383, 461, 484, 523, 591 and 677; 369, 429, 484, 523, 606 and 659; 369, 434, 484, 530, 591 and 659; 376, 437, 484, 561, 603 and 666; 383, 462, 500, 523 , 591 and 659; 383, 428, 484, 562, 591 and 659; 400, 463, 484, 523, 616 and 660; 376, 464, 484, 523, 602 and 677; 400, 434, 506, 549, 591 and 659; 369, 436, 507, 523, 59 1 W659; 404, 429, 484, 523, 591 W659; 384, 429, 484, 523, 616 W659; 369, 429, 484, 523, 591 W659; 377, 465, 484, 523, 630 W660; 413, 459, 484, 563, 591 W6 59; 369, 452, 484, 523, 591 and 663; 414, 466, 484, 523, 640 and 659; 373, 428, 484, 523, 591 and 659; 415, 428, 489, 564, 591 and 659; 369, 428, 484, 523, 591 and 671;400, 428, 484, 523, 641 and 677; 369, 428, 491, 565, 591 and 662; 403, 458, 508, 523, 642 and 664; 392, 467, 484, 523, 591 and 659; 369, 452, 509, 566, 643 and 659; 388 , 468, 490, 523, 591 and 659; 369, 452, 484, 523, 644 and 667; 377, 440, 484, 567, 606 and 659; 370, 428, 484, 523, 591 and 656; 384, 467, 487, 523, 591 and 659; 392, 46 9, 510, 568, 591 and 659; 378, 464, 484, 523, 606 and 659; 377, 428, 484, 569, 645 and 659; 416, 434, 484, 523, 603 and 659; 370, 428, 484, 523, 606 and 659; 370, 428, 5 11, 570, 628 and 678; 369, 452, 484, 571, 630 and 663; 376, 428, 502, 572, 591 and 664; 417, 428, 484, 523, 591 and 665; 392, 428, 484, 573, 591 and 670; 376, 428, 512, 523, 646 and 659; 377, 428, 484, 574, 591 and 670; 383, 428, 484, 523, 647 and 667; 381, 428, 493, 575, 591 and 659; 383, 470, 501, 523, 591 and 659; 404, 471, 484, 537 , 591 and 659; 418, 428, 484, 523, 635 and 670; 383, 472, 513, 576, 591 and 659; 419, 428, 484, 577, 606 and 659; 397, 428, 484, 523, 648 and 679; 372, 473, 484, 523, 59 1 W664; 383, 474, 484, 523, 592 W659; 372, 428, 484, 523, 591 W663; 420, 434, 484, 523, 595 W659; 370, 428, 514, 523, 591 W659; 369, 428, 484, 523, 591 W6 77; 383, 428, 484, 523, 600 and 659; 369, 475, 484, 523, 591 and 659; 421, 436, 484, 523, 649 and 664; 378, 452, 484, 523, 591 and 659; 376, 476, 515, 578, 641 and 659;376, 428, 504, 523, 591 and 667; 422, 469, 484, 523, 606 and 660; 383, 461, 484, 523, 616 and 659; 369, 428, 484, 523, 650 and 656; 369, 428, 516, 523, 591 and 659; 405 , 460, 484, 523, 618 and 659; 413, 431, 484, 523, 591 and 659; 382, ​​428, 484, 579, 621 and 671; 383, 428, 484, 523, 646 and 659; 372, 428, 484, 580, 591 and 660; 406, 42 9, 484, 527, 591 and 659; 383, 428, 517, 581, 595 and 659; 377, 437, 518, 582, 640 and 664; 369, 477, 487, 583, 651 and 659; 403, 464, 484, 534, 591 and 659; 383, 459, 4 84, 523, 606 and 659; 369, 454, 484, 584, 591 and 671; 372, 478, 519, 523, 591 and 680; 423, 429, 484, 523, 591 and 681; 383, 428, 484, 585, 591 and 659; 369, 434, 484, 557, 591 and 659; 382, ​​434, 484, 523, 649 and 659; 424, 479, 484, 523, 616 and 660; 376, 429, 484, 586, 591 and 666; 425, 428, 484, 523, 592 and 659; 369, 436, 484, 587 , 652 and 659; 403, 428, 520, 588, 638 and 659; 417, 460, 484, 523, 591 and 659; 409, 460, 484, 523, 623 and 664; 404, 452, 484, 523, 591 and 659; 369, 428, 484, 523, 59 1 and 682; 383, 428, 521, 553, 653 and 659; 372, 480, 493, 523, 591 and 659; 369, 428, 484, 523, 654 and 659; 369, 477, 484, 523, 648 and 659; 369, 481, 484, 560, 591 and 6 59; 369, 452, 484, 523, 591 and 667; 409, 428, 484, 580, 606 and 659; 384, 452, 484, 589, 593 and 661; 377, 482, 484, 523, 591 and 659; 410, 483, 484, 523, 591 and 659;384, 428, 489, 523, 591 and 659; 426, 429, 484, 523, 622 and 659; 376, 428, 484, 523, 637 and 676; 427, 42 8, 484, 523, 591 and 671; 373, 452, 506, 523, 591 and 659; 369, 428, 484, 590, 622 and 659; 369, 429, 521, 555, 591, and 661; 405, 428, 522, 523, 615, and 672; 376, 428, 510, 523, 591, and 659; 384, 428, 484, 523, 626, and 668; 410, 429, 484, 523, 591, and 659; 400, 452, 484, 523, 655, and 659; or 369, 434, 484, 523, 606, and 680.

[0013] In one embodiment, the antibody comprises the VH amino acid sequence of any of SEQ ID NO: 1-180.

[0014] In one embodiment, the antibody comprises the VL amino acid sequence of any of SEQ ID NO: 181-368.

[0015] In one embodiment, VH and VL comprise respectively in SEQ ID NO: Amino acid sequences shown in 1 and 181; 2 and 182; 3 and 183; 4 and 184; 5 and 185; 1 and 184; 6 and 184; 1 and 186; 7 and 1 87; 8 and 188; 9 and 189; 10 and 190; 4 and 191; 11 and 192; 12 and 193; 13 and 194; 14 and 195; 15 and 19 6; 16 and 184; 17 and 197; 18 and 198; 1 and 199; 19 and 200; 20 and 201; 21 and 202; 22 and 203; 23 and 204; 24 and 205; 25 and 184; 4 and 206; 26 and 207; 27 and 208; 28 and 209; 9 and 210; 29 and 211; 30 and 212; 31 and 213; 32 and 214; 33 and 215; 34 and 216; 17 and 217; 1 and 218; 35 and 184; 36 and 184; 3 5 and 219; 35 and 220; 37 and 184; 38 and 221; 39 and 222; 9 and 223; 9 and 224; 40 and 184; 41 and 225; 8 and 226; 42 and 227; 35 and 228; 43 and 229; 4 and 230; 9 and 231; 8 and 232; 1 and 233; 8 and 234; 44 and 1 84; 1 and 235; 45 and 236; 30 and 237; 46 and 184; 47 and 238; 48 and 239; 1 and 230; 49 and 190; 44 and 2 40; 50 and 184; 51 and 241; 52 and 242; 53 and 243; 54 and 184; 55 and 244; 56 and 245; 57 and 246; 5 8 and 247; 59 and 248; 60 and 249; 8 and 250; 61 and 184; 35 and 251; 62 and 252; 1 and 253; 63 and 254; 6 4 and 181; 65 and 255; 66 and 256; 67 and 257; 68 and 198; 35 and 258; 69 and 259; 70 and 260; 71 and 26 1; 72 and 262; 73 and 263; 74 and 264; 75 and 265; 76 and 266; 77 and 267; 4 and 205; 78 and 268; 1 and 26 9; 27 and 269; 79 and 269; 80 and 270; 81 and 269; 22 and 269; 82 and 269; 83 and 271; 84 and 272; 1 and 273; 8 and 274; 8 and 275; 22 and 276; 8 and 277; 85 and 278; 86 and 279; 87 and 269; 88 and 280; 89 and 2 69; 60 and 281; 90 and 269; 91 and 282; 22 and 283; 92 and 269; 93 and 284; 94 and 285; 95 and 286; 9 6 and 269; 73 and 287; 97 and 288; 68 and 289; 98 and 269; 99 and 290; 100 and 291; 4 and 292; 4 and 289;101 and 284; 66 and 289; 89 and 293; 102 and 294; 103 and 269; 22 and 295; 104 and 296; 105 and 297; 106 and 270; 107 and 269; 67 and 269; 62 and 298; 66 and 269; 108 and 299; 109 300; 110 and 301; 111 and 302; 112 and 269; 113 and 303; 1 and 304; 72 and 305; 114 and 306; 115 and 307; 116 and 269; 117 and 308; 118 and 269; 110 and 309; 119 and 310; 120 and 3 11; 121 and 269; 122 and 312; 123 and 289; 9 and 313; 124 and 314; 120 and 289; 125 and 315; 110 and 316; 126 and 317; 127 and 318; 49 and 319; 128 and 320; 9 and 321; 22 and 322; 1 29 & 323; 130 & 269; 131 & 324; 132 & 325; 133 & 326; 134 & 327; 53 & 328; 135 & 272; 136 & 329; 4 & 301; 137 & 330; 147 and 269; 17 and 338; 22 and 320; 4 and 339; 148 and 340; 1 49 and 341; 150 and 342; 151 and 343; 152 and 344; 94 and 289; 153 and 345; 154 and 346; 155 and 347; 22 and 348; 89 and 282; 156 and 349; 157 and 296; 158 and 350; 159 and 329; 24 and 351; 160 and 352; 161 and 269; 162 and 353; 163 and 269; 1 and 354; 164 and 355; 165 and 269; 1 and 356; 166 and 357; 167 and 358; 110 and 334; 87 and 359; 168 and 360; 169 and 26 or 89 and 368. ;

[0016] In one embodiment, the antibody is a single-chain variable fragment (scFv).

[0017] In one embodiment, the antibody comprises a heavy chain constant region or its Fc region optionally selected from the group consisting of: human IgG1, IgG2, IgG3, IgG4, IgA1, and IgA. 2。

[0018] In one embodiment, the heavy chain constant region is human IgG1.

[0019] In one embodiment, the heavy chain constant region is human IgG4.

[0020] In one embodiment, the amino acid sequence of the human IgG4 heavy chain constant region includes position P at position 228 according to the EU numbering system.

[0021] In one embodiment, the heavy chain constant region is a variant of the wild-type heavy chain constant region, wherein the variant heavy chain constant region binds to the Fcγ receptor (FcγR) with a lower affinity than the wild-type heavy chain constant region.

[0022] In one embodiment, the amino acid sequence of the heavy chain constant region includes: A at position 234; A at position 235; A, Q, or G at position 297; or A or G at position 329, each numbered according to the EU numbering system.

[0023] In one embodiment, the amino acid sequence of the heavy chain constant region includes: A at positions 234 and 235; A at positions 234, 235 and 329; or A at positions 234 and 235 and G at position 329, in each case numbered according to the EU numbering system.

[0024] In one embodiment, the heavy chain constant region is a variant of the wild-type heavy chain constant region, and wherein the variant heavy chain constant region has an increased affinity for human neonatal Fc receptor (FcRn) at pH 6 relative to the affinity of the wild-type heavy chain constant region for human neonatal Fc receptor (FcRn).

[0025] In one embodiment, the amino acid sequence of the heavy chain constant region comprises: L and S at positions 428 and 434, respectively; K, F and Y at positions 433, 434 and 436, respectively; or Y, T and E at positions 252, 254 and 256, respectively, in each case numbered according to the EU numbering system.

[0026] In one embodiment, the antibody comprises a light chain constant region, optionally a human κ or λ constant region.

[0027] In one aspect, this disclosure provides a polypeptide comprising VH, the VH comprising the CDRH1, CDRH2, and CDRH3 amino acid sequences of any one of the VH amino acid sequences shown in SEQ ID NO: 1-180.

[0028] In one embodiment, the polypeptide comprises the amino acid sequences of CDRH1, CDRH2, and CDRH3 as shown in the following items: SEQ ID NO: 369, 428 and 484; 370, 429 and 485; 371, 428 and 486; 372, 428 and 484; 373, 429 and 48 4; 374, 430 and 484; 375, 428 and 487; 376, 428 and 484; 377, 428 and 484; 378, 428 and 4 84; 379, 428 and 484; 372, 428 and 488; 376, 431 and 484; 380, 432 and 484; 372, 428 and 489; 381, 428 and 490; 382, ​​428 and 484; 381, 428 and 491; 377, 428 and 492; 376, 43 3 and 484; 383, 434 and 484; 383, 428 and 484; 384, 435 and 484; 369, 436 and 484; 372, 437 and 487; 385, 428 and 493; 386, 428 and 484; 372, 437 and 484; 387, 428 and 484; 385 , 428 and 484; 372, 438 and 484; 388, 428 and 494; 369, 439 and 484; 389, 428 and 484; 3 81, 428 and 484; 376, 440 and 495; 390, 441 and 484; 370, 442 and 484; 391, 428 and 484; 392, 432 and 484; 377, 443 and 484; 393, 428 and 484; 383, 444 and 489; 394, 428 and 48 4; 383, 444 and 496; 376, 434 and 484; 395, 445 and 497; 396, 446 and 487; 392, 428 and 4 84; 393, 428 and 498; 376, 428 and 495; 369, 440 and 484; 397, 428 and 484; 389, 447 and 484; 398, 448 and 492; 373, 449 and 490; 399, 428 and 484; 400, 450 and 484; 401, 42 8 and 484; 390, 428 and 484; 400, 428 and 499; 384, 429 and 484; 402, 436 and 484; 381, 451 and 484; 403, 428 and 484; 369, 429 and 484; 404, 429 and 484; 372, 429 and 484; 388 , 428 and 484; 405, 451 and 484; 406, 428 and 484; 400, 428 and 484; 404, 428 and 484; 3 84, 432 and 500; 376, 452 and 501; 407, 428 and 484; 375, 428 and 484; 408, 428 and 484;369, 428 and 497; 403, 453 and 484; 402, 454 and 484; 383, 434 and 500; 376, 455 and 502; 383, 435 and 484; 376, 428 and 490; 369, 428 and 503; 409, 428 and 484; 383, 428 and 504; 369, 434 and 484; 369, 456 and 484; 370, 457 and 484; 404, 458 and 499; 410, 428 and 484; 383, 459 and 484; 407, 428 and 489; 374, 434 and 484; 411, 460 and 505; 383, 428 and 485; 386, 460 and 4 90; 412, 455 and 493; 383, 461 and 484; 376, 437 and 484; 383, 462 and 500; 400, 463 and 484; 376, 464 and 484; 400, 434 and 506; 369, 436 and 507; 377, 465 and 484; 413, 459 and 484; 3 69, 452 and 484; 414, 466 and 484; 373, 428 and 484; 415, 428 and 489; 369, 428 and 491; 403, 458 and 508; 392, 467 and 484; 369, 452 and 509; 388, 468 and 490; 377, 440 and 484; 370, 42 8 and 484; 384, 467 and 487; 392, 469 and 510; 378, 464 and 484; 416, 434 and 484; 370, 428 and 511; 376, 428 and 502; 417, 428 and 484; 376, 428 and 512; 381, 428 and 493; 383, 470 and 50 1; 404, 471 and 484; 418, 428 and 484; 383, 472 and 513; 419, 428 and 484; 372, 473 and 484; 383, 474 and 484; 420, 434 and 484; 370, 428 and 514; 369, 475 and 484; 421, 436 and 484; 378 , 452 and 484; 376, 476 and 515; 376, 428 and 504; 422, 469 and 484; 369, 428 and 516; 405, 460 and 484; 413, 431 and 484; 406, 429 and 484; 383, 428 and 517; 377, 437 and 518; 369, 477 Japanese 487; 403, 464 Japanese 484; 369, 454 Japanese 484; 372, 478 Japanese 519; 423, 429 Japanese 484; 382, ​​434 Japanese 484; 424, 479 Japanese 484; 376, 429 Japanese 484; 425, 428 Japanese 484; 403, 428 Japanese 520; 417, 460 Japanese 484;409, 460 and 484; 404, 452 and 484; 383, 428 and 521; 372, 480 and 493; 369, 477 and 484; 369, 481 and 484; 384, 452 and 484; 377, 482 and 484; 410, 483 and 484; 384, 428 and 489; 426, 429 and 484; 427, 428 and 484; 373, 452 and 506; 369, 429 and 521; 405, 428 and 522; 376, 428 and 510; 384, 428 and 484; 410, 429 and 484; or 400, 452 and 484.

[0029] In one embodiment, the VH comprises the amino acid sequences of CDRH1, CDRH2, and CDRH3 as shown in the following items: SEQ ID NO: 369, 428 and 484; 370, 429 and 485; 371, 428 and 486; 372, 428 and 484; 373, 429 and 48 4; 374, 430 and 484; 375, 428 and 487; 376, 428 and 484; 377, 428 and 484; 378, 428 and 4 84; 379, 428 and 484; 372, 428 and 488; 376, 431 and 484; 380, 432 and 484; 372, 428 and 489; 381, 428 and 490; 382, ​​428 and 484; 381, 428 and 491; 377, 428 and 492; 376, 43 3 and 484; 383, 434 and 484; 383, 428 and 484; 384, 435 and 484; 369, 436 and 484; 372, 437 and 487; 385, 428 and 493; 386, 428 and 484; 372, 437 and 484; 387, 428 and 484; 385 , 428 and 484; 372, 438 and 484; 388, 428 and 494; 369, 439 and 484; 389, 428 and 484; 3 81, 428 and 484; 376, 440 and 495; 390, 441 and 484; 370, 442 and 484; 391, 428 and 484; 392, 432 and 484; 377, 443 and 484; 393, 428 and 484; 383, 444 and 489; 394, 428 and 48 4; 383, 444 and 496; 376, 434 and 484; 395, 445 and 497; 396, 446 and 487; 392, 428 and 4 84; 393, 428 and 498; 376, 428 and 495; 369, 440 and 484; 397, 428 and 484; 389, 447 and 484; 398, 448 and 492; 373, 449 and 490; 399, 428 and 484; 400, 450 and 484; 401, 42 8 and 484; 390, 428 and 484; 400, 428 and 499; 384, 429 and 484; 402, 436 and 484; 381, 451 and 484; 403, 428 and 484; 369, 429 and 484; 404, 429 and 484; 372, 429 and 484; 388 , 428 and 484; 405, 451 and 484; 406, 428 and 484; 400, 428 and 484; 404, 428 and 484; 3 84, 432 and 500; 376, 452 and 501; 407, 428 and 484; 375, 428 and 484; 408, 428 and 484;369, 428 and 497; 403, 453 and 484; 402, 454 and 484; 383, 434 and 500; 376, 455 and 502; 383, 435 and 484; 376, 428 and 490; 369, 428 and 503; 409, 428 and 484; 383, 428 and 504; 369, 434 and 484; 369, 456 and 484; 370, 457 and 484; 404, 458 and 499; 410, 428 and 484; 383, 459 and 484; 407, 428 and 489; 374, 434 and 484; 411, 460 and 505; 383, 428 and 485; 386, 460 and 4 90; 412, 455 and 493; 383, 461 and 484; 376, 437 and 484; 383, 462 and 500; 400, 463 and 484; 376, 464 and 484; 400, 434 and 506; 369, 436 and 507; 377, 465 and 484; 413, 459 and 484; 3 69, 452 and 484; 414, 466 and 484; 373, 428 and 484; 415, 428 and 489; 369, 428 and 491; 403, 458 and 508; 392, 467 and 484; 369, 452 and 509; 388, 468 and 490; 377, 440 and 484; 370, 42 8 and 484; 384, 467 and 487; 392, 469 and 510; 378, 464 and 484; 416, 434 and 484; 370, 428 and 511; 376, 428 and 502; 417, 428 and 484; 376, 428 and 512; 381, 428 and 493; 383, 470 and 50 1; 404, 471 and 484; 418, 428 and 484; 383, 472 and 513; 419, 428 and 484; 372, 473 and 484; 383, 474 and 484; 420, 434 and 484; 370, 428 and 514; 369, 475 and 484; 421, 436 and 484; 378 , 452 and 484; 376, 476 and 515; 376, 428 and 504; 422, 469 and 484; 369, 428 and 516; 405, 460 and 484; 413, 431 and 484; 406, 429 and 484; 383, 428 and 517; 377, 437 and 518; 369, 477 Japanese 487; 403, 464 Japanese 484; 369, 454 Japanese 484; 372, 478 Japanese 519; 423, 429 Japanese 484; 382, ​​434 Japanese 484; 424, 479 Japanese 484; 376, 429 Japanese 484; 425, 428 Japanese 484; 403, 428 Japanese 520; 417, 460 Japanese 484;409, 460, and 484; 404, 452, and 484; 383, 428, and 521; 372, 480, and 493; 369, 477, and 484; 369, 481, and 484; 8, and 489; 426, 429, and 484; 427, 428, and 484; 373, 452, and 506; 369, 429, and 521; 405, 428, and 522; 376, 428, and 510; ;

[0030] In one embodiment, the VH comprises any of the amino acid sequences shown in SEQ ID NO: 1-180.

[0031] In one aspect, this disclosure provides a polypeptide comprising a VL containing the CDRL1, CDRL2, and CDRL3 amino acid sequences of any one of the VH amino acid sequences shown in SEQ ID NO: 181-368.

[0032] In one embodiment, the polypeptide comprises the amino acid sequences CDRL1, CDRL2, and CDRL3 shown in the following items, respectively: SEQ ID NO: 523, 591 and 656; 523, 592 and 657; 523, 593 and 658; 523, 591 and 659; 523, 594 and 65 9; 523, 595 and 660; 523, 596 and 659; 524, 591 and 659; 523, 591 and 661; 523, 591 and 6 62; 523, 597 and 658; 523, 598 and 662; 525, 599 and 659; 523, 600 and 663; 523, 591 and 664; 523, 601 and 659; 526, 597 and 665; 523, 602 and 659; 527, 591 and 661; 528, 59 1 and 662; 529, 603 and 662; 523, 604 and 666; 523, 605 and 667; 530, 606 and 659; 523, 607 and 659; 523, 608 and 659; 523, 609 and 662; 531, 591 and 663; 523, 608 and 661; 523 , 610 and 659; 523, 611 and 668; 523, 611 and 658; 523, 596 and 662; 523, 612 and 667; 5 23, 613 and 668; 523, 591 and 669; 523, 591 and 663; 523, 614 and 659; 532, 615 and 662; 523, 616 and 670; 523, 591 and 668; 523, 617 and 671; 533, 595 and 659; 523, 618 and 65 9; 534, 619 and 662; 535, 620 and 659; 536, 621 and 659; 537, 603 and 671; 523, 622 and 6 59; 523, 617 and 659; 523, 623 and 659; 538, 607 and 672; 523, 616 and 671; 523, 624 and 659; 523, 620 and 659; 523, 625 and 660; 523, 602 and 671; 523, 611 and 663; 523, 62 6 and 670; 523, 606 and 673; 523, 627 and 671; 523, 628 and 671; 539, 591 and 662; 523, 591 and 670; 523, 611 and 659; 537, 613 and 671; 540, 598 and 659; 541, 591 and 659; 542 , 629 and 659; 523, 591 and 671; 523, 630 and 667; 543, 631 and 659; 523, 632 and 664; 5 23, 597 and 661; 523, 633 and 659; 544, 607 and 659; 523, 630 and 659; 523, 591 and 665;523, 610 and 674; 523, 634 and 671; 545, 591 and 661; 523, 635 and 667; 546, 591 and 659; 523, 636 and 664; 547, 591 and 663; 548, 619 and 659; 523, 637 and 659; 523, 638 and 659; 549, 591 and 659; 550, 591 and 675; 551, 591 and 659; 552, 591 and 659; 553, 591 and 676; 554, 591 and 659; 523, 591 and 676; 555, 606 and 659; 556, 591 and 659; 523, 637 and 677; 557, 591 and 6 59; 558, 591 and 659; 523, 591 and 677; 553, 639 and 659; 549, 591 and 667; 559, 617 and 666; 523, 591 and 672; 523, 606 and 659; 523, 592 and 670; 560, 591 and 667; 530, 591 and 659; 5 61, 603 and 666; 562, 591 and 659; 523, 616 and 660; 523, 602 and 677; 523, 616 and 659; 523, 630 and 660; 563, 591 and 659; 523, 640 and 659; 564, 591 and 659; 523, 641 and 677; 565, 59 1 and 662; 523, 642 and 664; 566, 643 and 659; 523, 644 and 667; 567, 606 and 659; 568, 591 and 659; 569, 645 and 659; 523, 603 and 659; 570, 628 and 678; 571, 630 and 663; 572, 591 and 66 4; 573, 591 and 670; 523, 646 and 659; 574, 591 and 670; 523, 647 and 667; 575, 591 and 659; 537, 591 and 659; 523, 635 and 670; 576, 591 and 659; 577, 606 and 659; 523, 648 and 679; 523 , 592 and 659; 523, 595 and 659; 523, 600 and 659; 523, 649 and 664; 578, 641 and 659; 523, 591 and 667; 523, 606 and 660; 523, 650 and 656; 579, 621 and 671; 580, 591 and 660; 527, 591 Japanese 659; 581, 595 Japanese 659; 582, 640 Japanese 664; 583, 651 Japanese 659; 534, 591 Japanese 659; 584, 591 Japanese 671; 523, 591 Japanese 680; 523, 591 Japanese 681; 585, 591 Japanese 659; 523, 649 Japanese 659; 586, 591 Japanese 666;587, 652 and 659; 588, 638 and 659; 523, 623 and 664; 523, 591 and 682; 553, 653 and 659; 523, 654 and 659; 523, 648 and 659; 560, 591 and 659; 580, 606 and 659; 589, 593 and 661; 523, 637 and 676; 590, 622 and 659; 555, 591 and 661; 523, 615 and 672; 523, 626 and 668; 523, 655 and 659; or 523, 606 and 680.

[0033] In the embodiments, VL comprises the amino acid sequences CDRL1, CDRL2, and CDRL3 shown in the following items, respectively: SEQ ID NO: 523, 591 and 656; 523, 592 and 657; 523, 593 and 658; 523, 591 and 659; 523, 594 and 659 ;523, 595 and 660; 523, 596 and 659; 524, 591 and 659; 523, 591 and 661; 523, 591 and 66 2; 523, 597 and 658; 523, 598 and 662; 525, 599 and 659; 523, 600 and 663; 523, 591 and 6 64; 523, 601 and 659; 526, 597 and 665; 523, 602 and 659; 527, 591 and 661; 528, 591 and 6 62; 529, 603 and 662; 523, 604 and 666; 523, 605 and 667; 530, 606 and 659; 523, 607 and 659; 523, 608 and 659; 523, 609 and 662; 531, 591 and 663; 523, 608 and 661; 523, 610 and 659; 523, 611 and 668; 523, 611 and 658; 523, 596 and 662; 523, 612 and 667; 523, 61 3 and 668; 523, 591 and 669; 523, 591 and 663; 523, 614 and 659; 532, 615 and 662; 523, 61 6 and 670; 523, 591 and 668; 523, 617 and 671; 533, 595 and 659; 523, 618 and 659; 534, 6 19 and 662; 535, 620 and 659; 536, 621 and 659; 537, 603 and 671; 523, 622 and 659; 523, 617 and 659; 523, 623 and 659; 538, 607 and 672; 523, 616 and 671; 523, 624 and 659; 523 , 620 and 659; 523, 625 and 660; 523, 602 and 671; 523, 611 and 663; 523, 626 and 670; 523 , 606 and 673; 523, 627 and 671; 523, 628 and 671; 539, 591 and 662; 523, 591 and 670; 52 3, 611 and 659; 537, 613 and 671; 540, 598 and 659; 541, 591 and 659; 542, 629 and 659; 5 23, 591 and 671; 523, 630 and 667; 543, 631 and 659; 523, 632 and 664; 523, 597 and 661; 523, 633 and 659; 544, 607 and 659; 523, 630 and 659; 523, 591 and 665; 523, 610 and 674;523, 634 and 671; 545, 591 and 661; 523, 635 and 667; 546, 591 and 659; 523, 636 and 664; 547, 591 and 663; 548, 619 and 659; 523, 637 and 659; 523, 638 and 659; 549, 591 and 659; 550, 591 and 675; 551, 591 and 659; 552, 591 and 659; 553, 591 and 676; 554, 591 and 659; 523, 591 and 676; 555, 606 and 659; 556, 591 and 659; 523, 637 and 677; 557, 591 and 659; 558, 591 and 6 59; 523, 591 and 677; 553, 639 and 659; 549, 591 and 667; 559, 617 and 666; 523, 591 and 672; 523, 606 and 659; 523, 592 and 670; 560, 591 and 667; 530, 591 and 659; 561, 603 and 666; 5 62, 591 and 659; 523, 616 and 660; 523, 602 and 677; 523, 616 and 659; 523, 630 and 660; 563, 591 and 659; 523, 640 and 659; 564, 591 and 659; 523, 641 and 677; 565, 591 and 662; 523, 64 2 and 664; 566, 643 and 659; 523, 644 and 667; 567, 606 and 659; 568, 591 and 659; 569, 645 and 659; 523, 603 and 659; 570, 628 and 678; 571, 630 and 663; 572, 591 and 664; 573, 591 and 67 0; 523, 646 and 659; 574, 591 and 670; 523, 647 and 667; 575, 591 and 659; 537, 591 and 659; 523, 635 and 670; 576, 591 and 659; 577, 606 and 659; 523, 648 and 679; 523, 592 and 659; 523 , 595 and 659; 523, 600 and 659; 523, 649 and 664; 578, 641 and 659; 523, 591 and 667; 523, 606 and 660; 523, 650 and 656; 579, 621 and 671; 580, 591 and 660; 527, 591 and 659; 581, 595 Japanese 659; 582, 640 and 664; 583, 651 and 659; 534, 591 and 659; 584, 591 and 671; 523, 591 and 680; 523, 591 and 681; 585, 591 and 659; 523, 649 and 659; 586, 591 and 666; 587, 652 and 659;588, 638 and 659; 523, 623 and 664; 523, 591 and 682; 553, 653 and 659; 523, 654 and 659; 523, 648 and 659; 560, 591 and 659; 580, 606 and 659; 589, 593 and 661; 523, 637 and 676; 590, 622 and 659; 555, 591 and 661; 523, 615 and 672; 523, 626 and 668; 523, 655 and 659; or 523, 606 and 680. ;

[0034] In one embodiment, the VL comprises any of the amino acid sequences shown in SEQ ID NO: 181-368.

[0035] In the embodiments, the antibodies or peptides disclosed herein are conjugated with cytotoxic agents, cell growth inhibitors, toxins, radionuclides, or detectable markers.

[0036] In one aspect, this disclosure provides a polynucleotide that encodes the VH and / or VL of an antibody or polypeptide disclosed herein.

[0037] In one aspect, this disclosure provides a vector comprising the polynucleotides disclosed herein.

[0038] In one embodiment, the vector is an adeno-associated virus (AAV) vector.

[0039] In one aspect, this disclosure provides a recombinant host cell comprising: (a) Polynucleotides disclosed in this article; (b) The medium in which this article is published; (c) a first polynucleotide encoding the VH or heavy chain of the antibody disclosed herein; and a second polynucleotide encoding the VL or light chain of the antibody disclosed herein; or (d) A first vector comprising a first polynucleotide encoding a VH or heavy chain of an antibody disclosed herein; and a second vector comprising a second polynucleotide encoding a VL or light chain of an antibody disclosed herein.

[0040] In one aspect, this disclosure provides a pharmaceutical composition comprising an antibody or peptide disclosed herein, a polynucleotide disclosed herein, a vector disclosed herein, or a host cell disclosed herein, and a pharmaceutically acceptable carrier or excipient.

[0041] In one aspect, this disclosure provides a method for producing an antibody or polypeptide, the method comprising culturing a host cell disclosed herein under suitable conditions to allow the polynucleotide to be expressed and to produce the antibody or polypeptide.

[0042] In one aspect, this disclosure provides a method for inhibiting PC activity in a subject, the method comprising administering to the subject an effective amount of the antibody or peptide disclosed herein, the polynucleotide disclosed herein, the vector disclosed herein, the host cell disclosed herein, or the pharmaceutical composition disclosed herein.

[0043] In one aspect, this disclosure provides a method for treating a subject with an inflammatory or degenerative disease, the method comprising administering to the subject an effective amount of the disclosed antibody or peptide, the disclosed polynucleotide, the disclosed vector, the disclosed host cell, or the disclosed pharmaceutical composition.

[0044] In one aspect, this disclosure provides the use of the antibodies or peptides disclosed herein, the polynucleotides disclosed herein, the vectors disclosed herein, the host cells disclosed herein, or the pharmaceutical compositions disclosed herein for the manufacture of a medicament for the treatment of a subject with an inflammatory or degenerative disease.

[0045] In one aspect, this disclosure provides antibodies or peptides disclosed herein, polynucleotides disclosed herein, vectors disclosed herein, host cells disclosed herein, or pharmaceutical compositions disclosed herein for use in medicine.

[0046] In one aspect, this disclosure provides antibodies or peptides disclosed herein, polynucleotides disclosed herein, vectors disclosed herein, host cells disclosed herein, or pharmaceutical compositions disclosed herein for use in treating inflammatory or degenerative diseases in a subject of need.

[0047] In one embodiment, the inflammatory or degenerative disease is selected from the group consisting of: organ reperfusion injury such as myocardial infarction-induced reperfusion injury, Kawasaki disease, non-alcoholic steatohepatitis (NASH), organ transplant rejection, atherosclerosis, type I or type II diabetes, rheumatoid arthritis, osteoporosis, acute lung injury, asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, pain, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), age-related macular degeneration (AMD), stroke, Huntington's disease, frontotemporal dementia (FTD), multiple sclerosis (MS), isolated demyelinating diseases of the central nervous system, osteoarthritis, Crohn's disease, and ulcerative colitis. Detailed Implementation

[0048] This disclosure provides a polypeptide that specifically binds to PC ( For example(Antibodies). Also provided are pharmaceutical compositions comprising these peptides, nucleic acids encoding these peptides, expression vectors and host cells for preparing these peptides, and methods for treating subjects using these peptides. The peptides provided herein are particularly advantageous because they bind to PCs with high affinity, exhibit good stability, anti-stress and immunogenic properties, and can be produced in high yields. The peptides provided herein are particularly useful for treating inflammatory or degenerative diseases in subjects.

[0049] As used herein, the term "antibody" includes full-length antibodies, antigen-binding fragments of full-length antibodies, and molecules containing antibody CDR, VH region, and / or VL region. Examples of antibodies include, but are not limited to, monoclonal antibodies, recombinant antibodies, monospecific antibodies, multispecific antibodies (including bispecific antibodies), human antibodies, humanized antibodies, chimeric antibodies, immunoglobulins, synthetic antibodies, tetrameric antibodies containing two heavy chain molecules and two light chain molecules, antibody light chain monomers, antibody heavy chain monomers, antibody light chain dimers, antibody heavy chain dimers, antibody light chain-antibody heavy chain pairs, intracellular antibodies, heteroconjugate antibodies, antibody-drug conjugates, single-domain antibodies, monovalent antibodies, single-chain antibodies or single-chain Fv (scFv), camel-derived antibodies, affinity molecules, Fab fragments, F(ab')2 fragments, disulfide-linked Fv (sdFv), and anti-idiotypic (anti-Id) antibodies (including...). For example Anti-Id antibodies, and antigen-binding fragments of any of the above. In some embodiments, the antibodies described herein refer to a population of polyclonal antibodies. Antibodies can be any type of immunoglobulin molecule ( For example IgG, IgE, IgM, IgD, IgA or IgY), any class ( For example IgG1, IgG2, IgG3, IgG4, IgA1 or IgA2) or any subclass ( For example (IgG2a or IgG2b). In some embodiments, the antibodies described herein are IgG antibodies or their class (IgG2a or IgG2b). For example (or a subclass of human IgG1 or IgG4). In a specific embodiment, the antibody is a humanized monoclonal antibody. In another specific embodiment, the antibody is a human monoclonal antibody.

[0050] "Multispecific antibodies" are antibodies that specifically bind to two or more different antigens or two or more different regions of the same antigen. For exampleBispecific antibodies. Multispecific antibodies include bispecific antibodies containing two different antigen-binding sites (excluding the Fc region). Multispecific antibodies may include, for example, recombinant antibodies, human antibodies, humanized antibodies, surface-reconstructed antibodies, chimeric antibodies, immunoglobulins, synthetic antibodies, tetramer antibodies containing two heavy chains and two light chains, antibody light chain monomers, heteroconjugated antibodies, linked single-chain antibodies or linked single-chain Fv (scFv), camelified antibodies, affinity molecules, linked Fab fragments, F(ab')2 fragments, chemically linked Fvs, and disulfide-linked Fvs (sdFvs). Multispecific antibodies can be any type of immunoglobulin molecule ( For example IgG, IgE, IgM, IgD, IgA or IgY), any class ( For example IgG1, IgG2, IgG3, IgG4, IgA1 or IgA2) or any subclass ( For example IgG2a or IgG2b). In some embodiments, the multispecific antibodies described herein are IgG antibodies or their class ( ). For example (or subclasses of human IgG1, IgG2, or IgG4).

[0051] As used herein, the term "CDR" or "complementarity-determining region" refers to a discontinuous antigen-binding site found within the variable region of heavy and light chain polypeptides. For example, Kabat... et al. J. Biol. Chem. 252, 6609-6616 (1977) and Kabat et al. Sequences of protein of immunological interest.(1991), Chothia et al. J. Mol. Biol. 196:901-917 (1987) and MacCallum et al. These specific regions have been described in J. Mol. Biol. 262:732-745 (1996), all of which are incorporated herein by reference in their full text, wherein definitions include overlaps or subsets of amino acid residues when compared with one another. In some embodiments, the term “CDR” is as defined by MacCallum et al. J. Mol. Biol. 262:732-745 (1996) and Martin A. “Protein Sequence and StructureAnalysis of Antibody Variable Domains,” in Antibody EngineeringCDR is defined in Kontermann and Dübel (eds.), Chapter 31, pp. 422-439, Springer-Verlag, Berlin (2001). In some embodiments, the term "CDR" is as defined by Kabat. et al. J. Biol. Chem. 252, 6609-6616 (1977) and Kabat et al. The CDR is defined as in Sequences of Protein of Immunological Interest (1991). In some embodiments, different conventions are used to define the heavy chain CDR and light chain CDR of the antibody. In some embodiments, the heavy chain CDR and / or light chain CDR are defined by performing structural analysis of the antibody and identifying predicted affinity for the target molecule (…). For example The CDRs are defined by the residues in the variable region that are in contact with the epitope region of the PC. CDRH1, CDRH2, and CDRH3 represent heavy chain CDRs, and CDRL1, CDRL2, and CDRL3 represent light chain CDRs.

[0052] As used herein, the terms “variable region” and “variable domain” are used interchangeably and are common in the art. A variable region typically refers to a portion of an antibody, generally a portion of the light or heavy chain, typically about 110 to 120 or 110 to 125 amino acids from the amino terminus of the mature heavy chain, and about 90 to 115 amino acids from the mature light chain. These vary considerably in sequence between antibodies and are responsible for the binding and specificity of a particular antibody to its specific antigen. Sequence variability is concentrated in regions called complementarity-determining regions (CDRs), while more highly conserved regions within the variable region are called frame regions (FRs). Without wishing to be bound by any particular mechanism or theory, it is believed that the CDRs of the light and heavy chains are primarily responsible for antibody-antigen interactions and specificity. In some embodiments, the variable region is a human variable region. In some embodiments, the variable region comprises rodent or mouse CDRs and human frame regions (FRs). In some embodiments, the variable region comprises rodent or mouse CDRs and primate (…) For example (Non-human primates) Framework region (FR).

[0053] As used in this article, the terms "VH" and "VL" refer to the variable regions of the antibody heavy chain and light chain, respectively, such as Kabat. et al. For example The document described in (1991) Sequences of Proteins of Immunological Interest (NIH Publication No. 91-3242, Bethesda) is incorporated herein by reference in its entirety.

[0054] As used herein, the term "constant region" is common in the art. The constant region is the antibody portion. For example The carboxyl terminus of the light chain and / or heavy chain does not directly participate in antibody-antigen binding, but it can exhibit various effector functions, such as interaction with Fc receptors. For example ,Fc γ receptor).

[0055] As used herein, the term "heavy chain" when referring to antibodies can refer to any different type based on the amino acid sequence of the constant region. For example α (α), δ (δ), ε (ε), γ (γ), and µ (µ) represent the IgA, IgD, IgE, IgG, and IgM antibody classes, respectively, including IgG subclasses. For example IgG1, IgG2, IgG3 and IgG4.

[0056] As used herein, the term "light chain" when referring to antibodies can refer to any different type based on the amino acid sequence of the constant region. For example , κ (κ) or λ (λ). The amino acid sequence of the light chain is well known in the art. In a specific embodiment, the light chain is the human light chain.

[0057] As used herein, the terms “specific binding,” “specific recognition,” “immune-specific binding,” and “immune-specific recognition” are similar terms in the antibody context and refer to binding to an antigen ( For example A molecule that binds to an epitope or immune complex, as understood by those skilled in the art. For example, a molecule that binds specifically to an antigen may bind to other peptides or polypeptides, typically with lower affinity, such as through... For example Immunoassay, BIAcore ® The determination was made using a KinExA 3000 instrument (Sapidyne Instruments, Boise, ID) or other assays known in the art. In a specific embodiment, the molecules that specifically bind to the antigen are in at least two logarithmic proportions (...). For example (a factor of 10), 2.5 logarithms, 3 logarithms, 4 logarithms of K A Or greater than the K value when the molecule nonspecifically binds to another antigen. A It binds to the antigen.

[0058] As used in this article, the term "affinity" refers to a single binding site of a molecule ( For example Antibody) and its binding partner ( et al.The total strength of non-covalent interactions between antigens. Unless otherwise stated, as used herein, "binding affinity" refers to intrinsic binding affinity, which reflects the binding pair (antigens). et al. Affinity refers to the 1:1 interaction between members of an antibody and an antigen. The affinity of molecule X for its partner Y can typically be represented by the dissociation constant (Kd). Affinity can be measured by methods known in the art, including those described herein.

[0059] As used herein, the term "EU numbering system" refers to the EU numbering convention for the constant regions of antibodies, such as Edelman, GM. For example Proc. Natl. Acad. USA, 63, 78-85 (1969) and Kabat For example As described in Sequences of Proteins of Immunological Interest, US Dept. Health and Human Services, 5th edition, 1991, each of these references is incorporated herein by reference in its entirety.

[0060] As used herein, the term "treat / treating / treatment" refers to the therapeutic or preventative measures described herein. A method of "treatment" involves administering antibodies to a subject who has a disease or ailment or is susceptible to such a disease or ailment in order to prevent, cure, delay, reduce, or mitigate the severity of the disease or ailment or a relapse of the disease or ailment, or to improve one or more of its symptoms, or to prolong the subject's survival beyond what would be expected in the absence of such treatment.

[0061] As used in this article, the term "effective amount" in the context of administering a therapy to a subject refers to the amount of therapy that achieves the desired preventive or therapeutic effect.

[0062] As used herein, the term "subject" includes any human or non-human animal. In some embodiments, the subject is a human or a non-human mammal. In some embodiments, the subject is a human.

[0063] As used herein, with respect to antibodies or polynucleotides, the term "isolated" refers to the presence of one or more contaminants in the natural source of the antibody or polynucleotide. et al.Antibodies or polynucleotides isolated from polypeptides, polynucleotides, lipids, or carbohydrates, etc. All instances of "isolated antibodies" described herein are also expected to be, but not necessarily, isolated antibodies. All instances of "isolated polynucleotides" described herein are also expected to be, but not necessarily, isolated polynucleotides. All instances of "antibodies" described herein are also expected to be, but not necessarily, isolated antibodies. All instances of "polynucleotides" described herein are also expected to be, but not necessarily, isolated polynucleotides.

[0064] Mathematical algorithms can be used to process two sequences ( For example The determination of the "percentage of identity" between two sequences (amino acid sequences or nucleic acid sequences). Specific, non-limiting examples of mathematical algorithms used to compare two sequences are those of Karlin S and Altschul SF (1990) PNAS 87: 2264-2268, modified as in Karlin S and Altschul SF (1993) PNAS 90: 5873-5877, each of which is incorporated herein by reference in its entirety. This algorithm is incorporated in Altschul SF. For example The NBLAST and XBLAST procedures in (1990) J Mol Biol 215: 403 are incorporated herein by reference in their entirety. The NBLAST nucleotide procedure parameter set ( et al. For a score of 100 and a word length of 12, perform a BLAST nucleotide search to obtain nucleotide sequences homologous to the nucleic acid molecules described herein. The XBLAST procedure parameter set ( Idem A BLAST protein search was performed with a score of 50 and a word length of 3 to obtain amino acid sequences homologous to the protein molecules described herein. To obtain gap alignments for comparative purposes, methods such as those in Altschul SF can be used. For example The gap BLAST described in (1997) Nuc Acids Res 25: 3389-3402 is incorporated herein by reference in its entirety. Alternatively, PSI BLAST can be used to perform iterative searches to detect distance relationships between molecules. See, for example When using BLAST, gap BLAST, and PSI Blast procedures, the corresponding procedures can be used ( For example The default parameters for XBLAST and NBLAST are ( et al.(See the National Center for Biotechnology Information (NCBI) website, ncbi.nlm.nih.gov). Another specific, non-limiting example of a mathematical algorithm for sequence alignment is the algorithm of Myers and Miller, 1988, CABIOS 4:11-17, which is incorporated herein by reference in its entirety. This algorithm is incorporated into the ALIGN program (version 2.0), which is part of the GCG sequence alignment software package. When comparing amino acid sequences using the ALIGN program, the PAM120 weighted residue table, vacancy length penalty of 12, and vacancy penalty of 4 can be used.

[0065] Whether gaps are allowed or not, techniques similar to those described above can be used to determine the percentage of identity between two sequences. When calculating the percentage of identity, typically only exact matches are counted.

[0066] In one aspect, this disclosure provides a polypeptide that specifically binds to PC ( et al. (Antibody). The amino acid sequences of exemplary antibodies are listed in Table 1.

[0067]

[0068]

[0069]

[0070]

[0071]

[0072]

[0073]

[0074]

[0075]

[0076]

[0077]

[0078]

[0079] In some embodiments, this disclosure provides an antibody that specifically binds to PC, the antibody comprising a VH domain including one, two, or all three CDRs of the VH domains listed in Table 1. In some embodiments, the antibody comprises CDRH1 of the VH domains listed in Table 1. In some embodiments, the antibody comprises CDRH2 of the VH domains listed in Table 1. In some embodiments, the antibody comprises CDRH3 of the VH domains listed in Table 1.

[0080] In some embodiments, this disclosure provides an antibody that specifically binds to PC, the antibody comprising a VL domain including one, two, or all three CDRs of the VL domains listed in Table 1. In some embodiments, the antibody comprises CDRL1 of the VL domains listed in Table 1. In some embodiments, the antibody comprises CDRL2 of the VL domains listed in Table 1. In some embodiments, the antibody comprises CDRL3 of the VL domains listed in Table 1.

[0081] The individual CDRs of the antibodies disclosed herein can be determined according to any CDR numbering scheme known in the art.

[0082] In some embodiments, one or more of the CDRs of the antibodies disclosed herein can be based on Kabat. See , J. Biol. Chem. 252, 6609-6616 (1977) and Kabat For example The Sequences of Protein of Immunological Interest (1991) are used to determine this, and each of these references is incorporated herein by reference in its entirety.

[0083] In some embodiments, this disclosure provides antibodies that specifically bind to PC and comprise a CDR of an antibody as disclosed in Table 1 herein, as determined by the Kabat numbering scheme.

[0084] In some embodiments, one or more of the CDRs of the antibodies disclosed herein may be determined according to the Chothia numbering scheme, which refers to the position of the immunoglobulin structural loop (CDR). et al. , et al. , Chothia C and Lesk AM, (1987), JMol Biol 196: 901-917; Al-Lazikani B et al. (1997) J Mol Biol 273: 927-948; Chothia C et al. (1992) J Mol Biol 227: 799-817; Tramontano A See also(1990) J MolBiol 215(1): 175-82; and U.S. Patent No. 7,709,226, all of which are incorporated herein by reference in their entirety.

[0085] In some embodiments, this disclosure provides antibodies that specifically bind to PC and comprise a CDR of antibodies disclosed in Table 1 herein, as determined by the Chothia numbering system.

[0086] In some embodiments, one or more of the CDRs of the antibodies disclosed herein can be based on MacCallum RM. For example (1996) J Mol Biol 262: 732-745, which is cited and incorporated in its entirety into this paper. Antibody Engineering et al. , et al. , Martin A. “Protein Sequence and Structure Analysis of AntibodyVariable Domains,” For example Kontermann and Dübel, eds., Chapter 31, pp. 422-439, Springer-Verlag, Berlin (2001), which is incorporated herein by reference in its entirety.

[0087] In some embodiments, this disclosure provides antibodies that specifically bind to PC and comprise a CDR of an antibody as disclosed in Table 1 herein, as determined by the MacCallum numbering system.

[0088] In some embodiments, the CDR of the antibodies disclosed herein can be determined according to the IMGT numbering system, as described in: Lefranc MP, (1999) The Immunologist 7: 132-136; Lefranc MP For example (1999) Nucleic Acids Res 27: 209-212, each of which is incorporated herein by reference in its entirety; and Lefranc MP For example (2009) Nucleic Acids Res 37: D1006-D1012.

[0089] In some embodiments, this disclosure provides antibodies that specifically bind to PC and comprise a CDR of an antibody as disclosed in Table 1 herein, as determined by the IMGT numbering system.

[0090] In some embodiments, the CDR of the antibody disclosed herein can be determined according to the AbM numbering scheme, which refers to the AbM hypervariable region, representing a compromise between the Kabat CDR and the Chothia structural loop, and is used by the AbM antibody modeling software of Oxford Molecular (Oxford Molecular Group, Inc.), which is incorporated herein by reference in its entirety.

[0091] In some embodiments, this disclosure provides antibodies that specifically bind to PC and comprise a CDR of an antibody as disclosed in Table 1 herein, as determined by the AbM numbering scheme.

[0092] In some embodiments, the CDR of the antibodies disclosed herein may be determined according to the AHo numbering system, as described in Honegger and Plückthun, A., J. Mol.Biol.309:657-670 (2001), which is incorporated herein by reference in its entirety.

[0093] In some embodiments, this disclosure provides antibodies that specifically bind to PC and comprise a CDR of antibodies disclosed in Table 1 herein as determined by the AHo numbering system.

[0094] In some embodiments, the individual CDRs of the antibodies disclosed herein are determined independently according to one of the Kabat, Chothia, MacCallum, IMGT, AHo, or AbM numbering schemes or by structural analysis of the molecule, wherein the structural analysis identifies residues in the variable region predicted to contact the epitope region of the PC.

[0095] In some embodiments, this disclosure provides an antibody or peptide that specifically binds to PC, the antibody or peptide comprising: VH, which comprises the CDRH1, CDRH2, and CDRH3 amino acid sequences of any one of the VH amino acid sequences shown in SEQ ID NO: 1-180; and VL, which comprises the CDRL1, CDRL2, and CDRL3 amino acid sequences of any one of the VL amino acid sequences shown in SEQ ID NO: 181-368, wherein each CDR is independently determined according to one of the Kabat, Chothia, MacCallum, IMGT, AHo, or AbM numbering schemes or by structural analysis of the molecule, wherein the structural analysis identifies residues in the variable region predicted to contact the epitope region of PC.

[0096] In some embodiments, this disclosure provides antibodies or peptides that specifically bind to PC, wherein the antibody or peptide comprises the amino acid sequences CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, respectively, as shown in the VH and VL amino acid sequences in the following: SEQ ID NO: 1 and 181; 2 and 182; 3 and 183; 4 and 184; 5 and 185; 1 and 184; 6 and 184; 1 and 186; 7 and 187; 8 and 188; 9 and 189; 10 and 190; 4 and 191; 11 and 192; 12 and 193; 13 and 194; 14 and 195; 15 and 1 96; 16 and 184; 17 and 197; 18 and 198; 1 and 199; 19 and 200; 20 and 201; 21 and 202; 22 and 203; 23 and 204; 24 and 205; 25 and 184; 4 and 206; 26 and 207; 27 and 208; 28 and 209; 9 and 210 35 and 220 9 and 224; 40 and 184; 41 and 225; 8 and 226; 42 and 227; 35 and 228; 43 and 229; 4 and 230; 9 and 231; 8 and 232; 1 and 233; 8 and 234; 44 and 184; 1 and 235; 45 and 236; 30 and 237; 46 and 184; 4 7 & 238; 48 & 239; 1 & 230; 49 & 190; 44 & 240; 50 & 184; 51 & 241; 52 & 242; 53 & 243; 54 & 184; 55 & 244; 56 & 245; and 250; 61 and 184; 35 and 251; 62 and 252; 1 and 253; 63 and 254; 64 and 181; 65 and 255; 66 and 256; 67 and 257; 68 and 198; 35 and 258; 69 and 259; 70 and 260; 71 and 261; 72 and 262; 73 and 263; 74 and 264; 75 and 265; 76 and 266; 77 and 267; 4 and 205; 78 and 268; 1 and 269; 27 and 269; 79 and 269; 80 and 270; 81 and 269; 22 and 269; 82 and 269; 83 and 271; 84 and 272; 1 and 2 73; 8 and 274; 8 and 275; 22 and 276; 8 and 277; 85 and 278; 86 and 279; 87 and 269; 88 and 280; 89 and 269; 60 and 281; 90 and 269; 91 and 282; 22 and 283; 92 and 269; 93 and 284; 94 and 285;95 and 286; 96 and 269; 73 and 287; 97 and 288; 68 and 289; 98 and 269; 99 and 290; 100 and 291; 4 and 292; 4 and 289; 101 and 284; 66 and 289; 89 and 293; 102 and 294; 103 and 269; 22 and 295; 104 and 296; 105 and 297; 106 and 270; 107 and 269; 67 and 269; 62 and 298; 66 and 269; 108 and 299; 109 and 300; 110 and 301; 111 and 302; 112 and 269; 113 and 303; 1 and 304; 72 and 305; 114 and 306; 1 15 / 307; 116 / 269; 117 / 308; 118 / 269; 110 / 309; 119 / 310; 120 / 311; 121 / 269; 122 / 312; 123 / 289; 9 / 313; 124 / 314; 120 / 289; 125 / 315; 110 / 316; 126 / 317; 127 / 318; 49 / 319; 128 / 320; 9 / 321; 22 / 322; 129 / 323; 130 / 269; 131 / 324; 132 / 325; 133 / 326; 134 / 327; 53 / 328; 135 / 272; 136 / 329; 4 / 301 ; 137 & 330; 138 & 269; 1 & 284; 22 & 331; 139 & 269; 140 & 332; 141 & 269; 142 & 333; 143 & 334; 144 & 335; 101 & 298; 1 & 336; 145 & 269; 146 & 337; 147 & 269; 17 & 338; 22 & 320; 4 & 339; 148 & 340; 149 & 341; 150 & 342; 151 & 343; 152 & 344; 94 & 289; 153 & 345; 154 & 346; 155 & 347; 22 & 348; 89 & 282; 156 & 349; 157 & 296; 158 and 350; 159 and 329; 24 and 351; 160 and 352; 161 and 269; 162 and 353; 163 and 269; 1 and 354; 164 and 355; 165 and 269; 1 and 356; 166 and 357; 167 and 358; 110 and 334; 87 and 359; 168 and 360; 169 and 269; 170 and 269; 171 and 269; 172 and 361; 8 and 362; 173 and 304; 174 and 269; 1 and 363; 175 and 364; 176 and 365; 177 and 269; 178 and 366; 179 and 269; 180 and 367; or 89 and 368.

[0097] In some embodiments, this disclosure provides an antibody or peptide that specifically binds to PC, wherein the antibody or peptide comprises a VH containing the amino acid sequences CDRH1, CDRH2, and CDRH3 shown in the following items: SEQ ID NO: 369, 428 and 484; 370, 429 and 485; 371, 428 and 486; 372, 428 and 484; 373, 429 and 484; 374, 430 and 484; 375, 428 and 487; 376, 428 and 484; 377, 428 and 484; 378, 372, 428 and 484; 381, 428 and 491; 377, 428 and 4 92; 376, 433 and 484; 383, 434 and 484; 383, 428 and 484; 384, 435 and 484; 369, 436 and 484; 372, 437 and 487; 385, 428 and 493; 386, 428 and 484; 372, 437 and 484; 3 87, 428 and 484; 385, 428 and 484; 372, 438 and 484; 388, 428 and 494; 369, 439 and 484; 389, 428 and 484; 381, 428 and 484; 376, 440 and 495; 390, 441 and 484; 370, 44 2 and 484; 391, 428 and 484; 392, 432 and 484; 377, 443 and 484; 393, 428 and 484; 383, 444 and 489; 394, 428 and 484; 383, 444 and 496; 376, 434 and 484; 395, 445 and 49 7; 396, 446 and 487; 392, 428 and 484; 393, 428 and 498; 376, 428 and 495; 369, 440 and 484; 397, 428 and 484; 389, 447 and 484; 398, 448 and 492; 373, 449 and 490; 399 , 428 and 484; 400, 450 and 484; 401, 428 and 484; 390, 428 and 484; 400, 428 and 499; 384, 429 and 484; 402, 436 and 484; 381, 451 and 484; 403, 428 and 484; 369, 429 and 484; 404, 429 and 484; 372, 429 and 484; 388, 428 and 484; 405, 451 and 484; 406, 428 and 484; 400, 428 and 484; 404, 428 and 484; 384, 432 and 500; 376, 452 and 501;407, 428 and 484; 375, 428 and 484; 408, 428 and 484; 369, 428 and 497; 403, 453 and 484; 402, 454 and 484; 383, 434 and 500; 376, 455 and 502; 383, 435 and 484; 376, 428 and 490; 369, 428 and 503; 409, 428 and 484; 383, 428 and 504; 369, 434 and 484; 369, 456 and 484; 370, 457 and 484; 404, 458 and 499; 410, 428 and 484; 383, 459 and 484; 407, 428 and 489; 374, 434 and 4 84; 411, 460 and 505; 383, 428 and 485; 386, 460 and 490; 412, 455 and 493; 383, 461 and 484; 376, 437 and 484; 383, 462 and 500; 400, 463 and 484; 376, 464 and 484; 400, 434 and 506; 3 69, 436 and 507; 377, 465 and 484; 413, 459 and 484; 369, 452 and 484; 414, 466 and 484; 373, 428 and 484; 415, 428 and 489; 369, 428 and 491; 403, 458 and 508; 392, 467 and 484; 369, 45 2 and 509; 388, 468 and 490; 377, 440 and 484; 370, 428 and 484; 384, 467 and 487; 392, 469 and 510; 378, 464 and 484; 416, 434 and 484; 370, 428 and 511; 376, 428 and 502; 417, 428 and 48 4; 376, 428 and 512; 381, 428 and 493; 383, 470 and 501; 404, 471 and 484; 418, 428 and 484; 383, 472 and 513; 419, 428 and 484; 372, 473 and 484; 383, 474 and 484; 420, 434 and 484; 370 , 428 and 514; 369, 475 and 484; 421, 436 and 484; 378, 452 and 484; 376, 476 and 515; 376, 428 and 504; 422, 469 and 484; 369, 428 and 516; 405, 460 and 484; 413, 431 and 484; 406, 429 Japanese 484; 383, 428 and 517; 377, 437 and 518; 369, 477 and 487; 403, 464 and 484; 369, 454 and 484; 372, 478 and 519; 423, 429 and 484; 382, ​​434 and 484; 424, 479 and 484; 376, 429 and 484;425, 428 and 484; 403, 428 and 520; 417, 460 and 484; 409, 460 and 484; 404, 452 and 484; 383, 428 and 521; 372, 480 and 493; 369, 477 and 484; 369, 481 and 484; 384, 452 and 484; 377, 482 and 484; 410, 483 and 484; 384, 428 and 489; 426, 429 and 484; 427, 428 and 484; 373, 452 and 506; 369, 429 and 521; 405, 428 and 522; 376, 428 and 510; 384, 428 and 484; 410, 429 and 484; or 400, 452 and 484.

[0098] In some embodiments, this disclosure provides an antibody or polypeptide that specifically binds to PC, wherein the antibody or polypeptide comprises a VL containing the amino acid sequences CDRL1, CDRL2, and CDRL3 as shown in the following items: SEQ ID NO: 523, 591 and 656; 523, 592 and 657; 523, 593 and 658; 523, 591 and 659; 523, 594 and 659; 523, 595 and 660; 523, 596 and 659; 524, 591 and 659; 523, 591 and 661; 523, 591 and 662; 523, 597 and 658; 523, 598 and 662; 525, 599 and 659; 523, 600 and 663; 523, 591 and 664; 523, 601 and 659; 526, 597 and 665; 523, 602 and 659; 527, 591 and 6 523, 608 and 659; 523, 609 and 662; 531, 591 and 663; 5 23, 608, and 661; 523, 610, and 659; 523, 611, and 668; 523, 611, and 658; 523, 596, and 662; 523, 612, and 667; 4 and 659; 532, 615 and 662; 523, 616 and 670; 523, 591 and 668; 523, 617 and 671; 533, 595 and 659; 523, 618 and 659; 534, 619 and 662; 535, 620 and 659; 536, 621 and 65 9; 537, 603 and 671; 523, 622 and 659; 523, 617 and 659; 523, 623 and 659; 538, 607 and 672; 523, 616 and 671; 523, 624 and 659; 523, 620 and 659; 523, 625 and 660; 523 , 602 and 671; 523, 611 and 663; 523, 626 and 670; 523, 606 and 673; 523, 627 and 671; 523, 628 and 671; 539, 591 and 662; 523, 591 and 670; 523, 611 and 659; 537, 613 and 671; 540, 598 and 659; 541, 591 and 659; 542, 629 and 659; 523, 591 and 671; 523, 630 and 667; 543, 631 and 659; 523, 632 and 664; 523, 597 and 661; 523, 633 and 659;544, 607 and 659; 523, 630 and 659; 523, 591 and 665; 523, 610 and 674; 523, 634 and 671; 545, 591 and 661; 523, 635 and 667; 546, 591 and 659; 523, 636 and 664; 547, 591 and 663; 548, 619 and 659; 523, 637 and 659; 523, 638 and 659; 549, 591 and 659; 550, 591 and 675; 551, 591 and 659; 552, 591 and 659; 553, 591 and 676; 554, 591 and 659; 523, 591 and 676; 555, 606 and 6 59; 556, 591 and 659; 523, 637 and 677; 557, 591 and 659; 558, 591 and 659; 523, 591 and 677; 553, 639 and 659; 549, 591 and 667; 559, 617 and 666; 523, 591 and 672; 523, 606 and 659; 5 23, 592 and 670; 560, 591 and 667; 530, 591 and 659; 561, 603 and 666; 562, 591 and 659; 523, 616 and 660; 523, 602 and 677; 523, 616 and 659; 523, 630 and 660; 563, 591 and 659; 523, 64 0 and 659; 564, 591 and 659; 523, 641 and 677; 565, 591 and 662; 523, 642 and 664; 566, 643 and 659; 523, 644 and 667; 567, 606 and 659; 568, 591 and 659; 569, 645 and 659; 523, 603 and 65 9; 570, 628 and 678; 571, 630 and 663; 572, 591 and 664; 573, 591 and 670; 523, 646 and 659; 574, 591 and 670; 523, 647 and 667; 575, 591 and 659; 537, 591 and 659; 523, 635 and 670; 576 , 591 and 659; 577, 606 and 659; 523, 648 and 679; 523, 592 and 659; 523, 595 and 659; 523, 600 and 659; 523, 649 and 664; 578, 641 and 659; 523, 591 and 667; 523, 606 and 660; 523, 650 Japanese 656; 579, 621 Japanese 671; 580, 591 Japanese 660; 527, 591 Japanese 659; 581, 595 Japanese 659; 582, 640 Japanese 664; 583, 651 Japanese 659; 534, 591 Japanese 659; 584, 591 Japanese 671; 523, 591 Japanese 680; 523, 591 Japanese 681;585, 591 and 659; 523, 649 and 659; 586, 591 and 666; 587, 652 and 659; 588, 638 and 659; 523, 623 and 664; 523, 591 and 682; 553, 653 and 659; 523, 654 and 659; 523, 648 and 659; 560, 591 and 659; 580, 606 and 659; 589, 593 and 661; 523, 637 and 676; 590, 622 and 659; 555, 591 and 661; 523, 615 and 672; 523, 626 and 668; 523, 655 and 659; or 523, 606 and 680.

[0099] In some embodiments, this disclosure provides an antibody or peptide that specifically binds to PC, wherein the antibody or peptide comprises: VH, which includes CDRH1, CDRH2, and CDRH3 regions; and VL, which includes CDRL1, CDRL2, and CDRL3 regions, wherein the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 regions comprise amino acid sequences respectively shown in the following items: SEQ ID NO: 369, 428, 484, 523, 591 and 656; 370, 429, 485, 523, 592 and 657; 371, 428, 486, 523, 593 and 658; 372, 428, 484, 523, 591 and 659; 373, 429, 4 84, 523, 594 and 659; 369, 428, 484, 523, 591 and 659; 374, 430, 484, 523, 591 and 659; 369, 428, 484, 523, 595 and 660; 375, 428, 487, 523, 59 6 and 659; 376, 428, 484, 524, 591 and 659; 377, 428, 484, 523, 591 and 661; 378, 428, 484, 523, 591 and 662; 372, 428, 484, 523, 597 and 658; 379 , 428, 484, 523, 598 and 662; 372, 428, 488, 525, 599 and 659; 376, 431, 484, 523, 600 and 663; 380, 432, 484, 523, 591 and 664; 372, 428, 489, 523, 601 and 659; 381, 428, 490, 523, 591 and 659; 382, ​​428, 484, 526, 597 and 665; 381, 428, 491, 523, 602 and 659; 369, 428, 484, 527, 591 and 6 61; 377, 428, 492, 528, 591 and 662; 376, 433, 484, 529, 603 and 662; 383, 434, 484, 523, 604 and 666; 383, 428, 484, 523, 605 and 667; 384, 43 5, 484, 530, 606 and 659; 369, 436, 484, 523, 607 and 659; 372, 437, 487, 523, 591 and 659; 372, 428, 484, 523, 608 and 659; 385, 428, 493, 523 , 609 and 662; 386, 428, 484, 531, 591 and 663; 372, 437, 484, 523, 608 and 661; 377, 428, 484, 523, 610 and 659; 387, 428, 484, 523, 611 and 668;385, 428, 484, 523, 611 and 658; 372, 438, 484, 523, 596 and 662; 388, 428, 494, 523, 612 and 667; 369, 439, 484, 523, 613 and 668; 389, 428, 484, 523, 591 and 669; 38 2, 428, 484, 523, 591 and 663; 369, 428, 484, 523, 614 and 659; 381, 428, 484, 523, 591 and 659; 376, 440, 495, 523, 591 and 659; 381, 428, 484, 532, 615 and 662; 381, 4 28, 484, 523, 616 and 670; 390, 441, 484, 523, 591 and 659; 370, 442, 484, 523, 591 and 668; 391, 428, 484, 523, 617 and 671; 377, 428, 484, 533, 595 and 659; 377, 428, 484, 523, 618 and 659; 392, 432, 484, 523, 591 and 659; 377, 443, 484, 534, 619 and 662; 376, 428, 484, 535, 620 and 659; 393, 428, 484, 536, 621 and 659; 381, 428, 484 , 537, 603 and 671; 383, 444, 489, 523, 622 and 59; 372, 428, 484, 523, 617 and 659; 377, 428, 484, 523, 623 and 659; 376, 428, 484, 538, 607 and 672; 369, 428, 484, 523 , 616 and 671; 376, 428, 484, 523, 624 and 659; 394, 428, 484, 523, 591 and 659; 369, 428, 484, 523, 620 and 659; 383, 444, 496, 523, 625 and 660; 385, 428, 484, 523, 60 2 and 671; 376, 434, 484, 523, 591 and 659; 395, 445, 497, 523, 611 and 663; 396, 446, 487, 523, 626 and 670; 369, 428, 484, 523, 617 and 659; 392, 428, 484, 523, 591 and 6 62; 394, 428, 484, 523, 606 and 673; 393, 428, 498, 523, 591 and 659; 376, 428, 495, 523, 627 and 671; 369, 440, 484, 523, 628 and 671; 397, 428, 484, 539, 591 and 662;389, 447, 484, 523, 591 and 659; 398, 448, 492, 523, 591 and 670; 373, 449, 490, 523, 611 and 659; 399, 428, 484, 537, 613 and 671; 400, 450, 484, 540, 598 and 659; 401 , 428, 484, 541, 591 and 659; 390, 428, 484, 542, 629 and 659; 376, 428, 484, 523, 591 and 671; 400, 428, 499, 523, 591 and 659; 381, 428, 484, 523, 630 and 667; 384, 42 9, 484, 543, 631 and 659; 369, 428, 484, 523, 632 and 664; 402, 436, 484, 523, 597 and 661; 381, 451, 484, 523, 591 and 656; 403, 428, 484, 523, 633 and 659; 369, 429, 4 84, 544, 607 and 659; 404, 429, 484, 523, 630 and 659; 372, 429, 484, 523, 602 and 659; 381, 428, 484, 523, 591 and 665; 388, 428, 484, 523, 610 and 674; 405, 451, 484, 523, 634 and 671; 406, 428, 484, 545, 591 and 661; 400, 428, 484, 523, 635 and 667; 404, 428, 484, 546, 591 and 659; 384, 432, 500, 523, 636 and 664; 376, 452, 501, 547 , 591 and 663; 407, 428, 484, 548, 619 and 659; 375, 428, 484, 523, 637 and 659; 372, 428, 484, 523, 607 and 659; 408, 428, 484, 523, 638 and 659; 386, 428, 484, 523, 59 1 W659; 369, 428, 497, 523, 591 W659; 403, 453, 484, 549, 591 W659; 402, 454, 484, 523, 591 W659; 383, 428, 484, 523, 591 W659; 383, 434, 500, 523, 591 W6 59; 376, 455, 502, 550, 591 and 675; 383, 435, 484, 523, 591 and 664; 369, 428, 484, 523, 602 and 659; 376, 428, 484, 551, 591 and 659; 376, 428, 484, 552, 591 and 659;383, 428, 484, 553, 591 and 676; 376, 428, 484, 554, 591 and 659; 376, 428, 490, 523, 591 and 676; 369, 428, 503, 555, 606 and 659; 409, 428, 484, 523, 591 and 659; 383 , 428, 504, 556, 591 and 659; 369, 434, 484, 523, 591 and 659; 390, 428, 484, 523, 637 and 677; 369, 456, 484, 523, 591 and 659; 370, 457, 484, 557, 591 and 659; 383, 42 8, 484, 558, 591 and 659; 404, 458, 499, 523, 591 and 659; 410, 428, 484, 523, 591 and 677; 383, 459, 484, 553, 639 and 659; 407, 428, 489, 549, 591 and 667; 374, 434, 4 84, 523, 591 and 659; 404, 428, 484, 559, 617 and 666; 411, 460, 505, 523, 591 and 672; 372, 429, 484, 523, 606 and 659; 383, 428, 485, 523, 591 and 659; 386, 460, 490, 523, 601 and 659; 412, 455, 493, 523, 592 and 670; 372, 428, 484, 560, 591 and 667; 372, 428, 484, 523, 606 and 659; 383, 461, 484, 523, 591 and 677; 369, 429, 484, 523 , 606 and 659; 369, 434, 484, 530, 591 and 659; 376, 437, 484, 561, 603 and 666; 383, 462, 500, 523, 591 and 659; 383, 428, 484, 562, 591 and 659; 400, 463, 484, 523, 61 6 and 660; 376, 464, 484, 523, 602 and 677; 400, 434, 506, 549, 591 and 659; 369, 436, 507, 523, 591 and 659; 404, 429, 484, 523, 591 and 659; 384, 429, 484, 523, 616 and 6 59; 369, 429, 484, 523, 591 and 659; 377, 465, 484, 523, 630 and 660; 413, 459, 484, 563, 591 and 659; 369, 452, 484, 523, 591 and 663; 414, 466, 484, 523, 640 and 659;373, 428, 484, 523, 591 and 659; 415, 428, 489, 564, 591 and 659; 369, 428, 484, 523, 591 and 671; 400, 428, 484, 523, 641 and 677; 369, 428, 491, 565, 591 and 662; 403 , 458, 508, 523, 642 and 664; 392, 467, 484, 523, 591 and 659; 369, 452, 509, 566, 643 and 659; 388, 468, 490, 523, 591 and 659; 369, 452, 484, 523, 644 and 667; 377, 44 0, 484, 567, 606 and 659; 370, 428, 484, 523, 591 and 656; 384, 467, 487, 523, 591 and 659; 392, 469, 510, 568, 591 and 659; 378, 464, 484, 523, 606 and 659; 377, 428, 4 84, 569, 645 and 659; 416, 434, 484, 523, 603 and 659; 370, 428, 484, 523, 606 and 659; 370, 428, 511, 570, 628 and 678; 369, 452, 484, 571, 630 and 663; 376, 428, 502, 572, 591 and 664; 417, 428, 484, 523, 591 and 665; 392, 428, 484, 573, 591 and 670; 376, 428, 512, 523, 646 and 659; 377, 428, 484, 574, 591 and 670; 383, 428, 484, 523 , 647 and 667; 381, 428, 493, 575, 591 and 659; 383, 470, 501, 523, 591 and 659; 404, 471, 484, 537, 591 and 659; 418, 428, 484, 523, 635 and 670; 383, 472, 513, 576, 59 1 W659; 419, 428, 484, 577, 606 W659; 397, 428, 484, 523, 648 W679; 372, 473, 484, 523, 591 W664; 383, 474, 484, 523, 592 W659; 372, 428, 484, 523, 591 W6 63; 420, 434, 484, 523, 595 and 659; 370, 428, 514, 523, 591 and 659; 369, 428, 484, 523, 591 and 677; 383, 428, 484, 523, 600 and 659; 369, 475, 484, 523, 591 and 659;421, 436, 484, 523, 649 and 664; 378, 452, 484, 523, 591 and 659; 376, 476, 515, 578, 641 and 659; 376, 428, 504, 523, 591 and 667; 422, 469, 484, 523, 606 and 660; 383 , 461, 484, 523, 616 and 659; 369, 428, 484, 523, 650 and 656; 369, 428, 516, 523, 591 and 659; 405, 460, 484, 523, 618 and 659; 413, 431, 484, 523, 591 and 659; 382, ​​42 8, 484, 579, 621 and 671; 383, 428, 484, 523, 646 and 659; 372, 428, 484, 580, 591 and 660; 406, 429, 484, 527, 591 and 659; 383, 428, 517, 581, 595 and 659; 377, 437, 5 18, 582, 640 and 664; 369, 477, 487, 583, 651 and 659; 403, 464, 484, 534, 591 and 659; 383, 459, 484, 523, 606 and 659; 369, 454, 484, 584, 591 and 671; 372, 478, 519, 523, 591 and 680; 423, 429, 484, 523, 591 and 681; 383, 428, 484, 585, 591 and 659; 369, 434, 484, 557, 591 and 659; 382, ​​434, 484, 523, 649 and 659; 424, 479, 484, 523 , 616 and 660; 376, 429, 484, 586, 591 and 666; 425, 428, 484, 523, 592 and 659; 369, 436, 484, 587, 652 and 659; 403, 428, 520, 588, 638 and 659; 417, 460, 484, 523, 59 1 and 659; 409, 460, 484, 523, 623 and 664; 404, 452, 484, 523, 591 and 659; 369, 428, 484, 523, 591 and 682; 383, 428, 521, 553, 653 and 659; 372, 480, 493, 523, 591 and 6 59; 369, 428, 484, 523, 654 and 659; 369, 477, 484, 523, 648 and 659; 369, 481, 484, 560, 591 and 659; 369, 452, 484, 523, 591 and 667; 409, 428, 484, 580, 606 and 659;384, 452, 484, 589, 593 and 661; 377, 482, 484, 523, 591 and 659; 410, 483, 484, 523, 591 and 659; 384, 428, 489, 523, 591 and 659; 426, 429, 484, 523, 622 and 659; 376, 428, 484, 523, 637 and 676; 427, 428, 484, 523, 591 and 671; 373, 452, 506, 523, 591 and 659; 369, 428, 484, 590, 622 and 659; 369, 429, 521, 555, 591 and 661; 405, 428, 522, 523, 615 and 672; 376, 428, 510, 523, 591 and 659; 384, 428, 484, 523, 626 and 668; 410, 429, 484, 523, 591 and 659; 400, 452, 484, 523, 655 and 659; or 369, 434, 484, 523, 606 and 680. ;

[0100] In some embodiments, this disclosure provides an antibody or polypeptide that specifically binds to PC, the antibody or polypeptide comprising VH, the VH comprising at least 75%, 80%, 85%, 90%, 95%, or 100% of any of the amino acid sequences shown in SEQ ID NO: 1-180. For example The amino acid sequence is at least 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical. In some embodiments, this disclosure provides an antibody or polypeptide that specifically binds to PC, the antibody or polypeptide comprising VH, the VH comprising any of the amino acid sequences shown in SEQ ID NO: 1-180. In some embodiments, the amino acid sequence of VH consists of any of the amino acid sequences shown in SEQ ID NO: 1-180.

[0101] In some embodiments, this disclosure provides an antibody or polypeptide that specifically binds to PC, the antibody or polypeptide comprising a VL containing at least 75%, 80%, 85%, 90%, 95%, or 100% of any of the amino acid sequences shown in SEQ ID NO: 181-368. For exampleThe amino acid sequence is identical (at least 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%). In some embodiments, this disclosure provides an antibody or peptide that specifically binds to PC, the antibody or peptide comprising VL, wherein VH comprises any of the amino acid sequences shown in SEQ ID NO: 181-368. In some embodiments, the amino acid sequence of VL consists of any of the amino acid sequences shown in SEQ ID NO: 181-368.

[0102] In some embodiments, this disclosure provides an antibody or polypeptide that specifically binds to PC, the antibody or polypeptide comprising: VH, which comprises at least 75%, 80%, 85%, 90%, 95%, or 100% of any of the amino acid sequences shown in SEQ ID NO: 1-180. For example The amino acid sequence is at least 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence shown in SEQ ID NO: 181-368; and VL, which contains at least 75%, 80%, 85%, 90%, 95%, or 100% of any of the amino acid sequences shown in SEQ ID NO: 181-368. For example The amino acid sequence is identical (at least 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%). In some embodiments, this disclosure provides an antibody or polypeptide that specifically binds to PC, the antibody or polypeptide comprising: VH, which comprises any of the amino acid sequences shown in SEQ ID NO: 1-180; and VL, which comprises any of the amino acid sequences shown in SEQ ID NO: 181-368. In some embodiments, the amino acid sequence of VH consists of any of the amino acid sequences shown in SEQ ID NO: 1-180; and the amino acid sequence of VL consists of any of the amino acid sequences shown in SEQ ID NO: 181-368.

[0103] In some embodiments, this disclosure provides an antibody or polypeptide that specifically binds to PC, the antibody or polypeptide comprising the VH and VL amino acid sequences shown in the following items: SEQ ID NO: 1 and 181; 2 and 182; 3 and 183; 4 and 184; 5 and 185; 1 and 184; 6 and 184; 1 and 186; 7 and 187; 8 and 188; 9 and 189; 10 and 190; 4 and 191; 11 and 192; 12 and 193; 13 and 194; 14 and 195; 15 and 196; 1 6 and 184; 17 and 197; 18 and 198; 1 and 199; 19 and 200; 20 and 201; 21 and 202; 22 and 203; 23 and 2 04; 24 and 205; 25 and 184; 4 and 206; 26 and 207; 27 and 208; 28 and 209; 9 and 210; 29 and 211; 3 0 and 212; 31 and 213; 32 and 214; 33 and 215; 34 and 216; 17 and 217; 1 and 218; 35 and 184; 36 and 184; 35 and 219; 35 and 220; 37 and 184; 38 and 221; 39 and 222; 9 and 223; 9 and 224; 40 and 184; 41 and 225; 8 and 226; 42 and 227; 35 and 228; 43 and 229; 4 and 230; 9 and 231; 8 and 232; 1 and 233; 8 and 234; 44 and 184; 1 and 235; 45 and 236; 30 and 237; 46 and 184; 47 and 238; 48 and 239; 1 and 23 0; 49 and 190; 44 and 240; 50 and 184; 51 and 241; 52 and 242; 53 and 243; 54 and 184; 55 and 244; 56 and 245; 57 and 246; 58 and 247; 59 and 248; 60 and 249; 8 and 250; 61 and 184; 35 and 251; 62 71 and 261; 72 and 262; 73 and 263; 74 and 264; 75 and 265; 76 and 266; 77 and 267; 4 and 205; 78 and 268; 1 and 269; 27 and 269; 79 and 269; 80 and 270; 81 and 269; 22 and 2 69; 82 and 269; 83 and 271; 84 and 272; 1 and 273; 8 and 274; 8 and 275; 22 and 276; 8 and 277; 85 and 278; 86 and 279; 87 and 269; 88 and 280; 89 and 269; 60 and 281; 90 and 269; 91 and 282; 22 and 28 3; 92 and 269; 93 and 284; 94 and 285; 95 and 286; 96 and 269; 73 and 287; 97 and 288; 68 and 289;98 and 269; 99 and 290; 100 and 291; 4 and 292; 4 and 289; 101 and 284; 66 and 289; 89 and 293; 102 and 294; 103 and 269; 22 and 295; 104 and 296; 105 and 297; 106 and 270; 107 and 269; 67 and 269; 62 and 298; 66 and 269; 108 and 299; 109 and 300; 110 and 301; 111 and 302; 112 and 269; 113 and 303; 1 and 304; 72 and 305; 114 and 306; 115 and 307; 116 and 269; 117 and 308; 118 Japanese 269; 110 Japanese 309; 119 Japanese 310; 120 Japanese 311; 121 Japanese 269; 122 Japanese 312; 123 Japanese 289; 9 Japanese 313; 124 Japanese 314; 120 Japanese 289; 125 Japanese 315; 110 Japanese 316; 126 Japanese 317; 127 Japanese 318; 49 Japanese 319; 128 Japanese 320; 9 Japanese 321; 22 Japanese 322; 129 Japanese 323; 130 Japanese 269; 131 Japanese 324; 132 Japanese 325; 133 Japanese 326; 134 Japanese 327; 53 Japanese 328; 135 Japanese 272; 136 Japanese 329; 4 Japanese 301; 137 Japanese 330; 138 Japanese 269; 1 284; 22; 331; 139; 269; 140; 332; 141; 269; 142; 333; 143; 334; 144; 335; 101; 298; 1; 336; 145; 269; 146; 337; 147; 269; 17; 338; 22; 320; 4; 339; 148; 340; 149; 341; 150; 342; 151; 343; 152; 344; 94; 289; 153; 345; 154; 346; 155; 347; 22; 348; 89; 282; 156; 349; 157; 296; 158; 350; 1 59 and 329; 24 and 351; 160 and 352; 161 and 269; 162 and 353; 163 and 269; 1 and 354; 164 and 355; 165 and 269; 1 and 356; 166 and 357; 167 and 358; 110 and 334; 87 and 359; 168 and 360; 169 and 269; 170 and 269; 171 and 269; 172 and 361; 8 and 362; 173 and 304; 174 and 269; 1 and 363; 175 and 364; 176 and 365; 177 and 269; 178 and 366; 179 and 269; 180 and 367; or 89 and 368.

[0104] In some embodiments, the amino acid sequences of VH and VL consist of the amino acid sequences shown in the following items, respectively: SEQ ID NO: 1 and 181; 2 and 182; 3 and 183; 4 and 184; 5 and 185; 1 and 184; 6 and 184; 1 and 186; 7 and 187; 8 and 188 ; 9 and 189; 10 and 190; 4 and 191; 11 and 192; 12 and 193; 13 and 194; 14 and 195; 15 and 196; 16 and 1 84; 17 and 197; 18 and 198; 1 and 199; 19 and 200; 20 and 201; 21 and 202; 22 and 203; 23 and 204; 2 4 and 205; 25 and 184; 4 and 206; 26 and 207; 27 and 208; 28 and 209; 9 and 210; 29 and 211; 30 and 212 ;31 and 213; 32 and 214; 33 and 215; 34 and 216; 17 and 217; 1 and 218; 35 and 184; 36 and 184; 35 and 219; 35 and 220; 37 and 184; 38 and 221; 39 and 222; 9 and 223; 9 and 224; 40 and 184; 41 and 225; 8 and 226; 42 and 227; 35 and 228; 43 and 229; 4 and 230; 9 and 231; 8 and 232; 1 and 233; 8 and 234; 44 and 184; 1 and 235; 45 and 236; 30 and 237; 46 and 184; 47 and 238; 48 and 239; 1 and 230; 49 and 190; 44 and 240; 50 and 184; 51 and 241; 52 and 242; 53 and 243; 54 and 184; 55 and 244; 56 and 245; 57 and 24 6; 58 and 247; 59 and 248; 60 and 249; 8 and 250; 61 and 184; 35 and 251; 62 and 252; 1 and 253; 63 and 254; 64 and 181; 65 and 255; 66 and 256; 67 and 257; 68 and 198; 35 and 258; 69 and 259; 70 and 260 ;71 and 261; 72 and 262; 73 and 263; 74 and 264; 75 and 265; 76 and 266; 77 and 267; 4 and 205; 78 and 2 68; 1 and 269; 27 and 269; 79 and 269; 80 and 270; 81 and 269; 22 and 269; 82 and 269; 83 and 271; 8 4 and 272; 1 and 273; 8 and 274; 8 and 275; 22 and 276; 8 and 277; 85 and 278; 86 and 279; 87 and 269; 8 8 and 280; 89 and 269; 60 and 281; 90 and 269; 91 and 282; 22 and 283; 92 and 269; 93 and 284; 94 and 2 85; 95 and 286; 96 and 269; 73 and 287; 97 and 288; 68 and 289; 98 and 269; 99 and 290; 100 and 291;4 and 292; 4 and 289; 101 and 284; 66 and 289; 89 and 293; 102 and 294; 103 and 269; 22 and 295; 104 and 296; 105 and 297; 106 and 270; 107 and 269; 67 and 269; 62 and 298; 66 and 269; 108 and 299; 109 and 300; 110 and 301; 111 and 302; 112 and 269; 113 and 303; 1 and 304; 72 and 305; 114 and 306; 115 and 307; 116 and 269; 117 and 308; 118 and 269; 110 and 309; 119 310; 120 and 311; 121 and 269; 122 and 312; 123 and 289; 9 and 313; 124 and 314; 120 and 289; 125 and 315; 110 and 316; 126 and 317; 127 and 318; 49 and 319; 128 and 320; 9 and 321; 22 and 322; 129 and 323; 130 and 269; 131 and 324; 132 and 325; 133 and 326; 134 and 327; 53 and 328; 135 and 272; 136 and 329; 4 and 301; 137 and 330; 138 and 269; 1 and 284; 22 and 331 ; 139 & 269; 140 & 332; 141 & 269; 142 & 333; 143 & 334; 144 & 335; 101 & 298; 1 & 336; 145 & 269; 146 & 337; 147 & 269; 17 & 338; 22 & 320; 4 & 339; 148 & 340; 149 & 341; 150 & 342; 151 & 343; 152 & 344; 94 & 289; 153 & 345; 154 & 346; 155 & 347; 22 & 348; 89 & 282; 156 & 349; 157 & 296; 158 & 350; 159 & 329 ;24 and 351;160 and 352;161 and 269;162 and 353;163 and 269;1 and 354;164 and 355;165 and 269;1 and 356;166 and 357;167 and 358;110 and 334;87 and 359;168 and 360;169 and 269;170 and 269;171 and 269;172 and 361;8 and 362;173 and 304;174 and 269;1 and 363;175 and 364;176 and 365;177 and 269;178 and 366;179 and 269;180 and 367;or 89 and 368. ;

[0105] Any antibody form can be used in the antibodies disclosed herein. In some embodiments, the antibody is a single-chain antibody or a single-chain Fv (scFv). In some embodiments, the antibody is a scFv fused to an Fc region (scFv-Fc). In some embodiments, the antibody is a Fab fragment. In some embodiments, the antibody is an F(ab')2 fragment.

[0106] In some embodiments, the antibodies or peptides disclosed herein are multispecific antibodies that specifically bind to PC and a second antigen. For example (Bispecific antibody).

[0107] In some embodiments, the antibodies or peptides disclosed herein are conjugated to cytotoxic agents, cell growth inhibitors, toxins, radionuclides, or detectable markers. In some embodiments, the cytotoxic agents are capable of inducing cell death or destruction upon contact with them. In some embodiments, the cell growth inhibitors are capable of preventing or significantly reducing proliferation and / or inhibiting the activity or function of cells upon contact with them. In some embodiments, the cytotoxic agent or cell growth inhibitor is a chemotherapeutic agent. In some embodiments, the radionuclide is selected from the group consisting of isotopes. 3 H, 14 C 32 P, 35 S, 36 Cl、 51 Cr 57 Co、 58 Co、 59 Fe、 67 Cu、 90 Y、 99 Tc, 111 In、 117 Lu、 121 I, 124 I, 125 I, 131 I, 198 Au、 211 At、 213 Bi、 225 Ac and 186 Re. In some embodiments, the detectable marker may contain a fluorescent portion or a click chemical handle.

[0108] Any immunoglobulin (Ig) constant region may be used in the peptides and antibodies disclosed herein. In some embodiments, the Ig region is a human IgG, IgE, IgM, IgD, IgA, or IgY immunoglobulin molecule, or any class of immunoglobulin molecules. For example IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2) or any subclass ( See (IgG2a and IgG2b).

[0109] In some embodiments, this disclosure provides a polypeptide that specifically binds to PC ( For example (Antibody), the polypeptide contains a heavy chain constant region optionally selected from the group consisting of: human IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2.

[0110] In some embodiments, this disclosure provides a polypeptide that specifically binds to PC ( For example The polypeptide contains a heavy chain constant region, which is a variant of the wild-type heavy chain constant region, wherein the variant heavy chain constant region binds to FcγR with a lower affinity than the wild-type heavy chain constant region.

[0111] In some embodiments, this disclosure provides an antibody that specifically binds to PC, the antibody comprising a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 683 or 684. In some embodiments, this disclosure provides an antibody that specifically binds to PC, the antibody comprising a heavy chain constant region consisting of the amino acid sequence of SEQ ID NO: 683 or 684. In some embodiments, this disclosure provides an antibody that specifically binds to PC, the antibody comprising any allotype or iso-allotype of IgG1 heavy chain constant region. In some embodiments, this disclosure provides an antibody that specifically binds to PC, the antibody comprising an allotype of IgG1 heavy chain constant region selected from the group consisting of: G1m1(a), G1m2(x), G1m3(f), and G1m17(z). For example , For example , Jefferis and Lefranc (2009) mAbs 1(4): 332-338.

[0112] In some embodiments, one, two or more mutations ( For example Amino acid substitution) is introduced into the Fc region of the antibody described in this article ( For example According to the EU numbering system, the CH2 domain (residues 231-340 of human IgG1) and / or the CH3 domain (residues 341-447 of human IgG1) and / or the hinge region (residues 216-230 of the EU numbering system) can be used to modify one or more functional properties of the antibody, such as serum half-life, complement binding, Fc receptor binding and / or antigen-dependent cytotoxicity.

[0113] In some embodiments, one, two or more mutations ( For example The introduction of amino acid substitutions into the hinge region of the antibody described herein alters the number of cysteine ​​residues in the hinge region. For example (increase or decrease), such as For exampleAs described in U.S. Patent No. 5,677,425, which is incorporated herein by reference in its entirety, the number of cysteine ​​residues in the hinge region can be altered to... For example Promotes the assembly of light and heavy chains, or alters ( In vivo (This can increase or decrease) the stability of antibodies.

[0114] In a specific embodiment, one, two, or more amino acid mutations are performed ( See, for example (replacement, insertion, or deletion) introduced into the IgG constant region or its FcRn binding fragment (preferably Fc or hinge-Fc fragment) to alter ( For example (to decrease or increase) antibodies In vivo half life. For example International Publication Nos. WO 02 / 060919; WO 98 / 23289; and WO 97 / 34631; and U.S. Patent Nos. 5,869,046, 6,121,022, 6,277,375, and 6,165,745, all of which are incorporated herein by reference in their entirety, as will change ( In vivo (to decrease or increase) antibodies For example Examples of mutations in half-life. In some embodiments, one, two, or more amino acids are mutated ( See (Substitution, insertion, or deletion) is introduced into the IgG constant region or its FcRn binding fragment (preferably Fc or hinge-Fc fragment) to reduce antibody levels. See Half-life. In other embodiments, one, two, or more amino acids are mutated ( et al. (Substitution, insertion, or deletion) is introduced into the IgG constant region or its FcRn binding fragment (preferably Fc or hinge-Fc fragment) to increase antibody levels. For example Half-life. In specific embodiments, the antibody may have one or more amino acid mutations in the second constant (CH2) domain (residues 231-340 of human IgG1) and / or the third constant (CH3) domain (residues 341-447 of human IgG1). For example (replacement), numbered according to the EU numbering system. In a specific embodiment, the constant region of the IgG1 of the antibody described herein includes methionine (M) to tyrosine (Y) substitution at position 252, serine (S) to threonine (T) substitution at position 254, and threonine (T) to glutamic acid (E) substitution at position 256, according to the EU numbering system. For example U.S. Patent No. 7,658,921, which is incorporated herein by reference in its entirety. This type of mutant IgG (referred to as the “YTE mutant”) has shown a fourfold increase in half-life compared to the wild-type version of the same antibody. For example Dall'Acqua WF et al.(2006) J Biol Chem 281: 23514-24, which is incorporated herein by reference in its entirety. In some embodiments, the antibody comprises an IgG constant region containing one, two, three or more amino acid substitutions at positions 251-257, 285-290, 308-314, 385-389 and 428-436 according to the EU numbering system.

[0115] In some embodiments, one, two or more mutations ( For example Amino acid substitution) is introduced into the Fc region of the antibody described in this article ( See, for example According to the EU numbering system, the CH2 domain (residues 231-340 of human IgG1) and / or the CH3 domain (residues 341-447 of human IgG1) and / or the hinge region (residues 216-230 according to the EU numbering system) are used to increase or decrease antibody response to Fc receptors on the surface of effector cells. See, for example The affinity of an antibody for an activated Fc receptor. Mutations in the Fc region of an antibody that decrease or increase its affinity for the Fc receptor, and techniques for introducing such mutations into the Fc receptor or fragments thereof, are known to those skilled in the art. Examples of mutations that can be performed in the Fc receptor to alter the antibody's affinity for the Fc receptor are described in [the relevant section]. et al. Smith P et al. (2012) PNAS 109: 6181-6186, U.S. Patent No. 6,737,056 and International Publications WO 02 / 060919; WO 98 / 23289; and WO 97 / 34631, all of which are incorporated herein by reference in their entirety.

[0116] In some embodiments, the antibody comprises a variant of the wild-type heavy chain constant region, wherein the variant heavy chain constant region binds FcγRIIB with a higher affinity for FcγRIIB than the wild-type heavy chain constant region. In some embodiments, the variant heavy chain constant region is a variant human heavy chain constant region. For exampleThe variable human IgG1, variable human IgG2, or variable human IgG4 heavy chain constant region. In some embodiments, the variable human IgG heavy chain constant region contains one or more of the following amino acid mutations according to the EU numbering system: G236D, P238D, S239D, S267E, L328F, and L328E. In some embodiments, the variable human IgG heavy chain constant region comprises a group of amino acid mutations selected from the group consisting of the following according to the EU numbering system: S267E and L328F; P238D and L328E; P238D and one or more substitutions selected from the group consisting of: E233D, G237D, H268D, P271G and A330R; P238D, E233D, G237D, H268D, P271G and A330R; G236D and S267E; S239D and S267E; V262E, S267E and L328F; and V264E, S267E and L328F. In some embodiments, FcγRIIB is expressed on cells selected from the group consisting of macrophages, monocytes, B cells, dendritic cells, endothelial cells and activated T cells.

[0117] In a further embodiment, one, two, or more amino acid substitutions are introduced into the Fc region of the IgG constant region to alter the effector function of the antibody. For example, one or more amino acid residues selected from amino acid residues 234, 235, 236, 237, 239, 243, 267, 292, 297, 300, 318, 320, 322, 328, 330, 332, and 396, numbered according to the EU numbering system, can be replaced with different amino acid residues, giving the antibody a modified affinity for the effector ligand but retaining the antigen-binding ability of the parent antibody. The effector ligand whose affinity is modified can be, for example, an Fc receptor or a C1 component of complement. This method is described in more detail in U.S. Patent Nos. 5,624,821 and 5,648,260, each of which is incorporated herein by reference in its entirety. In some embodiments, deletion or inactivation of the constant region domain (through point mutation or other means) can reduce Fc receptor binding of circulating antibodies, thereby increasing tumor localization. See, for example U.S. Patents 5,585,097 and 8,591,886, each of which is incorporated herein by reference in its entirety, describe mutations that result in the deletion or inactivation of constant regions and thereby increase tumor localization. In some embodiments, one or more amino acid substitutions may be introduced into the Fc region of the antibody described herein to remove potential glycosylation sites on the Fc region, which can reduce Fc receptor binding (…). For example Shields RL See, for example(2001) J Biol Chem 276: 6591-604, which is incorporated herein by reference in its entirety. In various embodiments, one or more of the following mutations may be made in the constant region of the antibody described herein: N297A substitution; N297Q substitution; L234A substitution; L234F substitution; L235A substitution; L235F substitution; L235V substitution; L237A substitution; S239D substitution; E233P substitution; L234V substitution; L235A substitution; C236 deletion; P238A substitution; S239D substitution; F243L substitution; D265A substitution; S267E substitution; L328F substitution; R292P substitution; Y300L substitution; A327Q substitution; P329A substitution; A330L substitution; I332E substitution; or P396L substitution, these mutations being numbered according to the EU numbering system.

[0118] In some embodiments, mutations selected from the group consisting of D265A, P329A, and combinations thereof according to EU numbering system can be performed in the constant region of the antibody described herein. In some embodiments, mutations selected from the group consisting of L235A, L237A, and combinations thereof according to EU numbering system can be performed in the constant region of the antibody described herein. In some embodiments, mutations selected from the group consisting of S267E, L328F, and combinations thereof according to EU numbering system can be performed in the constant region of the antibody described herein. In some embodiments, mutations selected from the group consisting of S239D, I332E, optionally A330L, and combinations thereof according to EU numbering system can be performed in the constant region of the antibody described herein. In some embodiments, mutations selected from the group consisting of L235V, F243L, R292P, Y300L, P396L, and combinations thereof according to EU numbering system can be performed in the constant region of the antibody described herein. In some embodiments, mutations selected from the group consisting of S267E, L328F and combinations thereof, according to the EU numbering system, can be performed in the constant region of the antibody described herein.

[0119] In specific embodiments, the antibodies described herein comprise a constant region of IgG1 having amino acid substitutions of N297Q or N297A according to the EU numbering system. In some embodiments, the antibodies described herein comprise a constant region of IgG1 having mutations selected from the group consisting of D265A, P329A, and combinations thereof according to the EU numbering system. In another embodiment, the antibodies described herein comprise a constant region of IgG1 having mutations selected from the group consisting of L234A, L235A, and combinations thereof according to the EU numbering system. In yet another embodiment, the antibodies described herein comprise a constant region of IgG1 having mutations selected from the group consisting of L234F, L235F, N297A, and combinations thereof according to the EU numbering system. In some embodiments, the amino acid residues at positions L234, L235, and D265 (according to the EU numbering system) in the constant region of the antibodies described herein are not L, L, and D, respectively. This method is described in detail in International Publication No. WO 14 / 108483, which is incorporated herein by reference in its entirety. In some embodiments, the amino acids corresponding to positions L234, L235, and D265 in the human IgG1 heavy chain are numbered F, E, and A according to the EU numbering system; or A, A, and A, respectively.

[0120] In some embodiments, one or more amino acid residues 329, 331, and 322 (as numbered according to the EU numbering system) in the constant region of the antibody described herein may be replaced with different amino acid residues, such that the antibody exhibits altered C1q binding and / or reduced or eliminated complement-dependent cytotoxicity (CDC). This method is described in U.S. Patent No. 6,194,551 (Idusogie). See, for example The invention is described in more detail in [the patent], which is incorporated herein by reference in its entirety. In some embodiments, the ability of the antibody to fix complement is altered by changing one or more amino acid residues at positions 231 to 238 (according to EU numbering system numbers) in the N-terminal region of the CH2 domain of the antibody described herein. This method is further described in International Publication No. WO 94 / 29351, which is incorporated herein by reference in its entirety. In some embodiments, the Fc region of the antibody described herein is modified by mutating one or more amino acid residues at the following positions (according to EU numbering system numbers) In vivo(Introducing amino acid substitutions) to increase the antibody's ability to mediate antibody-dependent cytotoxicity (ADCC) and / or increase the antibody's affinity for the Fcg receptor: 238, 239, 248, 249, 252, 254, 255, 256, 258, 265, 267, 268, 269, 270, 272, 276, 278, 280, 283, 285, 286, 289, 290, 292, 293, 294, 295, 29 6, 298, 301, 303, 305, 307, 309, 312, 315, 320, 322, 324, 326, 327, 328, 329, 330, 331, 333, 334, 335, 337, 338, 340, 360, 373, 376, 378, 382, ​​388, 389, 398, 414, 416, 419, 430, 434, 435, 437, 438, or 439. This method is further described in international publication number WO 00 / 42072, which is incorporated herein by reference in its entirety.

[0121] In some embodiments, the antibodies described herein comprise a modified constant region of IgG1, wherein the modification enhances the antibody-mediated antibody-dependent cytotoxicity (ADCC). In some embodiments, 0.1, 1, or 10 µg / mL of the antibody is capable of inducing cell death in at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% of PC-expressing cells within 1, 2, or 3 hours, as assessed by methods described herein and / or known to those skilled in the art. In some embodiments, the modified constant region of IgG1 comprises S239D and I332E substitutions according to the EU numbering system. In some embodiments, the modified constant region of IgG1 comprises S239D, A330L, and I332E substitutions according to the EU numbering system. In some embodiments, the modified constant region of IgG1 comprises L235V, F243L, R292P, Y300L, and P396L substitutions according to the EU numbering system. In some embodiments, the antibody is capable of inducing cell death in effector T cells and Treg cells, wherein the percentage of Treg cells undergoing cell death is at least 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.5, 3, 3.5, 4, 4.5, or 5 times higher than the percentage of effector T cells undergoing cell death.

[0122] In some embodiments, the antibody described herein comprises a constant region of an IgG4 antibody, and a serine residue at amino acid residue 228 of the heavy chain, numbered according to the EU numbering system, is substituted for a proline residue. In some embodiments, this disclosure provides an antibody that specifically binds to PC, the antibody comprising a heavy chain constant region containing the amino acid sequence of SEQ ID NO: 684.

[0123] In some embodiments, any constant region mutation or modification described herein may be introduced into one or both heavy chain constant regions of an antibody having two heavy chain constant regions described herein.

[0124] This document provides compositions comprising the anti-PC antibody disclosed herein, having the desired purity in a physiologically acceptable carrier, excipient, or stabilizer. For example Remington's Pharmaceutical Sciences (1990) Mack Publishing Co., Easton, PA). Acceptable carriers, excipients, or stabilizers are non-toxic to the recipient at the doses and concentrations used and include: buffers such as phosphates, citrates, and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (such as octadecyl dimethyl benzyl ammonium chloride; hexamethyl diammonium chloride; benzalkonium chloride, benzyl chloride; phenol, butanol, or benzyl alcohol; alkyl esters of p-hydroxybenzoate, such as methyl or propyl p-hydroxybenzoate; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-methylbenzyl chloride). Phenols); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrin; chelating agents, such as EDTA; sugars, such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions, such as sodium; metal complexes ( See (Zn-protein complex); and / or nonionic surfactants, such as TWEEN™, PLURONIC™ or polyethylene glycol (PEG).

[0125] In specific embodiments, the pharmaceutical composition comprises the disclosed antiPC antibody in a pharmaceutically acceptable carrier and optionally one or more additional prophylactic or therapeutic agents. In some embodiments, the antibody is the sole active ingredient contained in the pharmaceutical composition. The pharmaceutical compositions described herein can be used to reduce or inhibit PC activity and to treat conditions such as inflammatory diseases. In some embodiments, this disclosure relates to a pharmaceutical composition comprising the disclosed antiPC antibody for use as a medicine. In another embodiment, this disclosure relates to a pharmaceutical composition for use in a method for treating an inflammatory disease.

[0126] Pharmaceutically acceptable carriers used in parenteral preparations include aqueous carriers, non-aqueous carriers, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifiers, multivalent chelating agents or chelating agents, and other pharmaceutically acceptable substances. Examples of aqueous carriers include sodium chloride injection, Ringer's injection, isotonic glucose injection, sterile water injection, and glucose and lactated Ringer's injection. Non-aqueous parenteral carriers include plant-derived fixed oils, cottonseed oil, corn oil, sesame oil, and peanut oil. Antimicrobial agents at antibacterial or antifungal concentrations can be added to parenteral preparations packaged in multi-dose containers. These parenteral preparations include phenol or cresol, mercury preparations, benzyl alcohol, chlorobutanol, methylparaben and propylparaben, thimerosal, benzalkonium chloride, and benzyl chloride. Isotonic agents include sodium chloride and glucose. Buffers include phosphates and citrates. Antioxidants include sodium bisulfate. Local anesthetics include procaine hydrochloride. Suspensions and dispersants include sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Emulsifiers include polysorbate 80 (TWEEN). ® 80). Multivalent chelating agents or chelating agents for metal ions include EDTA. Drug carriers also include ethanol, polyethylene glycol, and propylene glycol for water-soluble mediators; and sodium hydroxide, hydrochloric acid, citric acid, or lactic acid for pH adjustment.

[0127] Pharmaceutical compositions can be formulated for administration to a subject via any route. Specific examples of routes of administration include intranasal, oral, pulmonary, transdermal, intradermal, and parenteral administration. Parenteral administration characterized by subcutaneous, intramuscular, or intravenous injection is also considered herein. Injectable formulations can be prepared in conventional forms, as liquid solutions or suspensions, solid forms suitable for dissolving or suspending in a liquid prior to injection, or as emulsions. Injectable formulations, solutions, and emulsions also contain one or more excipients. Suitable excipients are, for example, water, saline, glucose, glycerol, or ethanol. Additionally, if desired, the pharmaceutical composition to be administered may also contain small amounts of non-toxic excipients, such as wetting agents or emulsifiers, pH buffers, stabilizers, solubility enhancers, and other such agents, such as, for example, sodium acetate, sorbitol monolaurate, triethanolamine oleate, and cyclodextrin.

[0128] Antibody formulations intended for parenteral administration include sterile solutions for injection, sterile dried soluble products (such as lyophilized powders, including subcutaneous tablets) prepared for combination with solvents before use, sterile suspensions prepared for injection, sterile dried insoluble products prepared for combination with mediators before use, and sterile emulsions. Solutions may be aqueous or non-aqueous.

[0129] If administered intravenously, suitable carriers include physiological saline or phosphate-buffered saline (PBS), as well as solutions containing thickeners and solubilizers such as glucose, polyethylene glycol, and polypropylene glycol and mixtures thereof.

[0130] Prepare a topical mixture containing antibodies as described above for both local and systemic application. The resulting mixture may be a solution, suspension, emulsion, etc., and may be formulated into creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes, foams, aerosols, rinses, sprays, suppositories, bandages, skin patches, or any other formulation suitable for local application.

[0131] The anti-PC antibody disclosed herein can be formulated into an aerosol for topical application, such as by inhalation. For example For example U.S. Patent Nos. 4,044,126, 4,414,209, and 4,364,923 describe aerosols for delivering steroids that can be used to treat inflammatory diseases, particularly asthma (and are incorporated herein by reference in their entirety). These formulations for application to the respiratory tract can be in the form of an aerosol or solution for use in a nebulizer, or as a fine powder for inhalation, alone or in combination with an inert carrier such as lactose. In this case, the particles of the formulation will have a diameter of less than 50 micrometers in some embodiments and less than 10 micrometers in others.

[0132] The anti-PC antibodies disclosed herein can be formulated for topical or localized applications, such as in the form of gels, creams, and lotions, to the skin and mucous membranes, including the eyes, and for intracranial or intraspinal applications. Topical application is intended for transdermal delivery and may also be used for application to the eyes or mucous membranes, or for inhalation therapy. Nasal solutions of the antibodies, alone or in combination with other pharmaceutically acceptable excipients, may also be administered.

[0133] Transdermal patches, including iontophoresis therapy and electrophoresis devices, are well known to those skilled in the art and can be used to administer antibodies. For example, such patches are disclosed in U.S. Patent Nos. 6,267,983, 6,261,595, 6,256,533, 6,167,301, 6,024,975, 6,010,715, 5,985,317, 5,983,134, 5,948,433, and 5,860,957, all of which are incorporated herein by reference in their entirety.

[0134] In some embodiments, the pharmaceutical composition comprising the antibody described herein is a lyophilized powder that can be reconstituted for administration as a solution, emulsion, and other mixture. It can also be reconstituted and formulated into a solid or gel. The lyophilized powder is prepared by dissolving the antibody described herein or a pharmaceutically acceptable derivative thereof in a suitable solvent. In some embodiments, the lyophilized powder is sterile. The solvent may contain excipients that improve the stability of the powder or a reconstituted solution prepared from the powder, or other pharmacological components. Excipients that can be used include, but are not limited to, dextran, sorbitol, fructose, corn syrup, xylitol, glycerol, glucose, sucrose, or other suitable agents. The solvent may also contain a buffer, such as citrate, sodium phosphate, or potassium phosphate, or other such buffers known to those skilled in the art, and in some embodiments, approximately neutral pH. The solution is then sterilely filtered and then lyophilized under standard conditions known to those skilled in the art to provide the desired formulation. In some embodiments, the resulting solution will be aliquoted into vials for lyophilization. Each vial will contain a single or multiple doses of the compound. The lyophilized powder can be stored under suitable conditions, such as at about 4°C to room temperature. Reconstitute the lyophilized powder with water for injection to provide a formulation for parenteral administration. For reconstitution, the lyophilized powder is added to sterile water or another suitable carrier. The precise amount depends on the compound selected. This amount can be determined empirically.

[0135] The anti-PC antibodies disclosed herein and other compositions provided herein can also be formulated to target specific tissues, receptors, or other regions of the body of a subject to be treated. Many such targeting methods are well known to those skilled in the art. This document contemplates the use of all such targeting methods in the compositions of the invention. Non-limiting examples of targeting methods are provided. For example For exampleU.S. Patent Nos. 6,316,652, 6,274,552, 6,271,359, 6,253,872, 6,139,865, 6,131,570, 6,120,751, 6,071,495, 6,060,082, 6,048,736, 6,039,975, 6,004,534, 5,985,307, 5,972,366, 5,900,252, 5,840,674, 5,759,542, and 5,709,874, all of which are incorporated herein by reference in their entirety.

[0136] To be used For example The applied composition can be sterile. This is achieved via... For example Filtration using sterile filter membranes is easily achieved.

[0137] On the other hand, this disclosure provides a method for treating a subject using the anti-PC antibody disclosed herein. The anti-PC antibody disclosed herein can be used to treat any disease or condition in a subject that benefits from reduced oxidized phospholipid function.

[0138] In some embodiments, the anti-PC antibodies disclosed herein are particularly useful for inhibiting the activity of PCs in a subject. In some embodiments, the anti-PC antibodies disclosed herein are particularly useful for inhibiting the inflammatory activity of PCs in a subject. In some embodiments, the anti-PC antibodies disclosed herein are particularly useful for treating inflammatory or degenerative diseases. In some embodiments, the anti-PC antibodies disclosed herein can be used as anti-inflammatory agents and / or anti-atherosclerotic agents. In some embodiments, the anti-PC antibodies disclosed herein can be used to treat pain. In some embodiments, the anti-PC antibodies disclosed herein can be used to treat osteoporosis. In some embodiments, the anti-PC antibodies disclosed herein can be used to treat fibrotic diseases, including but not limited to pulmonary fibrosis. In some embodiments, the anti-PC antibodies disclosed herein can be used to treat NETosis-driven diseases, including but not limited to anti-neutrophil cytoplasmic antibody (ANCA) vasculitis and type 1 diabetes. In some embodiments, the anti-PC antibodies disclosed herein can be used to treat chronic obstructive pulmonary disease (COPD). In some embodiments, the anti-PC antibodies disclosed herein can be used to treat acute respiratory illness, acute fulminant pneumonia, or other similar conditions. In some embodiments, the anti-PC antibodies disclosed herein can be used to treat severe asthma. In some embodiments, the anti-PC antibodies disclosed herein can be used to treat patients with acute hepatitis or non-alcoholic steatohepatitis (NASH) and metabolic syndrome. In some embodiments, the anti-PC antibodies disclosed herein can be used as anti-atherosclerotic agents to treat cardiovascular disease and calcified aortic stenosis (CAS). In some embodiments, the anti-PC antibodies disclosed herein can be used to treat patients with acute coronary syndrome or "progressive angina". In some embodiments, the anti-PC antibodies disclosed herein can be used to treat high-risk patients (…). For example Active measures for patients with a predisposition to stroke or who have developed atherosclerosis. In some embodiments, the anti-PC antibodies disclosed herein can be used to treat high-risk patients with coronary artery disease (CAD). Therefore, the anti-PC antibodies disclosed herein can be used to treat inflammatory diseases and conditions, cardiovascular diseases, and diseases related to oxidized phospholipids, including but not limited to atherosclerosis, acute coronary syndrome, acute myocardial infarction, myocardial infarction (heart attack), stable and unstable angina, aneurysm, coronary artery disease (CAD), ischemic heart disease, myocardial ischemia, cardiac death and sudden cardiac death, cardiomyopathy, congestive heart failure, heart failure, stenosis, peripheral artery disease (PAD), intermittent claudication, severe limb ischemia, and stroke. For example U.S. Patent No. 11,008,381, which is incorporated herein by reference in its entirety.

[0139] In some embodiments, the anti-PC antibodies disclosed herein can be used to treat cardiovascular disease, atherosclerosis, rheumatoid arthritis, osteoarthritis, and lung tissue injury.For example (caused by smoking), brain damage, apoptosis, aging, Crohn's disease, ulcerative colitis, fatty liver disease ( See, for example NASH and non-alcoholic fatty liver disease (NAFLD). Therefore, the anti-PC antibody disclosed in this article can be used to treat inflammatory diseases and conditions, cardiovascular diseases, liver diseases and conditions (NASH, NASH, and NAFLD). For example This document describes the use of anti-PC antibodies to treat non-alcoholic fatty liver disease (NASH), non-alcoholic steatohepatitis (NAFLD), and diseases associated with oxidative stress and injury. In some embodiments, the anti-PC antibodies disclosed herein can be used to treat NAFLD. In some embodiments, the anti-PC antibodies disclosed herein can be used to treat or inhibit the formation of atherosclerosis. For example U.S. Patent No. 11,168,148, which is incorporated herein by reference in its entirety.

[0140] In some embodiments, the anti-PC antibodies disclosed herein can be used to treat reperfusion injury. In some embodiments, reperfusion injury includes organ reperfusion injury. In some embodiments, reperfusion injury includes ischemia-reperfusion injury. In some embodiments, organ reperfusion injury is induced by ischemic events (e.g., myocardial infarction-induced reperfusion injury). In some embodiments, the anti-PC antibodies disclosed herein may be used to treat subjects who are at risk of or have already experienced ischemic events, including but not limited to ischemic events associated with conditions selected from the group consisting of: cerebral ischemia; intestinal ischemia; spinal cord ischemia; cardiovascular ischemia; myocardial ischemia associated with myocardial infarction; myocardial ischemia associated with congestive heart failure (CHF); ischemia associated with age-related macular degeneration (AME); hepatic ischemia; renal / kidney ischemia; skin ischemia; vasoconstriction-induced tissue ischemia; penile ischemia due to priapism and erectile dysfunction; ischemia associated with thromboembolic diseases; ischemia associated with microvascular diseases; ischemia associated with thrombosis; and ischemia associated with diabetic ulcers, gangrenous diseases, post-traumatic syndrome, cardiac arrest resuscitation, hypothermia, peripheral nerve injury, and neuropathy. In some embodiments, the anti-PC antibodies disclosed herein can be used to treat subjects at risk of or who have already suffered ischemic events caused by induced injury (including, but not limited to, surgery, transplantation, accidental trauma, and mechanical support devices). In some embodiments, the anti-PC antibodies disclosed herein can be used to treat subjects at risk of or who have already suffered ischemic events caused by cardiac surgery, kidney surgery, brain surgery, liver surgery, and bypass surgery. In some embodiments, the anti-PC antibodies disclosed herein can be used to treat acute ischemic stroke. In some embodiments, the anti-PC antibodies disclosed herein can be used to treat reperfusion-driven indications, including organ transplantation (such as liver, heart, and kidney). In some embodiments, the anti-PC antibodies disclosed herein can be used to treat thrombosis-related diseases, including but not limited to sickle cell disease, deep vein thrombosis, pulmonary embolism, cardiac embolism, hypercoagulable state, thrombotic tendency, factor V Leiden, antithrombin III deficiency, protein C deficiency, protein S deficiency, prothrombin gene mutation (G20210A), hyperhomocysteinemia, antiphospholipid antibody syndrome (APS), anticardiolipin antibody (ACLA) thrombotic syndrome, and lupus anticoagulant (LA) syndrome. In some embodiments, the anti-PC antibodies disclosed herein can be used to treat or inhibit atherosclerosis. For example U.S. Patent Application Serial No. 16 / 759,331, which is incorporated herein by reference in its entirety.

[0141] In some embodiments, the anti-PC antibodies disclosed herein may be used to treat diseases or conditions mediated by Toll-like receptor 2 (TLR2), including but not limited to Kawasaki disease (including IVIG-refractory Kawasaki disease), type 2 diabetes, rheumatoid arthritis, dermatitis, multiple sclerosis, systemic lupus erythematosus, ulcerative colitis, Graves' disease, Shoegren's syndrome, autoimmune thyroid disease, or vasculitis. For example U.S. Patent Application Serial No. 16 / 965,271, which is incorporated herein by reference in its entirety.

[0142] In some embodiments, the anti-PC antibodies disclosed herein can be used to treat bacterial infections. In some embodiments, the anti-PC antibodies disclosed herein can be used to treat neuroinflammatory diseases, including but not limited to amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Alzheimer's disease (AD). In some embodiments, the anti-PC antibodies disclosed herein can be used to treat Huntington's disease, frontotemporal dementia (FTD), multiple sclerosis (MS), clinically isolated syndrome (CIS), and other demyelinating diseases of the central nervous system. In some embodiments, the anti-PC antibodies disclosed herein can be used to treat ocular diseases, including but not limited to age-related macular degeneration (AMD) and geographic atrophy (GA).

[0143] In some embodiments, these methods further include administering additional therapeutic agents to the subject. In some embodiments, the additional therapeutic agents are HMG-CoA reductase inhibitors (statins), immunosuppressants, ezetimibe, peroxisomes, niacin, squalene inhibitors, proliferation-activating receptor (PPAR) agonists, cholesterol ester transfer protein (CETP) inhibitors, apolipoprotein A-1 Milan, corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), steroidal anti-inflammatory drugs (SIAIDs), analgesics, growth factors, anti-atherosclerotic drugs, antiproliferative agents, HSP, β-2-glycoprotein-1, and any derivatives and analogs thereof.

[0144] HMGCoA reductase inhibitors (statins) are well-known medications that effectively lower low-density lipoprotein (LDL) cholesterol levels by inhibiting enzymes that regulate the rate of cholesterol production and increasing the liver's clearance of LDL-cholesterol (LDL-C) present in the blood. Non-limiting examples of commonly prescribed statins include atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin.

[0145] Non-limiting examples of immunosuppressants include biologics (such as infliximab, abatacept, adalimumab, anaspirin, sertozumab, etanercept, golimumab, ixekizumab, natezumab, rituximab, secukinumab, tocilizumab, ustekinumab, cananumab, and vedolizumab), calcineurin inhibitors (such as cyclosporine and tacrolimus), mTOR inhibitors (such as sirolimus and everolimus), hypoxanthine mononucleotide dehydrogenase (IMDH) inhibitors (such as azathioprine, leflunomide, and mycophenolate mofetil), methotrexate, monoclonal antibodies (such as dazumab and baliximab), moromumab-CD3 and Janus kinase inhibitors (such as tofacitinib).

[0146] Ezetimibe is the first of a new class of cholesterol absorption inhibitors that effectively and selectively inhibits the absorption of dietary and bile cholesterol at the brush border of the intestinal epithelium without affecting the absorption of triglycerides or fat-soluble vitamins. Therefore, ezetimibe reduces the delivery of total cholesterol to the liver, thereby inducing increased LDL receptor expression and leading to increased removal of LDL-C from plasma.

[0147] Peroxisomes are single-membrane organelles present in almost all eukaryotic cells. One of the most important metabolic processes in peroxisomes is the β-oxidation of long-chain and very long-chain fatty acids. Peroxisomes also participate in bile acid synthesis, cholesterol synthesis, phospholipid synthesis, amino acid metabolism, and purine metabolism.

[0148] Niacin is a known medication that lowers total cholesterol, LDL cholesterol, and triglyceride levels while increasing high-density lipoprotein (HDL) cholesterol levels. Three types of niacin medications exist: immediate-release, time-release, and sustained-release. Niacin, or niacin, is a water-soluble B vitamin that, when administered at doses far exceeding vitamin requirements, can improve all lipoproteins.

[0149] Squalene is an isoprene-like compound structurally similar to β-carotene and is an intermediate metabolite in cholesterol synthesis. In humans, approximately 60% of dietary squalene is absorbed. It is typically transported in serum bound to very low-density lipoprotein and is widely distributed in human tissues, with the highest concentration in the skin. In the skin, it is one of the main components of skin surface lipids. Squalene inhibitors ( For example Monooxygenases and synthases are used as inhibitors of cholesterol biosynthesis.

[0150] Proliferation-activating receptor (PPAR) agonists ( For exampleFibrates (also known as fibrates) are fatty acid-activating members of the nuclear receptor superfamily, playing a crucial role in lipid and glucose metabolism and associated with obesity-related metabolic diseases such as hyperlipidemia, insulin resistance, and coronary artery disease. Fibrates typically and effectively lower elevated plasma triglycerides and cholesterol, acting as PPAR agonists. The most significant effects of fibrates include lowering plasma triglyceride-rich lipoproteins (TRL). In individuals with elevated baseline plasma concentrations, LDL-C levels are generally lower, while HDL-C levels are generally higher when baseline plasma concentrations are low. Non-limiting examples of commonly prescribed fibrates include bezafibrate, gemfibrozil, and fenofibrate.

[0151] Cholesterol ester transfer protein (CETP) inhibitors play a major role in atherosclerosis by reducing the accumulation of cholesterol esters in macrophages and arterial walls, thereby reducing foam cell formation and affecting cholesterol absorption. Avasimib is currently the most promising known CETP inhibitor.

[0152] Apolipoprotein A-1 Milan is commonly used as a recombinant complex with phospholipids (ETC-216) and causes significant regression of coronary atherosclerosis.

[0153] Non-restrictive examples of nonsteroidal anti-inflammatory drugs (NSAIDs) include: cyclochalcones, such as piroxicam, isoxicam, tenoxicam, sudoxicam, and CP-14,304; salicylates, such as aspirin, disalicylate, benzylpyridinium chloride, triamcinolone acetonide, safapirine, soprine, diflunisal, and fendusal; and acetic acid derivatives, such as diclofenac, fenclofenac, indomethacin, sulindac, tometidine, isocolic acid, furofenac, thiophene, zidomecin, acimetidine, fentiac, zolpidem, and clindamycin. Acids such as oxifene, biphenylacetic acid, and ketorolac; fenamic acid derivatives such as mefenamic acid, meclofenamic acid, flufenamic acid, niflufenic acid, and tofenamic acid; propionic acid derivatives such as ibuprofen, naproxen, benzoxalofen, flurbiprofen, ketoprofen, fenprofen, fenbufen, indoprofen, pirprofen, carprofen, oxaprazin, pranoprofen, imidofen, thioprofen, sulprofen, aminprofen, and thiaprofen acid; and pyrazole derivatives such as phenylbutazone, hydroxybutazine, fepranoprofen, azaprofen, and trimethoprim.

[0154] Non-limiting examples of steroidal anti-inflammatory drugs include, but are not limited to, corticosteroids such as hydrocortisone, hydroxytriamcinolone, alpha-methyldexamethasone, dexamethasone phosphate, beclomethasone dipropionate, clobetasol valerate, desonide, desoxymethasone acetate, dexamethasone, diclomethasone, diflubenzuron acetate, diflubenzuron valerate, fluclofenoxate, fluclocortisone, flumethasone neovalerate, fluocinolone acetonide, fluocinolone acetate, flucodone, flucodone, and fluprednidene acetate. Acetate), fluazinam, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone, cortisone, tododozane, flucinonide, fluazinam, difluorocortisone diacetate, fluadrenerol, fluazinam, difluorocortisone diacetate, fluazinam, fluazinam, difluorocortisone diacetate, fluazinam acetate, methylhydroxysone, amoxicillin. Ancifenadine, betamethasone and its other esters, chlorprednisolone, chlorprednisolone acetate, chlorcotropene, clerocinolone, dichlorophenone, difluoroprednisolone, fluclofenoxane, flunisolone, flumexone, fluprednisolone, hydrocortisone valerate, hydrocortisone cyclopentylpropionate, hydrocortisone ester, methylprednisolone, peramisone, prednisolone, prednisolone, beclomethasone dipropionate, triamcinolone and mixtures thereof.

[0155] Non-limiting examples of analgesics (pain relievers) include aspirin and other salicylates (such as choline or magnesium salicylate), ibuprofen, ketoprofen, naproxen sodium, and acetaminophen.

[0156] Growth factors are hormones with multiple functions, including regulating adhesion molecule production, altering cell proliferation, increasing angiogenesis, enhancing collagen synthesis, regulating bone metabolism, and altering cell migration to a given region. Non-limiting examples of growth factors include insulin-like growth factor-1 (IGF-1), transforming growth factor-β (TGF-β), and bone morphogenetic protein (BMP).

[0157] Non-limiting examples of antiproliferative agents include: alkylating agents such as nitrogen mustard, ethyleneimine and methylmelamine, alkyl sulfonates, nitrosoureas and triazines; antimetabolites such as folic acid analogs, pyrimidine analogs and purine analogs; natural products such as vinca alkaloids, epipodophyllotoxin, antibiotics, enzymes, taxanes, biological response modifiers; other agents such as platinum coordination complexes, anthraquinones, anthracyclines, substituted ureas, methylhydrazine derivatives, adrenocortical inhibitors; or hormones or antagonists such as adrenocortical hormones, progestins, estrogens, antiestrogens, androgens, antiandrogens, or gonadotropin-releasing hormone analogs. Specific examples of chemotherapeutic agents include, for example, nitrogen mustard, epipodophyllotoxin, antibiotics, platinum coordination complexes, bleomycin, doxorubicin, paclitaxel, etoposide, 4-OH cyclophosphamide, and cisplatin.

[0158] The HSP family consists of approximately 25 proteins, distinguished by their molecular weight and possessing a highly conserved structure. Almost all humans exhibit cellular and humoral immune responses to microbial heat shock protein 60 (HSP60). Due to the high antigenic homology between microorganisms (bacteria and parasites) and human HSP60, the “cost” of microbial immunization may be the risk of cross-reactivity with human HSP60 expressed on stressed endothelial cells. True autoimmunity against altered autologous HSP60 may also trigger this process (Wick et al., TRENDS in Immunology. 2001; 22(12):665-669). In several experimental autoimmune diseases (arthritis, type 1 diabetes), HSPs are considered target autoantigens. Anti-HSP65 and anti-HSP60 antibodies have been shown to be associated with atherosclerotic lesions in humans. Studies in rabbits and mice have shown that antibodies against HSP65 or HSP60 can be effective against atherosclerotic lesions. For example Immunization with the formulation generates an HSP65-induced immune response that enhances atherosclerotic formation. Since autoimmune processes target HSP65 as a potential antigen candidate, inducing a non-responsive state through mucosal “tolerance” has been employed to block these responses. Our team reported that HSP65-fed mice showed reduced early atherosclerosis compared to mice fed BSA or PBS (Harats et al., J Am Coll Cardiol. 2002; 40:1333-1338). Maron further supports this, demonstrating that nasal HSP vaccination reduces inflammatory processes associated with atherosclerosis (Maron et al., Circulation. 2002; 106:1708-1715).

[0159] β-2-glycoprotein I (β2GPI) is a phospholipid-binding protein that has been shown to be a target of prothrombotic antiphospholipid antibodies. It has recently been demonstrated to drive immune-mediated responses and enhance atherosclerosis in mice. β-antibodies against β-2-GPI have the ability to activate monocytes and endothelial cells and can induce an immune response against β2GPI in atherosclerotic mice, thereby accelerating atherosclerosis. When β2GPI-reactive lymph nodes and splenocytes are transferred to LDL receptor-deficient mice, they promote the formation of fatty streaks, demonstrating the direct pro-atherosclerotic effect of β2GPI-specific lymphocytes. Induction of immune tolerance to β2GPI by pre-oral administration of the antigen resulted in a significant reduction in the degree of atherosclerotic lesions. Therefore, β2GPI is a candidate player in atherosclerotic plaques and may serve as an immunomodulator of plaque progression. Oral administration of β2GPI inhibited the responsiveness of lymph node cells to β2GPI in mice immunized against human proteins. After induction with the corresponding protein, the production of IL-4 and IL-10 in the lymph node cells of β2GPI-tolerant mice immunized against β2GPI was upregulated. Therefore, oral administration of β2GPI is an effective means of inhibiting the formation of atherosclerosis in mice (George et al., Cardiovasc Res. 2004; 62(3):603-9).

[0160] In some embodiments, the anti-PC antibody or pharmaceutical composition disclosed herein works synergistically with additional therapeutic agents.

[0161] In some embodiments, this disclosure relates to antibody and / or pharmaceutical compositions of this disclosure for use in methods of this disclosure, wherein the method further includes administering an additional therapeutic agent to a subject. In some embodiments, this disclosure relates to (a) an antibody and / or pharmaceutical composition of this disclosure, and (b) an additional therapeutic agent for use as a medicine. In some embodiments, this disclosure relates to (a) an antibody and / or pharmaceutical composition of this disclosure, and (b) an additional therapeutic agent for use in methods for treating inflammatory diseases. In further embodiments, this disclosure relates to a pharmaceutical composition, kit, or multi-component kit comprising (a) an antibody and / or pharmaceutical composition of this disclosure, and (b) an additional therapeutic agent. In some embodiments, additional therapeutic agents are HMG-CoA reductase inhibitors (statins), immunosuppressants, ezetimibe, peroxisomes, niacin, squalene inhibitors, proliferation-activating receptor (PPAR) agonists, cholesterol ester transfer protein (CETP) inhibitors, apolipoprotein A-1 Milan, nonsteroidal anti-inflammatory drugs, steroidal anti-inflammatory drugs, analgesics, growth factors, anti-atherosclerotic drugs, antiproliferative agents, HSP, and β-2-glycoprotein-I.

[0162] Anti-PC antibodies and other therapeutic agents ( For exampleHMG-CoA reductase inhibitors (statins), immunosuppressants, ezetimibe, peroxisomes, niacin, squalene inhibitors, proliferation-activating receptor (PPAR) agonists, cholesterol ester transfer protein (CETP) inhibitors, apolipoprotein A-1 Milan, nonsteroidal anti-inflammatory drugs, steroidal anti-inflammatory drugs, analgesics, growth factors, anti-atherosclerotic drugs, antiproliferative agents, HSP or β-2-glycoprotein-I) can be administered alone, sequentially or simultaneously as a single dosage form.

[0163] The antibody or pharmaceutical compositions described herein can be delivered to subjects via a variety of routes. These include, but are not limited to, parenteral, intranasal, intratracheal, oral, intradermal, topical, intramuscular, intraperitoneal, transdermal, intravenous, intratumoral, conjunctival, intraarterial, and subcutaneous routes. Lung administration is also possible. For example The antibody or pharmaceutical composition described herein is used as a spray by using an inhaler or nebulizer and a formulation containing a nebulizing agent. In some embodiments, the antibody or pharmaceutical composition described herein is delivered subcutaneously or intravenously. In some embodiments, the antibody or pharmaceutical composition described herein is delivered intra-arterially. In some embodiments, the antibody or pharmaceutical composition described herein is delivered intratumorally. In some embodiments, the antibody or pharmaceutical composition described herein is delivered to the tumor draining lymph nodes.

[0164] The amount of antibody or composition effective in the treatment and / or prevention of a disease will depend on the nature of the disease and can be determined using standard clinical techniques.

[0165] The precise dosage used in the composition will also depend on the route of administration and the severity of the infection or disease it causes, and should be determined based on the practitioner's judgment and the individual subject's circumstances. For example, the effective dosage can also vary depending on the method of administration, target site, patient's physiological state (including age, weight, and health status), whether the patient is human or animal, and whether other drugs or treatments administered are prophylactic or therapeutic. Typically, the patient is human, but treatment can also be given to non-human mammals, including genetically modified mammals. Optimal titration of the therapeutic dose is performed to optimize safety and efficacy.

[0166] The anti-PC antibodies described herein can also be used to determine OxPL levels in biological samples using classical immunohistochemical methods known to those skilled in the art, including immunoassays such as enzyme-linked immunosorbent assay (ELISA), immunoprecipitation, or Western blotting. Suitable antibody assay markers are known in the art and include: enzyme labels, such as glucose oxidase; radioactive isotopes, such as iodine (…). 125 I, 121 I), carbon ( 14 C), sulfur 35 S), tritium ( 3 H), Indium121 In) and technetium ( 99 Tc); luminescent labels, such as luminol; and fluorescent labels, such as fluorescein and rhodamine, as well as biotin. Such labels can be used to label the antibodies described herein. Alternatively, a second antibody recognizing the anti-PC antibody described herein can be labeled and used in combination with the anti-PC antibody to detect OxPL levels. Therefore, in some embodiments, this disclosure relates to the anti-PC antibody of this disclosure being used for... In vitro Use in detecting OxPL in biological samples. In another embodiment, this disclosure relates to the use of the anti-PC antibody of this disclosure for... See, for example or For example The purpose is to determine and / or detect OxPL levels in biological samples, optionally wherein the anti-PC antibody is conjugated with a radionuclide or a detectable label, and / or carries the label described herein, and / or is used in immunohistochemical methods.

[0167] The determination of OxPL levels aims to include direct ( In vitro By measuring or estimating the absolute OxPL level) or relatively ( For example In vitro The OxPL level in a first biological sample is qualitatively or quantitatively measured or estimated by comparing it with a disease-related OxPL level in a second biological sample. The OxPL level in the first biological sample can be measured or estimated and compared with a standard OxPL level, such as that obtained from a second biological sample from an individual without the disease, or determined by averaging levels across a population of individuals without the disease. As will be understood in the art, once the "standard" OxPL level is known, it can be repeatedly used as a standard for comparison. Therefore, in another embodiment, this disclosure relates to a method for determining and / or detecting OxPL levels (e.g., human OxPL levels) in biological samples. In vivo Methods that include qualitatively or quantitatively measuring or estimating the level of OxPL (e.g., human OxPL) in biological samples using immunohistochemical methods.

[0168] As used herein, the term "biological sample" refers to any biological sample obtained from a subject, cell line, tissue, or other cellular source that may contain oxidized phospholipids. (This is used for samples obtained from animals...) For example Methods for obtaining tissue biopsies and body fluids from humans or cynomolgus monkeys are well known in the art. Biological samples include peripheral blood mononuclear cells (PBMCs).

[0169] The anti-PC antibodies described herein can be used for prognostic, diagnostic, monitoring, and screening applications, including those well-known and standard to those skilled in the art and based on this specification. See and See Applications. Used for et al.Assays and kits for assessing and evaluating the status and / or immune response of the immune system can be used to predict, diagnose, and monitor patient samples, including those known to have or suspected of having immune system dysfunction, or those concerning anticipated or expected immune system responses or antigenic responses. The assessment and evaluation of the immune system status and / or immune response can also be used to determine a patient's suitability for a clinical trial of a drug or for a specific therapeutic agent or antibody (including combinations thereof) relative to the administration of different agents or antibodies. For example Applications include targeted cell therapy and immunomodulation, as well as radiographic imaging of immune responses. Therefore, in some embodiments, this disclosure relates to the anti-PC antibody and / or pharmaceutical composition of this disclosure used as a diagnostic agent. In some embodiments, this disclosure relates to the anti-PC antibody and / or pharmaceutical composition of this disclosure for use in methods for predicting, diagnosing, and / or monitoring subjects suffering from or suspected of having immune system dysfunction and / or regarding expected or desired immune system responses or antigen responses. In another embodiment, this disclosure relates to the anti-PC antibody of this disclosure used to... For example or For example The purpose of measuring and / or detecting human OxPL levels in biological samples of subjects to predict, diagnose, and / or monitor subjects with or suspected of having immune system dysfunction and / or regarding expected or desired immune system or antigen responses.

[0170] In some embodiments, anti-PC antibodies can be used for immunohistochemistry of biopsy samples. In some embodiments, the method is... For example Methods. In another embodiment, anti-PC antibodies can be used to detect levels of OxPL or OxPL-containing cells, and these levels can then be associated with certain disease symptoms. The anti-PC antibodies described herein may carry detectable or functional markers and / or be conjugated to radionuclides or detectable markers. When fluorescent markers are used, the specific binding members can be identified and quantified using currently available microscopy and fluorescence activated cell sorting analysis (FACS) or a combination of two methodological procedures known in the art. The anti-PC antibodies described herein may carry or be conjugated to fluorescent markers. Exemplary fluorescent markers include, for example, reactive and conjugated probes. et al. Aminocoumarin, fluorescein and Texas Red, Alexa Fluor dye, Cy dye and DyLight dye. Anti-PC antibodies may carry radiolabels or radionuclides or may be conjugated to radiolabels or radionuclides, such as isotopes. 3 H, 14 C 32 P, 35 S, 36 Cl、 51 Cr 57 Co、 58Co、 59 Fe、 67 Cu、 90 Y、 99 Tc, 111 In、 117 Lu、 121 I, 124 I, 125 I, 131 I, 198 Au、 211 At、 213 Bi、 225 Ac and 186 Re. When using radiolabeling, currently available counting procedures known in the art can be used to identify and quantify the specific binding of anti-PC antibodies to PC. In the case where the label is an enzyme, detection can be performed using any currently used colorimetric, spectrophotometric, fluorescence spectrophotometric, amperometric, or gas assay technique known in the art. This can be achieved by contacting a sample or control sample with the anti-PC antibody under conditions that allow for the formation of a complex between the anti-PC antibody and PC. Any complexes formed between the anti-PC antibody and PC are detected and compared in the sample and control. Given the specific binding of the anti-PC antibody to PC described herein, the anti-PC antibody can be used for the specific detection of PC. The anti-PC antibody described herein can also be used to purify PC via immunoaffinity purification. This document also includes an assay system, which can be prepared in the form of a test kit, reagent kit, or multi-component kit, for the quantitative analysis of, for example, the presence of PC / PC ligand complexes. The system, test kit, reagent kit, or multi-component kit may contain labeled components. For example Labeled antibodies and one or more other immunochemical reagents.

[0171] On the other hand, this article provides: a polynucleotide comprising a nucleotide sequence encoding a portion thereof of the antibody described herein or a fragment thereof that specifically binds to the PC antigen ( See, for example VL and / or VH; and light chains and / or heavy chains); and carriers, See, for example Contains for use in host cells ( et al. , et al. Vectors for recombinant expression of such polynucleotides in mammalian cells. This document provides polynucleotides containing nucleotide sequences encoding the heavy chain and / or light chain of any antibody provided herein, and vectors containing such polynucleotide sequences. For example They are in the host cell ( See, for example Expression vectors that are effectively expressed in mammalian cells.

[0172] As used in this article, “isolated” polynucleotides or nucleic acid molecules are those present in natural sources of nucleic acid molecules ( For example"Isolated" nucleic acid molecules, such as cDNA molecules, are polynucleotides or nucleic acid molecules isolated from other nucleic acid molecules (in mice or humans). Furthermore, "isolated" nucleic acid molecules, such as cDNA molecules, may be substantially free of other cellular material or culture medium when produced by recombinant technology, or substantially free of chemical precursors or other chemicals when chemically synthesized. For example, the phrase "substantially free" includes having less than about 15%, 10%, 5%, 2%, 1%, 0.5%, or 0.1% (especially less than about 10%) of other substances. For example Preparations of polynucleotides or nucleic acid molecules (including cellular material, culture medium, other nucleic acid molecules, chemical precursors, and / or other chemical substances). In specific embodiments, nucleic acid molecules encoding the antibodies described herein are isolated or purified.

[0173] In certain respects, this document provides polynucleotides comprising a nucleotide sequence encoding an antibody that specifically binds to PC and comprises an amino acid sequence as described herein, and antibodies that compete with such antibodies for binding to PC. For example Antibodies that bind to the same epitopes in a dose-dependent manner, or antibodies that bind to such antibodies.

[0174] In some respects, this document provides polynucleotides comprising nucleotide sequences encoding a light or heavy chain of an antibody described herein. The polynucleotide may comprise nucleotide sequences encoding a light chain of a VL FR and CDR comprising an antibody described herein. For example (Table 1) or the nucleotide sequence encoding the heavy chain containing the antibody described herein (VHFR and CDR). For example For example (See Table 1). In some embodiments, the polynucleotide encodes the VH, VL, heavy chain, and / or light chain described herein. In another embodiment, the polynucleotide encodes the first VH and first VL described herein. In another embodiment, the polynucleotide encodes the second VH and second VL described herein. In another embodiment, the polynucleotide encodes the first heavy chain and first light chain described herein. In another embodiment, the polynucleotide encodes the second heavy chain and second light chain described herein. In another embodiment, the polynucleotide encodes the VH and / or VL, or heavy chain and / or light chain, of the antibody described herein.

[0175] This article also provides polynucleotides encoding anti-PC antibodies, which For example Optimization was achieved through codon / RNA optimization, replacement with heterologous signal sequences, and elimination of unstable elements in mRNA. This generated a fragment encoding an anti-PC antibody. For example Optimized nucleic acids (light chain, heavy chain, VH domain, or VL domain) used for recombinant expression by introducing codon changes and / or eliminating repressor regions in mRNA can be adjusted accordingly. For exampleThe optimization methods described in U.S. Patent Nos. 5,965,726; 6,174,666; 6,291,664; 6,414,132; and 6,794,498 are all incorporated herein by reference in their entirety. For example, potential splicing sites and unstable elements within RNA ( See, for example Elements rich in A / T or A / U can be mutated without altering the amino acids encoded by the nucleic acid sequence to increase the stability of the RNA used for recombinant expression. These changes exploit the degeneracy of the genetic code. For example Using alternative codons for the same amino acid. In some embodiments, it may be necessary to change one or more codons to encode a conserved mutation. For example Similar amino acids with similar chemical structure and properties and / or functions to the original amino acids. Such methods can increase the expression of anti-PC antibodies or fragments thereof by at least 1, 2, 3, 4, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 times or more relative to the expression of anti-PC antibodies encoded by unoptimized polynucleotides.

[0176] In some embodiments, the encoding is the anti-PC antibody described herein or a fragment thereof ( Namely An optimized polynucleotide sequence (VL domain and / or VH domain) can be coupled with a fragment encoding the anti-PC antibody described herein or a fragment thereof. For example Antisense of unoptimized polynucleotide sequences (VL domain and / or VH domain) et al. (Complementary) polynucleotide hybridization. In specific embodiments, an optimized nucleotide sequence encoding the anti-PC antibody or fragment described herein hybridizes under high-tightness conditions with an antisense polynucleotide sequence encoding an unoptimized polynucleotide sequence encoding the anti-PC antibody or fragment described herein. In specific embodiments, an optimized nucleotide sequence encoding the anti-PC antibody or fragment described herein hybridizes under high-tightness, medium-tightness, or low-tightness hybridization conditions with an antisense polynucleotide sequence encoding an unoptimized polynucleotide sequence encoding the anti-PC antibody or fragment described herein. Information regarding hybridization conditions has been described. For example US Patent Application Publication No. US 2005 / 0048549 ( For example (paragraphs 72-73), which are incorporated into this article in their entirety by reference.

[0177] Polynucleotides can be obtained and their nucleotide sequences determined by any method known in the art. The antibody described herein ( For example The nucleotide sequences of the antibodies described in Table 1 and their modified forms can be determined using methods well known in the art. For exampleIt is known that nucleotide codons encoding specific amino acids are assembled in a manner that produces nucleic acids encoding antibodies. These antibody-encoding polynucleotides can be assembled from chemically synthesized oligonucleotides. For example As described in Kutmeier G See, for example (1994), BioTechniques 17: 242-6, which is incorporated herein by reference in its entirety, briefly describes the synthesis of overlapping oligonucleotides containing sequence portions encoding antibodies, the annealing and ligation of these oligonucleotides, and the subsequent amplification of the ligated oligonucleotides by PCR.

[0178] Alternatively, methods well known in the art can be used ( See, for example PCR and other molecular cloning methods) from suitable sources ( For example The nucleic acid production of hybridomas generates polynucleotides encoding antigen-binding regions or antibodies as described herein. For example, PCR amplification using synthetic primers that hybridize to the 3' and 5' ends of a known sequence can be performed using genomic DNA obtained from hybridoma cells that produce antibodies of interest. Such PCR amplification methods can be used to obtain nucleic acids containing sequences encoding light and / or heavy chains of antibodies. Such PCR amplification methods can also be used to obtain nucleic acids containing sequences encoding variable light and / or variable heavy chain regions of antibodies. The amplified nucleic acids can be cloned into vectors for expression in host cells and used for further cloning.

[0179] If a clone of a nucleic acid containing a specific antigen-binding region or antibody is unavailable, but the sequence of the antigen-binding region or antibody molecule is known, it can be chemically synthesized or obtained from a suitable source. For example Antibody cDNA libraries, or cDNA libraries derived from nucleic acids (preferably polyA+RNA) isolated from any tissue or cell expressing antibodies (such as hybridoma cells selectively expressing the antibodies described herein), can be amplified by PCR using synthetic primers capable of hybridizing to the 3' and 5' ends of the sequence, or identified by cloning using oligonucleotide probes specific to a particular gene sequence. For example cDNA clones from a cDNA library encoding antibodies are used to obtain nucleic acids encoding immunoglobulins. The amplified nucleic acids generated by PCR can then be cloned into a reproducible cloning vector using any method well-known in the art.

[0180] Using conventional methods ( For example DNA encoding the anti-PC antibodies described herein can be readily isolated and sequenced using oligonucleotide probes capable of specifically binding to genes encoding both the heavy and light chains of anti-PC antibodies. Hybridoma cells can serve as a source of such DNA. Once isolated, the DNA can be placed in an expression vector and then transfected into host cells, such as... For exampleCells, simian COS cells, Chinese hamster ovary (CHO) cells ( For example (CHO cells from CHO GS System™ (Lonza) or myeloma cells that do not produce additional immunoglobulins to obtain the synthesis of anti-PC antibodies in recombinant host cells.)

[0181] To generate an intact antibody or antigen-binding region, PCR primers comprising the VH or VL nucleotide sequence, a restriction site, and flanking sequences protecting the restriction site can be used to amplify the VH or VL sequence in the scFv clone. Using cloning techniques known to those skilled in the art, the PCR-amplified VH domain can be cloned into the constant region of the heavy chain expression chain (SCFV). For example The vector expressing the human γ1 or human γ4 constant region can be used to clone the PCR-amplified VL domain into the expression light chain constant region (the human γ1 or human γ4 constant region). For example The vector expressing the VH or VL domain is placed in a vector containing the human κ or λ constant region. In some embodiments, the vector for expressing the VH or VL domain includes an EF-1α promoter, a secretion signal, a cloning site for the variable region, a constant region, and a selection marker such as neomycin. The VH and VL domains can also be cloned into a vector expressing the essential constant region. The heavy chain transformation vector and the light chain transformation vector are then co-transfected into a cell line using techniques known to those skilled in the art to generate a full-length antibody (expressing the human κ or λ constant region). For example Stable or transient cell lines of IgG.

[0182] DNA can also be modified, for example by replacing mouse sequences with coding sequences of human heavy and light chain constant regions, or by covalently linking all or part of the coding sequence of a non-immunoglobulin polypeptide to an immunoglobulin coding sequence.

[0183] Also provided are polynucleotides that hybridize with polynucleotides encoding the antibodies described herein under high-strictness, medium-strictness, or low-strictness hybridization conditions. In specific embodiments, the polynucleotides described herein hybridize with polynucleotides encoding the VH domain and / or VL domain provided herein under high-strictness, medium-strictness, or low-strictness hybridization conditions.

[0184] Hybridization conditions have been described in the art and are known to those skilled in the art. For example, hybridization under stringent conditions may involve hybridization of DNA bound to a filter membrane in 6x sodium chloride / sodium citrate (SSC) at about 45°C, followed by one or more washes in 0.2x SSC / 0.1% SDS at about 50-65°C; hybridization under highly stringent conditions may involve hybridization of nucleic acids bound to a filter membrane in 6x SSC at about 45°C, followed by one or more washes in 0.1x SSC / 0.2% SDS at about 68°C. Hybridization under other stringent conditions is known to those skilled in the art and has been described. For example ,See, for example Ausubel FM For example Edited by, (1989) Current Protocols in Molecular Biology, Volume I, Green Publishing Associates, Inc. and John Wiley & Sons, Inc., New York, pp. 6.3.1–6.3.6 and 2.10.3, which are incorporated herein by reference in their entirety.

[0185] In some respects, this article provides expressions ( For example (recombinantly) the cells that specifically bind to the PC described in this article ( Namely (host cells), as well as related polynucleotides and expression vectors. This article provides vectors containing polynucleotides (host cells), and related polynucleotides and expression vectors. For example (Expression vector), the polynucleotide contains a nucleotide sequence encoding an anti-PC antibody or fragment, for use in host cells, preferably in mammalian cells ( et al. Recombinant expression in CHO cells. This article also provides information on recombinant expression of the anti-PC antibody described herein. For example The host cell of such vectors (human or humanized antibodies). In a specific aspect, this document provides a method for generating the antibodies described herein, the method comprising expressing the antibody from a host cell.

[0186] The antibody that specifically binds to PC described in this article ( For example Recombinant expression of the full-length antigen-binding region or antibody, or the heavy chain and / or light chain of the antibody described herein, typically involves constructing an expression vector containing a polynucleotide encoding the antibody. Once the expression of the antibody molecule described herein, the heavy chain and / or light chain of the antibody, or a fragment thereof is obtained, the expression process typically involves constructing an expression vector containing a polynucleotide encoding the antibody. For example If a polynucleotide (containing a heavy chain and / or light chain variable region) is used to generate the antibody molecule, the vector used to generate the antibody molecule can be produced using recombinant DNA technology with techniques well known in the art. Therefore, this article describes the expression of a polynucleotide containing an antibody or antibody fragment (…). For example Methods for preparing proteins using polynucleotides (light or heavy chains) encoding nucleotide sequences. Methods well known to those skilled in the art can be used to construct proteins containing antibodies or antibody fragments (…). For example Expression vectors containing coding sequences (light or heavy chains) and appropriate transcription and translation control signals. These methods include, for example... Escherichia coli Recombinant DNA technology, synthesis technology For exampleGene recombination. Also provided are reproducible vectors containing nucleotide sequences encoding antibody molecules, heavy or light chains of antibodies, variable regions of heavy or light chains of antibodies or fragments thereof, or heavy or light chain CDRs, operatively linked to a promoter. Such vectors may, for example, include nucleotide sequences encoding constant regions of antibody molecules (…). et al. International Publication Nos. WO 86 / 05807 and WO89 / 01036; and U.S. Patent No. 5,122,464, which is incorporated herein by reference in its entirety, and the variable region of an antibody can be cloned into this vector to express the entire heavy chain, the entire light chain, or both the entire heavy chain and the light chain.

[0187] In some embodiments, the vector comprises polynucleotides encoding the VH, VL, heavy chain, and / or light chain of the antibody described herein. In another embodiment, the vector comprises polynucleotides encoding the VH and VL of the antibody described herein. In yet another embodiment, the vector comprises polynucleotides encoding the heavy chain and light chain of the antibody described herein.

[0188] Expression vectors can be transferred into cells using conventional techniques. Escherichia coli The host cell can then be cultured using conventional techniques to produce an antibody or fragment thereof as described herein. Therefore, this document provides a host cell containing a polynucleotide encoding an antibody or fragment thereof, a heavy or light chain thereof, a fragment thereof, or a single-chain antibody as described herein, operatively linked to a promoter for expressing such a sequence in the host cell.

[0189] In another embodiment, the host cell comprises polynucleotides encoding VH and VL of the antibody described herein. In another embodiment, the host cell comprises a vector containing polynucleotides encoding VH and VL of the antibody described herein. In another embodiment, the host cell comprises a first polynucleotide encoding VH of the antibody described herein and a second polynucleotide encoding VL of the antibody described herein. In yet another embodiment, the host cell comprises a first vector and a second vector, the first vector containing a first polynucleotide encoding VH of the antibody described herein and the second vector containing a second polynucleotide encoding VL of the antibody described herein.

[0190] In specific embodiments, heavy chain / heavy chain variable regions expressed by a first cell associate with light chain / light chain variable regions of a second cell to form the anti-PC antibody described herein. In some embodiments, a host cell population comprising such a first host cell and such a second host cell is provided herein.

[0191] In some embodiments, this document provides a vector population comprising a first vector and a second vector, the first vector comprising a polynucleotide encoding a light chain / light chain variable region of the anti-PC antibody described herein, and the second vector comprising a polynucleotide encoding a heavy chain / heavy chain variable region of the anti-PC antibody described herein.

[0192] Multiple host expression vector systems can be used to express the antibody molecules described in this article. For example (US Patent No. 5,807,715, which is incorporated herein by reference in its entirety). Such host expression systems represent agents that can produce and subsequently purify coding sequences of interest, but also represent those that can be transformed or transfected with appropriate nucleotide coding sequences. Bacillus subtilis Cells expressing the antibody molecules described herein. These include, but are not limited to, those using... For example Microorganisms, such as bacteria, transformed with recombinant phage DNA, plasmid DNA, or copious DNA expression vectors containing antibody coding sequences. Saccharomyces , Pichia pastoris and For example For example );use For example Yeast transformed with a recombinant yeast expression vector containing an antibody coding sequence ( For example , For example and For example For example );use For example Recombinant viral expression vectors containing antibody coding sequences ( Chlamydomonas reinhardtii Insect cell systems infected with baculoviruses; using For example Recombinant viral expression vector ( For example Cauliflower mosaic virus (CaMV); Tobacco mosaic virus (TMV) infection or use For example Recombinant plasmid expression vectors containing antibody coding sequences ( Escherichia coli Plant cell systems transformed with Ti plasmid (Ti plasmid) For example Green algae, such as et al. ); or containing Escherichia coli mammalian cell systems of recombinant expression constructs ( For example COS ( For example The recombinant expression construct contains a genome derived from mammalian cells (COS1 or COS), CHO, BHK, MDCK, HEK 293, NS0, PER.C6, VERO, CRL7O3O, HsS78Bst, HeLa and NIH3T3, HEK-293T, HepG2, SP210, R1.1, BW, LM, BSC1, BSC40, YB / 20 and BMT10 cells). For example (metallothionein promoter) or from mammalian viruses ( For example(Adenovirus late promoter; vaccinia virus 7.5K promoter). In specific embodiments, the cells used to express the antibodies described herein are Chinese hamster ovary (CHO) cells, such as CHO cells from the CHO GS System™ (Lonza). In some embodiments, the heavy and / or light chains of the antibodies produced by CHO cells may have N-terminal glutamine or glutamate residues substituted with pyroglutamic acid. In some embodiments, the cells used to express the antibodies described herein are human cells. For example Human cell lines. In specific embodiments, the mammalian expression vector is pOptiVEC™ or pcDNA3.3. In some embodiments, bacterial cells such as... See, for example or eukaryotic cells ( See, for example Mammalian cells, particularly those used to express complete recombinant antibody molecules, are efficient systems for antibody expression. For example, mammalian cells such as CHO cells, when combined with vectors such as major intermediate early gene promoter elements from human cytomegalovirus, are efficient antibody expression systems (Foecking MK and Hofstetter H (1986) Gene 45: 101-5; and Cockett MI). For example (1990) Biotechnology 8(7): 662-7, each of which is incorporated herein by reference in its entirety. In some embodiments, the antibodies described herein are produced by CHO cells or NSO cells. In specific embodiments, the expression of the nucleotide sequence encoding the antibody described herein that specifically binds to PC is regulated by a constitutive promoter, an inducible promoter, or a tissue-specific promoter.

[0193] In bacterial systems, a variety of expression vectors can be advantageously selected based on the intended use of the antibody molecule to be expressed. For example, when producing large quantities of such antibodies, a vector that directs the high-level expression of an easily purified fusion protein product may be needed to generate the drug composition containing the antibody molecule. Such vectors include, but are not limited to, those... For exampleExpression vectors such as pUR278 (Ruether U and Mueller-Hill B (1983) EMBO J 2: 1791-1794), in which the coding sequence can be individually linked to a vector within a framework containing the lacZ coding region, yield fusion proteins; pIN vectors (Inouye S and Inouye M (1985) Nuc Acids Res 13: 3101-3109; Van Heeke G and Schuster SM (1989) JBiol Chem 24: 5503-5509); and so on, all of which are incorporated herein by reference in their full text. For example, pGEX vectors can also be used to express exogenous peptides as fusion proteins with glutathione 5-transferase (GST). Generally, such fusion proteins are soluble and can be readily purified from lysed cells by adsorption and binding to matrix glutathione agarose beads, followed by elution in the presence of free glutathione. The pGEX vector is designed to include thrombin or factor Xa protease cleavage sites, allowing the cloned target gene product to be released from the GST portion.

[0194] For example, in insect systems, For example Nucleopolyhedrovirus (AcNPV) can be used as a vector for expressing exogenous genes. This virus... For example Cellular growth. The coding sequence can be cloned separately into a non-essential region of the virus (e.g., the polyhedral protein gene) and placed under the control of an AcNPV promoter (e.g., the polyhedral protein promoter).

[0195] In mammalian host cells, numerous virus-based expression systems can be utilized. When using adenovirus as an expression vector, the coding sequence of interest can be ligated into the adenoviral transcription / translation control complex. In vitro Late promoter and triple leader sequence. Then it can be... In vivo or See, for example Recombination inserts the chimeric gene into the adenovirus genome. In a non-essential region of the viral genome (… See, for example Insertion into the E1 or E3 region will produce a recombinant virus that is viable and capable of expressing the molecule in an infected host. In situLogan J and Shenk T (1984) PNAS 81(12): 3655-9, which is incorporated herein by reference in its entirety. Efficient translation of the inserted coding sequence may also require specific start signals. These signals include the ATG start codon and adjacent sequences. Furthermore, the start codon must be in phase with the reading frame of the desired coding sequence to ensure translation of the entire insert. These exogenous translation control signals and start codons can be of various sources, including natural and synthetic. Expression efficiency can be enhanced by including appropriate transcriptional enhancer elements, transcription terminators, etc. For example Bitter G For example , (1987) Methods Enzymol.153: 516-544, which is incorporated herein by reference in its entirety.

[0196] Additionally, host cell lines can be selected to regulate the expression of the inserted sequence or to modify and process the gene product in a specific manner as desired. Such modifications to protein products ( Escherichia coli glycosylation) and processing ( Bacillus subtilis (Cleavage) can be important for protein function. Different host cells have characteristic and specific mechanisms for post-translational processing and modification of proteins and gene products. Appropriate cell lines or host systems can be selected to ensure proper modification and processing of expressed exogenous proteins. For this purpose, eukaryotic host cells with appropriate cellular mechanisms for processing primary transcripts, glycosylation, and phosphorylation of gene products can be used. Such mammalian host cells include, but are not limited to, CHO, VERO, BHK, HeLa, MDCK, HEK 293, NIH 3T3, W138, BT483, Hs578T, HTB2, BT2O and T47D, NSO (a mouse myeloma cell line that does not endogenously produce any immunoglobulin chains), CRL7O3O, COS ( For example The anti-PC antibodies described herein are generated in mammalian cells such as COS1 or COS, PER.C6, VERO, HsS78Bst, HEK-293T, HepG2, SP210, R1.1, BW, LM, BSC1, BSC40, YB / 20, BMT10, and HsS78Bst cells. In some embodiments, the anti-PC antibodies described herein are generated in mammalian cells such as CHO cells.

[0197] In specific embodiments, the antibodies described herein have reduced or no fucose content. Such antibodies can be produced using techniques known to those skilled in the art. For example, antibodies can be expressed in cells lacking or devoid of fucosylation capacity. In a specific example, a cell line with two alleles knocked out of α1,6-fucosyltransferase can be used to produce antibodies with reduced fucose content.® The Lonza system is an example of such a system that can be used to generate antibodies with reduced fucose content.

[0198] For long-term, high-yield production of recombinant proteins, stable expression cells can be generated. For example, cell lines that stably express the anti-PC antibody described herein can be engineered. In specific embodiments, the cells provided herein stably express light chain / light chain variable regions and heavy chain / heavy chain variable regions, which associate to form the antigen-binding region or antibody described herein.

[0199] In some respects, instead of using expression vectors containing viral replication origins, appropriate expression control elements can be used ( For example The recombinant plasmid transforms host cells with DNA controlled by promoters, enhancers, sequences, transcription terminators, polyadenylation sites, etc. After the introduction of exogenous DNA / polynucleotides, engineered cells can be grown in enrichment media for 1–2 days and then switched to selective media. The selective markers in the recombinant plasmid confer resistance to the selected medium and allow cells to stably integrate the plasmid into their chromosomes and grow to form lesions, which can then be cloned and amplified into cell lines. This method can be advantageously used to engineer cell lines expressing anti-PC or fragments thereof as described herein. Such engineered cell lines can be particularly used for screening and evaluating compositions that interact directly or indirectly with antibody molecules.

[0200] Many selection systems can be used, including but not limited to Wigler Mn2 herpes simplex virus thymidine kinase (HSV-M) in TK cells, HGPRT cells, or APRT cells, respectively. Saccharomyces (1977) Cell 11(1): 223-32), hypoxanthine-guanine phosphoribosyltransferase (Szybalska EH and Szybalski W (1962) PNAS 48(12): 2026-2034) and adenine phosphoribosyltransferase (Lowy I Pichia pastoris (1980) Cell 22(3): 817-23) genes, all of which are incorporated herein by reference in their full text. Furthermore, antimetabolite resistance can be used as a basis for selecting the following genes: For example It confers resistance to methotrexate (Wigler M) For example (1980) PNAS 77(6): 3567-70; O'Hare K For example (1981) PNAS 78: 1527-31); For example, which conferred resistance to mycophenolic acid (Mulligan RC and Berg P (1981) PNAS 78(4): 2072-6); neo, which conferred resistance to aminoglycoside G-418 (Wu GY and Wu CH (1991) Biotherapy 3: 87-95; Tolstoshev P (1993) Ann Rev Pharmacol Toxicol 32: 573-596; Mulligan RC (1993) Science 260: 926-932; and Morgan RA and Anderson WF (1993) Ann Rev Biochem 62: 191-217; Nabel GJ and Felgner PL (1993) Trends Biotechnol 11(5): 211-5); and For example It confers resistance to hygromycin (Santerre RF). For example (1984) Gene 30(1-3): 147-56), all of which are incorporated herein by reference in their full text. Well-known methods in the field of recombinant DNA technology can be routinely applied to select the desired recombinant clone, and such methods are described, for example, in Ausubel FM. For example (Editor), Current Protocols in Molecular Biology, John Wiley & Sons, NY (1993); Kriegler M, Gene Transfer and Expression, A Laboratory Manual, Stockton Press, NY (1990); and in Chapters 12 and 13, Dracopoli NC For example (Ed.), Current Protocols in Human Genetics, John Wiley & Sons, NY (1994); Colbère-Garapin F For example In vitro (1981) J Mol Biol 150: 1-14, all of which are incorporated herein by reference in their full text.

[0201] Antibody molecule expression levels can be increased through vector amplification (see relevant reviews). In vivoBebbington CR and Henschel CCG, The use of vectors based on gene amplification for the expression of cloned genes in mammalian cells in DNA cloning, Vol. 3 (Academic Press, New York, 1987), which is incorporated herein by reference in its entirety. When the marker in the vector system is amplifiable, an increase in the level of inhibitors present in the host cell culture will increase the copy number of the marker gene. Since the amplified region is associated with the gene of interest, protein yield will also increase (Crouse GF). See, for example (1983) MolCell Biol 3: 257-66, which is incorporated herein by reference in its entirety.

[0202] Host cells can be co-transfected with two or more expression vectors described herein, the first vector encoding a heavy-chain-derived polypeptide and the second vector encoding a light-chain-derived polypeptide. Both vectors may contain the same selection marker, enabling the heavy-chain and light-chain polypeptides to be expressed equatorially. Host cells can be co-transfected with varying amounts of the two or more expression vectors. For example, host cells can be transfected with either the first or second expression vector in the following ratios: approximately 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:12, 1:15, 1:20, 1:25, 1:30, 1:35, 1:40, 1:45, or 1:50.

[0203] Alternatively, a single vector encoding and capable of expressing both heavy and light chain polypeptides can be used. In this case, the light chain should be placed before the heavy chain to avoid excessive amounts of toxic free heavy chain (Proudfoot NJ (1986) Nature 322: 562-565; and Köhler G (1980) PNAS 77: 2197-2199, each of which is incorporated herein by reference in its entirety). The coding sequences for the heavy and light chains can comprise cDNA or genomic DNA. The expression vector can be monocistronic or polycistronic. Polycistronic nucleic acid constructs can encode 2, 3, 4, 5, 6, 7, 8, 9, 10 or more gene / nucleotide sequences, or gene / nucleotide sequences in the range of 2 to 5, 5 to 10, or 10 to 20. For example, bicistronic nucleic acid constructs can contain a promoter, a first gene (…), and a second gene in the following order: See, for example The heavy chain of the antibody described in this article) and the second gene ( In situ(The light chain of the antibody described in this article). In this expression vector, transcription of both genes can be driven by promoters, while translation of the mRNA from the first gene can proceed via a cap-dependent scanning mechanism, and translation of the mRNA from the second gene can proceed via a cap-independent mechanism. For example This was conducted by IRES.

[0204] Once the antibody molecules described herein are generated through recombinant expression, they can be purified using any method known in the art for purifying immunoglobulin molecules, such as chromatography. For example Ion exchange, affinity (particularly by means of affinity for a specific antigen after protein A, and fractionation column chromatography), centrifugation, differential solubility, or any other standard technique used for protein purification. Furthermore, the antibodies described herein can be fused with heterologous polypeptide sequences described herein or known in the art to facilitate purification.

[0205] In specific embodiments, the antibodies described herein are isolated or purified. In some embodiments, the isolated antibody is an antibody that is substantially free of other antibodies having an antigen specificity different from that of the isolated antibody. For example, in some embodiments, the antibody formulations described herein are substantially free of cellular material and / or chemical precursors. The phrase “substantially free of cellular material” includes antibody formulations in which the antibody is isolated from the cellular components of the cells from which the antibody was isolated or recombined. Thus, antibodies that are substantially free of cellular material include heterologous proteins (also referred to herein as “contaminating proteins”) and / or antibody variants (e.g., different post-translational modifications of the antibody or other different versions of the antibody) having less than about 30%, 20%, 10%, 5%, 2%, 1%, 0.5%, or 0.1% (on a dry weight basis). Escherichia coli Antibody preparations containing antibody fragments. When recombinant antibodies are produced, they are typically also essentially free of culture medium. Bacillus subtilis The culture medium constitutes less than approximately 20%, 10%, 2%, 1%, 0.5%, or 0.1% of the protein formulation volume. When antibodies are produced through chemical synthesis, they typically contain virtually no chemical precursors or other chemicals. For example It is isolated from chemical precursors or other chemicals involved in protein synthesis. Therefore, such antibody formulations contain less than about 30%, 20%, 10%, or 5% (by dry weight) of chemical precursors or compounds other than the antibody of interest. In specific embodiments, the antibodies described herein are isolated or purified.

[0206] Anti-PC antibodies or fragments thereof can be produced by any method known in the art for synthesizing proteins or antibodies, such as by chemical synthesis or by recombinant expression techniques. Unless otherwise stated, the methods described herein employ conventional techniques from molecular biology, microbiology, genetic analysis, recombinant DNA, organic chemistry, biochemistry, PCR, oligonucleotide synthesis and modification, nucleic acid hybridization, and related fields within the scope of this art. These techniques are described, for example, in the references cited herein and are fully explained therein. et al. Maniatis T Escherichia coli (1982) Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press; Sambrook J For example (1989), Molecular Cloning: A Laboratory Manual, 2nd Edition, Cold Spring Harbor Laboratory Press; Sambrook J et al. (2001) Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Ausubel FM For example Current Protocols in Molecular Biology, John Wiley & Sons (1987 and annual update); Current Protocols in Immunology, John Wiley & Sons (1987 and annual update) Gait (ed.) (1984) Oligonucleotide Synthesis: A Practical Approach, IRL Press; Eckstein (ed.) (1991) Oligonucleotides and Analogues: A Practical Approach, IRL Press; Birren B For example (Edited) (1999) Genome Analysis: A Laboratory Manual, Cold Spring Harbor Laboratory Press. All of these references are incorporated in this paper in their full text by reference.

[0207] In specific embodiments, the antibodies described herein are prepared, expressed, generated, or isolated by any means involving generation. For example Through the synthesis of DNA sequences and genetic engineering. In some embodiments, such antibodies are contained in animals or mammals (…). For example ,people) For example Sequences that are not naturally present in the antibody germline library ( For example (DNA sequence or amino acid sequence).

[0208] In one aspect, this document provides a method for preparing anti-PC antibodies, the method comprising culturing the cells or host cells described herein. In some embodiments, the method involves... For example In one respect, this article provides a method for preparing anti-PC antibodies, the method comprising using the cells or host cells described herein (…). For example Cells or host cells containing polynucleotides encoding the antibodies described herein express ( For example (Recombinant expression) antibodies. In some embodiments, the cells are isolated cells. In some embodiments, exogenous polynucleotides have been introduced into the cells. In some embodiments, the method further includes the step of purifying the antibodies obtained from the cells or host cells.

[0209] In some embodiments, antibodies are generated by expressing polynucleotides and generating antibodies by expressing polynucleotides encoding VH and VL of the antibody described herein in cells under suitable conditions. In another embodiment, antibodies are generated by expressing polynucleotides encoding the heavy chain and light chain of the antibody described herein in cells under suitable conditions. In some embodiments, antibodies are generated by expressing polynucleotides and generating antibodies by expressing a first polynucleotide encoding VH of the antibody described herein and a second polynucleotide encoding VL of the antibody described herein in cells under suitable conditions. In some embodiments, antibodies are generated by expressing polynucleotides and generating antibodies by expressing a first polynucleotide encoding the heavy chain of the antibody described herein and a second polynucleotide encoding the light chain of the antibody described herein in cells under suitable conditions.

[0210] The methods used to generate polyclonal antibodies are known in the art. See Chapter 11, in: Short Protocols in Molecular Biology, (2002) 5th Edition, Ausubel FM See Edited by John Wileyand Sons, New York, whose full text is incorporated herein by reference.

[0211] Monoclonal antibodies can be prepared using a variety of techniques known in the art, including hybridoma, recombinant, and phage display techniques, or combinations thereof. For example, hybridoma techniques can be used to generate monoclonal antibodies, including those known in the art and, for example, those described in Harlow E and Lane D, *Antibodies: A Laboratory Manual*, (Cold Spring Harbor Laboratory Press, 2nd edition, 1988); and Hammerling GJ. See The techniques taught in Monoclonal Antibodies and T-Cell Hybridomas 563 681 (Elsevier, NY, 1981) are incorporated herein by reference in their entirety. As used herein, the term “monoclonal antibody” is not limited to antibodies produced by hybridoma techniques. For example, monoclonal antibodies can be recombinantly generated from host cells expressing exogenous antibodies or fragments thereof, such as the light and / or heavy chains of such antibodies.

[0212] In specific embodiments, such as the "monoclonal antibody" used herein, the antibody is derived from a single cell ( For example Antibodies produced by hybridomas or host cells that generate recombinant antibodies, wherein the antibodies specifically bind to PCs, such as... For example The antibody is determined by ELISA or other antigen binding or competitive binding assays known in the art or provided herein. In some embodiments, the monoclonal antibody may be a chimeric antibody or a humanized antibody. In some embodiments, the monoclonal antibody is a monovalent antibody or a multivalent antibody. For example (Bivalent) antibodies. In some embodiments, the monoclonal antibody is a monospecific or multispecific antibody (…). For example (Bispecific antibodies). The monoclonal antibodies described herein can be prepared, for example, by the hybridoma method described in Kohler G and Milstein C (1975) Nature 256: 495, which is incorporated herein by reference in its entirety, or may be... For example Isolation from phage libraries using techniques such as those described herein. Other methods for preparing clonal cell lines and monoclonal antibodies expressed therefrom are well known in the art. For example Chapter 11, in: Short Protocols in Molecular Biology, (2002) 5th Edition, Ausubel FM For example ).

[0213] As used in this article, when the antibody contains at least two ( For exampleWhen there are two or more monovalent binding regions, the antibody binds to the antigen multivalently. For example (Bivalent), each monovalent binding region can bind to an epitope on the antigen. Each monovalent binding region can bind to the same or different epitopes on the antigen.

[0214] The use of hybridoma technology to generate and screen for specific antibodies is a routine and well-known method in the art. For example, in hybridoma methods, mice or other suitable host animals, such as sheep, goats, rabbits, rats, hamsters, or macaques, are immunized to induce lymphocytes that produce or are capable of producing antibodies that will specifically bind to proteins used for immunization. For example (PC). Alternatively, it can be... For example The lymphocytes are then immunized. The lymphocytes are then fused with myeloma cells using a suitable fusion agent (such as polyethylene glycol) to form hybridoma cells (Goding JW (ed.), Monoclonal Antibodies: Principles and Practice, pp. 59-103 (Academic Press, 1986), which is incorporated herein by reference in its entirety). Additionally, RIMMS (Repeated Immunization Multiple Sites) technology can be used to immunize animals (Kilpatrick KE). In vivo (1997) Hybridoma 16:381-9, which is incorporated herein by reference in its entirety.

[0215] In some embodiments, an antigen ( See, for example immunize mice (or other animals, such as rats, monkeys, donkeys, pigs, sheep, hamsters, or dogs) with PC (presumably referring to a specific type of immunoglobulin), and once an immune response is detected, For example If antigen-specific antibodies are detected in mouse serum, the mouse spleen is harvested and spleen cells are isolated. The spleen cells are then combined with any suitable myeloma cells (e.g., from the American Type Culture Collection (ATCC)) using well-known techniques. ® Cells from the Manassas (VA) cell line SP20 were fused to form hybridomas. Hybridomas were selected and cloned using limiting dilution. In some embodiments, lymph nodes from immunized mice were harvested and fused with NSO myeloma cells.

[0216] The hybridoma cells thus prepared are seeded and grown in a suitable culture medium, preferably containing one or more substances that inhibit the growth or survival of unfused parental myeloma cells. For example, if the parental myeloma cells lack hypoxanthine-guanine phosphoribosyltransferase (HGPRT or HPRT), the hybridoma culture medium typically includes hypoxanthine, aminopterin, and thymidine (HAT medium), which prevent the growth of HGPRT-deficient cells.

[0217] Specific embodiments utilize myeloma cells that are efficiently fused, support stable high-level antibody production, and are sensitive to culture media such as HAT medium. These myeloma cell lines include mouse myeloma cell lines, such as the NSO cell line or cell lines derived from MOPC-21 and MPC-11 mouse tumors, available from the Salk Institute Cell Distribution Center, San Diego, CA, USA, and SP-2 or X63-Ag8.653 cells, available from the American Type Culture Collection (Rockville, MD, USA). Human myeloma and mouse-human xenologous myeloma cell lines have also been described for the production of human monoclonal antibodies (Kozbor D (1984) J Immunol 133: 3001-5; Brodeur). In vivo Monoclonal Antibody Production Techniques and Applications, pp. 51-63 (Marcel Dekker, Inc., New York, 1987), each of which is incorporated herein by reference in its entirety.

[0218] The production of monoclonal antibodies against PC in the culture medium in which hybridoma cells are grown is determined. The binding specificity of the monoclonal antibodies produced by hybridoma cells is determined by methods known in the art, such as immunoprecipitation or by... For example It is determined by combining assays such as radioimmunoassay (RIA) or enzyme-linked immunosorbent assay (ELISA).

[0219] After identifying hybridoma cells that produce antibodies with the desired specificity, affinity, and / or activity, the clones can be subcloned using a limiting dilution procedure and grown using standard methods (Goding JW, Monoclonal Antibodies: Principles and Practice). In vivo Suitable culture media for this purpose include, for example, D-MEM or RPMI 1640 media. Additionally, hybridoma cells can be cultured in animals. For example It grows as an ascites tumor.

[0220] Monoclonal antibodies secreted by subclones are appropriately separated from culture medium, ascites, or serum using conventional immunoglobulin purification methods, such as protein A-agarose, hydroxyapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography.

[0221] The antibodies mentioned in this article include SeeAntibody fragments that recognize PCs can be generated using any technique known to those skilled in the art. For example, the Fab and F(ab')2 fragments described herein can be generated by proteolytic cleavage of immunoglobulin molecules using enzymes such as papain (to generate the Fab fragment) or pepsin (to generate the F(ab')2 fragment). The Fab fragment corresponds to one of the two identical arms of the antibody molecule and contains a complete light chain paired with the VH and CH1 domains of the heavy chain. The F(ab')2 fragment contains two antigen-binding arms of the antibody molecule linked by disulfide bonds in the hinge region.

[0222] Furthermore, the antibodies described herein can also be generated using various phage display methods known in the art. In phage display methods, functional antibody domains are displayed on the surface of phage particles carrying polynucleotide sequences encoding them. Specifically, from animal cDNA libraries ( See DNA sequences encoding the VH and VL domains were amplified from human or mouse cDNA libraries of affected tissues. The DNA encoding the VH and VL domains was recombined with scFv adapters by PCR and cloned into a phage vector. The vector was then... et al. Electroporation and infection with helper phages For example The phages used in these methods are typically filamentous phages, including fd and M13, and the VH and VL domains are usually recombinantly fused with phage gene III or gene VIII. Phages expressing antigen-binding regions that bind to specific antigens can be selected or identified along with the antigen. For example The use of labeled antigens or antigens that bind to or are captured by solid surfaces or beads. Examples of phage display methods that can be used to prepare the antibodies described herein include Brinkman U. For example (1995) J Immunol Methods 182: 41-50; Ames RS For example (1995) J Immunol Methods 184: 177-186; Kettleborough CA et al. (1994) Eur J Immunol 24: 952-958; Persic L For example(1997) Gene 187: 9-18; Burton DR and Barbas CF (1994) Advan Immunol 57: 191-280; PCT application number PCT / GB91 / 001134; International publication number WO 90 / 02809, WO 91 / 10737, WO 92 / 01047, WO 92 / 18619, WO 93 / 11236, WO 95 / 15982, WO 95 / 20401 and WO 97 / 13844; and those disclosed in U.S. Patent Nos. 5,698,426, 5,223,409, 5,403,484, 5,580,717, 5,427,908, 5,750,753, 5,821,047, 5,571,698, 5,427,908, 5,516,637, 5,780,225, 5,658,727, 5,733,743, and 5,969,108, all of which are incorporated herein by reference in their entirety.

[0223] As described in the references above, after phage selection, antibody-coding regions from phages can be isolated and used to generate complete antibodies (containing human antibodies or any other desired antigen-binding fragments) and expressed in any desired host (including mammalian cells, insect cells, plant cells, yeast, and bacteria). See, for example As described below, techniques for recombinantly generating antibody fragments (such as Fab, Fab', and F(ab')2 fragments) can also be used using methods known in the art, such as PCT Publication No. WO 92 / 22324; Mullinax RL See, for example (1992) BioTechniques 12(6):864-9; Sawai H et al. (1995) Am J Reprod Immunol 34: 26-34; and Better M et al. (1988) Science 240: 1041-1043, all of which are incorporated in this paper in their full text by reference.

[0224] In some embodiments, to generate complete antibodies, PCR primers comprising a VH or VL nucleotide sequence, a restriction site, and flanking sequences protecting the restriction site can be used to extract the antibody from the template ( For example (scFv cloning) amplifies the VH or VL sequence. Using cloning techniques known to those skilled in the art, the PCR-amplified VH domain can be cloned into a vector expressing the VH constant region, and the PCR-amplified VL domain can be cloned into a vector expressing the VL constant region (scFv cloning). See, for exampleThe human κ or λ constant region is expressed in a vector. Sequences of the human κ and λ constant regions are known to those skilled in the art. Examples of human κ and λ constant region sequences are shown in SEQ ID NO: 688-693. The VH and VL domains can also be cloned into a vector expressing the essential constant region. The heavy chain transformation vector and the light chain transformation vector are then co-transfected into a cell line using techniques known to those skilled in the art to generate a full-length antibody (…). For example Stable or transient cell lines of IgG.

[0225] Chimeric antibodies are molecules in which different portions of the antibody are derived from different immunoglobulin molecules. For example, a chimeric antibody may contain a variable region of a mouse or rat monoclonal antibody fused to a constant region of a human antibody. Methods for generating chimeric antibodies are known in the art. See, for example , Morrison SL (1985) Science 229: 1202-7; Oi VT and Morrison SL (1986) BioTechniques 4: 214-221; Gillies SD See, for example (1989) JImmunol Methods 125: 191-202; and U.S. Patent Nos. 5,807,715, 4,816,567, 4,816,397 and 6,331,415, all of which are incorporated herein by reference in their entirety.

[0226] Humanized antibodies can bind to a predetermined antigen and contain a framework region that is substantially the amino acid sequence of human immunoglobulins and a region that is substantially the amino acid sequence of non-human immunoglobulins. See, for example The humanized antibody contains the CDR of the amino acid sequence of mouse immunoglobulin. In some embodiments, the humanized antibody also comprises at least a portion of the immunoglobulin constant region (Fc), typically at least a portion of the human immunoglobulin constant region. The antibody may also include the CH1, hinge, CH2, CH3, and CH4 regions of the heavy chain. The humanized antibody may be selected from any class of immunoglobulins, including IgM, IgG, IgD, IgA, and IgE, and any isotypes, including IgG1, IgG2, IgG3, and IgG4. Humanized antibodies can be generated using a variety of techniques known in the art, including but not limited to CDR transplantation (European Patent No. EP 239400; International Publication No. WO 91 / 09967; and US Patent Nos. 5,225,539, 5,530,101 and 5,585,089), veneer or surface reconstruction (European Patent Nos. EP 592106 and EP 519596; Padlan EA (1991) Mol Immunol 28(4 / 5): 489-498; Studnicka GM). In vivo(1994) Prot Engineering 7(6):805-814; and Roguska MA For example (1994) PNAS 91: 969-973), chain refactoring (US Patent No. 5,565,332), and See US Patent No. 6,407,213, US Patent No. 5,766,886, International Publication No. WO 93 / 17105; Tan P See (2002) J Immunol 169: 1119-25; Caldas C et al. (2000) Protein Eng. 13(5): 353-60; Morea V For example (2000) Methods 20(3): 267-79; Baca M For example (1997) JBiol Chem 272(16): 10678-84; Roguska MA For example (1996) Protein Eng 9(10): 895904; Couto JR For example (1995) Cancer Res. 55 (Supplement 23): 5973s-5977s; Couto JR For example (1995) Cancer Res 55(8): 1717-22; Sandhu JS (1994) Gene 150(2): 409-10; and Pedersen JT For example (1994) J Mol Biol 235(3): 959-73, all of which are incorporated into this paper in their full text by reference. For example Application publication number US 2005 / 0042664 A1 (February 24, 2005) and international publication number WO 2008 / 020079, which are incorporated herein by reference in their entirety.

[0227] The preparation of multispecific antibodies has been described. For example The method of using bispecific antibodies. For example U.S. Patent Nos. 7,951,917; 7,183,076; 8,227,577; 5,837,242; 5,989,830; 5,869,620; 6,132,992; and 8,586,713, all of which are incorporated herein by reference in their entirety.

[0228] Bispecific, bivalent antibodies and their preparation methods are described, for example, in U.S. Patent Nos. 5,731,168, 5,807,706, 5,821,333 and U.S. Application Publications Nos. 2003 / 020734 and 2002 / 0155537; each of these documents is incorporated herein by reference in its entirety. Bispecific, tetravalent antibodies and their preparation methods are described, for example, in International Application Publications Nos. WO 02 / 096948 and WO 00 / 44788; the disclosures of these two documents are incorporated herein by reference in their entirety. For example International application publication numbers WO 93 / 17715, WO 92 / 08802, WO 91 / 00360 and WO 92 / 05793; Tutt See, for example J. Immunol. 147:60-69 (1991); U.S. Patent Nos. 4,474,893; 4,714,681; 4,925,648; 5,573,920; and 5,601,819; and Kostelny For example , J. Immunol.148:1547-1553 (1992); Each of these references is incorporated herein by reference in its entirety.

[0229] As described in this article, bispecific antibodies can be based on, for example... For example International publication numbers WO 2011 / 131746, WO 2011 / 147986, WO 2008 / 119353 and WO 2013 / 060867, and Labrijn AF For example The DuoBody technology platform (Genmab A / S) described in PNAS 110(13): 5145-5150 (2013) generates the product. The DuoBody technology can be used to bind half of a first monospecific antibody or a first antigen-binding region containing two heavy chains and two light chains to half of a second monospecific antibody or a second antigen-binding region containing two heavy chains and two light chains. The resulting heterodimer contains one heavy chain and one light chain from the first antibody or the first antigen-binding region, paired with one heavy chain and one light chain from the second antibody or the second antigen-binding region. The resulting heterodimer is a bispecific antibody when the two monospecific antibodies or antigen-binding regions recognize different epitopes on different antigens.

[0230] DuoBody technology requires that each monospecific antibody or antigen-binding region include a heavy chain constant region with a single-point mutation in the CH3 domain. The point mutation allows for stronger interactions between the CH3 domains in the resulting bispecific antibody than between the CH3 domains in the monospecific antibody or antigen-binding region. The single-point mutation in each monospecific antibody or antigen-binding region is located at residues 366, 368, 370, 399, 405, 407, or 409 in the CH3 domain of the heavy chain constant region, according to the EU numbering system. For example As described in International Publication No. WO 2011 / 131746. Furthermore, compared to another monospecific antibody or antigen-binding region, a single-point mutation is located at a different residue in a monospecific antibody or antigen-binding region. For example, a monospecific antibody or antigen-binding region may contain the mutation F405L (… For example (a mutation from phenylalanine to leucine at residue 405), while another monospecific antibody or antigen-binding region may contain the mutant K409R ( For example The mutation at residue 409, from lysine to arginine, is numbered according to the EU numbering system. The heavy chain constant region or antigen-binding region of a monospecific antibody can be an isotype of IgG1, IgG2, IgG3, or IgG4. For example (human IgG1 isotype), and the bispecific antibodies produced by DuoBody technology can retain Fc-mediated effector functions.

[0231] Another method for generating bispecific antibodies is known as the "mortar and pestle structure" strategy. For example International Publication WO2006 / 028936). In this technology, mismatches in Ig heavy chains are reduced by mutating selected amino acids at the interface of the CH3 domain in IgG. At the site where the two heavy chains directly interact within the CH3 domain, an amino acid with a small side chain (jaw) is introduced into the sequence of one heavy chain, and an amino acid with a large side chain (knuckle) is introduced into the corresponding interacting residue site on the other heavy chain. In some embodiments, the compositions of this disclosure have immunoglobulin chains, wherein the CH3 domain has been modified by mutating selected amino acids that interact at the interface between two polypeptides to preferentially form bispecific antibodies. The bispecific antibodies can be composed of the same subclass ( For example IgG1 or IgG3) or different subclasses ( In vitro It is composed of immunoglobulin chains (IgG1 and IgG3 or IgG3 and IgG4).

[0232] In some cases, bispecific antibodies may contain heterodimers of IgG4 and IgG1, IgG4 and IgG2, IgG4 and IgG3, or IgG1 and IgG3 chains. Such heterodimer heavy chain antibodies can be routinely engineered, for example, by modifying selected amino acids at the interface that forms the CH3 domain in human IgG4 and IgG1 or IgG3 to facilitate heterodimer heavy chain formation.

[0233] In some embodiments, the antibody described herein that binds to the same epitope of PC as the anti-PC antibody described herein is a human antibody. In some embodiments, the competitive blocking (PC) antibody described herein... See, for example (In a dose-dependent manner) The antibody that binds to PC as described herein is a human antibody. Human antibodies can be produced using any method known in the art. For example, transgenic mice that cannot express functional endogenous immunoglobulins but can express human immunoglobulin genes can be used. In particular, human heavy chain and light chain immunoglobulin gene complexes can be randomly or through homologous recombination introduced into mouse embryonic stem cells. Alternatively, in addition to human heavy chain and light chain genes, human variable regions, constant regions, and diversity regions can be introduced into mouse embryonic stem cells. Mouse heavy chain and light chain immunoglobulin genes can be defunctionalized, either alone or simultaneously with the introduction of human immunoglobulin gene loci through homologous recombination. In particular, J H The homozygous deletion of the region prevents the production of endogenous antibodies. Modified embryonic stem cells were expanded and microinjected into blastocysts to generate chimeric mice. These chimeric mice were then cultured to produce homozygous offspring expressing human antibodies. Using selected antigens, For example All or part of the antigen ( In vitro Transgenic mice are immunized in a normal manner using a hybridoma technique (PC). Monoclonal antibodies against the antigen can be obtained from the immunized transgenic mice using conventional hybridoma technology. The human immunoglobulin transgenes carried by the transgenic mice rearrange during B cell differentiation, subsequently undergoing class switching and somatic mutations. Therefore, using this technique, therapeutically useful IgG, IgA, IgM, and IgE antibodies can be generated. An overview of this technique for generating human antibodies is provided below. For example Lonberg N and Huszar D (1995) Int Rev Immunol 13:65-93, which is incorporated herein by reference in its entirety. A detailed discussion of this technique for producing human antibodies and human monoclonal antibodies, and the protocols used to produce such antibodies, is provided. In vitroInternational Publications Nos. WO 98 / 24893, WO 96 / 34096, and WO 96 / 33735; and U.S. Patent Nos. 5,413,923, 5,625,126, 5,633,425, 5,569,825, 5,661,016, 5,545,806, 5,814,318, and 5,939,598, all of which are incorporated herein by reference in their entirety. Examples of mice capable of producing human antibodies include XenoMouse. TM (Abgenix, Inc.; U.S. Patent Nos. 6,075,181 and 6,150,184), Huab-Mouse TM (Medarex, Inc. / Gen Pharm; U.S. Patent Nos. 5,545,806 and 5,569,825), TransChromo Mouse TM (Kirin) and KM Mouse TM (Medarex / Kirin), all of these references are incorporated into this paper in their full text by reference.

[0234] Human antibodies that specifically bind to PCs can be prepared by a variety of methods known in the art, including the phage display method described above using an antibody library derived from human immunoglobulin sequences. In vivo U.S. Patent Nos. 4,444,887, 4,716,111 and 5,885,793; and International Publications Nos. WO 98 / 46645, WO 98 / 50433, WO 98 / 24893, WO 98 / 16654, WO 96 / 34096, WO 96 / 33735 and WO 91 / 10741, all of which are incorporated herein by reference in their entirety.

[0235] In some embodiments, mouse-human hybridomas can be used to generate human antibodies. For example, human peripheral blood lymphocytes transformed with Epstein-Barr virus (EBV) can be fused with mouse myeloma cells to generate mouse-human hybridomas that secrete human monoclonal antibodies, and these mouse-human hybridomas can be screened to identify those that secrete specific binding target antigens. For example Hybridomas of human monoclonal antibodies (PC). Such methods are known and described in the art. See See Shinmoto H et al. (2004) Cytotechnology 46: 19-23; Naganawa Y For example (2005) Human Antibodies 14: 27-31, each of which is incorporated herein by reference in its entirety.

[0236] Kits containing one or more antibodies or pharmaceutical compositions or conjugates described herein are also provided. In specific embodiments, this document provides a pharmaceutical package or kit comprising one or more containers filled with one or more components of the pharmaceutical compositions described herein, such as one or more antibodies provided herein. In some embodiments, the kit contains the pharmaceutical compositions described herein and any prophylactic or therapeutic agents, such as those described herein. Optionally, associated with such containers may be a notification in the form prescribed by a government agency regulating the manufacture, use, or sale of the pharmaceutical or biological product, reflecting approval obtained by the manufacturing, using, or selling entity for human administration.

[0237] Kits for use with the methods described above are also provided. In some embodiments, the kit contains the antibody described herein, preferably purified antibody, in one or more containers. In a specific embodiment, the kit described herein contains substantially isolated PC antigen as a control. In another specific embodiment, the kit described herein further contains a control antibody that does not react with the PC antigen. In yet another specific embodiment, the kit described herein contains one or more elements for detecting the binding of the antibody to the PC antigen. For example The antibody may be conjugated to a detectable substrate such as a fluorescent compound, enzyme-catalyzed substrate, radioactive compound, or luminescent compound, or a second antibody recognizing a first antibody may be conjugated to a detectable substrate. In specific embodiments, the kits provided herein may include recombinant or chemically synthesized PC antigens. The PC antigens provided in the kits may also be attached to a solid support. In more specific embodiments, the detection tool of the above kits includes a solid support to which the PC antigen is attached. This kit may also include non-attached reporter molecular marker anti-human antibodies or anti-mouse / rat antibodies. In this embodiment, the binding of the antibody to the PC antigen can be detected by the binding of the reporter molecular marker antibody. In some embodiments, this disclosure relates to kits of this disclosure for use in... For example Use for determining and / or detecting PC antigens in biological samples.

[0238] The following examples are provided in an illustrative rather than restrictive manner.

[0239] A multi-factor optimization platform is used for antibody optimization. This platform is designed to optimize affinity, risk removal, thermostability, species cross-reactivity, and selective activation.

[0240] The E06 variable heavy chain (VH) and variable κ (VK) CDR sequences were grafted onto four fully human VH lineages (VH1-46, VH3-15, VH3-23, VH5-51) and four fully human VK lineages (VK1-39, VK2-28, VK3-15, VK4-1), respectively. Of the sixteen combinations prepared, two were selected for platform library construction: E06_VK1-39 / VH3-23 and E06_VK4-1 / VH3-23. Table 2 lists the individual VH and VK sequences.

[0241]

[0242] Phage display libraries of scFv reconstructed framework grafts were designed based on structural and sequence analysis to retain CDR residues identified as exhibiting key target-binding interactions. The remaining CDR residues were used for guided 3-way sequence space exploration to maximize tolerance to human residues while limiting potential impacts on target binding. First, CDRH1, CDRH2, CDRL1, CDRL2, and CDRL3 were modified from parental CDRs to human germline CDRs, with a maximum of four modifications per CDR. Second, CDRH1, CDRH2, CDRL1, CDRL2, and CDRL3 were modified from germline CDRs to parental CDR residues, with a maximum of four modifications per CDR. Third, single-amino acid NNK scans were performed on all CDRs, omitting residue modifications that would pose a biochemical risk. The E06 VK1-39 / VH3-23 and VK4-1 / VH3-23 scFv libraries were combined to obtain a total size of 4 × 10⁻⁶. 9 A transformation element (referred to as the "platform library").

[0243] Phosphocholine (PC) conjugate peptides were used for phage panning and scFv screening via ELISA. Table 3 summarizes the information on the PC conjugate peptides used.

[0244]

[0245] PC = p-Diazophenylphosphocholine Phage-peptide complexes were captured using streptavidin-coated beads on biotinylated peptides. After washing, the bound phages were eluted with triethylamine and titrated to determine enrichment. Following each round of panning, the eluted phages were used for infection. For example ER2738 is used to propagate phage particles for subsequent rounds of selection.

[0246] Single colonies (380 colonies each; 1140 colonies total) from the fourth round of panning arms were cultured and Sanger sequencing was performed on the scFv. 736 unique sequences were rearranged into 96-well plates and initially screened for peptides 1, 4, 5, and 8 by scFv ELISA.

[0247] A total of 368 unique bindings from peptide 5 and / or peptide 1 from primary screening were rearranged and secondary screening was performed on peptides 1, 4, 5, and 8, as well as BSA, by ELISA (n=2). A total of 257 unique scFvs were identified, which showed good reproducibility between primary and secondary screening data and between replicates. These 257 sequences specifically bind to at least one of peptide 1 and peptide 5, but not to peptide 4, peptide 8, or BSA (the threshold for positive OD450 was determined using the mean OD450 + 3x SD of the negative control (PD-1 specific scFv): see Example 2 for methodology).

[0248] Periplasmic extract (PPE) containing scFv was generated via osmotic shock. Starting cultures (700 μL / well of 2 × YT containing 2% glucose, tetracycline (15 µg / mL), and carbenicillin (100 µg / mL) in 5–10 μL glycerol stock solution) were inoculated with this solution and grown overnight at 30 °C and 700 rpm. The next day, expression cultures (1 mL / well of 2 × YT containing 0.1% glucose and carbenicillin (100 µg / mL) in 30 μL of the starting culture were inoculated with this solution and grown at 37 °C and 700 rpm until OD600 ≥ 0.5. The cultures were induced with 1 mM IPTG and grown at 25 °C and 700 rpm for 6 hours.

[0249] Six hours later, the plates were centrifuged to precipitate the bacteria and stored overnight at -20°C. The next day, the precipitate was thawed and resuspended in 80 μL of peptidoglycan extraction buffer containing protease inhibitors, and incubated on a shaker at 4°C and 500 rpm for 10 minutes. After 10 minutes, 240 μL of water and protease inhibitors were added to each well, and the plates were incubated at 4°C and 500 rpm for 1 hour. The plates were then centrifuged at 4300 xg for 10 minutes at 4°C. The supernatant was filtered through a filter plate and stored at -80°C.

[0250] For ELISA analysis of scFv binding, 96-well polystyrene plates were coated overnight at 4°C with peptides 1, 4, 5, 8, or 100 μL BSA (10 μg / mL) in PBS. The plates were washed three times with PBS-Tween and blocked for 1 hour at room temperature with 100 μL 1% BSA-TBS. At room temperature, the 96-well streptavidin-coated plates were then coated for 1 hour with 100 μL biotinylated PC-peptide (1 μg / mL) in PBS.

[0251] All plates were washed three times with PBS-Tween. Then, 40 μL of PPE aliquots were added to each plate along with 50 μL of 10% BSA, and the plates were incubated at room temperature for 1 hour. After washing, 100 μL of HRP-conjugated anti-V5 in 5% BSA was added, and the plates were incubated at room temperature for 30 minutes. The plates were washed, and 100 μL of TMB substrate was added. The color was developed at room temperature, and the reaction was terminated with 100 μL of 1N HCl. The amount of scFv bound to each well was quantified based on absorbance measurements at 450 nm (OD450). Table 4 summarizes the binding data for the 257 unique scFvs identified in Example 1.

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259] 48 scFv were selected and reconstituted into human IgG1 with the parental E06 antibody using standard techniques. For antibody binding ELISA analysis, 384-well polystyrene microtiter plates were coated with 20 μL of antigen (5 μg / mL PC-BSA) in PBS at room temperature for 2 hours. The plates were washed three times with DELFIA® wash buffer and then blocked with 20 μL / well 1% BSA-TBS at room temperature for 1 hour. After washing, 15 μL of titrated antibody in 1% BSA-TBS was added to the wells and incubated at room temperature for 1 hour. After further washing, 15 μL / well DELFIA® Eu-N1 anti-human IgG secondary antibody in TBS was added to the wells and incubated at room temperature for 1 hour. The plates were washed again and incubated with DELFIA® enhancement buffer for 5 minutes at room temperature. The amount of antibody bound to each well was quantified according to TRF. Binding data for the parental E06 IgG1 antibody and various IgG1 binders are summarized in Table 5. No binding to BSA was detected for any of the antibodies shown in Table 5.

[0260] The physical properties of the antibodies (melting temperature, aggregation temperature, and polydispersity index) were determined using an Uncle instrument (Unchained Labs). The physical properties of the parental E06 IgG1 antibody and various IgG1 binding agents are summarized in Table 5.

[0261]

[0262]

[0263]

[0264] Example 4: Further IgG characterization Further analysis was conducted on the antibody yield, stress assay, and immunogenicity characteristics of the selected human IgG1 antibodies (see Example 3). Yields were determined by transfecting HEK293 cells and subsequently expressing them in 25 mL cultures. For several antibodies, yields were determined in scale-up 40 μL transiently transfected cultures. Antibody products were purified using protein A, and the amount of antibody obtained was measured by absorbance at 280 nm (OD280). Yield values ​​for parental E06 IgG1 antibodies and selected IgG1 binders are shown in Table 6.

[0265]

[0266] Parental E06 IgG1 antibody and human IgG1 PcOxP_DB01_H08 antibody were analyzed in a forced degradation study to compare the relative stability and stress resistance between the antibodies. Samples of each antibody were subjected to temperature stress, oxidative stress, and low and high pH stress, and the samples were analyzed and compared with non-stressed samples. Various analytical techniques were used to analyze the samples. In addition to concentration measurements and visual inspection, chemical stability was assessed by protein-level RPC-MS at intact and reduced antibody levels, peptide mapping under reducing conditions, iCIEF analysis, and CGE-SDS under both reducing and non-reducing conditions. Physical stability was assessed using SE-HPLC.

[0267] For temperature stress, samples of each antibody were stored at 40°C for 2, 3, or 4 weeks. For low pH stress, the pH of samples of each antibody was adjusted to 3.2 using 0.12 M HCl, and the samples were incubated at 25°C for 2 hours, followed by buffer exchange back to the formulation buffer. For high pH stress (forced deamidation), the pH of samples of each antibody was adjusted to 9.0 using 0.5 M Tris pH 11, and the samples were incubated at 37°C for 3 days, followed by buffer exchange back to the formulation buffer. For oxidative stress, 3% H2O2 solution was added to samples of each antibody to achieve a final concentration of 0.03%, and the samples were incubated at 25°C for 1 day, followed by buffer exchange back to the formulation buffer. The results of stress tests and stability analyses are qualitatively summarized in Table 7 (“+”: moderately stable; “++”: highly stable).

[0268] Table 7: Stress test and stability comparison.

[0269]

[0270] use et al. Epibase® Immunogenicity Assay (Lonza Biologics) For example Epibase® platform (Lonza Biologics) and See, for example The ISPRI™ platform (EpiVax, Inc.) predicts the parental E06 IgG1 antibody and human IgG1 PcOxP_DB01_H08 and PcOxP_DB03_C03 antibodies. See, for example Immunogenicity. An overview of immunogenicity is summarized in Table 8. Overall, immunogenicity assays showed that PcOxP_DB01_H08 and PcOxP_DB03_C03 exhibited low immunogenicity risk and favorable characteristics compared to several marketed antibody drugs.

[0271]

[0272] *: 32 donor samples, KLH positive control showed 100% effect. **: A score of 0 indicates that the predicted immunogenic response occurred in approximately 5% of patients. sequence list

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302] * * * This invention is not limited to the specific embodiments described herein. In fact, various modifications to the invention will become apparent to those skilled in the art from the foregoing description, in addition to those described. Such modifications are intended to fall within the scope of the appended claims.

[0303] All references cited in this article ( et al. Publications, patents, or patent applications are incorporated herein by reference in their entirety for all purposes, to the same extent as each individual reference ( et al. For example See, for example For example For example For example For example For example For example For example For example For example See, for example For example For example Namely For example et al. For example For example For example For example For example Escherichia coli For example et al. Escherichia coli For example For example For example For example For example See, for example See, for example For example For example For example For example For example For example For example For example For example For example See, for example For example For example Namely For example et al. For example For example For example For example For example Escherichia coli For example et al. Escherichia coli For example For example For example For example For example See For example et al. For example For example For example For example For example For example For example For example For example For example In vitro In vivo See, for example See, for example In situ For example For example Escherichia coli Bacillus subtilis For example For example Saccharomyces Pichia pastoris For example For example For example For example For example For example For example For example For example In vitro In vivo See, for example See, for example In situ For example For example Escherichia coli Bacillus subtilis For example et al. Escherichia coli For example et al. For example For example For example For example For example For example For example For example For example See See See For example For example For example For example For example For example For example For example For example For example For example In vivo See, for example For example In vivo For example In vivo For example See See et al. For example For example For example For example et al. For example See, for example See, for example et al. et al. For example See, for example For example See, for example See, for example See, for example In vivo For example See See et al. For example For example For example For example For example For example For example For example For example For example See, for example For example For example For example For example For example For example For example For example For example For example In vitro See, for example For example In vitro For example In vitro In vivo For example See See et al. For example For example For example For example et al. For example See, for example See, for example et al. et al. For example See, for example For example For example For example For example For example For example For example For example For example See, for example For example For example Namely For example et al. For example For example For example For example For example Escherichia coli For example et al. Escherichia coli For example For example For example For example For example See, for example See, for example For example For example For example For example For example For example For example For example For example For example See, for example For example For example Namely For example et al. For example For example For example For (Publications, patents, or patent applications) are specifically and separately cited in their entirety for all purposes.

[0304] Other embodiments are defined in the following claims.

Claims

1. An antibody that specifically binds to phosphorycholine (PC), the antibody comprising: VH, which comprises the CDRH1, CDRH2, and CDRH3 amino acid sequences of any one of the VH amino acid sequences shown in SEQ ID NO: 1-180; and VL, which comprises the CDRL1, CDRL2, and CDRL3 amino acid sequences of any one of the VL amino acid sequences shown in SEQ ID NO: 181-368.

2. The antibody according to claim 1, wherein the antibody comprises the amino acid sequences CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 respectively, as shown in the VH and VL amino acid sequences in the following: SEQ ID NO: 1 and 181; 2 and 182; 3 and 183; 4 and 184; 5 and 185; 1 and 184; 6 and 184; 1 and 186; 7 and 187; 8 and 188; 9 and 189; 10 and 190; 4 and 191; 11 and 192; 12 and 193; 13 and 194; 14 and 195; 15 and 196; 16 and 184; 17 and 197; 18 and 198; 1 and 199; 19 and 200; 20 and 201; 21 and 202; 22 and 203; 23 and 204; 24 and 205; 25 and 184; 4 and 206; 26 and 207; 27 and 208; 28 and 209; 9 and 210; 29 and 211; 30 and 212; 31 and 213; 32 and 214; 33 and 215; 34 and 216; 17 and 217; 1 and 218; 35 and 184; 36 and 184; 35 and 219; 35 and 220; 37 and 184; 38 and 221; 39 and 222; 9 and 223; 9 and 22 4; 40 and 184; 41 and 225; 8 and 226; 42 and 227; 35 and 228; 43 and 229; 4 and 230; 9 and 231; 8 and 232; 1 and 233; 8 and 234; 44 and 184; 1 and 23 5; 45 and 236; 30 and 237; 46 and 184; 47 and 238; 48 and 239; 1 and 230; 49 and 190; 44 and 240; 50 and 184; 51 and 241; 52 and 242; 53 and 243; 54 and 184; 55 and 244; 56 and 245; 57 and 246; 58 and 247; 59 and 248; 60 and 249; 8 and 250; 61 and 184; 35 and 251; 62 and 252; 1 and 253; 63 and 254; 64 and 181; 65 and 255; 66 and 256; 67 and 257; 68 and 198; 35 and 258; 69 and 259; 70 and 260; 71 and 261; 72 and 262; 73 and 263; 74 and 264; 75 and 265; 76 and 266; 77 and 267; 4 and 205; 78 and 268; 1 and 269; 27 and 269; 79 and 269; 80 and 270; 81 and 269; 22 and 269; 82 and 269; 83 and 271; 84 and 272; 1 and 273; 8 and 274; 8 and 275; 22 and 276; 8 and 277; 85 and 278; 86 and 279; 87 and 269; 88 and 280; 89 and 269; 60 and 281; 90 and 269; 91 and 282; 22 and 283; 92 and 269; 93 Japanese 284; Japanese 285; Japanese 285; Japanese 286; Japanese 269; Japanese 287; Japanese 287; Japanese 288; Japanese 289; Japanese 269; Japanese 290; Japanese 291; Japanese 292; Japanese 289; Japanese 289; Japanese 101; Japanese 284; Japanese 289; Japanese 89; Japanese 293; Japanese 102; Japanese 294; Japanese 103; Japanese 269; Japanese 22; Japanese 295 ; 104 and 296; 105 and 297; 106 and 270; 107 and 269; 67 and 269; 62 and 298; 66 and 269; 108 and 299; 109 and 300; 110 and 301; 111 and 302; 112 and 269; 113 and 303; 1 and 304; 72 and 305; 114 and 306; 1 15 and 307; 116 and 269; 117 and 308; 118 and 269; 110 and 309; 119 and 310; 120 and 311; 121 and 269; 122 and 312; 123 and 289; 9 and 313; 124 and 314; 120 and 289; 125 and 315; 110 and 316; 126 and 317 ; 127 and 318; 49 and 319; 128 and 320; 9 and 321; 22 and 322; 129 and 323; 130 and 269; 131 and 324; 132 and 325; 133 and 326; 134 and 327; 53 and 328; 135 and 272; 136 and 329; 4 and 301; 137 and 330; 13 8 / 269; 1 / 284; 22 / 331; 139 / 269; 140 / 332; 141 / 269; 142 / 333; 143 / 334; 144 / 335; 101 / 298; 1 / 336; 145 / 269; 146 / 337; 147 / 269; 17 / 338; 22 / 320; 4 / 339;148 and 340; 149 and 341; 150 and 342; 151 and 343; 152 and 344; 94 and 289; 153 and 345; 154 and 346; 155 and 347; 22 and 348; 89 and 282; 156 and 349; 157 and 296; 158 and 350; 159 and 329; 24 and 351; 160 and 352; 161 and 269; 162 and 353; 163 and 269; 1 and 354; 164 and 355 ; 165 and 269; 1 and 356; 166 and 357; 167 and 358; 110 and 334; 87 and 359; 168 and 360; 169 and 269; 170 and 269; 171 and 269; 172 and 361; 8 and 362; 173 and 304; 174 and 269; 1 and 363; 175 and 364; 176 and 365; 177 and 269; 178 and 366; 179 and 269; 180 and 367; or 89 and 368. ; 3. The antibody according to claim 1 or 2, wherein the antibody comprises the amino acid sequences of CDRH1, CDRH2 and CDRH3 respectively shown in the following: SEQ ID NO: 369, 428 and 484; 370, 429 and 485; 371, 428 and 486; 372, 428 and 484; 373, 429 and 484; 374, 430 and 484; 375, 428 and 487; 376, 428 and 484; 377, 428 and 484; 378, 428 and 484; 379, 428 and 484; 372, 428 and 488; 376, 431 and 484; 380, 432 and 484; 372, 428 and 489; 381, 428 and 490; 382, ​​428 and 484; 381, 428 and 491; 377, 428 and 492; 376 , 433 and 484; 383, 434 and 484; 383, 428 and 484; 384, 435 and 484; 369, 436 and 484; 372, 437 and 487; 385, 428 and 493; 386, 428 and 484; 372, 437 and 484; 387, 428 and 48 4; 385, 428 and 484; 372, 438 and 484; 388, 428 and 494; 369, 439 and 484; 389, 428 and 484; 381, 428 and 484; 376, 440 and 495; 390, 441 and 484; 370, 442 and 484; 391, 42 8 and 484; 392, 432 and 484; 377, 443 and 484; 393, 428 and 484; 383, 444 and 489; 394, 428 and 484; 383, 444 and 496; 376, 434 and 484; 395, 445 and 497; 396, 446 and 487; 3 92, 428 and 484; 393, 428 and 498; 376, 428 and 495; 369, 440 and 484; 397, 428 and 484 ;389, 447 and 484; 398, 448 and 492; 373, 449 and 490; 399, 428 and 484; 400, 450 and 4 84; 401, 428 and 484; 390, 428 and 484; 400, 428 and 499; 384, 429 and 484; 402, 436 and 484; 381, 451 and 484; 403, 428 and 484; 369, 429 and 484; 404, 429 and 484; 372, 429 and 484; 388, 428 and 484; 405, 451 and 484; 406, 428 and 484; 400, 428 and 484; 40 4, 428 and 484; 384, 432 and 500; 376, 452 and 501; 407, 428 and 484; 375, 428 and 484;408, 428 and 484; 369, 428 and 497; 403, 453 and 484; 402, 454 and 484; 383, 434 and 500; 376, 455 and 502; 383, 435 and 484; 376, 428 and 490; 369, 428 and 503; 409, 428 and 484; 383, 428 and 504; 369, 434 and 484; 369, 456 and 484; 370, 457 and 484; 404, 458 and 499; 410, 428 and 484; 383, 459 and 484; 407, 428 and 489; 374, 434 and 484; 411, 460 and 505; 383, 428 and 4 85; 386, 460 and 490; 412, 455 and 493; 383, 461 and 484; 376, 437 and 484; 383, 462 and 500; 400, 463 and 484; 376, 464 and 484; 400, 434 and 506; 369, 436 and 507; 377, 465 and 484; 4 13, 459 and 484; 369, 452 and 484; 414, 466 and 484; 373, 428 and 484; 415, 428 and 489; 369, 428 and 491; 403, 458 and 508; 392, 467 and 484; 369, 452 and 509; 388, 468 and 490; 377, 44 0 and 484; 370, 428 and 484; 384, 467 and 487; 392, 469 and 510; 378, 464 and 484; 416, 434 and 484; 370, 428 and 511; 376, 428 and 502; 417, 428 and 484; 376, 428 and 512; 381, 428 and 49 3; 383, 470 and 501; 404, 471 and 484; 418, 428 and 484; 383, 472 and 513; 419, 428 and 484; 372, 473 and 484; 383, 474 and 484; 420, 434 and 484; 370, 428 and 514; 369, 475 and 484; 421 , 436 and 484; 378, 452 and 484; 376, 476 and 515; 376, 428 and 504; 422, 469 and 484; 369, 428 and 516; 405, 460 and 484; 413, 431 and 484; 406, 429 and 484; 383, 428 and 517; 377, 437 Japanese 518; 369, 477 and 487; 403, 464 and 484; 369, 454 and 484; 372, 478 and 519; 423, 429 and 484; 382, ​​434 and 484; 424, 479 and 484; 376, 429 and 484; 425, 428 and 484; 403, 428 and 520;417, 460 and 484; 409, 460 and 484; 404, 452 and 484; 383, 428 and 521; 372, 480 and 493; 369, 477 and 484; 369, 481 and 484; 384, 452 and 484; 377, 482 and 484; 410, 483 and 484; 384, 428 and 489; 426, 429 and 484; 427, 428 and 484; 373, 452 and 506; 369, 429 and 521; 405, 428 and 522; 376, 428 and 510; 384, 428 and 484; 410, 429 and 484; or 400, 452 and 484.

4. The antibody according to any one of the preceding claims, wherein the antibody comprises the amino acid sequences of CDRL1, CDRL2 and CDRL3 respectively shown in the following: SEQ ID NO: 523, 591 and 656; 523, 592 and 657; 523, 593 and 658; 523, 591 and 659; 523, 594 and 659; 523, 595 and 660; 523, 596 and 659; 524, 591 and 659; 523, 591 and 661; 523, 591 and 662; 523, 597 and 658; 523, 598 and 662; 525, 599 and 659; 523, 600 and 663; 523, 591 and 664; 523, 601 and 659; 526, 597 and 665; 523, 602 and 659; 527, 591 and 661; 528 , 591 and 662; 529, 603 and 662; 523, 604 and 666; 523, 605 and 667; 530, 606 and 659; 523, 607 and 659; 523, 608 and 659; 523, 609 and 662; 531, 591 and 663; 523, 608 and 66 1; 523, 610 and 659; 523, 611 and 668; 523, 611 and 658; 523, 596 and 662; 523, 612 and 667; 523, 613 and 668; 523, 591 and 669; 523, 591 and 663; 523, 614 and 659; 532, 61 5 and 662; 523, 616 and 670; 523, 591 and 668; 523, 617 and 671; 533, 595 and 659; 523, 618 and 659; 534, 619 and 662; 535, 620 and 659; 536, 621 and 659; 537, 603 and 671; 5 23, 622 and 659; 523, 617 and 659; 523, 623 and 659; 538, 607 and 672; 523, 616 and 671 ;523, 624 and 659; 523, 620 and 659; 523, 625 and 660; 523, 602 and 671; 523, 611 and 6 63; 523, 626, and 670; 523, 606, and 673; 523, 627, and 671; 523, 628, and 671; 539, 591, and 662; 523, 591, and 670; 523, 611, and 659; 591 and 659; 542, 629 and 659; 523, 591 and 671; 523, 630 and 667; 543, 631 and 659; 52 3, 632 and 664; 523, 597 and 661; 523, 633 and 659; 544, 607 and 659; 523, 630 and 659;523, 591 and 665; 523, 610 and 674; 523, 634 and 671; 545, 591 and 661; 523, 635 and 667; 546, 591 and 659; 523, 636 and 664; 547, 591 and 663; 548, 619 and 659; 523, 637 and 659; 523, 638 and 659; 549, 591 and 659; 550, 591 and 675; 551, 591 and 659; 552, 591 and 659; 553, 591 and 676; 554, 591 and 659; 523, 591 and 676; 555, 606 and 659; 556, 591 and 659; 523, 637 and 6 77; 557, 591 and 659; 558, 591 and 659; 523, 591 and 677; 553, 639 and 659; 549, 591 and 667; 559, 617 and 666; 523, 591 and 672; 523, 606 and 659; 523, 592 and 670; 560, 591 and 667; 5 30, 591 and 659; 561, 603 and 666; 562, 591 and 659; 523, 616 and 660; 523, 602 and 677; 523, 616 and 659; 523, 630 and 660; 563, 591 and 659; 523, 640 and 659; 564, 591 and 659; 523, 64 1 and 677; 565, 591 and 662; 523, 642 and 664; 566, 643 and 659; 523, 644 and 667; 567, 606 and 659; 568, 591 and 659; 569, 645 and 659; 523, 603 and 659; 570, 628 and 678; 571, 630 and 66 3; 572, 591 and 664; 573, 591 and 670; 523, 646 and 659; 574, 591 and 670; 523, 647 and 667; 575, 591 and 659; 537, 591 and 659; 523, 635 and 670; 576, 591 and 659; 577, 606 and 659; 523 , 648 and 679; 523, 592 and 659; 523, 595 and 659; 523, 600 and 659; 523, 649 and 664; 578, 641 and 659; 523, 591 and 667; 523, 606 and 660; 523, 650 and 656; 579, 621 and 671; 580, 591 Japanese 660; 527, 591 Japanese 659; 581, 595 Japanese 659; 582, 640 Japanese 664; 583, 651 Japanese 659; 534, 591 Japanese 659; 584, 591 Japanese 671; 523, 591 Japanese 680; 523, 591 Japanese 681; 585, 591 Japanese 659; 523, 649 Japanese 659;586, 591 and 666; 587, 652 and 659; 588, 638 and 659; 523, 623 and 664; 523, 591 and 682; 553, 653 and 659; 523, 654 and 659; 523, 648 and 659; 560, 591 and 659; 580, 606 and 659; 589, 593 and 661; 523, 637 and 676; 590, 622 and 659; 555, 591 and 661; 523, 615 and 672; 523, 626 and 668; 523, 655 and 659; or 523, 606 and 680.

5. The antibody according to any one of the preceding claims, wherein the antibody comprises the amino acid sequences of CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 shown in the following: SEQ ID NO: 369, 428, 484, 523, 591 and 656; 370, 429, 485, 523, 592 and 657; 371, 428, 486, 523, 593 and 658; 372, 428, 484, 523, 591 and 659; 373, 429, 484, 523, 59 4 and 659; 369, 428, 484, 523, 591 and 659; 374, 430, 484, 523, 591 and 659; 369, 428, 484, 523, 595 and 660; 375, 428, 487, 523, 596 and 659; 376, 428, 484, 524, 591 and 659; 377, 428, 484, 523, 591 and 661; 378, 428, 484, 523, 591 and 662; 372, 428, 484, 523, 597 and 658; 379, 428, 484, 523, 598 and 662; 372, 42 8, 488, 525, 599 and 659; 376, 431, 484, 523, 600 and 663; 380, 432, 484, 523, 591 and 664; 372, 428, 489, 523, 601 and 659; 381, 428, 490, 523, 591 and 659; 382, 428, 484, 526, 597 and 665; 381, 428, 491, 523, 602 and 659; 369, 428, 484, 527, 591 and 661; 377, 428, 492, 528, 591 and 662; 376, 433, 484, 529, 60 3 and 662; 383, 434, 484, 523, 604 and 666; 383, 428, 484, 523, 605 and 667; 384, 435, 484, 530, 606 and 659; 369, 436, 484, 523, 607 and 659; 372, 437, 487, 523, 591 and 659; 372, 428, 484, 523, 608 and 659; 385, 428, 493, 523, 609 and 662; 386, 428, 484, 531, 591 and 663; 372, 437, 484, 523, 608 and 661; 377, 42 8, 484, 523, 610 and 659; 387, 428, 484, 523, 611 and 668; 385, 428, 484, 523, 611 and 658; 372, 438, 484, 523, 596 and 662; 388, 428, 494, 523, 612 and 667;369, 439, 484, 523, 613 and 668; 389, 428, 484, 523, 591 and 669; 382, ​​428, 484, 523, 591 and 663; 369, 428, 484, 523, 614 and 659; 381, 428, 484, 523, 591 and 659; 37 6, 440, 495, 523, 591 and 659; 381, 428, 484, 532, 615 and 662; 381, 428, 484, 523, 616 and 670; 390, 441, 484, 523, 591 and 659; 370, 442, 484, 523, 591 and 668; 391, 4 28, 484, 523, 617 and 671; 377, 428, 484, 533, 595 and 659; 377, 428, 484, 523, 618 and 659; 392, 432, 484, 523, 591 and 659; 377, 443, 484, 534, 619 and 662; 376, 428, 484, 535, 620 and 659; 393, 428, 484, 536, 621 and 659; 381, 428, 484, 537, 603 and 671; 383, 444, 489, 523, 622 and 59; 372, 428, 484, 523, 617 and 659; 377, 428, 484, 523, 623 and 659; 376, 428, 484, 538, 607 and 672; 369, 428, 484, 523, 616 and 671; 376, 428, 484, 523, 624 and 659; 394, 428, 484, 523, 591 and 659; 369, 428, 484, 523 , 620 and 659; 383, 444, 496, 523, 625 and 660; 385, 428, 484, 523, 602 and 671; 376, 434, 484, 523, 591 and 659; 395, 445, 497, 523, 611 and 663; 396, 446, 487, 523, 62 6 and 670; 369, 428, 484, 523, 617 and 659; 392, 428, 484, 523, 591 and 662; 394, 428, 484, 523, 606 and 673; 393, 428, 498, 523, 591 and 659; 376, 428, 495, 523, 627 and 6 71; 369, 440, 484, 523, 628 and 671; 397, 428, 484, 539, 591 and 662; 389, 447, 484, 523, 591 and 659; 398, 448, 492, 523, 591 and 670; 373, 449, 490, 523, 611 and 659;399, 428, 484, 537, 613 and 671; 400, 450, 484, 540, 598 and 659; 401, 428, 484, 541, 591 and 659; 390, 428, 484, 542, 629 and 659; 376, 428, 484, 523, 591 and 671; 400 , 428, 499, 523, 591 and 659; 381, 428, 484, 523, 630 and 667; 384, 429, 484, 543, 631 and 659; 369, 428, 484, 523, 632 and 664; 402, 436, 484, 523, 597 and 661; 381, 45 1, 484, 523, 591 and 656; 403, 428, 484, 523, 633 and 659; 369, 429, 484, 544, 607 and 659; 404, 429, 484, 523, 630 and 659; 372, 429, 484, 523, 602 and 659; 381, 428, 4 84, 523, 591 and 665; 388, 428, 484, 523, 610 and 674; 405, 451, 484, 523, 634 and 671; 406, 428, 484, 545, 591 and 661; 400, 428, 484, 523, 635 and 667; 404, 428, 484, 546, 591 and 659; 384, 432, 500, 523, 636 and 664; 376, 452, 501, 547, 591 and 663; 407, 428, 484, 548, 619 and 659; 375, 428, 484, 523, 637 and 659; 372, 428, 484, 523 , 607 and 659; 408, 428, 484, 523, 638 and 659; 386, 428, 484, 523, 591 and 659; 369, 428, 497, 523, 591 and 659; 403, 453, 484, 549, 591 and 659; 402, 454, 484, 523, 59 1 W659; 383, 428, 484, 523, 591 W659; 383, 434, 500, 523, 591 W659; 376, 455, 502, 550, 591 W675; 383, 435, 484, 523, 591 W664; 369, 428, 484, 523, 602 W6 59; 376, 428, 484, 551, 591 and 659; 376, 428, 484, 552, 591 and 659; 383, 428, 484, 553, 591 and 676; 376, 428, 484, 554, 591 and 659; 376, 428, 490, 523, 591 and 676;369, 428, 503, 555, 606 and 659; 409, 428, 484, 523, 591 and 659; 383, 428, 504, 556, 591 and 659; 369, 434, 484, 523, 591 and 659; 390, 428, 484, 523, 637 and 677; 369 , 456, 484, 523, 591 and 659; 370, 457, 484, 557, 591 and 659; 383, 428, 484, 558, 591 and 659; 404, 458, 499, 523, 591 and 659; 410, 428, 484, 523, 591 and 677; 383, 45 9, 484, 553, 639 and 659; 407, 428, 489, 549, 591 and 667; 374, 434, 484, 523, 591 and 659; 404, 428, 484, 559, 617 and 666; 411, 460, 505, 523, 591 and 672; 372, 429, 4 84, 523, 606 and 659; 383, 428, 485, 523, 591 and 659; 386, 460, 490, 523, 601 and 659; 412, 455, 493, 523, 592 and 670; 372, 428, 484, 560, 591 and 667; 372, 428, 484, 523, 606 and 659; 383, 461, 484, 523, 591 and 677; 369, 429, 484, 523, 606 and 659; 369, 434, 484, 530, 591 and 659; 376, 437, 484, 561, 603 and 666; 383, 462, 500, 523 , 591 and 659; 383, 428, 484, 562, 591 and 659; 400, 463, 484, 523, 616 and 660; 376, 464, 484, 523, 602 and 677; 400, 434, 506, 549, 591 and 659; 369, 436, 507, 523, 59 1 W659; 404, 429, 484, 523, 591 W659; 384, 429, 484, 523, 616 W659; 369, 429, 484, 523, 591 W659; 377, 465, 484, 523, 630 W660; 413, 459, 484, 563, 591 W6 59; 369, 452, 484, 523, 591 and 663; 414, 466, 484, 523, 640 and 659; 373, 428, 484, 523, 591 and 659; 415, 428, 489, 564, 591 and 659; 369, 428, 484, 523, 591 and 671;400, 428, 484, 523, 641 and 677; 369, 428, 491, 565, 591 and 662; 403, 458, 508, 523, 642 and 664; 392, 467, 484, 523, 591 and 659; 369, 452, 509, 566, 643 and 659; 388 , 468, 490, 523, 591 and 659; 369, 452, 484, 523, 644 and 667; 377, 440, 484, 567, 606 and 659; 370, 428, 484, 523, 591 and 656; 384, 467, 487, 523, 591 and 659; 392, 46 9, 510, 568, 591 and 659; 378, 464, 484, 523, 606 and 659; 377, 428, 484, 569, 645 and 659; 416, 434, 484, 523, 603 and 659; 370, 428, 484, 523, 606 and 659; 370, 428, 5 11, 570, 628 and 678; 369, 452, 484, 571, 630 and 663; 376, 428, 502, 572, 591 and 664; 417, 428, 484, 523, 591 and 665; 392, 428, 484, 573, 591 and 670; 376, 428, 512, 523, 646 and 659; 377, 428, 484, 574, 591 and 670; 383, 428, 484, 523, 647 and 667; 381, 428, 493, 575, 591 and 659; 383, 470, 501, 523, 591 and 659; 404, 471, 484, 537 , 591 and 659; 418, 428, 484, 523, 635 and 670; 383, 472, 513, 576, 591 and 659; 419, 428, 484, 577, 606 and 659; 397, 428, 484, 523, 648 and 679; 372, 473, 484, 523, 59 1 W664; 383, 474, 484, 523, 592 W659; 372, 428, 484, 523, 591 W663; 420, 434, 484, 523, 595 W659; 370, 428, 514, 523, 591 W659; 369, 428, 484, 523, 591 W6 77; 383, 428, 484, 523, 600 and 659; 369, 475, 484, 523, 591 and 659; 421, 436, 484, 523, 649 and 664; 378, 452, 484, 523, 591 and 659; 376, 476, 515, 578, 641 and 659;376, 428, 504, 523, 591 and 667; 422, 469, 484, 523, 606 and 660; 383, 461, 484, 523, 616 and 659; 369, 428, 484, 523, 650 and 656; 369, 428, 516, 523, 591 and 659; 405 , 460, 484, 523, 618 and 659; 413, 431, 484, 523, 591 and 659; 382, ​​428, 484, 579, 621 and 671; 383, 428, 484, 523, 646 and 659; 372, 428, 484, 580, 591 and 660; 406, 42 9, 484, 527, 591 and 659; 383, 428, 517, 581, 595 and 659; 377, 437, 518, 582, 640 and 664; 369, 477, 487, 583, 651 and 659; 403, 464, 484, 534, 591 and 659; 383, 459, 4 84, 523, 606 and 659; 369, 454, 484, 584, 591 and 671; 372, 478, 519, 523, 591 and 680; 423, 429, 484, 523, 591 and 681; 383, 428, 484, 585, 591 and 659; 369, 434, 484, 557, 591 and 659; 382, ​​434, 484, 523, 649 and 659; 424, 479, 484, 523, 616 and 660; 376, 429, 484, 586, 591 and 666; 425, 428, 484, 523, 592 and 659; 369, 436, 484, 587 , 652 and 659; 403, 428, 520, 588, 638 and 659; 417, 460, 484, 523, 591 and 659; 409, 460, 484, 523, 623 and 664; 404, 452, 484, 523, 591 and 659; 369, 428, 484, 523, 59 1 and 682; 383, 428, 521, 553, 653 and 659; 372, 480, 493, 523, 591 and 659; 369, 428, 484, 523, 654 and 659; 369, 477, 484, 523, 648 and 659; 369, 481, 484, 560, 591 and 6 59; 369, 452, 484, 523, 591 and 667; 409, 428, 484, 580, 606 and 659; 384, 452, 484, 589, 593 and 661; 377, 482, 484, 523, 591 and 659; 410, 483, 484, 523, 591 and 659;384, 428, 489, 523, 591 and 659; 426, 429, 484, 523, 622 and 659; 376, 428, 484, 523, 637 and 676; 427, 428, 484, 523, 591 and 671; 373, 452, 506, 523, 591 and 659; 369, 428, 484, 590, 622 and 659; 369, 429, 521, 555, 591 sum 661; 405, 428, 522, 523, 615 sum 672; 376, 428, 510, 523, 591 sum 659; 384, 428, 484, 523, 62 6 sum 668; 410, 429, 484, 523, 591 sum 659; 400, 452, 484, 523, 655 sum 659; or 369, 434, 484, 523, 606 sum 680. ; 6. The antibody according to any one of the preceding claims, wherein the antibody comprises the VH amino acid sequence of any one of SEQ ID NO: 1-180.

7. The antibody according to any one of the preceding claims, wherein the antibody comprises the VL amino acid sequence of any one of SEQ ID NO: 181-368.

8. The antibody according to any one of the preceding claims, wherein the VH and VL comprise the amino acid sequences shown in the following: SEQ ID NO: 1 and 181; 2 and 182; 3 and 183; 4 and 184; 5 and 185; 1 and 184; 6 and 184; 1 and 186; 7 and 187; 8 and 188; 9 and 189; 10 and 190; 4 and 191; 11 and 192; 12 and 193; 13 and 194; 14 and 195; 15 and 196; 16 and 184; 17 and 197; 18 and 198; 1 and 199; 19 and 200; 20 and 201; 21 and 202; 22 and 203; 23 and 204; 24 and 205; 25 and 184; 4 and 206; 26 and 207; 27 and 208; 28 and 209; 9 and 210; 29 and 211; 30 and 212; 31 and 213; 32 and 214; 33 and 215; 34 and 216; 17 and 217; 1 and 218; 35 and 184; 36 and 184; 35 and 219; 35 and 220; 37 and 184; 38 and 221; 39 and 222; 9 and 223; 9 and 22 4; 40 and 184; 41 and 225; 8 and 226; 42 and 227; 35 and 228; 43 and 229; 4 and 230; 9 and 231; 8 and 232; 1 and 233; 8 and 234; 44 and 184; 1 and 23 5; 45 and 236; 30 and 237; 46 and 184; 47 and 238; 48 and 239; 1 and 230; 49 and 190; 44 and 240; 50 and 184; 51 and 241; 52 and 242; 53 and 243; 54 and 184; 55 and 244; 56 and 245; 57 and 246; 58 and 247; 59 and 248; 60 and 249; 8 and 250; 61 and 184; 35 and 251; 62 and 252; 1 and 253; 63 and 254; 64 and 181; 65 and 255; 66 and 256; 67 and 257; 68 and 198; 35 and 258; 69 and 259; 70 and 260; 71 and 261; 72 and 262; 73 and 263; 74 and 264; 75 and 265; 76 and 266; 77 and 267; 4 and 205; 78 and 268; 1 and 269; 27 and 269; 79 and 269; 80 and 270; 81 and 269; 22 and 269; 82 and 269; 83 and 271; 84 and 272; 1 and 273; 8 and 274; 8 and 275; 22 and 276; 8 and 277; 85 and 278; 86 and 279; 87 and 269; 88 and 280; 89 and 269; 60 and 281; 90 and 269; 91 and 282; 22 and 283; 92 and 269; 93 Japanese 284; Japanese 285; Japanese 285; Japanese 286; Japanese 269; Japanese 287; Japanese 287; Japanese 288; Japanese 289; Japanese 269; Japanese 290; Japanese 291; Japanese 292; Japanese 289; Japanese 289; Japanese 101; Japanese 284; Japanese 289; Japanese 89; Japanese 293; Japanese 102; Japanese 294; Japanese 103; Japanese 269; Japanese 22; Japanese 295 ; 104 and 296; 105 and 297; 106 and 270; 107 and 269; 67 and 269; 62 and 298; 66 and 269; 108 and 299; 109 and 300; 110 and 301; 111 and 302; 112 and 269; 113 and 303; 1 and 304; 72 and 305; 114 and 306; 1 15 and 307; 116 and 269; 117 and 308; 118 and 269; 110 and 309; 119 and 310; 120 and 311; 121 and 269; 122 and 312; 123 and 289; 9 and 313; 124 and 314; 120 and 289; 125 and 315; 110 and 316; 126 and 317 ; 127 and 318; 49 and 319; 128 and 320; 9 and 321; 22 and 322; 129 and 323; 130 and 269; 131 and 324; 132 and 325; 133 and 326; 134 and 327; 53 and 328; 135 and 272; 136 and 329; 4 and 301; 137 and 330; 13 8 / 269; 1 / 284; 22 / 331; 139 / 269; 140 / 332; 141 / 269; 142 / 333; 143 / 334; 144 / 335; 101 / 298; 1 / 336; 145 / 269; 146 / 337; 147 / 269; 17 / 338; 22 / 320; 4 / 339;148 and 340; 149 and 341; 150 and 342; 151 and 343; 152 and 344; 94 and 289; 153 and 345; 154 and 346; 155 and 347; 22 and 348; 89 and 282; 156 and 349; 157 and 296; 158 and 350; 159 and 329; 24 and 351; 160 and 352; 161 and 269; 162 and 353; 163 and 269; 1 and 354; 164 and 355 ; 165 and 269; 1 and 356; 166 and 357; 167 and 358; 110 and 334; 87 and 359; 168 and 360; 169 and 269; 170 and 269; 171 and 269; 172 and 361; 8 and 362; 173 and 304; 174 and 269; 1 and 363; 175 and 364; 176 and 365; 177 and 269; 178 and 366; 179 and 269; 180 and 367; or 89 and 368. ; 9. The antibody according to any one of the preceding claims, wherein the antibody is a single-chain variable fragment (scFv).

10. The antibody according to any one of claims 1 to 8, wherein the antibody comprises a heavy chain constant region or its Fc region optionally selected from the group consisting of: IgG1, IgG2, IgG3, IgG4, IgA1, and IgA 2。 11. The antibody of claim 10, wherein the heavy chain constant region is human IgG1.

12. The antibody of claim 10, wherein the heavy chain constant region is human IgG4.

13. The antibody of claim 12, wherein the amino acid sequence of the human IgG4 heavy chain constant region includes position 228 according to the EU numbering system.

14. The antibody according to any one of claims 10 to 13, wherein the heavy chain constant region is a variant of the wild-type heavy chain constant region, wherein the variant heavy chain constant region binds to the Fcγ receptor (FcγR) with a lower affinity than the wild-type heavy chain constant region.

15. The antibody of claim 14, wherein the amino acid sequence of the heavy chain constant region comprises: A at position 234; A at position 235; A, Q, or G at position 297; or A or G at position 329, in each case numbered according to the EU numbering system.

16. The antibody of claim 14, wherein the amino acid sequence of the heavy chain constant region comprises: A at positions 234 and 235; A at positions 234, 235 and 329; or A at positions 234 and 235 and G at position 329, in each case numbered according to the EU numbering system.

17. The antibody according to any one of claims 10 to 16, wherein the heavy chain constant region is a variant of the wild-type heavy chain constant region, and wherein the variant heavy chain constant region has increased affinity for human neonatal Fc receptor (FcRn) at pH 6 relative to the affinity of the wild-type heavy chain constant region for human neonatal Fc receptor (FcRn).

18. The antibody of claim 17, wherein the amino acid sequence of the heavy chain constant region comprises: L and S at positions 428 and 434, respectively; K, F and Y at positions 433, 434 and 436, respectively; or Y, T and E at positions 252, 254 and 256, respectively, in each case numbered according to the EU numbering system.

19. The antibody according to any one of claims 1 to 18, comprising a light chain constant region, optionally a human κ or λ constant region.

20. A polypeptide comprising VH, said VH comprising the CDRH1, CDRH2 and CDRH3 amino acid sequences of any one of the VH amino acid sequences shown in SEQ ID NO: 1-180.

21. The polypeptide of claim 20, wherein the polypeptide comprises the amino acid sequences of CDRH1, CDRH2 and CDRH3 respectively shown in the following: SEQ ID NO: 369, 428 and 484; 370, 429 and 485; 371, 428 and 486; 372, 428 and 484; 373, 429 and 484; 374, 430 and 484; 375, 428 and 487; 376, 428 and 484; 377, 428 and 484; 378, 428 and 484; 379, 428 and 484; 372, 428 and 488; 376, 431 and 484; 380, 432 and 484; 372, 428 and 489; 381, 428 and 490; 382, ​​428 and 484; 381, 428 and 491; 377, 428 and 492; 376 , 433 and 484; 383, 434 and 484; 383, 428 and 484; 384, 435 and 484; 369, 436 and 484; 372, 437 and 487; 385, 428 and 493; 386, 428 and 484; 372, 437 and 484; 387, 428 and 48 4; 385, 428 and 484; 372, 438 and 484; 388, 428 and 494; 369, 439 and 484; 389, 428 and 484; 381, 428 and 484; 376, 440 and 495; 390, 441 and 484; 370, 442 and 484; 391, 42 8 and 484; 392, 432 and 484; 377, 443 and 484; 393, 428 and 484; 383, 444 and 489; 394, 428 and 484; 383, 444 and 496; 376, 434 and 484; 395, 445 and 497; 396, 446 and 487; 3 92, 428 and 484; 393, 428 and 498; 376, 428 and 495; 369, 440 and 484; 397, 428 and 484 ;389, 447 and 484; 398, 448 and 492; 373, 449 and 490; 399, 428 and 484; 400, 450 and 4 84; 401, 428 and 484; 390, 428 and 484; 400, 428 and 499; 384, 429 and 484; 402, 436 and 484; 381, 451 and 484; 403, 428 and 484; 369, 429 and 484; 404, 429 and 484; 372, 429 and 484; 388, 428 and 484; 405, 451 and 484; 406, 428 and 484; 400, 428 and 484; 40 4, 428 and 484; 384, 432 and 500; 376, 452 and 501; 407, 428 and 484; 375, 428 and 484;408, 428 and 484; 369, 428 and 497; 403, 453 and 484; 402, 454 and 484; 383, 434 and 500; 376, 455 and 502; 383, 435 and 484; 376, 428 and 490; 369, 428 and 503; 409, 428 and 484; 383, 428 and 504; 369, 434 and 484; 369, 456 and 484; 370, 457 and 484; 404, 458 and 499; 410, 428 and 484; 383, 459 and 484; 407, 428 and 489; 374, 434 and 484; 411, 460 and 505; 383, 428 and 4 85; 386, 460 and 490; 412, 455 and 493; 383, 461 and 484; 376, 437 and 484; 383, 462 and 500; 400, 463 and 484; 376, 464 and 484; 400, 434 and 506; 369, 436 and 507; 377, 465 and 484; 4 13, 459 and 484; 369, 452 and 484; 414, 466 and 484; 373, 428 and 484; 415, 428 and 489; 369, 428 and 491; 403, 458 and 508; 392, 467 and 484; 369, 452 and 509; 388, 468 and 490; 377, 44 0 and 484; 370, 428 and 484; 384, 467 and 487; 392, 469 and 510; 378, 464 and 484; 416, 434 and 484; 370, 428 and 511; 376, 428 and 502; 417, 428 and 484; 376, 428 and 512; 381, 428 and 49 3; 383, 470 and 501; 404, 471 and 484; 418, 428 and 484; 383, 472 and 513; 419, 428 and 484; 372, 473 and 484; 383, 474 and 484; 420, 434 and 484; 370, 428 and 514; 369, 475 and 484; 421 , 436 and 484; 378, 452 and 484; 376, 476 and 515; 376, 428 and 504; 422, 469 and 484; 369, 428 and 516; 405, 460 and 484; 413, 431 and 484; 406, 429 and 484; 383, 428 and 517; 377, 437 Japanese 518; 369, 477 and 487; 403, 464 and 484; 369, 454 and 484; 372, 478 and 519; 423, 429 and 484; 382, ​​434 and 484; 424, 479 and 484; 376, 429 and 484; 425, 428 and 484; 403, 428 and 520;417, 460 and 484; 409, 460 and 484; 404, 452 and 484; 383, 428 and 521; 372, 480 and 493; 369, 477 and 484; 369, 481 and 484; 384, 452 and 484; 377, 482 and 484; 410, 483 and 484; 384, 428 and 489; 426, 429 and 484; 427, 428 and 484; 373, 452 and 506; 369, 429 and 521; 405, 428 and 522; 376, 428 and 510; 384, 428 and 484; 410, 429 and 484; or 400, 452 and 484.

22. The polypeptide of claim 20, wherein the VH comprises the amino acid sequences of CDRH1, CDRH2 and CDRH3 respectively shown in the following: SEQ ID NO: 369, 428 and 484; 370, 429 and 485; 371, 428 and 486; 372, 428 and 484; 373, 429 and 484; 374, 430 and 484; 375, 428 and 487; 376, 428 and 484; 377, 428 and 484; 378, 428 and 484; 379, 428 and 484; 372, 428 and 488; 376, 431 and 484; 380, 432 and 484; 372, 428 and 489; 381, 428 and 490; 382, ​​428 and 484; 381, 428 and 491; 377, 428 and 492; 376 , 433 and 484; 383, 434 and 484; 383, 428 and 484; 384, 435 and 484; 369, 436 and 484; 372, 437 and 487; 385, 428 and 493; 386, 428 and 484; 372, 437 and 484; 387, 428 and 48 4; 385, 428 and 484; 372, 438 and 484; 388, 428 and 494; 369, 439 and 484; 389, 428 and 484; 381, 428 and 484; 376, 440 and 495; 390, 441 and 484; 370, 442 and 484; 391, 42 8 and 484; 392, 432 and 484; 377, 443 and 484; 393, 428 and 484; 383, 444 and 489; 394, 428 and 484; 383, 444 and 496; 376, 434 and 484; 395, 445 and 497; 396, 446 and 487; 3 92, 428 and 484; 393, 428 and 498; 376, 428 and 495; 369, 440 and 484; 397, 428 and 484 ;389, 447 and 484; 398, 448 and 492; 373, 449 and 490; 399, 428 and 484; 400, 450 and 4 84; 401, 428 and 484; 390, 428 and 484; 400, 428 and 499; 384, 429 and 484; 402, 436 and 484; 381, 451 and 484; 403, 428 and 484; 369, 429 and 484; 404, 429 and 484; 372, 429 and 484; 388, 428 and 484; 405, 451 and 484; 406, 428 and 484; 400, 428 and 484; 40 4, 428 and 484; 384, 432 and 500; 376, 452 and 501; 407, 428 and 484; 375, 428 and 484;408, 428 and 484; 369, 428 and 497; 403, 453 and 484; 402, 454 and 484; 383, 434 and 500; 376, 455 and 502; 383, 435 and 484; 376, 428 and 490; 369, 428 and 503; 409, 428 and 484; 383, 428 and 504; 369, 434 and 484; 369, 456 and 484; 370, 457 and 484; 404, 458 and 499; 410, 428 and 484; 383, 459 and 484; 407, 428 and 489; 374, 434 and 484; 411, 460 and 505; 383, 428 and 4 85; 386, 460 and 490; 412, 455 and 493; 383, 461 and 484; 376, 437 and 484; 383, 462 and 500; 400, 463 and 484; 376, 464 and 484; 400, 434 and 506; 369, 436 and 507; 377, 465 and 484; 4 13, 459 and 484; 369, 452 and 484; 414, 466 and 484; 373, 428 and 484; 415, 428 and 489; 369, 428 and 491; 403, 458 and 508; 392, 467 and 484; 369, 452 and 509; 388, 468 and 490; 377, 44 0 and 484; 370, 428 and 484; 384, 467 and 487; 392, 469 and 510; 378, 464 and 484; 416, 434 and 484; 370, 428 and 511; 376, 428 and 502; 417, 428 and 484; 376, 428 and 512; 381, 428 and 49 3; 383, 470 and 501; 404, 471 and 484; 418, 428 and 484; 383, 472 and 513; 419, 428 and 484; 372, 473 and 484; 383, 474 and 484; 420, 434 and 484; 370, 428 and 514; 369, 475 and 484; 421 , 436 and 484; 378, 452 and 484; 376, 476 and 515; 376, 428 and 504; 422, 469 and 484; 369, 428 and 516; 405, 460 and 484; 413, 431 and 484; 406, 429 and 484; 383, 428 and 517; 377, 437 Japanese 518; 369, 477 and 487; 403, 464 and 484; 369, 454 and 484; 372, 478 and 519; 423, 429 and 484; 382, ​​434 and 484; 424, 479 and 484; 376, 429 and 484; 425, 428 and 484; 403, 428 and 520;417, 460 and 484; 409, 460 and 484; 404, 452 and 484; 383, 428 and 521; 372, 480 and 493; 369, 477 and 484; 369, 481 and 484; 384, 452 and 484; 377, 482 and 484; 410, 483 and 484; 384, 428 and 489; 426, 429 and 484; 427, 428 and 484; 373, 452 and 506; 369, 429 and 521; 405, 428 and 522; 376, 428 and 510; 384, 428 and 484; 410, 429 and 484; or 400, 452 and 484.

23. The polypeptide of claim 20, wherein the VH comprises any of the amino acid sequences shown in SEQ ID NO: 1-180.

24. A polypeptide comprising a VL, said VL comprising the CDRL1, CDRL2, and CDRL3 amino acid sequences of any one of the VL amino acid sequences shown in SEQ ID NO: 181-368.

25. The polypeptide of claim 24, wherein the polypeptide comprises the amino acid sequences CDRL1, CDRL2, and CDRL3 respectively shown in the following: SEQ ID NO: 523, 591 and 656; 523, 592 and 657; 523, 593 and 658; 523, 591 and 659; 523, 594 and 659; 523, 595 and 660; 523, 596 and 659; 524, 591 and 659; 523, 591 and 661; 523, 591 and 662; 523, 597 and 658; 523, 598 and 662; 525, 599 and 659; 523, 600 and 663; 523, 591 and 664; 523, 601 and 659; 526, 597 and 665; 523, 602 and 659; 527, 591 and 661; 528 , 591 and 662; 529, 603 and 662; 523, 604 and 666; 523, 605 and 667; 530, 606 and 659; 523, 607 and 659; 523, 608 and 659; 523, 609 and 662; 531, 591 and 663; 523, 608 and 66 1; 523, 610 and 659; 523, 611 and 668; 523, 611 and 658; 523, 596 and 662; 523, 612 and 667; 523, 613 and 668; 523, 591 and 669; 523, 591 and 663; 523, 614 and 659; 532, 61 5 and 662; 523, 616 and 670; 523, 591 and 668; 523, 617 and 671; 533, 595 and 659; 523, 618 and 659; 534, 619 and 662; 535, 620 and 659; 536, 621 and 659; 537, 603 and 671; 5 23, 622 and 659; 523, 617 and 659; 523, 623 and 659; 538, 607 and 672; 523, 616 and 671 ;523, 624 and 659; 523, 620 and 659; 523, 625 and 660; 523, 602 and 671; 523, 611 and 6 63; 523, 626, and 670; 523, 606, and 673; 523, 627, and 671; 523, 628, and 671; 539, 591, and 662; 523, 591, and 670; 523, 611, and 659; 591 and 659; 542, 629 and 659; 523, 591 and 671; 523, 630 and 667; 543, 631 and 659; 52 3, 632 and 664; 523, 597 and 661; 523, 633 and 659; 544, 607 and 659; 523, 630 and 659;523, 591 and 665; 523, 610 and 674; 523, 634 and 671; 545, 591 and 661; 523, 635 and 667; 546, 591 and 659; 523, 636 and 664; 547, 591 and 663; 548, 619 and 659; 523, 637 and 659; 523, 638 and 659; 549, 591 and 659; 550, 591 and 675; 551, 591 and 659; 552, 591 and 659; 553, 591 and 676; 554, 591 and 659; 523, 591 and 676; 555, 606 and 659; 556, 591 and 659; 523, 637 and 6 77; 557, 591 and 659; 558, 591 and 659; 523, 591 and 677; 553, 639 and 659; 549, 591 and 667; 559, 617 and 666; 523, 591 and 672; 523, 606 and 659; 523, 592 and 670; 560, 591 and 667; 5 30, 591 and 659; 561, 603 and 666; 562, 591 and 659; 523, 616 and 660; 523, 602 and 677; 523, 616 and 659; 523, 630 and 660; 563, 591 and 659; 523, 640 and 659; 564, 591 and 659; 523, 64 1 and 677; 565, 591 and 662; 523, 642 and 664; 566, 643 and 659; 523, 644 and 667; 567, 606 and 659; 568, 591 and 659; 569, 645 and 659; 523, 603 and 659; 570, 628 and 678; 571, 630 and 66 3; 572, 591 and 664; 573, 591 and 670; 523, 646 and 659; 574, 591 and 670; 523, 647 and 667; 575, 591 and 659; 537, 591 and 659; 523, 635 and 670; 576, 591 and 659; 577, 606 and 659; 523 , 648 and 679; 523, 592 and 659; 523, 595 and 659; 523, 600 and 659; 523, 649 and 664; 578, 641 and 659; 523, 591 and 667; 523, 606 and 660; 523, 650 and 656; 579, 621 and 671; 580, 591 Japanese 660; 527, 591 Japanese 659; 581, 595 Japanese 659; 582, 640 Japanese 664; 583, 651 Japanese 659; 534, 591 Japanese 659; 584, 591 Japanese 671; 523, 591 Japanese 680; 523, 591 Japanese 681; 585, 591 Japanese 659; 523, 649 Japanese 659;586, 591 and 666; 587, 652 and 659; 588, 638 and 659; 523, 623 and 664; 523, 591 and 682; 553, 653 and 659; 523, 654 and 659; 523, 648 and 659; 560, 591 and 659; 580, 606 and 659; 589, 593 and 661; 523, 637 and 676; 590, 622 and 659; 555, 591 and 661; 523, 615 and 672; 523, 626 and 668; 523, 655 and 659; or 523, 606 and 680.

26. The polypeptide of claim 24, wherein the VL comprises the amino acid sequences CDRL1, CDRL2, and CDRL3 respectively shown in the following: SEQ ID NO: 523, 591 and 656; 523, 592 and 657; 523, 593 and 658; 523, 591 and 659; 523, 594 and 659; 523, 595 and 660; 523, 596 and 659; 524, 591 and 659; 523, 591 and 661; 523, 591 and 662; 523, 597 and 658; 523, 598 and 662; 525, 599 and 659; 523, 600 and 663; 523, 591 and 664; 523, 601 and 659; 526, 597 and 665; 523, 602 and 659; 527, 591 and 661; 528 , 591 and 662; 529, 603 and 662; 523, 604 and 666; 523, 605 and 667; 530, 606 and 659; 523, 607 and 659; 523, 608 and 659; 523, 609 and 662; 531, 591 and 663; 523, 608 and 66 1; 523, 610 and 659; 523, 611 and 668; 523, 611 and 658; 523, 596 and 662; 523, 612 and 667; 523, 613 and 668; 523, 591 and 669; 523, 591 and 663; 523, 614 and 659; 532, 61 5 and 662; 523, 616 and 670; 523, 591 and 668; 523, 617 and 671; 533, 595 and 659; 523, 618 and 659; 534, 619 and 662; 535, 620 and 659; 536, 621 and 659; 537, 603 and 671; 5 23, 622 and 659; 523, 617 and 659; 523, 623 and 659; 538, 607 and 672; 523, 616 and 671 ;523, 624 and 659; 523, 620 and 659; 523, 625 and 660; 523, 602 and 671; 523, 611 and 6 63; 523, 626, and 670; 523, 606, and 673; 523, 627, and 671; 523, 628, and 671; 539, 591, and 662; 523, 591, and 670; 523, 611, and 659; 591 and 659; 542, 629 and 659; 523, 591 and 671; 523, 630 and 667; 543, 631 and 659; 52 3, 632 and 664; 523, 597 and 661; 523, 633 and 659; 544, 607 and 659; 523, 630 and 659;523, 591 and 665; 523, 610 and 674; 523, 634 and 671; 545, 591 and 661; 523, 635 and 667; 546, 591 and 659; 523, 636 and 664; 547, 591 and 663; 548, 619 and 659; 523, 637 and 659; 523, 638 and 659; 549, 591 and 659; 550, 591 and 675; 551, 591 and 659; 552, 591 and 659; 553, 591 and 676; 554, 591 and 659; 523, 591 and 676; 555, 606 and 659; 556, 591 and 659; 523, 637 and 6 77; 557, 591 and 659; 558, 591 and 659; 523, 591 and 677; 553, 639 and 659; 549, 591 and 667; 559, 617 and 666; 523, 591 and 672; 523, 606 and 659; 523, 592 and 670; 560, 591 and 667; 5 30, 591 and 659; 561, 603 and 666; 562, 591 and 659; 523, 616 and 660; 523, 602 and 677; 523, 616 and 659; 523, 630 and 660; 563, 591 and 659; 523, 640 and 659; 564, 591 and 659; 523, 64 1 and 677; 565, 591 and 662; 523, 642 and 664; 566, 643 and 659; 523, 644 and 667; 567, 606 and 659; 568, 591 and 659; 569, 645 and 659; 523, 603 and 659; 570, 628 and 678; 571, 630 and 66 3; 572, 591 and 664; 573, 591 and 670; 523, 646 and 659; 574, 591 and 670; 523, 647 and 667; 575, 591 and 659; 537, 591 and 659; 523, 635 and 670; 576, 591 and 659; 577, 606 and 659; 523 , 648 and 679; 523, 592 and 659; 523, 595 and 659; 523, 600 and 659; 523, 649 and 664; 578, 641 and 659; 523, 591 and 667; 523, 606 and 660; 523, 650 and 656; 579, 621 and 671; 580, 591 Japanese 660; 527, 591 Japanese 659; 581, 595 Japanese 659; 582, 640 Japanese 664; 583, 651 Japanese 659; 534, 591 Japanese 659; 584, 591 Japanese 671; 523, 591 Japanese 680; 523, 591 Japanese 681; 585, 591 Japanese 659; 523, 649 Japanese 659;586, 591 and 666; 587, 652 and 659; 588, 638 and 659; 523, 623 and 664; 523, 591 and 682; 553, 653 and 659; 523, 654 and 659; 523, 648 and 659; 560, 591 and 659; 580, 606 and 659; 589, 593 and 661; 523, 637 and 676; 590, 622 and 659; 555, 591 and 661; 523, 615 and 672; 523, 626 and 668; 523, 655 and 659; or 523, 606 and 680.

27. The polypeptide of claim 24, wherein the VL comprises any of the amino acid sequences shown in SEQ ID NO: 181-368.

28. The antibody or polypeptide according to any one of the preceding claims, wherein the antibody or polypeptide is conjugated with a cytotoxic agent, a cell growth inhibitor, a toxin, a radionuclide, or a detectable label.

29. A polynucleotide encoding the VH and / or VL of an antibody according to any one of claims 1 to 19 or a polypeptide according to any one of claims 20 to 27.

30. A vector comprising the polynucleotide according to claim 29.

31. The vector of claim 30, wherein the vector is an adeno-associated virus (AAV) vector.

32. A recombinant host cell comprising: (a) The polynucleotide according to claim 29; (b) The carrier according to claim 30 or 31; (c) a first polynucleotide encoding the VH or heavy chain of the antibody according to any one of claims 1 to 19, and a second polynucleotide encoding the VL or light chain of the antibody according to any one of claims 1 to 19; or (d) A first vector comprising a first polynucleotide encoding the VH or heavy chain of an antibody according to any one of claims 1 to 19, and a second vector comprising a second polynucleotide encoding the VL or light chain of an antibody according to any one of claims 1 to 19.

33. A pharmaceutical composition comprising an antibody or polypeptide according to any one of claims 1 to 28, a polynucleotide according to claim 29, a carrier according to claim 30 or 31 or a host cell according to claim 32, and a pharmaceutically acceptable carrier or excipient.

34. A method for producing an antibody or polypeptide, the method comprising culturing a host cell according to claim 32 under suitable conditions to express the polynucleotide and produce the antibody or polypeptide.

35. A method for inhibiting PC activity in a subject, the method comprising administering to the subject an effective amount of an antibody or polypeptide according to any one of claims 1 to 28, a polynucleotide according to claim 29, a carrier according to claim 30 or 31, a host cell according to claim 32, or a pharmaceutical composition according to claim 33.

36. A method of treating a subject with an inflammatory or degenerative disease, the method comprising administering to the subject an effective amount of an antibody or polypeptide according to any one of claims 1 to 28, a polynucleotide according to claim 29, a carrier according to claim 30 or 31, a host cell according to claim 32, or a pharmaceutical composition according to claim 33.

37. The method of claim 36, wherein the inflammatory disease or degenerative disease is selected from the group consisting of: organ reperfusion injury such as myocardial infarction-induced reperfusion injury, Kawasaki disease, non-alcoholic steatohepatitis (NASH), organ transplant rejection, atherosclerosis, type I or type II diabetes, rheumatoid arthritis, osteoporosis, acute lung injury, asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, pain, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), age-related macular degeneration (AMD), stroke, Huntington's disease, frontotemporal dementia (FTD), multiple sclerosis (MS), isolated demyelinating diseases of the central nervous system, osteoarthritis, Crohn's disease, and ulcerative colitis.

38. Use of the antibody or polypeptide according to any one of claims 1 to 28, the polynucleotide according to claim 29, the carrier according to claim 30 or 31, the host cell according to claim 32, or the pharmaceutical composition according to claim 33 for the manufacture of a medicament for the treatment of an inflammatory or degenerative disease in a subject of need.

39. The use according to claim 38, wherein the inflammatory disease or degenerative disease is selected from the group consisting of: organ reperfusion injury such as myocardial infarction-induced reperfusion injury, Kawasaki disease, non-alcoholic steatohepatitis (NASH), organ transplant rejection, atherosclerosis, type I or type II diabetes, rheumatoid arthritis, osteoporosis, acute lung injury, asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, pain, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), age-related macular degeneration (AMD), stroke, Huntington's disease, frontotemporal dementia (FTD), multiple sclerosis (MS), isolated demyelinating diseases of the central nervous system, osteoarthritis, Crohn's disease, and ulcerative colitis.

40. The antibody or polypeptide according to any one of claims 1 to 28, the polynucleotide according to claim 29, the carrier according to claim 30 or 31, the host cell according to claim 32, or the pharmaceutical composition according to claim 33, for use in medicine.

41. An antibody or polypeptide according to any one of claims 1 to 28, a polynucleotide according to claim 29, a carrier according to claim 30 or 31, a host cell according to claim 32, or a pharmaceutical composition according to claim 33, for use in treating an inflammatory or degenerative disease in a subject of need.

42. The use according to claim 41, wherein the inflammatory disease or degenerative disease is selected from the group consisting of: organ reperfusion injury such as myocardial infarction-induced reperfusion injury, Kawasaki disease, non-alcoholic steatohepatitis (NASH), organ transplant rejection, atherosclerosis, type I or type II diabetes, rheumatoid arthritis, osteoporosis, acute lung injury, asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, pain, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), age-related macular degeneration (AMD), stroke, Huntington's disease, frontotemporal dementia (FTD), multiple sclerosis (MS), isolated demyelinating diseases of the central nervous system, osteoarthritis, Crohn's disease, and ulcerative colitis.

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