Binding agents and methods of use thereof

Abstract

The present disclosure includes agents, such as antibodies and chimeric antigen receptors, that specifically bind to CLL-1, as well as methods of making and using such agents.

Description

[0001] Related Applications

[0002] This application claims the benefit of the following provisional applications under 35 USC 119(e): U.S. Provisional Application No. 63 / 329,664, filed on April 11, 2022, and U.S. Provisional Application No. 63 / 399,588, filed on August 19, 2022, both of which are incorporated herein by reference in their entirety.

[0003] References to Electronic Sequence Listings

[0004] The contents of the electronic sequence listing (V029170034WO00-SEQ-CEW.xml; size: 875,826 bytes; creation date: April 11, 2023) are incorporated herein by reference in their entirety. Background Art

[0005] C-type lectin-like molecule-1 (CLL-1), also known as CLEC12A, is a member of the C-type lectin-like receptor family that is commonly expressed on acute myeloid leukemia (AML) cells. AML remains a major therapeutic challenge and unmet need in hematological oncology. AML is a disease that causes uncontrolled accumulation of immature myeloid blasts in the bone marrow and peripheral blood, and the disease has multiple subtypes, which poses a challenge to the development of comprehensive targeted therapies. Despite the increased understanding of the molecular genetics of the disease, relatively few new therapies have been approved for AML. Therefore, new therapeutic agents for AML are still needed. Summary of the invention

[0006] In one aspect, the present disclosure relates to an anti-CLL-1 antibody or an antigen-binding fragment thereof comprising SEQ ID NO: 15, 29, 43, 57, 71, 85, 99, 113, 127, 141, 155, 169, 174, 179, 184, 189, 194,199, 204, 209, 214, 219, 224, 229, 234, 239, 244, 249, 254, 259, 264, 269, 275, 280, 285, 290, 295, 309, 323, 337, 351, 365, 418, 422, 426, 430, 434,438, 442, 446, 450, 454, 458, 462, 466, 470, 474, 478, 482, 486, 490, 494,498, 502, 506, 510, 514, 518, 522, 526, 530, 534, 538, 542, 546, 550, 554,558, 562, 566, 570, 574, 578, 582, 586, 590, 594, 598, 602, 606, 610, 614,618, 622, 626, 630, 634, 638, 642, 646, 650, 654, 658, 662, 666, 670, 674,678, 682, 686, 690, 694, 698, 702, 706, 710, 714, 718, 722, 726, 730, 734,738, 742, 746, 750, 754, 758, 762, 766, 774, 779, 784, 788, 793, 798, 801,804, 808, 819, 831, 837, 849, 900, 905, The amino acid sequence of 910, 918, or 920.

[0007] In one aspect, the present disclosure relates to an anti-CLL-1 antibody or an antigen-binding fragment thereof comprising SEQ ID NO: 2-7, 16-21, 30-35, 44-49, 58-63, 72-77, 86-91, 100-105, 114-119, 128-133,142-147, 156-161, 170-172, 175-177, 180-182, 185-187, 190-192, 195-197, 200-202, 205-207, 210-212, 215-217, 220-222, 225-227, 230-232, 235-237, 240-242,245-247, 250-252, 255-257, 260-262, 265-267, 271-273, 276-278, 281-283, 286-288, 291-293, 296-301, 310-315, 324-329, 338-343, 352-357, 419-421, 423-425,427-429, 431-433, 435-437, 439-441, 443-445, 447-449, 451-453, 455-457, 459-461, 463-465, 467-469, 471-473, 475-477, 479-481, 483-485, 487-489, 491-493,495-497, 499-501, 503-505, 507-509, 511-513, 515-517, 519-521, 523-525, 527-529, 531-533, 535-537, 539-541, 543-545, 547-549, 551-553, 555-557, 559-561,563-565, 567-569, 571-573, 575-577, 579-581, 583-585, 587-589, 591-593, 595-597, 599-601, 603-605, 607-609, 611-613, 615-617, 619-621, 623-625, 627-629,631-633, 635-637, 639-641, 643-645, 647-649, 651-653, 655-657, 659-661, 663-665, 667-669, 671-673, 675-677, 679-681, 683-685,687-689, 691-693, 695-697,699-701, 703-705, 707-709, 711-713, 715-717, 719-721, 723-725, 727-729, 731-733, 735-737, 739-741, 743-745, 747-749, 751-753, 755-757, 759-761, 763-765,767-769, 770-772, 775-777, 780-782, 785-786, 789-791, 794-796, 799, at least one complementarity determining region (CDR) sequence of 802, 805-806, 820-825, 838-843, 850-854, 861-866, 896-898, 901-903, 906-908, or 911-916.

[0008] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises SEQ ID NO: 2-7, 16-21, 30-35, 44-49, 58-63, 72-77, 86-91, 100-105, 114-119, 128-133, 142-147,156-161, 170-172, 175-177, 180-182, 185-187, 190-192, 195-197, 200-202, 205-207, 210-212, 215-217, 220-222, 225-227, 230-232, 235-237, 240-242, 245-247,250-252, 255-257, 260-262, 265-267, 271-273, 276-278, 281-283, 286-288, 291-293, 296-301, 310-315, 324-329, 338-343, 352-357, 419-421, 423-425, 427-429,431-433, 435-437, 439-441, 443-445, 447-449, 451-453, 455-457, 459-461, 463-465, 467-469, 471-473, 475-477, 479-481, 483-485, 487-489, 491-493, 495-497,499-501, 503-505, 507-509, 511-513, 515-517, 519-521, 523-525, 527-529, 531-533, 535-537, 539-541, 543-545, 547-549, 551-553, 555-557, 559-561, 563-565,567-569, 571-573, 651-653, 655-657, 659-661, 663-665, 667-669, 671-673, 675-677, 679-681, 683-685,687-689, 691-693, 695-697, 699-701,703-705, 707-709, 711-713, 715-717, 719-721, 723-725, 727-729, 731-733, 735-737, 739-741, 743-745, 747-749, 751-753, 755-757, 759-761, 763-765, 767-769,, 770-772, 775-777, 780-782, 785-786, 789-791, 794-796, 799, 802, 805-806,820-825, 838-843, 850-854, 861-866, 896-898, 901-903, 906-908, or three CDR sequences of 911-916. ,

[0009] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises SEQ ID NO: 2-7, 16-21, 30-35, 44-49, 58-63, 72-77, 86-91, 100-105, 114-119, 128-133, 142-147,156-161, 170-172, 175-177, 180-182, 185-187, 190-192, 195-197, 200-202, 205-207, 210-212, 215-217, 220-222, 225-227, 230-232, 235-237, 240-242, 245-247,250-252, 255-257, 260-262, 265-267, 271-273, 276-278, 281-283, 286-288, 291-293, 296-301, 310-315, 324-329, 338-343, 352-357, 419-421, 423-425, 427-429,431-433, 435-437, 439-441, 443-445, 447-449, 451-453, 455-457, 459-461, 463-465, 467-469, 471-473, 475-477, 479-481, 483-485, 487-489, 491-493, 495-497,499-501, 503-505, 507-509, 511-513, 515-517, 519-521, 523-525, 527-529, 531-533, 535-537, 539-541, 543-545, 547-549, 551-553, 555-557, 559-561, 563-565,567-569, 571-573, 651-653, 655-657, 659-661, 663-665, 667-669, 671-673, 675-677, 679-681, 683-685,687-689, 691-693, 695-697, 699-701,703-705, 707-709, 711-713, 715-717, 719-721, 723-725, 727-729, 731-733, 735-737, 739-741, 743-745, 747-749, 751-753, 755-757, 759-761, 763-765, 767-769,770-772, 775-777, 780-782, 785-786, 789-791, 794-796, 799, Six CDR sequences of 802, 805-806, 820-825, 838-843, 850-854, 861-866, 896-898, 901-903, 906-908, or 911-916. ,

[0010] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises SEQ ID NO: 5-7, 19-21, 33-35, 47-49, 61-63, 75-77, 89-91, 103-105, 117-119, 131-133, 145-147,159-161, 170-172, 175-177, 180-182, 185-187, 190-192, 195-197, 200-202, 205-207, 210-212, 215-217, 220-222, 225-227, 230-232, 235-237, 240-242, 245-247,250-252, 255-257, 260-262, 265-267, 271-273, 276-278, 281-283, 286-288, 291-293, 299-301, 313-315, 327-329, 341-343, 355-357, 423-425, 431-433, 439-441,447-449, 455-457, 463-465, 471-473, 479-481, 487-489, 495-497, 503-505, 511-513, 519-521, 527-529, 535-537, 543-545, 551-553, 559-561, 567-569, 575-577,583-585, 591-593, 599-601, 607-609, 615-617, 623-625, 631-633, 639-641, 647-649, 655-657, 663-665, 671-673, 679-681, 687-689, 695-697, 703-705, 711-713,715-746, 748-808, The three heavy chain CDR sequences are 816-817, 823-825, 828-829, 834-835, 841-843, 846-847, 852-854, 857-858, 869-870, 880-881, 892-893, 896-910, 914-916, or 919-920.

[0011] In another aspect, the present disclosure relates to an anti-CLL-1 antibody or an antigen-binding fragment thereof comprising SEQ ID NO: 2-7, 16-21, 30-35, 44-49, 58-63, 72-77, 86-91, 100,-105, 114-119, 128-133, 142-147, 156-161, 170-172, 175-177, 180-182, 185-187, 190-192, 195-197,200-202, 205-207, 210-212, 215-217, 220-222, 225-227, 230-232, 235-237, 240-242, 245-247, 250-252, 255-257, 260-262, 265-267, 271-273, 276-278, 281-283,286-288, 291-293, 296-301, 310-315, 324-329, 338-343, 352-357, 419-421, 423-425, 427-429, 431-433, 435-437, 439-441, 443-445, 447-449, 451-453, 455-457,459-461, 463-465, 467-469, 471-473, 475-477, 479-481, 483-485, 487-489, 491-493, 495-497, 499-501, 503-505, 507-509, 511-513, 515-517, 519-521, 523-525,527-529, 531-533, 535-537, 539-541, 543-545, 547-549, 551-553, 555-557, 559-561, 563-565, 567-569, 61-613, 615-617, 619-621, 623-625, 627-629, 631-633, 635-637, 639-641, 643-645, 647-649, 651-653, 655-657, 659-661,663-665, 667-669, 671-673, 675-677, 679-681,683-685, 687-689, 691-693, 695-697, 699-701, 703-705, 707-709, 711-713, 715-717, 719-721, 723-725, 727-729,731-733, 735-737, 739-741, 743-745, 747-749, 751-753, 755-757, 759-761, 763-765, 767-769, 671-673, 675-677, 679-681, 683-685, 687-689, 691-693, 695-697,699-701, 703-705, 707-709, 711-713, 715-717, 719-721, 723-725, 727-729, 731-733, 735-737, 739-741, 743-745, 747-749, 751-753, 755-757, 759-761, 763-765,767-769, 770-772, 775-777, 780-782, 785-786, 789-791, 794-796, 799, 802, CDR1, CDR2 and CDR3 of 805-806, 820-825, 838-843, 850-854, 896-898, 901-903, 906-908, or 911-916. ,

[0012] In another aspect, the present disclosure relates to an anti-CLL-1 antibody or an antigen-binding fragment thereof comprising an antibody that is SEQ ID NO: 2-7, 16-21, 30-35, 44-49, 58-63, 72-77, 86-91, 100,-105, 114-119, 128-133, 142-147, 156-161, 170-172, 175-177, 180-182, 185-187, 190-192, 195-197,200-202, 205-207, 210-212, 215-217, 220-222, 225-227, 230-232, 235-237, 240-242, 245-247, 250-252, 255-257, 260-262, 265-267, 271-273, 276-278, 281-283,286-288, 291-293, 296-301, 310-315, 324-329, 338-343, 352-357, 419-421, 423-425, 427-429, 431-433, 435-437, 439-441, 443-445, 447-449, 451-453, 455-457,459-461, 463-465, 467-469, 471-473, 475-477, 479-481, 483-485, 487-489, 491-493, 495-497, 499-501, 503-505, 507-509, 511-513, 515-517, 519-521, 523-525,527-529, 531-533, 535-537, 539-541, 543-545, 547-549, 551-553, 555-557, 559-561, 563-565, 567-569, 61-613, 615-617, 619-621, 623-625, 627-629, 631-633, 635-637, 639-641, 643-645, 647-649, 651-653, 655-657, 659-661,663-665, 667-669, 671-673, 675-677, 679-681,683-685, 687-689, 691-693, 695-697, 699-701, 703-705, 707-709, 711-713, 715-717, 719-721, 723-725, 727-729,731-733, 735-737, 739-741, 743-745, 747-749, 751-753, 755-757, 759-761, 763-765, 767-769, 770-772, 775-777, 780-782, 785-786, 789-791, 794-796, 799, 802,805-806, 820-825, 838-843, 850-854, 896-898, 901-903, 906-908, or 911-916 CDRs (e.g., CDR1, CDR2, and / or CDR3) having at least one CDR that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical.

[0013] In another aspect, the present disclosure relates to an anti-CLL-1 antibody or an antigen-binding fragment thereof, comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a light chain variable region consisting of SEQ ID NO: 5, 19, 33, 47, 61, 75, 89, 103, 117, 131, 145, 159, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 271, 276, 281, 286, 291, 299,313, 327, 341, 355, 423, 431, 439, 447, 455, 463, 471, 479, 487, 495, 503,511, 519, 527, 535, 543, 551, 559, 567, 575, 583, 591, 599, 607, 615, 623,631, 639, 647, 655, 663, 671, 679, 687, 695, 703, 711, 715, 719, 723, 727,731, 735, 739, 743, 747, 751, 755, 759, 763, 767, 770, 775, 780, 785, 789,794, 823, 841, 852, 896, 901, 906, or 914;6, 20, 34, 48, 62, 76, 90, 104, 118, 132, 146, 160, 171, 176, 181, 186, 191, 196, 201, 206, 211, 216, 221, 226, 231, 236, 241, 246, 251, 256, 261, 266, 272, 277, 282, 287, 292, 300, 314, 328, 342 356, 424, 432, 440, 448, 456, 464, 472,480, 488, 496, 504, 512, 520, 528, 536, 544, 552, 560, 568, 576, 584, 592,600, 608, 616, 624, 632, 640, 648, 656, 664, 672, 680, 688, 696, 704, 712,716, 720, 724, 728, 732, 736, 740, 744, 748, 752, 756, 760, 764, 768, 771,776, 781, 786, 790, 795, 799, 802, 805, 824, 842, 853, 897, 902, 907, or 915;73, 78, 283, 288, 293, 301, 315, 329, 343, 357, 425, 433, 441, 449, 457, 465, 473, 486, 491, 508, 512, 520, 530, 541, 552, 564, 576, 581, 582, 587, 590, 608, 611, 613, 621, 631, 643, 657, 661, 671, 681, 691, 732, 733, 741, 749, 750, 765, 776 481, 489, 497, 505, 513, 521, 529,537, 545, 553, 561, 569, 577, 585, 593, 601, 609, 617, 625, 633, 641, 649,657, 665, 673, 681, 689, 697, 705, 713, 717, 721, 725, 729, 733, 737, 741,745, 749, 753, 757, 761, 765, 769, 772, 777, 782, 791, 796, 806, 825, 843, 854, 898, 903, 908 or 916; the light chain variable region comprises a CDR3 provided by SEQ ID NO: 2, 16, 30,44, 58, 72, 86, 100, 114, 128, 142, 156, 296, 310, 324, 338, 352, 419, 427,435, 443, 451, 459, 467, 475, 483, 491, 499, 507, 515, 523, 531, 539, 547,555, 563, 571, 579, 587, 595, 603, 611, 619, 627, 635, 643, 651, 659, 667,675, 683, 691, 699, 707, 820, 838, 850, or 911;64, 652, 660, 668, 672, 684, 692, 700, 711, 720, 730, 740, 751, 761, 772, 780, 790, 801, 802, 803, 804, 805, 806, 807, 808, 809, 810, 811, 812, 813, 814, 815, 816, 817, 818, 819, 820, 821, 822, 823, 824, 825, 826, 827, 828, 829, 830, 831, 832, 833, 834, 835, 836, 837, 838, 839, 840, 841, 842, 843, 844 477, 485, 493, 501, 509, 517, 525, 533, 541, 549, 557, 565, 573, 581, 589, 597, 605, 610, 611, 612, 620, 630, 647, 651, 662, 676, 684, 692, 700, 708, 821, 839, or 91; and a CDR2 provided by SEQ ID NO: 4,18, 32, 46, 60, 74, 88, 102, 116, 130, 144, 158, 298, 312, 326, 340, 354,421, 429, 437, 445, 453, 461, 469, 477, 485, 493, 501, 509, 517, 525, 533, 541, 549, 557, 565, 573, 581, 589, 597, 605, CDR3 provided by 613, 621, 629, 637, 645, 653,661, 669, 677, 685, 693, 701, 709, 822, 840, 851, or 913. ;

[0014] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 5, a CDR2 provided by SEQ ID NO: 6, and a CDR3 provided by SEQ ID NO: 7; the light chain variable region comprises a CDR1 provided by SEQ ID NO: 2, a CDR2 provided by SEQ ID NO: 3, and a CDR3 provided by SEQ ID NO: 4.

[0015] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 19, a CDR2 provided by SEQ ID NO: 20, and a CDR3 provided by SEQ ID NO: 21; and the light chain variable region comprises a CDR1 provided by SEQ ID NO: 16, a CDR2 provided by SEQ ID NO: 17, and a CDR3 provided by SEQ ID NO: 18.

[0016] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 33, a CDR2 provided by SEQ ID NO: 34, and a CDR3 provided by SEQ ID NO: 35; and the light chain variable region comprises a CDR1 provided by SEQ ID NO: 30, a CDR2 provided by SEQ ID NO: 31, and a CDR3 provided by SEQ ID NO: 32.

[0017] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 47, a CDR2 provided by SEQ ID NO: 48, and a CDR3 provided by SEQ ID NO: 49; the light chain variable region comprises a CDR1 provided by SEQ ID NO: 44, a CDR2 provided by SEQ ID NO: 45, and a CDR3 provided by SEQ ID NO: 46.

[0018] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 61, a CDR2 provided by SEQ ID NO: 62, and a CDR3 provided by SEQ ID NO: 63; and the light chain variable region comprises a CDR1 provided by SEQ ID NO: 58, a CDR2 provided by SEQ ID NO: 59, and a CDR3 provided by SEQ ID NO: 60.

[0019] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 75, a CDR2 provided by SEQ ID NO: 76, and a CDR3 provided by SEQ ID NO: 77; the light chain variable region comprises a CDR1 provided by SEQ ID NO: 72, a CDR2 provided by SEQ ID NO: 73, and a CDR3 provided by SEQ ID NO: 74.

[0020] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 89, a CDR2 provided by SEQ ID NO: 90, and a CDR3 provided by SEQ ID NO: 91; and the light chain variable region comprises a CDR1 provided by SEQ ID NO: 86, a CDR2 provided by SEQ ID NO: 87, and a CDR3 provided by SEQ ID NO: 88.

[0021] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 103, a CDR2 provided by SEQ ID NO: 104, and a CDR3 provided by SEQ ID NO: 105; and the light chain variable region comprises a CDR1 provided by SEQ ID NO: 100, a CDR2 provided by SEQ ID NO: 101, and a CDR3 provided by SEQ ID NO: 102.

[0022] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 117, a CDR2 provided by SEQ ID NO: 118, and a CDR3 provided by SEQ ID NO: 119; the light chain variable region comprises a CDR1 provided by SEQ ID NO: 114, a CDR2 provided by SEQ ID NO: 115, and a CDR3 provided by SEQ ID NO: 116.

[0023] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 131, a CDR2 provided by SEQ ID NO: 132, and a CDR3 provided by SEQ ID NO: 133; and the light chain variable region comprises a CDR1 provided by SEQ ID NO: 128, a CDR2 provided by SEQ ID NO: 129, and a CDR3 provided by SEQ ID NO: 130.

[0024] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 145, a CDR2 provided by SEQ ID NO: 146, and a CDR3 provided by SEQ ID NO: 147; the light chain variable region comprises a CDR1 provided by SEQ ID NO: 142, a CDR2 provided by SEQ ID NO: 143, and a CDR3 provided by SEQ ID NO: 144.

[0025] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 159, a CDR2 provided by SEQ ID NO: 160, and a CDR3 provided by SEQ ID NO: 161; the light chain variable region comprises a CDR1 provided by SEQ ID NO: 156, a CDR2 provided by SEQ ID NO: 157, and a CDR3 provided by SEQ ID NO: 158.

[0026] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 299, a CDR2 provided by SEQ ID NO: 300, and a CDR3 provided by SEQ ID NO: 301; and the light chain variable region comprises a CDR1 provided by SEQ ID NO: 296, a CDR2 provided by SEQ ID NO: 297, and a CDR3 provided by SEQ ID NO: 298.

[0027] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 313, a CDR2 provided by SEQ ID NO: 314, and a CDR3 provided by SEQ ID NO: 315; and the light chain variable region comprises a CDR1 provided by SEQ ID NO: 310, a CDR2 provided by SEQ ID NO: 311, and a CDR3 provided by SEQ ID NO: 312.

[0028] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 327, a CDR2 provided by SEQ ID NO: 328, and a CDR3 provided by SEQ ID NO: 329; the light chain variable region comprises a CDR1 provided by SEQ ID NO: 324, a CDR2 provided by SEQ ID NO: 325, and a CDR3 provided by SEQ ID NO: 326.

[0029] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 341, a CDR2 provided by SEQ ID NO: 342, and a CDR3 provided by SEQ ID NO: 343; and the light chain variable region comprises a CDR1 provided by SEQ ID NO: 338, a CDR2 provided by SEQ ID NO: 339, and a CDR3 provided by SEQ ID NO: 340.

[0030] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 355, a CDR2 provided by SEQ ID NO: 356, and a CDR3 provided by SEQ ID NO: 357; and the light chain variable region comprises a CDR1 provided by SEQ ID NO: 352, a CDR2 provided by SEQ ID NO: 353, and a CDR3 provided by SEQ ID NO: 354.

[0031] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 423, a CDR2 provided by SEQ ID NO: 424, and a CDR3 provided by SEQ ID NO: 425; and the light chain variable region comprises a CDR1 provided by SEQ ID NO: 418, a CDR2 provided by SEQ ID NO: 419, and a CDR3 provided by SEQ ID NO: 421.

[0032] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 431, a CDR2 provided by SEQ ID NO: 432, and a CDR3 provided by SEQ ID NO: 433; and the light chain variable region comprises a CDR1 provided by SEQ ID NO: 427, a CDR2 provided by SEQ ID NO: 428, and a CDR3 provided by SEQ ID NO: 429.

[0033] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 439, a CDR2 provided by SEQ ID NO: 440, and a CDR3 provided by SEQ ID NO: 441; and the light chain variable region comprises a CDR1 provided by SEQ ID NO: 435, a CDR2 provided by SEQ ID NO: 436, and a CDR3 provided by SEQ ID NO: 437.

[0034] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 447, a CDR2 provided by SEQ ID NO: 448, and a CDR3 provided by SEQ ID NO: 449; and the light chain variable region comprises a CDR1 provided by SEQ ID NO: 443, a CDR2 provided by SEQ ID NO: 444, and a CDR3 provided by SEQ ID NO: 445.

[0035] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 455, a CDR2 provided by SEQ ID NO: 456, and a CDR3 provided by SEQ ID NO: 457; and the light chain variable region comprises a CDR1 provided by SEQ ID NO: 451, a CDR2 provided by SEQ ID NO: 452, and a CDR3 provided by SEQ ID NO: 453.

[0036] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 463, a CDR2 provided by SEQ ID NO: 464, and a CDR3 provided by SEQ ID NO: 465; and the light chain variable region comprises a CDR1 provided by SEQ ID NO: 459, a CDR2 provided by SEQ ID NO: 460, and a CDR3 provided by SEQ ID NO: 461.

[0037] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 471, a CDR2 provided by SEQ ID NO: 472, and a CDR3 provided by SEQ ID NO: 473; and the light chain variable region comprises a CDR1 provided by SEQ ID NO: 467, a CDR2 provided by SEQ ID NO: 468, and a CDR3 provided by SEQ ID NO: 469.

[0038] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 479, a CDR2 provided by SEQ ID NO: 480, and a CDR3 provided by SEQ ID NO: 481; the light chain variable region comprises a CDR1 provided by SEQ ID NO: 479, a CDR2 provided by SEQ ID NO: 480, and a CDR3 provided by SEQ ID NO: 481.

[0039] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 487, a CDR2 provided by SEQ ID NO: 488, and a CDR3 provided by SEQ ID NO: 489; and the light chain variable region comprises a CDR1 provided by SEQ ID NO: 483, a CDR2 provided by SEQ ID NO: 484, and a CDR3 provided by SEQ ID NO: 485.

[0040] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 495, a CDR2 provided by SEQ ID NO: 496, and a CDR3 provided by SEQ ID NO: 497; and the light chain variable region comprises a CDR1 provided by SEQ ID NO: 491, a CDR2 provided by SEQ ID NO: 492, and a CDR3 provided by SEQ ID NO: 493.

[0041] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 503, a CDR2 provided by SEQ ID NO: 504, and a CDR3 provided by SEQ ID NO: 505; and the light chain variable region comprises a CDR1 provided by SEQ ID NO: 499, a CDR2 provided by SEQ ID NO: 500, and a CDR3 provided by SEQ ID NO: 501.

[0042] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 511, a CDR2 provided by SEQ ID NO: 512, and a CDR3 provided by SEQ ID NO: 513; and the light chain variable region comprises a CDR1 provided by SEQ ID NO: 507, a CDR2 provided by SEQ ID NO: 508, and a CDR3 provided by SEQ ID NO: 509.

[0043] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 519, a CDR2 provided by SEQ ID NO: 520, and a CDR3 provided by SEQ ID NO: 521; and the light chain variable region comprises a CDR1 provided by SEQ ID NO: 515, a CDR2 provided by SEQ ID NO: 516, and a CDR3 provided by SEQ ID NO: 517.

[0044] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 527, a CDR2 provided by SEQ ID NO: 528, and a CDR3 provided by SEQ ID NO: 529; the light chain variable region comprises a CDR1 provided by SEQ ID NO: 523, a CDR2 provided by SEQ ID NO: 524, and a CDR3 provided by SEQ ID NO: 525.

[0045] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 535, a CDR2 provided by SEQ ID NO: 536, and a CDR3 provided by SEQ ID NO: 537; and the light chain variable region comprises a CDR1 provided by SEQ ID NO: 531, a CDR2 provided by SEQ ID NO: 532, and a CDR3 provided by SEQ ID NO: 533.

[0046] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 543, a CDR2 provided by SEQ ID NO: 544, and a CDR3 provided by SEQ ID NO: 545; and the light chain variable region comprises a CDR1 provided by SEQ ID NO: 539, a CDR2 provided by SEQ ID NO: 540, and a CDR3 provided by SEQ ID NO: 541.

[0047] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 551, a CDR2 provided by SEQ ID NO: 552, and a CDR3 provided by SEQ ID NO: 553; and the light chain variable region comprises a CDR1 provided by SEQ ID NO: 547, a CDR2 provided by SEQ ID NO: 548, and a CDR3 provided by SEQ ID NO: 549.

[0048] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 559, a CDR2 provided by SEQ ID NO: 560, and a CDR3 provided by SEQ ID NO: 561; and the light chain variable region comprises a CDR1 provided by SEQ ID NO: 555, a CDR2 provided by SEQ ID NO: 556, and a CDR3 provided by SEQ ID NO: 557.

[0049] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 567, a CDR2 provided by SEQ ID NO: 568, and a CDR3 provided by SEQ ID NO: 569; the light chain variable region comprises a CDR1 provided by SEQ ID NO: 563, a CDR2 provided by SEQ ID NO: 564, and a CDR3 provided by SEQ ID NO: 565.

[0050] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 575, a CDR2 provided by SEQ ID NO: 576, and a CDR3 provided by SEQ ID NO: 577; the light chain variable region comprises a CDR1 provided by SEQ ID NO: 571, a CDR2 provided by SEQ ID NO: 572, and a CDR3 provided by SEQ ID NO: 573.

[0051] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 583, a CDR2 provided by SEQ ID NO: 584, and a CDR3 provided by SEQ ID NO: 585; and the light chain variable region comprises a CDR1 provided by SEQ ID NO: 579, a CDR2 provided by SEQ ID NO: 580, and a CDR3 provided by SEQ ID NO: 581.

[0052] In some embodiments, the anti-CLL-1 antibody, or an antigen-binding fragment thereof, comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 591, a CDR2 provided by SEQ ID NO: 592, and a CDR3 provided by SEQ ID NO: 593; the light chain variable region comprises a CDR1 provided by SEQ ID NO: 591, a CDR2 provided by SEQ ID NO: 592, and a CDR3 provided by SEQ ID NO: 593.

[0053] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises: a heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 599, a CDR2 provided by SEQ ID NO: 600, and a CDR3 provided by SEQ ID NO: 601; and a light chain variable region comprising a CDR1 provided by SEQ ID NO: 595, a CDR2 provided by SEQ ID NO: 596, and a CDR3 provided by SEQ ID NO: 597.

[0054] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 607, a CDR2 provided by SEQ ID NO: 608, and a CDR3 provided by SEQ ID NO: 609; and the light chain variable region comprises a CDR1 provided by SEQ ID NO: 603, a CDR2 provided by SEQ ID NO: 604, and a CDR3 provided by SEQ ID NO: 605.

[0055] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 615, a CDR2 provided by SEQ ID NO: 616, and a CDR3 provided by SEQ ID NO: 617; the light chain variable region comprises a CDR1 provided by SEQ ID NO: 611, a CDR2 provided by SEQ ID NO: 612, and a CDR3 provided by SEQ ID NO: 613.

[0056] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 623, a CDR2 provided by SEQ ID NO: 624, and a CDR3 provided by SEQ ID NO: 625; and the light chain variable region comprises a CDR1 provided by SEQ ID NO: 619, a CDR2 provided by SEQ ID NO: 620, and a CDR3 provided by SEQ ID NO: 621.

[0057] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 631, a CDR2 provided by SEQ ID NO: 632, and a CDR3 provided by SEQ ID NO: 633; ​​and the light chain variable region comprises a CDR1 provided by SEQ ID NO: 627, a CDR2 provided by SEQ ID NO: 628, and a CDR3 provided by SEQ ID NO: 629.

[0058] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 639, a CDR2 provided by SEQ ID NO: 640, and a CDR3 provided by SEQ ID NO: 641; and the light chain variable region comprises a CDR1 provided by SEQ ID NO: 635, a CDR2 provided by SEQ ID NO: 636, and a CDR3 provided by SEQ ID NO: 637.

[0059] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 647, a CDR2 provided by SEQ ID NO: 648, and a CDR3 provided by SEQ ID NO: 649; and the light chain variable region comprises a CDR1 provided by SEQ ID NO: 643, a CDR2 provided by SEQ ID NO: 644, and a CDR3 provided by SEQ ID NO: 645.

[0060] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 655, a CDR2 provided by SEQ ID NO: 656, and a CDR3 provided by SEQ ID NO: 657; and the light chain variable region comprises a CDR1 provided by SEQ ID NO: 651, a CDR2 provided by SEQ ID NO: 652, and a CDR3 provided by SEQ ID NO: 653.

[0061] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 663, a CDR2 provided by SEQ ID NO: 664, and a CDR3 provided by SEQ ID NO: 665; and the light chain variable region comprises a CDR1 provided by SEQ ID NO: 659, a CDR2 provided by SEQ ID NO: 659, and a CDR3 provided by SEQ ID NO: 661.

[0062] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 671, a CDR2 provided by SEQ ID NO: 672, and a CDR3 provided by SEQ ID NO: 673; and the light chain variable region comprises a CDR1 provided by SEQ ID NO: 667, a CDR2 provided by SEQ ID NO: 668, and a CDR3 provided by SEQ ID NO: 669.

[0063] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 679, a CDR2 provided by SEQ ID NO: 680, and a CDR3 provided by SEQ ID NO: 681; and the light chain variable region comprises a CDR1 provided by SEQ ID NO: 675, a CDR2 provided by SEQ ID NO: 676, and a CDR3 provided by SEQ ID NO: 677.

[0064] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 687, a CDR2 provided by SEQ ID NO: 688, and a CDR3 provided by SEQ ID NO: 689; the light chain variable region comprises a CDR1 provided by SEQ ID NO: 683, a CDR2 provided by SEQ ID NO: 684, and a CDR3 provided by SEQ ID NO: 685.

[0065] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 695, a CDR2 provided by SEQ ID NO: 696, and a CDR3 provided by SEQ ID NO: 697; the light chain variable region comprises a CDR1 provided by SEQ ID NO: 691, a CDR2 provided by SEQ ID NO: 692, and a CDR3 provided by SEQ ID NO: 693.

[0066] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 703, a CDR2 provided by SEQ ID NO: 704, and a CDR3 provided by SEQ ID NO: 705; and the light chain variable region comprises a CDR1 provided by SEQ ID NO: 699, a CDR2 provided by SEQ ID NO: 700, and a CDR3 provided by SEQ ID NO: 701.

[0067] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 provided by SEQ ID NO: 711, a CDR2 provided by SEQ ID NO: 712, and a CDR3 provided by SEQ ID NO: 713; and the light chain variable region comprises a CDR1 provided by SEQ ID NO: 707, a CDR2 provided by SEQ ID NO: 708, and a CDR3 provided by SEQ ID NO: 709.

[0068] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 823, a CDR2 provided by SEQ ID NO: 824, and a CDR3 provided by SEQ ID NO: 825; and a light chain variable region comprising a CDR1 provided by SEQ ID NO: 820, a CDR2 provided by SEQ ID NO: 821, and a CDR3 provided by SEQ ID NO: 822.

[0069] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 841, a CDR2 provided by SEQ ID NO: 842, and a CDR3 provided by SEQ ID NO: 843; and a light chain variable region comprising a CDR1 provided by SEQ ID NO: 838, a CDR2 provided by SEQ ID NO: 839, and a CDR3 provided by SEQ ID NO: 840.

[0070] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 852, a CDR2 provided by SEQ ID NO: 853, and a CDR3 provided by SEQ ID NO: 854; and a light chain variable region comprising a CDR1 provided by SEQ ID NO: 850, a CDR2 provided by SEQ ID NO: 839, and a CDR3 provided by SEQ ID NO: 851.

[0071] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 914, a CDR2 provided by SEQ ID NO: 915, and a CDR3 provided by SEQ ID NO: 916; and a light chain variable region comprising a CDR1 provided by SEQ ID NO: 911, a CDR2 provided by SEQ ID NO: 912, and a CDR3 provided by SEQ ID NO: 913.

[0072] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises a CDR1 provided by SEQ ID NO: 715, a CDR2 provided by SEQ ID NO: 716, and a CDR3 provided by SEQ ID NO: 717. In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises a CDR1 provided by SEQ ID NO: 719, a CDR2 provided by SEQ ID NO: 720, and a CDR3 provided by SEQ ID NO: 721. In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises a CDR1 provided by SEQ ID NO: 723, a CDR2 provided by SEQ ID NO: 724, and a CDR3 provided by SEQ ID NO: 725. In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises a CDR1 provided by SEQ ID NO: 727, a CDR2 provided by SEQ ID NO: 728, and a CDR3 provided by SEQ ID NO: 729. In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises a CDR1 provided by SEQ ID NO: 731, a CDR2 provided by SEQ ID NO: 732, and a CDR3 provided by SEQ ID NO: 733. In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises a CDR1 provided by SEQ ID NO: 739, a CDR2 provided by SEQ ID NO: 740, and a CDR3 provided by SEQ ID NO: 741.

[0073] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises a CDR1 provided by SEQ ID NO: 743, a CDR2 provided by SEQ ID NO: 744, and a CDR3 provided by SEQ ID NO: 745. In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises a CDR1 provided by SEQ ID NO: 747, a CDR2 provided by SEQ ID NO: 748, and a CDR3 provided by SEQ ID NO: 749. In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises a CDR1 provided by SEQ ID NO: 751, a CDR2 provided by SEQ ID NO: 752, and a CDR3 provided by SEQ ID NO: 753. In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises a CDR1 provided by SEQ ID NO: 755, a CDR2 provided by SEQ ID NO: 756, and a CDR3 provided by SEQ ID NO: 757. In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises a CDR1 provided by SEQ ID NO: 759, a CDR2 provided by SEQ ID NO: 760, and a CDR3 provided by SEQ ID NO: 761. In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises a CDR1 provided by SEQ ID NO: 763, a CDR2 provided by SEQ ID NO: 764, and a CDR3 provided by SEQ ID NO: 765. In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises a CDR1 provided by SEQ ID NO: 767, a CDR2 provided by SEQ ID NO: 768, and a CDR3 provided by SEQ ID NO: 769.

[0074] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises a CDR1 provided by SEQ ID NO: 770, a CDR2 provided by SEQ ID NO: 771, and a CDR3 provided by SEQ ID NO: 772. In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises a CDR1 provided by SEQ ID NO: 775, a CDR2 provided by SEQ ID NO: 776, and a CDR3 provided by SEQ ID NO: 777. In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises a CDR1 provided by SEQ ID NO: 780, a CDR2 provided by SEQ ID NO: 781, and a CDR3 provided by SEQ ID NO: 782. In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises a CDR1 provided by SEQ ID NO: 785, a CDR2 provided by SEQ ID NO: 786, and a CDR3 provided by SEQ ID NO: 777.

[0075] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises a CDR1 provided by SEQ ID NO: 789, a CDR2 provided by SEQ ID NO: 790, and a CDR3 provided by SEQ ID NO: 791.

[0076] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises a CDR1 provided by SEQ ID NO: 794, a CDR2 provided by SEQ ID NO: 795, and a CDR3 provided by SEQ ID NO: 796. In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises a CDR1 provided by SEQ ID NO: 785, a CDR2 provided by SEQ ID NO: 799, and a CDR3 provided by SEQ ID NO: 777. In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises a CDR1 provided by SEQ ID NO: 785, a CDR2 provided by SEQ ID NO: 802, and a CDR3 provided by SEQ ID NO: 777. In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises a CDR1 provided by SEQ ID NO: 789, a CDR2 provided by SEQ ID NO: 805, and a CDR3 provided by SEQ ID NO: 806. In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises a CDR1 provided by SEQ ID NO: 901, a CDR2 provided by SEQ ID NO: 902, and a CDR3 provided by SEQ ID NO: 903. In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises a CDR1 provided by SEQ ID NO: 906, a CDR2 provided by SEQ ID NO: 907, and a CDR3 provided by SEQ ID NO: 908.

[0077] In another aspect, the present disclosure relates to an anti-CLL-1 antibody or an antigen-binding fragment thereof, comprising a VHH comprising a VHH consisting of SEQ ID NO: 5, 19, 33, 47, 61, 75, 89, 103, 117, 131, 145, 159, 170,175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245,250, 255, 260, 265, 271, 276, 281, 286, 291, 299, 313, 327, 341, 355, 423, 431, 439, 447, 455, 463, 471, 479, 487, 495, 503, 511, 519, 527, 535, 543,551, 559, 567, 575, 583, 591, 599, 607, 615, 623, 631, 639, 647, 655, 663,671, 679, 687, 695, 703, 711, 715, 719, 723, 727, 731, 735, 739, 743, 747,751, 755, 759, 763, 767, 6, 20, 34, 48, 62, 76, 90, 104, 118,132, 146, 160, 171, 176, 181, 186, 191, 196, 201, 206, 211, 216, 221, 226, 231, 236, 241, 246, 251, 256, 261, 266, 272, 277, 282, 287, 640, 648, 656, 664, 672, 680, 688, 696, 704, 712, 716, 720, 724, 728, 732,736, 740, 744, 748, 752, 756, 760, 764, 768, 771, 776, 781, 786, 790, 795,799, 802, 805, 824, 842, 853, 897, 902, 907, or 915; and a CDR2 provided by SEQ ID NO:7, 21, 35, 49, 63, 77, 91, 105, 119, 133, 147, 161, 172, 177, 182, 187, 192, 197, 202, 207, 212, 217, 222, 227, 232, 237, 242, 247, 252, 257, 262, 267,273, 278, 283, 288, 293, 301, 315, 329, 343, 357, 425, 433, 441, 449, 457,465, 473, 481, 489, 497, 505, 513, 521, 529, 537, 545, 553, 561, 569, 577,585, 593, 601, 609, 617, 625, 633, 641, 649, 657, 665, 673, 681, 689, 697,705, 713, 717, 721, 725, 729, 733, 737, 741, 745, 749, 753, 757, 761, 765,769, 772, 777, 782, 791, 796, 806, 825, 843, 854, 898, 903, 908, or 916. ,

[0078] In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 170, a CDR2 provided by SEQ ID NO: 171, and a CDR3 provided by SEQ ID NO: 172. In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 175, a CDR2 provided by SEQ ID NO: 176, and a CDR3 provided by SEQ ID NO: 177. In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 180, a CDR2 provided by SEQ ID NO: 181, and a CDR3 provided by SEQ ID NO: 182. In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 185, a CDR2 provided by SEQ ID NO: 186, and a CDR3 provided by SEQ ID NO: 187. In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 190, a CDR2 provided by SEQ ID NO: 191, and a CDR3 provided by SEQ ID NO: 192. In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 195, a CDR2 provided by SEQ ID NO: 196, and a CDR3 provided by SEQ ID NO: 197. In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 200, a CDR2 provided by SEQ ID NO: 201, and a CDR3 provided by SEQ ID NO: 202. In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 205, a CDR2 provided by SEQ ID NO: 206, and a CDR3 provided by SEQ ID NO: 207. In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 210, a CDR2 provided by SEQ ID NO: 211, and a CDR3 provided by SEQ ID NO: 212. In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 215, a CDR2 provided by SEQ ID NO: 216, and a CDR3 provided by SEQ ID NO: 217. In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 220, a CDR2 provided by SEQ ID NO: 221, and a CDR3 provided by SEQ ID NO: 222. In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 225, a CDR2 provided by SEQ ID NO: 226, and a CDR3 provided by SEQ ID NO: 227.In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 230, a CDR2 provided by SEQ ID NO: 231, and a CDR3 provided by SEQ ID NO: 232. In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 235, a CDR2 provided by SEQ ID NO: 236, and a CDR3 provided by SEQ ID NO: 237. In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 240, a CDR2 provided by SEQ ID NO: 241, and a CDR3 provided by SEQ ID NO: 242. In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 245, a CDR2 provided by SEQ ID NO: 246, and a CDR3 provided by SEQ ID NO: 247. In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 250, a CDR2 provided by SEQ ID NO: 251, and a CDR3 provided by SEQ ID NO: 252. In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 255, a CDR2 provided by SEQ ID NO: 256, and a CDR3 provided by SEQ ID NO: 257. In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 260, a CDR2 provided by SEQ ID NO: 261, and a CDR3 provided by SEQ ID NO: 262. In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 265, a CDR2 provided by SEQ ID NO: 266, and a CDR3 provided by SEQ ID NO: 267. In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 271, a CDR2 provided by SEQ ID NO: 272, and a CDR3 provided by SEQ ID NO: 273. In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 276, a CDR2 provided by SEQ ID NO: 277, and a CDR3 provided by SEQ ID NO: 278. In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 281, a CDR2 provided by SEQ ID NO: 282, and a CDR3 provided by SEQ ID NO: 283. In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 286, a CDR2 provided by SEQ ID NO: 287, and a CDR3 provided by SEQ ID NO: 288.In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 291, a CDR2 provided by SEQ ID NO: 292, and a CDR3 provided by SEQ ID NO: 293. In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 715, a CDR2 provided by SEQ ID NO: 716, and a CDR3 provided by SEQ ID NO: 717. In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 719, a CDR2 provided by SEQ ID NO: 720, and a CDR3 provided by SEQ ID NO: 721. In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 723, a CDR2 provided by SEQ ID NO: 724, and a CDR3 provided by SEQ ID NO: 725. In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 727, a CDR2 provided by SEQ ID NO: 728, and a CDR3 provided by SEQ ID NO: 729. In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 731, a CDR2 provided by SEQ ID NO: 732, and a CDR3 provided by SEQ ID NO: 733. In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 735, a CDR2 provided by SEQ ID NO: 736, and a CDR3 provided by SEQ ID NO: 737. In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 739, a CDR2 provided by SEQ ID NO: 740, and a CDR3 provided by SEQ ID NO: 741. In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 743, a CDR2 provided by SEQ ID NO: 744, and a CDR3 provided by SEQ ID NO: 745. In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 747, a CDR2 provided by SEQ ID NO: 748, and a CDR3 provided by SEQ ID NO: 749. In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 751, a CDR2 provided by SEQ ID NO: 752, and a CDR3 provided by SEQ ID NO: 753. In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 755, a CDR2 provided by SEQ ID NO: 756, and a CDR3 provided by SEQ ID NO: 757.In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 759, a CDR2 provided by SEQ ID NO: 760, and a CDR3 provided by SEQ ID NO: 761. In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 763, a CDR2 provided by SEQ ID NO: 764, and a CDR3 provided by SEQ ID NO: 765. In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 767, a CDR2 provided by SEQ ID NO: 768, and a CDR3 provided by SEQ ID NO: 769.

[0079] In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 770, a CDR2 provided by SEQ ID NO: 771, and a CDR3 provided by SEQ ID NO: 772. In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 775, a CDR2 provided by SEQ ID NO: 776, and a CDR3 provided by SEQ ID NO: 777. In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 780, a CDR2 provided by SEQ ID NO: 781, and a CDR3 provided by SEQ ID NO: 782. In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 785, a CDR2 provided by SEQ ID NO: 786, and a CDR3 provided by SEQ ID NO: 777. In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 789, a CDR2 provided by SEQ ID NO: 790, and a CDR3 provided by SEQ ID NO: 791. In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 794, a CDR2 provided by SEQ ID NO: 795, and a CDR3 provided by SEQ ID NO: 796. In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 785, a CDR2 provided by SEQ ID NO: 799, and a CDR3 provided by SEQ ID NO: 777. In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 785, a CDR2 provided by SEQ ID NO: 802, and a CDR3 provided by SEQ ID NO: 777. In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 789, a CDR2 provided by SEQ ID NO: 805, and a CDR3 provided by SEQ ID NO: 806. In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 823, a CDR2 provided by SEQ ID NO: 824, and a CDR3 provided by SEQ ID NO: 825. In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 823, a CDR2 provided by SEQ ID NO: 824, and a CDR3 provided by SEQ ID NO: 825. In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 841, a CDR2 provided by SEQ ID NO: 842, and a CDR3 provided by SEQ ID NO: 843.In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 852, a CDR2 provided by SEQ ID NO: 853, and a CDR3 provided by SEQ ID NO: 854. In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 896, a CDR2 provided by SEQ ID NO: 897, and a CDR3 provided by SEQ ID NO: 898. In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 901, a CDR2 provided by SEQ ID NO: 902, and a CDR3 provided by SEQ ID NO: 903. In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 906, a CDR2 provided by SEQ ID NO: 907, and a CDR3 provided by SEQ ID NO: 908. In some embodiments, the VHH comprises a CDR1 provided by SEQ ID NO: 914, a CDR2 provided by SEQ ID NO: 915, and a CDR3 provided by SEQ ID NO: 916.

[0080] In another aspect, the present disclosure relates to an anti-CLL-1 antibody or an antigen-binding fragment thereof, comprising a VHH comprising the amino acid sequence of SEQ ID NO: 174, 179, 184, 189, 194, 199, 204, 209, 214, 219, 224, 229, 234, 239, 244, 249, 254, 259, 264, 269, 275, 280, 285, 290, 295, 714, 718,722, 726, 730, 734, 738, 742, 746, 750, 754, 758, 762, or 766.

[0081] In another aspect, the present disclosure relates to an anti-CLL-1 antibody or an antigen-binding fragment thereof, comprising a VHH comprising SEQ ID NO: 5-7, 19-21, 33-35, 47-49, 61-63, 75-77, 89-91, 103-105,117-119, 131-133, 145-147, 159-161, 170-172, 175-177, 180-182, 185-187, 190-192, 195-197, 200-202, 205-207, 210-212, 215-217, 220-222, 225-227, 230-232,235-237, 240-242, 245-247, 250-252, 255-257, 260-262, 265-267, 271-273, 276-278, 281-283, 286-288, 291-293, 299-301, 313-315, 327-329, 341-343, 355-357,423-425, 431-433, 439-441, 447-449, 455-457, 463-465, 471-473, 479-481, 487-489, 495-497, 503-505, 511-513, 519-521, 527-529, 535-537, 543-545, 551-553,559-561, 567-569, 575-577, 583-585, 591-593, 599-601, 607-609, 615-617, 623-625, 631-633, 639-641, 647-649, 655-657, 663-665, 671-673, 679-681, 687-689,695-697, 703-705, 711-713, 715-717, 719-821, 723-725, 727-729, 731-733, 735-737, 739-741, 743-745, 747-749, 751-753, 755-757, 759-761, 763-765, 767-772,775-777, 780-782, 785-786, 789-791, 794-796, 799, 802, 805-806, 823-825, 841-843, 852-854, 896-898, 901-903, 906-908,or the CDR sequence of 914-916. ,

[0082] In another aspect, the present disclosure relates to an anti-CLL-1 antibody or an antigen-binding fragment thereof, comprising a VHH comprising SEQ ID NO: 5-7, 19-21, 33-35, 47-49, 61-63, 75-77, 89-91, 103-105,117-119, 131-133, 145-147, 159-161, 170-172, 175-177, 180-182, 185-187, 190-192, 195-197, 200-202, 205-207, 210-212, 215-217, 220-222, 225-227, 230-232,235-237, 240-242, 245-247, 250-252, 255-257, 260-262, 265-267, 271-273, 276-278, 281-283, 286-288, 291-293, 299-301, 313-315, 327-329, 341-343, 355-357,423-425, 431-433, 439-441, 447-449, 455-457, 463-465, 471-473, 479-481, 487-489, 495-497, 503-505, 511-513, 519-521, 527-529, 535-537, 543-545, 551-553,559-561, 567-569, 575-577, 583-585, 591-593, 599-601, 607-609, 615-617, 623-625, 631-633, 639-641, 647-649, 655-657, 663-665, 671-673, 679-681, 687-689,695-697, 703-705, 711-713, 715-717, 719-821, 723-725, 727-729, 731-733, 735-737, 739-741, 743-745, 747-749, 751-753, 755-757, 759-761, 763-765, 767-772,775-777, 780-782, 785-786, 789-791, 794-796, 799, 802, 805-806, 823-825, 841-843, 852-854, 896-898, 901-903, 906-908,or CDR1, CDR2 and CDR3 of 914-916.

[0083] In another aspect, the present disclosure relates to an anti-CLL-1 antibody or an antigen-binding fragment thereof, comprising a VHH comprising SEQ ID NO: 5-7, 19-21, 33-35, 47-49, 61-63, 75-77, 89-91, 103-105,117-119, 131-133, 145-147, 159-161, 170-172, 175-177, 180-182, 185-187, 190-192, 195-197, 200-202, 205-207, 210-212, 215-217, 220-222, 225-227, 230-232,235-237, 240-242, 245-247, 250-252, 255-257, 260-262, 265-267, 271-273, 276-278, 281-283, 286-288, 291-293, 299-301, 313-315, 327-329, 341-343, 355-357,423-425, 431-433, 439-441, 447-449, 455-457, 463-465, 471-473, 479-481, 487-489, 495-497, 503-505, 511-513, 519-521, 527-529, 535-537, 543-545, 551-553,559-561, 567-569, 575-577, 583-585, 591-593, 599-601, 607-609, 615-617, 623-625, 631-633, 639-641, 647-649, 655-657, 663-665, 671-673, 679-681, 687-689,695-697, 703-705, 711-713, 715-717, 719-821, 723-725, 727-729, 731-733, 735-737, 739-741, 743-745, 747-749, 751-753, 755-757, 759-761, 763-765, 767-772,775-777, 780-782, 785-786, 789-791, 794-796, 799, 802, 805-806, 823-825, 841-843, 852-854, 896-898, 901-903, 906-908,or at least one CDR (e.g., CDR1, CDR2, and / or CDR3) of 914-916. ,

[0084] In another aspect, the present disclosure relates to an anti-CLL-1 antibody or antigen-binding fragment thereof, comprising a VHH comprising the same sequence as SEQ ID NO: 5-7, 19-21, 33-35, 47-49, 61-63, 75-77, 89-91, 103-105,117-119, 131-133, 145-147, 159-161, 170-172, 175-177, 180-182, 185-187, 190-192, 195-197, 200-202, 205-207, 210-212, 215-217, 220-222, 225-227, 230-232,235-237, 240-242, 245-247, 250-252, 255-257, 260-262, 265-267, 271-273, 276-278, 281-283, 286-288, 291-293, 299-301, 313-315, 327-329, 341-343, 355-357,423-425, 431-433, 439-441, 447-449, 455-457, 463-465, 471-473, 479-481, 487-489, 495-497, 503-505, 511-513, 519-521, 527-529, 535-537, 543-545, 551-553,559-561, 567-569, 575-577, 583-585, 591-593, 599-601, 607-609, 615-617, 623-625, 631-633, 639-641, 647-649, 655-657, 663-665, 671-673, 679-681, 687-689,695-697, 703-705, 711-713, 715-717, 719-821, 723-725, 727-729, 731-733, 735-737, 739-741, 743-745, 747-749, 751-753, 755-757, 759-761, 763-765, 767-772,775-777, 780-782, 785-786, 789-791, 794-796, 799, 802, 805-806, 823-825, 841-843, 852-854, 896-898, 901-903, 906-908,or 914-916 CDRs (e.g., CDR1, CDR2 and / or CDR3) have at least one CDR that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical.

[0085] In some embodiments, the antibody or its antigen binding fragment is a monoclonal antibody or its antigen binding fragment. In some embodiments, the antibody or its antigen binding fragment is a humanized antibody or its antigen binding fragment. In another aspect, the present disclosure relates to an anti-CLL-1 antibody or its antigen binding fragment that competes with the antibody or its antigen binding fragment described herein for binding to CLL-1. In some embodiments, the antibody or its antigen binding fragment comprises a CH2 constant domain and a CH3 constant domain.

[0086] In some embodiments, the antibody or antigen-binding fragment thereof comprises SEQ ID NO: 15, 29, 43, 57, 71, 85, 99, 113, 127, 141, 155, 169, 174, 179, 184, 189, 194, 199, 204, 209, 214, 219, 224, 229, 234, 239, 244, 249, 254, 259, 264, 269, 275, 280, 285, 290, 295, 309, 323, 337, 351, 365, 418, 422, 426, 430, 434, 438, 442, 446,450, 454, 458, 462, 466, 470, 474, 478, 482, 486, 490, 494, 498, 502, 506,510, 514, 518, 522, 526, 530, 534, 538, 542, 546, 550, 554, 558, 562, 566,570, 574, 578, 582, 586, 590, 584, 598, 602, 606, 610, 614, 618, 622, 626,630, 634, 638, 642, 646, 650, 654, 658, 662, 666, 670, 674, 678, 682, 686,690, 694, 698, 702, 706, 710, 714, 718, 722, 726, 730, 734, 738, 742, 746,750, 754, 758, 762, 766, 774, 779, 784, 788, 793, 798, 801, 804, 808, 817,829, 831, 835, 837, 847, 849, 858, An amino acid sequence of 860, 893, 900, 905, 910, or 920.

[0087] In some embodiments, the antibody or antigen-binding fragment thereof is a heavy chain antibody.In some embodiments, the antibody or antigen-binding fragment thereof is a camelid antibody.

[0088] In some embodiments, the antibody is of the IgG1, IgG2, IgG3, or IgG4 type.

[0089] In another aspect, the disclosure relates to a chimeric antigen receptor comprising any one of the antibodies described herein or an antigen-binding fragment thereof.

[0090] In another aspect, the disclosure relates to a cell expressing any one of the chimeric antigen receptors described herein. In some embodiments, the cell is an immune effector cell. In some embodiments, the cell is a lymphocyte. In some embodiments, the cell is a T cell. In some embodiments, the cell is a natural killer (NK) cell.

[0091] In another aspect, the disclosure relates to a pharmaceutical composition comprising any of the antibodies described herein, any of the chimeric antigen receptors described herein, or any of the cells described herein and a pharmaceutically acceptable excipient.

[0092] In another aspect, the disclosure relates to a nucleic acid comprising a nucleic acid sequence encoding any of the antibodies or antigen-binding fragments thereof described herein, or any of the chimeric antigen receptors described herein. In another aspect, the disclosure relates to a vector comprising any of the nucleic acids described herein.

[0093] In another aspect, the disclosure relates to a cell comprising any of the nucleic acids or vectors described herein. In some embodiments, the nucleic acid comprises a polypeptide having the same sequence as SEQ ID NO: 8, 10, 12, 14, 22, 24, 26, 28, 36, 38, 40, 42, 50, 52, 54, 56, 64, 66, 68, 70, 78, 80, 82, 84, 92, 94, 96, 98, 106, 108, 110, 112, 120, 122, 124, 126, 134, 136, 138, 140, 148, 150, 152, 154, 162, 164, 166, 168, 173, 178, 183, 188, 193, 198, 203, 208, 213,218, 223, 228, 233, 238, 243, 248, 253, 258, 263, 268, 274, 279, 284, 289,294, 302, 304, 306, 308, 316, 318, 320, 322, 330, 332, 334, 336, 344, 346,348, 350, 358, 360, 362, 364, 773, 778, 783, 787, 792, 797, 800, 803, 807,826, The sequence of any one of 828, 830, 832, 834, 836, 844, 846, 848, 855, 857, 859, 904, 909, 917, 919, or 921 has a sequence with 95%-99% identity.In some embodiments, the nucleic acid comprises SEQ ID NO: 8, 10, 12, 14, 22, 24, 26, 28, 36, 38, 40, 42, 50, 52, 54, 56, 64, 66, 68, 70, 78, 80, 82, 84, 92, 94, 96, 98, 106, 108, 110, 112, 120, 122,124, 126, 134, 136, 138, 140, 148, 150, 152, 154, 162, 164, 166, 168, 173,178, 183, 188, 193, 198, 203, 208, 213, 218, 223, 228, 233, 238, 243, 248,253, 258, 263, 268, 274, 279, 284, 289, 294, 302, 304, 306, 308, 316, 318,320, 322, 330, 332, 334, 336, 344, 346, 348, 350, 358, 360, 362, 364, 773,778, 783, 787, 792, 797, 800, 803, 807, The sequence of any one of 826, 828, 830, 832, 834, 836, 844,846, 848, 855, 857, 859, 904, 909, 917, 919, or 921.

[0094] In some embodiments, the vector further comprises a promoter sequence, which is a SFFV promoter, an EF1α promoter, a tEF1a promoter, a hPGK promoter, a SFFV promoter, or a MND promoter.

[0095] In some embodiments, the vector is a DNA vector, an RNA vector, a plasmid, a lentiviral vector, an adenoviral vector, or a retroviral vector.

[0096] In some embodiments, the cell is an immune cell. In some embodiments, the immune cell is a T cell, a natural killer (NK) cell, a cytotoxic T lymphocyte (CTL), and a regulatory T cell.

[0097] In another aspect, the disclosure relates to a method of producing any of the antibodies or antigen-binding fragments thereof, the method comprising culturing a cell described herein under conditions suitable for expression of the antibody or antigen-binding fragment thereof.

[0098] In another aspect, the disclosure relates to a method for treating a CLL-1 related disease or condition, the method comprising administering to a subject in need an effective amount of any of the antibodies described herein or their antigen-binding fragments, any of the antibody drug conjugates described herein, or any of the cells described herein. In some embodiments, the CLL-1 related disease or condition is myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). In some embodiments, the method further comprises administering to the subject an effective amount of a chemotherapeutic agent or an oncolytic therapeutic agent.

[0099] In another aspect, the present disclosure relates to a CAR comprising a CLL-1 binding domain, a transmembrane domain, and an intracellular signaling domain, wherein the CLL-1 binding domain comprises a heavy chain variable region and / or a light chain variable region; wherein the transmembrane domain comprises a transmembrane domain of a protein selected from CD8α or CD28; and wherein the intracellular signaling domain comprises a signaling domain of CD3ζ. In some embodiments, the heavy chain variable region and the light chain variable region are connected by a linker. In some embodiments, the CLL-1 binding domain comprises at least one of a single chain variable fragment (scFv), a VH fragment, a VHH fragment, or a VL fragment. In some embodiments, the CLL-1 binding domain is connected to the transmembrane domain via a hinge region. In some embodiments, the hinge region includes a hinge region of a protein selected from CD8α, IgG4, or CD28.

[0100] In some embodiments, CAR also includes one or more costimulatory domains.In some embodiments, one or more costimulatory domains include the signaling domains of 4-1BB and / or CD28.

[0101] In some embodiments, the CLL-1 binding domain includes any of the anti-CLL-1 antibodies described herein, or an antigen-binding fragment thereof.

[0102] In another aspect, the disclosure relates to a method for treating a subject suffering from or at risk of a neoplastic disease or malignancy of the blood associated with CLL-1 expression, the method comprising administering to the subject a therapeutically effective amount of any of the antibodies described herein or their antigen-binding fragments, any of the antibody drug conjugates described herein, or any of the cells described herein. In some embodiments, the neoplastic disease or malignancy of the blood associated with CLL-1 expression is myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). In some embodiments, the method further comprises administering to the subject an effective amount of a chemotherapeutic agent or an oncolytic therapeutic agent.

[0103] In another aspect, the disclosure relates to a method for treating a subject suffering from or at risk of a neoplastic disease or malignancy of the blood associated with CLL-1 expression, the method comprising administering to the subject a therapeutically effective amount of any of the antibodies described herein, its antigen-binding fragment, antibody drug conjugate, chimeric antigen receptor or cell. In some embodiments, the neoplastic disease or malignancy of the blood associated with CLL-1 expression is myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). In some embodiments, the method further comprises administering to the subject an effective amount of a chemotherapeutic agent or an oncolytic therapeutic agent.

[0104] In some embodiments, the method further comprises administering a hematopoietic cell population, wherein the hematopoietic cell is genetically engineered so that the gene encoding CLL-1 targeted by the antigen binding domain is engineered to reduce or eliminate the expression of CLL-1. In some embodiments, immune cells, hematopoietic cells, or both are allogeneic or autologous. In some embodiments, hematopoietic cells are hematopoietic stem cells. In some embodiments, hematopoietic stem cells are from bone marrow cells or peripheral blood mononuclear cells (PBMC). In some embodiments, hematopoietic stem cells are CD34+ / CLL-1-. In some embodiments, hematopoietic cells are prepared by editing endogenous genes encoding CLL-1 to reduce or eliminate the expression of CLL-1. In some embodiments, endogenous genes are edited by CRISPR-Cas9.

[0105] In some embodiments, the subject has or has been diagnosed with a hematopoietic malignancy or premalignancy characterized by expression of CLL-1 on malignant or premalignant cells. In some embodiments, the subject has Hodgkin's lymphoma, non-Hodgkin's lymphoma, leukemia, or multiple myeloma. In some embodiments, the leukemia is acute myeloid leukemia, myelodysplastic syndrome, chronic myeloid leukemia, acute lymphoblastic leukemia, or chronic lymphoblastic leukemia. BRIEF DESCRIPTION OF THE DRAWINGS

[0106] Figures 1A-1E Flow cytometry analysis of the target cell binding ability of CLL-1 antibodies is shown. The cell binding ability of CLL-1 antibodies was analyzed by HL-60 wild-type (WT) cells ( Figure 1A )、U937 cells( Figure 1B ) or HL-60 CLL-1 knockout (KO) control cells ( Figure 1C ) was evaluated by flow cytometry analysis. Figures 1A-1CIn each case, the CLL-1 antibody was compared to the secondary antibody only control (SEC ONLY). The ability of the control anti-hCLL-1 antibody to bind to HL-60 WT (right peak, indicated by asterisks) and HL-60 KO cells (left peak) ( Figure 1D ) was evaluated by flow cytometry. The ability of the control hCLL-1 antibody to bind to U937 cells ( Figure 1E ) were assessed by flow cytometry and show cells stained with labeled primary and secondary antibodies (right peak, indicated by asterisks) versus unstained control cells (left peak).

[0107] Figure 2A and 2B Shown are graphs of flow cytometry analysis of exemplary NFAT-responsive reporter cell lines as described herein. Figure 2A Flow cytometry data of Jurkat cells containing mOrange reporter under the control of the constitutively active E1Fα promoter and mTurquoise reporter (mTurq) under the control of the IL-2 reporter system described herein are shown. Cells were not activated ("-PMA / ion", top row), or activated with phorbol myristate acetate (PMA) and ionomycin ("+PMA / ion", bottom row). The left column of the figure shows cells expressing the mOrange reporter; the middle column shows cells expressing the mTurquoise reporter; and the right column shows cells expressing CD69 (CD69+), an indicator of T cell activation. Figure 2B Flow cytometry data of Jurkat cells containing mTurquoise reporter (mTurq) under the control of the constitutively active E1Fα promoter and mOrange reporter under the control of the IL-2 reporter system described herein are shown. Cells were not activated ("-PMA / ion", top row), or activated with phorbol myristate acetate (PMA) and ionomycin ("+PMA / ion", bottom row). The left column of the figure shows cells expressing the mTurquoise reporter; the middle column shows cells expressing the mOrange reporter; and the right column shows cells expressing CD69 (CD69+), an indicator of T cell activation.

[0108] Figure 3 Shows quantitative Figure 2A and 2BFigure 2 shows a flow cytometric analysis of the cells of the present invention. The y-axis shows the percentage of cells expressing the second reporter (FR2) (under the control of the IL-2 reporter system described herein) based on cells expressing the first reporter (FR1) (under the control of the constitutively active promoter EF1a). Cells were not activated ("-PMA / ion") or activated with phorbol myristate acetate (PMA) and ionomycin ("+PMA / ion"). "EF1a_mOrange_IL-2_mTurq" refers to Jurkat cells containing the mOrange reporter (FR1) under the control of the constitutively active E1Fα promoter and the mTurquoise reporter (mTurq) (FR2) under the control of the IL-2 reporter system described herein. "EF1a_mTurq_IL-2_mOrange" refers to Jurkat cells containing the mTurquoise reporter (FR1) under the control of the constitutively active E1Fα promoter and the mOrange reporter (FR2) under the control of the IL-2 reporter system described herein.

[0109] Figure 4 A summary of biochemical and cell-based assays used to characterize anti-CLL-1 antibodies and conjugates is shown.

[0110] Figure 5A and 5B Shown are the results of enzyme-linked immunosorbent assay (ELSA) analysis of anti-CLL-1 antibody clones. Figure 5A Dose-dependent binding of the indicated anti-CLL-1 antibody clones to biotinylated recombinant CLL-1 is shown. Figure 5B Dose-dependent binding of the indicated anti-CLL-1 conjugates to biotinylated recombinant CLL-1 is shown.

[0111] Figures 6A-6C Quantification of specific binding of the indicated anti-CLL-1 binders calculated from flow cytometric analysis is shown. Fig. 6A Anti-CLL-1 conjugates in contact with HL-60 WT cells are shown. Figure 6B Anti-CLL-1 conjugates in contact with CLL-1 positive U937 cells are shown. Figure 6C Anti-CLL-1 conjugates in contact with CLL-1 negative HEK293 control cells are shown. The dotted line represents the levels obtained from control samples stained with secondary antibody only.

[0112] Figures 7A-7C Shown are multipoint flow cytometric analyses of dose-dependent binding of the indicated anti-CLL-1 binders to HL-60 WT cells expressing CLL-1. Fig. 7ACell surface binding analysis of anti-CLL-1 binders clones 1-6 is shown. Figure 7B Cell surface binding analysis of anti-CLL-1 binders clones 7-12 and 20 VH is shown. Figure 7C Cell surface binding analysis of anti-CLL-1 binder clones 38-42 is shown.

[0113] Fig. 8A and 8B Shown is a bar graph of reciprocal EC50 values ​​calculated by ELISA analysis of binding of the indicated anti-CLL-1 binders to biotinylated recombinant human CLL-1 extracellular domain protein isoforms (CLL1-K244 or CLL1-Q244). For each binder, the left column corresponds to binding to CLL-1 containing lysine at amino acid position 244 (CLL1-K244) and the right column corresponds to binding to CLL-1 containing glutamine at amino acid position 244 (CLL1-Q244). Fig. 8A Results from anti-CLL-1 binders identified based on panning with biotinylated recombinant CLL-1 Q244 are shown. Figure 8B Shown are results from anti-CLL-1 binders identified based on sequential panning with biotinylated recombinant human CLL-1 Q244 and biotinylated recombinant human CLL-1 K244.

[0114] Fig. 9 Shown is a heat map representation of data generated from ELISA analysis of the competitive binding activity of the indicated anti-CLL-1 binders to the extracellular domain of Fc-tagged recombinant CLL-1 protein.

[0115] Figures 10A-10C Biolayer interferometry (BLItz) assay analysis of the binding kinetics of the indicated anti-CLL-1 binders to the biotinylated recombinant CLL-1 protein extracellular domain is shown. Fig. 10A BLItz assay binding analysis graphs for each of the designated CLL-1 antibody conjugates are shown. The binding curves for each of the CLL-1 antibody conjugates at 1 μM are shown. Fig. 10B BLItz assay binding analysis graphs for each of the designated anti-CLL-1 binders are shown. Binding curves for each of the CLL-1 antibody binders at 1 μM are shown. Fig. 10C Shows from Fig. 10A and 10B Quantification of EC50 (nM) values ​​and Ka and Kd values ​​for each anti-CLL-1 binder calculated from the data in.

[0116] Figures 11A-11LResults from binding kinetics and affinity assays of the indicated CLL-1 antibody conjugates to CLL-1 protein using the Octet® platform are shown. Human recombinant CLL-1 protein was used at a concentration of 10 μg / mL, and the conjugates were diluted to 100, 33.33, 11.11, and 3.70 nM for assay. Fig. 12A Anti-CLL-1 binder clone 1 is shown. Fig. 12B Figure 12A shows an anti-CLL-1 binder clone 2. Figure 12C shows an anti-CLL-1 binder clone 3. Figure 12D shows an anti-CLL-1 binder clone 4. Figure 12E shows an anti-CLL-1 binder clone 5. Figure 12F shows an anti-CLL-1 binder clone 6. Figure 12G shows an anti-CLL-1 binder 75. Figure 12H shows an anti-CLL-1 binder clone 8. Figure 12I shows an anti-CLL-1 binder clone 10. Figure 12J shows an anti-CLL-1 binder clone 11. Figure 12K shows an anti-CLL-1 binder clone 12. Figure 12L shows an anti-CLL-1 binder clone 20.

[0117] Fig. 12A and 12B Biochemical characterization of the indicated anti-CLL-1 binders is shown. Fig. 12A The binding affinities of the indicated anti-CLL-1 binders are shown. NB = no binding detected; ND = binding assay not performed. Fig. 12B A summary of the binding characteristics of anti-CLL-1 binders using the indicated assays is shown.

[0118] Figures 13A-13C Shown are the results from flow cytometric analysis of the indicated anti-CLL-1 VH binders with HEK293 cells expressing CLL-1 variants. Fig.13A Binding of the indicated anti-CLL-1 VH binders to HEK293 cells expressing CLL-1 containing lysine at amino acid position 244 (293-CLL1-K244) is shown. Fig. 13B Binding of the indicated anti-CLL-1 VH binders to HEK293 cells expressing CLL-1 containing glutamine at amino acid position 244 (293-CLL1-Q244) is shown. Fig. 13C Binding of the indicated anti-CLL-1 VH binders to CLL-1-empty HEK293 control cells (293-empty) is shown. The dotted line represents the signal from cells stained with secondary antibody only.

[0119] Fig.14 A summary of the binding affinities of the indicated CLL-1 binders to the CLL-1 (K244) or CLL-1 (Q244) protein isoforms is shown.

[0120] Figures 15A and 15B show the CLL-1 specific activation analysis when Jurkat CD4 T cells expressing the specified CLL-1 directed chimeric antigen receptor (CAR) were co-cultured with HL-60 WT target cells evaluated by the IL-2 reporter system (IRS, as described in Figure 2). Figure 15A shows the results of flow cytometry analysis of CD69 and FR2 expression after co-culture of specified CLL-1 CAR-T cells with HL-60 WT cells. The difference percentage (difference %) was calculated by subtracting the CD69 and FR2 expression percentages (background signals) of CLL-1 CAR-T cells co-cultured with HL-60 CLL-1 KO cells from the CD69 and FR2 expression percentages (specific signals) of CLL-1 CAR-T cells co-cultured with HL-60 WT cells. N = 2. For each CLL-1CAR T binder, the points on the left correspond to CD69 expression, and the points on the right correspond to FR2 expression. FIG. 15B shows the results of IncuCyte live cell imaging analysis of FR2 levels from CLL-1 CAR-T cells co-cultured with HL-60 WT cells. N=1.

[0121] Figure 16A-16G shows an analysis of in vitro co-cultures of CLL-1-positive AML cell lines and CLL-1-directed CAR-T cells containing specified CLL-1 conjugates. Figure 16A shows the transduction efficiency of each of the primary T cells of the CLL-1 CAR constructs determined by anti-human IgG (H+L) reactivity determined by flow cytometry. Figure 16B shows the binding of specified CLL-1 CAR-T cells to target cells expressing CLL-1 K244 (K) or CLL-1 Q244 (Q) isotypes determined by flow cytometry. N = 2. Figure 16C shows the changes in the viability of CFSE-labeled HL-60 WT cells or CLL1 KO HL-60 target cells after co-culture with specified CLL-1-directed CAR-T cells. Vitality is normalized to donor-matched untransduced control cells (UTD). N = 2. Figure 16D shows CLL-1 directed CAR-T cell activation based on CD25 and CD69 expression (CD25+CD69+) assessed by flow cytometry after co-culture of CAR-T cells with HL-60 WT cells, HL-60 KO cells, or effector cells alone. N = 2. Figure 16E shows the level of secreted IL-2 produced after co-culture of CLL-1 CAR-T cells with HL-60 WT cells, HL-60 KO cells, or effector cells alone. Figure 16F shows the level of secreted IFN-γ produced after co-culture of CLL-1 CAR-T cells with HL-60 WT cells, HL-60 KO cells, or effector cells alone. Figure 16G shows the level of secreted TNF-α produced after co-culture of CLL-1 CAR-T cells with HL-60 WT cells, HL-60 KO cells, or effector cells alone. For Figures 18E-18G Each of the designated CLL-1 CAR-T cells in the , each column from left to right refers to individual effector cells, CLL1 KO HL60, and WT HL60, respectively.

[0122] Fig.17A -17H shows analysis of in vitro co-cultures containing CLL-1-positive AML cell lines and CLL-1-specific CAR-T cells. Fig.17A The transduction efficiency of primary T cells for each of the CLL-1-specific CAR constructs, as determined by protein L reactivity, is shown. Fig. 17BBinding of the designated CLL-1-specific CAR-T cells to target cells containing CLL-1 K244 (CLL1 K) or CLL-1 Q244 (CLL1 Q) protein isoforms as determined by flow cytometry is shown. N = 2. FIG. 17C shows changes in cell viability of CFSE-labeled HL-60 WT cells or HL-60CLL-1 KO target cells after 24 hours of co-culture with CLL-1-specific CAR-T cells. Viability was normalized to donor-matched UTD control cells. N = 3. FIG. 17D shows changes in cell viability of CFSE-labeled HL-60 WT cells or HL-60CLL-1 KO target cells after 48 hours of co-culture with CLL-1-specific CAR-T cells. Viability was normalized to donor-matched UTD control cells. N = 2. Figure 17E shows the activation of CLL-1-specific CAR-T cells based on CD25 and CD69 expression (CD25+CD69+) assessed by flow cytometry after co-culture of CAR-T cells with HL-60 WT cells, HL-60 CLL-1 KO cells, or effector cells alone (CAR alone). N = 3. Figure 17F shows the levels of secreted IFN-γ cytokines produced after co-culture of CLL-1-specific CAR-T cells with HL-60 WT cells, HL-60 CLL-1 KO cells, or effector cells alone. Figure 17G shows the levels of secreted IL-2 cytokines produced after co-culture of CLL-1-specific CAR-T cells with HL-60 WT cells, HL-60 CLL-1 KO cells, or effector cells alone. Figure 17H ​​shows the levels of secreted TNF-α cytokines produced after co-culture of CLL-1-specific CAR-T cells with HL-60 WT cells, HL-60 CLL-1 KO cells, or effector cells alone. For Figures 19F-19H , N = 1. For each of the designated CLL-1-specific CAR-T cells, each column from left to right refers to WT HL60, CLL1 KO HL60, and effector cells alone, respectively. DETAILED DESCRIPTION

[0123] This disclosure is based in part on the discovery of novel agents that selectively bind to CLL-1. In some embodiments, the agent is an antibody that selectively binds to CLL-1. In some embodiments, the antibody includes a heavy chain variable domain. In some embodiments, the antibody is a single domain antibody. In some embodiments, the antibody comprises a heavy chain variable domain and a light chain variable domain. In some embodiments, the antibody includes a heavy chain variable domain and one or more constant domains. The disclosure also describes a chimeric antigen receptor that selectively binds to CLL-1. The present invention also relates to nucleic acids encoding the antibody or chimeric antigen receptor, methods for producing the antibody or chimeric antigen receptor, and methods for treating malignancies (e.g., acute myeloid leukemia (AML), myelodysplastic syndrome (MDS)) using the antibody or chimeric antigen receptor.

[0124] Antibody

[0125] The term "antibody" is used herein in the broadest sense and encompasses various antibody structures, including but not limited to: monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies) and / or antibody fragments (preferably those fragments that exhibit the desired antigen binding activity). The antibodies described herein can be immunoglobulins, heavy chain antibodies, light chain antibodies, LRR-based antibodies, or other protein scaffolds with antibody-like properties, as well as other immune binding moieties known in the art, including, for example, Fab, Fab', Fab'2, Fab2, Fab3, F(ab')2, Fd, Fv, Feb, scFv, SMIP, double antibodies, three antibodies, four antibodies, micro antibodies, Nanobody® (single domain antibodies), large antibodies, tandab, DVD, BiTe, TandAb, etc., or any combination thereof. In some embodiments, the antibody is a heavy chain antibody. In some embodiments, the antibody is a camelid antibody. In some embodiments, the antibody is a llama antibody. In some embodiments, the antibody is an alpaca antibody. In some embodiments, the antibody is a mouse antibody. In some embodiments, the antibody is a human antibody. In certain embodiments, the antibody is an initial human antibody. In some embodiments, the antibody comprises a heavy chain variable region and one or more constant regions (e.g., CH2 and CH3). In some embodiments, the antibody is a Nanobody®, also referred to as a single domain antibody or "VHH". The subunit structure and three-dimensional configuration of different classes of antibodies are known in the art.

[0126] "Monoclonal antibody" or "mAb" refers to an antibody obtained from a substantially homogeneous antibody population, i.e., the individual antibodies constituting the population are identical and / or bind to the same epitope (e.g., containing naturally occurring mutations or generated during the production of a monoclonal antibody preparation), except for possible variant antibodies, which are usually present in small amounts. Compared to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on the antigen.

[0127] "Antigen binding fragment" refers to a portion of an intact antibody that binds to the antigen to which the intact antibody binds. An antigen binding fragment of an antibody comprises any naturally occurring, enzymatically obtainable, synthetic or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. Exemplary antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2; diabodies; linear antibodies; single-chain antibody molecules (e.g., scFv), single-domain antibody molecules (e.g., only VHH or VH or VL domains); and multispecific antibodies formed by antibody fragments. In some embodiments, the antigen binding fragment of an antibody described herein is an scFv. In some embodiments, the antigen binding fragment of an antibody described herein is only a VHH domain. As with a complete antibody molecule, an antigen binding fragment can be monospecific or multispecific (e.g., bispecific). A multispecific antigen binding fragment of an antibody may include at least two different variable domains, each of which is capable of specifically binding to a separate antigen or a different epitope of the same antigen.

[0128] A "multispecific antibody" refers to an antibody comprising at least two different antigen-binding domains that recognize and specifically bind to at least two different antigens. A "bispecific antibody" is a type of multispecific antibody and refers to an antibody comprising two different antigen-binding domains that recognize and specifically bind to at least two different antigens.

[0129] "Different antigens" may refer to different and / or distinct proteins, polypeptides or molecules; and different and / or distinct epitopes, which may be contained within a protein, polypeptide or another molecule.

[0130] The term "epitope" refers to an antigenic determinant that interacts with a specific antigen binding site in the variable region of an antibody molecule, called a paratope. A single antigen may have more than one epitope. Therefore, different antibodies may bind to different regions of an antigen and may have different biological effects. The term "epitope" also refers to a site to which B cells and / or T cells of an antigen respond. It also refers to the region of the antigen to which an antibody binds. An epitope may be defined as structural or functional. A functional epitope is typically a subset of a structural epitope and has those residues that directly contribute to the affinity of the interaction. An epitope may also be conformational, that is, composed of nonlinear amino acids. In certain embodiments, an epitope may include a determinant grouped as a chemically active surface of a molecule such as an amino acid, a sugar side chain, a phosphoryl group, or a sulfonyl group, and in certain embodiments, may have a specific three-dimensional structural characteristic and / or a specific charge characteristic.

[0131] As used herein, "selectively binds", "selectively binds", "specifically binds", or "specifically binds" with respect to an antigen binding portion (e.g., an antigen binding portion of an antibody) and an antigen target means that the antigen binding portion preferentially binds to the antigen target and does not bind to entities that are not antigen targets. A certain degree of nonspecific binding may occur between the antigen binding portion and non-targets. In some embodiments, the antigen binding portion selectively binds to the antigen target if the binding between the antigen binding portion and the antigen target is greater than 2-fold, greater than 5-fold, greater than 10-fold, or greater than 100-fold compared to the binding of the antigen binding portion to the non-target. In some embodiments, the antigen binding portion selectively binds to the antigen target if the binding affinity is less than about 10 -5 , less than about 10 -6 M, less than about 10 -7 M, less than about 10 -8 M or less than about 10 -9 M, then the antigen binding moiety selectively binds to the antigen target. In some embodiments, the antigen binding moiety selectively binds to the epitope of the antigen target if the binding between the antigen binding moiety and the epitope of the antigen target is greater than 2 times, greater than 5 times, greater than 10 times, or greater than 100 times as compared to the binding of the antigen binding moiety to a non-target or another epitope of the antigen target. In some embodiments, the antigen binding moiety selectively binds to the epitope of the antigen target if the binding affinity is less than about 10 -5 M, less than about 10 -6 M, less than about 10 -7 M, less than about 10 -8 M or less than about 10 -9 M, the antigen binding portion selectively binds to the epitope of the antigen target.

[0132] In some embodiments, antibodies or fragments thereof selectively bind to the same epitope or overlapping epitopes that often cross-compete for binding antigens. Therefore, in some embodiments, the disclosure provides antibodies or fragments thereof that cross-compete with exemplary antibodies or fragments thereof disclosed herein. In some embodiments, "cross-compete (cross-compete, cross-competition)" or "compete (compete, competition)" means antibodies or fragments thereof that compete for the same epitope or binding site on the target. Such competition can be determined by a determination that a reference antibody or fragment thereof prevents or inhibits the specific binding of a test antibody or fragment thereof and vice versa. Many types of competitive binding assays can be used to determine whether a test molecule competes with a reference molecule for binding. Examples of assays that can be employed include solid phase direct or indirect radioimmunoassays (RIA), solid phase direct or indirect enzyme immunoassays (EIA), sandwich competition assays (see, e.g., Stahli et al. Methods in Enzymology (1983) 9:242-253), solid phase direct biotin-avidin EIA (see, e.g., Kirkland et al., J. Immunol. (1986) 137:3614-9), solid phase direct labeling assays, solid phase direct labeling sandwich assays, Luminex (Jia et al. "A novel method of Multiplexed Competitive Antibody Binning for the characterization of monoclonal antibodies" J. Immunological Methods (2004) 288, 91-98) and surface plasmon resonance (Song et al. "Epitope Mapping of Ibalizumab, a Humanized Anti-CD4 Monoclonal Antibody with Anti-HIV-1 Activity in Infected Patients" J. Virol. (2010) 84, 6935-42). In some embodiments, when the competing antibody or fragment thereof is present in excess, it inhibits binding of the reference antibody or fragment thereof to the common antigen by at least 50%, 55%, 60%, 65%, 70%, or 75%. In some cases, binding is inhibited by at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more.

[0133] The antibody can be an immunoglobulin molecule of four polypeptide chains, such as two heavy (H) chains and two light (L) chains. In some embodiments, the light chain is a lambda light chain. In some embodiments, the light chain is a kappa light chain. The heavy chain can include a heavy chain variable domain and a heavy chain constant domain. The heavy chain constant domain can include any one or more of the CH1 region, hinge region, CH2 region, CH3 region, and in some cases CH4 region. The light chain can include a light chain variable domain and a light chain constant domain. The light chain constant domain can include CL.

[0134] The heavy chain variable domain of the heavy chain and the light chain variable domain of the light chain can be further subdivided into variable regions interspersed with more conservative regions called complementary determining regions (CDRs) called framework regions (FRs). In some embodiments, such heavy chain and / or light chain variable domains can each include three CDRs and four framework regions, arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4, one or more of which can be engineered as described herein. The CDRs in the heavy chain are respectively referred to as "CDRH1", "CDRH2" and "CDRH3", and the CDRs in the light chain are respectively referred to as "CDRL1", "CDRL2" and "CDRL3". Alternatively, the CDRs in the heavy chain are respectively referred to as "HC CDR1", "HC CDR2" and "HC CDR3", and the CDRs in the light chain are respectively referred to as "LC CDR1", "LC CDR2" and "LC CDR3".

[0135] There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and some of them can be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant domains corresponding to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively.

[0136] Exemplary Anti-CLL-1 Antibodies

[0137] Provided herein are anti-CLL-1 binders and antigen-binding fragments thereof that selectively bind to CLL-1. In some embodiments, the anti-CLL-1 binders described herein are single-chain variable fragments (scFv) or single-chain antibodies.

[0138] In some embodiments, the conjugate is a single domain antibody. A single domain antibody is an antibody in which the complementary determining region is a part of a single domain polypeptide. Examples include, but are not limited to, heavy chain antibodies, antibodies naturally lacking light chains, single domain antibodies derived from conventional 4-chain antibodies, engineered antibodies, and single domain scaffolds other than those derived from antibodies. Single domain antibodies can be derived from any species, including, but not limited to, mice, humans, camels, llamas, goats, rabbits, and cattle. According to one aspect of the present disclosure, single domain antibodies as used herein are naturally occurring single domain antibodies, referred to as heavy chain antibodies lacking light chains. Such single domain antibodies are disclosed in, for example, International Publication WO 94 / 04678. Such variable domains derived from heavy chain antibodies naturally lacking light chains are referred to herein as "VHH" or "Nanobody®". Such VHH can be derived from camelid species, such as antibodies produced in camels, dromedaries, llamas, llamas, alpacas, and guanacos. Species other than Camelidae may produce heavy chain antibodies that naturally lack light chains; such VHHs are within the scope of the present disclosure. In some embodiments, the antibody is a Nanobody® or "VHH" and comprises a heavy chain variable region. In some embodiments, the antibody comprises a heavy chain variable region and one or more heavy chain constant regions. In some embodiments, the antibody comprises a heavy chain variable region and does not include one or more heavy chain constant regions. In some embodiments, the antibody comprises a heavy chain variable region and does not include a light chain region (a light chain variable region or a light chain constant region).

[0139] The amino acid residues of the VHH domain of Camelidae are numbered according to the general numbering of VH domains given by Kabat et al., "Sequence of proteins of immunological interest," US Public Health Services, NIH (Bethesda, MD), publication number 91-3242 (1991); see also Riechmann et al., J. Immunol. (1999) 231:25-38. According to this numbering, FR1 includes the amino acid residues at positions 1-30, CDR1 includes the amino acid residues at positions 31-35, FR2 includes the amino acids at positions 36-49, CDR2 includes the amino acid residues at positions 50-65, FR3 includes the amino acid residues at positions 66-94, CDR3 includes the amino acid residues at positions 95-102, and FR4 includes the amino acid residues at positions 103-113.

[0140] However, it should be noted that (as is well known in the art for VH and VHH domains) the total number of amino acid residues in each CDR may be different and may not correspond to the total number of amino acid residues indicated by the Kabat numbering (i.e., one or more positions according to the Kabat numbering may not be occupied in the actual sequence, or the actual sequence may contain more amino acid residues than allowed by the Kabat numbering). This means that, in general, the numbering according to Kabat may or may not correspond to the actual number of amino acid residues in the actual sequence.

[0141] Alternative methods for numbering the amino acid residues of a VH domain are known in the art, which methods may also be applied in a similar manner to VHH domains. However, unless otherwise indicated, the numbering according to Kabat will be followed in the present disclosure and applied to VHH domains as described above.

[0142] In some embodiments, the position numbers of amino acid residues can be referenced based on the corresponding amino acid residue in a reference sequence.

[0143] The present disclosure provides antibodies that may include various heavy chains described herein. In some embodiments, the antibody includes two heavy chains and a light chain. In some embodiments, the antibody includes two heavy chains, which may be two identical heavy chains (having the same amino acid sequence) or different heavy chains (having different amino acid sequences). In some embodiments, the antibody includes two heavy chains, which may bind to the same epitope or different epitopes of the target antigen. In some embodiments, the antibody includes two heavy chains, which may bind to epitopes of different target antigens. In some embodiments, the present disclosure encompasses an antibody comprising at least one heavy chain as disclosed herein, at least one heavy chain framework domain as disclosed herein, and / or at least one heavy chain CDR sequence as disclosed herein.

[0144] In some embodiments, the antibodies disclosed herein are homodimer monoclonal antibodies. In some embodiments, the antibodies disclosed herein are heterodimer antibodies. In some embodiments, the antibodies are, for example, typical antibodies or double antibodies, three antibodies, four antibodies, micro antibodies, Nanobody® (single domain antibodies), large antibodies, tandab, DVD, BiTe, scFv, TandAb scFv, Fab, Fab2, Fab3, F(ab')2, etc., or any combination thereof. In some embodiments, the antibody is a heavy chain antibody. In some embodiments, the antibody is a camelid antibody. In some embodiments, the antibody is a llama antibody. In some embodiments, the antibody is an alpaca antibody. In some embodiments, the antibody includes a heavy chain variable region and one or more constant regions. In some embodiments, the antibody is Nanobody®, also referred to as a single domain antibody or "VHH". In some embodiments, the antibody includes one, two or three immunoglobulin constant domains (e.g., selected from CH1, CH2, CH3 and CH4). In some embodiments, the antibody includes one, two or three IgG1 constant domains. In some embodiments, the antibody comprises a CH2 and a CH3 domain. In some embodiments, the antibody comprises a CH fusion. Exemplary IgG1 CH2 and CH3 domains for use in antibodies of the present disclosure are provided below:

[0145] APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAK GQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO: 1)

[0146] In some embodiments, the antibody is a single chain antibody.

[0147] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises SEQ ID NO: 15, 29, 43, 57, 71, 85, 99, 113, 127, 141, 155, 169, 309, 323, 337, 351, 365, 418, 422, 426, 430, 434, 438, 442, 446, 450, 454, 458, 462, 466, 470, 474, 478, 482, 486, 490, 494, 498, 502, 506, 510, 514, 518, 522, 526, 530, 534, 62, 666, 670, 674, 678, 682, 686, 690, 694, 698, 702, 706, 710, 714, 718, 722, 726, 730, 734, 872, 879, 881, 883, 891, 893, 895, 900, 905, 910, 918, or 920.

[0148] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises SEQ ID NO: SEQ ID NO:9, 11, 13, 15, 23, 25, 27, 29, 37, 39, 41, 43, 51, 53, 55, 57, 65, 67, 69, 71, 79, 81, 83, 85, 93, 95, 97, 99, 107, 109, 111, 113, 121, 123, 125, 127,135, 137, 139, 141, 149, 151, 153, 155, 163, 165, 167, 169, 174, 179, 184,189, 194, 199, 204, 209, 214, 219, 224, 229, 234, 239, 244, 249, 254, 259,264, 269, 275, 280, 285, 290, 295, 303, 305, 307, 309, 317, 319, 321, 323,331, 333, 335, 337, 345, 347, 349, 351, 359, 361, 363, 365, 367-368, 418,422, 426, 430, 434, 438, 442, 446, 450, 454, 458, 462, 466, 470, 474, 478,482, 486, 490, 494, 498, 502, 506, 510, 514, 518, 522, 526, 530, 534, 538,542, 546, 550, 554, 558, 562, 566, 570, 574, 578, 582, 586, 590, 594, 598,602, 606, 610, 614, 618, 622, 626, 630, 634, 638, 642, 646, 650, 654, 658,662, 666, 670, 674, 678, 682, 686, 690, 694, 698, 702, 706, 710, 714, 718,722, 726, 730, 734, 738, 742, 746, 750, 754, 758, 762, 766, 774, 779, 784,788, 793, 798, 801, 804, 808, 815, 817, 819, 827, 829, 831, 833,Amino acid sequence of 835, 837,845, 847, 849, 856, 858, 860, 868, 870, 872, 879, 881, 883, 891, 893, 895,900, 905, 910, 918, 920. In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises SEQ ID NO: 15, 29, 43, 57, 71, 85, 99, 113, 127, 141, 155, 169, 309, 323, 337, 351, 365, 418, 422, 426, 430, 434, 438, 442, 446, 450, 454, 458, 462, 466, 470, 474, 478, 482, 486, 490, 494, 498, 502, 506, 510, 514, 518, 522, 526, 530, 534, 62, 666, 670, 674, 678, 682, 686, 690, 694, 698, 702, 706, 710, 714, 718, 722, 726, 730, 862, 866, 874, 879, 881, 883, 891, 893, 895, 900, 905, 910, 918, or 920.

[0149] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises a CDR comprising SEQ ID NO: 2-7, 16-21, 30-35, 44-49, 58-63, 72-77, 86-91, 100-105, 114-119, 128-133,142-147, 156-161, 170-172, 175-177, 180-182, 185-187, 190-192, 195-197, 200-202, 205-207, 210-212, 215-217, 220-222, 225-227, 230-232, 235-237, 240-242,245-247, 250-252, 255-257, 260-262, 265-267, 271-273, 276-278, 281-283, 286-288, 291-293, 296-301, 310-315, 324-329, 338-343, 352-357, 419-421, 423-425,427-429, 431-433, 435-437, 439-441, 443-445, 447-449, 451-453, 455-457, 459-461, 463-465, 467-469, 471-473, 475-477, 479-481, 483-485, 487-489, 491-493,495-497, 499-501, 503-505, 507-509, 511-513, 515-517, 519-521, 523-525, 527-529, 531-533, 535-537, 539-541, 543-545, 547-549, 551-553, 555-557, 559-561,563-565, 567-569, 571-573, 575-577, 579-581, 583-585, 587-589, 591-593, 595-597, 599-601, 603-605, 607-609, 611-613, 615-617, 619-621, 623-625, 627-629,631-633, 635-637, 639-641, 643-645, 647-649, 651-653, 655-657, 659-661, 663-665, 667-669, 671-673, 675-677, 679-681,683-685, 687-689, 691-693, 695-697,699-701, 703-705, 707-709, 711-713, 715-717, 719-721, 723-725, 727-729, 731-733, 735-737, 739-741, 743-745, 747-749, 751-753, 755-757, 759-761, 763-765,767-769, 770-772, 775-777, 780-782, 785-786, 789-791, 794-796, 799, 802, 805-806, 809-813, 820-825, 838-843, 850-854, 861-866, 873-877, 884-889, 896-898,901-903, 906-908, or 911-916o. ,

[0150] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises SEQ ID NO: 5-7, 19-21, 33-35, 47-49, 61-63, 75-77, 89-91, 103-105, 117-119, 131-133, 145-147,159-161, 170-172, 175-177, 180-182, 185-187, 190-192, 195-197, 200-202, 205-207, 210-212, 215-217, 220-222, 225-227, 230-232, 235-237, 240-242, 245-247,250-252, 255-257, 260-262, 265-267, 271-273, 276-278, 281-283, 286-288, 291-293, 299-301, 313-315, 327-329, 341-343, 355-357, 423-425, 431-433, 439-441,447-449, 455-457, 463-465, 471-473, 479-481, 487-489, 495-497, 503-505, 511-513, 519-521, 527-529, 535-537, 543-545, 551-553, 559-561, 567-569, 575-577,583-585, 591-593, 599-601, 607-609, 615-617, 623-625, 631-633, 639-641, 647-649, 655-657, 663-665, 671-673, 679-681, 687-689, 695-697, 703-705, 711-713,715-746, 748-808, 811-813, 816-817, 823-825, 828-829, 834-835, 841-843, 846-847, 852-854, 857-858, 864-866, 869-870, 875-877, 880-881, 887-889, 892-893,896-910, 914-916, or 919-920.In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises SEQ ID NO: 2-4, 16-18, 30-32, 44-46, 58-60, 72-74, 86-88, 100-102, 114-116, 128-130, 142-144, 156-158, 296-298,310-312, 324-326, 338-340, 352-354, 419-421, 427-429, 435-437, 443-445, 451-453, 459-461, 467-469, 475-477, 483-485, 491-493, 61-621, 627-629, 635-637, 643-645, 651-653,659-661, 667-669, 675-677, 683-685, 691-693, 699-701, 707-709, Light chain CDR1, CDR2, and CDR3 encompassed within any of 809-810, 820-822, 838-840, 850-851, 861-863, 873-874, 884-886, or 911-913.

[0151] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises SEQ ID NO: 5-7, 19-21, 33-35, 47-49, 61-63, 75-77, 89-91, 103-105, 117-119, 131-133, 145-147,159-161, 170-172, 175-177, 180-182, 185-187, 190-192, 195-197, 200-202, 205-207, 210-212, 215-217, 220-222, 225-227, 230-232, 235-237, 240-242, 245-247,250-252, 255-257, 260-262, 265-267, 271-273, 276-278, 281-283, 286-288, 291-293, 299-301, 313-315, 327-329, 341-343, 355-357, 423-425, 431-433, 439-441,447-449, 455-457, 463-465, 471-473, 479-481, 487-489, 495-497, 503-505, 511-513, 519-521, 527-529, 535-537, 543-545, 551-553, 559-561, 567-569, 575-577,583-585, 591-593, 599-601, 607-609, 615-617, 623-625, 631-633, 639-641, 647-649, 655-657, 663-665, 671-673, 679-681, 687-689, 695-697, 703-705, 711-713,715-746, 748-808, 811-813, 816-817, 823-825, 828-829, 834-835, 841-843, 846-847, 852-854, 857-858, 864-866, 869-870, 875-877, 880-881, 887-889, 892-893,896-910, 914-916, or 919-920, and a heavy chain CDR1, CDR2, and CDR3 encompassed within any one of SEQ ID NOs: 2-4, 16-18, 30-32, 44-46, 58-60, 72-74, 86-88, 100-102,114-116, 128-130,142-144, 156-158, 296-298, 310-312, 324-326, 338-340, 352-354, 419-421, 427-429, 435-437, 443-445, 451-453, 459-461, 467-469, 475-477, 483-485, 491-493,499-501, 507-509, 515-517, 523-525, 531-533, 539-541, 547-549, 555-557, 563-565, 571-573, 579-581, 587-589, 595-597, 603-605, 611-613, 619-621, 627-629,635-637, 643-645, 651-653, 659-661, 667-669, 675-677, 683-685, 691-693, 699-701, 707-709, 809-810, 820-822, 838-840, 850-851, 861-863, 873-874, 884-886, or the light chain CDR1, CDR2 and CDR3 encompassed within any one of 911-913.

[0152] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises SEQ ID NO: 2-7, 16-21, 30-35, 44-49, 58-63, 72-77, 86-91, 100,-105, 114-119, 128-133, 142-147,156-161, 170-172, 175-177, 180-182, 185-187, 190-192, 195-197, 200-202, 205-207, 210-212, 215-217, 220-222, 225-227, 230-232, 235-237, 240-242, 245-247,250-252, 255-257, 260-262, 265-267, 271-273, 276-278, 281-283, 286-288, 291-293, 296-301, 310-315, 324-329, 338-343, 352-357, 419-421, 423-425, 427-429,431-433, 435-437, 439-441, 443-445, 447-449, 451-453, 455-457, 459-461, 463-465, 467-469, 471-473, 475-477, 479-481, 483-485, 487-489, 491-493, 495-497,499-501, 503-505, 507-509, 511-513, 515-517, 519-521, 523-525, 527-529, 531-533, 535-537, 539-541, 543-545, 547-549, 551-553, 555-557, 559-561, 563-565,567-569, 571-573, 651-653, 655-657, 659-661, 663-665, 667-669, 671-673, 675-677, 679-681, 683-685,687-689, 691-693, 695-697, 699-701,703-705, 707-709, 711-713, 715-717, 719-721, 723-725, 727-729, 731-733, 735-737, 739-741, 743-745, 747-749, 751-753, 755-757, 759-761, 763-765, 767-769,770-772, 775-777, 780-782, 785-786, 789-791, 794-796, 799, at least one CDR (e.g., CDR1, CDR2, and / or CDR3) of any one of 802, 805-806, 809-813, 820-825, 838-843, 850-854, 861-866, 873-877, 884-889, 896-898, 901-903,906-908, or 911-916. ,

[0153] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises SEQ ID NO: 2-7, 16-21, 30-35, 44-49, 58-63, 72-77, 86-91, 100,-105, 114-119, 128-133, 142-147,156-161, 170-172, 175-177, 180-182, 185-187, 190-192, 195-197, 200-202, 205-207, 210-212, 215-217, 220-222, 225-227, 230-232, 235-237, 240-242, 245-247,250-252, 255-257, 260-262, 265-267, 271-273, 276-278, 281-283, 286-288, 291-293, 296-301, 310-315, 324-329, 338-343, 352-357, 419-421, 423-425, 427-429,431-433, 435-437, 439-441, 443-445, 447-449, 451-453, 455-457, 459-461, 463-465, 467-469, 471-473, 475-477, 479-481, 483-485, 487-489, 491-493, 495-497,499-501, 503-505, 507-509, 511-513, 515-517, 519-521, 523-525, 527-529, 531-533, 535-537, 539-541, 543-545, 547-549, 551-553, 555-557, 559-561, 563-565,567-569, 571-573, 651-653, 655-657, 659-661, 663-665, 667-669, 671-673, 675-677, 679-681, 683-685,687-689, 691-693, 695-697, 699-701,703-705, 707-709, 711-713, 715-717, 719-721, 723-725, 727-729, 731-733, 735-737, 739-741, 743-745, 747-749, 751-753, 755-757, 759-761, 763-765, 767-769,770-772, 775-777, 780-782, 785-786, 789-791, 794-796, 799, two CDRs (e.g., CDR1, CDR2, and / or CDR3) of any one of 802, 805-806, 809-813, 820-825, 838-843, 850-854, 861-866, 873-877, 884-889, 896-898, 901-903,906-908, or 911-916. ,

[0154] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises SEQ ID NO: 2-7, 16-21, 30-35, 44-49, 58-63, 72-77, 86-91, 100,-105, 114-119, 128-133, 142-147,156-161, 170-172, 175-177, 180-182, 185-187, 190-192, 195-197, 200-202, 205-207, 210-212, 215-217, 220-222, 225-227, 230-232, 235-237, 240-242, 245-247,250-252, 255-257, 260-262, 265-267, 271-273, 276-278, 281-283, 286-288, 291-293, 296-301, 310-315, 324-329, 338-343, 352-357, 419-421, 423-425, 427-429,431-433, 435-437, 439-441, 443-445, 447-449, 451-453, 455-457, 459-461, 463-465, 467-469, 471-473, 475-477, 479-481, 483-485, 487-489, 491-493, 495-497,499-501, 503-505, 507-509, 511-513, 515-517, 519-521, 523-525, 527-529, 531-533, 535-537, 539-541, 543-545, 547-549, 551-553, 555-557, 559-561, 563-565,567-569, 571-573, 651-653, 655-657, 659-661, 663-665, 667-669, 671-673, 675-677, 679-681, 683-685,687-689, 691-693, 695-697, 699-701,703-705, 707-709, 711-713, 715-717, 719-721, 723-725, 727-729, 731-733, 735-737, 739-741, 743-745, 747-749, 751-753, 755-757, 759-761, 763-765, 767-769,770-772, 775-777, 780-782, 785-786, 789-791, 794-796, 799, three CDRs (e.g., CDR1, CDR2, and / or CDR3) of any one of 802, 805-806, 809-813, 820-825, 838-843, 850-854, 861-866, 873-877, 884-889, 896-898, 901-903, 906-908, or 911-916. ,

[0155] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises SEQ ID NO: 2-7, 16-21, 30-35, 44-49, 58-63, 72-77, 86-91, 100,-105, 114-119, 128-133, 142-147,156-161, 170-172, 175-177, 180-182, 185-187, 190-192, 195-197, 200-202, 205-207, 210-212, 215-217, 220-222, 225-227, 230-232, 235-237, 240-242, 245-247,250-252, 255-257, 260-262, 265-267, 271-273, 276-278, 281-283, 286-288, 291-293, 296-301, 310-315, 324-329, 338-343, 352-357, 419-421, 423-425, 427-429,431-433, 435-437, 439-441, 443-445, 447-449, 451-453, 455-457, 459-461, 463-465, 467-469, 471-473, 475-477, 479-481, 483-485, 487-489, 491-493, 495-497,499-501, 503-505, 507-509, 511-513, 515-517, 519-521, 523-525, 527-529, 531-533, 535-537, 539-541, 543-545, 547-549, 551-553, 555-557, 559-561, 563-565,567-569, 571-573, 651-653, 655-657, 659-661, 663-665, 667-669, 671-673, 675-677, 679-681, 683-685,687-689, 691-693, 695-697, 699-701,703-705, 707-709, 711-713, 715-717, 719-721, 723-725, 727-729, 731-733, 735-737, 739-741, 743-745, 747-749, 751-753, 755-757, 759-761, 763-765, 767-769,770-772, 775-777, 780-782, 785-786, 789-791, 794-796, 799, four CDRs (e.g., CDR1, CDR2, and / or CDR3) of any one of 802, 805-806, 809-813, 820-825, 838-843, 850-854, 861-866, 873-877, 884-889, 896-898, 901-903,906-908, or 911-916. ,

[0156] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises SEQ ID NO: 2-7, 16-21, 30-35, 44-49, 58-63, 72-77, 86-91, 100,-105, 114-119, 128-133, 142-147,156-161, 170-172, 175-177, 180-182, 185-187, 190-192, 195-197, 200-202, 205-207, 210-212, 215-217, 220-222, 225-227, 230-232, 235-237, 240-242, 245-247,250-252, 255-257, 260-262, 265-267, 271-273, 276-278, 281-283, 286-288, 291-293, 296-301, 310-315, 324-329, 338-343, 352-357, 419-421, 423-425, 427-429,431-433, 435-437, 439-441, 443-445, 447-449, 451-453, 455-457, 459-461, 463-465, 467-469, 471-473, 475-477, 479-481, 483-485, 487-489, 491-493, 495-497,499-501, 503-505, 507-509, 511-513, 515-517, 519-521, 523-525, 527-529, 531-533, 535-537, 539-541, 543-545, 547-549, 551-553, 555-557, 559-561, 563-565,567-569, 571-573, 651-653, 655-657, 659-661, 663-665, 667-669, 671-673, 675-677, 679-681, 683-685,687-689, 691-693, 695-697, 699-701,703-705, 707-709, 711-713, 715-717, 719-721, 723-725, 727-729, 731-733, 735-737, 739-741, 743-745, 747-749, 751-753, 755-757, 759-761, 763-765, 767-769,770-772, 775-777, 780-782, 785-786, 789-791, 794-796, 799, five CDRs (e.g., CDR1, CDR2, and / or CDR3) of any one of 802, 805-806, 809-813, 820-825, 838-843, 850-854, 861-866, 873-877, 884-889, 896-898, 901-903,906-908, or 911-916. ,

[0157] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises SEQ ID NO: 2-7, 16-21, 30-35, 44-49, 58-63, 72-77, 86-91, 100,-105, 114-119, 128-133, 142-147,156-161, 170-172, 175-177, 180-182, 185-187, 190-192, 195-197, 200-202, 205-207, 210-212, 215-217, 220-222, 225-227, 230-232, 235-237, 240-242, 245-247,250-252, 255-257, 260-262, 265-267, 271-273, 276-278, 281-283, 286-288, 291-293, 296-301, 310-315, 324-329, 338-343, 352-357, 419-421, 423-425, 427-429,431-433, 435-437, 439-441, 443-445, 447-449, 451-453, 455-457, 459-461, 463-465, 467-469, 471-473, 475-477, 479-481, 483-485, 487-489, 491-493, 495-497,499-501, 503-505, 507-509, 511-513, 515-517, 519-521, 523-525, 527-529, 531-533, 535-537, 539-541, 543-545, 547-549, 551-553, 555-557, 559-561, 563-565,567-569, 571-573, 651-653, 655-657, 659-661, 663-665, 667-669, 671-673, 675-677, 679-681, 683-685,687-689, 691-693, 695-697, 699-701,703-705, 707-709, 711-713, 715-717, 719-721, 723-725, 727-729, 731-733, 735-737, 739-741, 743-745, 747-749, 751-753, 755-757, 759-761, 763-765, 767-769,770-772, 775-777, 780-782, 785-786, 789-791, 794-796, 799, six CDRs (e.g., CDR1, CDR2, and / or CDR3) of any one of 802, 805-806, 809-813, 820-825, 838-843, 850-854, 861-866, 873-877, 884-889, 896-898, 901-903,906-908, or 911-916. ,

[0158] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises an antibody that is identical to SEQ ID NO: 2-7, 16-21, 30-35, 44-49, 58-63, 72-77, 86-91, 100,-105, 114-119, 128-133, 142-147,156-161, 170-172, 175-177, 180-182, 185-187, 190-192, 195-197, 200-202, 205-207, 210-212, 215-217, 220-222, 225-227, 230-232, 235-237, 240-242, 245-247,250-252, 255-257, 260-262, 265-267, 271-273, 276-278, 281-283, 286-288, 291-293, 296-301, 310-315, 324-329, 338-343, 352-357, 419-421, 423-425, 427-429,431-433, 435-437, 439-441, 443-445, 447-449, 451-453, 455-457, 459-461, 463-465, 467-469, 471-473, 475-477, 479-481, 483-485, 487-489, 491-493, 495-497,499-501, 503-505, 507-509, 511-513, 515-517, 519-521, 523-525, 527-529, 531-533, 535-537, 539-541, 543-545, 547-549, 551-553, 555-557, 559-561, 563-565,567-569, 61-613, 615-617, 619-621, 623-625, 627-629, 631-633,635-637, 639-641, 643-645, 647-649, 651-653, 655-657, 659-661, 663-665, 667-669, 671-673, 675-677, 679-681, 683-685,687-689, 691-693, 695-697, 699-701,703-705, 707-709, 711-713, 715-717, 719-721, 723-725, 727-729, 731-733, 735-737, 739-741, 743-745, 747-749, 751-753, 755-757, 759-761, 763-765, 767-769,770-772, 775-777, 780-782, 785-786, 789-791, 794-796, 799, 802, 805-806, 809-813, 820-825, 838-843, 850-854, 861-866, 873-877, 884-889, 896-898, 901-903,906-908, or 911-916 CDRs (e.g., CDR1, CDR2, and / or CDR3) having at least one CDR that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or 100% identical.

[0159] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises an antibody that is identical to SEQ ID NO: 15, 29, 43, 57, 71, 85, 99, 113, 127, 141, 155, 169, 309, 323, 337, 351, 365, 418, 422, 426, 430, 434, 438, 442, 446, 450, 454, 458, 462, 466, 470, 474, 478, 482, 486, 490, 494, 498, 502, 506, 510, 514, 518, 522, 526, 530, 534, 62, 666, 670, 674, 678, 682, 686, 690, 694, 698, 702, 706, 710, 714, 718, 722, 726, 730, 734, 738, 742, 746, 750, 754, 758, 762, 766, 774, 779, 784,788, 793, 798, 801, 804, 808, 815, 817, 819, 827, 829, 831, 833, 835, 837,845, 847, 849, 856, 858, 860, 868, 870, 872, 879, 881, 883, 891, 893, 895,900, 905, 910, 918, or 920. -197, 200-202, 205-207, 210-212, 215-217, 220-222, 225-227, 230-232, 231-233, 232-234, 233-235, 236-237, 238-239, 240-241, 241-242, 243-243, 244-244, 245-245, 246-247, 248-249, 250-251, 252-252, 253-253, 254-254, 256-256, 257-257, 258-258, 259-260, 261-261, 262-262, 263-263, 264-265235-237, 240-242, 245-247, 250-252, 255-257, 260-262, 265-267, 271-273,276-278, 281-283, 286-288, 291-293, 296-301, 310-315, 324-329, 338-343, 352-357, 419-421, 423-425, 427-429, 431-433, 435-437, 439-441, 443-445, 447-449,451-453, 455-457, 459-461, 463-465, 467-469, 471-473, 475-477, 479-481, 483-485, 487-489, 491-493, 495-497, 499-501, 503-505, 507-509, 511-513, 515-517,519-521, 523-525, 527-529, 531-533, 535-537, 539-541, 543-545, 547-549, 551-553, 555-557, 559-561, 563-565, 567-569, 571-573, 575-577, 579-581, 583-585,587-589, 591-593, 595-597, 599-601, 603-605, 607-609, 611-613, 615-617, 619-621, 623-625, 627-629, 631-633, 635-637, 639-641, 643-645, 647-649, 651-653,655-657, 659-661, 663-665, 667-669, 671-673, 675-677, 679-681, 683-685, 687-689, 691-693, 695-697, 699-701, 703-705, 707-709, 711-713, 715-717, 719-721,723-725, 727-729, 731-733, 735-737, 739-741, 743-745, 747-749, 751-753, 755-757, 759-761, 763-765, 767-769, 770-772, 775-777, 780-782, 785-786, 789-791,794-796, 799,at least one CDR of any one of 802, 805-806, 809-813, 820-825, 838-843, 850-854, 861-866, 873-877, 884-889, 896-898, 901-903, 906-908, or 911-916.

[0160] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises an antibody that is identical to SEQ ID NO: 2-7, 16-21, 30-35, 44-49, 58-63, 72-77, 86-91, 100,-105, 114-119, 128-133, 142-147,156-161, 170-172, 175-177, 180-182, 185-187, 190-192, 195-197, 200-202, 205-207, 210-212, 215-217, 220-222, 225-227, 230-232, 235-237, 240-242, 245-247,250-252, 255-257, 260-262, 265-267, 271-273, 276-278, 281-283, 286-288, 291-293, 296-301, 310-315, 324-329, 338-343, 352-357, 419-421, 423-425, 427-429,431-433, 435-437, 439-441, 443-445, 447-449, 451-453, 455-457, 459-461, 463-465, 467-469, 471-473, 475-477, 479-481, 483-485, 487-489, 491-493, 495-497,499-501, 503-505, 507-509, 511-513, 515-517, 519-521, 523-525, 527-529, 531-533, 535-537, 539-541, 543-545, 547-549, 551-553, 555-557, 559-561, 563-565,567-569, 61-613, 615-617, 619-621, 623-625, 627-629, 631-633,635-637, 639-641, 643-645, 647-649, 651-653, 655-657, 659-661, 663-665, 667-669, 671-673, 675-677, 679-681, 683-685,687-689, 691-693, 695-697, 699-701,703-705, 707-709, 711-713, 715-717, 719-721, 723-725, 727-729, 731-733, 735-737, 739-741, 743-745, 747-749, 751-753, 755-757, 759-761, 763-765, 767-769,770-772, 775-777, 780-782, 785-786, 789-791, 794-796, 799, 802, 805-806, 809-813, 820-825, 838-843, 850-854, 861-866, 873-877, 884-889, 896-898, 901-903, 906-908, or 911-916 have at least one CDR that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9% or 100% identical.

[0161] In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises at least one CDR corresponding to SEQ ID NO: 2-7, 16-21, 30-35, 44-49, 58-63, 72-77, 86-91, 100,-105, 114-119, 128-133, 142-147, 156-161, 170-172, 175-177, 180-182, 185-187, 190-192,195-197, 200-202, 205-207, 210-212, 215-217, 220-222, 225-227, 230-232, 235-237, 240-242, 245-247, 250-252, 255-257, 260-262, 265-267, 271-273, 276-278,281-283, 286-288, 291-293, 296-301, 310-315, 324-329, 338-343, 352-357, 419-421, 423-425, 427-429, 431-433, 435-437, 439-441, 443-445, 447-449, 451-453,455-457, 459-461, 463-465, 467-469, 471-473, 475-477, 479-481, 483-485, 487-489, 491-493, 495-497, 499-501, 503-505, 507-509, 511-513, 515-517, 519-521,523-525, 527-529, 531-533, 535-537, 539-541, 543-545, 547-549, 551-553, 555-557, 559-561, 563-565, 567-569, 571-573, 575-577, 579-581, 583-585, 587-589,591-593, 595-597, 599-601, 603-605, 607-609, 611-613, 615-617, 619-621, 623-625, 627-629, 631-633, 635-637, 639-641, 643-645, 647-649, 651-653, 655-657,659-661, 663-665, 667-669, 671-673, 675-677,679-681, 683-685, 687-689, 691-693, 695-697, 699-701, 703-705, 707-709, 711-713, 715-717, 719-721, 723-725,727-729, 731-733, 735-737, 739-741, 743-745, 747-749, 751-753, 755-757, 759-761, 763-765, 767-769, 770-772, 775-777, 780-782, 785-786, Any of the CDRs (e.g., CDR1, CDR2, and / or CDR3) provided by 789-791, 794-796,799, 802, 805-806, 809-813, 820-825, 838-843, 850-854, 861-866, 873-877, 884-889, 896-898, 901-903, 906-908, or 911-916 has one or more (e.g., 1, 2, 3, 4, 5 or more) additions, deletions, or substitutions.

[0162] The present disclosure particularly provides an anti-CLL-1 antibody or antigen-binding fragment thereof comprising a VHH. In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises a VHH comprising SEQ ID NO: 174, 179, 184, 189, 194, 199, 204, 209, 214, 219, 224, 229, 234, 239, 244, 249, 254, 259, 264, 269, 275, 280, 285, 290, 295, 714, 718, 722, 726, 730, 734, 738, 742, 746, 750, 754, 758, 762, 766 774, 779, 784, 788, 793, The amino acid sequence of 798, 801, 804, 808,817, 829, 835, 847, 858, 870, 881, 893, 900, 905, 910, or 920. In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises a VHH comprising SEQ ID NO: 5-7, 19-21, 33-35, 47-49, 61-63, 75-77, 89-91, 103-105, 117-119, 131-133, 145-147, 159-161, 170-172, 175-177, 180-182, 185-187, 190-192, 195-197, 200-202, 205-207, 210-212, 215-217, 220-222, 225-227, 230-232, 235-237, 240-242, 245-247,250-252, 255-257, 260-262, 265-267, 271-273, 276-278, 281-283, 286-288, 291-293, 299-301, 313-315, 327-329, 341-343, 355-357, 423-425, 431-433, 439-441,447-449, 455-457, 463-465, 471-473, 479-481, 487-489, 495-497, 503-505, 511-513, 519-521, 527-529, 535-537, 543-545, 551-553, 559-561, 567-569, 575-577,583-585, 591-593, 599-601,607-609, 615-617, 623-625, 631-633, 639-641, 647-649, 655-657, 663-665, 671-673, 679-681, 687-689, 695-697, 703-705, 711-713,715-717, 719-821, 723-725, 727-729, 731-733, 735-737, 739-741, 743-745, 747-749, 751-753, 755-757, 759-761, 763-765, The CDR sequences provided by any one of 767-769, 770-772, 775-777, 780-782,785-786, 789-791, 794-796, 799, 802, 805-806, 809-813, 820-825, 838-843, 850-854, 861-866, 873-877, 884-889, 896-898, 901-903, 906-908, or 911-916. In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises a VHH comprising SEQ ID NO: 5-7, 19-21, 33-35, 47-49, 61-63, 75-77, 89-91, 103-105, 117-119,131-133, 145-147, 159-161, 170-172, 175-177, 180-182, 185-187, 190-192, 195-197, 200-202, 205-207, 210-212, 215-217, 220-222, 225-227, 230-232, 235-237,240-242, 245-247, 250-252, 255-257, 260-262, 265-267, 271-273, 276-278, 281-283, 286-288, 291-293, 299-301, 313-315, 327-329, 341-343, 355-357, 423-425,431-433, 439-441, 447-449, 455-457, 463-465, 471-473, 479-481, 487-489, 495-497, 503-505, 511-513, 519-521, 527-529, 535-537, 543-545, 551-553,559-561,567-569, 575-577, 583-585, 591-593, 599-601, 607-609, 615-617, 623-625, 631-633, 639-641, 647-649, 655-657, 663-665, 671-673, 679-681, 687-689, 695-697,703-705, 711-713, 715-717, 719-821, 723-725, 727-729, 731-733, 735-737, 739-741, 743-745, 747-749, 751-753, 755-757, 759-761, 763-765, 767-769, 770-772,775-777, 780-782, 785-786, 789-791, 794-796, 799, 802, 805-806, 809-813, 820-825, 838-843, 850-854, 861-866, 873-877, 884-889, 896-898, 901-903, CDR1, CDR2 and CDR3 encompassed within any of 906-908, or 911-916. In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises a VHH comprising SEQ ID NO: 5-7, 19-21, 33-35, 47-49, 61-63,75-77, 89-91, 103-105, 117-119, 131-133, 145-147, 159-161, 170-172, 175-177,180-182, 185-187, 190-192, 195-197, 200-202, 205-207, 210-212, 215-217, 220-222, 225-227, 230-232, 235-237, 240-242, 245-247, 250-252, 255-257, 260-262,265-267, 271-273, 276-278, 281-283, 286-288, 291-293, 299-301, 313-315, 327-329, 341-343, 355-357, 423-425, 431-433, 439-441, 447-449, 455-457, 463-465,471-473, 479-481, 487-489, 495-497,503-505, 511-513, 519-521, 527-529, 535-537, 543-545, 551-553, 559-561, 567-569, 575-577, 583-585, 591-593, 599-601,607-609, 615-617, 623-625, 631-633, 639-641, 647-649, 655-657, 663-665, 671-673, 679-681, 687-689, 695-697, 703-705, 711-713, 715-717, 719-821, 723-725,727-729, 731-733, 735-737, 739-741, 743-745, 747-749, 751-753, 755-757, 759-761, 763-765, 767-769, 770-772, 775-777, 780-782, 785-786, 789-791, 794-796,799, 802, 805-806, 809-813, 820-825, 838-843, 850-854, 861-866, At least one CDR (e.g., CDR1, CDR2 and / or CDR3) provided by any of 873-877, 884-889, 896-898, 901-903, 906-908, or 911-916. In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises a VHH comprising a VHH comprising the same sequence as SEQ ID NO: 5-7, 19-21, 33-35, 47-49, 61-63, 75-77, 89-91, 103-105,117-119, 131-133, 145-147, 159-161, 170-172, 175-177, 180-182, 185-187, 190-192, 195-197, 200-202, 205-207, 210-212, 215-217, 220-222, 225-227, 230-232, 235-237, 240-242, 245-247, 250-252, 255-257, 260-262, 265-267, 271-273, 276-278, 281-283, 286-288, 291-293, 299-301, 313-315, 327-329, 341-343, 355-357,423-425,431-433, 439-441, 447-449, 455-457, 463-465, 471-473, 479-481, 487-489, 495-497, 503-505, 511-513, 519-521, 527-529, 535-537, 543-545, 551-553,559-561, 567-569, 575-577, 583-585, 591-593, 599-601, 607-609, 615-617, 623-625, 631-633, 639-641, 647-649, 655-657, 663-665, 671-673, 679-681, 687-689,695-697, 703-705, 711-713, 715-717, 719-821, 723-725, 727-729, 731-733, 735-737, 739-741, 743-745, 747-749, 751-753, 755-757, 759-761, 763-765, 767-769,770-772, 775-777, 780-782, 785-786, CDRs provided by any of 789-791, 794-796, 799, 802, 805-806, 809-813, 820-825, 838-843, 850-854, 861-866, 873-877, 884-889, 896-898, 901-903, 906-908, or 911-916 In some embodiments, the present invention comprises at least one CDR (e.g., CDR1, CDR2 and / or CDR3) having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9% or 100% identity. In some embodiments, the anti-CLL-1 antibody or antigen-binding fragment thereof comprises a VHH comprising at least one CDR corresponding to SEQ ID NO: 5-7, 19-21, 33-35, 47-49, 61-63, 75-77, 89-91, 103-105, 117-119, 131-133, 145-147, 159-161, 170-172, 175-177, 180-182, 185-187, 190-192, 195-197, 200-202, 205-207,210-212, 215-217, 220-222, 225-227, 230-232, 235-237, 240-242, 245-247, 250-252, 255-257, 260-262, 265-267, 271-273, 276-278, 281-283, 286-288, 291-293,299-301, 313-315, 327-329, 341-343, 355-357, 423-425, 431-433, 439-441, 447-449, 455-457, 463-465, 471-473, 479-481, 487-489, 495-497, 503-505, 511-513,519-521, 527-529, 535-537, 543-545, 551-553, 559-561, 567-569, 575-577, 583-585, 591-593, 599-601, 607-609, 615-617, 623-625, 631-633, 639-641, 647-649,655-657, 663-665, 671-673, 679-681, 687-689, 695-697, 703-705, 711-713, 715-717, 719-821, 723-725, 727-729, 731-733, 735-737, 739-741, 743-745, 747-749,751-753, 755-757, 759-761, 763-765, 767-769, 770-772, 775-777, 780-782, 785-786, 789-791, 794-796, 799, 802, 805-806, Any of the CDRs (e.g., CDR1, CDR2, and / or CDR3) provided by 809-813, 820-825, 838-843, 850-854,861-866, 873-877, 884-889, 896-898, 901-903, 906-908, or 911-916 has one or more (e.g., 1, 2, 3, 4, 5 or more) additions, deletions, or substitutions.

[0163] In some embodiments, the anti-CLL-1 antibody or its antigen-binding fragment is a monoclonal antibody or its antigen-binding fragment. In some embodiments, the anti-CLL-1 antibody or its antigen-binding fragment is a humanized antibody or its antigen-binding fragment. In some embodiments, the anti-CLL-1 antibody or its antigen-binding fragment is a camelid antibody or is derived from a camelid antibody.

[0164] In some embodiments, the present disclosure provides an anti-CLL-1 antibody or an antigen-binding fragment thereof that binds to an antibody comprising SEQ ID NO: 2-7, 9, 11, 13, 15, 16-21, 23, 25, 27, 29, 30-35, 37, 39, 41, 43,44-49, 51, 53, 55, 57, 58-63, 65, 67, 69, 71, 72-77, 79, 81, 83, 85, 86-91,93, 95, 97, 99, 100-105, 107, 109, 111, 113, 114-119, 121, 123, 125, 127,128-133, 135, 137, 139, 141, 142-147, 149, 151, 153, 155, 156-161, 163, 165,167, 169, 170-172, 174, 175-177, 179, 180-182, 184, 185-187 189, 190-192,194, 195-197, 199, 200-202, 204, 205-207, 209, 210-212, 214, 215-217, 219,220-222, 224, 225-227, 229, 230-232, 234, 235-237, 239, 240-242, 244, 245-247, 249, 250-252, 254, 255-257, 259, 260-262, 264, 265-267, 269, 271-273,275, 276-278, 280, 281-283, 285, 286-288, 290, 291-293, 295, 296-301, 303,305, 307, 309, 310-315, 317, 319, 321, 323, 324-329, 331, 333, 335, 337, 338-343, 345, 347, 349, 351, 352-357, 359, 363, 418-772, 774-777, 779-782, 784-786, 788-791, 793-796, 798-799, 801-802, 804-806, 808-813, 815, 817, 819-825,827, 829, 831, 833, 835, 837-843, 845, 847, 849-854, 856, 858,860-866, 868,870, 872-877, 879, 881, 883-889, 891, 893, 895-898, 900-903, 905-908, 910-916, 918, or 920, or an antigen-binding fragment thereof. In some embodiments, the present disclosure provides an anti-CLL-1 antibody or an antigen-binding fragment thereof that is present in an antibody or an antigen-binding fragment thereof comprising SEQ ID NO: 15, 29, 43, 57, 71, 85, 99, 113, 127, 141, 155, 169, 309, 323, 337, 351, 365, 418, 422, 426, 430, 434, 438, 442, 446, 450, 454, 458, 462, 466, 470, 474, 478, 482, 486, 490, 494, 498, 502, 506, 510, 514, 518, 522, 526, 530, 62, 666, 670, 674, 678, 682, 686, 690, 694, 698, 702, 706, 710, 714, 718, 722, 726, 730,734, 738, 742, 746, 750, 754, 758, 762, 766, 774, 779, 784, 788, 793, 798,801, 804, 808, 817, 829, 831, 835, 837, 847, 849, 858, 860, 870, 872, 881,883, 893, 895, 900, 905, 910, 920, or an antigen-binding fragment thereof.

[0165] In some embodiments, the present disclosure provides an anti-CLL-1 antibody or an antigen-binding fragment thereof, which is relative to wherein the anti-CLL-1 antibody comprises SEQ ID NO: 15, 29, 43, 57, 71, 85, 99, 113, 127, 141, 155,169, 309, 323, 337, 351, 365, 418, 422, 426, 430, 434, 438, 442, 446, 450,454, 458, 462, 466, 470, 474, 478, 482, 486, 490, 494, 498, 502, 506, 510, 514, 518, 522, 526, 530, 534, 538, 542, 546, 550, 554, 558, 562, 566, 570,574, 578, 582, 586, 590, 584, 598, 602, 606, 610, 614, 618, 622, 626, 630,634, 638, 642, 646, 650, 654, 658, 662, 666, 670, 674, 678, 682, 686, 690,694, 698, 702, 706, 710, 714, 718, 722, 726, 730, 734, 738, 742, 746, 750,754, 758, 762, 766, 774, 779, 784, 788, 793, 798, 801, 804, 808, 817, 829,831, 835, 837, 847, 849, 858, 860, 870, 872, 881, 883, 893, 895, 900, 905,910, 920 An anti-CLL-1 antibody or an antigen-binding fragment thereof having an amino acid sequence of , comprising 1 to 24 (e.g., 1, 2, 3, 4, 5, 10 or more) additions, deletions or substitutions, and, for example, the antibody or fragment selectively binds CLL-1.In some embodiments, the present disclosure provides an anti-CLL-1 antibody or an antigen-binding fragment thereof comprising the antibody and / or antigen-binding fragment of SEQ ID NO: 15, 29, 43, 57, 71, 85, 99, 113, 127, 141, 155, 169, 309, 323, 337, 351, 365, 418, 422, 426, 430, 434, 438, 442, 446, 450, 454, 458, 462, 466, 470, 474, 478, 482, 486, 490, 494, 498, 502, 506, 510, 514, 518, 522, 526, 530, 62, 666, 670, 674, 678, 682, 686, 690, 694, 698, 702,706, 710, 714, 718, 722, 726, 730, 734, 738, 742, 746, 750, 754, 758, 762,766, 774, 779, 784, 788, 793, 798, 801, 804, 808, 817, 829, 831, 835, 837,847, 849, 858, 860, 870, 872, 881, 883, 893, 895, 900, 905, 910, 920 An amino acid sequence having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence of, for example, the antibody or fragment selectively binds to CLL-1.

[0166] In some embodiments, the present disclosure provides an anti-CLL-1 antibody or an antigen-binding fragment thereof comprising SEQ ID NO: 5, 19, 33, 47, 61, 75, 89, 103, 117, 131, 145, 159, 170, 175, 180,185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255,260, 265, 271, 276, 281, 286, 291, 299, 313, 327, 341, 355, 423, 431, 439, 447, 455, 463, 471, 479, 487, 495, 503, 511, 519, 527, 535, 543, 551, 559,567, 575, 583, 591, 599, 607, 615, 623, 631, 639, 647, 655, 663, 671, 679,687, 695, 703, 711, 715, 719, 723, 727, 731, 735, 739, 743, 747, 751, 755,759, 763, 767, 770, 775, 6, 20, 34, 48, 62, 76, 90,104, 118, 132, 146, 160, 171, 176, 181, 186, 191, 196, 201, 206, 211, 216, 221, 226, 231, 236, 241, 246, 251, 256, 261, 266, 272, 277, 624, 632, 640, 648, 656, 664, 672, 680, 688, 696, 704, 712, 716, 720, 724,728, 732, 736, 740, 744, 748, 752, 756, 760, 764, 768, 771, 776, 781, 786,790, 795, 799, 802, 805, 812, 824, 842, 853, 865, 876, 888, 897, 902, 907, or 915 and a heavy chain CDR2 of SEQ ID NO: 7, 21, 35, 49, 63, 77, 91, 105, 119, 133,147, 161, 172, 177, 182, 187, 192, 197, 202, 207, 212, 217, 222, 227, 232,237, 242, 247, 252, 257, 262, 267, 273, 278, 283, 288, 293, 301, 315, 329,343, 357, 425, 433, 441, 449, 457, 465, 473, 481, 489, 497, 505, 513, 521,529, 537, 545, 553, 561, 569, 577, 585, 593, 601, 609, 617, 43, 854, 866, 877, 889, 898, 903, 908, or 916. In some embodiments, the present disclosure provides an anti-CLL-1 antibody or an antigen-binding fragment thereof comprising SEQ ID NO: 2, 16, 30, 44, 58, 72, 86, 100, 114, 128, 142, 156, 296, 310, 324, 338, 352, 419, 427, 435, 443, 451, 459, 467, 475, 483, 491, 499, 507, 515, 523, 531, 539, 547, 555, 563, 571, 579, 587, 595, 603, 611, 619, 627, 635, 643, 651, 659, 667,675, 683, 691, 699, 707, 809, 820, 838, 850, 861, 873, 884, or 911; SEQ ID NO: 3, 17, 31, 45, 59, 73, 87, 101, 115, 129, 143, 157, 297, 311, 325, 339, 353, 420, 428, 436, 444, 452, 460, 468, 476, 484, 492, 500, 508, 516, 524, 532, 540, 548, 556, 564, 46, 477, 484, 492, 512, 520, 536, 544, 552, 560, 572, 580, 588, 596, 604, 612, 620, 628, 636, 644, 652, 660, 668, 676, 684, 692, 700, 708, 821, 839, 862, 885, or 912 and a light chain CDR2 as provided in SEQ ID NO: 4, 18, 32, 46, 60, 74, 88, 102, 116, 130, 144, 158, 298, 312, 326, 340, 354, 421, 429, 437, 445, 453, 461, 469, 477, or a light chain CDR3 provided by 485,493, 501, 509, 517, 525, 533, 541, 549, 557, 565, 573, 581, 589, 597, 605,613, 621, 629, 637, 645, 653, 661, 669, 677, 685, 693, 701, 709, 810, 822,840, 851, 863, 874, 886, or 913.

[0167] In some embodiments, the present disclosure provides nucleic acids encoding any of the anti-CLL-1 antibodies described herein, or an antigen-binding fragment thereof. In some embodiments, the present disclosure provides nucleic acids encoding any one of the anti-CLL-1 antibodies or an antigen-binding fragment thereof relative to a sequence of SEQ ID NO: 2-7, 9, 11, 13, 15, 16-21, 23, 25, 27, 29, 30-35, 37, 39, 41, 43, 44-49, 51, 53, 55, 57, 58-63, 65, 67, 69, 71, 72-77, 79, 81, 83, 85, 86-91, 93, 95, 97, 99, 100-105, 107, 109, 111, 113, 114-119, 121, 123,125, 127, 128-133, 135, 137, 139, 141, 142-147, 149, 151, 153, 155, 156-161,163, 165, 167, 169, 170-172, 174, 175-177, 179, 180-182, 184, 185-187 189,190-192, 194, 195-197, 199, 200-202, 204, 205-207, 209, 210-212, 214, 215-217, 219, 220-222, 224, 225-227, 229, 230-232, 234, 235-237, 239, 240-242,244, 245-247, 249, 250-252, 254, 255-257, 259, 260-262, 264, 265-267, 269,271-273, 275, 276-278, 280, 281-283, 285, 286-288, 290, 291-293, 295, 296-301, 303, 305, 307, 309, 310-315, 317, 319, 321, 323, 324-329, 331, 333, 335,337, 338-343, 345, 347, 349, 351, 352-357, 359, 361, 363, 418-772, 774-777,779-782, 784-786, 788-791, 793-796, 798-799, 801-802, 804-806,808-813, 815,817, 819-825, 827, 829, 831, 833, 835, 837-843, 845, 847, 849-854, 856, 858,860-866, 868, 870, 872-877, 879, 881, 883-889, 891, 893, 895-898, 900-903,905-908, 910-916, 918, or 920, comprising 1 to 24 (e.g., 1, 2, 3, 4, 5, 10 or more) additions, deletions or substitutions, and, for example, the antibody or fragment selectively binds to CLL-1. In some embodiments, the present disclosure provides nucleic acids encoding any one of the anti-CLL-1 antibodies or an antigen-binding fragment thereof relative to a sequence comprising SEQ ID NO: 15, 29, 43, 57, 71, 85, 99, 113, 127, 141, 155, 169,309, 323, 337, 351, 365, 418, 422, 426, 430, 434, 438, 442, 446, 450, 454, 458, 462, 466, 470, 474, 478, 482, 486, 490, 494, 498, 502, 506, 510, 610, 614, 618, 622, 626, 630, 634, 638, 642, 646, 650, 654, 658, 662, 666, 670, 674, 678, 682, 686, 690, 694,698, 702, 706, 710, 714, 718, 722, 726, 730, 734, 738, 742, 746, 750, 754,758, 762, 766, 774, 779, 784, 788, 793, 798, 801, 804, 808, 817, 829, 831,835, 837, 847, 849, 858, 860, 870, 872, 881, 883, 893, 895,An anti-CLL-1 antibody or antigen-binding fragment thereof having an amino acid sequence of 900, 905, 910, 920, comprises 1 to 24 (e.g., 1, 2, 3, 4, 5, 10 or more) additions, deletions or substitutions, and, for example, the antibody or fragment selectively binds to CLL-1. In some embodiments, the present disclosure provides nucleic acids encoding any one of the anti-CLL-1 antibodies or an antigen-binding fragment thereof, any one of the anti-CLL-1 antibodies or an antigen-binding fragment thereof comprising a fragment of SEQ ID NO: 2-7, 9, 11, 13, 15, 16-21, 23, 25, 27, 29, 30-35, 37, 39, 41, 43, 44-49, 51, 53, 55, 57, 58-63, 65, 67, 69, 71, 72-77, 79, 81, 83, 85, 86-91, 93, 95, 97, 99, 100-105, 107, 109, 111, 113, 114-119, 121, 123, 125, 127, 128-133, 135, 137, 139,141, 142-147, 149, 151, 153, 155, 156-161, 163, 165, 167, 169, 170-172, 174,175-177, 179, 180-182, 184, 185-187 189, 190-192, 194, 195-197, 199, 200-202,204, 205-207, 209, 210-212, 214, 215-217, 219, 220-222, 224, 225-227, 229,230-232, 234, 235-237, 239, 240-242, 244, 245-247, 249, 250-252, 254, 255-257, 259, 260-262, 264, 265-267, 269, 271-273, 275, 276-278, 280, 281-283,285, 286-288, 290, 291-293, 295, 296-301, 303, 305, 307, 309, 310-315, 317,319, 321, 323, 324-329, 331, 333, 335, 337, 338-343, 345, 347, 349, 351, 352-357, 359, 361, 363, 418-772, 774-777,860-866, 868, 870, 872-877, 879,881, 883-889, 891, 893, 895-898, 900-903, 905-908, 910-916, The amino acid sequence of 918, or 920 has at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity. And, for example, the antibody or fragment selectively binds to CLL-1. In some embodiments, the present disclosure provides nucleic acids encoding any one of the anti-CLL-1 antibodies or an antigen-binding fragment thereof, any one of the anti-CLL-1 antibodies or an antigen-binding fragment thereof comprising a fragment identical to SEQ ID NO: 15, 29, 43, 57, 71, 85, 99, 113, 127, 141, 155, 169, 309, 323, 337, 351, 365, 418, 422, 426, 430, 434, 438, 442, 446, 450, 454, 458, 462, 466, 470, 474, 478, 482, 486, 490, 494, 498,502, 506, 510, 514, 62, 666, 670, 674, 678, 682, 686, 690, 694, 698, 702, 706, 710, 714, 718, 722, 726, 730, 734, 738,742, 746, 750, 754, 758, 762, 766, 774, 779, 784, 788, 793, 798, 801, 804,808, 817, 829, 831,835, 837, 847, 849, 858, 860, 870, 872, 881, 883, 893,895, 900, 905, 910, 920 have an amino acid sequence with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity, and, for example, the antibody or fragment selectively binds to CLL-1. ,

[0168] In some embodiments, the present disclosure provides a nucleic acid having SEQ ID NO: 8, 12, 14, 26, 228, 36, 40, 42, 50, 54, 56, 64, 68, 70, 78, 82, 84, 92, 96, 98, 106,110, 112, 120, 122, 124, 126, 134, 138, 140, 148, 152, 154, 162, 166, 168,173, 178, 183, 188, 193, 198, 203, 208, 213, 218, 223, 228, 233, 238, 243,248, 253, 258, 263, 268, 274, 279, 284, 289, 294, 302, 306, 308, 316, 320,322, 330, 334, 336, 344, 348, 350, 358, 362, 364, 773, 778, 783, 787, 792,797, 800, 803, 807, 814, 816, 818, 826, 828, 830, 832, 834, 836, 844, 846,848, 855, 857, 859, 867, 869, 871, 878, 880, 882, 890, 892, 894, 899, 904, 909, 917, 919, or 921, and the nucleic acid encodes an antibody or antigen-binding fragment thereof that binds CLL-1.In some embodiments, the present disclosure provides a nucleic acid that is identical to SEQ ID NO: 8, 12, 14, 26, 228, 36, 40, 42, 50, 54, 56, 64, 68, 70, 78, 82, 84, 92, 96, 98,106, 110, 112, 120, 122, 124, 126, 134, 138, 140, 148, 152, 154, 162, 166,168, 173, 178, 183, 188, 193, 198, 203, 208, 213, 218, 223, 228, 233, 238,243, 248, 253, 258, 263, 268, 274, 279, 284, 289, 294, 302, 306, 308, 316,320, 322, 330, 334, 336, 344, 348, 350, 358, 362, 364, 773, 778, 783, 787,792, 797, 800, 803, 807, 814, 816, 818, 826, 828, 830, 832, 834, 836, 844,846, 848, 855, 857, Any of the sequences provided in 859, 867, 869, 871, 878, 880, 882, 890, 892, 894, 899,904, 909, 917, 919, 921 has at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity, and the nucleic acid encodes a CLL-1 binding antibody or antigen-binding fragment thereof.

[0169] The present disclosure particularly provides methods for preparing anti-CLL-1 antibodies or antigen-binding fragments thereof. Methods for preparing antibodies are known in the art. For example, monoclonal antibodies can be produced using a variety of known techniques, such as the standard somatic cell hybridization technique described by Kohler and Milstein, Nature (1975) 256: 495. Other techniques for producing monoclonal antibodies, such as viral or oncogenic transformation of B lymphocytes or phage display techniques using human antibody gene libraries, can also be used.

[0170] In some embodiments, human antibodies are obtained by cloning heavy and light chain genes directly from human B cells obtained from human subjects.B cells are separated from peripheral blood (e.g., by flow cytometry, e.g., FACS), B cell markers are stained to the B cells, and antigen binding is assessed.The RNA encoding the heavy chain variable region and the light chain variable region (or the whole heavy chain and light chain) is extracted and reversely transcribed into DNA, and antibody genes are amplified from the DNA (e.g., by PCR) and sequenced.Then, known antibody sequences can be used to express recombinant human antibodies for known target antigens.In some cases, human antibodies can be prepared by administering immunogens to transgenic animals, which have been modified to produce complete human antibodies or complete antibodies with human variable regions in response to antigen attacks.Such animals generally contain all or part of human immunoglobulin loci, which replace endogenous immunoglobulin loci or exist outside chromosomes or are randomly integrated into the chromosomes of animals.In such transgenic mice, endogenous immunoglobulin loci are generally inactivated. Human variable regions from intact antibodies produced by such animals can be further modified, for example, by combining with different human constant regions.

[0171] In some cases, antibodies can also be prepared by hybridoma-based methods. In some embodiments, the animal system used to generate hybridomas that produce human monoclonal antibodies is a murine system. The generation of hybridomas in mice is well known in the art and includes immunization protocols and techniques for separating and fusing immune spleen cells. Human myeloma and mouse-human heteromyeloma cell lines used to produce human monoclonal antibodies have been described.

[0172] Human antibodies can also be generated by isolating Fv clone variable domain sequences selected from human-derived phage display libraries. Such variable domain sequences can then be combined with the desired human constant domains.

[0173] In some embodiments, the present disclosure provides a method of producing an antibody or an antigen-binding fragment thereof, the method comprising culturing a host cell containing a nucleic acid encoding any of the anti-CLL-1 antibodies described herein. In some embodiments, the method involves culturing a cell culture medium comprising SEQ ID NO: 8, 10, 12, 14, 24, 26, 228, 36, 38, 40, 42, 50, 52, 54, 56, 64, 66, 68, 70, 78, 80, 82, 84, 92, 94, 96, 98, 106, 108, 110, 112, 120, 122, 124, 126, 134, 136, 138, 140, 148, 150, 152, 154, 162, 164, 166, 168, 173, 178, 183, 188,193, 198, 203, 208, 213, 218, 223, 228, 233, 238, 243, 248, 253, 258, 263,268, 274, 279, 284, 289, 294, 302, 304, 306, 308, 316, 318, 320, 322, 330,332, 334, 336, 344, 346, 348, 350, 358, 360, 362, 364, 773, 778, 783, 787,792, 797, 800, 803, In some embodiments, the method further comprises collecting, isolating and / or purifying the antibody or antigen-binding fragment thereof.

[0174] Tables 1-114 provide the sequences of exemplary antibody clones, including exemplary single chain and single domain anti-CLL-1 antibodies.

[0175] Table 1: Anti-CLL-1 Binder Clone 1

[0176]

[0177]

[0178] Table 2: Anti-CLL-1 Binder Clone 2

[0179]

[0180]

[0181] Table 3: Anti-CLL-1 Binder Clone 3

[0182]

[0183]

[0184] Table 4: Anti-CLL-1 Binder Clone 4

[0185]

[0186]

[0187] Table 5: Anti-CLL-1 Binder Clone 5

[0188]

[0189]

[0190] Table 6: Anti-CLL-1 Binder Clone 6

[0191]

[0192]

[0193] Table 7: Anti-CLL-1 Binder Clone 7

[0194]

[0195]

[0196] Table 8: Anti-CLL-1 Binder Clone 8

[0197]

[0198]

[0199] Table 9: Anti-CLL-1 Binder Clone 9

[0200]

[0201]

[0202] Table 10: Anti-CLL-1 Binder Clone 10

[0203]

[0204]

[0205] Table 11: Anti-CLL-1 Binder Clone 11

[0206]

[0207]

[0208] Table 12: Anti-CLL-1 Binder Clone 12

[0209]

[0210]

[0211] Table 13: Anti-CLL-1 Binder Clone 13

[0212]

[0213] Table 14: Anti-CLL-1 Binder Clone 14

[0214]

[0215] Table 15: Anti-CLL-1 Binder Clone 15

[0216]

[0217] Table 16: Anti-CLL-1 Binder Clone 16

[0218]

[0219] Table 17: Anti-CLL-1 Binder Clone 17

[0220]

[0221] Table 18: Anti-CLL-1 Binder Clone 18

[0222]

[0223] Table 19: Anti-CLL-1 Binder Clone 19

[0224]

[0225] Table 20: Anti-CLL-1 Binder Clone 20

[0226]

[0227] Table 21: Anti-CLL-1 Binder Clone 21

[0228]

[0229] Table 22: Anti-CLL-1 Binder Clone 22

[0230]

[0231] Table 23: Anti-CLL-1 Binder Clone 23

[0232]

[0233] Table 24: Anti-CLL-1 Binder Clone 24

[0234]

[0235] Table 25: Anti-CLL-1 Binder Clone 25

[0236]

[0237] Table 26: Anti-CLL-1 Binder Clone 26

[0238]

[0239] Table 27: Anti-CLL-1 Binder Clone 27

[0240]

[0241] Table 28: Anti-CLL-1 Binder Clone 28

[0242]

[0243] Table 29: Anti-CLL-1 Binder Clone 29

[0244]

[0245] Table 30: Anti-CLL-1 Binder Clone 30

[0246]

[0247] Table 31: Anti-CLL-1 Binder Clone 31

[0248]

[0249] Table 32: Anti-CLL-1 Binder Clone 32

[0250]

[0251] Table 33: Anti-CLL-1 Binder Clone 33

[0252]

[0253] Table 34: Anti-CLL-1 Binder Clone 34

[0254]

[0255] Table 35: Anti-CLL-1 Binder Clone 35

[0256]

[0257] Table 36: Anti-CLL-1 Binder Clone 36

[0258]

[0259] Table 37: Anti-CLL-1 Binder Clone 37

[0260]

[0261] Table 38: Anti-CLL-1 Binder Clone 38

[0262]

[0263]

[0264] Table 39: Anti-CLL-1 Binder Clone 39

[0265]

[0266]

[0267] Table 40: Anti-CLL-1 Binder Clone 40

[0268]

[0269]

[0270] Table 41: Anti-CLL-1 Binder Clone 41

[0271]

[0272]

[0273] Table 42: Anti-CLL-1 Binder Clone 42

[0274]

[0275]

[0276] Table 43: Anti-CLL-1 Binder Clone 43

[0277]

[0278] Table 44: Anti-CLL-1 Binder Clone 44

[0279]

[0280] Table 45: Anti-CLL-1 Binder Clone 45

[0281]

[0282] Table 46: Anti-CLL-1 Binder Clone 46

[0283]

[0284] Table 47: Anti-CLL-1 Binder Clone 47

[0285]

[0286] Table 48: Anti-CLL-1 Binder Clone 48

[0287]

[0288] Table 49: Anti-CLL-1 Binder Clone 49

[0289]

[0290] Table 50: Anti-CLL-1 Binder Clone 50

[0291]

[0292] Table 51: Anti-CLL-1 Binder Clone 51

[0293]

[0294] Table 52: Anti-CLL-1 Binder Clone 52

[0295]

[0296] Table 53: Anti-CLL-1 Binder Clone 53

[0297]

[0298] Table 54: Anti-CLL-1 Binder Clone 54

[0299]

[0300] Table 55: Anti-CLL-1 Binder Clone 55

[0301]

[0302] Table 56: Anti-CLL-1 Binder Clone 56

[0303]

[0304] Table 57: Anti-CLL-1 Binder Clone 57

[0305]

[0306] Table 58: Anti-CLL-1 Binder Clone 58

[0307]

[0308] Table 59: Anti-CLL-1 Binder Clone 59

[0309]

[0310] Table 60: Anti-CLL-1 Binder Clone 60

[0311]

[0312] Table 61: Anti-CLL-1 Binder Clone 61

[0313]

[0314] Table 62: Anti-CLL-1 Binder Clone 62

[0315]

[0316] Table 63: Anti-CLL-1 Binder Clone 63

[0317]

[0318] Table 64: Anti-CLL-1 Binder Clone 64

[0319]

[0320] Table 65: Anti-CLL-1 Binder Clone 65

[0321]

[0322] Table 66: Anti-CLL-1 Binder Clone 66

[0323]

[0324] Table 67: Anti-CLL-1 Binder Clone 67

[0325]

[0326] Table 68: Anti-CLL-1 Binder Clone 68

[0327]

[0328] Table 69: Anti-CLL-1 Binder Clone 69

[0329]

[0330] Table 70: Anti-CLL-1 Binder Clone 70

[0331]

[0332] Table 71: Anti-CLL-1 Binder Clone 71

[0333]

[0334] Table 72: Anti-CLL-1 Binder Clone 72

[0335]

[0336] Table 73: Anti-CLL-1 Binder Clone 73

[0337]

[0338] Table 74: Anti-CLL-1 Binder Clone 74

[0339]

[0340] Table 75: Anti-CLL-1 Binder Clone 75

[0341]

[0342] Table 76: Anti-CLL-1 Binder Clone 76

[0343]

[0344] Table 77: Anti-CLL-1 Binder Clone 77

[0345]

[0346] Table 78: Anti-CLL-1 Binder Clone 78

[0347]

[0348] Table 79: Anti-CLL-1 Binder Clone 79

[0349]

[0350] Table 80: Anti-CLL-1 Binder Clone 80

[0351]

[0352] Table 81: Anti-CLL-1 Binder Clone 81

[0353]

[0354] Table 82: Anti-CLL-1 Binder Clone 82

[0355]

[0356] Table 83: Anti-CLL-1 Binder Clone 83

[0357]

[0358] Table 84: Anti-CLL-1 Binder Clone 84

[0359]

[0360] Table 85: Anti-CLL-1 Binder Clone 85

[0361]

[0362] Table 86: Anti-CLL-1 Binder Clone 86

[0363]

[0364] Table 87: Anti-CLL-1 Binder Clone 87

[0365]

[0366] Table 88: Anti-CLL-1 Binder Clone 88

[0367]

[0368] Table 89: Anti-CLL-1 Binder Clone 89

[0369]

[0370] Table 90: Anti-CLL-1 Binder Clone 90

[0371]

[0372] Table 91: Anti-CLL-1 Binder Clone 91

[0373]

[0374] Table 92: Anti-CLL-1 Binder Clone 92

[0375]

[0376] Table 93: Anti-CLL-1 Binder Clone 93

[0377]

[0378] Table 94. Anti-CLL-1 Binder Clone 94

[0379]

[0380] Table 95. Anti-CLL-1 Binder Clone 95

[0381]

[0382] Table 96. Anti-CLL-1 Binder Clone 96

[0383]

[0384] Table 97. Anti-CLL-1 Binder Clone 97

[0385]

[0386] Table 98. Anti-CLL-1 Binder Clone 98

[0387]

[0388] Table 99. Anti-CLL-1 Binder Clone 99

[0389]

[0390] Table 100. Anti-CLL-1 Binder Clone 100

[0391]

[0392] Table 101. Anti-CLL-1 Binder Clone 101

[0393]

[0394] Table 102. Anti-CLL-1 Binder Clone 102

[0395]

[0396] Table 103. Anti-CLL-1 Clone 103

[0397]

[0398]

[0399]

[0400] Table 104. Anti-CLL-1 humanized clone 104

[0401]

[0402]

[0403]

[0404] Table 105. Anti-CLL-1 Mouse Clone 104

[0405]

[0406]

[0407]

[0408] Table 106. Anti-CLL-1 Binder Clone 106

[0409]

[0410]

[0411]

[0412] Table 107. Anti-CLL-1 Human Clone 107

[0413]

[0414]

[0415]

[0416] Table 108. Anti-CLL-1 Clone 108

[0417]

[0418]

[0419]

[0420] Table 109. Anti-CLL-1 Clone 109

[0421]

[0422]

[0423]

[0424] Table 110. Anti-CLL-1 Clone 110

[0425]

[0426]

[0427]

[0428] Table 111. Anti-CLL-1 Clone 111

[0429]

[0430] Table 112. Anti-CLL-1 Clone 112

[0431]

[0432] Table 113. Anti-CLL-1 Clone 113

[0433]

[0434] Table 114. Anti-CLL-1 Initial Clone 114

[0435]

[0436]

[0437]

[0438] Fusion proteins and conjugates

[0439] In some embodiments, the present disclosure provides a fusion protein comprising (i) one or more single domain antibodies or antigen binding fragments thereof described herein (e.g., comprising one or more CDRs described herein); and (ii) one or more additional polypeptides. In some embodiments, the present disclosure provides a fusion protein comprising (i) one or more single domain antibodies or antigen binding fragments thereof described herein (e.g., comprising one or more CDRs described herein); and (ii) one or more additional domains. For example, a fusion protein can comprise one or more single domain antibodies described herein and one or more (e.g., 1, 2, 3, 4 or more) constant regions, or an Fc region. In some embodiments, as described in PCT publications WO2017 / 075537, WO2017 / 075533, WO2018156802, and WO2018156791, one or more single domain antibodies or antigen-binding fragments thereof described herein (e.g., one or more CDRs described herein) can be non-covalently or covalently conjugated, e.g., fused, to an antigen (e.g., an antigen target for cell therapy, such as a CAR-T cell or an antibody drug conjugate).

[0440] In some embodiments, the present disclosure provides a fusion protein including one or more VHHs as described herein and one or more other polypeptides or polypeptide domains. In some embodiments, other polypeptides include other antibodies or fragments thereof. Other antibodies include, for example, complete IgG, IgE and IgM, bispecific antibodies or multispecific antibodies (e.g., Zybodies®, etc.), single-chain Fv, polypeptide-Fc fusions, Fab, camel-shaped antibodies, shielded antibodies (e.g., Probodies®, small module immune drugs ("SMIPsTM"), single-chain or tandem double antibodies (TandAb®), VHH (including but not limited to those described in the present disclosure), Anticalins®, Nanobodies®, mini antibodies, BiTE®, ankyrin repeat proteins or DARPINs®, Avimers®, DART, TCR-like antibodies, Adnectins®, Affilins®, Trans-bodies®, Affibodies®, TrimerX®, trace proteins, Fynomers® and Centyrins®.

[0441] In some embodiments, one or more additional polypeptides or polypeptide domains comprise a second antigen binding domain, such as a second antigen binding domain that binds to the same target antigen (i.e., CLL-1), e.g., any of the anti-CLL-1 antibodies described herein, or an antigen binding fragment thereof. In some embodiments, one or more additional polypeptides or polypeptide domains comprise a second antigen binding domain, such as a second antigen binding domain that binds to a different target antigen (e.g., a different epitope from CLL-1).

[0442] In some embodiments, the antibodies of the present disclosure can be covalently attached to a drug (e.g., a cytotoxic agent, such as a toxin) in the form of an antibody drug conjugate (ADC) via a linker (e.g., via a disulfide bond or a non-cleavable thioether linker). The drug to which the antibody is covalently attached may have a cytotoxic or cell growth-inhibiting effect when not conjugated to the antibody. The ADC can be used to selectively deliver an effective dose of a cytotoxic agent to a cell (e.g., to a tumor tissue). The ADC can improve the bioavailability of the drug and / or antibody compared to when the drug and / or antibody is administered in its unconjugated form.

[0443] A variety of joint types and strategies are known in the art, and any or all of these types and strategies are considered for use in antibodies or ADCs disclosed herein. In some embodiments, the joint is biodegradable, for example, it can be cut by endogenous proteases (for example, present in target tissues and / or cells). In some embodiments, the joint includes a protease cleavable site. In some embodiments, the joint includes a pH-sensitive site, for example, a site sensitive to acidic pH, for example, a site hydrolyzed under acidic conditions. In some embodiments, the joint is stable under physiological conditions, for example, stability is sufficient to allow the antibody to target the drug to the target tissue before drug release. In some embodiments, the joint includes a disulfide bond, for example, a glutathione-sensitive disulfide bond. In some embodiments, the drug conjugated to the antibody is only active after the cutting of the joint. In some embodiments, the drug conjugated to the antibody is only active (for example, in the lysosome of the target cell) after the proteolytic digestion of the antibody. In some embodiments, the linker is a non-cleavable heterobifunctional thioether linker, e.g., a maleimide linker, e.g., a linker comprising an N-hydroxysuccinimide ester (succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate or SMCC).

[0444] A variety of drugs that are compatible with the ADCs of the present disclosure are known in the art, and any or all of these drugs are contemplated for use with the antibodies of the present disclosure.

[0445] A chimeric antigen receptor (CAR) comprising any of the anti-CLL-1 antibodies described herein or an antigen-binding fragment thereof is also within the scope of the present disclosure. CAR is an artificially constructed hybrid protein or polypeptide containing an antigen-binding domain (e.g., a single-chain variable fragment (scFv)) of one or more antibodies connected to a T cell signaling domain. The characteristics of CAR include its ability to redirect T cell specificity and reactivity to a selected target in a non-MHC-restricted manner using the antigen-binding properties of monoclonal antibodies. Non-MHC-restricted antigen recognition enables T cells expressing CAR to recognize antigens independent of antigen processing, thereby bypassing the main mechanism of tumor escape. In addition, when expressed in T cells, advantageously, CAR does not dimerize with endogenous T cell receptor (TCR) α and β chains. As used herein, the phrases "antigen specificity (antigen (ic) specificity)" and "eliciting an antigen-specific response" mean that CAR can specifically bind to an antigen and immune-recognize an antigen, so that the combination of CAR and an antigen induces an immune response.

[0446] In the conventional CAR containing the antigen binding domain of an antibody, there are three generations of CAR. "First generation" CAR is generally composed of an extracellular antigen binding domain (e.g., scFv) fused with a transmembrane domain, which is fused with a cytoplasm / intracellular signaling domain. The first generation of CAR can provide de novo antigen recognition, and activates both CD4+ and CD8+ T cells by the CD3ζ chain signaling domain in a single fusion molecule, without relying on HLA-mediated antigen presentation. "Second generation" CAR adds the intracellular signaling domain from various costimulatory signaling molecules (e.g., CD28, 4-1BB, ICOS, OX40, CD27, CD40 / My88 and NKGD2) to the cytoplasmic tail of CAR to provide additional signals to T cells. Second generation CAR includes those that provide costimulation (e.g., CD28 or 4-1BB) and activation (CD3ζ). "Third generation" CARs include those that provide multiple co-stimulatory domains (e.g., CD28 and 4-1BB) and provide an activating signaling domain (e.g., CD3ζ).

[0447] The CAR described herein comprises an extracellular portion of a CAR containing an anti-CLL-1 binding fragment, a transmembrane domain, and a signaling domain. In some embodiments, the CAR further comprises one or more of the following: a linker region, a hinge region, and a co-stimulatory signaling domain. In some embodiments, the CAR further comprises a signal peptide / signal sequence.

[0448] The CAR can consist of or consist essentially of one or more of the specified amino acid sequences described herein, such that other components (e.g., other amino acids) do not substantially alter the biological activity of the functional variant.

[0449] The CAR (including functional parts and functional variants) of the present disclosure can have any length, that is, can contain any number of amino acids, as long as the CAR (or its functional part or functional variant) maintains its biological activity (e.g., specific binding to a target antigen (e.g., CLL-1), detecting diseased cells in a mammal, or treating or preventing a disease in a mammal, etc.). For example, the CAR can be about 50 to about 5000 amino acids long, such as 50, 70, 75, 100, 125, 150, 175, 200, 300, 400, 500, 600, 700, 800, 900, 1000 or more amino acids in length.

[0450] In some embodiments, the CAR construct (comprising the functional part and functional variant of the present invention) may include a synthetic amino acid replacing one or more naturally occurring amino acids. Such synthetic amino acids are known in the art and include, for example, aminocyclohexanecarboxylic acid, norleucine, a-amino n-decanoic acid, homoserine, S-acetylaminomethyl-cysteine, trans-3- and trans-4-hydroxyproline, 4-aminophenylalanine, 4-nitrophenylalanine, 4-chlorophenylalanine, 4-carboxylphenylalanine, b-phenylserine, b-hydroxyphenylalanine, phenylglycine, a-naphthylalanine, cyclohexylalanine, cyclohexylglycine, dihydroindole- 2-carboxylic acid, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, aminomalonic acid, aminomalonic acid monoamide, N'-benzyl-N'-methyl-lysine, N',N'-dibenzyl-lysine, 6-hydroxylysine, ornithine, a-aminocyclopentanecarboxylic acid, a-aminocyclohexanecarboxylic acid, a-aminocycloheptanecarboxylic acid, a-(2-amino-2-norbornane)-carboxylic acid, a,g-diaminobutyric acid, a,b-diaminopropionic acid, homophenylalanine and a-tert-butylglycine.

[0451] In some embodiments, the CAR construct (including functional portions and functional variants) can be glycosylated, amidated, carboxylated, phosphorylated, esterified, N-acylated, cyclized through, for example, a disulfide bond, or converted into an acid addition salt and / or optionally dimerized or polymerized or conjugated.

[0452] In some embodiments, the CAR construct (including its functional part and functional variant) can be obtained by methods known in the art. In some embodiments, the CAR construct can be prepared by any suitable method for preparing a polypeptide or protein, including de novo synthesis. The CAR construct can be produced by recombinant production using standard recombinant methods using nucleic acids described herein. See, for example, Green et al., Molecular Cloning: A Laboratory Manual, 4th Edition, Cold Spring Harbor Press, Cold Spring Harbor, NY, 2012. Further, the various parts of some CAR constructs described herein (including its functional part and functional variant) can be separated and / or purified from sources such as plants, bacteria, insects, mammals, such as rats, people, etc. The method of separation and purification is well known in the art. Alternatively, the CAR construct described herein (including its functional part and functional variant) can be commercially synthesized by companies, such as Synpep (Dublin, CA), Peptide Technologies Corp. (Gaithersburg, MD) and Multiple Peptide Systems (San Diego, CA). In this regard, the CAR construct can be synthetic, recombinant, isolated and / or purified.

[0453] Further provided herein is a nucleic acid including a nucleotide sequence encoding any CAR construct described herein (including its functional part and functional variant). Nucleic acid as described herein may include a nucleotide sequence encoding any of the following: a leader sequence (e.g., a signal peptide), an antigen binding domain, a transmembrane domain, a joint region, a costimulatory signaling domain, and / or an intracellular T cell signaling domain.

[0454] In some aspects, any of any antigen binding domains described herein can be operably connected to another domain of CAR, such as a transmembrane domain or an intracellular domain, so as to be expressed in a cell. In some embodiments, the nucleic acid encoding the antigen binding domain is operably connected to the nucleic acid encoding the transmembrane domain and the nucleic acid encoding the intracellular domain.

[0455] In some embodiments, the nucleic acid encoding the anti-CLL-1 antigen binding domain is operably linked to a nucleic acid encoding a linker region, a nucleic acid encoding a transmembrane domain, and / or a nucleic acid encoding an intracellular domain (e.g., a co-stimulatory signaling domain, a signaling domain). In some embodiments, the CAR comprises any of the anti-CLL-1 antibodies described herein, or an antigen-binding fragment thereof (e.g., including one or more CDRs described herein). In some embodiments, the CAR comprises any one of SEQ ID NO: 15, 29, 43, 57, 71, 85, 99, 113, 127, 141, 155, 169, 309, 323, 337, 351, 365, 376-417, or 922-928, or comprises SEQ ID NO: 2-7, 9, 11, 13, 15, 16-21, 23, 25, 27, 29, 30-35, 37, 39, 41, 43, 44-49, 51, 53, 55, 57, 58-63, 65, 67, 69, 71, 72-77, 79, 81, 83, 85, 86-91, 93, 95, 97, 99, 100-105, 107, 109, 111,113, 114-119, 121, 123, 125, 127, 128-133, 135, 137, 139, 141, 142-147, 149,151, 153, 155, 156-161, 163, 165, 167, 169, 170-172, 174, 175-177, 179, 180-182, 184, 185-187 189, 190-192, 194, 195-197, 199, 200-202, 204, 205-207,209, 210-212, 214, 215-217, 219, 220-222, 224, 225-227, 229, 230-232, 234,235-237, 239, 240-242, 244, 245-247, 249, 250-252, 254, 255-257, 259, 260-262, 264, 265-267, 269, 271-273, 275, 276-278, 280, 281-283, 285, 286-288,290, 291-293, 295, 296-301, 303, 305, 307, 309, 310-315, 317, 319, 321, 323,324-329, 331, 333, 335,337, 338-343, 345, 347, 349, 351, 352-357, 359, 361,363, 365-369, 418, 422, 426, 430, 434, 438, 442, 446, 450, 454, 458, 462,466, 470, 474, 478, 482, 486, 490, 494, 498, 502, 506, 510, 514, 518, 522,526, 530, 534, 538, 542, 546, 550, 554, 558, 562, 566, 570, 574, 578, 582,586, 590, 584, 598, 602, 606, 610, 614, 618, 622, 626, 630, 634, 638, 642,646, 650, 654, 658, 662, 666, 670, 674, 678, 682, 686, 690, 694, 698, 702,706, 710, 714, 718, 722, 726, 730, 734, 738, 742, 746, 750, 754, Any one of the anti-CLL-1 antibodies of any one of 758, 762,766, 770-772, 775-777, 780-782, 785-786, 789-791, 794-796, 799, 802, 805-806,809-813, 820-825, 838-843, 850-854, 861-866, 873-877, 884-889, 896-898, 901-903, 906-908, or 911-916, or an antigen-binding fragment thereof. ,

[0456] In some embodiments, CAR includes a joint region. In some embodiments, the light chain variable region and the heavy chain variable region of the antigen binding domain can be connected to each other by a joint. In some embodiments, the antigen binding domain can be connected to another domain, such as a transmembrane domain, a hinge and / or an intracellular domain with a joint region. The joint can include any suitable amino acid sequence. In some embodiments, the joint is a Gly / Ser joint with a length of about 1 to about 100, about 3 to about 20, about 5 to about 30, about 5 to about 18 or about 3 to about 8 amino acids, and is composed of glycine residues and / or serine residues in order. Therefore, the Gly / Ser joint can be composed of glycine residues and / or serine residues. Preferably, the Gly / Ser joint includes the amino acid sequence of GGGGS (SEQ ID NO: 366), and multiple SEQ ID NOs can be present in the joint: 366 amino acid sequences. Any joint sequence can be used as a spacer between any other domain (such as a transmembrane domain) of the antigen binding domain and CAR. In some embodiments, the region linker is ([G]x[S]y)z, for example, wherein x can be 1-10, y can be 1-3, and z can be 1-5. In some embodiments, the linker region comprises the amino acid sequence GGGGSGGGGS (SEQ ID NO: 367). In some embodiments, the linker region comprises the amino acid sequence GGGGSGGGGSGGGGS (SEQ ID NO: 368). In some embodiments, the linker region comprises the amino acid sequence of any one of SEQ ID NOs: 11, 25, 39, 53, 67, 81, 95, 109, 123, 137, 151, 165, 305, 319, 333, 347, 361, or 366-369.

[0457] In some embodiments, the antigen binding domain includes one or more leader sequences (signal peptides, signal sequences), such as those described herein. In some embodiments, the leader sequence may be located at the amino terminus of the CAR in the CAR construct. The leader sequence may include any suitable leader sequence, for example, any CAR described herein may include any leader sequence, such as those described herein. In some embodiments, although the leader sequence can promote the expression of the released CAR on the surface of the cell, in order to make the CAR function, the presence of the leader sequence in the expressed CAR is not necessary. In some embodiments, after CAR is expressed on the cell surface, the leader sequence can be cut off. Therefore, in some embodiments, the released CAR (for example, surface expressed) lacks a leader sequence. In some embodiments, the CAR in the CAR construct lacks a guide sequence.

[0458] Hinge

[0459] In some embodiments, CAR includes a hinge / spacer region connecting the extracellular antigen binding domain to another domain such as a transmembrane domain. The hinge / spacer region can be flexible enough to allow the antigen binding domain to be oriented in different directions, thereby facilitating target antigen recognition. In some embodiments, the hinge domain is a part of the hinge domain of CD8α or CD28, for example, a fragment of at least 15 (e.g., 20, 25, 30, 35 or 40) continuous amino acids containing the hinge domain of CD8α or CD28.

[0460] In some embodiments, CAR includes a hinge domain, such as a hinge domain from CD8, CD28 or IgG4. In some embodiments, the hinge domain is a CD8 (e.g., CD8α) hinge domain. In some embodiments, the CD8 hinge domain is human (e.g., obtained from / derived from a human protein sequence). In some embodiments, the CD8 hinge domain comprises SEQ ID NO: 369, is composed of, or is substantially composed of.

[0461] CD8 hinge region

[0462] TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACD [SEQ ID NO: 369]

[0463] In some embodiments, the hinge domain is a CD28 hinge domain. In some embodiments, the CD28 hinge domain is human (e.g., obtained / derived from a human protein sequence). In some embodiments, the CD28 hinge domain comprises, consists of, or consists essentially of SEQ ID NO: 370.

[0464] CD28 hinge region

[0465] AAAIEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKP [SEQ ID NO: 370]

[0466] The hinge domain of an antibody, such as an IgG, IgA, IgM, IgE or IgD antibody, is also suitable for chimeric receptors described herein. In some embodiments, the hinge domain is a hinge domain that connects the constant domains CH1 and CH2 of an antibody. In some embodiments, the hinge domain is an antibody, and includes the hinge domain of the antibody and one or more constant regions of the antibody. In some embodiments, the hinge domain includes the hinge domain of the antibody and the CH3 constant region of the antibody. In some embodiments, the hinge domain includes the hinge domain of the antibody and the CH2 constant region and CH3 constant region of the antibody. In some embodiments, the antibody is an IgG, IgA, IgM, IgE or IgD antibody. In some embodiments, the antibody is an IgG antibody. In some embodiments, the antibody is an IgG1, IgG2, IgG3 or IgG4 antibody. In some embodiments, the hinge region includes the hinge region of the IgG1 antibody and the CH2 constant region and the CH3 constant region. In some embodiments, the hinge region includes the hinge region and the CH3 constant region of the IgG1 antibody. In some embodiments, the hinge domain is an IgG4 hinge domain.

[0467] CAR including hinge domain is also within the scope of the present disclosure, and the hinge domain is a non-naturally occurring peptide. In some embodiments, the hinge domain between the C-terminus of the extracellular ligand binding domain of the Fc receptor and the N-terminus of the transmembrane domain is a peptide joint, such as (GlyxSer) n joint, wherein x and n can be independently an integer between 3 and 12, including 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more. In some embodiments, the joint region includes SEQ ID NO: 11, 25, 39, 53, 67, 81, 95, 109, 123, 137, 151, 165, 305, 319, 333, 347, 361 or 366-369 in any one of the amino acid sequence.

[0468] Additional peptide linkers that can be used in the hinge domains of the chimeric receptors described herein are known in the art. See, for example, Wriggers et al. Current Trends in Peptide Science (2005) 80(6): 736-74 and PCT Publication WO 2012 / 088461.

[0469] In some embodiments, the hinge / spacer region of the CAR disclosed herein includes a natural or modified hinge region of a CD28 polypeptide as described herein. In certain embodiments, the hinge / spacer region of the CAR construct disclosed herein includes a natural or modified hinge region of a CD8α polypeptide as described herein. In certain embodiments, the hinge / spacer region of the CAR construct disclosed herein includes a natural or modified hinge region of an IgG4 polypeptide as described herein.

[0470] Transmembrane domain

[0471] About transmembrane domain, CAR can be designed to include the transmembrane domain that connects the antigen binding domain of CAR to the intracellular region of CAR.In some embodiments, transmembrane domain is associated with one or more domains in CAR.In some cases, transmembrane domain can be selected or modified by amino acid substitution to avoid such domain from binding to the transmembrane domain of the same or different surface membrane protein, thereby minimizing the interaction with other members of receptor complex.

[0472] The transmembrane domain can be derived from a natural or synthetic source. In the case where the source is natural, the domain can be derived from any membrane-bound protein or transmembrane protein. Particularly useful transmembrane regions in the present invention can be derived from (i.e., a transmembrane region comprising at least an α chain, a β chain or a ζ chain of a T cell receptor) CD28, CD3ε, CD45, CD4, CD5, CD8α, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD154, Toll-like receptor 1 (TLR1), TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8 and TLR9.

[0473] In some embodiments, the transmembrane domain may be synthetic, in which case the transmembrane domain will primarily include hydrophobic residues such as leucine and valine. Preferably, a triplet of phenylalanine, tryptophan and valine will be found at each end of the synthetic transmembrane domain.

[0474] In some embodiments, the transmembrane domain is a CD8 (e.g., CD8α) transmembrane domain. In some embodiments, the CD8 transmembrane domain is human (e.g., obtained / derived from a human protein sequence). In some embodiments, the CD8 transmembrane domain comprises, consists of, or consists essentially of SEQ ID NO: 371.

[0475] CD8 transmembrane region

[0476] IYIWAPLAGTCGVLLLSLVITLYC [SEQ ID NO: 371]

[0477] In some embodiments, the transmembrane domain is a CD28 transmembrane domain. In some embodiments, the CD28 transmembrane domain is human (e.g., obtained / derived from a human protein sequence). In some embodiments, the CD28 transmembrane domain comprises, consists of, or consists essentially of SEQ ID NO: 372.

[0478] CD28 transmembrane domain

[0479] FWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS[SEQ ID NO: 372]

[0480] Intracellular signaling domain

[0481] In some embodiments, the CAR construct comprises an intracellular signaling domain, which may be composed of one or more signaling domains and a co-stimulatory domain. The intracellular signaling domain of CAR is related to the activation of cells in which CAR is expressed. In some embodiments, the intracellular signaling domain of the CAR construct described herein is related to the activation of T lymphocytes or NK cells. In some embodiments, the signaling domain of the CAR construct described herein includes a domain involved in signal activation and / or transduction.

[0482] Examples of intracellular signaling domains for use in the CAR constructs described herein include, but are not limited to, the cytoplasmic portion of a surface receptor, a co-stimulatory molecule, and any molecules that act synergistically to initiate signal transduction in a cell (e.g., an immune cell (e.g., T lymphocyte), NK cell), as well as any derivatives or variants of these elements and any synthetic sequences with the same functional capability.

[0483] Examples of signaling domains that can be used for the intracellular signaling domain of the CAR described herein include, but are not limited to, fragments or domains from one or more molecules or receptors, including, but not limited to, TCR, CD3ζ (CD3 zeta), CD3γ, CD3δ, CD3ε, CD86, common FcRγ, FcRβ (Fcε Rib), CD79a, CD79b, FcγRIIa, DAP10, DAP 12, T cell receptor (TCR), CD27, CD28, 4-1BB (CD137), OX40, CD30, CD40, PD-1, ICOS, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, a ligand that specifically binds to CD83, CDS, ICAM-1, GITR, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80. (KLRF1), CD127, CD160, CD19, CD4, CD8α, CD8β, IL2Rβ, IL2Rγ, IL7Rα, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD l id, ITGAE, CD103, ITGAL, CD11a, LFA-1, ITGAM, CD11b, ITGAX, CD11c, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, TNFR2, TRANCE / RANKL, DNAM1(CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAMl, CRTAM, Ly9 (CD229), CD160 (BY55), PSGLl, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD 162), LTBR, ​​LAT, GADS, SLP-76, PAG / Cbp, NKp44, NKp30, NKp46, NKG2D, Toll-like receptor 1 (TLR1), TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, other costimulatory molecules described herein, any derivative, variant or fragment thereof, any synthetic sequence of a costimulatory molecule having the same functional capability, and any combination thereof.

[0484] Any cytoplasmic signaling domain can be used for the CAR described herein. In general, the cytoplasmic signaling domain transmits a signal, such as the interaction of an extracellular ligand binding domain with its ligand, to stimulate a cellular response, such as inducing an effector function (e.g., cytotoxicity) of a cell.

[0485] It will be apparent to one of ordinary skill in the art that a factor involved in T cell activation is phosphorylation of an immunoreceptor tyrosine-based activation motif (ITAM) of a cytoplasmic signaling domain. Any ITAM-containing domain known in the art can be used to construct the chimeric receptors described herein and included as part of the cytoplasmic signaling domain. Typically, the ITAM motif can include two repeats of the amino acid sequence YxxL / I separated by 6-8 amino acids, wherein each x is independently any amino acid, resulting in the conserved motif YxxL / Ix(6-8)YxxL / I. In some embodiments, the cytoplasmic signaling domain is from CD3ζ.

[0486] CD3ζ associates with TCR to generate a signal and contains an immunoreceptor tyrosine-based activation motif (ITAM). In some embodiments, the CD3ζ intracellular T cell signaling sequence is human (e.g., obtained from or derived from a human protein). In some embodiments, the CD3ζ intracellular T cell signaling sequence comprises an amino acid sequence of SEQ ID NO: 373 or 374 or a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity to an amino acid sequence of SEQ ID NO: 373 or 374, is composed of, or is essentially composed of. In some embodiments, the intracellular T cell signaling domain includes a CD3ζ containing one or more mutations and / or deleted ITAMs.

[0487] CD3ζ signaling domain (variant A)

[0488] RVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR [SEQ ID NO: 373]

[0489] CD3ζ signaling domain (variant B)

[0490] RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR [SEQ ID NO: 374]

[0491] In certain non-limiting embodiments, the intracellular signaling domain of CAR further includes at least one (e.g., 1, 2, 3 or more) co-stimulatory signaling domain. In some embodiments, the co-stimulatory signaling domain includes at least one co-stimulatory molecule that can provide optimal lymphocyte activation. Generally, in addition to stimulating antigen-specific signals, many immune cells also require co-stimulation to promote cell proliferation, differentiation and survival, and activate the effector functions of cells. The activation of the co-stimulatory signaling domain in host cells (e.g., immune cells) can induce cells to increase or decrease the production and secretion of cytokines, phagocytic properties, proliferation, differentiation, survival and / or cytotoxicity. The co-stimulatory signaling domain of any co-stimulatory protein can be compatible for use in the chimeric receptor described herein. The type of co-stimulatory signaling domain can be selected according to a variety of factors, such as the cell type expressing CAR (e.g., primary T cells, T cell lines, NK cell lines) and the desired immune effector function (e.g., cytotoxicity).

[0492] Examples of such co-stimulatory signaling domains include fragments or domains from one or more molecules or receptors, including but not limited to 4-1BB, CD28, ICOS, TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, CD116 receptor beta chain, CSF1-R, LRP1 / CD91, SR-A1, SR-A2, MARCO, SR-CL1, SR-CL2, SR-C, SR-E, CR1, CR3, CR4, dectin 1, DEC-205, DC-SIGN, CD14, CD36, LOX-1, CD11b, and any combination of any of the signaling domains listed in the above paragraphs. In some embodiments, the intracellular signaling domain of the CAR comprises any portion of one or more co-stimulatory signaling molecules, such as at least one signaling domain from CD3, FcεRIγ chain, any derivative or variant thereof (including any synthetic sequence thereof having the same functional capability), and any combination thereof.

[0493] In some embodiments, one or more co-stimulatory signaling domains (e.g., 1, 2, 3 or more) are included in a CAR construct having a CD3ζ intracellular T cell signaling sequence. In some embodiments, the one or more co-stimulatory signaling domains are selected from CD137 (4-1BB) and CD28; or a combination thereof. In some embodiments, CAR includes a 4-1BB (CD137) co-stimulatory signaling domain. In some embodiments, CAR includes a CD28 co-stimulatory signaling domain. In some embodiments, CAR includes both a 4-1BB co-stimulatory signaling domain and a CD28 co-stimulatory signaling domain.

[0494] 4-1BB, also known as CD137, transmits effective co-stimulatory signals to T cells, promotes differentiation and enhances the long-term survival of T lymphocytes. In some embodiments, the 4-1BB intracellular T cell signaling sequence is human (e.g., obtained from a human protein sequence / derived from a human protein sequence). In some embodiments, the 4-1BB intracellular T cell signaling sequence comprises SEQ ID NO: 375 amino acid sequence, is composed of it, or is essentially composed of it. In some embodiments, the 4-1BB co-stimulatory signaling domain comprises SEQ ID NO: 375 amino acid sequence or SEQ ID NO: 375 amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identity, is composed of it, or is essentially composed of it.

[0495] 4-1BB co-stimulatory signaling domain

[0496] KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL [SEQ ID NO: 375]

[0497] Some suitable costimulatory domains are provided herein, and other suitable costimulatory domains and costimulatory domain sequences will be apparent to those skilled in the art based on the present disclosure in view of the knowledge in the art. Suitable costimulatory domains include, for example, those described in Weinkove et al., Selecting costimulatory domains for chimeric antigen receptors: functional and clinical considerations, Clin Transl Immunology (2019) 8(5): e1049, the entire contents of which are incorporated herein by reference.

[0498] Between the antigen binding domain and the transmembrane domain of CAR, or between the intracellular signaling domain and the transmembrane domain of CAR, a spacer domain can be incorporated. As used herein, the term "spacer domain" generally means any oligopeptide or polypeptide used to connect the transmembrane domain to the antigen binding domain or the intracellular domain in a polypeptide chain. In some embodiments, the spacer domain may include up to 300 amino acids, preferably 10 to 100 amino acids, and most preferably 25 to 50 amino acids. In some embodiments, a short oligopeptide or polypeptide linker, preferably between 2 and 10 amino acids in length, can form a connection between the transmembrane domain of CAR and the intracellular domain. Examples of linkers include glycine-serine duplexes.

[0499] Signal peptide

[0500] In some embodiments, any CAR described herein may further include a signal peptide (signal sequence). Typically, a signal peptide is a short amino acid sequence that targets a certain site in a polypeptide cell. In some embodiments, the signal peptide directs CAR to the secretory pathway of the cell, and will allow CAR to be integrated and anchored into the lipid bilayer at the cell surface. Compatible with the signal sequence (including the signal sequence of naturally occurring protein or the non-naturally occurring signal sequence of synthesis) used in the chimeric receptor described herein will be apparent to those skilled in the art.

[0501] The CAR described herein can be prepared as a construct with, for example, a self-cleaving peptide so that the CAR construct containing the anti-CLL-1 CAR component is bicistronic, tricistronic, etc.

[0502] Various CAR constructs and multiple elements of CAR constructs (e.g., various CLL-1 binding domains, signal peptides, linkers, hinge sequences, transmembrane domains, costimulatory domains, and signaling domains) are disclosed herein, and those skilled in the art will be able to determine the sequences of these elements and other suitable elements known in the art based on the present disclosure and according to the knowledge in the art. Exemplary CAR element sequences, for example, CAR element sequences for CLL-1 binding domains, signal peptides, linkers, hinge sequences, transmembrane domains, costimulatory domains, and signaling domains, are disclosed, for example, throughout the specification and Tables 1-8, the entire contents of which are incorporated herein by reference.

[0503] Any of the anti-CLL-1 antibodies or antigen-binding fragments thereof can be used in a CAR construct together with any one or more of the additional components described herein (e.g., hinges, transmembrane domains, co-stimulatory domains, intracellular signaling domains). In some embodiments, the CAR construct comprises a CLL-1 binding domain (comprising SEQ ID NO: 2-7, 16-21, 30-35, 44-49, 58-63, 72-77, 86-91, 100,-105, 114-119, 128-133, 142-147, 156-161, 170-172, 175-177, 180-182, 185-187, 190-192, 195-197, 200-202, 205-207, 210-212, 215-217, 220-222, 225-227, 230-232, 235-237, 240-242, 245-247, 250-252, 2 55-257, 260-262, 265-267, 271-273, 276-278, 281-283, 286-288, 291-293, 296-301, 310-315, 324-329, 338-343, 352-357, 419-421, 423-425, 427-429, 431-433, 435-437, 439-441, 443-445, 447-449, 451-453, 455-457, 459-461, 463-465, 467-469, 471-473, 475 -477, 479-481, 483-485, 487-489, 491-493, 495-497, 499-501, 503-505, 507-509, 511-513, 515-517, 519-521, 523-525, 527-529, 531-533, 535-537, 539-541, 543-545, 547-549, 551-553, 555-557, 559-561, 563-565, 567-569, 571-573, 575-577, 579-581, 583-5 85, 587-589, 591-593, 595-597, 599-601, 603-605, 607-609, 611-613, 615-617, 619-621, 623-625, 627-629, 631-633, 635-637, 639-641, 643-645, 647-649, 651-653, 655-657, 659-661, 663-665, 667-669, 671-673, 675-677, 679-681, 683-685, 687-689, 691-693,695-697, 699-701, 703-705, 707-709, 711-713, 715-717, 719-721, 723-725, 727-729, 731-733, 735-737, 739-741, 743-745, 747-749, 751-753, 755-757, 759-761, 763-765, 767-769, 770-772, 775-777, 780- In some embodiments, the CAR construct comprises a CLL-1 binding domain (comprising SEQ ID NO: 2-7, 16-21, 30-35, 44-49, 58-63, 72-77, 86-91, 100,-105, 114-119, 128-133, 142-147, 156-161, 170-172, 175-177, 180-182, 185-187, 190-192, 195-197, 200-202, 205-207, 2 10-212, 215-217, 220-222, 225-227, 230-232, 235-237, 240-242, 245-247, 250-252, 255-257, 260-262, 265-267, 271-273, 276-278, 281-283, 286-288, 291-293, 296-301, 310 -315, 324-329, 338-343, 352-357, 419-421, 423-425, 427-429, 431-433, 435-437, 439-441, 443-445, 447-449, 451-453, 455-457, 459-461, 463-465, 467-469, 471-473, 475-476 77, 479-481, 483-485, 487-489, 491-493, 495-497, 499-501, 503-505, 507-509, 511-513, 515-517, 519-521, 523-525, 527-529, 531-533, 535-537, 539-541, 543-545, 547-549,551-553, 555-557, 559-561, 563-565, 567-569, 571-573, 575-577, 579-581, 583-585, 587-589, 591-593, 595-597, 599-601, 603-605, 607-609, 611-613, 615-617, 619-621, 623-625 , 627-629, 631-633, 635-637, 639-641, 643-645, 647-649, 651-653, 655-657, 659-661, 663-665, 667-669, 671-673, 675-677, 679-681, 683-685, 687-689, 691-693, 695-697, 699-70 1. 703-705, 707-709, 711-713, 715-717, 719-721, 723-725, 727-729, 731-733, 735-737, 739-741, 743-745, 747-749, 751-753, 755-757, 759-761, 763-765, 767-769, 770-772, 775-776 In some embodiments, the CAR construct comprises a CLL-1 binding domain (comprising SEQ ID NO: 2-7, 16-21, 30-35, 44-49, 58-63, 72-77, 86-91, 100,-105, 114-119, 128-133, 142-147, 156-161, 170-172, 175-177, 180-182, 185-187, 190-192, 195-197, 200-202, 205-207 、210-212、215-217、220-222、225-227、230-232、235-237、240-242、245-247、250-252、255-257、260-262、265-267、271-273、276-278、281-283、286-288、291-293、296-301、310-315, 324-329, 338-343, 352-357, 419-421, 423-425, 427-429, 431-433, 435-437, 439-441, 443-445, 447-449, 451-453, 455-457, 459-461, 463-465, 467-469, 471-473, 475-477, 479-481, 483-485, 487-489, 491-493, 495-497, 499-501, 503-505, 507-509, 511-513, 5 15-517, 519-521, 523-525, 527-529, 531-533, 535-537, 539-541, 543-545, 547-549, 551-553, 555-557, 559-561, 563-565, 567-569, 571-573, 575-577, 579-581, 583-585, 587-589, 591-593, 595-597, 599-601, 603-605, 607-609, 611-613, 615-617, 619-621, 623-625, 62 7-629, 631-633, 635-637, 639-641, 643-645, 647-649, 651-653, 655-657, 659-661, 663-665, 667-669, 671-673, 675-677, 679-681, 683-685, 687-689, 691-693, 695-697, 699-701, 703-705, 707-709, 711-713, 715-717, 719-721, 723-725, 727-729, 731-733, 735-737, 739 -741, 743-745, 747-749, 751-753, 755-757, 759-761, 763-765, 767-769, 770-772, 775-777, 780-782, 785-786, 789-791, 794-796, 799, 802, 805-806, 809-813, 820-825, 838-843, 850-854, 861-866, 873-877, 884-889, 896-898, 901-903, 906-908 or 911-916) (e.g., scFv), CD8α transmembrane domain, CD8α hinge domain, CD137 (4-1BB) co-stimulatory domain, and CD3ζ intracellular signaling domain.

[0504] As will be understood by those of ordinary skill in the art, one or more of the domains of an exemplary CAR construct may be replaced by another domain. For example, the exemplary CAR constructs provided below include a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) co-stimulatory domain, and a CD3ζ intracellular signaling domain, any one of which (such as a hinge domain, a transmembrane domain, a co-stimulatory domain, and / or an intracellular signaling domain) may be replaced by another domain (such as those described herein).

[0505] In some embodiments, the CAR comprises an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to the amino acid sequence set forth in any one of SEQ ID NOs: 376-417 or 922-928. In the amino acid sequences of the exemplary CAR constructs described herein, the following annotations may be used: Changxu Underline represents the hinge domain; Double underscore indicates the transmembrane domain; Italic with dotted underline represents a co-stimulatory domain; and Bold Underline Indicates the intracellular signaling domain.

[0506] 1. CAR Clone 1

[0507] As described herein, exemplary CAR constructs include a CLL-1 binding domain scFv (comprising SEQ ID NO: 15), a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) co-stimulatory domain, and a CD3ζ intracellular signaling domain. In some embodiments, the CAR comprises the amino acid sequence shown in SEQ ID NO: 376, or an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to the amino acid sequence shown in SEQ ID NO: 376.

[0508] SYVLTQPPSVSVAPGQTARITCGGNNIGSKSVHWYQQKPGQAPVLVVYDDSDRPSGIPERFSGSNSGNTATLTISRVEAGDEADYYCQVWDSSSDHPVFGGGTQLIILGGGGSGGGGSGGGGSQ VQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAREKDDILTGAYYYGMDVWGQGTTVTVSS TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYI WAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAY KQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGL YQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 376)

[0509] In some embodiments, the CAR construct shown in SEQ ID NO: 376 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., SFFV promoter, EF1α promoter, tEF1a promoter, hPGK promoter, SFFV promoter or MND promoter).

[0510] 2. CAR Clone 2

[0511] As described herein, an exemplary CAR construct comprises a CLL-1 binding domain scFv (comprising SEQ ID NO:29), a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) co-stimulatory domain, and a CD3ζ intracellular signaling domain.

[0512] In some embodiments, the CAR comprises the amino acid sequence shown in SEQ ID NO: 377, or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence shown in SEQ ID NO: 377.

[0513] QSVLTQPLSVSVALGQTARITCGGNNIGSKNVHWYQQKAGQAPVLVIQRDSNRPSGIPERFSGSNSGNTATLTISRAQAGDEADYFCQVWDSNTYVFGTGTKLTVLGGGGSGGGGSGGGG SEVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSYISSSGSTIYYADSVKGRFTISRDNAKNSLYLQMNSLRDEDTAVYYCARQSAEIVGAFDHWGQGTMVTVSS TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGT CGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQL YNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTA TKDTYDALHMQALPPR (SEQ ID NO: 377)

[0514] In some embodiments, the CAR construct shown in SEQ ID NO: 377 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., SFFV promoter, EF1α promoter, tEF1a promoter, hPGK promoter, SFFV promoter or MND promoter).

[0515] 3. CAR Clone 3

[0516] As described herein, an exemplary CAR construct comprises a CLL-1 binding domain scFv (comprising SEQ ID NO:43), a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) co-stimulatory domain, and a CD3ζ intracellular signaling domain.

[0517] In some embodiments, the CAR comprises the amino acid sequence shown in SEQ ID NO: 378, or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence shown in SEQ ID NO: 378.

[0518] QSALTQPPSASGSPGQSVTISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYEVGKRPSGVPDRFSGSKSGNTASLTVSGLQAEDEADYYCSSYTSSSTRVFGGGTKVTVLGGGGSGGGGS GGGGSEVQLVQSGAEVKKPGASVKVSCKVSGYTLTELSMHWVRQAPGKGLEWMGGFDPEDGETIYAQKFQGRVTMTEDTSTDTAYMELSSLRSEDTAVYYCATDPHMDVWGQGTMVTVSS TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTC GVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLY NELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTAT KDTYDALHMQALPPR (SEQ ID NO: 378)

[0519] In some embodiments, the CAR construct shown in SEQ ID NO: 378 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., SFFV promoter, EF1α promoter, tEF1a promoter, hPGK promoter, SFFV promoter or MND promoter).

[0520] 4. CAR Clone 4

[0521] As described herein, an exemplary CAR construct comprises a CLL-1 binding domain scFv (comprising SEQ ID NO:57), a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) co-stimulatory domain, and a CD3ζ intracellular signaling domain.

[0522] In some embodiments, the CAR comprises the amino acid sequence shown in SEQ ID NO: 379, or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence shown in SEQ ID NO: 379.

[0523] QSVVTQPPSVSAAPGQKVTISCSGSSPNIGKNYVSWYQQLPGTAPKLLIYDNNKRPSGIPDRFSGSKSGTSATLGITGLQTGDEADYYCGTWDSSLSGYVFGTGTKVTVLGGGGSGGGGSGGG GSQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFISHDGSNKYYADSVKGRSTISRDNSKSTLFLQMNSLRDEDTAVYFCAREGQLTTSWDFFDYWGHGTLVTVSS TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIW APLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYK QGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLY QGLSTATKDTYDALHMQALPPR (SEQ ID NO: 379)

[0524] In some embodiments, the CAR construct shown in SEQ ID NO: 379 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., SFFV promoter, EF1α promoter, tEF1a promoter, hPGK promoter, SFFV promoter or MND promoter).

[0525] 5. CAR Clone 5

[0526] As described herein, an exemplary CAR construct comprises a CLL-1 binding domain scFv (comprising SEQ ID NO:71), a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) co-stimulatory domain, and a CD3ζ intracellular signaling domain.

[0527] In some embodiments, the CAR comprises the amino acid sequence shown in SEQ ID NO: 380, or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence shown in SEQ ID NO: 380.

[0528] DIQLTQSPSSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPWTFGQGTKVEIKGGGGSGGGGSGGGGS QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFISHDGSNKYYADSVKGRSTISRDNSKSTLFLQMNSLRDEDTAVYFCAREGQLTTSWDFFDYWGHGTLVTVSS TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPL AGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQ NQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGL STATKDTYDALHMQALPPR (SEQ ID NO: 380)

[0529] In some embodiments, the CAR construct shown in SEQ ID NO: 380 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., SFFV promoter, EF1α promoter, tEF1a promoter, hPGK promoter, SFFV promoter or MND promoter).

[0530] 6. CAR Clone 6

[0531] As described herein, an exemplary CAR construct comprises a CLL-1 binding domain scFv (comprising SEQ ID NO:85), a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) co-stimulatory domain, and a CD3ζ intracellular signaling domain.

[0532] In some embodiments, the CAR comprises the amino acid sequence shown in SEQ ID NO: 381, or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence shown in SEQ ID NO: 381.

[0533] QSVLTQPPSVSAAPGQKVSIFCSGSSNIGKNYVSWYQQLPGTAPKLLIYENQHRPSGIPDRFSGSKSGTSATLGITGLQTGDEADYYCATWDDSLSAGVFGGGTELTVLGGGGSGGGGSGGGG SQLVQSGAEVRKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGFIYPGDSDTRYSPSFQGQVTISADKSISTAYLQRSSLKASDTAMYYCARLGGYSGYDSEVFYLDYWGQGTTVTVSS TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYI WAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAY KQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGL YQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 381)

[0534] In some embodiments, the CAR construct shown in SEQ ID NO: 381 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., SFFV promoter, EF1α promoter, tEF1a promoter, hPGK promoter, SFFV promoter or MND promoter).

[0535] 7. CAR Clone 7

[0536] As described herein, an exemplary CAR construct comprises a CLL-1 binding domain scFv (comprising SEQ ID NO:99), a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) co-stimulatory domain, and a CD3ζ intracellular signaling domain.

[0537] In some embodiments, the CAR comprises the amino acid sequence shown in SEQ ID NO: 382, ​​or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence shown in SEQ ID NO: 382.

[0538] QSALTQPPSASGSPGQSVTISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYEVGKRPSGVPDRFSGSKSGNTASLTVSGLQAEDEADYYCSSYTSSSTRVFGGGTKVTVLGGGGSGGGGS GGGGSEVQLVQSGAEVKKPGASVKVSCKVSGYTLTELSMHWVRQAPGKGLEWMGGFDPEDGETIYAQKFQGRVTMTEDTSTDTAYMELSSLRSEDTAVYYCATDPHMDVWGQGTMVTVSS TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTC GVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLY NELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTAT KDTYDALHMQALPPR (SEQ ID NO: 382)

[0539] In some embodiments, the CAR construct shown in SEQ ID NO: 382 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., SFFV promoter, EF1α promoter, tEF1a promoter, hPGK promoter, SFFV promoter or MND promoter).

[0540] 8. CAR Clone 8

[0541] As described herein, an exemplary CAR construct comprises a CLL-1 binding domain scFv (comprising SEQ ID NO: 113), a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) co-stimulatory domain, and a CD3ζ intracellular signaling domain.

[0542] In some embodiments, the CAR comprises the amino acid sequence shown in SEQ ID NO: 383, or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence shown in SEQ ID NO: 383.

[0543] DIQMTQSPSSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIKGGGGSGGGGSGGG GSQVQLVQSGAEVKKPGSSVKVSCKASGGTFTSYGISWVRQAPGQGLEWMGWISAYNGNTNYAQKLQGRVTMTTDTSSTAYMELRSLRAEDTAVYYCALPTADDAFDIWGQGTTVTVSS TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTC GVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLY NELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTAT KDTYDALHMQALPPR (SEQ ID NO: 383)

[0544] In some embodiments, the CAR construct shown in SEQ ID NO: 383 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., SFFV promoter, EF1α promoter, tEF1a promoter, hPGK promoter, SFFV promoter or MND promoter).

[0545] 9. CAR Clone 9

[0546] As described herein, an exemplary CAR construct comprises a CLL-1 binding domain scFv (comprising SEQ ID NO: 127), a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) co-stimulatory domain, and a CD3ζ intracellular signaling domain.

[0547] In some embodiments, the CAR comprises the amino acid sequence shown in SEQ ID NO: 384, or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence shown in SEQ ID NO: 384.

[0548] SYELTQPPSVSVAPGKTARITCGGNNIGSKSVHWYQQKPGQAPVLVVYDDSDRPSGIPERFSGSNSGNTATLTISRVEAGDEADYYCQVWDSGSDHPVVSGGGTQLIILGGGGSGGGGS GGGGSQVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAIGGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCANIDGTFWGQGTTVTVSS TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGV LLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNE LNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKD TYDALHMQALPPR (SEQ ID NO: 384)

[0549] In some embodiments, the CAR construct shown in SEQ ID NO: 384 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., SFFV promoter, EF1α promoter, tEF1a promoter, hPGK promoter, SFFV promoter or MND promoter).

[0550] 10. CAR Clone 10

[0551] As described herein, an exemplary CAR construct comprises a CLL-1 binding domain scFv (comprising SEQ ID NO: 141), a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) co-stimulatory domain, and a CD3ζ intracellular signaling domain.

[0552] In some embodiments, the CAR comprises the amino acid sequence shown in SEQ ID NO: 385, or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence shown in SEQ ID NO: 385.

[0553] DIQMTQSPSFLSASVGDRVTITCRASQGISSYLAWYQQKPGKAPKLLIYSASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYNSPTFGQGTRLEIKGGGGSGGGGSGGG GSQVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWMNPNSGNTGYAQKFQGRVTMTRNTSISTAYLELTSLTSDDTAVYYCARGDTGDFFDHWGQGTLVTVSS TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCG VLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYN ELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATK DTYDALHMQALPPR (SEQ ID NO: 385)

[0554] In some embodiments, the CAR construct shown in SEQ ID NO: 385 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., SFFV promoter, EF1α promoter, tEF1a promoter, hPGK promoter, SFFV promoter or MND promoter).

[0555] 11. CAR Clone 11

[0556] As described herein, an exemplary CAR construct comprises a CLL-1 binding domain scFv (comprising SEQ ID NO: 155), a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) co-stimulatory domain, and a CD3ζ intracellular signaling domain.

[0557] In some embodiments, the CAR comprises the amino acid sequence shown in SEQ ID NO: 386, or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence shown in SEQ ID NO: 386.

[0558] QSVLTQPASVSGSPGQSITISCTGTSSDVGASNSVSWYQRHPGKPPKLMIYDVSNRPSGISNRFSGSKSGNTASLTISGLQSEDEADYYCSSYTGSSTFVVFGGGTQLIILGGGGSGGGGSGG GGSEVQLVESGGGVVQPGGSLRLSCAASGFTFSSYWMSWVRQAPGKGLEWVANIRQDGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDAAVYYCAREQDTAMVAFDYWGQGTLVTVSS TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWA PLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQ GQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQ GLSTATKDTYDALHMQALPPR (SEQ ID NO: 386)

[0559] In some embodiments, the CAR construct shown in SEQ ID NO: 386 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., SFFV promoter, EF1α promoter, tEF1a promoter, hPGK promoter, SFFV promoter or MND promoter).

[0560] 12. CAR Clone 12

[0561] As described herein, an exemplary CAR construct comprises a CLL-1 binding domain scFv (comprising SEQ ID NO: 169), a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) co-stimulatory domain, and a CD3ζ intracellular signaling domain.

[0562] In some embodiments, the CAR comprises the amino acid sequence shown in SEQ ID NO: 387, or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence shown in SEQ ID NO: 387.

[0563] DIQMTQSPSSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTDFTLTISSPQPEDLATYYCQQANSFPFTFGQGTKVEIKGGGGSGGGGSGG GGSQVQLVQSGAEVKKPGSSVKVSCKASGYSFTRNDITWVRQANGRGLEWLGRLNPNNGDTVYAEVFQGRVAMTRDTSTDTAYMELASLKSSDDTAVYFCARGFWSFDVWGQGTMVTVSS TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGV LLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNE LNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKD TYDALHMQALPPR (SEQ ID NO: 387)

[0564] In some embodiments, the CAR construct shown in SEQ ID NO: 387 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., SFFV promoter, EF1α promoter, tEF1a promoter, hPGK promoter, SFFV promoter or MND promoter).

[0565] 13. CAR Clone 13

[0566] As described herein, an exemplary CAR construct comprises a CLL-1 binding domain VHH (comprising SEQ ID NO: 174), a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) co-stimulatory domain, and a CD3ζ intracellular signaling domain.

[0567] In some embodiments, the CAR comprises the amino acid sequence shown in SEQ ID NO: 388, or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence shown in SEQ ID NO: 388.

[0568] QVQLVQSGGGLVQPGGSLRLSCAASSFAFSAYEMSWVRQAPGQRLEWVSGITGSGGTTYYEDSVKGRFTISRDNSKNTLYLQMNTLRAEDTAMYYCVSHLGGTYGSGFSWGQGTLVTVSSS TTTPAPRPPTPAPTIASQPLSLR PEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSC RFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQK DKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 388)

[0569] In some embodiments, the CAR construct shown in SEQ ID NO: 388 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., SFFV promoter, EF1α promoter, tEF1a promoter, hPGK promoter, SFFV promoter or MND promoter).

[0570] 14. CAR Clone 14

[0571] As described herein, an exemplary CAR construct comprises a CLL-1 binding domain VHH (comprising SEQ ID NO: 179), a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) co-stimulatory domain, and a CD3ζ intracellular signaling domain.

[0572] In some embodiments, the CAR comprises the amino acid sequence shown in SEQ ID NO: 389, or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence shown in SEQ ID NO: 389.

[0573] QVQLVQSGGGLVQPGGSLRLSCAASDFAFDYYEMSWVRQAPGQGLEWVSSISGSGGTTLYADSVKGRFTISRDNSKNTLYLQMNTLRAEDTALYYCATEDPSSVYWGQGTLVTVSS TTTPAPRPPTPAPTIASQPLSLRPEACR PAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEE EEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAE AYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 389)

[0574] In some embodiments, the CAR construct shown in SEQ ID NO: 389 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., SFFV promoter, EF1α promoter, tEF1a promoter, hPGK promoter, SFFV promoter or MND promoter).

[0575] 15. CAR Clone 15

[0576] As described herein, an exemplary CAR construct comprises a CLL-1 binding domain VHH (comprising SEQ ID NO: 184), a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) co-stimulatory domain, and a CD3ζ intracellular signaling domain.

[0577] In some embodiments, the CAR comprises the amino acid sequence shown in SEQ ID NO: 390, or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence shown in SEQ ID NO: 390.

[0578] QVQLVQSGGGLVQPGGSLRLSCAASSFSFSDYEMSWVRQAPGQRLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNTLRAEDTATYYCVRVPLGHCSSTDCANPYWGQGTLVTVSS TTTPAPRPPTPAPTIASQPL SLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDG CSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNE LQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 390)

[0579] In some embodiments, the CAR construct shown in SEQ ID NO: 390 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., SFFV promoter, EF1α promoter, tEF1a promoter, hPGK promoter, SFFV promoter or MND promoter).

[0580] 16. CAR Clone 16

[0581] As described herein, an exemplary CAR construct comprises a CLL-1 binding domain VHH (comprising SEQ ID NO: 189), a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) co-stimulatory domain, and a CD3ζ intracellular signaling domain.

[0582] In some embodiments, the CAR comprises the amino acid sequence shown in SEQ ID NO: 391, or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence shown in SEQ ID NO: 391.

[0583] QVQLVQSGGGLVQPGGSLRLSCAASSFDFADYEMSWVRQAPGQRLEWVSTVSGSGGDTWYADSVKGRFTISRDNSKNTLYLQMNTLRAEDTAVYYCAKVGPKWELVDWGQGTLVTVSS TTTPAPRPPTPAPTIASQPLSLRPEA CRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFP EEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKM AEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 391)

[0584] In some embodiments, the CAR construct shown in SEQ ID NO: 391 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., SFFV promoter, EF1α promoter, tEF1a promoter, hPGK promoter, SFFV promoter or MND promoter).

[0585] 17. CAR Clone 17

[0586] As described herein, an exemplary CAR construct comprises a CLL-1 binding domain VHH (comprising SEQ ID NO: 194), a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) co-stimulatory domain, and a CD3ζ intracellular signaling domain.

[0587] In some embodiments, the CAR comprises the amino acid sequence shown in SEQ ID NO: 392, or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence shown in SEQ ID NO: 392.

[0588] QVQLVQSGGGLVQPGGSLRLSCAASSFSFSDYEMSWVRQAPGKGLEWVSLISGDGGSTYYADSVKGRFTISRDNSKNTLYLQMNTLRAEDTAMYYCARDPYYYGSGRITKLDYWGQGTLVTVSS TTTPAPRPPTPAPTIASQPL SLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDG CSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNE LQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 392)

[0589] In some embodiments, the CAR construct shown in SEQ ID NO: 392 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., SFFV promoter, EF1α promoter, tEF1a promoter, hPGK promoter, SFFV promoter or MND promoter).

[0590] 18. CAR Clone 18

[0591] As described herein, an exemplary CAR construct comprises a CLL-1 binding domain VHH (comprising SEQ ID NO: 199), a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) co-stimulatory domain, and a CD3ζ intracellular signaling domain.

[0592] In some embodiments, the CAR comprises the amino acid sequence shown in SEQ ID NO: 393, or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence shown in SEQ ID NO: 393.

[0593] QVQLVQSGGGLVQPGGSLRLSCAASGFSFSTYEMSWVRQAPGQRLEWLSGIIGNSGRTYYSDSVKGRFTISRDNSKNTLYLQMNTLRAEDTAMYYCARSRGGFDAFDIWGQGTMVTVSS TTTPAPRPPTPAPTIASQPLSLRPE ACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRF PEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDK MAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 393)

[0594] In some embodiments, the CAR construct shown in SEQ ID NO: 393 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., SFFV promoter, EF1α promoter, tEF1a promoter, hPGK promoter, SFFV promoter or MND promoter).

[0595] 19. CAR Clone 19

[0596] As described herein, an exemplary CAR construct comprises a CLL-1 binding domain VHH (comprising SEQ ID NO: 204), a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) co-stimulatory domain, and a CD3ζ intracellular signaling domain.

[0597] In some embodiments, the CAR comprises the amino acid sequence shown in SEQ ID NO: 394, or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence shown in SEQ ID NO: 394.

[0598] QVQLVQSGGGLVQPGGSLRLSCAASDFSFASYEMSWVRQAPGQGLEWVALIDNGGKTYYADSVKGRFTISRDNSKNTLYLQMNTLRAEDAALYYCVRDGGVAGPPTWGQGTLVTVSS TTTPAPRPPTPAPTIASQPLSLRPEAC RPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPE EEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMA EAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO:394)

[0599] In some embodiments, the CAR construct shown in SEQ ID NO: 394 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., SFFV promoter, EF1α promoter, tEF1a promoter, hPGK promoter, SFFV promoter or MND promoter).

[0600] 20. CAR Clone 20

[0601] As described herein, an exemplary CAR construct comprises a CLL-1 binding domain VHH (comprising SEQ ID NO: 209), a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) co-stimulatory domain, and a CD3ζ intracellular signaling domain.

[0602] In some embodiments, the CAR comprises the amino acid sequence shown in SEQ ID NO: 395, or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence shown in SEQ ID NO: 395.

[0603] QVQLVQSGGGLVQPGGSLRLSCAASDFSFSYYEMSWVRQAPGKGLEWVSTISGSGDSTYYADSVKGRFTISRDNTKNTLYLQMNTLRAEDTATYYCMTDGETWGTHRYTVYWGQGALVTVSS TTTPAPRPPTPAPTIASQPLSL RPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCS CRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQ KDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO:395)

[0604] In some embodiments, the CAR construct shown in SEQ ID NO: 395 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., SFFV promoter, EF1α promoter, tEF1a promoter, hPGK promoter, SFFV promoter or MND promoter).

[0605] 21. CAR Clone 21

[0606] As described herein, an exemplary CAR construct comprises a CLL-1 binding domain VHH (comprising SEQ ID NO: 214), a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) co-stimulatory domain, and a CD3ζ intracellular signaling domain.

[0607] In some embodiments, the CAR comprises the amino acid sequence shown in SEQ ID NO: 396, or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence shown in SEQ ID NO: 396.

[0608] QVQLVQSGGGLVQPGGSLRLSCAASDFSFYFYEMRWVRQAPGQGLEWVSTISGSGDSTYYADSVKGRFTISRDNSKNTLYLQMNTLRAEDTAVYYCARDPEVGGITGEYWGQGTLVTVSS TTTPAPRPPTPAPTIASQPLSLRP EACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCR FPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKD KMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO:396)

[0609] In some embodiments, the CAR construct shown in SEQ ID NO: 396 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., SFFV promoter, EF1α promoter, tEF1a promoter, hPGK promoter, SFFV promoter or MND promoter).

[0610] 22. CAR Clone 22

[0611] As described herein, an exemplary CAR construct comprises a CLL-1 binding domain VHH (comprising SEQ ID NO: 219), a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) co-stimulatory domain, and a CD3ζ intracellular signaling domain.

[0612] In some embodiments, the CAR comprises the amino acid sequence shown in SEQ ID NO: 397, or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence shown in SEQ ID NO: 397.

[0613] QVQLVQSGGGLVQPGGSLRLSCAASAFDFASYEMSWVRQAPGQRLEWVSGISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNTLRAEDTALYYCVKHTIRGVPEVWGQGTMVTVSS TTTPAPRPPTPAPTIASQPLSLRPEA CRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFP EEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKM AEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 397)

[0614] In some embodiments, the CAR construct shown in SEQ ID NO: 397 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., SFFV promoter, EF1α promoter, tEF1a promoter, hPGK promoter, SFFV promoter or MND promoter).

[0615] 23. CAR Clone 23

[0616] As described herein, an exemplary CAR construct comprises a CLL-1 binding domain VHH (comprising SEQ ID NO: 224), a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) co-stimulatory domain, and a CD3ζ intracellular signaling domain.

[0617] In some embodiments, the CAR comprises the amino acid sequence shown in SEQ ID NO: 398, or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence shown in SEQ ID NO: 398.

[0618] QVQLVQSGGGLVQPGGSLRLSCAASYFDFDDYEMSWVRQAPGKGLEWVAVISGGGRDTWYADSVKGRFTISRDNSKNTLYLQMNTLRAEDTAVYYCARDPYYQVDDKSAYGAFDIWGQGTAVTVSS TTTPAPRPPTPAPTIASQ PLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEE DGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLY NELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 398)

[0619] In some embodiments, the CAR construct shown in SEQ ID NO: 398 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., SFFV promoter, EF1α promoter, tEF1a promoter, hPGK promoter, SFFV promoter or MND promoter).

[0620] 24. CAR Clone 24

[0621] As described herein, an exemplary CAR construct comprises a CLL-1 binding domain VHH (comprising SEQ ID NO: 229), a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) co-stimulatory domain, and a CD3ζ intracellular signaling domain.

[0622] In some embodiments, the CAR comprises the amino acid sequence shown in SEQ ID NO: 399, or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence shown in SEQ ID NO: 399.

[0623] QVQLVQSGGGLVQPGGSLRLSCAASAFDFYDYEMSWVRQAPGQGLEWVSAISNSGDATYYADSVKGRFTISRDNSKNTLYLQMNTLRAEDTAVYYCTTIEDTLPSWGQGTLVTVSS TTTPAPRPPTPAPTIASQPLSLRPEACR PAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEE EEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAE AYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 399)

[0624] In some embodiments, the CAR construct shown in SEQ ID NO: 399 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., SFFV promoter, EF1α promoter, tEF1a promoter, hPGK promoter, SFFV promoter or MND promoter).

[0625] 25. CAR Clone 25

[0626] As described herein, an exemplary CAR construct comprises a CLL-1 binding domain VHH (comprising SEQ ID NO: 234), a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) co-stimulatory domain, and a CD3ζ intracellular signaling domain.

[0627] In some embodiments, the CAR comprises the amino acid sequence shown in SEQ ID NO: 400, or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence shown in SEQ ID NO: 400.

[0628] QVQLVQSGGGLVQPGGSLRLSCAASSFDFSSYEMSWVRQAPGQGLEWVSLISGSGDSTYYADSVKGRFTISRDNSKNTLYLQMNTLRAEDTALYYCARDPYYGGEYYFDYWGQGTLVTVSS TTTPAPRPPTPAPTIASQPLSLR PEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSC RFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQK DKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 400)

[0629] In some embodiments, the CAR construct shown in SEQ ID NO: 400 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., SFFV promoter, EF1α promoter, tEF1a promoter, hPGK promoter, SFFV promoter or MND promoter).

[0630] 26. CAR Clone 26

[0631] As described herein, an exemplary CAR construct comprises a CLL-1 binding domain VHH (comprising SEQ ID NO: 239), a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) co-stimulatory domain, and a CD3ζ intracellular signaling domain.

[0632] In some embodiments, the CAR comprises the amino acid sequence shown in SEQ ID NO: 401, or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence shown in SEQ ID NO: 401.

[0633] QVQLVQSGGGLVQPGGSLRLSCAASAFSFSSYEMSWVRQAPGQRLEWVAHINGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNTLRAEDTATYYCASSYSSSSQFEYWGQGTLVTVSS TTTPAPRPPTPAPTIASQPLSLRPE ACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRF PEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDK MAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO:401)

[0634] In some embodiments, the CAR construct shown in SEQ ID NO: 401 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., SFFV promoter, EF1α promoter, tEF1a promoter, hPGK promoter, SFFV promoter or MND promoter).

[0635] 27. CAR Clone 27

[0636] As described herein, an exemplary CAR construct comprises a CLL-1 binding domain VHH (comprising SEQ ID NO: 244), a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) co-stimulatory domain, and a CD3ζ intracellular signaling domain.

[0637] In some embodiments, the CAR comprises the amino acid sequence shown in SEQ ID NO: 402, or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence shown in SEQ ID NO: 402.

[0638] QVQLVQSGGGLVQPGGSLRLSCAASDFSFADYEMSWVRQAPGQGLEWVSLISGDGGSTYYADSVKGRFTISRDNSKNTLYLQMNTLRAEDTAVYYCARDPDSGSYWGGDYWGQGTLVTVSS TTTPAPRPPTPAPTIASQPLSLR PEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSC RFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQK DKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO:402)

[0639] In some embodiments, the CAR construct shown in SEQ ID NO: 402 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., SFFV promoter, EF1α promoter, tEF1a promoter, hPGK promoter, SFFV promoter or MND promoter).

[0640] 28. CAR Clone 28

[0641] As described herein, an exemplary CAR construct comprises a CLL-1 binding domain VHH (comprising SEQ ID NO: 249), a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) co-stimulatory domain, and a CD3ζ intracellular signaling domain.

[0642] In some embodiments, the CAR comprises the amino acid sequence shown in SEQ ID NO: 403, or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence shown in SEQ ID NO: 403.

[0643] QVQLVQSGGGLVQPGGSLRLSCAASDFYFADYEMSWVRQAPGKGLEWVSLISGDGGSTYYADSVKGRFTISRDNSKNTLYLQMNTLRAEDTATYYCARDPWDVWGQGTTVTVSS TTTPAPRPPTPAPTIASQPLSLRPEACRPA AGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEE GGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAY SEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO:403)

[0644] In some embodiments, the CAR construct shown in SEQ ID NO: 403 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., SFFV promoter, EF1α promoter, tEF1a promoter, hPGK promoter, SFFV promoter or MND promoter).

[0645] 29. CAR Clone 29

[0646] As described herein, an exemplary CAR construct comprises a CLL-1 binding domain VHH (comprising SEQ ID NO: 254), a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) co-stimulatory domain, and a CD3ζ intracellular signaling domain.

[0647] In some embodiments, the CAR comprises the amino acid sequence shown in SEQ ID NO: 404, or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence shown in SEQ ID NO: 404.

[0648] QVQLVQSGGGLVQPGGSLRLSCAASAFDFDSYEMSWVRQAPGQRLEWVSTISGHGGNTYYADSVKGRFTISRDNSKNTLYLQMNTLRAEDTAVYYCVRGDEAEMSTIRWGQGTLVTVSS TTTPAPRPPTPAPTIASQPLSLRPE ACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRF PEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDK MAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO:404)

[0649] In some embodiments, the CAR construct shown in SEQ ID NO: 404 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., SFFV promoter, EF1α promoter, tEF1a promoter, hPGK promoter, SFFV promoter or MND promoter).

[0650] 30. CAR Clone 30

[0651] As described herein, an exemplary CAR construct comprises a CLL-1 binding domain VHH (comprising SEQ ID NO: 259), a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) co-stimulatory domain, and a CD3ζ intracellular signaling domain.

[0652] In some embodiments, the CAR comprises the amino acid sequence shown in SEQ ID NO: 405, or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence shown in SEQ ID NO: 405.

[0653] QVQLVQSGGGLVQPGGSLRLSCAASDFDFDAYEMSWVRQAPGQGLEWVSVIYSDGSTYYADSVKGRFTISRDNSKNTLYLQMNTLRAEDTAIYYCAREKDNGDYGDFESWGQGTLVTVSS TTTPAPRPPTPAPTIASQPLSLRP EACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCR FPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKD KMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 405)

[0654] In some embodiments, the CAR construct shown in SEQ ID NO: 405 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., SFFV promoter, EF1α promoter, tEF1a promoter, hPGK promoter, SFFV promoter or MND promoter).

[0655] 31. CAR Clone 31

[0656] As described herein, an exemplary CAR construct comprises a CLL-1 binding domain VHH (comprising SEQ ID NO: 264), a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) co-stimulatory domain, and a CD3ζ intracellular signaling domain.

[0657] In some embodiments, the CAR comprises the amino acid sequence shown in SEQ ID NO: 406, or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence shown in SEQ ID NO: 406.

[0658] QVQLVQSGGGLVQPGGSLRLSCAASSFAFSDYEMSWVRQAPGQGLEWVSTISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNTLRAEDTAVYYCARDPADYDILTGGDYWGQGTLVTVSS TTTPAPRPPTPAPTIASQPLSL RPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCS CRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQ KDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 406)

[0659] In some embodiments, the CAR construct shown in SEQ ID NO: 406 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., SFFV promoter, EF1α promoter, tEF1a promoter, hPGK promoter, SFFV promoter or MND promoter).

[0660] 32. CAR Clone 32

[0661] As described herein, an exemplary CAR construct comprises a CLL-1 binding domain VHH (comprising SEQ ID NO: 269), a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) co-stimulatory domain, and a CD3ζ intracellular signaling domain.

[0662] In some embodiments, the CAR comprises the amino acid sequence shown in SEQ ID NO: 407, or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence shown in SEQ ID NO: 407.

[0663] QVQLVQSGGGLVQPGGSLRLSCAASDFDFSDYEMSWVRQAPGKGLEWVSAISDSGDTTYYADSVKGRFTISRDNSKNTLYLQMNTLRAEDTALYYCAKAPYYDILTGDDAFDTWGQGTMVTVSS TTTPAPRPPTPAPTIASQPL SLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDG CSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNE LQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 407)

[0664] In some embodiments, the CAR construct shown in SEQ ID NO: 407 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., SFFV promoter, EF1α promoter, tEF1a promoter, hPGK promoter, SFFV promoter or MND promoter).

[0665] 33. CAR Clone 33

[0666] As described herein, an exemplary CAR construct comprises a CLL-1 binding domain VHH (comprising SEQ ID NO: 275), a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) co-stimulatory domain, and a CD3ζ intracellular signaling domain.

[0667] In some embodiments, the CAR comprises the amino acid sequence shown in SEQ ID NO: 408, or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence shown in SEQ ID NO: 408.

[0668] QVQLVQSGGGLVQPGGSLRLSCAASYFDFDAYEMSWVRQAPGKGLEWVSLISGDGGSTYYADSVKGRFTISRDNSKNTLYLQMNTLRAEDTAVYFCVRDSGYSSFHWGQGTQVTVSSS TTTPAPRPPTPAPTIASQPLSLRPEA CRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFP EEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKM AEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 408)

[0669] In some embodiments, the CAR construct shown in SEQ ID NO: 408 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., SFFV promoter, EF1α promoter, tEF1a promoter, hPGK promoter, SFFV promoter or MND promoter).

[0670] 34. CAR Clone 34

[0671] As described herein, an exemplary CAR construct comprises a CLL-1 binding domain VHH (comprising SEQ ID NO: 280), a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) co-stimulatory domain, and a CD3ζ intracellular signaling domain.

[0672] In some embodiments, the CAR comprises the amino acid sequence shown in SEQ ID NO: 409, or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence shown in SEQ ID NO: 409.

[0673] QVQLVQSGGGLVQPGGSLRLSCAASYFDFAYYEMSWVRQAPGKGLEWVSLISGDGGSTYYADSVKGRFTISRDNSKNTLYLQMNTLRAEDTAVYYCARDPYYGGEYYFDYWGQGTLVTVSS TTTPAPRPPTPAPTIASQPLSLR PEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSC RFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQK DKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 409)

[0674] In some embodiments, the CAR construct shown in SEQ ID NO: 409 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., SFFV promoter, EF1α promoter, tEF1a promoter, hPGK promoter, SFFV promoter or MND promoter).

[0675] 35. CAR Clone 35

[0676] As described herein, an exemplary CAR construct comprises a CLL-1 binding domain VHH (comprising SEQ ID NO: 285), a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) co-stimulatory domain, and a CD3ζ intracellular signaling domain.

[0677] In some embodiments, the CAR comprises the amino acid sequence shown in SEQ ID NO: 410, or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence shown in SEQ ID NO: 410.

[0678] QVQLVQSGGGLVQPGGSLRLSCAASAFAFSSYEMSWVRQAPGKGLEWVSLISGDGGSTYYADSVKGRFTISRDNTKNTLYLQMNTLRAEDTAVYYCVRETESQDVVYWGQGTLVTVSS TTTPAPRPPTPAPTIASQPLSLRPEA CRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFP EEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKM AEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 410)

[0679] In some embodiments, the CAR construct shown in SEQ ID NO: 410 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., SFFV promoter, EF1α promoter, tEF1a promoter, hPGK promoter, SFFV promoter or MND promoter).

[0680] 36. CAR Clone 36

[0681] As described herein, an exemplary CAR construct comprises a CLL-1 binding domain VHH (comprising SEQ ID NO: 290), a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) co-stimulatory domain, and a CD3ζ intracellular signaling domain.

[0682] In some embodiments, the CAR comprises the amino acid sequence shown in SEQ ID NO: 411, or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence shown in SEQ ID NO: 411.

[0683] QVQLVQSGGGLVQPGGSLRLSCAASDFDFSDYEMSWVRQAPGKGLEWVSGIYSDGGTYYSDSVKGRFSISRDNSKNTLYLQMNTLRAEDTAVYYCARDPYYYGSGNLRFNDYWGQGTLVTVSS TTTPAPRPPTPAPTIASQPLS LRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGC SCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNEL QKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 411)

[0684] In some embodiments, the CAR construct shown in SEQ ID NO: 411 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., SFFV promoter, EF1α promoter, tEF1a promoter, hPGK promoter, SFFV promoter or MND promoter).

[0685] 37. CAR Clone 37

[0686] As described herein, an exemplary CAR construct comprises a CLL-1 binding domain VHH (comprising SEQ ID NO: 295), a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) co-stimulatory domain, and a CD3ζ intracellular signaling domain.

[0687] In some embodiments, the CAR comprises the amino acid sequence shown in SEQ ID NO: 412, or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence shown in SEQ ID NO: 412.

[0688] QVQLVQSGGGLVQPGGSLRLSCAASSFDFDDYEMSWVRQAPGKGLEWVSLISGDGGSTYYADSVKGRFTISRDNSKNTLYLQMNTLRAEDTAVYYCARDPFANQQGGDYWGQGTLVTVSS TTTPAPRPPTPAPTIASQPLSLRP EACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCR FPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKD KMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 412)

[0689] In some embodiments, the CAR construct shown in SEQ ID NO: 412 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., SFFV promoter, EF1α promoter, tEF1a promoter, hPGK promoter, SFFV promoter or MND promoter).

[0690] 38. CAR Clone 38

[0691] As described herein, an exemplary CAR construct comprises a CLL-1 binding domain scFv (comprising SEQ ID NO: 309), a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) co-stimulatory domain, and a CD3ζ intracellular signaling domain.

[0692] In some embodiments, the CAR comprises the amino acid sequence shown in SEQ ID NO: 413, or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence shown in SEQ ID NO: 413.

[0693] DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYTASSLQSGVPSRFSGSESGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVDIKGGGGSGGGGSGGG GSQVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWINPNSGGTNYAQKFQGRVTLTRDTSITTAYLELTSLTSDDTAVYYCARGDTGDFFDHWGQGTLVTVSS TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTC GVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLY NELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTAT KDTYDALHMQALPPR (SEQ ID NO: 413)

[0694] In some embodiments, the CAR construct shown in SEQ ID NO: 413 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., SFFV promoter, EF1α promoter, tEF1a promoter, hPGK promoter, SFFV promoter or MND promoter).

[0695] 39. CAR Clone 39

[0696] As described herein, an exemplary CAR construct comprises a CLL-1 binding domain scFv (comprising SEQ ID NO: 323), a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) co-stimulatory domain, and a CD3ζ intracellular signaling domain.

[0697] In some embodiments, the CAR comprises the amino acid sequence shown in SEQ ID NO: 414, or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence shown in SEQ ID NO: 414.

[0698] DIQMTQSPSSSLSASVGDRVTTTCRASQSISLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPITFGQGTRLEIKGGGGSGGGGSGGG GSQVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWMNPSSGNTGYAHEFQGRVTMTRNTSTGTAYMELSGLRSEDTAVYYCARGDTGDSFDYWGQGTLVTVSS TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTC GVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLY NELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTAT KDTYDALHMQALPPR (SEQ ID NO: 414)

[0699] In some embodiments, the CAR construct shown in SEQ ID NO: 414 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., SFFV promoter, EF1α promoter, tEF1a promoter, hPGK promoter, SFFV promoter or MND promoter).

[0700] 40. CAR Clone 40

[0701] As described herein, an exemplary CAR construct comprises a CLL-1 binding domain scFv (comprising SEQ ID NO: 337), a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) co-stimulatory domain, and a CD3ζ intracellular signaling domain.

[0702] In some embodiments, the CAR comprises the amino acid sequence shown in SEQ ID NO: 415, or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence shown in SEQ ID NO: 415.

[0703] QSVLTQPPSVSAAPGQKVTISCSGSSSNIGNNYVSWYQQLPGTAPKLLIYDNNKRPSGIPDRFSGSESGTSATLGITGLQTGDEADYYCGTWDSSLSAWVFGGGTQLIILGGGGSGGGGSGGGG SQVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGRTHYRSKWYNDYAVSVKSRITISADTSKNQFSLQLNSVTPEDTAVYYCARDRYTVRPDAFDIWGQGTTVTVSS TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIY IWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPA YKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDG LYQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 415)

[0704] In some embodiments, the CAR construct shown in SEQ ID NO: 415 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., SFFV promoter, EF1α promoter, tEF1a promoter, hPGK promoter, SFFV promoter or MND promoter).

[0705] 41. CAR Clone 41

[0706] As described herein, an exemplary CAR construct comprises a CLL-1 binding domain scFv (comprising SEQ ID NO: 351), a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) co-stimulatory domain, and a CD3ζ intracellular signaling domain.

[0707] In some embodiments, the CAR comprises the amino acid sequence shown in SEQ ID NO: 416, or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence shown in SEQ ID NO: 416.

[0708] QSVLTQPASVSGSLGQSITISCTGTSRDVGGYNFVSWYQQHPGKAPKLIIFDVTTRPSGLSDRFSASKSGNTASLTISGLQAEDEADYFCGSYTASDTMLFGGGTKLTVLGGGGSGGGGSG GGGSQVQLLESGGGVVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSGISWNSGSIGYADSVKGRFTVSRDNSKNTLYQQMNGLRAEDTAVYYCAREGRPTAFDYWGQGTTVTVSS TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLA GTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQN QLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLS TATKDTYDALHMQALPPR (SEQ ID NO: 416)

[0709] In some embodiments, the CAR construct shown in SEQ ID NO: 416 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., SFFV promoter, EF1α promoter, tEF1a promoter, hPGK promoter, SFFV promoter or MND promoter).

[0710] 42. CAR Clone 42

[0711] As described herein, an exemplary CAR construct comprises a CLL-1 binding domain scFv (comprising SEQ ID NO: 365), a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) co-stimulatory domain, and a CD3ζ intracellular signaling domain.

[0712] In some embodiments, the CAR comprises the amino acid sequence shown in SEQ ID NO: 417, or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence shown in SEQ ID NO: 417.

[0713] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPVTFGQGTKLEIKGGGGSGGGGSGGG GSQVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVIMTTDTSTSTAHMELRSLRSDDTAVYYCARDADEFGAFDIWGQGTTVTVSS TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGT CGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQL YNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTA TKDTYDALHMQALPPR (SEQ ID NO: 417)

[0714] In some embodiments, the CAR construct shown in SEQ ID NO: 417 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., SFFV promoter, EF1α promoter, tEF1a promoter, hPGK promoter, SFFV promoter or MND promoter).

[0715] 43. CAR clone 103.28z (control)

[0716] As described herein, an exemplary CAR construct comprises a CLL-1 binding domain scFv (comprising SEQ ID NO:922), a CD28 transmembrane domain, a CD28 hinge domain, a CD137 (4-1BB) co-stimulatory domain, and a CD3ζ intracellular signaling domain.

[0717] In some embodiments, the CAR comprises the amino acid sequence shown in SEQ ID NO: 922, or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence shown in SEQ ID NO: 922.

[0718] QVQLQESGPGLVKPSETLSLTCTVSGGSISSYYWSWIRQPPGKGLEWIGYIYYSGSTNYNPSLKSRVTISSVDTSKNQFSLKLSSVTAADTAVYYCVSLVYCGGDCYSGFDYWGQGTLVTVSS GGGGSGGGGSGGGGSDIQLTQSPSSSLSASVGDRVSFTCQASQDINNFLNWYQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQYGNLPFTFGGGTKVEIK AAAIEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWVLVVVGGV LACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSKRGRKKLLYIFKQPFMRP VQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRK NPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 922)

[0719] In some embodiments, the CAR construct shown in SEQ ID NO: 922 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., SFFV promoter, EF1α promoter, tEF1a promoter, hPGK promoter, SFFV promoter or MND promoter).

[0720] 44. CAR clone 103.bbz (control)

[0721] As described herein, an exemplary CAR construct comprises a CLL-1 binding domain scFv (comprising SEQ ID NO:923), a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) co-stimulatory domain, and a CD3ζ intracellular signaling domain.

[0722] In some embodiments, the CAR comprises the amino acid sequence shown in SEQ ID NO: 923, or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence shown in SEQ ID NO: 923.

[0723] DIQLTQSPSSSLSASVGDRVSFTCQASQDINNFLNWYQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQYGNLPFTFGGGTKVEIKGGGGSGGGGSGGGGS QVQLQESGPGLVKPSETLSLTCTVSGGSISSYYWSWIRQPPGKGLEWIGYIYYSGSTNYNPSLKSRVTISSVDTSKNQFSLKLSSVTAADTAVYYCVSLVYCGGDCYSGFDYWGQGTLVTVSS TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPL AGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQ NQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGL STATKDTYDALHMQALPPR (SEQ ID NO: 923)

[0724] In some embodiments, the CAR construct shown in SEQ ID NO: 923 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., SFFV promoter, EF1α promoter, tEF1a promoter, hPGK promoter, SFFV promoter or MND promoter).

[0725] 45. CAR clone h104

[0726] As described herein, an exemplary CAR construct comprises a CLL-1 binding domain scFv (comprising SEQ ID NO:924), a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) co-stimulatory domain, and a CD3ζ intracellular signaling domain.

[0727] In some embodiments, the CAR comprises the amino acid sequence shown in SEQ ID NO: 924, or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence shown in SEQ ID NO: 924.

[0728] DIQMTQSPSSSLSASVGDRVTITCKSSQSLLYSDNQKNYLAWYQQKPGKAPKLLIYWASTRESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYTYPYTFGQGTKLEIKSSGGGGSGGGGSG GGGSEVQLVQSGAEVKKPGASVKVSCKASGYTFTGYHMHWVRQAPGQRLEWMGRINPYNGAASHNQKFKDRVTITRDTSASTAYMELSSLRSEDTAVYYCARGWDYDGGYYAMDYWGQGTLVTVSS TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFAC DIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSAD APAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKG HDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 924)

[0729] In some embodiments, the CAR construct shown in SEQ ID NO: 924 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., SFFV promoter, EF1α promoter, tEF1a promoter, hPGK promoter, SFFV promoter or MND promoter).

[0730] 46. ​​CAR clone m104

[0731] As described herein, an exemplary CAR construct comprises a CLL-1 binding domain scFv (comprising SEQ ID NO:925), a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) co-stimulatory domain, and a CD3ζ intracellular signaling domain.

[0732] In some embodiments, the CAR comprises the amino acid sequence shown in SEQ ID NO: 925, or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence shown in SEQ ID NO: 925.

[0733] DIVMSQSPSSLAVSVGEKVTMSCKSSQSLLYSDNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVKAEDLAVYYCQQYYTYPYTFGGGTKLEIKGGGGSGGGGSGG GGSEVQLQQSGPELVKPGASVKISCKASGYSFTGYHMHWVKQSHVKSLEWIGRINPYNGAASHNQKFKDKATLTVDKSSSTAYMELHSLTSEDSAVYYCARGWDYDGGYYAMDYWGQGTSVTVSS TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDI YIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAP AYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHD GLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 925)

[0734] In some embodiments, the CAR construct shown in SEQ ID NO: 925 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., SFFV promoter, EF1α promoter, tEF1a promoter, hPGK promoter, SFFV promoter or MND promoter).

[0735] 47. CAR Clone 108

[0736] As described herein, an exemplary CAR construct comprises a CLL-1 binding domain scFv (comprising SEQ ID NO:926), a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) co-stimulatory domain, and a CD3ζ intracellular signaling domain.

[0737] In some embodiments, the CAR comprises the amino acid sequence shown in SEQ ID NO: 926, or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence shown in SEQ ID NO: 926.

[0738] QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDMSWVRQAPGQGLEWMGAINPSGDFTSYNEKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGVGWSFLDYWGQGTLVTVSSGGG GSGGGGSGGGGSDIQMTQSPSSSLSASVGDRVTITCQASQDVRTWLAWYQQKPGKAPKLLIYSASSLQTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSNYLPFTFGQGTKVEIKSS TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAG TCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQ LYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLST ATKDTYDALHMQALPPR (SEQ ID NO: 926)

[0739] In some embodiments, the CAR construct shown in SEQ ID NO: 926 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., SFFV promoter, EF1α promoter, tEF1a promoter, hPGK promoter, SFFV promoter or MND promoter).

[0740] 48. CAR Clone 109

[0741] As described herein, an exemplary CAR construct comprises a CLL-1 binding domain scFv (comprising SEQ ID NO:927), a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) co-stimulatory domain, and a CD3ζ intracellular signaling domain.

[0742] In some embodiments, the CAR comprises the amino acid sequence shown in SEQ ID NO: 927, or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence shown in SEQ ID NO: 927.

[0743] QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYAMDWVRQAPGQGLEWMGWISGQSGSTSYNEKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCAKWLDGPWFDVWGQGTLVTVSSGGG GSGGGGSGGGGSDIQMTQSPSSSLSASVGDRVITTCKASEDIHSDLAWYQQKPGKAPKLLIYSASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAYYLPLTFGQGTKVEIKSS TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAG TCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQ LYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLST ATKDTYDALHMQALPPR (SEQ ID NO: 927)

[0744] In some embodiments, the CAR construct shown in SEQ ID NO: 927 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., SFFV promoter, EF1α promoter, tEF1a promoter, hPGK promoter, SFFV promoter or MND promoter).

[0745] 49. CAR Clone 110

[0746] As described herein, an exemplary CAR construct comprises a CLL-1 binding domain scFv (comprising SEQ ID NO:928), a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) co-stimulatory domain, and a CD3ζ intracellular signaling domain.

[0747] In some embodiments, the CAR comprises the amino acid sequence shown in SEQ ID NO: 928, or an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence shown in SEQ ID NO: 928.

[0748] QVQLVQSGAEVKKPGASVKVSCKASGYTFTHYAMDWVRQAPGQGLEWMGGISPQSGGTSYNEKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARVHGDYHFDYWGQGTLVTVSSGGG GSGGGGSGGGGSDIQMTQSPSSSLSASVGDRVTITCQASQDVSTDLAWYQQKPGKAPKLLIYHASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYNYPLTFGQGTKVEIKSS TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAG TCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQ LYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLST ATKDTYDALHMQALPPR (SEQ ID NO: 928)

[0749] In some embodiments, the CAR construct shown in SEQ ID NO: 928 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., SFFV promoter, EF1α promoter, tEF1a promoter, hPGK promoter, SFFV promoter or MND promoter).

[0750] Any fusion protein, such as any CAR described herein, can be expressed in a cell and thereby presented on the surface of the cell. In some embodiments, the cell can be an immune cell, such as a T cell (ie, a T lymphocyte) or a NK cell. The T cell lymphocyte can be any T cell, such as a cultured T cell, e.g., a primary T cell, or a T cell from a cultured T cell line, e.g., TIB-153 TM , Jurkat, SupT1, etc., or T cells obtained from a mammal (e.g., primary T cells).

[0751] Nucleotide sequence and expression

[0752] The present disclosure includes nucleotide sequences encoding any one or more anti-CLL-1 antibodies described herein (e.g., VHHs described herein), or portions thereof (e.g., one or more CDRs described herein), and / or one or more fusion proteins described herein. In various cases, such nucleotide sequences can be present in a vector such as an expression vector. In various cases, such nucleotides can be present in the genome of a cell (e.g., a cell of a subject in need of treatment or a cell for producing an antibody, e.g., a mammalian cell for producing an antibody).

[0753] In some embodiments, any of the antibodies described herein are encoded by a polynucleotide contained in a vector (e.g., a viral vector). Optionally, the polynucleotide encoding a polypeptide as described herein can be codon optimized to enhance expression or stability. Codon optimization can be performed according to any standard method known in the art. In some embodiments, the expression of the polypeptide can be driven by a promoter of constitutive expression or a promoter of inducible expression. In some embodiments, the antibodies as described herein include a signal peptide. The signal peptide can be derived from any protein with an extracellular domain or secreted. Antibodies as described herein can include any signal peptide known in the art.

[0754] Retroviruses, such as lentiviruses, provide a convenient platform for the delivery of nucleic acid sequences encoding genes of interest or chimeric genes. The selected nucleic acid sequence can be inserted into a vector using techniques known in the art and packaged in retroviral particles. The recombinant virus can then be isolated and delivered to cells, for example, in vitro or ex vivo. Retroviral systems are well known in the art and are described in, for example, U.S. Patent No. 5,219,740; Kurth and Bannert (2010) "Retroviruses: Molecular Biology, Genomics and Pathogenesis" Calster Academic Press (ISBN: 978-1-90455-55-4); and Hu and Pathak Pharmacological Reviews (2000) 52: 493-512; these documents are incorporated herein by reference in their entirety. In some embodiments, the antibodies described herein are expressed in mammalian cells by transfection or electroporation of an expression vector comprising a nucleic acid encoding the antibody. Transfection methods or electroporation methods are known in the art.

[0755] In another aspect, the disclosure relates to a cell, e.g., a mammalian cell, or a nucleic acid, comprising any of the antibodies described herein; the nucleic acid encodes any of the antibodies described herein. In one embodiment, the cell includes an antibody as described herein, or a nucleic acid encoding an antibody as described herein. The cell or tissue, e.g., a mammalian cell or tissue, can be of human, primate, hamster, rabbit, rodent, cow, pig, sheep, horse, goat, dog or cat origin. In some embodiments, any other mammalian cell can be used. In some embodiments, the mammalian cell is a human cell.

[0756] Effective expression of the antibodies described herein can be assessed using standard assays (such as RT-PCR, FACS, Northern blots, protein blots, ELISA or immunohistochemistry) that detect mRNA, DNA or gene products of nucleic acids encoding the antibodies. In some embodiments, the antibodies described herein are encoded by recombinant nucleic acid sequences.

[0757] CLL-1 related diseases and / or conditions

[0758] The present disclosure particularly provides compositions and methods for treating diseases associated with the expression of CLL-1 or conditions associated with cells expressing CLL-1, including, for example, proliferative diseases (such as cancer or malignancy (e.g., hematopoietic malignancy)) or precancerous lesions (such as myelodysplasia, myelodysplastic syndrome, or preleukemia).

[0759] CLL-1, also known as CLEC12A, CD371, MICL and CLL1, is a C-type lectin domain family 12 member A protein. CLL-1 is expressed on most granulocytes and monocytes, but not on T cells, B cells, NK cells and erythrocytes, and is thought to function as a negative regulator of granulocyte and monocyte function. See, e.g., Wang et al. J. Hematol. Oncol. (2018) 11:7.

[0760] In some embodiments, hematopoietic malignancies or blood conditions are associated with CLL-1 expression. Hematopoietic malignancies are described as malignant abnormalities involving hematopoietic cells (e.g., blood cells, including progenitor cells and stem cells). Examples of hematopoietic malignancies include, but are not limited to, Hodgkin's lymphoma, non-Hodgkin's lymphoma, leukemia, or multiple myeloma. Exemplary leukemias include, but are not limited to, acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, or chronic lymphoblastic leukemia and chronic lymphoblastic leukemia.

[0761] In some embodiments, cells involved in hematopoietic malignancies are resistant to conventional or standard therapies for treating malignancies. For example, cells (e.g., cancer cells) can be resistant to chemotherapeutic agents and / or CAR T cells used to treat malignancies.

[0762] In some embodiments, leukemia is acute myeloid leukemia (AML). Acute myeloid leukemia (AML) is a bone marrow cancer that requires more effective therapy. According to data from the National Cancer Institute, more than 60,000 people in the United States suffer from AML, and less than 30% of patients survive five years after diagnosis. AML cells can be characterized and distinguished from other cells by detecting the expression of cell surface markers. AML cells can be CLL-1+, CD33+ (although some are CD33-), CD45+ and CDw52+. The characteristic of AML is a heterogeneous clonal neoplastic disease originating from transformed cells that gradually acquire key genetic changes that destroy key differentiation and growth regulatory pathways. See, for example, Dohner et al., NEJM, (2015) 373:1136. Without wishing to be bound by theory, it is believed that, in some embodiments, CLL-1 is expressed on myeloid leukemia cells and normal myeloid and monocytic precursors and is an attractive target for AML therapy.

[0763] In some embodiments, the hematopoietic malignancy or blood disease / condition associated with CLL-1 is a precancerous lesion, such as myelodysplasia, myelodysplastic syndrome or preleukemia. Myelodysplastic syndrome (MDS) is a blood medical disorder characterized by disordered and ineffective hematopoiesis or blood production. Therefore, the quantity and quality of hematopoietic cells irreversibly decline. Some patients with MDS may develop severe anemia, while others are asymptomatic. The classification scheme of MDS is known in the art, and its criteria specify the ratio or frequency of specific blood cell types such as myeloblasts, monocytes and erythrocyte precursors. MDS includes refractory anemia, refractory anemia with ringed iron-forming erythrocytes, refractory anemia with excessive mother cells, refractory anemia with excessive mother cells in transformation, chronic myelomonocytic leukemia (CML). In some embodiments, MDS can progress to AML.

[0764] In various cases, the antibodies and / or fusion proteins described herein and / or cells expressing any of the foregoing antibodies and / or fusion proteins can treat CLL-1-related conditions (e.g., AML, MDS), alleviate CLL-1-related conditions, reduce the prevalence of CLL-1-related conditions, reduce the frequency of CLL-1-related conditions, or reduce the level or amount of one or more symptoms or biomarkers of CLL-1-related conditions. Specific symptoms and symptom progression vary from subject to subject. Therefore, in some embodiments, the antibodies and / or fusion proteins described herein are administered to subjects in need, such as subjects with CLL-1-related conditions (e.g., AML, MDS). In some embodiments, the administration of any antibody and / or fusion protein described herein prevents cancer or hematopoietic malignancies or premalignant tumors, including alleviating one or more symptoms of the disease and / or delaying the progression of the disease.

[0765] In some cases, a subject may initially respond to therapy (e.g., for hematopoietic malignancies) but subsequently relapse. In some embodiments, a subject's hematopoietic malignancies (e.g., AML) relapse or are susceptible to relapse after administration of one or more prior therapies. In some embodiments, administration of any of the antibodies and / or fusion proteins described herein can reduce the risk of relapse or the severity of relapse in a subject.

[0766] In some embodiments, one or more anti-CLL-1 antibodies described herein are used to treat one or more conditions described herein, for example, one or more diseases or conditions associated with CLL-1 expression. In some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of an antibody or antigen-binding fragment thereof described herein, or a cell expressing any of the foregoing antibodies, or an antibody-drug conjugate described herein. In some embodiments, one or more anti-CLL-1 antibodies described herein, including a fusion protein comprising any of the anti-CLL-1 antibodies, are used to treat a disease or condition associated with CLL-1 expression. In some embodiments, one or more anti-CLL-1 antibodies described herein are used to treat a method of treating a neoplastic disease or malignancy of the blood associated with CLL-1 expression. In some embodiments, one or more anti-CLL-1 antibodies described herein are used to treat a method of treating MDS or AML.

[0767] In various cases, administration of the antibodies and / or fusion proteins described herein reduces the prevalence, frequency, level, and / or amount of one or more symptoms or biomarkers of a CLL-1-associated condition as compared to a previously measured value or a reference value for the subject, for example, reduces one or more symptoms or biomarkers by at least 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 100%.

[0768] In some embodiments, the antibodies and / or fusion proteins described herein can be used in many diagnostic and / or therapeutic applications. For example, the detectable labeled form of the antibodies described herein can be used to detect the presence or amount of CLL-1 in a sample (e.g., a biological sample). The antibodies and / or fusion proteins described herein can be used to study in vitro assays for the inhibition of CLL-1 activity. In some embodiments, the antibodies and / or fusion proteins described herein can be used as positive controls in assays designed to identify additional novel compounds that inhibit CLL-1 or can be used to treat CLL-1 related conditions.

[0769] The antibodies and / or fusion proteins described herein can be used to monitor subjects, e.g., subjects suffering from one or more CLL-1-related conditions, suspected of having one or more CLL-1-related conditions, at risk of developing one or more CLL-1-related conditions, or receiving treatment for one or more CLL-1-related conditions. Monitoring can include determining the amount or activity of CLL-1 in the subject, e.g., in the serum of the subject. The subject can be evaluated in one or more of the following time periods: before the start of treatment; during treatment; or after one or more elements of the treatment that have been administered. Evaluation can include evaluating whether further treatment is needed, e.g., evaluating whether the dose, frequency of administration, or duration of treatment should be changed. Evaluation can also include evaluating whether the selected treatment method needs to be increased or stopped, e.g., increasing or stopping any of the treatments described herein for CLL-1-related conditions.

[0770] Measuring the interaction between antibodies and CLL-1

[0771] The binding properties of the antibodies described herein to CLL-1 can be measured by methods known in the art, for example, one of the following methods: BIACORE TMAnalysis, enzyme-linked immunosorbent assay (ELISA), X-ray crystallography, sequence analysis, and scanning mutagenesis. Surface plasmon resonance (SPR) can be used to analyze the binding interaction of antibodies and CLL-1. SPR or biomolecular interaction analysis (BIA) detects biospecific interactions in real time without labeling any interactants. The mass change at the binding surface of the BIA chip (indicating a binding event) causes the refractive index of light near the surface to change. The change in refractive index produces a detectable signal that is measured to indicate a real-time reaction between biomolecules. Methods using SPR are described, for example, in U.S. Patent No. 5,641,640; Raether (1988) Surface Plasmons Springer Verlag; Sjolander and Urbaniczky (1991) Anal. Chem. 63:2338-2345; Szabo et al. (1995) Curr. Opin. Struct. Biol. 5:699-705 and online resources provided by BIAcore International AB (Uppsala, Sweden). Alternatively, the KinExA® (Kinetic Exclusion Assay) assay available from Sapidyne Instruments, Inc. (Boise, Id.) may also be used.

[0772] The information from SPR can be used to provide the equilibrium dissociation constant (K) for the binding of the antibody to CLL-1. D ) and kinetic parameters (including K on and K off ). Such data can be used to compare different molecules. Information from SPR can also be used to develop structure-activity relationships (SAR). Variant amino acids at a given position that are associated with a specific binding parameter (e.g., high affinity) can be identified.

[0773] In certain embodiments, the antibodies described herein exhibit high affinity for binding to CLL-1. In various embodiments, the antibodies described herein have a high affinity for binding to CLL-1. D Less than about 10 -4 , 10 -5 , 10 -6 , 10 -7 , 10 -8 , 10 -9 , 10 -10 , 10 -11 , 10 -12 , 10 -13 , 10 -14 or 10 -15M. In some cases, the antibodies described herein are directed against the K of CLL-1 D Between 0.001 and 1 nM, e.g., 0.001 nM, 0.005 nM, 0.01 nM, 0.05 nM, 0.1 nM, 0.5 nM or 1 nM.

[0774] In some embodiments, the antibodies described herein bind to a specific epitope of CLL-1, for example, including one or more specific amino acids of CLL-1. Without wishing to be bound by theory, disruption of the availability of specific amino acids of the CLL-1 epitope of the antibodies described herein (e.g., by mutagenesis or due to binding of a competing antibody) can reduce or eliminate the binding of the antibody. In therapeutic applications or product manufacturing requiring multiple anti-CLL-1 antibodies to interact with CLL-1, it may be important to select or design anti-CLL-1 antibodies that target non-competitive CLL-1 epitopes to avoid interference with each other.

[0775] Combination therapy

[0776] In some embodiments, the anti-CLL-1 antibodies described herein, or portions thereof (e.g., one or more CDRs described herein), and / or one or more fusion proteins described herein are administered in combination with one or more additional therapeutic agents (such as chemotherapeutic agents or oncolytic therapeutic agents). As used herein, "combination therapy" refers to the administration of two or more different agents in an overlapping regimen, thereby exposing the subject to the two agents at the same time. When used in combination therapy, the two or more different agents may be administered simultaneously or separately. Combination administration may include simultaneous administration of two or more agents in the same dosage form, simultaneous administration in a separate dosage form, and separate administration. That is, two or more agents may be formulated together in the same dosage form and administered simultaneously. Alternatively, two or more agents may be administered simultaneously, wherein the drugs are present in separate formulations. In another alternative, a first agent may be administered, followed by administration of one or more additional agents. In a separate administration regimen, two or more agents may be administered a few minutes, hours, or days apart.

[0777] As used herein, the term "chemotherapeutic agent" or "oncolytic therapeutic agent" (e.g., anticancer drug, e.g., anticancer therapy, e.g., immune cell therapy) has its art-understood meaning, and refers to one or more pro-apoptotic agents, cytostatic agents and / or cytotoxic agents and / or hormonal agents, for example, specifically including agents used and / or recommended for the treatment of one or more diseases, conditions or disorders associated with undesirable cell proliferation. In some embodiments, the chemotherapeutic agent and / or oncolytic therapeutic agent can be or include a platinum compound (e.g., cisplatin, carboplatin and oxaliplatin), an alkylating agent (e.g., cyclophosphamide, ifosfamide, chlorambucil, nitrogen mustard, oxaliplatin, cyclophosphamide ... mustard, thiotepa, melphalan, busulfan, procarbazine, streptozocin, temozolomide, dacarbazine, and bendamustine), antitumor antibiotics (e.g., daunorubicin, doxorubicin, idarubicin, epirubicin, mitoxantrone, bleomycin, mytomycin C, plicamycin, and actinomycin D The invention relates to dactinomycin, taxanes (e.g., paclitaxel and docetaxel), antimetabolites (e.g., 5-fluorouracil, cytarabine, premetrexed, thioguanine, floxuridine, capecitabine, and methotrexate), nucleoside analogs (e.g., fludarabine, clofarabine, cladribine, pentostatin, and nelarabine), topoisomerase inhibitors (e.g., topotecan and irinotecan), hypomethylating agents (e.g., azacitidine and decitabine), proteasome inhibitors (e.g.,bortezomib), epipodophyllotoxins (e.g., etoposide and teniposide), DNA synthesis inhibitors (e.g., hydroxyurea), vinca alkaloids (e.g., vicristine, vindesine, vinorelbine, and vinblastine), tyrosine kinase inhibitors (e.g., imatinib, dasatinib), , nilotinib, sorafenib, and sunitinib), nitrosoureas (e.g., carmustine, fotemustine, and lomustine), altretamine, mitotane, angiogenesis inhibitors (e.g., thalidomide and lenalidomide), steroids (e.g., prednisone), , dexamethasone, and prednisolone), hormonal agents (e.g., tamoxifen, raloxifene, leuprolide, bicaluatmide, granisetron, and flutamide), aromatase inhibitors (e.g., letrozole and anastrozole), arsenic trioxide , tretinoin, non-selective cyclooxygenase inhibitors (e.g., nonsteroidal anti-inflammatory agents, salicylates, aspirin, piroxicam, ibuprofen, indomethacin, naprosyn, diclofenac, tolmetin, ketoprofen, nabumetone, and oxaprozin), selective cyclooxygenase-2 (COX-2) inhibitors, or any combination thereof.

[0778] In certain embodiments, chemotherapeutic agents and / or oncolytic therapeutic agents for anti-cancer treatment include biologics, such as tumor infiltrating lymphocytes, CAR T cells, antibodies, antigens, therapeutic vaccines (e.g., prepared from the patient's own tumor cells or other substances (such as antigens produced by certain tumors)), immunomodulators (e.g., cytokines, e.g., immunomodulatory drugs or biological response modifiers), checkpoint inhibitors or other immune preparations. In certain embodiments, immune preparations include immunoglobulins, immunostimulators (e.g., bacterial vaccines, colony stimulating factors, interferons, interleukins, therapeutic vaccines, vaccine combinations, viral vaccines) and / or immunosuppressants (e.g., calcineurin inhibitors, interleukin inhibitors, TNFα inhibitors). In certain embodiments, hormonal agents include agents used in anti-androgen therapy (e.g., Ketoconazole, Abiraterone, TAK-700, TOK-OOl, Bicalutamide, Nilutamide, Flutamide, Enzalutamide, ARN-509).

[0779] Additional chemotherapeutic and / or oncolytic therapeutic agents include immune checkpoint therapy agents (e.g., pembrolizumab, nivolumab, ipilimumab, atezolizumab, avelumab, durvalumab, tremelimumab, or cemiplimab), other monoclonal antibodies (e.g., rituximab, cetuximab, panetumumab, tositumomab, trastuzumab, alemtuzumab, gemtuzumab, ozogamicin), bevacizumab, catumaxomab, denosumab, obinutuzumab, ofatumumab, ramucirumab, pertuzumab, nimotuzumab, lambrolizumab, pidilizumab, siltuximab, BMS-936559, RG7446 / MPDL3280A, MEDI4736), antibody-drug conjugates (e.g., brentuximab vedotin (ADCETRIS®, Seattle Genetics); ado-trastuzumab bemtansine (KADCYLA®, Roche); Gemtuzumab ozogamicin (Wyeth); CMC-544; SAR3419; CDX-011; PSMA-ADC; BT-062; and IMGN901 (see, e.g., Sassoon et al., Methods Mol. Biol. (2013) 1045: 1-27; Bouchard et al., Bioorganic Med. Chem. Lett. (2014) 24: 5357-5363)), or any combination thereof.

[0780] In some embodiments, the combined administration of an anti-CLL-1 antibody or a portion thereof (e.g., one or more CDRs described herein), and / or one or more fusion proteins described herein, and an additional therapeutic agent improves cancer to a greater extent than that produced by a single anti-CLL-1 antibody or additional therapeutic agent. The difference between the combined effect and the effect of each agent alone can be a statistically significant difference. In some embodiments, the combined effect can be a synergistic effect. In some embodiments, the combined administration of an anti-CLL-1 antibody or a portion thereof (e.g., one or more CDRs described herein), and / or one or more fusion proteins described herein, and an additional therapeutic agent allows the administration of an additional therapeutic agent, e.g., an approved dosing regimen of an additional therapeutic agent, at a reduced dose, reduced number of doses, and / or reduced dose frequency compared to a standard dosing regimen.

[0781] In some embodiments, the treatment methods described herein are performed on subjects for whom other treatments for their medical conditions have failed or have been less successful by other means. Additionally, the treatment methods described herein can be performed in combination with one or more additional treatments for the medical condition. For example, the method may include administering a cancer regimen, e.g., non-myeloablative chemotherapy, surgery, hormone therapy, and / or radiation therapy, before, substantially simultaneously with, or after administering an anti-CLL-1 antibody described herein or a portion thereof (e.g., one or more CDRs described herein), and / or one or more fusion proteins described herein, or a composition thereof.

[0782] Aspects of the present disclosure relate to administering hematopoietic cells that are genetically modified to reduce or eliminate the expression of CLL-1, for example, in the context of treating a subject who needs such hematopoietic stem cells, the subject may include, for example, a subject with a hematological malignancy (e.g., AML or premalignancy, e.g., MDS), and who is receiving an immunotherapy regimen targeting CLL-1 (e.g., CLL-1-antibody drug-conjugate or CLL-1 CAR-T or CAR-NK therapy). This treatment regimen may involve, for example, the following steps: (1) administering a therapeutically effective amount of any of the anti-CLL-1 antibodies, its CLL-1 binding fragments, including fusion proteins, e.g., CAR, and cells expressing any of the foregoing, e.g., CAR-T or CAR-NK cells, as described herein or understood by a technician based on the present disclosure; and (2) administering (e.g., infusion or re-infusion) autologous or allogeneic hematopoietic stem cells to the patient, wherein the CLL-1 expression of the hematopoietic cells is reduced or eliminated. In some embodiments, the hematopoietic cells are genetically modified to reduce the expression of CLL-1. In some embodiments, hematopoietic cells are genetically modified to eliminate expression of CLL-1. In some embodiments, hematopoietic cells are genetically modified to reduce or eliminate expression of a CLL-1 epitope bound by an antibody, a CLL-1 binding fragment thereof, or a portion thereof (e.g., one or more CDRs described herein), and / or one or more fusion proteins described herein.

[0783] Formulation and administration

[0784] In various embodiments, any of the antibodies described herein or portions thereof (e.g., one or more CDRs described herein), and / or one or more fusion proteins can be incorporated into a pharmaceutical composition. Such pharmaceutical compositions can be used, for example, to prevent and / or treat diseases, e.g., cancers, such as AML, MDS. Pharmaceutical compositions can be formulated by methods known to those skilled in the art (such as Remington's Pharmaceutical Sciences, 17th edition, Alfonso R. Gennaro, ed., Mack Publishing Company, Easton, Pa. (1985)).

[0785] In some embodiments, the pharmaceutical composition can be formulated to include a pharmaceutically acceptable carrier or excipient. Examples of pharmaceutically acceptable carriers include, but are not limited to, any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delaying agents that are physiologically compatible. The compositions of the present invention may include a pharmaceutically acceptable salt, for example, an acid addition salt or a base addition salt.

[0786] In some embodiments, compositions comprising antibodies as described herein, e.g., sterile formulations for injection, can be formulated according to conventional pharmaceutical practice using distilled water for injection as a vehicle. For example, physiological saline or isotonic solutions containing glucose and other supplements such as D-sorbitol, D-mannose, D-mannitol and sodium chloride can be used as aqueous solutions for injection, optionally in combination with suitable solubilizers, such as, e.g., alcohols such as ethanol and / or polyols such as propylene glycol or polyethylene glycol, and / or nonionic surfactants such as polysorbate 80™ or HCO-50.

[0787] As disclosed herein, the pharmaceutical composition can be in any form known in the art. Such forms include, for example, liquid, semisolid and solid dosage forms, such as liquid solutions (e.g., solutions for injection and infusion), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories.

[0788] The selection or use of any particular form may depend in part on the intended mode of administration and therapeutic application. For example, a composition containing a composition for systemic or local delivery can be in the form of an injectable or insoluble solution. Therefore, the composition can be formulated to be administered by parenteral means (e.g., intravenous, subcutaneous, intraperitoneal or intramuscular injection). As used herein, parenteral administration refers to an administration mode, usually by injection, in addition to enteral administration and topical administration, and includes but is not limited to intravenous, intranasal, intraocular, pulmonary, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intrapulmonary, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, intracerebral, intracranial, intracarotid and intrasternal injection and infusion.

[0789] The administration route may be parenteral administration, such as administration by injection, nasal administration, pulmonary administration or transdermal administration. Systemic or local administration may be performed by intravenous injection, intramuscular injection, intraperitoneal injection or subcutaneous injection.

[0790] In some embodiments, the pharmaceutical composition of the present invention can be formulated as a solution, microemulsion, dispersion, liposome or other ordered structures suitable for stable storage at high concentration. Sterile injectable solutions can be prepared by mixing the required amount of the composition as described herein with one or a combination of the above-listed components as needed in a suitable solvent, followed by filtration sterilization. Typically, dispersions are prepared by mixing the composition as described herein into a sterile vehicle, the sterile vehicle including a basic dispersion medium and other required components from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the method for preparation comprises vacuum drying and freeze drying, which produces a powder of the composition as described herein plus any additional desired components from its previously aseptically filtered solution (see below). Suitable fluidity of the solution can be maintained, for example, by using coatings such as lecithin, by maintaining the desired particle size in the case of dispersions, and by using a surfactant. Extended absorption of injectable compositions can be achieved by including an agent that delays absorption in the composition, such as monostearate and gelatin.

[0791] The pharmaceutical composition can be administered parenterally in the form of an injectable formulation, which includes a sterile solution or suspension in water or another pharmaceutically acceptable liquid. For example, the pharmaceutical composition can be prepared by appropriately combining the therapeutic molecule with a pharmaceutically acceptable vehicle or medium, such as sterile water and saline, vegetable oil, emulsifier, suspending agent, surfactant, stabilizer, flavoring excipient, diluent, vehicle, preservative, adhesive, and then mixing with the unit dosage form required for generally acceptable pharmaceutical practice. The amount of the active ingredient contained in the pharmaceutical preparation is such that a suitable dose is provided within a specified range. Non-limiting examples of oily liquids include sesame oil and soybean oil, and can be combined with benzyl benzoate or benzyl alcohol as a solubilizer. Other items that can be included are buffers such as phosphate buffers or sodium acetate buffers, soothing agents such as procaine hydrochloride, stabilizers such as benzyl alcohol or phenol, and antioxidants. The formulated injection can be packaged in a suitable ampoule.

[0792] In various embodiments, subcutaneous administration can be achieved with the aid of a device such as a syringe, a prefilled syringe, an automatic injector (e.g., disposable or reusable), a pen injector, a patch injector, a wearable injector, a portable syringe infusion pump with a subcutaneous infusion set, or other devices for subcutaneous injection in combination with an antibody drug.

[0793] The injection system of the present disclosure can adopt the delivery pen described in U.S. Patent No. 5,308,341. The pen device most commonly used for self-delivery of insulin to patients with diabetes is well known in the art. Such devices may include at least one injection needle (e.g., a 31-gauge needle with a length of about 5 to 8 mm), which is usually pre-filled with a therapeutic solution of one or more treatment unit doses, and can be used to quickly deliver the solution to the subject while minimizing pain. A drug delivery pen includes a vial holder, in which a therapeutic drug or other drug can be accommodated. The pen can be a completely mechanical device, or it can be combined with an electronic circuit system to accurately set and / or indicate the drug dose injected into the user's body. See, for example, U.S. Patent No. 6,192,891. In some embodiments, the needle of the pen device is disposable, and the kit includes one or more disposable replacement needles. Pen devices suitable for delivering any of the compositions of the present invention are also described in, for example, U.S. Pat. Nos. 6,277,099, 6,200,296, and 6,146,361, the disclosures of each of which are incorporated herein by reference in their entirety. Microneedle-based pen devices are described in, for example, U.S. Pat. No. 7,556,615, the disclosures of which are incorporated herein by reference in their entirety. See also precision pen injector (PPI) devices, MOLLY TM , manufactured by Scandinavian Health Ltd.

[0794] In some embodiments, the compositions described herein can be delivered therapeutically to a subject by topical administration. As used herein, "topical administration" or "local delivery" can refer to delivery that is independent of the composition or agent being transported to its intended target tissue or site through the vascular system. For example, the composition can be delivered by injection or implantation of the composition or agent or by injection or implantation of a device containing the composition or agent. In certain embodiments, after topical administration near a target tissue or site, the composition or agent or one or more components thereof can diffuse to an intended target tissue or site that is not the site of administration.

[0795] In some embodiments, the compositions can be formulated for storage at a temperature below 0°C (e.g., -20°C or -80°C). In some embodiments, the compositions can be formulated for storage at 2-8°C (e.g., 4°C) for up to 2 years (e.g., one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, 10 months, 11 months, 1 year, 11 / 2 years, or 2 years). Thus, in some embodiments, the compositions described herein are stable for storage at 2-8°C (e.g., 4°C) for at least 1 year.

[0796] In some embodiments, the pharmaceutical composition can be formulated as a solution. In some embodiments, the composition can be formulated as a buffer solution such as a concentration suitable for storage at 2-8°C (e.g., 4°C).

[0797] Compositions comprising one or more antibodies as described herein can be formulated into immunoliposome compositions. Such formulations can be prepared by methods known in the art. Liposomes with enhanced circulation time are disclosed, for example, in U.S. Pat. No. 5,013,556.

[0798] In certain embodiments, the compound can be formulated with a carrier that will protect the compound from rapid release, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Many methods for preparing such formulations are generally known in the art. See, for example, J. R. Robinson (1978) "Sustained and Controlled Release Drug Delivery Systems", Marcel Dekker, Inc., New York, New York.

[0799] In some embodiments, the administration of antibodies as described herein is achieved by administering nucleic acids encoding antibodies to the subject. Nucleic acids encoding therapeutic antibodies as described herein can be incorporated into gene constructs and used as part of a gene therapy regimen to deliver nucleic acids that can be used to express and produce antibodies in cells. The expression constructs of such components can be administered in any therapeutically effective carrier form, for example, any formulation or composition capable of effectively delivering component genes to cells in vivo. The method includes inserting the subject's gene into a viral vector, including recombinant retroviruses, adenoviruses, adeno-associated viruses, lentiviruses, and herpes simplex virus-1 (HSV-1), or recombinant bacteria or eukaryotic plasmids. Viral vectors can directly transfect cells; plasmid DNA can be delivered by means of, for example, cationic liposomes (lipofectin) or derived polylysine conjugates, gramicidin S, artificial viral envelopes, or other such intracellular carriers, as well as direct injection of gene constructs or CaPO 4Delivery is accomplished by precipitation (see, e.g., WO 04 / 060407). Examples of suitable retroviruses include pLJ, pZIP, pWE, and pEM, which are known to those skilled in the art (see, e.g., Eglitis et al. Science (19785) 230:1395-1398; Danos and Mulligan Proc Natl Acad Sci USA (1988) 85:6460-6464; Wilson et al. Proc Natl Acad Sci USA (1988) 85:3014-3018; Armentano et al. Proc Natl Acad Sci USA (1990) 87:6141-6145; Huber et al. Proc Natl Acad Sci USA (1991) 88:8039-8043; Ferry et al. Proc Natl Acad Sci USA (1991) 88:8377-8381; Chowdhury et al. Science (1991) 254:1802-1805; van Beusechem et al. Proc Natl Acad Sci USA (1992) 89:7640-7644; Kay et al. Human Gene Therapy (1992) 3:641-647; Dai et al. Proc Natl Acad Sci USA (1992) 89:10892-10895; Hwu et al. J Immunol (1993) 150:4104-4115; U.S. Patents 4,868,116 and 4,980,286; and PCT Publications WO89 / 07136, WO89 / 02468, WO89 / 05345, and WO92 / 07573). Another viral gene delivery system uses adenovirus-derived vectors (see, e.g., Berkner et al. BioTechniques (1988) 6:616; Rosenfeld et al. Science (1991) 252:431-434; and Rosenfeld et al. Cell (1992) 68:143-155). Suitable adenovirus vectors derived from adenovirus strain Ad 5 type d1324 or other adenovirus strains (e.g., Ad2, Ad3, Ad7, etc.) are known to those skilled in the art. Yet another viral vector system for delivering subject genes is adeno-associated virus (AAV).See, e.g., Flotte et al. Am J Respir Cell Mol Biol (1992) 7:349-356; Samulski et al. J Virol (1989) 63:3822-3828; and McLaughlin et al. J Virol (1989) 62:1963-1973.

[0800] In some embodiments, provided herein are compositions in unit dosage form, which may be suitable for self-administration. Such unit dosage forms may be provided in containers, typically such as vials, cartridges, prefilled syringes or disposable pens. For example, the applicator (such as a dosing device) described in U.S. Patent 6,302,855 may also be used, for example, with an injection system as described herein.

[0801] The appropriate dose of the compositions described herein (which is capable of treating or preventing the condition of the subject) may depend on a number of factors, including, for example, the age, sex, and weight of the subject to be treated and the specific inhibitory compound used. For example, different doses of a composition comprising an antibody described herein or a portion thereof (e.g., one or more CDRs described herein), and / or one or more fusion proteins, compared to the doses of different formulations of the antibody, may be necessary for treating a subject with cancer (e.g., AML). Other factors that affect the dose administered to the subject include, for example, the type or severity of the condition. Other factors may include, for example, other medical conditions that affect the subject simultaneously or in advance, the subject's general health, the subject's genetic predisposition, diet, administration time, excretion rate, drug combination, and any other additional therapeutic agent administered to the subject. It should also be understood that the specific dose and treatment regimen for any particular subject may also be adjusted based on the judgment of the treating...

Claims

1. An anti-CLL-1 antibody or an antigen-binding fragment thereof comprising SEQ ID NO: 15, 29, 43, 57, 71, 85, 99, 113, 127, 141, 155, 169, 174, 179, 184, 189, 194, 199, 204, 209, 214, 219, 224, 229, 234, 239, 244, 249, 254, 259, 264, 269, 275, 280, 285, 290, 295, 309, 32 3, 337, 351, 365, 418, 422, 426, 430, 434, 438, 442, 446, 450, 454, 458, 462, 466, 470, 474, 478, 482, 486, 490, 494, 498, 502, 506, 510, 514, 518, 522, 526, 530, 534, 538, 542, 546, 55 0, 554, 558, 562, 566, 570, 574, 578, 582, 586, 590, 594, 598, 602, 606, 610, 614, 618, 622, 626, 630, 634, 638, 642, 646, 650, 654, 658, 662, 666, 670, 674, 678, 682, 686, 690, 694, 698 8, 702, 706, 710, 714, 718, 722, 726, 730, 734, 738, 742, 746, 750, 754, 758, 762, 766, 774, 779, 784, 788, 793, 798, 801, 804, 808, 819, 831, 837, 849, 900, 905, 910, 918 or 920 of the amino acid sequence.

2. An anti-CLL-1 antibody or an antigen-binding fragment thereof comprising SEQ ID NO: 2-7, 16-21, 30-35, 44-49, 58-63, 72-77, 86-91, 100-105, 114-119, 128-133, 142-147, 156-161, 170-172, 175-177, 180-182, 185-187, 190-192, 195-197, 200-202, 205-207, 210-212, 215-217, 220-222, 225-227, 230-232, 235-237, 240-242, 245-247, 250-252, 255-257, 260-262, 265-267, 271-273、276-278、281-283、286-288、291-293、296-301、310-315、324-329、338-343、352-357、419-421、423-425、427-429、431-433、435-437、439-441、443-445、447-449、451-453、455-457、459-461、463-465、467-469、471-473、475-477、479-481、483-485、487-489、491-493、495-497、 499-501、503-505、507-509、511-513、515-517、519-521、523-525、527-529、531-533、535-537、539-541、543-545、547-549、551-553、555-557、559-561、563-565、567-569、571-573、575-577、579-581、583-585、587-589、591-593、595-597、599-601、603-605、607-609、611-613、615-617、 619-621, 623-625, 627-629, 631-633, 635-637, 639-641, 643-645, 647-649, 651-653, 655-657, 659-661, 663-665, 667-669, 671-673, 675-677, 679-681, 683-685, 687-689, 691-693, 695-697, 699-701, 703-705, 707-709, 711-713, 715-717, 719-721, 723-725, 727-729, 731-733, 735-737,at least one complementarity determining region (CDR) sequence of 739-741, 743-745, 747-749, 751-753, 755-757, 759-761, 763-765, 767-769, 770-772, 775-777, 780-782, 785-786, 789-791, 794-796, 799, 802, 805-806, 820-825, 838-843, 850-854, 861-866, 896-898, 901-903, 906-908, or 911-916.

3. The anti-CLL-1 antibody or antigen-binding fragment thereof of claim 2, comprising SEQ ID NO: 2-7, 16-21, 30-35, 44-49, 58-63, 72-77, 86-91, 100-105, 114-119, 128-133, 142-147, 156-161, 170-172, 175-177, 180-182, 185-187, 190-192, 195-197, 200-202, 205-207, 210-212, 215-217, 220-222, 225-227, 230-232, 235-237, 240-242, 245-247, 250-252, 255-257, 260-262, 265-267 7, 271-273, 276-278, 281-283, 286-288, 291-293, 296-301, 310-315, 324-329, 338-343, 352-357, 419-421, 423-425, 427-429, 431-433, 435-437, 439-441, 443-445, 447-449, 451-453, 455-457, 459-461, 463-465, 467-469, 471-473, 475-477, 479-481, 483-485, 487-489, 491-493, 495- 497, 499-501, 503-505, 507-509, 511-513, 515-517, 519-521, 523-525, 527-529, 531-533, 535-537, 539-541, 543-545, 547-549, 551-553, 555-557, 559-561, 563-565, 567-569, 571-573, 575-577, 579-581, 583-585, 587-589, 591-593, 595-597, 599-601, 603-605, 607-609, 611-613, 61 5-617, 619-621, 623-625, 627-629, 631-633, 635-637, 639-641, 643-645, 647-649, 651-653, 655-657, 659-661, 663-665, 667-669, 671-673, 675-677, 679-681, 683-685, 687-689, 691-693, 695-697, 699-701, 703-705, 707-709, 711-713, 715-717, 719-721, 723-725, 727-729, 731-733,735-737, 739-741, 743-745, 747-749, 751-753, 755-757, 759-761, 763-765, 767-769, 770-772, 775-777, 780-782, 785-786, 789-791, 794-796, 799, 802, 805-806, 820-825, 838-843, 850-854, 861-866, 896-898, 901-903, 906-908 or 911-916.

4. The anti-CLL-1 antibody or antigen-binding fragment thereof of claim 2, comprising SEQ ID NO: 2-7, 16-21, 30-35, 44-49, 58-63, 72-77, 86-91, 100-105, 114-119, 128-133, 142-147, 156-161, 170-172, 175-177, 180-182, 185-187, 190-192, 195-197, 200-202, 205-207, 210-212, 215-217, 220-222, 225-227, 230-232, 235-237, 240-242, 245-247, 250-252, 255-257, 260-262, 265-267 7, 271-273, 276-278, 281-283, 286-288, 291-293, 296-301, 310-315, 324-329, 338-343, 352-357, 419-421, 423-425, 427-429, 431-433, 435-437, 439-441, 443-445, 447-449, 451-453, 455-457, 459-461, 463-465, 467-469, 471-473, 475-477, 479-481, 483-485, 487-489, 491-493, 495- 497, 499-501, 503-505, 507-509, 511-513, 515-517, 519-521, 523-525, 527-529, 531-533, 535-537, 539-541, 543-545, 547-549, 551-553, 555-557, 559-561, 563-565, 567-569, 571-573, 575-577, 579-581, 583-585, 587-589, 591-593, 595-597, 599-601, 603-605, 607-609, 611-613, 61 5-617, 619-621, 623-625, 627-629, 631-633, 635-637, 639-641, 643-645, 647-649, 651-653, 655-657, 659-661, 663-665, 667-669, 671-673, 675-677, 679-681, 683-685, 687-689, 691-693, 695-697, 699-701, 703-705, 707-709, 711-713, 715-717, 719-721, 723-725, 727-729, 731-733,735-737, 739-741, 743-745, 747-749, 751-753, 755-757, 759-761, 763-765, 767-769, 770-772, 775-777, 780-782, 785-786, 789-791, 794-796, 799, 802, 805-806, 820-825, 838-843, 850-854, 861-866, 896-898, 901-903, 906-908 or 911-916.

5. The anti-CLL-1 antibody or antigen-binding fragment thereof of claim 2, comprising SEQ ID NO: 5-7, 19-21, 33-35, 47-49, 61-63, 75-77, 89-91, 103-105, 117-119, 131-133, 145-147, 159-161, 170-172, 175-177, 180-182, 185-187, 190-192, 195-197, 200-202, 205-207, 210-212, 215-217, 220-222, 225-227, 230-232, 235- 237, 240-242, 245-247, 250-252, 255-257, 260-262, 265-267, 271-273, 276-278, 281-283, 286-288, 291-293, 299-301, 313-315, 327-329, 341-343, 355-357, 423-425, 431-433, 439-441, 447-449, 455-457, 463-465, 471-473, 4 79-481, 487-489, 495-497, 503-505, 511-513, 519-521, 527-529, 535-537, 543-545, 551-553, 559-561, 567-569, 575-577, 583-585, 591-593, 599-601, 607-609, 615-617, 623-625, 631-633, 639-641, 647-649, 655-657, 663-669 852-854, 857-858, 869-870, 880-881, 892-893, 896-910, 914-916 or 919-920.

6. An anti-CLL-1 antibody or an antigen-binding fragment thereof comprising SEQ ID NO: 2-7, 16-21, 30-35, 44-49, 58-63, 72-77, 86-91, 100,-105, 114-119, 128-133, 142-147, 156-161, 170-172, 175-177, 180-182, 185-187, 190-192, 195-197, 200-202, 205-207, 210-212, 215-217, 220-222, 225-227, 230-232, 235-237, 240-242, 245-247, 250-252, 255-257, 260-262, 265-267 , 271-273, 276-278, 281-283, 286-288, 291-293, 296-301, 310-315, 324-329, 338-343, 352-357, 419-421, 423-425, 427-429, 431-433, 435-437, 439-441, 443-445, 447-449, 451-453, 455-457, 459-461, 463-465, 467-469, 471-473, 475-477, 479-481, 483-485, 487-489, 491-493, 495-497 、499-501、503-505、507-509、511-513、515-517、519-521、523-525、527-529、531-533、535-537、539-541、543-545、547-549、551-553、555-557、559-561、563-565、567-569、571-573、575-577、579-581、583-585、587-589、591-593、595-597、599-601、603-605、607-609、611-613、615-617 、619-621、623-625、627-629、631-633、635-637、639-641、643-645、647-649、651-653、655-657、659-661、663-665、667-669、671-673、675-677、679-681、683-685、687-689、691-693、695-697、699-701、703-705、707-709、711-713、715-717、719-721、723-725、727-729、731-733、735-737、739-741, 743-745, 747-749, 751-753, 755-757, 759-761, 763-765, 767-769, 770-772, 775-777, 780-782, 785-786, 789-791, 794-796, 799, 802, 805-806, 820-825, 838-843, 850-854, 896-898, 901-903, 906-908 or 911-916 CDR1, CDR2 and CDR3.

7. An anti-CLL-1 antibody or an antigen-binding fragment thereof comprising SEQ ID NO: 2-7, 16-21, 30-35, 44-49, 58-63, 72-77, 86-91, 100,-105, 114-119, 128-133, 142-147, 156-161, 170-172, 175-177, 180-182, 185-187, 190-192, 195-197, 200-202, 205-207, 210-212, 215-217, 220-222, 225-227, 230-232, 235-237, 240-242, 245-247, 250-252, 255-257, 260-262, 265-267 , 271-273, 276-278, 281-283, 286-288, 291-293, 296-301, 310-315, 324-329, 338-343, 352-357, 419-421, 423-425, 427-429, 431-433, 435-437, 439-441, 443-445, 447-449, 451-453, 455-457, 459-461, 463-465, 467-469, 471-473, 475-477, 479-481, 483-485, 487-489, 491-493, 495-497 、499-501、503-505、507-509、511-513、515-517、519-521、523-525、527-529、531-533、535-537、539-541、543-545、547-549、551-553、555-557、559-561、563-565、567-569、571-573、575-577、579-581、583-585、587-589、591-593、595-597、599-601、603-605、607-609、611-613、615-617 、619-621、623-625、627-629、631-633、635-637、639-641、643-645、647-649、651-653、655-657、659-661、663-665、667-669、671-673、675-677、679-681、683-685、687-689、691-693、695-697、699-701、703-705、707-709、711-713、715-717、719-721、723-725、727-729、731-733、735-737、CDRs of 739-741, 743-745, 747-749, 751-753, 755-757, 759-761, 763-765, 767-769, 770-772, 775-777, 780-782, 785-786, 789-791, 794-796, 799, 802, 805-806, 820-825, 838-843, 850-854, 896-898, 901-903, 906-908, or 911-916 (e.g., CDR1, CDR2 and / or CDR3) have at least one CDR that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical.

8. An anti-CLL-1 antibody or an antigen-binding fragment thereof, comprising a heavy chain variable region, wherein the heavy chain variable region comprises SEQ ID NO: 5, 19, 33, 47, 61, 75, 89, 103, 117, 131, 145, 159, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 271, 276, 281, 286, 291, 299, 313, 327, 341, 355, 423, 431, 439, 447, 455, 463, 471, 479, 487, 495, 503, 511, 519, 520, 27, 535, 543, 551, 559, 567, 575, 583, 591, 599, 607, 615, 623, 631, 639, 647, 655, 663, 671, 679, 687, 695, 703, 711, 715, 719, 723, 727, 731, 735, 739, 743, 747, 751, 755, 759, 763, 767, 770, 775, 780, 785, 789, 794, 823, 841, 852, 896, 901, 906 or 914; ID NO: 6, 20, 34, 48, 62, 76, 90, 104, 118, 132, 146, 160, 171, 176, 181, 186, 191, 196, 201, 206, 211, 2 16, 221, 226, 231, 236, 241, 246, 251, 256, 261, 266, 272, 277, 282, 287, 292, 300, 314, 328, 342 356, 424, 432, 440, 448, 456, 464, 472, 480, 488, 496, 504, 512, 520, 528, 536, 544, 552, 560, 568, 576, 584, 592, 600, 608, 616, 624, 632, 640, 648, 656, 664, 672, 680, 688 , 696, 704, 712, 716, 720, 724, 728, 732, 736, 740, 744, 748, 752, 756, 760, 764, 768, 771, 776, 781, 786, 790, 795, 799, 802, 805, 824, 842, 853, 897, 902, 907 or 915;and SEQ ID NO: 7, 21, 35, 49, 63, 77, 91, 105, 119, 133, 147, 161, 172, 177, 182, 187, 192, 197, 202, 207, 212, 217, 222, 227, 232, 237, 242, 247, 252, 257, 262, 267, 273, 278, 283, 288, 293, 301, 315, 329, 343, 357, 425, 433, 441, 449, 457, 465, 473, 481, 489, 497, 505, 513, 521 , 529, 537, 545, 553, 561, 569, 577, 585, 593, 601, 609, 617, 625, 633, 641, 649, 657, 665, 673, 681, 689, 697, 705, 713, 717, 721, 725, 729, 733, 737, 741, 745, 749, 753, 757, 761, 765, 769, 772, 777, 782, 791, 796, 806, 825, 843, 854, 898, 903, 908 or 916;And a light chain variable region, the light chain variable region comprising SEQ ID NO: 643, 651, 659, 667, 675, 683, 691, 699, 707, 820, 838, 850, or 911, wherein the CDR1 is provided in 644, 652, 660, 668, 676, 684, 692, 700, 708, 821, 839 or 912, and a CDR2 provided by SEQ ID NO: 4, 18, 32, 46, 60, 74, 88, 102, 116, 130, 144, 158, 298, 312, 326, 340, 354, 421, 429, 437, 445, 453, 461, 469, 477, 485, 493, 501, 509, 517, 525, 533, 541, 549, 557, 565, 573, 581, 589, 597, 605, 613, 621, 629, 637, 645, 653, 661, 669, 677, 685, 693, 701, 709, 822, 840, 851, or 913. ; 9. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 5, CDR2 provided by SEQ ID NO: 6, and CDR3 provided by SEQ ID NO: 7; and a light chain variable region comprising CDR1 provided by SEQ ID NO: 2, CDR2 provided by SEQ ID NO: 3, and CDR3 provided by SEQ ID NO:

4.

10. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 19, CDR2 provided by SEQ ID NO: 20, and CDR3 provided by SEQ ID NO: 21; and a light chain variable region comprising CDR1 provided by SEQ ID NO: 16, CDR2 provided by SEQ ID NO: 17, and CDR3 provided by SEQ ID NO:

18.

11. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 33, a CDR2 provided by SEQ ID NO: 34, and a CDR3 provided by SEQ ID NO: 35; and a light chain variable region comprising a CDR1 provided by SEQ ID NO: 30, a CDR2 provided by SEQ ID NO: 31, and a CDR3 provided by SEQ ID NO:

32.

12. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 47, CDR2 provided by SEQ ID NO: 48, and CDR3 provided by SEQ ID NO: 49; and a light chain variable region comprising CDR1 provided by SEQ ID NO: 44, CDR2 provided by SEQ ID NO: 45, and CDR3 provided by SEQ ID NO:

46.

13. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 61, CDR2 provided by SEQ ID NO: 62, and CDR3 provided by SEQ ID NO: 63; and a light chain variable region comprising CDR1 provided by SEQ ID NO: 58, CDR2 provided by SEQ ID NO: 59, and CDR3 provided by SEQ ID NO:

60.

14. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 75, CDR2 provided by SEQ ID NO: 76, and CDR3 provided by SEQ ID NO: 77; and a light chain variable region comprising CDR1 provided by SEQ ID NO: 72, CDR2 provided by SEQ ID NO: 73, and CDR3 provided by SEQ ID NO:

74.

15. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 89, a CDR2 provided by SEQ ID NO: 90, and a CDR3 provided by SEQ ID NO: 91; and a light chain variable region comprising a CDR1 provided by SEQ ID NO: 86, a CDR2 provided by SEQ ID NO: 87, and a CDR3 provided by SEQ ID NO:

88.

16. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 103, a CDR2 provided by SEQ ID NO: 104, and a CDR3 provided by SEQ ID NO: 105; and a light chain variable region comprising a CDR1 provided by SEQ ID NO: 100, a CDR2 provided by SEQ ID NO: 101, and a CDR3 provided by SEQ ID NO:

102.

17. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 117, a CDR2 provided by SEQ ID NO: 118, and a CDR3 provided by SEQ ID NO: 119; and a light chain variable region comprising a CDR1 provided by SEQ ID NO: 114, a CDR2 provided by SEQ ID NO: 115, and a CDR3 provided by SEQ ID NO:

116.

18. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 131, a CDR2 provided by SEQ ID NO: 132, and a CDR3 provided by SEQ ID NO: 133; and a light chain variable region comprising a CDR1 provided by SEQ ID NO: 128, a CDR2 provided by SEQ ID NO: 129, and a CDR3 provided by SEQ ID NO:

130.

19. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 145, a CDR2 provided by SEQ ID NO: 146, and a CDR3 provided by SEQ ID NO: 147; and a light chain variable region comprising a CDR1 provided by SEQ ID NO: 142, a CDR2 provided by SEQ ID NO: 143, and a CDR3 provided by SEQ ID NO:

144.

20. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 159, a CDR2 provided by SEQ ID NO: 160, and a CDR3 provided by SEQ ID NO: 161; and a light chain variable region comprising a CDR1 provided by SEQ ID NO: 156, a CDR2 provided by SEQ ID NO: 157, and a CDR3 provided by SEQ ID NO:

158.

21. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 299, a CDR2 provided by SEQ ID NO: 300, and a CDR3 provided by SEQ ID NO: 301; and a light chain variable region comprising a CDR1 provided by SEQ ID NO: 296, a CDR2 provided by SEQ ID NO: 297, and a CDR3 provided by SEQ ID NO:

298.

22. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 313, a CDR2 provided by SEQ ID NO: 314, and a CDR3 provided by SEQ ID NO: 315; and a light chain variable region comprising a CDR1 provided by SEQ ID NO: 310, a CDR2 provided by SEQ ID NO: 311, and a CDR3 provided by SEQ ID NO:

312.

23. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 327, a CDR2 provided by SEQ ID NO: 328, and a CDR3 provided by SEQ ID NO: 329; and a light chain variable region comprising a CDR1 provided by SEQ ID NO: 324, a CDR2 provided by SEQ ID NO: 325, and a CDR3 provided by SEQ ID NO:

326.

24. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 341, a CDR2 provided by SEQ ID NO: 342, and a CDR3 provided by SEQ ID NO: 343; and a light chain variable region comprising a CDR1 provided by SEQ ID NO: 338, a CDR2 provided by SEQ ID NO: 339, and a CDR3 provided by SEQ ID NO:

340.

25. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 355, a CDR2 provided by SEQ ID NO: 356, and a CDR3 provided by SEQ ID NO: 357; and a light chain variable region comprising a CDR1 provided by SEQ ID NO: 352, a CDR2 provided by SEQ ID NO: 353, and a CDR3 provided by SEQ ID NO:

354.

26. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 423, a CDR2 provided by SEQ ID NO: 424, and a CDR3 provided by SEQ ID NO: 425; and a light chain variable region comprising a CDR1 provided by SEQ ID NO: 418, a CDR2 provided by SEQ ID NO: 419, and a CDR3 provided by SEQ ID NO:

421.

27. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 431, a CDR2 provided by SEQ ID NO: 432, and a CDR3 provided by SEQ ID NO: 433; and a light chain variable region comprising a CDR1 provided by SEQ ID NO: 427, a CDR2 provided by SEQ ID NO: 428, and a CDR3 provided by SEQ ID NO:

429.

28. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 439, a CDR2 provided by SEQ ID NO: 440, and a CDR3 provided by SEQ ID NO: 441; and a light chain variable region comprising a CDR1 provided by SEQ ID NO: 435, a CDR2 provided by SEQ ID NO: 436, and a CDR3 provided by SEQ ID NO:

437.

29. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 447, a CDR2 provided by SEQ ID NO: 448, and a CDR3 provided by SEQ ID NO: 449; and a light chain variable region comprising a CDR1 provided by SEQ ID NO: 443, a CDR2 provided by SEQ ID NO: 444, and a CDR3 provided by SEQ ID NO:

445.

30. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 455, CDR2 provided by SEQ ID NO: 456, and CDR3 provided by SEQ ID NO: 457; and a light chain variable region comprising CDR1 provided by SEQ ID NO: 451, CDR2 provided by SEQ ID NO: 452, and CDR3 provided by SEQ ID NO:

453.

31. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 463, a CDR2 provided by SEQ ID NO: 464, and a CDR3 provided by SEQ ID NO: 465; and a light chain variable region comprising a CDR1 provided by SEQ ID NO: 459, a CDR2 provided by SEQ ID NO: 460, and a CDR3 provided by SEQ ID NO:

461.

32. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 471, CDR2 provided by SEQ ID NO: 472, and CDR3 provided by SEQ ID NO: 473; and a light chain variable region comprising CDR1 provided by SEQ ID NO: 467, CDR2 provided by SEQ ID NO: 468, and CDR3 provided by SEQ ID NO:

469.

33. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 479, a CDR2 provided by SEQ ID NO: 480, and a CDR3 provided by SEQ ID NO: 481; and a light chain variable region comprising a CDR1 provided by SEQ ID NO: 475, a CDR2 provided by SEQ ID NO: 476, and a CDR3 provided by SEQ ID NO:

477.

34. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 487, a CDR2 provided by SEQ ID NO: 488, and a CDR3 provided by SEQ ID NO: 489; and a light chain variable region comprising a CDR1 provided by SEQ ID NO: 483, a CDR2 provided by SEQ ID NO: 484, and a CDR3 provided by SEQ ID NO:

485.

35. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 495, CDR2 provided by SEQ ID NO: 496, and CDR3 provided by SEQ ID NO: 497; and a light chain variable region comprising CDR1 provided by SEQ ID NO: 491, CDR2 provided by SEQ ID NO: 492, and CDR3 provided by SEQ ID NO:

493.

36. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 503, a CDR2 provided by SEQ ID NO: 504, and a CDR3 provided by SEQ ID NO: 505; and a light chain variable region comprising a CDR1 provided by SEQ ID NO: 499, a CDR2 provided by SEQ ID NO: 500, and a CDR3 provided by SEQ ID NO:

501.

37. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 511, a CDR2 provided by SEQ ID NO: 512, and a CDR3 provided by SEQ ID NO: 513; and a light chain variable region comprising a CDR1 provided by SEQ ID NO: 507, a CDR2 provided by SEQ ID NO: 508, and a CDR3 provided by SEQ ID NO:

509.

38. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 519, a CDR2 provided by SEQ ID NO: 520, and a CDR3 provided by SEQ ID NO: 521; and a light chain variable region comprising a CDR1 provided by SEQ ID NO: 515, a CDR2 provided by SEQ ID NO: 516, and a CDR3 provided by SEQ ID NO:

517.

39. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 527, CDR2 provided by SEQ ID NO: 528, and CDR3 provided by SEQ ID NO: 529; and a light chain variable region comprising CDR1 provided by SEQ ID NO: 523, CDR2 provided by SEQ ID NO: 524, and CDR3 provided by SEQ ID NO:

525.

40. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 535, a CDR2 provided by SEQ ID NO: 536, and a CDR3 provided by SEQ ID NO: 537; and a light chain variable region comprising a CDR1 provided by SEQ ID NO: 531, a CDR2 provided by SEQ ID NO: 532, and a CDR3 provided by SEQ ID NO:

533.

41. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 543, a CDR2 provided by SEQ ID NO: 544, and a CDR3 provided by SEQ ID NO: 545; and a light chain variable region comprising a CDR1 provided by SEQ ID NO: 539, a CDR2 provided by SEQ ID NO: 540, and a CDR3 provided by SEQ ID NO:

541.

42. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 551, a CDR2 provided by SEQ ID NO: 552, and a CDR3 provided by SEQ ID NO: 553; and a light chain variable region comprising a CDR1 provided by SEQ ID NO: 547, a CDR2 provided by SEQ ID NO: 548, and a CDR3 provided by SEQ ID NO:

549.

43. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 559, a CDR2 provided by SEQ ID NO: 560, and a CDR3 provided by SEQ ID NO: 561; and a light chain variable region comprising a CDR1 provided by SEQ ID NO: 555, a CDR2 provided by SEQ ID NO: 556, and a CDR3 provided by SEQ ID NO:

557.

44. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 567, a CDR2 provided by SEQ ID NO: 568, and a CDR3 provided by SEQ ID NO: 569; and a light chain variable region comprising a CDR1 provided by SEQ ID NO: 563, a CDR2 provided by SEQ ID NO: 564, and a CDR3 provided by SEQ ID NO:

565.

45. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 575, a CDR2 provided by SEQ ID NO: 576, and a CDR3 provided by SEQ ID NO: 577; and a light chain variable region comprising a CDR1 provided by SEQ ID NO: 571, a CDR2 provided by SEQ ID NO: 572, and a CDR3 provided by SEQ ID NO:

573.

46. ​​An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 583, a CDR2 provided by SEQ ID NO: 584, and a CDR3 provided by SEQ ID NO: 585; and a light chain variable region comprising a CDR1 provided by SEQ ID NO: 579, a CDR2 provided by SEQ ID NO: 580, and a CDR3 provided by SEQ ID NO:

581.

47. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 591, CDR2 provided by SEQ ID NO: 592, and CDR3 provided by SEQ ID NO: 593; and a light chain variable region comprising CDR1 provided by SEQ ID NO: 594, CDR2 provided by SEQ ID NO: 595, and CDR3 provided by SEQ ID NO:

596.

48. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 599, a CDR2 provided by SEQ ID NO: 600, and a CDR3 provided by SEQ ID NO: 601; and a light chain variable region comprising a CDR1 provided by SEQ ID NO: 595, a CDR2 provided by SEQ ID NO: 596, and a CDR3 provided by SEQ ID NO:

597.

49. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 607, a CDR2 provided by SEQ ID NO: 608, and a CDR3 provided by SEQ ID NO: 609; and a light chain variable region comprising a CDR1 provided by SEQ ID NO: 603, a CDR2 provided by SEQ ID NO: 604, and a CDR3 provided by SEQ ID NO:

605.

50. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 615, CDR2 provided by SEQ ID NO: 616, and CDR3 provided by SEQ ID NO: 617; and a light chain variable region comprising CDR1 provided by SEQ ID NO: 611, CDR2 provided by SEQ ID NO: 612, and CDR3 provided by SEQ ID NO:

613.

51. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 623, a CDR2 provided by SEQ ID NO: 624, and a CDR3 provided by SEQ ID NO: 625; and a light chain variable region comprising a CDR1 provided by SEQ ID NO: 619, a CDR2 provided by SEQ ID NO: 620, and a CDR3 provided by SEQ ID NO:

621.

52. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 631, a CDR2 provided by SEQ ID NO: 632, and a CDR3 provided by SEQ ID NO: 633; ​​and a light chain variable region comprising a CDR1 provided by SEQ ID NO: 627, a CDR2 provided by SEQ ID NO: 628, and a CDR3 provided by SEQ ID NO:

629.

53. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 639, a CDR2 provided by SEQ ID NO: 640, and a CDR3 provided by SEQ ID NO: 641; and a light chain variable region comprising a CDR1 provided by SEQ ID NO: 635, a CDR2 provided by SEQ ID NO: 636, and a CDR3 provided by SEQ ID NO:

637.

54. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 647, a CDR2 provided by SEQ ID NO: 648, and a CDR3 provided by SEQ ID NO: 649; and a light chain variable region comprising a CDR1 provided by SEQ ID NO: 643, a CDR2 provided by SEQ ID NO: 644, and a CDR3 provided by SEQ ID NO:

645.

55. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 655, CDR2 provided by SEQ ID NO: 656, and CDR3 provided by SEQ ID NO: 657; and a light chain variable region comprising CDR1 provided by SEQ ID NO: 651, CDR2 provided by SEQ ID NO: 652, and CDR3 provided by SEQ ID NO:

653.

56. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 663, a CDR2 provided by SEQ ID NO: 664, and a CDR3 provided by SEQ ID NO: 665; and a light chain variable region comprising a CDR1 provided by SEQ ID NO: 659, a CDR2 provided by SEQ ID NO: 660, and a CDR3 provided by SEQ ID NO:

661.

57. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 671, a CDR2 provided by SEQ ID NO: 672, and a CDR3 provided by SEQ ID NO: 673; and a light chain variable region comprising a CDR1 provided by SEQ ID NO: 667, a CDR2 provided by SEQ ID NO: 668, and a CDR3 provided by SEQ ID NO:

669.

58. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 679, a CDR2 provided by SEQ ID NO: 680, and a CDR3 provided by SEQ ID NO: 681; and a light chain variable region comprising a CDR1 provided by SEQ ID NO: 675, a CDR2 provided by SEQ ID NO: 676, and a CDR3 provided by SEQ ID NO:

677.

59. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 687, a CDR2 provided by SEQ ID NO: 688, and a CDR3 provided by SEQ ID NO: 689; and a light chain variable region comprising a CDR1 provided by SEQ ID NO: 683, a CDR2 provided by SEQ ID NO: 684, and a CDR3 provided by SEQ ID NO:

685.

60. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 695, a CDR2 provided by SEQ ID NO: 696, and a CDR3 provided by SEQ ID NO: 697; and a light chain variable region comprising a CDR1 provided by SEQ ID NO: 691, a CDR2 provided by SEQ ID NO: 692, and a CDR3 provided by SEQ ID NO:

693.

61. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region, the heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 703, a CDR2 provided by SEQ ID NO: 704, and a CDR3 provided by SEQ ID NO: 705; and a light chain variable region, the light chain variable region comprising a CDR1 provided by SEQ ID NO: 699, a CDR2 provided by SEQ ID NO: 700, and a CDR3 provided by SEQ ID NO:

701.

62. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 711, a CDR2 provided by SEQ ID NO: 712, and a CDR3 provided by SEQ ID NO: 713; and a light chain variable region comprising a CDR1 provided by SEQ ID NO: 707, a CDR2 provided by SEQ ID NO: 708, and a CDR3 provided by SEQ ID NO:

709.

63. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 823, a CDR2 provided by SEQ ID NO: 824, and a CDR3 provided by SEQ ID NO: 825; and a light chain variable region comprising a CDR1 provided by SEQ ID NO: 820, a CDR2 provided by SEQ ID NO: 821, and a CDR3 provided by SEQ ID NO:

822.

64. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 841, a CDR2 provided by SEQ ID NO: 842, and a CDR3 provided by SEQ ID NO: 843; and a light chain variable region comprising a CDR1 provided by SEQ ID NO: 838, a CDR2 provided by SEQ ID NO: 839, and a CDR3 provided by SEQ ID NO:

840.

65. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 852, a CDR2 provided by SEQ ID NO: 853, and a CDR3 provided by SEQ ID NO: 854; and a light chain variable region comprising a CDR1 provided by SEQ ID NO: 850, a CDR2 provided by SEQ ID NO: 839, and a CDR3 provided by SEQ ID NO:

851.

66. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising: a heavy chain variable region comprising a CDR1 provided by SEQ ID NO: 914, a CDR2 provided by SEQ ID NO: 915, and a CDR3 provided by SEQ ID NO: 916; and a light chain variable region comprising a CDR1 provided by SEQ ID NO: 911, a CDR2 provided by SEQ ID NO: 912, and a CDR3 provided by SEQ ID NO:

913.

67. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising a CDR1 provided by SEQ ID NO: 715, a CDR2 provided by SEQ ID NO: 716, and a CDR3 provided by SEQ ID NO:

717.

68. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising a CDR1 provided by SEQ ID NO: 719, a CDR2 provided by SEQ ID NO: 720, and a CDR3 provided by SEQ ID NO:

721.

69. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising a CDR1 provided by SEQ ID NO: 723, a CDR2 provided by SEQ ID NO: 724, and a CDR3 provided by SEQ ID NO:

725.

70. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising a CDR1 provided by SEQ ID NO: 727, a CDR2 provided by SEQ ID NO: 728, and a CDR3 provided by SEQ ID NO:

729.

71. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising a CDR1 provided by SEQ ID NO: 731, a CDR2 provided by SEQ ID NO: 732, and a CDR3 provided by SEQ ID NO:

733.

72. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising a CDR1 provided by SEQ ID NO: 735, a CDR2 provided by SEQ ID NO: 736, and a CDR3 provided by SEQ ID NO:

737.

73. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising a CDR1 provided by SEQ ID NO: 739, a CDR2 provided by SEQ ID NO: 740, and a CDR3 provided by SEQ ID NO:

741.

74. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising a CDR1 provided by SEQ ID NO: 743, a CDR2 provided by SEQ ID NO: 744, and a CDR3 provided by SEQ ID NO:

745.

75. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising a CDR1 provided by SEQ ID NO: 747, a CDR2 provided by SEQ ID NO: 748, and a CDR3 provided by SEQ ID NO:

749.

76. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising a CDR1 provided by SEQ ID NO: 751, a CDR2 provided by SEQ ID NO: 752, and a CDR3 provided by SEQ ID NO:

753.

77. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising a CDR1 provided by SEQ ID NO: 755, a CDR2 provided by SEQ ID NO: 756, and a CDR3 provided by SEQ ID NO:

757.

78. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising a CDR1 provided by SEQ ID NO: 759, a CDR2 provided by SEQ ID NO: 760, and a CDR3 provided by SEQ ID NO:

761.

79. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising a CDR1 provided by SEQ ID NO: 763, a CDR2 provided by SEQ ID NO: 764, and a CDR3 provided by SEQ ID NO:

765.

80. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising a CDR1 provided by SEQ ID NO: 767, a CDR2 provided by SEQ ID NO: 768, and a CDR3 provided by SEQ ID NO:

769.

81. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising a CDR1 provided by SEQ ID NO: 770, a CDR2 provided by SEQ ID NO: 771, and a CDR3 provided by SEQ ID NO:

772.

82. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising a CDR1 provided by SEQ ID NO: 775, a CDR2 provided by SEQ ID NO: 776, and a CDR3 provided by SEQ ID NO:

777.

83. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising a CDR1 provided by SEQ ID NO: 780, a CDR2 provided by SEQ ID NO: 781, and a CDR3 provided by SEQ ID NO:

782.

84. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising a CDR1 provided by SEQ ID NO: 785, a CDR2 provided by SEQ ID NO: 786, and a CDR3 provided by SEQ ID NO:

777.

85. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising a CDR1 provided by SEQ ID NO: 789, a CDR2 provided by SEQ ID NO: 790, and a CDR3 provided by SEQ ID NO:

791.

86. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising a CDR1 provided by SEQ ID NO: 794, a CDR2 provided by SEQ ID NO: 795, and a CDR3 provided by SEQ ID NO:

796.

87. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising a CDR1 provided by SEQ ID NO: 785, a CDR2 provided by SEQ ID NO: 799, and a CDR3 provided by SEQ ID NO:

777.

88. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising a CDR1 provided by SEQ ID NO: 785, a CDR2 provided by SEQ ID NO: 802, and a CDR3 provided by SEQ ID NO:

777.

89. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising a CDR1 provided by SEQ ID NO: 789, a CDR2 provided by SEQ ID NO: 805, and a CDR3 provided by SEQ ID NO:

806.

90. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising a CDR1 provided by SEQ ID NO: 901, a CDR2 provided by SEQ ID NO: 902, and a CDR3 provided by SEQ ID NO:

903.

91. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 2 to 8, comprising a CDR1 provided by SEQ ID NO: 906, a CDR2 provided by SEQ ID NO: 907, and a CDR3 provided by SEQ ID NO:

908.

92. An anti-CLL-1 antibody or antigen-binding fragment thereof, comprising a VHH, wherein the VHH comprises SEQ ID NO: 5, 19, 33, 47, 61, 75, 89, 103, 117, 131, 145, 159, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 271, 276, 281, 286, 291, 299, 313, 327, 341, 355, 423, 431, 439, 447, 455, 463, 471, 479, 487, 495, 503, 511, 519, 520, 770, 775, 780, 785, 789, 794, 823, 841, 852, 896, 901, 906 or 914; SEQ ID NO: 6, 20, 34, 48, 62, 76, 90, 104, 118, 132, 146, 160, 171, 176, 181, 186, 191, 196, 201, 206, 211, 216, 221, 226, 231, 236, 241, 246, 251, 256, 261, 266, 272, 277, 282, 287, 292, 300, 314, 328, 342, 356, 424, 432, 440, 448, 456, 464, 472, 480, 488, 496, 504, 512, 520, 528, 5 36, 544, 552, 560, 568, 576, 584, 592, 600, 608, 616, 624, 632, 640, 648, 656, 664, 672, 680, 688, 696, 704, 712, 716, 720, 724, 728, 732, 736, 740, 744, 748, 752, 756, 760, 764, 768, 771, 776, 781, 786, 790, 795, 799, 802, 805, 824, 842, 853, 897, 902, 907, or 915;and SEQ ID NO: 7, 21, 35, 49, 63, 77, 91, 105, 119, 133, 147, 161, 172, 177, 182, 187, 192, 197, 202, 207, 212, 217, 222, 227, 232, 237, 242, 247, 252, 257, 262, 267, 273, 278, 283, 288, 293, 301, 315, 329, 343, 357, 425, 433, 441, 449, 457, 465, 473, 481, 489, 497, 505, 513, 521 , 529, 537, 545, 553, 561, 569, 577, 585, 593, 601, 609, 617, 625, 633, 641, 649, 657, 665, 673, 681, 689, 697, 705, 713, 717, 721, 725, 729, 733, 737, 741, 745, 749, 753, 757, 761, 765, 769, 772, 777, 782, 791, 796, 806, 825, 843, 854, 898, 903, 908 or 916. ; 93. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 170, a CDR2 provided by SEQ ID NO: 171, and a CDR3 provided by SEQ ID NO:

172.

94. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 175, a CDR2 provided by SEQ ID NO: 176, and a CDR3 provided by SEQ ID NO:

177.

95. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 180, a CDR2 provided by SEQ ID NO: 181, and a CDR3 provided by SEQ ID NO:

182.

96. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 185, a CDR2 provided by SEQ ID NO: 186, and a CDR3 provided by SEQ ID NO:

187.

97. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 190, a CDR2 provided by SEQ ID NO: 191, and a CDR3 provided by SEQ ID NO:

192.

98. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 195, a CDR2 provided by SEQ ID NO: 196, and a CDR3 provided by SEQ ID NO:

197.

99. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 200, a CDR2 provided by SEQ ID NO: 201, and a CDR3 provided by SEQ ID NO:

202.

100. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 205, a CDR2 provided by SEQ ID NO: 206, and a CDR3 provided by SEQ ID NO:

207.

101. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 210, a CDR2 provided by SEQ ID NO: 211, and a CDR3 provided by SEQ ID NO:

212.

102. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 215, a CDR2 provided by SEQ ID NO: 216, and a CDR3 provided by SEQ ID NO:

217.

103. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 220, a CDR2 provided by SEQ ID NO: 221, and a CDR3 provided by SEQ ID NO:

222.

104. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 225, a CDR2 provided by SEQ ID NO: 226, and a CDR3 provided by SEQ ID NO:

227.

105. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 230, a CDR2 provided by SEQ ID NO: 231, and a CDR3 provided by SEQ ID NO:

232.

106. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 235, a CDR2 provided by SEQ ID NO: 236, and a CDR3 provided by SEQ ID NO:

237.

107. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 240, a CDR2 provided by SEQ ID NO: 241, and a CDR3 provided by SEQ ID NO:

242.

108. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 245, a CDR2 provided by SEQ ID NO: 246, and a CDR3 provided by SEQ ID NO:

247.

109. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 250, a CDR2 provided by SEQ ID NO: 251, and a CDR3 provided by SEQ ID NO:

252.

110. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 255, a CDR2 provided by SEQ ID NO: 256, and a CDR3 provided by SEQ ID NO:

257.

111. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 260, a CDR2 provided by SEQ ID NO: 261, and a CDR3 provided by SEQ ID NO:

262.

112. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 265, a CDR2 provided by SEQ ID NO: 266, and a CDR3 provided by SEQ ID NO:

267.

113. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 271, a CDR2 provided by SEQ ID NO: 272, and a CDR3 provided by SEQ ID NO:

273.

114. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 276, a CDR2 provided by SEQ ID NO: 277, and a CDR3 provided by SEQ ID NO:

278.

115. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 281, a CDR2 provided by SEQ ID NO: 282, and a CDR3 provided by SEQ ID NO:

283.

116. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 286, a CDR2 provided by SEQ ID NO: 287, and a CDR3 provided by SEQ ID NO:

288.

117. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 291, a CDR2 provided by SEQ ID NO: 292, and a CDR3 provided by SEQ ID NO:

293.

118. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 715, a CDR2 provided by SEQ ID NO: 716, and a CDR3 provided by SEQ ID NO:

717.

119. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 719, a CDR2 provided by SEQ ID NO: 720, and a CDR3 provided by SEQ ID NO:

721.

120. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 723, a CDR2 provided by SEQ ID NO: 724, and a CDR3 provided by SEQ ID NO:

725.

121. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 727, a CDR2 provided by SEQ ID NO: 728, and a CDR3 provided by SEQ ID NO:

729.

122. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 731, a CDR2 provided by SEQ ID NO: 732, and a CDR3 provided by SEQ ID NO:

733.

123. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 735, a CDR2 provided by SEQ ID NO: 736, and a CDR3 provided by SEQ ID NO:

737.

124. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 739, a CDR2 provided by SEQ ID NO: 740, and a CDR3 provided by SEQ ID NO:

741.

125. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 743, a CDR2 provided by SEQ ID NO: 744, and a CDR3 provided by SEQ ID NO:

745.

126. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 747, a CDR2 provided by SEQ ID NO: 748, and a CDR3 provided by SEQ ID NO:

749.

127. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 751, a CDR2 provided by SEQ ID NO: 752, and a CDR3 provided by SEQ ID NO:

753.

128. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 755, a CDR2 provided by SEQ ID NO: 756, and a CDR3 provided by SEQ ID NO:

757.

129. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 759, a CDR2 provided by SEQ ID NO: 760, and a CDR3 provided by SEQ ID NO:

761.

130. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 763, a CDR2 provided by SEQ ID NO: 764, and a CDR3 provided by SEQ ID NO:

765.

131. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 767, a CDR2 provided by SEQ ID NO: 768, and a CDR3 provided by SEQ ID NO:

769.

132. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 770, a CDR2 provided by SEQ ID NO: 771, and a CDR3 provided by SEQ ID NO:

772.

133. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 775, a CDR2 provided by SEQ ID NO: 776, and a CDR3 provided by SEQ ID NO:

777.

134. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 780, a CDR2 provided by SEQ ID NO: 781, and a CDR3 provided by SEQ ID NO:

782.

135. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 785, a CDR2 provided by SEQ ID NO: 786, and a CDR3 provided by SEQ ID NO:

777.

136. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 789, a CDR2 provided by SEQ ID NO: 790, and a CDR3 provided by SEQ ID NO:

791.

137. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 794, a CDR2 provided by SEQ ID NO: 795, and a CDR3 provided by SEQ ID NO:

796.

138. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 785, a CDR2 provided by SEQ ID NO: 799, and a CDR3 provided by SEQ ID NO:

777.

139. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 785, a CDR2 provided by SEQ ID NO: 802, and a CDR3 provided by SEQ ID NO:

777.

140. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 789, a CDR2 provided by SEQ ID NO: 805, and a CDR3 provided by SEQ ID NO:

806.

141. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 823, a CDR2 provided by SEQ ID NO: 824, and a CDR3 provided by SEQ ID NO:

825.

142. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 823, a CDR2 provided by SEQ ID NO: 824, and a CDR3 provided by SEQ ID NO:

825.

143. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 841, a CDR2 provided by SEQ ID NO: 842, and a CDR3 provided by SEQ ID NO:

843.

144. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 92, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 852, a CDR2 provided by SEQ ID NO: 853, and a CDR3 provided by SEQ ID NO:

854.

145. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 9, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 896, a CDR2 provided by SEQ ID NO: 897, and a CDR3 provided by SEQ ID NO:

898.

146. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 9, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 901, a CDR2 provided by SEQ ID NO: 902, and a CDR3 provided by SEQ ID NO:

903.

147. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 9, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 906, a CDR2 provided by SEQ ID NO: 907, and a CDR3 provided by SEQ ID NO:

908.

148. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in claim 9, wherein the VHH comprises a CDR1 provided by SEQ ID NO: 914, a CDR2 provided by SEQ ID NO: 915, and a CDR3 provided by SEQ ID NO:

916.

149. An anti-CLL-1 antibody or antigen-binding fragment thereof, comprising a VHH comprising SEQ ID NO: 74, 779, 784, 788, 793, 798, 801, 804, 808, 829, 835, 847, 858, 900, 905, 910, or 920.

150. An anti-CLL-1 antibody or antigen-binding fragment thereof, comprising a VHH, wherein the VHH comprises SEQ ID NO: 5-7, 19-21, 33-35, 47-49, 61-63, 75-77, 89-91, 103-105, 117-119, 131-133, 145-147, 159-161, 170-172, 175-177, 180-182, 185-187, 190-192, 195-197, 200-202, 205-207, 210-212, 215-217, 220-222, 225-227, 230-232, 235-237, 240-242, 245-247, 250 -252, 255-257, 260-262, 265-267, 271-273, 276-278, 281-283, 286-288, 291-293, 299-301, 313-315, 327-329, 341-343, 355-357, 423-425, 431-433, 439-441, 447-449, 455-457, 463-465, 471-473, 479-481, 487-489, 495-497, 503-505, 511-513, 519-521 , 527-529, 535-537, 543-545, 551-553, 559-561, 567-569, 575-577, 583-585, 591-593, 599-601, 607-609, 615-617, 623-625, 631-633, 639-641, 647-649, 655-657, 663-665, 671-673, 679-681, 687-689, 695-697, 703-705, 711-713, 715-717, 719-821, 72 727-729, 731-733, 735-737, 739-741, 743-745, 747-749, 751-753, 755-757, 759-761, 763-765, 767-772, 775-777, 780-782, 785-786, 789-791, 794-796, 799, 802, 805-806, 823-825, 841-843, 852-854, 896-898, 901-903, 906-908 or 914-916 CDR sequence.

151. An anti-CLL-1 antibody or antigen-binding fragment thereof, comprising a VHH, wherein the VHH comprises SEQ ID NO: 5-7, 19-21, 33-35, 47-49, 61-63, 75-77, 89-91, 103-105, 117-119, 131-133, 145-147, 159-161, 170-172, 175-177, 180-182, 185-187, 190-192, 195-197, 200-202, 205-207, 210-212, 215-217, 220-222, 225-227, 230-232, 235-237, 240-242, 245-247, 250-2 52, 255-257, 260-262, 265-267, 271-273, 276-278, 281-283, 286-288, 291-293, 299-301, 313-315, 327-329, 341-343, 355-357, 423-425, 431-433, 439-441, 447-449, 455-457, 463-465, 471-473, 479-481, 487-489, 495-497, 503-505, 511-513, 519-521, 527 -529, 535-537, 543-545, 551-553, 559-561, 567-569, 575-577, 583-585, 591-593, 599-601, 607-609, 615-617, 623-625, 631-633, 639-641, 647-649, 655-657, 663-665, 671-673, 679-681, 687-689, 695-697, 703-705, 711-713, 715-717, 719-821, 723-725, 7 729, 731-733, 735-737, 739-741, 743-745, 747-749, 751-753, 755-757, 759-761, 763-765, 767-772, 775-777, 780-782, 785-786, 789-791, 794-796, 799, 802, 805-806, 823-825, 841-843, 852-854, 896-898, 901-903, 906-908 or 914-916 CDR1, CDR2 and CDR3.

152. An anti-CLL-1 antibody or antigen-binding fragment thereof, comprising a VHH, wherein the VHH comprises SEQ ID NO: 5-7, 19-21, 33-35, 47-49, 61-63, 75-77, 89-91, 103-105, 117-119, 131-133, 145-147, 159-161, 170-172, 175-177, 180-182, 185-187, 190-192, 195-197, 200-202, 205-207, 210-212, 215-217, 220-222, 225-227, 230-232, 235-237, 240-242, 245-247, 250 -252, 255-257, 260-262, 265-267, 271-273, 276-278, 281-283, 286-288, 291-293, 299-301, 313-315, 327-329, 341-343, 355-357, 423-425, 431-433, 439-441, 447-449, 455-457, 463-465, 471-473, 479-481, 487-489, 495-497, 503-505, 511-513, 519-521 , 527-529, 535-537, 543-545, 551-553, 559-561, 567-569, 575-577, 583-585, 591-593, 599-601, 607-609, 615-617, 623-625, 631-633, 639-641, 647-649, 655-657, 663-665, 671-673, 679-681, 687-689, 695-697, 703-705, 711-713, 715-717, 719-821, 723 -725, 727-729, 731-733, 735-737, 739-741, 743-745, 747-749, 751-753, 755-757, 759-761, 763-765, 767-772, 775-777, 780-782, 785-786, 789-791, 794-796, 799, 802, 805-806, 823-825, 841-843, 852-854, 896-898, 901-903, 906-908, or 914-916.

153. An anti-CLL-1 antibody or antigen-binding fragment thereof, comprising a VHH, wherein the VHH comprises a VHH that is identical to SEQ ID NO: 5-7, 19-21, 33-35, 47-49, 61-63, 75-77, 89-91, 103-105, 117-119, 131-133, 145-147, 159-161, 170-172, 175-177, 180-182, 185-187, 190-192, 195-197, 200-202, 205-207, 210-212, 215-217, 220-222, 225-227, 230-232, 235-237, 240-242, 245-247, 25 0-252, 255-257, 260-262, 265-267, 271-273, 276-278, 281-283, 286-288, 291-293, 299-301, 313-315, 327-329, 341-343, 355-357, 423-425, 431-433, 439-441, 447-449, 455-457, 463-465, 471-473, 479-481, 487-489, 495-497, 503-505, 511-513, 519-5 21, 527-529, 535-537, 543-545, 551-553, 559-561, 567-569, 575-577, 583-585, 591-593, 599-601, 607-609, 615-617, 623-625, 631-633, 639-641, 647-649, 655-657, 663-665, 671-673, 679-681, 687-689, 695-697, 703-705, 711-713, 715-717, 719-821, CDRs of 723-725, 727-729, 731-733, 735-737, 739-741, 743-745, 747-749, 751-753, 755-757, 759-761, 763-765, 767-772, 775-777, 780-782, 785-786, 789-791, 794-796, 799, 802, 805-806, 823-825, 841-843, 852-854, 896-898, 901-903, 906-908, or 914-916 (e.g., CDR1, CDR2 and / or CDR3) having at least one CDR that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical.

154. The anti-CLL-1 antibody or antigen-binding fragment thereof of any one of claims 1 to 153, wherein the antibody or antigen-binding fragment thereof is a monoclonal antibody or antigen-binding fragment thereof.

155. The anti-CLL-1 antibody or antigen-binding fragment thereof of any one of claims 1 to 154, wherein the antibody or antigen-binding fragment thereof is a humanized antibody or antigen-binding fragment thereof.

156. An anti-CLL-1 antibody or antigen-binding fragment thereof that competes with the antibody or antigen-binding fragment thereof as described in any one of claims 1 to 155.

157. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 1 to 156, wherein the antibody or antigen-binding fragment thereof comprises a CH2 constant domain and a CH3 constant domain.

158. The anti-CLL-1 antibody or antigen-binding fragment thereof of claim 157, wherein the antibody or antigen-binding fragment thereof comprises SEQ ID NO: 15, 29, 43, 57, 71, 85, 99, 113, 127, 141, 155, 169, 174, 179, 184, 189, 194, 199, 204, 209, 214, 219, 224, 229, 234, 239, 244, 249, 254, 259, 264, 269, 275, 280, 285, 290, 295, 309, 323, 337 、351、365、418、422、426、430、434、438、442、446、450、454、458、462、466、470、474、478、482、486、490、494、498、502、506、510、514、518、522、526、530、534、538、542、546、550、554、558、 562, 566, 570, 574, 578, 582, 586, 590, 584, 598, 602, 606, 610, 614, 618, 622, 626, 630, 634, 638, 642, 646, 650, 654, 658, 662, 666, 670, 674, 678, 682, 686, 690, 694, 698, 702, 706, 710, 7 The amino acid sequence of 14, 718, 722, 726, 730, 734, 738, 742, 746, 750, 754, 758, 762, 766, 774, 779, 784, 788, 793, 798, 801, 804, 808, 817, 829, 831, 835, 837, 847, 849, 858, 860, 893, 900, 905, 910, 920.

159. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 1 to 158, wherein the antibody or antigen-binding fragment thereof is a heavy chain antibody.

160. The anti-CLL-1 antibody or antigen-binding fragment thereof of any one of claims 1 to 159, wherein the antibody or antigen-binding fragment thereof is a camelid antibody.

161. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 1 to 159, wherein the antibody or antigen-binding fragment thereof is a llama antibody.

162. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 1 to 159, wherein the antibody or antigen-binding fragment thereof is an alpaca antibody.

163. An anti-CLL-1 antibody or antigen-binding fragment thereof as described in any one of claims 1 to 158, wherein the antibody is of IgG1-type, IgG2-type, IgG3-type or IgG4-type.

164. A chimeric antigen receptor comprising any one of the antibodies or antigen-binding fragments thereof as described in any one of claims 1 to 163.

165. A cell expressing the chimeric antigen receptor of claim 164.

166. The cell of claim 165, wherein the cell is an immune effector cell.

167. The cell of claim 165 or claim 166, wherein the cell is a lymphocyte.

168. The cell of any one of claims 165 to 167, wherein the cell is a T cell.

169. The cell of any one of claims 165 to 167, wherein the cell is a natural killer (NK) cell.

170. A pharmaceutical composition comprising at least one antibody as described in any one of claims 1 to 163, the chimeric antigen receptor as described in claim 164, or the cell as described in any one of claims 165 to 169 and a pharmaceutically acceptable excipient.

171. A nucleic acid comprising a nucleic acid sequence encoding the antibody or antigen-binding fragment thereof as described in any one of claims 1 to 163, or the chimeric antigen receptor as described in claim 164.

172. The nucleic acid of claim 172, wherein the nucleic acid comprises the sequence of SEQ ID NO: 8, 10, 12, 14, 22, 24, 26, 28, 36, 38, 40, 42, 50, 52, 54, 56, 64, 66, 68, 70, 78, 80, 82, 84, 92, 94, 96, 98, 106, 108, 110, 112, 120, 122, 124, 126, 134, 136, 138, 140, 148, 150, 152, 154, 162, 164, 166, 168, 173, 178, 183, 188, 193, 198, 203, 208, 213, 218, 223, 228, 233, 238, 243, 248, 253, 258, 95-99% identical to any of 263, 268, 274, 279, 284, 289, 294, 302, 304, 306, 308, 316, 318, 320, 322, 330, 332, 334, 336, 344, 346, 348, 350, 358, 360, 362, 364, 773, 778, 783, 787, 792, 797, 800, 803, 807, 826, 828, 830, 832, 834, 836, 844, 846, 848, 855, 857, 859, 904, 909, 917, 919, or 921.

173. The nucleic acid of claim 172, wherein the nucleic acid comprises SEQ ID NO: 8, 10, 12, 14, 22, 24, 26, 28, 36, 38, 40, 42, 50, 52, 54, 56, 64, 66, 68, 70, 78, 80, 82, 84, 92, 94, 96, 98, 106, 108, 110, 112, 120, 122, 124, 126, 134, 136, 138, 140, 148, 150, 152, 154, 162, 164, 166, 168, 173, 178, 183, 188, 193, 198, 203, 208, 213, 218, 223, 228, 233, 238, 243, 248, 79, 800, 803, 807, 826, 828, 830, 832, 834, 836, 844, 846, 848, 855, 857, 859, 904, 909, 917, 919, or 921.

174. A vector comprising the nucleic acid of any one of claims 171 to 173.

175. A cell comprising the nucleic acid of any one of claims 171 to 173 or the vector of claim 174.

176. The cell of claim 175, wherein the cell is an immune cell.

177. The cell of claim 176, wherein the immune cell is a T cell, a natural killer (NK) cell, a cytotoxic T lymphocyte (CTL), or a regulatory T cell.

178. A method of producing an antibody or an antigen-binding fragment thereof, comprising culturing a cell as described in any one of claims 165 to 169 or 175 to 177 under conditions suitable for expression of the antibody or antigen-binding fragment thereof.

179. A method for treating a CLL-1 related disease or condition, the method comprising administering to a subject in need thereof an effective amount of an antibody or antigen-binding fragment thereof as described in any one of claims 1 to 163, or a cell as described in any one of claims 165 to 169 or 175 to 177.

180. The method of claim 179, wherein the CLL-1-related disease or condition is myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).

181. The method of claim 179 or claim 180, further comprising administering to the subject an effective amount of a chemotherapeutic or oncolytic therapeutic agent.

182. A method for treating a subject having or at risk for a hematological neoplastic disease or malignancy associated with CLL-1 expression, the method comprising administering to the subject a therapeutically effective amount of an antibody or antigen-binding fragment thereof as described in any one of claims 1 to 163, or a cell as described in any one of claims 165 to 169 or 175 to 177.

183. The method of claim 182, wherein the neoplastic disease or malignancy of the blood associated with CLL-1 expression is myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).

184. The method of claim 182 or claim 183, further comprising administering to the subject an effective amount of a chemotherapeutic or oncolytic therapeutic agent.

185. A chimeric antigen receptor (CAR), wherein the chimeric antigen receptor (CAR) comprises a CLL-1 binding domain, a transmembrane domain and an intracellular signaling domain, wherein the CLL-1 binding domain comprises a heavy chain variable region and / or a light chain variable region; wherein the transmembrane domain comprises a transmembrane domain of a protein selected from CD8α or CD28; and wherein the intracellular signaling domain includes the signaling domain of CD3ζ.

186. The CAR of claim 185, wherein the heavy chain variable region and the light chain variable region are connected by a linker.

187. The CAR of claim 185 or claim 186, wherein the CLL-1 binding domain comprises at least one of a single-chain variable fragment (scFv), a VH fragment, a VHH fragment, or a VL fragment.

188. A CAR as described in any one of claims 185 to 187, wherein the CLL-1 binding domain is connected to the transmembrane domain via a hinge region.

189. A CAR as described in claim 188, wherein the hinge region comprises the hinge region of a protein selected from CD8α, IgG4 or CD28.

190. The CAR of any one of claims 185 to 189, further comprising one or more co-stimulatory domains.

191. A CAR as described in claim 190, wherein the one or more co-stimulatory domains include a signaling domain of 4-1BB and / or CD28.

192. A CAR as described in any one of claims 185 to 191, wherein the CLL-1 binding domain comprises the anti-CLL-1 antibody or its antigen-binding fragment, or any one of claims 1 to 164.

193. A nucleic acid encoding the CAR of any one of claims 185 to 192.

194. A nucleic acid as described in claim 193, wherein the isolated nucleic acid is selected from SEQ ID NO: 8, 10, 12, 14, 22, 24, 26, 28, 36, 38, 40, 42, 50, 52, 54, 56, 64, 66, 68, 70, 78, 80, 82, 84, 92, 94, 96, 98, 106, 108, 110, 112, 120, 122, 124, 126, 134, 136, 138, 140, 148, 150, 152, 154, 162, 164, 166, 168, 173, 178, 183, 188, 193, 198, 203, 208, 213, 218, 223, 228, 233, 238, 243, 248, 253, 258 , 263, 268, 274, 279, 284, 289, 294, 302, 304, 306, 308, 316, 318, 320, 322, 330, 332, 334, 336, 344, 346, 348, 350, 358, 360, 362, 364, 773, 778, 783, 787, 792, 797, 800, 803, 807, 826, 828, 830, 832, 834, 836, 844, 846, 848, 855, 857, 859, 904, 909, 917, 919 or 921 having 95%-99% sequence identity.

195. The nucleic acid of claim 194, wherein the isolated nucleic acid comprises a nucleic acid selected from the group consisting of SEQ ID NO: 8, 10, 12, 14, 22, 24, 26, 28, 36, 38, 40, 42, 50, 52, 54, 56, 64, 66, 68, 70, 78, 80, 82, 84, 92, 94, 96, 98, 106, 108, 110, 112, 120, 122, 124, 126, 134, 136, 138, 140, 148, 150, 152, 154, 162, 164, 166, 168, 173, 178, 183, 188, 193, 198, 203, 208, 213, 218, 223, 228, 233, 238, 243, 248, 79, 800, 803, 807, 826, 828, 830, 832, 834, 836, 844, 846, 848, 855, 857, 859, 904, 909, 917, 919, 921.

196. A nucleic acid as described in any one of claims 193 to 195, wherein the CAR sequence is operably linked to a promoter sequence.

197. The nucleic acid of claim 196, wherein the promoter sequence is SFFV promoter, EF1α promoter, tEF1a promoter, hPGK promoter, SFFV promoter or MND promoter.

198. An expression vector comprising a nucleic acid molecule encoding a CAR as described in any one of claims 193 to 197.

199. The expression vector of claim 198, wherein the vector is a DNA vector, an RNA vector, a plasmid, a lentiviral vector, an adenoviral vector or a retroviral vector.

200. An immune effector cell comprising a CAR as described in any one of claims 185 to 192 or a nucleic acid molecule as described in any one of claims 193 to 197.

201. The immune effector cell of claim 202, wherein the cell is selected from the group consisting of: T cells, natural killer (NK) cells, cytotoxic T lymphocytes (CTLs), regulatory T cells, human embryonic stem cells, and pluripotent stem cells that can differentiate into lymphoid cells.

202. A cell population comprising at least one immune effector cell as described in claim 200 or claim 201.

203. A pharmaceutical composition comprising the cell population as described in claim 202 and a pharmaceutically acceptable carrier.

204. A method for treating hematopoietic malignancies, comprising administering to a subject in need thereof an effective amount of a CAR as described in any one of claims 185 to 192, an immune effector cell as described in claim 200 or claim 201, or a cell population as described in claim 202, or a pharmaceutical composition as described in claim 203.

205. The method of claim 204, wherein the method further comprises administering a population of hematopoietic cells, wherein the hematopoietic cells are genetically engineered such that the gene encoding CLL-1 targeted by the antigen binding domain is engineered to reduce or eliminate expression of CLL-1.

206. The method of claim 205, wherein the immune cells, the hematopoietic cells, or both are allogeneic or autologous.

207. The method of any one of claims 205 to 206, wherein the hematopoietic cells are hematopoietic stem cells.

208. The method of claim 207, wherein the hematopoietic stem cells are from bone marrow cells or peripheral blood mononuclear cells (PBMC).

209. The method of claim 207 or claim 208, wherein the hematopoietic stem cell is CD34+ / CLL-1-.

210. The method of any one of claims 205 to 209, wherein the hematopoietic cells are prepared by editing an endogenous gene encoding CLL-1 to reduce or eliminate expression of CLL-1.

211. The method of claim 210, wherein the endogenous gene is edited by CRISPR-Cas9.

212. The method of any one of claims 204 to 211, wherein the subject suffers from or has been diagnosed with a hematopoietic malignancy or a premalignancy characterized by expression of CLL-1 on malignant or premalignant cells.

213. The method of any one of claims 204 to 212, wherein the subject has Hodgkin's lymphoma, non-Hodgkin's lymphoma, leukemia, or multiple myeloma.

214. The method of claim 213, wherein the leukemia is acute myeloid leukemia, myelodysplastic syndrome, chronic myeloid leukemia, acute lymphoblastic leukemia, or chronic lymphoblastic leukemia.

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