Binders and methods of using same

JP2025513855A5Pending Publication Date: 2026-04-20VOR BIOPHARMA INC
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Patent Information

Authority / Receiving Office
JP · JP
Patent Type
Applications
Current Assignee / Owner
VOR BIOPHARMA INC
Filing Date
2023-04-11
Publication Date
2026-04-20

AI Technical Summary

Technical Problem

The prior art is difficult to effectively treat acute myeloid leukemia (AML), especially due to the diversity of AML and its resistance to existing targeted therapies.

Method used

An anti-CLL-1 monoclonal antibody or antigen-binding fragment thereof has been developed, containing specific heavy and light chain variant region sequences for targeting and neutralizing CLL-1 proteins.

Benefits of technology

By targeting CLL-1, antibodies can effectively recognize and bind AML cells, thereby potentially inhibiting the growth and division of AML cells, providing a new method for treating AML.

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Abstract

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

[Technical Field]

[0001] Related Applications This application claims the benefit under 35 U.S.C. § 119 of U.S. Provisional Patent Application No. 63 / 329,664, filed April 11, 2022, and U.S. Provisional Patent Application No. 63 / 399,588, filed August 19, 2022, which are incorporated herein by reference in their entireties.

[0002] Electronic Sequence Listing Reference The contents of the electronic sequence listing (V029170034WO00-SEQ-CEW.xml, size: 875,826 bytes, and creation date: April 11, 2023) are incorporated herein by reference in their entirety. [Background technology]

[0003] C-type lectin-like molecule-1 (CLL-1), which may also be referred to as CLEC12A, is a member of the C-type lectin-like receptor family that is frequently expressed on acute myeloid leukemia (AML) cells. AML remains a major therapeutic challenge and an unmet medical need in hematological oncology. AML is a disease that results in the uncontrolled accumulation of immature myeloblasts in the bone marrow and peripheral blood, and the disease has multiple subtypes that contribute to the challenges of developing comprehensive targeted therapies. Despite an increasing understanding of the molecular genetics of the disease, relatively few novel therapies have been approved for AML. Therefore, there remains a need for novel therapies for AML. Summary of the Invention

[0004] In one aspect, the present disclosure provides the nucleic acids of SEQ ID NOs: 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, 71 The present invention relates to an anti-CLL-1 antibody, or an antigen-binding fragment thereof, comprising the amino acid sequence of: 8, 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.

[0005] In one aspect, the present disclosure provides SEQ ID NOs: 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, 26 5-267, 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, 5 63-565, 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, 623-62 5, 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,The present invention relates to an anti-CLL-1 antibody, or an antigen-binding fragment thereof, comprising at least one complementarity-determining region (CDR) sequence selected from the group consisting of 751 to 753, 755 to 757, 759 to 761, 763 to 765, 767 to 769, 770 to 772, 775 to 777, 780 to 782, 785 to 786, 789 to 791, 794 to 796, 799, 802, 805 to 806, 820 to 825, 838 to 843, 850 to 854, 861 to 866, 896 to 898, 901 to 903, 906 to 908, and 911 to 916.

[0006] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, is selected from the group consisting of SEQ ID NOs: 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, 256-258, 260-262, 264-266, 266-268, 270-272, 274-276, 278-279, 280-282, 284-285, 286-287, 288-289, 290-292, 300-302, 304-305, 306-307, 308-309, 310-312, 314-315, 316-317, 318-319, 320-321, 322-323, 324-325, 326-327, 328-329, 330-332 252, 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, 487-488 89, 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, 5 51-553, 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, 611-61 3, 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,The CDR sequences include three of 739 to 741, 743 to 745, 747 to 749, 751 to 753, 755 to 757, 759 to 761, 763 to 765, 767 to 769, 770 to 772, 775 to 777, 780 to 782, 785 to 786, 789 to 791, 794 to 796, 799, 802, 805 to 806, 820 to 825, 838 to 843, 850 to 854, 861 to 866, 896 to 898, 901 to 903, 906 to 908, or 911 to 916.

[0007] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, is selected from the group consisting of SEQ ID NOs: 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, 256-258, 260-262, 264-266, 266-268, 270-272, 274-276, 278-279, 280-282, 284-285, 286-287, 288-289, 290-292, 300-302, 304-305, 306-307, 308-309, 310-312, 314-315, 316-317, 318-319, 320-321, 322-323, 324-325, 326-327, 328-329, 330-332 252, 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, 487-488 89, 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, 5 51-553, 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, 611-61 3, 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,The CDR sequences include six of 739 to 741, 743 to 745, 747 to 749, 751 to 753, 755 to 757, 759 to 761, 763 to 765, 767 to 769, 770 to 772, 775 to 777, 780 to 782, 785 to 786, 789 to 791, 794 to 796, 799, 802, 805 to 806, 820 to 825, 838 to 843, 850 to 854, 861 to 866, 896 to 898, 901 to 903, 906 to 908, or 911 to 916.

[0008] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, is selected from the group consisting of SEQ ID NOs: 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 The heavy chain CDR sequences include three of the following: to 665, 671 to 673, 679 to 681, 687 to 689, 695 to 697, 703 to 705, 711 to 713, 715 to 746, 748 to 808, 816 to 817, 823 to 825, 828 to 829, 834 to 835, 841 to 843, 846 to 847, 852 to 854, 857 to 858, 869 to 870, 880 to 881, 892 to 893, 896 to 910, 914 to 916, or 919 to 920.

[0009] In another aspect, the present disclosure provides SEQ ID NOs: 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, 26 5-267, 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, 5 63-565, 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, 623-62 5, 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~ The present invention relates to an anti-CLL-1 antibody, or an antigen-binding fragment thereof, comprising CDR1, CDR2, and CDR3 of 753, 755 to 757, 759 to 761, 763 to 765, 767 to 769, 770 to 772, 775 to 777, 780 to 782, 785 to 786, 789 to 791, 794 to 796, 799, 802, 805 to 806, 820 to 825, 838 to 843, 850 to 854, 896 to 898, 901 to 903, 906 to 908, or 911 to 916.

[0010] In another aspect, the present disclosure provides SEQ ID NOs: 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, 26 5-267, 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, 5 63-565, 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, 623-62 5, 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, 90 The present invention relates to an anti-CLL-1 antibody, or an antigen-binding fragment thereof, comprising at least one CDR that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a CDR (e.g., CDR1, CDR2, and / or CDR3) of CDRs 6 to 908, or 911 to 916.

[0011] In another aspect, the present disclosure provides the nucleic acids of SEQ ID NOs: 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, and CDR1 provided by SEQ ID NOs: 6, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 78, 79, 82, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105 0, 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, and CDR2 provided by SEQ ID NOs: 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, 7 57, 761, 765, 769, 772, 777, 782, 791, 796, 806, 825, 843, 854, 898, 903, 908, or 916 and a heavy chain variable region comprising 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, CDR1 provided by SEQ ID NOs: 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, 572, 580, 588, 596, 604, 612, 62 0, 628, 636, 644, 652, 660, 668, 676, 684, 692, 700, 708, 821, 839, or 91, and CDR2 provided by SEQ ID NOs: 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,and a light chain variable region comprising a CDR3 provided by any of the following: 645, 653, 661, 669, 677, 685, 693, 701, 709, 822, 840, 851, or 913.

[0012] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises 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.

[0013] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises 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.

[0014] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 33, CDR2 provided by SEQ ID NO: 34, and CDR3 provided by SEQ ID NO: 35, and a light chain variable region comprising CDR1 provided by SEQ ID NO: 30, CDR2 provided by SEQ ID NO: 31, and CDR3 provided by SEQ ID NO: 32.

[0015] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises 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.

[0016] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises 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.

[0017] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises 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.

[0018] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 89, CDR2 provided by SEQ ID NO: 90, and CDR3 provided by SEQ ID NO: 91, and a light chain variable region comprising CDR1 provided by SEQ ID NO: 86, CDR2 provided by SEQ ID NO: 87, and CDR3 provided by SEQ ID NO: 88.

[0019] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 103, CDR2 provided by SEQ ID NO: 104, and CDR3 provided by SEQ ID NO: 105, and a light chain variable region comprising CDR1 provided by SEQ ID NO: 100, CDR2 provided by SEQ ID NO: 101, and CDR3 provided by SEQ ID NO: 102.

[0020] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 117, CDR2 provided by SEQ ID NO: 118, and CDR3 provided by SEQ ID NO: 119, and a light chain variable region comprising CDR1 provided by SEQ ID NO: 114, CDR2 provided by SEQ ID NO: 115, and CDR3 provided by SEQ ID NO: 116.

[0021] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 131, CDR2 provided by SEQ ID NO: 132, and CDR3 provided by SEQ ID NO: 133, and a light chain variable region comprising CDR1 provided by SEQ ID NO: 128, CDR2 provided by SEQ ID NO: 129, and CDR3 provided by SEQ ID NO: 130.

[0022] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 145, CDR2 provided by SEQ ID NO: 146, and CDR3 provided by SEQ ID NO: 147, and a light chain variable region comprising CDR1 provided by SEQ ID NO: 142, CDR2 provided by SEQ ID NO: 143, and CDR3 provided by SEQ ID NO: 144.

[0023] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 159, CDR2 provided by SEQ ID NO: 160, and CDR3 provided by SEQ ID NO: 161, and a light chain variable region comprising CDR1 provided by SEQ ID NO: 156, CDR2 provided by SEQ ID NO: 157, and CDR3 provided by SEQ ID NO: 158.

[0024] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 299, CDR2 provided by SEQ ID NO: 300, and CDR3 provided by SEQ ID NO: 301, and a light chain variable region comprising CDR1 provided by SEQ ID NO: 296, CDR2 provided by SEQ ID NO: 297, and CDR3 provided by SEQ ID NO: 298.

[0025] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 313, CDR2 provided by SEQ ID NO: 314, and CDR3 provided by SEQ ID NO: 315, and a light chain variable region comprising CDR1 provided by SEQ ID NO: 310, CDR2 provided by SEQ ID NO: 311, and CDR3 provided by SEQ ID NO: 312.

[0026] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 327, CDR2 provided by SEQ ID NO: 328, and CDR3 provided by SEQ ID NO: 329, and a light chain variable region comprising CDR1 provided by SEQ ID NO: 324, CDR2 provided by SEQ ID NO: 325, and CDR3 provided by SEQ ID NO: 326.

[0027] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 341, CDR2 provided by SEQ ID NO: 342, and CDR3 provided by SEQ ID NO: 343, and a light chain variable region comprising CDR1 provided by SEQ ID NO: 338, CDR2 provided by SEQ ID NO: 339, and CDR3 provided by SEQ ID NO: 340.

[0028] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 355, CDR2 provided by SEQ ID NO: 356, and CDR3 provided by SEQ ID NO: 357, and a light chain variable region comprising CDR1 provided by SEQ ID NO: 352, CDR2 provided by SEQ ID NO: 353, and CDR3 provided by SEQ ID NO: 354.

[0029] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 423, CDR2 provided by SEQ ID NO: 424, and CDR3 provided by SEQ ID NO: 425, and a light chain variable region comprising CDR1 provided by SEQ ID NO: 418, CDR2 provided by SEQ ID NO: 419, and CDR3 provided by SEQ ID NO: 421.

[0030] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 431, CDR2 provided by SEQ ID NO: 432, and CDR3 provided by SEQ ID NO: 433, and a light chain variable region comprising CDR1 provided by SEQ ID NO: 427, CDR2 provided by SEQ ID NO: 428, and CDR3 provided by SEQ ID NO: 429.

[0031] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 439, CDR2 provided by SEQ ID NO: 440, and CDR3 provided by SEQ ID NO: 441, and a light chain variable region comprising CDR1 provided by SEQ ID NO: 435, CDR2 provided by SEQ ID NO: 436, and CDR3 provided by SEQ ID NO: 437.

[0032] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 447, CDR2 provided by SEQ ID NO: 448, and CDR3 provided by SEQ ID NO: 449, and a light chain variable region comprising CDR1 provided by SEQ ID NO: 443, CDR2 provided by SEQ ID NO: 444, and CDR3 provided by SEQ ID NO: 445.

[0033] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises 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.

[0034] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 463, CDR2 provided by SEQ ID NO: 464, and CDR3 provided by SEQ ID NO: 465, and a light chain variable region comprising CDR1 provided by SEQ ID NO: 459, CDR2 provided by SEQ ID NO: 460, and CDR3 provided by SEQ ID NO: 461.

[0035] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises 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.

[0036] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 479, CDR2 provided by SEQ ID NO: 480, and CDR3 provided by SEQ ID NO: 481, and a light chain variable region comprising CDR1 provided by SEQ ID NO: 479, CDR2 provided by SEQ ID NO: 480, and CDR3 provided by SEQ ID NO: 481.

[0037] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 487, CDR2 provided by SEQ ID NO: 488, and CDR3 provided by SEQ ID NO: 489, and a light chain variable region comprising CDR1 provided by SEQ ID NO: 483, CDR2 provided by SEQ ID NO: 484, and CDR3 provided by SEQ ID NO: 485.

[0038] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises 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.

[0039] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 503, CDR2 provided by SEQ ID NO: 504, and CDR3 provided by SEQ ID NO: 505, and a light chain variable region comprising CDR1 provided by SEQ ID NO: 499, CDR2 provided by SEQ ID NO: 500, and CDR3 provided by SEQ ID NO: 501.

[0040] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 511, CDR2 provided by SEQ ID NO: 512, and CDR3 provided by SEQ ID NO: 513, and a light chain variable region comprising CDR1 provided by SEQ ID NO: 507, CDR2 provided by SEQ ID NO: 508, and CDR3 provided by SEQ ID NO: 509.

[0041] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 519, CDR2 provided by SEQ ID NO: 520, and CDR3 provided by SEQ ID NO: 521, and a light chain variable region comprising CDR1 provided by SEQ ID NO: 515, CDR2 provided by SEQ ID NO: 516, and CDR3 provided by SEQ ID NO: 517.

[0042] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises 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.

[0043] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 535, CDR2 provided by SEQ ID NO: 536, and CDR3 provided by SEQ ID NO: 537, and a light chain variable region comprising CDR1 provided by SEQ ID NO: 531, CDR2 provided by SEQ ID NO: 532, and CDR3 provided by SEQ ID NO: 533.

[0044] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 543, CDR2 provided by SEQ ID NO: 544, and CDR3 provided by SEQ ID NO: 545, and a light chain variable region comprising CDR1 provided by SEQ ID NO: 539, CDR2 provided by SEQ ID NO: 540, and CDR3 provided by SEQ ID NO: 541.

[0045] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 551, CDR2 provided by SEQ ID NO: 552, and CDR3 provided by SEQ ID NO: 553, and a light chain variable region comprising CDR1 provided by SEQ ID NO: 547, CDR2 provided by SEQ ID NO: 548, and CDR3 provided by SEQ ID NO: 549.

[0046] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 559, CDR2 provided by SEQ ID NO: 560, and CDR3 provided by SEQ ID NO: 561, and a light chain variable region comprising CDR1 provided by SEQ ID NO: 555, CDR2 provided by SEQ ID NO: 556, and CDR3 provided by SEQ ID NO: 557.

[0047] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 567, CDR2 provided by SEQ ID NO: 568, and CDR3 provided by SEQ ID NO: 569, and a light chain variable region comprising CDR1 provided by SEQ ID NO: 563, CDR2 provided by SEQ ID NO: 564, and CDR3 provided by SEQ ID NO: 565.

[0048] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 575, CDR2 provided by SEQ ID NO: 576, and CDR3 provided by SEQ ID NO: 577, and a light chain variable region comprising CDR1 provided by SEQ ID NO: 571, CDR2 provided by SEQ ID NO: 572, and CDR3 provided by SEQ ID NO: 573.

[0049] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 583, CDR2 provided by SEQ ID NO: 584, and CDR3 provided by SEQ ID NO: 585, and a light chain variable region comprising CDR1 provided by SEQ ID NO: 579, CDR2 provided by SEQ ID NO: 580, and CDR3 provided by SEQ ID NO: 581.

[0050] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises 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: 591, CDR2 provided by SEQ ID NO: 592, and CDR3 provided by SEQ ID NO: 593.

[0051] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 599, CDR2 provided by SEQ ID NO: 600, and CDR3 provided by SEQ ID NO: 601, and a light chain variable region comprising CDR1 provided by SEQ ID NO: 595, CDR2 provided by SEQ ID NO: 596, and CDR3 provided by SEQ ID NO: 597.

[0052] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 607, CDR2 provided by SEQ ID NO: 608, and CDR3 provided by SEQ ID NO: 609, and a light chain variable region comprising CDR1 provided by SEQ ID NO: 603, CDR2 provided by SEQ ID NO: 604, and CDR3 provided by SEQ ID NO: 605.

[0053] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises 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.

[0054] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 623, CDR2 provided by SEQ ID NO: 624, and CDR3 provided by SEQ ID NO: 625, and a light chain variable region comprising CDR1 provided by SEQ ID NO: 619, CDR2 provided by SEQ ID NO: 620, and CDR3 provided by SEQ ID NO: 621.

[0055] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 631, CDR2 provided by SEQ ID NO: 632, and CDR3 provided by SEQ ID NO: 633, and a light chain variable region comprising CDR1 provided by SEQ ID NO: 627, CDR2 provided by SEQ ID NO: 628, and CDR3 provided by SEQ ID NO: 629.

[0056] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 639, CDR2 provided by SEQ ID NO: 640, and CDR3 provided by SEQ ID NO: 641, and a light chain variable region comprising CDR1 provided by SEQ ID NO: 635, CDR2 provided by SEQ ID NO: 636, and CDR3 provided by SEQ ID NO: 637.

[0057] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 647, CDR2 provided by SEQ ID NO: 648, and CDR3 provided by SEQ ID NO: 649, and a light chain variable region comprising CDR1 provided by SEQ ID NO: 643, CDR2 provided by SEQ ID NO: 644, and CDR3 provided by SEQ ID NO: 645.

[0058] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises 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.

[0059] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 663, CDR2 provided by SEQ ID NO: 664, and CDR3 provided by SEQ ID NO: 665, and a light chain variable region comprising CDR1 provided by SEQ ID NO: 659, CDR2 provided by SEQ ID NO: 659, and CDR3 provided by SEQ ID NO: 661.

[0060] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 671, CDR2 provided by SEQ ID NO: 672, and CDR3 provided by SEQ ID NO: 673, and a light chain variable region comprising CDR1 provided by SEQ ID NO: 667, CDR2 provided by SEQ ID NO: 668, and CDR3 provided by SEQ ID NO: 669.

[0061] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 679, CDR2 provided by SEQ ID NO: 680, and CDR3 provided by SEQ ID NO: 681, and a light chain variable region comprising CDR1 provided by SEQ ID NO: 675, CDR2 provided by SEQ ID NO: 676, and CDR3 provided by SEQ ID NO: 677.

[0062] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 687, CDR2 provided by SEQ ID NO: 688, and CDR3 provided by SEQ ID NO: 689, and a light chain variable region comprising CDR1 provided by SEQ ID NO: 683, CDR2 provided by SEQ ID NO: 684, and CDR3 provided by SEQ ID NO: 685.

[0063] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 695, CDR2 provided by SEQ ID NO: 696, and CDR3 provided by SEQ ID NO: 697, and a light chain variable region comprising CDR1 provided by SEQ ID NO: 691, CDR2 provided by SEQ ID NO: 692, and CDR3 provided by SEQ ID NO: 693.

[0064] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 703, CDR2 provided by SEQ ID NO: 704, and CDR3 provided by SEQ ID NO: 705, and a light chain variable region comprising CDR1 provided by SEQ ID NO: 699, CDR2 provided by SEQ ID NO: 700, and CDR3 provided by SEQ ID NO: 701.

[0065] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 711, CDR2 provided by SEQ ID NO: 712, and CDR3 provided by SEQ ID NO: 713, and a light chain variable region comprising CDR1 provided by SEQ ID NO: 707, CDR2 provided by SEQ ID NO: 708, and CDR3 provided by SEQ ID NO: 709.

[0066] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 823, CDR2 provided by SEQ ID NO: 824, and CDR3 provided by SEQ ID NO: 825, and a light chain variable region comprising CDR1 provided by SEQ ID NO: 820, CDR2 provided by SEQ ID NO: 821, and CDR3 provided by SEQ ID NO: 822.

[0067] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 841, CDR2 provided by SEQ ID NO: 842, and CDR3 provided by SEQ ID NO: 843, and a light chain variable region comprising CDR1 provided by SEQ ID NO: 838, CDR2 provided by SEQ ID NO: 839, and CDR3 provided by SEQ ID NO: 840.

[0068] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 852, CDR2 provided by SEQ ID NO: 853, and CDR3 provided by SEQ ID NO: 854, and a light chain variable region comprising CDR1 provided by SEQ ID NO: 850, CDR2 provided by SEQ ID NO: 839, and CDR3 provided by SEQ ID NO: 851. In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising CDR1 provided by SEQ ID NO: 914, CDR2 provided by SEQ ID NO: 915, and CDR3 provided by SEQ ID NO: 916, and a light chain variable region comprising CDR1 provided by SEQ ID NO: 911, CDR2 provided by SEQ ID NO: 912, and CDR3 provided by SEQ ID NO: 913.

[0069] 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.

[0070] 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. 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.

[0071] 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.

[0072] 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.

[0073] In another aspect, the present disclosure provides the nucleic acids of SEQ ID NOs: 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, 56 CDR1 provided by SEQ ID NOs: 6, 20, 34, 48, 62, 76, 90, 104, 118, 132, 146, 160, 171, 176, 180, 182, 184, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 239, 243, 244, 239, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 28 81, 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, 44 8, 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 CDR2 provided by SEQ ID NOs: 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.

[0074] In some embodiments, a 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, a 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, a 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, a 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, a 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, a 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, a 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, a 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, a 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, a 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, a 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, a 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, a 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, a 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, a 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, a 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, a 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, a 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, a 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, a 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, a 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, a 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, a 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, a 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, a 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, a 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, a 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, a 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, a 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, a 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, a 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, a 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, a 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, a 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, a 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, a 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, a 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, a 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, a 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.

[0075] In some embodiments, a 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, a 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, a 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, a 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, a 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, a 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, a 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, a 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, a 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, a 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, a 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, a 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, a 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, a 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, a 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, a 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, a 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.

[0076] In another aspect, the disclosure is directed to an anti-CLL-1 antibody, or 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.

[0077] In another aspect, the present disclosure provides the nucleic acids of SEQ ID NOs: 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, 5 35~537, 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, 73 The present invention relates to an anti-CLL-1 antibody, or an antigen-binding fragment thereof, comprising a VHH comprising the CDR sequence of 5 to 737, 739 to 741, 743 to 745, 747 to 749, 751 to 753, 755 to 757, 759 to 761, 763 to 765, 767 to 772, 775 to 777, 780 to 782, 785 to 786, 789 to 791, 794 to 796, 799, 802, 805 to 806, 823 to 825, 841 to 843, 852 to 854, 896 to 898, 901 to 903, 906 to 908, or 914 to 916.

[0078] In another aspect, the present disclosure provides the nucleic acids of SEQ ID NOs: 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, 73 The present invention relates to an anti-CLL-1 antibody or an antigen-binding fragment thereof, comprising a VHH comprising CDR1, CDR2, and CDR3 of 9 to 741, 743 to 745, 747 to 749, 751 to 753, 755 to 757, 759 to 761, 763 to 765, 767 to 772, 775 to 777, 780 to 782, 785 to 786, 789 to 791, 794 to 796, 799, 802, 805 to 806, 823 to 825, 841 to 843, 852 to 854, 896 to 898, 901 to 903, 906 to 908, or 914 to 916.

[0079] In another aspect, the present disclosure provides the nucleic acids of SEQ ID NOs: 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, 5 51-553, 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, 7 The present invention relates to an anti-CLL-1 antibody, or an antigen-binding fragment thereof, comprising a VHH comprising at least one CDR (e.g., CDR1, CDR2, and / or CDR3) of 47 to 749, 751 to 753, 755 to 757, 759 to 761, 763 to 765, 767 to 772, 775 to 777, 780 to 782, 785 to 786, 789 to 791, 794 to 796, 799, 802, 805 to 806, 823 to 825, 841 to 843, 852 to 854, 896 to 898, 901 to 903, 906 to 908, or 914 to 916.

[0080] In another aspect, the present disclosure provides the nucleic acids of SEQ ID NOs: 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, 5 83~585, 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, 703~7 05, 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, 7 The present invention relates to an anti-CLL-1 antibody, or an antigen-binding fragment thereof, comprising a VHH comprising at least one CDR that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the CDR (e.g., CDR1, CDR2, and / or CDR3) of 75-777, 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.

[0081] In some embodiments, the antibody, or antigen-binding fragment thereof, is a monoclonal antibody, or antigen-binding fragment thereof. In some embodiments, the antibody, or antigen-binding fragment thereof, is a humanized antibody, or antigen-binding fragment thereof. In another aspect, the present disclosure is directed to an anti-CLL-1 antibody, or antigen-binding fragment thereof, that competes for binding to CLL-1 with an antibody, or antigen-binding fragment thereof, described herein. In some embodiments, the antibody, or antigen-binding fragment thereof, comprises a CH2 constant domain and a CH3 constant domain.

[0082] In some embodiments, the antibody, or antigen-binding fragment thereof, is selected from the group consisting of SEQ ID NOs: 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, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 5, 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, 71 714, 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, 893, 900, 905, 910, or 920 amino acid sequences.

[0083] 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.

[0084] In some embodiments, the antibody is an IgG1, IgG2, IgG3, or IgG4 type antibody.

[0085] In another aspect, the present disclosure is directed to a chimeric antigen receptor comprising any of the antibodies, or antigen-binding fragments thereof, described herein.

[0086] In another aspect, the present disclosure is directed to a cell expressing any 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.

[0087] In another aspect, the present disclosure is directed 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.

[0088] In another aspect, the present disclosure is directed 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 present disclosure is directed to a vector comprising any of the nucleic acids described herein.

[0089] In another aspect, the present disclosure is directed to a cell comprising any of the nucleic acids or vectors described herein. In some embodiments, the nucleic acid is selected from the group consisting of SEQ ID NOs: 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, 250, 252, 254, 256, 258, 260, 262, 264, 266, 268, 273, 278, 283, 288, 293, 300, 304, 306, 308, 313, 318, 323, 328, 333, 338, 343, 348, 350, 352, 354, 362, 364, 366, 368, 373, 378, 383, 384, 385, 386, 53, 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.In some embodiments, the nucleic acid is selected from the group consisting of SEQ ID NOs: 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, 24 3, 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.

[0090] In some embodiments, the vector further comprises a promoter sequence that is an SFFV promoter, an EF1α promoter, a tEF1a promoter, an hPGK promoter, an SFFV promoter, or an MND promoter.

[0091] In some embodiments, the vector is a DNA vector, an RNA vector, a plasmid, a lentiviral vector, an adenoviral vector, or a retroviral vector.

[0092] In some embodiments, the cells are immune cells, hi some embodiments, the immune cells are T cells, natural killer (NK) cells, cytotoxic T lymphocytes (CTLs), and regulatory T cells.

[0093] In another aspect, the disclosure is directed to a method of producing an antibody, or antigen-binding fragment thereof, the method comprising culturing a cell described herein under conditions suitable for expression of the antibody or antigen-binding fragment thereof.

[0094] In another aspect, the present disclosure is directed to a method of treating a CLL-1-related disease or disorder, the method comprising administering to a subject in need thereof an effective amount of any of the antibodies, or antigen-binding fragments thereof, any of the antibody-drug conjugates described herein, or any of the cells described herein. In some embodiments, the CLL-1-related disease or disorder 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.

[0095] In another aspect, the present disclosure is directed 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, the transmembrane domain comprises a transmembrane domain of a protein selected from CD8α or CD28, and 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 by a hinge region. In some embodiments, the hinge region comprises a hinge region of a protein selected from CD8α, IgG4, or CD28.

[0096] In some embodiments, the CAR further comprises one or more costimulatory domains, hi some embodiments, the one or more costimulatory domains comprise the signaling domains of 4-1BB and / or CD28.

[0097] In some embodiments, the CLL-1 binding domain comprises any of the anti-CLL-1 antibodies, or antigen-binding fragments thereof, described herein.

[0098] In another aspect, the present disclosure is directed to a method of treating a subject having or at risk of having a hematological neoplastic disease or malignancy associated with CLL-1 expression, the method comprising administering to the subject a therapeutically effective amount of any of the antibodies, or antigen-binding fragments thereof, any of the antibody-drug conjugates described herein, or any of the cells described herein. In some embodiments, the hematological neoplastic disease or malignancy 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 oncolytic therapeutic agent.

[0099] In another aspect, the present disclosure is directed to a method of treating a subject having or at risk of having a hematological neoplastic disease or malignancy associated with CLL-1 expression, the method comprising administering to the subject a therapeutically effective amount of any of the antibodies, antigen-binding fragments thereof, antibody-drug conjugates, chimeric antigen receptors, or cells described herein. In some embodiments, the hematological neoplastic disease or malignancy 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 oncolytic therapeutic agent.

[0100] In some embodiments, the method further comprises administering a population of hematopoietic cells, wherein the hematopoietic cells have been genetically engineered such that the gene encoding CLL-1 targeted by the antigen binding domain has been engineered to reduce or eliminate expression of CLL-1. In some embodiments, the immune cells, the hematopoietic cells, or both, are allogeneic or autologous. In some embodiments, the hematopoietic cells are hematopoietic stem cells. In some embodiments, the hematopoietic stem cells are derived from bone marrow cells or peripheral blood mononuclear cells (PBMCs). In some embodiments, the hematopoietic stem cells are CD34+ / CLL-1-. In some embodiments, the hematopoietic cells are prepared by editing an endogenous gene encoding CLL-1 to reduce or eliminate expression of CLL-1. In some embodiments, the endogenous gene is edited by CRISPR-Cas9.

[0101] In some embodiments, the subject has or has been diagnosed with a hematopoietic malignancy or pre-malignancy characterized by expression of CLL-1 in malignant or pre-malignant 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 explanation of the drawings]

[0102] [Figure 1A]Figures 1A-1E show flow cytometry analysis plots of the target cell binding ability of CLL-1 antibodies. The cell binding ability of CLL-1 antibodies was assessed by flow cytometry analysis on HL-60 wild-type (WT) cells (Figure 1A), U937 cells (Figure 1B), or HL-60 CLL-1 knockout (KO) control cells (Figure 1C). In each case shown in Figures 1A-1C, the CLL-1 antibody was compared to a 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 an asterisk) and HL-60 KO cells (left peak) (Figure 1D) was assessed by flow cytometry. The ability of the control hCLL-1 antibody to bind to U937 cells (Figure 1E) was assessed by flow cytometry, staining the cells with primary and secondary labeled antibodies (right peak indicated by an asterisk) against unstained control cells (left peak). [Figure 1B] Figures 1A-1E show flow cytometry analysis plots of the target cell binding ability of CLL-1 antibodies. The cell binding ability of CLL-1 antibodies was assessed by flow cytometry analysis on HL-60 wild-type (WT) cells (Figure 1A), U937 cells (Figure 1B), or HL-60 CLL-1 knockout (KO) control cells (Figure 1C). In each case shown in Figures 1A-1C, the CLL-1 antibody was compared to a 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 an asterisk) and HL-60 KO cells (left peak) (Figure 1D) was assessed by flow cytometry. The ability of the control hCLL-1 antibody to bind to U937 cells (Figure 1E) was assessed by flow cytometry, staining the cells with primary and secondary labeled antibodies (right peak indicated by an asterisk) against unstained control cells (left peak). [Figure 1C]Figures 1A-1E show flow cytometry analysis plots of the target cell binding ability of CLL-1 antibodies. The cell binding ability of CLL-1 antibodies was assessed by flow cytometry analysis on HL-60 wild-type (WT) cells (Figure 1A), U937 cells (Figure 1B), or HL-60 CLL-1 knockout (KO) control cells (Figure 1C). In each case shown in Figures 1A-1C, the CLL-1 antibody was compared to a 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 an asterisk) and HL-60 KO cells (left peak) (Figure 1D) was assessed by flow cytometry. The ability of the control hCLL-1 antibody to bind to U937 cells (Figure 1E) was assessed by flow cytometry, staining the cells with primary and secondary labeled antibodies (right peak indicated by an asterisk) against unstained control cells (left peak). [Figure 1D] Figures 1A-1E show flow cytometry analysis plots of the target cell binding ability of CLL-1 antibodies. The cell binding ability of CLL-1 antibodies was assessed by flow cytometry analysis on HL-60 wild-type (WT) cells (Figure 1A), U937 cells (Figure 1B), or HL-60 CLL-1 knockout (KO) control cells (Figure 1C). In each case shown in Figures 1A-1C, the CLL-1 antibody was compared to a 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 an asterisk) and HL-60 KO cells (left peak) (Figure 1D) was assessed by flow cytometry. The ability of the control hCLL-1 antibody to bind to U937 cells (Figure 1E) was assessed by flow cytometry, staining the cells with primary and secondary labeled antibodies (right peak indicated by an asterisk) against unstained control cells (left peak). [Figure 1E]Figures 1A-1E show flow cytometry analysis plots of the target cell binding ability of CLL-1 antibodies. The cell binding ability of CLL-1 antibodies was assessed by flow cytometry analysis on HL-60 wild-type (WT) cells (Figure 1A), U937 cells (Figure 1B), or HL-60 CLL-1 knockout (KO) control cells (Figure 1C). In each case shown in Figures 1A-1C, the CLL-1 antibody was compared to a 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 an asterisk) and HL-60 KO cells (left peak) (Figure 1D) was assessed by flow cytometry. The ability of the control hCLL-1 antibody to bind to U937 cells (Figure 1E) was assessed by flow cytometry, staining the cells with primary and secondary labeled antibodies (right peak indicated by an asterisk) against unstained control cells (left peak). [Figure 2A] Figures 2A and 2B show flow cytometry analysis plots of exemplary NFAT-responsive reporter cell lines described herein. Figure 2A shows flow cytometry data from Jurkat cells containing the mOrange reporter molecule under the control of a constitutively active E1F alpha promoter and the mTurquoise reporter molecule (mTurq) under the control of the IL-2 reporter system described herein. Cells were either unactivated ("-PMA / Ion," top row) or activated using phorbol myristate acetate (PMA) and ionomycin ("+PMA / Ion," bottom row). The left column of the plots shows cells expressing the mOrange reporter molecule. The middle column shows cells expressing the mTurquoise reporter molecule. The right column shows cells expressing CD69 (CD69+), an indicator of T cell activation. [Figure 2B]Figures 2A and 2B show flow cytometry analysis plots of exemplary NFAT-responsive reporter cell lines described herein. Figure 2B shows flow cytometry data from Jurkat cells containing an mTurquoise reporter molecule (mTurq) under the control of a constitutively active E1F alpha promoter and an mOrange reporter molecule under the control of the IL-2 reporter system described herein. Cells were either unactivated ("-PMA / Ion," top row) or activated using phorbol myristate acetate (PMA) and ionomycin ("+PMA / Ion," bottom row). The left column of plots shows cells expressing the mTurquoise reporter molecule. The middle column shows cells expressing the mOrange reporter molecule. The right column shows cells expressing CD69 (CD69+), an indicator of T cell activation. [Figure 3] Figure 3 shows plots quantifying the flow cytometry analysis of Figures 2A and 2B. The y-axis indicates the percentage of cells expressing a second reporter molecule (FR2) under the control of the IL-2 reporter system described herein, based on cells expressing a first reporter molecule (FR1) under the control of the constitutively active promoter, EF1a. Cells were either unactivated ("-PMA / Ion") or activated using phorbol myristate acetate (PMA) and ionomycin ("+PMA / Ion"). "EF1a_mOrange_IL-2_mTurq" indicates Jurkat cells containing the mOrange reporter molecule (FR1) under the control of the constitutively active E1F alpha promoter and the mTurquoise reporter molecule (mTurq) (FR2) under the control of the IL-2 reporter system described herein. "EF1a_mTurq_IL-2_mOrange" refers to Jurkat cells containing an mTurquoise reporter molecule (FR1) under the control of a constitutively active E1F alpha promoter and an mOrange reporter molecule (FR2) under the control of the IL-2 reporter system described herein. [Figure 4]FIG. 4 shows an overview of the biochemical and cell-based assays used to characterize anti-CLL-1 antibodies and binders. [Figure 5A] Figures 5A and 5B show the results of enzyme-linked immunosorbent assay (ELSA) analysis of anti-CLL-1 antibody clones. Figure 5A shows the dose-dependent binding of the indicated anti-CLL-1 antibody clones to biotinylated recombinant CLL-1. [Figure 5B] Figures 5A and 5B show the results of enzyme-linked immunosorbent assay (ELSA) analysis of anti-CLL-1 antibody clones. Figure 5B shows the dose-dependent binding of the indicated anti-CLL-1 binders to biotinylated recombinant CLL-1. [Figure 6A] Figures 6A-6C show quantification of specific binding of the indicated anti-CLL-1 binding agents, calculated from flow cytometry analysis. Figure 6A shows anti-CLL-1 binding agents in contact with HL-60 WT cells. [Figure 6B] Figures 6A-6C show quantification of specific binding of the indicated anti-CLL-1 binding agents, calculated from flow cytometry analysis. Figure 6B shows anti-CLL-1 binding agents in contact with CLL-1-positive U937 cells. [Figure 6C] Figures 6A-6C show quantification of specific binding of the indicated anti-CLL-1 binding agents, calculated from flow cytometry analysis. Figure 6C shows the anti-CLL-1 binding agents in contact with CLL-1-negative HEK293 control cells. The dotted line indicates the level obtained from a control sample stained with secondary antibody only. [Figures 7A-7B] Figures 7A-7C show multipoint flow cytometry analysis of dose-dependent binding of the indicated anti-CLL-1 binders to CLL-1-expressing HL-60 WT cells. Figure 7A shows cell surface binding analysis of anti-CLL-1 binder clones 1-6. Figure 7B shows cell surface binding analysis of anti-CLL-1 binder clones 7-12 and 20VH. [Figure 7C] Figures 7A-7C show multipoint flow cytometry analysis of dose-dependent binding of the indicated anti-CLL-1 binders to CLL-1-expressing HL-60 WT cells. Figure 7C shows cell surface binding analysis of anti-CLL-1 binder clones 38-42. [Figure 8A] Figures 8A and 8B show bar graphs of reciprocal EC50 values ​​calculated by ELISA analysis of the 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 a lysine at amino acid position 244 (CLL1-K244), and the right column corresponds to binding to CLL-1 containing a glutamine at amino acid position 244 (CLL1-Q244). Figure 8A shows results from panning of anti-CLL-1 binders with biotinylated recombinant CLL-1 Q244. [Figure 8B] Figures 8A and 8B show bar graphs of reciprocal EC50 values ​​calculated by ELISA analysis of the 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 a lysine at amino acid position 244 (CLL1-K244), and the right column corresponds to binding to CLL-1 containing a glutamine at amino acid position 244 (CLL1-Q244). Figure 8B shows 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. [Figure 9] FIG. 9 shows a heat map representation of data generated from ELISA analysis of the competitive binding activity of the indicated pairs of anti-CLL-1 binders to the Fc-tagged recombinant CLL-1 protein extracellular domain. [Figure 10A] Figures 10A-10C show 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. Figure 10A shows plots of the BLItz assay binding analysis of each of the indicated CLL-1 antibody binders. Binding curves for each of the CLL-1 antibody binders at 1 μM are shown. [Figure 10B]Figures 10A-10C show 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. Figure 10B shows plots of the BLItz assay binding analysis of each of the indicated anti-CLL-1 binders. Binding curves for each of the CLL-1 antibody binders at 1 μM are shown. [Figure 10C] Figures 10A-10C show 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. Figure 10C shows quantification of the EC50 (nM) values ​​and K and K values ​​of each anti-CLL-1 binder calculated from the data in Figures 10A and 10B. [Figure 11A] 11A-11L show results from binding kinetics and affinity assays of the indicated CLL-1 antibody binders to CLL-1 protein using the Octet® platform. Human recombinant CLL-1 protein was used at 10 μg / mL, and binders were diluted to 100, 33.33, 11.11, and 3.70 nM for the assay. [Figure 11B] 11A-11L show results from binding kinetics and affinity assays of the indicated CLL-1 antibody binders to CLL-1 protein using the Octet® platform. Human recombinant CLL-1 protein was used at 10 μg / mL, and binders were diluted to 100, 33.33, 11.11, and 3.70 nM for the assay. [Figure 11C] 11A-11L show results from binding kinetics and affinity assays of the indicated CLL-1 antibody binders to CLL-1 protein using the Octet® platform. Human recombinant CLL-1 protein was used at 10 μg / mL, and binders were diluted to 100, 33.33, 11.11, and 3.70 nM for the assay. [Figure 11D]11A-11L show results from binding kinetics and affinity assays of the indicated CLL-1 antibody binders to CLL-1 protein using the Octet® platform. Human recombinant CLL-1 protein was used at 10 μg / mL, and binders were diluted to 100, 33.33, 11.11, and 3.70 nM for the assay. [Figure 11E] 11A-11L show results from binding kinetics and affinity assays of the indicated CLL-1 antibody binders to CLL-1 protein using the Octet® platform. Human recombinant CLL-1 protein was used at 10 μg / mL, and binders were diluted to 100, 33.33, 11.11, and 3.70 nM for the assay. [Figure 11F] 11A-11L show results from binding kinetics and affinity assays of the indicated CLL-1 antibody binders to CLL-1 protein using the Octet® platform. Human recombinant CLL-1 protein was used at 10 μg / mL, and binders were diluted to 100, 33.33, 11.11, and 3.70 nM for the assay. [Figure 11G] 11A-11L show results from binding kinetics and affinity assays of the indicated CLL-1 antibody binders to CLL-1 protein using the Octet® platform. Human recombinant CLL-1 protein was used at 10 μg / mL, and binders were diluted to 100, 33.33, 11.11, and 3.70 nM for the assay. [Figure 11H] 11A-11L show results from binding kinetics and affinity assays of the indicated CLL-1 antibody binders to CLL-1 protein using the Octet® platform. Human recombinant CLL-1 protein was used at 10 μg / mL, and binders were diluted to 100, 33.33, 11.11, and 3.70 nM for the assay. [Figure 11I]11A-11L show results from binding kinetics and affinity assays of the indicated CLL-1 antibody binders to CLL-1 protein using the Octet® platform. Human recombinant CLL-1 protein was used at 10 μg / mL, and binders were diluted to 100, 33.33, 11.11, and 3.70 nM for the assay. [Figure 11J] 11A-11L show results from binding kinetics and affinity assays of the indicated CLL-1 antibody binders to CLL-1 protein using the Octet® platform. Human recombinant CLL-1 protein was used at 10 μg / mL, and binders were diluted to 100, 33.33, 11.11, and 3.70 nM for the assay. [Figure 11K] 11A-11L show results from binding kinetics and affinity assays of the indicated CLL-1 antibody binders to CLL-1 protein using the Octet® platform. Human recombinant CLL-1 protein was used at 10 μg / mL, and binders were diluted to 100, 33.33, 11.11, and 3.70 nM for the assay. [Figure 11L] 11A-11L show results from binding kinetics and affinity assays of the indicated CLL-1 antibody binders to CLL-1 protein using the Octet® platform. Human recombinant CLL-1 protein was used at 10 μg / mL, and binders were diluted to 100, 33.33, 11.11, and 3.70 nM for the assay. [Figure 12A]Figure 12A shows anti-CLL-1 binder clone 1. Figure 12B shows anti-CLL-1 binder clone 2. Figure 12C shows anti-CLL-1 binder clone 3. Figure 12D shows anti-CLL-1 binder clone 4. Figure 12E shows anti-CLL-1 binder clone 5. Figure 12F shows anti-CLL-1 binder clone 6. Figure 12G shows anti-CLL-1 binder 75. Figure 12H shows anti-CLL-1 binder clone 8. Figure 12I shows anti-CLL-1 binder clone 10. Figure 12J shows anti-CLL-1 binder clone 11. Figure 12K shows anti-CLL-1 binder clone 12. Figure 12L shows anti-CLL-1 binder clone 20. Figures 12FA and 12B show biochemical characteristics of the indicated anti-CLL-1 binders. Figure 12A shows the binding affinity of the indicated anti-CLL-1 binding agents. NB = no binding detected, ND = binding assay not performed. [Figure 12B] FIG. 12B shows a summary of the binding properties of anti-CLL-1 binding agents using the assays indicated. [Figure 13A] Figures 13A-13C show results from flow cytometry analysis of the indicated anti-CLL-1 VH binders to HEK293 cells expressing CLL-1 variants. Figure 13A shows binding of the indicated anti-CLL-1 VH binders to HEK293 cells expressing CLL-1 containing a lysine at amino acid position 244 (293-CLL1-K244). [Figure 13B] Figures 13A-13C show results from flow cytometry analysis of the indicated anti-CLL-1 VH binders to HEK293 cells expressing CLL-1 variants. Figure 13A shows binding of the indicated anti-CLL-1 VH binders to HEK293 cells expressing CLL-1 containing a lysine at amino acid position 244 (293-CLL1-K244). Figure 13B shows binding of the indicated anti-CLL-1 VH binders to HEK293 cells expressing CLL-1 containing a glutamine at amino acid position 244 (293-CLL1-Q244). [Figure 13C]Figures 13A-13C show results from flow cytometry analysis of the indicated anti-CLL-1 VH binders to HEK293 cells expressing CLL-1 variants. Figure 13A shows binding of the indicated anti-CLL-1 VH binders to HEK293 cells expressing CLL-1 containing a lysine at amino acid position 244 (293-CLL1-K244). Figure 13C shows binding of the indicated anti-CLL-1 VH binders to anti-CLL-1-null HEK293 control cells (293-null). The dotted line represents the signal from cells stained with secondary antibody only. [Figure 14]Figure 14 shows a summary of the binding affinity of the indicated CLL-1 binders for the CLL-1(K244) or CLL-1(Q244) protein isoforms. Figures 15A and 15B show analysis of CLL-1-specific activation of Jurkat CD4 T cells expressing the indicated CLL-1-directed chimeric antigen receptors (CARs) when cocultured with HL-60 WT target cells, as assessed by the IL-2 receptor system (IRS, as indicated in the figure). Figure 15A shows results from flow cytometry analysis of CD69 and FR2 expression after coculture of the indicated CLL-1 CAR-T cells with HL-60 WT cells. The delta percentage (Delta%) was calculated by subtracting the CD69 and FR2 expression percentage in CLL-1 CAR-T cells cocultured with HL-60 CLL-1 KO cells (background signal) from the CD69 and FR2 expression percentage in CLL-1 CAR-T cells cocultured with HL-60 WT cells (specific signal). N=2. For each CLL-1 CAR T binder, the left dot corresponds to CD69 expression, and the right dot corresponds to FR2 expression. Figure 15B shows results from an IncuCyte live-cell imaging analysis of FR2 levels in CLL-1 CAR-T cells cocultured with HL-60 WT cells. N=1. Figures 16A-16G show an analysis of in vitro cocultures comprising a CLL-1-positive AML cell line and CLL-1-directed CAR-T cells containing the indicated CLL-1 binders. Figure 16A shows the transduction efficiency of primary T cells for each of the CLL-1 CAR constructs, as determined by anti-human IgG (H+L) reactivity by flow cytometry. Figure 16B shows binding of the indicated CLL-1 CAR-T cells to target cells expressing either the CLL-1 K244 (K) or CLL-1 Q244 (Q) isoform, as determined by flow cytometry. N=2. Figure 16C shows the change in viability of CFSE-labeled HL-60 WT or CLL1 KO HL-60 target cells after coculture with the indicated CLL-1-directed CAR-T cells. Viability was 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 coculture of CAR-T cells with HL-60 WT cells, HL-60 KO cells, or effector cells alone. N=2. Figure 16E shows the levels of secreted IL-2 produced after coculture of CLL-1 CAR-T cells with HL-60 WT cells, HL-60 KO cells, or effector cells alone. Figure 16F shows the levels of secreted IFN-γ produced after coculture of CLL-1 CAR-T cells with HL-60 WT cells, HL-60 KO cells, or effector cells alone. Figure 16G shows the levels of secreted TNF-α produced after coculture of CLL-1 CAR-T cells with HL-60 WT cells, HL-60 KO cells, or effector cells alone. For each of the indicated CLL-1 CAR-T cells in Figures 18E-18G, the columns refer from left to right to effector alone, CLL1 KO HL60, and WT HL60. [Figure 17A] Figures 17A-17H show an analysis of in vitro co-cultures containing CLL-1-positive AML cells and CLL-1-specific CAR-T cells. Figure 17A shows the transduction efficiency of primary T cells for each of the CLL-1-specific CAR constructs as determined by protein L reactivity. [Figure 17B]Figure 17B shows binding of the indicated CLL-1-specific CAR-T cells to target cells containing either the CLL-1 K244 (CLL1 K) or CLL-1 Q244 (CLL1 Q) protein isoforms, as determined by flow cytometry. N=2. Figure 17C shows the change in cell viability of CFSE-labeled HL-60 WT or HL-60 CLL-1 KO target cells after 24 hours of coculture with CLL-1-specific CAR-T cells. Viability was normalized to donor-matched UTD control cells. N=3. Figure 17D shows the change in cell viability of CFSE-labeled HL-60 WT or HL-60 CLL-1 KO target cells after 48 hours of coculture with CLL-1-specific CAR-T cells. Viability was normalized to donor-matched UTD control cells. N=2. Figure 17E shows CLL-1-specific CAR-T cell activation based on CD25 and CD69 expression (CD25+CD69+) assessed by flow cytometry after coculture 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 cytokine produced after coculture 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 cytokine produced after coculture 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 cytokine 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 18A] . [Figure 18B] . [Figure 18C] . [Figure 18D] . [Figure 18E] . [Figure 18F] . [Figure 18G] . [Figure 19A]For Figures 19F-19H, N = 1. For each of the CLL-1-specific CAR-T cells shown, columns refer from left to right to WT HL60, CLL1 KO HL60, and effector alone. [Figure 19B] . [Figure 19C] . [Figure 19D] . [Figure 19E] . [Figure 19F] . [Figure 19G] . [Figure 19H] . DETAILED DESCRIPTION OF THE INVENTION

[0103] The present 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 comprises 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 comprises a heavy chain variable domain and one or more constant domains. The present disclosure also describes chimeric antigen receptors that selectively bind to CLL-1. The disclosure also relates to nucleic acids encoding such antibodies or chimeric antigen receptors, methods of producing such antibodies or chimeric antigen receptors, and methods of therapeutic use thereof to treat malignancies (e.g., acute myeloid leukemia (AML), myelodysplastic syndromes (MDS)).

[0104] antibody The term "antibody" is used herein in the broadest sense and encompasses a variety of antibody structures, including, but not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and / or antibody fragments (preferably, fragments thereof that exhibit the desired antigen-binding activity). The antibodies described herein may be immunoglobulins, heavy chain antibodies, light chain antibodies, LRR-based antibodies, or other protein scaffolds with antibody-like properties, as well as other immunological binding moieties known in the art, including, for example, Fab, Fab', Fab'2, Fab2, Fab3, F(ab')2, Fd, Fv, Feb, scFv, SMIP, diabody, triabody, tetrabody, minibody, Nanobody® (single domain antibody), maxibody, 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 murine antibody. In some embodiments, the antibody is a human antibody. In some embodiments, the antibody is a naive 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 called a single domain antibody, or "VHH." The subunit structures and three-dimensional configurations of different classes of antibodies are known in the art.

[0105] A "monoclonal antibody" or "mAb" refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical and / or bind to the same epitope, with the exception of possible variant antibodies (e.g., containing natural mutations or arising during production of the monoclonal antibody preparation), which are generally present in minor amounts. In contrast 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 an antigen.

[0106] An "antigen-binding fragment" refers to a portion of an intact antibody that binds to the antigen to which the intact antibody binds. Antigen-binding fragments of antibodies include 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'), diabodies, linear antibodies, single-chain antibody molecules (e.g., scFv), single-chain antibody molecules (e.g., VHH, VH, or VL domains only), and multispecific antibodies formed from 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 intact antibody molecules, antigen-binding fragments may be monospecific or multispecific (e.g., bispecific). A multispecific antigen-binding fragment of an antibody may comprise at least two different variable domains, each capable of specifically binding to a separate antigen or a different epitope of the same antigen.

[0107] A "multispecific antibody" refers to an antibody that contains 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 that contains two different antigen-binding domains that recognize and specifically bind to at least two different antigens.

[0108] "Different antigens" may refer to different and / or distinct proteins, polypeptides, or molecules, as well as different and / or distinct epitopes, which may be contained within one protein, polypeptide, or another molecule.

[0109] The term "epitope" refers to an antigenic determinant that interacts with a specific antigen-binding site within the variable region of an antibody molecule, known as the paratope. A single antigen can have more than one epitope. Thus, different antibodies may bind different regions of an antigen and have different biological effects. The term "epitope" also refers to the site on an antigen to which B cells and / or T cells respond. It also refers to the region of an antigen bound by an antibody. Epitopes can be defined as structural or functional. Functional epitopes are generally a subset of structural epitopes and contain residues that directly contribute to the affinity of the interaction. Epitopes can also be conformational, i.e., composed of nonlinear amino acids. In certain embodiments, epitopes can include determinants that are chemically active surface groupings of molecules, such as amino acids, sugar side chains, phosphoryl groups, or sulfonyl groups, and in certain embodiments, can have specific three-dimensional structural characteristics and / or specific charge characteristics.

[0110] As used herein, "selective binding," "selectively binds," "specific binding," or "specifically binds," with respect to an antigen-binding moiety (e.g., of an antibody) and an antigen target, refers to the preferential association of the antigen-binding moiety with the antigen target and not with entities that are not the antigen target. Some non-specific binding between the antigen-binding moiety and the non-target may occur. In some embodiments, an antigen-binding moiety selectively binds to an antigen target when the binding between the antigen-binding moiety and the antigen target is more than 2-fold, more than 5-fold, more than 10-fold, or more than 100-fold greater than the binding between the antigen-binding moiety and the non-target ... has a binding affinity of about 10 -5 Less than M, about 10 -6 Less than M, about 10 -7 Less than M, about 10 -8Less than M or about 10 -9 In some embodiments, an antigen-binding moiety selectively binds to an epitope of an antigen target when the binding between the antigen-binding moiety and the epitope of the antigen target is more than 2-fold, more than 5-fold, more than 10-fold, or more than 100-fold greater than the binding between the antigen-binding moiety and a non-target or another epitope of the antigen target. ... -5 Less than M, about 10 -6 Less than M, about 10 -7 Less than M, about 10 -8 Less than M or about 10 -9 It selectively binds to the epitope of the antigen target when its M is less than M.

[0111] In some embodiments, an antibody or fragment thereof selectively binds to the same or overlapping epitope that will largely cross-compete for binding to the antigen. Thus, in some embodiments, the present disclosure provides antibodies or fragments thereof that cross-compete with the exemplary antibodies or fragments thereof disclosed herein. In some embodiments, "cross-compete," "compete," "cross-compete," or "compete" means that an antibody or fragment thereof competes for the same epitope or binding site on a target. Such competition may be determined by an assay in which a reference antibody or fragment thereof prevents or inhibits specific binding of a test antibody or fragment thereof, or 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 competitive assays (see, e.g., Stahl 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 a competing antibody or fragment thereof is present in excess, it inhibits binding of a reference antibody or fragment thereof to a 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.

[0112] An antibody may be an immunoglobulin molecule of four polypeptide chains, e.g., 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 may comprise a heavy chain variable domain and a heavy chain constant domain. The heavy chain constant domain may comprise any one or more of a CH1, hinge, CH2, CH3, and, in some cases, a CH4 region. The light chain may comprise a light chain variable domain and a light chain constant domain. The light chain constant domain may comprise a CL.

[0113] The heavy chain variable domain of a heavy chain and the light chain variable domain of a light chain are typically further subdivided into regions of variability called complementarity-determining regions (CDRs), interspersed with more conserved regions called framework regions (FRs). In some embodiments, such heavy and / or light chain variable domains can each comprise three CDRs and four framework regions, arranged from amino to carboxyl terminus in the following order: 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 referred to as "CDRH1," "CDRH2," and "CDRH3," respectively, and the CDRs in the light chain are referred to as "CDRL1," "CDRL2," and "CDRL3." Alternatively, the CDRs in the heavy chain are referred to as "HC CDR1," "HC CDR2," and "HC CDR3," respectively, and the CDRs in the light chain are referred to as "LC CDR1," "LC CDR2," and "LC CDR3."

[0114] There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, several of which can be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy-chain constant domains that correspond to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively.

[0115] Exemplary Anti-CLL-1 Antibodies Provided herein are anti-CLL-1 binding agents, and antigen-binding fragments thereof, that selectively bind to CLL-1. In some embodiments, the anti-CLL-1 binding agents described herein are single-chain variable fragments (scFv) or single-chain antibodies.

[0116] In some embodiments, the binding agent is a single-domain antibody. A single-domain antibody is an antibody whose complementarity-determining regions are part of a single-domain polypeptide. Examples include, but are not limited to, heavy chain antibodies, antibodies naturally devoid of light chains, single-domain antibodies derived from traditional four-chain antibodies, engineered antibodies, and single-domain scaffolds other than those derived from antibodies. Single-domain antibodies may be derived from any species, including, but not limited to, mouse, human, camel, llama, goat, rabbit, and cow. According to one aspect of the present disclosure, a single-domain antibody as used herein is a naturally occurring single-domain antibody known as a heavy-chain antibody devoid of light chains. Such single-domain antibodies are disclosed, for example, in WO 94 / 04678. Such variable domains derived from heavy-chain antibodies naturally devoid of light chains are referred to herein as "VHHs" or "Nanobodies®." Such VHHs may be derived from antibodies produced in Camelidae species, such as camel, dromedary, llama, vicuña, alpaca, and guanaco, for example. Other non-Camelidae species may produce heavy chain antibodies that naturally lack light chains, and 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 but does not comprise one or more heavy chain constant regions. In some embodiments, the antibody comprises a heavy chain variable region but does not comprise a light chain region (light chain variable region or light chain constant region).

[0117] Amino acid residues in VHH domains from Camelidae are numbered according to the conventional numbering system for VH domains given by Kabat et al., "Sequence of proteins of immunological interest," U.S. Public Health Service, NIH (Bethesda, MD), Publication No. 91-3242 (1991); see also Riechmann et al., J. Immunol. Methods (1999) 231:25-38. According to this numbering system, FR1 comprises amino acid residues at positions 1-30, CDR1 comprises amino acid residues at positions 31-35, FR2 comprises amino acid residues at positions 36-49, CDR2 comprises amino acid residues at positions 50-65, FR3 comprises amino acid residues at positions 66-94, CDR3 comprises amino acid residues at positions 95-102, and FR4 comprises amino acid residues at positions 103-113.

[0118] 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 of the CDRs may vary 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 Kabat). This generally means that the Kabat numbering may or may not correspond to the actual numbering of amino acid residues in the actual sequence.

[0119] Alternative methods for numbering the amino acid residues of VH domains can be applied in a similar manner to VHH domains and are known in the art, however, in this disclosure we will follow the Kabat numbering applied to VHH domains described above unless otherwise indicated.

[0120] In some embodiments, the position numbering of amino acid residues may be referenced based on the corresponding amino acid residue in a reference sequence.

[0121] The present disclosure provides antibodies that can include various heavy chains described herein. In some embodiments, the antibodies include two heavy and light chains. In some embodiments, the antibodies include two heavy chains, which can be the same heavy chains (having the same amino acid sequence) or different heavy chains (having different amino acid sequences). In some embodiments, the antibodies include two heavy chains that can bind to the same epitope or different epitopes of a target antigen. In some embodiments, the antibodies include two heavy chains that can bind to different epitopes of a target antigen. In some embodiments, the present disclosure encompasses antibodies that include at least one heavy chain disclosed herein, at least one heavy chain framework domain disclosed herein, and / or at least one heavy chain CDR sequence disclosed herein.

[0122] In some embodiments, the antibodies disclosed herein are homodimeric monoclonal antibodies. In some embodiments, the antibodies disclosed herein are heterodimeric antibodies. In some embodiments, the antibodies are, for example, a typical antibody or a diabody, triabody, tetrabody, minibody, Nanobody® (single domain antibody), maxibody, 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 comprises a heavy chain variable region and one or more constant regions. In some embodiments, the antibody is a Nanobody®, also known as a single domain antibody or "VHH." In some embodiments, the antibody comprises one, two, or three immunoglobulin constant domains (e.g., selected from CH1, CH2, CH3, and CH4). In some embodiments, the antibody comprises one, two, or three IgG1 constant domains. In some embodiments, the antibody comprises CH2 and CH3 domains. In some embodiments, the antibody comprises a CH fusion. Exemplary IgG1 CH2 and CH3 domains for use in the antibodies of the disclosure are provided below. APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1)

[0123] In some embodiments, the antibody is a single chain antibody.

[0124] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, is selected from the group consisting of SEQ ID NOs: 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, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 540, 541, 542, 543, 544, 545, 546, , 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, 6 26, 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, 78 4, 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 amino acid sequences.

[0125] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, is selected from the group consisting of SEQ ID NOs: 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, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 241, 242, 243, 2 9, 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, 4 78, 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, 835, 837, 845, 847, 849, 856, 858, 860, 868, 870, 872, 879, 881, 883, 891, 893, 895, 900, 905, 910, 918, 920 amino acid sequences.In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, is selected from the group consisting of SEQ ID NOs: 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, 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, 7 98, 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.

[0126] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, is selected from the group consisting of SEQ ID NOs: 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, 256-258, 260-262, 264-266, 266-268, 270-272, 274-276, 278-279, 280-282, 284-285, 286-287, 288-289, 290-292, 300-302, 304-305, 306-307, 308-309, 310-312, 314-315, 316-317, 318-319, 320-321, 322-323, 324-325, 326-327, 328-329, 330-332 252, 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, 487-488 89, 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, 5 51-553, 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, 611-61 3, 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,The CDRs include any one of the sequences of 739 to 741, 743 to 745, 747 to 749, 751 to 753, 755 to 757, 759 to 761, 763 to 765, 767 to 769, 770 to 772, 775 to 777, 780 to 782, 785 to 786, 789 to 791, 794 to 796, 799, 802, 805 to 806, 809 to 813, 820 to 825, 838 to 843, 850 to 854, 861 to 866, 873 to 877, 884 to 889, 896 to 898, 901 to 903, 906 to 908, and 911 to 916o.

[0127] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, is selected from the group consisting of SEQ ID NOs: 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, 487-488 89, 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, 70 823 to 825, 828 to 829, 834 to 835, 841 to 843, 846 to 847, 852 to 854, 857 to 858, 864 to 866, 869 to 870, 875 to 877, 880 to 881, 887 to 889, 892 to 893, 896 to 910, 914 to 916, or 919 to 920.In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, is selected from the group consisting 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, 328-329, 330-332, 332-334, 334-335, 336-337, 338-339, 340-341, 342-343, 344-345, 346-347, 348-349, 350 6, 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, 5 39~541, 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 to 685, 691 to 693, 699 to 701, 707 to 709, 809 to 810, 820 to 822, 838 to 840, 850 to 851, 861 to 863, 873 to 874, 884 to 886, or 911 to 913.

[0128] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, is selected from the group consisting of SEQ ID NOs: 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, 253-254, 255-256, 257-258, 260-262, 263-264, 265-266, 267-268, 268-269, 270-271, 272-273, 274-275, 276-277, 278-279, 280-282, 284-285, 286-287, 288-289, 290-292, 300-301, 302-303, 304-305, 306-307, 308-309, 310-311, 312-313, 314-315 252, 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, 4 39-441, 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, 559-56 1, 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, 68 7~689, 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 to 870, 875 to 877, 880 to 881, 887 to 889, 892 to 893, 896 to 910, 914 to 916, or 919 to 920, and a heavy chain CDR1, CDR2, and CDR3 included in any one of SEQ ID NOs: 2 to 4, 16 to 18, 30 to 32, 44 to 46, 58 to 60, 72 to 74, 86 to 88, 100 to 102, 114 to 116, 128 to 130, 142 to 144, 156 to 158, 296 to 298, 310 to 312, 324 to 326, 338 to 340, 352 to 354, 419 to 421, 427 to 429, 435 to 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- and a light chain CDR1, CDR2, and CDR3 included in any one of 629, 635 to 637, 643 to 645, 651 to 653, 659 to 661, 667 to 669, 675 to 677, 683 to 685, 691 to 693, 699 to 701, 707 to 709, 809 to 810, 820 to 822, 838 to 840, 850 to 851, 861 to 863, 873 to 874, 884 to 886, or 911 to 913.

[0129] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, is selected from the group consisting of SEQ ID NOs: 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, 256-258, 260-262, 264-266, 266-268, 270-272, 274-276, 278-279, 280-282, 284-285, 286-287, 288-289, 290-292, 300-302, 304-305, 306-307, 308-309, 310-312, 314-315, 316-317, 318-319, 320-321, 322-323, 324-325, 326-327, 328-329, 330-332 252, 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, 487-488 89, 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, 5 51-553, 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, 611-61 3, 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 to 741, 743 to 745, 747 to 749, 751 to 753, 755 to 757, 759 to 761, 763 to 765, 767 to 769, 770 to 772, 775 to 777, 780 to 782, 785 to 786, 789 to 791, 794 to 796, 799, 802, 805 to 806, 809 to 813, 820 to 825, 838 to 843, 850 to 854, 861 to 866, 873 to 877, 884 to 889, 896 to 898, 901 to 903, 906 to 908, or 911 to 916. ,

[0130] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, is selected from the group consisting of SEQ ID NOs: 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, 256-258, 260-262, 264-266, 266-268, 270-272, 274-276, 278-279, 280-282, 284-285, 286-287, 288-289, 290-292, 300-302, 304-305, 306-307, 308-309, 310-312, 314-315, 316-317, 318-319, 320-321, 322-323, 324-325, 326-327, 328-329, 330-332 252, 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, 487-488 89, 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, 5 51-553, 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, 611-61 3, 615-617, 619621, 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. ,

[0131] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, is selected from the group consisting of SEQ ID NOs: 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, 256-258, 260-262, 264-266, 266-268, 270-272, 274-276, 278-279, 280-282, 284-285, 286-287, 288-289, 290-292, 300-302, 304-305, 306-307, 308-309, 310-312, 314-315, 316-317, 318-319, 320-321, 322-323, 324-325, 326-327, 328-329, 330-332 252, 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, 487-488 89, 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, 5 51-553, 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, 611-61 3, 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 to 741, 743 to 745, 747 to 749, 751 to 753, 755 to 757, 759 to 761, 763 to 765, 767 to 769, 770 to 772, 775 to 777, 780 to 782, 785 to 786, 789 to 791, 794 to 796, 799, 802, 805 to 806, 809 to 813, 820 to 825, 838 to 843, 850 to 854, 861 to 866, 873 to 877, 884 to 889, 896 to 898, 901 to 903, 906 to 908, or 911 to 916. ,

[0132] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, is selected from the group consisting of SEQ ID NOs: 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, 256-258, 260-262, 264-266, 266-268, 270-272, 274-276, 278-279, 280-282, 284-285, 286-287, 288-289, 290-292, 300-302, 304-305, 306-307, 308-309, 310-312, 314-315, 316-317, 318-319, 320-321, 322-323, 324-325, 326-327, 328-329, 330-332 252, 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, 487-488 89, 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, 5 51-553, 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, 611-61 3, 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. ,

[0133] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, is selected from the group consisting of SEQ ID NOs: 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, 256-258, 260-262, 264-266, 266-268, 270-272, 274-276, 278-279, 280-282, 284-285, 286-287, 288-289, 290-292, 300-302, 304-305, 306-307, 308-309, 310-312, 314-315, 316-317, 318-319, 320-321, 322-323, 324-325, 326-327, 328-329, 330-332 252, 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, 487-488 89, 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, 5 51-553, 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, 611-61 3, 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. ,

[0134] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, is selected from the group consisting of SEQ ID NOs: 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, 256-258, 260-262, 264-266, 266-268, 270-272, 274-276, 278-279, 280-282, 284-285, 286-287, 288-289, 290-292, 300-302, 304-305, 306-307, 308-309, 310-312, 314-315, 316-317, 318-319, 320-321, 322-323, 324-325, 326-327, 328-329, 330-332 252, 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, 487-488 89, 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, 5 51-553, 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, 611-61 3, 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. ,

[0135] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, is selected from the group consisting of SEQ ID NOs: 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, 256-258, 260-262, 264-266, 266-268, 270-272, 274-276, 278-279, 280-282, 284-285, 286-287, 288-289, 290-292, 300-302, 304-305, 306-307, 308-309, 310-312, 314-315, 316-317, 318-319, 320-321, 322-323, 324-325, 326-327, 328-329, 330-332 252, 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, 487-488 89, 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, 5 51-553, 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, 611-61 3, 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~ and 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 to the CDR (e.g., CDR1, CDR2, and / or CDR3) of 898, 901-903, 906-908, or 911-916.

[0136] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, is selected from the group consisting of SEQ ID NOs: 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, 815, 817, 819, 8 At least one CDR (e.g., CDR1, CDR2, and / or CDR3) shown in any one of SEQ ID NOs: 2 to 7, 16 to 21, 30 to 35, 44 to 49, 58 to 63, 72 to 77, 86 to 91, 100 to 105, 114 to 119, 128 to 133, 142 to 147, 156 to 161, 170 to 172, 2, 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, 6 43~645, 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, 75 1 to 753, 755 to 757, 759 to 761, 763 to 765, 767 to 769, 770 to 772, 775 to 777, 780 to 782, 785 to 786, 789 to 791, 794 to 796, 799, 802, 805 to 806, 809 to 813, 820 to 825, 838 to 843, 850 to 854, 861 to 866, 873 to 877, 884 to 889, 896 to 898, 901 to 903, 906 to 908, or 911 to 916.

[0137] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, is selected from the group consisting of SEQ ID NOs: 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, 256-258, 260-262, 264-266, 266-268, 270-272, 274-276, 278-279, 280-282, 284-285, 286-287, 288-289, 290-292, 300-302, 304-305, 306-307, 308-309, 310-312, 314-315, 316-317, 318-319, 320-321, 322-323, 324-325, 326-327, 328-329, 330-332 252, 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, 487-488 89, 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, 5 51-553, 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, 611-61 3, 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, 9 and 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 to the CDR (e.g., CDR1, CDR2, and / or CDR3) of any one of SEQ ID NOs: 01 to 903, 906 to 908, or 911 to 916.

[0138] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, is selected from the group consisting of SEQ ID NOs: 2-7, 1621, 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, 253-254, 255-256, 257-258, 258-259, 260-261, 262-263, 264-265, 266-267, 268-269, 270-272, 272-273, 274-275, 276-277, 278-279, 280-282, 284-285, 286-287, 288-289, 290-292, 300-301, 302-303, 304-305, 306-307, 308-309, 310-311, 312-313, 52, 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, 4 27-429, 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, 487-488 9, 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, 55 1-553, 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, 86 1 to 866, 873 to 877, 884 to 889, 896 to 898, 901 to 903, 906 to 908, or 911 to 916. The CDRs (e.g., CDR1, CDR2, and / or CDR3) provided by the sequences 1 to 866, 873 to 877, 884 to 889, 896 to 898, 901 to 903, 906 to 908, or 911 to 916 include at least one CDR having one or more (e.g., 1, 2, 3, 4, 5, or more) additions, deletions, or substitutions.

[0139] The present disclosure provides, inter alia, anti-CLL-1 antibodies, or antigen-binding fragments thereof, comprising VHHs. In some embodiments, the anti-CLL-1 antibodies, or antigen-binding fragments thereof, are selected from the group consisting of SEQ ID NOs: 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, 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 the amino acid sequence of SEQ ID NOs: 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, 313-314 15, 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, 55 9~561, 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, 7 and VHHs comprising CDR sequences provided by any one of 94 to 796, 799, 802, 805 to 806, 809 to 813, 820 to 825, 838 to 843, 850 to 854, 861 to 866, 873 to 877, 884 to 889, 896 to 898, 901 to 903, 906 to 908, or 911 to 916. In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, is selected from the group consisting of SEQ ID NOs: 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, 205-206, 207-208, 209-210, 211-212, 213-214, 215-216, 217-218, 219-220, 221-222, 222-224, 223-225, 224-226, 225-227, 226-228, 227-229, 230-231, 232-233, 234-235, 236-237, 238-239, 240-241, 242-243, 244-245, 246-247, 248-249, 250-251, 252-253, 254-255, 256-257, 258-259, 260-261, 262-263, 264-265, 266-267, 268-269, 270-272 207, 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, 355-356 57, 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, 591-59 3, 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,and VHHs comprising light chain CDR1, CDR2, and CDR3 included in any one of 743 to 745, 747 to 749, 751 to 753, 755 to 757, 759 to 761, 763 to 765, 767 to 769, 770 to 772, 775 to 777, 780 to 782, 785 to 786, 789 to 791, 794 to 796, 799, 802, 805 to 806, 809 to 813, 820 to 825, 838 to 843, 850 to 854, 861 to 866, 873 to 877, 884 to 889, 896 to 898, 901 to 903, 906 to 908, and 911 to 916. In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, is selected from the group consisting of SEQ ID NOs: 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, 212-214, 214-216, 216-218, 218-219, 220-221, 222-223, 224-225, 226-227, 228-229, 230-231, 232-233, 234-235, 236-237, 238-239, 240-241, 242-243, 244-245, 246-247, 248-249, 250-251, 252-253, 254-255, 256-257, 258-259, 260-261, 262-263, 264-265, 266-267, 268-269, 270-272, 272-273, 274-275, 276-277, 278-279 212, 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, 431-4 33, 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, 615-61 7, 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, 906-908, or 911-916. In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, is selected from the group consisting of SEQ ID NOs: 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, 439-44 41, 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, 63 1~633, 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, 906-908, or 911-916 Thus, the present invention also includes VHHs comprising 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 to a CDR (e.g., CDR1, CDR2, and / or CDR3) provided herein. In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, is selected from the group consisting of SEQ ID NOs: 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, 195-196, 197-198, 198-200, 200-201, 201-202, 202-203, 203-204, 204-205, 205-206, 206-207, 207-208, 208-209, 210-211, 211-212, 212-213, 214-215, 216-217, 218-219, 220-221, 222-223, 224-225, 226-227, 228-229, 230-231, 232-233, 234-235, 236-237, 238-239, 240-242, 242-243, 244-245, 246-247, 248-249, 250-251, 252-253, 254-255, 256-257, 258-259 7, 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, 3 13-315, 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, 906-908, or 911-916.

[0140] In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, is a monoclonal antibody, or antigen-binding fragment thereof. In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, is a humanized antibody, or antigen-binding fragment thereof. In some embodiments, the anti-CLL-1 antibody, or antigen-binding fragment thereof, is a camelid antibody or is derived from a camelid antibody.

[0141] In some embodiments, the present disclosure provides SEQ ID NOs: 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, 156-157, 157-158, 158-160, 160-162, 162-163, 163-164, 164-165, 165-166, 166-167, 167-168, 168-169, 170-171, 172-173, 174-175, 176-177, 178-179, 179-180, 181-182, 182-183, 183-184, 184-185, 185-186, 187-188, 189-200, 190-20 161, 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, 210-211 2, 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, 2 64, 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, 80 The present invention provides an anti-CLL-1 antibody, or an antigen-binding fragment thereof, which competes with an antibody, or an antigen-binding fragment thereof, comprising an amino acid sequence selected from the group consisting of: 1 to 802, 804 to 806, 808 to 813, 815, 817, 819 to 825, 827, 829, 831, 833, 835, 837 to 843, 845, 847, 849 to 854, 856, 858, 860 to 866, 868, 870, 872 to 877, 879, 881, 883 to 889, 891, 893, 895 to 898, 900 to 903, 905 to 908, 910 to 916, 918, or 920.In some embodiments, the present disclosure provides the sequences of SEQ ID NOs: 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, 8 The present invention provides an anti-CLL-1 antibody, or an antigen-binding fragment thereof, that competes with an antibody, or an antigen-binding fragment thereof, comprising an amino acid sequence selected from the group consisting of: 01, 804, 808, 817, 829, 831, 835, 837, 847, 849, 858, 860, 870, 872, 881, 883, 893, 895, 900, 905, 910, and 920.

[0142] In some embodiments, the present disclosure provides anti-CLL-1 antibodies, or antigen-binding fragments thereof, comprising 1 to 24 (e.g., 1, 2, 3, 4, 5, 10, or more) additions, deletions, or substitutions to the anti-CLL-1 antibodies, or antigen-binding fragments thereof, wherein the anti-CLL-1 antibodies are selected from the group consisting of SEQ ID NOs: 15, 29, 43, 57, 71, 85, 99, 113, 127, 141, 155, 169, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 23, 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, 575, 576, 577, 578, 580, 582, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599, 600, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 619, 620, 621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638, 6 74, 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, 746 829, 831, 835, 837, 847, 849, 858, 860, 870, 872, 881, 883, 893, 895, 900, 905, 910, 920, for example, wherein the antibody or fragment selectively binds to CLL-1.In some embodiments, the present disclosure provides the nucleic acids of SEQ ID NOs: 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, 6 74, 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, 87 900, 905, 910, 920, or an anti-CLL-1 antibody, or an antigen-binding fragment thereof, comprising an amino acid sequence having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 0, 872, 881, 883, 893, 895, 900, 905, 910, 920, e.g., the antibody or fragment selectively binds to CLL-1.

[0143] In some embodiments, the disclosure provides anti-CLL-1 antibodies, or antigen-binding fragments thereof, selected from the group consisting of SEQ ID NOs: 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, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553 heavy chain CDR1 provided by 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, 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, 812, 824, 842, 853, 865, 876, 888, 897, 902, 907, or 915, and a heavy chain 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, 813, 825, 843, 854, 866, 877, 889, 898, 903, 908, or 916. In some embodiments, the disclosure provides anti-CLL-1 antibodies, or antigen-binding fragments thereof, selected from the group consisting of SEQ ID NOs: 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, 492, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569 99, 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 provided by 911 Light chain CDR1, SEQ ID NOs: 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, 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 provided by SEQ ID NOs: 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, 810, 822, 840, 851, 863, 874, 886, or 913.

[0144] In some embodiments, the present disclosure provides nucleic acids encoding any of the anti-CLL-1 antibodies, or antigen-binding fragments thereof, described herein. In some embodiments, the present disclosure provides nucleic acids encoding any of the anti-CLL-1 antibodies, or antigen-binding fragments thereof, comprising 1 to 24 (e.g., 1, 2, 3, 4, 5, 10, or more) additions, deletions, or substitutions relative to the anti-CLL-1 antibodies, or antigen-binding fragments thereof, wherein the anti-CLL-1 antibodies are selected from the group consisting of SEQ ID NOs: 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, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116-21, 116, 117, 118, 119, 120, 121, 122, 123, 124, 12 9, 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,In some embodiments, the antibody or fragment selectively binds to CLL-1. In some embodiments, the antibody or fragment selectively binds to CLL-1. The antibody or fragment selectively binds to CLL-1 comprises the amino acid sequence of SEQ ID NOs: 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. In some embodiments, the antibody or fragment selectively binds to CLL-1. In some embodiments, the antibody or fragment selectively binds to CLL-1. In some embodiments, the antibody or fragment selectively binds to CLL-1. 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, 74 2, 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, and for example, the antibody or fragment selectively binds to CLL-1. In some embodiments, the present disclosure provides SEQ ID NOs: 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, 21 9, 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, 3 23, 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, Nucleic acids encoding an anti-CLL-1 antibody, or any of its antigen-binding fragments, are provided, including an amino acid sequence having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of 868, 870, 872-877, 879, 881, 883-889, 891, 893, 895-898, 900-903, 905-908, 910-916, 918, or 920, e.g., the antibody or fragment selectively binds to CLL-1. In some embodiments, the present disclosure provides SEQ ID NOs: 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, 575, 576, 577, 578, 580, 582, 586, 587, 588, 589, 590, 594, 595, 596, 597, 598, 599, 600, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 619, 620, 621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638, 639, 640, 641, 642, 643, 644, 645, 646, 647, 78, 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, 72 6, 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 and / or 920, wherein the nucleic acid encodes an anti-CLL-1 antibody, or an antigen-binding fragment thereof, comprising an amino acid sequence having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, S

[0145] In some embodiments, the present disclosure provides the sequences of SEQ ID NOs: 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, 156, 158, 160, 162, 164, 166, 168, 170, 172, 176, 178, 179, 180, 182, 184, 186, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 224, 226, 234, 238, 140, 148, 152, 153, 154, 155, 156, 157, 158, 159, 169, 170, 171, 172, 173, 174 4, 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, 317, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, ​​383, 384, 385, 386, 387, 388, 38 20, 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 encoding an antibody or antigen-binding fragment thereof that binds to CLL-1.In some embodiments, the present disclosure provides the sequences of SEQ ID NOs: 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, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 226, 227, 228, 230, 231, 232, 233, 234, 235, 236, 237, 238, 240, 248, 240, 248, 252, 254, 252, 254, 262, 266, 268 8, 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, 78 809, 917, 919, 921, 922, 923, 924, 925, 926, 927, 928, 929, 930, 932, 934, 936, 937, 938, 939, 940, 941, 942, 943, 944, 945, 946, 947, 948, 949, 950, 951, 952, 953, 954, 955, 956, 957, 958, 959, 960, 961, 962, 963, 964, 965, 966, 967, 968, 969, 970, 971, 972, 973, 974, 975, 976, 977, 978, 979, 980, 981, 982, 983, 984, 985, 986, 987, 988, 989, 990, 992, 994, 995, 996, 997, 998, 999, 900, 901, 902, 903, 904, 905, 906, 907, 908, 909, 910, 911, 912, 913, 914, 915, 916, 917, 918, 919, 921, and encoding an antibody or antigen-binding fragment thereof that binds CLL-1.

[0146] The present disclosure provides, inter alia, a method for producing an anti-CLL-1 antibody or an antigen-binding fragment thereof. Methods for producing antibodies are known in the art. For example, monoclonal antibodies can be produced using various known techniques, such as the standard somatic cell hybridization technique described in Kohler and Milstein, Nature (1975) 256:495. Other techniques for producing monoclonal antibodies can also be used, such as viral or oncogenic transformation of B lymphocytes, or phage display technology using a library of human antibody genes.

[0147] In some embodiments, human antibodies are obtained by cloning heavy and light chain genes directly from human B cells obtained from a human subject. B cells are isolated from peripheral blood (e.g., by flow cytometry, e.g., FACS), stained for B cell markers, and assessed for antigen binding. RNA encoding the heavy and light chain variable regions (or entire heavy and light chains) is extracted and reverse transcribed into DNA, from which antibody genes are amplified (e.g., by PCR) and sequenced. The known antibody sequences can then be used to express recombinant human antibodies against known target antigens. In some cases, human antibodies can be prepared by administering an immunogen to a modified transgenic animal to produce intact human antibodies or intact antibodies with human variable regions in response to antigen challenge. Such animals typically contain all or a portion of human immunoglobulin loci, which replace endogenous immunoglobulin loci or are present extrachromosomally or randomly integrated into the animal's chromosomes. In such transgenic mice, endogenous immunoglobulin loci are generally inactivated, and the human variable regions from intact antibodies produced by such animals can be further modified, for example, by combining them with different human constant regions.

[0148] In some cases, antibodies may also be produced by hybridoma-based methods. In some embodiments, the animal system for generating hybridomas that produce human monoclonal antibodies is the murine system. Hybridoma production in mice, including immunization protocols and techniques for isolating and fusing immune splenocytes, is well known in the art. Human myeloma and mouse-human heteromyeloma cell lines for the production of human monoclonal antibodies have been described.

[0149] Human antibodies can also be generated by isolating Fv clone variable domain sequences selected from human-derived phage display libraries, which may then be combined with desired human constant domains.

[0150] In some embodiments, the present disclosure provides a method of producing an antibody, or antigen-binding fragment thereof, comprising culturing a host cell containing nucleic acid encoding any of the anti-CLL-1 antibodies described herein. In some embodiments, the method comprises culturing a host cell containing nucleic acid encoding any of SEQ ID NOs: 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, 142, 144, 146, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199 , 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, 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, 921 under conditions suitable for expression of the antibody or antigen-binding fragment thereof. In some embodiments, the method further comprises collecting, isolating, and / or purifying the antibody or antigen-binding fragment thereof.

[0151] Sequences of exemplary antibody clones, including exemplary single chain and single domain anti-CLL-1 antibodies, are provided in Tables 1-114. [Table 1] [Table 2] [Table 3]

Table 4

Table 5

Table 6

Table 7

Table 8

Table 9

Table 10

Table 11

Table 12

Table 13

Table 14

Table 15

Table 17

Table 18

Table 19

Table 33

Table 50

Table 91

Table 99

Table 100

[0152] Fusion Proteins and Conjugates In some embodiments, the present disclosure provides fusion proteins comprising (i) one or more single domain antibodies described herein, or antigen-binding fragments thereof (e.g., comprising one or more CDRs described herein), and (ii) one or more additional polypeptides. In some embodiments, the present disclosure provides fusion proteins comprising (i) one or more single domain antibodies described herein, or antigen-binding fragments thereof (e.g., comprising one or more CDRs described herein), and (ii) one or more additional domains. For example, the fusion protein can comprise one or more single domain antibodies described herein and one or more (e.g., one, two, three, four, or more) constant regions or Fc regions. In some embodiments, one or more single domain antibodies described herein, or antigen-binding fragments thereof (e.g., one or more CDRs described herein), can be non-covalently or covalently linked, e.g., fused, to an antigen (e.g., an antigen target for cell therapy such as CAR-T cells or antibody drug conjugates), as described, for example, in PCT Publication Nos. 2017 / 075537, 2017 / 075533, 2018 / 156802, and 2018 / 156791.

[0153] In some embodiments, the present disclosure provides fusion proteins comprising one or more VHHs described herein and one or more additional polypeptides or polypeptide domains, in some embodiments, the additional polypeptides comprise additional antibodies or fragments thereof. Additional antibodies include, for example, intact IgG, IgE, and IgM, bispecific or multispecific antibodies (such as, for example, Zybodies®), single chain Fvs, polypeptide-Fc fusions, Fabs, camelid antibodies, shielding antibodies (such as, for example, Probodies®), small modular immunopharmaceuticals ("SMIPs®"), single chain or tandem diabodies (TandAbs®), VHHs (including but not limited to those described in this disclosure), Anticalin®, Nanobodies®, minibodies, BiTEs®, ankyrin repeat proteins or DARPINs®, Avimers®, DARTs, TCR-like antibodies, Adnectins®, Affilins®, Trans-bodies®, Affibodies®, TrimerX®, microproteins, Fynomers®, and Centyrin®.

[0154] In some embodiments, the 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, or antigen-binding fragments thereof, described herein. In some embodiments, the 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., not an epitope of CLL-1).

[0155] In some embodiments, antibodies of the present disclosure can be covalently attached to a drug (e.g., a cytotoxic agent such as a toxin) via a linker (e.g., via a disulfide or non-cleavable thioether linker) as an antibody-drug conjugate (ADC). The agent to which the antibody is covalently attached can have cytotoxic or cytostatic effects when not conjugated to the antibody. ADCs can be used to selectively deliver an effective dose of a cytotoxic agent to a cell (e.g., tumor tissue). ADCs can improve the bioavailability of the agent and / or antibody compared to when the agent and / or antibody are administered in unconjugated form.

[0156] Various linker types and strategies are known in the art, any or all of which are contemplated for use with the antibodies or ADCs of the present disclosure. In some embodiments, the linker is biodegradable, e.g., cleavable by endogenous proteases (e.g., present in the target tissue and / or cells). In some embodiments, the linker comprises a protease-cleavable site. In some embodiments, the linker comprises a pH-sensitive site, e.g., a site sensitive to acidic pH that hydrolyzes under acidic conditions. In some embodiments, the linker is stable under physiological conditions, e.g., sufficiently stable so that the antibody targets the target tissue before release of the drug. In some embodiments, the linker comprises a disulfide bond, e.g., a glutathione-sensitive disulfide bond. In some embodiments, the drug conjugated to the antibody is active only after cleavage of the linker. In some embodiments, the drug conjugated to the antibody is active only after proteolytic digestion of the antibody (e.g., in the lysosomes of the target cell). In some embodiments, the linker is a non-cleavable heterobifunctional thioether linker, for example, a maleimide linker, such as N-hydroxysuccinimide ester (succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate or SMCC.

[0157] A variety of drugs compatible with the ADCs of the present disclosure are known in the art, any or all of which are contemplated for use with the antibodies of the present disclosure.

[0158] Also within the scope of the present disclosure are chimeric antigen receptors (CARs) comprising any of the anti-CLL-1 antibodies or antigen-binding fragments thereof described herein. CARs are artificially constructed hybrid proteins or polypeptides comprising the antigen-binding domain of one or more antibodies (e.g., single-chain variable fragments (scFvs)) linked to a T cell signaling domain. Characteristics of CARs include the ability to utilize the antigen-binding properties of monoclonal antibodies to redirect T cell specificity and reactivity to selected targets in an MHC-unrestricted manner. Non-MHC-restricted antigen recognition confers on CAR-expressing T cells the ability to recognize antigens independent of antigen processing, thereby circumventing a major tumor escape mechanism. Furthermore, when expressed in T cells, CARs advantageously do not dimerize with the alpha and beta chains of the endogenous T cell receptor (TCR). As used herein, the terms "antigen-specific" and "elicit an antigen-specific response" mean that the CAR can specifically bind to and immunologically recognize an antigen such that binding of the CAR to the antigen elicits an immune response.

[0159] There are three generations of conventional CARs containing an antibody antigen-binding domain. "First-generation" CARs typically consist of a transmembrane domain fused to a cytoplasmic / intracellular signaling domain and an extracellular antigen-binding domain (e.g., scFv) fused to the transmembrane domain. First-generation CARs provide novel antigen recognition and can activate both CD4+ and CD8+ T cells independently of HLA-mediated antigen presentation via their CD3ζ chain signaling domain in a single fusion molecule. "Second-generation" CARs add intracellular signaling domains derived from various costimulatory signaling molecules (e.g., CD28, 4-1BB, ICOS, OX40, CD27, CD40 / My88, and NKGD2) to the cytoplasmic tail of the CAR to deliver additional signals to T cells. Second-generation CARs include CARs that provide both costimulation (e.g., CD28 or 4-1BB) and activation (CD3ζ). "Third generation" CARs include CARs that provide multiple costimulatory domains (e.g., CD28 and 4-1BB) and an activation signaling domain (e.g., CD3ζ).

[0160] The CARs described herein comprise an extracellular portion of the CAR, including an anti-CLL-1 binding fragment, a transmembrane domain, and a signaling domain. In some embodiments, the CAR further comprises one or more of a linker region, a hinge region, and a costimulatory signaling domain. In some embodiments, the CAR further comprises a signal peptide / signal sequence.

[0161] A CAR may consist of, or consist essentially of, a particular amino acid sequence or sequences described herein, such that the biological activity of the functional variant is not substantially altered by other components, e.g., other amino acids.

[0162] The CARs (including functional portions and functional variants) of the present disclosure may be of any length, i.e., may contain any number of amino acids, provided that the CAR (or functional portion or functional variant thereof) retains biological activity, such as the ability to specifically bind to a target antigen (e.g., CLL-1), detect diseased cells in a mammal, or treat or prevent disease in a mammal. For example, a CAR may be about 50 to about 5,000 amino acids in length, such as 50, 70, 75, 100, 125, 150, 175, 200, 300, 400, 500, 600, 700, 800, 900, 1,000, or more amino acids in length.

[0163] In some embodiments, a CAR construct (including functional portions and functional variants of the invention) may comprise a synthetic amino acid in place of one or more naturally occurring amino acids. Such synthetic amino acids are known in the art and include, for example, aminocyclohexanecarboxylic acid, norleucine, α-amino n-decanoic acid, homoserine, S-acetylaminomethyl-cysteine, trans-3- and trans-4-hydroxyproline, 4-aminophenylalanine, 4-nitrophenylalanine, 4-chlorophenylalanine, 4-carboxyphenylalanine, β-phenylserine. Examples include b-hydroxyphenylalanine, phenylglycine, a-naphthylalanine, cyclohexylalanine, cyclohexylglycine, indoline-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.

[0164] In some embodiments, the CAR constructs (including functional portions and functional variants) may be glycosylated, amidated, carboxylated, phosphorylated, esterified, N-acylated, cyclized, e.g., via disulfide bridges, or converted into acid addition salts, and / or may optionally be dimerized or multimerized, or conjugated.

[0165] In some embodiments, CAR constructs (including functional portions and functional variants thereof) may be obtained by methods known in the art. In some embodiments, CAR constructs may be made by any suitable method for making polypeptides or proteins, including de novo synthesis. CAR constructs may be recombinantly produced using the nucleic acids described herein using standard recombinant methods. See, for example, Green et al., Molecular Cloning: A Laboratory Manual, 4th ed., Cold Spring Harbor Press, Cold Spring Harbor, NY 2012. Furthermore, portions of the CAR constructs described herein (including functional portions and functional variants thereof) may be isolated and / or purified from sources such as, for example, plants, bacteria, insects, mammals, e.g., rats and humans. Isolation and purification methods are known in the art. Alternatively, the CAR constructs described herein (including functional portions and variants thereof) may be commercially synthesized by companies such as Synpep (Dublin, Calif.), Peptide Technologies Corp. (Gaithersburg, Md.), and Multiple Peptide Systems (San Diego, Calif.). In this regard, the CAR constructs may be synthetic, recombinant, isolated, and / or purified.

[0166] Further provided herein are nucleic acids comprising a nucleotide sequence encoding any of the CAR constructs described herein (including functional portions and functional variants thereof). The nucleic acids described herein can comprise a nucleotide sequence encoding any of the leader sequences (e.g., signal peptides), antigen-binding domains, transmembrane domains, linker regions, costimulatory signaling domains, and / or intracellular T cell signaling domains described herein.

[0167] In some aspects, any of the antigen binding domains described herein can be operably linked to another domain of the CAR, such as a transmembrane domain or an intracellular domain, for expression within a cell. In some embodiments, the nucleic acid encoding the antigen binding domain is operably linked to the nucleic acid encoding the transmembrane domain and the nucleic acid encoding the intracellular domain.

[0168] 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 costimulatory signaling domain, a signaling domain). In some embodiments, the CAR comprises any of the anti-CLL-1 antibodies or antigen-binding fragments thereof described herein (e.g., comprising one or more CDRs described herein). In some embodiments, the CAR is provided in any one of SEQ ID NOs: 15, 29, 43, 57, 71, 85, 99, 113, 127, 141, 155, 169, 309, 323, 337, 351, 365, 376-417, or 922-928, or in any one of SEQ ID NOs: 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, 68 6, 690, 694, 698, 702, 706, 710, 714, 718, 722, 726, 730, 734, 738, 742, 746, 750, 754, 758, 762, 766, 770-772, 775-777, 780-782, 785-786, 789-791, 794-796, 799, 802, 8 The present invention also includes an anti-CLL-1 antibody or an antigen-binding fragment thereof, including any one of the following: 805 to 806, 809 to 813, 820 to 825, 838 to 843, 850 to 854, 861 to 866, 873 to 877, 884 to 889, 896 to 898, 901 to 903, 906 to 908, or 911 to 916.

[0169] In some embodiments, the CAR comprises a linker region. In some embodiments, the light chain variable region and heavy chain variable region of the antigen-binding domain may be linked to each other by a linker. In some embodiments, the antigen-binding domain may be linked to another domain, such as a transmembrane domain, hinge, and / or intracellular domain, via the linker region. The linker may comprise any suitable amino acid sequence. In some embodiments, the linker is a Gly / Ser linker that is 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 in length and consists of glycine and / or serine residues. Thus, the Gly / Ser linker may consist of glycine and / or serine residues. Preferably, the Gly / Ser linker comprises the amino acid sequence GGGGS (SEQ ID NO: 366), and multiple instances of the amino acid sequence of SEQ ID NO: 366 may be present within the linker. Any linker sequence may be used as a spacer between the antigen-binding domain and any other domain of the CAR, such as the transmembrane domain. In some embodiments, the linker region is ([G]x[S]y)z, e.g., where 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.

[0170] In some embodiments, the antigen-binding domain comprises 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 within the CAR construct. The leader sequence may comprise any suitable leader sequence, for example, any CAR described herein may comprise any leader sequence, such as those described herein. In some embodiments, the leader sequence may facilitate expression of a CAR released onto the cell surface, but the presence of a leader sequence in an expressed CAR is not essential for the function of the CAR. In some embodiments, the leader sequence may be cleaved off upon expression of the CAR on the cell surface. Thus, in some embodiments, the released CAR (e.g., a surface-expressed CAR) lacks a leader sequence. In some embodiments, the CAR within the CAR construct lacks a leader sequence.

[0171] hinge In some embodiments, the CAR comprises a hinge / spacer region that links the extracellular antigen-binding domain to another domain, such as a transmembrane domain. The hinge / spacer region may be flexible enough to allow the antigen-binding domain to orient in various directions to facilitate recognition of the target antigen. In some embodiments, the hinge domain is a portion of the hinge domain of CD8α or CD28, e.g., a fragment containing at least 15 (e.g., 20, 25, 30, 35, or 40) consecutive amino acids of the hinge domain of CD8α or CD28.

[0172] In some embodiments, the CAR comprises a hinge domain, such as that of CD8, CD28, or IgG4. In some embodiments, the hinge domain is that of CD8 (e.g., CD8α). In some embodiments, the CD8 hinge domain is human (e.g., obtained / derived from a human protein sequence). In some embodiments, the CD8 hinge domain comprises, consists of, or consists essentially of SEQ ID NO: 369. CD8 hinge region TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACD [SEQ ID NO: 369]

[0173] 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. CD28 hinge region AAAIEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKP [SEQ ID NO: 370]

[0174] Hinge domains of antibodies, such as, for example, IgG, IgA, IgM, IgE, or IgD antibodies, are also suitable for use in the 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 hinge domain and comprises an antibody hinge domain and one or more antibody constant regions. In some embodiments, the hinge domain comprises an antibody hinge domain and an antibody CH3 constant region. In some embodiments, the hinge domain comprises an antibody hinge domain and an antibody CH2 and CH3 constant region. 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 comprises the hinge region and CH2 and CH3 constant regions of an IgG1 antibody. In some embodiments, the hinge region comprises an IgG1 antibody hinge region and a CH3 constant region, hi some embodiments, the hinge domain is an IgG4 hinge domain.

[0175] CARs comprising hinge domains that are non-naturally occurring peptides are also within the scope of this disclosure. In some embodiments, the hinge domain between the C-terminus of the extracellular ligand-binding domain of an Fc receptor and the N-terminus of the transmembrane domain is a peptide linker, such as, for example, a (GlyxSer)n linker, where x and n can independently be integers between 3 and 12, including 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more. 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.

[0176] Additional peptide linkers that can be used in the hinge domains of the chimeric receptors described herein are known in the art. See, e.g., Wriggers et al. Current Trends in Peptide Science (2005) 80(6):736-74, and PCT Publication No. 2012 / 088461.

[0177] In some embodiments, the hinge / spacer region of a CAR of the present disclosure comprises a native or modified hinge region of a CD28 polypeptide described herein. In certain embodiments, the hinge / spacer region of a CAR construct of the present disclosure comprises a native or modified hinge region of a CD8α polypeptide described herein. In certain embodiments, the hinge / spacer region of a CAR construct of the present disclosure comprises a native or modified hinge region of an IgG4 polypeptide described herein.

[0178] Transmembrane domain With respect to the transmembrane domain, the CAR may be designed to include a transmembrane domain that connects the antigen-binding domain of the CAR to the intracellular region of the CAR. In some embodiments, the transmembrane domain is naturally associated with one or more of the domains of the CAR. In some instances, the transmembrane domain can be selected or modified by amino acid substitution to avoid binding of such domains to transmembrane domains of the same or different surface membrane proteins, thereby minimizing interactions with other members of the receptor complex.

[0179] The transmembrane domain may be derived from either natural or synthetic sources. If the source is natural, the domain may be derived from any membrane-bound or transmembrane protein. Transmembrane regions particularly useful in the present invention may be derived from (i.e., comprise) at least the transmembrane regions of the alpha, beta, or zeta chains of the T-cell receptor, CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD8α, 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.

[0180] In some embodiments, the transmembrane domain may be synthetic, in which case it comprises predominantly hydrophobic residues such as leucine and valine. Preferably, a triad of phenylalanine, tryptophan, and valine is present at each end of a synthetic transmembrane domain.

[0181] In some embodiments, the transmembrane domain is the transmembrane domain of CD8 (e.g., CD8α). 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. CD8 transmembrane region IYIWAPLAGTCGVLLLSLVITLYC [SEQ ID NO: 371]

[0182] In some embodiments, the transmembrane domain is the transmembrane domain of CD28. 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. CD28 transmembrane domain FWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS [SEQ ID NO: 372]

[0183] Intracellular signaling domains In some embodiments, the CAR construct comprises an intracellular signaling domain, which may be composed of one or more signaling domains and a costimulatory domain. The intracellular signaling domain of a CAR is involved in the activation of the cell in which the CAR is expressed. In some embodiments, the intracellular signaling domain of a CAR construct described herein is involved in the activation of T lymphocytes or NK cells. In some embodiments, the signaling domain of a CAR construct described herein comprises a domain involved in signal activation and / or transduction.

[0184] Examples of intracellular signaling domains for use in the CAR constructs described herein include, but are not limited to, the cytoplasmic portions of surface receptors, costimulatory molecules, and any molecules that act in concert to initiate signaling 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 that have the same function.

[0185] Examples of signaling domains that can be used in the intracellular signaling domain of the CARs described herein include, but are not limited to, TCR, CD3 zeta (CD3ζ), CD3 gamma, CD3 delta, CD3 epsilon, CD86, common FcR gamma, FcR beta (Fc Epsilon Rib), CD79a, CD79b, Fc gamma RIIa, 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, ligands that specifically bind to CD83, CDS, ICAM-1, GITR, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRF1), CD127, CD160, CD19, CD4, CD8 alpha, CD8 beta, IL2R beta, IL2R gamma, IL7R alpha, 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, Lyl08), 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 function, and any combination thereof.

[0186] Any cytoplasmic signaling domain can be used in the CARs described herein. Generally, the cytoplasmic signaling domain relays a signal, such as the interaction of an extracellular ligand-binding domain with its ligand, and stimulates a cellular response, such as inducing a cellular effector function (e.g., cytotoxicity).

[0187] As will be apparent to those skilled in the art, a factor involved in T cell activation is phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) in the cytoplasmic signaling domain. Any ITAM-containing domain known in the art may be used to generate the chimeric receptors described herein, and an ITAM-containing domain may be included as part of the cytoplasmic signaling domain. Generally, an ITAM motif may contain two repeats of the amino acid sequence YxxL / I, separated by 6-8 amino acids. Each x may independently be any amino acid, generating the conserved motif YxxL / Ix(6-8)YxxL / I. In some embodiments, the cytoplasmic signaling domain is derived from CD3ζ.

[0188] CD3ζ associates with the TCR to 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, consists of, or consists essentially of the amino acid sequence of SEQ ID NO: 373 or 374, or a 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 of SEQ ID NO: 373 or 374. In some embodiments, the intracellular T cell signaling domain comprises CD3ζ containing one or more mutated and / or deleted ITAMs. CD3ζ signaling domain (variant A) RVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR [SEQ ID NO: 373] CD3ζ signaling domain (variant B) RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR [SEQ ID NO: 374]

[0189] In certain non-limiting embodiments, the intracellular signaling domain of the CAR further comprises at least one (e.g., one, two, three, or more) costimulatory signaling domain. In some embodiments, the costimulatory signaling domain comprises at least one costimulatory molecule that can provide optimal lymphocyte activation. Generally, many immune cells require costimulation in addition to antigen-specific signal stimulation to promote cell proliferation, differentiation, and survival and to activate cell effector functions. Activation of a costimulatory signaling domain in a host cell (e.g., an immune cell) can cause the cell to increase or decrease cytokine production and secretion, phagocytic ability, proliferation, differentiation, survival, and / or cytotoxicity. The costimulatory signaling domain of any costimulatory protein may be compatible for use in the chimeric receptors described herein. The type of costimulatory signaling domain can be selected depending on factors such as the type of cell in which the CAR is expressed (e.g., primary T cells, T cell lines, NK cell lines) and the desired immune effector function (e.g., cytotoxicity).

[0190] Examples of such costimulatory signaling domains include, but are not limited to, fragments or domains derived from one or more molecules or receptors including 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, in any combination with any of the signaling domains listed in the paragraph above. In some embodiments, the intracellular signaling domain of the CAR comprises any portion of one or more costimulatory signaling molecules, such as, for example, at least one signaling domain derived from CD3, Fc epsilon RI gamma chain, any derivative or variant thereof (including any synthetic sequence thereof that has the same function), and any combination thereof.

[0191] In some embodiments, one or more costimulatory signaling domains (e.g., 1, 2, 3, or more) are contained within the CAR construct along with the CD3ζ intracellular T cell signaling sequence. In some embodiments, the one or more costimulatory signaling domains are selected from CD137 (4-1BB) and CD28, or a combination thereof. In some embodiments, the CAR comprises a 4-1BB (CD137) costimulatory signaling domain. In some embodiments, the CAR comprises a CD28 costimulatory signaling domain. In some embodiments, the CAR comprises both a 4-1BB costimulatory signaling domain and a CD28 costimulatory signaling domain.

[0192] 4-1BB, also known as CD137, delivers a potent costimulatory signal to T cells, promoting T lymphocyte differentiation and enhancing long-term survival of T lymphocytes. In some embodiments, the 4-1BB intracellular signaling sequence is human (e.g., obtained / derived from a human protein sequence). In some embodiments, the 4-1BB intracellular T cell signaling sequence comprises, consists of, or consists essentially of the amino acid sequence of SEQ ID NO: 375. In some embodiments, the 4-1BB costimulatory signaling domain comprises, consists of, or consists essentially of the amino acid sequence of SEQ ID NO: 375, or a 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 of SEQ ID NO: 375. 4-1BB costimulatory signaling domain KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL [SEQ ID NO: 375]

[0193] Some suitable costimulatory domains are provided herein, and other suitable costimulatory domains and costimulatory domain sequences will be apparent to those of skill in the art based on this disclosure in light of the state of 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.

[0194] A spacer domain may be incorporated between the antigen-binding domain and the transmembrane domain of a CAR, or between the intracellular signaling domain and the transmembrane domain of a CAR. As used herein, the term "spacer domain" generally refers to any oligopeptide or polypeptide that functions to link a transmembrane domain to either the antigen-binding domain or the intracellular domain in a polypeptide chain. In some embodiments, a spacer domain may comprise up to 300 amino acids, preferably 10-100 amino acids, and most preferably 25-50 amino acids. In some embodiments, a short oligopeptide or polypeptide linker, preferably 2-10 amino acids in length, may form the link between the transmembrane domain and the intracellular domain of a CAR. An example of a linker is a glycine-serine doublet.

[0195] signal peptide In some embodiments, any of the CARs described herein may further comprise a signal peptide (signal sequence). Generally, a signal peptide is a short amino acid sequence that targets a polypeptide to a site in a cell. In some embodiments, the signal peptide directs the CAR to the cell's secretory pathway and integrates and anchors the CAR within the lipid bilayer on the cell surface. Signal sequences, including signal sequences of natural proteins or synthetic, non-natural signal sequences, that are compatible for use in the chimeric receptors described herein will be apparent to those of skill in the art.

[0196] The CARs described herein may be prepared in constructs, for example, with self-cleaving peptides, such that the CAR construct containing the anti-CLL-1 CAR component is bicistronic, tricistronic, etc.

[0197] Disclosed herein are various CAR constructs and numerous elements of CAR constructs (e.g., various CLL-1 binding domains, signal peptides, linkers, hinge sequences, transmembrane domains, costimulatory domains, and signaling domains). Based on this disclosure, one of skill in the art will be able to ascertain the sequences of these and additional suitable elements known in the art in light of the knowledge of the art. For example, sequences of exemplary CAR elements, such as CLL-1 binding domains, signal peptides, linkers, hinge sequences, transmembrane domains, costimulatory domains, and signaling domains, are disclosed, for example, throughout the specification and in Tables 1-8 in WO / 2016 / 120218, the entire contents of which are incorporated herein by reference.

[0198] Any of the anti-CLL-1 antibodies, or antigen-binding fragments thereof, can be used in a CAR construct along with any one or more of the additional components described herein, e.g., a hinge, a transmembrane domain, a costimulatory domain, an intracellular signaling domain. In some embodiments, the CAR construct is selected from the group consisting of SEQ ID NOs: 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, 242-244, 244-246, 246-248, 248-249, 250-251, 252-253, 254-255, 256-257, 258-259, 260-261, 262-263, 264-265, 266-267, 268-269, 270-272, 274-275, 276-277, 278-279, 280-282, 284-285, 286-287, 288-289, 290-292, 300-301, 302-303, 304-305, 306-307, 308-309, 310-311, 3 2, 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, 57 9~581, 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 911-916, a CLL-1 binding domain, a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain. In some embodiments, the CAR construct is selected from the group consisting of SEQ ID NOs: 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, 193-194, 195-196, 197-198, 198-200, 199-201, 200-201, 201-202, 202-203, 204-205, 206-207, 208-209, 210-211, 212-213, 214-215, 216-217, 218-219, 220-221, 222-223, 224-225, 226-227, 228-229, 230-231, 232-233, 234-235, 236-237, 238-239, 240-241, 242-243, 244-245, 246-247, 248-249, 250-251, 252-253, 254-255, 256-257, 258-259, 260-261, 262-263, 264-265, 2 5-197, 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, 463-464 5, 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, 627-62 9, 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, 83 and a CLL-1 binding domain comprising three of the CDR sequences provided by 8-843, 850-854, 861-866, 873-877, 884-889, 896-898, 901-903, 906-908, or 911-916 (e.g., VHH), a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain. In some embodiments, the CAR construct is selected from the group consisting of SEQ ID NOs: 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, 5 07~509, 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, 567~56 9, 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- a CLL-1 binding domain comprising six of the CDR sequences provided by 757, 759 to 761, 763 to 765, 767 to 769, 770 to 772, 775 to 777, 780 to 782, 785 to 786, 789 to 791, 794 to 796, 799, 802, 805 to 806, 809 to 813, 820 to 825, 838 to 843, 850 to 854, 861 to 866, 873 to 877, 884 to 889, 896 to 898, 901 to 903, 906 to 908, or 911 to 916 (e.g., scFv), a CD8α transmembrane domain, a CD8α hinge domain;Contains the CD137 (4-1BB) costimulatory domain and the CD3ζ intracellular signaling domain.

[0199] As will be appreciated by those skilled in the art, one or more of the domains of the exemplary CAR constructs can be replaced by another domain. For example, the exemplary CAR construct provided below comprises a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain, and any one of the domains (such as the hinge domain, transmembrane domain, costimulatory domain, and / or intracellular signaling domain) can be replaced by another domain, such as those described herein.

[0200] In some embodiments, the CAR comprises 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 set forth in any one of SEQ ID NOs: 376-417, or 922-928. In the amino acid sequences of exemplary CAR constructs described herein, the following annotations may be used: long dashed underlines indicate hinge domains, double underlines indicate transmembrane domains, dotted underlined italics indicate costimulatory domains, and bold underlines indicate intracellular signaling domains.

[0201] 1.CAR Clone 1 As described herein, an exemplary CAR construct comprises a CLL-1 binding domain scFv comprising SEQ ID NO: 15, a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain. In some embodiments, the CAR comprises SEQ ID NO: 376, 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 set forth in SEQ ID NO: 376. [ka]

[0202] In some embodiments, the CAR construct set forth in SEQ ID NO: 376 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., an SFFV promoter, an EF1α promoter, a tEF1a promoter, an hPGK promoter, an SFFV promoter, or an MND promoter).

[0203] 2. CAR Clone 2 An exemplary CAR construct described herein comprises a CLL-1 binding domain scFv comprising SEQ ID NO: 29, a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain.

[0204] In some embodiments, the CAR comprises an amino acid sequence comprising the sequence set forth 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 set forth in SEQ ID NO: 377. [ka]

[0205] In some embodiments, the CAR construct set forth in SEQ ID NO: 377 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., an SFFV promoter, an EF1α promoter, a tEF1a promoter, an hPGK promoter, an SFFV promoter, or an MND promoter).

[0206] 3. CAR Clone 3 An exemplary CAR construct described herein comprises a CLL-1 binding domain scFv comprising SEQ ID NO: 43, a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain.

[0207] In some embodiments, the CAR comprises an amino acid sequence comprising the sequence set forth 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 set forth in SEQ ID NO: 378. [ka]

[0208] In some embodiments, the CAR construct set forth in SEQ ID NO: 378 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., an SFFV promoter, an EF1α promoter, a tEF1a promoter, an hPGK promoter, an SFFV promoter, or an MND promoter).

[0209] 4. CAR Clone 4 An exemplary CAR construct described herein comprises a CLL-1 binding domain scFv comprising SEQ ID NO: 57, a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain.

[0210] In some embodiments, the CAR comprises an amino acid sequence comprising the sequence set forth 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 set forth in SEQ ID NO: 379. [ka]

[0211] In some embodiments, the CAR construct set forth in SEQ ID NO: 379 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., an SFFV promoter, an EF1α promoter, a tEF1a promoter, an hPGK promoter, an SFFV promoter, or an MND promoter).

[0212] 5.CAR Clone 5 An exemplary CAR construct described herein comprises a CLL-1 binding domain scFv comprising SEQ ID NO: 71, a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain.

[0213] In some embodiments, the CAR comprises an amino acid sequence comprising the sequence set forth 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 set forth in SEQ ID NO: 380. [ka]

[0214] In some embodiments, the CAR construct set forth in SEQ ID NO: 380 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., an SFFV promoter, an EF1α promoter, a tEF1a promoter, an hPGK promoter, an SFFV promoter, or an MND promoter).

[0215] 6. CAR Clone 6 An exemplary CAR construct described herein comprises a CLL-1 binding domain scFv comprising SEQ ID NO: 85, a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain.

[0216] In some embodiments, the CAR comprises an amino acid sequence comprising the sequence set forth 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 set forth in SEQ ID NO: 381. [ka]

[0217] In some embodiments, the CAR construct set forth in SEQ ID NO: 381 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., an SFFV promoter, an EF1α promoter, a tEF1a promoter, an hPGK promoter, an SFFV promoter, or an MND promoter).

[0218] 7. CAR Clone 7 An exemplary CAR construct described herein comprises a CLL-1 binding domain scFv comprising SEQ ID NO: 99, a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain.

[0219] In some embodiments, the CAR comprises an amino acid sequence comprising the sequence set forth 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 set forth in SEQ ID NO: 382. [ka]

[0220] In some embodiments, the CAR construct set forth in SEQ ID NO: 382 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., an SFFV promoter, an EF1α promoter, a tEF1a promoter, an hPGK promoter, an SFFV promoter, or an MND promoter).

[0221] 8. CAR Clone 8 An exemplary CAR construct described herein comprises a CLL-1 binding domain scFv comprising SEQ ID NO: 113, a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain.

[0222] In some embodiments, the CAR comprises an amino acid sequence comprising the sequence set forth 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 set forth in SEQ ID NO: 383. [ka]

[0223] In some embodiments, the CAR construct set forth in SEQ ID NO: 383 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., an SFFV promoter, an EF1α promoter, a tEF1a promoter, an hPGK promoter, an SFFV promoter, or an MND promoter).

[0224] 9. CAR Clone 9 An exemplary CAR construct described herein comprises a CLL-1 binding domain scFv comprising SEQ ID NO: 127, a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain.

[0225] In some embodiments, the CAR comprises an amino acid sequence comprising the sequence set forth 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 set forth in SEQ ID NO: 384. [ka]

[0226] In some embodiments, the CAR construct set forth in SEQ ID NO: 384 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., an SFFV promoter, an EF1α promoter, a tEF1a promoter, an hPGK promoter, an SFFV promoter, or an MND promoter).

[0227] 10.CAR Clone 10 An exemplary CAR construct described herein comprises a CLL-1 binding domain scFv comprising SEQ ID NO: 141, a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain.

[0228] In some embodiments, the CAR comprises an amino acid sequence comprising the sequence set forth 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 set forth in SEQ ID NO: 385. [ka]

[0229] In some embodiments, the CAR construct set forth in SEQ ID NO: 385 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., an SFFV promoter, an EF1α promoter, a tEF1a promoter, an hPGK promoter, an SFFV promoter, or an MND promoter).

[0230] 11.CAR Clone 11 An exemplary CAR construct described herein comprises a CLL-1 binding domain scFv comprising SEQ ID NO: 155, a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain.

[0231] In some embodiments, the CAR comprises an amino acid sequence comprising the sequence set forth 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 set forth in SEQ ID NO: 386. [ka]

[0232] In some embodiments, the CAR construct set forth in SEQ ID NO: 386 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., an SFFV promoter, an EF1α promoter, a tEF1a promoter, an hPGK promoter, an SFFV promoter, or an MND promoter).

[0233] 12.CAR Clone 12 An exemplary CAR construct described herein comprises a CLL-1 binding domain scFv comprising SEQ ID NO: 169, a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain.

[0234] In some embodiments, the CAR comprises an amino acid sequence comprising the sequence set forth 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 set forth in SEQ ID NO: 387. [ka]

[0235] In some embodiments, the CAR construct set forth in SEQ ID NO: 387 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., an SFFV promoter, an EF1α promoter, a tEF1a promoter, an hPGK promoter, an SFFV promoter, or an MND promoter).

[0236] 13.CAR Clone 13 An exemplary CAR construct described herein comprises a CLL-1 binding domain VHH comprising SEQ ID NO: 174, a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain.

[0237] In some embodiments, the CAR comprises an amino acid sequence comprising the sequence set forth 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 set forth in SEQ ID NO: 388. [ka]

[0238] In some embodiments, the CAR construct set forth in SEQ ID NO: 388 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., an SFFV promoter, an EF1α promoter, a tEF1a promoter, an hPGK promoter, an SFFV promoter, or an MND promoter).

[0239] 14. CAR Clone 14 An exemplary CAR construct described herein comprises a CLL-1 binding domain VHH comprising SEQ ID NO: 179, a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain.

[0240] In some embodiments, the CAR comprises an amino acid sequence comprising the sequence set forth 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 set forth in SEQ ID NO: 389. [ka]

[0241] In some embodiments, the CAR construct set forth in SEQ ID NO: 389 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., an SFFV promoter, an EF1α promoter, a tEF1a promoter, an hPGK promoter, an SFFV promoter, or an MND promoter).

[0242] 15.CAR Clone 15 An exemplary CAR construct described herein comprises a CLL-1 binding domain VHH comprising SEQ ID NO: 184, a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain.

[0243] In some embodiments, the CAR comprises an amino acid sequence comprising the sequence set forth 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 set forth in SEQ ID NO: 390. [ka]

[0244] In some embodiments, the CAR construct set forth in SEQ ID NO: 390 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., an SFFV promoter, an EF1α promoter, a tEF1a promoter, an hPGK promoter, an SFFV promoter, or an MND promoter).

[0245] 16.CAR Clone 16 An exemplary CAR construct described herein comprises a CLL-1 binding domain VHH comprising SEQ ID NO: 189, a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain.

[0246] In some embodiments, the CAR comprises an amino acid sequence comprising the sequence set forth 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 set forth in SEQ ID NO: 391. [ka]

[0247] In some embodiments, the CAR construct set forth in SEQ ID NO: 391 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., an SFFV promoter, an EF1α promoter, a tEF1a promoter, an hPGK promoter, an SFFV promoter, or an MND promoter).

[0248] 17.CAR Clone 17 An exemplary CAR construct described herein comprises a CLL-1 binding domain VHH comprising SEQ ID NO: 194, a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain.

[0249] In some embodiments, the CAR comprises an amino acid sequence comprising the sequence set forth 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 set forth in SEQ ID NO: 392. [ka]

[0250] In some embodiments, the CAR construct set forth in SEQ ID NO: 392 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., an SFFV promoter, an EF1α promoter, a tEF1a promoter, an hPGK promoter, an SFFV promoter, or an MND promoter).

[0251] 18.CAR Clone 18 An exemplary CAR construct described herein comprises a CLL-1 binding domain VHH comprising SEQ ID NO: 199, a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain.

[0252] In some embodiments, the CAR comprises an amino acid sequence comprising the sequence set forth 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 set forth in SEQ ID NO: 393. [ka]

[0253] In some embodiments, the CAR construct set forth in SEQ ID NO: 393 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., an SFFV promoter, an EF1α promoter, a tEF1a promoter, an hPGK promoter, an SFFV promoter, or an MND promoter).

[0254] 19. CAR Clone 19 An exemplary CAR construct described herein comprises a CLL-1 binding domain VHH comprising SEQ ID NO: 204, a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain.

[0255] In some embodiments, the CAR comprises an amino acid sequence comprising the sequence set forth 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 set forth in SEQ ID NO: 394. [ka]

[0256] In some embodiments, the CAR construct set forth in SEQ ID NO: 394 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., an SFFV promoter, an EF1α promoter, a tEF1a promoter, an hPGK promoter, an SFFV promoter, or an MND promoter).

[0257] 20.CAR Clone 20 An exemplary CAR construct described herein comprises a CLL-1 binding domain VHH comprising SEQ ID NO: 209, a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain.

[0258] In some embodiments, the CAR comprises an amino acid sequence comprising the sequence set forth 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 set forth in SEQ ID NO: 395. [ka]

[0259] In some embodiments, the CAR construct set forth in SEQ ID NO: 395 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., an SFFV promoter, an EF1α promoter, a tEF1a promoter, an hPGK promoter, an SFFV promoter, or an MND promoter).

[0260] 21. CAR Clone 21 An exemplary CAR construct described herein comprises a CLL-1 binding domain VHH comprising SEQ ID NO: 214, a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain.

[0261] In some embodiments, the CAR comprises an amino acid sequence comprising the sequence set forth 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 set forth in SEQ ID NO: 396. [ka]

[0262] In some embodiments, the CAR construct set forth in SEQ ID NO: 396 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., an SFFV promoter, an EF1α promoter, a tEF1a promoter, an hPGK promoter, an SFFV promoter, or an MND promoter).

[0263] 22.CAR Clone 22 An exemplary CAR construct described herein comprises a CLL-1 binding domain VHH comprising SEQ ID NO: 219, a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain.

[0264] In some embodiments, the CAR comprises an amino acid sequence comprising the sequence set forth 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 set forth in SEQ ID NO: 397. [ka]

[0265] In some embodiments, the CAR construct set forth in SEQ ID NO: 397 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., an SFFV promoter, an EF1α promoter, a tEF1a promoter, an hPGK promoter, an SFFV promoter, or an MND promoter).

[0266] 23.CAR Clone 23 An exemplary CAR construct described herein comprises a CLL-1 binding domain VHH comprising SEQ ID NO: 224, a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain.

[0267] In some embodiments, the CAR comprises an amino acid sequence comprising the sequence set forth 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 set forth in SEQ ID NO: 398. [ka]

[0268] In some embodiments, the CAR construct set forth in SEQ ID NO: 398 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., an SFFV promoter, an EF1α promoter, a tEF1a promoter, an hPGK promoter, an SFFV promoter, or an MND promoter).

[0269] 24.CAR Clone 24 An exemplary CAR construct described herein comprises a CLL-1 binding domain VHH comprising SEQ ID NO: 229, a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain.

[0270] In some embodiments, the CAR comprises an amino acid sequence comprising the sequence set forth 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 set forth in SEQ ID NO: 399. [ka]

[0271] In some embodiments, the CAR construct set forth in SEQ ID NO: 399 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., an SFFV promoter, an EF1α promoter, a tEF1a promoter, an hPGK promoter, an SFFV promoter, or an MND promoter).

[0272] 25.CAR Clone 25 An exemplary CAR construct described herein comprises a CLL-1 binding domain VHH comprising SEQ ID NO: 234, a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain.

[0273] In some embodiments, the CAR comprises an amino acid sequence comprising the sequence set forth 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 set forth in SEQ ID NO:400. [ka]

[0274] In some embodiments, the CAR construct set forth in SEQ ID NO: 400 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., an SFFV promoter, an EF1α promoter, a tEF1a promoter, an hPGK promoter, an SFFV promoter, or an MND promoter).

[0275] 26. CAR Clone 26 An exemplary CAR construct described herein comprises a CLL-1 binding domain VHH comprising SEQ ID NO: 239, a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain.

[0276] In some embodiments, the CAR comprises an amino acid sequence comprising the sequence set forth 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 set forth in SEQ ID NO:401. [ka]

[0277] In some embodiments, the CAR construct set forth in SEQ ID NO: 401 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., an SFFV promoter, an EF1α promoter, a tEF1a promoter, an hPGK promoter, an SFFV promoter, or an MND promoter).

[0278] 27. CAR Clone 27 An exemplary CAR construct described herein comprises a CLL-1 binding domain VHH comprising SEQ ID NO: 244, a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain.

[0279] In some embodiments, the CAR comprises an amino acid sequence comprising the sequence set forth 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 set forth in SEQ ID NO:402. [ka]

[0280] In some embodiments, the CAR construct set forth in SEQ ID NO: 402 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., an SFFV promoter, an EF1α promoter, a tEF1a promoter, an hPGK promoter, an SFFV promoter, or an MND promoter).

[0281] 28. CAR Clone 28 An exemplary CAR construct described herein comprises a CLL-1 binding domain VHH comprising SEQ ID NO: 249, a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain.

[0282] In some embodiments, the CAR comprises an amino acid sequence comprising the sequence set forth 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 set forth in SEQ ID NO:403. [ka]

[0283] In some embodiments, the CAR construct set forth in SEQ ID NO: 403 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., an SFFV promoter, an EF1α promoter, a tEF1a promoter, an hPGK promoter, an SFFV promoter, or an MND promoter).

[0284] 29. CAR Clone 29 An exemplary CAR construct described herein comprises a CLL-1 binding domain VHH comprising SEQ ID NO: 254, a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain.

[0285] In some embodiments, the CAR comprises an amino acid sequence comprising the sequence set forth 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 set forth in SEQ ID NO:404. [ka]

[0286] In some embodiments, the CAR construct set forth in SEQ ID NO: 404 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., an SFFV promoter, an EF1α promoter, a tEF1a promoter, an hPGK promoter, an SFFV promoter, or an MND promoter).

[0287] 30.CAR Clone 30 An exemplary CAR construct described herein comprises a CLL-1 binding domain VHH comprising SEQ ID NO: 259, a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain.

[0288] In some embodiments, the CAR comprises an amino acid sequence comprising the sequence set forth 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 set forth in SEQ ID NO:405. [ka]

[0289] In some embodiments, the CAR construct set forth in SEQ ID NO: 405 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., an SFFV promoter, an EF1α promoter, a tEF1a promoter, an hPGK promoter, an SFFV promoter, or an MND promoter).

[0290] 31. CAR Clone 31 An exemplary CAR construct described herein comprises a CLL-1 binding domain VHH comprising SEQ ID NO: 264, a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain.

[0291] In some embodiments, the CAR comprises an amino acid sequence comprising the sequence set forth 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 set forth in SEQ ID NO:406. [ka]

[0292] In some embodiments, the CAR construct set forth in SEQ ID NO: 406 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., an SFFV promoter, an EF1α promoter, a tEF1a promoter, an hPGK promoter, an SFFV promoter, or an MND promoter).

[0293] 32.CAR Clone 32 An exemplary CAR construct described herein comprises a CLL-1 binding domain VHH comprising SEQ ID NO: 269, a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain.

[0294] In some embodiments, the CAR comprises an amino acid sequence comprising the sequence set forth 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 set forth in SEQ ID NO:407. [ka]

[0295] In some embodiments, the CAR construct set forth in SEQ ID NO: 407 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., an SFFV promoter, an EF1α promoter, a tEF1a promoter, an hPGK promoter, an SFFV promoter, or an MND promoter).

[0296] 33. CAR Clone 33 An exemplary CAR construct described herein comprises a CLL-1 binding domain VHH comprising SEQ ID NO: 275, a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain.

[0297] In some embodiments, the CAR comprises an amino acid sequence comprising the sequence set forth 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 set forth in SEQ ID NO:408. [ka]

[0298] In some embodiments, the CAR construct set forth in SEQ ID NO: 408 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., an SFFV promoter, an EF1α promoter, a tEF1a promoter, an hPGK promoter, an SFFV promoter, or an MND promoter).

[0299] 34. CAR Clone 34 An exemplary CAR construct described herein comprises a CLL-1 binding domain VHH comprising SEQ ID NO: 280, a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain.

[0300] In some embodiments, the CAR comprises an amino acid sequence comprising the sequence set forth 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 set forth in SEQ ID NO:409. [ka]

[0301] In some embodiments, the CAR construct set forth in SEQ ID NO: 409 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., an SFFV promoter, an EF1α promoter, a tEF1a promoter, an hPGK promoter, an SFFV promoter, or an MND promoter).

[0302] 35.CAR Clone 35 An exemplary CAR construct described herein comprises a CLL-1 binding domain VHH comprising SEQ ID NO: 285, a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain.

[0303] In some embodiments, the CAR comprises an amino acid sequence comprising the sequence set forth 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 set forth in SEQ ID NO:410. [ka]

[0304] In some embodiments, the CAR construct set forth in SEQ ID NO: 410 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., an SFFV promoter, an EF1α promoter, a tEF1a promoter, an hPGK promoter, an SFFV promoter, or an MND promoter).

[0305] 36. CAR Clone 36 An exemplary CAR construct described herein comprises a CLL-1 binding domain VHH comprising SEQ ID NO: 290, a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain.

[0306] In some embodiments, the CAR comprises an amino acid sequence comprising the sequence set forth 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 set forth in SEQ ID NO:411. [ka]

[0307] In some embodiments, the CAR construct set forth in SEQ ID NO: 411 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., an SFFV promoter, an EF1α promoter, a tEF1a promoter, an hPGK promoter, an SFFV promoter, or an MND promoter).

[0308] 37. CAR Clone 37 An exemplary CAR construct described herein comprises a CLL-1 binding domain VHH comprising SEQ ID NO: 295, a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain.

[0309] In some embodiments, the CAR comprises an amino acid sequence comprising the sequence set forth 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 set forth in SEQ ID NO:412. [ka]

[0310] In some embodiments, the CAR construct set forth in SEQ ID NO: 412 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., an SFFV promoter, an EF1α promoter, a tEF1a promoter, an hPGK promoter, an SFFV promoter, or an MND promoter).

[0311] 38. CAR Clone 38 An exemplary CAR construct described herein comprises a CLL-1 binding domain scFv comprising SEQ ID NO: 309, a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain.

[0312] In some embodiments, the CAR comprises an amino acid sequence comprising the sequence set forth 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 set forth in SEQ ID NO:413. [ka]

[0313] In some embodiments, the CAR construct set forth in SEQ ID NO: 413 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., an SFFV promoter, an EF1α promoter, a tEF1a promoter, an hPGK promoter, an SFFV promoter, or an MND promoter).

[0314] 39. CAR Clone 39 An exemplary CAR construct described herein comprises a CLL-1 binding domain scFv comprising SEQ ID NO: 323, a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain.

[0315] In some embodiments, the CAR comprises an amino acid sequence comprising the sequence set forth 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 set forth in SEQ ID NO:414. [ka]

[0316] In some embodiments, the CAR construct set forth in SEQ ID NO: 414 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., an SFFV promoter, an EF1α promoter, a tEF1a promoter, an hPGK promoter, an SFFV promoter, or an MND promoter).

[0317] 40. CAR Clone 40 An exemplary CAR construct described herein comprises a CLL-1 binding domain scFv comprising SEQ ID NO: 337, a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain.

[0318] In some embodiments, the CAR comprises an amino acid sequence comprising the sequence set forth 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 set forth in SEQ ID NO:415. [ka]

[0319] In some embodiments, the CAR construct set forth in SEQ ID NO: 415 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., an SFFV promoter, an EF1α promoter, a tEF1a promoter, an hPGK promoter, an SFFV promoter, or an MND promoter).

[0320] 41. CAR Clone 41 An exemplary CAR construct described herein comprises a CLL-1 binding domain scFv comprising SEQ ID NO: 351, a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain.

[0321] In some embodiments, the CAR comprises an amino acid sequence comprising the sequence set forth 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 set forth in SEQ ID NO:416. [ka]

[0322] In some embodiments, the CAR construct set forth in SEQ ID NO: 416 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., an SFFV promoter, an EF1α promoter, a tEF1a promoter, an hPGK promoter, an SFFV promoter, or an MND promoter).

[0323] 42. CAR Clone 42 An exemplary CAR construct described herein comprises a CLL-1 binding domain scFv comprising SEQ ID NO: 365, a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain.

[0324] In some embodiments, the CAR comprises an amino acid sequence comprising the sequence set forth 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 set forth in SEQ ID NO:417. [ka]

[0325] In some embodiments, the CAR construct set forth in SEQ ID NO: 417 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., an SFFV promoter, an EF1α promoter, a tEF1a promoter, an hPGK promoter, an SFFV promoter, or an MND promoter).

[0326] 43.CAR clone 103.28z (control) An exemplary CAR construct described herein comprises a CLL-1 binding domain scFv comprising SEQ ID NO: 922, a CD28 transmembrane domain, a CD28 hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain.

[0327] In some embodiments, the CAR comprises an amino acid sequence comprising the sequence set forth 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 set forth in SEQ ID NO:922. [ka]

[0328] In some embodiments, the CAR construct set forth in SEQ ID NO: 922 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., an SFFV promoter, an EF1α promoter, a tEF1a promoter, an hPGK promoter, an SFFV promoter, or an MND promoter).

[0329] 44.CAR clone 103.bbz (control) An exemplary CAR construct described herein comprises a CLL-1 binding domain scFv comprising SEQ ID NO: 923, a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain.

[0330] In some embodiments, the CAR comprises an amino acid sequence comprising the sequence set forth 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 set forth in SEQ ID NO:923.

[0331] [ka]

[0332] In some embodiments, the CAR construct set forth in SEQ ID NO: 923 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., an SFFV promoter, an EF1α promoter, a tEF1a promoter, an hPGK promoter, an SFFV promoter, or an MND promoter).

[0333] 45.CAR clone h104 An exemplary CAR construct described herein comprises a CLL-1 binding domain scFv comprising SEQ ID NO: 924, a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain.

[0334] In some embodiments, the CAR comprises an amino acid sequence comprising the sequence set forth 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 set forth in SEQ ID NO:924. [ka]

[0335] In some embodiments, the CAR construct set forth in SEQ ID NO: 924 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., an SFFV promoter, an EF1α promoter, a tEF1a promoter, an hPGK promoter, an SFFV promoter, or an MND promoter).

[0336] 46.CAR clone m104 An exemplary CAR construct described herein comprises a CLL-1 binding domain scFv comprising SEQ ID NO: 925, a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain.

[0337] In some embodiments, the CAR comprises an amino acid sequence comprising the sequence set forth 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 set forth in SEQ ID NO:925. [ka]

[0338] In some embodiments, the CAR construct set forth in SEQ ID NO: 925 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., an SFFV promoter, an EF1α promoter, a tEF1a promoter, an hPGK promoter, an SFFV promoter, or an MND promoter).

[0339] 47.CAR Clone 108 An exemplary CAR construct described herein comprises a CLL-1 binding domain scFv comprising SEQ ID NO: 926, a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain.

[0340] In some embodiments, the CAR comprises an amino acid sequence comprising the sequence set forth 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 set forth in SEQ ID NO:926. [ka]

[0341] In some embodiments, the CAR construct set forth in SEQ ID NO: 926 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., an SFFV promoter, an EF1α promoter, a tEF1a promoter, an hPGK promoter, an SFFV promoter, or an MND promoter).

[0342] 48.CAR Clone 109 An exemplary CAR construct described herein comprises a CLL-1 binding domain scFv comprising SEQ ID NO: 927, a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain.

[0343] In some embodiments, the CAR comprises an amino acid sequence comprising the sequence set forth 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 set forth in SEQ ID NO:927. [ka]

[0344] In some embodiments, the CAR construct set forth in SEQ ID NO: 927 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., an SFFV promoter, an EF1α promoter, a tEF1a promoter, an hPGK promoter, an SFFV promoter, or an MND promoter).

[0345] 49.CAR Clone 110 An exemplary CAR construct described herein comprises a CLL-1 binding domain scFv comprising SEQ ID NO: 928, a CD8α transmembrane domain, a CD8α hinge domain, a CD137 (4-1BB) costimulatory domain, and a CD3ζ intracellular signaling domain.

[0346] In some embodiments, the CAR comprises an amino acid sequence comprising the sequence set forth 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 set forth in SEQ ID NO:928. [ka]

[0347] In some embodiments, the CAR construct set forth in SEQ ID NO: 928 is encoded in a recombinant expression vector. In some embodiments, the recombinant expression vector comprises a promoter (e.g., an SFFV promoter, an EF1α promoter, a tEF1a promoter, an hPGK promoter, an SFFV promoter, or an MND promoter).

[0348] Any of the fusion proteins, such as any of the CARs 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 (i.e., a T lymphocyte) or an NK cell. The T cell lymphocyte can be any T cell, such as a cultured T cell, for example, a primary T cell, or a T cell from a cultured T cell line, such as TIB-153™, Jurkat, SupT1, or a T cell (e.g., a primary T cell) obtained from a mammal.

[0349] Nucleotide sequence and expression 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 may be present in a vector, such as an expression vector. In various cases, such nucleotides may be present in the genome of a cell, such as a cell of a subject in need of treatment, or a cell for the production of an antibody, e.g., a mammalian cell for the production of an antibody.

[0350] In some embodiments, any of the antibodies described herein is encoded by a polynucleotide contained in a vector, e.g., a viral vector. Optionally, a polynucleotide encoding a polypeptide 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, expression of the polypeptide can be driven by a constitutively expressed promoter or an inducibly expressed promoter. In some embodiments, the antibodies described herein comprise a signal peptide. The signal peptide can be derived from any protein that has an extracellular domain or is secreted. The antibodies described herein can comprise any signal peptide known in the art.

[0351] Retroviruses, such as lentiviruses, provide a convenient platform for delivering nucleic acid sequences encoding genes or chimeric genes of interest. A selected nucleic acid sequence can be inserted into a vector and packaged into retroviral particles using techniques known in the art. 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, for example, in U.S. Pat. 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, which are incorporated herein by reference in their entireties. In some embodiments, the antibodies described herein are expressed in mammalian cells via transfection or electroporation of an expression vector containing a nucleic acid encoding the antibody. Transfection or electroporation methods are known in the art.

[0352] In another aspect, the present disclosure relates to a cell, e.g., a mammalian cell, comprising any of the antibodies described herein or a nucleic acid encoding any of the antibodies described herein. In one embodiment, the cell comprises an antibody described herein or a nucleic acid encoding such an antibody described herein. The cell or tissue, e.g., a mammalian cell or tissue, can be from a human, primate, hamster, rabbit, rodent, cow, pig, sheep, horse, goat, dog, or cat. In some embodiments, any other mammalian cell can be used. In some embodiments, the mammalian cell is human.

[0353] Efficient expression of the antibodies described herein can be assessed using standard assays that detect mRNA, DNA, or gene products of nucleic acids encoding the antibodies, such as RT-PCR, FACS, Northern blotting, Western blotting, ELISA, or immunohistochemistry, etc. In some embodiments, the antibodies described herein are encoded by recombinant nucleic acid sequences.

[0354] CLL-1-related diseases and / or disorders The present disclosure provides, inter alia, compositions and methods for treating diseases associated with expression of CLL-1 or conditions associated with cells expressing CLL-1, including, for example, proliferative diseases such as cancer or malignancies (e.g., hematopoietic malignancies), or precancerous conditions such as myelodysplasia, myelodysplastic syndrome, or preleukemia.

[0355] 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, B, 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.

[0356] In some embodiments, hematopoietic malignancies or blood disorders are associated with CLL-1 expression. Hematopoietic malignancies are described as malignant disorders 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 lymphocytic leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia or chronic lymphoblastic leukemia, and chronic lymphocytic leukemia.

[0357] In some embodiments, cells involved in hematopoietic malignancies are resistant to conventional or standard therapeutic agents used to treat the malignancy. For example, the cells (e.g., cancer cells) may be resistant to chemotherapeutic agents and / or CAR T cells used to treat the malignancy.

[0358] In some embodiments, the leukemia is acute myeloid leukemia (AML). Acute myeloid leukemia (AML) is a cancer of the bone marrow and requires effective treatment. According to the National Cancer Institute, more than 60,000 people in the United States suffer from AML, with fewer than 30% surviving 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+. AML is characterized as a heterogeneous, clonal neoplastic disease originating from transformed cells that gradually acquire significant genetic alterations that disrupt important differentiation and growth control pathways. See, e.g., Dohner et al., NEJM, (2015) 373:1136. Without wishing to be bound by theory, in some embodiments, it is believed that CLL-1 is expressed on myeloid leukemia cells as well as normal myeloid and monocytic precursors, making it a promising target for the treatment of AML.

[0359] In some embodiments, the hematopoietic malignancy or blood disease / disorder associated with CLL-1 is a precancerous condition such as myelodysplasia, myelodysplastic syndrome, or preleukemia. Myelodysplastic syndrome (MDS) is a hematological condition characterized by unregulated and ineffective hematopoiesis or blood production. Thus, the number and quality of blood-forming cells are irreversibly reduced. Some MDS patients develop severe anemia, while others are asymptomatic. Classification schemes for MDS are known in the art, including criteria specifying the proportion or frequency of specific blood cell types, such as myeloblasts, monocytes, and erythrocyte precursors. MDS includes refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess transformed blasts, and chronic myelomonocytic leukemia (CML). In some embodiments, MDS can progress to AML.

[0360] In various cases, antibodies and / or fusion proteins and / or cells expressing any of the foregoing described herein treat, alleviate, reduce the prevalence, reduce the frequency, or reduce the level or amount of one or more symptoms or biomarkers of a CLL-1-associated disorder (e.g., AML, MDS). Specific symptoms and symptom progression vary between subjects. Thus, in some embodiments, an antibody and / or fusion protein described herein is administered to a subject in need thereof, e.g., a subject with a CLL-1-associated disorder (e.g., AML, MDS). In some embodiments, administration of any of the antibodies and / or fusion proteins described herein prevents cancer or hematopoietic malignancies or pre-malignancies, including reducing one or more symptoms and / or delaying disease progression.

[0361] In some cases, a subject may initially respond to a therapy (e.g., for a hematopoietic malignancy) and then experience a relapse. In some embodiments, a subject has had or is prone to relapse of a hematopoietic malignancy (e.g., AML) after administration of one or more prior therapies. In some embodiments, administration of any of the antibodies and / or fusion proteins described herein reduces the subject's risk of relapse or the severity of the relapse.

[0362] In some embodiments, one or more anti-CLL-1 antibodies described herein are used in a method for treating one or more disorders described herein, e.g., one or more diseases or disorders 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 described herein, or an antigen-binding fragment thereof, or a cell expressing any of the foregoing, or an antibody-drug conjugate described herein. In some embodiments, one or more anti-CLL-1 antibodies described herein, including fusion proteins comprising any of the anti-CLL-1 antibodies, are used in a method for treating a disease or disorder associated with CLL-1 expression. In some embodiments, one or more anti-CLL-1 antibodies described herein are used in a method for treating hematologic neoplastic diseases and malignancies associated with CLL-1 expression. In some embodiments, one or more anti-CLL-1 antibodies described herein are used in a method for treating MDS or AML.

[0363] In various cases, administration of the antibodies and / or fusion proteins described herein results in a reduction in the prevalence, frequency, level, and / or amount of one or more symptoms or biomarkers of a CLL-1-associated disorder, e.g., at least a 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 100% reduction in the one or more symptoms or biomarkers compared to a previous measurement or reference value in the subject.

[0364] In some embodiments, the antibodies and / or fusion proteins described herein can be used in a number of diagnostic and / or therapeutic applications. For example, detectably labeled versions of the antibodies described herein can be used in assays 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 in in vitro assays to study 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 useful for inhibiting CLL-1 or treating CLL-1-associated disorders.

[0365] The antibodies and / or fusion proteins described herein can be used, for example, in monitoring a subject who has, is suspected of having, is at risk of developing, or is undergoing treatment for one or more CLL-1-associated disorders. Monitoring can include determining the amount or activity of CLL-1 in the subject, e.g., in the subject's serum. The subject can be evaluated at one or more of the following time periods: before initiating treatment, during treatment, or after one or more components of treatment have been administered. Evaluation can include assessing the need for further treatment, e.g., whether dosage, frequency of administration, or duration of treatment should be changed. Evaluation can also include assessing the need to add or remove selected therapeutic approaches, e.g., adding or removing any of the treatments for CLL-1-associated disorders described herein.

[0366] Measurement of antibody and CLL-1 interactions The binding properties of the antibodies described herein to CLL-1 can be measured by methods known in the art, such as one of the following: BIACORE™ analysis, enzyme-linked immunosorbent assay (ELISA), X-ray crystallography, sequence analysis, and systematic mutagenesis. The binding interaction between an antibody and CLL-1 can be analyzed using surface plasmon resonance (SPR). SPR, or biomolecular interaction analysis (BIA), detects biospecific interactions in real time without labeling the interactants. A change in mass at the binding surface of the BIA chip (indicating a binding event) results in a change in the refractive index of light near the surface. The change in refractive index generates a detectable signal that is measured as an indication of the real-time reaction between biological molecules. 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). Additionally, the KinExA® (Kinetic Exclusion Assay) assay available from Sapidyne Instruments (Boise, Id) can also be used.

[0367] Information from SPR was used to determine the equilibrium dissociation constant (K) for antibody binding to CLL-1. D ), and K on and K. off SPR can provide accurate and quantitative measurements of kinetic parameters, including the binding affinity of a given amino acid. 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 can be identified to correlate with specific binding parameters, such as high affinity.

[0368] In certain embodiments, the antibodies described herein exhibit high affinity for binding to CLL-1. In various embodiments, the K D is 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 -15 In certain instances, the K of the antibodies described herein against CLL-1 is D is 0.001 to 1 nM, for example, 0.001 nM, 0.005 nM, 0.01 nM, 0.05 nM, 0.1 nM, 0.5 nM, or 1 nM.

[0369] In some embodiments, the antibodies described herein bind to a specific epitope of CLL-1, e.g., including one or more specific amino acids of CLL-1. Without intending to be bound by theory, disrupting the availability of specific amino acids of the CLL-1 epitope of the antibodies described herein (e.g., by mutagenesis or by binding with a competing antibody) may reduce or eliminate antibody binding. In therapeutic applications or product manufacturing where interaction of multiple anti-CLL-1 antibodies with CLL-1 is desired, it may be important to select or design anti-CLL-1 antibodies that target non-competing CLL-1 epitopes to prevent them from interfering with each other.

[0370] Combination therapy 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 those situations in which two or more different agents are administered in an overlapping regimen, such that the subject is exposed to both agents simultaneously. When used in combination therapy, the two or more different agents can be administered simultaneously or separately. Combination administration can include simultaneous administration of two or more agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, two or more agents can be formulated together in the same dosage form and administered simultaneously. Alternatively, two or more agents can be administered simultaneously, where the agents are in separate formulations. In another alternative, one or more additional agents can be administered immediately after administering the first agent. In separate administration protocols, two or more agents can be administered minutes apart, hours apart, or days apart.

[0371] As used herein, the term "chemotherapeutic agent" or "oncolytic therapeutic agent" (e.g., anti-cancer agent, e.g., anti-cancer therapy, e.g., immune cell therapy) has its art-understood meaning, referring to one or more pro-apoptotic, cytostatic, and / or cytotoxic, and / or hormonal agents, including, for example, agents utilized and / or recommended in treating one or more diseases, disorders, or conditions associated with unwanted cell proliferation. In some embodiments, the chemotherapeutic agent and / or oncolytic therapeutic agent is selected from the group consisting of platinum compounds (e.g., cisplatin, carboplatin, and oxaliplatin), alkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil, nitrogen mustard, thiotepa, melphalan, busulfan, procarbazine, streptozocin, temozolomide, dacarbazine, and bendamustine), antitumor antibiotics (e.g., daunorubicin, cyclosporine, doxorubicin, idarubicin, epirubicin, mitoxantrone, bleomycin, mitomycin C, plicamycin, and 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, clarithromycin, cyclosporine ... thiazol-3, ... steroids (e.g., prednisone, dexamethasone, and prednisolone), hormones (e.g., tamoxifen, raloxifene, leuprolide, thalidomide, thalidomide), steroids (e.g. ...The anti-inflammatory agent may be or may include a selective cyclooxygenase inhibitor (e.g., nonsteroidal anti-inflammatory drugs, salicylates, aspirin, piroxicam, ibuprofen, indomethacin, naprosyn, diclofenac, tolmetin, ketoprofen, nabumetone, and oxaprozin), a selective cyclooxygenase-2 (COX-2) inhibitor, or any combination thereof.

[0372] In certain embodiments, chemotherapeutic and / or oncolytic therapeutic agents for anti-cancer treatment include biologic agents such as tumor-infiltrating lymphocytes, CAR T cells, antibodies, antigens, therapeutic vaccines (e.g., made from a patient's own tumor cells or other substances such as antigens produced by a particular tumor), immunomodulators (e.g., cytokines, e.g., immunomodulators or biological response modifiers), checkpoint inhibitors, or other immunologic agents. In certain embodiments, immunologic agents include immunoglobulins, immunostimulants (e.g., bacterial vaccines, colony-stimulating factors, interferons, interleukins, therapeutic vaccines, vaccine combinations, viral vaccines), and / or immunosuppressants (e.g., calcineurin inhibitors, interleukin inhibitors, TNF-alpha inhibitors). In certain embodiments, hormonal agents include anti-androgen therapy agents (e.g., ketoconazole, abiraterone, TAK-700, TOK-OOl, bicalutamide, nilutamide, flutamide, enzalutamide, ARN-509).

[0373] Additional chemotherapeutic and / or oncolytic therapeutic agents include immune checkpoint therapy (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 emtansine (KADCYLA®, Roche), gemtuzumab ozogamicin (Wyeth), CMC-544, SAR3419, CDX-011, PSMA-ADC, BT-062, and IMGN901 (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.

[0374] In some embodiments, the combined administration of an anti-CLL-1 antibody or portion thereof (e.g., one or more CDRs described herein) and / or one or more fusion proteins with an additional therapeutic agent results in amelioration of cancer to a greater extent than that produced by either the anti-CLL-1 antibody or the additional therapeutic agent alone. The difference between the combined effect and the effect of each agent alone may be statistically significant. In some embodiments, the combined effect may be synergistic. In some embodiments, the combined administration of an anti-CLL-1 antibody or portion thereof (e.g., one or more CDRs described herein) and / or one or more fusion proteins with an additional therapeutic agent allows for administration of the additional therapeutic agent at a reduced dose, reduced number of doses, and / or reduced frequency of doses compared to a standard dosing regimen, e.g., the approved dosing regimen of the additional therapeutic agent.

[0375] In some embodiments, the therapeutic methods described herein are administered to subjects who have failed other treatments for a condition or have been treated unsuccessfully by other means. Additionally, the therapeutic methods described herein can be administered in conjunction with one or more additional treatments for a condition. For example, the method can include administering a cancer regimen, e.g., non-myeloablative chemotherapy, surgery, hormone therapy, and / or radiation, prior to, substantially simultaneously with, or following administration of an anti-CLL-1 antibody or portion thereof (e.g., one or more CDRs described herein) and / or one or more fusion proteins described herein, or compositions thereof.

[0376] Aspects of the present disclosure include the administration of hematopoietic cells genetically modified to reduce or eliminate expression of CLL-1 in the context of treating a subject in need of such hematopoietic stem cells, which may include, for example, a subject with a hematologic malignancy, e.g., AML, or a precancerous condition, e.g., MDS, and receiving a CLL-1-targeted immunotherapy regimen, e.g., a CLL-1-antibody-drug conjugate or a CLL-1 CAR-T or CAR-NK therapy. Such a therapeutic regimen may involve, for example, (1) administering a therapeutically effective amount of any of the anti-CLL-1 antibodies, CLL-1-binding fragments thereof, including, for example, a fusion protein such as a CAR, and cells expressing any of the foregoing, e.g., CAR-T or CAR-NK cells, as described herein or apparent to one of skill in the art based on this disclosure, and (2) administering (e.g., infusing or reinfusing) to the patient autologous or allogeneic hematopoietic stem cells in which the hematopoietic cells have reduced or eliminated expression of CLL-1. In some embodiments, hematopoietic cells are genetically modified to reduce 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, CLL-1-binding fragment thereof, or portion thereof (e.g., one or more CDRs described herein), and / or one or more fusion proteins described herein.

[0377] Formulation and Administration In various embodiments, any of the antibodies or portions thereof (e.g., one or more CDRs described herein), and / or one or more fusion proteins described herein may be incorporated into pharmaceutical compositions. Such pharmaceutical compositions may be useful, for example, for the prevention and / or treatment of diseases, e.g., cancers such as AML, MDS, etc. Pharmaceutical compositions may be formulated by methods known to those skilled in the art, such as those described in Remington's Pharmaceutical Sciences, 17th edition, ed. Alfonso R. Gennaro, Mack Publishing Company, Easton, Pa. (1985).

[0378] In some embodiments, the pharmaceutical composition may be formulated to include a pharmaceutically acceptable carrier or excipient. Examples of pharmaceutically acceptable carriers include, but are not limited to, any and all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. The compositions of the present invention may include pharmaceutically acceptable salts, such as acid addition salts or base addition salts.

[0379] In some embodiments, compositions comprising the antibodies described herein, e.g., sterile injectable preparations, can be formulated according to conventional pharmaceutical practice using distilled water for injection as a vehicle. For example, isotonic solutions containing saline or glucose, other D-sorbitol, D-mannose, D-mannitol, sodium chloride, etc., can be used as injectable aqueous solutions, optionally in combination with suitable solubilizing agents, e.g., alcohols such as ethanol and / or polyhydric alcohols such as propylene glycol or polyethylene glycol, and / or non-ionic surfactants such as Polysorbate 80™ or HCO-50.

[0380] As disclosed herein, pharmaceutical compositions can be in any form known in the art, including, for example, liquid, semi-solid, and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes, and suppositories.

[0381] The selection or use of any particular form may depend, in part, on the intended mode of administration and therapeutic application. For example, compositions containing compositions intended for systemic or local delivery may be in the form of an injectable or infusible solution. Thus, compositions may be formulated for administration by parenteral modes (e.g., intravenous, subcutaneous, intraperitoneal, or intramuscular injection). As used herein, parenteral administration refers to modes of administration other than enteral and topical administration, usually by injection, and includes, but is not limited to, intravenous, intranasal, intraocular, pulmonary, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intrapulmonary, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, intracranial, intracranial, carotid, and intrasternal injections and infusions.

[0382] The route of administration can be parenteral, e.g., by injection, intranasal, pulmonary, or transdermal. Administration can be systemic or local, by intravenous, intramuscular, intraperitoneal, or subcutaneous injection.

[0383] In some embodiments, the pharmaceutical compositions of the present invention can be formulated as solutions, microemulsions, dispersions, liposomes, or other ordered structures suitable for stable storage at high concentrations. Sterile injectable solutions can be prepared by incorporating the compositions described herein in the required amount in an appropriate solvent containing one or a combination of the ingredients listed above, as needed, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the compositions described herein into a sterile vehicle containing a basic dispersion medium and the required other ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, methods for preparation include vacuum drying and freeze-drying, whereby a powder of the compositions described herein plus any additional desired ingredients (see below) is obtained from a previously sterile-filtered solution. The proper fluidity of the solution can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. Prolonged absorption of the injectable composition can be achieved by including an agent that delays absorption, such as monostearate salts and gelatin, in the composition.

[0384] Pharmaceutical compositions can be administered parenterally in the form of injectable formulations, including sterile solutions or suspensions in water or another pharmaceutically acceptable liquid. For example, pharmaceutical compositions can be formulated by appropriately combining a therapeutic molecule with a pharmaceutically acceptable vehicle or medium, such as sterile water and saline, vegetable oils, emulsifiers, suspending agents, surfactants, stabilizers, flavoring agents, diluents, excipients, preservatives, and binders, and then mixing in a unit dosage form required in accordance with generally accepted pharmaceutical practice. The amount of active ingredient contained in the pharmaceutical formulation is such that a suitable dosage within the specified range is provided. Non-limiting examples of oily liquids include sesame oil and soybean oil, which may be combined with benzyl benzoate or benzyl alcohol as a solubilizer. Other items that may be included are buffers such as phosphate buffer or sodium acetate buffer, sedatives such as procaine hydrochloride, stabilizers such as benzyl alcohol or phenol, and antioxidants. The formulated injectable solution can be packaged in a suitable ampule.

[0385] In various embodiments, subcutaneous administration can be achieved by a device such as, for example, a syringe, a prefilled syringe, an auto-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 device for combining an antibody drug for subcutaneous injection.

[0386] The injection system of the present disclosure can use a delivery pen, as described in U.S. Pat. No. 5,308,341. Pen-type devices, most commonly used for self-delivery of insulin to diabetic patients, are well known in the art. Such devices may include at least one injection needle (e.g., a 31-gauge needle approximately 5-8 mm long) and are typically pre-filled with one or more therapeutic unit doses of a therapeutic solution, useful for rapidly delivering the solution to a subject as painlessly as possible. One drug delivery pen includes a vial holder that can receive a vial of a therapeutic agent or other drug. The pen may be a completely mechanical device or may be combined with electronic circuitry to accurately set and / or indicate the dose of medication to be injected to the user. See, e.g., U.S. Pat. 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 delivery of any one of the presently characterized compositions are described, for example, in U.S. Patent 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, for example, in U.S. Patent No. 7,556,615, the disclosure of which is incorporated herein by reference in its entirety. See also MOLLY™, a precision pen injector (PPI) device manufactured by Scandinavian Health Ltd.

[0387] In some embodiments, the compositions described herein can be therapeutically delivered to a subject by local administration. As used herein, "local administration" or "local delivery" can refer to delivery of a composition or agent that does not rely on transport to its intended target tissue or site via the vascular system. For example, a 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 local administration near the target tissue or site, the composition or agent, or one or more components thereof, can diffuse to the intended target tissue or site that is not the site of administration.

[0388] In some embodiments, the compositions can be formulated for storage at temperatures 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., 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 1½ years, or 2 years). Thus, in some embodiments, the compositions described herein are stable upon storage at 2-8° C. (e.g., 4° C.) for at least 1 year.

[0389] In some embodiments, the pharmaceutical composition may be formulated as a solution, e.g., a buffered solution at a concentration suitable for storage at 2-8°C (e.g., 4°C).

[0390] The composition comprising one or more antibodies described herein can be formulated into an immunoliposome composition. Such formulations can be prepared by methods known in the art. Liposomes with extended circulation time are disclosed, for example, in U.S. Patent No. 5,013,556.

[0391] In certain embodiments, the compositions can be formulated with carriers that will protect the compound against rapid release, such as controlled-release formulations, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for preparing such formulations are known in the art. See, for example, JR Robinson (1978) "Sustained and Controlled Release Drug Delivery Systems," Marcel Dekker, Inc., New York.

[0392] In some embodiments, administration of an antibody described herein is achieved by administering to a subject a nucleic acid encoding the antibody. Nucleic acids encoding the therapeutic antibodies described herein can be incorporated into genetic constructs used as part of gene therapy protocols to deliver nucleic acids that can be used to express and produce the antibody intracellularly. Such component expression constructs can be administered in any therapeutically effective carrier, such as any formulation or composition capable of effectively delivering the component genes to cells in vivo. Approaches include viral vectors, including recombinant retroviruses, adenoviruses, adeno-associated viruses, lentiviruses, and herpes simplex virus-1 (HSV-1), or insertion of the gene of interest into recombinant bacterial or eukaryotic plasmids. Viral vectors can directly transfect cells, and plasmid DNA can be delivered with the aid of, for example, cationic liposomes (lipofectin) or derivatized polylysine conjugates, gramicidin S, artificial viral envelopes, or other such intracellular carriers, as well as direct injection of the genetic construct or CaPO precipitates (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, for example, 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. 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. Patent Nos. 4,868,116 and 4,980,286; and PCT Publication Nos. 89 / 07136, 89 / 02468, 89 / 05345, and 92 / 07573. Another viral gene delivery system utilizes 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 the adenovirus strain Ad type 5 dl324 or other strains of adenovirus (e.g., Ad2, Ad3, Ad7, etc.) are known to those skilled in the art. Yet another viral vector system useful for delivery of a gene of interest is the 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.

[0393] In some embodiments, the compositions provided herein are in unit dosage form, and the unit dosage form may be suitable for self-administration.Such unit dosage form may be provided in a container, typically a vial, a cartridge, a pre-filled syringe, or a disposable pen.For example, an administration device such as the administration device described in U.S. Patent No. 6,302,855 may also be used with the injection system described herein.

[0394] The appropriate dose of the compositions described herein, which can treat or prevent a disorder in a subject, can depend on various factors, including, for example, the age, sex, and weight of the subject being treated, as well as the particular inhibitory compound used. For example, different doses of one 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, may be required to treat a subject with cancer (e.g., AML) compared with doses of different formulations of the antibody. Other factors that influence the dose administered to a subject include, for example, the type or severity of the disorder. Other factors include, for example, other medical disorders concurrently or previously affecting the subject, the subject's general health, the subject's genetic predisposition, diet, duration of administration, excretion rate, drug combinations, and other additional therapies administered to the subject. It should also be understood that the specific dose and treatment regimen for any particular subject can be adjusted based on the judgment of the treating physician.

[0395] The pharmaceutical solution may contain a therapeutically effective amount of a composition described herein. Such an effective amount can be readily determined by one of skill in the art based, in part, on the efficacy of the administered composition or, if more than one agent is used, the combined efficacy of the composition and one or more additional active agents. A therapeutically effective amount of a composition described herein may also vary depending on factors such as the individual's disease state, age, sex, and weight, as well as the ability of the composition (and one or more additional active agents) to elicit a desired response in the individual, e.g., improvement in at least one condition parameter, e.g., improvement in at least one symptom of cancer (e.g., AML). For example, a therapeutically effective amount of a composition described herein may inhibit (reduce the severity or eliminate the occurrence of) and / or prevent a particular disorder and / or any one of the symptoms of a particular disorder known in the art or described herein. A therapeutically effective amount is also one in which any toxic or detrimental effects of the composition are outweighed by the therapeutically beneficial effects.

[0396] Suitable human doses of any of the compositions described herein can be further evaluated, for example, in a Phase I dose-escalation study. See, e.g., van Gurp et al. Am J Transplantation (2008) 8(8):1711-1718, Hanouska et al. Clin Cancer Res (2007) 13(2, part 1):523-531, and Hetherington et al. Antimicrobial Agents and Chemotherapy (2006) 50(10):3499-3500.

[0397] Toxicity and therapeutic efficacy of the compositions can be determined by known pharmaceutical procedures in cell culture or experimental animals (e.g., animal models of any of the cancers described herein). These procedures can be performed, for example, using LD 50 (lethal dose for 50% of the population) and ED 50 It can be used to determine the dose that is therapeutically effective in 50% of the population. The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD 50 / ED 50 The therapeutic index can be expressed as a ratio. Compositions described herein that exhibit high therapeutic indices are preferred. Compositions that exhibit toxic side effects may be used, but care must be taken to design a delivery system that targets such compounds to the site of the affected tissue, minimizing potential damage to normal cells, thereby reducing side effects. Those skilled in the art will appreciate that the data obtained from cell culture assays and animal studies can be used to formulate a range of dosages for use in humans. Appropriate dosages of the compositions described herein generally provide an ED 50 The circulating concentration of the composition is within a range comprising: (a) a therapeutically effective dose of 100 mg / kg of erythropoietin (E2) or 100 mg / kg of erythropoietin (E1) or ... 50 The antibody may be formulated in animal models to achieve a circulating plasma concentration range that includes the antibody's circulating concentration (i.e., the concentration of antibody that achieves a half-maximal inhibition of symptoms). Such information can be used to more accurately determine useful doses in humans. Levels in plasma can be measured, for example, by high performance liquid chromatography. In some embodiments, for example, when local administration (e.g., to the eye or joint) is desired, cell culture or animal modeling can be used to determine the dose necessary to achieve a therapeutically effective concentration in the local site.

[0398] CAR and CAR-T cell characterization assays In various embodiments, one or more CAR characterization assays are used to assess the activity of a CAR comprising any of the anti-CLL-1 antibodies described herein and the activation of cells (e.g., T cells) expressing the CAR.

[0399] Several suitable CAR characterization assays are provided herein. Exemplary CAR characterization assays include cytotoxicity assays (e.g., chromium ( 51These assays include, but are not limited to, Cr) release assays, luciferase-mediated bioluminescence i...

Claims

1. An anti-CLL-1 antibody or its antigen-binding fragment containing the amino acid sequence represented by SEQ ID NO:

15.

2. A chimeric antigen receptor (CAR) comprising the anti-CLL-1 antibody or its antigen-binding fragment as described in claim 1.

3. The CAR according to claim 2, wherein the transmembrane domain comprises a transmembrane domain of a protein selected from CD8α or CD28, and the intracellular signaling domain comprises a signaling domain of CD3ζ.

4. The CAR according to claim 3, wherein an anti-CLL-1 antibody or its antigen-binding fragment is connected to a transmembrane domain by a hinge region.

5. The CAR according to claim 4, wherein the hinge region comprises a hinge region of a protein selected from CD8α, IgG4, or CD28.

6. The CAR according to claim 3, further comprising one or more co-stimulatory domains, the one or more co-stimulatory domains comprising a signaling domain of 4-1BB and / or CD28.

7. A nucleic acid comprising the antibody or antigen-binding fragment thereof as described in claim 1, and a nucleic acid sequence encoding the CAR as described in claim 2.

8. An expression vector comprising the nucleic acid molecule described in claim 7.

9. A cell that expresses the CAR described in claim 2, or a cell comprising the nucleic acid described in claim 7 or the expression vector described in claim 8.

10. The cell according to claim 9, wherein the cell is an immune effector cell.

11. The cell according to claim 9, wherein the cell is a lymphocyte.

12. The cell according to claim 9, wherein the cell is a T cell or a natural killer (NK) cell.

13. A pharmaceutical composition comprising at least one of the antibodies described in claim 1 or the CARs described in claim 2, and a pharmaceutically acceptable excipient.

14. A pharmaceutical composition according to claim 13 for use as a medicine.

15. The pharmaceutical composition according to claim 14 for use in the treatment of cancer.

16. A pharmaceutical composition comprising the cells described in claim 9 and a pharmaceutically acceptable excipient.

17. A pharmaceutical composition according to claim 16 for use as a medicine.

18. The pharmaceutical composition according to claim 17 for use in the treatment of cancer.