Il13-binding polypeptides and uses thereof
Patent Information
- Authority / Receiving Office
- WO · WO
- Patent Type
- Applications
- Current Assignee / Owner
- Filing Date
- 2025-09-02
- Publication Date
- 2026-04-09
AI Technical Summary
Current therapies for IL13-associated skin conditions, such as atopic dermatitis, prurigo nodularis, and chronic spontaneous urticaria, fail to provide fast and prolonged symptom control, and existing treatments like dupilumab, tralokinumab, and lebrikizumab suffer from limitations including target-mediated drug disposition and frequent dosing requirements.
Development of high-affinity biparatopic polypeptides that bind to IL13, comprising specific CDR sequences, offering rapid itch relief, extended half-life, and reduced injection frequency, thereby addressing the limitations of existing treatments.
The polypeptides provide effective, prolonged symptom control with less frequent dosing, reduced side effects, and improved safety profiles compared to current therapies.
Abstract
Description
IL13-BINDING POLYPEPTIDES AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. provisional patent application serial number 63 / 690,300, filed September 3, 2024, U.S. provisional patent application serial number 63 / 769,268, filed March 10, 2025, U.S. provisional patent application serial number 63 / 849,614, filed July 23, 2025, U.S. provisional patent application serial number 63 / 850,984, filed July 25, 2025, U.S. provisional patent application serial number 63 / 854,207, filed July 30, 2025, and U.S. provisional patent application serial number 63 / 863,138, filed August 13, 2025, each of which is incorporated herein by reference in its entirety. REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY
[0002] The content of the electronically submitted sequence listing (Name: 5614_004PC06_Sequencelisting_ST26.xml; Size: 658,532 bytes; and Date of Creation: August 27, 2025), filed with the application, is incorporated herein by reference in its entirety. FIELD
[0003] The present disclosure relates to IL13-binding polypeptides, and methods of using IL13-binding polypeptides to modulate the biological activity of IL13. Such methods include, but are not limited to, methods of treating pruritic conditions, atopic dermatitis, prurigo nodularis, and chronic spontaneous urticaria. BACKGROUND
[0004] Interleukin 13 (IL13) is a cytokine produced by T helper type 2 (Th2) cells and has been implicated in the pathophysiology of several skin disorders, such as pruritic conditions, allergic diseases, and other inflammatory conditions. IL13 signals through a shared receptor with IL4 via a heterodimer receptor complex comprising IL4 receptor alpha (IL4Rα) and IL13 receptor alpha 1 (IL13Rα1), and it is implicated as a central regulator in IgE synthesis, mucus hypersecretion, airway hyperresponsiveness (AHR), and fibrosis. Many of the clinical problems associated with dermatitis and other skin disorders are thought to be associated with IL13 activity.
[0005] Chronic inflammatory skin diseases such as atopic dermatitis (AD), prurigo nodularis (PN), and chronic spontaneous urticaria (CSU) lead to intensely pruritic skin lesions resulting in severe scratching. Topical steroids and calcineurin inhibitors are not sufficient to managesymptoms in AD, PN, or CSU patients. Existing therapies include dupilumab (targeting IL4Rα) and tralokinumab and lebrikizumab (both targeting IL13), establishing a new standard of care in AD, CSU, and other inflammatory skin diseases. Overall, however, there remains a strong need for improved therapies for treating IL13-associated conditions, including therapies that have the potential to induce fast and prolonged control of symptoms in patients with chronic inflammatory skin disease. SUMMARY
[0006] Provided herein are high affinity and potent biparatopic polypeptides that bind to the IL13 ligand, thereby having the potential to induce fast and prolonged control of pruritus in patients with chronic inflammatory skin disease.
[0007] The polypeptides disclosed herein provide for multiple advantages and improvements over standard-of-care treatments and / or treatments still in development. Such advantages and improvements include, but are not limited to, greater efficacy against lesions and itches, greater safety (e.g., less conjunctivitis), rapid itch relief (days to weeks), extended half-life, avoidance of target-mediated drug disposition (TMDD), and more convenient and / or less frequent dosing, which leads to reduced injection burden. Such advantages and improvements allow the polypeptides disclosed herein to be used as treatment options for nonresponding and / or relapsed patients who received standard-of-care treatments and / or treatments still in development.
[0008] In some aspects, provided herein are polypeptides that bind IL13. In some aspects, the polypeptide binds IL13 comprises one or more IL13 co-binders. In some aspects, provided herein is a co-binder that binds IL13, comprising a Variable Heavy domain of Heavy chain 1 (VHH1) and a Variable Heavy domain of Heavy chain 2 (VHH2), wherein the VHH1 and / or the VHH2 comprises a CDR3 comprising the amino acid sequence of SEQ ID NO:442 or SEQ ID NO:443 according to IMGT numbering. In some aspects, the CDR3 comprises an amino acid sequence selected from SEQ ID NOs:36, 47, 61, 64, 472-526, 531, 534, 543, 546, 555, 558, 567, 570, 579, 582, 591, 594, 603, 606, 615, 618, 627, 630, 639, and 642.
[0009] In some aspects, the VHH1 comprises a CDR1 comprising the amino acid sequence of SEQ ID NOs:31, 67, 75, 83, 91, 99, 107, 115, 123, 131, 139, 147, 155, 163, 171, 179, 187, 195, 203, 211, 219, 227, 235, 243, 251, 259, 267, 275, 283, 291, 299, 307, 315, 323, 331, 339, 347, 355, 363, 371, 379, 387, 395, 403, 411, 419, 427, or 435 according to Kabat numbering, or comprising the amino acid sequence of SEQ ID NOs:34, 529, 541, 553, 565, 577, 589, 601, 613, 625, or 637 according to IMGT numbering, or comprising the amino acid sequence of SEQ IDNOs:37, 535, 547, 559, 571, 583, 595, 607, 619, 631, or 643 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NOs:32, 68, 76, 84, 92, 100, 108, 116, 124, 132, 140, 148, 156, 164, 172, 180, 188, 196, 204, 212, 220, 228, 236, 244, 252, 260, 268, 276, 284, 292, 300, 308, 316, 324, 332, 340, 348, 356, 364, 372, 380, 388, 396, 404, 412, 420, 428, or 436 according to Kabat numbering, or comprising the amino acid sequence of SEQ ID NOs:35, 530, 542, 554, 566, 578, 590, 602, 614, 626, or 638 according to IMGT numbering, or comprising the amino acid sequence of SEQ ID NOs:38, 536, 548, 560, 572, 584, 596, 608, 620, 632, or 644 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NOs:33, 60, 69, 77, 85, 93, 101, 109, 117, 125, 133, 141, 149, 157, 165, 173, 181, 189, 197, 205, 213, 221, 229, 237, 245, 253, 261, 269, 277, 285, 293, 301, 309, 317, 325, 333, 341, 349, 357, 365, 373, 381, 389, 397, 405, 413, 421, 429, or 437 according to Kabat numbering, or comprising the amino acid sequence of SEQ ID NOs:36, 61, 442, 443, 531, 543, 555, 567, 579, 591, 603, 615, 627, or 639 according to IMGT numbering, or comprising the amino acid sequence of SEQ ID NOs:39, 62, 537, 549, 561, 573, 585, 597, 609, 621, 633, or 645 according to Chothia numbering.
[0010] In some aspects, the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NOs:42, 71, 79, 87, 95, 103, 111, 119, 127, 135, 143, 151, 159, 167, 175, 183, 191, 199, 207, 215, 223, 231, 239, 247, 255, 263, 271, 279, 287, 295, 303, 311, 319, 327, 335, 343, 351, 359, 367, 375, 383, 391, 399, 407, 415, 423, 431, or 439 according to Kabat numbering, or comprising the amino acid sequence of SEQ ID NOs:45, 532, 544, 556, 568, 580, 592, 604, 616, 628, or 640 according to IMGT numbering, or comprising the amino acid sequence of SEQ ID NOs:48, 538, 550, 562, 574, 586, 598, 610, 622, 634, or 646 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NOs:43, 72, 80, 88, 96, 104, 112, 120, 128, 136, 144, 152, 160, 168, 176, 184, 192, 200, 208, 216, 224, 232, 240, 248, 256, 264, 272, 280, 288, 296, 304, 312, 320, 328, 336, 344, 352, 360, 368, 376, 384, 392, 400, 408, 416, 424, 432, or 440 according to Kabat numbering, or comprising the amino acid sequence of SEQ ID NOs:46, 533, 545, 557, 569, 581, 593, 605, 617, 629, or 641 according to IMGT numbering, or comprising the amino acid sequence of SEQ ID NOs:49, 539, 551, 563, 575, 587, 599, 611, 623, 635, or 647 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NOs:44, 63, 73, 81, 89, 97, 105, 113, 121, 129, 137, 145, 153, 161, 169, 177, 185, 193, 201, 209, 217, 225, 233, 241, 249, 257, 265, 273, 281, 289, 297, 305, 313, 321, 329, 337, 345, 353, 361, 369, 377, 385, 393, 401, 409, 417, 425, 433, or 441 according to Kabatnumbering, or comprising the amino acid sequence of SEQ ID NOs:47, 64, 442, 443, 534, 546, 558, 570, 582, 594, 606, 618, 630, or 642 according to IMGT numbering, or comprising the amino acid sequence of SEQ ID NOs:50, 65, 540, 552, 564, 576, 588, 600, 612, 624, 636, or 648 according to Chothia numbering.
[0011] In some aspects, the VHH1 comprises a CDR1 comprising the amino acid sequence of SEQ ID NOs:31, 67, 75, 83, 91, 99, 107, 115, 123, 131, 139, 147, 155, 163, 171, 179, 187, 195, 203, 211, 219, 227, 235, 243, 251, 259, 267, 275, 283, 291, 299, 307, 315, 323, 331, 339, 347, 355, 363, 371, 379, 387, 395, 403, 411, 419, 427, or 435 according to Kabat numbering, or comprising the amino acid sequence of SEQ ID NOs:34, 529, 541, 553, 565, 577, 589, 601, 613, 625, or 637 according to IMGT numbering, or comprising the amino acid sequence of SEQ ID NOs:37, 535, 547, 559, 571, 583, 595, 607, 619, 631, or 643 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NOs:32, 68, 76, 84, 92, 100, 108, 116, 124, 132, 140, 148, 156, 164, 172, 180, 188, 196, 204, 212, 220, 228, 236, 244, 252, 260, 268, 276, 284, 292, 300, 308, 316, 324, 332, 340, 348, 356, 364, 372, 380, 388, 396, 404, 412, 420, 428, or 436 according to Kabat numbering, or comprising the amino acid sequence of SEQ ID NOs:35, 530, 542, 554, 566, 578, 590, 602, 614, 626, or 638 according to IMGT numbering, or comprising the amino acid sequence of SEQ ID NOs:38, 536, 548, 560, 572, 584, 596, 608, 620, 632, or 644 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NOs:33, 60, 69, 77, 85, 93, 101, 109, 117, 125, 133, 141, 149, 157, 165, 173, 181, 189, 197, 205, 213, 221, 229, 237, 245, 253, 261, 269, 277, 285, 293, 301, 309, 317, 325, 333, 341, 349, 357, 365, 373, 381, 389, 397, 405, 413, 421, 429, or 437 according to Kabat numbering, or comprising the amino acid sequence of SEQ ID NOs:36, 61, 442, 443, 531, 543, 555, 567, 579, 591, 603, 615, 627, or 639 according to IMGT numbering, or comprising the amino acid sequence of SEQ ID NOs:39, 62, 537, 549, 561, 573, 585, 597, 609, 621, 633, or 645 according to Chothia numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NOs:42, 71, 79, 87, 95, 103, 111, 119, 127, 135, 143, 151, 159, 167, 175, 183, 191, 199, 207, 215, 223, 231, 239, 247, 255, 263, 271, 279, 287, 295, 303, 311, 319, 327, 335, 343, 351, 359, 367, 375, 383, 391, 399, 407, 415, 423, 431, or 439 according to Kabat numbering, or comprising the amino acid sequence of SEQ ID NOs:45, 532, 544, 556, 568, 580, 592, 604, 616, 628, or 640 according to IMGT numbering, or comprising the amino acid sequence of SEQ ID NOs:48, 538, 550, 562, 574, 586, 598, 610, 622, 634, or 646 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NOs:43, 72, 80, 88,96, 104, 112, 120, 128, 136, 144, 152, 160, 168, 176, 184, 192, 200, 208, 216, 224, 232, 240, 248, 256, 264, 272, 280, 288, 296, 304, 312, 320, 328, 336, 344, 352, 360, 368, 376, 384, 392, 400, 408, 416, 424, 432, or 440 according to Kabat numbering, or comprising the amino acid sequence of SEQ ID NOs:46, 533, 545, 557, 569, 581, 593, 605, 617, 629, or 641 according to IMGT numbering, or comprising the amino acid sequence of SEQ ID NOs:49, 539, 551, 563, 575, 587, 599, 611, 623, 635, or 647 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NOs:44, 63, 73, 81, 89, 97, 105, 113, 121, 129, 137, 145, 153, 161, 169, 177, 185, 193, 201, 209, 217, 225, 233, 241, 249, 257, 265, 273, 281, 289, 297, 305, 313, 321, 329, 337, 345, 353, 361, 369, 377, 385, 393, 401, 409, 417, 425, 433, or 441 according to Kabat numbering, or comprising the amino acid sequence of SEQ ID NOs:47, 64, 442, 443, 534, 546, 558, 570, 582, 594, 606, 618, 630, or 642 according to IMGT numbering, or comprising the amino acid sequence of SEQ ID NOs:50, 65, 540, 552, 564, 576, 588, 600, 612, 624, 636, or 648 according to Chothia numbering.
[0012] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:31 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:32 according to Kabat numbering; and CDR3 comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:42 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:43 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:443 according to IMGT numbering.
[0013] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:31 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:32 according to Kabat numbering; and CDR3 comprising the amino acid sequence of SEQ ID NO:33 according to Kabat numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:42 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:43 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:44 according to Kabat numbering.
[0014] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:31 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:32 according to Kabat numbering; and CDR3 comprising theamino acid sequence of SEQ ID NO:60 according to Kabat numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:42 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:43 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:63 according to Kabat numbering.
[0015] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:31 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:32 according to Kabat numbering; and CDR3 comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:42 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:43 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:63 according to Kabat numbering.
[0016] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:31 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:32 according to Kabat numbering; and CDR3 comprising the amino acid sequence of SEQ ID NO:60 according to Kabat numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:42 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:43 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:443 according to IMGT numbering.
[0017] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:34 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:35 according to IMGT numbering; and CDR3 comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:45 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:46 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:443 according to IMGT numbering.
[0018] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:34 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:35 according to IMGT numbering; and CDR3 comprising theamino acid sequence of SEQ ID NO:36 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:45 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:46 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:47 according to IMGT numbering.
[0019] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:34 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:35 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:61 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:45 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:46 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:64 according to IMGT numbering.
[0020] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:34 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:35 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:45 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:46 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:64 according to IMGT numbering.
[0021] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:34 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:35 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:61 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:45 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:46 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:443 according to IMGT numbering.
[0022] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:37 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:38 according to Chothia numbering; and a CDR3 comprising theamino acid sequence of SEQ ID NO:442 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:48 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:49 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:443 according to IMGT numbering.
[0023] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:37 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:38 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:39 according to Chothia numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:48 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:49 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:50 according to Chothia numbering.
[0024] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:37 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:38 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:62 according to Chothia numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:48 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:49 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:65 according to Chothia numbering.
[0025] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:37 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:38 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:48 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:49 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:65 according to Chothia numbering.
[0026] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:37 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:38 according to Chothia numbering; and a CDR3 comprising theamino acid sequence of SEQ ID NO:62 according to Chothia numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:48 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:49 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:443 according to IMGT numbering.
[0027] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:67 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:68 according to Kabat numbering; and CDR3 comprising the amino acid sequence of SEQ ID NO:69 according to Kabat numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:71 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:72 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering.
[0028] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:67 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:68 according to Kabat numbering; and CDR3 comprising the amino acid sequence of SEQ ID NO:69 according to Kabat numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:71 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:72 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:73 according to Kabat numbering.
[0029] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:529 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:530 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:531 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:532 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:533 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering.
[0030] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:529 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:530 according to IMGT numbering; and a CDR3 comprising theamino acid sequence of SEQ ID NO:531 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:532 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:533 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:534 according to IMGT numbering.
[0031] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:535 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:536 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:537 according to Chothia numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:538 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:539 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering.
[0032] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:535 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:536 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:537 according to Chothia numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:538 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:539 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:540 according to Chothia numbering.
[0033] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:131 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:132 according to Kabat numbering; and CDR3 comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:135 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:136 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:137 according to Kabat numbering.
[0034] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:131 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:132 according to Kabat numbering; and CDR3 comprising theamino acid sequence of SEQ ID NO:133 according to Kabat numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:135 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:136 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:137 according to Kabat.
[0035] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:541 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:542 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:544 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:545 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:546 according to IMGT numbering.
[0036] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:541 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:542 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:543 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:544 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:545 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:546 according to IMGT numbering.
[0037] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:547 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:548 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:550 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:551 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:552 according to Chothia numbering.
[0038] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:547 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:548 according to Chothia numbering; and a CDR3comprising the amino acid sequence of SEQ ID NO:549 according to Chothia numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:550 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:551 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:552 according to Chothia numbering.
[0039] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:139 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:140 according to Kabat numbering; and CDR3 comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:143 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:144 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:145 according to Kabat numbering.
[0040] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:139 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:140 according to Kabat numbering; and CDR3 comprising the amino acid sequence of SEQ ID NO:141 according to Kabat numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:143 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:144 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:145 according to Kabat numbering.
[0041] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:553 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:554 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:556 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:557 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:558 according to IMGT numbering.
[0042] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:553 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:554 according to IMGT numbering; and a CDR3 comprising theamino acid sequence of SEQ ID NO:555 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:556 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:557 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:558 according to IMGT numbering.
[0043] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:559 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:560 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:562 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:563 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:564 according to Chothia numbering.
[0044] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:559 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:560 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:561 according to Chothia numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:562 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:563 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:564 according to Chothia numbering.
[0045] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:171 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:172 according to Kabat numbering; and CDR3 comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:175 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:176 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:177 according to Kabat numbering.
[0046] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:171 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:172 according to Kabat numbering; and CDR3 comprising theamino acid sequence of SEQ ID NO:173 according to Kabat numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:175 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:176 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:177 according to Kabat numbering.
[0047] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:565 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:566 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:568 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:569 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:570 according to IMGT numbering.
[0048] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:565 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:566 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:567 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:568 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:569 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:570 according to IMGT numbering.
[0049] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:571 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:572 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:574 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:575 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:576 according to Chothia numbering.
[0050] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:571 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:572 according to Chothia numbering; and a CDR3comprising the amino acid sequence of SEQ ID NO:573 according to Chothia numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:574 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:575 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:576 according to Chothia numbering.
[0051] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:187 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:188 according to Kabat numbering; and CDR3 comprising the amino acid sequence of SEQ ID NO:189 according to Kabat numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:191 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:192 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering.
[0052] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:187 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:188 according to Kabat numbering; and CDR3 comprising the amino acid sequence of SEQ ID NO:189 according to Kabat numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:191 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:192 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:193 according to Kabat numbering.
[0053] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:577 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:578 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:579 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:580 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:581 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering.
[0054] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:577 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:578 according to IMGT numbering; and a CDR3 comprising theamino acid sequence of SEQ ID NO:579 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:580 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:581 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:582 according to IMGT numbering.
[0055] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:583 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:584 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:585 according to Chothia numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:586 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:587 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering.
[0056] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:583 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:584 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:585 according to Chothia numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:586 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:587 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:588 according to Chothia numbering.
[0057] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:195 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:196 according to Kabat numbering; and CDR3 comprising the amino acid sequence of SEQ ID NO:197 according to Kabat numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:199 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:200 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering.
[0058] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:195 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:196 according to Kabat numbering; and CDR3 comprising theamino acid sequence of SEQ ID NO:197 according to Kabat numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:199 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:200 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:201 according to Kabat numbering.
[0059] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:589 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:590 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:591 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:592 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:593 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering.
[0060] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:589 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:590 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:591 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:592 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:593 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:594 according to IMGT numbering.
[0061] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:595 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:596 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:597 according to Chothia numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:598 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:599 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering.
[0062] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:595 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:596 according to Chothia numbering; and a CDR3comprising the amino acid sequence of SEQ ID NO:597 according to Chothia numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:598 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:599 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:600 according to Chothia numbering.
[0063] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:203 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:204 according to Kabat numbering; and CDR3 comprising the amino acid sequence of SEQ ID NO:205 according to Kabat numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:207 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:208 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering.
[0064] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:203 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:204 according to Kabat numbering; and CDR3 comprising the amino acid sequence of SEQ ID NO:205 according to Kabat numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:207 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:208 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:209 according to Kabat numbering.
[0065] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:601 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:602 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:603 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:604 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:605 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering.
[0066] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:601 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:602 according to IMGT numbering; and a CDR3 comprising theamino acid sequence of SEQ ID NO:603 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:604 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:605 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:606 according to IMGT numbering.
[0067] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:607 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:608 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:609 according to Chothia numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:610 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:611 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering.
[0068] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:607 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:608 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:609 according to Chothia numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:610 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:611 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:612 according to Chothia numbering.
[0069] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:211 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:212 according to Kabat numbering; and CDR3 comprising the amino acid sequence of SEQ ID NO:213 according to Kabat numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:215 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:216 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering.
[0070] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:211 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:212 according to Kabat numbering; and CDR3 comprising theamino acid sequence of SEQ ID NO:213 according to Kabat numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:215 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:216 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:217 according to Kabat numbering.
[0071] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:613 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:614 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:615 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:616 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:617 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering.
[0072] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:613 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:614 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:615 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:616 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:617 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:618 according to IMGT numbering.
[0073] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:619 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:620 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:621 according to Chothia numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:622 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:623 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering.
[0074] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:619 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:620 according to Chothia numbering; and a CDR3comprising the amino acid sequence of SEQ ID NO:621 according to Chothia numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:622 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:623 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:624 according to Chothia numbering.
[0075] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:395 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:396 according to Kabat numbering; and CDR3 comprising the amino acid sequence of SEQ ID NO:443 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:399 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:400 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering.
[0076] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:395 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:396 according to Kabat numbering; and CDR3 comprising the amino acid sequence of SEQ ID NO:397 according to Kabat numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:399 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:400 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering.
[0077] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:395 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:396 according to Kabat numbering; and CDR3 comprising the amino acid sequence of SEQ ID NO:443 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:399 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:400 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:401 according to Kabat numbering.
[0078] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:395 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:396 according to Kabat numbering; and CDR3 comprising theamino acid sequence of SEQ ID NO:397 according to Kabat numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:399 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:400 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:401 according to Kabat numbering.
[0079] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:625 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:626 according to IMGT numbering; and CDR3 comprising the amino acid sequence of SEQ ID NO:443 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:628 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:629 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering.
[0080] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:625 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:626 according to IMGT numbering; and CDR3 comprising the amino acid sequence of SEQ ID NO:627 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:628 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:629 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering.
[0081] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:625 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:626 according to IMGT numbering; and CDR3 comprising the amino acid sequence of SEQ ID NO:443 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:628 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:629 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:630 according to IMGT numbering.
[0082] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:625 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:626 according to IMGT numbering; and CDR3 comprising theamino acid sequence of SEQ ID NO:627 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:628 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:629 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:630 according to IMGT numbering.
[0083] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:631 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:632 according to Chothia numbering; and CDR3 comprising the amino acid sequence of SEQ ID NO:443 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:634 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:635 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering.
[0084] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:631 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:632 according to Chothia numbering; and CDR3 comprising the amino acid sequence of SEQ ID NO:633 according to Chothia numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:634 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:635 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering.
[0085] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:631 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:632 according to Chothia numbering; and CDR3 comprising the amino acid sequence of SEQ ID NO:443 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:634 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:635 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:636 according to Chothia numbering.
[0086] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:631 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:632 according to Chothia numbering; and CDR3 comprisingthe amino acid sequence of SEQ ID NO:633 according to Chothia numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:634 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:635 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:636 according to Chothia numbering.
[0087] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:403 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:404 according to Kabat numbering; and CDR3 comprising the amino acid sequence of SEQ ID NO:443 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:407 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:408 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering.
[0088] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:403 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:404 according to Kabat numbering; and CDR3 comprising the amino acid sequence of SEQ ID NO:405 according to Kabat numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:407 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:408 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering.
[0089] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:403 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:404 according to Kabat numbering; and CDR3 comprising the amino acid sequence of SEQ ID NO:443 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:407 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:408 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:409 according to Kabat numbering.
[0090] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:403 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:404 according to Kabat numbering; and CDR3 comprising theamino acid sequence of SEQ ID NO:405 according to Kabat numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:407 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:408 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:409 according to Kabat numbering.
[0091] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:637 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:638 according to IMGT numbering; and CDR3 comprising the amino acid sequence of SEQ ID NO:443 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:640 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:641 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering.
[0092] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:637 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:638 according to IMGT numbering; and CDR3 comprising the amino acid sequence of SEQ ID NO:639 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:640 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:641 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering.
[0093] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:637 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:638 according to IMGT numbering; and CDR3 comprising the amino acid sequence of SEQ ID NO:443 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:640 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:641 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:642 according to IMGT numbering.
[0094] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:637 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:638 according to IMGT numbering; and CDR3 comprising theamino acid sequence of SEQ ID NO:639 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:640 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:641 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:642 according to IMGT numbering.
[0095] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:643 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:644 according to Chothia numbering; and CDR3 comprising the amino acid sequence of SEQ ID NO:443 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:646 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:647 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering.
[0096] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:643 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:644 according to Chothia numbering; and CDR3 comprising the amino acid sequence of SEQ ID NO:645 according to Chothia numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:646 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:647 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering.
[0097] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:643 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:644 according to Chothia numbering; and CDR3 comprising the amino acid sequence of SEQ ID NO:443 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:646 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:647 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:648 according to Chothia numbering.
[0098] In some aspects, the VHH1 of the co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:643 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:644 according to Chothia numbering; and CDR3 comprisingthe amino acid sequence of SEQ ID NO:645 according to Chothia numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:646 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:647 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:648 according to Chothia numbering.
[0099] In some aspects, the VHH1 comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to SEQ ID NOs:29, 30, 66, 74, 82, 90, 98, 106, 114, 122, 130, 138, 146, 154, 162, 170, 178, 186, 194, 202, 210, 218, 226, 234, 242, 250, 258, 266, 274, 282, 290, 298, 306, 314, 322, 330, 338, 346, 354, 362, 370, 378, 386, 394, 402, 410, 418, 426, 434, 444, 445 or 446; the VHH1 comprises an amino acid sequence of SEQ ID NOs:29, 30, 66, 74, 82, 90, 98, 106, 114, 122, 130, 138, 146, 154, 162, 170, 178, 186, 194, 202, 210, 218, 226, 234, 242, 250, 258, 266, 274, 282, 290, 298, 306, 314, 322, 330, 338, 346, 354, 362, 370, 378, 386, 394, 402, 410, 418, 426, 434, 444, 445 or 446; the VHH2 comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to SEQ ID NOs:40, 41, 70, 78, 86, 94, 102, 110, 118, 126, 134, 142, 150, 158, 166, 174, 182, 190, 198, 206, 214, 222, 230, 238, 246, 254, 262, 270, 278, 286, 294, 302, 310, 318, 326, 334, 342, 350, 358, 366, 374, 382, 390, 398, 406, 414, 422, 430, 438, 447, 448, 449 or 450; the VHH2 comprises an amino acid sequence of SEQ ID NOs:40, 41, 70, 78, 86, 94, 102, 110, 118, 126, 134, 142, 150, 158, 166, 174, 182, 190, 198, 206, 214, 222, 230, 238, 246, 254, 262, 270, 278, 286, 294, 302, 310, 318, 326, 334, 342, 350, 358, 366, 374, 382, 390, 398, 406, 414, 422, 430, 438, 447, 448, 449 or 450; the VHH1 comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to SEQ ID NOs:29, 30, 66, 74, 82, 90, 98, 106, 114, 122, 130, 138, 146, 154, 162, 170, 178, 186, 194, 202, 210, 218, 226, 234, 242, 250, 258, 266, 274, 282, 290, 298, 306, 314, 322, 330, 338, 346, 354, 362, 370, 378, 386, 394, 402, 410, 418, 426, 434, 444, 445 or 446; and the VHH2 comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to SEQ ID NOs:40, 41, 70, 78, 86, 94, 102, 110, 118, 126, 134, 142, 150, 158, 166, 174, 182, 190, 198, 206, 214, 222, 230, 238, 246, 254, 262, 270, 278, 286, 294, 302, 310, 318, 326, 334, 342, 350, 358, 366, 374, 382, 390, 398, 406, 414, 422, 430, 438, 447, 448, 449 or 450; the VHH1 comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to SEQ ID NOs:29, 30, 66,74, 82, 90, 98, 106, 114, 122, 130, 138, 146, 154, 162, 170, 178, 186, 194, 202, 210, 218, 226, 234, 242, 250, 258, 266, 274, 282, 290, 298, 306, 314, 322, 330, 338, 346, 354, 362, 370, 378, 386, 394, 402, 410, 418, 426, 434, 444, 445 or 446; and the VHH2 comprises an amino acid sequence of SEQ ID NOs:40, 41, 70, 78, 86, 94, 102, 110, 118, 126, 134, 142, 150, 158, 166, 174, 182, 190, 198, 206, 214, 222, 230, 238, 246, 254, 262, 270, 278, 286, 294, 302, 310, 318, 326, 334, 342, 350, 358, 366, 374, 382, 390, 398, 406, 414, 422, 430, 438, 447, 448, 449 or 450; the VHH1 comprises an amino acid sequence of SEQ ID NOs:29, 30, 66, 74, 82, 90, 98, 106, 114, 122, 130, 138, 146, 154, 162, 170, 178, 186, 194, 202, 210, 218, 226, 234, 242, 250, 258, 266, 274, 282, 290, 298, 306, 314, 322, 330, 338, 346, 354, 362, 370, 378, 386, 394, 402, 410, 418, 426, 434, 444, 445 or 446; and the VHH2 comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to SEQ ID NOs:40, 41, 70, 78, 86, 94, 102, 110, 118, 126, 134, 142, 150, 158, 166, 174, 182, 190, 198, 206, 214, 222, 230, 238, 246, 254, 262, 270, 278, 286, 294, 302, 310, 318, 326, 334, 342, 350, 358, 366, 374, 382, 390, 398, 406, 414, 422, 430, 438, 447, 448, 449 or 450; or the VHH1 comprises an amino acid sequence of SEQ ID NOs:29, 30, 66, 74, 82, 90, 98, 106, 114, 122, 130, 138, 146, 154, 162, 170, 178, 186, 194, 202, 210, 218, 226, 234, 242, 250, 258, 266, 274, 282, 290, 298, 306, 314, 322, 330, 338, 346, 354, 362, 370, 378, 386, 394, 402, 410, 418, 426, 434, 444, 445 or 446; and the VHH2 comprises an amino acid sequence of SEQ ID NOs:40, 41, 70, 78, 86, 94, 102, 110, 118, 126, 134, 142, 150, 158, 166, 174, 182, 190, 198, 206, 214, 222, 230, 238, 246, 254, 262, 270, 278, 286, 294, 302, 310, 318, 326, 334, 342, 350, 358, 366, 374, 382, 390, 398, 406, 414, 422, 430, 438, 447, 448, 449 or 450.
[0100] In some aspects, the VHH1 comprises the amino acid sequence of SEQ ID NO:29, and the VHH2 comprises the amino acid sequence of SEQ ID NO:40; the VHH1 comprises the amino acid sequence of SEQ ID NO:29, and the VHH2 comprises the amino acid sequence of SEQ ID NO:41; the VHH1 comprises the amino acid sequence of SEQ ID NO:29, and the VHH2 comprises the amino acid sequence of SEQ ID NO:447; the VHH1 comprises the amino acid sequence of SEQ ID NO:29, and the VHH2 comprises the amino acid sequence of SEQ ID NO:448; the VHH1 comprises the amino acid sequence of SEQ ID NO:29, and the VHH2 comprises the amino acid sequence of SEQ ID NO:449; the VHH1 comprises the amino acid sequence of SEQ ID NO:29, and the VHH2 comprises the amino acid sequence of SEQ ID NO:450; the VHH1 comprises the amino acid sequence of SEQ ID NO:30, and the VHH2 comprises the amino acid sequence of SEQ ID NO:40; the VHH1 comprises the amino acidsequence of SEQ ID NO:30, and the VHH2 comprises the amino acid sequence of SEQ ID NO:41; the VHH1 comprises the amino acid sequence of SEQ ID NO:30, and the VHH2 comprises the amino acid sequence of SEQ ID NO:447; the VHH1 comprises the amino acid sequence of SEQ ID NO:30, and the VHH2 comprises the amino acid sequence of SEQ ID NO:448; the VHH1 comprises the amino acid sequence of SEQ ID NO:30, and the VHH2 comprises the amino acid sequence of SEQ ID NO:449; the VHH1 comprises the amino acid sequence of SEQ ID NO:30, and the VHH2 comprises the amino acid sequence of SEQ ID NO:450; the VHH1 comprises the amino acid sequence of SEQ ID NO:444, and the VHH2 comprises the amino acid sequence of SEQ ID NO:41; the VHH1 comprises the amino acid sequence of SEQ ID NO:445, and the VHH2 comprises the amino acid sequence of SEQ ID NO:41; the VHH1 comprises the amino acid sequence of SEQ ID NO:446, and the VHH2 comprises the amino acid sequence of SEQ ID NO:41; the VHH1 comprises the amino acid sequence of SEQ ID NO:444, and the VHH2 comprises the amino acid sequence of SEQ ID NO:447; the VHH1 comprises the amino acid sequence of SEQ ID NO:444, and the VHH2 comprises the amino acid sequence of SEQ ID NO:448; the VHH1 comprises the amino acid sequence of SEQ ID NO:444, and the VHH2 comprises the amino acid sequence of SEQ ID NO:449; the VHH1 comprises the amino acid sequence of SEQ ID NO:444, and the VHH2 comprises the amino acid sequence of SEQ ID NO:450; the VHH1 comprises the amino acid sequence of SEQ ID NO:445, and the VHH2 comprises the amino acid sequence of SEQ ID NO:447; the VHH1 comprises the amino acid sequence of SEQ ID NO:445, and the VHH2 comprises the amino acid sequence of SEQ ID NO:448; the VHH1 comprises the amino acid sequence of SEQ ID NO:445, and the VHH2 comprises the amino acid sequence of SEQ ID NO:449; the VHH1 comprises the amino acid sequence of SEQ ID NO:445, and the VHH2 comprises the amino acid sequence of SEQ ID NO:450; the VHH1 comprises the amino acid sequence of SEQ ID NO:446, and the VHH2 comprises the amino acid sequence of SEQ ID NO:447; the VHH1 comprises the amino acid sequence of SEQ ID NO:446, and the VHH2 comprises the amino acid sequence of SEQ ID NO:448; the VHH1 comprises the amino acid sequence of SEQ ID NO:446, and the VHH2 comprises the amino acid sequence of SEQ ID NO:449; or the VHH1 comprises the amino acid sequence of SEQ ID NO:446, and the VHH2 comprises the amino acid sequence of SEQ ID NO:450; the VHH1 comprises the amino acid sequence of SEQ ID NO:444, and the VHH2 comprises the amino acid sequence of SEQ ID NO:40; the VHH1 comprises the amino acid sequence of SEQ ID NO:445, and the VHH2comprises the amino acid sequence of SEQ ID NO:40; and the VHH1 comprises the amino acid sequence of SEQ ID NO:446, and the VHH2 comprises the amino acid sequence of SEQ ID NO:40.
[0101] In some aspects, the VHH1 is connected to the VHH2 by a linker. In some aspects, the co-binder has the structure: [VHH1] – linker – [VHH2].
[0102] In some aspects, the linker is from about 5 to about 50 amino acids in length. In some aspects, the linker is from about 15 to about 45 amino acids in length. In some aspects, the linker is from about 34 to about 42 amino acids in length. In some aspects, the linker is from about 37 to about 39 amino acids in length. In some aspects, the linker is about 38 amino acids in length. In some aspects, the linker comprises the amino acid sequence of SEQ ID NO:451.
[0103] In some aspects, the co-binder has an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to SEQ ID NO:51, 52 or 453-471. In some aspects, the co-binder has an amino acid sequence of SEQ ID NO:51, 52 or 453-471. In some aspects, the co-binder has an amino acid sequence of SEQ ID NO:52, or amino acid residues 2-280 of SEQ ID NO:52.
[0104] In some aspects, the co-binder further comprises an Fc region. In some aspects, the Fc region comprises an IgG1, IgG2, IgG3, or IgG4 Fc region. In some aspects, the Fc region comprises a human Fc region. In some aspects, the Fc region comprises one or more substitutions, deletions, insertions, or any combination thereof. In some aspects, the one or more substitutions comprise C220S, M252Y, S254T, T256E, L234A, L235A, L309Y, Q311M, M428L, N434S, or any combination thereof, according to the EU numbering system. In some aspects, the Fc region substitutions comprise C220S, M252Y, S254T, T256E, L234A and L235A. In some aspects, the Fc region substitutions comprise C220S, L234A, L235A, M428L and N434S. In some aspects, the Fc region substitutions comprise C220S, L234A, L235A, L309Y, Q311M and M428L. In some aspects, the Fc region substitutions comprise C220, L234A, L235A, M252Y, S254T, T256E, M428L and N434S. In some aspects, the Fc region substitutions comprise C220, L234A, L235A, M252Y, S254T, T256E, L309Y, Q311M and M428L. In some aspects, the C-terminus of the Fc region is Lysine. In some aspects, the C terminus of the Fc region is not Lysine, or the C-terminal Lysine of the Fc region has been removed. In some aspects, the Fc region comprises the amino acid sequence of SEQ ID NO:59 or amino acid residues 1-231 of SEQ ID NO:59.
[0105] Also provided herein is a multimeric co-binder, comprising one or more of the co- binders described herein.
[0106] Also provided herein is a bispecific polypeptide comprising: (i) a first co-binder that specifically binds IL13 comprising a first Variable Heavy domain of Heavy chain 1 (VHH1) and a second VHH (VHH2), and (ii) a second co-binder that specifically binds a target antigen comprising a third VHH (VHH3) and a fourth VHH (VHH4), wherein the first co-binder comprises a co-binder described herein; and wherein the target antigen of the second co-binder is IL4RA, IL13RA, IL31, IL31RA, OSMR, Ox40, Ox40L, TSLP, IL17, TNFα, CD20, CD19, CD25, IL4, IL23, IgE, CD11α, IL6R, α4-Intergrin, IL12, IL1β, BlyS, CKIT, SIGLEC-6, SIGLEC-8, TL1A, TXLNA, IL13RA, OSMR-beta, PD1, PDL1, IL17A, IL17B, IL17RB, IL17C, IL17RA, IL17RB, IL17RE, IL17D, IL17E, IL17F, IL17RC, IL17A / A, IL-17A / F, IL-17F / F, TNF-β, CD103, CD132, IL23R, IL-23p19, IL6, gp130, α4-β7, IL1, IL1α, IL1RA, IL1R1, IL1RL1, IL1RL2, IL1RAcP, IL1R2, IL2, IL2R, IL2Rβ, IL2Rγ, IL3, IL3Rα, CSF2RB, IL5, IL5Rα, IL7, IL7R, IL7Rα, IL7α, γ-chain, IL8, IL9, IL-9R, IL10, IL10Rα, IL10Rβ, IL11, IL11Rα, IL12A, IL12B, IL12Rβ1, IL12Rβ2, IL14, IL15, IL15Rα, IL16, IL18, IL18Rα, IL18RAcP, IL18BP, IL19, IL20, IL20Rα, IL20Rβ, IL21, IL21R, IL22, IL22Rα1, IL22Rα2, IL24, IL25, IL25 / IL17E, IL26, IL27, IL27Rα, IL28A, IL28B, IL28RA, IL29, IL32, PR3, PKCε, PKCδ, STAT3, Paxillin, IL33, IL34, CSF-1R, IL35, IL36A, IL36B, IL36G, IL36RA, IL37, IL18R1, IL38, EPO, GM-CSF, G-CSF, M-CSF, Eotaxin, IL1β, APRIL, BAFF-R, TACI, CD28, CTLA-4, CD80, CD86, TGF-β, CD40L, MCP-1, BASFF, MMPs, Elastase, MIF, Cathepsin G, Cathepsin K, IFN-γ, ROS, NO, RANTES, RANKL, PGE2, ADAMTSs, NGF, BDNF, NPY, MIG, BLC, IP- 10, PDGF, CXCR1, or CXCR2. In some aspects, the target antigen of the second co-binder is IL31.
[0107] Also provided herein are pharmaceutical compositions comprising any one or more of the co-binders described herein, the multimeric co-binders described herein, the bispecific polypeptide described herein, and a pharmaceutically acceptable carrier.
[0108] Also provided herein are isolated nucleic acids encoding any one or more of the co- binders described herein, the multimeric co-binders described herein, or the bispecific polypeptides described herein. Further provided herein are vectors comprising any one or more of the nucleic acids described herein. Further provided herein is an in vitro or ex vivo cell comprising any one or more of the nucleic acids described herein. Further provided herein is an in vitro or ex vivo cell comprising any one or more of the vectors described herein.
[0109] Also provided herein is an in vitro or ex vivo cell that expresseses one or more co- binders described herein, the multimeric co-binders described herein, or one or more bispecific polypeptides described herein.
[0110] Also provided herein are methods of producing any one or more of the co-binders described herein, the multimeric co-binders described herein, or the bispecific polypeptide described herein, comprising transfecting a nucleic acid described herein into a host cell under conditions suitable for expression of the co-binder, multimeric co-binder, or bispecific polypeptide.
[0111] Also provided herein are methods for treating a subject having an IL13-associated condition comprising administering to the subject a pharmaceutically effective amount of any one or more of the co-binders described herein, the multimeric co-binders described herein, or the bispecific polypeptide described herein or a pharmaceutical composition thereof.
[0112] In some aspects, the subject is a human subject.
[0113] In some aspects, the IL13-associated condition is a pruritic condition. In some aspects, the IL13-associated condition is atopic dermatitis, prurigo nodularis, or chronic spontaneous urticaria.
[0114] In some aspects, the IL13-associated condition is airway hyperresponsiveness, allergic asthma, allergic conjunctivitis, allergic contact dermatitis, allergic lung disease, allergic rhinitis, alopecia areata, Alzheimer's disease, aspirin-exacerbated respiratory disease, asthma, atopic dermatitis, atopic keratoconjunctivitis, bronchial asthma, bullous pemphigoid, chronic hand eczema, chronic inducible urticaria, chronic obstructive pulmonary disease, chronic pruritus of unknown origin, chronic Rhinosinusitis with nasal polyposis, chronic spontaneous urticaria, colitis, dermatitis, eczema, eosinophilic chronic obstructive pulmonary disease (COPD), eosinophilic esophagitis, eosinophilic gastritis, eosinophilic duodenitis, epidermolysis bullosa, food allergy, goblet cell metaplasia, hepaticfibrosis, Hodgkin's disease, idiopathic pulmonary fibrosis, Netherton syndrome, progressive systemic sclerosis, prurigo nodularis, rheumatoid arthritis, sinusitis, Sjogren's syndrome, systemic lupus erythematosus, systemic sclerosis, type 1 diabetes, or ulcerative colitis.
[0115] In some aspects, the co-binder, multimeric co-binder, bispecific polypeptide, or pharmaceutical composition is administered parenterally. In some aspects, the co-binder, multimeric co-binder, bispecific polypeptide, or pharmaceutical composition is administered by an intravenous route, a subcutaneous route, an intramuscular route, or an intraperitoneal route.
[0116] In some aspects, the method comprises administering to the subject one or more therapeutic agent in combination with the co-binder, the multimeric co-binder, bispecific polypeptide, or the pharmaceutical composition. In some aspects, the one or more therapeutic agent is an antibody, a small molecule inhibitor, and / or a systemic immunosuppressant agent. In some aspects, the one or more therapeutic agent comprises a topical corticosteroid, a calcineurin inhibitor, anti-IL4RA antibody, an anti-IL13RA antibody, an anti-OSMR antibody, an anti-Ox40 antibody, an anti-Ox40L antibody, an anti-TSLP antibody an anti-IL17 antibody, an anti-TNFα antibody, an anti-CD20 antibody, an anti-CD19 antibody, an anti-CD25 antibody, an anti-IL4 antibody, an anti-IL23 antibody, an anti-IL31 antibody, an anti-IgE antibody, an anti-CD11α antibody, anti-IL6R antibody, anti-α4-Intergrin antibody, an anti-IL12 antibody, an anti-IL1β antibody, an anti-BlyS antibody, an anti-CKIT antibody, an anti-SIGLEC-6 antibody, abatacept, belatacept, an anti-SIGLEC-8 antibody, STAT inhibitor, a JAK inhibitor, a PI3K inhibitor, an AKT inhibitor, a MAPK inhibitor, or a MRGPRX2 inhibitor.
[0117] Also provided herein are methods of detecting human IL13 in a biological sample comprising contacting the biological sample with one or more of the co-binders described herein, the multimeric co-binders described herein, or the bispecific polypeptides described herein under conditions permissive for binding of the co-binder, multimeric co-binder or bispecific polypeptide to a human IL13 and detecting whether a complex is formed between the co-binder, multimeric co-binder or bispecific polypeptide and the human IL13 in the biological sample. In some aspects, wherein the biological sample is a serum sample. BRIEF DESCRIPTION OF THE DRAWINGS
[0118] FIGS.1A-1C shows anti-IL13 single binder selection flow cytometry plots with each panel pair representing the results from a single immunized animal. FIG.1A shows round 1 (R1) MACS flow plot images taken from flow cytometry analysis of R1 MACS eluates for 0 nM IL13 and 10 nM IL13 stained samples. FIG.1B and FIG.1C show round 2 (R2) FACS and round (R3) FACS images, respectively, representing flow plots for sorting human anti-IL13 single binder displaying yeast cells at 0 and 10 nM human IL13 concentration.
[0119] FIG.2 shows anti-IL13 co-binder selection flow cytometry plots. Round 1 (R1) and round 2 (R2) MACS flow plot images were taken from flow cytometry analysis of R1 and R2 MACS eluates for 0 nM and 0.3 nM IL13 stained samples for R1 and 0 nM and 30 pM IL13 stained samples for R2. R3 FACS was performed for sorting human anti-IL13 single binder displaying yeast cells at 0 and 0.1 nM human IL13 concentration.
[0120] FIG.3 is a plot showing dose-dependent inhibition activity of 3G12 co-binder using IL13 dimerization assays.3G12-YTE-Fc was diluted from 30 µg / ml with 3x dilution for 12 points and incubated with equal volume of 10 ng / ml IL13 / IL31 in ASSAYCOMPLETETMCell Plating 0 Reagent (Eurofins DiscoverX) for 1 hour at room temperature.3G12 was then added to IL13 receptor dimerization reporter cells. RLU was read and normalized to IL13 activity without IL13 only control and presented as percentage. For comparison, 3G12-YTE-Fc, lebrikizumab (anti-IL13 hIgG4 monoclonal), or tralokinumab were diluted and incubated with IL13 and assessed for IL13 receptor dimerization, respectively.
[0121] FIG.4 is a schematic exemplifying a bi-specific format of SEQ ID NO:527, which comprises the anti-IL13 co-binder 3G12 and an anti-IL31 co-binder.
[0122] FIGS.5A-5B are plots showing dose-dependent inhibition activity of anti-IL31 and anti-IL13 bispecific polypeptide (SEQ ID NO:527) using IL13 and IL31 dimerization assays. Anti-IL31 and anti-IL13 bispecific polypeptide was diluted from 30 µg / ml with 3x dilution for 12 points and incubated with equal volume of 10 ng / ml IL13 / IL31 in AssayCompleteTM Cell Plating 0 Reagent (Eurofins DiscoverX) for 1hr at room temperature. The complex was then added to IL13 receptor dimerization reporter cells (FIG.5A) and IL31 receptor dimerization reporter cells (FIG.5B). RLU was read and normalized to IL13 / IL31 activity with and without cytokines and presented as 100 and 0 percent activity, respectively. For comparison, lebrikizumab (anti-IL13 hIgG4 monoclonal) or IL31 co-binder 1C10-Fc (SEQ ID NO:528) was diluted and incubated with IL13 / IL31 and assessed for IL13 and IL31 receptor dimerization, respectively. DESCRIPTION OF THE SEQUENCES
[0123] Table 1 provides a listing of certain sequences referenced herein. Table 1. Description of Certain SequencesDESCRIPTION OF THE ASPECTS I. Exemplary Definitions
[0124] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.
[0125] The complete disclosures of all publications cited herein are incorporated herein by reference in their entireties as if each were individually set forth in full herein and incorporated.
[0126] Unless otherwise defined, scientific and technical terms used in connection with the present disclosure shall have the meanings that are commonly understood by those of ordinary skill in the art. Further, unless otherwise required by context or expressly indicated, singular terms shall include pluralities and plural terms shall include the singular. For any conflict in definitions between various sources or references, the definition provided herein will control.
[0127] In general, the numbering of the residues in an antibody heavy chain is that of the EU index as in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991). Use of the term “or” herein is not meant to imply that alternatives are mutually exclusive.
[0128] In this application, the use of “or” means “and / or” unless expressly stated or understood by one skilled in the art. In the context of a multiple dependent claim, the use of “or” refers back to more than one preceding independent or dependent claim.
[0129] The terms “polypeptide” and “protein” are used interchangeably to refer to a polymer of amino acid residues, and are not limited to a minimum length. Such polymers of amino acid residues may contain natural or non-natural amino acid residues, and include, but are not limited to, peptides, oligopeptides, dimers, trimers, and multimers of amino acid residues. Both full- length proteins and fragments thereof are encompassed by the definition. The terms also include post-expression modifications of the polypeptide, for example, glycosylation, sialylation, acetylation, phosphorylation, and the like. Furthermore, for purposes of the present disclosure, a “polypeptide” refers to a protein which includes modifications, such as deletions, additions, and substitutions (generally conservative in nature), to the native sequence, as long as the protein maintains the desired activity. These modifications may be deliberate, as through site-directed mutagenesis, or may be accidental, such as through mutations of hosts which produce the proteins or errors due to PCR amplification.
[0130] The terms “multimer” and “multimeric” refer to a complex of two or more component molecules, such as two or more polypeptides. A multimer includes, but is not limited to, a dimer or a trimer. Within a multimer, the two or more component molecules may be the same (i.e., the multimer is a homomultimer), or one or more of the two or more component molecules may be different from the other component molecules (i.e., the multimer is a heteromultimer).
[0131] The terms “IL13,” and “interleukin-13” as used herein refer to any native, mature IL13 that results from processing of an IL13 precursor in a cell. The term includes IL13 from any vertebrate source, including mammals such as primates (e.g., humans and cynomolgus or rhesus monkeys) and rodents (e.g., mice and rats), unless otherwise indicated. The term also includes naturally occurring variants of IL13, such as splice variants or allelic variants. Nonlimiting exemplary human IL13 amino acid sequences are shown in Table 1 (see SEQ ID NOs: 27 and 28). See also UniProtKB / Swiss-Prot Accession: P35225.
[0132] The term “specifically binds” to an antigen or epitope is a term that is well understood in the art, and methods to determine such specific binding are also well known in the art. A molecule is said to exhibit “specific binding” or “preferential binding” if it reacts or associates more frequently, more rapidly, with greater duration and / or with greater affinity with a particular cell or substance than it does with alternative cells or substances. A single-domain antibody (sdAb) or VHH-containing polypeptide (e.g., co-binder) “specifically binds” or “preferentially binds” to a target if it binds with greater affinity, avidity, more readily, and / or with greater duration than it binds to other substances. For example, a sdAb or VHH-containing polypeptide (e.g., co-binder) that specifically or preferentially binds to a IL13 epitope is a sdAb or VHH- containing polypeptide (e.g., co-binder) that binds this epitope with greater affinity, avidity, more readily, and / or with greater duration than it binds to other IL13 epitopes or non-IL13 epitopes. It is also understood by reading this definition that; for example, a sdAb or VHH-containing polypeptide (e.g., co-binder) that specifically or preferentially binds to a first target may or may not specifically or preferentially bind to a second target. As such, “specific binding” or “preferential binding” does not necessarily require (although it can include) exclusive binding. Generally, but not necessarily, reference to binding means preferential binding. “Specificity” refers to the ability of a binding protein to selectively bind an antigen.
[0133] The terms “inhibition” or “inhibit” refer to a decrease or cessation of any phenotypic characteristic or to the decrease or cessation in the incidence, degree, or likelihood of that characteristic. To “reduce” or “inhibit” is to decrease, reduce or arrest an activity, function,and / or amount as compared to a reference. In some aspects, by “reduce” or “inhibit” is meant the ability to cause an overall decrease of 10% or greater. In some aspects, by “reduce” or “inhibit” is meant the ability to cause an overall decrease of 50% or greater. In some aspects, by “reduce” or “inhibit” is meant the ability to cause an overall decrease of 75%, 85%, 90%, 95%, or greater. In some aspects, the amount noted above is inhibited or decreased over a period of time, relative to a control over the same period of time.
[0134] The term “antibody” is used in the broadest sense and encompasses various polypeptides that comprise antibody-like antigen-binding domains, including but not limited to conventional antibodies (typically comprising at least one heavy chain and at least one light chain), single-domain antibodies (sdAbs, comprising at least one VHH domain and an Fc region), VHH-containing polypeptides (polypeptides comprising at least one VHH domain), and fragments or multimers of any of the foregoing so long as they exhibit the desired antigen- binding activity. In some aspects, an antibody comprises a dimerization domain. Such dimerization domains include, but are not limited to, heavy chain constant domains (comprising CH1, hinge, CH2, and CH3 domains, where CH1 typically pairs with a light chain constant domain, CL, and where the hinge mediates dimerization) and Fc regions (comprising hinge, CH2, and CH3, where the hinge mediates dimerization).
[0135] As used herein, the term “binding moiety” refers to a molecule or a portion of a molecule which binds a specific target molecule. A binding moiety can comprise a protein, peptide, nucleic acid, carbohydrate, lipid, or small molecular weight compound. In some aspects, a binding moiety comprises an antibody. In some aspects, a binding moiety comprises an antigen-binding domain of an antibody. In some aspects, a binding moiety comprises an antibody or an antigen-binding domain. In some aspects, a binding moiety comprises a heavy chain variable region of an antibody. In some aspects, a binding moiety comprises a light chain variable region of an antibody. In some aspects, a binding moiety comprises a variable region of an antibody. In some aspects, a binding moiety comprises an antibody mimetic. In some aspects, a binding moiety comprises a small molecular weight component. In some aspects, a binding molecule (e.g., a polypeptide) has only one binding moiety. In some aspects, a binding molecule (e.g., a polypeptide) has two binding moieties. In some aspects, a binding molecule (e.g., a polypeptide) has three or more binding moieties. In some aspects, the two or more binding moieties on one binding molecule (e.g., a polypeptide) are the same. In some aspects, the two or more binding moieties on one binding molecule (e.g., a polypeptide) are different. For example, abinding molecule (e.g., a polypeptide) can have two binding moieties, both being antigen binding domains, such as VHHs. For another example, a binding molecule (e.g., a polypeptide) can also have two binding moieties, one being a VHH, and the other being scFv.
[0136] The term “antigen-binding domain” as used herein refers to a portion of an antibody sufficient to bind an antigen. In some aspects, an antigen binding domain of a conventional antibody comprises three heavy chain CDRs and three light chain CDRs. Thus, in some aspects, an antigen binding domain comprises a heavy chain variable region comprising CDR1-FR2- CDR2-FR3-CDR3, and any portions of FR1 and / or FR4 required to maintain binding to antigen, and a light chain variable region comprising CDR1-FR2-CDR2-FR3-CDR3, and any portions of FR1 and / or FR4 required to maintain binding to antigen. In some aspects, an antigen-binding domain of an sdAb or VHH-containing polypeptide comprises three CDRs of a VHH domain (e.g., CDR1, CDR2, and CDR3). Thus, in some aspects, an antigen binding domain of an sdAb or VHH-containing polypeptide comprises a VHH domain comprising CDR1-FR2-CDR2-FR3- CDR3, and any portions of FR1 and / or FR4 required to maintain binding to antigen.
[0137] The term “VHH” or “VHH domain” or “VHH antigen-binding domain” as used herein refers to the Variable Heavy domain of a Heavy chain, or the antigen-binding portion of a single- domain antibody, such as a camelid antibody, llama antibody, alpaca antibody, or shark antibody. In some aspects, a VHH comprises three CDRs and four framework regions, designated FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. In some aspects, a VHH may be truncated at the N- terminus or C-terminus such that it comprises only a partial FR1 and / or FR4, or lacks one or both of those framework regions, so long as the VHH substantially maintains antigen binding and specificity.
[0138] The terms “single domain antibody” and “sdAb” are used interchangeably herein to refer to an antibody comprising at least one monomeric domain, such as a VHH domain, without a light chain, and an Fc region. In some aspects, an sdAb is a dimer of two polypeptides wherein each polypeptide comprises at least one VHH domain and an Fc region. As used herein, the terms “single domain antibody” and “sdAb” encompass polypeptides that comprise multiple VHH domains, such as a polypeptide having the structure VHH1-VHH2-Fc, wherein VHH1 and VHH2 may be the same or different.
[0139] The term “VHH-containing polypeptide” refers to a polypeptide that comprises at least one VHH domain. In some aspects, a VHH polypeptide comprises two, three, or four or more VHH domains, wherein each VHH domain may be the same or different. In some aspects, aVHH-containing polypeptide comprises an Fc region. In some such aspects, the VHH-containing polypeptide may be referred to as an sdAb. Further, in some such aspects, the VHH polypeptide may form a dimer. Nonlimiting structures of VHH-containing polypeptides, which are also sdAbs, include VHH1-VHH2-Fc, wherein VHH1 and VHH2 may be the same or different. In some aspects of such structures, one VHH may be connected to another VHH by a linker, or one VHH may be connected to the Fc by a linker. In some such aspects, the linker comprises 5-50 amino acids. In some such aspects, the linker comprises 8 to 40 amino acids. In some aspects, the linker comprises 12 to 37 amino acids. In some aspects, the linker is composed of glycine and serine. In some aspects, the linker is composed of glycine, serine, and other amino acids. Some examples of polypeptide linkers are described in WO2022147463, which is incorporated herein by reference in its entirety. In some aspects, when a VHH-containing polypeptide comprises an Fc, it forms a dimer. Thus, the structure VHH1-VHH2-Fc, if it forms a dimer, is considered to be tetravalent (i.e., the dimer has four VHH domains).
[0140] The term “single binder” refers to a single domain binder, e.g., VHH, capable of specifically binding a target antigen. A general structure, for example, of a single binder is as follows: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4, in which FR1 to FR4 refer to framework regions 1 to 4, respectively, and in which CDR1 to CDR3 refer to the complementarity determining regions 1 to 3, respectively.
[0141] The term “co-binder” refers to two single domain binding moieties, e.g., VHHs, joined together by an optional linker peptide in which each single binder is capable of simultaneously binding the same target antigen, e.g., IL13, as the other single binder. A co-binder may comprise two biparatopic single binders. For example, each single binder is capable of specifically binding to the same target antigen (e.g., bind at a non-overlapping epitope) allowing each single binder to simultaneously bind the target. A general structure, for example, of a co-binder is as follows: 1st Single Binder-Linker-2nd Single Binder or VHH1-linker-VHH2, wherein the N-terminal region of the 2nd single binder or VHH2 may be truncated, see WO 2022 / 147463. In some aspects, a IL13 co-binder, for example, is capable of binding to IL13 at a binding affinity at least about 2 folds, 3 folds, 4 folds, 5 folds, 6 folds, 7 folds, 8 folds, 9 folds, 10 folds, 11 folds, 12 folds, 13 folds, 14 folds, 15 folds 16 folds, 17 folds, 18 folds, 19 folds, or 20 folds stronger than each of the first IL13 and the second IL13 binders.
[0142] The term “biparatopic” refers to two or more antibodies, two or more “single binders”, one or more “co-binder(s)” that recognize and bind two different epitopes of the same targetantigen. For example, each single binder, such as a VHH, of a co-binder binds to the same target antigen at nonoverlapping epitopes, which allows both single binders to bind the same target antigen simultaneously.
[0143] The term “monoclonal antibody” refers to an antibody (including an sdAb or VHH- containing polypeptide) of a substantially homogeneous population of antibodies, that is, the individual antibodies comprising the population are identical except for possible naturally- occurring mutations that may be present in minor amounts.
[0144] The term “CDR” denotes a complementarity determining region as defined by at least one manner of identification to one of skill in the art. In some aspects, CDRs can be defined in accordance with any of the IMGT numbering scheme, the Chothia numbering scheme, the Kabat numbering scheme, a combination of any two or three of the IMGT, Kabat, and Chothia numbering schemes, the AbM definition, and / or the contact definition. A VHH comprises three CDRs, designated CDR1, CDR2, and CDR3.
[0145] The term “heavy chain constant region” as used herein refers to a region comprising at least three heavy chain constant domains, CH1, hinge, CH2, and CH3. Of course, non-function- altering deletions and alterations within the domains are encompassed within the scope of the term “heavy chain constant region,” unless designated otherwise. Nonlimiting exemplary heavy chain constant regions include γ, δ, and α. Nonlimiting exemplary heavy chain constant regions also include ε and μ. Each heavy constant region corresponds to an antibody isotype. For example, an antibody comprising a γ constant region is an IgG antibody, an antibody comprising a δ constant region is an IgD antibody, and an antibody comprising an α constant region is an IgA antibody. Further, an antibody comprising a μ constant region is an IgM antibody, and an antibody comprising an ε constant region is an IgE antibody. Certain isotypes can be further subdivided into subclasses. For example, IgG antibodies include, but are not limited to, IgG1 (comprising a γ1 constant region), IgG2 (comprising a γ2 constant region), IgG3 (comprising a γ3 constant region), and IgG4 (comprising a γ4 constant region) antibodies; IgA antibodies include, but are not limited to, IgA1 (comprising an α1 constant region) and IgA2 (comprising an α2 constant region) antibodies; and IgM antibodies include, but are not limited to, IgM1 and IgM2.
[0146] A “Fc region” as used herein refers to a portion of a heavy chain constant region comprising CH2 and CH3. In some aspects, an Fc region comprises a hinge, CH2, and CH3. In various aspects, when an Fc region comprises a hinge, wherein the hinge mediates dimerizationbetween two Fc-containing polypeptides. In some aspects, the Fc region further comprises a full or partial hinge region. In some aspects, the full or partial hinge region comprises a cysteine (C) to serine (S) mutation. An Fc region may be of any antibody heavy chain constant region isotype discussed herein. In some aspects, an Fc region is an IgG1, IgG2, IgG3, or IgG4.
[0147] An “acceptor human framework” as used herein is a framework comprising the amino acid sequence of a heavy chain variable domain (VH) framework derived from a human immunoglobulin framework or a human consensus framework, as discussed herein. An acceptor human framework derived from a human immunoglobulin framework or a human consensus framework can comprise the same amino acid sequence thereof, or it can contain amino acid sequence changes. In some aspects, the number of amino acid changes are fewer than 10, or fewer than 9, or fewer than 8, or fewer than 7, or fewer than 6, or fewer than 5, or fewer than 4, or fewer than 3, across all the human frameworks in a single antigen binding domain, such as a VHH.
[0148] A “humanized VHH” as used herein refers to a VHH in which one or more framework regions have been substantially replaced with human framework regions. In some instances, certain framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, the humanized VHH can comprise residues that are found neither in the original VHH nor in the human framework sequences, but are included to further refine and optimize sdAb VHH-containing polypeptide performance. In some aspects, a humanized sdAb or VHH-containing polypeptide comprises a human Fc region. As will be appreciated, a humanized sequence can be identified by its primary sequence and does not necessarily denote the process by which the antibody was created.
[0149] The terms “label” and “detectable label” mean a moiety attached to an antibody or its analyte to render a reaction (for example, binding) between the members of the specific binding pair, detectable. The labeled member of the specific binding pair is referred to as “detectably labeled.” Thus, the term “labeled binding protein” refers to a protein with a label incorporated that provides for the identification of the binding protein. In some aspects, the label is a detectable marker that can produce a signal that is detectable by visual or instrumental means, for example, incorporation of a radiolabeled amino acid or attachment to a polypeptide of biotinyl moieties that can be detected by marked avidin (for example, streptavidin containing a fluorescent marker or enzymatic activity that can be detected by optical or colorimetric methods). Examples of labels for polypeptides include, but are not limited to, the following: radioisotopesor radionuclides (for example,3H,14C,35S,90Y,99Tc,111In,125I,131I,177Lu,166Ho, or153Sm); chromogens, fluorescent labels (for example, FITC, rhodamine, lanthanide phosphors), enzymatic labels (for example, horseradish peroxidase, luciferase, alkaline phosphatase); chemiluminescent markers; biotinyl groups; predetermined polypeptide epitopes recognized by a secondary reporter (for example, leucine zipper pair sequences, binding sites for secondary antibodies, metal binding domains, epitope tags); and magnetic agents, such as gadolinium chelates. Representative examples of labels commonly employed for immunoassays include moieties that produce light, for example, acridinium compounds, and moieties that produce fluorescence, for example, fluorescein. In this regard, the moiety itself may not be detectably labeled but may become detectable upon reaction with yet another moiety.
[0150] “Affinity” refers to the strength of the sum total of noncovalent interactions between a single binding site of a molecule (for example, an antibody, such as an sdAb, or VHH-containing polypeptide) and its binding partner (for example, an antigen). The affinity or the apparent affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (kD) or the kD-apparent, respectively. Affinity can be measured by common methods known in the art (such as, for example, ELISA KD, KinExA, flow cytometry, and / or surface plasmon resonance (SPR) devices), including those described herein. Such methods include, but are not limited to, methods involving BIACORE®, OCTET®, or flow cytometry.
[0151] The terms “kD,” “KD,” “Kd,” “Kd” or “Kd value” as used interchangeably to refer to the equilibrium dissociation constant of an antigen-binding molecule (e.g., an antibody or VHH) and antigen interaction. When the term “kD” is used herein, it includes kD and kD-apparent. The equilibrium dissociation constant (Kd) is calculated as the ratio of koff / kon. The term “kon” refers to the rate constant for association of an antibody to an antigen and the term “koff” refers to the rate constant for dissociation of an antibody from the antibody / antigen complex.
[0152] The term “binds” to an antigen or epitope is a term that is well understood in the art, and methods to determine such binding are also well known in the art. A molecule is said to exhibit “binding” if it reacts, associates with, or has affinity for a particular cell or substance and the reaction, association, or affinity is detectable by one or more methods known in the art, such as, for example, immunoblot, ELISA KD, KinEx A, surface plasmon resonance devices, or biolayer interferometry (BLI).
[0153] “Surface plasmon resonance” denotes an optical phenomenon that allows for the analysis of real-time biospecific interactions by detection of alterations in protein concentrationswithin a biosensor matrix, for example using the BIACORE™ system (BIAcore International AB, a GE Healthcare company, Uppsala, Sweden and Piscataway, N.J.). For further descriptions, see Jonsson et al. (1993) Ann. Biol. Clin.51: 19-26.
[0154] An “effector-positive Fc region” possesses an effector function of a native sequence Fc region.
[0155] An “effector null Fc region” lacks one or more effector function(s) of a native sequence Fc region.
[0156] Exemplary “effector functions” include Fc receptor binding; Clq binding and complement dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell- mediated cytotoxicity (ADCC); phagocytosis; down regulation of cell surface receptors (for example B-cell receptor); and B-cell activation, etc. Such effector functions generally require the Fc region to be combined with a binding domain (for example, an antibody binding domain) and can be assessed using various assays.
[0157] A “variant Fc region” comprises an amino acid sequence which differs from that of a native sequence Fc region by virtue of at least one amino acid modification. In some aspects, a “variant Fc region” comprises an amino acid sequence which differs from that of a native sequence Fc region by virtue of at least one amino acid modification, yet retains at least one effector function of the native sequence Fc region. In some aspects, a “variant Fc region” comprises an amino acid sequence which differs from that of a native sequence Fc region by virtue of at least one amino acid modification, and the variant Fc region has a modified effector function. In some aspects, a “variant Fc region” comprises an amino acid sequence which differs from that of a native sequence Fc region by virtue of at least one amino acid modification, and the variant Fc region is an effector null Fc region. In some aspects, the variant Fc region has at least one amino acid substitution compared to a native sequence Fc region or to the Fc region of a parent polypeptide, for example, from about one to about ten amino acid substitutions, and preferably, from about one to about five amino acid substitutions in a native sequence Fc region or in the Fc region of the parent polypeptide. In some aspects, the variant Fc region herein will possess at least about 80% sequence identity with a native sequence Fc region and / or with an Fc region of a parent polypeptide, at least about 90% sequence identity therewith, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity therewith.
[0158] As used herein, “percent (%) amino acid sequence identity” and “homology” with respect to a peptide, polypeptide or antibody sequence are defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the specific peptide or polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or MEGALIGNTM(DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.
[0159] An amino acid substitution may include but are not limited to the replacement of one amino acid in a polypeptide with another amino acid. Exemplary substitutions are shown in Table 2. Amino acid substitutions may be introduced into a polypeptide of interest and the products screened for a desired activity, for example, retained / improved antigen binding, decreased immunogenicity, or improved ADCC or CDC. Table 2. Amino acid residues
[0160] Amino acids may be grouped according to common side-chain properties: (1) hydrophobic: Norleucine, Met, Ala, Val, Leu, Ile; (2) neutral hydrophilic: Cys, Ser, Thr, Asn, Gln; (3) acidic: Asp, Glu; (4) basic: His, Lys, Arg; (5) residues that influence chain orientation: Gly, Pro; (6) aromatic: Trp, Tyr, Phe.
[0161] Non-conservative substitutions will entail exchanging a member of one of these classes for another class.
[0162] The term “vector” is used to describe a polynucleotide that can be engineered to contain a cloned polynucleotide or polynucleotides that can be propagated in a host cell. A vector can include one or more of the following elements: an origin of replication, one or more regulatory sequences (such as, for example, promoters and / or enhancers) that regulate the expression of the polypeptide of interest, and / or one or more selectable marker genes (such as, for example, antibiotic resistance genes and genes that can be used in colorimetric assays, for example, β- galactosidase). The term “expression vector” refers to a vector that is used to express a polypeptide of interest in a host cell.
[0163] A “host cell” refers to a cell that may be or has been a recipient of a vector or isolated polynucleotide. Host cells may be prokaryotic cells or eukaryotic cells. Exemplary eukaryoticcells include mammalian cells, such as primate or non-primate animal cells; fungal cells, such as yeast; plant cells; and insect cells. Nonlimiting exemplary mammalian cells include, but are not limited to, NSO cells, PER.C6® cells (Crucell), and 293 and CHO cells, and their derivatives, such as 293-6E, CHO-DG44, CHO-K1, CHO-S, and CHO-DS cells. Host cells include progeny of a single host cell, and the progeny may not necessarily be completely identical (in morphology or in genomic DNA complement) to the original parent cell due to natural, accidental, or deliberate mutation. A host cell includes cells transfected in vivo with a polynucleotide(s) as provided herein.
[0164] The term “isolated” as used herein refers to a molecule that has been separated from at least some of the components with which it is typically found in nature or produced. For example, a polypeptide is referred to as “isolated” when it is separated from at least some of the components of the cell in which it was produced. Where a polypeptide is secreted by a cell after expression, physically separating the supernatant containing the polypeptide from the cell that produced it is considered to be “isolating” the polypeptide. Similarly, a polynucleotide is referred to as “isolated” when it is not part of the larger polynucleotide (such as, for example, genomic DNA or mitochondrial DNA, in the case of a DNA polynucleotide) in which it is typically found in nature, or is separated from at least some of the components of the cell in which it was produced, for example, in the case of an RNA polynucleotide. Thus, a DNA polynucleotide that is contained in a vector inside a host cell may be referred to as “isolated”.
[0165] The terms “individual” and “subject” are used interchangeably herein to refer to an animal; for example, a mammal. In some aspects, methods of treating mammals, including, but not limited to, humans, rodents, and simians, are provided. In some examples, an “individual” or “subject” refers to an individual or subject in need of treatment for a disease or disorder. In some aspects, the subject to receive the treatment can be a patient, designating the fact that the subject has been identified as having a disease or disorder of relevance to the treatment, or being at adequate risk of contracting the disease or disorder.
[0166] A “disease” or “disorder” as used herein refers to a condition where treatment is needed and / or desired.
[0167] As used herein, “IL13-associated condition” refers to any condition, disorder, or disease that involves aberrant expression, activity, or function of the IL13 protein within a biological context, such as in vivo in a subject. For example, an IL13-associated condition may involveincreased IL13 expression, excessive IL13 activity, and / or any IL13 dysfunction that results in a condition where treatment is needed and / or desired.
[0168] As used herein, “treatment” is an approach for obtaining beneficial or desired clinical results. “Treatment” as used herein, covers any administration or application of a therapeutic for disease in a mammal, including a human. For purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, any one or more of: alleviation of one or more symptoms, diminishment of extent of disease, preventing or delaying spread (for example, metastasis) of disease, preventing or delaying recurrence of disease, delay or slowing of disease progression, amelioration of the disease state, inhibiting the disease or progression of the disease, inhibiting or slowing the disease or its progression, arresting its development, and remission (whether partial or total). Also encompassed by “treatment” is a reduction of pathological consequence of a proliferative disease. The methods provided herein contemplate any one or more of these aspects of treatment. In-line with the above, the term treatment does not require one-hundred percent removal of all aspects of the disorder.
[0169] A “therapeutically effective amount” of a substance / molecule, agonist or antagonist may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the substance / molecule, agonist or antagonist to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of the substance / molecule, agonist or antagonist are outweighed by the therapeutically beneficial effects. A therapeutically effective amount may be delivered in one or more administrations. A therapeutically effective amount refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic and / or prophylactic result.
[0170] The terms “pharmaceutical formulation” and “pharmaceutical composition” are used interchangeably and refer to a preparation which is in such form as to permit the biological activity of the active ingredient(s) to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered. Such formulations may be sterile.
[0171] A “pharmaceutically acceptable carrier” refers to a non-toxic solid, semisolid, or liquid filler, diluent, encapsulating material, formulation auxiliary, or carrier conventional in the art for use with a therapeutic agent that together comprise a “pharmaceutical composition” for administration to a subject. A pharmaceutically acceptable carrier is non-toxic to recipients at the dosages and concentrations employed and are compatible with other ingredients of theformulation. The pharmaceutically acceptable carrier is appropriate for the formulation employed. II. Exemplary IL13 Binding Polypeptides
[0172] Provided herein are polypeptides that bind IL13, e.g., IL13 co-binder. In some aspects, the co-binder that binds IL13 comprises one or more IL13 binding Variable Heavy Domain of Heavy Chains (VHHs). In some aspects, the IL13 co-binder comprises a first VHH (VHH1) and / or a second VHH (VHH2).
[0173] In some aspects, a co-binder that binds IL13 comprises a VHH1 and a VHH2, wherein the VHH1 and / or the VHH2 comprises a CDR3 comprising the amino acid sequence of SEQ ID NO:442 or SEQ ID NO:443 according to IMGT numbering. In some aspects, the CDR3 comprises an amino acid sequence selected from SEQ ID NOs:36, 47, 61, 64, 472-526, 531, 534, 543, 546, 555, 558, 567, 570, 579, 582, 591, 594, 603, 606, 615, 618, 627, 630, 639, and 642 according to IMGT numbering.
[0174] In some aspects, the VHH1 of the IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:131, SEQ ID NO:139, SEQ ID NO:155, SEQ ID NO:163, or SEQ ID NO:171 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:132, SEQ ID NO:140, SEQ ID NO:156, SEQ ID NO:164, or SEQ ID NO:172 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:133, SEQ ID NO:141, SEQ ID NO:157, SEQ ID NO:165, or SEQ ID NO:173 according to Kabat numbering or comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering; and the VHH2 of the IL13 cobinder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:135, SEQ ID NO:143, SEQ ID NO:159, SEQ ID NO:167, or SEQ ID NO:175 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:136, SEQ ID NO:144, SEQ ID NO:160, SEQ ID NO:168, or SEQ ID NO:176 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:137, SEQ ID NO:145, SEQ ID NO:161, SEQ ID NO:169, or SEQ ID NO:177 according to Kabat numbering.
[0175] In some aspects, the VHH1 of the IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:541, SEQ ID NO:553, or SEQ ID NO:565 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:542, SEQ ID NO:554, or SEQ ID NO:566 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442, SEQ ID NO:543, SEQ ID NO:555, or SEQ ID NO:567 according to IMGT numbering; and the VHH2 of the IL13 cobinder comprises a CDR1comprising the amino acid sequence of SEQ ID NO:544, SEQ ID NO:556, or SEQ ID NO:568 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:545, SEQ ID NO:557, or SEQ ID NO:569 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:546, SEQ ID NO:558, or SEQ ID NO:570 according to IMGT numbering.
[0176] In some aspects, the VHH1 of the IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:547, SEQ ID NO:559, or SEQ ID NO:571 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:548, SEQ ID NO:560, or SEQ ID NO:572 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:549, SEQ ID NO:561, or SEQ ID NO:573 according to Chothia numbering or SEQ ID NO:442 according to IMGT numbering; and the VHH2 of the IL13 cobinder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:550, SEQ ID NO:562, or SEQ ID NO:574 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:551, SEQ ID NO:563, or SEQ ID NO:575 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:552, SEQ ID NO:564, or SEQ ID NO:576 according to Chothia numbering.
[0177] In some aspects, the VHH1 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:67, SEQ ID NO:75, SEQ ID NO:83, SEQ ID NO:91, SEQ ID NO:99, SEQ ID NO:107, SEQ ID NO:115, SEQ ID NO:123, SEQ ID NO:147, SEQ ID NO:179, SEQ ID NO:187, SEQ ID NO:195, SEQ ID NO:203, or SEQ ID NO:211 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:68, SEQ ID NO:76, SEQ ID NO:84, SEQ ID NO:92, SEQ ID NO:100, SEQ ID NO:108, SEQ ID NO:116, SEQ ID NO:124, SEQ ID NO:148, SEQ ID NO:180, SEQ ID NO:188, SEQ ID NO:196, SEQ ID NO:204, or SEQ ID NO:212 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:69, SEQ ID NO:77, SEQ ID NO:85, SEQ ID NO:93, SEQ ID NO:101, SEQ ID NO:109, SEQ ID NO:117, SEQ ID NO:125, SEQ ID NO:149, SEQ ID NO:181, SEQ ID NO:189, SEQ ID NO:197, SEQ ID NO:205, or SEQ ID NO:213 according to Kabat numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:71, SEQ ID NO:79, SEQ ID NO:87, SEQ ID NO:95, SEQ ID NO:103, SEQ ID NO:111, SEQ ID NO:119, SEQ ID NO:127, SEQ ID NO:151, SEQ ID NO:183, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:207, or SEQ ID NO:215 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:72, SEQ ID NO:80, SEQ ID NO:88, SEQ ID NO:96, SEQ ID NO:104,SEQ ID NO:112, SEQ ID NO:120, SEQ ID NO:128, SEQ ID NO:152, SEQ ID NO:184, SEQ ID NO:192, SEQ ID NO:200, SEQ ID NO:208, or SEQ ID NO:216 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:73, SEQ ID NO:81, SEQ ID NO:89, SEQ ID NO:97, SEQ ID NO:105, SEQ ID NO:113, SEQ ID NO:121, SEQ ID NO:129, SEQ ID NO:153, SEQ ID NO:185, SEQ ID NO:193, SEQ ID NO:201, SEQ ID NO:209, or SEQ ID NO:217 according to Kabat numbering or comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering.
[0178] In some aspects, the VHH1 of the IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:529, SEQ ID NO:577, SEQ ID NO:589, SEQ ID NO:601, or SEQ ID NO:613 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:530, SEQ ID NO:578, SEQ ID NO:590, SEQ ID NO:602, or SEQ ID NO:614 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:531, SEQ ID NO:579, SEQ ID NO:591, SEQ ID NO:603, or SEQ ID NO:615 according to IMGT numbering; and the VHH2 of the IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:532, SEQ ID NO:580, SEQ ID NO:592, SEQ ID NO:604, or SEQ ID NO:616 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:533, SEQ ID NO:581, SEQ ID NO:593, SEQ ID NO:605, or SEQ ID NO:617 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442, SEQ ID NO:534, SEQ ID NO:582, SEQ ID NO:594, SEQ ID NO:606, or SEQ ID NO:618 according to IMGT numbering.
[0179] In some aspects, the VHH1 of the IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:535, SEQ ID NO:583, SEQ ID NO:595, SEQ ID NO:607, or SEQ ID NO:619 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:536, SEQ ID NO:584, SEQ ID NO:596, SEQ ID NO:608, or SEQ ID NO:620 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:537, SEQ ID NO:585, SEQ ID NO:597, SEQ ID NO:609, or SEQ ID NO:621 according to Chothia numbering; and the VHH2 of the IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:538, SEQ ID NO:586, SEQ ID NO:598, SEQ ID NO:610, or SEQ ID NO:622 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:539, SEQ ID NO:587, SEQ ID NO:599, SEQ ID NO:611, or SEQ ID NO:623 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:540, SEQ ID NO:588, SEQ ID NO:600, SEQ ID NO:612, or SEQ IDNO:624 according to Chothia numbering, or comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering.
[0180] In some aspects, the VHH1 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:219, SEQ ID NO:235, SEQ ID NO:243, SEQ ID NO:251, SEQ ID NO:259, SEQ ID NO:267, SEQ ID NO:275, SEQ ID NO:283, SEQ ID NO:291, SEQ ID NO:299, SEQ ID NO:307, SEQ ID NO:315, SEQ ID NO:323, SEQ ID NO:331, SEQ ID NO:339, SEQ ID NO:347, SEQ ID NO:355, SEQ ID NO:363, or SEQ ID NO:371 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:220, SEQ ID NO:236, SEQ ID NO:244, SEQ ID NO:252, SEQ ID NO:260, SEQ ID NO:268, SEQ ID NO:276, SEQ ID NO:284, SEQ ID NO:292, SEQ ID NO:300, SEQ ID NO:308, SEQ ID NO:316, SEQ ID NO:324, SEQ ID NO:332, SEQ ID NO:340, SEQ ID NO:348, SEQ ID NO:356, SEQ ID NO:364, or SEQ ID NO:372 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:221, SEQ ID NO:237, SEQ ID NO:245, SEQ ID NO:253, SEQ ID NO:261, SEQ ID NO:269, SEQ ID NO:277, SEQ ID NO:285, SEQ ID NO:293, SEQ ID NO:301, SEQ ID NO:309, SEQ ID NO:317, SEQ ID NO:325, SEQ ID NO:333, SEQ ID NO:341, SEQ ID NO:349, SEQ ID NO:357, SEQ ID NO:365, or SEQ ID NO:373 according to Kabat numbering or comprising the amino acid sequence of SEQ ID NO:443 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:223, SEQ ID NO:239, SEQ ID NO:247, SEQ ID NO:255, SEQ ID NO:263, SEQ ID NO:271, SEQ ID NO:279, SEQ ID NO:287, SEQ ID NO:295, SEQ ID NO:303, SEQ ID NO:311, SEQ ID NO:319, SEQ ID NO:327, SEQ ID NO:335, SEQ ID NO:343, SEQ ID NO:351, SEQ ID NO:359, SEQ ID NO:367, or SEQ ID NO:375 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:224, SEQ ID NO:240, SEQ ID NO:248, SEQ ID NO:256, SEQ ID NO:264, SEQ ID NO:272, SEQ ID NO:280, SEQ ID NO:288, SEQ ID NO:296, SEQ ID NO:304, SEQ ID NO:312, SEQ ID NO:320, SEQ ID NO:328, SEQ ID NO:336, SEQ ID NO:344, SEQ ID NO:352, SEQ ID NO:360, SEQ ID NO:368, or SEQ ID NO:376 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:225, SEQ ID NO:241, SEQ ID NO:249, SEQ ID NO:257, SEQ ID NO:265, SEQ ID NO:273, SEQ ID NO:281, SEQ ID NO:289, SEQ ID NO:297, SEQ ID NO:305, SEQ ID NO:313, SEQ ID NO:321, SEQ ID NO:329, SEQ ID NO:337, SEQ ID NO:345, SEQ ID NO:353, SEQ ID NO:361, SEQ ID NO:369, or SEQ ID NO:377 according to Kabat numbering.
[0181] In some aspects, the VHH1 of the IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:227 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:228 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:229 according to Kabat numbering; and the VHH2 of the IL13 co-binder comprises a VHH2 comprising a CDR1 comprising the amino acid sequence of SEQ ID NO:231 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:232 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:233 according to Kabat numbering or comprising the amino acid sequence of SEQ ID NO:443 according to IMGT numbering.
[0182] In some aspects, the VHH1 of the IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:31 or SEQ ID NO:435 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:32 or SEQ ID NO:436 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:33, SEQ ID NO:60, or SEQ ID NO:437 according to Kabat numbering or comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering; and the VHH2 of the IL13 co- binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:42 or SEQ ID NO:439 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:43 or SEQ ID NO:440 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:44, SEQ ID NO:63, or SEQ ID NO:441 according to Kabat numbering or comprising the amino acid sequence of SEQ ID NO:443 according to IMGT numbering.
[0183] In some aspects, the VHH1 of the IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:379, SEQ ID NO:387, SEQ ID NO:395, SEQ ID NO:403, SEQ ID NO:411, SEQ ID NO:419, or SEQ ID NO:427 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:380, SEQ ID NO:388, SEQ ID NO:396, SEQ ID NO:404, SEQ ID NO:412, SEQ ID NO:420, or SEQ ID NO:428 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:381, SEQ ID NO:389, SEQ ID NO:397, SEQ ID NO:405, SEQ ID NO:413, SEQ ID NO:421, or SEQ ID NO:429 according to Kabat numbering or comprising the amino acid sequence of SEQ ID NO:443 according to IMGT numbering; and the VHH2 of the IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:383, SEQ ID NO:391, SEQ ID NO:399, SEQ ID NO:407, SEQ ID NO:415, SEQ ID NO:423, or SEQ ID NO:431 according to Kabatnumbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:384, SEQ ID NO:392, SEQ ID NO:400, SEQ ID NO:408, SEQ ID NO:416, SEQ ID NO:424, or SEQ ID NO:432 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:385, SEQ ID NO:393, SEQ ID NO:401, SEQ ID NO:409, SEQ ID NO:417, SEQ ID NO:425, or SEQ ID NO:433 according to Kabat numbering or comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering.
[0184] In some aspects, the VHH1 of the IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:625 or SEQ ID NO:637 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:626 or SEQ ID NO:638 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:443, SEQ ID NO:627 or SEQ ID NO:639 according to IMGT numbering; and the VHH2 of the IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:628 or SEQ ID NO:640 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:629 or SEQ ID NO:641 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442, SEQ ID NO:630, or SEQ ID NO:642 according to IMGT numbering.
[0185] In some aspects, the VHH1 of the IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:631 or SEQ ID NO:643 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:632 or SEQ ID NO:644 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:633 or SEQ ID NO:645 according to Chothia numbering or SEQ ID NO:443 according to IMGT numbering; and the VHH2 of the IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:634 or SEQ ID NO:646 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:635 or SEQ ID NO:647 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:636 or SEQ ID NO:648 according to Chothia numbering or SEQ ID NO:442 according to IMGT numbering.
[0186] Also provided herein is a polypeptide that binds IL13, e.g., IL13 co-binder, comprising a VHH1 and / or a VHH2 that specifically binds to IL13. In some aspects, the VHH1 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:131, SEQ ID NO:139, SEQ ID NO:155, SEQ ID NO:163, or SEQ ID NO:171 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:132, SEQ ID NO:140, SEQ ID NO:156,SEQ ID NO:164, or SEQ ID NO:172 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:133, SEQ ID NO:141, SEQ ID NO:157, SEQ ID NO:165, or SEQ ID NO:173 according to Kabat numbering or comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:135, SEQ ID NO:143, SEQ ID NO:159, SEQ ID NO:167, or SEQ ID NO:175 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:136, SEQ ID NO:144, SEQ ID NO:160, SEQ ID NO:168, or SEQ ID NO:176 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:137, SEQ ID NO:145, SEQ ID NO:161, SEQ ID NO:169, or SEQ ID NO:177 according to Kabat numbering.
[0187] Also provided herein is a polypeptide that binds IL13, e.g., IL13 co-binder, comprising a VHH1 and / or a VHH2 that specifically binds to IL13. In some aspects, the VHH1 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:541, SEQ ID NO:553, or SEQ ID NO:565 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:542, SEQ ID NO:554, or SEQ ID NO:566 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442, SEQ ID NO:543, SEQ ID NO:555, or SEQ ID NO:567 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:544, SEQ ID NO:556, or SEQ ID NO:568 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:545, SEQ ID NO:557, or SEQ ID NO:569 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:546, SEQ ID NO:558, or SEQ ID NO:570 according to IMGT numbering.
[0188] Also provided herein is a polypeptide that binds IL13, e.g., IL13 co-binder, comprising a VHH1 and / or a VHH2 that specifically binds to IL13. In some aspects, the VHH1 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:547, SEQ ID NO:559, or SEQ ID NO:571 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:548, SEQ ID NO:560, or SEQ ID NO:572 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:549, SEQ ID NO:561, or SEQ ID NO:573 according to Chothia numbering, or SEQ ID NO:442 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:550, SEQ ID NO:562, or SEQ ID NO:574 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:551, SEQ ID NO:563, or SEQ ID NO:575 according to Chothianumbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:552, SEQ ID NO:564, or SEQ ID NO:576 according to Chothia numbering.
[0189] In some aspects, the VHH1 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:67, SEQ ID NO:75, SEQ ID NO:83, SEQ ID NO:91, SEQ ID NO:99, SEQ ID NO:107, SEQ ID NO:115, SEQ ID NO:123, SEQ ID NO:147, SEQ ID NO:179, SEQ ID NO:187, SEQ ID NO:195, SEQ ID NO:203, or SEQ ID NO:211 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:68, SEQ ID NO:76, SEQ ID NO:84, SEQ ID NO:92, SEQ ID NO:100, SEQ ID NO:108, SEQ ID NO:116, SEQ ID NO:124, SEQ ID NO:148, SEQ ID NO:180, SEQ ID NO:188, SEQ ID NO:196, SEQ ID NO:204, or SEQ ID NO:212 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:69, SEQ ID NO:77, SEQ ID NO:85, SEQ ID NO:93, SEQ ID NO:101, SEQ ID NO:109, SEQ ID NO:117, SEQ ID NO:125, SEQ ID NO:149, SEQ ID NO:181, SEQ ID NO:189, SEQ ID NO:197, SEQ ID NO:205, or SEQ ID NO:213 according to Kabat numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:71, SEQ ID NO:79, SEQ ID NO:87, SEQ ID NO:95, SEQ ID NO:103, SEQ ID NO:111, SEQ ID NO:119, SEQ ID NO:127, SEQ ID NO:151, SEQ ID NO:183, SEQ ID NO:191, SEQ ID NO:199, SEQ ID NO:207, or SEQ ID NO:215 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:72, SEQ ID NO:80, SEQ ID NO:88, SEQ ID NO:96, SEQ ID NO:104, SEQ ID NO:112, SEQ ID NO:120, SEQ ID NO:128, SEQ ID NO:152, SEQ ID NO:184, SEQ ID NO:192, SEQ ID NO:200, SEQ ID NO:208, or SEQ ID NO:216 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:73, SEQ ID NO:81, SEQ ID NO:89, SEQ ID NO:97, SEQ ID NO:105, SEQ ID NO:113, SEQ ID NO:121, SEQ ID NO:129, SEQ ID NO:153, SEQ ID NO:185, SEQ ID NO:193, SEQ ID NO:201, SEQ ID NO:209, or SEQ ID NO:217 according to Kabat numbering or comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering.
[0190] In some aspects, the VHH1 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:529, SEQ ID NO:577, SEQ ID NO:589, SEQ ID NO:601, or SEQ ID NO:613 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:530, SEQ ID NO:578, SEQ ID NO:590, SEQ ID NO:602, or SEQ ID NO:614 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:531, SEQ ID NO:579, SEQ ID NO:591, SEQ ID NO:603, or SEQ ID NO:615 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:532, SEQID NO:580, SEQ ID NO:592, SEQ ID NO:604, or SEQ ID NO:616 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:533, SEQ ID NO:581, SEQ ID NO:593, SEQ ID NO:605, or SEQ ID NO:617 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442, SEQ ID NO:534, SEQ ID NO:582, SEQ ID NO:594, SEQ ID NO:606, or SEQ ID NO:618 according to IMGT numbering.
[0191] In some aspects, the VHH1 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:535, SEQ ID NO:583, SEQ ID NO:595, SEQ ID NO:607, or SEQ ID NO:619 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:536, SEQ ID NO:584, SEQ ID NO:596, SEQ ID NO:608, or SEQ ID NO:620 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:537, SEQ ID NO:585, SEQ ID NO:597, SEQ ID NO:609, or SEQ ID NO:621 according to Chothia numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:538, SEQ ID NO:586, SEQ ID NO:598, SEQ ID NO:610, or SEQ ID NO:622 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:539, SEQ ID NO:587, SEQ ID NO:599, SEQ ID NO:611, or SEQ ID NO:623 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:540, SEQ ID NO:588, SEQ ID NO:600, SEQ ID NO:612, or SEQ ID NO:624 according to Chothia numbering or SEQ ID NO:442 according to IMGT numbering.
[0192] In some aspects, the VHH1 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:219, SEQ ID NO:235, SEQ ID NO:243, SEQ ID NO:251, SEQ ID NO:259, SEQ ID NO:267, SEQ ID NO:275, SEQ ID NO:283, SEQ ID NO:291, SEQ ID NO:299, SEQ ID NO:307, SEQ ID NO:315, SEQ ID NO:323, SEQ ID NO:331, SEQ ID NO:339, SEQ ID NO:347, SEQ ID NO:355, SEQ ID NO:363, or SEQ ID NO:371 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:220, SEQ ID NO:236, SEQ ID NO:244, SEQ ID NO:252, SEQ ID NO:260, SEQ ID NO:268, SEQ ID NO:276, SEQ ID NO:284, SEQ ID NO:292, SEQ ID NO:300, SEQ ID NO:308, SEQ ID NO:316, SEQ ID NO:324, SEQ ID NO:332, SEQ ID NO:340, SEQ ID NO:348, SEQ ID NO:356, SEQ ID NO:364, or SEQ ID NO:372 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:221, SEQ ID NO:237, SEQ ID NO:245, SEQ ID NO:253, SEQ ID NO:261, SEQ ID NO:269, SEQ ID NO:277, SEQ ID NO:285, SEQ ID NO:293, SEQ ID NO:301, SEQ ID NO:309, SEQ ID NO:317, SEQ ID NO:325, SEQ ID NO:333, SEQ ID NO:341, SEQ ID NO:349, SEQ ID NO:357, SEQ ID NO:365, or SEQ ID NO:373 according toKabat numbering or comprising the amino acid sequence of SEQ ID NO:443 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:223, SEQ ID NO:239, SEQ ID NO:247, SEQ ID NO:255, SEQ ID NO:263, SEQ ID NO:271, SEQ ID NO:279, SEQ ID NO:287, SEQ ID NO:295, SEQ ID NO:303, SEQ ID NO:311, SEQ ID NO:319, SEQ ID NO:327, SEQ ID NO:335, SEQ ID NO:343, SEQ ID NO:351, SEQ ID NO:359, SEQ ID NO:367, or SEQ ID NO:375 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:224, SEQ ID NO: 240, SEQ ID NO: 248, SEQ ID NO:256, SEQ ID NO:264, SEQ ID NO: 272, SEQ ID NO: 280, SEQ ID NO: 288, SEQ ID NO:296, SEQ ID NO:304, SEQ ID NO: 312, SEQ ID NO: 320, SEQ ID NO: 328, SEQ ID NO:336, SEQ ID NO:344, SEQ ID NO: 352, SEQ ID NO: 360, SEQ ID NO:368, or SEQ ID NO:376 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:225, SEQ ID NO:241, SEQ ID NO:249, SEQ ID NO:257, SEQ ID NO:265, SEQ ID NO:273, SEQ ID NO:281, SEQ ID NO:289, SEQ ID NO:297, SEQ ID NO:305, SEQ ID NO:313, SEQ ID NO:321, SEQ ID NO:329, SEQ ID NO:337, SEQ ID NO:345, SEQ ID NO:353, SEQ ID NO:361, SEQ ID NO:369, or SEQ ID NO:377 according to Kabat numbering.
[0193] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:227 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:228 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:229 according to Kabat numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:231 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:232 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:233 according to Kabat numbering or comprising the amino acid sequence of SEQ ID NO:443 according to IMGT numbering.
[0194] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:31 or SEQ ID NO:435 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:32 or SEQ ID NO:436 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:33, SEQ ID NO:60, or SEQ ID NO:437 according to Kabat numbering or comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering; and the VHH2 of an IL13 co- binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:42 or SEQ IDNO:439 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:43 or SEQ ID NO:440 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:44, SEQ ID NO:63, or SEQ ID NO:441 according to Kabat numbering or comprising the amino acid sequence of SEQ ID NO:443 according to IMGT numbering.
[0195] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:379, SEQ ID NO:387, SEQ ID NO:395, SEQ ID NO:403, SEQ ID NO:411, SEQ ID NO:419, or SEQ ID NO:427 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:380, SEQ ID NO:388, SEQ ID NO:396, SEQ ID NO:404, SEQ ID NO:412, SEQ ID NO:420, or SEQ ID NO:428 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:381, SEQ ID NO:389, SEQ ID NO:397, SEQ ID NO:405, SEQ ID NO:413, SEQ ID NO:421, or SEQ ID NO:429 according to Kabat numbering or comprising the amino acid sequence of SEQ ID NO:443 according to IMGT numbering; and the VHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:383, SEQ ID NO:391, SEQ ID NO:399, SEQ ID NO:407, SEQ ID NO:415, SEQ ID NO:423, or SEQ ID NO:431 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:384, SEQ ID NO:392, SEQ ID NO:400, SEQ ID NO:408, SEQ ID NO:416, SEQ ID NO:424, or SEQ ID NO:432 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:385, SEQ ID NO:393, SEQ ID NO:401, SEQ ID NO:409, SEQ ID NO:417, SEQ ID NO:425, or SEQ ID NO:433 according to Kabat numbering or comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering.
[0196] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:625 or SEQ ID NO:637 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:626 or SEQ ID NO:638 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:443, SEQ ID NO:627, or SEQ ID NO:639 according to IMGT numbering; and the VHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:628 or SEQ ID NO:640 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:629 or SEQ ID NO:641 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442, SEQ ID NO:630, or SEQ ID NO:642 according to IMGT numbering.
[0197] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:631 or SEQ ID NO:643 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:632 or SEQ ID NO:644 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:633, or SEQ ID NO:645 according to Chothia numbering or SEQ ID NO:443 according to IMGT numbering; and the VHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:634 or SEQ ID NO:646 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:635 or SEQ ID NO:647 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:636 or SEQ ID NO:648 according to Chothia numbering or SEQ ID NO:442 according to IMGT numbering.
[0198] In some aspects, the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:480, SEQ ID NO:481, SEQ ID NO:483, SEQ ID NO:484, SEQ ID NO:485, or SEQ ID NO:442 according to IMGT numbering.
[0199] In some aspects, the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:472, SEQ ID NO:473, SEQ ID NO:474, SEQ ID NO:475, SEQ ID NO:476, SEQ ID NO:477, SEQ ID NO:478, SEQ ID NO:479, SEQ ID NO:482, SEQ ID NO:486, SEQ ID NO:487, SEQ ID NO:488, SEQ ID NO:489, SEQ ID NO:490, or SEQ ID NO:442 according to IMGT numbering.
[0200] In some aspects, the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:491, SEQ ID NO:493, SEQ ID NO:494, SEQ ID NO:495, SEQ ID NO:496, SEQ ID NO:497, SEQ ID NO:498, SEQ ID NO:499, SEQ ID NO:500, SEQ ID NO:501, SEQ ID NO:502, SEQ ID NO:503, SEQ ID NO:504, SEQ ID NO:505, SEQ ID NO:506, SEQ ID NO:507, SEQ ID NO:508, SEQ ID NO:509, SEQ ID NO:510, or SEQ ID NO:443 according to IMGT numbering.
[0201] In some aspects, the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:492 or SEQ ID NO:443 according to IMGT numbering.
[0202] In some aspects, the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:36, SEQ ID NO:61, SEQ ID NO:525, or SEQ ID NO:442 according to IMGT numbering; and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:47, SEQ ID NO:64, SEQ ID NO:526, or SEQ ID NO:443 according to IMGT numbering.
[0203] In some aspects, the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:511, SEQ ID NO:513, SEQ ID NO:515, SEQ ID NO:517, SEQ ID NO:519, SEQ ID NO:521, SEQ ID NO:523, or SEQ ID NO:443 according to IMGT numbering; and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:512, SEQ ID NO:514, SEQ ID NO:516, SEQ ID NO:518, SEQ ID NO:520, SEQ ID NO:522, SEQ ID NO:524, or SEQ ID NO:442 according to IMGT numbering.
[0204] In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:131 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:132 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:133 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:480 or SEQ ID NO:442 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:135 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:136 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:137 according to Kabat numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:139 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:140 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:141 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:481 or SEQ ID NO:442 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:143 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:144 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:145 according to Kabat numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:155 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:156 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:157 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:483 or SEQ ID NO:442 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:159 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:160 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:161 according to Kabat numbering. In someaspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:163 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:164 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:165 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:484 or SEQ ID NO:442 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:167 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:168 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:169 according to Kabat numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:171 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:172 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:173 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:485 or SEQ ID NO:442 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:175 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:176 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:177 according to Kabat numbering.
[0205] In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:67 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:68 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:69 according to Kabat numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:71 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:72 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:73 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:472 or SEQ ID NO:442 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:75 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:76 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:77 according to Kabat numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:79 according to Kabat numbering, the CDR2 of the VHH2 comprises the aminoacid sequence of SEQ ID NO:80 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:81 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:473 or SEQ ID NO:442 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:83 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:84 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:85 according to Kabat numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:87 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:88 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:89 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:474 or SEQ ID NO:442 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:91 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:92 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:93 according to Kabat numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:95 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:96 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:97 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:475 or SEQ ID NO:442 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:99 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:100 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:101 according to Kabat numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:103 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:104 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:105 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:476 or SEQ ID NO:442 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:107 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:108 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ IDNO:109 according to Kabat numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:111 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:112 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:113 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:477 or SEQ ID NO:442 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:115 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:116 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:117 according to Kabat numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:119 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:120 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:121 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:478 or SEQ ID NO:442 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:123 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:124 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:125 according to Kabat numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:127 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:128 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:129 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:479 or SEQ ID NO:442 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:147 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:148 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:149 according to Kabat numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:151 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:152 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:153 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:482 or SEQ ID NO:442 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:179 according to Kabat numbering,the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:180 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:181 according to Kabat numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:183 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:184 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:185 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:486 or SEQ ID NO:442 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:187 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:188 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:189 according to Kabat numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:191 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:192 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:193 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:487 or SEQ ID NO:442 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:195 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:196 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:197 according to Kabat numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:199 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:200 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:201 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:488 or SEQ ID NO:442 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:203 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:204 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:205 according to Kabat numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:207 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:208 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:209 according to Kabat numbering or comprises the amino acid sequence of SEQID NO:489 or SEQ ID NO:442 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:211 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:212 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:213 according to Kabat numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:215 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:216 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:217 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:490 or SEQ ID NO:442 according to IMGT numbering.
[0206] In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:219 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:220 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:221 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:491 or SEQ ID NO:443 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:223 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:224 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:225 according to Kabat numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:235 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:236 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:237 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:493 or SEQ ID NO:443 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:239 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:240 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:241 according to Kabat numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:243 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:244 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:245 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:494 or SEQ ID NO:443according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:247 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:248 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:249 according to Kabat numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:251 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:252 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:253 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:495 or SEQ ID NO:443 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:255 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:256 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:257 according to Kabat numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:259 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:260 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:261 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:496 or SEQ ID NO:443 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:263 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:264 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:265 according to Kabat numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:267 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:268 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:269 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:497 or SEQ ID NO:443 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:271 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:272 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:273 according to Kabat numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:275 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:276according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:277 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:498 or SEQ ID NO:443 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:279 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:280 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:281 according to Kabat numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:283 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:284 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:285 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:499 or SEQ ID NO:443 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:287 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:288 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:289 according to Kabat numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:291 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:292 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:293 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:500 or SEQ ID NO:443 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:295 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:296 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:297 according to Kabat numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:299 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:300 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:301 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:501 or SEQ ID NO:443 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:303 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:304 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:305 according to Kabatnumbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:307 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:308 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:309 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:502 or SEQ ID NO:443 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:311 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:312 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:313 according to Kabat numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:315 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:316 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:317 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:503 or SEQ ID NO:443 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:319 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:320 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:321 according to Kabat numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:323 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:324 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:325 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:504 or SEQ ID NO:443 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:327 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:328 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:329 according to Kabat numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:331 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:332 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:333 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:505 or SEQ ID NO:443 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:335 according to Kabatnumbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:336 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:337 according to Kabat numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:339 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:340 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:341 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:506 or SEQ ID NO:443 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:343 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:344 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:345 according to Kabat numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:347 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:348 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:349 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:507 or SEQ ID NO:443 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:351 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:352 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:353 according to Kabat numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:355 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:356 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:357 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:508 or SEQ ID NO:443 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:359 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:360 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:361 according to Kabat numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:363 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:364 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:365 according to Kabatnumbering or comprises the amino acid sequence of SEQ ID NO:509 or SEQ ID NO:443 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:367 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:368 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:369 according to Kabat numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:371 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:372 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:373 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:510 or SEQ ID NO:443 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:375 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:376 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:377 according to Kabat numbering.
[0207] In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:227 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:228 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:229 according to Kabat numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:231 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:232 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:233 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:492 or SEQ ID NO:443 according to IMGT numbering.
[0208] In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:31 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:32 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:33 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:36 or SEQ ID NO:442 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:42 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:43 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:44 according to Kabat numbering or comprises the amino acidsequence of SEQ ID NO:47 or SEQ ID NO:443 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:31 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:32 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:60 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:61 or SEQ ID NO:442 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:42 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:43 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:63 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:64 or SEQ ID NO:443 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:435 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:436 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:437 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:525 or SEQ ID NO:442 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:439 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:440 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:441 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:526 or SEQ ID NO:443 according to IMGT numbering.
[0209] In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:379 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:380 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:381 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:511 or SEQ ID NO:443 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:383 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:384 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:385 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:512 or SEQ ID NO:442 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:387according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:388 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:389 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:513 or SEQ ID NO:443 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:391 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:392 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:393 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:514 or SEQ ID NO:442 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:395 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:396 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:397 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:515 or SEQ ID NO:443 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:399 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:400 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:401 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:516 or SEQ ID NO:442 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:403 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:404 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:405 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:517 or SEQ ID NO:443 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:407 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:408 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:409 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:518 or SEQ ID NO:442 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:411 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:412 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:413 according to Kabat numbering orcomprises the amino acid sequence of SEQ ID NO:519 or SEQ ID NO:443 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:415 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:416 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:417 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:520 or SEQ ID NO:442 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:419 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:420 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:421 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:521 or SEQ ID NO:443 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:423 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:424 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:425 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:522 or SEQ ID NO:442 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:427 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:428 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:429 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:523 or SEQ ID NO:443 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:431 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:432 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:433 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:524 or SEQ ID NO:442 according to IMGT numbering.
[0210] In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:31 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:32 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:33 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:36 or SEQ ID NO:442 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:42according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:43 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:44 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:47 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:31 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:32 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:60 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:61 or SEQ ID NO:442 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:42 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:43 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:63 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:64 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:435 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:436 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:437 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:525 or SEQ ID NO:442 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:439 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:440 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:441 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:526 according to IMGT numbering.
[0211] In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:379 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:380 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:381 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:511 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:383 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:384 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:385 according to Kabat numbering or comprises the amino acid sequence of SEQID NO:512 or SEQ ID NO:442 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:387 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:388 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:389 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:513 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:391 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:392 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:393 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:514 or SEQ ID NO:442 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:395 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:396 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:397 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:515 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:399 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:400 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:401 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:516 or SEQ ID NO:442 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:403 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:404 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:405 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:517 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:407 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:408 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:409 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:518 or SEQ ID NO:442 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:411 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:412 according to Kabat numbering, and the CDR3 of the VHH1comprises the amino acid sequence of SEQ ID NO:413 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:519 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:415 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:416 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:417 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:520 or SEQ ID NO:442 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:419 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:420 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:421 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:521 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:423 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:424 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:425 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:522 or SEQ ID NO:442 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:427 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:428 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:429 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:523 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:431 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:432 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:433 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:524 or SEQ ID NO:442 according to IMGT numbering.
[0212] In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:31 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:32 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:33 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:36 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:42 according to Kabatnumbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:43 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:44 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:47 or SEQ ID NO:443 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:31 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:32 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:60 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:61 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:42 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:43 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:63 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:64 or SEQ ID NO:443 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:435 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:436 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:437 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:525 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:439 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:440 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:441 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:526 or SEQ ID NO:443 according to IMGT numbering.
[0213] In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:379 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:380 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:381 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:511 or SEQ ID NO:443 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:383 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:384 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:385 according to Kabat numbering or comprises the aminoacid sequence of SEQ ID NO:512 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:387 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:388 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:389 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:513 or SEQ ID NO:443 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:391 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:392 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:393 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:514 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:395 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:396 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:397 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:515 or SEQ ID NO:443 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:399 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:400 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:401 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:516 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:403 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:404 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:405 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:517 or SEQ ID NO:443 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:407 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:408 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:409 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:518 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:411 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:412 according to Kabat numbering,and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:413 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:519 or SEQ ID NO:443 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:415 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:416 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:417 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:520 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:419 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:420 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:421 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:521 or SEQ ID NO:443 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:423 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:424 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:425 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:522 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:427 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:428 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:429 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:523 or SEQ ID NO:443 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:431 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:432 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:433 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:524 according to IMGT numbering.
[0214] In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:131 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:132 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:133 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:480 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:135 according to Kabatnumbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:136 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:137 according to Kabat numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:139 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:140 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:141 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:481 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:143 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:144 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:145 according to Kabat numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:155 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:156 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:157 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:483 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:159 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:160 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:161 according to Kabat numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:163 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:164 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:165 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:484 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:167 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:168 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:169 according to Kabat numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:171 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:172 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:173 according to Kabat numbering or comprises the amino acid sequence of SEQID NO:485 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:175 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:176 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:177 according to Kabat numbering.
[0215] In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:67 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:68 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:69 according to Kabat numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:71 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:72 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:73 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:472 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:75 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:76 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:77 according to Kabat numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:79 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:80 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:81 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:473 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:83 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:84 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:85 according to Kabat numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:87 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:88 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:89 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:474 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:91 according to Kabat numbering, the CDR2 of the VHH1comprises the amino acid sequence of SEQ ID NO:92 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:93 according to Kabat numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:95 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:96 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:97 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:475 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:99 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:100 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:101 according to Kabat numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:103 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:104 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:105 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:476 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:107 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:108 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:109 according to Kabat numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:111 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:112 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:113 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:477 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:115 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:116 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:117 according to Kabat numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:119 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:120 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:121 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:478 according to IMGT numbering. In some aspects, the CDR1 ofthe VHH1 comprises the amino acid sequence of SEQ ID NO:123 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:124 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:125 according to Kabat numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:127 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:128 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:129 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:479 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:147 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:148 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:149 according to Kabat numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:151 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:152 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:153 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:482 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:179 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:180 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:181 according to Kabat numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:183 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:184 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:185 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:486 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:187 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:188 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:189 according to Kabat numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:191 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:192 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ IDNO:193 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:487 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:195 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:196 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:197 according to Kabat numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:199 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:200 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:201 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:488 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:203 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:204 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:205 according to Kabat numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:207 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:208 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:209 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:489 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:211 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:212 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:213 according to Kabat numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:215 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:216 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:217 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:490 according to IMGT numbering.
[0216] In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:219 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:220 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:221 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:491 according to IMGT numbering; and theCDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:223 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:224 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:225 according to Kabat numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:235 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:236 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:237 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:493 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:239 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:240 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:241 according to Kabat numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:243 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:244 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:245 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:494 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:247 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:248 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:249 according to Kabat numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:251 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:252 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:253 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:495 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:255 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:256 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:257 according to Kabat numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:259 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:260 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequenceof SEQ ID NO:261 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:496 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:263 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:264 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:265 according to Kabat numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:267 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:268 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:269 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:497 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:271 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:272 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:273 according to Kabat numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:275 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:276 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:277 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:498 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:279 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:280 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:281 according to Kabat numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:283 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:284 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:285 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:499 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:287 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:288 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:289 according to Kabat numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:291 according to Kabat numbering, the CDR2 of the VHH1comprises the amino acid sequence of SEQ ID NO:292 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:293 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:500 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:295 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:296 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:297 according to Kabat numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:299 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:300 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:301 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:501 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:303 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:304 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:305 according to Kabat numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:307 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:308 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:309 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:502 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:311 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:312 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:313 according to Kabat numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:315 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:316 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:317 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:503 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:319 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:320 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:321 according to Kabat numbering. In someaspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:323 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:324 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:325 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:504 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:327 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:328 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:329 according to Kabat numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:331 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:332 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:333 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:505 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:335 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:336 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:337 according to Kabat numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:339 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:340 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:341 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:506 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:343 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:344 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:345 according to Kabat numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:347 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:348 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:349 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:507 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:351 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:352according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:353 according to Kabat numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:355 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:356 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:357 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:508 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:359 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:360 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:361 according to Kabat numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:363 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:364 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:365 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:509 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:367 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:368 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:369 according to Kabat numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:371 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:372 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:373 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:510 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:375 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:376 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:377 according to Kabat numbering.
[0217] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:541 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:542 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442 or SEQ ID NO:543 according to IMGT numbering; and the VHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acidsequence of SEQ ID NO:544 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:545 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:546 according to IMGT numbering.
[0218] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:541 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:542 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:543 according to IMGT numbering; and the VHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:544 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:545 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:546 according to IMGT numbering.
[0219] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:547 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:548 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:549 according to Chothia numbering or SEQ ID NO:442 according to IMGT numbering; and the VHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:550 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:551 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:552 according to Chothia numbering.
[0220] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:547 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:548 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:549 according to Chothia numbering; and the VHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:550 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:551 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:552 according to Chothia numbering.
[0221] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:553 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:554 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442 or SEQ ID NO:555 according to IMGTnumbering; and the VHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:556 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:557 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:558 according to IMGT numbering.
[0222] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:553 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:554 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:555 according to IMGT numbering; and the VHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:556 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:557 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:558 according to IMGT numbering.
[0223] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:559 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:560 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:561 according to Chothia numbering or SEQ ID NO:442 according to IMGT numbering; and the VHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:562 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:563 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:564 according to Chothia numbering.
[0224] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:559 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:560 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:561 according to Chothia numbering; and the VHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:562 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:563 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:564 according to Chothia numbering.
[0225] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:565 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:566 according to IMGT numbering; and a CDR3comprising the amino acid sequence of SEQ ID NO:442 or SEQ ID NO:567 according to IMGT numbering; and the VHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:568 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:569 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:570 according to IMGT numbering.
[0226] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:565 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:566 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:567 according to IMGT numbering; and the VHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:568 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:569 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:570 according to IMGT numbering.
[0227] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:571 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:572 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:573 according to Chothia numbering or SEQ ID NO:442 according to IMGT numbering; and the VHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:574 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:575 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:576 according to Chothia numbering.
[0228] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:571 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:572 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:573 according to Chothia numbering; and the VHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:574 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:575 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:576 according to Chothia numbering.
[0229] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:529 according to IMGT numbering; a CDR2 comprising theamino acid sequence of SEQ ID NO:530 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:531 according to IMGT numbering; and the VHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:532 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:533 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442 or SEQ ID NO:534 according to IMGT numbering.
[0230] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:529 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:530 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:531 according to IMGT numbering; and the VHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:532 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:533 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:534 according to IMGT numbering.
[0231] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:535 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:536 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:537 according to Chothia numbering; and the VHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:538 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:539 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:540 according to Chothia numbering or SEQ ID NO:442 according to IMGT numbering.
[0232] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:535 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:536 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:537 according to Chothia numbering; and the VHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:538 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:539 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:540 according to Chothia numbering.
[0233] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:577 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:578 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:579 according to IMGT numbering; and the VHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:580 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:581 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442 or SEQ ID NO:582 according to IMGT numbering.
[0234] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:577 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:578 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:579 according to IMGT numbering; and the VHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:580 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:581 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:582 according to IMGT numbering.
[0235] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:583 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:584 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:585 according to Chothia numbering; and the VHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:586 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:587 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:588 according to Chothia numbering or SEQ ID NO:442 according to IMGT numbering.
[0236] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:583 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:584 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:585 according to Chothia numbering; and the VHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:586 according to Chothia numbering; a CDR2 comprising the amino acid sequence ofSEQ ID NO:587 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:588 according to Chothia numbering.
[0237] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:589 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:590 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:591 according to IMGT numbering; and the VHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:592 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:593 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442 or SEQ ID NO:594 according to IMGT numbering.
[0238] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:589 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:590 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:591 according to IMGT numbering; and the VHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:592 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:593 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:594 according to IMGT numbering.
[0239] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:595 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:596 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:597 according to Chothia numbering; and the VHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:598 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:599 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:600 according to Chothia numbering or SEQ ID NO:442 according to IMGT numbering.
[0240] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:595 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:596 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:597 according to Chothia numbering; and the VHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQID NO:598 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:599 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:600 according to Chothia numbering.
[0241] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:601 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:602 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:603 according to IMGT numbering; and the VHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:604 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:605 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442 or SEQ ID NO:606 according to IMGT numbering.
[0242] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:601 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:602 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:603 according to IMGT numbering; and the VHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:604 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:605 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:606 according to IMGT numbering.
[0243] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:607 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:608 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:609 according to Chothia numbering; and the VHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:610 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:611 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:612 according to Chothia numbering or SEQ ID NO:442 according to IMGT numbering.
[0244] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:607 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:608 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:609 according to Chothia numbering; andthe VHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:610 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:611 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:612 according to Chothia numbering.
[0245] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:613 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:614 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:615 according to IMGT numbering; and the VHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:616 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:617 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442 or SEQ ID NO:618 according to IMGT numbering.
[0246] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:613 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:614 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:615 according to IMGT numbering; and the VHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:616 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:617 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:618 according to IMGT numbering.
[0247] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:619 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:620 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:621 according to Chothia numbering; and the VHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:622 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:623 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:624 according to Chothia numbering or SEQ ID NO:442 according to IMGT numbering.
[0248] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:619 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:620 according to Chothia numbering; and a CDR3comprising the amino acid sequence of SEQ ID NO:621 according to Chothia numbering; and the VHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:622 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:623 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:624 according to Chothia numbering.
[0249] In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:227 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:228 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:229 according to Kabat numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:231 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:232 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:233 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:492 according to IMGT numbering.
[0250] In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:31 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:32 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:33 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:36 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:42 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:43 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:44 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:47 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:31 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:32 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:60 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:61 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:42 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:43 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:63 according to Kabat numbering or comprises the amino acidsequence of SEQ ID NO:64 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:435 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:436 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:437 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:525 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:439 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:440 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:441 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:526 according to IMGT numbering.
[0251] In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:379 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:380 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:381 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:511 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:383 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:384 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:385 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:512 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:387 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:388 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:389 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:513 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:391 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:392 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:393 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:514 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:395 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:396 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequenceof SEQ ID NO:397 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:515 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:399 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:400 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:401 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:516 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:403 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:404 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:405 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:517 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:407 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:408 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:409 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:518 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:411 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:412 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:413 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:519 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:415 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:416 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:417 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:520 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:419 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:420 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:421 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:521 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:423 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:424 according to Kabat numbering, and theCDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:425 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:522 according to IMGT numbering. In some aspects, the CDR1 of the VHH1 comprises the amino acid sequence of SEQ ID NO:427 according to Kabat numbering, the CDR2 of the VHH1 comprises the amino acid sequence of SEQ ID NO:428 according to Kabat numbering, and the CDR3 of the VHH1 comprises the amino acid sequence of SEQ ID NO:429 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:523 according to IMGT numbering; and the CDR1 of the VHH2 comprises the amino acid sequence of SEQ ID NO:431 according to Kabat numbering, the CDR2 of the VHH2 comprises the amino acid sequence of SEQ ID NO:432 according to Kabat numbering, and the CDR3 of the VHH2 comprises the amino acid sequence of SEQ ID NO:433 according to Kabat numbering or comprises the amino acid sequence of SEQ ID NO:524 according to IMGT numbering.
[0252] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:625 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:626 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:443 or SEQ ID NO:627 according to IMGT numbering; and the VHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:628 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:629 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442 or SEQ ID NO:630 according to IMGT numbering.
[0253] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:625 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:626 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:443 or SEQ ID NO:627 according to IMGT numbering; and the VHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:628 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:629 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:630 according to IMGT numbering.
[0254] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:625 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:626 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:627 according to IMGT numbering; and theVHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:628 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:629 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442 or SEQ ID NO:630 according to IMGT numbering.
[0255] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:625 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:626 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:627 according to IMGT numbering; and the VHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:628 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:629 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:630 according to IMGT numbering.
[0256] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:631 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:632 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:633 according to Chothia numbering or SEQ ID NO:443 according to IMGT numbering; and the VHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:634 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:635 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:636 according to Chothia numbering or SEQ ID NO:442 according to IMGT numbering.
[0257] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:631 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:632 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:633 according to Chothia numbering; and the VHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:634 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:635 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:636 according to Chothia numbering or SEQ ID NO:442 according to IMGT numbering.
[0258] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:631 according to Chothia numbering; a CDR2 comprisingthe amino acid sequence of SEQ ID NO:632 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:633 according to Chothia numbering or SEQ ID NO:443 according to IMGT numbering; and the VHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:634 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:635 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:636 according to Chothia numbering.
[0259] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:631 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:632 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:633 according to Chothia numbering; and the VHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:634 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:635 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:636 according to Chothia numbering.
[0260] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:637 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:638 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:443 or SEQ ID NO:639 according to IMGT numbering; and the VHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:640 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:641 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442 or SEQ ID NO:642 according to IMGT numbering.
[0261] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:637 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:638 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:639 according to IMGT numbering; and the VHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:640 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:641 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:442 or SEQ ID NO:642 according to IMGT numbering.
[0262] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:637 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:638 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:443 or SEQ ID NO:639 according to IMGT numbering; and the VHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:640 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:641 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:642 according to IMGT numbering.
[0263] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:637 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:638 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:639 according to IMGT numbering; and the VHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:640 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:641 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:642 according to IMGT numbering.
[0264] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:643 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:644 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:645 according to Chothia numbering or SEQ ID NO:443 according to IMGT numbering; and the VHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:646 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:647 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:648 according to Chothia numbering or SEQ ID NO:442 according to IMGT numbering.
[0265] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:643 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:644 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:645 according to Chothia numbering; and the VHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:646 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:647 according to Chothia numbering; and a CDR3 comprising the amino acidsequence of SEQ ID NO:648 according to Chothia numbering or SEQ ID NO:442 according to IMGT numbering.
[0266] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:643 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:644 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:645 according to Chothia numbering or SEQ ID NO:443 according to IMGT numbering; and the VHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:646 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:647 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:648 according to Chothia numbering.
[0267] In some aspects, the VHH1 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:643 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:644 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:645 according to Chothia numbering; and the VHH2 of an IL13 co-binder comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:646 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:647 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:648 according to Chothia numbering.
[0268] In some aspects, the VHH1 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:130 or amino acid residues 2-115 of SEQ ID NO:130; and the VHH2 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:134. In some aspects, the VHH1 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:138, or amino acid residues 2-115 of SEQ ID NO:138; and the VHH2 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:142. In some aspects, the VHH1 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:154, or amino acid residues 2- 115 of SEQ ID NO:154; and the VHH2 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ IDNO:158. In some aspects, the VHH1 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:162, or amino acid residues 2-115 of SEQ ID NO:162; and the VHH2 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:166. In some aspects, the VHH1 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:170, or amino acid residues 2-115 of SEQ ID NO:170; and the VHH2 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:174.
[0269] In some aspects, the VHH1 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:66, or amino acid residues 2-126 of SEQ ID NO:66; and the VHH2 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:70. In some aspects, the VHH1 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:74, or amino acid residues 2-126 of SEQ ID NO:74; and the VHH2 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:78. In some aspects, the VHH1 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:82, or amino acid residues 2- 126 of SEQ ID NO:82; and the VHH2 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:86. In some aspects, the VHH1 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:90, or amino acid residues 2-126 of SEQ ID NO:90; and the VHH2 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:94. In some aspects, the VHH1 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:98, or amino acid residues 2-126 of SEQ ID NO:98; and the VHH2 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:102. In some aspects, the VHH1 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%,at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:106, or amino acid residues 2- 126 of SEQ ID NO:106; and the VHH2 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:110. In some aspects, the VHH1 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:114, or amino acid residues 2-126 of SEQ ID NO:114; and the VHH2 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:118. In some aspects, the VHH1 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:122, or amino acid residues 2-126 of SEQ ID NO:122; and the VHH2 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:126. In some aspects, the VHH1 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:146, or amino acid residues 2- 126 of SEQ ID NO:146; and the VHH2 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:150. In some aspects, the VHH1 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:178, or amino acid residues 2-126 of SEQ ID NO:178; and the VHH2 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:182. In some aspects, the VHH1 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:186, or amino acid residues 2-126 of SEQ ID NO:186; and the VHH2 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:190. In some aspects, the VHH1 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:194, or amino acid residues 2- 126 of SEQ ID NO:194; and the VHH2 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:198. In some aspects, the VHH1 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:202, or amino acid residues 2-126 of SEQ ID NO:202; and the VHH2 comprises an aminoacid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:206. In some aspects, the VHH1 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:210, or amino acid residues 2-126 of SEQ ID NO:210; and the VHH2 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:214.
[0270] In some aspects, the VHH1 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:218, or amino acid residues 2-129 of SEQ ID NO:218; and the VHH2 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:222. In some aspects, the VHH1 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:234, or amino acid residues 2-129 of SEQ ID NO:234; and the VHH2 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:238. In some aspects, the VHH1 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:242, or amino acid residues 2- 129 of SEQ ID NO:242; and the VHH2 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:246. In some aspects, the VHH1 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:250, or amino acid residues 2-129 of SEQ ID NO:250; and the VHH2 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:254. In some aspects, the VHH1 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:258, or amino acid residues 2-129 of SEQ ID NO:258; and the VHH2 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:262. In some aspects, the VHH1 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:266, or amino acid residues 2- 129 of SEQ ID NO:266; and the VHH2 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ IDNO:270. In some aspects, the VHH1 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:274, or amino acid residues 2-129 of SEQ ID NO:274; and the VHH2 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:278. In some aspects, the VHH1 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:282, or amino acid residues 2-129 of SEQ ID NO:282; and the VHH2 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:286. In some aspects, the VHH1 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:290, or amino acid residues 2- 129 of SEQ ID NO:290; and the VHH2 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:294. In some aspects, the VHH1 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:298, or amino acid residues 2-129 of SEQ ID NO:298; and the VHH2 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:302. In some aspects, the VHH1 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:306, or amino acid residues 2-129 of SEQ ID NO:306; and the VHH2 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:310. In some aspects, the VHH1 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:314, or amino acid residues 2- 129 of SEQ ID NO:314; and the VHH2 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:318. In some aspects, the VHH1 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:322, or amino acid residues 2-129 of SEQ ID NO:322; and the VHH2 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:326. In some aspects, the VHH1 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or atleast 99% identical to SEQ ID NO:330, or amino acid residues 2-129 of SEQ ID NO:330; and the VHH2 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:334. In some aspects, the VHH1 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:338, or amino acid residues 2- 129 of SEQ ID NO:338; and the VHH2 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:342. In some aspects, the VHH1 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:346, or amino acid residues 2-129 of SEQ ID NO:346; and the VHH2 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:350. In some aspects, the VHH1 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:354, or amino acid residues 2-129 of SEQ ID NO:354; and the VHH2 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:358. In some aspects, the VHH1 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:362, or amino acid residues 2- 129 of SEQ ID NO:362; and the VHH2 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:366. In some aspects, the VHH1 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:370, or amino acid residues 2-129 of SEQ ID NO:370; and the VHH2 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:374.
[0271] In some aspects, the VHH1 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:226, or amino acid residues 2-116 of SEQ ID NO:226; and the VHH2 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:230.
[0272] In some aspects, the VHH1 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ IDNO:29, or amino acid residues 2-115 of SEQ ID NO:29; and the VHH2 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:40. In some aspects, the VHH1 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:30, or amino acid residues 2-115 of SEQ ID NO:30; and the VHH2 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:41. In some aspects, the VHH1 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:434, or amino acid residues 2- 115 of SEQ ID NO:434; and the VHH2 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:438.
[0273] In some aspects, the VHH1 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:378, or amino acid residues 2-129 of SEQ ID NO:378; and the VHH2 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:382. In some aspects, the VHH1 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:386, or amino acid residues 2-129 of SEQ ID NO:386; and the VHH2 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:390. In some aspects, the VHH1 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:394, or amino acid residues 2- 129 of SEQ ID NO:394; and the VHH2 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:398. In some aspects, the VHH1 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:402, or amino acid residues 2-129 of SEQ ID NO:402; and the VHH2 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:406. In some aspects, the VHH1 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:410, or amino acid residues 2-129 of SEQ ID NO:410; and theVHH2 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:414. In some aspects, the VHH1 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:418, or amino acid residues 2- 129 of SEQ ID NO:418; and the VHH2 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:422. In some aspects, the VHH1 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:426, or amino acid residues 2-129 of SEQ ID NO:426; and the VHH2 comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:430.
[0274] In some aspects, the VHH1 comprises the amino acid sequence of SEQ ID NO:130, or amino acid residues 2-115 of SEQ ID NO:130; and the VHH2 comprises the amino acid sequence of SEQ ID NO:134. In some aspects, the VHH1 comprises the amino acid sequence of SEQ ID NO:138, or amino acid residues 2-115 of SEQ ID NO:138; and the VHH2 comprises the amino acid sequence of SEQ ID NO:142. In some aspects, the VHH1 comprises the amino acid sequence of SEQ ID NO:154, or amino acid residues 2-115 of SEQ ID NO:154; and the VHH2 comprises the amino acid sequence of SEQ ID NO:158. In some aspects, the VHH1 comprises the amino acid sequence of SEQ ID NO:162, or amino acid residues 2-115 of SEQ ID NO:162; and the VHH2 comprises the amino acid sequence of SEQ ID NO:166. In some aspects, the VHH1 comprises the amino acid sequence of SEQ ID NO:170, or amino acid residues 2-115 of SEQ ID NO:170; and the VHH2 comprises the amino acid sequence of SEQ ID NO:174.
[0275] In some aspects, the VHH1 comprises the amino acid sequence of SEQ ID NO:66, or amino acid residues 2-126 of SEQ ID NO:66; and the VHH2 comprises the amino acid sequence of SEQ ID NO:70. In some aspects, the VHH1 comprises the amino acid sequence of SEQ ID NO:74, or amino acid residues 2-126 of SEQ ID NO:74; and the VHH2 comprises the amino acid sequence of SEQ ID NO:78. In some aspects, the VHH1 comprises the amino acid sequence of SEQ ID NO:82, or amino acid residues 2-126 of SEQ ID NO:82; and the VHH2 comprises the amino acid sequence of SEQ ID NO:86. In some aspects, the VHH1 comprises the amino acid sequence of SEQ ID NO:90, or amino acid residues 2-126 of SEQ ID NO:90; and the VHH2 comprises the amino acid sequence of SEQ ID NO:94. In some aspects, the VHH1 comprises the amino acid sequence of SEQ ID NO:98, or amino acid residues 2-126 of SEQ ID NO:98; and theVHH2 comprises the amino acid sequence of SEQ ID NO:102. In some aspects, the VHH1 comprises the amino acid sequence of SEQ ID NO:106, or amino acid residues 2-126 of SEQ ID NO:106; and the VHH2 comprises the amino acid sequence of SEQ ID NO:110. In some aspects, the VHH1 comprises the amino acid sequence of SEQ ID NO:114, or amino acid residues 2-126 of SEQ ID NO:114; and the VHH2 comprises the amino acid sequence of SEQ ID NO:118. In some aspects, the VHH1 comprises the amino acid sequence of SEQ ID NO:122, or amino acid residues 2-126 of SEQ ID NO:122; and the VHH2 comprises the amino acid sequence of SEQ ID NO:126. In some aspects, the VHH1 comprises the amino acid sequence of SEQ ID NO:146, or amino acid residues 2-126 of SEQ ID NO:146; and the VHH2 comprises the amino acid sequence of SEQ ID NO:150. In some aspects, the VHH1 comprises the amino acid sequence of SEQ ID NO:178, or amino acid residues 2-126 of SEQ ID NO:178; and the VHH2 comprises the amino acid sequence of SEQ ID NO:182. In some aspects, the VHH1 comprises the amino acid sequence of SEQ ID NO:186, or amino acid residues 2-126 of SEQ ID NO:186; and the VHH2 comprises the amino acid sequence of SEQ ID NO:190. In some aspects, the VHH1 comprises the amino acid sequence of SEQ ID NO:194, or amino acid residues 2-126 of SEQ ID NO:194; and the VHH2 comprises the amino acid sequence of SEQ ID NO:198. In some aspects, the VHH1 comprises the amino acid sequence of SEQ ID NO:202, or amino acid residues 2-126 of SEQ ID NO:202; and the VHH2 comprises the amino acid sequence of SEQ ID NO:206. In some aspects, the VHH1 comprises the amino acid sequence of SEQ ID NO:210, or amino acid residues 2-126 of SEQ ID NO:210; and the VHH2 comprises the amino acid sequence of SEQ ID NO:214.
[0276] In some aspects, the VHH1 comprises the amino acid sequence of SEQ ID NO:218, or amino acid residues 2-129 of SEQ ID NO:218; and the VHH2 comprises the amino acid sequence of SEQ ID NO:222. In some aspects, the VHH1 comprises the amino acid sequence of SEQ ID NO:234, or amino acid residues 2-129 of SEQ ID NO:234; and the VHH2 comprises the amino acid sequence of SEQ ID NO:238. In some aspects, the VHH1 comprises the amino acid sequence of SEQ ID NO:242, or amino acid residues 2-129 of SEQ ID NO:242; and the VHH2 comprises the amino acid sequence of SEQ ID NO:246. In some aspects, the VHH1 comprises the amino acid sequence of SEQ ID NO:250, or amino acid residues 2-129 of SEQ ID NO:250; and the VHH2 comprises the amino acid sequence of SEQ ID NO:254. In some aspects, the VHH1 comprises the amino acid sequence of SEQ ID NO:258, or amino acid residues 2-129 of SEQ ID NO:258; and the VHH2 comprises the amino acid sequence of SEQ ID NO:262. In someaspects, the VHH1 comprises the amino acid sequence of SEQ ID NO:266, or amino acid residues 2-129 of SEQ ID NO:266; and the VHH2 comprises the amino acid sequence of SEQ ID NO:270. In some aspects, the VHH1 comprises the amino acid sequence of SEQ ID NO:274, or amino acid residues 2-129 of SEQ ID NO:274; and the VHH2 comprises the amino acid sequence of SEQ ID NO:278. In some aspects, the VHH1 comprises the amino acid sequence of SEQ ID NO:282, or amino acid residues 2-129 of SEQ ID NO:282; and the VHH2 comprises the amino acid sequence of SEQ ID NO:286. In some aspects, the VHH1 comprises the amino acid sequence of SEQ ID NO:290, or amino acid residues 2-129 of SEQ ID NO:290; and the VHH2 comprises the amino acid sequence of SEQ ID NO:294. In some aspects, the VHH1 comprises the amino acid sequence of SEQ ID NO:298, or amino acid residues 2-129 of SEQ ID NO:298; and the VHH2 comprises the amino acid sequence of SEQ ID NO:302. In some aspects, the VHH1 comprises the amino acid sequence of SEQ ID NO:306, or amino acid residues 2-129 of SEQ ID NO:306; and the VHH2 comprises the amino acid sequence of SEQ ID NO:310. In some aspects, the VHH1 comprises the amino acid sequence of SEQ ID NO:314, or amino acid residues 2-129 of SEQ ID NO:314; and the VHH2 comprises the amino acid sequence of SEQ ID NO:318. In some aspects, the VHH1 comprises the amino acid sequence of SEQ ID NO:322, or amino acid residues 2-129 of SEQ ID NO:322; and the VHH2 comprises the amino acid sequence of SEQ ID NO:326. In some aspects, the VHH1 comprises the amino acid sequence of SEQ ID NO:330, or amino acid residues 2-129 of SEQ ID NO:330; and the VHH2 comprises the amino acid sequence of SEQ ID NO:334. In some aspects, the VHH1 comprises the amino acid sequence of SEQ ID NO:338, or amino acid residues 2-129 of SEQ ID NO:338; and the VHH2 comprises the amino acid sequence of SEQ ID NO:342. In some aspects, the VHH1 comprises the amino acid sequence of SEQ ID NO:346, or amino acid residues 2-129 of SEQ ID NO:346; and the VHH2 comprises the amino acid sequence of SEQ ID NO:350. In some aspects, the VHH1 comprises the amino acid sequence of SEQ ID NO:354, or amino acid residues 2-129 of SEQ ID NO:354; and the VHH2 comprises the amino acid sequence of SEQ ID ...
Claims
1. CLAIMS What is Claimed is:
1. A co-binder that binds IL13, comprising a Variable Heavy domain of Heavy chain 1 (VHH1) and a Variable Heavy domain of Heavy chain 2 (VHH2), wherein the VHH1 and / or the VHH2 comprises a CDR3 comprising the amino acid sequence of SEQ ID NO:442 or SEQ ID NO:443 according to IMGT numbering.
2. The co-binder of claim 1, wherein the CDR3 comprises an amino acid sequence selected from SEQ ID NOs:36, 47, 61, 64, 472-526, 531, 534, 543, 546, 555, 558, 567, 570, 579, 582, 591, 594, 603, 606, 615, 618, 627, 630, 639, and 642.
3. The co-binder of any one of claims 1 to 2, wherein: a) the VHH1 comprises a CDR1 comprising the amino acid sequence of SEQ ID NOs:31, 67, 75, 83, 91, 99, 107, 115, 123, 131, 139, 147, 155, 163, 171, 179, 187, 195, 203, 211, 219, 227, 235, 243, 251, 259, 267, 275, 283, 291, 299, 307, 315, 323, 331, 339, 347, 355, 363, 371, 379, 387, 395, 403, 411, 419, 427, or 435 according to Kabat numbering, or comprising the amino acid sequence of SEQ ID NOs:34, 529, 541, 553, 565, 577, 589, 601, 613, 625, or 637 according to IMGT numbering, or comprising the amino acid sequence of SEQ ID NOs:37, 535, 547, 559, 571, 583, 595, 607, 619, 631, or 643 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NOs:32, 68, 76, 84, 92, 100, 108, 116, 124, 132, 140, 148, 156, 164, 172, 180, 188, 196, 204, 212, 220, 228, 236, 244, 252, 260, 268, 276, 284, 292, 300, 308, 316, 324, 332, 340, 348, 356, 364, 372, 380, 388, 396, 404, 412, 420, 428, or 436 according to Kabat numbering, or comprising SEQ ID NOs:35, 530, 542, 554, 566, 578, 590, 602, 614, 626, or 638 according to IMGT numbering, or comprising SEQ ID NOs:38, 536, 548, 560, 572, 584, 596, 608, 620, 632, or 644 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NOs:33, 60, 69, 77, 85, 93, 101, 109, 117, 125, 133, 141, 149, 157, 165, 173, 181, 189, 197, 205, 213, 221, 229, 237, 245, 253, 261, 269, 277, 285, 293, 301, 309, 317, 325, 333, 341, 349, 357, 365, 373, 381, 389, 397, 405, 413, 421, 429, or 437 according to Kabat numbering, or comprising the amino acid sequence of SEQ ID NOs:36, 61, 442, 443, 531, 543, 555, 567, 579, 591, 603, 615, 627, or 639 according to IMGT numbering, or comprising the amino acid sequence of SEQ ID NOs:39, 62, 537, 549, 561, 573, 585, 597, 609, 621, 633, or 645 according to Chothia numbering;b) the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NOs:42, 71, 79, 87, 95, 103, 111, 119, 127, 135, 143, 151, 159, 167, 175, 183, 191, 199, 207, 215, 223, 231, 239, 247, 255, 263, 271, 279, 287, 295, 303, 311, 319, 327, 335, 343, 351, 359, 367, 375, 383, 391, 399, 407, 415, 423, 431, or 439 according to Kabat numbering, or comprising the amino acid sequence of SEQ ID NOs:45, 532, 544, 556, 568, 580, 592, 604, 616, 628, or 640 according to IMGT numbering, or comprising the amino acid sequence of SEQ ID NOs:48, 538, 550, 562, 574, 586, 598, 610, 622, 634, or 646 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NOs:43, 72, 80, 88, 96, 104, 112, 120, 128, 136, 144, 152, 160, 168, 176, 184, 192, 200, 208, 216, 224, 232, 240, 248, 256, 264, 272, 280, 288, 296, 304, 312, 320, 328, 336, 344, 352, 360, 368, 376, 384, 392, 400, 408, 416, 424, 432, or 440 according to Kabat numbering, or comprising the amino acid sequence of SEQ ID NOs:46, 533, 545, 557, 569, 581, 593, 605, 617, 629, or 641 according to IMGT numbering, or comprising the amino acid sequence of SEQ ID NOs:49, 539, 551, 563, 575, 587, 599, 611, 623, 635, or 647 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NOs:44, 63, 73, 81, 89, 97, 105, 113, 121, 129, 137, 145, 153, 161, 169, 177, 185, 193, 201, 209, 217, 225, 233, 241, 249, 257, 265, 273, 281, 289, 297, 305, 313, 321, 329, 337, 345, 353, 361, 369, 377, 385, 393, 401, 409, 417, 425, 433, or 441 according to Kabat numbering, or comprising the amino acid sequence of SEQ ID NOs:47, 64, 442, 443, 534, 546, 558, 570, 582, 594, 606, 618, 630, or 642 according to IMGT numbering, or comprising the amino acid sequence of SEQ ID NOs:50, 65, 540, 552, 564, 576, 588, 600, 612, 624, 636, or 648 according to Chothia numbering; or c) the VHH1 comprises a CDR1 comprising the amino acid sequence of SEQ ID NOs:31, 67, 75, 83, 91, 99, 107, 115, 123, 131, 139, 147, 155, 163, 171, 179, 187, 195, 203, 211, 219, 227, 235, 243, 251, 259, 267, 275, 283, 291, 299, 307, 315, 323, 331, 339, 347, 355, 363, 371, 379, 387, 395, 403, 411, 419, 427, or 435 according to Kabat numbering, or comprising the amino acid sequence of SEQ ID NOs:34, 529, 541, 553, 565, 577, 589, 601, 613, 625, or 637 according to IMGT numbering, or comprising the amino acid sequence of SEQ ID NOs:37, 535, 547, 559, 571, 583, 595, 607, 619, 631, or 643 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NOs:32, 68, 76, 84, 92, 100, 108, 116, 124, 132, 140, 148, 156, 164, 172, 180, 188, 196, 204, 212, 220, 228, 236, 244, 252, 260, 268, 276, 284, 292, 300, 308, 316, 324, 332, 340, 348, 356, 364, 372, 380, 388, 396, 404, 412, 420, 428, or 436 according to Kabat numbering, or comprising SEQ ID NOs:35, 530, 542, 554, 566, 578, 590, 602, 614, 626, or 638 according to IMGT numbering, or comprising SEQ ID NOs:38, 536, 548,560, 572, 584, 596, 608, 620, 632, or 644 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NOs:33, 60, 69, 77, 85, 93, 101, 109, 117, 125, 133, 141, 149, 157, 165, 173, 181, 189, 197, 205, 213, 221, 229, 237, 245, 253, 261, 269, 277, 285, 293, 301, 309, 317, 325, 333, 341, 349, 357, 365, 373, 381, 389, 397, 405, 413, 421, 429, or 437 according to Kabat numbering, or comprising the amino acid sequence of SEQ ID NOs:36, 61, 442, 443, 531, 543, 555, 567, 579, 591, 603, 615, 627, or 639 according to IMGT numbering, or comprising the amino acid sequence of SEQ ID NOs:39, 62, 537, 549, 561, 573, 585, 597, 609, 621, 633, or 645 according to Chothia numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NOs:42, 71, 79, 87, 95, 103, 111, 119, 127, 135, 143, 151, 159, 167, 175, 183, 191, 199, 207, 215, 223, 231, 239, 247, 255, 263, 271, 279, 287, 295, 303, 311, 319, 327, 335, 343, 351, 359, 367, 375, 383, 391, 399, 407, 415, 423, 431, or 439 according to Kabat numbering, or comprising the amino acid sequence of SEQ ID NOs:45, 532, 544, 556, 568, 580, 592, 604, 616, 628, or 640 according to IMGT numbering, or comprising the amino acid sequence of SEQ ID NOs:48, 538, 550, 562, 574, 586, 598, 610, 622, 634, or 646 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NOs:43, 72, 80, 88, 96, 104, 112, 120, 128, 136, 144, 152, 160, 168, 176, 184, 192, 200, 208, 216, 224, 232, 240, 248, 256, 264, 272, 280, 288, 296, 304, 312, 320, 328, 336, 344, 352, 360, 368, 376, 384, 392, 400, 408, 416, 424, 432, or 440 according to Kabat numbering, or comprising the amino acid sequence of SEQ ID NOs:46, 533, 545, 557, 569, 581, 593, 605, 617, 629, or 641 according to IMGT numbering, or comprising the amino acid sequence of SEQ ID NOs:49, 539, 551, 563, 575, 587, 599, 611, 623, 635, or 647 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NOs:44, 63, 73, 81, 89, 97, 105, 113, 121, 129, 137, 145, 153, 161, 169, 177, 185, 193, 201, 209, 217, 225, 233, 241, 249, 257, 265, 273, 281, 289, 297, 305, 313, 321, 329, 337, 345, 353, 361, 369, 377, 385, 393, 401, 409, 417, 425, 433, or 441 according to Kabat numbering, or comprising the amino acid sequence of SEQ ID NOs:47, 64, 442, 443, 534, 546, 558, 570, 582, 594, 606, 618, 630, or 642 according to IMGT numbering, or comprising the amino acid sequence of SEQ ID NOs:50, 65, 540, 552, 564, 576, 588, 600, 612, 624, 636, or 648 according to Chothia numbering.
4. The co-binder of any of the preceding claims, wherein a) the VHH1 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:31 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:32 according to Kabat numbering; and CDR3 comprising the amino acidsequence of SEQ ID NO:442 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:42 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:43 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:443 according to IMGT numbering; b) the VHH1 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:31 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:32 according to Kabat numbering; and CDR3 comprising the amino acid sequence of SEQ ID NO:33 according to Kabat numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:42 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:43 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:44 according to Kabat numbering; c) the VHH1 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:31 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:32 according to Kabat numbering; and CDR3 comprising the amino acid sequence of SEQ ID NO:60 according to Kabat numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:42 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:43 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:63 according to Kabat numbering; d) the VHH1 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:31 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:32 according to Kabat numbering; and CDR3 comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:42 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:43 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:63 according to Kabat numbering; or e) the VHH1 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:31 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:32 according to Kabat numbering; and CDR3 comprising the amino acid sequence of SEQ ID NO:60 according to Kabat numbering; and the VHH2 comprisesa CDR1 comprising the amino acid sequence of SEQ ID NO:42 according to Kabat numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:43 according to Kabat numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:443 according to IMGT numbering.
5. The co-binder of any of the preceding claims, wherein a) the VHH1 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:34 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:35 according to IMGT numbering; and CDR3 comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:45 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:46 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:443 according to IMGT numbering; b) the VHH1 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:34 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:35 according to IMGT numbering; and CDR3 comprising the amino acid sequence of SEQ ID NO:36 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:45 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:46 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:47 according to IMGT numbering; c) the VHH1 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:34 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:35 according to IMGT numbering; and CDR3 comprising the amino acid sequence of SEQ ID NO:61 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:45 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:46 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:64 according to IMGT numbering; d) the VHH1 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:34 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:35 according to IMGT numbering; and CDR3 comprising the amino acidsequence of SEQ ID NO:442 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:45 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:46 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:64 according to IMGT numbering; or e) the VHH1 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:34 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:35 according to IMGT numbering; and CDR3 comprising the amino acid sequence of SEQ ID NO:61 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:45 according to IMGT numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:46 according to IMGT numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:443 according to IMGT numbering.
6. The co-binder of any of the preceding claims, wherein a) the VHH1 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:37 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:38 according to Chothia numbering; and CDR3 comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:48 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:49 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:443 according to IMGT numbering; b) the VHH1 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:37 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:38 according to Chothia numbering; and CDR3 comprising the amino acid sequence of SEQ ID NO:39 according to Chothia numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:48 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:49 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:50 according to Chothia numbering; c) the VHH1 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:37 according to Chothia numbering; a CDR2 comprising the amino acid sequence ofSEQ ID NO:38 according to Chothia numbering; and CDR3 comprising the amino acid sequence of SEQ ID NO:62 according to Chothia numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:48 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:49 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:65 according to Chothia numbering; d) the VHH1 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:37 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:38 according to Chothia numbering; and CDR3 comprising the amino acid sequence of SEQ ID NO:442 according to IMGT numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:48 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:49 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:65 according to Chothia numbering; or e) the VHH1 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:37 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:38 according to Chothia numbering; and CDR3 comprising the amino acid sequence of SEQ ID NO:62 according to Chothia numbering; and the VHH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:48 according to Chothia numbering; a CDR2 comprising the amino acid sequence of SEQ ID NO:49 according to Chothia numbering; and a CDR3 comprising the amino acid sequence of SEQ ID NO:443 according to IMGT numbering.
7. The co-binder of any one of the preceding claims, wherein: a) the VHH1 comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to SEQ ID NOs:29, 30, 66, 74, 82, 90, 98, 106, 114, 122, 130, 138, 146, 154, 162, 170, 178, 186, 194, 202, 210, 218, 226, 234, 242, 250, 258, 266, 274, 282, 290, 298, 306, 314, 322, 330, 338, 346, 354, 362, 370, 378, 386, 394, 402, 410, 418, 426, 434, 444, 445 or 446; b) the VHH1 comprises an amino acid sequence of SEQ ID NOs:29, 30, 66, 74, 82, 90, 98, 106, 114, 122, 130, 138, 146, 154, 162, 170, 178, 186, 194, 202, 210, 218, 226,234, 242, 250, 258, 266, 274, 282, 290, 298, 306, 314, 322, 330, 338, 346, 354, 362, 370, 378, 386, 394, 402, 410, 418, 426, 434, 444, 445 or 446; c) the VHH2 comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to SEQ ID NOs:40, 41, 70, 78, 86, 94, 102, 110, 118, 126, 134, 142, 150, 158, 166, 174, 182, 190, 198, 206, 214, 222, 230, 238, 246, 254, 262, 270, 278, 286, 294, 302, 310, 318, 326, 334, 342, 350, 358, 366, 374, 382, 390, 398, 406, 414, 422, 430, 438, 447, 448, 449 or 450; d) the VHH2 comprises an amino acid sequence of SEQ ID NOs:40, 41, 70, 78, 86, 94, 102, 110, 118, 126, 134, 142, 150, 158, 166, 174, 182, 190, 198, 206, 214, 222, 230, 238, 246, 254, 262, 270, 278, 286, 294, 302, 310, 318, 326, 334, 342, 350, 358, 366, 374, 382, 390, 398, 406, 414, 422, 430, 438, 447, 448, 449 or 450; e) the VHH1 comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to SEQ ID NOs:29, 30, 66, 74, 82, 90, 98, 106, 114, 122, 130, 138, 146, 154, 162, 170, 178, 186, 194, 202, 210, 218, 226, 234, 242, 250, 258, 266, 274, 282, 290, 298, 306, 314, 322, 330, 338, 346, 354, 362, 370, 378, 386, 394, 402, 410, 418, 426, 434, 444, 445 or 446; and the VHH2 comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to SEQ ID NOs:40, 41, 70, 78, 86, 94, 102, 110, 118, 126, 134, 142, 150, 158, 166, 174, 182, 190, 198, 206, 214, 222, 230, 238, 246, 254, 262, 270, 278, 286, 294, 302, 310, 318, 326, 334, 342, 350, 358, 366, 374, 382, 390, 398, 406, 414, 422, 430, 438, 447, 448, 449 or 450; f) the VHH1 comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to SEQ ID NOs:29, 30, 66, 74, 82, 90, 98, 106, 114, 122, 130, 138, 146, 154, 162, 170, 178, 186, 194, 202, 210, 218, 226, 234, 242, 250, 258, 266, 274, 282, 290, 298, 306, 314, 322, 330, 338, 346, 354, 362, 370, 378, 386, 394, 402, 410, 418, 426, 434, 444, 445 or 446; and the VHH2 comprises an amino acid sequence of SEQ ID NOs:40, 41, 70, 78, 86, 94, 102, 110, 118, 126, 134, 142, 150, 158, 166, 174, 182, 190, 198, 206, 214, 222, 230, 238, 246, 254, 262, 270, 278, 286, 294, 302, 310, 318, 326, 334, 342, 350, 358, 366, 374, 382, 390, 398, 406, 414, 422, 430, 438, 447, 448, 449 or 450;g) the VHH1 comprises an amino acid sequence of SEQ ID NOs:29, 30, 66, 74, 82, 90, 98, 106, 114, 122, 130, 138, 146, 154, 162, 170, 178, 186, 194, 202, 210, 218, 226, 234, 242, 250, 258, 266, 274, 282, 290, 298, 306, 314, 322, 330, 338, 346, 354, 362, 370, 378, 386, 394, 402, 410, 418, 426, 434, 444, 445 or 446; and the VHH2 comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to SEQ ID NOs:40, 41, 70, 78, 86, 94, 102, 110, 118, 126, 134, 142, 150, 158, 166, 174, 182, 190, 198, 206, 214, 222, 230, 238, 246, 254, 262, 270, 278, 286, 294, 302, 310, 318, 326, 334, 342, 350, 358, 366, 374, 382, 390, 398, 406, 414, 422, 430, 438, 447, 448, 449 or 450; or h) the VHH1 comprises an amino acid sequence of SEQ ID NOs:29, 30, 66, 74, 82, 90, 98, 106, 114, 122, 130, 138, 146, 154, 162, 170, 178, 186, 194, 202, 210, 218, 226, 234, 242, 250, 258, 266, 274, 282, 290, 298, 306, 314, 322, 330, 338, 346, 354, 362, 370, 378, 386, 394, 402, 410, 418, 426, 434, 444, 445 or 446; and the VHH2 comprises an amino acid sequence of SEQ ID NOs:40, 41, 70, 78, 86, 94, 102, 110, 118, 126, 134, 142, 150, 158, 166, 174, 182, 190, 198, 206, 214, 222, 230, 238, 246, 254, 262, 270, 278, 286, 294, 302, 310, 318, 326, 334, 342, 350, 358, 366, 374, 382, 390, 398, 406, 414, 422, 430, 438, 447, 448, 449 or 450.
8. The co-binder of any one of the preceding claims, wherein a) the VHH1 comprises SEQ ID NO:29, and the VHH2 comprises SEQ ID NO:40; b) the VHH1 comprises SEQ ID NO:29, and the VHH2 comprises SEQ ID NO:41; c) the VHH1 comprises SEQ ID NO:30, and the VHH2 comprises SEQ ID NO:40; d) the VHH1 comprises SEQ ID NO:30, and the VHH2 comprises SEQ ID NO:41; e) the VHH1 comprises SEQ ID NO:30, and the VHH2 comprises SEQ ID NO:447; f) the VHH1 comprises SEQ ID NO:30, and the VHH2 comprises SEQ ID NO:448; g) the VHH1 comprises SEQ ID NO:30, and the VHH2 comprises SEQ ID NO:449; h) the VHH1 comprises SEQ ID NO:30, and the VHH2 comprises SEQ ID NO:450; i) the VHH1 comprises SEQ ID NO:444, and the VHH2 comprises SEQ ID NO:41; j) the VHH1 comprises SEQ ID NO:445, and the VHH2 comprises SEQ ID NO:41; k) the VHH1 comprises SEQ ID NO:446, and the VHH2 comprises SEQ ID NO:41; l) the VHH1 comprises SEQ ID NO:444, and the VHH2 comprises SEQ ID NO:447; m) the VHH1 comprises SEQ ID NO:444, and the VHH2 comprises SEQ ID NO:448; n) the VHH1 comprises SEQ ID NO:444, and the VHH2 comprises SEQ ID NO:449;o) the VHH1 comprises SEQ ID NO:444, and the VHH2 comprises SEQ ID NO:450; p) the VHH1 comprises SEQ ID NO:445, and the VHH2 comprises SEQ ID NO:447; q) the VHH1 comprises SEQ ID NO:445, and the VHH2 comprises SEQ ID NO:448; r) the VHH1 comprises SEQ ID NO:445, and the VHH2 comprises SEQ ID NO:449; s) the VHH1 comprises SEQ ID NO:445, and the VHH2 comprises SEQ ID NO:450; t) the VHH1 comprises SEQ ID NO:446, and the VHH2 comprises SEQ ID NO:447; u) the VHH1 comprises SEQ ID NO:446, and the VHH2 comprises SEQ ID NO:448; v) the VHH1 comprises SEQ ID NO:446, and the VHH2 comprises SEQ ID NO:449; or w) the VHH1 comprises SEQ ID NO:446, and the VHH2 comprises SEQ ID NO:
450.
9. The co-binder of any one of the preceding claims, wherein the VHH1 is connected to the VHH2 by a linker.
10. The co-binder of claim 9, wherein the co-binder has the structure: [VHH1] – linker – [VHH2].
11. The co-binder of claim 9 or 10, wherein the linker is from about 5 to about 50 amino acids in length.
12. The co-binder of claims 9 to 11, wherein the linker is from about 15 to about 45 amino acids in length.
13. The co-binder of claims 9 to 12, wherein the linker is from about 34 to about 42 amino acids in length.
14. The co-binder of claims 9 to 13, wherein the linker is from about 37 to about 39 amino acids in length.
15. The co-binder of claims 9 to 14, wherein the linker is about 38 amino acids in length.
16. The co-binder of claims 9 to 15, wherein the linker comprises the amino acid sequence of SEQ ID NO:
451.
17. The co-binder of claims 1 to 16, wherein the co-binder has an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to SEQ ID NO:51, 52 or 453-471.
18. The co-binder of claim 17, wherein the co-binder has an amino acid sequence of SEQ ID NO:51, 52 or 453-471.
19. The co-binder of claim 17 or 18, wherein the co-binder has an amino acid sequence of SEQ ID NO:52, or amino acid residues 2-280 of SEQ ID NO:
52.
20. The co-binder of any preceding claim, further comprising an Fc region.
21. The co-binder of claim 20, wherein the Fc region comprises an IgG1, IgG2, IgG3, or IgG4 Fc region.
22. The co-binder of claim 20 and 21, wherein the Fc region comprises a human Fc region.
23. The co-binder of claims 20 to 22, wherein the Fc region comprises one or more substitutions, deletions, insertions, or any combination thereof.
24. The co-binder of claim 23, wherein the one or more substitutions comprise C220S, M252Y, S254T, T256E, L234A, L235A, L309Y, Q311M, M428L, N434S or any combination thereof, according to the EU numbering system.
25. The co-binder of claims 20 to 24, wherein the C-terminus of the Fc region is Lysine.
26. The co-binder of claims 20 to 25, wherein the C terminus of the Fc region is not Lysine, or the C-terminal Lysine of the Fc region has been removed.
27. The co-binder of claims 20-26, wherein the Fc region comprises the amino acid sequence of SEQ ID NO:59 or amino acid residues 1-231 of SEQ ID NO:
59.
28. A multimeric co-binder, comprising one or more of the co-binders of claims 1-27.
29. A bispecific polypeptide that binds IL13 and a target antigen, wherein the polypeptide comprises: a first co-binder that specifically binds IL13 comprising a first Variable Heavy domain of Heavy chain 1 (VHH1) and a second VHH (VHH2), and a second co-binder that specifically binds target antigen comprising a third VHH (VHH3) and a fourth VHH (VHH4), wherein the first co-binder comprises the co-binder according to any one of claims 1 to 27; andwherein the target antigen of the second co-binder is IL4RA, IL13RA, IL31, IL31RA, OSMR, Ox40, Ox40L, TSLP, IL17, TNFα, CD20, CD19, CD25, IL4, IL23, IgE, CD11α, IL6R, α4-Intergrin, IL12, IL1β, BlyS, CKIT, SIGLEC-6, SIGLEC-8, TL1A, TXLNA, IL13RA, OSMR- beta, PD1, PDL1, IL17A, IL17B, IL17RB, IL17C, IL17RA, IL17RB, IL17RE, IL17D, IL17E, IL17F, IL17RC, IL17A / A, IL-17A / F, IL-17F / F, TNF-β, CD103, CD132, IL23R, IL-23p19, IL6, gp130, α4-β7, IL1, IL1α, IL1RA, IL1R1, IL1RL1, IL1RL2, IL1RAcP, IL1R2, IL2, IL2R, IL2Rβ, IL2Rγ, IL3, IL3Rα, CSF2RB, IL5, IL5Rα, IL7, IL7R, IL7Rα, IL7α, γ-chain, IL8, IL9, IL-9R, IL10, IL10Rα, IL10Rβ, IL11, IL11Rα, IL12A, IL12B, IL12Rβ1, IL12Rβ2, IL14, IL15, IL15Rα, IL16, IL18, IL18Rα, IL18RAcP, IL18BP, IL19, IL20, IL20Rα, IL20Rβ, IL21, IL21R, IL22, IL22Rα1, IL22Rα2, IL24, IL25, IL25 / IL17E, IL26, IL27, IL27Rα, IL28A, IL28B, IL28RA, IL29, IL32, PR3, PKCε, PKCδ, STAT3, Paxillin, IL33, IL34, CSF-1R, IL35, IL36A, IL36B, IL36G, IL36RA, IL37, IL18R1, IL38, EPO, GM-CSF, G-CSF, M-CSF, Eotaxin, IL1β, APRIL, BAFF-R, TACI, CD28, CTLA-4, CD80, CD86, TGF-β, CD40L, MCP-1, BASFF, MMPs, Elastase, MIF, Cathepsin G, Cathepsin K, IFN-γ, ROS, NO, RANTES, RANKL, PGE2, ADAMTSs, NGF, BDNF, NPY, MIG, BLC, IP-10, PDGF, CXCR1, or CXCR2.
30. The bispecific polypeptide of claim 29, wherein the target antigen of the second co-binder is IL31.
31. A pharmaceutical composition comprising the co-binder of any one of claims 1 to 27, the multimeric co-binder of claim 28, the bispecific polypeptide of claims 29 and 30 and a pharmaceutically acceptable carrier.
32. An isolated nucleic acid that encodes the co-binder of any one of claims 1 to 27, the multimeric co-binder of claim 28, or the bispecific polypeptide of claims 29 and 30.
33. A vector comprising the nucleic acid of claim 32.
34. An in vitro or ex vivo cell comprising the nucleic acid of claim 32 or the vector of claim 33.
35. An in vitro or ex vivo cell that expresses the co-binder of any one of claims 1 to 27, the multimeric co-binder of claim 28, or the bispecific polypeptide of claims 29 and 30.
36. A method of producing the co-binder of any one of claims 1 to 27, the multimeric co- binder of claim 28, or the bispecific polypeptide of claims 29 and 30, comprising transfecting the nucleic acid of claim 32 into a host cell under conditions suitable for expression of the co-binder, multimeric co-binder, or bispecific polypeptide.
37. A method of treating a subject having an IL13-associated condition comprising administering to the subject a therapeutically effective amount of the co-binder of any one of claims 1 to 27, the multimeric co-binder of claim 28, the bispecific polypeptide of claims 29 and 30, or pharmaceutical composition of claim 31.
38. The method of claim 37, wherein the subject is a human subject.
39. The method of claim 37 or 38, wherein the IL13-associated condition is a pruritic condition.
40. The method of claims 37 to 39, wherein the IL13-associated condition is atopic dermatitis, prurigo nodularis, or chronic spontaneous urticaria.
41. The method of claims 37 to 39, wherein the IL13-associated condition is airway hyperresponsiveness, allergic asthma, allergic conjunctivitis, allergic contact dermatitis, allergic lung disease, allergic rhinitis, alopecia areata, Alzheimer's disease, aspirin-exacerbated respiratory disease, asthma, atopic dermatitis, atopic keratoconjunctivitis, bronchial asthma, bullous pemphigoid, chronic hand eczema, chronic inducible urticaria, chronic obstructive pulmonary disease, chronic pruritus of unknown origin, chronic Rhinosinusitis with nasal polyposis, chronic spontaneous urticaria, colitis, dermatitis, eczema, eosinophilic chronic obstructive pulmonary disease (COPD), eosinophilic esophagitis, eosinophilic gastritis, eosinophilic duodenitis, epidermolysis bullosa, food allergy, goblet cell metaplasia, hepatic fibrosis, Hodgkin's disease, idiopathic pulmonary fibrosis, Netherton syndrome, progressive systemic sclerosis, prurigo nodularis, rheumatoid arthritis, sinusitis, Sjogren's syndrome, systemic lupus erythematosus, systemic sclerosis, type 1 diabetes, or ulcerative colitis.
42. The method of any one of claims 37 to 41, wherein the co-binder, multimeric co-binder, bispecific polypeptide, or pharmaceutical composition is administered parenterally.
43. The method of any one of claims 37 to 42, wherein the co-binder, multimeric co-binder, bispecific polypeptide, or pharmaceutical composition is administered by an intravenous route, a subcutaneous route, an intramuscular route, or an intraperitoneal route.
44. The method of any one of claims 37 to 43, wherein the method comprises administering to the subject one or more therapeutic agent in combination with the co-binder, the multimeric co-binder, bispecific polypeptide, or the pharmaceutical composition.
45. The method of claim 44, wherein the one or more therapeutic agent comprises an antibody, a small molecule inhibitor, and / or a systemic immunosuppressant agent.
46. The method of claim 44 or 45, wherein the one or more therapeutic agent comprises a topical corticosteroid, a calcineurin inhibitor, anti-IL4RA antibody, an anti-IL13RA antibody, an anti-OSMR antibody, an anti-Ox40 antibody, an anti-Ox40L antibody, an anti-TSLP antibody an anti-IL17 antibody, an anti-TNFα antibody, an anti-CD20 antibody, an anti-CD19 antibody, an anti-CD25 antibody, an anti-IL4 antibody, an anti-IL23 antibody, an anti-IL31 antibody, an anti- IgE antibody, an anti-CD11α antibody, anti-IL6R antibody, anti-α4-Intergrin antibody, an anti- IL12 antibody, an anti-IL1β antibody, an anti-BlyS antibody, an anti-CKIT antibody, an anti- SIGLEC-6 antibody, abatacept, belatacept, an anti-SIGLEC-8 antibody, STAT inhibitor, a JAK inhibitor, a PI3K inhibitor, an AKT inhibitor, a MAPK inhibitor, or a MRGPRX2 inhibitor.
47. A method of detecting human IL13 in a biological sample comprising contacting the biological sample with the co-binder of any one of claims 1 to 27, the multimeric co-binder of claim 28, or the bispecific polypeptide of claims 29 and 30 under conditions permissive for binding of the co-binder, multimeric co-binder or bispecific polypeptide to a human IL13 and detecting whether a complex is formed between the co-binder, multimeric co-binder or bispecific polypeptide and the human IL13 in the biological sample.
48. The method of claim 47, wherein the biological sample is a serum sample.
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