Conditionally activated antigen-binding polypeptide complexes and methods of use thereof

Abstract

Disclosed are antigen-binding polypeptide complexes (e.g., antibodies and antigen-binding fragments thereof) having predetermined structural characteristics. Also disclosed are polynucleotides and vectors encoding such polypeptide complexes; cells, pharmaceutical compositions, and kits containing such polypeptide complexes; and methods of using such polypeptide complexes.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63 / 292,382, filed December 21, 2021, which is incorporated herein by reference in its entirety.

[0002] Reference to an Electronically Submitted Sequence Listing The contents of the electronically submitted sequence listing (Name: 4850_007PC02_SequenceListing_ST26; Size: 1,326,277 bytes; and Creation Date: December 20, 2022) are incorporated herein by reference in their entirety.

[0003] Field The present disclosure relates to antigen-binding polypeptide complexes (e.g., antibodies and antigen-binding fragments thereof) having predetermined structural characteristics. The present disclosure also relates to conditionally activated antigen-binding polypeptide complexes (e.g., antibodies and antigen-binding fragments thereof) having predetermined structural characteristics. The present disclosure further relates to polynucleotides and vectors encoding such polypeptide complexes; cells, pharmaceutical compositions, and kits containing such polypeptide complexes; and methods of using such polypeptide complexes. [Background technology]

[0004] background Immunotherapy is the treatment of diseases by activating or suppressing the immune system. In recent years, immunotherapy has attracted great interest from researchers and clinicians, especially for its promise in treating cancer and infectious diseases. Therapeutic antibodies are a key type of polyimmunotherapy. Therapeutic antibodies can be monospecific, meaning they have specificity for one antigen or epitope. Therapeutic antibodies have also been engineered to have specificity for two different antigens or epitopes (i.e., bispecific antibodies) or multiple different antigens or epitopes (trispecific antibodies, tetraspecific antibodies, etc.). Monospecific, bispecific, and multispecific antibodies have also been combined to form multitargeting strategies to treat complex human diseases, such as cancer and infectious diseases.

[0005] Cancer immunotherapy has seen significant advances over the past few decades. Recent developments include checkpoint inhibitors and T cell engagers. With the approval of blinatumomab in 2014, bispecific T cell engagers have become an extremely active field for next-generation anticancer therapeutics. Bispecific T cell engagers are antibodies that recognize antigens expressed on target tumor cells and simultaneously engage the CD3 subunit of the T cell receptor on cytotoxic T cells, functioning as an artificial immune synapse to mediate tumor cell lysis by cytotoxic T cells.

[0006] While bispecific T cell engager antibodies exhibit high antitumor efficacy, they also have strong side effects, particularly cytokine release syndrome (CRS), which is associated with on-target off-tumor toxicity for solid tumor targets, and may limit the therapeutic potential of these antibodies. On-target off-tumor toxicity occurs when bispecific T cell engager antibodies bind to cancer antigens expressed on cells found in normal, non-cancerous tissues in addition to cancer antigens expressed on cancer cells, thereby recruiting cytotoxic T cells to and damaging normal tissues. Because few solid tumor antigens are exclusively tumor-specific, such toxicity poses a major challenge for cancer immunotherapy using bispecific T cell or natural killer (NK) cell engagers.

[0007] There is a need for bispecific or multispecific antigen-binding polypeptide complexes that can bind specific target molecules or combinations of target molecules and activate cytotoxic T cells only in the vicinity of tumor cells or within the tumor microenvironment. There is a further need for bispecific or multispecific T cell engager antibodies that provide high efficacy with manageable adverse events (AD) and, at the same time, a wider therapeutic window and better tolerability. Summary of the Invention

[0008] overview Provided herein is an antigen-binding polypeptide complex comprising a first polypeptide, a second polypeptide, and a third polypeptide, wherein the first polypeptide has a structure represented by VL1-L1-VH1-L2-Fc; VH1-L1-VL1-L2-Fc; VH1-L3-VL1-L4-Fc; or VL1-L3-VH1-L4-Fc; the second polypeptide has a structure represented by VH2-L5-VH3-L6-CH1-L7-Fc or VH3-L5-VH2-L6-CH1-L7-Fc; the third polypeptide has a structure represented by VL2-L8-VL3-L9-CL or VL3-L8-VL2-L9-CL; and VL1 is a first polypeptide. VH1 is a first immunoglobulin heavy chain variable region; VH2 is a second immunoglobulin heavy chain variable region; VH3 is a third immunoglobulin heavy chain variable region; Fc is a region comprising immunoglobulin heavy chain constant region 2 (CH2), immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; CH1 is immunoglobulin heavy chain constant region 1; CL is an immunoglobulin light chain constant region; and L1-L9 are amino acid linkers.

[0009] Provided herein is an antigen-binding polypeptide complex comprising a first polypeptide, a second polypeptide, a third polypeptide, and a fourth polypeptide, wherein the first polypeptide has a structure represented by VL1-L1-CL or VH1-L1-CL; the second polypeptide has a structure represented by VH1-L2-CH1-L3-Fc or VL1-L2-CH1-L3-Fc; the third polypeptide has a structure represented by VH2-L4-VH3-L5-CH1-L6-Fc or VH3-L4-VH2-L5-CH1-L6-Fc; and the fourth polypeptide has a structure represented by VL2-L7-VL3-L8-CL or VL3-L7-VL2-L8-CL. VL1 is a first immunoglobulin light chain variable region; VL2 is a second immunoglobulin light chain variable region; VL3 is a third immunoglobulin light chain variable region; VH1 is a first immunoglobulin heavy chain variable region; VH2 is a second immunoglobulin heavy chain variable region; VH3 is a third immunoglobulin heavy chain variable region; Fc is a region comprising immunoglobulin heavy chain constant region 2 (CH2), immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; CH1 is immunoglobulin heavy chain constant region 1; CL is an immunoglobulin light chain constant region; and L1-L8 are amino acid linkers.

[0010] Provided herein is an antigen-binding polypeptide complex comprising a first polypeptide, a second polypeptide, and a third polypeptide, wherein the first polypeptide is selected from the group consisting of VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc; VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc; or VH1-L5-VL2 the second polypeptide has a structure represented by VH3-L9-VH4-L10-CH1-L11-Fc or VH4-L9-VH3-L10-CH1-L11-Fc; the third polypeptide has a structure represented by VL3-L12-VL4-L13-CL or VL4-L12-VL3-L13-CL; VL4 is a fourth immunoglobulin light chain variable region; VH1 is a first immunoglobulin heavy chain variable region; VH2 is a second immunoglobulin heavy chain variable region; VH3 is a third immunoglobulin light chain variable region; VH4 is a fourth immunoglobulin heavy chain variable region; Fc is a region comprising immunoglobulin heavy chain constant region 2 (CH2), immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; CH1 is immunoglobulin heavy chain constant region 1; CL is an immunoglobulin light chain constant region; and L1-L13 are amino acid linkers.

[0011] Provided herein is an antigen-binding polypeptide complex comprising a first polypeptide, a second polypeptide, and a third polypeptide, wherein the first polypeptide is selected from the group consisting of VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc; VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc; or VH1-L the second polypeptide has a structure represented by VH3-L9-VH4-CH1-Fc; or VH4-L9-VH3-CH1-Fc; the third polypeptide has a structure represented by VL3-L10-VL4-CL; or VL4-L10-VL3-CL; VL1 is the first immunoglobulin VH1 is a first immunoglobulin heavy chain variable region; VH2 is a second immunoglobulin heavy chain variable region; VH3 is a third immunoglobulin light chain variable region; VH4 is a fourth immunoglobulin heavy chain variable region; Fc is a region comprising immunoglobulin heavy chain constant region 2 (CH2), immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; CH1 is immunoglobulin heavy chain constant region 1; CL is an immunoglobulin light chain constant region; and L1-L10 are amino acid linkers.

[0012] Provided herein is an antigen-binding polypeptide complex comprising a first polypeptide and a second polypeptide, wherein the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc; VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc; or VH1-L5-VL2-L6-VH2-L7-VL1-L8-Fc. the second polypeptide has a structure represented by VL3-L9-VL4-L10-VH4-L11-VH3-L12-Fc; VL3-L9-VH4-L10-VL4-L11-VH3-L12-Fc; VH3-L13-VH4-L14-VL4-L15-VL3-L16-Fc; or VH3-L13-VL4-L14-VH4-L15-VL3-L16-Fc; and VL1 is a first immunoglobulin that specifically binds to a tumor-associated antigen. VH1 is a first immunoglobulin heavy chain variable region that specifically binds to the tumor-associated antigen; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to the tumor-associated antigen; VH3 is a third immunoglobulin heavy chain variable region that specifically binds to CD3; VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds to the tumor-associated antigen; Fc is a region comprising immunoglobulin heavy chain constant region 2 (CH2), immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; and L1 to L16 are amino acid linkers.

[0013] Provided herein is an antigen-binding polypeptide complex comprising a first polypeptide and a second polypeptide, wherein the first polypeptide has the structure selected from the group consisting of VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L10-Fc; VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-Fc; VH1-L6-VL2-L7-VH2-L8-VL1-L9-CH1-L10-Fc; VL1-L11-VL2-L12-VH2-L13-VH1-L14 -CL-L15-Fc;VL1-L11-VH2-L12-VL2-L13-VH1-L14-CL-L15-Fc;VH1-L16- VH2-L17-VL2-L18-VL1-L19-CL-L20-Fc;VH1-L16-VL2-L17-VH2-L18-VL1 -L19-CL-L20-Fc;VL1-L21-VL2-L22-VH2-L23-VH1-L24-CH1-L25-CL-L26 -Fc;VL1-L21-VH2-L22-VL2-L23-VH1-L24-CH1-L25-CL-L26-Fc;VH1-L27- VH2-L28-VL2-L29-VL1-L30-CH1-L31-CL-L32-Fc;VH1-L27-VL2-L28-VH2 -L29-VL1-L30-CH1-L31-CL-L32-Fc;VL1-L33-VL2-L34-VH2-L35-VH1-L3 6-CL-L37-CH1-L38-Fc; VL1-L33-VH2-L34-VL2-L35-VH1-L36-CL-L37-CH1-L38-Fc; the second polypeptide has the structure represented by VH1-L39-VL2-L40-VH2-L41-VL1-L42-CL-L43-CH1-L44-Fc; VL3-L45-VL4-L46-VH4-L47-VH3-L48-CH1-L49-Fc; VL3-L45-VH4-L46-VL4-L47-VH3-L48-CH1-L49-Fc; VH3-L50-VH4-L51-VL4-L52-VL3-L53-CH1-L54-Fc; VH3-L50-VL4-L51-VH4-L52-VL3-L53-CH1-L54-Fc;VL3-L55-VL4-L56-VH4-L57-VH3-L58-CL-L59-Fc;VL3-L55-VH4-L56-VL4 -L57-VH3-L58-CL-L59-Fc;VH3-L60-VH4-L61-VL4-L62-VL3-L63-CL-L64- Fc;VH3-L60-VL4-L61-VH4-L62-VL3-L63-CL-L64-Fc;VL3-L65-VL4-L66-V H4-L67-VH3-L68-CH1-L69-CL-L70-Fc;VL3-L65-VH4-L66-VL4-L67-VH3-L 68-CH1-L69-CL-L70-Fc;VH3-L71-VH4-L72-VL4-L73-VL3-L74-CH1-L75-C L-L76-Fc;VH3-L71-VL4-L72-VH4-L73-VL3-L74-CH1-L75-CL-L76-Fc;VL3 -L77-VL4-L78-VH4-L79-VH3-L80-CL-L81-CH1-L82-Fc;VL3-L77-VH4-L78 -VL4-L79-VH3-L80-CL-L81-CH1-L82-Fc;VH3-L83-VH4-L84-VL4-L85-VL3 or VH3-L83-VL4-L84-VH4-L85-VL3-L86-CL-L87-CH1-L88-Fc; wherein VL1 is a first immunoglobulin light chain variable region that specifically binds to a tumor-associated antigen; VL2 is a second immunoglobulin light chain variable region that specifically binds to a tumor-associated antigen; VL3 is a third immunoglobulin light chain variable region that specifically binds to CD3; and VL4 is a fourth immunoglobulin light chain variable region that specifically binds to a tumor-associated antigen; H1 is a first immunoglobulin heavy chain variable region that specifically binds to a tumor-associated antigen; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to a tumor-associated antigen; VH3 is a third immunoglobulin heavy chain variable region that specifically binds to CD3; VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds to a tumor-associated antigen; Fc is a region comprising immunoglobulin heavy chain constant region 2 (CH2), immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; CH1 is immunoglobulin heavy chain constant region 1;An antigen-binding polypeptide complex is provided, wherein CL is an immunoglobulin light chain constant region; and L1-L88 are amino acid linkers.

[0014] In some embodiments, one or more linkers L1-L88 have a length of 0 amino acids to about 50 amino acids. In some embodiments, one or more linkers L1-L88 are non-immunogenic. In some embodiments, one or more linkers L1-L88 do not contain a consensus T-cell epitope.

[0015] In some embodiments, one or more of the linkers L1-L88 are cleavable linkers. In some embodiments, the cleavable linker is cleaved by a matrix metalloprotease (MMP), a type II transmembrane serine protease, or an MMP and a type II transmembrane serine protease. In some embodiments, the MMP is MMP1, MMP2, MMP7, MMP8, MMP9, MMP13, or a combination thereof. In some embodiments, the type II transmembrane serine protease is matriptase, hepsin, or a combination thereof. In some embodiments, the matriptase is matriptase 1, matriptase 2, matriptase 3, or a combination thereof. In some embodiments, the cleavable linker is cleaved by urokinase or legumain.

[0016] In some embodiments, the cleavable linker is GPAALV, GSGRKG, GPLGLTG, GPSGLVG, GLVGRKAG, GPAGLVG, GPAGLVSG, STRKAGG, ASTRKAG, or ASTRKAGG (SEQ ID NOs: 22-31), or a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% identity to any one of SEQ ID NOs: 22-31. In some embodiments, one or more of linkers L1 through L88 is g, a, gss, asg, ggssg, gssgs, gtvaa, asggs, astgg, ggsgs, asggsg, ggsgssg, ggsggssgss, sggsgssggs, ggsggsgsggggsasgsg, ggsggsgsggggsasgsg, gggssggggsggsgsggsgs, ggggsggsgsggggsasgsg, gggssggsgsggsgsggsgsgssg, gggssggsgsggsgsgssg, gggssggggsgsggsgsgssg, gggsgsgggsgggsgsggsgssg, gggg The amino acid sequence of sggggsggggsggggsggggsggggsggggsggggsggggs, ggggsgsggsgggssggggsggggsggggsggggsggggsggggssss, or ggggsgsggsgggssggggsggggsggggsggggsggggsggggssssgs (SEQ ID NOs: 1 to 21), or any one of SEQ ID NOs: 444, 567, 576 (GGS), and 607, or any one of SEQ ID NOs: 1 to 21 and any one of SEQ ID NOs: 444, 567, 576 (GGS), and 607, is at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% identical to.

[0017] In some embodiments, one of VH1, VH2, VH3, or VH4 specifically binds CD3. In some embodiments, one of VL1, VL2, VL3, or VL4 specifically binds CD3. In some embodiments, VH1 and VL1, VH2 and VL2, VH3 and VL3, or VH4 and VL4 specifically bind CD3.

[0018] In some embodiments, a VH1, VH2, VH3, or VH4 that specifically binds to CD3 comprises a CDR1 comprising an amino acid sequence having at least 90% identity, at least 95% identity, or 100% identity to any one of SEQ ID NOs: 32, 40, 96, 433, 524, 667, 703, 739, 767, 803, 839, 851, and 859; and a CDR3 comprising an amino acid sequence having at least 90% identity, at least 95% identity, or 100% identity to any one of SEQ ID NOs: 34, 42, 98, 435, 526, 669, 705, 741, 769, 805, 841, 853, and 861; and a VL1, VL2, VL3 that specifically binds to CD3. L3 or VL4 comprises a CDR1 comprising an amino acid sequence having at least 90% identity, at least 95% identity, or 100% identity to any one of SEQ ID NOs: 35, 44, 99, 446, 456, 466, 476, 520, 663, 699, 735, 763, 799, 835, 855, and 863; a CDR2 comprising an amino acid sequence having at least 90% identity, at least 95% identity, or 100% identity to any one of SEQ ID NOs: 37, 46, 101, 448, 458, 468, 478, 522, 665, 701, 737, 765, 801, 837, 857, and 865.In some embodiments, a VH1, VH2, VH3, or VH4 that specifically binds to CD3 comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity to any one of SEQ ID NOs: 38, 43, 102, 423, 432, 523, 666, 702, 738, 766, 802, 838, 850, and 858, and a VL1, VL2, VL3, or VL4 that specifically binds to CD3 comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity to any one of SEQ ID NOs: 39, 47, 103, 422, 445, 455, 465, 475, 519, 662, 698, 734, 762, 798, 834, 854, and 862.

[0019] In some embodiments, one or more of VH1, VH2, VH3, or VH4 specifically bind to a tumor-associated antigen (TAA). In some embodiments, one or more of VL1, VL2, VL3, or VL4 specifically bind to a TAA. In some embodiments, VH1 and VL1, VH2 and VL2, VH3 and VL3, and / or VH4 and VL4 specifically bind to a TAA. In some embodiments, the TAA is selected from the group consisting of A2AR, APRIL, ATPDase, BAFF, BAFFR, BCMA, BlyS, BTK, BTLA, B7DC, B7H1, B7H2, B7H3, B7H4, B7H5, B7H6, B7H7, B7RP1, B7-4, C3, C5, CCL2, CCL3, CCL4, CCL5, CCL7, CCL8, CCL11, CCL15, CCL17, CCL19, CCL20, CCL21, CCL25, CCR3, CCR4, CD1 6A, CD19, CD20, CD24, CD27, CD28, CD30, CD38, CD39, CD40, CD40L, CD47, CD52, CD70, CD80, CD86, CD123, CD133, CD137, CD137L , CD160, CD272, CEACAM5, CLEC9, CLEC91, CRTH2, CSF-1, CSF-2, CSF-3, CXCL1, CXCL2, CXCL4, CXCL12, CXCL13, CXCR3, cMet, CT LA4, DLL3, DLL4, DNGR-1, E-cadherin, EGFR, ENTPD1, ​​EpCAM, FCER1, FCER1A, FCER2, FGFR, FLAP, FOLH1, Gi24, GITR, GITRL, GPR5, GP100, GPRC5D, HER2, HER3, ICOSL, ICOS, HHLA2, HMGB1, HVEM, IDO, IFNa, IgE, IGF1R, IL2R beta, IL1, ILIA, IL1B, IL1F10, IL2, IL4, IL4Ra, IL5, IL5R, IL6, IL7, IL7Ra, IL8, IL9, IL9R, IL10, rhILlO, IL12, IL13, IL13Ral, IL13Ra2, IL15, IL17, IL17Rb, IL 18, IL22, IL23, IL25, IL7, IL33, IL35, ITGB4, ITK, KIR, LAG3, LAMP1, leptin, LPFS2, MHC class II, MUC-1, MUC-16, NCR3LG1, NKG2D,In some embodiments, the TAA is NKp46, NTPDase-1, OX40, OX40L, PD-1, PD-L1, PD-L2, PROM1, S152, SIRP alpha, SISP1, SLC, SPG64, ST2, STEAP1, STEAP2, Syk kinase, STEAP1, TROP2, TACI, TDO, TGFbeta, T14, TIGIT, TIM3, TLR, TLR2, TLR4, TLR5, TLR9, TMEF1, TNFa, TNFRSF7, Tp55, TREM1, TSLP, TSLPR, TWEAK, VEGF, VISTA, Vstm3, or WUCAM, or a combination thereof. In some embodiments, the TAA is CD19. In some embodiments, the TAA is CD20. In some embodiments, the TAA is cMet. In some embodiments, the TAA is Trop2.

[0020] In some embodiments, one or more of VH1, VH2, VH3, or VH4 that specifically bind to a TAA has an amino acid sequence that has at least 90% identity, at least 95% identity, or 100% identity to any one of SEQ ID NOs: 64, 72, 80, 88, 104, 112, 120, 128, 389, 409, 419, 429, 659, 695, 731, 397, 508, 540, 552, 757, 793, 829, 875, 500, 749, 785, 821, 649, 685, 775, 847, 625, 641, 677, and 713. CDR1 comprising the sequence; CDR2 comprising an amino acid sequence having at least 90% identity, at least 95% identity, or 100% identity to any one of SEQ ID NOs: 65, 73, 81, 89, 105, 113, 121, 129, 390, 410, 420, 430, 660, 696, 732, 398, 509, 541, 553, 758, 794, 830, 876, 501, 750, 786, 822, 650, 686, 776, 848, 626, 642, 678, and 714; and and one or more of VL1, VL2, VL3, or VL4 that specifically bind to a TAA include a CDR3 comprising an amino acid sequence having at least 90% identity, at least 95% identity, or 100% identity to any one of SEQ ID NOs: 130, 391, 411, 421, 431, 661, 697, 733, 399, 510, 542, 554, 759, 795, 831, 877, 502, 751, 787, 823, 651, 687, 777, 849, 627, 643, 679, and 715; CDR1 comprising an amino acid sequence having at least 90% identity, at least 95% identity, or 100% identity to any one of SEQ ID NOs: 23, 131, 385, 405, 415, 441, 452, 462, 472, 655, 691, 727, 393, 486, 504, 536, 548, 753, 789, 825, 871, 879, 490, 496, 745, 781, 817, 645, 681, 771, 843, 621, 637, 673, and 709; SEQ ID NOs: 68, 76, 84, 92, 108, 116, 124, 132, 386 (YTS);a CD comprising an amino acid sequence having at least 90% identity, at least 95% identity, or 100% identity to any one of 406(YTS), 416(YTS), 442(YTS), 453(YTS), 463(YTS), 473(YTS), 656, 692, 728, 394, 487(AT), 505(AT), 537, 549, 754, 790, 826, 872, 880, 491(DA), 497(DA), 746, 782, 818, 646, 682, 772, 844, 622, 638, 674, and 710; R2; and a CDR3 comprising an amino acid sequence having at least 90% identity, at least 95% identity, or 100% identity to any one of SEQ ID NOs: 69, 77, 85, 93, 109, 117, 125, 133, 387, 407, 417, 443, 454, 464, 474, 657, 693, 729, 395, 488, 506, 538, 550, 755, 791, 827, 873, 881, 492, 498, 747, 783, 819, 647, 683, 773, 845, 623, 639, 675, and 711. In some embodiments, one or more of VH1, VH2, VH3, or VH4 that specifically binds to a TAA comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity to any one of SEQ ID NOs: 70, 78, 86, 94, 102, 110, 118, 126, 134, 388, 408, 418, 428, 584, 658, 694, 730, 396, 403, 507, 539, 551, 756, 792, 828, 883, 866, 874, 499, 544, 556, 748, 784, 820, 528, 648, 684, 774, 846, 624, 640, 676, and 712;One or more of VL1, VL2, VL3 or VL4 that specifically bind to a TAA are selected from the group consisting of SEQ ID NOs: 71, 79, 87, 95, 103, 111, 119, 127, 135, 384, 404, 414, 440, 451, 461, 471, 583, 654, 690, 726, 392, 402, 485, 503, 535, 547, 752, 788 , 824, 870, 878, 489, 495, 543, 555, 744, 780, 816, 882, 527, 644, 680, 770, 842, 620, 636, 672, and 708;

[0021] In some embodiments, one or more of VH1, VH2, VH3, or VH4 specifically bind to an immunostimulatory receptor. In some embodiments, one or more of VL1, VL2, VL3, or VL4 specifically bind to an immunostimulatory receptor. In some embodiments, VH1 and VL1, VH2 and VL2, VH3 and VL3, and / or VH4 and VL4 specifically bind to an immunostimulatory receptor. In some embodiments, the immunostimulatory receptor is CD28.

[0022] In some embodiments, a VH1, VH2, VH3, or VH4 that specifically binds to an immunostimulatory receptor comprises: a CDR1 comprising an amino acid sequence having at least 90% identity, at least 95% identity, or 100% identity to any one of SEQ ID NOs: 48, 56, 649, 685, 775, and 847; a CDR2 comprising an amino acid sequence having at least 90% identity, at least 95% identity, or 100% identity to any one of SEQ ID NOs: 49, 57, 650, 686, 776, and 848; and a CDR3 comprising an amino acid sequence having at least 90% identity, at least 95% identity, or 100% identity to any one of SEQ ID NOs: 50, 58, 651, 687, 777, and 849. and VL1, VL2, VL3, or VL4 that specifically binds to an immunostimulatory receptor comprises a CDR1 comprising an amino acid sequence having at least 90% identity, at least 95% identity, or 100% identity to any one of SEQ ID NOs: 51, 59, 645, 681, 771, and 843; a CDR2 comprising an amino acid sequence having at least 90% identity, at least 95% identity, or 100% identity to any one of SEQ ID NOs: 52, 60, 646, 682, 772, and 844; and a CDR3 comprising an amino acid sequence having at least 90% identity, at least 95% identity, or 100% identity to any one of SEQ ID NOs: 53, 61, 647, 683, 773, and 845. In some aspects, VH1, VH2, VH3 or VH4 that specifically binds to an immunostimulatory receptor comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity to any one of SEQ ID NOs: 54, 62, 528, 648, 684, 774 and 846, and VL1, VL2, VL3 or VL4 that specifically binds to an immunostimulatory receptor comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity to any one of SEQ ID NOs: 55, 63, 527, 644, 680, 770 and 842.

[0023] In some embodiments, L5, L8, or L5 and L8 are cleavable linkers. In some embodiments, L4, L7, or L4 and L7 are cleavable linkers. In some embodiments, L9, L12, or L9 and L12 are cleavable linkers. In some embodiments, VH3 and VL3 specifically bind to CD3. In some embodiments, VH1 and VL1, and / or VH2 and VL2 specifically bind to a TAA. In some embodiments, VH1 and VL1, or VH2 and VL2 specifically bind to CD28. In some embodiments, VH4 and VL4 specifically bind to CD3. In some embodiments, one or more of VH1 and VL1, VH2 and VL2, and VH3 and VL3 specifically bind to a TAA. In some embodiments, VH1 and VL1 specifically bind to a TAA, VH2 and VL2 specifically bind to a TAA, and VH3 and VL3 specifically bind to CD28. In some embodiments, VH1 and VL1 specifically bind to CD28, VH2 and VL2 specifically bind to a TAA, and VH3 and VL3 specifically bind to a TAA. In some embodiments, VH1 and VL1 specifically bind to cMet, VH2 and VL2 specifically bind to Trop2, and VH3 and VL3 specifically bind to CD28. In some embodiments, VH1 and VL1 specifically bind to Trop2, VH2 and VL2 specifically bind to cMet, and VH3 and VL3 specifically bind to CD28. In some embodiments, VH1 and VL1 specifically bind to cMet, VH2 and VL2 specifically bind to CD28, and VH3 and VL3 specifically bind to Trop2. In some embodiments, VH1 and VL1 specifically bind to CD28, VH2 and VL2 specifically bind to cMet, and VH3 and VL3 specifically bind to Trop2. In some embodiments, VH1 and VL1 specifically bind to Trop2, VH2 and VL2 specifically bind to CD28, and VH3 and VL3 specifically bind to cMet. In some embodiments, VH1 and VL1 specifically bind to CD28, VH2 and VL2 specifically bind to Trop2, and VH3 and VL3 specifically bind to cMet.In some embodiments, VH1 and VL1 specifically bind to CD19, VH2 and VL2 specifically bind to CD20, and VH3 and VL3 specifically bind to CD28. In some embodiments, VH1 and VL1 specifically bind to CD20, VH2 and VL2 specifically bind to CD19, and VH3 and VL3 specifically bind to CD28. In some embodiments, VH1 and VL1 specifically bind to CD19, VH2 and VL2 specifically bind to CD28, and VH3 and VL3 specifically bind to CD20. In some embodiments, VH1 and VL1 specifically bind to CD20, VH2 and VL2 specifically bind to CD28, and VH3 and VL3 specifically bind to CD19. In some embodiments, VH1 and VL1 specifically bind to CD28, VH2 and VL2 specifically bind to CD19, and VH3 and VL3 specifically bind to CD20. In some embodiments, VH1 and VL1 specifically bind to CD28, VH2 and VL2 specifically bind to CD20, and VH3 and VL3 specifically bind to CD19.

[0024] In some embodiments, L1, L3, or L1 and L3 are cleavable linkers, or L5, L7, or L5 and L7 are cleavable linkers. In some embodiments, L9, L11, or L9 and L11 are cleavable linkers, or L13, L15, or L13 and L15 are cleavable linkers. In some embodiments, VH1 and VL1, VH2 and VL2, VH3 and VL3, or VH4 and VL4 specifically bind to CD3. In some embodiments, one or more of VH1 and VL1, VH2 and VL2, VH3 and VL3, and VH4 and VL4 specifically bind to a TAA. In some embodiments, VH1 and VL1, VH2 and VL2, VH3 and VL3, or VH4 and VL4 specifically bind to CD28.

[0025] In some aspects, the antigen-binding polypeptide complex described herein is an antibody or antigen-binding fragment thereof.

[0026] In some embodiments, the immunoglobulin hinge comprises an upper hinge region, a middle hinge region, a lower hinge region, or a combination thereof.

[0027] In some embodiments, the Fc region comprises at least one knob-into-hole modification. In some embodiments, the antigen-binding polypeptide complex is an IgG1 or IgG4 antibody, and the knob-into-hole modifications include, based on the EU numbering scheme, (i) knob substitutions of S354C and T366W, and hole substitutions of Y349C, T366S, L368A, and Y407V; (ii) hole substitutions of L234A, L235A, and P329A; (iii) hole substitutions of L234A and L235A; (iv) hole substitutions of M428L and N433S; (v) hole substitutions of M252Y, S254T, and T256E; or (vi) combinations thereof.

[0028] Also provided herein is an antibody or antigen-binding fragment thereof comprising an antigen-binding polypeptide complex described herein.

[0029] Also provided herein is a pharmaceutical composition comprising an antigen-binding polypeptide complex, or an antibody or antigen-binding fragment thereof, described herein, and a pharmaceutically acceptable carrier.

[0030] Provided herein are kits comprising an antigen-binding polypeptide complex, an antibody or antigen-binding fragment thereof, or a pharmaceutical composition described herein, and instructions for use.

[0031] Also provided herein are specific methods of using the antigen-binding polypeptide complexes, antibodies or antigen-binding fragments thereof, pharmaceutical compositions, or kits described herein, or combinations thereof. Provided herein are methods for treating cancer, comprising administering to a subject in need thereof an antigen-binding polypeptide complex, antibody or antigen-binding fragment thereof, or pharmaceutical composition described herein. In some embodiments, the cancer is a solid cancer. In some embodiments, the cancer is breast cancer, lung cancer, gastric cancer, prostate cancer, cervical cancer, urothelial cancer, or pancreatic cancer. In some embodiments, the cancer is a blood cancer. In some embodiments, the blood cancer is leukemia or lymphoma. In some embodiments, the leukemia or lymphoma is B-cell leukemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), Burkitt's lymphoma, lymphoplasmacytic lymphoma (Waldenstrom's macroglobulinemia), prolymphocytic leukemia (PLL), or hairy cell leukemia (HCL). [Brief explanation of the drawings]

[0032] [Figure 1A] Figure 1 shows the construction of a masked trispecific T cell engager. Fv1-Fv2 are directed against tumor-associated antigens (TAA) or immune co-stimulatory receptors. The third Fv targets CD3. [Figure 1B] Figure 1 shows the construction of a masked tetraspecific T cell engager. Fv1-Fv3 are directed against tumor-associated antigens (TAA) or immune co-stimulatory receptors. The fourth Fv targets CD3. [Figure 2] 1 shows SDS-PAGE results of in vitro cleavage of the exemplary masked tetraspecific molecules shown, which were treated with either the MTP or MMP9 protease as specified. [Figure 3]ELISA binding results for exemplary masked tetraspecific molecules shown in Figure 2, with or without protease treatment, or a negative isotype (control IgG1) are shown. Identified molecules, cleaved or not by MTP or MMP9, were tested for binding affinity to Trop2 and cMet. [Figure 4] ELISA binding results for the exemplary masked tetraspecific molecules shown in Figure 2, with or without protease treatment, or a negative isotype (control IgG1) are shown. Identified molecules, cleaved or not by MTP or MMP9, were tested for binding affinity to CD28. [Figure 5] ELISA binding results for the exemplary masked tetraspecific molecules shown in FIG. 2, with or without protease treatment, or a negative isotype (control IgG1) are shown. Identified molecules, cleaved or not by MTP or MMP9, were tested for binding affinity to CD3. [Figure 6] Figure 1 shows cytolysis (E:T:10:1) of HCC1954 tumor cells by peripheral blood mononuclear cells (PBMCs) mediated by the exemplary masked tetraspecific molecule shown in Figure 2 or a negative isotype (control IgG1) from PBMCs of two donors (KP63250 and KP63251). [Figure 7] 1 shows ELISA binding results of the indicated exemplary unmasked tetraspecific molecules, or a negative isotype (hIgG1LALPA) control, to their respective targets Trop2, hcMet, hCD28, and hCD3. [Figure 8] Shown is CD69+ activation of CD2+ T cells from PBMCs of two different donors with an exemplary unmasked tetraspecific molecule or a negative isotype (IgG1LALPA) control. [Figure 9] ELISA binding results (OD650) of MX612 and MX613 to their targets hTrop2, hcMet, hCD28, and hCD3 are shown. Results from a control antibody (control IgG) that does not bind these targets are also shown. [Figure 10] 1 shows the simultaneous co-binding of MX612 to its targets hTrop2, hcMet, hCD28, and hCD3 as measured by biolayer interferometry. [Figure 11] Figure 1 shows the simultaneous co-binding of MX446 to its targets hTrop2, hcMet, hCD28, and hCD3 as measured by biolayer interferometry. [Figure 12] 1 shows the ability of an exemplary unmasked tetraspecific molecule to activate CD4+ and CD8+ T cells (CD69+). Results from PBMCs from six different donors are shown in the absence of target tumor cells and after treatment with 1 nM MX446 and MX612. Results from a negative control (isotype IgG1LALPA; "-control") and a positive control (CD3+CD28mAb; "+control") are also shown. [Figure 13A] 1 shows the ability of an exemplary unmasked tetraspecific molecule to trigger the release of cytokines IL-2, IFN-gamma, IL-6, and TNF-alpha. Results from PBMCs from six different donors are shown in the absence of target tumor cells and after treatment with 1 nM MX446 and MX612. [Figure 13B] Figure 1 shows the ability of an exemplary unmasked tetraspecific molecule to trigger the release of cytokines IL-2, IFN-gamma, IL-6, and TNF-alpha. Results from PBMCs from six different donors are shown in the absence of target tumor cells and after treatment with 1 nM MX446 and MX612. Results from a negative control (isotype IgG1LALPA; "-control") and a positive control (CD3+CD28 mAb; "+control") are also shown. [Figure 14A] This figure shows the ability of an exemplary unmasked tetraspecific molecule to trigger the release of cytokines IL-2, IFN-gamma, IL-6, and TNF-alpha. Results from PBMCs from six different donors are shown in the presence of HCC1954 and after treatment with 62.5 pM MX446 and MX612. Results from a negative control (isotype IgG1LALPA; "-control") are also shown. [Figure 14B]This figure shows the ability of an exemplary unmasked tetraspecific molecule to trigger the release of cytokines IL-2, IFN-gamma, IL-6, and TNF-alpha. Results from PBMCs from six different donors are shown in the presence of HCC1954 and after treatment with 62.5 pM MX446 and MX612. Results from a negative control (isotype IgG1LALPA; "-control") are also shown. [Figure 15A] Figure 1 shows the ability of an exemplary unmasked tetraspecific molecule to trigger the release of cytokines IL-2, IFN-gamma, IL-6, and TNF-alpha. Results from PBMCs from six different donors are shown in the presence of BT20 and after treatment with 62.5 pM MX446 and MX612. Results from a negative control (isotype IgG1LALPA; "-control") are also shown. [Figure 15B] Figure 1 shows the ability of an exemplary unmasked tetraspecific molecule to trigger the release of cytokines IL-2, IFN-gamma, IL-6, and TNF-alpha. Results from PBMCs from six different donors are shown in the presence of BT20 and after treatment with 62.5 pM MX446 and MX612. Results from a negative control (isotype IgG1LALPA; "-control") are also shown. [Figure 16A] Figure 1 shows tumor cell line lysis (E:T 5:1) by exemplary unmasked tetraspecific molecules or negative controls from PBMCs. HCC1954, BT-20, HCC1143, and HCC70 breast cancer cells, PC3 and DU145 prostate cancer cells, and Hs746T and N87 gastric cancer cells were used. Cell lysis rates and EC50 values ​​(pM) after treatment with MX446 and MX612 are shown. Results from the negative control (isotype IgG1LALAPA) are also shown. [Figure 16B]Figure 1 shows tumor cell line lysis (E:T 5:1) by exemplary unmasked tetraspecific molecules or negative controls from PBMCs. HCC1954, BT-20, HCC1143, and HCC70 breast cancer cells, PC3 and DU145 prostate cancer cells, and Hs746T and N87 gastric cancer cells were used. Cell lysis rates and EC50 values ​​(pM) after treatment with MX446 and MX612 are shown. Results from the negative control (isotype IgG1LALAPA) are also shown. [Figure 17] 1 summarizes the cytolytic efficacy of various tumor cell lines mediated by exemplary unmasked tetraspecific molecules. [Figure 18A] 1 shows the binding of exemplary unmasked tetraspecific molecules to their targets hTrop2, hcMet, hCD28, and hCD3 as measured by biolayer interferometry. Results are shown for cells treated with MX974. [Figure 18B] 1 shows the binding of exemplary unmasked tetraspecific molecules to their targets hTrop2, hcMet, hCD28, and hCD3 as measured by biolayer interferometry. Results are shown for cells treated with MX975. [Figure 18C] 1 shows the binding of exemplary unmasked tetraspecific molecules to their targets hTrop2, hcMet, hCD28, and hCD3 as measured by biolayer interferometry. Results are shown for cells treated with MX976. [Figure 19] Figure 1 shows in vitro cytolysis of HCC1954 tumor cells by an exemplary unmasked tetraspecific molecule. Cytolysis (E:T:5:1) mediated by MX974, MX975, and MX976 or a negative control from PBMCs was measured from a representative donor after 48 and 72 hours of incubation at 37°C. Results are shown as percent lysis of cells with increasing concentrations of antibody. Results from the negative control (hIgG1LALAPA) are also shown. [Figure 20]Activation of CD4+ and CD8+ T cells (CD69+) from PBMCs by an exemplary masked tetraspecific molecule is shown. Results are shown as the percentage of CD69+ cells from six donors after treatment with MX444 or MX634 at 1 nM in the absence of target tumor cells. Results from a negative control (isotype IgG1LALPA; "-control") and a positive control (CD3+CD28mAb; "+control") are also shown. [Figure 21A] Figure 1 shows the ability of an exemplary unmasked tetraspecific molecule to trigger the release of cytokines IL-2, IFN-gamma, IL-6, and TNF-alpha. Results from PBMCs from six different donors are shown in the absence of target tumor cells and after treatment with 1 nM MX444 and MX634. Results from a negative control (isotype IgG1LALPA; "-control") and a positive control (CD3+CD28 mAb; "+control") are also shown. [Figure 21B] Figure 1 shows the ability of an exemplary unmasked tetraspecific molecule to trigger the release of cytokines IL-2, IFN-gamma, IL-6, and TNF-alpha. Results from PBMCs from six different donors are shown in the absence of target tumor cells and after treatment with 1 nM MX444 and MX634. Results from a negative control (isotype IgG1LALPA; "-control") and a positive control (CD3+CD28 mAb; "+control") are also shown. [Figure 22A] Figure 1 shows the ability of an exemplary unmasked tetraspecific molecule to trigger the release of cytokines IL-2, IFN-gamma, IL-6, and TNF-alpha. Results from PBMCs from six different donors are shown in the absence of target tumor cells and after treatment with 1 nM MX444 and MX634. Results from a negative control (isotype IgG1LALPA; "-control") and a positive control (CD3+CD28 mAb; "+control") are also shown. [Figure 22B]Figure 1 shows the ability of an exemplary unmasked tetraspecific molecule to trigger the release of cytokines IL-2, IFN-gamma, IL-6, and TNF-alpha. Results from PBMCs from six different donors are shown in the absence of target tumor cells and after treatment with 1 nM MX444 and MX634. Results from a negative control (isotype IgG1LALPA; "-control") and a positive control (CD3+CD28 mAb; "+control") are also shown. [Figure 23A] This figure shows the ability of an exemplary unmasked tetraspecific molecule to trigger the release of cytokines IL-2, IFN-gamma, IL-6, and TNF-alpha. Results from PBMCs from six different donors are shown in the presence of HCC1954 and after treatment with 62.5 pM MX444 and MX634. Results from a negative control (isotype IgG1LALPA; "-control") are also shown. [Figure 23B] This figure shows the ability of an exemplary unmasked tetraspecific molecule to trigger the release of cytokines IL-2, IFN-gamma, IL-6, and TNF-alpha. Results from PBMCs from six different donors are shown in the presence of HCC1954 and after treatment with 62.5 pM MX444 and MX634. Results from a negative control (isotype IgG1LALPA; "-control") are also shown. [Figure 24A] Figure 1 shows the ability of an exemplary unmasked tetraspecific molecule to trigger the release of cytokines IL-2, IFN-gamma, IL-6, and TNF-alpha. Results from PBMCs from six different donors are shown in the presence of BT20 and after treatment with 62.5 pM MX444 and MX634. Results from a negative control (isotype IgG1LALPA; "-control") are also shown. [Figure 24B] Figure 1 shows the ability of an exemplary unmasked tetraspecific molecule to trigger the release of cytokines IL-2, IFN-gamma, IL-6, and TNF-alpha. Results from PBMCs from six different donors are shown in the presence of BT20 and after treatment with 62.5 pM MX444 and MX634. Results from a negative control (isotype IgG1LALPA; "-control") are also shown. [Figure 25] 1 summarizes the cytolytic efficacy of various tumor cell lines mediated by exemplary unmasked tetraspecific molecules. [Figure 26] The structures of MX433, MX434, MX435 and MX436 are shown. [Figure 27] Exemplary unmasked tetraspecific molecules MX433, MX434, MX435, and MX436 demonstrate the ability to bind to their targets when tested by ELISA. Binding results to hCD19, hCD28, and hCD3 are shown. Results from a negative control (hIgG1LALPA) are also shown. [Figure 28] The structures of MX647, MX648, MX685 and MX686 are shown. [Figure 29] Exemplary unmasked tetraspecific molecules MX647, MX648, MX685, and MX686 demonstrate the ability to bind to their targets when tested by ELISA. Binding results to hCD19, hCD28, and hCD3 are shown. [Figure 30] Figure 1 shows surface staining of hCD20-expressing Epi293 cells with exemplary unmasked tetraspecific molecules. The molecules tested were MX647, MX789, MX788, MX787, MX786, MX685, MX793, MX792, MX791, and MX790. Staining with a negative control (hIgG1LALPA) is also shown. [Figure 31] The structures of MX647, MX648, MX685, MX786 and MX790 are shown. [Figure 32] Figure 1 shows the ability of exemplary unmasked tetraspecific molecules to activate T cells (CD69+). The molecules tested were MX647, MX648, MX685, MX786, and MX790. The percentage of CD69+ cells from PBMCs of a representative donor in the absence of tumor cells and after treatment with MX647, MX648, MX685, MX786, and MX790 is shown. EC50 values ​​(pM) and results from a negative control (hIgG1LALAPA) are also shown. [Figure 33]Figure 1 shows the measurement of cell lysis (E:T:5:1) mediated by MX647, MX648, MX685, MX786, and MX790 or a negative control (hIgG1LALAPA) from PBMCs. Results are presented as percentage lysis at increasing concentrations of antibody. EC50 (pM) and Rmax values ​​are also shown. [Figure 34] Figure 1 shows cytokine release from PBMCs from a representative donor in the absence of target tumor cells and after treatment with 8 pM or 40 pM MX647, MX648, MX685, MX786, and MX790. Results from a negative control (hIgG1LALPA) are also shown. [Figure 35] Figure 1 shows cytokine release from PBMCs from a representative donor in the presence of Z-138 tumor cells and after treatment with 8 pM or 40 pM MX647, MX648, MX685, MX786, and MX790. Results from a negative control (hIgG1LALAPA) are also shown. [Figure 36] 1 shows surface staining of exemplary trispecific molecules MX848, MX856, and MX857 on hCD20-expressing Epi293 cells. Staining with a negative control (control) is also shown. [Figure 37] Figure 1 shows in vitro cytolysis (E:T:3:1) of Z-138 tumor cells mediated by MX857 or negative control (hIgG1LALAPA) from PBMCs from two representative donors. Results are presented as percent lysis of cells at increasing concentrations of antibody. [Figure 38] 1 shows surface staining of 12.5 nM MX846, MX854, and MX855 on hCD20-expressing Epi293 cells. Staining with a negative control (control) is also shown. [Figure 39A] 1 shows surface staining of 12.5 nM MX850, MX851, MX852, and MX853 on hCD20-expressing Epi293 cells. Staining with the negative control (Control) is also shown. [Figure 39B]1 shows surface staining of 12.5 nM MX850, MX851, MX852, and MX853 on hCD20-expressing Epi293 cells. Staining with the negative control (Control) is also shown. [Figure 40] Figure 1 shows in vitro cytolysis of Z-138 tumor cells mediated by MX855. Results are presented as percentage of cell lysis with increasing concentrations of antibody. [Figure 41A] 1 shows the binding of MX977 and MX978 to their targets CD20, CD19, CD28 and CD3 by biolayer interferometry. [Figure 41B] 1 shows the binding of MX977 and MX978 to their targets CD20, CD19, CD28 and CD3 by biolayer interferometry. [Figure 42] Surface staining of hCD20-expressing Epi293 cells with 12.5 nM MX977 and MX978 is shown. Staining with a negative control (hIgGLALAPA) is also shown. [Figure 43] Figure 1 shows in vitro cytolysis (E:T:5:1) of Toledo tumor cells mediated by MX977, MX978, or a negative control (hIgG1LALAPA) from PBMCs from a representative donor. Results are presented as percent cell lysis with increasing concentrations of antibody. DETAILED DESCRIPTION OF THE INVENTION

[0033] Detailed Description of the Invention The present invention is directed to antigen-binding polypeptide complexes (e.g., antibodies or antigen-binding fragments thereof) with improved characteristics. In some aspects, the invention enables the generation of multispecific and multifunctional antigen-binding polypeptide complexes through the expression of complementary self-assembling heavy and light chains expressed with a single polypeptide per arm and, optionally, with the addition of an amino acid linker. This multifunctionality allows the antigen-binding polypeptide complexes of the invention to bind to specific combinations of target molecules for selectivity or breadth / neutralization, bring together two or more cell types, deliver activation signals to targets, modify the disease microenvironment, and enhance binding avidity for improved efficacy.

[0034] Various terms relating to aspects of the present disclosure are used throughout the specification and claims. Such terms should be given their ordinary meaning in the art unless otherwise indicated. Other specifically defined terms should be interpreted in a manner consistent with the definitions provided herein.

[0035] definition As used herein, the term "antigen-binding polypeptide complex" refers to a group of two, three, four, or more associated polypeptides, wherein at least one polypeptide has the ability to specifically bind to one or more antigens. Antigen-binding polypeptide complexes include, but are not limited to, antibodies or antigen-binding fragments thereof.

[0036] The term "antibody" includes, but is not limited to, glycoprotein immunoglobulins that specifically bind to an antigen and comprise at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each H chain comprises a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region comprises three constant domains, CH1, CH2, and CH3. Each L chain comprises a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region comprises one constant domain, namely, CL. The VH and VL regions can be further subdivided into regions of hypervariability called complementarity-determining regions (CDRs) interspersed with more conserved regions called framework regions (FRs). Each VH and VL comprises three CDRs and four FRs arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain binding domains that interact with antigens. The constant regions of the antibody can mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system. The heavy chain may or may not have a C-terminal lysine. Unless otherwise specified herein, amino acids in the variable regions are numbered using the Kabat numbering system, and those in the constant regions are numbered using the EU system.

[0037] The term "monoclonal antibody," as used herein, refers to an antibody produced by a single clone of B cells and binding to the same epitope. In contrast, the term "polyclonal antibody" refers to a population of antibodies produced by different B cells and binding to different epitopes of the same antigen. The term "antibody" includes, by way of example, monoclonal and polyclonal antibodies; chimeric and humanized antibodies; human or non-human antibodies; whole synthetic antibodies; and single-chain antibodies. Non-human antibodies can be humanized by recombinant methods to reduce their immunogenicity in humans.

[0038] The antibody may be a modified antibody (e.g., by mutation, deletion, substitution, conjugation to a non-antibody moiety). For example, the antibody may include one or more variant amino acids (compared to a naturally occurring antibody) that alter the properties (e.g., functional properties) of the antibody. Several such modifications are known in the art that, for example, affect half-life in patients, effector functions, and / or the immune response to the antibody. The term antibody also includes artificial polypeptide constructs that contain at least one antibody-derived antigen-binding site.

[0039] An "antigen-binding fragment" refers to one or more fragments or portions of an antibody that retain the ability to specifically bind to the antigen bound by the intact antibody. It has been shown that the antigen-binding function of an antibody can be performed by fragments or portions of a full-length antibody. An antigen-binding fragment may contain the antigenic determining region (e.g., complementarity-determining region (CDR)) of an intact antibody. Examples of antigen-binding fragments of antibodies include, but are not limited to, Fab, Fab', F(ab')2, and Fv fragments, linear antibodies, and single-chain antibodies. Antigen-binding fragments of antibodies can be derived from any animal species, such as rodents (e.g., mice, rats, or hamsters) and humans, or can be artificially generated.

[0040] Furthermore, although the two domains of the Fv fragment, i.e., VL and VH, are encoded by separate genes, they can be joined using recombinant methods by a synthetic linker that allows them to be produced as a single protein chain in which the VL and VH regions pair to form a monovalent molecule (known as a single-chain Fv (scFv); see, e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883). Such single-chain antibodies are also intended to be encompassed by the term "antigen-binding fragment" of an antibody.

[0041] Antigen-binding fragments are obtained using conventional techniques known to those of skill in the art, and the fragments are screened for utility in the same manner as are intact antibodies. Antigen-binding fragments can be produced by recombinant DNA techniques or by enzymatic or chemical cleavage of intact immunoglobulins.

[0042] As used herein, the term "variable region" typically refers to a portion of an antibody, usually a portion of either the light or heavy chain, typically approximately the amino-terminal 110-120 or 110-125 amino acids in a mature heavy chain and approximately 90-115 amino acids in a mature light chain, which differ extensively in sequence among antibodies and are responsible for the binding and specificity of a particular antibody for its particular antigen. Variability in sequence is concentrated in those regions called complementarity-determining regions (CDRs), while the more highly conserved regions in the variable domain are called framework regions (FRs). Without wishing to be bound by any particular mechanism or theory, it is believed that the CDRs of the light and heavy chains are primarily responsible for the interaction and specificity of the antibody with the antigen. In some embodiments, the variable region is a mammalian variable region, e.g., a human, mouse, or rabbit variable region. In some embodiments, the variable region comprises rodent or murine CDRs and human framework regions (FRs). In some embodiments, the variable region is a primate (e.g., non-human primate) variable region. In some embodiments, the variable region comprises rodent or murine CDRs and primate (eg, non-human primate) framework regions (FR).

[0043] The term "complementarity determining region" or "CDR" as used herein refers to each of the regions of an antibody variable domain that are hypervariable in sequence and / or form structurally defined loops (hypervariable loops) and / or contain antigen-contacting residues. An antibody may contain six CDRs, e.g., three CDRs in the VH and three CDRs in the VL.

[0044] The terms "VL," "VL region," and "VL domain" are used interchangeably herein to refer to a light chain variable region of an antigen-binding polypeptide complex, antibody, or antigen-binding fragment thereof. In some aspects, a VL region is referred to herein as VL1 to denote a first light chain variable region, VL2 to denote a second light chain variable region, VL3 to denote a third light chain variable region, etc. A listed VL region (e.g., VL1) can have the same or different antigen-binding characteristics and / or the same or different sequence as another listed VL region (e.g., VL2).

[0045] The terms "VH," "VH region," and "VH domain" are used interchangeably herein to refer to a heavy chain variable region of an antigen-binding polypeptide complex, antibody, or antigen-binding fragment thereof. In some aspects, a VH region is referred to herein as VH1 to denote a first heavy chain variable region, VH2 to denote a second heavy chain variable region, VH3 to denote a third heavy chain variable region, etc. A listed VH region (e.g., VH1) can have the same or different antigen-binding characteristics and / or the same or different sequence as another listed VH region (e.g., VH2).

[0046] As used herein, "Kabat numbering" and similar terms refer to an art-recognized system for numbering amino acid residues in the heavy and light chain variable regions of an antibody or antigen-binding fragment thereof. In some embodiments, CDRs can be determined according to the Kabat numbering system (see, e.g., Kabat EA & Wu TT (1971) Ann NY Acad Sci 190:382-391 and Kabat EA et al., (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, USDapartment of Health and Human Services, NIH Publication No. 91-3242). Using the Kabat numbering system, the CDRs in an antibody heavy chain molecule are typically located at amino acid positions 31-35 (which may optionally include one or two additional amino acids following 35, designated 35A and 35B in the Kabat numbering scheme) (CDR1), amino acid positions 50-65 (CDR2), and amino acid positions 95-102 (CDR3). Using the Kabat numbering system, the CDRs in an antibody light chain molecule are typically located at amino acid positions 24-34 (CDR1), amino acid positions 50-56 (CDR2), and amino acid positions 89-97 (CDR3).

[0047] As used herein, the terms "constant region" or "constant domain" are used interchangeably to refer to a portion of an antigen-binding polypeptide complex, an antibody, or an antigen-binding fragment thereof, e.g., the carboxyl-terminal portion of the light chain and / or heavy chain, which is not directly involved in binding the antibody to an antigen but may exhibit various effector functions, e.g., interacting with the Fc region. Constant regions typically have a more conserved amino acid sequence than variable regions. In some embodiments, an antigen-binding polypeptide complex, an antibody, or an antigen-binding fragment thereof comprises a constant region or a portion thereof sufficient for antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC).

[0048] As used herein, the terms "fragment crystallizable region," "Fc region," or "Fc domain" are used interchangeably herein to refer to the tail region of an antibody that interacts with cell surface receptors called Fc receptors and several proteins of the complement system. The Fc region typically includes the CH2 and CH3 regions and, optionally, the immunoglobulin hinge.

[0049] As used herein, the terms "immunoglobulin hinge," "hinge," "hinge domain," or "hinge region" are used interchangeably to refer to an antigen-binding polypeptide complex, the extension of the heavy chain between the Fab and Fc portions of an antibody or antigen-binding fragment thereof. The hinge provides structure, positioning, and flexibility that aid in the normal function of an antibody (e.g., for cross-linking two antigens or binding two antigenic determinants on the same antigen molecule). Immunoglobulin hinges are divided into upper, middle, and lower hinge regions, which can be separated based on structural and / or genetic components. Immunoglobulin hinges of the present invention may contain one, two, or all three of these regions. Structurally, the upper hinge region extends from the C-terminus of CH1 to the first hinge disulfide bond. The middle hinge region extends from the first cysteine ​​to the last cysteine ​​in the hinge. The lower hinge region extends from the last cysteine ​​to the glycine of CH2. Cysteines present in the hinge form interchain disulfide bonds that link the immunoglobulin monomers.

[0050] As used herein, the term "Fab" refers to the region of an antibody that binds to an antigen, which typically consists of one constant and one variable domain from each of the heavy and light chains.

[0051] As used herein, the term "heavy chain" refers to an antigen-binding polypeptide complex, a portion of an antibody or antigen-binding fragment thereof, typically composed of a heavy chain variable region (VH), heavy chain constant region 1 (CH1), heavy chain constant region 2 (CH2), and heavy chain constant region 3 (CH3). A typical antibody is composed of two heavy chains and two light chains. When used in reference to antibodies, heavy chains can refer to any of the different types, e.g., alpha (α), delta (δ), epsilon (ε), gamma (γ), and mu (μ), based on the amino acid sequence of the constant region, which give rise to the IgA, IgD, IgE, IgG, and IgM classes of antibodies, respectively (including IgG subclasses, e.g., IgG1, IgG2, IgG3, and IgG4). Heavy chain amino acid sequences are known in the art. In some embodiments, the heavy chain is a human heavy chain.

[0052] As used herein, the term "light chain" refers to an antigen-binding polypeptide complex, a portion of an antibody or antigen-binding fragment thereof, typically composed of a light chain variable region (VL) and a light chain constant region (CL). A typical antibody is composed of two light chains and two heavy chains. When used in reference to an antibody, light chain can refer to any of different types, e.g., kappa (κ) or lambda (λ), based on the amino acid sequence of the constant region. Light chain amino acid sequences are known in the art. In some embodiments, the light chain is a human light chain.

[0053] The term "chimeric" antibody or antigen-binding fragment thereof refers to an antibody or antigen-binding fragment thereof whose amino acid sequences are derived from two or more species. Typically, the variable regions of both the light and heavy chains correspond to the variable regions of an antibody or antigen-binding fragment thereof from one mammalian species (e.g., mouse, rat, rabbit, etc.) having the desired specificity, affinity, and capacity, while the constant regions are homologous to antibody or antigen-binding fragment sequences from another species (usually human) to avoid eliciting an immune response in that species.

[0054] The term "humanized" antibody or antigen-binding fragment thereof refers to a form of a non-human (e.g., murine) antibody or antigen-binding fragment that is a specific immunoglobulin chain, chimeric immunoglobulin, or fragment thereof that contains minimal non-human (e.g., murine) sequence. Typically, a humanized antibody or antigen-binding fragment thereof is a human immunoglobulin in which residues from the complementarity-determining regions (CDRs) are replaced by residues from the CDRs of a non-human species (e.g., mouse, rat, rabbit, hamster) having the desired specificity, affinity, and capacity (Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-327 (1988); Verhoeyen et al., Science 239:1534-1536 (1988)). In some embodiments, Fv framework region (FR) residues of a human immunoglobulin are replaced with corresponding residues in an antibody or fragment from a non-human species having the desired specificity, affinity, and capacity. Humanized antibodies or antigen-binding fragments thereof can be further modified by substitution of additional residues either in the Fv framework regions and / or within the replaced non-human residues to refine and optimize the specificity, affinity, and / or capacity of the antibody or antigen-binding fragment. Humanized antibodies or antigen-binding fragments thereof usually comprise substantially all of at least one, and typically two or three, variable domains containing all or substantially all of the CDR regions corresponding to a non-human immunoglobulin, while all or substantially all of the FR regions are of a human immunoglobulin consensus sequence. Humanized antibodies or antigen-binding fragments thereof can also comprise at least a portion of a constant region, typically that of a human immunoglobulin. Examples of methods used to generate humanized antibodies are known and are described, for example, in U.S. Pat. No. 5,225,539; Roguska et al., Proc. Natl. Acad. Sci., USA, 91(3):969-973 (1994); and Roguska et al., Protein Eng. 9(10):895-904 (1996).

[0055] The term "human" antibody or antigen-binding fragment thereof, as used herein, means an antibody or antigen-binding fragment thereof having an amino acid sequence derived from a human immunoglobulin gene locus, and such an antibody or antigen-binding fragment is produced using recombinant techniques known in the art. This definition of a human antibody or antigen-binding fragment thereof includes intact or full-length antibodies and fragments thereof.

[0056] An "isolated" polypeptide complex, antibody, antigen-binding fragment thereof, polynucleotide, vector, or cell is a polypeptide complex, antibody, antigen-binding fragment thereof, polynucleotide, vector, or cell that is in a form not found in nature. Isolated polypeptide complexes, antibodies, antigen-binding fragments thereof, polynucleotides, vectors, or cells include those that have been purified to the extent that they are no longer in a form found in nature. In some embodiments, an isolated polypeptide complex, antibody, antigen-binding fragment thereof, polynucleotide, vector, or cell is substantially pure. As used herein, "substantially pure" refers to a material that is at least 50% pure (i.e., free from contaminants), at least 90% pure, at least 95% pure, at least 98% pure, or at least 99% pure.

[0057] The terms "polypeptide," "peptide," and "protein" are used interchangeably herein to refer to polymers of amino acids of any length. A polymer can be linear or branched, it can comprise modified amino acids, and it can be interrupted by non-amino acids. The term also encompasses amino acid polymers that are modified, naturally or by intervention; for example, by disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification, such as conjugation with a labeling component. The definition also includes, for example, polypeptides containing one or more analogs of an amino acid (including, for example, unnatural amino acids, etc.), as well as other modifications known in the art. The polypeptides of the invention are based on antibodies, and it is understood that in some aspects the polypeptides can occur as single chains or associated chains.

[0058] The use of the alternative (e.g., "or") should be understood to mean either one, both, or any combination thereof of the alternatives. As used herein, the indefinite article "a" or "an" should be understood to refer to "one or more" of any described or listed components.

[0059] As used herein, the term "and / or" should be interpreted as a specific disclosure of each of the two specified features or components (with or without the other). Thus, when the term "and / or" is used herein in phrases such as "A and / or B," it is intended to include "A and B," "A or B," "A" (alone), and "B" (alone). Similarly, when the term "and / or" is used in phrases such as "A, B, and / or C," it is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0060] Where embodiments are described herein using words such as "comprising," "having," and the like, it is understood that other similar embodiments described in terms of "consisting of" and / or "consisting essentially of" are also provided.

[0061] As used herein, the term "about" refers to a value or composition that is within an acceptable error range for a particular value or composition as determined by one of ordinary skill in the art, which will depend in part on how the value or composition is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean within or more than 1 standard deviation per practice in the art. Alternatively, "about" can mean a range of up to 10% or 20% (i.e., ±10% or ±20%). For example, about 3 mg can include any number between 2.7 mg and 3.3 mg (for 10%) or between 2.4 mg and 3.6 mg (for 20%). Furthermore, particularly with respect to biological systems or processes, the term can mean a value up to an order of magnitude or up to 5 times greater. When a particular value or composition is provided in this application and claims, unless otherwise stated, the meaning of "about" should be assumed to be within an acceptable error range for that particular value or composition.

[0062] As described herein, any numerical range, concentration range, percentage range, ratio range, or integer range, unless otherwise indicated, is understood to include any integer and, where appropriate, fractional values ​​thereof (e.g., tenths and hundredths of integers) within the stated range.

[0063] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. For example, the Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed., 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 5th ed., 2013, Academic Press; and the Oxford Dictionary of Biochemistry and Molecular Biology, 2006, Oxford University Press, provide those skilled in the art with a general dictionary of many of the terms used in this disclosure.

[0064] Units, prefixes, and symbols are denoted in their International System of Units (SI) accepted form. Numerical ranges are inclusive of the numerical values ​​defining the range. The headings provided herein are not limitations of the various aspects of the present disclosure that may be effected by reference to the specification as a whole. Accordingly, terms defined herein are more fully defined by reference to the specification in its entirety.

[0065] Various aspects are described in further detail in the following sections.

[0066] Antigen-binding polypeptide complex In some embodiments, the present invention is directed to antigen-binding polypeptide complexes having predetermined structural characteristics as further described herein. In some embodiments, the antigen-binding polypeptide complexes of the present invention (e.g., antibodies or antigen-binding fragments thereof) comprise one or more cleavable linkers as further described herein. In some embodiments, the antigen-binding polypeptide complexes of the present invention (e.g., antibodies or antigen-binding fragments thereof) comprise interferon alpha as further described herein.

[0067] In some embodiments, an antigen-binding polypeptide complex of the invention (e.g., an antibody or antigen-binding fragment thereof) comprises a VH and / or VL that specifically binds to CD3. In some embodiments, one of the VH1, VH2, VH3, or VH4 of an antigen-binding polypeptide described herein specifically binds to CD3. In some embodiments, one of the VL1, VL2, VL3, or VL4 of an antigen-binding polypeptide described herein specifically binds to CD3. In some embodiments, the VH1 and VL1, VH2 and VL2, VH3 and VL3, or VH4 and VL4 of an antigen-binding polypeptide described herein specifically binds to CD3.

[0068] In some embodiments, a VH and / or VL that specifically binds CD3 is masked by another VH and / or VL connected to the VH and / or VL that specifically binds CD3 by interferon alpha and / or a cleavable linker.

[0069] In some aspects, the VH1 and VH2 of the antigen-binding polypeptide complexes described herein are connected by a cleavable linker. In some aspects, the VH1 and VL2 of the antigen-binding polypeptide complexes described herein are connected by a cleavable linker. In some aspects, the VL1 and VH2 of the antigen-binding polypeptide complexes described herein are connected by a cleavable linker. In some aspects, the VL1 and VL2 of the antigen-binding polypeptide complexes described herein are connected by a cleavable linker. In some aspects, the VH1 and VH2 of the antigen-binding polypeptide complexes described herein are connected by a non-cleavable linker (GS linker) having the amino acid sequence of GS. In some aspects, the VH1 and VL2 of the antigen-binding polypeptide complexes described herein are connected by a GS linker. In some aspects, the VL1 and VL2 of the antigen-binding polypeptide complexes described herein are connected by a GS linker.

[0070] In some aspects, the VL2 and VL1 of the antigen-binding polypeptide complexes described herein are connected by a cleavable linker. In some aspects, the VH2 and VL1 of the antigen-binding polypeptide complexes described herein are connected by a cleavable linker. In some aspects, the VL2 and VH1 of the antigen-binding polypeptide complexes described herein are connected by a cleavable linker. In some aspects, the VH2 and VH1 of the antigen-binding polypeptide complexes described herein are connected by a cleavable linker. In some aspects, the VL2 and VL1 of the antigen-binding polypeptide complexes described herein are connected by a GS linker. In some aspects, the VH2 and VL1 of the antigen-binding polypeptide complexes described herein are connected by a GS linker. In some aspects, the VL2 and VH1 of the antigen-binding polypeptide complexes described herein are connected by a GS linker. In some aspects, the VH2 and VH1 of the antigen-binding polypeptide complexes described herein are connected by a GS linker.

[0071] In some aspects, the VH3 and VH4 of the antigen-binding polypeptide complexes described herein are connected by a cleavable linker. In some aspects, the VH3 and VL4 of the antigen-binding polypeptide complexes described herein are connected by a cleavable linker. In some aspects, the VL3 and VH4 of the antigen-binding polypeptide complexes described herein are connected by a cleavable linker. In some aspects, the VL3 and VL4 of the antigen-binding polypeptide complexes described herein are connected by a cleavable linker. In some aspects, the VH3 and VH4 of the antigen-binding polypeptide complexes described herein are connected by a GS linker. In some aspects, the VL3 and VH4 of the antigen-binding polypeptide complexes described herein are connected by a GS linker. In some aspects, the VL3 and VL4 of the antigen-binding polypeptide complexes described herein are connected by a GS linker.

[0072] In some aspects, the VL4 and VL3 of the antigen-binding polypeptide complexes described herein are connected by a cleavable linker. In some aspects, the VH4 and VL3 of the antigen-binding polypeptide complexes described herein are connected by a cleavable linker. In some aspects, the VL4 and VH3 of the antigen-binding polypeptide complexes described herein are connected by a cleavable linker. In some aspects, the VH4 and VH3 of the antigen-binding polypeptide complexes described herein are connected by a cleavable linker. In some aspects, the VL4 and VL3 of the antigen-binding polypeptide complexes described herein are connected by a GS linker. In some aspects, the VH4 and VL3 of the antigen-binding polypeptide complexes described herein are connected by a GS linker. In some aspects, the VL4 and VH3 of the antigen-binding polypeptide complexes described herein are connected by a GS linker. In some aspects, the VH4 and VH3 of the antigen-binding polypeptide complexes described herein are connected by a GS linker.

[0073] In some aspects, the VH1 and VH2 of the antigen-binding polypeptide complexes described herein are connected by a cleavable linker, and the VL2 and VL1 of the antigen-binding polypeptide complexes described herein are connected by a GS linker. In some aspects, the VH1 and VL2 of the antigen-binding polypeptide complexes described herein are connected by a cleavable linker, and the VH2 and VL1 of the antigen-binding polypeptide complexes described herein are connected by a GS linker. In some aspects, the VL1 and VH2 of the antigen-binding polypeptide complexes described herein are connected by a cleavable linker, and the VL2 and VH1 of the antigen-binding polypeptide complexes described herein are connected by a GS linker. In some aspects, the VL1 and VL2 of the antigen-binding polypeptide complexes described herein are connected by a cleavable linker, and the VH2 and VH1 of the antigen-binding polypeptide complexes described herein are connected by a GS linker. In some aspects, the VH1 and VH2 of the antigen-binding polypeptide complexes described herein are connected by a GS linker, and the VL2 and VL1 of the antigen-binding polypeptide complexes described herein are connected by a cleavable linker. In some aspects, the VH1 and VL2 of the antigen-binding polypeptide complexes described herein are connected by a GS linker, and the VH2 and VL1 of the antigen-binding polypeptide complexes described herein are connected by a cleavable linker. In some aspects, the VL1 and VH2 of the antigen-binding polypeptide complexes described herein are connected by a GS linker, and the VL2 and VH1 of the antigen-binding polypeptide complexes described herein are connected by a cleavable linker. In some aspects, the VL1 and VL2 of the antigen-binding polypeptide complexes described herein are connected by a GS linker, and the VH2 and VH1 of the antigen-binding polypeptide complexes described herein are connected by a cleavable linker.

[0074] In some aspects, the VH3 and VH4 of the antigen-binding polypeptide complexes described herein are connected by a cleavable linker, and the VL4 and VL3 of the antigen-binding polypeptide complexes described herein are connected by a GS linker. In some aspects, the VH3 and VL4 of the antigen-binding polypeptide complexes described herein are connected by a cleavable linker, and the VH4 and VL3 of the antigen-binding polypeptide complexes described herein are connected by a GS linker. In some aspects, the VL3 and VH4 of the antigen-binding polypeptide complexes described herein are connected by a cleavable linker, and the VL4 and VH3 of the antigen-binding polypeptide complexes described herein are connected by a GS linker. In some aspects, the VL3 and VL4 of the antigen-binding polypeptide complexes described herein are connected by a cleavable linker, and the VH4 and VH3 of the antigen-binding polypeptide complexes described herein are connected by a GS linker. In some aspects, the VH3 and VH4 of the antigen-binding polypeptide complexes described herein are connected by a GS linker, and the VL4 and VL3 of the antigen-binding polypeptide complexes described herein are connected by a cleavable linker. In some aspects, the VH3 and VL4 of the antigen-binding polypeptide complexes described herein are connected by a GS linker, and the VH4 and VL3 of the antigen-binding polypeptide complexes described herein are connected by a cleavable linker. In some aspects, the VL3 and VH4 of the antigen-binding polypeptide complexes described herein are connected by a GS linker, and the VL4 and VH3 of the antigen-binding polypeptide complexes described herein are connected by a cleavable linker. In some aspects, the VL3 and VL4 of the antigen-binding polypeptide complexes described herein are connected by a GS linker, and the VH4 and VH3 of the antigen-binding polypeptide complexes described herein are connected by a cleavable linker.

[0075] In some aspects, one or more of the VH1, VH2, VH3, or VH4 of the antigen-binding polypeptide complexes described herein specifically bind to a tumor-associated antigen (TAA). In some aspects, one or more of the VL1, VL2, VL3, or VL4 of the antigen-binding polypeptide complexes described herein specifically bind to a TAA. In some aspects, VH1 and VL1, VH2 and VL2, VH3 and VL3, and / or VH4 and VL4, or antigen-binding polypeptide complexes described herein, specifically bind to a TAA.

[0076] In some embodiments, one or more of the VH1, VH2, VH3, or VH4 of an antigen-binding polypeptide complex described herein specifically binds to CD28. In some embodiments, one or more of the VL1, VL2, VL3, or VL4 of an antigen-binding polypeptide complex described herein specifically binds to CD28. In some embodiments, VH1 and VL1, VH2 and VL2, VH3 and VL3, and / or VH4 and VL4, or an antigen-binding polypeptide complex described herein specifically binds to CD28.

[0077] In some aspects, the invention provides an antigen-binding polypeptide complex comprising a first polypeptide, a second polypeptide, and a third polypeptide, wherein the first polypeptide has a structure represented by VL1-L1-VH1-L2-Fc; VH1-L3-VL1-L4-Fc; VH1-L1-VL1-L2-Fc; or VL1-L3-VH1-L4-Fc; the second polypeptide has a structure represented by VH2-L5-VH3-L6-CH1-L7-Fc or VH3-L5-VH2-L6-CH1-L7-Fc; the third polypeptide has a structure represented by VL2-L8-VL3-L9-CL or VL3-L8-VL2-L9-CL; and VL1 is is a first immunoglobulin light chain variable region; VL2 is a second immunoglobulin light chain variable region; VL3 is a third immunoglobulin light chain variable region; VH1 is a first immunoglobulin heavy chain variable region; VH2 is a second immunoglobulin heavy chain variable region; VH3 is a third immunoglobulin heavy chain variable region; Fc is a region comprising immunoglobulin heavy chain constant region 2 (CH2), immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; CH1 is immunoglobulin heavy chain constant region 1; CL is an immunoglobulin light chain constant region; and L1-L9 are amino acid linkers. In some embodiments, the first polypeptide has a structure represented by VL1-L1-VH1-L2-Fc; VH1-L3-VL1-L4-Fc; VH1-L1-VL1-L2-Fc; or VL1-L3-VH1-L4-Fc; the second polypeptide has a structure represented by VH2-L5-VH3-L6-CH1-L7-Fc; and the third polypeptide has a structure represented by VL2-L8-VL3-L9-CL. In some embodiments, the first polypeptide has a structure represented by VL1-L1-VH1-L2-Fc; VH1-L3-VL1-L4-Fc; VH1-L1-VL1-L2-Fc; or VL1-L3-VH1-L4-Fc; the second polypeptide has a structure represented by VH2-L5-VH3-L6-CH1-L7-Fc; and the third polypeptide has a structure represented by VL3-L8-VL2-L9-CL.In some embodiments, the first polypeptide has a structure represented by VL1-L1-VH1-L2-Fc; VH1-L3-VL1-L4-Fc; VH1-L1-VL1-L2-Fc; or VL1-L3-VH1-L4-Fc; the second polypeptide has a structure represented by VH3-L5-VH2-L6-CH1-L7-Fc, and the third polypeptide has a structure represented by VL2-L8-VL3-L9-CL. In some embodiments, the first polypeptide has a structure represented by VL1-L1-VH1-L2-Fc; VH1-L3-VL1-L4-Fc; VH1-L1-VL1-L2-Fc; or VL1-L3-VH1-L4-Fc; the second polypeptide has a structure represented by VH3-L5-VH2-L6-CH1-L7-Fc; and the third polypeptide has a structure represented by VL3-L8-VL2-L9-CL. In some aspects, the invention provides an antigen-binding polypeptide complex comprising a first polypeptide, a second polypeptide, and a third polypeptide, wherein the first polypeptide has a structure represented by VL1-L1-VH1-L2-Fc or VH1-L3-VL1-L4-Fc; the second polypeptide has a structure represented by VH2-L5-VH3-L6-CH1-L7-Fc; the third polypeptide has a structure represented by VL2-L8-VL3-L9-CL; VL1 is a first immunoglobulin light chain variable region; and VL2 is a second immunoglobulin light chain variable region. VH1 is a first immunoglobulin heavy chain variable region; VH2 is a second immunoglobulin heavy chain variable region; VH3 is a third immunoglobulin heavy chain variable region; Fc is a region comprising immunoglobulin heavy chain constant region 2 (CH2), immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; CH1 is immunoglobulin heavy chain constant region 1; CL is an immunoglobulin light chain constant region; and L1-L9 are amino acid linkers.

[0078] In some aspects, the invention provides an antigen-binding polypeptide complex comprising a first polypeptide, a second polypeptide, a third polypeptide, and a fourth polypeptide, wherein the first polypeptide has a structure represented by VL1-L1-CL or VH1-L1-CL; the second polypeptide has a structure represented by VH1-L2-CH1-L3-Fc or VL1-L2-CH1-L3-Fc; the third polypeptide has a structure represented by VH2-L4-VH3-L5-CH1-L6-Fc or VH3-L4-VH2-L5-CH1-L6-Fc; and the fourth polypeptide is represented by VL2-L7-VL3-L8-CL or VL3-L7-VL2-L8-CL. VL1 is a first immunoglobulin light chain variable region; VL2 is a second immunoglobulin light chain variable region; VL3 is a third immunoglobulin light chain variable region; VH1 is a first immunoglobulin heavy chain variable region; VH2 is a second immunoglobulin heavy chain variable region; VH3 is a third immunoglobulin heavy chain variable region; Fc is a region comprising immunoglobulin heavy chain constant region 2 (CH2), immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; CH1 is immunoglobulin heavy chain constant region 1; CL is an immunoglobulin light chain constant region; and L1-L8 are amino acid linkers.In some aspects, the invention provides an antigen-binding polypeptide complex comprising a first polypeptide, a second polypeptide, a third polypeptide, and a fourth polypeptide, wherein the first polypeptide has a structure represented by VL1-L1-CL; the second polypeptide has a structure represented by VH1-L2-CH1-L3-Fc; the third polypeptide has a structure represented by VH2-L4-VH3-L5-CH1-L6-Fc or VH3-L4-VH2-L5-CH1-L6-Fc; the fourth polypeptide has a structure represented by VL2-L7-VL3-L8-CL or VL3-L7-VL2-L8-CL; and VL1 is a first polypeptide. VH1 is a first immunoglobulin heavy chain variable region; VH2 is a second immunoglobulin heavy chain variable region; VH3 is a third immunoglobulin heavy chain variable region; Fc is a region comprising immunoglobulin heavy chain constant region 2 (CH2), immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; CH1 is immunoglobulin heavy chain constant region 1; CL is an immunoglobulin light chain constant region; and L1-L8 are amino acid linkers.In some aspects, the invention provides an antigen-binding polypeptide complex comprising a first polypeptide, a second polypeptide, a third polypeptide, and a fourth polypeptide, wherein the first polypeptide has a structure represented by VH1-L1-CL; the second polypeptide has a structure represented by VL1-L2-CH1-L3-Fc; the third polypeptide has a structure represented by VH2-L4-VH3-L5-CH1-L6-Fc or VH3-L4-VH2-L5-CH1-L6-Fc; the fourth polypeptide has a structure represented by VL2-L7-VL3-L8-CL or VL3-L7-VL2-L8-CL; and VL1 is a first polypeptide. VH1 is a first immunoglobulin heavy chain variable region; VH2 is a second immunoglobulin heavy chain variable region; VH3 is a third immunoglobulin heavy chain variable region; Fc is a region comprising immunoglobulin heavy chain constant region 2 (CH2), immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; CH1 is immunoglobulin heavy chain constant region 1; CL is an immunoglobulin light chain constant region; and L1-L8 are amino acid linkers. In some embodiments, a first polypeptide has a structure represented by VL1-L1-CL; a second polypeptide has a structure represented by VH1-L2-CH1-L3-Fc; a third polypeptide has a structure represented by VH2-L4-VH3-L5-CH1-L6-Fc; and a fourth polypeptide has a structure represented by VL2-L7-VL3-L8-CL. In some embodiments, a first polypeptide has a structure represented by VL1-L1-CL; a second polypeptide has a structure represented by VH1-L2-CH1-L3-Fc; a third polypeptide has a structure represented by VH3-L4-VH2-L5-CH1-L6-Fc; and a fourth polypeptide has a structure represented by VL2-L7-VL3-L8-CL.In some embodiments, a first polypeptide has a structure represented by VL1-L1-CL; a second polypeptide has a structure represented by VH1-L2-CH1-L3-Fc; a third polypeptide has a structure represented by VH2-L4-VH3-L5-CH1-L6-Fc; and a fourth polypeptide has a structure represented by VL3-L7-VL2-L8-CL. In some embodiments, a first polypeptide has a structure represented by VL1-L1-CL; a second polypeptide has a structure represented by VH1-L2-CH1-L3-Fc; a third polypeptide has a structure represented by VH3-L4-VH2-L5-CH1-L6-Fc; and a fourth polypeptide has a structure represented by VL3-L7-VL2-L8-CL. In some embodiments, a first polypeptide has a structure represented by VH1-L1-CL; a second polypeptide has a structure represented by VL1-L2-CH1-L3-Fc; a third polypeptide has a structure represented by VH2-L4-VH3-L5-CH1-L6-Fc; and a fourth polypeptide has a structure represented by VL2-L7-VL3-L8-CL. In some embodiments, a first polypeptide has a structure represented by VH1-L1-CL; a second polypeptide has a structure represented by VL1-L2-CH1-L3-Fc; a third polypeptide has a structure represented by VH3-L4-VH2-L5-CH1-L6-Fc; and a fourth polypeptide has a structure represented by VL2-L7-VL3-L8-CL. In some embodiments, the first polypeptide has a structure represented by VH1-L1-CL; the second polypeptide has a structure represented by VL1-L2-CH1-L3-Fc; the third polypeptide has a structure represented by VH2-L4-VH3-L5-CH1-L6-Fc; and the fourth polypeptide has a structure represented by VL3-L7-VL2-L8-CL.In some embodiments, the first polypeptide has a structure represented by VH1-L1-CL; the second polypeptide has a structure represented by VL1-L2-CH1-L3-Fc; the third polypeptide has a structure represented by VH3-L4-VH4-L5-CH1-L6-Fc; and the fourth polypeptide has a structure represented by VL3-L7-VL2-L8-CL.

[0079] In some aspects, the invention provides an antigen-binding polypeptide complex comprising a first polypeptide, a second polypeptide, and a third polypeptide, wherein the first polypeptide is selected from the group consisting of VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc; VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc; or VH1- the second polypeptide has a structure represented by VH3-L9-VH4-L10-CH1-L11-Fc or VH4-L9-VH3-L10-CH1-L11-Fc; and the third polypeptide has a structure represented by VL3-L12-VL4-L13-CL or VL4-L12-VL3-L13-CL. VL1 is a first immunoglobulin light chain variable region; VL2 is a second immunoglobulin light chain variable region; VL3 is a third immunoglobulin light chain variable region; VL4 is a fourth immunoglobulin light chain variable region; VH1 is a first immunoglobulin heavy chain variable region; VH2 is a second immunoglobulin heavy chain variable region; VH3 is a third immunoglobulin heavy chain variable region; VH4 is a fourth immunoglobulin heavy chain variable region; Fc is a region comprising immunoglobulin heavy chain constant region 2 (CH2), immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; CH1 is immunoglobulin heavy chain constant region 1; CL is an immunoglobulin light chain constant region; and L1-L13 are amino acid linkers. In some embodiments, the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc; VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc; or VH1-L5-VL2-L6-VH2-L7-VL1-L8-Fc; the second polypeptide has a structure represented by VH3-L9-VH4-L10-CH1-L11-Fc, and the third polypeptide has a structure represented by VL3-L12-VL4-L13-CL.In some embodiments, the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc; VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc; or VH1-L5-VL2-L6-VH2-L7-VL1-L8-Fc; the second polypeptide has a structure represented by VH3-L9-VH4-L10-CH1-L11-Fc; and the third polypeptide has a structure represented by VL4-L12-VL3-L13-CL. In some embodiments, the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc; VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc; or VH1-L5-VL2-L6-VH2-L7-VL1-L8-Fc; the second polypeptide has a structure represented by VH4-L9-VH3-L10-CH1-L11-Fc, and the third polypeptide has a structure represented by VL3-L12-VL4-L13-CL. In some embodiments, the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc; VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc; or VH1-L5-VL2-L6-VH2-L7-VL1-L8-Fc; the second polypeptide has a structure represented by VH4-L9-VH3-L10-CH1-L11-Fc; and the third polypeptide has a structure represented by VL4-L12-VL3-L13-CL. In some embodiments, the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; or VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc; the second polypeptide has a structure represented by VH3-L9-VH4-L10-CH1-L11-Fc; and the third polypeptide has a structure represented by VL3-L12-VL4-L13-CL.In some embodiments, the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc or VH1-L5-VL2-L6-VH2-L7-VL1-L8-Fc; the second polypeptide has a structure represented by VH3-L9-VH4-L10-CH1-L11-Fc; and the third polypeptide has a structure represented by VL3-L12-VL4-L13-CL. In some embodiments, the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; the second polypeptide has a structure represented by VH3-L9-VH4-L10-CH1-L11-Fc; and the third polypeptide has a structure represented by VL3-L12-VL4-L13-CL. In some embodiments, the first polypeptide has a structure represented by VH1-L5-VL2-L6-VH2-L7-VL1-L8-Fc; the second polypeptide has a structure represented by VH3-L9-VH4-L10-CH1-L11-Fc; and the third polypeptide has a structure represented by VL3-L12-VL4-L13-CL.

[0080] In some aspects, the invention provides an antigen-binding polypeptide complex comprising a first polypeptide, a second polypeptide, and a third polypeptide, wherein the first polypeptide is VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc; VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc; or the first polypeptide has a structure represented by VH1-L5-VL2-L6-VH2-L7-VL1-L8-Fc; the second polypeptide has a structure represented by VH3-L9-VH4-CH1-Fc; or VH4-L9-VH3-CH1-Fc; the third polypeptide has a structure represented by VL3-L10-VL4-CL or VL4-L10-VL3-CL; VL1 is the first immunization VH1 is a first immunoglobulin heavy chain variable region; VH2 is a second immunoglobulin heavy chain variable region; VH3 is a third immunoglobulin light chain variable region; VH4 is a fourth immunoglobulin heavy chain variable region; Fc is a region comprising immunoglobulin heavy chain constant region 2 (CH2), immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; CH1 is immunoglobulin heavy chain constant region 1; CL is an immunoglobulin light chain constant region; and L1-L10 are amino acid linkers. In some embodiments, the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc; VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc; or VH1-L5-VL2-L6-VH2-L7-VL1-L8-Fc; the second polypeptide has a structure represented by VH3-L9-VH4-CH1--Fc, and the third polypeptide has a structure represented by VL3-L10-VL4-CL.In some embodiments, the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc; VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc; or VH1-L5-VL2-L6-VH2-L7-VL1-L8-Fc; the second polypeptide has a structure represented by VH3-L9-VH4-CH1-Fc; and the third polypeptide has a structure represented by VL4-L10-VL3-CL. In some embodiments, the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc; VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc; or VH1-L5-VL2-L6-VH2-L7-VL1-L8-Fc; the second polypeptide has a structure represented by VH4-L9-VH3-CH1-Fc, and the third polypeptide has a structure represented by VL3-L10-VL4-CL. In some embodiments, the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc; VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc; or VH1-L5-VL2-L6-VH2-L7-VL1-L8-Fc; the second polypeptide has a structure represented by VH4-L9-VH3-CH1-Fc; and the third polypeptide has a structure represented by VL4-L10-VL3-CL. In some embodiments, the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; or VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc; the second polypeptide has a structure represented by VH3-L9-VH4-CH1-Fc; and the third polypeptide has a structure represented by VL3-L10-VL4-CL.In some embodiments, the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc or VH1-L5-VL2-L6-VH2-L7-VL1-L8-Fc; the second polypeptide has a structure represented by VH3-L9-VH4-CH1-Fc; and the third polypeptide has a structure represented by VL3-L10-VL4-CL. In some embodiments, the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; the second polypeptide has a structure represented by VH3-L9-VH4-CH1-Fc; and the third polypeptide has a structure represented by VL3-L10-VL4-CL. In some embodiments, the first polypeptide has a structure represented by VH1-L5-VL2-L6-VH2-L7-VL1-L8-Fc; the second polypeptide has a structure represented by VH3-L9-VH4-CH1-Fc; and the third polypeptide has a structure represented by VL3-L10-VL4-CL.

[0081] In some aspects, the invention provides an antigen-binding polypeptide complex comprising a first polypeptide and a second polypeptide, wherein the first polypeptide is represented by: VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc; VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc; or VH1-L5-VL2-L6-VH2-VL1-L8-Fc. the second polypeptide has a structure represented by VL3-L9-VL4-L10-VH4-L11-VH3-L12-Fc; VL3-L9-VH4-L10-VL4-L11-VH3-L12-Fc; VH3-L13-VH4-L14-VL4-L15-VL3-L16-Fc; or VH3-L13-VL4-L14-VH4-L15-VL3-L16-Fc; and VL1 is a first immunoglobulin that specifically binds to a tumor-associated antigen. VH1 is a first immunoglobulin heavy chain variable region that specifically binds to the tumor-associated antigen; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to the tumor-associated antigen; VH3 is a third immunoglobulin heavy chain variable region that specifically binds to CD3; VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds to the tumor-associated antigen; Fc is a region comprising immunoglobulin heavy chain constant region 2 (CH2), immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; and L1 to L16 are amino acid linkers.In some embodiments, the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc; VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc; or VH1-L5-VL2-L6-VH2-VL1-L8-Fc; and the second polypeptide has a structure represented by VL3-L9-VL4-L10-VH4-L11-VH3-L12-Fc. In some embodiments, the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc; VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc; or VH1-L5-VL2-L6-VH2-VL1-L8-Fc; and the second polypeptide has a structure represented by VL3-L9-VH4-L10-VL4-L11-VH3-L12-Fc. In some embodiments, the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc; VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc; or VH1-L5-VL2-L6-VH2-VL1-L8-Fc; and the second polypeptide has a structure represented by VH3-L13-VH4-L14-VL4-L15-VL3-L16-Fc. In some embodiments, the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc; VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc; or VH1-L5-VL2-L6-VH2-VL1-L8-Fc; and the second polypeptide has a structure represented by VH3-L13-VL4-L14-VH4-L15-VL3-L16-Fc.In some embodiments, the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc or VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc; and the second polypeptide has a structure represented by VL3-L9-VL4-L10-VH4-L11-VH3-L12-Fc or VH3-L13-VH4-L14-VL4-L15-VL3-L16-Fc. In some embodiments, the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc and the second polypeptide has a structure represented by VL3-L9-VL4-L10-VH4-L11-VH3-L12-Fc. In some embodiments, the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc and the second polypeptide has a structure represented by VH3-L13-VH4-L14-VL4-L15-VL3-L16-Fc. In some embodiments, the first polypeptide has a structure represented by VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc and the second polypeptide has a structure represented by VL3-L9-VL4-L10-VH4-L11-VH3-L12-Fc. In some embodiments, the first polypeptide has a structure represented by VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc and the second polypeptide has a structure represented by VH3-L13-VH4-L14-VL4-L15-VL3-L16-Fc.

[0082] In some embodiments, the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc and the second polypeptide has a structure represented by VL3-L5-VL4-L6-VH4-L7-VH3-L8-Fc; where VL1 is a first immunoglobulin light chain variable region that specifically binds Trop2, cMet, CD3, or CD28; VL2 is a second immunoglobulin light chain variable region that specifically binds Trop2, cMet, CD3, or CD28; VL3 is a third immunoglobulin light chain variable region that specifically binds Trop2, cMet, CD3, or CD28; and VL4 is a fourth immunoglobulin light chain variable region that specifically binds Trop2, cMet, CD3, or CD28. VH1 is a first immunoglobulin heavy chain variable region that specifically binds to Trop2, cMet, CD3, or CD28; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to Trop2, cMet, CD3, or CD28; VH3 is a third immunoglobulin heavy chain variable region that specifically binds to Trop2, cMet, CD3, or CD28; VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds to Trop2, cMet, CD3, or CD28; Fc is a region comprising immunoglobulin heavy chain constant region 2 (CH2), immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; and L1-L8 are amino acid linkers. For example, VL1 is a first immunoglobulin light chain variable region that specifically binds Trop2; VL2 is a second immunoglobulin light chain variable region that specifically binds cMet; VL3 is a third immunoglobulin light chain variable region that specifically binds CD3; VL4 is a fourth immunoglobulin light chain variable region that specifically binds CD28; VH1 is a first immunoglobulin heavy chain variable region that specifically binds Trop2; VH2 is a second immunoglobulin heavy chain variable region that specifically binds cMet; VH3 is a third immunoglobulin heavy chain variable region that specifically binds CD3; and VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds CD28.For example, VL1 is a first immunoglobulin light chain variable region that specifically binds Trop2; VL2 is a second immunoglobulin light chain variable region that specifically binds cMet; VL3 is a third immunoglobulin light chain variable region that specifically binds CD28; VL4 is a fourth immunoglobulin light chain variable region that specifically binds CD3; VH1 is a first immunoglobulin heavy chain variable region that specifically binds Trop2; VH2 is a second immunoglobulin heavy chain variable region that specifically binds cMet; VH3 is a third immunoglobulin heavy chain variable region that specifically binds CD28; and VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds CD3. For example, VL1 is a first immunoglobulin light chain variable region that specifically binds cMet; VL2 is a second immunoglobulin light chain variable region that specifically binds Trop2; VL3 is a third immunoglobulin light chain variable region that specifically binds CD3; VL4 is a fourth immunoglobulin light chain variable region that specifically binds CD28; VH1 is a first immunoglobulin heavy chain variable region that specifically binds cMet; VH2 is a second immunoglobulin heavy chain variable region that specifically binds Trop2; VH3 is a third immunoglobulin heavy chain variable region that specifically binds CD3; and VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds CD28. For example, VL1 is a first immunoglobulin light chain variable region that specifically binds cMet; VL2 is a second immunoglobulin light chain variable region that specifically binds Trop2; VL3 is a third immunoglobulin light chain variable region that specifically binds CD28; VL4 is a fourth immunoglobulin light chain variable region that specifically binds CD3; VH1 is a first immunoglobulin heavy chain variable region that specifically binds cMet; VH2 is a second immunoglobulin heavy chain variable region that specifically binds Trop2; VH3 is a third immunoglobulin heavy chain variable region that specifically binds CD28; and VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds CD3.In some embodiments, the antigen-binding polypeptide complex comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity to SEQ ID NOs: 204 and 511. In some embodiments, the antigen-binding polypeptide complex comprises an amino acid sequence encoded by a polynucleotide having at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity to SEQ ID NOs: 205 and 512.

[0083] In some embodiments, the first polypeptide has a structure represented by VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc and the second polypeptide has a structure represented by VL3-L5-VH4-L6-VL4-L7-VH3-L8-Fc; where VL1 is a first immunoglobulin light chain variable region that specifically binds Trop2, cMet, CD3, or CD28; VL2 is a second immunoglobulin light chain variable region that specifically binds Trop2, cMet, CD3, or CD28; VL3 is a third immunoglobulin light chain variable region that specifically binds Trop2, cMet, CD3, or CD28; and VL4 is a fourth immunoglobulin light chain variable region that specifically binds Trop2, cMet, CD3, or CD28. VH1 is a first immunoglobulin heavy chain variable region that specifically binds to Trop2, cMet, CD3, or CD28; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to Trop2, cMet, CD3, or CD28; VH3 is a third immunoglobulin heavy chain variable region that specifically binds to Trop2, cMet, CD3, or CD28; VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds to Trop2, cMet, CD3, or CD28; Fc is a region comprising immunoglobulin heavy chain constant region 2 (CH2), immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; and L1-L8 are amino acid linkers. For example, VL1 is a first immunoglobulin light chain variable region that specifically binds cMet; VL2 is a second immunoglobulin light chain variable region that specifically binds CD28; VL3 is a third immunoglobulin light chain variable region that specifically binds Trop2; VL4 is a fourth immunoglobulin light chain variable region that specifically binds CD3; VH1 is a first immunoglobulin heavy chain variable region that specifically binds cMet; VH2 is a second immunoglobulin heavy chain variable region that specifically binds CD28; VH3 is a third immunoglobulin heavy chain variable region that specifically binds Trop2; and VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds CD3.In some embodiments, the antigen-binding polypeptide complex comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity to SEQ ID NOs: 634 and 652. In some embodiments, the antigen-binding polypeptide complex comprises an amino acid sequence encoded by a polynucleotide having at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity to SEQ ID NOs: 635 and 653.

[0084] In some embodiments, the first polypeptide has a structure represented by VH1-L1-VL2-L2-VH2-L3-VL1-L4-Fc and the second polypeptide has a structure represented by VH3-L5-VL4-L6-VH4-L7-VL3-L8-Fc; where VL1 is a first immunoglobulin light chain variable region that specifically binds Trop2, cMet, CD3, or CD28; VL2 is a second immunoglobulin light chain variable region that specifically binds Trop2, cMet, CD3, or CD28; VL3 is a third immunoglobulin light chain variable region that specifically binds Trop2, cMet, CD3, or CD28; and VL4 is a fourth immunoglobulin light chain variable region that specifically binds Trop2, cMet, CD3, or CD28. VH1 is a first immunoglobulin heavy chain variable region that specifically binds to Trop2, cMet, CD3, or CD28; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to Trop2, cMet, CD3, or CD28; VH3 is a third immunoglobulin heavy chain variable region that specifically binds to Trop2, cMet, CD3, or CD28; VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds to Trop2, cMet, CD3, or CD28; Fc is a region comprising immunoglobulin heavy chain constant region 2 (CH2), immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; and L1-L8 are amino acid linkers. For example, VL1 is a first immunoglobulin light chain variable region that specifically binds cMet; VL2 is a second immunoglobulin light chain variable region that specifically binds CD28; VL3 is a third immunoglobulin light chain variable region that specifically binds Trop2; VL4 is a fourth immunoglobulin light chain variable region that specifically binds CD3; VH1 is a first immunoglobulin heavy chain variable region that specifically binds cMet; VH2 is a second immunoglobulin heavy chain variable region that specifically binds CD28; VH3 is a third immunoglobulin heavy chain variable region that specifically binds Trop2; and VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds CD3.In some embodiments, the antigen-binding polypeptide complex comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity to SEQ ID NOs: 670 and 688. In some embodiments, the antigen-binding polypeptide complex comprises an amino acid sequence encoded by a polynucleotide having at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity to SEQ ID NOs: 671 and 689.

[0085] In some embodiments, the first polypeptide has a structure represented by VH1-L1-VH2-L2-VL2-L3-VL1-L4-Fc and the second polypeptide has a structure represented by VH3-L5-VH4-L6-VL4-L7-VL3-L8-Fc; where VL1 is a first immunoglobulin light chain variable region that specifically binds Trop2, cMet, CD3, or CD28; VL2 is a second immunoglobulin light chain variable region that specifically binds Trop2, cMet, CD3, or CD28; VL3 is a third immunoglobulin light chain variable region that specifically binds Trop2, cMet, CD3, or CD28; and VL4 is a fourth immunoglobulin light chain variable region that specifically binds Trop2, cMet, CD3, or CD28. VH1 is a first immunoglobulin heavy chain variable region that specifically binds to Trop2, cMet, CD3, or CD28; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to Trop2, cMet, CD3, or CD28; VH3 is a third immunoglobulin heavy chain variable region that specifically binds to Trop2, cMet, CD3, or CD28; VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds to Trop2, cMet, CD3, or CD28; Fc is a region comprising immunoglobulin heavy chain constant region 2 (CH2), immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; and L1-L8 are amino acid linkers. For example, VL1 is a first immunoglobulin light chain variable region that specifically binds cMet; VL2 is a second immunoglobulin light chain variable region that specifically binds CD28; VL3 is a third immunoglobulin light chain variable region that specifically binds Trop2; VL4 is a fourth immunoglobulin light chain variable region that specifically binds CD3; VH1 is a first immunoglobulin heavy chain variable region that specifically binds cMet; VH2 is a second immunoglobulin heavy chain variable region that specifically binds CD28; VH3 is a third immunoglobulin heavy chain variable region that specifically binds Trop2; and VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds CD3.In some embodiments, the antigen-binding polypeptide complex comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity to SEQ ID NOs: 706 and 724. In some embodiments, the antigen-binding polypeptide complex comprises an amino acid sequence encoded by a polynucleotide having at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity to SEQ ID NOs: 707 and 725.

[0086] In some embodiments, the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc and the second polypeptide has a structure represented by VL3-L5-VL4-L6-VH4-L7-VH3-L8-Fc; VL1 is a first immunoglobulin light chain variable region that specifically binds CD19, CD20, CD3, or CD28; VL2 is a second immunoglobulin light chain variable region that specifically binds CD19, CD20, CD3, or CD28; VL3 is a third immunoglobulin light chain variable region that specifically binds CD19, CD20, CD3, or CD28; and VL4 is a fourth immunoglobulin light chain variable region that specifically binds CD19, CD20, CD3, or CD28. VH1 is a first immunoglobulin heavy chain variable region that specifically binds to CD19, CD20, CD3, or CD28; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to CD19, CD20, CD3, or CD28; VH3 is a third immunoglobulin heavy chain variable region that specifically binds to CD19, CD20, CD3, or CD28; VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds to CD19, CD20, CD3, or CD28; Fc is a region comprising immunoglobulin heavy chain constant region 2 (CH2), immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; and L1 to L8 are amino acid linkers. For example, VL1 is a first immunoglobulin light chain variable region that specifically binds to CD19; VL2 is a second immunoglobulin light chain variable region that specifically binds to CD20; VL3 is a third immunoglobulin light chain variable region that specifically binds to CD3; VL4 is a fourth immunoglobulin light chain variable region that specifically binds to CD28; VH1 is a first immunoglobulin heavy chain variable region that specifically binds to CD19; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to CD20; VH3 is a third immunoglobulin heavy chain variable region that specifically binds to CD3; and VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds to CD28.For example, VL1 is a first immunoglobulin light chain variable region that specifically binds to CD20; VL2 is a second immunoglobulin light chain variable region that specifically binds to CD19; VL3 is a third immunoglobulin light chain variable region that specifically binds to CD3; VL4 is a fourth immunoglobulin light chain variable region that specifically binds to CD28; VH1 is a first immunoglobulin heavy chain variable region that specifically binds to CD20; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to CD19; VH3 is a third immunoglobulin heavy chain variable region that specifically binds to CD3; and VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds to CD28. For example, VL1 is a first immunoglobulin light chain variable region that specifically binds to CD19; VL2 is a second immunoglobulin light chain variable region that specifically binds to CD20; VL3 is a third immunoglobulin light chain variable region that specifically binds to CD28; VL4 is a fourth immunoglobulin light chain variable region that specifically binds to CD3; VH1 is a first immunoglobulin heavy chain variable region that specifically binds to CD19; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to CD20; VH3 is a third immunoglobulin heavy chain variable region that specifically binds to CD28; and VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds to CD3. For example, VL1 is a first immunoglobulin light chain variable region that specifically binds to CD20; VL2 is a second immunoglobulin light chain variable region that specifically binds to CD19; VL3 is a third immunoglobulin light chain variable region that specifically binds to CD28; VL4 is a fourth immunoglobulin light chain variable region that specifically binds to CD3; VH1 is a first immunoglobulin heavy chain variable region that specifically binds to CD20; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to CD19; VH3 is a third immunoglobulin heavy chain variable region that specifically binds to CD28; and VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds to CD3.

[0087] In some embodiments, the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc and the second polypeptide has a structure represented by VL3-L5-VL4-L6-VH4-L7-VH3-L8-Fc; VL1 is a first immunoglobulin light chain variable region that specifically binds CD20, CD3, or CD28; VL2 is a second immunoglobulin light chain variable region that specifically binds CD20, CD3, or CD28; VL3 is a third immunoglobulin light chain variable region that specifically binds CD20, CD3, or CD28; and VL4 is a fourth immunoglobulin light chain variable region that specifically binds CD20, CD3, or CD28. VH1 is a first immunoglobulin heavy chain variable region that specifically binds to CD20, CD3, or CD28; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to CD20, CD3, or CD28; VH3 is a third immunoglobulin heavy chain variable region that specifically binds to CD20, CD3, or CD28; VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds to CD20, CD3, or CD28; Fc is a region comprising immunoglobulin heavy chain constant region 2 (CH2), immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; and L1 to L8 are amino acid linkers. For example, VL1 is a first immunoglobulin light chain variable region that specifically binds to CD20; VL2 is a second immunoglobulin light chain variable region that specifically binds to CD20; VL3 is a third immunoglobulin light chain variable region that specifically binds to CD3; VL4 is a fourth immunoglobulin light chain variable region that specifically binds to CD20; VH1 is a first immunoglobulin heavy chain variable region that specifically binds to CD20; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to CD20; VH3 is a third immunoglobulin heavy chain variable region that specifically binds to CD3; and VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds to CD20.For example, VL1 is a first immunoglobulin light chain variable region that specifically binds to CD20; VL2 is a second immunoglobulin light chain variable region that specifically binds to CD20; VL3 is a third immunoglobulin light chain variable region that specifically binds to CD3; VL4 is a fourth immunoglobulin light chain variable region that specifically binds to CD28; VH1 is a first immunoglobulin heavy chain variable region that specifically binds to CD20; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to CD20; VH3 is a third immunoglobulin heavy chain variable region that specifically binds to CD3; and VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds to CD28. For example, VL1 is a first immunoglobulin light chain variable region that specifically binds to CD20; VL2 is a second immunoglobulin light chain variable region that specifically binds to CD20; VL3 is a third immunoglobulin light chain variable region that specifically binds to CD3; VL4 is a fourth immunoglobulin light chain variable region that specifically binds to CD28; VH1 is a first immunoglobulin heavy chain variable region that specifically binds to CD20; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to CD20; VH3 is a third immunoglobulin heavy chain variable region that specifically binds to CD3; and VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds to CD28.

[0088] In some embodiments, the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc and the second polypeptide has a structure represented by VL3-L5-VL4-L6-VH4-L7-VH3-L8-Fc; VL1 is a first immunoglobulin light chain variable region that specifically binds CD20, BCMA, CD3, or CD28; VL2 is a second immunoglobulin light chain variable region that specifically binds CD20, BCMA, CD3, or CD28; VL3 is a third immunoglobulin light chain variable region that specifically binds CD20, BCMA, CD3, or CD28; and VL4 is a fourth immunoglobulin light chain variable region that specifically binds CD20, BCMA, CD3, or CD28. VH1 is a first immunoglobulin heavy chain variable region that specifically binds to CD20, BCMA, CD3, or CD28; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to CD20, BCMA, CD3, or CD28; VH3 is a third immunoglobulin heavy chain variable region that specifically binds to CD20, BCMA, CD3, or CD28; VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds to CD20, BCMA, CD3, or CD28; Fc is a region comprising immunoglobulin heavy chain constant region 2 (CH2), immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; and L1 to L8 are amino acid linkers. For example, VL1 is a first immunoglobulin light chain variable region that specifically binds to CD20; VL2 is a second immunoglobulin light chain variable region that specifically binds to BCMA; VL3 is a third immunoglobulin light chain variable region that specifically binds to CD3; VL4 is a fourth immunoglobulin light chain variable region that specifically binds to CD28; VH1 is a first immunoglobulin heavy chain variable region that specifically binds to CD20; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to BCMA; VH3 is a third immunoglobulin heavy chain variable region that specifically binds to CD3; and VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds to CD28.For example, VL1 is a first immunoglobulin light chain variable region that specifically binds to CD20; VL2 is a second immunoglobulin light chain variable region that specifically binds to BCMA; VL3 is a third immunoglobulin light chain variable region that specifically binds to CD28; VL4 is a fourth immunoglobulin light chain variable region that specifically binds to CD3; VH1 is a first immunoglobulin heavy chain variable region that specifically binds to CD20; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to BCMA; VH3 is a third immunoglobulin heavy chain variable region that specifically binds to CD28; and VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds to CD3. For example, VL1 is a first immunoglobulin light chain variable region that specifically binds BCMA; VL2 is a second immunoglobulin light chain variable region that specifically binds CD20; VL3 is a third immunoglobulin light chain variable region that specifically binds CD3; VL4 is a fourth immunoglobulin light chain variable region that specifically binds CD28; VH1 is a first immunoglobulin heavy chain variable region that specifically binds BCMA; VH2 is a second immunoglobulin heavy chain variable region that specifically binds CD20; VH3 is a third immunoglobulin heavy chain variable region that specifically binds CD3; and VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds CD28. For example, VL1 is a first immunoglobulin light chain variable region that specifically binds BCMA; VL2 is a second immunoglobulin light chain variable region that specifically binds CD20; VL3 is a third immunoglobulin light chain variable region that specifically binds CD28; VL4 is a fourth immunoglobulin light chain variable region that specifically binds CD3; VH1 is a first immunoglobulin heavy chain variable region that specifically binds BCMA; VH2 is a second immunoglobulin heavy chain variable region that specifically binds CD20; VH3 is a third immunoglobulin heavy chain variable region that specifically binds CD28; and VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds CD3.For example, VL1 is a first immunoglobulin light chain variable region that specifically binds to CD20; VL2 is a second immunoglobulin light chain variable region that specifically binds to CD20; VL3 is a third immunoglobulin light chain variable region that specifically binds to CD28; VL4 is a fourth immunoglobulin light chain variable region that specifically binds to CD3; VH1 is a first immunoglobulin heavy chain variable region that specifically binds to CD20; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to CD20; VH3 is a third immunoglobulin heavy chain variable region that specifically binds to CD28; and VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds to CD3.

[0089] In some embodiments, the first polypeptide has a structure represented by VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc and the second polypeptide has a structure represented by VL3-L5-VH4-L6-VL4-L7-VH3-L8-Fc; VL1 is a first immunoglobulin light chain variable region that specifically binds CD20, CD19, CD3, or CD28; VL2 is a second immunoglobulin light chain variable region that specifically binds CD20, CD19, CD3, or CD28; VL3 is a third immunoglobulin light chain variable region that specifically binds CD20, CD19, CD3, or CD28; and VL4 is a fourth immunoglobulin light chain variable region that specifically binds CD20, CD19, CD3, or CD28. VH1 is a first immunoglobulin heavy chain variable region that specifically binds to CD20, CD19, CD3, or CD28; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to CD20, CD19, CD3, or CD28; VH3 is a third immunoglobulin heavy chain variable region that specifically binds to CD20, CD19, CD3, or CD28; VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds to CD20, CD19, CD3, or CD28; Fc is a region comprising immunoglobulin heavy chain constant region 2 (CH2), immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; and L1 to L8 are amino acid linkers. For example, VL1 is a first immunoglobulin light chain variable region that specifically binds to CD19; VL2 is a second immunoglobulin light chain variable region that specifically binds to CD20; VL3 is a third immunoglobulin light chain variable region that specifically binds to CD3; VL4 is a fourth immunoglobulin light chain variable region that specifically binds to CD28; VH1 is a first immunoglobulin heavy chain variable region that specifically binds to CD19; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to CD20; VH3 is a third immunoglobulin heavy chain variable region that specifically binds to CD3; and VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds to CD28.In some embodiments, the antigen-binding polypeptide complex comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity to SEQ ID NOs: 742 and 760. In some embodiments, the antigen-binding polypeptide complex comprises an amino acid sequence encoded by a polynucleotide having at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity to SEQ ID NOs: 743 and 761.

[0090] In some embodiments, the first polypeptide has a structure represented by VH1-L1-VL2-L2-VH2-L3-VL1-L4-Fc and the second polypeptide has a structure represented by VH3-L5-VL4-L6-VH4-L7-VL3-L8-Fc; VL1 is a first immunoglobulin light chain variable region that specifically binds CD20, CD19, CD3, or CD28; VL2 is a second immunoglobulin light chain variable region that specifically binds CD20, CD19, CD3, or CD28; VL3 is a third immunoglobulin light chain variable region that specifically binds CD20, CD19, CD3, or CD28; and VL4 is a fourth immunoglobulin light chain variable region that specifically binds CD20, CD19, CD3, or CD28. VH1 is a first immunoglobulin heavy chain variable region that specifically binds to CD20, CD19, CD3, or CD28; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to CD20, CD19, CD3, or CD28; VH3 is a third immunoglobulin heavy chain variable region that specifically binds to CD20, CD19, CD3, or CD28; VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds to CD20, CD19, CD3, or CD28; Fc is a region comprising immunoglobulin heavy chain constant region 2 (CH2), immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; and L1 to L8 are amino acid linkers. For example, VL1 is a first immunoglobulin light chain variable region that specifically binds to CD19; VL2 is a second immunoglobulin light chain variable region that specifically binds to CD20; VL3 is a third immunoglobulin light chain variable region that specifically binds to CD3; VL4 is a fourth immunoglobulin light chain variable region that specifically binds to CD28; VH1 is a first immunoglobulin heavy chain variable region that specifically binds to CD19; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to CD20; VH3 is a third immunoglobulin heavy chain variable region that specifically binds to CD3; and VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds to CD28.In some embodiments, the antigen-binding polypeptide complex comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity to SEQ ID NOs: 778 and 796. In some embodiments, the antigen-binding polypeptide complex comprises an amino acid sequence encoded by a polynucleotide having at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity to SEQ ID NOs: 779 and 797.

[0091] In some embodiments, the antigen-binding polypeptide complex comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity to SEQ ID NOs: 206 and 513. In some embodiments, the antigen-binding polypeptide complex comprises an amino acid sequence encoded by a polynucleotide having at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity to SEQ ID NOs: 207 and 514. In some embodiments, the antigen-binding polypeptide complex comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity to SEQ ID NOs: 204 and 511. In some embodiments, the antigen-binding polypeptide complex comprises an amino acid sequence encoded by a polynucleotide having at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity to SEQ ID NOs: 205 and 512. In some embodiments, the antigen-binding polypeptide complex comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity to SEQ ID NOs: 274 and 513. In some embodiments, the antigen-binding polypeptide complex comprises an amino acid sequence encoded by a polynucleotide having at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity to SEQ ID NOs: 275 and 514. In some embodiments, the antigen-binding polypeptide complex comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity to SEQ ID NOs: 228 and 511. In some embodiments, the antigen-binding polypeptide complex comprises an amino acid sequence encoded by a polynucleotide having at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity to SEQ ID NOs: 229 and 512. In some embodiments, the antigen-binding polypeptide complex comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity to SEQ ID NOs: 206, 160, and 162.In some embodiments, the antigen-binding polypeptide complex comprises an amino acid sequence encoded by a polynucleotide having at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity to SEQ ID NOs: 207, 161, and 163. In some embodiments, the antigen-binding polypeptide complex comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity to SEQ ID NOs: 206, 160, and 174. In some embodiments, the antigen-binding polypeptide complex comprises an amino acid sequence encoded by a polynucleotide having at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity to SEQ ID NOs: 207, 161, and 175. In some embodiments, the antigen-binding polypeptide complex comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity to SEQ ID NOs: 206, 162, and 176. In some embodiments, the antigen-binding polypeptide complex comprises an amino acid sequence encoded by a polynucleotide having at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity to SEQ ID NOs: 207, 163, and 177. In some embodiments, the antigen-binding polypeptide complex comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity to SEQ ID NOs: 204, 160, and 162. In some embodiments, the antigen-binding polypeptide complex comprises an amino acid sequence encoded by a polynucleotide having at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity to SEQ ID NOs: 205, 161, and 163. In some embodiments, the antigen-binding polypeptide complex comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity to SEQ ID NOs: 204, 160, and 174.In some embodiments, the antigen-binding polypeptide complex comprises an amino acid sequence encoded by a polynucleotide having at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity to SEQ ID NOs: 205, 161, and 175. In some embodiments, the antigen-binding polypeptide complex comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity to SEQ ID NOs: 204, 162, and 176. In some embodiments, the antigen-binding polypeptide complex comprises an amino acid sequence encoded by a polynucleotide having at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity to SEQ ID NOs: 205, 163, and 177.

[0092] In some aspects, the invention provides an antigen-binding polypeptide complex comprising a first polypeptide and a second polypeptide, wherein the first polypeptide is represented by the following sequence: VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc; VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc; or VH1-L5-VL2-L6-VH2-L7-VL1-L8-Fc. the second polypeptide has a structure represented by VL3-L9-VL4-L10-VH4-L11-VH3-L12-Fc; VL3-L9-VH4-L10-VL4-L11-VH3-L12-Fc; VH3-L13-VH4-L14-VL4-L15-VL3-L16-Fc; or VH3-L13-VL4-L14-VH4-L15-VL3-L16-Fc; and VL1 is a first immunoglobulin that specifically binds to a tumor-associated antigen. VH1 is a first immunoglobulin heavy chain variable region that specifically binds to the tumor-associated antigen; VH2 is a second immunoglobulin light chain variable region that specifically binds to the tumor-associated antigen; VL3 is a third immunoglobulin light chain variable region that specifically binds to the tumor-associated antigen; VL4 is a fourth immunoglobulin light chain variable region that specifically binds to CD3; VH1 is a first immunoglobulin heavy chain variable region that specifically binds to the tumor-associated antigen; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to the tumor-associated antigen; VH3 is a third immunoglobulin heavy chain variable region that specifically binds to the tumor-associated antigen; VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds to CD3; Fc is a region comprising immunoglobulin heavy chain constant region 2 (CH2), immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; and L1 to L16 are amino acid linkers. In some embodiments, the first polypeptide has a sequence of VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc; VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc;or the first polypeptide has a structure represented by VH1-L5-VL2-L6-VH2-L7-VL1-L8-Fc, and the second polypeptide has a structure represented by VL3-L9-VL4-L10-VH4-L11-VH3-L12-Fc. In some embodiments, the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; or VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc or VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc or VH1-L5-VL2-L6-VH2-L7-VL1-L8-Fc, and the second polypeptide has a structure represented by VL3-L9-VH4-L10-VL4-L11-VH3-L12-Fc. In some embodiments, the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; or VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc or VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc or VH1-L5-VL2-L6-VH2-L7-VL1-L8-Fc, and the second polypeptide has a structure represented by VH3-L13-VH4-L14-VL4-L15-VL3-L16-Fc. In some embodiments, the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; or VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc or VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc or VH1-L5-VL2-L6-VH2-L7-VL1-L8-Fc, and the second polypeptide has a structure represented by VH3-L13-VL4-L14-VH4-L15-VL3-L16-Fc. In some embodiments, the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc or VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc;The second polypeptide has a structure represented by VL3-L9-VL4-L10-VH4-L11-VH3-L12-Fc or VH3-L13-VH4-L14-VL4-L15-VL3-L16-Fc. In some embodiments, the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc and the second polypeptide has a structure represented by VL3-L9-VL4-L10-VH4-L11-VH3-L12-Fc. In some embodiments, the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc and the second polypeptide has a structure represented by VH3-L13-VH4-L14-VL4-L15-VL3-L16-Fc. In some embodiments, the first polypeptide has a structure represented by VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc and the second polypeptide has a structure represented by VL3-L9-VL4-L10-VH4-L11-VH3-L12-Fc. In some embodiments, a first polypeptide has a structure represented by VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc, and a second polypeptide has a structure represented by VH3-L13-VH4-L14-VL4-L15-VL3-L16-Fc. In some embodiments, the invention provides an antigen-binding polypeptide complex comprising a first polypeptide and a second polypeptide, wherein the first polypeptide is represented by the following sequence: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-Fc; VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-Fc; VH1-L6-VL2-L 7-VH2-L8-VL1-L9-CH1-L10-Fc;VL1-L11-VL2-L12-VH2-L13-VH1-L14-CL-L15-Fc;VL1-L11-VH2-L12-VL2-L13-VH1- L14-CL-L15-Fc;VH1-L16-VH2-L17-VL2-L18-VL1-L19-CL-L20-Fc;VH1-L16-VL2-L17-VH2-L18-VL1-L19-CL-L20-Fc;VL1-L21-VL2-L22-VH2-L23-VH1-L24-CH1-L25-CL-L26-Fc;VL1-L21-VH2-L22-VL2-L23-VH1-L24-CH1-L25-CL-L26-Fc;VH1-L27-VH2-L28-VL2- L29-VL1-L30-CH1-L31-CL-L32-Fc;VH1-L27-VL2-L28-VH2-L29-VL1-L30-CH1-L31-CL-L32-Fc;VL1-L33-VL2-L34-VH2-L35-VH1-L36-CL-L37-CH VH1-L39-VL2-L40-VH2-L41-VL1-L42-CL-L43-CH1-L44-Fc; VL1-L38-Fc; VL1-L33-VH2-L34-VL2-L35-VH1-L36-CL-L37-CH1-L38-Fc; VH1-L39-VH2-L40-VL2-L41-VL1-L42-CL-L43-CH1-L44-Fc; or VH1-L39-VL2-L40-VH2-L41-VL1-L42-CL-L43-CH1-L44-Fc; and the second polypeptide has a structure represented by VL3-L45-VL4-L46-VH4-L47-VH3-L48-CH1-L49-Fc; VL3-L45-VH4-L 46-VL4-L47-VH3-L48-CH1-L49-Fc;VH3-L50-VH4-L51-VL4-L52-VL3-L5 3-CH1-L54-Fc;VH3-L50-VL4-L51-VH4-L52-VL3-L53-CH1-L54-Fc;VL3-L 55-VL4-L56-VH4-L57-VH3-L58-CL-L59-Fc;VL3-L55-VH4-L56-VL4-L57 -VH3-L58-CL-L59-Fc;VH3-L60-VH4-L61-VL4-L62-VL3-L63-CL-L64-Fc; VH3-L60-VL4-L61-VH4-L62-VL3-L63-CL-L64-Fc;VL3-L65-VL4-L66-VH 4-L67-VH3-L68-CH1-L69-CL-L70-Fc;VL3-L65-VH4-L66-VL4-L67-VH3-L 68-CH1-L69-CL-L70-Fc;VH3-L71-VH4-L72-VL4-L73-VL3-L74-CH1-L75-CL-L76-Fc;VH3-L71-VL4-L72-VH4-L73-VL3-L74-CH1-L75-CL-L76-Fc;VL3-L77-VL4-L78-VH4-L79-VH3-L80-CL-L81-CH1-L82-Fc;VL3-L77-VH4-L78-VL4-L79-VH3-L80-CL- L81-CH1-L82-Fc; VH3-L83-VH4-L84-VL4-L85-VL3-L86-CL-L87-CH1-L88-Fc; or VH3-L83-VL4-L84-VH VL1 is a first immunoglobulin light chain variable region that specifically binds to a tumor-associated antigen; VL2 is a second immunoglobulin light chain variable region that specifically binds to a tumor-associated antigen; VL3 is a third immunoglobulin light chain variable region that specifically binds to CD3; and VL4 is a tumor-associated antigen. VH1 is a first immunoglobulin heavy chain variable region that specifically binds to a tumor-associated antigen; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to a tumor-associated antigen; VH3 is a third immunoglobulin heavy chain variable region that specifically binds to CD3; VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds to a tumor-associated antigen; Fc is a region comprising immunoglobulin heavy chain constant region 2 (CH2), immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; CH1 is immunoglobulin heavy chain constant region 1; CL is an immunoglobulin light chain constant region; and L1 to L88 are amino acid linkers. In some embodiments, the first polypeptide has the structure of: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-Fc; VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-Fc; VH1-L6-VL2-L7- VH2-L8-VL1-L9-CH1-L10-Fc;VL1-L11-VL2-L12-VH2-L13-VH1-L14-CL-L15-Fc;VL1-L11- VH2-L12-VL2-L13-VH1-L14-CL-L15-Fc;VH1-L16-VH2-L17-VL2-L18-VL1-L19-CL-L20-Fc;VH1-L16-VL2-L17-VH2-L18-VL1-L19-CL-L20-Fc;VL1-L21-VL2-L22-VH2-L23-VH1-L24-CH1-L25-CL-L26-Fc;VL1-L21 -VH2-L22-VL2-L23-VH1-L24-CH1-L25-CL-L26-Fc;VH1-L27-VH2-L28-VL2-L29-VL1-L30-CH1-L31-CL-L32-Fc;VH1-L2 7-VL2-L28-VH2-L29-VL1-L30-CH1-L31-CL-L32-Fc;VL1-L33-VL2-L34-VH2-L35-VH1-L36-CL-L37-CH1-L38-Fc;VL1-L33-VH2-L34-VL2-L35-VH1-L36-CL-L37-CH1-L38-Fc;VH1-L39-VH2-L40-VL2-L41-VL1-L42-CL-L43-CH1-L44-Fc;or; the first polypeptide has the structure represented by VH1-L39-VL2-L40-VH2-L41-VL1-L42-CL-L43-CH1-L44-Fc; and the second polypeptide has the structure represented by VL3-L45-VL4-L46-VH4-L47-VH3-L48-CH1-L49-Fc. In some embodiments, the first polypeptide has the sequence of: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-Fc; VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-Fc; VH1-L6-VL2-L7-VH2-L8-VL1-L9-CH1-L10-Fc; VL1-L11-VL2-L12-VH2-L13-VH1-L14 -CL-L15-Fc;VL1-L11-VH2-L12-VL2-L13-VH1-L14-CL-L15-Fc;VH1-L16-VH2-L17-VL2-L18-VL1-L19-CL-L20-Fc;VH1-L16- VL2-L17-VH2-L18-VL1-L19-CL-L20-Fc;VL1-L21-VL2-L22-VH2-L23-VH1-L24-CH1-L25-CL-L26-Fc;VL1-L21-VH2-L22-VL2- L23-VH1-L24-CH1-L25-CL-L26-Fc;VH1-L27-VH2-L28-VL2-L29-VL1-L30-CH1-L31-CL-L32-Fc;VH1-L27-VL2-L28-VH2-L29 -VL1-L30-CH1-L31-CL-L32-Fc;VL1-L33-VL2-L34-VH2-L35-VH1-L36-CL-L37-CH1-L38-Fc;VL1-L33-VH2-L34-VL2-L35-VH1 -L36-CL-L37-CH1-L38-Fc; VH1-L39-VH2-L40-VL2-L41-VL1-L42-CL-L43-CH1-L44-Fc; or VH1-L39-VL2-L40-VH2-L41-VL1-L42-CL-L43-CH1-L44-Fc; and the second polypeptide has the structure VL3-L45-VH4-L46-VL4-L47-VH3-L48-CH1-L49-Fc.In some embodiments, the first polypeptide has the sequence of: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-Fc; VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-Fc; VH1-L6-VL2-L7-VH2-L8-VL1-L9-CH1-L10-Fc; VL1-L11-VL2-L12-VH2-L13-VH1-L14 -CL-L15-Fc;VL1-L11-VH2-L12-VL2-L13-VH1-L14-CL-L15-Fc;VH1-L16-VH2-L17-VL2-L18-VL1-L19-CL-L20-Fc;VH1-L16- VL2-L17-VH2-L18-VL1-L19-CL-L20-Fc;VL1-L21-VL2-L22-VH2-L23-VH1-L24-CH1-L25-CL-L26-Fc;VL1-L21-VH2-L22-VL2- L23-VH1-L24-CH1-L25-CL-L26-Fc;VH1-L27-VH2-L28-VL2-L29-VL1-L30-CH1-L31-CL-L32-Fc;VH1-L27-VL2-L28-VH2-L29 -VL1-L30-CH1-L31-CL-L32-Fc;VL1-L33-VL2-L34-VH2-L35-VH1-L36-CL-L37-CH1-L38-Fc;VL1-L33-VH2-L34-VL2-L35-VH1 -L36-CL-L37-CH1-L38-Fc; VH1-L39-VH2-L40-VL2-L41-VL1-L42-CL-L43-CH1-L44-Fc; or VH1-L39-VL2-L40-VH2-L41-VL1-L42-CL-L43-CH1-L44-Fc; and the second polypeptide has the structure VH3-L50-VH4-L51-VL4-L52-VL3-L53-CH1-L54-Fc.In some embodiments, the first polypeptide has the sequence of: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-Fc; VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-Fc; VH1-L6-VL2-L7-VH2-L8-VL1-L9-CH1-L10-Fc; VL1-L11-VL2-L12-VH2-L13-VH1-L14 -CL-L15-Fc;VL1-L11-VH2-L12-VL2-L13-VH1-L14-CL-L15-Fc;VH1-L16-VH2-L17-VL2-L18-VL1-L19-CL-L20-Fc;VH1-L16- VL2-L17-VH2-L18-VL1-L19-CL-L20-Fc;VL1-L21-VL2-L22-VH2-L23-VH1-L24-CH1-L25-CL-L26-Fc;VL1-L21-VH2-L22-VL2- L23-VH1-L24-CH1-L25-CL-L26-Fc;VH1-L27-VH2-L28-VL2-L29-VL1-L30-CH1-L31-CL-L32-Fc;VH1-L27-VL2-L28-VH2-L29 -VL1-L30-CH1-L31-CL-L32-Fc;VL1-L33-VL2-L34-VH2-L35-VH1-L36-CL-L37-CH1-L38-Fc;VL1-L33-VH2-L34-VL2-L35-VH1 -L36-CL-L37-CH1-L38-Fc; VH1-L39-VH2-L40-VL2-L41-VL1-L42-CL-L43-CH1-L44-Fc; or VH1-L39-VL2-L40-VH2-L41-VL1-L42-CL-L43-CH1-L44-Fc; and the second polypeptide has the structure VH3-L50-VL4-L51-VH4-L52-VL3-L53-CH1-L54-Fc.In some embodiments, the first polypeptide has the sequence of: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-Fc; VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-Fc; VH1-L6-VL2-L7-VH2-L8-VL1-L9-CH1-L10-Fc; VL1-L11-VL2-L12-VH2-L13-VH1-L14 -CL-L15-Fc;VL1-L11-VH2-L12-VL2-L13-VH1-L14-CL-L15-Fc;VH1-L16-VH2-L17-VL2-L18-VL1-L19-CL-L20-Fc;VH1-L16- VL2-L17-VH2-L18-VL1-L19-CL-L20-Fc;VL1-L21-VL2-L22-VH2-L23-VH1-L24-CH1-L25-CL-L26-Fc;VL1-L21-VH2-L22-VL2 -L23-VH1-L24-CH1-L25-CL-L26-Fc;VH1-L27-VH2-L28-VL2-L29-VL1-L30-CH1-L31-CL-L32-Fc;VH1-L27-VL2-L28-VH2-L2 9-VL1-L30-CH1-L31-CL-L32-Fc;VL1-L33-VL2-L34-VH2-L35-VH1-L36-CL-L37-CH1-L38-Fc;VL1-L33-VH2-L34-VL2-L35-V VH1-L36-CL-L37-CH1-L38-Fc; VH1-L39-VH2-L40-VL2-L41-VL1-L42-CL-L43-CH1-L44-Fc; or VH1-L39-VL2-L40-VH2-L41-L1-L42-CL-L43-CH1-L44-Fc; and the second polypeptide has the structure VL3-L55-VL4-L56-VH4-L57-VH3-L58-CL-L59-Fc.In some embodiments, the first polypeptide has the sequence of: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-Fc; VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-Fc; VH1-L6-VL2-L7-VH2-L8-VL1-L9-CH1-L10-Fc; VL1-L11-VL2-L12-VH2-L13-VH1-L14 -CL-L15-Fc;VL1-L11-VH2-L12-VL2-L13-VH1-L14-CL-L15-Fc;VH1-L16-VH2-L17-VL2-L18-VL1-L19-CL-L20-Fc;VH1-L16- VL2-L17-VH2-L18-VL1-L19-CL-L20-Fc;VL1-L21-VL2-L22-VH2-L23-VH1-L24-CH1-L25-CL-L26-Fc;VL1-L21-VH2-L22-VL2- L23-VH1-L24-CH1-L25-CL-L26-Fc;VH1-L27-VH2-L28-VL2-L29-VL1-L30-CH1-L31-CL-L32-Fc;VH1-L27-VL2-L28-VH2-L29 -VL1-L30-CH1-L31-CL-L32-Fc;VL1-L33-VL2-L34-VH2-L35-VH1-L36-CL-L37-CH1-L38-Fc;VL1-L33-VH2-L34-VL2-L35-VH and the second polypeptide has a structure represented by VL3-L55-VH4-L56-VL4-L57-VH3-L58-CL-L59-Fc; VH1-L39-VH2-L40-VL2-L41-VL1-L42-CL-L43-CH1-L44-Fc; or VH1-L39-VL2-L40-VH2-L41-VL1-L42-CL-L43-CH1-L44-Fc; and the second polypeptide has a structure represented by VL3-L55-VH4-L56-VL4-L57-VH3-L58-CL-L59-Fc.In some embodiments, the first polypeptide has the sequence of: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-Fc; VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-Fc; VH1-L6-VL2-L7-VH2-L8-VL1-L9-CH1-L10-Fc; VL1-L11-VL2-L12-VH2-L13-VH1-L14 -CL-L15-Fc;VL1-L11-VH2-L12-VL2-L13-VH1-L14-CL-L15-Fc;VH1-L16-VH2-L17-VL2-L18-VL1-L19-CL-L20-Fc;VH1-L16- VL2-L17-VH2-L18-VL1-L19-CL-L20-Fc;VL1-L21-VL2-L22-VH2-L23-VH1-L24-CH1-L25-CL-L26-Fc;VL1-L21-VH2-L22-VL2- L23-VH1-L24-CH1-L25-CL-L26-Fc;VH1-L27-VH2-L28-VL2-L29-VL1-L30-CH1-L31-CL-L32-Fc;VH1-L27-VL2-L28-VH2-L29 -VL1-L30-CH1-L31-CL-L32-Fc;VL1-L33-VL2-L34-VH2-L35-VH1-L36-CL-L37-CH1-L38-Fc;VL1-L33-VH2-L34-VL2-L35-VH In some embodiments, the first polypeptide has a structure represented by VH1-L1-VL2-L36-CL-L37-CH1-L38-Fc; VH1-L39-VH2-L40-VL2-L41-VL1-L42-CL-L43-CH1-L44-Fc; or VH1-L39-VL2-L40-VH2-L41-VL1-L42-CL-L43-CH1-L44-Fc; and the second polypeptide has a structure represented by VH3-L60-VH4-L61-VL4-L62-VL3-L63-CL-L64-Fc. In some embodiments, the first polypeptide has a structure represented by VL1-L1-VL2-. L2-VH2-L3-VH1-L4-CH1-L5-Fc;VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-Fc;VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L1 0-Fc;VH1-L6-VL2-L7-VH2-L8-VL1-L9-CH1-L10-Fc;VL1-L11-VL2-L12-VH2-L13-VH1-L14-CL-L15-Fc;VL1-L11-VH2-L 12-VL2-L13-VH1-L14-CL-L15-Fc;VH1-L16-VH2-L17-VL2-L18-VL1-L19-CL-L20-Fc;VH1-L16-VL2-L17-VH2-L18-VL1- L19-CL-L20-Fc;VL1-L21-VL2-L22-VH2-L23-VH1-L24-CH1-L25-CL-L26-Fc;VL1-L21-VH2-L22-VL2-L23-VH1-L24-CH1- L25-CL-L26-Fc;VH1-L27-VH2-L28-VL2-L29-VL1-L30-CH1-L31-CL-L32-Fc;VH1-L27-VL2-L28-VH2-L29-VL1-L30-CH1 -L31-CL-L32-Fc;VL1-L33-VL2-L34-VH2-L35-VH1-L36-CL-L37-CH1-L38-Fc;VL1-L33-VH2-L34-VL2-L35-VH1-L36-CL -L37-CH1-L38-Fc; VH1-L39-VH2-L40-VL2-L41-VL1-L42-CL-L43-CH1-L44-Fc; or VH1-L39-VL2-L40-VH2-L41-VL1-L42-CL-L43-CH1-L44-Fc; and the second polypeptide has the structure VH3-L60-VL4-L61-VH4-L62-VL3-L63-CL-L64-Fc.In some embodiments, the first polypeptide has the sequence of: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-Fc; VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-Fc; VH1-L6-VL2-L7-VH2-L8-VL1-L9-CH1-L10-Fc; VL1-L11-VL2-L12-VH2-L13-VH1-L14-C L-L15-Fc;VL1-L11-VH2-L12-VL2-L13-VH1-L14-CL-L15-Fc;VH1-L16-VH2-L17-VL2-L18-VL1-L19-CL-L20-Fc;VH1-L16-VL2 -L17-VH2-L18-VL1-L19-CL-L20-Fc;VL1-L21-VL2-L22-VH2-L23-VH1-L24-CH1-L25-CL-L26-Fc;VL1-L21-VH2-L22-VL2-L23- VH1-L24-CH1-L25-CL-L26-Fc;VH1-L27-VH2-L28-VL2-L29-VL1-L30-CH1-L31-CL-L32-Fc;VH1-L27-VL2-L28-VH2-L29-VL1- L30-CH1-L31-CL-L32-Fc;VL1-L33-VL2-L34-VH2-L35-VH1-L36-CL-L37-CH1-L38-Fc;VL1-L33-VH2-L34-VL2-L35-VH1-L36- CL-L37-CH1-L38-Fc; VH1-L39-VH2-L40-VL2-L41-VL1-L42-CL-L43-CH1-L44-Fc; or VH1-L39-VL2-L40-VH2-L41-VL1-L42-CL-L43-CH1-L44-Fc; and the second polypeptide has the structure represented by VL3-L65-VL4-L66-VH4-L67-VH3-L68-CH1-L69-CL-L70-Fc.In some embodiments, the first polypeptide has the sequence of: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-Fc; VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-Fc; VH1-L6-VL2-L7-VH2-L8-VL1-L9-CH1-L10-Fc; VL1-L11-VL2-L12-VH2-L13-VH1-L14-C L-L15-Fc;VL1-L11-VH2-L12-VL2-L13-VH1-L14-CL-L15-Fc;VH1-L16-VH2-L17-VL2-L18-VL1-L19-CL-L20-Fc;VH1-L16-VL2 -L17-VH2-L18-VL1-L19-CL-L20-Fc;VL1-L21-VL2-L22-VH2-L23-VH1-L24-CH1-L25-CL-L26-Fc;VL1-L21-VH2-L22-VL2-L23- VH1-L24-CH1-L25-CL-L26-Fc;VH1-L27-VH2-L28-VL2-L29-VL1-L30-CH1-L31-CL-L32-Fc;VH1-L27-VL2-L28-VH2-L29-VL1- L30-CH1-L31-CL-L32-Fc;VL1-L33-VL2-L34-VH2-L35-VH1-L36-CL-L37-CH1-L38-Fc;VL1-L33-VH2-L34-VL2-L35-VH1-L36- and the second polypeptide has the structure represented by VL3-L65-VH4-L66-VL4-L67-VH3-L68-CH1-L69-CL-L70-Fc.In some embodiments, the first polypeptide has the sequence of: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-Fc; VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-Fc; VH1-L6-VL2-L7-VH2-L8-VL1-L9-CH1-L10-Fc; VL1-L11-VL2-L12-VH2-L13-VH1-L14-C L-L15-Fc;VL1-L11-VH2-L12-VL2-L13-VH1-L14-CL-L15-Fc;VH1-L16-VH2-L17-VL2-L18-VL1-L19-CL-L20-Fc;VH1-L16-VL2 -L17-VH2-L18-VL1-L19-CL-L20-Fc;VL1-L21-VL2-L22-VH2-L23-VH1-L24-CH1-L25-CL-L26-Fc;VL1-L21-VH2-L22-VL2-L23- VH1-L24-CH1-L25-CL-L26-Fc;VH1-L27-VH2-L28-VL2-L29-VL1-L30-CH1-L31-CL-L32-Fc;VH1-L27-VL2-L28-VH2-L29-VL1- L30-CH1-L31-CL-L32-Fc;VL1-L33-VL2-L34-VH2-L35-VH1-L36-CL-L37-CH1-L38-Fc;VL1-L33-VH2-L34-VL2-L35-VH1-L36- and the second polypeptide has the structure represented by VH3-L71-VH4-L72-VL4-L73-VL3-L74-CH1-L75-CL-L76-Fc.In some embodiments, the first polypeptide has the sequence of: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-Fc; VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-Fc; VH1-L6-VL2-L7-VH2-L8-VL1-L9-CH1-L10-Fc; VL1-L11-VL2-L12-VH2-L13-VH1-L14-C L-L15-Fc;VL1-L11-VH2-L12-VL2-L13-VH1-L14-CL-L15-Fc;VH1-L16-VH2-L17-VL2-L18-VL1-L19-CL-L20-Fc;VH1-L16-VL2 -L17-VH2-L18-VL1-L19-CL-L20-Fc;VL1-L21-VL2-L22-VH2-L23-VH1-L24-CH1-L25-CL-L26-Fc;VL1-L21-VH2-L22-VL2-L23- VH1-L24-CH1-L25-CL-L26-Fc;VH1-L27-VH2-L28-VL2-L29-VL1-L30-CH1-L31-CL-L32-Fc;VH1-L27-VL2-L28-VH2-L29-VL1- L30-CH1-L31-CL-L32-Fc;VL1-L33-VL2-L34-VH2-L35-VH1-L36-CL-L37-CH1-L38-Fc;VL1-L33-VH2-L34-VL2-L35-VH1-L36- and the second polypeptide has the structure represented by VH3-L71-VL4-L72-VH4-L73-VL3-L74-CH1-L75-CL-L76-Fc.In some embodiments, the first polypeptide has the sequence of: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-Fc; VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-Fc; VH1-L6-VL2-L7-VH2-L8-VL1-L9-CH1-L10-Fc; VL1-L11-VL2-L12-VH2-L13-VH1-L14-C L-L15-Fc;VL1-L11-VH2-L12-VL2-L13-VH1-L14-CL-L15-Fc;VH1-L16-VH2-L17-VL2-L18-VL1-L19-CL-L20-Fc;VH1-L16-VL2 -L17-VH2-L18-VL1-L19-CL-L20-Fc;VL1-L21-VL2-L22-VH2-L23-VH1-L24-CH1-L25-CL-L26-Fc;VL1-L21-VH2-L22-VL2-L23- VH1-L24-CH1-L25-CL-L26-Fc;VH1-L27-VH2-L28-VL2-L29-VL1-L30-CH1-L31-CL-L32-Fc;VH1-L27-VL2-L28-VH2-L29-VL1- L30-CH1-L31-CL-L32-Fc;VL1-L33-VL2-L34-VH2-L35-VH1-L36-CL-L37-CH1-L38-Fc;VL1-L33-VH2-L34-VL2-L35-VH1-L36- and the second polypeptide has the structure represented by VL3-L77-VL4-L78-VH4-L79-VH3-L80-CL-L81-CH1-L82-Fc. In some embodiments, the first polypeptide is VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-Fc; VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-Fc; VH1-L6-VL2-L7-VH2-L8-.VL1-L9-CH1-L10-Fc;VL1-L11-VL2-L12-VH2-L13-VH1-L14-CL-L15-Fc;VL1-L11-VH2-L12-VL2-L13- VH1-L14-CL-L15-Fc;VH1-L16-VH2-L17-VL2-L18-VL1-L19-CL-L20-Fc;VH1-L16-VL2-L17-VH2-L18-V L1-L19-CL-L20-Fc;VL1-L21-VL2-L22-VH2-L23-VH1-L24-CH1-L25-CL-L26-Fc;VL1-L21-VH2-L22-V L2-L23-VH1-L24-CH1-L25-CL-L26-Fc;VH1-L27-VH2-L28-VL2-L29-VL1-L30-CH1-L31-CL-L32-Fc;VH 1-L27-VL2-L28-VH2-L29-VL1-L30-CH1-L31-CL-L32-Fc;VL1-L33-VL2-L34-VH2-L35-VH1-L36-CL-L 37-CH1-L38-Fc;VL1-L33-VH2-L34-VL2-L35-VH1-L36-CL-L37-CH1-L38-Fc;VH1-L39-VH2-L40-VL2-L or VH1-L39-VL2-L40-VH2-L41-VL1-L42-CL-L43-CH1-L44-Fc; and the second polypeptide has the structure VL3-L77-VH4-L78-VL4-L79-VH3-L80-CL-L81-CH1-L82-Fc.In some embodiments, the first polypeptide has the sequence of: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-Fc; VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-Fc; VH1-L6-VL2-L7-VH2-L8-VL1-L9-CH1-L10-Fc; VL1-L11-VL2-L12-VH2-L13-VH1-L14-C L-L15-Fc;VL1-L11-VH2-L12-VL2-L13-VH1-L14-CL-L15-Fc;VH1-L16-VH2-L17-VL2-L18-VL1-L19-CL-L20-Fc;VH1-L16-VL2 -L17-VH2-L18-VL1-L19-CL-L20-Fc;VL1-L21-VL2-L22-VH2-L23-VH1-L24-CH1-L25-CL-L26-Fc;VL1-L21-VH2-L22-VL2-L23- VH1-L24-CH1-L25-CL-L26-Fc;VH1-L27-VH2-L28-VL2-L29-VL1-L30-CH1-L31-CL-L32-Fc;VH1-L27-VL2-L28-VH2-L29-VL1- L30-CH1-L31-CL-L32-Fc;VL1-L33-VL2-L34-VH2-L35-VH1-L36-CL-L37-CH1-L38-Fc;VL1-L33-VH2-L34-VL2-L35-VH1-L36- and the second polypeptide has the structure represented by VH3-L83-VH4-L84-VL4-L85-VL3-L86-CL-L87-CH1-L88-Fc.In some embodiments, the first polypeptide has the sequence of: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-Fc; VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-Fc; VH1-L6-VL2-L7-VH2-L8-VL1-L9-CH1-L10-Fc; VL1-L11-VL2-L12-VH2-L13-VH1-L14-C L-L15-Fc;VL1-L11-VH2-L12-VL2-L13-VH1-L14-CL-L15-Fc;VH1-L16-VH2-L17-VL2-L18-VL1-L19-CL-L20-Fc;VH1-L16-VL2 -L17-VH2-L18-VL1-L19-CL-L20-Fc;VL1-L21-VL2-L22-VH2-L23-VH1-L24-CH1-L25-CL-L26-Fc;VL1-L21-VH2-L22-VL2-L23- VH1-L24-CH1-L25-CL-L26-Fc;VH1-L27-VH2-L28-VL2-L29-VL1-L30-CH1-L31-CL-L32-Fc;VH1-L27-VL2-L28-VH2-L29-VL1- L30-CH1-L31-CL-L32-Fc;VL1-L33-VL2-L34-VH2-L35-VH1-L36-CL-L37-CH1-L38-Fc;VL1-L33-VH2-L34-VL2-L35-VH1-L36- CL-L37-CH1-L38-Fc; VH1-L39-VH2-L40-VL2-L41-VL1-L42-CL-L43-CH1-L44-Fc; or VH1-L39-VL2-L40-VH2-L41-VL1-L42-CL-L43-CH1-L44-Fc; and the second polypeptide has the structure VH3-L83-VL4-L84-VH4-L85-VL3-L86-CL-L87-CH1-L88-Fc.In some embodiments, the first polypeptide has the sequence VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-Fc; VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-Fc; VL1-L11-VL2-L12-VH2-L13-VH1-L14-CL-L15-Fc; VH1-L16-VH2-L17-VL2-L18-VL1-L19-CL-L20-Fc; VL1-L21-VL2-L22-VH1-L23-CL-L24-Fc; H2-L23-VH1-L24-CH1-L25-CL-L26-Fc; VH1-L27-VH2-L28-VL2-L29-VL1-L30-CH1-L31-CL-L32-Fc; VL1-L33-VL2-L34-VH2-L35-VH1-L36-CL-L37-CH1-L38-Fc; or VH1-L39-VH2-L40-VL2-L41-VL1-L42-CL-L43-CH1-L44-Fc; The second polypeptide is VL3-L45-VL4-L46-VH4-L47-VH3-L48-CH1-L49-Fc; VH3-L50-VH4-L51-VL4-L52-VL3-L53-CH1-L54-Fc; VL3-L55-VL4-L56-VH4-L57-VH3-L58-CL-L59-Fc; VH3-L60-VH4-L61-VL4-L62-VL3-L63-CL-L64-Fc; VL3-L65-VL4-L66-VH VH3-L67-VH3-L68-CH1-L69-CL-L70-Fc; VH3-L71-VH4-L72-VL4-L73-VL3-L74-CH1-L75-CL-L76-Fc; VL3-L77-VL4-L78-VH4-L79-VH3-L80-CL-L81-CH1-L82-Fc; or VH3-L83-VH4-L84-VL4-L85-VL3-L86-CL-L87-CH1-L88-Fc.

[0093] In some other aspects, the invention provides an antigen-binding polypeptide complex comprising a first polypeptide and a second polypeptide, wherein the first polypeptide is VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; or VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc; or VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc; or VH1 -L5-VL2-L6-VH2-L7-VL1-L8-Fc; and the second polypeptide has a structure represented by VL3-L9-VL4-L10-VH4-L11-VH3-L12-Fc; or VL3-L9-VH4-L10-VL4-L11-VH3-L12-Fc; or VH3-L13-VH4-L14-VL4-L15-VL3-L16-Fc; or VH3-L13-VL VL1 is a first immunoglobulin light chain variable region; VL2 is a second immunoglobulin light chain variable region; VL3 is a third immunoglobulin light chain variable region; VL4 is a fourth immunoglobulin light chain variable region; VH1 is a first immunoglobulin heavy chain variable region; VH2 is a second immunoglobulin heavy chain variable region; VH3 is a third immunoglobulin heavy chain variable region; VH4 is a fourth immunoglobulin heavy chain variable region; Fc is a region comprising immunoglobulin heavy chain constant region 2 (CH2), immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; and L1 through L16 are amino acid linkers. In some embodiments, the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc; VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc; or VH1-L5-VL2-L6-VH2-L7-VL1-L8-Fc, and the second polypeptide has a structure represented by VL3-L9-VL4-L10-VH4-L11-VH3-L12-Fc.In some embodiments, the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; or VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc or VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc or VH1-L5-VL2-L6-VH2-L7-VL1-L8-Fc, and the second polypeptide has a structure represented by VL3-L9-VH4-L10-VL4-L11-VH3-L12-Fc. In some embodiments, the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; or VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc or VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc or VH1-L5-VL2-L6-VH2-L7-VL1-L8-Fc, and the second polypeptide has a structure represented by VH3-L13-VH4-L14-VL4-L15-VL3-L16-Fc. In some embodiments, the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; or VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc or VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc or VH1-L5-VL2-L6-VH2-L7-VL1-L8-Fc, and the second polypeptide has a structure represented by VH3-L13-VL4-L14-VH4-L15-VL3-L16-Fc. In some embodiments, the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc or VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc; and the second polypeptide has a structure represented by VL3-L9-VL4-L10-VH4-L11-VH3-L12-Fc or VH3-L13-VH4-L14-VL4-L15-VL3-L16-Fc. In some embodiments, the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc, and the second polypeptide has a structure represented by VL3-L9-VL4-L10-VH4-L11-VH3-L12-Fc.In some embodiments, the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc and the second polypeptide has a structure represented by VH3-L13-VH4-L14-VL4-L15-VL3-L16-Fc. In some embodiments, the first polypeptide has a structure represented by VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc and the second polypeptide has a structure represented by VL3-L9-VL4-L10-VH4-L11-VH3-L12-Fc. In some embodiments, the first polypeptide has a structure represented by VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc, and the second polypeptide has a structure represented by VH3-L13-VH4-L14-VL4-L15-VL3-L16-Fc.

[0094] In some other aspects, the invention provides an antigen-binding polypeptide complex comprising a first polypeptide and a second polypeptide, wherein the first polypeptide is VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; or VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc; or VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc; or VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc; the second polypeptide has a structure represented by VL3-L9-VL4-L10-VH4-L11-VH3-L12-Fc; or VL3-L9-VH4-L10-VL4-L11-VH3-L12-Fc; or VH3-L13-VH4-L14-VL4-L15-VL3-L16-Fc; or VH3-L13-VL4- VL1 is a first immunoglobulin light chain variable region; VL2 is a second immunoglobulin light chain variable region; VL3 is a third immunoglobulin light chain variable region; VL4 is a fourth immunoglobulin light chain variable region; VH1 is a first immunoglobulin heavy chain variable region; VH2 is a second immunoglobulin heavy chain variable region; VH3 is a third immunoglobulin heavy chain variable region; VH4 is a fourth immunoglobulin heavy chain variable region; Fc is a region comprising immunoglobulin heavy chain constant region 2 (CH2), immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; and L1-L16 are amino acid linkers. In some embodiments, the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc; VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc; or VH1-L5-VL2-L6-VH2-VL1-L8-Fc; and the second polypeptide has a structure represented by VL3-L9-VL4-L10-VH4-L11-VH3-L12-Fc.In some embodiments, the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc; VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc; or VH1-L5-VL2-L6-VH2-VL1-L8-Fc; and the second polypeptide has a structure represented by VL3-L9-VH4-L10-VL4-L11-VH3-L12-Fc. In some embodiments, the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc; VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc; or VH1-L5-VL2-L6-VH2-VL1-L8-Fc; and the second polypeptide has a structure represented by VH3-L13-VH4-L14-VL4-L15-VL3-L16-Fc. In some embodiments, the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc; VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc; or VH1-L5-VL2-L6-VH2-VL1-L8-Fc; and the second polypeptide has a structure represented by VH3-L13-VL4-L14-VH4-L15-VL3-L16-Fc. In some embodiments, the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc or VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc; and the second polypeptide has a structure represented by VL3-L9-VL4-L10-VH4-L11-VH3-L12-Fc or VH3-L13-VH4-L14-VL4-L15-VL3-L16-Fc. In some embodiments, the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc, and the second polypeptide has a structure represented by VL3-L9-VL4-L10-VH4-L11-VH3-L12-Fc.In some embodiments, the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc and the second polypeptide has a structure represented by VH3-L13-VH4-L14-VL4-L15-VL3-L16-Fc. In some embodiments, the first polypeptide has a structure represented by VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc and the second polypeptide has a structure represented by VL3-L9-VL4-L10-VH4-L11-VH3-L12-Fc. In some embodiments, the first polypeptide has a structure represented by VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc, and the second polypeptide has a structure represented by VH3-L13-VH4-L14-VL4-L15-VL3-L16-Fc.

[0095] In some aspects, the invention provides an antigen-binding polypeptide complex comprising a first polypeptide and a second polypeptide, wherein the first polypeptide is one of the following: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-Fc; VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-Fc; VH1-L6-VL2-L7-VH2-L8-VL1-L9-CH1-L10-Fc; VL1-L11-VL2-L12-VH2-L13-VH 1-L14-CL-L15-Fc;VL1-L11-VH2-L12-VL2-L13-VH1-L14-CL-L15-Fc;VH1 -L16-VH2-L17-VL2-L18-VL1-L19-CL-L20-Fc;VH1-L16-VL2-L17-VH2-L18 -VL1-L19-CL-L20-Fc;VL1-L21-VL2-L22-VH2-L23-VH1-L24-CH1-L25-CL- L26-Fc;VL1-L21-VH2-L22-VL2-L23-VH1-L24-CH1-L25-CL-L26-Fc;VH1-L 27-VH2-L28-VL2-L29-VL1-L30-CH1-L31-CL-L32-Fc;VH1-L27-VL2-L28- VH2-L29-VL1-L30-CH1-L31-CL-L32-Fc;VL1-L33-VL2-L34-VH2-L35-VH1- L36-CL-L37-CH1-L38-Fc;VL1-L33-VH2-L34-VL2-L35-VH1-L36-CL-L37-C H1-L38-Fc;VH1-L39-VH2-L40-VL2-L41-VL1-L42-CL-L43-CH1-L44-Fc;also the second polypeptide has a structure represented by VH1-L39-VL2-L40-VH2-L41-VL1-L42-CL-L43-CH1-L44-Fc; the second polypeptide has a structure represented by VL3-L45-VL4-L46-VH4-L47-VH3-L48-CH1-L49-Fc; VL3-L45-VH4-L46-VL4-L47-VH3-L48-CH1-L49-Fc; VH3-L50-VH4-L51-VL4-L52-VL3-L53-CH1-L54-Fc; VH3-L50-VL4-L51-VH4-L52-VL3-L53-CH1-L54-Fc;VL3-L55-VL4-L56-VH4-L57-VH3-L58-CL-L59-Fc;VL3-L55-VH4-L56-VL4 -L57-VH3-L58-CL-L59-Fc;VH3-L60-VH4-L61-VL4-L62-VL3-L63-CL-L64- Fc;VH3-L60-VL4-L61-VH4-L62-VL3-L63-CL-L64-Fc;VL3-L65-VL4-L66-V H4-L67-VH3-L68-CH1-L69-CL-L70-Fc;VL3-L65-VH4-L66-VL4-L67-VH3-L 68-CH1-L69-CL-L70-Fc;VH3-L71-VH4-L72-VL4-L73-VL3-L74-CH1-L75-C L-L76-Fc;VH3-L71-VL4-L72-VH4-L73-VL3-L74-CH1-L75-CL-L76-Fc;VL3 -L77-VL4-L78-VH4-L79-VH3-L80-CL-L81-CH1-L82-Fc;VL3-L77-VH4-L78 -VL4-L79-VH3-L80-CL-L81-CH1-L82-Fc;VH3-L83-VH4-L84-VL4-L85-VL3 or VH3-L83-VL4-L84-VH4-L85-VL3-L86-CL-L87-CH1-L88-Fc; wherein VL1 is a first immunoglobulin light chain variable region that specifically binds to a tumor-associated antigen; VL2 is a second immunoglobulin light chain variable region that specifically binds to a tumor-associated antigen; VL3 is a third immunoglobulin light chain variable region that specifically binds to a tumor-associated antigen; VL4 is a fourth immunoglobulin light chain variable region that specifically binds to CD3; H1 is a first immunoglobulin heavy chain variable region that specifically binds to a tumor-associated antigen; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to a tumor-associated antigen; VH3 is a third immunoglobulin heavy chain variable region that specifically binds to a tumor-associated antigen; VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds to CD3; Fc is a region containing immunoglobulin heavy chain constant region 2 (CH2), immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; CH1 is immunoglobulin heavy chain constant region 1;and L1-L88 are amino acid linkers. In some embodiments, the first polypeptide has a sequence similar to or similar to VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-Fc; VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-Fc; VH1-L6-VL2-L7-VH2-L8-VL1-L9-CH1-L10-Fc; VL1-L11-VL2-L12-VH2-L13-VH1-L14 -CL-L15-Fc;VL1-L11-VH2-L12-VL2-L13-VH1-L14-CL-L15-Fc;VH1-L16-VH2-L17-VL2-L18-VL1-L19-CL-L20-Fc;VH1-L16- VL2-L17-VH2-L18-VL1-L19-CL-L20-Fc;VL1-L21-VL2-L22-VH2-L23-VH1-L24-CH1-L25-CL-L26-Fc;VL1-L21-VH2-L22-VL2- L23-VH1-L24-CH1-L25-CL-L26-Fc;VH1-L27-VH2-L28-VL2-L29-VL1-L30-CH1-L31-CL-L32-Fc;VH1-L27-VL2-L28-VH2-L29 -VL1-L30-CH1-L31-CL-L32-Fc;VL1-L33-VL2-L34-VH2-L35-VH1-L36-CL-L37-CH1-L38-Fc;VL1-L33-VH2-L34-VL2-L35-VH1 -L36-CL-L37-CH1-L38-Fc; VH1-L39-VH2-L40-VL2-L41-VL1-L42-CL-L43-CH1-L44-Fc; or VH1-L39-VL2-L40-VH2-L41-VL1-L42-CL-L43-CH1-L44-Fc; and the second polypeptide has the structure VL3-L45-VL4-L46-VH4-L47-VH3-L48-CH1-L49-Fc. In some embodiments, the first polypeptide has the structure: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-Fc;VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-Fc;VH1-L6-VL2-L7-VH2-L8-VL1-L9-CH1-L10-Fc;VL1-L11-VL2-L 12-VH2-L13-VH1-L14-CL-L15-Fc;VL1-L11-VH2-L12-VL2-L13-VH1-L14-CL-L15-Fc;VH1-L16-VH2-L17-VL2- L18-VL1-L19-CL-L20-Fc;VH1-L16-VL2-L17-VH2-L18-VL1-L19-CL-L20-Fc;VL1-L21-VL2-L22-VH2-L23-VH1 -L24-CH1-L25-CL-L26-Fc;VL1-L21-VH2-L22-VL2-L23-VH1-L24-CH1-L25-CL-L26-Fc;VH1-L27-VH2-L28-VL2 -L29-VL1-L30-CH1-L31-CL-L32-Fc;VH1-L27-VL2-L28-VH2-L29-VL1-L30-CH1-L31-CL-L32-Fc;VL1-L33-VL 2-L34-VH2-L35-VH1-L36-CL-L37-CH1-L38-Fc;VL1-L33-VH2-L34-VL2-L35-VH1-L36-CL-L37-CH1-L38-Fc;V H1-L39-VH2-L40-VL2-L41-VL1-L42-CL-L43-CH1-L44-Fc; or VH1-L39-VL2-L40-VH2-L41-VL1-L42-CL-L43-CH1-L44-Fc; and the second polypeptide has the structure VL3-L45-VH4-L46-VL4-L47-VH3-L48-CH1-L49-Fc. In some embodiments, the first polypeptide is VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-Fc; VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-Fc; VH1-L6-VL2-L7-VH2-L8-VL1-L9-CH1-L10-Fc; VL1-L11-VL2-L12-VH2-L13-VH1-L14-CL-L15-Fc; VL1-L11-VH2-L12-VL2-L13-VH1-L14-CL-L15-Fc;VH1-L16-VH2-L17-VL2-L18-VL1-L19-CL-L20-Fc;VH1-L16-VL2-L17-VH2-L18-VL1-L 19-CL-L20-Fc;VL1-L21-VL2-L22-VH2-L23-VH1-L24-CH1-L25-CL-L26-Fc;VL1-L21- VH2-L22-VL2-L23-VH1-L24-CH1-L25-CL-L26-Fc;VH1-L27-VH2-L28-VL2-L29-VL1-L 30-CH1-L31-CL-L32-Fc;VH1-L27-VL2-L28-VH2-L29-VL1-L30-CH1-L31-CL-L32-Fc; VL1-L33-VL2-L34-VH2-L35-VH1-L36-CL-L37-CH1-L38-Fc;VL1-L33-VH2-L34-VL2-L 35-VH1-L36-CL-L37-CH1-L38-Fc;VH1-L39-VH2-L40-VL2-L41-VL1-L42-CL-L43-CH1 -L44-Fc; or VH1-L39-VL2-L40-VH2-L41-VL1-L42-CL-L43-CH1-L44-Fc; and the second polypeptide has the structure VH3-L50-VH4-L51-VL4-L52-VL3-L53-CH1-L54-Fc. In some embodiments, the first polypeptide has the sequence of: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-Fc; VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-Fc; VH1-L6-VL2-L7-VH2-L8-VL1-L9-CH1-L10-Fc; VL1-L11-VL2-L12-VH2-L 13-VH1-L14-CL-L15-Fc;VL1-L11-VH2-L12-VL2-L13-VH1-L14-CL-L15-Fc;VH1-L16-VH2-L17-VL2-L18-VL1-L19-CL- L20-Fc;VH1-L16-VL2-L17-VH2-L18-VL1-L19-CL-L20-Fc;VL1-L21-VL2-L22-VH2-L23-VH1-L24-CH1-L25-CL-L26-Fc;VL1-L21-VH2-L22-VL2-L23-VH1-L24-CH1-L25-CL-L26-Fc;VH1-L27-VH2-L28-VL2-L29-VL1-L30-CH1-L31-CL-L32-Fc;VH1-L27-VL2-L28-VH2-L29-VL1-L30-CH1-L31-CL-L32-Fc;VL1-L33-VL2-L34-VH2-L35-VH1-L36-CL-L37-CH1-L38-Fc;VL1-L; 33-VH2-L34-VL2-L35-VH1-L36-CL-L37-CH1-L38-Fc; VH1-L39-VH2-L40-VL2-L41-VL1-L42-CL-L43-CH1-L44-Fc; or VH1-L39-VL2-L40-VH2-L41-VL1-L42-CL-L43-CH1-L44-Fc; and the second polypeptide has the structure VH3-L50-VL4-L51-VH4-L52-VL3-L53-CH1-L54-Fc.In some embodiments, the first polypeptide has the sequence of: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-Fc; VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-Fc; VH1-L6-VL2-L7-VH2-L8-VL1-L9-CH1-L10-Fc; VL1-L11-VL2-L12-VH2-L13-VH1-L14 -CL-L15-Fc;VL1-L11-VH2-L12-VL2-L13-VH1-L14-CL-L15-Fc;VH1-L16-VH2-L17-VL2-L18-VL1-L19-CL-L20-Fc;VH1-L16- VL2-L17-VH2-L18-VL1-L19-CL-L20-Fc;VL1-L21-VL2-L22-VH2-L23-VH1-L24-CH1-L25-CL-L26-Fc;VL1-L21-VH2-L22-VL2- L23-VH1-L24-CH1-L25-CL-L26-Fc;VH1-L27-VH2-L28-VL2-L29-VL1-L30-CH1-L31-CL-L32-Fc;VH1-L27-VL2-L28-VH2-L29 -VL1-L30-CH1-L31-CL-L32-Fc;VL1-L33-VL2-L34-VH2-L35-VH1-L36-CL-L37-CH1-L38-Fc;VL1-L33-VH2-L34-VL2-L35-VH VH1-L36-CL-L37-CH1-L38-Fc; VH1-L39-VH2-L40-VL2-L41-VL1-L42-CL-L43-CH1-L44-Fc; or VH1-L39-VL2-L40-VH2-L41-VL1-L42-CL-L43-CH1-L44-Fc; and the second polypeptide has the structure represented by VL3-L55-VL4-L56-VH4-L57-VH3-L58-CL-L59-Fc.In some embodiments, the first polypeptide has the sequence of: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-Fc; VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-Fc; VH1-L6-VL2-L7-VH2-L8-VL1-L9-CH1-L10-Fc; VL1-L11-VL2-L12-VH2-L13-VH1-L14 -CL-L15-Fc;VL1-L11-VH2-L12-VL2-L13-VH1-L14-CL-L15-Fc;VH1-L16-VH2-L17-VL2-L18-VL1-L19-CL-L20-Fc;VH1-L16- VL2-L17-VH2-L18-VL1-L19-CL-L20-Fc;VL1-L21-VL2-L22-VH2-L23-VH1-L24-CH1-L25-CL-L26-Fc;VL1-L21-VH2-L22-VL2- L23-VH1-L24-CH1-L25-CL-L26-Fc;VH1-L27-VH2-L28-VL2-L29-VL1-L30-CH1-L31-CL-L32-Fc;VH1-L27-VL2-L28-VH2-L29 -VL1-L30-CH1-L31-CL-L32-Fc;VL1-L33-VL2-L34-VH2-L35-VH1-L36-CL-L37-CH1-L38-Fc;VL1-L33-VH2-L34-VL2-L35-VH and the second polypeptide has a structure represented by VL3-L55-VH4-L56-VL4-L57-VH3-L58-CL-L59-Fc; VH1-L39-VH2-L40-VL2-L41-VL1-L42-CL-L43-CH1-L44-Fc; or VH1-L39-VL2-L40-VH2-L41-VL1-L42-CL-L43-CH1-L44-Fc; and the second polypeptide has a structure represented by VL3-L55-VH4-L56-VL4-L57-VH3-L58-CL-L59-Fc.In some embodiments, the first polypeptide has the sequence of: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-Fc; VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-Fc; VH1-L6-VL2-L7-VH2-L8-VL1-L9-CH1-L10-Fc; VL1-L11-VL2-L12-VH2-L13-VH1-L14 -CL-L15-Fc;VL1-L11-VH2-L12-VL2-L13-VH1-L14-CL-L15-Fc;VH1-L16-VH2-L17-VL2-L18-VL1-L19-CL-L20-Fc;VH1-L16- VL2-L17-VH2-L18-VL1-L19-CL-L20-Fc;VL1-L21-VL2-L22-VH2-L23-VH1-L24-CH1-L25-CL-L26-Fc;VL1-L21-VH2-L22-VL2- L23-VH1-L24-CH1-L25-CL-L26-Fc;VH1-L27-VH2-L28-VL2-L29-VL1-L30-CH1-L31-CL-L32-Fc;VH1-L27-VL2-L28-VH2-L29 -VL1-L30-CH1-L31-CL-L32-Fc;VL1-L33-VL2-L34-VH2-L35-VH1-L36-CL-L37-CH1-L38-Fc;VL1-L33-VH2-L34-VL2-L35-VH the first polypeptide has a structure represented by VH3-L60-VH4-L61-VL4-L62-VL3-L63-CL-L64-Fc; VH1-L39-VH2-L40-VL2-L41-VL1-L42-CL-L43-CH1-L44-Fc; or VH1-L39-VL2-L40-VH2-L41-VL1-L42-CL-L43-CH1-L44-Fc; and the second polypeptide has a structure represented by VH3-L60-VH4-L61-VL4-L62-VL3-L63-CL-L64-Fc.In some embodiments, the first polypeptide has the sequence of: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-Fc; VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-Fc; VH1-L6-VL2-L7-VH2-L8-VL1-L9-CH1-L10-Fc; VL1-L11-VL2-L12-VH2-L13-VH1-L14 -CL-L15-Fc;VL1-L11-VH2-L12-VL2-L13-VH1-L14-CL-L15-Fc;VH1-L16-VH2-L17-VL2-L18-VL1-L19-CL-L20-Fc;VH1-L16- VL2-L17-VH2-L18-VL1-L19-CL-L20-Fc;VL1-L21-VL2-L22-VH2-L23-VH1-L24-CH1-L25-CL-L26-Fc;VL1-L21-VH2-L22-VL2- L23-VH1-L24-CH1-L25-CL-L26-Fc;VH1-L27-VH2-L28-VL2-L29-VL1-L30-CH1-L31-CL-L32-Fc;VH1-L27-VL2-L28-VH2-L29 -VL1-L30-CH1-L31-CL-L32-Fc;VL1-L33-VL2-L34-VH2-L35-VH1-L36-CL-L37-CH1-L38-Fc;VL1-L33-VH2-L34-VL2-L35-VH the first polypeptide has a structure represented by VH3-L60-VL4-L61-VH4-L62-VL3-L63-CL-L64-Fc; VH1-L39-VH2-L40-VL2-L41-VL1-L42-CL-L43-CH1-L44-Fc; or VH1-L39-VL2-L40-VH2-L41-VL1-L42-CL-L43-CH1-L44-Fc; and the second polypeptide has a structure represented by VH3-L60-VL4-L61-VH4-L62-VL3-L63-CL-L64-Fc.In some embodiments, the first polypeptide has the sequence of: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-Fc; VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-Fc; VH1-L6-VL2-L7-VH2-L8-VL1-L9-CH1-L10-Fc; VL1-L11-VL2-L12-VH2-L13-VH1-L14-C L-L15-Fc;VL1-L11-VH2-L12-VL2-L13-VH1-L14-CL-L15-Fc;VH1-L16-VH2-L17-VL2-L18-VL1-L19-CL-L20-Fc;VH1-L16-VL2 -L17-VH2-L18-VL1-L19-CL-L20-Fc;VL1-L21-VL2-L22-VH2-L23-VH1-L24-CH1-L25-CL-L26-Fc;VL1-L21-VH2-L22-VL2-L23- VH1-L24-CH1-L25-CL-L26-Fc;VH1-L27-VH2-L28-VL2-L29-VL1-L30-CH1-L31-CL-L32-Fc;VH1-L27-VL2-L28-VH2-L29-VL1- L30-CH1-L31-CL-L32-Fc;VL1-L33-VL2-L34-VH2-L35-VH1-L36-CL-L37-CH1-L38-Fc;VL1-L33-VH2-L34-VL2-L35-VH1-L36- CL-L37-CH1-L38-Fc; VH1-L39-VH2-L40-VL2-L41-VL1-L42-CL-L43-CH1-L44-Fc; or VH1-L39-VL2-L40-VH2-L41-VL1-L42-CL-L43-CH1-L44-Fc; and the second polypeptide has the structure represented by VL3-L65-VL4-L66-VH4-L67-VH3-L68-CH1-L69-CL-L70-Fc.In some embodiments, the polypeptide is VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5- Fc;VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-Fc;VH1-L6-VL2-L7-VH2-L8-VL1-L9-CH1-L10-Fc;VL1-L11-VL2-L 12-VH2-L13-VH1-L14-CL-L15-Fc;VL1-L11-VH2-L12-VL2-L13-VH1-L14-CL-L15-Fc;VH1-L16-VH2-L17-VL2-L18 -VL1-L19-CL-L20-Fc;VH1-L16-VL2-L17-VH2-L18-VL1-L19-CL-L20-Fc;VL1-L21-VL2-L22-VH2-L23-VH1-L24-CH 1-L25-CL-L26-Fc;VL1-L21-VH2-L22-VL2-L23-VH1-L24-CH1-L25-CL-L26-Fc;VH1-L27-VH2-L28-VL2-L29-VL1- L30-CH1-L31-CL-L32-Fc;VH1-L27-VL2-L28-VH2-L29-VL1-L30-CH1-L31-CL-L32-Fc;VL1-L33-VL2-L34-VH2-L35 -VH1-L36-CL-L37-CH1-L38-Fc;VL1-L33-VH2-L34-VL2-L35-VH1-L36-CL-L37-CH1-L38-Fc;VH1-L39-VH2-L40-V L2-L41-VL1-L42-CL-L43-CH1-L44-Fc; or VH1-L39-VL2-L40-VH2-L41-VL1-L42-CL-L43-CH1-L44-Fc. the second polypeptide has the structure represented by VL3-L65-VH4-L66-VL4-L67-VH3-L68-CH1-L69-CL-L70-Fc. In some embodiments, the first polypeptide has the sequence of: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-Fc; VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-Fc; VH1-L6-VL2-L7-VH2-L8-VL1-L9-CH1-L10-Fc; VL1-L11-VL2-L12-VH2-L13-VH1-L14-C L-L15-Fc;VL1-L11-VH2-L12-VL2-L13-VH1-L14-CL-L15-Fc;VH1-L16-VH2-L17-VL2-L18-VL1-L19-CL-L20-Fc;VH1-L16-VL2 -L17-VH2-L18-VL1-L19-CL-L20-Fc;VL1-L21-VL2-L22-VH2-L23-VH1-L24-CH1-L25-CL-L26-Fc;VL1-L21-VH2-L22-VL2-L23 -VH1-L24-CH1-L25-CL-L26-Fc;VH1-L27-VH2-L28-VL2-L29-VL1-L30-CH1-L31-CL-L32-Fc;VH1-L27-VL2-L28-VH2-L29-VL1 -L30-CH1-L31-CL-L32-Fc;VL1-L33-VL2-L34-VH2-L35-VH1-L36-CL-L37-CH1-L38-Fc;VL1-L33-VH2-L34-VL2-L35-VH1-L36 -CL-L37-CH1-L38-Fc; VH1-L39-VH2-L40-VL2-L41-VL1-L42-CL-L43-CH1-L44-Fc; or VH1-L39-VL2-L40-VH2-L41-L1-L42-CL-L43-CH1-L44-Fc; and the second polypeptide has the structure VH3-L71-VH4-L72-VL4-L73-VL3-L74-CH1-L75-CL-L76-Fc.In some embodiments, the first polypeptide has the sequence of: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-Fc; VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-Fc; VH1-L6-VL2-L7-VH2-L8-VL1-L9-CH1-L10-Fc; VL1-L11-VL2-L12-VH2-L13-VH1-L14-C L-L15-Fc;VL1-L11-VH2-L12-VL2-L13-VH1-L14-CL-L15-Fc;VH1-L16-VH2-L17-VL2-L18-VL1-L19-CL-L20-Fc;VH1-L16-VL2 -L17-VH2-L18-VL1-L19-CL-L20-Fc;VL1-L21-VL2-L22-VH2-L23-VH1-L24-CH1-L25-CL-L26-Fc;VL1-L21-VH2-L22-VL2-L23- VH1-L24-CH1-L25-CL-L26-Fc;VH1-L27-VH2-L28-VL2-L29-VL1-L30-CH1-L31-CL-L32-Fc;VH1-L27-VL2-L28-VH2-L29-VL1- L30-CH1-L31-CL-L32-Fc;VL1-L33-VL2-L34-VH2-L35-VH1-L36-CL-L37-CH1-L38-Fc;VL1-L33-VH2-L34-VL2-L35-VH1-L36- and the second polypeptide has the structure represented by VH3-L71-VL4-L72-VH4-L73-VL3-L74-CH1-L75-CL-L76-Fc.In some embodiments, the first polypeptide has the sequence of: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-Fc; VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-Fc; VH1-L6-VL2-L7-VH2-L8-VL1-L9-CH1-L10-Fc; VL1-L11-VL2-L12-VH2-L13-VH1-L14-C L-L15-Fc;VL1-L11-VH2-L12-VL2-L13-VH1-L14-CL-L15-Fc;VH1-L16-VH2-L17-VL2-L18-VL1-L19-CL-L20-Fc;VH1-L16-VL2 -L17-VH2-L18-VL1-L19-CL-L20-Fc;VL1-L21-VL2-L22-VH2-L23-VH1-L24-CH1-L25-CL-L26-Fc;VL1-L21-VH2-L22-VL2-L23- VH1-L24-CH1-L25-CL-L26-Fc;VH1-L27-VH2-L28-VL2-L29-VL1-L30-CH1-L31-CL-L32-Fc;VH1-L27-VL2-L28-VH2-L29-VL1- L30-CH1-L31-CL-L32-Fc;VL1-L33-VL2-L34-VH2-L35-VH1-L36-CL-L37-CH1-L38-Fc;VL1-L33-VH2-L34-VL2-L35-VH1-L36- and the second polypeptide has the structure represented by VL3-L77-VL4-L78-VH4-L79-VH3-L80-CL-L81-CH1-L82-Fc.In some embodiments, the first polypeptide has the sequence of: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-Fc; VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-Fc; VH1-L6-VL2-L7-VH2-L8-VL1-L9-CH1-L10-Fc; VL1-L11-VL2-L12-VH2-L13-VH1-L14-C L-L15-Fc;VL1-L11-VH2-L12-VL2-L13-VH1-L14-CL-L15-Fc;VH1-L16-VH2-L17-VL2-L18-VL1-L19-CL-L20-Fc;VH1-L16-VL2 -L17-VH2-L18-VL1-L19-CL-L20-Fc;VL1-L21-VL2-L22-VH2-L23-VH1-L24-CH1-L25-CL-L26-Fc;VL1-L21-VH2-L22-VL2-L23- VH1-L24-CH1-L25-CL-L26-Fc;VH1-L27-VH2-L28-VL2-L29-VL1-L30-CH1-L31-CL-L32-Fc;VH1-L27-VL2-L28-VH2-L29-VL1- L30-CH1-L31-CL-L32-Fc;VL1-L33-VL2-L34-VH2-L35-VH1-L36-CL-L37-CH1-L38-Fc;VL1-L33-VH2-L34-VL2-L35-VH1-L36- and the second polypeptide has the structure represented by VL3-L77-VH4-L78-VL4-L79-VH3-L80-CL-L81-CH1-L82-Fc.In some embodiments, the first polypeptide has the sequence of: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-Fc; VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-Fc; VH1-L6-VL2-L7-VH2-L8-VL1-L9-CH1-L10-Fc; VL1-L11-VL2-L12-VH2-L13-VH1-L14-C L-L15-Fc;VL1-L11-VH2-L12-VL2-L13-VH1-L14-CL-L15-Fc;VH1-L16-VH2-L17-VL2-L18-VL1-L19-CL-L20-Fc;VH1-L16-VL2 -L17-VH2-L18-VL1-L19-CL-L20-Fc;VL1-L21-VL2-L22-VH2-L23-VH1-L24-CH1-L25-CL-L26-Fc;VL1-L21-VH2-L22-VL2-L23- VH1-L24-CH1-L25-CL-L26-Fc;VH1-L27-VH2-L28-VL2-L29-VL1-L30-CH1-L31-CL-L32-Fc;VH1-L27-VL2-L28-VH2-L29-VL1- L30-CH1-L31-CL-L32-Fc;VL1-L33-VL2-L34-VH2-L35-VH1-L36-CL-L37-CH1-L38-Fc;VL1-L33-VH2-L34-VL2-L35-VH1-L36- and the second polypeptide has the structure represented by VH3-L83-VH4-L84-VL4-L85-VL3-L86-CL-L87-CH1-L88-Fc.In some embodiments, the first polypeptide has the sequence of: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-Fc; VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-Fc; VH1-L6-VL2-L7-VH2-L8-VL1-L9-CH1-L10-Fc; VL1-L11-VL2-L12-VH2-L13-VH1-L14-C L-L15-Fc;VL1-L11-VH2-L12-VL2-L13-VH1-L14-CL-L15-Fc;VH1-L16-VH2-L17-VL2-L18-VL1-L19-CL-L20-Fc;VH1-L16-VL2 -L17-VH2-L18-VL1-L19-CL-L20-Fc;VL1-L21-VL2-L22-VH2-L23-VH1-L24-CH1-L25-CL-L26-Fc;VL1-L21-VH2-L22-VL2-L23- VH1-L24-CH1-L25-CL-L26-Fc;VH1-L27-VH2-L28-VL2-L29-VL1-L30-CH1-L31-CL-L32-Fc;VH1-L27-VL2-L28-VH2-L29-VL1- L30-CH1-L31-CL-L32-Fc;VL1-L33-VL2-L34-VH2-L35-VH1-L36-CL-L37-CH1-L38-Fc;VL1-L33-VH2-L34-VL2-L35-VH1-L36- In some embodiments, the first polypeptide has the structure VH3-L83-VL4-L84-VH4-L85-VL3-L86-CL-L87-CH1-L88-Fc. In some embodiments, the first polypeptide has the structure VL1-L1-VL2-L2-VH2. -L3-VH1-L4-CH1-L5-Fc;VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-Fc;VL1-L11-VL2-L12-VH2-L13-VH1-L14-CL -L15-Fc;VH1-L16-VH2-L17-VL2-L18-VL1-L19-CL-L20-Fc;VL1-L21-VL2-L22-VH2-L23-VH1-L24-CH1-L25-CL-L2 VH1-L27-VH2-L28-VL2-L29-VL1-L30-CH1-L31-CL-L32-Fc; VL1-L33-VL2-L34-VH2-L35-VH1-L36-CL-L37-CH1-L38-Fc; or VH1-L39-VH2-L40-VL2-L41-VL1-L42-CL-L43-CH1-L44-Fc; wherein the second polypeptide is VL3-L45- VL4-L46-VH4-L47-VH3-L48-CH1-L49-Fc;VH3-L50-VH4-L51-VL4-L52-VL3-L53-CH1-L54-Fc;VL3-L55-VL4-L56- VH4-L57-VH3-L58-CL-L59-Fc;VH3-L60-VH4-L61-VL4-L62-VL3-L63-CL-L64-Fc;VL3-L65-VL4-L66-VH4-L67-VH3 -L68-CH1-L69-CL-L70-Fc; VH3-L71-VH4-L72-VL4-L73-VL3-L74-CH1-L75-CL-L76-Fc; VL3-L77-VL4-L78-VH4-L79-VH3-L80-CL-L81-CH1-L82-Fc; or VH3-L83-VH4-L84-VL4-L85-VL3-L86-CL-L87-CH1-L88-Fc.

[0096] Any one of the first polypeptides described herein can be combined with any one of the second, third and / or fourth polypeptides described herein to form an antigen-binding polypeptide complex of the invention.

[0097] All of the disclosures relating to antigen-binding polypeptide complex structures described herein apply to and can be combined with all of the target antigens described herein and all of the VH and VL regions described herein, including all of the VH and VL sequences and CDR sequences described herein.

[0098] In some embodiments, the antigen-binding polypeptide complex (e.g., an antibody or antigen-binding fragment thereof) specifically binds to a tumor-associated antigen (TAA). In some embodiments, the antigen-binding polypeptide complex specifically binds at least one epitope on the TAA. In some embodiments, the light chain variable region (VL) and the corresponding heavy chain variable region (VH) of the antigen-binding polypeptide complex specifically bind to the TAA. In some embodiments, the TAA is selected from the group consisting of A2AR, APRIL, ATPDase, BAFF, BAFFR, BCMA, BlyS, BTK, BTLA, B7DC, B7H1, B7H2, B7H3, B7H4, B7H5, B7H6, B7H7, B7RP1, B7-4, C3, C5, CCL2, CCL3, CCL4, CCL5, CCL7, CCL8, CCL11, CCL15, CCL17, CCL19, CCL20, CCL21, CCL25, CCR3, CCR4 , CD16A, CD19, CD20, CD24, CD27, CD28, CD30, CD38, CD39, CD40, CD40L, CD47, CD52, CD70, CD80, CD86, CD123, CD133, CD137, CD137L, CD160, CD272, CEACAM5, CLEC9, CLEC91, CRTH2, CSF-1, CSF-2, CSF-3, CXCL1, CXCL2, CXCL4, CXCL12, CXCL13, CXCR3, cMet, CTLA4, DLL3, DLL4, DNGR-1, E-cadherin, EGFR, ENTPD1, ​​EpCAM, FCER1, FCER1A, FCER2, FGFR, FLAP, FOLH1, Gi24, GITR, GI TRL, GPR5, GP100, GPRC5D, HER2, HER3, ICOSL, ICOS, HHLA2, HMGB1, HVEM, IDO, IFNa, IgE, IGF1R, IL2Rbeta, IL1, ILIA, IL1B, I L1F10, IL2, IL4, IL4Ra, IL5, IL5R, IL6, IL7, IL7Ra, IL8, IL9, IL9R, IL10, rhILlO, IL12, IL13, IL13Ral, IL13Ra2, IL15, IL 17, IL17Rb, IL18, IL22, IL23, IL25, IL7, IL33, IL35, ITGB4, ITK, KIR, LAG3, LAMP1, leptin, LPFS2, MHC class II, MUC-1, MUC-16,NCR3LG1, NKG2D, NKp46, NTPDase-1, OX40, OX40L, PD-1, PD-L1, PD-L2, PROM1, S152, SIRP alpha, SISP1, SLC, SPG64, ST2, STEAP1, STEAP2, Syk kinase, STEAP1, TROP2, TACI, TDO, TGFBETA, T14, TIGIT, TIM3, TLR, TLR2, TLR4, TLR5, TLR9, TMEF1, TNFa, TNFRSF7, Tp55, TREM1, TSLP, TSLPR, TWEAK, VEGF, VISTA, Vstm3, or WUCAM, or a combination thereof. In some embodiments, the antigen-binding polypeptide complex is selected from the group consisting of A2AR, APRIL, ATPDase, BAFF, BAFFR, BCMA, BlyS, BTK, BTLA, B7DC, B7H1, B7H2, B7H3, B7H4, B7H5, B7H6, B7H7, B7RP1, B7-4, C3, C5, CCL2, CCL3, CCL4, CCL5, CCL7, CCL8, CCL11, CCL15, CCL17, CCL8, CCL9, CCL10, CCL11, CCL12, CCL13, CCL14, CCL15, CCL16, CCL17, CCL18, CCL19, CCL20, CCL21, CCL22, CCL23, CCL24, CCL25, CCL26, CCL27, CCL28, CCL29, CCL30, CCL31, CCL32, CCL33, CCL34, CCL35, CCL36, CCL37, CCL38, CCL39, CCL40, CCL41, CCL42, CCL43, CCL44, CCL45, CCL46, CCL47, CCL48, CCL49, CCL50, CCL51, CCL52, CCL53, CCL54, CCL55, CCL56, CCL57, CCL58, CCL59, CCL60, CCL61, CCL62, CCL63, CCL64, CCL65, CCL66, CCL67, CCL68, CCL69 ... CL19, CCL20, CCL21, CCL25, CCR3, CCR4, CD16A, CD19, CD20, CD24, CD27, CD28, CD30, CD38, CD39, CD40, CD40L, CD47, CD52, CD70, CD80, CD86, CD123, CD133, CD137, CD137L, CD160, CD272, CEACAM5, CLEC9, CLEC91, CRTH2, CS F-1, CSF-2, CSF-3, CXCL1, CXCL2, CXCL4, CXCL12, CXCL13, CXCR3, cMet, CTLA4, DLL3, DLL4, DNGR-1, E-cadherin, EGFR, ENTPD1, ​​EpCAM, FCER1, FCER1A, FCER2, FGFR, FLAP, FOLH1, Gi24, GITR, GITRL, GPR5, GP100, GPRC5D, HER 2, HER3, ICOSL, ICOS, HHLA2, HMGB1, HVEM, IDO, IFNa, IgE, IGF1R, IL2Rbeta, IL1, ILIA, IL1B, IL1F10, IL2, IL4 , IL4Ra, IL5, IL5R, IL6, IL7, IL7Ra, IL8, IL9, IL9R, IL10, rhILlO, IL12, IL13, IL13Ral, IL13Ra2, IL15, IL17,IL17Rb, IL18, IL22, IL23, IL25, IL7, IL33, IL35, ITGB4, ITK, KIR, LAG3, LAMP1, leptin, LPFS2, MHC class II, MUC-1, MUC-1 6, NCR3LG1, NKG2D, NKp46, NTPDase-1, OX40, OX40L, PD-1, PD-L1, PD-L2, PROM1, S152, SIRP alpha, SISP1, SLC, SPG64, S The VL1 may specifically bind to T2, STEAP1, STEAP2, Syk kinase, STEAP1, TROP2, TACI, TDO, TGFBETA, T14, TIGIT, TIM3, TLR, TLR2, TLR4, TLR5, TLR9, TMEF1, TNFα, TNFRSF7, Tp55, TREM1, TSLP, TSLPR, TWEAK, VEGF, VISTA, Vstm3, or WUCAM, or a combination thereof. For example, the VL1 may specifically bind to CD3. For example, the VL1 may specifically bind to Trop2. For example, the VL1 may specifically bind to cMet. For example, the VL1 may specifically bind to CD19. For example, the VL1 may specifically bind to CD20. In some embodiments, the antigen-binding polypeptide complex is selected from the group consisting of A2AR, APRIL, ATPDase, BAFF, BAFFR, BCMA, BlyS, BTK, BTLA, B7DC, B7H1, B7H2, B7H3, B7H4, B7H5, B7H6, B7H7, B7RP1, B7-4, C3, C5, CCL2, CCL3, CCL4, CCL5, CCL7, CCL8, CCL11, CCL15, CCL17, CCL19, CCL20, CCL21, CCL25, CCR3, CCR4, CD16A, CD19, CD20, CD24, CD27, CD28, CD30, CD38, CD39, CD40, CD40L, CD47, CD52, CD70, CD80, CD86, CD123, CD133, CD137, CD137L, CD160, CD272, CEACAM5, CLEC9, CLEC91, CRTH2, CSF-1, C SF-2, CSF-3, CXCL1, CXCL2, CXCL4, CXCL12, CXCL13, CXCR3, cMet, CTLA4, DLL3, DLL4, DNGR-1, E-cadherin, EGFR, ENTPD1, ​​EpCAM, FCER1, FCER1A, FCER2,FGFR, FLAP, FOLH1, Gi24, GITR, GITRL, GPR5, GP100, GPRC5D, HER2, HER3, ICOSL, ICOS, HHLA2, HMGB1, HVEM, IDO, IFNa, IgE, IGF1R, IL2R beta, IL1, ILIA, IL1B, IL1F10, IL2, IL4, IL4Ra, IL5, I L5R, IL6, IL7, IL7Ra, IL8, IL9, IL9R, IL10, rhILlO, IL12, IL13, IL13Ral, IL13Ra2, IL15, IL17 , IL17Rb, IL18, IL22, IL23, IL25, IL7, IL33, IL35, ITGB4, ITK, KIR, LAG3, LAMP1, leptin, LPFS2, The VL2 specifically binds to MHC class II, MUC-1, MUC-16, NCR3LG1, NKG2D, NKp46, NTPDase-1, OX40, OX40L, PD-1, PD-L1, PD-L2, PROM1, S152, SIRP alpha, SISP1, SLC, SPG64, ST2, STEAP1, STEAP2, Syk kinase, STEAP1, TROP2, TACI, TDO, TGFBETA, T14, TIGIT, TIM3, TLR, TLR2, TLR4, TLR5, TLR9, TMEF1, TNFα, TNFRSF7, Tp55, TREM1, TSLP, TSLPR, TWEAK, VEGF, VISTA, Vstm3, or WUCAM, or a combination thereof. For example, the VL2 specifically binds to CD3. For example, the VL2 specifically binds to Trop2. For example, VL2 may specifically bind to cMet. For example, VL2 may specifically bind to CD19. For example, VL2 may specifically bind to CD20. In some embodiments, the antigen-binding polypeptide complex may bind to any of A2AR, APRIL, ATPDase, BAFF, BAFFR, BCMA, BlyS, BTK, BTLA, B7DC, B7H1, B7H2, B7H3, B7H4, B7H5, B7H6, B7H7, B7RP1, B7-4, C3, C5, CCL2, CCL3, CCL4, CCL5, CCL7, CCL8, CCL11, CCL15, CCL17, CCL19, CCL20, CCL21, CCL25, CCR3, CCR4, CD16A, CD19, CD20, CD24, CD27, CD28, CD30, CD38,CD39, CD40, CD40L, CD47, CD52, CD70, CD80, CD86, CD123, CD133, CD137, CD137L, CD160, CD272, CEACAM5, CLEC9, CLEC91, CRTH2, CS F-1, CSF-2, CSF-3, CXCL1, CXCL2, CXCL4, CXCL12, CXCL13, CXCR3, cMet, CTLA4, DLL3, DLL4, DNGR-1, E-cadherin, EGFR, ENTPD1, ​​EpCAM , FCER1, FCER1A, FCER2, FGFR, FLAP, FOLH1, Gi24, GITR, GITRL, GPR5, GP100, GPRC5D, HER2, HER3, ICOSL, ICOS, HHLA2, HMGB1, HVEM , IDO, IFNa, IgE, IGF1R, IL2Rbeta, IL1, ILIA, IL1B, IL1F10, IL2, IL4, IL4Ra, IL5, IL5R, IL6, IL7, IL7Ra, IL8, IL9, IL9R, IL10, rhI LlO, IL12, IL13, IL13Ral, IL13Ra2, IL15, IL17, IL17Rb, IL18, IL22, IL23, IL25, IL7, IL33, IL35, ITGB4, ITK, KIR, LAG3, LAMP1, Putin, LPFS2, MHC class II, MUC-1, MUC-16, NCR3LG1, NKG2D, NKp46, NTPDase-1, OX40, OX40L, PD-1, PD-L1, PD-L2, PROM1, S152, SIRP Al The VL3 may specifically bind to pha, SISP1, SLC, SPG64, ST2, STEAP1, STEAP2, Syk kinase, STEAP1, TROP2, TACI, TDO, TGFBETA, T14, TIGIT, TIM3, TLR, TLR2, TLR4, TLR5, TLR9, TMEF1, TNFα, TNFRSF7, Tp55, TREM1, TSLP, TSLPR, TWEAK, VEGF, VISTA, Vstm3, or WUCAM, or a combination thereof. For example, the VL3 may specifically bind to CD3. For example, the VL3 may specifically bind to Trop2. For example, the VL3 may specifically bind to cMet. For example, the VL3 may specifically bind to CD19. For example, the VL3 may specifically bind to CD20. In some embodiments,The antigen-binding polypeptide complexes include A2AR, APRIL, ATPDase, BAFF, BAFFR, BCMA, BlyS, BTK, BTLA, B7DC, B7H1, B7H2, B7H3, B7H4, B7H5, B7H6, B7H7, B7RP1, B7-4, C3, C5, CCL2, CCL3, CCL4, CCL5, CCL, 7, CCL8, CCL11, CCL15, CCL17, CCL19, CCL20, CCL21, CCL25, CCR3, CCR4, CD16A, CD19, CD20, CD24, CD27, CD28, CD30, CD38, CD39, CD40, CD40L, CD4 7, CD52, CD70, CD80, CD86, CD123, CD133, CD137, CD137L, CD160, CD272, CEACAM5, CLEC9, CLEC91, CRTH2, CSF-1, CSF-2, CSF-3, CXCL1, CXCL2, CXCL 4, CXCL12, CXCL13, CXCR3, cMet, CTLA4, DLL3, DLL4, DNGR-1, E-cadherin, EGFR, ENTPD1, ​​EpCAM, FCER1, FCER1A, FCER2, FGFR, FLAP, FOLH1, Gi24, GIT R, GITRL, GPR5, GP100, GPRC5D, HER2, HER3, ICOSL, ICOS, HHLA2, HMGB1, HVEM, IDO, IFNa, IgE, IGF1R, IL2Rbeta, IL1, ILIA, IL1B, IL1F10, IL2, IL4, IL4Ra, IL5, IL5R, IL6, IL7, IL7Ra, IL8, IL9, IL9R, IL10, rhILlO, IL12, IL13, IL13Ral, IL13Ra2, IL15, IL17, IL17Rb, IL18, IL22, IL23, IL25, IL 7, IL33, IL35, ITGB4, ITK, KIR, LAG3, LAMP1, leptin, LPFS2, MHC class II, MUC-1, MUC-16, NCR3LG1, NKG2D, NKp46, NTPDase-1, OX40, OX40L, PD-1, PD-L The VL4 specifically binds to CD3. For example, the VL4 specifically binds to CD3. For example, the VL4 specifically binds to CD3.For example, VL4 may specifically bind to Trop2. For example, VL4 may specifically bind to cMet. For example, VL4 may specifically bind to CD19. For example, VL4 may specifically bind to CD20. In some embodiments, the antigen-binding polypeptide complex may bind to any of A2AR, APRIL, ATPDase, BAFF, BAFFR, BCMA, BlyS, BTK, BTLA, B7DC, B7H1, B7H2, B7H3, B7H4, B7H5, B7H6, B7H7, B7RP1, B7-4, C3, C5, CCL2, CCL3, CCL4, CCL5, CCL7, CCL8, CCL11, CCL15, CCL17, CCL19, CCL20, CCL21, CCL25, CCR3, CCR4, CD16A, CD19, CD2 0, CD24, CD27, CD28, CD30, CD38, CD39, CD40, CD40L, CD47, CD52, CD70, CD80, CD86, CD123, CD133, CD137, CD137L, CD160, CD272, CEACAM5, CLEC9, CLEC91, CRTH2, CSF-1, CSF-2, CSF-3, CXCL1, CXCL2, CXCL4, CXCL12, CXCL13, CXCR3, cMet, CTLA4, DLL3, DLL4, DNGR-1, E-cadherin, EGF R, ENTPD1, ​​EpCAM, FCER1, FCER1A, FCER2, FGFR, FLAP, FOLH1, Gi24, GITR, GITRL, GPR5, GP100, GPRC5D, HER2, HER3, ICOSL, ICOS, HHLA2, HM GB1, HVEM, IDO, IFNa, IgE, IGF1R, IL2R beta, IL1, ILIA, IL1B, IL1F10, IL2, IL4, IL4Ra, IL5, IL5R, IL6, IL7, IL7Ra, IL8, IL9, IL9R, IL10, rh ILlO, IL12, IL13, IL13Ral, IL13Ra2, IL15, IL17, IL17Rb, IL18, IL22, IL23, IL25, IL7, IL33, IL35, ITGB4, ITK, KIR, LAG3, LAMP1, leptin, LP FS2, MHC class II, MUC-1, MUC-16, NCR3LG1, NKG2D, NKp46, NTPDase-1, OX40, OX40L, PD-1, PD-L1, PD-L2, PROM1, S152, SIRP alpha, SISP1, SLC,The VH1 may specifically bind to SPG64, ST2, STEAP1, STEAP2, Syk kinase, STEAP1, TROP2, TACI, TDO, TGFBETA, T14, TIGIT, TIM3, TLR, TLR2, TLR4, TLR5, TLR9, TMEF1, TNFα, TNFRSF7, Tp55, TREM1, TSLP, TSLPR, TWEAK, VEGF, VISTA, Vstm3, or WUCAM, or a combination thereof. For example, the VH1 may specifically bind to CD3. For example, the VH1 may specifically bind to Trop2. For example, the VH1 may specifically bind to cMet. For example, the VH1 may specifically bind to CD19. For example, the VH1 may specifically bind to CD20. In some embodiments, the antigen-binding polypeptide complex is selected from the group consisting of A2AR, APRIL, ATPDase, BAFF, BAFFR, BCMA, BlyS, BTK, BTLA, B7DC, B7H1, B7H2, B7H3, B7H4, B7H5, B7H6, B7H7, B7RP1, B7-4, C3, C5, CCL2, CCL3, CCL4, CCL5, CCL7, CCL8, CCL11, CC L15, CCL17, CCL19, CCL20, CCL21, CCL25, CCR3, CCR4, CD16A, CD19, CD20, CD24, CD27, CD28, CD30, CD38, CD39, CD40, CD40L, CD47, CD52, CD70, CD80, CD86, CD123, CD133, CD137, CD137L, CD160, CD272, CEACAM5 , CLEC9, CLEC91, CRTH2, CSF-1, CSF-2, CSF-3, CXCL1, CXCL2, CXCL4, CXCL12, CXCL13, CXCR3, cMet, CTLA 4, DLL3, DLL4, DNGR-1, E-cadherin, EGFR, ENTPD1, ​​EpCAM, FCER1, FCER1A, FCER2, FGFR, FLAP, FOLH1, Gi24, GITR, GITRL, GPR5, GP100, GPRC5D, HER2, HER3, ICOSL, ICOS, HHLA2, HMGB1, HVEM, IDO, IFNa, IgE, IGF1R , IL2R beta, IL1, ILIA, IL1B, IL1F10, IL2, IL4, IL4Ra, IL5, IL5R, IL6, IL7, IL7Ra, IL8, IL9, IL9R, IL10,rhILlO, IL12, IL13, IL13Ral, IL13Ra2, IL15, IL17, IL17Rb, IL18, IL22, IL23, IL25, IL7, IL33, IL35, ITGB4, ITK, KIR, LAG3, LAMP1 , leptin, LPFS2, MHC class II, MUC-1, MUC-16, NCR3LG1, NKG2D, NKp46, NTPDase-1, OX40, OX40L, PD-1, PD-L1, PD-L2, PROM1, S152, SIRP The VH2 may specifically bind to INF1, SISP1, SLC, SPG64, ST2, STEAP1, STEAP2, Syk kinase, STEAP1, TROP2, TACI, TDO, TGFBETA, T14, TIGIT, TIM3, TLR, TLR2, TLR4, TLR5, TLR9, TMEF1, TNFα, TNFRSF7, Tp55, TREM1, TSLP, TSLPR, TWEAK, VEGF, VISTA, Vstm3, or WUCAM, or a combination thereof. For example, the VH2 may specifically bind to CD3. For example, the VH2 may specifically bind to Trop2. For example, the VH2 may specifically bind to cMet. For example, the VH2 may specifically bind to CD19. For example, the VH2 may specifically bind to CD20. In some embodiments, the antigen-binding polypeptide complex is selected from the group consisting of A2AR, APRIL, ATPDase, BAFF, BAFFR, BCMA, BlyS, BTK, BTLA, B7DC, B7H1, B7H2, B7H3, B7H4, B7H5, B7H6, B7H7, B7RP1, B7-4, C3, C5, CCL2, CCL3, CCL4, CCL5, CCL7, CCL8, CCL11, CCL15, CCL17, CCL19, CCL20, CCL21, CCL25, CCR3, CCR4, CD16A, CD 19, CD20, CD24, CD27, CD28, CD30, CD38, CD39, CD40, CD40L, CD47, CD52, CD70, CD80, CD86, CD123, CD133, CD137, CD137L, CD160, CD272, CEACAM5, CLEC9, CLEC91, CRTH2, CSF-1, CSF-2, CSF-3, CXCL1, CXCL2, CXCL4, CXCL12, CXCL13, CXCR3, cMet, CTLA4, DLL3, DLL4, DNGR-1,E-cadherin, EGFR, ENTPD1, ​​EpCAM, FCER1, FCER1A, FCER2, FGFR, FLAP, FOLH1, Gi24, GITR, GITRL, GPR5, GP100, GPRC5D, HER2, HER3, ICOSL, ICOS, HHLA2, HMGB1, HVEM, IDO, IFNa, IgE, IGF1R, IL2R beta, IL1, ILI A, IL1B, IL1F10, IL2, IL4, IL4Ra, IL5, IL5R, IL6, IL7, IL7Ra, IL8, IL9, IL9R, IL10, rhILlO, IL12, IL 13, IL13Ral, IL13Ra2, IL15, IL17, IL17Rb, IL18, IL22, IL23, IL25, IL7, IL33, IL35, ITGB4, ITK, KIR, The VH3 specifically binds to LAG3, LAMP1, leptin, LPFS2, MHC class II, MUC-1, MUC-16, NCR3LG1, NKG2D, NKp46, NTPDase-1, OX40, OX40L, PD-1, PD-L1, PD-L2, PROM1, S152, SIRP alpha, SISP1, SLC, SPG64, ST2, STEAP1, STEAP2, Syk kinase, STEAP1, TROP2, TACI, TDO, TGFBETA, T14, TIGIT, TIM3, TLR, TLR2, TLR4, TLR5, TLR9, TMEF1, TNFα, TNFRSF7, Tp55, TREM1, TSLP, TSLPR, TWEAK, VEGF, VISTA, Vstm3, or WUCAM, or a combination thereof. For example, the VH3 can specifically bind to CD3. For example, a VH3 may specifically bind to Trop2. For example, a VH3 may specifically bind to cMet. For example, a VH3 may specifically bind to CD19. For example, a VH3 may specifically bind to CD20. In some embodiments, the antigen-binding polypeptide complex comprises an antigen-binding polypeptide selected from the group consisting of A2AR, APRIL, ATPDase, BAFF, BAFFR, BCMA, BlyS, BTK, BTLA, B7DC, B7H1, B7H2, B7H3, B7H4, B7H5, B7H6, B7H7, B7RP1, B7-4, C3, C5, CCL2, CCL3, CCL4, CCL5, CCL7, CCL8, CCL11, CCL15, CCL17, CCL19, CCL20, CCL21, CCL25, CCR3, CCR4,CD16A、CD19、CD20、CD24、CD27、CD28、CD30、CD38、CD39、CD40、CD40L、CD47、CD52、CD70、CD80、CD86、CD123、CD133、CD137、CD137L、CD160、CD272、CEACAM5、CLEC9、CLEC9、 1, CRTH2, CSF-1, CSF-2, CSF-3, CXCL1, CXCL2, CXCL4, CXCL12, CXCL13, CXCR3, cMet, CTLA4, DLL3, DLL4, DNGR-1, E-ka Doherin, EGFR, ENTPD1, ​​EpCAM, FCER1, FCER1A, FCER2, FGFR, FLAP, FOLH1, Gi24, GITR, GITRL, GPR5, GP100, GPRC5D, HER 2, HER3, ICOSL, ICOS, HHLA2, HMGB1, HVEM, IDO, IFNa, IgE, IGF1R, IL2R beta, IL1, ILIA, IL1B, IL1F10, IL2, IL4, IL4R a, IL5, IL5R, IL6, IL7, IL7Ra, IL8, IL9, IL9R, IL10, rhILlO, IL12, IL13, IL13Ral, IL13Ra2, IL15, IL17, IL17Rb, IL 18, IL22, IL23, IL25, IL7, IL33, IL35, ITGB4, ITK, KIR, LAG3, LAMP1, leptin, LPFS2, MHC class II, MUC-1, MUC-16, NCR3LG1, NKG2D, NKp46, NTPDase-1, OX40, OX40L, PD-1, PD-L1, PD-L2, PROM1, S152, SIRP alpha, SISP1, SLC, SPG64, ST2, ST The VH4 may specifically bind to EAP1, STEAP2, Syk kinase, STEAP1, TROP2, TACI, TDO, TGFBETA, T14, TIGIT, TIM3, TLR, TLR2, TLR4, TLR5, TLR9, TMEF1, TNFα, TNFRSF7, Tp55, TREM1, TSLP, TSLPR, TWEAK, VEGF, VISTA, Vstm3, or WUCAM, or a combination thereof. For example, the VH4 may specifically bind to CD3. For example, the VH4 may specifically bind to Trop2. For example, the VH4 may specifically bind to cMet. For example, the VH4 may specifically bind to CD19. For example, the VH4 may specifically bind to CD20. In some embodiments, the antigen-binding polypeptide comprises a VH1 and a VL1 that specifically bind to cMet, a VH2 and a VL2 that specifically bind to Trop2, a VH3 and a VL3 that specifically bind to CD28, and a VH4 and a VL4 that specifically bind to CD3.In some embodiments, the antigen-binding polypeptide comprises a VH1 and VL1 that specifically binds Trop2, a VH2 and VL2 that specifically binds cMet, a VH3 and VL3 that specifically binds CD28, and a VH4 and VL4 that specifically binds CD3. In some embodiments, the antigen-binding polypeptide comprises a VH1 and VL1 that specifically binds cMet, a VH2 and VL2 that specifically binds CD28, a VH3 and VL3 that specifically binds Trop2, and a VH4 and VL4 that specifically binds CD3. In some embodiments, the antigen-binding polypeptide comprises a VH1 and VL1 that specifically binds Trop2, a VH2 and VL2 that specifically binds CD28, a VH3 and VL3 that specifically binds cMet, and a VH4 and VL4 that specifically binds CD3. In some embodiments, the antigen-binding polypeptide comprises a VH1 and VL1 that specifically binds CD28, a VH2 and VL2 that specifically binds cMet, a VH3 and VL3 that specifically binds Trop2, and a VH4 and VL4 that specifically binds CD3. In some embodiments, the antigen-binding polypeptide comprises a VH1 and VL1 that specifically binds CD28, a VH2 and VL2 that specifically binds Trop2, a VH3 and VL3 that specifically binds cMet, and a VH4 and VL4 that specifically binds CD3. In some embodiments, the antigen-binding polypeptide comprises a VH1 and VL1 that specifically binds CD19, a VH2 and VL2 that specifically binds CD20, a VH3 and VL3 that specifically binds CD28, and a VH4 and VL4 that specifically binds CD3. In some embodiments, the antigen-binding polypeptide comprises a VH1 and VL1 that specifically bind to CD20, a VH2 and VL2 that specifically bind to CD19, a VH3 and VL3 that specifically bind to CD28, and a VH4 and VL4 that specifically bind to CD3. In some embodiments, the antigen-binding polypeptide comprises a VH1 and VL1 that specifically bind to CD19, a VH2 and VL2 that specifically bind to CD28, a VH3 and VL3 that specifically bind to CD20, and a VH4 and VL4 that specifically bind to CD3.In some embodiments, the antigen-binding polypeptide comprises a VH1 and VL1 that specifically binds CD20, a VH2 and VL2 that specifically binds CD28, a VH3 and VL3 that specifically binds CD19, and a VH4 and VL4 that specifically binds CD3. In some embodiments, the antigen-binding polypeptide comprises a VH1 and VL1 that specifically binds CD28, a VH2 and VL2 that specifically binds CD19, a VH3 and VL3 that specifically binds CD20, and a VH4 and VL4 that specifically binds CD3. In some embodiments, the antigen-binding polypeptide comprises a VH1 and VL1 that specifically binds CD28, a VH2 and VL2 that specifically binds CD20, a VH3 and VL3 that specifically binds CD19, and a VH4 and VL4 that specifically binds CD3. For the avoidance of doubt, all of the antigen-binding polypeptide complex structures described herein may be combined with any one or more of the targets described herein. Any disclosure herein relating to targets for the antigen-binding polypeptide complexes of the invention is generally applicable and applies equally and unconditionally to any antigen-binding polypeptide complex described herein. VL1, VL2, VL3, VL4, VH1, VH2, VH3, and / or VH4 of any antigen-binding polypeptide complex described herein may independently bind to any one of the particularly preferred targets.

[0099] In some embodiments, the antigen-binding polypeptide complex of the invention comprises a VL that specifically binds to a TAA, wherein the VL is selected from the group consisting of: 67, 75, 83, 91, 107, 115, 123, 131, 385, 405, 415, 441, 452, 462, 472, 655, 691, 727, 393, 486, 504, 536, 548, 753, 789, 825, 871, 879, 490, 496, 745, 781, 817, 645, 681, 771, 843, 6 CDR1 comprising an amino acid sequence having at least 90% identity, at least 95% identity, or 100% identity to any one of SEQ ID NOs: 21, 637, 673, 709, and 871; SEQ ID NOs: 68, 76, 84, 92, 108, 116, 124, 132, 386(YTS); 406(YTS), 416(YTS), 442(YTS), 453(YTS), 463(YTS), 473(YTS), 656, 692, 728, 394, 487(AT), 5 05(AT), 537, 549, 754, 790, 826, 872, 880, 491(DA), 497(DA), 746, 782, 818, 646, 682, 772, 844, 622, 638, 674, 710, and 872; and a CDR2 comprising an amino acid sequence having at least 90% identity, at least 95% identity, or 100% identity to any one of SEQ ID NOs: 69, 77, 85, 93, 109, 117, 125, 133, 387, a VL having a CDR3 comprising an amino acid sequence having at least 90% identity, at least 95% identity, or 100% identity to any one of 407, 417, 443, 454, 464, 474, 657, 693, 729, 395, 488, 506, 538, 550, 755, 791, 827, 873, 881, 492, 498, 747, 783, 819, 647, 683, 773, 845, 623, 639, 675, 711, and 873; and a VH that specifically binds to a TAA, wherein the VH is selected from the group consisting of SEQ ID NOs: 64, 72, 80, 88, 104, 112, 120, 128, 389, 409, 419, 429, 659, 695, 731, 397, 508, 540, 552, 757, 793, 829, 875, 500, 749, 785, 821, 649, 685, 775, 847, 625, 641, 677, 713, and and 867; CDR1 comprising an amino acid sequence having at least 90% identity, at least 95% identity, or 100% identity to any one of SEQ ID NOs: 65, 73, 81, 89, 105, 113, 121, 129, 390, 410, 420, 430, 660, 696, 732, 398, 509, 541, 553, 758, 794, 830, 876, 501, 75 CDR2 comprising an amino acid sequence having at least 90% identity, at least 95% identity, or 100% identity to any one of SEQ ID NOs: 66, 74, 82, 90, 106, 114, 122, 130, 391, 411, 421, 431, 661, 697, 733, 399, 510, 542, 554, 759, 795, 831, 877, 502, 751, 787, 823, 651, 687, 777, 849, 627, 643, 679, 715 and 869.

[0100] In some aspects, a VL that specifically binds to CD38 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 67; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 68; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 69; and a VH that specifically binds to CD38 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 64; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 65; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 66. In some embodiments, a VL that specifically binds to cMet comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 75; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 76; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 77; and a VH that specifically binds to cMet comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 72; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 73; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 74. In some embodiments, a VL that specifically binds to Trop2 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 83; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 84; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 85; and a VH that specifically binds to Trop2 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 80; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 81; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 82.In some embodiments, a VL that specifically binds to Trop2 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 91; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 92; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 93; and a VH that specifically binds to Trop2 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 88; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 89; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 90. In some aspects, a VL that specifically binds to CD3 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 99; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 100; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 101; and a VH that specifically binds to CD3 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 96; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 97; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 98. In some aspects, a VL that specifically binds to CD20 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 107, a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 108, and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 109; and a VH that specifically binds to CD20 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 104, a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 105, and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 106.In some aspects, a VL that specifically binds to CD20 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 115; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 116; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 117; and a VH that specifically binds to CD20 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 112; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 113; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 114. In some aspects, a VL that specifically binds to CD19 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 123; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 124; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 125; and a VH that specifically binds to CD19 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 120; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 121; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 122. In some aspects, a VL that specifically binds to CD19 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 131; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 132; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 133; and a VH that specifically binds to CD19 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 128; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 129; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 130.In some embodiments, a VL that specifically binds to Trop2 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 385; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 386 (YTS); and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 387; and a VH that specifically binds to Trop2 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 389; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 390; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 391. In some embodiments, a VL that specifically binds to Trop2 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 405; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 406 (YTS); and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 407; and a VH that specifically binds to Trop2 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 409; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 410; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 411. In some embodiments, a VL that specifically binds to Trop2 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 415; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 416 (YTS); and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 417; and a VH that specifically binds to Trop2 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 419; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 420; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 421.In some embodiments, a VL that specifically binds to Trop2 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 441; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 442 (YTS); and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 443; and a VH that specifically binds to Trop2 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 429; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 430; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 431. In some embodiments, a VL that specifically binds to Trop2 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 452; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 453 (YTS); and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 454; and a VH that specifically binds to Trop2 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 429; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 430; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 431. In some embodiments, a VL that specifically binds to Trop2 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 462; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 463 (YTS); and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 464; and a VH that specifically binds to Trop2 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 429; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 430; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 431.In some embodiments, a VL that specifically binds to Trop2 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 472; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 473 (YTS); and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 474; and a VH that specifically binds to Trop2 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 429; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 430; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 431. In some embodiments, a VL that specifically binds to Trop2 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 655; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 656; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 657; and a VH that specifically binds to Trop2 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 659; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 660; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 661. In some embodiments, a VL that specifically binds to Trop2 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 691, a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 692, and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 693; and a VH that specifically binds to Trop2 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 695, a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 696, and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 697. A VL that specifically binds to Trop2 comprises a CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 727; a CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 728; and a CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 729; a VH that specifically binds to Trop2 comprises a CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 731; a CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 732; and a CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 733. In some embodiments, a VL that specifically binds to HER2 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 393; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 394; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 395; and a VH that specifically binds to HER2 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 397; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 398; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 399. In some aspects, a VL that specifically binds to CD20 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 486; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 487 (AT); and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 488; and a VH that specifically binds to CD20 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 508; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 509; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 510.In some aspects, a VL that specifically binds to CD20 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 504; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 505 (AT); and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 506; and a VH that specifically binds to CD20 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 508; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 509; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 510. In some aspects, a VL that specifically binds to CD20 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 536; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 537; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 538; and a VH that specifically binds to CD20 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 540; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 541; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 542. In some aspects, a VL that specifically binds to CD20 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 548; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 549; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 550; and a VH that specifically binds to CD20 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 552; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 553; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 554.In some aspects, a VL that specifically binds to CD20 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 753; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 754; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 755; and a VH that specifically binds to CD20 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 757; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 758; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 759. In some aspects, a VL that specifically binds to CD20 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 789; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 790; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 791; and a VH that specifically binds to CD20 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 793; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 794; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 795. In some aspects, a VL that specifically binds to CD20 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 825; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 826; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 827; and a VH that specifically binds to CD20 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 829; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 830; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 831.In some aspects, a VL that specifically binds to CD20 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 871; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 872; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 873; and a VH that specifically binds to CD20 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 871; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 872; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 873. In some aspects, a VL that specifically binds to CD20 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 879; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 880; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 881; and a VH that specifically binds to CD20 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 875; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 876; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 877. In some aspects, a VL that specifically binds to CD19 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 490; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 491 (AT); and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 492; and a VH that specifically binds to CD19 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 500; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 501; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 502.In some aspects, a VL that specifically binds to CD19 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 496; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 497(AT); and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 498; and a VH that specifically binds to CD19 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 500; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 501; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 502. In some aspects, a VL that specifically binds to CD19 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 745; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 746; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 747; and a VH that specifically binds to CD19 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 749; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 750; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 751. In some aspects, a VL that specifically binds to CD19 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 781; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 782; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 783; and a VH that specifically binds to CD19 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 785; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 786; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 787.In some aspects, a VL that specifically binds to CD19 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 817; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 818; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 819; and a VH that specifically binds to CD19 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 821; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 822; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 823. In some aspects, a VL that specifically binds to CD28 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 645; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 646; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 647; and a VH that specifically binds to CD28 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 649; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 650; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 651. In some embodiments, a VL that specifically binds to CD28 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 681, a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 682, and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 683; a VH that specifically binds to CD28 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 685, a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 686, and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 687. In some embodiments, a VL that specifically binds to CD28 comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 771. a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 772; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 772; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 773; a VH that specifically binds to CD28 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 775; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 776; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 777. In some aspects, a VL that specifically binds to CD28 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 843; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 844; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 845; and a VH that specifically binds to CD28 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 847; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 848; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 849. In some aspects, a VL that specifically binds to BCMA comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 621; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 622; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 623; and a VH that specifically binds to BCMA comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 625; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 626; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 627.In some embodiments, a VL that specifically binds to cMet comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 637; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 638; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 639; and a VH that specifically binds to cMet comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 641; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 642; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 643. In some embodiments, a VL that specifically binds to cMet comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 673; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 674; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 675; and a VH that specifically binds to cMet comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 677; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 678; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 679. In some embodiments, a VL that specifically binds to cMet comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 709; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 710; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 711; and a VH that specifically binds to cMet comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 713; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 714; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 715.In some embodiments, a VL that specifically binds to CD20 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 871, a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 872, and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 873; and a VH that specifically binds to CD20 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 867, a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 868, and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 869. As used herein, "at least 90% identity" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identity to the reference sequence set forth. In some embodiments, a VL that specifically binds to CD38 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 67, a CDR2 comprising the amino acid sequence of SEQ ID NO: 68, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 69; a VH that specifically binds to CD38 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 64, a CDR2 comprising the amino acid sequence of SEQ ID NO: 65, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 66. In some embodiments, a VL that specifically binds to cMet comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 75, a CDR2 comprising the amino acid sequence of SEQ ID NO: 76, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 77; and a VH that specifically binds to cMet comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 72, a CDR2 comprising the amino acid sequence of SEQ ID NO: 73, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 74. In some embodiments, a VL that specifically binds to Trop2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 83; a CDR2 comprising the amino acid sequence of SEQ ID NO: 84; and a CDR3 comprising the amino acid sequence of SEQ ID NO: 85; and a VH that specifically binds to Trop2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 80; a CDR2 comprising the amino acid sequence of SEQ ID NO: 81; and a CDR3 comprising the amino acid sequence of SEQ ID NO: 82.In some embodiments, a VL that specifically binds to Trop2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:91, a CDR2 comprising the amino acid sequence of SEQ ID NO:92, and a CDR3 comprising the amino acid sequence of SEQ ID NO:93; a VH that specifically binds to Trop2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:88, a CDR2 comprising the amino acid sequence of SEQ ID NO:89, and a CDR3 comprising the amino acid sequence of SEQ ID NO:90. In some embodiments, a VL that specifically binds to CD3 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:99, a CDR2 comprising the amino acid sequence of SEQ ID NO:100, and a CDR3 comprising the amino acid sequence of SEQ ID NO:101; and a VH that specifically binds to CD3 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:96, a CDR2 comprising the amino acid sequence of SEQ ID NO:97, and a CDR3 comprising the amino acid sequence of SEQ ID NO:98. In some embodiments, a VL that specifically binds to CD20 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 107, a CDR2 comprising the amino acid sequence of SEQ ID NO: 108, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 109; a VH that specifically binds to CD20 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 104, a CDR2 comprising the amino acid sequence of SEQ ID NO: 105, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 106. In some embodiments, a VL that specifically binds to CD20 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 115, a CDR2 comprising the amino acid sequence of SEQ ID NO: 116, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 117; and a VH that specifically binds to CD20 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 112, a CDR2 comprising the amino acid sequence of SEQ ID NO: 113, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 114. In some aspects, a VL that specifically binds to CD19 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 123; a CDR2 comprising the amino acid sequence of SEQ ID NO: 124; and a CDR3 comprising the amino acid sequence of SEQ ID NO: 125; and a VH that specifically binds to CD19 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 120; a CDR2 comprising the amino acid sequence of SEQ ID NO: 121; and a CDR3 comprising the amino acid sequence of SEQ ID NO: 122.In some embodiments, a VL that specifically binds to CD19 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 131, a CDR2 comprising the amino acid sequence of SEQ ID NO: 132, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 133; a VH that specifically binds to CD19 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 128, a CDR2 comprising the amino acid sequence of SEQ ID NO: 129, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 130. In some embodiments, a VL that specifically binds to Trop2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 385, a CDR2 comprising the amino acid sequence of SEQ ID NO: 386 (YTS), and a CDR3 comprising the amino acid sequence of SEQ ID NO: 387; and a VH that specifically binds to Trop2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 389, a CDR2 comprising the amino acid sequence of SEQ ID NO: 390, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 391. In some embodiments, a VL that specifically binds to Trop2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 405, a CDR2 comprising the amino acid sequence of SEQ ID NO: 406 (YTS), and a CDR3 comprising the amino acid sequence of SEQ ID NO: 407; a VH that specifically binds to Trop2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 409, a CDR2 comprising the amino acid sequence of SEQ ID NO: 410, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 411. In some embodiments, a VL that specifically binds to Trop2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 415, a CDR2 comprising the amino acid sequence of SEQ ID NO: 416 (YTS), and a CDR3 comprising the amino acid sequence of SEQ ID NO: 417; and a VH that specifically binds to Trop2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 419, a CDR2 comprising the amino acid sequence of SEQ ID NO: 420, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 421. In some embodiments, a VL that specifically binds to Trop2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 441; a CDR2 comprising the amino acid sequence of SEQ ID NO: 442 (YTS); and a CDR3 comprising the amino acid sequence of SEQ ID NO: 443; and a VH that specifically binds to Trop2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 429; a CDR2 comprising the amino acid sequence of SEQ ID NO: 430; and a CDR3 comprising the amino acid sequence of SEQ ID NO: 431.In some embodiments, a VL that specifically binds to Trop2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 452, a CDR2 comprising the amino acid sequence of SEQ ID NO: 453 (YTS), and a CDR3 comprising the amino acid sequence of SEQ ID NO: 454; a VH that specifically binds to Trop2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 429, a CDR2 comprising the amino acid sequence of SEQ ID NO: 430, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 431. In some embodiments, a VL that specifically binds to Trop2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 462, a CDR2 comprising the amino acid sequence of SEQ ID NO: 463 (YTS), and a CDR3 comprising the amino acid sequence of SEQ ID NO: 464; a VH that specifically binds to Trop2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 429, a CDR2 comprising the amino acid sequence of SEQ ID NO: 430, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 431. In some embodiments, a VL that specifically binds to Trop2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 472, a CDR2 comprising the amino acid sequence of SEQ ID NO: 473 (YTS), and a CDR3 comprising the amino acid sequence of SEQ ID NO: 474; a VH that specifically binds to Trop2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 429, a CDR2 comprising the amino acid sequence of SEQ ID NO: 430, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 431. In some embodiments, a VL that specifically binds to Trop2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 655, a CDR2 comprising the amino acid sequence of SEQ ID NO: 656, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 657; A VH that specifically binds comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 659, a CDR2 comprising the amino acid sequence of SEQ ID NO: 660, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 661. In some embodiments, a VL that specifically binds to Trop2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 691, a CDR2 comprising the amino acid sequence of SEQ ID NO: 692, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 693; a VH that specifically binds to Trop2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 695, a CDR2 comprising the amino acid sequence of SEQ ID NO: 696, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 697. In some embodiments, a VL that specifically binds to Trop2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 727, a CDR2 comprising the amino acid sequence of SEQ ID NO: 728, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 729; a VH that specifically binds to Trop2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 731, a CDR2 comprising the amino acid sequence of SEQ ID NO: 732, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 733. In some embodiments, a VL that specifically binds to HER2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 393, a CDR2 comprising the amino acid sequence of SEQ ID NO: 394, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 395; a VH that specifically binds to HER2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 397, a CDR2 comprising the amino acid sequence of SEQ ID NO: 398, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 399. In some embodiments, a VL that specifically binds to CD20 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 486, a CDR2 comprising the amino acid sequence of SEQ ID NO: 487(AT), and a CDR3 comprising the amino acid sequence of SEQ ID NO: 488; a VH that specifically binds to CD20 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 508, a CDR2 comprising the amino acid sequence of SEQ ID NO: 509, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 510.In some embodiments, a VL that specifically binds to CD20 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 504, a CDR2 comprising the amino acid sequence of SEQ ID NO: 505(AT), and a CDR3 comprising the amino acid sequence of SEQ ID NO: 506; a VH that specifically binds to CD20 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 508, a CDR2 comprising the amino acid sequence of SEQ ID NO: 509, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 510. In some embodiments, a VL that specifically binds to CD20 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 536, a CDR2 comprising the amino acid sequence of SEQ ID NO: 537, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 538; and a VH that specifically binds to CD20 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 540, a CDR2 comprising the amino acid sequence of SEQ ID NO: 541, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 542. In some embodiments, a VL that specifically binds to CD20 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 548, a CDR2 comprising the amino acid sequence of SEQ ID NO: 549, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 550; a VH that specifically binds to CD20 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 552, a CDR2 comprising the amino acid sequence of SEQ ID NO: 553, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 554. In some embodiments, a VL that specifically binds to CD20 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 753, a CDR2 comprising the amino acid sequence of SEQ ID NO: 754, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 755; and a VH that specifically binds to CD20 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 757, a CDR2 comprising the amino acid sequence of SEQ ID NO: 758, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 759. In some aspects, a VL that specifically binds to CD20 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 789; a CDR2 comprising the amino acid sequence of SEQ ID NO: 790; and a CDR3 comprising the amino acid sequence of SEQ ID NO: 791; and a VH that specifically binds to CD20 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 793; a CDR2 comprising the amino acid sequence of SEQ ID NO: 794; and a CDR3 comprising the amino acid sequence of SEQ ID NO: 795.In some embodiments, a VL that specifically binds to CD20 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 825, a CDR2 comprising the amino acid sequence of SEQ ID NO: 826, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 827; and a VH that specifically binds to CD20 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 829, a CDR2 comprising the amino acid sequence of SEQ ID NO: 830, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 831. In some embodiments, a VL that specifically binds to CD20 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 871, a CDR2 comprising the amino acid sequence of SEQ ID NO: 872, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 873. In some embodiments, a VL that specifically binds to CD20 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 879, a CDR2 comprising the amino acid sequence of SEQ ID NO: 880, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 881; a VH that specifically binds to CD20 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 875, a CDR2 comprising the amino acid sequence of SEQ ID NO: 876, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 877. In some embodiments, a VL that specifically binds to CD19 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 490, a CDR2 comprising the amino acid sequence of SEQ ID NO: 491(AT), and a CDR3 comprising the amino acid sequence of SEQ ID NO: 492; and a VH that specifically binds to CD19 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 500, a CDR2 comprising the amino acid sequence of SEQ ID NO: 501, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 502. In some aspects, a VL that specifically binds to CD19 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 496; a CDR2 comprising the amino acid sequence of SEQ ID NO: 497(AT); and a CDR3 comprising the amino acid sequence of SEQ ID NO: 498; and a VH that specifically binds to CD19 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 500; a CDR2 comprising the amino acid sequence of SEQ ID NO: 501; and a CDR3 comprising the amino acid sequence of SEQ ID NO: 502.In some embodiments, a VL that specifically binds to CD19 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 745, a CDR2 comprising the amino acid sequence of SEQ ID NO: 746, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 747; a VH that specifically binds to CD19 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 749, a CDR2 comprising the amino acid sequence of SEQ ID NO: 750, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 751. In some embodiments, a VL that specifically binds to CD19 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 781, a CDR2 comprising the amino acid sequence of SEQ ID NO: 782, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 783; and a VH that specifically binds to CD19 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 785, a CDR2 comprising the amino acid sequence of SEQ ID NO: 786, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 787. In some embodiments, a VL that specifically binds to CD19 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 817, a CDR2 comprising the amino acid sequence of SEQ ID NO: 818, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 819; a VH that specifically binds to CD19 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 821, a CDR2 comprising the amino acid sequence of SEQ ID NO: 822, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 823. In some embodiments, a VL that specifically binds to CD28 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 645, a CDR2 comprising the amino acid sequence of SEQ ID NO: 646, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 647; and a VH that specifically binds to CD28 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 649, a CDR2 comprising the amino acid sequence of SEQ ID NO: 650, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 651. In some embodiments, a VL that specifically binds to CD28 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 681; a CDR2 comprising the amino acid sequence of SEQ ID NO: 682; and a CDR3 comprising the amino acid sequence of SEQ ID NO: 683; and a VH that specifically binds to CD28 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 685; a CDR2 comprising the amino acid sequence of SEQ ID NO: 686; and a CDR3 comprising the amino acid sequence of SEQ ID NO: 687.In some embodiments, a VL that specifically binds to CD28 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 771, a CDR2 comprising the amino acid sequence of SEQ ID NO: 772, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 773; a VH that specifically binds to CD28 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 775, a CDR2 comprising the amino acid sequence of SEQ ID NO: 776, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 777. In some embodiments, a VL that specifically binds to CD28 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 843, a CDR2 comprising the amino acid sequence of SEQ ID NO: 844, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 845; and a VH that specifically binds to CD28 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 847, a CDR2 comprising the amino acid sequence of SEQ ID NO: 848, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 849. In some embodiments, a VL that specifically binds to BCMA comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 621, a CDR2 comprising the amino acid sequence of SEQ ID NO: 622, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 623; a VH that specifically binds to BCMA comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 625, a CDR2 comprising the amino acid sequence of SEQ ID NO: 626, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 627. In some embodiments, a VL that specifically binds cMet comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 637, a CDR2 comprising the amino acid sequence of SEQ ID NO: 638, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 639; and a VH that specifically binds cMet comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 641, a CDR2 comprising the amino acid sequence of SEQ ID NO: 642, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 643. In some embodiments, a VL that specifically binds to cMet comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 673; a CDR2 comprising the amino acid sequence of SEQ ID NO: 674; and a CDR3 comprising the amino acid sequence of SEQ ID NO: 675; and a VH that specifically binds to cMet comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 677; a CDR2 comprising the amino acid sequence of SEQ ID NO: 678; and a CDR3 comprising the amino acid sequence of SEQ ID NO: 679.In some embodiments, a VL that specifically binds to cMet comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 709; a CDR2 comprising the amino acid sequence of SEQ ID NO: 710; and a CDR3 comprising the amino acid sequence of SEQ ID NO: 711; and a VH that specifically binds to cMet comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 713; a CDR2 comprising the amino acid sequence of SEQ ID NO: 714; and a CDR3 comprising the amino acid sequence of SEQ ID NO: 715.

[0101] In some embodiments, a VL that specifically binds to a TAA is at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical to any one of SEQ ID NOs: 71, 79, 87, 95, 103, 111, 119, 127, 135, 384, 404, 414, 440, 451, 461, 471, 583, 654, 690, 726, 392, 402, 485, 503, 535, 547, 752, 788, 824, 882, 870, 878, 489, 495, 543, 555, 744, 780, 816, 527, 644, 680, 770, 842, 620, 636, 672, and 708. a VH that specifically binds to a TAA comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity to any one of SEQ ID NOs: 70, 78, 86, 94, 102, 110, 118, 126, 134, 388, 408, 418, 428, 584, 658, 694, 730, 396, 403, 507, 539, 551, 756, 792, 828, 883, 866, 874, 499, 544, 556, 748, 784, 820, 528, 648, 684, 774, 846, 624, 640, 676, and 712. In some embodiments, a VL that specifically binds to CD38 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 71; and a VH that specifically binds to CD38 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 70.In some embodiments, a VL that specifically binds to cMet comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 79; and a VH that specifically binds to cMet comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 78. In some embodiments, a VL that specifically binds to Trop2 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 87; and a VH that specifically binds to Trop2 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 86. In some embodiments, a VL that specifically binds to Trop2 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO:95; and a VH that specifically binds to Trop2 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO:94. In some embodiments, a VL that specifically binds to CD3 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 103; and a VH that specifically binds to CD3 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 102.In some embodiments, a VL that specifically binds to CD20 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 111; and a VH that specifically binds to CD20 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 110. In some embodiments, a VL that specifically binds to CD20 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 119; and a VH that specifically binds to CD20 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 118. In some embodiments, a VL that specifically binds to CD20 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 111; and a VH that specifically binds to CD20 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 118. In some embodiments, a VL that specifically binds to CD20 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 119; and a VH that specifically binds to CD20 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 110.In some embodiments, a VL that specifically binds to CD19 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 127; and a VH that specifically binds to CD19 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 126. In some embodiments, a VL that specifically binds to CD19 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 135 or 882; and a VH that specifically binds to CD19 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 134 or 883. In some embodiments, a VL that specifically binds Trop2 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 384; and a VH that specifically binds Trop2 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 388. In some embodiments, a VL that specifically binds to Trop2 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 404; and a VH that specifically binds to Trop2 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 408.In some embodiments, a VL that specifically binds to Trop2 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 414; and a VH that specifically binds to Trop2 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 418. In some embodiments, a VL that specifically binds to Trop2 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 440; and a VH that specifically binds to Trop2 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 428. In some embodiments, a VL that specifically binds to Trop2 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 451; and a VH that specifically binds to Trop2 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 428. In some embodiments, a VL that specifically binds to Trop2 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 461; and a VH that specifically binds to Trop2 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 428.In some embodiments, a VL that specifically binds to Trop2 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 471; and a VH that specifically binds to Trop2 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 428. In some embodiments, a VL that specifically binds Trop2 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 583; and a VH that specifically binds Trop2 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 584. In some embodiments, a VL that specifically binds to Trop2 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 654; and a VH that specifically binds to Trop2 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 658. In some embodiments, a VL that specifically binds Trop2 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 690; and a VH that specifically binds Trop2 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 694. In some embodiments, a VL that specifically binds Trop2 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 726; and a VH that specifically binds Trop2 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 730.In some embodiments, a VL that specifically binds to CD20 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 485; and a VH that specifically binds to CD20 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 507. In some embodiments, a VL that specifically binds to CD19 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 489; and a VH that specifically binds to CD19 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 499. In some embodiments, a VL that specifically binds to HER2 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 392; and a VH that specifically binds to HER2 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 396. In some embodiments, a VL that specifically binds to HER2 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 402; and a VH that specifically binds to HER2 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 403.In some embodiments, a VL that specifically binds to CD20 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 503; and a VH that specifically binds to CD20 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 507. In some embodiments, a VL that specifically binds to CD20 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 535; and a VH that specifically binds to CD20 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 539. In some embodiments, a VL that specifically binds to CD20 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 547; and a VH that specifically binds to CD20 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 551. In some embodiments, a VL that specifically binds to CD20 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 752; and a VH that specifically binds to CD20 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 756.In some embodiments, a VL that specifically binds to CD20 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 788; and a VH that specifically binds to CD20 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 792. In some embodiments, a VL that specifically binds to CD20 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 824; and a VH that specifically binds to CD20 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 828. In some embodiments, a VL that specifically binds to CD20 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 878; and a VH that specifically binds to CD20 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 874. In some embodiments, a VL that specifically binds to CD19 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 495; and a VH that specifically binds to CD19 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 499.In some embodiments, a VL that specifically binds to CD19 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 543; and a VH that specifically binds to CD19 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 544. In some embodiments, a VL that specifically binds to CD19 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 555; and a VH that specifically binds to CD19 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 556. In some embodiments, a VL that specifically binds to CD19 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 744; and a VH that specifically binds to CD19 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 748. In some embodiments, a VL that specifically binds to CD19 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 780; and a VH that specifically binds to CD19 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 784.In some embodiments, a VL that specifically binds to CD19 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 816; and a VH that specifically binds to CD19 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 820. In some embodiments, a VL that specifically binds to CD28 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 527; and a VH that specifically binds to CD28 has at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 528. In some embodiments, a VL that specifically binds CD28 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 644; and a VH that specifically binds CD28 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 648. In some embodiments, a VL that specifically binds to CD28 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 680; and a VH that specifically binds to CD28 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 684. In some embodiments, a VL that specifically binds to CD28 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 770; and a VH that specifically binds to CD28 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 774. In some embodiments, a VL that specifically binds to CD28 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 842; and a VH that specifically binds to CD28 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 846.In some embodiments, a VL that specifically binds BCMA comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 620; and a VH that specifically binds BCMA comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 624. In some embodiments, a VL that specifically binds cMet comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 636; and a VH that specifically binds cMet comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 640. In some embodiments, a VL that specifically binds cMet comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 672; and a VH that specifically binds cMet comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 676. In some embodiments, a VL that specifically binds cMet comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 708; and a VH that specifically binds cMet comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 712.In some embodiments, a VL that specifically binds to CD20 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 870, and a VH that specifically binds to CD20 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 866. In some embodiments, a VL that specifically binds CD19 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to DIQLTQSPASLAVSLGQRATISCKASQSVDYDGDSYLNWYQQIPGQPPKLLIYDASNLVSGIPPRFSGSGSGTDFTLNIHPVEKVDAATYHCQQSTEDPWTFGGGTKLEIK (SEQ ID NO: 882), A VH that specifically binds to D19 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to QVQLQQSGAELVRPGSSVKISCKASGYAFSSYWMNWVKQRPGQGLEWIGQIWPGDGDTNYNGKFKGKATLTADESSSTAYMQLSSLASEDSAVYFCARRETTTVGRYYYAMDYWGQGTTVTVSS (SEQ ID NO: 883).

[0102] In some embodiments, the antigen-binding polypeptide complexes (e.g., antibodies or antigen-binding fragments thereof) of the invention specifically bind to CD3. In some embodiments, the antigen-binding polypeptide complexes specifically bind to CD3 and one or more TAAs, such as A2AR, APRIL, ATPDase, BAFF, BAFFR, BCMA, BlyS, BTK, BTLA, B7DC, B7H1, B7H2, B7H3, B7H4, B7H5, B7H6, B7H7, B7RP1, B7-4, C3, C5, CCL2, CCL3, CCL4, CCL5, CCL7, CCL8, CCL11, CCL15, CCL17, CCL19, CCL20, CCL21, CCL25, CCR3, CCR4, CD1 6A, CD19, CD20, CD24, CD27, CD28, CD30, CD38, CD39, CD40, CD40L, CD47, CD52, CD70, CD80, CD86, CD123, CD133, CD137, CD137L, CD160, CD272, C EACAM5, CLEC9, CLEC91, CRTH2, CSF-1, CSF-2, CSF-3, CXCL1, CXCL2, CXCL4, CXCL12, CXCL13, CXCR3, cMet, CTLA4, DLL3, DLL4, DNGR-1, E-cadherin , EGFR, ENTPD1, ​​EpCAM, FCER1, FCER1A, FCER2, FGFR, FLAP, FOLH1, Gi24, GITR, GITRL, GPR5, GP100, GPRC5D, HER2, HER3, ICOSL, ICOS, HHLA2, HM GB1, HVEM, IDO, IFNa, IgE, IGF1R, IL2R beta, IL1, ILIA, IL1B, IL1F10, IL2, IL4, IL4Ra, IL5, IL5R, IL6, IL7, IL7Ra, IL8, IL9, IL9R, IL10, rhILl O, IL12, IL13, IL13Ral, IL13Ra2, IL15, IL17, IL17Rb, IL18, IL22, IL23, IL25, IL7, IL33, IL35, ITGB4, ITK, KIR, LAG3, LAMP1, leptin, LPFS2, MH C class II, MUC-1, MUC-16, NCR3LG1, NKG2D, NKp46, NTPDase-1, OX40, OX40L, PD-1, PD-L1, PD-L2, PROM1, S152, SIRP alpha, SISP1, SLC, SPG64, ST2,The antigen-binding polypeptide complex may specifically bind to STEAP1, STEAP2, Syk kinase, STEAP1, TROP2, TACI, TDO, TGFBETA, T14, TIGIT, TIM3, TLR, TLR2, TLR4, TLR5, TLR9, TMEF1, TNFα, TNFRSF7, Tp55, TREM1, TSLP, TSLPR, TWEAK, VEGF, VISTA, Vstm3, or WUCAM. For example, the antigen-binding polypeptide complex may specifically bind CD3, CD19, and CD20. For example, the antigen-binding polypeptide complex may specifically bind CD3, cMet, and Trop2.

[0103] A2AR、APRIL、ATPDase、BAFF、BAFFR、BCMA、BlyS、BTK、BTLA、B7DC、B7H1、B7H 2、B7H3、B7H4、B7H5、B7H6、B7H7、B7RP1、B7-4、C3、C5、CCL2、CCL3、CCL4、CCL 5、CCL7、CCL8、CCL11、CCL15、CCL17、CCL19、CCL20、CCL21、CCL25、CCR3、CCR 4、CD16A、CD19、CD20、CD24、CD27、CD28、CD30、CD38、CD39、CD40、CD40L、CD47 、CD52、CD70、CD80、CD86、CD123、CD133、CD137、CD137L、CD160、CD272、CEAC AM5、CLEC9、CLEC91、CRTH2、CSF-1、CSF-2、CSF-3、CXCL1、CXCL2、CXCL4、CXC L12、CXCL13、CXCR3、cMet、CTLA4、DLL3、DLL4、DNGR-1、E-カドヘリン、EGFR、ENTP D1、EpCAM、FCER1、FCER1A、FCER2、FGFR、FLAP、FOLH1、Gi24、GITR、GITRL、GPR 5、GP100、GPRC5D、HER2、HER3、ICOSL、ICOS、HHLA2、HMGB1、HVEM、IDO、IFNa、 IgE、IGF1R、IL2Rベータ、IL1、ILIA、IL1B、IL1F10、IL2、IL4、IL4Ra、IL5、IL5R、 IL6、IL7、IL7Ra、IL8、IL9、IL9R、IL10、rhILlO、IL12、IL13、IL13Ral、IL13R a2、IL15、IL17、IL17Rb、IL18、IL22、IL23、IL25、IL7、IL33、IL35、ITGB4、ITK 、KIR、LAG3、LAMP1、レプチン、LPFS2、MHCクラスII、MUC-1、MUC-16、NCR3LG1、NKG2D 、NKp46、NTPDase-1、OX40、OX40L、PD-1、PD-L1、PD-L2、PROM1、S152、SIRPアルファ、SISP1、SLC、SPG64、ST2、STEAP1、STEAP2、Sykキナーゼ、STEAP1、TROP2、TACI 、TDO、TGFBETA、T14、TIGIT、TIM3、TLR、TLR2、TLR4、TLR5、TLR9、TMEF1、TNFa、Antigen-binding sequences (e.g., CDRs, VH, VL, heavy and light chain sequences from antibodies) for TNFRSF7, Tp55, TREM1, TSLP, TSLPR, TWEAK, VEGF, VISTA, Vstm3, or WUCAM are well known. For example, the sequences of CD3, CD19, CD28, and CD38 are well known and include, but are not limited to, GenBank Accession Nos. AAA39272.1, AAA39159.1, ABN79462.1, AVW80143.1, AVW80142.1, AVW80141.1, AAB34430.1, AAB34429.1, CAD45042.1, 4CMH_C, and 4CMH_B. Such sequences have also been reported in, for example, Wernly et al., Cells, 9(2):295, 2020; Arakawa et al., Journal of Biochemistry, 120(3):657-662, 1996; Cole et al., Transplantation, 68(4):563-571, 1999; Li et al., International Immunopharmacology, 62:299-308, 2018; Castella et al., Methods & Clinical Development, 12:134-144, 2019; Sun et al., Molecular Immunology, 41(9):929-938, 2004; Iwaszkiewicz-Grzes et al., Cytotherapy, 22(11):629-641, 2020, Rosinski et al., Transplant Direct, 1(2): e7, 2015; Ellis et al., J Immunology, 155(2): 925-937, 1995; Stevenson et al., Blood, 77(5): 1071-1079, 1991; Chillemi et al., Molecular Medicine, 19: 99-108, 2013, International Publication No. WO2020 / 076853.

[0104] Additionally, molecular biology and recombinant DNA techniques for generating, screening, and manipulating antigen-binding complexes and antibodies containing such sequences are well known, see, e.g., Adair et al., Human Antibodies, 5(1-2):41-47, 1994; Kostelny et al., J Immunol, 148(5):1547-1553 (1992), Shiraiwa et al., Methods, 154:10-20, 2019; and Zola, “Monoclonal Antibodies: A Manual of Techniques,” 1987, 1 st Ed., CRC Press; and Steinitz, Human Antibodies, 18(1-2):1-10, 2009.

[0105] In some embodiments, the VL and corresponding VH of the antigen-binding polypeptide complex specifically bind to CD3. In some embodiments, one VL and one corresponding VH of the antigen-binding polypeptide complex specifically bind to CD3. In some embodiments, VL3 and VH3 specifically bind to CD3. In some embodiments, VL3 comprises a CDR1 comprising an amino acid sequence having at least 90% identity, at least 95% identity, or 100% identity to any one of SEQ ID NOs: 35, 44, 99, 446, 456, 466, 476, 520, 663, 699, 735, 763, 799, 835, 855, and 863; a CDR2 comprising an amino acid sequence having at least 90% identity, at least 95% identity, or 100% identity to any one of SEQ ID NOs: 37, 46, 101, 448, 458, 468, 478, 522, 665, 701, 737, 765, 801, 837, 857, and 865; or VH3 comprises a CDR3 comprising an amino acid sequence having 100% identity; VH3 comprises a CDR1 comprising an amino acid sequence having at least 90% identity, at least 95% identity, or 100% identity to any one of SEQ ID NOs: 32, 40, 96, 433, 524, 667, 703, 739, 767, 803, 839, 851, and 859; 40, 852 and 860; and CDR3 comprising an amino acid sequence having at least 90% identity, at least 95% identity, or 100% identity to any one of SEQ ID NOs: 34, 42, 98, 435, 526, 669, 705, 741, 769, 805, 841, 853 and 861.In some aspects, the VL3 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 35; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 36; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 37; and the VH3 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 32; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 33; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 34. In some aspects, the VL3 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 44; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 45; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 46; and the VH3 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 40; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 41; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 42. In some aspects, the VL3 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 446; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 447(DT); and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 448; and the VH3 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 433; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 434; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 435.In some aspects, the VL3 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 456; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 457 (DT); and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 458; and the VH3 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 433; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 434; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 435. In some aspects, the VL3 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 466; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 467 (DT); and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 468; and the VH3 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 433; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 434; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 435. In some aspects, the VL3 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 476; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 477(DT); and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 478; and the VH3 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 433; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 434; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 435.In some aspects, the VL3 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 520; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 521; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 522; and the VH3 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 524; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 525; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 526. In some aspects, the VL3 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 663; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 664; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 665; and the VH3 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 667; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 668; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 669. In some aspects, the VL3 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 699; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 700; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 701; and the VH3 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 703; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 704; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 705.In some aspects, the VL3 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 735; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 736; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 737, and the VH3 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 739; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 740; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 741. In some aspects, the VL3 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 763; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 764; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 765; and the VH3 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 767; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 768; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 769. In some aspects, the VL3 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 799; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 800; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 801; and the VH3 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 803; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 804; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 805.In some aspects, the VL3 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 835; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 836, and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 837; the VH3 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 839; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 840; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 841. In some aspects, the VL3 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 855; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 856; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 857; and the VH3 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 851; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 852; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 853. In some aspects, the VL3 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 863; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 864; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 865; and the VH3 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 859, a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 860; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 861.In some embodiments, the VL3 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 99; a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 100; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 100; and the VH3 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 96, a CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 97; and a CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 98. As used herein, "at least 90% identity" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% identity to the reference sequence set forth. , 99% and 100% identity are included. In some embodiments, the VL3 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 35, a CDR2 comprising the amino acid sequence of SEQ ID NO: 36, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 37; the VH3 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 32, a CDR2 comprising the amino acid sequence of SEQ ID NO: 33, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 34. In some embodiments, the VL3 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 44, a CDR2 comprising the amino acid sequence of SEQ ID NO: 45, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 46; and the VH3 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 40, a CDR2 comprising the amino acid sequence of SEQ ID NO: 41, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 42. In some embodiments, the VL3 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 446, a CDR2 comprising the amino acid sequence of SEQ ID NO: 447(DT), and a CDR3 comprising the amino acid sequence of SEQ ID NO: 448; the VH3 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 433, a CDR2 comprising the amino acid sequence of SEQ ID NO: 434, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 435. In some embodiments, the VL3 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 456, a CDR2 comprising the amino acid sequence of SEQ ID NO: 457(DT), and a CDR3 comprising the amino acid sequence of SEQ ID NO: 458; and the VH3 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 433, a CDR2 comprising the amino acid sequence of SEQ ID NO: 434, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 435. In some aspects, the VL3 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 466, a CDR2 comprising the amino acid sequence of SEQ ID NO: 467(DT), and a CDR3 comprising the amino acid sequence of SEQ ID NO: 468; the VH3 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 433, a CDR2 comprising the amino acid sequence of SEQ ID NO: 434, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 435. In some aspects, the VL3 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 476, a CDR2 comprising the amino acid sequence of SEQ ID NO: 477(DT), and a CDR3 comprising the amino acid sequence of SEQ ID NO: 478; and the VH3 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 433, a CDR2 comprising the amino acid sequence of SEQ ID NO: 434, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 435.In some embodiments, the VL3 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 520, a CDR2 comprising the amino acid sequence of SEQ ID NO: 521, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 522; the VH3 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 524, a CDR2 comprising the amino acid sequence of SEQ ID NO: 525, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 526. In some embodiments, the VL3 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 663, a CDR2 comprising the amino acid sequence of SEQ ID NO: 664, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 665; and the VH3 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 667, a CDR2 comprising the amino acid sequence of SEQ ID NO: 668, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 669. In some embodiments, the VL3 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 699, a CDR2 comprising the amino acid sequence of SEQ ID NO: 700, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 701; the VH3 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 703, a CDR2 comprising the amino acid sequence of SEQ ID NO: 704, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 705. In some embodiments, the VL3 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 735, a CDR2 comprising the amino acid sequence of SEQ ID NO: 736, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 737, and the VH3 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 739, a CDR2 comprising the amino acid sequence of SEQ ID NO: 740, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 741. In some embodiments, the VL3 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 763, a CDR2 comprising the amino acid sequence of SEQ ID NO: 764, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 765; the VH3 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 767, a CDR2 comprising the amino acid sequence of SEQ ID NO: 768, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 769. In some embodiments, the VL3 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 799, a CDR2 comprising the amino acid sequence of SEQ ID NO: 800, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 801; and the VH3 comprises a CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 803, a CDR2 comprising the amino acid sequence of SEQ ID NO: 804, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 805.In some embodiments, the VL3 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 835, a CDR2 comprising the amino acid sequence of SEQ ID NO: 836, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 837; the VH3 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 839, a CDR2 comprising the amino acid sequence of SEQ ID NO: 840, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 841. In some embodiments, the VL3 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 855, a CDR2 comprising the amino acid sequence of SEQ ID NO: 856, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 857; and the VH3 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 851, a CDR2 comprising the amino acid sequence of SEQ ID NO: 852, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 853. In some embodiments, the VL3 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 863, a CDR2 comprising the amino acid sequence of SEQ ID NO: 864, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 865; the VH3 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 859, a CDR2 comprising the amino acid sequence of SEQ ID NO: 860, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 861. In some embodiments, the VL3 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 99, a CDR2 comprising the amino acid sequence of SEQ ID NO: 100, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 101; and the VH3 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 96, a CDR2 comprising the amino acid sequence of SEQ ID NO: 97, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 98. As used herein, "at least 90% identity" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identity to the set forth reference sequence. In some embodiments, the VL3 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 35; a CDR2 comprising the amino acid sequence of SEQ ID NO: 36; and a CDR3 comprising the amino acid sequence of SEQ ID NO: 37; and the VH3 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 32; a CDR2 comprising the amino acid sequence of SEQ ID NO: 33; and a CDR3 comprising the amino acid sequence of SEQ ID NO: 34.In some aspects, the VL3 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 44; a CDR2 comprising the amino acid sequence of SEQ ID NO: 45; and a CDR3 comprising the amino acid sequence of SEQ ID NO: 46; and the VH3 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 40; a CDR2 comprising the amino acid sequence of SEQ ID NO: 41; and a CDR3 comprising the amino acid sequence of SEQ ID NO: 42. In some aspects, VL3 comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical to any one of SEQ ID NOs: 39, 47, 103, 422, 445, 455, 465, 475, 519, 662, 698, 734, 762, 798, 834, 854, and 862; and / or VH3 comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical to any one of SEQ ID NOs: 38, 43, 102, 423, 432, 523, 666, 702, 738, 766, 802, 838, 850, and 858. In some embodiments, VL3 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 39; and / or VH3 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 38. In some embodiments, VL3 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 47; and / or VH3 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 43.In some embodiments, VL3 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 39; and / or VH3 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 43. In some embodiments, VL3 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 47; and / or VH3 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 38. In some embodiments, VL3 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 422; and / or VH3 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 423. In some aspects, VL3 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 445; and / or VH3 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 432.In some aspects, VL3 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 455; and / or VH3 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 432. In some embodiments, VL3 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 465; and / or VH3 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 432. VL3 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 475; and / or VH3 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 432. In some embodiments, VL3 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 519; and / or VH3 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity) to SEQ ID NO: 523. In some embodiments, VL3 comprises an amino acid sequence having at least 80% identity (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%...

Claims

1. 1. An antigen-binding polypeptide complex comprising a first polypeptide, a second polypeptide, and a third polypeptide, The first polypeptide comprises: VL1-L1-VH1-L2-Fc; VH1-L3-VL1-L4-Fc; <h2 style=";text-align:left;direction:ltr">412 ...<h2 style=";text-align:left;direction:ltr"> or VL1-L3-VH1-L4-Fc having a structure represented by: The second polypeptide comprises: VH2-L5-VH3-L6-CH1-L7-Fc; or VH3-L5-VH2-L6-CH1-L7-Fc having a structure represented by: The third polypeptide comprises: VL2-L8-VL3-L9-CL; or VL3-L8-VL2-L9-CL having a structure represented by: VL1 is the first immunoglobulin light chain variable region; VL2 is a second immunoglobulin light chain variable region; VL3 is the third immunoglobulin light chain variable region; VH1 is the first immunoglobulin heavy chain variable region; VH2 is a second immunoglobulin heavy chain variable region; VH3 is the third immunoglobulin heavy chain variable region; Fc is the region containing immunoglobulin heavy chain constant region 2 (CH2), immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; CH1 is immunoglobulin heavy chain constant region 1; CL is an immunoglobulin light chain constant region; and L1-L9 are amino acid linkers; The antigen-binding polypeptide complex.

2. the antigen-binding polypeptide complex comprises a first polypeptide, a second polypeptide, and a third polypeptide; The first polypeptide comprises: VL1-L1-VH1-L2-Fc; or VH1-L3-VL1-L4-Fc having a structure represented by: The second polypeptide comprises: VH2-L5-VH3-L6-CH1-L7-Fc having a structure represented by: The third polypeptide comprises: VL2-L8-VL3-L9-CL having a structure represented by: VL1 is the first immunoglobulin light chain variable region; VL2 is a second immunoglobulin light chain variable region; VL3 is the third immunoglobulin light chain variable region; VH1 is the first immunoglobulin heavy chain variable region; VH2 is a second immunoglobulin heavy chain variable region; VH3 is the third immunoglobulin heavy chain variable region; Fc is the region containing immunoglobulin heavy chain constant region 2 (CH2), immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; CH1 is immunoglobulin heavy chain constant region 1; CL is an immunoglobulin light chain constant region; and L1-L9 are amino acid linkers; The antigen-binding polypeptide complex of claim 1.

3. 1. An antigen-binding polypeptide complex comprising a first polypeptide, a second polypeptide, a third polypeptide, and a fourth polypeptide, The first polypeptide comprises: VL1-L1-CL; or VH1-L1-CL having a structure represented by: The second polypeptide comprises: VH1-L2-CH1-L3-Fc; or VL1-L2-CH1-L3-Fc having a structure represented by: The third polypeptide comprises: VH2-L4-VH3-L5-CH1-L6-Fc; or VH3-L4-VH2-L5-CH1-L6-Fc having a structure represented by: The fourth polypeptide comprises: VL2-L7-VL3-L8-CL; or VL3-L7-VL2-L8-CL having a structure represented by: VL1 is the first immunoglobulin light chain variable region; VL2 is a second immunoglobulin light chain variable region; VL3 is the third immunoglobulin light chain variable region; VH1 is the first immunoglobulin heavy chain variable region; VH2 is a second immunoglobulin heavy chain variable region; VH3 is the third immunoglobulin heavy chain variable region; Fc is the region containing immunoglobulin heavy chain constant region 2 (CH2), immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; CH1 is immunoglobulin heavy chain constant region 1; CL is an immunoglobulin light chain constant region; and L1-L8 are amino acid linkers; The antigen-binding polypeptide complex.

4. the antigen-binding polypeptide complex comprises a first polypeptide, a second polypeptide, a third polypeptide, and a fourth polypeptide; The first polypeptide comprises: VL1-L1-CL having a structure represented by: The second polypeptide comprises: VH1-L2-CH1-L3-Fc having a structure represented by: The third polypeptide comprises: VH2-L4-VH3-L5-CH1-L6-Fc having a structure represented by: The fourth polypeptide comprises: VL2-L7-VL3-L8-CL having a structure represented by: VL1 is the first immunoglobulin light chain variable region; VL2 is a second immunoglobulin light chain variable region; VL3 is the third immunoglobulin light chain variable region; VH1 is the first immunoglobulin heavy chain variable region; VH2 is a second immunoglobulin heavy chain variable region; VH3 is the third immunoglobulin heavy chain variable region; Fc is the region containing immunoglobulin heavy chain constant region 2 (CH2), immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; CH1 is immunoglobulin heavy chain constant region 1; CL is an immunoglobulin light chain constant region; and L1-L8 are amino acid linkers; The antigen-binding polypeptide complex of claim 3.

5. 1. An antigen-binding polypeptide complex comprising a first polypeptide, a second polypeptide, and a third polypeptide, The first polypeptide comprises: VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc; <h2 style=";text-align:left;direction:ltr">41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 ...<h2 style=";text-align:left;direction:ltr"> or VH1-L5-VL2-L6-VH2-L7-VL1-L8-Fc having a structure represented by: The second polypeptide comprises: VH3-L9-VH4-L10-CH1-L11-Fc; or VH4-L9-VH3-L10-CH1-L11-Fc having a structure represented by: The third polypeptide comprises: VL3-L12-VL4-L13-CL; or VL4-L12-VL3-L13-CL and having a structure represented by VL1 is the first immunoglobulin light chain variable region; VL2 is a second immunoglobulin light chain variable region; VL3 is the third immunoglobulin light chain variable region; VL4 is the fourth immunoglobulin light chain variable region; VH1 is the first immunoglobulin heavy chain variable region; VH2 is a second immunoglobulin heavy chain variable region; VH3 is the third immunoglobulin heavy chain variable region; VH4 is the fourth immunoglobulin heavy chain variable region; Fc is the region containing immunoglobulin heavy chain constant region 2 (CH2), immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; CH1 is immunoglobulin heavy chain constant region 1; CL is an immunoglobulin light chain constant region; and L1-L13 are amino acid linkers; or The first polypeptide comprises: VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc; VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc; or VH1-L5-VL2-L6-VH2-L7-VL1-L8-Fc having a structure represented by: The second polypeptide comprises: VH3-L9-VH4-CH1-Fc; or VH4-L9-VH3-CH1-Fc having a structure represented by: The third polypeptide comprises: VL3-L12-VL4-CL; or VL4-L12-VL3-CL and having a structure represented by VL1 is the first immunoglobulin light chain variable region; VL2 is a second immunoglobulin light chain variable region; VL3 is the third immunoglobulin light chain variable region; VL4 is the fourth immunoglobulin light chain variable region; VH1 is the first immunoglobulin heavy chain variable region; VH2 is a second immunoglobulin heavy chain variable region; VH3 is the third immunoglobulin heavy chain variable region; VH4 is the fourth immunoglobulin heavy chain variable region; Fc is the region containing immunoglobulin heavy chain constant region 2 (CH2), immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; CH1 is immunoglobulin heavy chain constant region 1; CL is an immunoglobulin light chain constant region; and L1-L10 are amino acid linkers; The antigen-binding polypeptide complex.

6. the antigen-binding polypeptide complex comprises a first polypeptide, a second polypeptide, and a third polypeptide; The first polypeptide comprises: <h2 style=";text-align:left;direction:ltr">41.51.2018<h2 style=";text-align:left;direction:ltr"> or VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc having a structure represented by: The second polypeptide comprises: VH3-L9-VH4-L10-CH1-L11-Fc having a structure represented by: The third polypeptide comprises: VL3-L12-VL4-L13-CL having a structure represented by: VL1 is the first immunoglobulin light chain variable region; VL2 is a second immunoglobulin light chain variable region; VL3 is the third immunoglobulin light chain variable region; VL4 is the fourth immunoglobulin light chain variable region; VH1 is the first immunoglobulin heavy chain variable region; VH2 is a second immunoglobulin heavy chain variable region; VH3 is the third immunoglobulin heavy chain variable region; VH4 is the fourth immunoglobulin heavy chain variable region; Fc is the region containing immunoglobulin heavy chain constant region 2 (CH2), immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; CH1 is immunoglobulin heavy chain constant region 1; CL is an immunoglobulin light chain constant region; and L1-L13 are amino acid linkers; or The first polypeptide comprises: VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; or VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc having a structure represented by: The second polypeptide comprises: VH3-L9-VH4-CH1-Fc having a structure represented by: The third polypeptide comprises: VL3-L10-VL4-CL having a structure represented by: VL1 is the first immunoglobulin light chain variable region; VL2 is a second immunoglobulin light chain variable region; VL3 is the third immunoglobulin light chain variable region; VL4 is the fourth immunoglobulin light chain variable region; VH1 is the first immunoglobulin heavy chain variable region; VH2 is a second immunoglobulin heavy chain variable region; VH3 is the third immunoglobulin heavy chain variable region; VH4 is the fourth immunoglobulin heavy chain variable region; Fc is the region containing immunoglobulin heavy chain constant region 2 (CH2), immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; CH1 is immunoglobulin heavy chain constant region 1; CL is an immunoglobulin light chain constant region; and L1-L10 are amino acid linkers; 6. The antigen-binding polypeptide complex of claim 5.

7. 1. An antigen-binding polypeptide complex comprising a first polypeptide and a second polypeptide, The first polypeptide comprises: VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc; <h2 style=";text-align:left;direction:ltr">41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 ...<h2 style=";text-align:left;direction:ltr"> or VH1-L5-VL2-L6-VH2-L7-VL1-L8-Fc having a structure represented by: The second polypeptide comprises: VL3-L9-VL4-L10-VH4-L11-VH3-L12-Fc; VL3-L9-VH4-L10-VL4-L11-VH3-L12-Fc; VH3-L13-VH4-L14-VL4-L15-VL3-L16-Fc; or VH3-L13-VL4-L14-VH4-L15-VL3-L16-Fc having a structure represented by: VL1 is the first immunoglobulin light chain variable region that specifically binds to a tumor-associated antigen; VL2 is a second immunoglobulin light chain variable region that specifically binds a tumor-associated antigen; VL3 is a third immunoglobulin light chain variable region that specifically binds CD3; VL4 is a fourth immunoglobulin light chain variable region that specifically binds a tumor-associated antigen; VH1 is the first immunoglobulin heavy chain variable region that specifically binds to a tumor-associated antigen; VH2 is a second immunoglobulin heavy chain variable region that specifically binds a tumor-associated antigen; VH3 is a third immunoglobulin heavy chain variable region that specifically binds CD3; VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds a tumor-associated antigen; Fc is a region containing immunoglobulin heavy chain constant region 2 (CH2), immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; and L1-L16 are amino acid linkers; The antigen-binding polypeptide complex.

8. the antigen-binding polypeptide complex comprises a first polypeptide and a second polypeptide; The first polypeptide comprises: <h2 style=";text-align:left;direction:ltr">41.51.2018<h2 style=";text-align:left;direction:ltr"> or VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc having a structure represented by: The second polypeptide comprises: VL3-L9-VL4-L10-VH4-L11-VH3-L12-Fc; or VH3-L13-VH4-L14-VL4-L15-VL3-L16-Fc having a structure represented by: VL1 is the first immunoglobulin light chain variable region that specifically binds to a tumor-associated antigen; VL2 is a second immunoglobulin light chain variable region that specifically binds a tumor-associated antigen; VL3 is a third immunoglobulin light chain variable region that specifically binds CD3; VL4 is a fourth immunoglobulin light chain variable region that specifically binds a tumor-associated antigen; VH1 is the first immunoglobulin heavy chain variable region that specifically binds to a tumor-associated antigen; VH2 is a second immunoglobulin heavy chain variable region that specifically binds a tumor-associated antigen; VH3 is a third immunoglobulin heavy chain variable region that specifically binds CD3; VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds a tumor-associated antigen; Fc is a region containing immunoglobulin heavy chain constant region 2 (CH2), immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; and L1-L16 are amino acid linkers; 8. The antigen-binding polypeptide complex of claim 7.

9. 1. An antigen-binding polypeptide complex comprising a first polypeptide and a second polypeptide, The first polypeptide comprises: having a structure represented by: The second polypeptide comprises: having a structure represented by: VL1 is the first immunoglobulin light chain variable region that specifically binds to a tumor-associated antigen; VL2 is a second immunoglobulin light chain variable region that specifically binds a tumor-associated antigen; VL3 is a third immunoglobulin light chain variable region that specifically binds CD3; VL4 is a fourth immunoglobulin light chain variable region that specifically binds a tumor-associated antigen; VH1 is the first immunoglobulin heavy chain variable region that specifically binds to a tumor-associated antigen; VH2 is a second immunoglobulin heavy chain variable region that specifically binds a tumor-associated antigen; VH3 is a third immunoglobulin heavy chain variable region that specifically binds CD3; VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds a tumor-associated antigen; Fc is the region containing immunoglobulin heavy chain constant region 2 (CH2), immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; CH1 is immunoglobulin heavy chain constant region 1; CL is an immunoglobulin light chain constant region; and L1-L88 are amino acid linkers; The antigen-binding polypeptide complex.

10. the antigen-binding polypeptide complex comprises a first polypeptide and a second polypeptide; The first polypeptide comprises: having a structure represented by: The second polypeptide comprises: having a structure represented by: VL1 is the first immunoglobulin light chain variable region that specifically binds to a tumor-associated antigen; VL2 is a second immunoglobulin light chain variable region that specifically binds a tumor-associated antigen; VL3 is a third immunoglobulin light chain variable region that specifically binds CD3; VL4 is a fourth immunoglobulin light chain variable region that specifically binds a tumor-associated antigen; VH1 is the first immunoglobulin heavy chain variable region that specifically binds to a tumor-associated antigen; VH2 is a second immunoglobulin heavy chain variable region that specifically binds a tumor-associated antigen; VH3 is a third immunoglobulin heavy chain variable region that specifically binds CD3; VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds a tumor-associated antigen; Fc is the region containing immunoglobulin heavy chain constant region 2 (CH2), immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; CH1 is immunoglobulin heavy chain constant region 1; CL is an immunoglobulin light chain constant region; and L1-L88 are amino acid linkers; 10. The antigen-binding polypeptide complex of claim 9.

11. The antigen-binding polypeptide complex of any one of claims 1 to 10, wherein one or more of the linkers L1 to L88 have a length of from 0 amino acids to about 50 amino acids.

12. The antigen-binding polypeptide complex of any one of claims 1 to 11, wherein one or more of the linkers L1 to L88 are non-immunogenic.

13. 13. The antigen-binding polypeptide complex of any one of claims 1 to 12, wherein one or more of the linkers L1 to L88 does not contain a consensus T-cell epitope.

14. The antigen-binding polypeptide complex of any one of claims 1 to 13, wherein one or more of the linkers L1 to L88 is a cleavable linker.

15. The antigen-binding polypeptide complex of claim 14, wherein the cleavable linker is cleaved by a matrix metalloprotease (MMP), a type II transmembrane serine protease, or an MMP and a type II transmembrane serine protease.

16. 16. The antigen-binding polypeptide complex of claim 15, wherein the MMP is MMP1, MMP2, MMP7, MMP8, MMP9, MMP13, or a combination thereof.

17. 16. The antigen-binding polypeptide complex of claim 15, wherein the type II transmembrane serine protease is matriptase, hepsin, or a combination thereof.

18. 18. The antigen-binding polypeptide complex of claim 17, wherein the matriptase is matriptase 1, matriptase 2, matriptase 3, or a combination thereof.

19. The antigen-binding polypeptide complex of claim 14, wherein the cleavable linker is cleaved by urokinase or legumain.

20. The cleavable linker is (SEQ ID NOs:22-31), or a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% identity to any one of SEQ ID NOs:22-31.

21. One or more of the linkers L1 to L88 are 21. The antigen-binding polypeptide complex of any one of claims 1 to 20, comprising an amino acid sequence of any one of SEQ ID NOs: 1-21, SEQ ID NOs: 444, 567, 576 (GGS) and 607, or a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% identity to any one of SEQ ID NOs: 1-21 and 444, 567, 576 (GGS) and 607.

22. 22. The antigen-binding polypeptide complex of any one of claims 1 to 21, wherein one of VH1, VH2, VH3 or VH4 specifically binds to CD3.

23. 23. The antigen-binding polypeptide complex of any one of claims 1 to 22, wherein one of VL1, VL2, VL3 or VL4 specifically binds to CD3.

24. 24. The antigen-binding polypeptide complex of any one of claims 1 to 23, wherein VH1 and VL1, VH2 and VL2, VH3 and VL3, or VH4 and VL4 specifically bind to CD3.

25. The VH1, VH2, VH3 or VH4 that specifically binds to CD3 comprises a CDR1 comprising an amino acid sequence having at least 90% identity, at least 95% identity, or 100% identity to any one of SEQ ID NOs: 32, 40, 96, 433, 524, 667, 703, 739, 767, 803, 839, 851 and 859; and a CDR2 comprising an amino acid sequence having at least 90% identity, at least 95% identity, or 100% identity to any one of SEQ ID NOs: 34, 42, 98, 435, 526, 669, 705, 741, 769, 805, 841, 853, and 861; and The VL1, VL2, VL3 or VL4 that specifically binds to CD3 comprises a CDR1 having an amino acid sequence having at least 90% identity, at least 95% identity, or 100% identity to any one of SEQ ID NOs: 35, 44, 99, 446, 456, 466, 476, 520, 663, 699, 735, 763, 799, 835, 855 and 863; and a CDR2 comprising an amino acid sequence having at least 90% identity, at least 95% identity, or 100% identity to any one of SEQ ID NOs: 37, 46, 101, 448, 458, 468, 478, 522, 665, 701, 737, 765, 801, 837, 857, and 865.

25. An antigen-binding polypeptide complex according to any one of claims 1 to 24.

26. The VH1, VH2, VH3 or VH4 that specifically binds to CD3 comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity to any one of SEQ ID NOs: 38, 43, 102, 423, 432, 523, 666, 702, 738, 766, 802, 838, 850 and 858, and the VL1, VL2 that specifically binds to CD3 26. The antigen-binding polypeptide complex of any one of claims 1 to 25, wherein VL1, VL2, VL3, or VL4 comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity to any one of SEQ ID NOs: 39, 47, 103, 422, 445, 455, 465, 475, 519, 662, 698, 734, 762, 798, 834, 854, and 862.

27. 27. The antigen-binding polypeptide complex of any one of claims 1 to 26, wherein one or more of VH1, VH2, VH3 or VH4 specifically binds to a tumor-associated antigen (TAA).

28. 28. The antigen-binding polypeptide complex of any one of claims 1 to 27, wherein one or more of VL1, VL2, VL3 or VL4 specifically binds to a TAA.

29. 29. The antigen-binding polypeptide complex of any one of claims 1 to 28, wherein VH1 and VL1, VH2 and VL2, VH3 and VL3, and / or VH4 and VL4 specifically bind to a TAA.

30. The aforementioned TAA includes A2AR, APRIL, ATPase, BAFF, BAFFR, BCMA, BlyS, BTK, BTLA, B7DC, B7H1, B7H2, B7H3, B7H4, B7H5, B7H6, B7H7, B7RP1, B7-4, C3, C5, CCL2, CCL3, CCL4, CCL5, CCL7, CCL8, CCL11, CCL15, CCL17, CCL19, CCL20, CCL21, CCL25, CCR3, CCR4, CD16A, CD19, CD20, CD24, CD27, CD28, CD30, CD38, CD39, CD40, CD40L, CD47, CD52, CD70, CD80, CD86, CD123, CD133, CD137, CD137L, CD160, CD272, CEACAM5, CLEC9, CLEC91, CRTH2, CSF-1, CSF-2, CSF-3, CXCL1, CXCL2, CXCL4, CXCL12, CXCL13, CXCR3, cMet, CTLA4, DLL3, DLL4, DNG-R1, E-cadherin, EGFR, ENTPD1, EpCAM, FcER1, FcER1A, FcER2, FGFR, FLAP, FOLH1, Gi24, GITR, GITRL, GPR5, GP100, GPRC5D, HER2, HER3, ICOS-L, ICOS, HHLA2, HMGB1, HVEM, IDO, IFNα, IgE, IGF1R, IL2Rβ, IL1, IL1A, IL1B, IL1F10, IL2, IL4, IL4Ra, IL5, IL5R, IL6, IL7, IL7Ra, IL8, IL9, IL9R, IL10, rhIL10, IL12, IL13, IL13Ra1, IL13Ra2, IL15, IL17, IL17Rb, IL18, IL22, IL23, IL25, IL7, IL33, IL35, ITGB4, ITK, KIR, LAG3, LAMP1, leptin, LPFS2, MHC class II, MUC-1, MUC-16, NCR3LG1, NKG2D, NKp46, NTPDase-1, OX40, OX40L, PD-1, PD-L1, PD-L2, PROM1, S152, SIRPα, SISP1, SLC, SPG64, ST2, STEAP1, STEAP2, Syk kinase, STEAP1, TROP2, TACI, TDO, TGFβ, T14, TIGIT, TIM3, TLR, TLR2, TLR4, TLR5, TLR9, TMEF1,30. The antigen-binding polypeptide complex of any one of claims 1 to 29, which is TNFa, TNFRSF7, Tp55, TREM1, TSLP, TSLPR, TWEAK, VEGF, VISTA, Vstm3, or WUCAM.

31. The VH1, VH2, VH3 or VH4 that specifically binds to a TAA is selected from the group consisting of SEQ ID NOs: 64, 72, 80, 8104, 112, 120, 128, 389, 409, 419, 429, 659, 695, 731, 397, 508, 540, 552, 757, 793, 829, 875, 500, 749, 785, 821, 649, 685, 775, 847, 625, CDR1 comprising an amino acid sequence having at least 90% identity, at least 95% identity, or 100% identity to any one of SEQ ID NOs: 65, 73, 81, 89, 105, 113, 121, 129, 390, 410, 420, 430, 660, 696, 732, 398, 509, 541, 553, 758, 794, 830, CDR2 comprising an amino acid sequence having at least 90% identity, at least 95% identity, or 100% identity to any one of SEQ ID NOs: 66, 74, 82, 90, 106, 114, 122, 130, 391, 411, 421, 431, 661, 697, 733, 399, 510, 542, 554, 759, 795, 831, 877, 502, 751, 787, 823, 651, 687, 777, 849, 627, 643, 679, 715, and 869; and One or more of the VL1, VL2, VL3 or VL4 that specifically binds to a TAA are selected from the group consisting of SEQ ID NOs: 67, 75, 83, 91, 107, 115, 123, 131, 385, 405, 415, 441, 452, 462, 472, 655, 691, 727, 393, 486, 504, 536, 548, 753, 789, 825, 871, 879, 490, 496, 745, 781, 817, 645, 681, 771, 843, 621, 637, 6 CDR1 comprising an amino acid sequence having at least 90% identity, at least 95% identity, or 100% identity to any one of SEQ ID NOs: 68, 76, 84, 92, 108, 116, 124, 132, 386 (YTS); 406 (YTS), 416 (YTS), 442 (YTS), 453 (YTS), 463 (YTS), 473 (YTS), 656, 692, 728, 394, 487 (AT), 505 (AT), 510 (AT), 520 (AT), 530 (AT), 540 (AT), 550 (AT), 560 (AT), 570 (AT), 572 (AT), 574 (AT), 576 (AT), 578 (AT), 576 (AT), 578 (AT), 576 (AT), 578 (AT), 576 (AT), 578 (AT), 576 (AT), 578 (AT), 576 (AT), 578 (AT), 578 (AT), 576 ... and a CDR2 comprising an amino acid sequence having at least 90% identity, at least 95% identity, or 100% identity to any one of SEQ ID NOs: 69, 77, 85, 93, 109, 117, 125, 133, 387, 390, 491(DA), 497(DA), 746, 782, 818, 646, 682, 772, 844, 622, 638, 674, 710, and 872; 407, 417, 443, 454, 464, 474, 657, 693, 729, 395, 488, 506, 538, 550, 755, 791, 827, 873, 881, 492, 498, 747, 783, 819, 647, 683, 773, 845, 623, 639, 675, 711, and 873, 31. An antigen-binding polypeptide complex according to any one of claims 1 to 30.

32. One or more of the VH1, VH2, VH3 or VH4 that specifically binds to a TAA are selected from the group consisting of SEQ ID NOs: 70, 78, 86, 94, 102, 110, 118, 126, 134, 388, 408, 418, 428, 584, 658, 694, 730, 396, 403, 507, 539, 551, 756, 792, 883, 828, 866, 874, 4 99, 544, 556, 748, 784, 820, 528, 648, 684, 774, 846, 624, 640, 676, and 712; and or one or more of VL4 are selected from the group consisting of SEQ ID NOs: 71, 79, 87, 95, 103, 111, 119, 127, 135, 384, 404, 414, 440, 451, 461, 471, 583, 654, 690, 726, 392, 402, 485, 503, 535, 547, 752, 788, 824, 882, 870, 878, 489, 495, 54 32. The antigen-binding polypeptide complex of any one of claims 1 to 31, comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity to any one of SEQ ID NO:3, 555, 744, 780, 816, 527, 644, 680, 770, 842, 620, 636, 672, and 708.

33. 33. The antigen-binding polypeptide complex of any one of claims 1 to 32, wherein one or more of VH1, VH2, VH3 or VH4 specifically binds to an immunostimulatory receptor.

34. 34. The antigen-binding polypeptide complex of any one of claims 1 to 33, wherein one or more of VL1, VL2, VL3 or VL4 specifically binds to an immunostimulatory receptor.

35. 35. The antigen-binding polypeptide complex of any one of claims 1 to 34, wherein VH1 and VL1, VH2 and VL2, VH3 and VL3, and / or VH4 and VL4 specifically bind to an immunostimulatory receptor.

36. 36. The antigen-binding polypeptide complex of any one of claims 1 to 35, wherein the immunostimulatory receptor is CD28.

37. The VH1, VH2, VH3 or VH4 that specifically binds to an immunostimulatory receptor comprises a CDR1 comprising an amino acid sequence having at least 90% identity, at least 95% identity, or 100% identity to any one of SEQ ID NOs: 48, 56, 649, 685, 775, 847, 721, and 811; a CDR2 comprising an amino acid sequence having at least 90% identity, at least 95% identity, or 100% identity to any one of SEQ ID NOs: 49, 57, 650, 686, 776, 848, 722, and 812; and a CDR3 comprising an amino acid sequence having at least 90% identity, at least 95% identity, or 100% identity to any one of SEQ ID NOs: 50, 58, 651, 687, 777, 849, 723, and 813; and The VL1, VL2, VL3 or VL4 that specifically binds to an immunostimulatory receptor comprises a CDR1 comprising an amino acid sequence having at least 90% identity, at least 95% identity, or 100% identity to any one of SEQ ID NOs: 51, 59, 645, 681, 771, 843, 717, and 807; a CDR2 comprising an amino acid sequence having at least 90% identity, at least 95% identity, or 100% identity to any one of SEQ ID NOs: 52, 60, 646, 682, 772, 844, 718, and 808; and a CDR3 comprising an amino acid sequence having at least 90% identity, at least 95% identity, or 100% identity to any one of SEQ ID NOs: 53, 61, 647, 683, 773, 845, 719, and 809.

37. An antigen-binding polypeptide complex according to any one of claims 1 to 36.

38. The antigen-binding polypeptide complex of any one of claims 1 to 37, wherein the VH1, VH2, VH3 or VH4 that specifically binds to an immunostimulatory receptor comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity to any one of SEQ ID NOs: 54, 62, 528, 648, 684, 774 and 846, and the VL1, VL2, VL3 or VL4 that specifically binds to an immunostimulatory receptor comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity to any one of SEQ ID NOs: 55, 63, 527, 644, 680, 770 and 842.

39. The antigen-binding polypeptide complex of claim 1, wherein L5, L8, or L5 and L8 are cleavable linkers.

40. 40. The antigen-binding polypeptide complex of claim 39, wherein VH3 and VL3 specifically bind to CD3.

41. 41. The antigen-binding polypeptide complex of claim 39 or 40, wherein VH1 and VL1, and / or VH2 and VL2 specifically bind to a TAA.

42. 42. The antigen-binding polypeptide complex of any one of claims 39 to 41, wherein VH1 and VL1, or VH2 and VL2, specifically bind to CD28.

43. The antigen-binding polypeptide complex of claim 3, wherein L4, L7, or L4 and L7 are cleavable linkers.

44. 44. The antigen-binding polypeptide complex of claim 43, wherein VH3 and VL3 specifically bind to CD3.

45. 45. An antigen-binding polypeptide complex as described in claim 43 or 44, wherein VH1 and VL1, and / or VH2 and VL2 specifically bind to a TAA.

46. 46. ​​An antigen-binding polypeptide complex according to any one of claims 44 to 45, wherein VH1 and VL1, or VH2 and VL2, specifically bind to CD28.

47. The antigen-binding polypeptide complex of claim 5, wherein L9, L12, or L9 and L12 are cleavable linkers.

48. 48. The antigen-binding polypeptide complex of claim 47, wherein VH4 and VL4 specifically bind to CD3.

49. 49. The antigen-binding polypeptide complex of claim 47 or 48, wherein one or more of VH1 and VL1, VH2 and VL2, and VH3 and VL3 specifically bind to a TAA.

50. 50. The antigen-binding polypeptide complex of any one of claims 47 to 49, wherein VH1 and VL1 specifically bind to a TAA, VH2 and VL2 specifically bind to a TAA, and VH3 and VL3 specifically bind to CD28.

51. 50. The antigen-binding polypeptide complex of any one of claims 47 to 49, wherein VH1 and VL1 specifically bind to CD28, VH2 and VL2 specifically bind to a TAA, and VH3 and VL3 specifically bind to a TAA.

52. 50. The antigen-binding polypeptide complex of any one of claims 47-49, wherein VH1 and VL1 specifically bind cMet, VH2 and VL2 specifically bind Trop2, and VH3 and VL3 specifically bind CD28.

53. 50. The antigen-binding polypeptide complex of any one of claims 47-49, wherein VH1 and VL1 specifically bind Trop2, VH2 and VL2 specifically bind cMet, and VH3 and VL3 specifically bind CD28.

54. 50. The antigen-binding polypeptide complex of any one of claims 47-49, wherein VH1 and VL1 specifically bind cMet, VH2 and VL2 specifically bind CD28, and VH3 and VL3 specifically bind Trop2.

55. 50. The antigen-binding polypeptide complex of any one of claims 47 to 49, wherein VH1 and VL1 specifically bind CD28, VH2 and VL2 specifically bind cMet, and VH3 and VL3 specifically bind Trop2.

56. 50. The antigen-binding polypeptide complex of any one of claims 47-49, wherein VH1 and VL1 specifically bind Trop2, VH2 and VL2 specifically bind CD28, and VH3 and VL3 specifically bind cMet.

57. 50. The antigen-binding polypeptide complex of any one of claims 47-49, wherein VH1 and VL1 specifically bind CD28, VH2 and VL2 specifically bind Trop2, and VH3 and VL3 specifically bind cMet.

58. 9. The antigen-binding polypeptide complex of claim 7 or 8, wherein L1, L3, or L1 and L3 are cleavable linkers, or L5, L7, or L5 and L7 are cleavable linkers.

59. 9. The antigen-binding polypeptide complex of claim 7 or 8, wherein L9, L11, or L9 and L11 are cleavable linkers, or L13, L15, or L13 and L15 are cleavable linkers.

60. 61. The antigen-binding polypeptide complex of claim 59 or 60, wherein VH1 and VL1, VH2 and VL2, VH3 and VL3, or VH4 and VL4 specifically bind to CD3.

61. 61. The antigen-binding polypeptide complex of any one of claims 59 to 60, wherein one or more of VH1 and VL1, VH2 and VL2, VH3 and VL3, and VH4 and VL4 specifically bind to a TAA.

62. 61. The antigen-binding polypeptide complex of any one of claims 59 to 60, wherein VH1 and VL1, VH2 and VL2, VH3 and VL3, or VH4 and VL4 specifically bind to CD28.

63. 64. The antigen-binding polypeptide complex of any one of claims 1 to 63, which is an antibody or antigen-binding fragment thereof.

64. 64. The antigen-binding polypeptide complex of any one of claims 1 to 63, wherein the immunoglobulin hinge comprises an upper hinge region, a middle hinge region, a lower hinge region, or a combination thereof.

65. 66. The antigen-binding polypeptide complex of any one of claims 1 to 65, wherein the Fc region comprises at least one knob-into-hole modification.

66. the antigen-binding polypeptide complex is an IgG1 or IgG4 antibody, and the knob-into-hole modification is, based on the EU numbering scheme, (i) knob substitutions of S354C and T366W, and hole substitutions of Y349C, T366S, L368A, and Y407V; (ii) hole substitutions at L234A, L235A and P329A; (iii) hole substitutions at L234A and L235A; (iv) M428L and N433S hole substitutions; (v) M252Y, S254T and T256E hole substitutions; or (vi) Combinations thereof 67. The antigen-binding polypeptide complex of claim 66, comprising:

67. 68. An antibody or antigen-binding fragment thereof comprising an antigen-binding polypeptide complex according to any one of claims 1 to 67.

68. A pharmaceutical composition comprising an antigen-binding polypeptide complex of any one of claims 1 to 61, or an antibody or antigen-binding fragment thereof of claim 68, and a pharma- ceutically acceptable carrier.

69. 70. A kit comprising an antigen-binding polypeptide complex according to any one of claims 1 to 67, an antibody or antigen-binding fragment thereof according to claim 68, or a pharmaceutical composition according to claim 69, and instructions for use.

70. 70. A method for treating cancer comprising administering to a subject in need thereof an antigen-binding polypeptide complex of any one of claims 1 to 67, an antibody or antigen-binding fragment thereof of claim 68, or a pharmaceutical composition of claim 69.

71. 72. The method of claim 71, wherein the cancer is a solid tumor.

72. 72. The method of claim 71, wherein the cancer is breast cancer, lung cancer, gastric cancer, prostate cancer, cervical cancer, urothelial cancer, or pancreatic cancer.

73. 72. The method of claim 71, wherein the cancer is a hematological cancer.

74. 75. The method of claim 74, wherein the hematological cancer is leukemia or lymphoma.

75. 76. The method of claim 75, wherein the leukemia or lymphoma is B-cell leukemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL) follicular lymphoma, chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), Burkitt's lymphoma, lymphoplasmacytic lymphoma (Waldenstrom's macroglobulinemia), prolymphocytic leukemia (PLL), or hairy cell leukemia (HCL).

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